application of integrated transition metal-catalyzed...
TRANSCRIPT
Application of integrated transition metal-catalyzed reactions
and a double Reformatsky reaction for process development
March 2016
Masahiro Mineno
The Graduate School of Natural Science and Technology
(Doctor Course)
OKAYAMA UNIVERSTITY
Contents
Page
Chapter 1. General Introduction 1
Chapter 2. Rapid access to diverse -carbolines through sequential transition metal
catalyzed amination and direct C-H arylation
17
Chapter 3. An integrated transition metal-catalyzed reaction strategy for an -carboline
based Aurora B kinase inhibitors
41
Chapter 4. Double Reformatsky reaction: divergent synthesis of -hydroxy--ketoesters 59
Chapter 5. A rapid and diverse construction of 6-substituted-5,6-dihydro-4-hydroxy-
2-pyrones through a double Reformatsky reaction
95
List of Publications 115
Acknowledgement 119
Chapter 1
1
Chapter 1
General Introduction
Close relationship between process chemistry and organic synthesis
Pharmaceutical process chemistry has recently attracted significant attention in both academia and industry,
and the growing interest in process chemistry is reflected in the large number of papers and books recently
published. The fundamental role and responsibility of process chemistry is to supply multi-kilogram quantities
of active pharmaceutical ingredient (API) in a timely manner to support pharmaceutical development such as
through toxicology, formulation and human clinical studies, and to establish a clean and cost-effective
manufacturing process of the drug candidate for future commercial manufacture.
Over the past few decades, process chemistry R&D organizations in the pharmaceutical industry have
undergone a remarkable transformation to address the increasing complexity of target compounds, shortening
development time scales and increasing regulatory expectations. In the past, process chemistry was associated
with scaling up reactions from the small quantities prepared in the research lab to the larger quantities at the
plant facilities, and process development often relied on employing the original synthetic process rather than
exploring alternative synthetic approaches. On the other hand, as demands to shorten the development time
scale have been increased, companies have found that investment in the early process design can save resources
and costs and shorten overall development time. Additionally, as regulatory expectations have been increased,
more emphasis has been placed on process understanding to ensure consistent quality.
Process chemistry involves a wide variety of disciplines, such as synthetic organic chemistry, chemical
engineering, physical chemistry, analytical chemistry, environmental science, safety engineering, regulatory
science and intellectual property. Among them, synthetic organic chemistry is the most important discipline; i.e.
Chapter 1
2
synthetic route design and process optimization by understanding the reaction mechanism. Herein, particular
attentions are paid to two topics related to synthetic organic chemistry; "Route selection" and "Process
understanding".
Route selection
Route selection is one of the most fundamental activities in process chemistry R&D. The considerations for
route selection are mainly driven by long-term objectives such as consistent quality, process and chemical
safety, environmental impact, cost efficiency, process robustness and ultimately meeting the regulatory
expectations.
In the early development stage, process chemistry R&D organizations sometimes employ the discovery route
with only minor modifications, in order to provide API for early clinical studies within the limited time scale.
However, in the meantime, the discovery route should be carefully evaluated as the future commercial process
from a process chemistry perspective because it has typically been chosen for its ability to access a variety of
targets that were of interest to the discovery chemists. Thereafter, the process chemists should set out to
identify an adequate synthetic route for a scalable synthesis, and develop a reliable and cost-effective
manufacturing process by utilizing their knowledge and experience digging out relevant literature precedents.
In some cases, it is accomplished by using different reagents and starting materials and reordering steps in a
route. In other cases, replacement of an original route in early development stage with a totally different
synthetic route is required for commercial production.
In route selection, process chemists have different criteria from discovery chemists. In addition to synthetic
efficiency, a range of practical aspects such as quality, safety, cost, product purification, availability of starting
materials, environmental impact and intellectual property have to be taken into consideration. Among them,
"quality" is a primary concern because the pharmaceutical product ends up in humans. Quality can be further
subdivided into two areas; (i) physical properties (polymorph, particle size distribution and crystallinity) and (ii)
impurities (related substances, enantiomers, heavy metals, solvents and genotoxic impurities). Physical
properties sometimes affect the solubility and bioavailability of the pharmaceutical product, which might cause
Chapter 1
3
variable therapeutic effects. Impurities might cause unexpected side effects in patients in some cases, and
therefore the acceptable limits for each impurity must be carefully set before production, based on a convincing
rationale, such as the results of toxicological studies and criteria defined in the International Conference on
Harmonization (ICH) guidelines.1
In order to develop a desirable synthetic route, process chemists need to combine various kinds of chemical
reactions utilizing traditional and cutting-edge technologies. Sometimes, while exploring potentially efficient
reactions, new and unexplored synthetic methods/technologies will be incorporated into the manufacturing
process. An example of exploring a new synthetic method and a subsequent route scouting is discussed in
Chapters 2 and 3.2,3
Process understanding
Once a desirable synthetic route is identified, process chemists make every effort for the process
optimization to obtain process robustness. In order to ensure the consistent yield and quality, a number of
chemical and physical parameters in the process should be carefully optimized and then controlled. To govern
all the factors, process chemists have to fully understand the chemistry involved and conduct reactions and
productions. Understanding the reaction mechanism of not only the main reaction but also the side reactions
leads to better process control and batch-to-batch consistency. Process refinements and improvements can be
provided by a comprehensive understanding of the chemistry. For the better understanding of the process, the
discipline of synthetic organic chemistry is essential for predicting reaction mechanism and defining process
parameters.
In the course of such detailed and comprehensive investigation of process understanding, it is not unusual to
find unexpected and unprecedented reactions. To maintain and improve the quality of APIs, process chemists
have to address unprecedented challenges by not only making the most of current knowledge but also through
exploring new discoveries. In Chapters 4 and 5, an example of the process understanding leading to a new
application of a classical reaction is described.4,5
Chapter 1
4
Organometallic reactions as essential tools in process chemistry
When addressing route design and development in process development, carbon-carbon (C-C) bond forming
reactions are the most important class of transformations. Among the variety of transformations, organometallic
reactions are an essential tool to make new C-C bonds for constructing the frame works of complex organic
molecules. Herein, organometallic C-C bond forming reactions are looked into from the process chemistry
perspective, dividing into two categories; transition metal-catalyzed C-C bond forming reactions and
stoichiometric C-C bond forming reactions using polar organometallic compounds.
Transition metal-catalyzed C-C bond forming reaction
Catalytic reactions are attractive from the viewpoints of green sustainable chemistry and cost effectiveness.
Over the past few decades, transition metal-catalyzed cross-coupling reactions have become one of the most
utilized tools to assemble carbon-carbon and carbon-heteroatom bonds. The cross-coupling reactions have
multiple advantages in process chemistry, as follows.6 First, the catalytic method contributes to green
sustainable chemistry as mentioned above. Next, the cross-coupling reactions offer a shorter route from readily
accessible starting materials to the desired products, minimizing side-products and waste. Also, the reaction
conditions are usually mild and applicable to a very broad range of substrates. The mildness and functional
group compatibility allow us to utilize transition metal-catalyzed cross-coupling reactions late in synthetic
routes, which enable more convergent approaches to complex target compounds.
Cross-coupling reaction was first reported more than 40 years ago,7 but the novel transformations were not
embraced in process chemistry until the methodology matured because process chemists have to provide API
with high quality and generally use the reactions that have proven reliability and are mechanistically well
understood. However, since the 1990s, process chemists have applied cross-coupling reactions to the synthesis
of many drug candidates on a large scale, for example, Suzuki-Miyaura coupling for Losartan8 and Valsartan,
9
Mizoroki-Heck reaction for Montelukast,10
Sonogashira coupling for Terbinafine,11
Negishi coupling for
Ezetimibe,12
Kumada-Tamao-Corriu coupling for Difunisal13
and Buchwald-Hartwig amination for Imatinib14
Chapter 1
5
(Figure 1). The value of transition metal-catalyzed cross-coupling reactions has thus been widely recognized,
and Professors Heck, Negishi and Suzuki were awarded the Nobel Prize in 2010.
Figure 1. Pharmaceutical products employing cross-coupling reactions
Furthermore, for the recent decade, transition-metal-catalyzed C-H activation/direct functionalization has
emerged as a promising tool of simple and atom-economical synthetic transformation for the assembly of
carbon–carbon and carbon-heteroatom bonds.15
Compared to the conventional cross-coupling reactions that
require extra steps to prepare organometallic compounds from a raw material, the C-H activation/C-C bond
forming process can eliminate the need to prepare organometallic precursors, thus making this reaction a
cost-effective and eco-friendly system (Figure 2). While developments of site selective functionalizations are
still challenges, the low waste and easily accessible transition-metal catalyzed direct C-H
activation/functionalizations will become one of the most important and useful transformations in large scale
synthesis.16
Chapter 1
6
Figure 2. Cross coupling reaction and direct C-H activation/functionalization
In chapters 2 and 3, an example of route selection employing transition metal-catalyzed Buchwald-Hartwig
amination and direct C-H arylation is described.2,3
The synthetic route established is attractive not only in
higher isolated yield and operational simplicity but also green sustainable chemistry because the preparations
of organometallic precursors are not necessary in both the transition metal-catalyzed reactions.
.
Stoichiometric C-C bond forming reactions using polar organometallic compounds
Highly polarized carbon-metal species, such as organolithium, organomagnesium and organozinc compounds,
were found more than 150 years ago,17
and nowadays they are widely used in the pharmaceutical industry.
Major advantages of polar organometallic reagents are their high reactivity and sufficient stability. As the
degree and pattern of polarity vary significantly with the element and its coordination state, the reactivity and
selectivity can be theoretically adjusted by choosing the appropriate metal element, adding coordinating
reagents, or forming ate complexes.18
Additionally, a variety of functional groups can be introduced on
organometallic compounds by transmetallation and halogen-metal exchange. Owing to these beneficial
attributes, organometallic reactions are often employed in pharmaceutical process chemistry especially when
exploring a new synthetic route of complex compounds.
Of a number of polar organometallic reagents, organolithium and organomagnesium have been at the center
in synthetic organic chemistry as well as process chemistry, largely due to their high nucleophilicity, basicity
and commercial availability. Particularly, organomagnesium halides, known as Grignard reagents,19
have been
Chapter 1
7
widely used in process chemistry for many years, giving high yields as well as minimizing the number of steps
in a synthetic sequence. Conversely, the high nucleophilicity often limits the functional group tolerance. Thus
the presence of carbonyl, nitro or nitrile functions in the precursor of organolithium and organomagnesium
reagents causes a serious compatibility problem.
Compared to organolithium and organomagnesium compounds, organozinc compounds had not received
much attention for a long time in process chemistry. The major drawback of organozinc compounds was the
low nucleophilic reactivity. However, the drawback of the low reactivity has been recently turned into a
beneficial feature for functional group tolerance, which becomes an advantage over organolithium and
magnesium reagents. For example, zinc-mediated Reformatsky reaction is known as a ester-stabilized
reaction,20
while Grignard reagents easily react with esters (Scheme 1).21
Thus, organozinc-mediated reactions
have recently attracted renewed attentions due to their high tolerance toward functional groups, in both
synthetic organic chemistry and process chemistry.21
In chapters 4 and 5, a development of
organozinc-mediated reaction and its application to biologically important compounds with high functional
group tolerance are described.4,5
Scheme 1. Differences in reactivity toward ester in Reformatsky reagent and Grignard reagent
Chapter 1
8
This thesis consists of the following two topics. The first topic concerns the early route selection for a drug
candidate, using transition metal-catalyzed Buchwald-Hartwig amination and direct C-H arylation. The
second one focused on the development of a zinc-mediated "double Reformatsky reaction" and its application
to the synthesis of biologically active compounds, which was found during the course of process
understanding for a synthetic procedure of a drug candidate.
Chapter 1
9
Route selection for an -carboline-based Aurora B kinase inhibitor
using integrated transition metal-catalyzed reactions
In Chapters 2 and 3, an early route selection of a drug candidate, featuring an integrated transition
metal-catalyzed reaction strategy, is described. In the course of drug discovery efforts into small molecule
Aurora B kinase inhibitors, the discovery team identified multifunctionalized-carboline
([2,3-b]pyridoindole)-based compounds as highly promising candidates with antineoplastic activity.23
In the
project, in order to accelerate the development timescale, the process chemistry organization was involved early
in the development where dozens of multifunctionalized -carbolines were still nominated as precandidates for
clinical studies. Therefore, our initial effort was turned toward the establishment of a synthetic procedure for
-carbolines enabling both functional group versatility and reaction efficiency on scale-up. As a synthetic
strategy to meet our expectations, a sequential transition metal-catalyzed reaction system of Buchwald-Hartwig
amination and direct C-H arylation was selected (Scheme 2). Although the synthetic strategy was previously
reported by Sakamoto and co-workers,24
their catalytic system suffered from harsh reaction conditions and low
yield in the direct C-H arylation, and was only applied to one example of a non-substituted -carboline.
Therefore, we initially focused on improving the reaction condition and exploring the scope of functional
group compatibility. After intensive investigation particularly into catalyst system optimization, an efficient
method involving direct C-H arylation has been established to allow the rapid and divergent synthesis of
-carbolines with various substituents. In Chapter 2, the results are described in detail.2
Scheme 2. Synthetic strategy toward -carbolines
Chapter 1
10
After compound 1 was selected as a drug candidate for an Aurora B kinase inhibitor with suitable profile
for further clinical studies, we embarked on the investigation of the process design and development of
compound 1 (Scheme 3). The above-mentioned integrated transition metal-catalyzed reaction strategy was
employed instead of a discovery route that employed conventional cyclization systems.25
Although the
application of this strategy to the synthesis of 1 would encounter some specific issues such as the preparation
of the aryl iodide with suitable substituents at suitable positions and the tolerance of functional groups in the
reaction condition, an efficient and practical synthetic process was finally established (Scheme 3). The new
synthetic route is more practical than the former one, from the viewpoints of process robustness and the
availability of starting compounds. Furthermore, the process eliminates complicated column chromatography
purifications, and all intermediates could be isolated as crystals following simple workup. Overall, the new
process contributed to a considerable enhancement of the total yield, from 11% to 48%. The details of the
process development are described in Chapter 3.3
Scheme 3. Changes in bond disconnection
Chapter 1
11
Process understanding leading to a new aspect of the Reformatsky
reaction: development of a double Reformatsky reaction
In Chapters 4 and 5, an example of the process understanding leading to a new aspect of a classical
Reformatsky reaction is described. Reformatsky reaction was first reported in 1887 and has played an important
role in organic synthesis for many years. The reaction involves formation of a -hydroxyalkanoate from a zinc
alkanoate and aldehyde or ketone by means of zinc.22
During the course of a API process optimization
employing a Reformatsky reaction, an unexpected byproduct, a -hydroxy--ketoester derivative, was
observed in a Reformatsky reaction step (Scheme 4).
Scheme 4. Process understanding leading to an establishment of a double Reformatsky reacion
In order to control the amount of the byproduct, understanding the root cause of the generation of the
byproduct was necessary. Additionally, according to our literature survey, the reaction to afford
-hydroxy--ketoesters directly from carbonyl compounds and zinc alkanoates had not been reported. Hence,
an investigation on evaluating the reaction promotion factors and elucidating the reaction mechanism for the
Chapter 1
12
generation of the -hydroxy--ketoester was initiated. As a result of the comprehensive study, it was found that
the -hydroxy--ketoester was formed via a stepwise addition of a Reformatsky reagent. A noteworthy feature
of the reaction system is its high tolerance of functional groups, due to the moderate nucleophilicity of
organozinc reagents and the mild reaction conditions. In Chapter 4, the results of the investigation for the
"Double Reformatsky reaction" including its scope and limitation and mechanistic study are described in
detail.4
Subsequently in Chapter 5, as an application of the newly-developed double Reformatsky reaction, a rapid
and diverse synthesis of biologically important 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones through a
double Reformatsky reaction followed by lactonization is described.5 Due to its advantages of high functional
group tolerance and reaction site discrimination between aldehyde, nitrile and ester groups in the substrate, the
protocol can provide the dihydropyrones with various functional groups. Furthermore, the protocol has been
successfully applied to the rapid total synthesis of naturally occurring Yangonin (Scheme 5).
Scheme 5. Application of double Reformatsky reaction to biologically active compounds
Chapter 1
13
References and notes
1. For the International Conference on Harmonization website, go to http://www.ich.org/home.html
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2015, 80, 1564.
4. Mineno, M.; Sawai, Y.; Kanno, K.; Sawada, N.; Mizufune, H. J. Org. Chem. 2013, 78, 5843.
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6. For the selected reviews see: (a) Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177. (b) Torborg, C.;
Beller, M. Adv. Synth.Catal. 2009, 351, 3027. (c) Cobert, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651.
7. For reviews on the history of cross-coupling reactions, see: (a) Johansson Seechurn, C. C. C.; Kitching,
M. O.; Colacot, T. J.; Snieckus, V.; Angew. Chem. Int. Ed. 2012, 51, 5062. (b) Bellina, F.; Rossi, R. Chem.
Rev. 2010, 110, 1082.
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B.; Belley, M.; Leblanc, Y. J. Org. Chem. 1993, 58, 3731. (b) Larsen, R. D.; Corley, E. G.; King, A. O.;
Carroll, J. D.; Davis, P.; Verhoeven, T. R.; Reider, P. J.; Labelle, M.; Gauthier, J. Y.; Xiang, Y. B.;
Zamboni, R. J. J. Org. Chem. 1996, 61, 3398
11. Beutler, U.; Mazacek, J.; Penn, G.; Schenkel, B.; Wasmuth, D. Chimia, 1996, 50, 154.
Chapter 1
14
12. Vaccaro, W. D.; Sher, R.; Davis, H. R. Bioorg. Med. Chem., 1998, 6, 1429.
13. Whitehead, B. F.; Ho. P. T. C.; Suttele, A. B.; Pandite, A. N. PCT Int. Appl., WO 2007143483
A220071213, 2007.
14. Loiseleur, O.; Kaufmann, D.; Abel, S.; Buerger, H. M.; Meisenbach, M.; Schmitz, B.; Sedelmeier, G.
PCT Int. Appl., WO 03066613 A1 2003814, 2003.
15. Representative recent reviews on C−H activation: (a) Mesganaw, T.; Ellman, J. A. Org. Process Res. Dev.
2014, 18, 1097. (b) Ackermann, L. J. Org. Chem. 2014, 79, 8948. (c) Tani, S.; Uehara, T. N.; Yamaguchi,
J.; Itami, K. Chem. Sci. 2014, 5, 123 (d) Tsurugi, H.; Yamamoto, K.; Nagae, H.; Kaneko, H.; Mashima, K.
Dalton Trans. 2014, 43, 2331. (e) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C. Adv. Synth. Catal. 2014,
356, 17. (f) Kakiuchi, F.; Kochi, T.; Murai, S. Synlett 2014, 25, 2390. (g) Gao, K.; Yoshikai, N. Acc.
Chem. Res. 2014, 47, 1208. (h) Girard, S. A.; Knauber, T.; Li, C.-J. Angew. Chem., Int. Ed. 2014, 53,
74−100. (i) De Sarkar, S.; Liu, W.; Kozhushkov, S. I.; Ackermann, L. Adv. Synth. Catal. 2014, 356, 1461.
(j) Zhang, X.-S.; Chen, K.; Shi, Z.-J. Chem. Sci. 2014, 5, 2146. (k) Wencel-Delord, J.; Glorius, F. Nat.
Chem 2013, 5, 369. (l) Rouquet, G.; Chatani, N. Angew. Chem., Int. Ed. 2013, 52, 11726. (m) Yamaguchi,
J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960. (n) Engle, K. M.; Mei, T.-S.;
Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (o) Hickman, A. J.; Sanford, M. S. Nature 2012, 484,
177. (p) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885. (q) Baudoin, O. Chem.
Soc. Rev. 2011, 40, 4902. (r) Satoh, T.; Miura, M. Chem. Eur. J. 2010, 16, 11212. (s) Daugulis, O. Top.
Curr. Chem. 2010, 292, 57. (t) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41,
1013. (u) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (v) Bergman, R. G. Nature
2007, 446, 391..
16. For selected examples (a) Choy, A.; Colbry, N.; Huber, C.; Pamment, M.; Van Dunie, J. Org. Process
Res. Dev, 2008, 12, 884. (b) Kiser, E. J.; Magano, J.; Shine, R. J.; Chen, M. H. Org. Process Res. Dev,
2012, 16, 255. (c) Ouellet, S. G.; Roy, A.; Molinaro, C.; Angelaud, R.; Marcoux, J.-F.; O'Shea, P. D.;
Davies, I. W. J. Org. Chem, 2011, 76, 1436. (d) Cambell, A. N.; Cole, K. P.; Martinelli, J. R.; May, S. A.;
Mitchell, D.; Pollock, P. M.; Sullivan, K. A. Org. Process Res. Dev. 2013, 17, 273.
Chapter 1
15
17. Frankland, E. Liebigs Ann. Chem. 1849, 71, 171
18. For the recent reviews, see; (a) Tilly,D.; Chevallier, F.; Mongin, F.; Gros, F.C. Chem. Rev. 2014, 114,
1207. (a) Mulvey, R. E.; Mongin, F.; Uchiyama, M.; Kondo, Y. Angew. Chem., Int. Ed. 2007, 46, 3802.
(b) Mulvey, R. E. Acc. Chem. Res. 2009, 42, 743. (c) Mulvey, R. E. Dalton Trans. 2013, 42, 6676. (d)
Reich, H. J. Chem. Rev. 2013, 113, 7130. (e) Harrison-Marchand, A.; Mongin, F. Chem. Rev. 2013, 113,
7470. (f) Mongin, F.; Harrison-Marchand, A. Chem. Rev. 2013, 113, 7563.
19. Grignard, V. C. R. Acad. Sci. 1900, 1322.
20. Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210.
21. For the selected reviews see: (a) Ocampo, R.; Dolibier, Jr, W. R. Tetrahedron 2004, 60, 9325, (b) Fürstner,
A. Synthesis 1989, 571.
22. For the selected reviews see: (a) Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333. (b) Knochel, P.
Angew. Chem. Int. Ed. 2000, 39, 4414. (c) Knochel, P. Synlett. 1995, 393. (d) Knochel, P.; Singer, R. D.
Chem. Rev. 1993, 93, 2117.
23. Brown, J. W.; Dong, Q.; Gong, X.; Kaldor, S. W.; Liu, Y.; Paraselli, B. R.; Scorah, N.; Stafford, J. A.;
Wallace, M. B. WO 2007044779. Chem. Abstr 2007.146. 441771.
24. Iwaki, T.; Yasuhara. A.; Sakamoto, T. J. Chem. Soc., Perkin Trans I, 1999, 1505.
25. Farrell1, P.; Shi, L.; Matuszkiewicz, J.; Alakrishna, D.; Hoshino, T.; Zhang, L.; Elliott, S.; Fabrey, R.; Lee1,
B.; Halkowycz, P.; Sang, B.; Ishino, S.; Nomura, T.; Teratani, M.; Ohta, Y.; Grimshaw, C.; Paraselli, B.;
Satou, T.; de Jong. R. Mol. Cancer Ther. 2013, 12, 460.
Chapter 1
16
Chapter 2
17
Chapter 2
Rapid access to diverse -carbolines through sequential transition
metal catalyzed amination and direct C-H arylation
Abstract
An efficient sequence of Pd catalyzed amination and direct C-H arylation for a synthesis of
pharmacologically important -carbolines is described. The outstanding feature in the synthetic sequence is
that a combination of DBU and 2-(dicyclohexylphosphino)biphenyl (DCHPB) plays a critical role to not only
enhance the reactivity but also suppress hydrodehalogenation in the direct C-H arylation step. The reaction
protocol provides -carbolines with various substituents including base-sensitive ester and ketone moieties in
moderate to excellent yields. Moreover, combination with Cu catalyzed amination further enhanced the
versatility of the -carboline synthesis.
Chapter 2
18
Introduction
-Carbolines (pyrido[2,3-b]indoles) (1) have recently received much interest since the discovery of various
biologically active natural products, such as mescengricin (2),1
neocryptolepine (3),2
grossularine-1 (4a) and
grossularine-2 (4b)3 (Figure 1).
Additionally, synthetic -carbolines have been found to exhibit a wide variety
of biological properties, such as anxiolytic,1,4
anti-inflammatory5 and CNS-stimulating activities.
6 Furthermore,
the tricyclic ring system has recently attracted increasing attention as a pharmacophore for kinase inhibitors,
such as cyclin-dependent kinase (CDK) inhibitors,7 glycogen synthetase kinase (GSK) inhibitors,
8 and
anaplastic lymphoma kinase (ALK) inhibitors,9 which are being explored as various anticancer and
antidiabetic agents. These attractive biological properties have intrigued the synthetic chemists and
encouraged them to develop new synthetic pathways to these ring systems.
Figure 1. Chemical structures of -carboline (1) and -carboline structure based biologically active natural
products.
For the preparation of this ring system, various synthetic methods have been developed and they can be
classified into the following four strategies; (i) intramolecular biaryl coupling reaction of N-arylaminopyridine
derivatives,10,11
(ii) intramolecular amination reaction to form the pyrrole C-N bond,12-14
(iii)
Chapter 2
19
benzannulation,15-17
and (iv) pyridine ring formation (Scheme 1).18-22
Scheme 1. Common -carboline syntheses
Among these synthetic methods, the Graebe-Ullmann reaction, classified as an intramolecular biaryl
coupling strategy (i), has been most often employed, due to the easy access to the penultimate precursors.9-11
However, the reaction requires a benzotriazole intermediate, which is considered a significant drawback
because of the high temperature conditions needed for cyclization with a potential risk of explosion. Even in
the case of the modified reaction employing UV light, or microwave irradiation, the protocol is still not
practical.11b,e
Likewise, other protocols have drawbacks from a practical perspective, particularly for the
preparation of complex substrates. For example, the intramolecular amination strategy (ii) requires the
preparation of 3-(2-aminophenyl)-2-fluoropyridine,12
3-(2-nitrophenyl)pyridine,13
or
3-(2-azidophenyl)pyridine,14
which are prepared by a combination of biaryl coupling and functionalization
at the ortho position of the phenyl ring. Regarding the benzannulation strategy (iii), the complicated
7-aza-indole derivatives are prepared for aromatization reaction after a Fisher’s indole synthesis15
or a
Diels-Alder reaction,8b,16
and an intramolecular Friedel-Crafts type acylation.17
As for the pyridine ring
formation strategy (iv), multi-step syntheses are also required for the substrate, such as
N-phenyl-aminopyrazine derivatives for the Diels-Alder reaction,18
2-aminoindole derivatives7a,19
and
Chapter 2
20
3-substituted indoles20
for cyclization. Thus, while those strategies provide regiospecific syntheses of
substituted -carbolines, they require complex substrates as the precursors, which causes multi-step syntheses
for their preparation and limits both the availability of the starting materials and the scope for further
functionalization on the -carboline. Additionally, substituent diversity on the benzene ring has not been
systematically studied to date, in comparison with that on the pyridine ring.
Sakamoto and co-workers have reported an intramolecular biaryl coupling strategy, utilizing a sequential Pd
catalyzed cross coupling method employing amination and direct C-H arylation.21
The method offered an
effective and convenient access to carbolines, particularly from the viewpoint of substrate preparations, but
it needs harsh conditions (reflux in DMF for 67 h) and gave the product in low yield (31%) for the direct C-H
arylation, and was only applied to one example of a non-substituted -carboline. Therefore, a mild and
efficient protocol for direct C-H arylation is still desired, which would contribute to the easy and rapid
accesses to various -carbolines.
In the course of our drug research and development, an efficient synthetic strategy for -carbolines with
various substituents on the benzene ring was required, and we developed several Pd catalyzed syntheses,
which we disclosed in a patent.22
Herein, we describe in more detail our studies on a versatile and practical
synthetic protocol for -carbolines through a sequence of transition metal catalyzed amination and direct C-H
arylation (Scheme 2).
Scheme 2. Synthetic strategy toward -carboline
Chapter 2
21
Results and discussion
Our initial studies were commenced by establishing an efficient catalyst system for Pd catalyzed amination
of 2-amino-3-bromopyridine (5) with aryl iodide (6). To identify the optimal reaction condition for this
reaction, an extensive screening of catalyst systems, including ligands and bases, was performed, which
identified the ligand XANTPHOS (4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene) in the presence of
Pd(OAc)2 and Cs2CO3 as the most active catalyst system for the amination.
Next, our efforts were turned toward the Pd catalyzed direct C-H arylation. Direct C-H arylation of
3-bromo-5-methyl-N-phenylpyridine-2-amine (7a) was examined under the original conditions reported by
Sakamoto group21
(Table 1, run 1), and it was found that only a small amount of the desired -carboline (1a)
was obtained with undesired 8a arising from hydrodebromination of 7a, as expected.23
The result led us to further investigate how to enhance the reactivity and suppress the side reaction. First, a
series of bases were examined in the presence of Pd(OAc)2 in DMAc (Table 1).
Table 1. Base effect on direct C-H arylation of 7aa
Run Base Conversion (%)b
Run Base Conversion (%)b
1a 8a 1a 8a
1 K2CO3 2 1 6 NEt3 11 22
2 Cs2CO3 7 3 7 Cy2NMe 6 16
3 NaOAc 10 1 8 DABCO 20 <1
4 K3PO4 13 3 9 DBU 32 <1
5 i-Pr2NEt 11 16 10 DBN 50 <1
a Reaction condition: 7a (1.0 mmol), Pd(OAc)2 (5 mol%), Base (2 equiv), DMAc (1 mL), 130 oC, 5h. b Determined by HPLC
analysis.
Chapter 2
22
Although some prior literature suggested that inorganic bases are effective to enhance the reaction rate and
suppress the hydrodebromination,24
several inorganic bases (Cs2CO3, NaOAc, and K3PO4) were found to be
ineffective in this reaction, giving low conversions and a considerable amount of 8a (runs 2-4). Next, organic
amines were examined, and it was found that although alkyl acyclic amines (i-Pr2NEt, Et3N,25
and Cy2NMe)26
gave a large amount of 8a (runs 5-7), satisfactory results could be obtained with cyclic tertiary amines
DABCO (1,4-diazabicyclo[2.2.2]octane),27
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), and DBN
(1,5-diazabicyclo[4.3.0]non-5-ene), which exclusively provided 1a in moderate yield (runs 8-10). While DBN
displays the highest conversion among cyclic tertiary amines, DBU was finally selected as the optimal base
for the reaction, on consideration of its wide applicability even for base-sensitive substituents.28
With DBU as the base, the influence of ligand on the reactivity was examined. A screening of different ligands
was performed at 130 oC for 1 h in the presence of 5 mol% of Pd(OAc)2 and 2.0 equiv of DBU (Table 2). A
large number of ligands including monodentate triarylphosphines (PPh3, P(o-Tolyl)3), trialkyl phosphines
(P(t-Bu)3, P(t-Bu)2Me, PCy3), dialkylbiphenylphosphines (2-dicyclo hexylphosphino-2',4',6'-triisopropyl
biphenyl (XPhos), 2-dicyclohexyl phosphino-2'-(N,N-dimethylamino)biphenyl (Davephos),
2-(di-tert-butylphosphino)biphenyl (DTBPB), 2-(dicyclohexylphosphino)biphenyl (DCHPB), bidentate
phosphines, (dppp, dppf, rac-BINAP, XANTPHOS) and N-heterocyclic carbene
(1,3-bis(2,6-diisopropylphenyl) imidazolium chloride ([IPr]HCl)) were screened. As shown in Table 2, the
DCHPB-based catalyst system gave fast reaction that reached full conversion within 1 h (run 9), though
P(t-Bu)2Me (run 4) gave moderate conversion among monodentate triarylphosphines and bulky
trialkylphosphines, standard ligands for intramolecular direct C-H arylations.29
To our knowledge, it is
uncommon that dialkylbiphenylphosphines such as DCHPB is effective in this kind of intramolecular C-H
arylation.30
Furthermore, since DCHPB was quite effective for the reaction, compared with other
dialkylbiphenylphosphines (X-Phos, DavePhos, and DTBPB) (runs 6-8), we consider a balance of bulkiness
between dialkyl and biphenyl group on the phosphine might be a key to accelerate the reaction.31
Chapter 2
23
Table 2. Ligand effect on direct C-H arylation of 7aa
Run Ligand
Conversion (%)b
Run Ligand
Conversion (%)b
1a 8a 1a 8a
1 PPh3 19 - 8 DTBPBe 12 -
2 P(o-Tolyl)3 6 - 9 DCHPBf 99 -
3 P(t-Bu)3 17 - 10 DPPE 26 -
4 P(t-Bu)2Me 73 - 11 DPPF 27 -
5 PCy3 42 - 12 rac-BINAP 6 3
6 X-Phosc 56 - 13 XANTPHOS 13 -
7 DavePhosd 4 - 14 [IPr]HCl 4 2
a Reaction condition: 7a (1.0 mmol), Pd(OAc)2 (5 mol%), Ligand (10 mol%), DBU (2 equiv), DMAc (1 mL), 130 oC, 1h.
b Determined by HPLC analysis. c 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. d 2-dicyclohexylphosphino-2'-(N,N-dimethyl
amino)biphenyl. e 2-(di-tert-butylphosphino)biphenyl. f 2-(dicyclo hexylphosphino)biphenyl.
Having established the optimal catalyst systems for both the Pd catalyzed amination and direct C-H
arylation, a versatile synthesis of -carbolines was addressed (Table 3).32
Gratifyingly, it was found that
various electronically and structurally diverse substrates could be applied in this sequence. As can be seen in
the synthesis of 1g, 1h, 1j, and 1k, a variety of base-sensitive functional groups including ester, ketone, nitrile
and amide were tolerant. Additionally, the catalyst system also worked even in the presence of bromide and
chloride substituents on the -carbolines, allowing the opportunity for further other transition metal catalyzed
functionalizations (1m and 1n). It is noteworthy from practical perspectives that this reaction system was
successfully performed on multigram scales and allowed isolation of the desired -carboline products as
nearly pure materials by just adding water to the resulting reaction mixture.
Chapter 2
24
Table 3. Synthesis of -carboline 1 by a sequence of Pd catalyzed amination and direct C-H arylationa
1a 1b 1c 1d
87%b/ 97% 63% / 87% 24% / 99% 81%
c/ 97%
1e 1f 1g 1h
91%c/ 95% 20% / 86% 43% / 59% (81%)
d 45% / 84%
1j 1k 1m 1n
68% / 99% 38% / 65% (93%)
d 67% /15% 79%
c/ 55% (87%)
d
a Percentage on the left refers to isolated yield of 7 obtained by the first cross coupling reaction. Percentage on the right refers to
isolated yield of 1 obtained by the second cross coupling reaction. Standard reaction condition for the first coupling: 5 (10.7 mmol), 6
(10.7 mmol), Pd(OAc)2 (5 mol%), XANTPHOS (5 mol%), Cs2CO3 (1.4 equiv), anisole (30 ml), 130 oC, Standard reaction condition
for the second coupling: 7 (3.1 mmol), Pd(OAc)2 (5 mol%), DCHPB (10 mol%), DBU (2 equiv), DMAc (3 ml), 130 oC. b Solvent:
t-BuOH (reflux), c Catalyst: Pd2(dba)3, ligand: dppf, solvent: toluene (100 oC). d HPLC assay yield.
Moreover, to confirm the regioselectivity of the Pd catalyzed cyclization, the reaction starting from
3-substituted aryl iodide (6p) was attempted, and it was found that the 7-substituted -carboline (1p) was
exclusively obtained, with no 5-substitued compound (1p') detected (Scheme 3). Thus, we achieved selective
Chapter 2
25
functionalization at the 6-, 7-, and 8-positions of the -carbolines. As for the preparation of 5-substituted
-carbolines, the 8-substituent appears to be essential, as shown in the synthesis for 1n.
Scheme 3. Regioselective direct C-H arylation
Thus, having established a versatile and practical -carboline synthesis employing sequential Pd catalyzed
amination and direct C-H arylation, our interests were then directed toward extending the application to
include Cu catalyzed amination. Copper is considered a more attractive catalyst than palladium due to its
relative inexpensiveness, ready availability, lower toxicity and robustness even under atmospheric condition.33
Also, Cu catalyzed amination could be expected to broaden the range of the applicable substrates for the
system.34
For optimization of the reaction, the coupling reaction of 5 with 6e was investigated. Initially, several
different ligands (N,N’-dimethylaminocyclohexane, 1,10-phenathroline, 2-acetylcyclohexanone,35
ethylene
glycol, L-proline, ethanolamine) were screened in the presence of CuI, and K2CO3. Consequently,
ethanolamine was found as the best ligand for the reaction (Scheme 4). The reaction system was then
successfully applied to other aryl iodides (6a, 6g and 6q), providing desired products in moderate yield. The
obtained N-arylpyridin-2-amines (7) successfully underwent the Pd catalyzed direct C-H arylation to provide
the corresponding series of -carbolines (1). It is noteworthy that the aryl iodide with a hydroxy methyl group
Chapter 2
26
(6q), which was considered difficult to be applied to the Pd catalyzed amination, could be successfully
converted to 7q without involving intermolecular O-arylation, and the subsequent Pd catalyzed C-H arylation
was carried out with no intramolecular O-arylation.
Scheme 4. -Carboline synthesis through Cu catalyzed amination and Pd catalyzed direct C-H arylation
Conclusion
We have developed a versatile and practical synthetic protocol for pharmacologically important
-carbolines, through a sequence of Pd catalyzed amination and direct C-H arylation. The outstanding feature
in the direct C-H arylation is that a combination of DBU and DCHPB plays a critical role to not only enhance
the reactivity but also suppress hydrodehalogenation. The reaction system enables the versatile synthesis of
-carbolines in moderate to excellent yields. Moreover, the combination with Cu catalyzed amination afforded
a wide diversity of -carbolines. The protocol readily affords various -carbolines that could be useful for
new drug development.
Chapter 2
27
Experimental Section
General
All materials were purchased from commercial suppliers and used without further purification. Melting
points were recorded on a Büchi B-540 micromelting apparatus and were uncorrected. NMR spectra were run
at either 300 MHz (1H)/ 75 MHz (13C) (Bruker DPX-300) or 500 MHz (1H)/ 125 MHz (13C) (Bruker
UltraShield-500 PLUS). Chemical shifts are reported as values using tetramethylsilane as an internal
standard and coupling constants (J) are given in hertz (Hz).
General Procedure for 7 (Pd catalyzed procedure)
Under N2 atmosphere, to a solution of palladium acetate (120 mg, 0.53 mmol, 5 mol%) and XANTPHOS
(309 mg, 0.53 mmol, 5 mol%) in anisole (30 mL) was added 3-bromo-5-methyl-pyridin-2-ylamine (5) (2.0 g,
10.7 mmol, 1.0 equiv), aryl iodides (6) (10.7 mmol) and cesium carbonate (4.9 g, 15.0 mmol, 1.4 equiv), and
the mixture was stirred at 130 oC for 1-13 h. After cooling to room temperature, water (40 mL) was added to
the mixture. The mixture was concentrated in vacuo and ethyl acetate (100 mL) was added to the residue. The
organic layer was washed with water (20 mL) and concentrated in vacuo to give the crude product, which was
purified by flash chromatography to give 7.
3-Bromo-5-methyl-N-phenylpyridine-2-amine (7a). The title compound was prepared from 5 (9.4 g) and
iodobenzene (6a) (10.2 g), according to the general procedure using t-BuOH as a solvent under reflux
conditions. Yield: 87% (11.5 g). White solid; mp 62.5-64.5 oC.
1H-NMR (300 MHz, CDCl3): 2.24 (s, 3 H),
6.89 (brs, 1 H), 7.01-7.06 (m, 1 H), 7.31-7.36 (m, 2 H), 7.58-7.61 (m, 3 H), 7.80 (s, 1 H). 13
C-NMR (75 MHz,
CDCl3): 17.1, 106.1, 119.4, 122.3, 125.1, 128.9, 140.2, 140.9, 146.1, 149.8. HRMS (FAB): m/z [M-H]+
(calcd. for C12H11BrN2: 261.0027; found: 261.0027.).
Chapter 2
28
3-Bromo-5-methyl-N-1-naphtylpyridine-2-amine (7b). The title compound was prepared according to the
general procedure. Yield: 63% (2.1 g), Brown solid; mp 127.7-132.6 oC.
1H-NMR (500 MHz, DMSO-d6): δ
2.15 (s, 3H), 7.41-7.53 (m, 3H), 7.55-7.61 (m, 1H), 7.71-7.78 (m, 2H), 7.80-7.87 (m, 2H), 7.90-7.96 (m, 1H),
8.16 (s, 1H). 13
C-NMR (125 MHz, DMSO-d6): δ 16.4, 105.5, 121.5, 122.9, 124.4, 124.8, 125.6, 125.7, 125.8,
128.1, 129.1, 134.0, 136.7, 141.2, 146.1, 152.0. HRMS (FAB): m/z [M-H]+ (calcd. for C16H13BrN2: 311.0184;
found: 311.0179).
N-([1,1'-Biphenyl]-4-yl)-3-bromo-5-methylpyridin-2-amine (7c). The title compound was prepared
according to the general procedure. Yield: 24% (860 mg), Yellow solid; mp 90.0-91.3 oC.
1H-NMR (500 MHz,
DMSO-d6): δ 2.21 (s, 3H), 7.28-7.34 (m, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.59 (m, 2H), 7.62-7.68 (m, 2H), 7.73
(m, 2H), 7.80-7.89 (m, 1H), 8.00-8.07 (m, 1H), 8.10 (s, 1H). 13
C-NMR (125 MHz, DMSO-d6): δ 16.5, 106.1,
120.0, 125.7, 126.0, 126.5, 126.6, 128.8, 133.1, 140.0, 140.5, 141.6, 145.9, 149.9. HRMS (EI): m/z [M]+
(calcd. for C18H15BrN2: 337.0340; found: 337.0341).
N-([1,1'-biphenyl]-2-yl)-3-bromo-5-methylpyridin-2-amine (7d). The title compound was prepared under
the following conditions; catalyst: Pd2(dba)3, ligand: dppf, solvent: toluene, base: NaOt-Bu, temperature: 100
oC. Yield: 2.9 g (81%). Off-white solid; mp 229.2-231.2
oC.
1H-NMR (500 MHz, DMSO-d6): 2.14 (s, 3 H),
7.14 (td, J = 7.5, 1.4 Hz, 1 H), 7.26 (dd, J = 7.6, 1.9 Hz, 1H), 7.31-7.49 (m, 8 H), 7.72 (d, J = 2.2 Hz, 1H),
7.92 (dd, J = 1.7, 0.8 Hz, 1 H), 8.15 (dd, J = 8.2, 1.3 Hz, 1 H). 13
C-NMR (125 MHz, DMSO-d6): 16.4, 105.6,
121.6, 122.8, 125.1, 127.6, 127.9, 128.8, 128.9, 129.9, 133.1, 137.3, 138.5, 141.0, 145.8, 149.8. HRMS (EI):
m/z [M-H]+ (calcd. for C18H15BrN2: 337.0340; found:
337.0337).
3-Bromo-N-(2-methoxyphenyl)-5-methylpyridine-2-amine (7e). The title compound was prepared from 5
(10.0 g) and 2-iodoanisole (6e) (12.5 g), according to the general procedure under the following conditions;
catalyst: Pd2(dba)3, ligand: dppf, solvent: toluene, base: NaOt-Bu, temperature: 100 oC. Yield: 91% (14.8 g),
White solid; mp 111.8-114.4 oC.
1H-NMR (500 MHz, DMSO-d6): δ 2.20 (s, 3H), 3.91 (s, 3H), 6.87-7.00 (m,
Chapter 2
29
2H), 7.01-7.12 (m, 1H), 7.71 (s, 1H), 7.80-7.90 (m, 1H), 7.99-8.11 (m, 1H), 8.39-8.50 (m, 1H). 13
C-NMR (125
MHz, DMSO-d6): δ 16.5, 56.0, 106.1, 110.5, 117.5, 120.5, 121.4, 125.2, 129.5, 141.1, 145.9, 147.7, 149.2.
HRMS (EI): m/z [M]+ (calcd. for C13H13BrN2O: 292.0211; found: 292.0205).
3-Bromo-5-methyl-N-[4-(methylthio)phenylpyridine-2-amine (7f). The title compound was prepared
according to the general procedure. Yield: 20% (500 mg); White solid; mp 54.5-57.3 oC.
1H-NMR (500 MHz,
DMSO-d6): δ 2.19 (s, 3H), 2.44 (s, 3H), 7.16-7.25 (m, 2H), 7.54-7.63 (m, 2H), 7.81 (d, J = 2.5 Hz, 1H),
7.92-8.03 (m, 2H). 13
C-NMR (125 MHz, DMSO-d6): δ 16.2, 16.4, 105.8, 120.6, 125.4, 127.5, 129.5, 138.7,
141.5, 145.8, 149.9. HRMS (FAB): m/z [M-H]+ (calcd. for C13H13BrN2S: 306.9905; found: 306.9904).
Methyl 3-[(3-bromo-5-methylpyridin-2-yl)amino]-2-methylbenzoate (7g). The title compound was
prepared from 5 (6.2 g) and methyl 3-iodo-2-methylbenzoate (6g) (9.2 g), according to the general procedure
using toluene as a solvent at 100 oC. Yield: 43% (4.8 g). White solid; mp 63.9-64.7
oC.
1H-NMR (500 MHz,
DMSO-d6): δ 2.15 (s, 3H), 2.26 (s, 3H), 3.83 (s, 3H), 7.27 (t, J = 7.9 Hz, 1H), 7.51-7.56 (m, 1H), 7.56-7.61 (m,
1H), 7.75-7.79 (m, 2H), 7.81-7.87 (m, 1H). 13
C-NMR (125 MHz, DMSO-d6): δ 15.1, 16.4, 52.0, 105.2, 124.6,
125.6, 129.0, 131.4, 133.5, 140.3, 141.2, 146.0, 148.0, 151.3, 168.0. HRMS (EI): m/z [M]+ (calcd. for
C15H15BrN2O2: 334.0317; found: 334.0313).
1-{4-[(3-Bromo-5-methylpyridin-2-yl)amino] phenyl}ethanone (7h). The title compound was prepared
according to the general procedure. Yield: 1.5 g (45%); White solid; mp 91.9-93.0 oC.
1H-NMR (500 MHz,
DMSO-d6): δ 2.23 (s, 3H), 2.50 (s, 3H), 7.67-7.74 (m, 2H), 7.83-7.89 (m, 2H), 7.91 (d, J =2.2 Hz, 1H), 8.06 -
8.11 (m, 1H), 8.50 (s, 1H). 13
C-NMR (125 MHz, DMSO-d6): δ 16.5, 26.2, 107.3, 117.6, 127.4, 129.2, 129.3,
141.9, 145.9, 146.0, 149.1, 196.0. HRMS (FAB): m/z [M-H]+ (calcd. for C14H13BrN2O: 303.0133; found:
303.0132).
Chapter 2
30
4-[(3-Bromo-5-methylpyridin-2-yl)amino]benzonitrile (7j). The title compound was prepared from 5 (2.0
g) and 4-iodobenzonitrile (6j) (2.5 g), according to the general procedure. Yield: 68% (2.1 g). Off-white solid.
mp 163.4-165.3 oC.
1H-NMR (500 MHz, DMSO-d6): δ 2.24 (s, 3H), 7.67 (dd, J = 7.0, 1.9 Hz, 2H), 7.77 (dd, J
= 7.0, 1.9 Hz, 2H), 7.92 (s, 1H), 8.10 (s, 1H), 8.64 (s, 1H). 13
C-NMR (125 MHz, DMSO-d6): δ 16.6, 101.8,
107.6, 118.3, 119.6, 127.9, 132.7, 142.1, 145.7, 146.0, 148.8. HRMS (FAB): m/z [M-H]+ (calcd. for
C13H10BrN3: 285.9980; found: 285.9972).
3-[3-Bromo-5-methylpyridin-2-yl)amino]-2-methyl-N-(1-methylpiperidin-4-yl)benzamide (7k). The title
compound was prepared from 5 (350 mg) and 3-iodo-2-methyl-N-(1-methylpiperidin-4-yl)benzamide (6k)
(670 mg), according to the general procedure. Yield: 38% (295 mg). Reddish white solid. mp 262.1-266.5 oC.
1H-NMR (500 MHz, DMSO-d6): δ 1.46-1.59 (m, 2H), 1.72-1.81 (m, 2H), 1.90-1.99 (m, 2H), 2.12 (s, 3H),
2.15 (s, 3H), 2.16 (s, 3H), 2.66-2.80 (m, 2H), 3.59-3.79 (m, 1H), 6.98-7.11 (m, 1H), 7.19 (t, J = 7.7 Hz, 1H),
7.52 (d, J = 7.3 Hz, 1H), 7.60 (s, 1H), 7.74-7.82 (m, 1H), 7.82-7.90 (m, 1H), 8.21 (d, J = 7.9 Hz, 1H).
13C-NMR (125 MHz, DMSO-d6): δ 14.4, 16.4, 31.4, 45.96, 46.04, 54.3, 105.3, 122.7, 124.6, 125.4, 129.3,
133.5, 138.9, 139.5, 141.2, 126.0, 151.1, 168.6. HRMS (EI): m/z [M]
+ (calcd. for C20H25BrN4O: 416.1212;
found: 416.1202).
3-Bromo-N-(2-bromophenyl)-5-methylpyridine-2-amine (7m). The title compound was prepared according
to the general procedure. Yield: 67% (2.5 g); Off-white solid; mp 54.7-56.5 o
C. 1H-NMR (500 MHz,
DMSO-d6): δ 2.21 (s, 3H), 6.90-7.06 (m, 1H), 7.35-7.42 (m, 1H), 7.65 (dd, J = 8.0, 1.7 Hz, 1H), 7.73 (s, 1H),
7.81-7.96 (m, 1H), 7.97-8.09 (m, 1H), 8.27 (dd, J = 8.4, 1.7 Hz, 1H). 13
C-NMR (125 MHz, DMSO-d6): δ 16.5,
106.2, 114.6, 121.6, 123.8, 126.2, 128.2, 132.4, 138.1, 141.4, 145.9, 149.3. HRMS (EI): m/z [M]+ (calcd. for
C12H10Br2N2: 339.9211; found: 339.9211.
3-Bromo-N-(5-chloro-2-methoxyphenyl)-5-methyl pyridine-2-amine (7n). The title compound was
prepared from 5 (9.8 g) and 4-chloro-2-iodo-1-methoxybenzene (6n) (13.4 g), according to the general
Chapter 2
31
procedure under the following conditions; catalyst: Pd2(dba)3, ligand: dppf, solvent: toluene, base: NaOt-Bu,
temperature: 100 oC. Yield: 79% (12.9 g). White solid. mp 139.2-141.2
oC.
1H-NMR (300 MHz, CDCl3): δ
2.23 (s, 3H), 3.92 (s, 3H), 6.77 (d, J = 8.6 Hz, 1H), 6.87 (dd, J = 8.6, 2.5 Hz, 1H), 7.59 (d, J = 1.5 Hz, 1H),
7.75 (brs, 1H), 8.05 (d, J = 1.0 Hz, 1H), 8.69 (d, J = 2.5 Hz, 1H). 13
C-NMR (75MHz, CDCl3) δ 17.1, 56.2,
106.8, 110.4, 117.1, 120.1, 125.4, 126.0, 131.2, 140.9, 146.0, 146.3, 149.3. MS: m/z = 327 [M+H]+. Anal.
calcd for C13H12N2OBrCl: C, 47.66; H, 3.69; N, 8.55; Br 24.39; Cl 10.82. found: C, 47.94; H, 3.62; N, 8.68;
Br, 24.36; Cl, 10.86.
Ethyl 3-((3-bromo-5-methylpyridin-2-yl)amino)-benzoate (7p). The title compound was prepared from 5
(10.0 g) and ethyl 2-iodobenzoate (6p) (14.8 g), according to the general procedure. 7p was telescoped to the
subsequent step. White solid. mp 50.8-52.8 oC.
1H-NMR (500 MHz, DMSO-d6): δ 1.33 (t, J = 7.1 Hz, 3H),
2.21 (s, 3H), 4.32 (q, J = 7.3 Hz, 2H), 7.40 (t, J = 7.9 Hz, 1H), 7.54 (dt, J = 7.7, 1.3 Hz, 1H), 7.85 (d, J = 2.2
Hz, 1H), 7.89 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 8.01 (dd, J = 1.9, 0.6 Hz, 1H), 8.23 (t, J = 2.1 Hz, 1H), 8.31 (s,
1H). 13
C-NMR (125 MHz, DMSO-d6): δ 14.2, 16.5, 60.6, 106.2, 120.2, 121.9, 124.1, 126.2, 128.5, 130.1,
141.4, 141.7, 145.8, 149.8, 165.9. MS (ESI): m/z = 335 [M+H]+. Anal Calcd for C15H15BrN2O2; C,53.75; H,
4.41; N, 8.36; Br, 23.84. found: C, 53.88; H, 4.43; N, 8.18; Br, 23.49.
General Procedure for 7 (Cu catalyzed procedure)
Under N2 atmosphere, to a solution of copper iodide (204 mg, 0.11 mmol, 10 mol%) and ethanolamine (131
mg, 0.22 mmol, 20 mol%) in anisole (30 mL) was added aryl iodides (6) (10.7 mmol),
3-bromo-5-methyl-pyridin-2-ylamine (5) (10.7 mmol) and potassium carbonate (2.2 g, 16.0 mmol, 1.5 equiv),
and the mixture was stirred at 130 oC for 4 - 18 h. After cooling to room temperature, water (30 mL) was
added to the mixture. The mixture was concentrated in vacuo and ethyl acetate (50 mL) was added to the
residue. The organic layer was washed with water (20 mL) and concentrated in vacuo to give the crude
product. The crude product was purified by flash chromatography to give the title compound.
Chapter 2
32
3-Bromo-N-(2-methoxyphenyl)-5-methylpyridine-2-amine (7e). The title compound was prepared from 5
(1.0 g) and 6e (1.3 g), according to the general procedure. Yield: 46% (720 mg).
3-Bromo-5-methyl-N-phenylpyridine-2-amine (7a). The title compound was prepared according to the
general procedure. Yield: 25% (700 mg).
Methyl 3-[(3-bromo-5-methylpyridin-2-yl)amino]-2-methylbenzoate (7g). The title compound was
prepared according to the general procedure. Yield: 32% (1.1 g).
{2-[(3-Bromo-5-methylpyridin-2-yl)amine]phenyl} methanol (7q). The title compound was prepared from
5 (1.5 g) and (2-iodophenyl)methanol (6q) (1.9 g), according to the general procedure. Yield: 20% (470
mg); Off-white solid; mp 129.3-131.8 oC.
1H-NMR (500 MHz, DMSO-d6): δ 2.20 (s, 3H), 4.56 (d, J = 5.0 Hz,
2H), 5.67 (t, J = 5.0 Hz, 1H), 6.96 (td, J = 7.4, 1.3 Hz, 1H), 7.25 (d, J = 7.3 Hz, 2H), 7.84 (d, J = 2.2 Hz, 1H),
7.93-8.00 (m, 1H), 8.09 (dd, J = 8.7, 1.1 Hz, 1H), 8.66 (s, 1H). 13
C-NMR (125 MHz, DMSO-d6): δ 16.5, 62.5,
105.7, 120.2, 121.5, 125.1, 127.5, 128.3, 130.5, 139.7, 141.3, 145.8, 150.0. HRMS (EI): m/z [M]+ (calcd. for
C13H13BrN2O: 292.0211; found: 292.0208).
General Procedure for 1
Under N2 atmosphere, to a solution of palladium acetate (21 mg, 0.09 mmol, 5 mol%) and
2-(di-cyclohexylphosphino)biphenyl (DCHPB) (65 mg, 0.19 mmol, 10 mol%) in N,N-dimethylacetamide (3
mL) was added N-arylpyridin-2-amines (7) (3.09 mmol) and DBU (942 mg, 6.19 mmol, 2.0 equiv), and the
mixture was stirred at 130 oC for 1-8 h. After cooling to room temperature, water (6 mL) was added to the
mixture. The mixture was then stirred at ambient temperature for 0.5 h before the precipitate was filtered and
washed with methanol (4 mL) and water (2 mL) to give the title compound.
Chapter 2
33
3-Methyl-9H-pyrido[2,3-b]indole (1a). The title compound was prepared from 7a (10.5 g), according to the
general procedure. Yield: 97% (7.5 g). Off-white solid. mp 269.4-271.4 oC.
1H-NMR (300 MHz, DMSO-d6):
2.45 (s, 3 H), 7.16-7.21 (m, 1 H), 7.39-7.48 (m, 2 H), 8.11 (d, J = 7.8 Hz, 1 H), 8.26 (d, J = 1.5 Hz, 1 H),
8.30 (s, 1 H), 11.59 (brs, 1 H). 13
C-NMR (75 MHz, DMSO-d6): 18.2, 111.3, 115.1, 119.3, 120.3, 121.2,
123.6, 126.5, 128.6, 139.3, 146.7, 150.7. HRMS (EI): m/z [M]+ (calcd. for C12H10N2: 182.0841; found:
182.0844.).
8-Methyl-11H-benzo[g]pyrido[2,3-b]indole (1b). The title compound was prepared from 7b (500 mg),
according to the general procedure. Yield: 87% (322 mg). Yellow solid. mp 301.1-303.5 o
C. 1H-NMR (500
MHz, DMSO-d6): δ 2.50 (s, 3H), 7.58 (ddd, J = 8.2, 6.8, 1.4 Hz, 1H), 7.64 (td, J = 7.5, 1.4 Hz, 1h), 7.67 (d, J
= 8.5 Hz, 1H), 8.04, (d, J = 7.9 Hz, 1H), 8.19 (d, J = 8.5 Hz, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.38 (dd, J = 1.9,
0.6 Hz, 1H), 8.60 (d, J = 7.6 Hz, 1H), 12.64 (brs, 1H). 13
C-NMR (125 MHz, DMSO-d6): δ 18.1, 114.9, 115.6,
119.66, 119.69, 121.2, 122.2, 124.1, 125.6, 127.9, 128.5, 132.2, 135.0, 141.2, 145.9, 149.7. HRMS (EI): m/z
[M]+ (calcd. for C16H12N2: 232.1000; found:
232.0996).
3-Methyl-6-phenyl-9H-pyrido[2,3-b]indole (1c). The title compound was prepared from 7c (500 mg),
according to the general procedure. Yield: 99% (375 mg). Pale yellow solid. mp 300.1-302.8 oC.
1H-NMR
(500 MHz, DMSO-d6): δ 2.47 (s, 3H), 7.31-7.38 (m, 1H), 7.49 (t, J = 7.9 Hz, 2H), 7.57 (d, J = 8.5 Hz, 1H),
7.69-7.92 (m, 3H), 8.17-8.36 (m, 1H), 8.46 (dt, J = 8.1, 1.1 Hz, 2H), 11.78 (s, 1H). 13
C-NMR (125 MHz,
DMSO-d6): δ 18.0, 111.6, 115.6, 119.2, 120.8, 123.7, 125.6, 126.5, 126.6, 128.9, 129.3, 131.8, 138.7, 141.0,
146.0, 150.4. HRMS (EI): m/z [M]+ (calcd. for C18H14N2: 258.1157; found: 258.1157).
3-Methyl-8-phenyl-9H-pyrido[2,3-b]indole (1d). The title compound was prepared from 7d (500 mg),
according to the general procedure. Yield: 97% (370 mg). White solid. mp 229.2-231.2 o
C. 1H-NMR (500
MHz, DMSO-d6): 2.47 (s, 3H), 7.31 (t, J = 7.6 Hz, 1H), 7.41-7.48 (m, 2H), 7.55 (t, J = 7.7 Hz, 2H), 7.71 (dd,
J = 8.2, 1.3 Hz, 2H), 8.14 (dd, J = 7.6, 1.3 Hz, 1H), 8.28 (d, J = 2.5 Hz, 2H), 8.34-8.39 (m, 1H), 11.51 (s, 1H).
Chapter 2
34
13C-NMR (125 MHz, DMSO-d
6): 18.0, 115.1, 119.8, 120.1, 121.2, 123.8, 125.2, 126.7, 127.3, 128.4, 128.5,
128.9, 136.4, 138.2, 146.8, 151.1. HRMS (EI): m/z [M]+ (calcd. for C18H14N2: 258.1157; found: 258.1154).
8-Methoxy-3-methyl-9H-pyrido[2,3-b]indole (1e). The title compound was prepared from 7e (32.0 g),
according to the general procedure. Yield: 95% (22.1 g). Brown solid. mp 215.9-220.2 oC.
1H-NMR (500 MHz,
DMSO-d6): δ 2.44 (s, 3H), 3.97 (s, 3H), 7.03 (d, J = 7.9 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 7.69 (d, J = 7.9 Hz,
1H), 8.27 (q, J = 2.6 Hz, 2H), 11.72 (s, 1H). 13
C-NMR (125 MHz, DMSO-d6): δ 18.0, 55.5, 107.3, 113.3,
115.1, 119.7, 121.2, 123.5, 128.4, 129.1, 145.7, 146.5, 150.3. HRMS (EI): m/z [M]+ (calcd. for C13H12N2O:
212.0950; found: 212.0946).
3-Methyl-6-(methylthio)-9H-pyrido[2,3-b]indole (1f). The title compound was prepared from 7f (400 mg),
according to the general procedure. Yield: 86% (253 mg). Orange solid. mp 155 oC dec.
1H-NMR (500 MHz,
DMSO-d6): δ 2.46 (s, 3H), 2.55 (s, 3H), 7.42-7.49 (m, 2H), 8.13 - 8.18 (m, 1H), 8.27-8.34 (m, 1H), 8.41-8.49
(m, 1H), 11.88 (s, 1H). 13
C-NMR (125 MHz, DMSO-d6): δ 17.2, 17.9, 112.0, 115.3, 120.7, 120.9, 123.8, 127.4,
127.6, 129.9, 137.5, 145.1, 149.5. HRMS (EI): m/z [M]+ (calcd. for C13H12N2S: 288.0721. found: 288.0711).
Methyl 3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxylate (1g). The title compound was prepared from 7g
(4.8 g), according to the general procedure. Yield: 59% (2.1 g). Off-white solid. mp 296.6-298.7 oC.
1H-NMR
(500 MHz, DMSO-d6): δ 2.46 (s, 3H), 2.77 (s, 3H), 3.87 (s, 3H), 7.67 (d, J = 8.2 Hz, 1H), 8.04 (d, J = 8.5 Hz,
1H), 8.37 (dd, J = 9.9, 2.4 Hz, 2H), 11.90 (s, 1H). 13
C-NMR (125 MHz, DMSO-d6): δ 14.9, 18.0, 51.8, 114.6,
118.1, 120.9, 122.4, 123.0, 124.2, 126.6, 129.3, 138.9, 148.0, 151.4, 168.0. HRMS (EI): m/z [M]+ (calcd. for
C15H14N2O2: 254.1055; found: 254.1056).
1-(3-Methyl-9H-pyrido[2,3-b]indol-6-yl)ethanone (1h). The title compound was prepared from 7h (1.0 g),
according to the general procedure. Yield: 84% (0.6 g). Off-white solid. mp 287.6-290.6 oC.
1H-NMR (500
MHz, DMSO-d6): δ 2.48 (s, 3H), 2.67 (s, 3H), 7.55 (d, J = 8.5 Hz, 1H), 8.07 (dd, J = 8.5, 1.9 Hz, 1H),
Chapter 2
35
8.22-8.42 (m, 1H), 8.51 (dd, J = 1.9, 0.6 Hz, 1H), 8.86 (d, J = 1.9 Hz, 1H), 12.14 (s, 1H). 13
C-NMR (125 MHz,
DMSO-d6): δ 18.0, 26.5, 111.0, 115.7, 120.0, 122.9, 124.6, 126.7, 129.0, 129.6, 142.1, 146.5, 150.6, 196.9.
HRMS (EI): m/z [M]+ (calcd. for C14H12N2O: 224.0950; found: 224.0948).
3-Methyl-9H-pyrido[2,3-b]indole-6-carbonitrile (1j). The title compound was prepared from 7j (1.0 g),
according to the general procedure. Yield: 99% (0.7 g). Pale yellow solid. mp 285.6-288.6 oC.
1H-NMR (500
MHz, DMSO-d6): δ 2.47 (s, 3H), 7.62 (d, J = 8.5 Hz, 1H), 7.80 (dd, J = 8.4, 1.7 Hz, 1H), 8.37 - 8.40 (m, 1H),
8.41-8.48 (m, 1H), 8.69 (d, J = 1.9 Hz, 1H), 12.27 (brs, 1H). 13
C-NMR (125 MHz, DMSO-d6): δ 18.0, 101.0,
112.2, 114.2, 120.2, 120.4, 125.0, 126.3, 129.4, 129.5, 141.2, 148.0, 150.8. HRMS (EI): m/z [M]+ (calcd. for
C13H9N3: 207.0796; found: 207.0789).
3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide (1k). The title compound
was prepared from 7k (250 mg), according to the general procedure. Yield: 65% (130 mg). White solid. mp
335.8-336.8 oC.
1H-NMR (500 MHz, DMSO-d6): δ 1.58 (d, J = 8.8 Hz, 2H), 1.84 (d, J = 11.3 Hz, 2H), 2.00 (t,
J = 10.9 Hz, 2H), 2.20 (s, 3H), 2.49 (s, 3H), 2.58 (s, 3H), 2.79 (d, J = 11.0 Hz, 2H), 3.77 (brs, 1H), 7.17 (d, J =
7.6 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 8.20 (d, J =7.8 Hz, 1H), 8.35 (d, J = 9.7 Hz, 1H), 11.7 (s, 1H). 13
C-NMR
(125 MHz, DMSO-d6): δ 14.0, 17.8, 28.8, 31.3, 45.8, 54.2, 113.7, 117.7, 118.0, 118.3, 121.0, 123.6, 124.1,
125.1, 128.6, 140.2, 151.0, 167.8. HRMS (EI): m/z [M]+ (calcd. for C20H24N4O: 336.1950; found: 336.1954).
8-Bromo-3-methyl-9H-pyrido[2,3-b]indole (1m). The title compound was prepared from 7m (500 mg),
according to the general procedure. Yield: 15% (90 mg). Yellow solid. mp 389.0 oC dec.
1H-NMR (500 MHz,
DMSO-d6): δ 2.47 (s, 3H), 7.16 (t, J = 7.7 Hz, 1H), 7.65 (d, J = 6.9 Hz, 1H), 8.15 (d, J = 7.3 Hz, 1H), 8.32 -
8.40 (m, 2H), 11.93 (brs, 1H). 13
C-NMR (125 MHz, DMSO-d6): δ 18.0, 103.7, 115.1, 120.3, 120.6, 122.0,
124.5, 128.9, 129.1, 137.7, 147.5, 150.6. HRMS (EI): m/z [M]+ (calcd. for C12H9BrN2: 259.9949; found:
259.9940).
Chapter 2
36
5-Chloro-8-methoxy-3-methyl-9H-pyrido[2,3-b] indole (1n). The title compound was prepared from 7n
(3.0 g), according to the general procedure. Yield: 55% (1.25 g). White solid. mp 299.5-301.5 oC.
1H-NMR
(300 MHz, DMSO-d6): δ 2.48 (s, 3H), 3.98 (s, 3H), 7.05 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 8.35 (d,
J = 1.7 Hz, 1H), 8.50 (d, J = 1.7 Hz, 1H), 12.11 (brs, 1H). 13
C-NMR (75 MHz, DMSO-d6): δ 18.2, 56.1, 108.1,
114.1, 117.9, 119.2, 119.6, 124.3, 129.9, 130.2, 144.9, 147.5, 150.1. MS: m/z = 247 [M+H]+. Anal. Calcd for
C13H11N2OCl: C, 63.29; H, 4.49; N, 11.36; Cl, 14.37. found: C, 63.21; H, 4.26; N, 11.44; Cl, 14.37
Ethyl 3-methyl-9H-pyrido[2,3-b]indole-7-carboxylate (1p). The title compound was prepared from
telescoped 7p, according to the general procedure. (6.4 g, 2 steps total: 47%). Yellow solid. mp 304.2-306.0 oC.
1H-NMR (500 MHz, DMSO-d6): δ 1.37 (t, J = 7.1 Hz, 3H), 2.47 (s, 3H), 4.37 (q, J = 6.9 Hz, 2H), 7.81 (dd, J
= 8.2, 1.6 Hz, 1H), 8.10 (d, J = 1.0 Hz, 1H), 8.23 (d, J = 8.2 Hz, 1H), 8.37 (s, 1H), 8.41 (s, 1H), 11.92 (s, 1H).
13C-NMR (125 MHz, DMSO-d6): δ 14.2, 18.0, 60.7, 112.3, 114.2, 119.7, 121.0, 123.9, 124.3, 127.3, 129.5,
138.4, 148.3, 151.4, 166.1.HRMS (EI): m/z [M]+ (calcd. for C15H14N2O2: 254.1055; found: 254.1054).
(3-Methyl-9H-pyrido[2,3-b]indol-8-yl)methanol (1q). The title compound was prepared from 7q (300 mg),
according to the general procedure. Yield: 88% (192 mg). Yellow solid. mp 226.1-229.8 oC.
1H-NMR (500
MHz, DMSO-d6): δ 2.46 (s, 3H), 4.86 (d, J = 5.7 Hz, 2H), 5.23 (t, J = 5.8 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H),
7.33 - 7.54 (m, 1H), 8.01 (d, J = 7.6 Hz, 1H), 8.28 (d, J = 2.5 Hz,1H), 8.31 (d, J=2.5 Hz, 1H), 11.48 (s, 1H).
13C-NMR (125 MHz, DMSO-d6): δ 18.0, 59.6, 115.0, 119.0, 119.4, 120.0, 123.5, 124.3, 125.5, 128.3, 136.6,
146.4, 150.7. HRMS (EI): m/z [M]+ (calcd. for C13H12N2O: 212.0950; found: 212.0947).
Chapter 2
37
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Chapter 2
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23. (a) Baelen, G. V.; Meyers, C.; Lemiére, G. L. F.; Hostyn, S.; Dommisse, R.; Maes, L.; Augustyns, K.;
Haemers, A. Pieters, L.; Maes, B. U. W. Tetrahedron 2008, 64, 11802. (b) Campeau, L.-C.; Parisien, M.;
Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581.
24. (a) Ackermann, L.; Althammer, A. Angew. Chem., Int. Ed. 2007, 46, 1. (b) Parisien, M.; Valette, D.;
Fagnou, K. J. Org. Chem. 2005, 70, 7578. (c) Zhang, Y.-M.; Razler, T.; Jackson, P. F. Tetrahedron Lett.
2002, 43, 8235. (d) Hennings, D. D.; Iwasa, S.; Rawal, V. H. J. Org. Chem. 1997, 2, 2.
25. Hennessy, E.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 12084
26. Littke, A.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989.
27. Lautens, M.; Fang, Y. B. Org. Lett. 2003, 5, 3679.
28. After our patent publication (Reference 22), some examples of Pd mediated direct C-H arylation with
DBU have been reported (a) Laha, J. K.; Petrou, P.; Cuny, G. D. J. Org. Chem. 2009, 74, 3152. (b)
Hostyn, S; Baelen, G. V.; Lemiére, G. L. F.; Maes, B. U. W. Adv. Synth. Catal. 2008, 350, 2653.
29. For the review see; Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174
Chapter 2
40
30. Some examples using o-biphenyl-based triarylphosphines in intramoleculat direct C-H arylation have
been reported; (a) Garcia-Cudrado, D.; de Mendoza, P.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M.
J. Am. Chem. Soc. 2007, 129, 6880. (b) Lafrance, M.; Blaquiere, N.; Fagnou, K. Eur. J. Org. Chem. 2007,
81. (c) Garcia-Cudrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006,
128, 1066. (d) Campeau, L.-C.; Parisien, M. Fagnou, K. J. Am. Chem. Soc. 2004, 126, 9186.
31. A combination effect between the other base and DCHBP has not been evaluated, and is considered to be
a next research area.
32. Application of one-pot procedure and employment of arylbromide as a substrate for the sequence have
not been investigated yet, which could be a next target.
33. Selected reviews see; (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (b) Kunz,
K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428.
34. Filipski, K. J.; Kohrt, J. T.; Casimiro-Garcia, A.; Huis, C. A.; Dudley, D. A.; Cody, W. L.; Bigge, C. F.;
Desiraju, S.; Sun, S.; Maiti, S. N.; Jaber, M. R.; Edmunds, J. J. Tetrahedron Lett. 2006, 47, 7677.
35. For a pioneering work; Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
Chapter 3
41
Chapter 3
An integrated transition metal-catalyzed reaction strategy for an
-carboline based Aurora B kinase inhibitors
Abstract
An efficient and practical synthetic process for an -carboline based Aurora Kinase B inhibitor was
achieved using an integrated Pd catalyzed cross coupling strategy. The process features a mild and efficient
method for construction of the -carboline core by employing a Pd catalyzed sequence of Buchwald-Hartwig
amination and intramolecular direct C-H arylation at the ortho position of an unsubstituted aniline moiety,
which is a key functionality for further derivatization with a Suzuki coupling via Sandmeyer iodination. The
process has eliminated expensive starting materials and column chromatography purifications, and enabled
considerable enhancement of the total yield from 11% to 48%.
Chapter 3
42
Introduction
The Aurora kinase family (-A, -B, and -C) are homologue serine-threonine protein kinases, which play
important roles in the formation and distribution of chromosomes and cytokinesis.1 Aurora B kinase is the
catalytic component of the chromosomal passenger complex, and thought to take critical roles for cell division
during the metaphase to anaphase stages. Hence, inhibition of Aurora B kinase activity has been considered as
an attractive target for pharmacological intervention in oncology drug field.2
During the course of our medicinal chemistry team's investigations into small molecule Aurora B kinase
inhibitors for antineoplastic activity, 1 was selected as a potent drug candidate in this area with suitable profile
for further clinical studies (Scheme 1).3
Scheme 1. Initial synthetic strategy for 1. Reagents and conditions: (a) Cu, NMP, 190 oC, 43%; (b) Pd2(dba)3,
PCy3, Cs2CO3, dioxane, reflux, 61%; (c) Fe, AcOH, 80 oC. 96%; (d) AcOH, reflux, 87%; (e) H2SO4, 120
oC,
96%; (f) HATU, TEA, DMF, 25 oC, 58%.
The synthetic challenges associated with the chemical structure were identified as efficient synthesis of the
-carboline (pyrido[2,3-b]indole) core and regioselective installation of several substituents. While an early
medicinal chemistry synthesis of 1 on laboratory scale enabled successful preparation of the material for early
Chapter 3
43
toxicological and pre-clinical studies, the synthesis of 1 for further clinical evaluation was hampered by the
limited scalability. In this context, a practical and scalable synthesis of 1 was required. Herein, we describe an
efficient synthesis of 1 employing integrated cross-coupling reactions.
Results and discussion
The initial synthesis for preparing small quantities of 1 is outlined in Scheme 1.4 The assembly of the
-carboline core was achieved by a sequence of Ullmann coupling of 2-fluoro-3-iodo-5-methyl pyridine (2)
with 2,3-dichloro-5-trifluoromethyl-6-methylnitrobenzene (3), followed by reduction of the nitro group, and
the final intramolecular cyclization with a SNAr reaction between the fluorine and aromatic amine. However,
the approach had several drawbacks from the viewpoint of large-scale preparation to support further
evaluation (e.g. clinical study), particularly in the Ullmann coupling step. For example, expensive and less
commercially available 2 and 3 were used. Potentially explosive high temperature cyclization (190 oC) of the
nitro compound 3 was needed. Also, this process was poorly reproducible in yield and quality; as the scale of
the Ullmann reaction increased, the isolated yield of 4 and the amount of byproducts arising from poor
regioselectivity and homo coupling were highly variable.
After considering these drawbacks of the previous synthesis, we sought to explore an alternative synthetic
strategy for the -carboline pharmacophore by employing a versatile Pd-catalyzed sequence of
Buchwald-Hartwig amination5 and direct C-H arylation.
6 After our initial study on using this strategy, we
reported the optimal catalyst systems: Pd(OAc)2/ XANTPHOS (4,5-bis(diphenylphosphino)-9,9’-dimethyl
xanthenes)/ Cs2CO3 for the amination, and Pd(OAc)2/ DCHPB (2-dicyclohexyl phosphino-2’-biphenyl)/ DBU
for the direct C-H arylation, respectively.8 The outstanding feature of the synthetic sequence is that a
combination of DCHPB and DBU plays a critical role to not only enhance the reactivity but also suppress the
hydrodehalogenation for the direct C-H arylation,9 and consequently the protocol enables a rapid and
divergent synthesis of -carbolines with various substituents, including base-sensitive ones such as ester
groups. Using this protocol, an improved synthetic strategy has been proposed, as outlined retrosynthetically
Chapter 3
44
in Scheme 2. The key points of our synthetic strategy include achieving the Pd-catalyzed cyclization for
-carboline 11 with an ester group to be amidated with amine 10 and a substituent to be converted to a leaving
group for Suzuki coupling reaction with 3-ethylsulfonylphenyl boronic acid 5.
Scheme 2. Retrosynthetic analysis of 1
1. Aryl iodide preparation
Our initial efforts centered on the preparation of the adequate aryl iodide for the Pd-catalyzed amination.10
Among a number of aromatic precursor candidates, readily available 2-methyl-5-nitrobenzoic acid derivatives
were selected for the iodination, envisaging the nitro group would contribute to the regioselective iodination
and would be converted to a halogen through a reduction of the nitro group followed by Sandmeyer reaction.
After an intensive screening of aromatic precursors and iodination methods, 2-methyl-5-nitrobenzoic acid (14)
was successfully iodinated by an effective iodination system (I2/ NaIO3/ conc. H2SO4)11
to afford the
corresponding aryl iodide (15) in 93% yield with high regioselectivity (Scheme 3).12
As the downstream Pd
catalyzed cross coupling reactions were inhibited by the carboxylic acid moiety and our preliminary study
showed that ester groups are tolerated under the sequence of Pd catalyzed reaction conditions,8 methyl
esterification of 15 was carried out using Fisher esterification conditions to provide 16 in 94% yield (Scheme
3).13
Chapter 3
45
Scheme 3. Preparation of aryl iodide 16
Chapter 3
46
Carboline construction
With the desired aryl iodide 16 in hand, our next efforts were turned to the construction of the -carboline
core. First, Pd catalyzed Buchwald-Hartwig amination with our previously-established catalyst system
(Pd(OAc)2/ XANTPHOS/ Cs2CO3) was conducted. The catalyst system was successfully applied to the
coupling of 16 with 2-amino-3-bromo-5-methyl pyridine (13). The reaction was completed within 5 hours,
and the coupling product 17 was obtained in 99% yield (Scheme 4).
Scheme 4. Synthesis of -Carboline 21
Subsequently, Pd catalyzed direct C-H arylation of 17 was addressed. However, the initial attempt to use
the optimized catalyst system (Pd(OAc)2/ DCHPB/ DBU) provided an undesired product 18 arising from ester
hydrolysis of 17 as the main product rather than the desired -carboline 19. On considering the unexpected
result that is inconsistent with our preliminary data that the ester group is tolerated under the reaction
conditions,8 we assumed that the hydrolysis was attributed to the strong electron-withdrawing property of the
Chapter 3
47
nitro group on the aromatic ring. Therefore, we expected that increasing electron density on the aromatic ring
by reduction of the nitro group to an amino group prior to direct C-H arylation would suppress the ester
hydrolysis of 17. In addition, we considered that the increased electron density of the amino aromatic would
promote electrophilic C-H insertion of Pd (II). Thus, we refocused our attentions on the alternative route, by
way of reducing the nitro group of 17 (Scheme 4).
Among the various precedent reduction methods for an aromatic nitro group, selective reduction of an
aromatic nitro function over an aromatic bromide was required for the synthesis. Some reduction systems with
metals in aqueous acidic solution were initially investigated. Although early studies using Fe- or Zn-based
reduction systems suffered from side reactions such as hydrodehalogenation and incomplete conversion,
Sn-based reduction system (SnCl2/ HCl) gave satisfactory results with 20 being exclusively obtained in 85%
yield (Scheme 4).
With 20 in hand, the optimal catalyst system (Pd(OAc)2/ DCHPB/ DBU) was again applied to
intramolecular cyclization of 20, and a full conversion was gratifyingly achieved with less than 3% of
hydrolyzed product 22. Undesired 22 was effectively removed through the work-up crystallization, and
crystalline 21 was finally isolated in 91% yield (Scheme 4). Importantly, the reaction was selective for
intramolecular direct C-H arylation, and no homocoupling product arising from the intra- and intermolecular
C-N coupling of aryl bromide with N-unsubstituted aniline group was observed.
3. Functional group introduction on the carboline
With the preparation of carboline 21 established, our subsequent efforts were focused on
functionalization of the -carboline. To accomplish the synthesis of 1, halogenation and arylation at the
5-position and amide formation at the 7-position is required. First, Sandmeyer reaction to halogenate the
amino group was examined. Although the initial examination for bromination suffered from some side
reactions including de-diazonation, the diazonation of 21 using NaNO2/ aq. HCl/ acetonitrile followed by
addition of aqueous KI solution afforded 23 in 93% yield (Scheme 5). Subsequently, Pd catalyzed Suzuki
coupling was studied, and the coupling of 23 with boronic acid 5 was achieved using Pd(PPh3)4 and K2CO3 to
Chapter 3
48
give 24 in 79% isolated yield, along with 8% of 9 arising from hydrolysis of 24. To further simplify the
sequential process, we attempted to combine the Suzuki coupling with the ester hydrolysis in one-pot. In fact,
after completion of the Suzuki coupling, hydrolysis with 10% KOH successfully provided 9 in 88% yield
from 23. Finally, amide formation of carboxylic acid 9 with 1-methylpiperidin-4-amine (10) was carried out in
the presence of HBTU in NMP to afford 1 in 88% yield.
Scheme 5. Synthesis of 1
Chapter 3
49
Conclusion
An efficient and practical synthesis for Aurora B kinase inhibitor 1 has been established using an integrated
Pd catalyzed cross coupling strategy. The synthesis features an efficient -carboline assembly, employing a
Pd catalyzed sequence of a Buchwald-Hartwig amination and an intramolecular direct C-H arylation at the
ortho position of an unsubstituted aniline moiety, which is then further derivatized by Sandmeyer iodination
and Suzuki coupling. The present strategy is more practical than the former one from the viewpoint of process
robustness, the availability of starting compounds, and the versatility of the synthetic approach. While the
former process relied on the Ullmann coupling reaction that is poorly reproducible on scale-up and largely
restricted to less commercially available and highly functionalized starting compounds, the current process
consists of an effective Pd catalyzed sequence from readily available starting compounds
(2-amino-3-bromopyridine and nitrobenzene derivatives), and the strategy should be applicable to other
derivatives. Furthermore, the process eliminates complicated column chromatography purifications, and all
intermediates could be isolated as crystals following simple workup. Overall, the new process contributed to a
considerable enhancement of the total yield, from 11% to 48%.
Chapter 3
50
Experimental Section
General
All chemicals were obtained from commercial suppliers and used without further purification. Degassing
solvents was conducted by repeating an evacuation/nitrogen refill cycle. 1H NMR and
13C NMR spectra were
recorded on 300 MHz and 500 MHz spectrometers with tetramethylsilane as an internal standard. Chemical
shifts are shown in ppm.
3-Iodo-2-methyl-5-nitrobenzoic acid (15): To a mixture of 2-methyl-5-nitrobenzoic acid (14) (10.0 g, 55.2
mmol), iodine (5.6 g, 22.1 mmol, 0.4 equiv) and concentrated sulfuric acid (40 ml) was added sodium iodate
(4.4 g, 22.1 mmol, 0.4 equiv) at 10-30 oC. The reaction mixture was stirred at 25-30
oC for 3 h. To a mixture
of sodium sulfite (17.4 g, 138.0 mmol, 2.5 equiv), water (100 ml) and methanol (40 ml) was added the
reaction mixture at 5-30 oC. After stirring at 20-30
oC for 2 h, the resulting precipitates were filtered and
washed with methanol/water (1/2, 20 ml x 2), and dried at 50 oC in vacuo to give 15.8 g (93% yield) of the
title compound as off white crystals. mp: 178.3 oC.
1H-NMR (500 MHz, DMSO-d6): 2.67 (s, 3H), 8.41 (d, J
= 2.5 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H). 13
C-NMR (125 MHz, DMSO-d6): 26.7, 104.6, 124.0, 133.1, 135.3,
145.8, 148.2, 167.6. HRMS (EI) m/z Calcd. for [M]+ C8H6INO4 306.9342; Found 306.9333.
Methyl 3-iodo-2-methyl-5-nitrobenzoate (16): To a mixture of 3-iodo-2-methyl-5-nitrobenzoic acid (15)
(15.0 g, 48.9 mmol) and methanol (75 ml) was added dropwise concentrated sulfuric acid (10.4 ml, 195.4
mmol, 4.0 equiv) below 50 oC. The mixture was stirred at 60
oC for 6 h. After stirring at 50
oC for 30 min, a
solution of sodium sulfite (1.2 g, 9.8 mmol, 0.2 equiv) and water (30 ml) was added to the mixture. The pH of
the mixture was adjusted to 8-9 with 5% aq NH3 at 50 oC. After cooling to room temperature, water (30 ml)
was added to the mixture. The mixture was stirred at 50 oC for 30 min and 5
oC for 1h. The resulting
precipitates were filtered and washed with methanol/H2O (1/2, 30 ml x 2), and dried at 50 oC in vacuo to give
the title compound 14.8 g (94% yield) as pale yellow crystals. mp: 64.9 oC.
1H-NMR (500 MHz, DMSO-d6):
Chapter 3
51
2.65 (s, 3H), 3.91 (s, 3H), 8.46 (d, J = 2.5 Hz, 1H), 8.72 (d, J = 2.5 Hz, 1H). 13
C-NMR (125 MHz, DMSO-d6):
26.7, 53.5, 104.8, 124.4, 132.4, 136.2, 145.8, 148.6, 166.1. HRMS (EI) m/z Calcd. for [M]+C9H8INO4
320.9498; Found 320.9492.
Methyl 3-[(3-bromo-5-methylpyridin-2-yl)amino]-2-methyl-5-nitrobenzoate (17): To a mixture of
palladium acetate (349.1 mg, 1.6 mmol, 0.05 equiv) and 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene
(XANTPHOS) (1.4 g, 2.3 mmol, 0.075 equiv) in degassed anisole (130 ml) were added methyl
3-iodo-2-methyl-5-nitrobenzoate (16) (10.0 g, 31.1 mmol, 1 equiv), 3-bromo-5-methyl-pyridin-2-ylamine (13)
(6.1 g, 32.7 mmol, 1.05 equiv) and cesium carbonate (14.2 g, 43.5 mmol, 1.4 equiv) under nitrogen
atmosphere. The resulting mixture was stirred at room temperature for 1 h and then stirred at 125 oC for 5h.
After the reaction mixture was cooled to room temperature, water (65 ml) was added to the mixture. The
mixture was concentrated in vacuo. The resulting residue was suspended in methanol (100 ml) and acetone
(20 ml). The pH of the mixture was adjusted to 6.5-7.5 with 6 mol/L aq HCl (ca. 10 ml). The mixture was
refluxed for 1 h and stirred at room temperature for 1.5 h. The resulting precipitates were filtered and washed
with methanol/acetone/water (10/2/1, 10 ml x 2) and dried at 60 oC in vacuo to give 11.7 g (99%) of the title
compound as dark brown crystals. mp : 187.3 oC.
1H-NMR (500 MHz, DMSO-d6): 2.20 (s, 3H), 2.37 (s, 3H),
3.91 (s, 3H), 7.89 (d, J = 1.6 Hz, 1H), 7.95 (d, J = 1.3 Hz, 1H), 8.16 (s, 1H), 8.29 (d, J = 2.5 Hz, 1H), 8.56 (d,
J = 2.5 Hz, 1H). 13
C-NMR (125 MHz, DMSO-d6): 16.3, 17.0, 53.2, 106.8, 119.6, 121.1, 126.9, 132.7, 140.8,
142.2, 142.5, 145.6, 146.5, 150.8, 166.8. HRMS (EI) m/z Calcd. for [M]+ C15H14BrN3O4 379.0168; Found
379.0159.
Methyl 5-amino-3-[(3-bromo-5-methylpyridin-2-yl)amino]-2-methylbenzoate (20): To a solution of
methyl 3-[(3-bromo-5-methylpyridin-2-yl)amino]-2-methyl-5-nitro-benzoate (17) (15.2 g, 40.0 mmol, 1
equiv) and tin (II) chloride dihydrate (28.0 g, 120.0 mmol, 3 equiv) in methanol (152 ml) was added
concentrated HCl (36%) (15.2 ml). The mixture was stirred at 50 oC for 4 h. The mixture was diluted with
tetrahydrofuran (228 ml). The pH of the mixture was adjusted to 7-9 with 25% ammonia solution (30.4 ml)
Chapter 3
52
under cooling in an ice bath, before 20% aq potassium sodium (+)-tartrate tetrahydrate solution (460 ml) was
added to the mixture. After the mixture was stirred at room temperature for 1 h, ethyl acetate (228 ml) and
NaCl (60.8 g) were added, and the mixture was stirred at room temperature for 1 h. The organic layer was
separated, and successively washed with 5% aq NaHCO3 (228 ml) and 20% aq NaCl (228 ml), and
concentrated in vacuo. The resulting residue was suspended in ethanol (80 ml) at room temperature for 0.5 h.
The resulting precipitates were filtered and washed with ethanol (20 ml) and further dried at 50 oC in vacuo to
give 11.9 g (85% yield) of the title compound as brown crystals. mp: 122.9 oC.
1H-NMR (500 MHz,
DMSO-d6): 2.11 (s, 3H), 2.16 (s, 3H), 3.79 (s, 3H), 5.12 (s, 2H), 6.83 (d, J = 2.5 Hz, 1H), 6.89 (d, J = 2.2 Hz,
1H), 7.51 (s, 1H), 7.76 (d, J = 1.0 Hz, 1H), 7.84 (d, J = 1.7 Hz, 1H). 13
C-NMR (125 MHz, DMSO-d6): 14.6,
16.9, 52.2, 105.7, 112.0, 115.2, 120.6, 124.7, 131.8, 141.0, 141.6, 146.5, 146.8, 151.9, 168.9. HRMS (EI) m/z
Calcd. for [M]+ C15H16BrN3O2 349.0426; Found: 349.0424.
Methyl 5-amino-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxylate (21): To a mixture of palladium
acetate (202.1 mg, 0.9 mmol, 0.03 equiv) and 2-(dicyclohexylphosphino) biphenyl (DCHPB) (630.9 mg, 1.8
mmol, 0.06 equiv) in degassed N,N-dimethyl acetamide (DMAc) (20 ml) were added DBU (0.9 g, 60.0 mmol,
2.0 equiv), methyl 5-amino-3-[(3-bromo-5-methyl pyridin-2-yl)amino]-2-methylbenzoate (20) (10.5 g, 30.0
mmol, 1 equiv) under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 0.5 h,
and then stirred at 130 oC for 1 h. The reaction mixture was cooled to room temperature, and water (40 ml)
was added to the mixture. The resulting slurry was stirred at room temperature for 0.5 h and in an ice bath for
0.5 h. The resulting precipitates were filtered and washed with water (10 ml x 2), and dried at 60 oC in vacuo
to give 7.4 g (91% yield) of the title compound as light yellow crystals. mp: 295.1 oC.
1H-NMR (500 MHz,
DMSO-d6): 2.46 (s, 3H), 2.60 (s, 3H), 3.84 (s, 3H), 5.67 (s, 2H), 6.99 (s, 1H), 8.24 (d, J = 1.3 Hz, 1H), 8.49
(d, J = 1.0 Hz, 1H), 11.62 (s, 1H). 13
C-NMR (125 MHz, DMSO-d6): 14.5, 18.6, 52.1, 106.6, 109.9, 110.3,
115.3, 123.9, 127.9, 130.3, 140.4, 142.3, 145.9, 151.2, 168.9. HRMS (EI) m/z Calcd. for [M]+ C15H15N3O2
269.1164; Found 269.1151.
Chapter 3
53
Methyl 5-iodo-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxylate (23): To a mixture of methyl
5-amino-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxylate (21) (2.7 g, 10.0 mmol) and 6 mol/L aq HCl (54
ml) was added dropwise sodium nitrite (724.5 mg, 10.5 mmol, 1.05 equiv) in water (54 ml) below 10 oC. The
mixture was stirred at 0-10 oC for 30 min. Potassium iodide (5.0 g, 30.0 mmol, 3.0 equiv) in water (54 ml)
was added dropwise to the mixture below 10 oC. The mixture was stirred at room temperature for 2 h.
Methanol (16 ml) and aqueous 10% sodium sulfite solution (54 ml) were added to the reaction mixture. The
pH of the reaction mixture was adjusted to 7 - 9 with 5 mol/L aq NaOH (55 ml) below 30 oC. The mixture was
stirred at 5-10 oC. The resulting precipitates were filtered and washed with cold water (20 ml x 2), and dried at
60 oC in vacuo to give 3.5 g (93% yield) of the title compound as brown crystals. mp: 270.5
oC.
1H-NMR (500
MHz, DMSO-d6): 2.51 (s, 3H), 2.74 (s, 3H), 3.88 (s, 3H), 8.06 (s, 1H), 8.47 (d, J = 1.0 Hz, 1H), 8.89 (s, 1H),
12.23 (s, 1H). 13
C-NMR (125 MHz, DMSO-d6): 15.2, 18.7, 52.6, 84.4, 115.7, 123.7, 124.0, 124.2, 128.1,
129.5, 131.1, 140.0, 149.3, 151.7, 167.0. HRMS (EI) m/z Calcd. for [M+] C15H13IN2O2 380.0022; Found
380.0027.
5-[3-(Ethylsulfonyl)phenyl]-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxylic acid (9): To a solution of
tetrakistriphenylphosphine palladium (Pd(PPh3)4) (174.0 mg, 0.15 mmol, 0.05 equiv), methyl
5-iodo-3,8-dimethyl-9H-pyrido[2,3-b]-indole-7-carboxylate (23) (1.1 g, 3.0 mmol) and
3-(ethylsulfonyl)phenylboronic acid (5) (1.3 g, 6.0 mmol, 2 equiv) in degassed N, N-dimethyl acetamide
(DMAc) (25 ml) was added potassium carbonate (829.2 mg, 6.0 mmol, 2.0 equiv) in water (10 ml). The
resulting mixture was stirred at room temperature for 0.5 h, and heated at 90 oC for 1 h. 2 mol/L aq NaOH
solution (30 ml) was added to the reaction mixture below 95 oC, and stirred at 90
oC for 1 h. After the mixture
was cooled to room temperature, the pH of the reaction mixture was adjusted to 5-7 with 6 mol/L aq HCl (10
ml) below 30 oC. The mixture was stirred in an ice bath for 0.5 h, the resulting precipitates were filtered and
washed with cold water (10 ml x 2), and dried at 60 oC in vacuo to give 1.1 g (88% yield) of the title
compound as gray crystals. mp: 332.5-338.5 oC (decompose).
1H-NMR (500 MHz, DMSO-d6): 1.18 (t, J =
7.3 Hz, 3H), 2.27 (s, 3H), 2.85 (s, 3H), 3.43 (q, J =7.5 Hz, 2H), 7.52 (s, 1H), 7.58 (s, 1H), 7.87-7.90 (m, 2H),
Chapter 3
54
8.02 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 8.12 (s, 1H), 8.35 (s, 1H), 12.23 (s, 1H). 13
C-NMR (125
MHz, DMSO-d6): 7.7, 15.3, 18.4, 49.5, 114.3, 119.1, 122.8, 123.0, 124.1, 127.6, 128.1, 129.5, 130.0, 130.7,
132.5, 134.5, 139.5, 140.0, 141.3, 148.3, 151.9, 169.7. HRMS (FAB-double-focusing magnetic sector) m/z
Calcd. for [M-H]- C22H20N2O4S 407.1055; Found 407.1066.
5-[3-(Ethylsulfonyl)phenyl]-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxa
mide (1): To N-methyl-2-pyrrolidinone (NMP) (94.7 ml) were added
5-[3-(ethylsulfonyl)phenyl]-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxylic acid (9) (33.9 g, 82.9 mmol).
The mixture was stirred at 65-75 oC until the dissolution of 9. After cooling to 25-35
oC,
N-methyl-4-aminopiperidine (10) (18.9 g, 165.8 mmol, 2.0 equiv) and
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (34.6 g, 91.2 mmol, 1.1
equiv) were added to the mixture. The mixture was stirred at 20-30 oC for 2 h, and water (24 ml) was added to
the reaction mixture. A solution of KOH (8.4 g, 149.2 mmol, 1.8 equiv) dissolved in water (26 ml) was added
dropwise to the mixture. Additional water (52 ml) was the added to the mixture. The mixture was stirred at
room temperature. The resulting precipitates were filtered and washed with 25% aq NMP (28 ml x 2) and
dried at 60 oC in vacuo to give 36.8 g (88% yield) of the title compound as brown crystals. mp: 240.2
oC.
1H-NMR (500 MHz, DMSO-d6): 1.19 (t, J = 7.4 Hz, 3H), 1.51-1.60 (m, 2H), 1.83 (d, J = 10.1 Hz, 2H),
1.91-2.04 (m, 2H), 2.17 (s, 3H), 2.28 (s, 3H), 2.61 (s, 3H), 2.76 (d, J = 12.0 Hz, 2H), 3.72-3.80 (m, 1H), 7.09
(s, 1H), 7.52 (s, 1H), 7.88-7.92 (m, 1H), 8.01-8.06 (m, 1H), 8.12 (t, J = 1.6 Hz, 1H), 8.27 (d, J = 7.6 Hz, 1H),
8.31 (s, 1H), 12.02 (s, 1H). 13
C-NMR (125 MHz, DMSO-d6): 7.7, 14.6, 18.4, 31.9, 46.5, 46.8, 49.5, 54.8,
114.5, 117.5, 119.0, 120.4, 124.0, 127.6, 128.2, 129.7, 130.7, 132.7, 134.5, 135.8, 139.4, 139.7, 141.4, 147.7,
151.7, 168.7. HRMS (ESI-orbitrap) m/z Calcd. for [M+H]+
C28H33N4O3S 505.2260; Found 505.2268.
Chapter 3
55
References and notes
1. For selected examples: (a) Carmena, M.; Earnshaw, W. C. Nat. Rev. Mol. Cell Biol. 2003, 4, 842. (b) Fu,
J.; Bian, M.; Jiang, Q.; Zhang, C. Mol, Cancer Res. 2007, 5, 1. (c) Carmena, M.; Ruchaud. S.; Earnshaw,
W. C. Curr. Opin. Cell Biol, 2009, 21, 796. (d) Andrew, P. D. Oncogene 2005, 24, 5005. (e) Meraldi, P.;
Honda, R.; Nigg, E. A. Curr. Opin. Genet. Dev. 2004, 14, 29.
2. For selected examples: (a) Boss, D. S.; Witteveen, P. O.; van der Sar, J.; Lolkema, M. P.; Voest, E. E.;
Stockman, P. K.; Ataman, O.; Wilson, D.; Das, S.; Schellens, J. H. Ann Oncol. 2011. 22, 431. (b) Pollard,
J. R.; Mortimore, M. J. Med. Chem. 2009, 52, 2629. (c) Cheung, C. H.; Coumar, M. S.; Hsieh H. P.;
Chang, J. Y. Expert Opin. Investig. Drugs 2009, 18, 379. (d) Anderson, K.; Lai, Z.; McDonald, O. B.;
Stuart, J. D.; Nartey, E. N.; Hardwicke, M. A.; Newlander, K.; Dhanak, D.; Adams, J.; Patrick, D.;
Copeland, R. A.; Tummino, P. J.; Yang, J. Biochem. J. 2009, 420, 259. (e) Hardwicke, M. A.;
Oleykowski, C. A.; Plant, R.; Wang, J.; Liao, Q.; Moss, K.; Newlander, K.; Adams, J. L.; Dhanak, D.;
Yang, J.; Lai, Z.; Sutton, D.; Patrick, D. Mol. Cancer Ther. 2009, 8, 1808. (f) Myrianthopoulos, V.;
Magiatis, P.; Ferandin, Y.; Skaltounis, A. L.; Meijer, L.; Mikros, E. J. Med. Chem. 2007, 50, 4027. (g)
Wilkinson, R. W.; Odedra, R.; Heaton, S. P.; Wedge, S. R.; Keen, N. J.; Crafter, C.; Foster, J. R.; Brady,
M. C.; Bigley, A.; Brown, E.; Byth, K. F, Barrass, N. C.; Mundt, K. E.; Foote, K. M.; Heron, N. M.; Jung,
F. H.; Mortlock, A. A.; Boyle, F. T.; Green, S. Clin. Cancer Res. 2007, 13, 3682. (h) Franceli, D.; Moll,
J.; Varasi, M.; Bravo, R.; Artico, R.; Berta, D.; Bindi, S.; Cameron, A.; Candiani, I.; Cappella, P.;
Carpinelli, P.; Croci, W.; Forte, B.; Giorgini, M. L.; Klapwijk, J.; Marsiglio, A.; Pesenti, E.; Rocchetti,
M.; Roletto, F.; Severino, D.; Soncini, C.; Storici, P.; Tonani, R.; Zugnoni, P.; Vianello, P. J. Med. Chem.
2006, 49, 7247. (i) Jung, F. H.; Pasquet, G.; Brempt, C. L.; Lohmann, J. M.; Warin, N.; Renaud, F.;
Germain, H.; Savi, C. D.; Roberts, N.; Johnsom, T.; Dousson, C.; Hill, G. B.; Mortlock, A. A.; Heron, N.;
Wilkinson, R. W.; Wedge, S. R.; Heaton, S. P.; Odedra, R.; Keen, N. J.; Green, S.; Brown, E.; Thompson,
K.; Brightwell, S. J. Med. Chem. 2006, 49, 955.
3. Farrell1, P.; Shi, L.; Matuszkiewicz, J.; Alakrishna, D.; Hoshino, T.; Zhang, L.; Elliott, S.; Fabrey, R.;
Chapter 3
56
Lee1, B.; Halkowycz, P.; Sang, B.; Ishino, S.; Nomura, T.; Teratani, M.; Ohta, Y.; Grimshaw, C.;
Paraselli, B.; Satou, T.; de Jong. R. Mol. Cancer Ther. 2013, 12, 460.
4. Brown, J. W.; Dong, Q.; Gong, X.; Kaldor, S. W.; Liu, Y.; Paraselli, B. R.; Scorah, N.; Stafford, J. A.;
Wallace, M. B. WO 2007044779. Chem. Abstr 2007.146. 441771.
5. For the reviews see; (a) Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 6338. (b) Stephen
L. Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv. Synth. Catal. 2006, 348, 23. (c)
Schlummer, B.; Scholz, S. B.; Adv. Synth. Catal. 2004, 346, 1599.
6. For the reviews see; (a) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem. Int. Ed. 2009, 48, 9792.
(b) Chen, X.; Engle, K. M.; Wang, D. -H.; Yu, J. –Q. Angew. Chem. Int. Ed. 2009, 48, 5094. (c) Alberico,
D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
7. (a) Mizuno, M.; Mizufune, H.; Sera, M.; Mineno, M.; Ueda, T. WO 2008016184; Chem. Abstr. 2008,
148, 239178. (b) Mineno, M.; Sera, M.; Ueda, T.; Mizuno, M.; Yamano. M.; Mizufune, H.; Zanka, A.
Tetrahedron 2014, 70, 5550.
8. As a result of our extended screening of bases and ligands for the direct C-H arylation, DBU was selected
as the optimal base to suppress the hydrodebromination, and DCHPB was selected as the optimal ligand
to enhance the reactivity (see Ref. 8(b)). In addition, after our patent publication (Ref. 8(a)), the
following reports have indicated DBU is an effective base for the direct C-H arylation. (a) Laha, J. K.;
Petrou, P.; Cuny, G. D. J. Org. Chem. 2009, 74, 3152; (b) Hostyn, S; Baelen, G. V.; Lemiére, G. L. F.;
Maes, B. U. W. Adv. Synth. Catal. 2008, 350, 2653.
9. To facilitate a Buchwald-Hartwig amination, aryl iodides were favorable. Any investigations for
bromination and chlorination have not been performed.
10. (a) Kraszkiewicz, L.; Sosnowski, M.; Skulsi, L. Synthesis 2006, 1195. (b)Kraszkiewicz, L.; Sosnowski,
M.; Skulsi, L. Tetrahedron 2004, 60, 9113. (c) Katayama, S.; Ae, N.; Nagata, R. J. Org. Chem. 2001, 66,
3474.
11. 2-Methyl-5-nitrobenzonitrile was unreactive toward iodination, probably due to its strong electron
deficiency.
Chapter 3
57
12. As both iodination and esterification were carried out under the similar reaction condition, integration of
these two processes in one pot was attempted. However, some sticky materials generated during the
esterification as the reaction proceeded, which prevented good agitation.
13. (a) Hennings, D. D.; Iwasa, S.; Rawal, V. H. J. Org. Chem. 1997, 62, 2. (b) Hennings, D. D.; Iwasa, S.;
Rawal, V. H. Tetrahedron Lett. 1997, 38, 6379.
Chapter 3
58
Chapter 4
59
Chapter 4
Double Reformatsky reaction:
divergent synthesis of -hydroxy--ketoester
Abstract
Double Reformatsky reaction, tandem addition of two molecules of zinc alkanoate to a carbonyl compound,
and its synthetic application to a series of -hydroxy--ketoesters has been developed. The key to accelerate
the double Reformatsky reaction is considered to be a complex-induced proximity effect of the in situ
generated zinc-alkoxide coordinated with the pyridyl group of the substrate or bidentate amines. A noteworthy
feature of the reaction system is its high tolerance of functional groups, due to the moderate nucleophilicity of
organozinc reagents and the mild reaction conditions. Moreover, spectroscopic and crystallographic analyses
of the zinc complex of the double Reformatsky product support the proposed mechanism of reaction site
discrimination for ketones, aldehydes, nitriles, carboxylic acid anhydrides and esters.
Chapter 4
60
Introduction
Metal mediated C-C bond formation is an essential tool for the development of synthetic routes to complex
organic molecules. In the history of organic chemistry, a large number of metal mediated nucleophilic
additions to electrophiles have been developed and applied to the synthesis of complex molecules. As most of
the targeted organic molecules contain electrophilic groups, the use of highly reactive organometallic reagents
has often been limited due to poor functional group tolerance. However, among the known organometallic
nucleophiles, organozinc reagents have recently attracted renewed attention due to their high tolerance toward
functional groups.1 In particular, the classical Reformatsky reaction has been considered as a practical tool to
produce various -hydroxyalkanoates from -haloalkanoates and aldehydes or ketones.2,3
In recent years, the
scope of the Reformatsky reaction has been extended beyond aldehydes and ketones, and continuous efforts
have been directed to the development of reactions with a great variety of electrophiles, such as nitriles4 and
carboxylic acid anhydrides.5 In contrast, ester groups are known to be essentially unreactive to Reformatsky
reaction. Though some reports of Reformatsky reaction proceeding with esters have emerged, most of them
are limited to cyclic and/or activated esters.6,7
In the course of our recent drug research and development program, we found an unexpected Reformatsky
reaction when 2-benzoylpyridine (1a) reacting with ethyl bromozincacetate at room temperature did not give
the desired -hydroxyalkanoates (2a) but -hydroxy--ketoester (3a) instead, as the sole product (Scheme 1).
Scheme 1. Unexpected Reformatsky Reaction of 1a
Chapter 4
61
The result intrigued us because this kind of reaction to afford -hydroxy--ketoesters directly from carbonyl
compounds and zinc alkanoates under such a mild condition has not been described to date. In addition, the
product -hydroxy--ketoester can be an important building block for various biologically active compounds.8
Extensive efforts have been devoted to the development of -hydroxy--ketoester synthetic methodology,
such as the addition of Chan’s diene,9 Wieler’s dianion
10 or diketene
11 to carbonyl compounds. While these
chemistries have contributed to the efficient syntheses of the compounds, especially in the field of asymmetric
synthesis, we expected our finding would lead to another convenient and efficient synthetic method for
-hydroxy--ketoesters using Reformatsky reagents, which have already been well-developed as a reliable
synthetic tool and recognized as highly functional group tolerant reagents. Consequently, the detailed
investigation of this reaction was considered to be a topic of great importance for organic synthesis.
Herein, we disclose the unusual addition of zinc alkanoates to the ester group of in situ generated
-hydroxyalkanoates and the establishment of a general synthesis of -hydroxy--ketoesters directly from
carbonyl compounds and zinc alkanoates under a mild condition.
Results and discussion
1. Reaction pathway
At the outset of this study, our efforts were focused on identifying the reaction pathway. The following two
plausible reaction pathways were considered; (i) self-condensation pathway: the attack of self-condensed
Reformatsky reagent (4) on carbonyl substrate (1) (Scheme 2, path a), (ii) stepwise addition pathway: after
usual Reformatsky reaction, the tandem attack of zinc alkanoate on -hydroxyalkanoates (2) (Scheme 2, path
b).
Chapter 4
62
Scheme 2. Plausible Reaction Pathways
An intensive survey of the prior literature revealed some reports suggesting the self-condensation
pathway.12
Newman and coworkers investigated the self-condensation of Reformatsky reagents and indicated
that self-condensation was promoted at higher temperatures and with decreasing bulkiness of ester alkyl
groups.13
Following their study, Vaughan and coworkers reported further studies on the behavior of
self-condensed Reformatsky reagents with carbonyl compounds.14
In both of their studies, self-condensed
Reformatsky reagents were considered to be unreactive toward carbonyl compounds. In addition, Utimoto and
coworkers reported a synthetic method to give -hydroxy--ketoesters directly from carbonyl compounds and
-haloalkanoates, through the intermediacy of SmI2, in which they disclosed that -haloalkanoates can be
self-condensed and the self-condensed samarium species coupled with carbonyl compounds to afford
-hydroxy--ketoesters.15
As for the stepwise addition pathway, there has been one example that demonstrated
a secondary attack of a Reformatsky reagent on the ester group of an ,-unsaturated ester, with a
dithioacetal moiety that was derived from a first Reformatsky reaction followed by subsequent dehydration.16
To identify if -hydroxy--ketoesters were formed via a self-condensation pathway or a stepwise addition
pathway, two model experiments were conducted. Firstly, the amount of self-condensed Reformatsky reagent
(4) generated during the reaction was evaluated (Scheme 3 (a)). Ethyl bromozincacetate was stirred under the
same condition as for Scheme 1 (at room temperature for 24 h), but 4 was obtained in less than 1% yield
(evaluated by GC),17
which indicated that self-condensation of Reformatsky reagents at room temperature
Chapter 4
63
only occurred at a very low level. Next, the product ratio under a reactivity-modulated condition (controlling
the reaction temperature) was investigated (Scheme 3 (b)). When a reaction mixture containing 1a and 3.5
equiv of ethyl bromozincacetate was stirred at -20 oC for 4 h, the ratio of 2a/3a was 97/3. Subsequently, the
mixture was stirred for 4 h at room temperature and the ratio of 2a/3a switched to 2/98, which indicated that
3a was formed via a stepwise addition pathway. Based on the identified reaction pathway, we termed this a
“double Reformatsky reaction”.
Scheme 3.
2. Evaluation of reaction promotion factors
2. 1. Lewis acid
We continued our studies by examining the factors that promoted the reaction. Initially, the effect of a
Lewis acid was studied. Reformatsky reaction is known to be accelerated by Lewis acids such as TMSCl18
and
TiCl4.19
Since a catalytic amount of TMSCl was used for the activation of zinc in the preparation of the
Reformatsky reagent, it was necessary to check if TMSCl was promoting the double Reformatsky reaction.
The reaction of 1a with a TMSCl-free Reformatsky reagent was attempted, and the reaction was found to
proceed to full conversion in the same manner as for the reaction with the TMSCl-contained Reformatsky
reagent, which demonstrated that the additional Lewis acid was not the driving force for the double
Chapter 4
64
Reformatsky reaction. 20
2. 2. Bulkiness of the Zinc Alkanoates
Our attention was subsequently directed to the bulkiness of the zinc alkanoate. Table 1 shows the
relationship between the bulkiness of the zinc alkanoate alkyl groups and the degree of double Reformatsky
reaction. Reactions with the less hindered methyl bromozincacetate and ethyl bromozincacetate were fully
completed (Runs 1, 2). Whereas, reaction with the more hindered isopropyl bromozincacetate stopped at
incomplete conversion, and the much hindered tert-butyl bromozincacetate only afforded a trace amount of
double adduct 3 (Runs 3, 4). The result indicated that the reaction can only readily proceed when the zinc
alkanoate has small unhindered alkyl groups.
Table 1. Effect of Bulkiness of the Zinc Alkanoatesa
Run R3 Ratio (1a/2/3)
b
1 Me 0/<1/>99
2 Et 0/<1/>99
3 i-Pr 0/75/25
4 t-Bu 0/98/2
a Reaction conditions: 1a (2.5 mmol), alkyl bromozincacetate (3.5 equiv), THF (16 mL), room temperature, 3 days, under N2.
b Determined by HPLC analysis
Chapter 4
65
2. 3. Substituent Effect of a 2-Pyridyl Group
Next, in order to clarify the substituent effect of the 2-pyridyl group, 7a, 21
the reactivity of structurally and
electrically analogous ketones (1) and aldehydes (5), with and without neighboring coordination groups, was
investigated. As shown in Table 2, 1a and 2-picolinaldehyde (5a), containing neighboring coordination groups,
were fully converted to the double Reformatsky products. In contrast, the reactions with other analogs
containing no neighboring coordination groups (1b-d and 5b-d) resulted in remarkably decreased reactivity
and incomplete conversions. The result indicated that a pyridine-nitrogen adjacent to the carbonyl group is
beneficial to obtain high conversion.
Table 2. Examination of the Substituent Effect of a 2-Pyridyl Groupa
Run Substrate R1 R
2 Conversion (%)
b
1 1a 2-Pyridyl Phenyl 98
2 1b Phenyl Phenyl 16
3 1c 3-Pyridyl Phenyl 41
4 1d 4-Pyridyl Phenyl 67
5 5a 2-Pyridyl H 97
6 5b Phenyl H 39
7 5c 3-Pyridyl H 7
8 5d 4-Pyridyl H 38
a Reaction conditions: Substrate (2.5 mmol), ethyl bromozincacetate (3.5 equiv), THF (16 mL), room temperature, 3 days, under N2.
b Determined by HPLC analysis.
Chapter 4
66
2. 4. Base effect
Subsequently, we attempted to extend the scope of available substrates without neighboring coordination
groups. To enhance the reactivity of simple substrates, we introduced bases as additives to the reaction, as
Ojida and coworkers indicated that pyridine might promote Reformatsky reaction (Table 3).21
Benzophenone
(1b) was used as a model substrate, with 5 equiv of ethyl bromozincacetate,22
and it was found that pyridine
gave considerable increase in reactivity (Runs 1, 2). Encouraged by this result, we further examined various
quantities and basicities of monodentate amines. However, it was found that the reactivity was independent of
the quantity and basicity of monodentate amines (Runs 3-6). On the other hand, we were encouraged to find
that bidentate amines significantly accelerated the reaction (Runs 7-10). In particular, TMEDA gave almost
full conversion and was selected as the base of choice for further studies (Run 10). Although more detailed
data should be accumulated to elucidate the beneficial effect of bidentate amines, we assume that they may
coordinate to zinc and dissociate the Reformatsky reagent dimeric complexes,23
enhancing the coordination
ability of the -zinc-alkoxide to the ester carbonyl as well as the reactivity of the Reformatsky reagent.
Inorganic bases did not promote the reaction (Runs 11, 12). Also, thiophene24
and L-Proline,25
which have
been reported as coordinating additives to zinc, did not remarkably promote the reaction (Runs 13, 14).
Chapter 4
67
Table 3. Effect of Base on Double Reformatsky Reaction of 1ba
Run Additive Conversion (%)b
1 - 48
2 Pyridine 78
3 Pyridine (4.0 equiv) 75
4 N-Methyl imidazole 67
5 i-Pr2NEt 52
6 DBU 67
7 2, 2-Bipyridine 91
8 1, 10-Phenanthroline 80
9 DABCO 91
10 TMEDA 95
11 K2CO3 64
12 NaHCO3 46
13 Thiophene 63
14 L-Proline 3
a Reaction conditions: Substrate (2.5 mmol), ethyl bromozincacetate (5.0 equiv), THF (23 mL), 25 oC, 3 days under N2.
b Determined by HPLC analysis.
Chapter 4
68
3. Scope and limitations
With an efficient procedure for the double Reformatsky reaction in hand,26
the reactions with ketones,
aldehydes, nitriles and carboxylic acid anhydrides were performed under the optimal conditions (ethyl
bromozincacetate (5.0 equiv), TMEDA (2.0 equiv) in THF) (Table 4).27
It was found that various
electronically and structurally diverse ketones and aldehydes could be used in the reaction to give the
corresponding -hydroxy--ketoesters in good to excellent yields (Runs 1-11). Interestingly, in the case of
p-formylbenzoic acid methyl ester (5h), the formyl moiety was readily converted to the -hydroxy--ketoester
whereas an ester on an aromatic ring remained unchanged (Run 6). Moreover, p-nitrobenzaldehyde (5i) and
p-bromobenzaldehyde (5j) underwent reaction leaving the nitro and halide groups unreacted, making the
method attractive for further functionalizations (Runs 7, 8). The reaction also proceeded well in the presence
of a hetero aryl group (Run 9). Other than arylaldehydes, the reaction with alkenylaldehyde (5l) and
alkylaldehyde (5m) gave the corresponding products in satisfactory yields, without any side reactions (Runs
10, 11). 28
To further expand the scope of this reaction, the application to nitriles and carboxylic acid anhydrides was
examined (Runs 12, 13). The reaction of zinc alkanoate with a nitrile, namely the Blaise reaction,4 is known to
provide -ketoesters after acidic work-up. Similarly, Reformatsky-type reaction with carboxylic acid
anhydride can also provide -ketoesters.5 If the double addition of zinc alkanoate proceeds for nitriles and
carboxylic acid anhydrides, , -diketoesters were expected to be obtained, which would expand the synthetic
utility of the reaction. However, when the double Reformatsky reactions of benzonitrile (7) and benzoic (ethyl
carbonic) anhydride (8) were attempted, both of them afforded -ketoester (9) as the sole product and no ,
-diketoesters (10) were observed.
Chapter 4
69
Table 4. Synthesis of Various -Hydroxy--ketoesters a
Run Substrate Product
Isolated yield
(%)
1
76
2
87
3
85
4
90
5b
87
6
90
7
73
Chapter 4
70
Run Substrate Product
Isolated yield
(%)
8
84
9
82
10
94
11
74
12
85
0
13
9c
10
55
0
a Reaction conditions: Substrate (2.5 mmol), ethyl bromozincacetate (5.0 equiv), TMEDA (2.0 equiv), THF (23 mL), 50 oC, 1-5 h,
under N2. b Ethyl bromozincacetate (10.0 equiv), TMEDA (4.0 equiv). c Isolated as keto-enol tautomer (mainly -ketoester
conformation).
All products from ketones and aldehydes in Table 4 were isolated in the form of ketoesters, and enol
structures were not observed. Furthermore, it should be stressed that all ketones and aldehydes were
exclusively converted to -hydroxy--ketoesters, and neither-dihydroxydiesters29
(11) nor -hyroxy--
Chapter 4
71
diketoesters30
(12) were detected (Figure 1).
Figure 1. Structure of 11 and 12 (Undetected Potential Byproducts)
4. Mechanistic consideration
Based on the above results, the mechanism for the double Reformatsky reaction, taking the example of
reactions with 5h, 7 and 8, can be considered as follows (Scheme 4). In the case of 5h, after the usual
Reformatsky reaction at the formyl moiety, the newly-formed terminal ester of intermediate A is activated by
the -zinc-alkoxide-TMEDA complex as an internal Lewis acid (complex-induced proximity effect), and it is
subject to secondary addition of zinc alkanoate, whereas the aromatic ester remains unreactive due to the
absence of any chelation-assisted activation (Scheme 4 (a)). After secondary addition of zinc alkanoate to the
-hydroxyester of A, zinc complex B is formed with an ester-conjugated enolate, as described below. The
conformation of B gives an appropriate explanation to the fact that 11 and 12 were never detected, because the
terminal ester of B will be stabilized by conjugation even under the activation by the internal Lewis acid. In
sharp contrast, after addition of zinc alkanoate to nitrile 7, complex C is formed and stabilized in
imine-enamine tautomeric equibrium with complex D, and consequently secondary addition of zinc alkanoate
is unlikely to occur (Scheme 4 (b)). Similarly, after addition of zinc alkanoate to carboxylic acid anhydride 8,
rapid -elimination provides ester-conjugated enolate F that is stabilized by conjugation, which probably
prohibits any further addition of zinc alkanoate (Scheme 4 (c)).
Chapter 4
72
Scheme 4. Plausible Reaction Mechanism
The assumption that doubly coupled intermediates such as complex B are in the form of ester-conjugated
enolates was reinforced by analytical results. In the course of this study, we obtained a white crystalline
precipitate after double Reformatsky reaction of 1a. As the precipitate was converted to 3a after simple acidic
workup, it was considered to be the zinc complex of 3a. Judging from the results of 1H NMR and ICP-MS, the
structure seemed to consist of three atoms of zinc, two molecules of 3a and one molecule of THF.31
The 1D and 2D NMR analyses of the zinc complex of 3a were conducted, and full assignment of the 1H and
13C chemical shifts was achieved by evaluating the HMQC and HMBC spectra.
32 During the evaluations, we
paid attention to a characteristic singlet proton that is considered to be an olefinic proton. According to the
HMBC spectra, the olefinic proton was found to be coupled with C16 and C19, which indicated that the
proton was H18, and the structure of the zinc complex of 3a involved the ester-conjugated enolate form
Chapter 4
73
(Figure 2). Furthermore, a single crystal was obtained from ethanol and acetone (zinc complex of 3a ethanol
solvate), and submitted for X-ray single crystal structure analysis, which revealed the intermolecular
coordination of the pyridyl group to zinc-alkoxide, as proposed in Figure 2.33
Additionally, the bond length of
C16-C18 (1.358 Å) is found to be a typical olefinic double bond length,34
which also endorses our assumption
that the doubly coupled intermediates are in the form of ester-conjugated enolates.
Figure 2. X-ray Crystal Structure of zinc complex of 3a (bond lengths for the crystal; C1-C15 = 1.560 Å,
C15-C16 =1.503 Å, C16-C18 = 1.358 Å, C1-O14 = 1.404 Å , C16-O17 = 1.318 Å, C19-O20 = 1.235 Å.)
The coordination of the pyridyl group to the zinc-alkoxide indicates the pyridyl group works in the same
manner as TMEDA. Therefore, it is considered that the double Reformatsky reaction of 1a to 3a proceeds
through the activation of the ester carbonyl group of intermediate 2a by the zinc-alkoxide coordinated with the
pyridyl group (Figure 3). Furthermore, the consideration that the zinc-alkoxide-pyridine complex works as an
internal Lewis acid is consistent with the observation that external Lewis acids, such as TMSCl, are not
required to promote the reaction.
Chapter 4
74
Figure 3. Potential Transition State of the Reaction of 2a to 3a
Conclusion
Double Reformatsky reaction and the synthesis of various -hydroxy--ketoesters have been developed.
The key to accelerate the double Reformatsky reaction is considered to be a complex-induced proximity effect
of the in situ generated zinc-alkoxide coordinated with the pyridyl group of the substrate or bidentate amines.
A noteworthy feature of the reaction system is its high tolerance of functional groups, due to the moderate
nucleophilicity of organozinc reagents and the mild reaction conditions. Moreover, NMR and X-ray single
crystal structure analyses of the zinc complex of the double Reformatsky product have supported the proposed
mechanism of reaction site discrimination for ketones, aldehydes, nitriles, carboxylic acid anhydrides and
ester. The present versatile synthesis can complement the known synthetic methods for
-hydroxy--ketoesters in terms of functional group flexibility. Furthermore, since several asymmetric
Reformatsky reactions have been reported,21,35
this method can potentially be applied to asymmetric reactions,
which is the focus of ongoing research.
Chapter 4
75
Experimental Section
General
All chemicals were obtained from commercial suppliers and used without further purification. NMR was
recorded on 500 MHz spectrometer with tetramethylsilane as an internal standard. Chemical shifts are shown
in ppm. High-resolution mass spectra (HRMS) were measured by ESI-Orbitrap mass spectrometer.
BrZnCH2CO2Me, BrZnCH2CO2Et, and BrZnCH2CO2i-Pr: Under N2 atmosphere, to a 200 mL
round-bottom flask were added zinc powder (11.5 g, 175.8 mmol, 2.0 equiv), dry THF (44 mL) and TMSCl
(0.96 g, 88.2 mmol, 0.1 equiv). The suspension was warmed to 40-50 oC and -Bromoester (88.2 mmol, 1.0
equiv) in THF (110 mL) was added dropwise to the suspension. After insoluble matter precipitated, the light
yellow supernatant solution was decanted and used for subsequent experiments.
TMSCl-free BrZnCH2CO2Et: To a 500 mL round-bottom flask were added zinc powder (20 g) and aqueous
0.1 N aq HCl (200 mL). The suspension was stirred vigorously for 10 min. The precipitate was collected by
filtration and dried in vacuo at 100 oC for 4 h. Under N2 atmosphere, to a 200 mL round-bottom flask were
added the above activated zinc (11.5 g, 175.8 mmol, 2.0 eq) and dry THF (44 mL). The suspension was
warmed to 40-50 oC and ethyl bromoacetate (14.7 g, 88.2 mmol, 1.0 eq) in THF (110 mL) was added
dropwise. After insoluble matter precipitated, the light yellow supernatant solution was decanted and used for
subsequent experiments.
BrZnCH2CO2t-Bu: To a 500 mL round-bottom flask were added zinc powder (20 g) and 0.1 N aq HCl (200
mL). After being stirred for 10 min at room temperature, the precipitate was collected by filtration and dried at
100 oC for at least 4 h. Under N2 atmosphere, to a 200 mL round-bottom flask were added the above activated
zinc powder (11.5 g, 175.8 mmol, 2.0 equiv), THF (44 mL) and TMSCl (0.96 g, 88.2 mmol, 0.1 equiv). The
suspension was warmed to 40-50 oC and tert-Butyl bromoacetate (17.2g, 88.2 mmol, 1.0 equiv) in THF (110
Chapter 4
76
mL) was added dropwise. After zinc powder precipitated, the light yellow supernatant solution was decanted
and used for subsequent experiments.
Ethyl 5-hydroxy-3-oxo-5-phenyl-5-(pyridin-2-yl)pentanoate (3a): To a 100 mL round-bottom flask were
added ca. 0.54 mol/L ethyl bromozincacetate/ THF solution (16.1 mL, ca. 8.7 mmol, 3.5 equiv), and
2-benzoyl pyridine (1a) (458.0 mg, 2.5 mmol). The yellow solution was stirred at room temperature for 24 h.
The mixture was diluted with EtOAc (50 mL). The solution was successively washed with 20% aq citric acid
(25 mL), 10% aq NaCl (25 mL), 5% aq NaHCO3 (25 mL), and water (25 mL). The organic layer was
concentrated in vacuo to give the crude oil. The crude oil was purified by flash chromatography
(EtOAc/Hexane) to give the title compound as a yellow oil (651.8 mg, 83% yield). 1H NMR (500 MHz,
DMSO-d6) 1.14 (t, J = 7.1 Hz, 3H), 3.46 (d, J = 15.8 Hz, 1H), 3.49 (s, 2H), 3.77 (d, J = 15.5 Hz, 1H), 4.03
(q, J = 7.3 Hz, 2H), 6.10 (s, 1H), 7.15-7.16 (m, 1H), 7.17-7.23 (m, 1H), 7.27 (t, J = 7.0 Hz, 2H), 7.45-7.47 (m,
2H), 7.59 (d, J = 7.9 Hz, 1H), 7.73-7.76 (m, 1H), 8.47-8.48 (m, 1H); 13
C NMR (125 MHz, DMSO-d6) 13.9,
50.2, 53.0, 60.3, 77.1, 120.3, 121.9, 125.3, 126.6, 127.9, 136.9, 146.2, 147.6, 164.6, 167.0, 201.9; HRMS
(ESI-Orbitrap) m/z: [M+H]+ Calcd for C18H20NO4 314.1387; Found 314.1376.
General Procedure: -hydroxy--ketoesters: To a 100 mL round-bottom flask were added ca. 0.54 mol/L
ethyl bromozincacetate/ THF solution (23.3 mL, ca. 12.5 mmol, 5 equiv), TMEDA (0.75 mL, 5 mmol, 2.0
equiv), and carbonyl compound (2.5 mmol, 1.0 equiv). The solution was warmed to 50 oC and stirred for 1-5 h.
After cooling to room temperature, the mixture was diluted with EtOAc (50 mL). The solution was
successively washed with 20% aq citric acid (25 mL), 10% aq NaCl (25 mL), 5% aq NaHCO3 (25 mL), and
water (25 mL). The organic layer was concentrated in vacuo to give the crude oil. The crude oil was purified
by flash chromatography (EtOAc/Hexane) to give the pure -hydroxy--ketoesters.
Ethyl 5-hydroxy-3-oxo-5, 5-diphenylpentanoate (3b): The title compound was prepared according to the
General Procedure, and isolated as a white solid (590.6 mg, 76% yield). mp 66-67 oC;
1H NMR (500 MHz,
Chapter 4
77
DMSO-d6)1.14 (t, J = 7.1 Hz, 3H), 3.48 (s, 2H), 3.55 (s, 2H), 4.02 (q, J = 7.3 Hz, 2H), 5.94 (s, 1H),
7.16-7.19 (m, 2H), 7.29 (t, J = 7.7 Hz, 4H), 7.42-7.44 (m, 4H); 13
C NMR (125 MHz, DMSO-d6) 13.9, 50.2,
53.7, 60.3, 75.8, 125.5, 126.4, 127.9, 147.2, 167.0, 202.0; HRMS (ESI-Orbitrap) m/z: [M+NH4]+ Calcd for
C19H24NO4 330.1700; Found 330.1703.
Ethyl 5, 5-bis(4-fluorophenyl)-5-hydroxy-3-oxopentanoate (3e): The title compound was prepared
according to the General Procedure, and isolated as a yellow oil (788.6 mg, 85% yield). 1H NMR (500 MHz,
CDCl3) 1.26 (t, J = 7.1 Hz, 3H), 3.42 (s, 2H), 3.53 (s, 2H), 4.18 (q, J = 7.3 Hz, 2H), 4.70 (s, 1H), 6.96-6.99
(m, 4H), 7.32-7.35 (m, 4H); 13
C NMR (125 MHz, CDCl3) 14.1, 50.3, 53.0, 61.8, 76.4, 115.2 (d, JC-F = 22.5
Hz), 127.4 (d, JC-F = 8.8 Hz), 141.7 (d, JC-F = 3.8 Hz), 161.9 (d, JC-F = 245.0 Hz), 166.6, 203.8; HRMS
(ESI-Orbitrap) m/z: [M+NH4]+ Calcd for C19H22F2NO4 366.1511; Found 366.1513.
Ethyl 5-hydroxy-5, 5-bis(4-methoxyphenyl)-3-oxopentanoate (3f): The title compound was prepared
according to the General Procedure, and isolated as a yellow oil (755.9mg, 87% yield). 1H NMR (500 MHz,
CDCl3) 1.26 (t, J = 7.3 Hz, 3H), 3.40 (s, 2H), 3.51 (s, 2H), 3.77 (s, 6H), 4.18 (q, J = 7.3 Hz, 2H), 4.53 (s,
1H), 6.81-6.83 (m, 4H), 7.26-7.28 (m, 4H); 13
C NMR (125 MHz, CDCl3) 14.1, 50.5, 53.2, 55.2, 61.6, 76.5,
113.6, 126.9, 138.4, 158.5, 166.7, 204.0; HRMS (ESI-Orbitrap) m/z: [M+NH4]+ Calcd for C21H28NO6
390.1911; Found 390.1909.
Ethyl 5-hydroxy-3-oxo-5-phenylpentanoate (6a): The title compound was prepared according to the
General Procedure, and isolated as a colorless oil (528.4mg, 90% yield). 1H NMR (500 MHz, CDCl3) 1.28 (t,
J = 7.2 Hz, 3H), 2.92 (dd, J = 17.3, 3.5Hz, 1H), 3.00 (dd, J = 17.3, 9.1 Hz, 1H), 3.48 (s, 2H), 4.19 (q, J = 7.2
Hz, 2H), 5.19 (dd, J = 9.1, 3.5 Hz, 1H), 7.20-7.42 (m, 5H). Analysis of the spectroscopic data matched
reported data.36
Chapter 4
78
Diethyl 5, 5'-(1, 4-phenylene)bis(5-hydroxy-3-oxopentanoate) (6g): The title compound was prepared
according to the General Procedure (terephthalaldehyde 14, 167.7 mg, 1.25 mmol), Reformatsky reagent (23.3
mL, 10 equiv), TMEDA (0.75 mL, 4 equiv) and isolated as a light yellow oil (856.9 mg, 87% yield). 1H NMR
(500 MHz, CDCl3) 1.28 (t, J = 7.1 Hz, 6H), 2.91 (dd, J = 17.5, 3.2 Hz, 2H), 2.99 (dd, J = 17.5, 9.1 Hz, 2H),
3.08 (brs, 2H), 3.49 (s, 4H), 4.20 (q, J = 7.1 Hz, 4H), 5.19 (dd, J = 9.1, 3.2 Hz, 2H), 7.35-7.36 (m, 4H); 13
C
NMR (125 MHz, CDCl3) 14.1, 49.9, 51.5, 61.6, 69.6, 125.9, 142.2, 166.9, 202.8; HRMS (ESI-Orbitrap)
m/z: [M+NH4]+ Calcd for C20H30NO8 412.1966; Found 412.1977.
Methyl 4-(5-ethoxy-1-hydroxy-3, 5-dioxopentyl)benzoate (6h): The title compound was prepared according
to the General Procedure, and isolated as an oil (614.4 mg, 84% yield). 1H NMR (500 MHz, CDCl3) 1.28 (t,
J = 7.1 Hz, 3H), 2.94 (dd, J = 17.6, 3.8 Hz, 1H), 2.99 (dd, J = 17.6, 8.5 Hz, 1H), 3.27 (brs, 1H), 3.49 (s, 2H),
3.91 (s, 3H), 4.20 (q, J = 7.0 Hz, 2H), 5.26 (dd, J = 8.5, 3.5 Hz,1H), 7.43-7.45 (m, 2H), 8.01-8.03 (m, 2H); 13
C
NMR (125 MHz, CDCl3) 14.1, 49.8, 51.4, 52.1, 61.6, 69.3, 125.5, 125.6, 129.5, 129.9, 147.6, 166.8, 202.6;
HRMS (ESI-Orbitrap) m/z: [M+H]+ Calcd for C15H18O6 295.1176; Found 295.1181.
Ethyl 5-hydroxy-5-(4-nitrophenyl)-3-oxopentanoate (6i): The title compound was prepared according to the
General Procedure, and isolated as an off-white solid (625.2 mg, 90% yield). mp 75-76 oC;
1H NMR (500
MHz, CDCl3) 1.29 (t, J = 7.1 Hz, 3H), 2.97-2.99 (m, 2H), 3.40 (d, J = 3.5 Hz, 1H), 3.51 (s, 2H), 4.21 (q, J =
7.3 Hz, 2H), 5.32 (ddd, J = 6.9, 5.2, 3.5 Hz 1H), 7.55-7.57 (m, 2H), 8.20-8.22 (m, 2H); 13
C NMR (125 MHz,
CDCl3) 14.1, 49.7, 51.2, 61.8, 68.9, 123.8, 126.5, 147.4, 149.7, 166.7, 202.5; HRMS (ESI-Orbitrap) m/z:
[M+H]+ Calcd for C13H15NO6 282.0972; Found 282.0974.
Ethyl 5-(4-bromophenyl)-5-hydroxy-3-oxopentanoate (6j): The title compound was prepared according to
the General Procedure, and isolated as a colorless oil (577.3 mg, 73% yield). 1H NMR (500 MHz, CDCl3)
(t, J = 7.1 Hz, 3H), 2.90 (d, J = 17.6, 3.4 Hz, 1H), 2.96 (dd, J = 17.6, 8.8 Hz, 1H), 3.12 (d, J = 3.4 Hz,
1H), 3.48 (s, 2H), 4.20 (q, J = 7.1 Hz, 2H), 5.16 (dt, J = 8.8, 3.4 Hz, 1H), 7.24-7.26 (m, 2H), 7.47-7.49 (m,
Chapter 4
79
2H); 13
C NMR (125 MHz, CDCl3) 14.1, 49.9, 51.4, 61.7, 69.2, 121.6, 127.4, 131.7, 141.5, 166.8, 202.7;
HRMS (ESI-Orbitrap) m/z: [M+H]+ Calcd for 315.0226 (
79Br) and 317.0206 (
81Br); Found 315.0230 (
79Br)
and 317.0208 (81
Br).
Ethyl 5-hydroxy-3-oxo-5-(thiophen-3-yl)pentanoate (6k): The title compound was prepared according to
the General Procedure, and isolated as yellow oil (496.6 mg, 82% yield). 1H NMR (500 MHz, CDCl3) 1.25
(t, J = 7.1 Hz, 3H), 2.91 (dd, J = 17.0, 3.6 Hz, 1H), 2.99 (dd, J = 17.0, 8.8 Hz, 1H), 3.46 (s, 2H), 3.56 (brs,
1H), 4.16 (q, J = 7.1 Hz, 2H), 5.21 (dd, J = 8.8, 3.6 Hz, 1H), 7.03 (dd, J = 5.0, 1.3 Hz, 1H), 7.18-7.19 (m, 1H),
7.27 (dd, J = 5.0, 3.0 Hz, 1H); 13
C NMR (125 MHz, CDCl3) 14.1, 49.8, 50.8, 61.5, 66.1, 121.0, 125.5, 126.3,
144.2, 167.1, 202.6; HRMS (ESI-Orbitrap) m/z: [M+H]+ Calcd for C11H15O4S 243.0686; Found 243.0688.
Ethyl-(6E)-5-hydroxy-3-oxo-7-phenylhept-6-enoate (6l): The title compound was prepared according to the
General Procedure, and isolated as a pale yellow oil (617.5 mg, 95% yield). 1H NMR (500 MHz, CDCl3)
1.27 (t, J = 7.3 Hz, 3H), 2.86-2.87 (m, 2H), 2.96 (brs, 1H), 3.50 (s, 2H), 4.20 (q, J = 7.3 Hz, 2H), 4.79 (d, J
= 6.0 Hz, 1H), 6.20 (dd, J = 15.9, 6.1 Hz, 1H), 6.63-6.66 (m, 1H), 7.40-7.26 (m, 1H), 7.29-7.32 (m, 2H),
7.36-7.38 (m, 2H); 13
C NMR (125 MHz, CDCl3) 14.1, 49.6, 50.0, 61.6, 68.4, 126.5, 127.8, 128.6, 129.9,
130.7, 136.4, 166.9, 202.7; HRMS (ESI-Orbitrap) m/z: [M+NH4]+ Calcd for C15H22NO4 280.1543; Found
280.1543.
Ethyl 5-hydroxy-3-oxo-7-phenylheptanoate (6m): The title compound was prepared according to the
General Procedure, and isolated as a yellow oil (486.2 mg, 74% yield). 1H NMR (500 MHz, CDCl3) 1.27 (t,
J = 7.1 Hz, 3H), 1.71-1.72 (m, 1H), 1.81-1.83 (m, 1H), 2.65-2.71 (m, 3H), 2.77-2.83 (m, 1H), 2.99 (brs, 1H),
3.44, 3.45 (ABq, J=15.8Hz, 2H), 4.08-4.12 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 7.16-7.20 (m, 3H), 7.26-7.29 (m,
2H); 13
C NMR (125 MHz, CDCl3) 14.1, 31.7, 38.1, 49.7, 49.9, 61.5, 66.8, 125.9, 128.43, 128.44, 141.7,
167.0, 203.6; HRMS (ESI-Orbitrap) m/z: [M+H]+ Calcd for C15H21O4 265.1434; Found 265.1435.
Chapter 4
80
Benzoic (ethyl carbonic) anhydride (8); To a solution of benzoic acid (353.0 mg, 2.5 mmol) and THF (5
mL) was added triethylamine (253.0 mg, 2.5 mmol, 1 equiv). The mixture was cooled to 0 ~ 10 oC. Ethyl
chloroformate (271.3 mg, 2.5 mmol, 1 equiv) was added to the mixture, and the solution was stirred for 0.5 h
at the same temperature. The precipitate was filtered off and washed with THF (2 mL x 2). The combined
filtrate was concentrated in vacuo to give the crude oil. The crude oil was used for further experiment without
any purification. 1H NMR (500 MHz, CDCl3) 1.42 (t, J = 7.1 Hz, 3H), 4.41 (q, J = 7.0 Hz, 2H), 7.49 (t, J =
7.9 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 8.08 (dd, J = 8.4, 1.7 Hz, 2H).
Ethyl 3-oxo-3-phenylpropanoate (9): The title compound was prepared according to the General Procedure
(The reaction mixture diluted with EtOAc and aqueous citric acid (20%) was stirred overnight) (benzonitrile
27, 257.6 mg, 2.5 mmol), and isolated as a light brown oil (410.0 mg, 85.3% yield)). Keto tautomer: 1H NMR
(500 MHz, CDCl3) 1.25 (t, J = 7.25 Hz, 3H), 3.99 (s, 2H), 4.21 (q, J = 7.15 Hz, 2H), 7.47 (t, J = 7.88 Hz,
2H), 7.59 (t, J = 7.41 Hz, 1H), 7.91-7.97 (m, 2 H); 13
C NMR (125 MHz, CDCl3) 14.1, 46.0, 61.4, 128.5,
128.8, 133.7, 136.1, 167.1, 192.5; Enol tautomer: 1H NMR (500 MHz, CDCl3) 1.33 (t, J = 7.1 Hz, 3H), 4.26
(q, J = 7.1 Hz, 2H), 5.67 (s, 1H), 7.38-7.45 (m, 3H), 7.74-7.81 (m, 2H), 12.60 (s, 1H); 13
C NMR (125 MHz,
CDCl3) 14.3, 60.3, 87.4, 126.0, 128.5, 131.2, 133.5, 171.4, 173.2; HRMS (ESI-Orbitrap) m/z: [M+H]+ Calcd
for C11H12O3 193.0859; Found 193.0861. Analysis of the spectroscopic data matched reported data.37
Zinc complex of 3a THF solvate: To a 100 mL round-bottom flask were added ca. 0.54 mol/L ethyl
bromozincacetate/ THF solution (16.1 mL, ca. 8.7 mmol, 3.5 equiv), and 2-benzoyl pyridine (1a) (458.0 mg,
2.5 mmol). The yellow solution was stirred at room temperature for 24 h. The white precipitate was collected
by filtration and washed with THF (4 mL), and dried in vacuo at 50 oC to give a white crystalline solid. mp
209-210 oC (decompose),
1H NMR (500 MHz, CDCl3) 1.14 (t, J = 7.1 Hz, 3H), 1.66-1.85 (m, 2H, 0.5THF),
2.68 (d, J = 12.6 Hz, 1H), 3.50-3.66 (m, 2H, 0.5THF), 3.82 (d, J = 12.6 Hz, 1H), 3.98 (dd, J = 10.9, 7.1 Hz,
1H), 4.14 (dd, J = 10.9, 7.1 Hz, 1H), 4.73 (s, 1H), 7.08-7.18 (m, 1H), 7.18-7.31 (m, 2H), 7.43-7.56 (m, 1H),
7.81 (d, J = 7.9 Hz, 2H), 8.01-8.13 (m, 1H), 8.25 (d, J = 8.2 Hz, 1H), 8.47 (dd, J = 5.2, 1.7 Hz, 1H); 13
C NMR
Chapter 4
81
(125 MHz, CDCl3) 14.0, 25.1, 51.4, 59.7, 67.0, 78.8, 89.1, 123.5, 123.9, 126.1, 126.4, 127.5, 139.5, 146.3,
149.2, 164.8, 172.3, 182.6.
Zinc complex of 3a ethanol solvate: Zinc complex of 3a THF solvate was dissolved in acetone and ethanol.
The solvent was evaporated under atmospheric pressure to give a colorless single crystal. mp 206-207 oC
(decompose); 1H NMR (500 MHz, CDCl3) 1.06 (t, J = 6.9 Hz, 1.5H, 0.5EtOH), 1.17 (t, J = 7.1 Hz, 3H),
2.72 (d, J = 12.6 Hz, 1H), 3.45 (qd, J = 7.0, 5.0 Hz, 1H, 0.5EtOH), 3.80 (d, J = 12.6 Hz, 1H), 3.91-4.08 (m,
1H), 4.08-4.26 (m, 1H), 4.74 (s, 1H), 7.08-7.20 (m, 1H), 7.20-7.34 (m, 2H), 7.42-7.60 (m, 1H), 7.79 (d, J =
7.9 Hz, 2H), 8.01-8.17 (m, 1H), 8.25 (d, J = 8.2 Hz, 1H), 8.39-8.60 (m, 1H); 13
C NMR (125 MHz, CDCl3)
14.1, 18.5, 51.3, 56.0, 59.8, 78.8, 89.1, 123.6, 124.0, 126.1, 126.4, 127.6, 139.6, 146.4, 149.2, 164.8, 172.4,
182.6. Crystal structure: see the Supporting Information (CCDC-923389)
Chapter 4
82
References and notes
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Fürstner, A. Synthesis 1989, 571.
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Y.; Ko, Y. O.; Hong, J. Y.; Hong, J.; Shin, H.; Lee, S.-g. J. Org. Chem. 2009, 74, 7556. (c) Chun, Y. S.;
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Res. & Dev. 1997, 1, 185. (b) Dolence, J. M.; Poulter, C. D. Tetrahedron 1996, 52, 119. (c) Gedge, D.
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Tetrahedron Lett. 1984, 25, 2605. (e) Warnhoff, E. W.; Wong, M. Y. H.; Raman, P. S. Can. J. Chem.
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Wattanasin, S. WO/2008/14311, 2008. (g) Li, H.; Tatlock, J.; Linton, A.; Gonzalez, J.; Borchardt, A.;
Chapter 4
83
Dragovich, P.; Jewell, T.; Prins, T.; Zhou, R.; Blazel, J.; Parge, H.; Love, R.; Hickey, M.; Doan, C.; Shi,
S.; Duggal, R.; Lewis, C.; Fuhrman, S. Bioorg. Med. Chem. Lett. 2006, 16, 4834. (h) Smith, T. E.;
Djang, M.; Velander, A. J.; Downey, C. W.; Carrol, K. A.; Alphen, S. Org. Lett. 2004, 6, 2317. (i)
Evans, D. A.; Jason, E. H.; Burch, J. D.; Jaeschke, G. J. Am. Chem. Soc. 2002, 124, 5654. (j) Romero,
D. L.; Manninen, P. R.; Han, F.; Romero, A. G. J. Org. Chem. 1999, 64, 4980. (k) Turner, S. R.;
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P.; Tomich, P. K.; Bohanon, M. J.; Horng, M.-M.; Lynn, J. C.; Cong, K.-T.; Hinshaw, R. R.;
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R. P.; Rathke, M. W. J. Org. Chem. 1977, 11, 2038. (c) Dippy, J. F. J.; Parkins, J. C. J. Chem. Soc.
1951, 1570
13. (a) Newman, M. S.; James Evans Jr, F. J. Am. Chem. Soc. 1955, 77, 946. (b) Hussey, A. S.; Newman,
M. S. J. Am. Chem. Soc. 1948, 70, 3024.
Chapter 4
84
14. (a) Vaughan, W. R.; Knoess, H. P. J. Org. Chem. 1970, 35, 2394. (b) Vaughan, W. R.; Bernstein, S. C.;
Lorber, M. E. J. Org. Chem. 1965, 30, 1790.
15. Utimoto, K.; Matsui, T.; Takai, T.; Matsubara, S. Chem. Lett. 1995, 197.
16. (a) Datta, A.; Ila, H.; Junjappa, H. J. Org. Chem. 1990, 55, 5589. (b) Datta, A.; Ila, H.; Junjappa, H.
Tetrahedron Lett. 1988, 29, 497.
17. The amount of 4 was estimated by GC yield of ethyl acetoacetate after acidic workup.
18. (a) Picontin, G.; Migniac, P. J. Org. Chem. 1987, 52, 4796. (b) Gawroński, J. K. Tetrahedron Lett.
1984, 25, 2605.
19. (a) Hayashi, M.; Sugiyama, M.; Toba, T.; Oguni, N. J. Chem. Soc. Chem. Commun. 1990, 767. (b)
Basile, T.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. Synthesis 1990, 305.
20. The reaction was performed at room temperature, and full conversion was achieved within 24 h.
21. Ojida, A.; Yamano, T.; Taya, N.; Tasaka, A. Org. Lett. 2002, 4, 3051
22. To increase the reactivity and shorten the reaction time, 5 equiv of Reformatsky reagent was used. The
detailed result of the effect of various amounts of Reformatsky reagent on the reactivity is described in
the Supporting Information.
23. (a) Miki, S.; Nakamoto, K.; Kawakami, J.; Handa, S.; Nuwa, S. Synthesis. 2008, 409. (b) Dekker, J.;
Budzelaar, P. H. M.; Boersma, J.; Van der Kerk, G. J. M.; Spek, A. J. Organometallics. 1984, 3, 1403.
24. Kloetzing, R. J., Thaler, T., Knochel, P. Org. Lett. 2006, 8, 1125.
25. For recent reports see; (a) Siddiqui, Z. N.; Catal. Sci. Tecnol., 2011, 1, 810. (b) Ravi, V.; Ramu, E.,
Vijay, K.; Rao, A. S. Chem. Pharm. Bull. 2007, 55, 8, 1254. (c) Fernadez, R.; Kofoed, J.; Machuqueiro,
M.; Darbre, T. Eur. J. Org. Chem. 2005, 5268.
26. Low-level metal impurities in the zinc had no impact on reactivity for the double Reformatsky reaction.
(see the Supporting Information)
27. The reaction temperature was raised to 50 oC to increase the reactivity and shorten the reaction time.
Chapter 4
85
28. 1, 4 addition of Reformatsky reagent to , -unsaturated aldehydes has been reported: (a) Menicagli,
R.; Samaritani, S. Tetrahedron 1996, 52, 1425. (b) Mazumdar, S. N.; Mahajan, M. D., Tetrahedron Lett.
1990, 31, 4215.
29. Tandem addition toward one carbonyl moiety; (a) El Alami, N.; Belaud, C.; Villieras, J. J. Organomet.
Chem. 1987, 319, 303. (b) Gawroński, J. K. Tetrahedron Lett. 1984, 25, 2605.
30. Polymerization is described in references 13 and 14, and references therein.
31. 1H NMR spectra of the precipitate indicated that it contained 0.5 molecule of THF per 3a. ICP-MS
spectra showed zinc metal makes up 18% of the whole weight of the precipitate.
32. 1H,
13C NMR, HMQC and HMBC spectra can be seen in the Supporting Information.
33. Details are described in the Supporting Information, including a CIF file and an ORTEP plot.
Additionally, CCDC-923389 contains all crystallographic data of this publication and is available free
of charge at The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
34. Representative bond lengths for the crystal; C1-C15 = 1.560 Å, C15-C16 =1.503 Å, C16-C18 = 1.358
Å, C1-O14 = 1.404 Å, C16-O17 = 1.318 Å, C19-O20 = 1.235 Å. Other bond lengths are described in
the Supporting Information.
35. For the selected examples see; (a) Fornalczyk, M.; Singh, K.; Stuart, A. M. Org. Biomol. Chem. 2012,
10, 3332. (b) Wolf. C.; Moskowitz, M. J. Org. Chem. 2011, 76, 6372. (c) Lin, N.; Chen, M.-M.; Luo,
R.-S.; Deng. Y.-Q.; Lu, G. Tetrahedron: Asymm. 2010, 21, 2816. (d) Tanaka, T.; Hayashi, M. Chem.
Lett. 2008, 37, 1298. (e) Cozzi, P. G.; Mignogna, A.; Vicennati, P. Adv. Synth. Catal. 2008, 350, 975.
(f) Fernández-Ibáñez, M. A.; Maciá, B.; Minnaard, A. J.; Feringa, B. L. Angew. Chem., Int. Ed. 2008,
47, 1317. (g) Cozzi, P. G. Angew. Chem., Int. Ed. 2006, 45, 2951. (h) Kloetzing, R. J.; Thaler, T.;
Knochel, P. Org. Lett. 2006, 8, 1125. (i) Fujiwara, Y.; Katagiri, T.; Uneyama, K. Tetrahedron Lett.
2003, 44, 6161. (j) Andrés, J. M.; Martín, Y.; Pedrosa, R.; Pérez-Encabo, A. Tetrahedron 1997, 53,
3787. (k) Mi, A.; Wang, Z.; Chen, Z.; Jiang, Y.; Chan, A. S. C.; Yang, T.-K. Tetrahedron: Asymm.
1995, 6, 2641. (l) Pini, D.; Mastantuono, A.; Salvadori, P. Tetrahedron: Asymm. 1994, 5, 1875. (m)
Soai, K.; Oshio, A.; Saito, T. J. Chem. Soc., Chem. Commun. 1993, 811.
Chapter 4
86
36. Xu, C.; Yuan, C. Tetrahedron 2005, 61, 2169.
37. Katritzky, A. R.; Wang, Z.; Wang, M.; Wilkerson, C. R.; Dennis Hall, C.; Akhmedov, N. G. J. Org.
Chem. 2004, 69, 6617.
Chapter 4
87
Supporting Information
Low-level metal impurities
Zinc mediated Simmons-Smith reaction is known to be affected by a quite low amount of lead.1 It is
generally known that there are two types of zinc metal preparations; one is electrolytic zinc, and the other is
distilled zinc. Distilled zinc is generally more likely to contain lead than electrolytic zinc. To see if the
residual metal affects the reactivity or not, we evaluated the reactivity with several different zincs, which were
prepared by several suppliers and in different ways. As shown in Table S-1, there was no relationship between
the reactivity and the residual metals.
Table S-1. The effect of low-level metal impurities on double Reformatsky reaction
Run Supplier
Purification
method
Component (%) Conversion
(3a, %)a Zn Pb Cd Fe
1 A Distilled 97.0 0.088 0.001 0.001 99
2 B Distilled 96.6 0.11 0.02 0.01 98
3 B Electrolytic >99.9 0.0016 0.0003 0.002 99
a Determined by HPLC
Chapter 4
88
The amount of Reformatsky reagent
The effect of various amounts of Reformatsky reagent on the reactivity was evaluated (Table S-2). The
study was performed at room temperature without additives. Theoretically, this reaction can be completed by
the use of 2 equiv of Reformatsky reagent. However, 2 equiv of Reformatsky reagent only afforded a small
amount of double Reformatsky product 3b (Run 2). The lower conversions do not appear to be due to
self-condensation of the Reformatsky reagent, since self-condensed Reformatsky reagents were hardly
detected during this study (checked by GC). The conversion could be improved by increasing the amount of
Reformatsky reagent (Runs 3 and 4).
Table S-2. The effect of various amounts of Reformatsky reagent on double Reformatsky reaction
Run Equiv of Reformatsky reagent Ratio (1b/2b/3b)a
1 1 99/1/0
2 2 2/90/8
3 3.5 0/84/16
4 5.0 0/52/48
a Determined by HPLC analysis.
Chapter 4
89
Details of X-ray single crystal structure analysis of zinc complex of 3a ethanol solvate
Crystal data for the zinc complex of 3a ethanol solvate [Zn3(C18H17NO4)2Br2(C2H5OH)]∙C2H5OH, MW =
1070.76; crystal size, 0.20 x 0.17 x 0.10 mm; colorless, block; monoclinic, space group P21/c, a = 14.6149(3)
Å, b = 14.4589(3) Å, c = 21.0849(4) Å, α = γ = 90, β = 109.251(8) V = 4206.4(3) Å3, Z = 4, Dx = 1.691
g/cm3, T = 100 K, μ = 4.7072 mm
-1, λ = 1.5419 Å, R1 = 0.045, wR2 = 0.094.
The crystal data for the zinc complex of 3a ethanol solvate was obtained by crystallization from
ethanol/acetone solution. All measurements were made on a Rigaku R-AXIS RAPID diffractometer using
graphite monochromated Cu-K radiation. The structure was solved by direct methods with SHELXS-972 and
was refined using full-matrix least-squares on F2 with SHELXL-97.
2 All non-H atoms were refined with
anisotropic displacement parameters.
CCDC-923389 contains all crystallographic data of this publication and is available free of charge at The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Figure S-1. ORTEP of the Zinc Complex of 3a ethanol solvate, thermal ellipsoids are drawn at 20%
probability level.
Chapter 4
90
Table S-3. Bond Length for the Zinc Complex of 3a ethanol solvate
Atom Atom Distance (Å) Atom Atom Distance (Å)
C1 C2 1.548(6) C1 C8 1.549(6)
C1 O14 1.404(5) C1 C15 1.560(5)
C2 N3 1.342(5) C2 C7 1.393(6)
N3 C4 1.347(6) N3 Zn48 2.070(4)
C4 C5 1.375(7) C5 C6 1.391(6)
C6 C7 1.377(6) C8 C9 1.395(6)
C8 C13 1.398(6) C9 C10 1.387(7)
C10 C11 1.381(7) C11 C12 1.374(7)
C12 C13 1.384(7) O14 Zn47 2.060(3)
O14 Zn48 2.075(3) C15 C16 1.503(7)
C16 O17 1.318(5) C16 C18 1.358(7)
O17 Zn47 2.013(3) O17 Zn50 2.074(3)
C18 C19 1.434(7) C19 O20 1.235(6)
C19 O21 1.343(6) O20 Zn50 2.106(4)
O21 C22 1.468(7) C22 C23 1.496(7)
C24 C25 1.540(7) C24 C31 1.547(6)
C24 O37 1.401(5) C24 C38 1.557(5)
C25 N26 1.341(5) C25 C30 1.394(6)
N26 C27 1.349(7) N26 Zn50 2.059(4)
C27 C28 1.369(6) C28 C29 1.375(6)
C29 C30 1.387(7) C31 C32 1.388(5)
C31 C36 1.397(6) C32 C33 1.396(6)
C33 C34 1.368(7) C34 C35 1.387(6)
C35 C36 1.384(6) O37 Zn47 2.006(3)
O37 Zn50 2.032(3) C38 C39 1.507(6)
C39 O40 1.307(5) C39 C41 1.363(5)
O40 Zn47 1.999(3) O40 Zn48 2.007(3)
C41 C42 1.433(6) C42 O43 1.242(5)
C42 O44 1.342(4) O43 Zn48 2.102(3)
O44 C45 1.458(5) C45 C46 1.494(6)
Zn47 O52 2.002(4) Zn48 Br49 2.3796(7)
Zn50 Br51 2.3620(6) O52 C53 1.406(6)
C53 C54 1.516(7)
Chapter 4
91
Zinc complex of 3a THF solvate: HMBC DMSO-d6
Chapter 4
92
Zinc complex of 3a THF solvate: HMQC DMSO-d6
Chapter 4
93
References cited in the Supporting Information
1. A catalytic amount of lead promotes further reduction of zinc carbenoid with zinc in THF to give the
geminal dizinc compound (CH2(ZnI)2)； (a) Matsubara, S.; Oshima, K.; Matsuoka, H.; Matsumoto, K.;
Ishikawa, K.; Matsubara, E. Chem. Lett. 2005, 34, 952. (b) Matsubara, S.; Oshima, K.; Utimoto, K. J.
Organomet. Chem. 2001, 617, 767. (c) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org.
Chem.1994, 59, 2668.
2. Sheldrick, G.M. Acta Cryst. A, 2008, 64, 112.
Chapter 4
94
Chapter 5
95
Chapter 5
A rapid and diverse construction of
6-substituted-5,6-dihydro-4-hydroxy-2-pyrones
through a double Reformatsky reaction
Abstract
A rapid and diverse synthesis of biologically important 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones
through a double Reformatsky reaction of aldehydes to -hydroxy--ketoesters followed by lactonization is
described. Due to the high functional group tolerance and reaction site discrimination between aldehyde,
nitrile and ester groups in the substrate, the protocol can provide the dihydropyrones with bromo, nitro,
carboxylic acid and -ketoester groups, which are suitable for the further derivatizations. Furthermore, the
protocol has been successfully applied to the rapid total synthesis of naturally occurring Yangonin.
Chapter 5
96
Introduction
6-Substituted-5,6-dihydro-2-pyrone is an important structural moiety found in a wide variety of biologically
active natural products. In particular, those with hydroxy or alkoxy groups at the C-4 position are common in
various types of natural sources. For example, Mescengricin is known as an inhibitor of L-glutamate
excitotoxicity in neutrons,1 and Jerangolid A and D are known to exhibit antifungal activity (Figure 1).
2 In
addition, piper methysticin (kava), an extract from roots that has been traditionally used as a folk medicine or
a ceremonial drink in the south pacific islands for thousands of years, contains various
6-substituted-5,6-dihydro-4-methoxy-2-pyrones such as (+)-Kavain and (+)-Methysticin (Figure 1).3,4
The
kavalactones display various and important biological properties such as anxiolytic, anticonvulsive,
muscle-relaxing, sedative and analgesic effects.3
Figure 1. Naturally occurring 5,6-dihydro-2-pyrones
Furthermore, in recent years, several synthetic 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones have also
been reported to demonstrate an array of biological properties, including as a non-peptide HIV protease
inhibitor 1 (Tipranavir),5 and an inhibitor of undecaprenyl pyrophosphate synthetase 2
(Figure 2).
6 Many
researchers have been attracted by these intriguing biological properties and have found that simple changes in
the substitution pattern often lead to diverse biological activities.7 As a result, much effort has been devoted to
Chapter 5
97
the development of the synthetic methodologies for 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones and the
derivatives.4-13
In particular, various synthetic protocols7d,m,9a,10b,e,13b,c,f,g
for the 6-aryl-substituted compounds
have been reported as historical backgrounds of discovery of HIV protease inhibitor and the structural
similarity to naturally occurring 6-aryl-2-pyrones7a,g,j,14
such as Anibine and 4-methoxyparacotoin.15
Figure 2. Synthetic 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones
Among known synthetic works on 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones and their derivatives, the
most common synthetic approach in drug discovery chemistry is lactonization of -hydroxy--ketoesters,
which are prepared via the reaction of acetoacetates with aldehydes in the presence of NaH and n-BuLi
(Weiler’s dianion method) (Scheme 1).5-8
Although this approach is facile and straightforward, the highly
reactive reagents, such as n-BuLi and NaH, could limit the scope of available substrates due to poor functional
group tolerance.16
While other methods utilizing dienes (Chan’s diene,9 Brassard’s diene,
4e,i,10 and their
analogous dienes),4g,11
diketene12
or other acetoacetate equivalents13c,f,g
have been reported, they are
considered to be less convenient to rapidly provide a wide range of this class of molecules, due to the need to
prepare the reagents or cryogenic reaction conditions.
Chapter 5
98
Scheme 1. Common approach to 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones
On the other hand, we have been recently engaged in developing a double Reformatsky reaction that can
readily provide -hydroxy--ketoesters with various functional groups via tandem addition of two molecules
of zinc alkanoate to a carbonyl compound.17
Beneficial aspects of the reaction are its mild reaction condition
and the moderate nucleophilicity of the organozinc reagent, which both contribute to high functional group
tolerance. Consequently, we expected that a sequence of the double Reformatsky reaction and a lactonization
would be a novel rapid synthetic procedure to give 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones with high
molecular diversity (Scheme 2). Herein, we describe an efficient protocol for the rapid and diverse
construction of 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones and its application to naturally occurring
kavalactones.
Scheme 2. Synthetic protocol for 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones via the double Reformatsky
reaction
Chapter 5
99
Results and discussion
To establish this protocol, benzaldehyde (3a) was initially employed as a model substrate (Table 1, Run 1).
The reaction of 3a with ethyl bromozincacetate in THF in the presence of TMEDA was carried out at 50 oC
for 3 h. In order to easily isolate the pyrone from the reaction mixture after the subsequent lactonization,
unnecessary zinc species were removed by extraction with ethyl acetate and aqueous citric acid. After the
organic layer was concentrated, lactonization was smoothly accomplished by a successive treatment of
aqueous NaOH and HCl. As a consequence, 4a, a key synthetic intermediate of 2,6 was obtained as crystals
directly from the reaction mixture. Encouraged by this result, the reactions with other aldehydes possessing
various functional groups were performed. Initially, the products from p-terephthalaldehyde (3b),
p-cyanobenzaldehyde (3c) and p-formylbenzoate (3d) were compared (Runs 2-4). In our previous paper, we
disclosed that the double Reformatsky reaction proceeds differently for aldehydes, nitriles, and esters: for
example, aldehydes are readily converted to -hydroxy--ketoesters, whereas nitriles are just converted to
-ketoesters, and esters remain unchanged.17
In fact, the reaction with 3b readily afforded the
di-5,6-dihydro-4-hydroxy-2-pyrone substituted product (4b) (Run 2). Meanwhile, the reaction of 3c gave 4c in
good yield, in which the formyl moiety is transferred to the 5,6-dihydro-4-hydroxy-2-pyrone structure, while
the nitrile moiety is converted to a -ketoester (Run 3).18
More interestingly, application of 3d to this reaction
provided 4d with the 5,6-dihydro-4-hydroxy-2-pyrone moiety and carboxylic acid derived from unreacted
ester (Run 4). Thus, the present synthetic protocol can discriminate between aldehydes, nitriles, and esters to
provide various functional groups. Also, functional groups such as bromide or nitro groups were tolerated (3e
and 3f), which allows an opportunity for further functionalizations (Runs 5 and 6). The reaction can also be
applied to hetero aryl aldehydes (Run 7). Other than arylaldehydes, the reaction with alkenylaldehyde (3h)
and alkylaldehyde (3i) gave the corresponding adducts 4h and 4i (Runs 8 and 9). It is noteworthy from a
practical perspective that all the products were readily isolated as crystals, directly from the reaction mixture.
Chapter 5
100
Table 1. Divergent synthesis of 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones via double Reformatsky
reactiona
Run Substrate Product Isolated yield (%)
1
81
2b
85
3
73
4
79
5
82
Chapter 5
101
Run Substrate Product Isolated yield (%)
6
86
7
47
8
69
9
59
a Reaction condition: 1) 3 (2.5 mmol), ethyl bromozincacetate (5.0 equiv), TMEDA (2.0 equiv), THF, 50 oC, 1-5 h under N2. 2) aq
NaOH (2.0 equiv), 3) aq HCl (3.0 equiv). b Reaction condition: 1) 3b (1.25 mmol), ethyl bromozincacetate (10.0 equiv), TMEDA (4.0
equiv), THF, 50 oC. 2) aq NaOH (4.0 equiv), 3) aq HCl (6.0 equiv). c Isolated as keto-enol tautomers of 3-oxopropanoate. The ratio of
keto tautomer to enol tautomer is 9:1, as judged by 1H NMR.
Chapter 5
102
Furthermore, the successful application to an alkenylaldehyde can lead to the rapid synthesis of
kavalactones, such as (±)-Kavain by the methylation of 4h (Scheme 3).
Scheme 3. Synthesis of (±)-Kavain
To further demonstrate the synthetic utility of this protocol, a rapid total synthesis of Yangonin was
investigated. Yangonin is one of the major components of kava extract as well as (+)-Kavain and
(+)-Methysticin, and it is reported to show a promising TNF- release inhibitory activity.3e
The intriguing
biological activities have aroused the interest of synthetic chemists to explore new synthetic pathways.4a,b,d,h,j,k
Among various synthetic pathways that have been reported, our double Reformatsky reaction based
methodology appeared to offer the most rapid synthesis of Yangonin (Scheme 4). Initially, commercially
available 4-methoxy cinnamaldehyde (3j) was converted to the corresponding -hydroxy--ketoester, with
almost full conversion, under the double Reformatsky reaction condition. After simple acidic workup to purge
zinc species, lactonization was smoothly accomplished with potassium carbonate in methanol as reported in
the literature.4g
After the solvent was switched to acetone, methylation was carried out with Me2SO4.
Subsequently, oxidation with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) in THF was conducted.
Finally, Yangonin was isolated in 47% yield from 3j.
Chapter 5
103
Scheme 4. Synthesis of Yangonin
Conclusion
An efficient and rapid synthetic protocol for biologically important
6-substituted-5,6-dihydro-4-hydroxy-2-pyrones through a sequence of double Reformatsky reaction and
lactonization has been developed. The reaction system offers high functional group tolerance, due to the
moderate nucleophilicity of the organozinc reagent. Additionally, the different transformations of aldehydes,
nitriles, and esters, enable diverse functionalizations of the products. Therefore, the present strategy provides a
powerful tool for the preparation of 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones with high molecular
diversity. Furthermore, the protocol has been successfully applied to the rapid total synthesis of naturally
occurring Yangonin. Further expansion of the scope of the protocol, including asymmetric reaction, is
currently underway.
Chapter 5
104
Experimental Section
General
All chemicals were obtained from commercial suppliers and used without further purification. NMR was
recorded on a 500 MHz spectrometer with tetramethylsilane as an internal standard. High-resolution mass
spectra (HRMS) were measured by ESI-Orbitrap mass spectrometer.
Preparation of ethyl bromozincacetate (THF solution): Under N2 atmosphere, to a 200 mL round-bottom
flask were added zinc powder (11.5 g, 175.8 mmol, 2.0 equiv) and dry THF (44 mL). TMSCl (0.96 g, 8.8
mmol, 0.1 equiv) was added to the suspension. The suspension was warmed to 40 - 50 oC. Ethyl bromoacetate
(14.7 g, 88.2 mmol, 1.0 equiv) in THF (110 mL) was added dropwise to the suspension. After insoluble matter
precipitated, the light yellow supernatant solution was decanted and used for subsequent experiments.
Synthesis of 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones
General Procedure: 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones: Under N2 atmosphere, to a 100 mL
round-bottom flask were added ca. 0.54 mol/L ethyl bromozincacetate (THF solution) (23.3 mL ca. 12.5
mmol, 5 equiv), TMEDA (0.75 mL, 5 mmol, 2.0 equiv), and aldehydes (3) (2.5 mmol, 1.0 equiv). The
solution was warmed to 50 oC and stirred for 1-5 h. After cooling to ambient temperature, the mixture was
diluted with EtOAc (50 mL). The solution was successively washed with 20% aq citric acid (25 mL), 10% aq
NaCl (25 mL), 5% aq NaHCO3 (25 mL) and water (25 mL). The organic layer was concentrated in vacuo to
give the crude oil. The crude oil was stirred in 0.2 N aq NaOH (25 mL) at ambient temperature. After being
stirred for 30 min, 0.2 N aq HCl (35 mL) was added dropwise to the solution, and the solution was stirred at
ambient temperature for 1 h. The precipitate was collected by filtration and washed with water 2 mL, and
dried in vacuo at 50 oC to give a crystalline solid.
Chapter 5
105
4-Hydroxy-6-phenyl-5,6-dihydro-2H-pyran-2-one (4a): The title compound was prepared according to the
General Procedure, and isolated as an off-white solid (385.1 mg, 81% yield). mp 124 - 125 oC;
1H NMR (500
MHz, CDCl3) 2.80 - 3.00 (m, 2H), 3.49 (d, J = 18.9 Hz, 1H), 3.68 (d, J = 19.2 Hz, 1H), 5.71 (dd, J = 10.2,
3.6 Hz, 1 H), 7.33 - 7.52 (m, 5H). Analysis of the spectroscopic data matched reported data.13d
6,6'-Benzene-1,4-diylbis(4-hydroxy-5,6-dihydro-2H-pyran-2-one) (4b): The title compound was prepared
according to the General Procedure (p-terephthalaldehyde (3b) (167.7 mg, 1.25 mmol), Reformatsky reagent
(23.5 mL, 10 equiv), TMEDA (0.75 mL, 4 equiv) and isolated as an off-white solid (322.2 mg, 85% yield).
mp 180 - 181 oC;
1H NMR (500 MHz, DMSO-d6) 2.60 (dd, J = 17.3, 4.1 Hz, 2H), 2.83 (ddd, J = 17.2, 11.8,
1.6 Hz, 2H), 4.96 - 5.19 (m, 2H), 5.48 (dd, J = 12.0, 4.1 Hz, 2H), 7.50 (s, 4H), 11.58 (brs, 2H); 13
C NMR (125
MHz, DMSO-d6) 34.1, 75.8, 90.8, 126.5, 139.1, 166.6, 172.7; HRMS (ESI-Orbitrap) m/z Calcd for
[M+H]+ C16H14O6 303.0863; Found 303.0864.
Ethyl 3-(4-(4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)phenyl)-3-oxopropanoate (4c): The title
compound was prepared according to the General Procedure, and isolated as a white solid (557.7 mg, 73%
yield as keto-enol tautomers of the 3-oxopropanoate; the ratio of keto tautomer to enol tautomer is 9:1, as
judged by 1H NMR). mp 100 - 101
oC;
(keto tautomer)
1H NMR (500 MHz, DMSO-d6) 1.19 (t, J = 7.1 Hz,
3H), 2.61 - 2.73 (m, 1H), 2.75 - 2.88 (m, 1H), 4.13 (q, J = 6.9 Hz, 2H), 4.21 (s, 2H), 5.07 (brs, 1H), 5.52 -
5.63 (m, 1H), 7.64 (m, 2H), 8.00 (m, 2H), 11.54 - 11.77 (m, 1H); 13
C NMR (125 MHz, DMSO-d6) 13.9,
33.9, 45.5, 60.6, 75.4, 90.7, 126.5, 128.6, 135.5, 144.7, 166.4, 167.6, 172.5, 193.0. (enol tautomer) 1H NMR
(500 MHz, DMSO-d6) 1.28 (t, J = 7.1 Hz, 3H), 2.37 (m, 1H), 2.60 (s, 1H), 2.66 - 2.67 (m, 1H), 2.82 - 2.84
(m, 1H), 4.25 (q, J = 6.9 Hz, 2H), 5.60 (m, 1H), 5.99 (s, 1H), 7.56 - 7.60 (m, 1H), 7.67 - 7.68 (m, 1H), 7.89 -
7.93 (m, 2H), 12.62 (s, 1H); 13
C NMR (125 MHz, DMSO-d6) 14.0, 33.8, 60.3, 75.2, 87.5, 118.5, 127.1,
132.4, 136.5, 144.4, 166.1, 169.9, 172.6, 192.9. HRMS (ESI-Orbitrap) m/z Calcd for [M+H]+ C16H17O6
305.1020; Found 305.1022.
Chapter 5
106
4-(4-Hydroxy-6-oxo-5,6-dihydro-2H-pyran-2-yl)benzoic acid (4d): The title compound was prepared
according to the General Procedure, and isolated as a brownish white solid (461.0 mg, 79% yield). mp 212 -
213 oC (decompose);
1H NMR (500 MHz, DMSO-d6) 2.61 - 2.70 (m, 1H), 2.74 - 2.87 (m, 1H), 5.07 (d, J =
1.3 Hz, 1H), 5.41 - 5.64 (m, 1H), 7.61 (m, 2H), 7.99 (m, 2H), 11.53 - 11.77 (m, 1H), 12.86 - 13.10 (m, 1H);
13C NMR (125 MHz, DMSO-d6) 34.0, 75.5, 90.8, 126.3, 129.5, 130.6, 143.9, 166.4, 166.9, 172.6; HRMS
(ESI-Orbitrap) m/z Calcd for [M+H]+ C12H10O5 235.0601; Found. 235.0601
6-(4-Bromophenyl)-4-hydroxy-5,6-dihydro-2H-pyran-2-one (4e): The title compound was prepared
according to the General Procedure, and isolated as an off-white solid (548.3 mg, 82% yield). mp 125 - 126
oC;
1H NMR (500 MHz, CDCl3) 2.83 (dd, J = 18.4, 10.9 Hz, 1H), 2.95 (dd, J = 18.3, 3.2 Hz, 1H), 3.51 (d,
J = 19.2 Hz, 1H), 3.69 (d, J = 18.9 Hz, 1H), 5.67 (dd, J = 10.9, 3.3 Hz, 1H), 7.29 (m, 2H), 7.58 (m, 2H); 13
C
NMR (125 MHz, CDCl3) 45.1, 47.0, 75.8, 123.4, 127.5, 132.4, 135.6, 166.5, 198.8; HRMS (ESI-Orbitrap)
m/z Calcd for [M+H]+ C11H10BrO3 268.9808 (
79Br) and 270.9787 (
81Br); Found 268.9811 (
79Br) and
270.9790 (81
Br).
4-Hydroxy-6-(4-nitrophenyl)-5,6-dihydro-2H-pyran-2-one (4f): The title compound was prepared
according to the General Procedure, and isolated as an off-white solid (504.0 mg, 86% yield). mp 152 - 154 oC
(decompose); 1
H NMR (500 MHz, DMSO-d6) 2.71 (dd, J = 17.3, 4.4 Hz, 1H), 2.81 (ddd, J = 17.3, 11.7,
1.6 Hz, 1H), 5.04 - 5.13 (m, 1H), 5.60 - 5.71 (m, 1H), 7.75 (m, 2H), 8.28 (m, 2H), 11.70 (brs, 1H); 13
C NMR
(125 MHz, DMSO-d6) 33.9, 75.0, 90.8, 123.6, 127.5, 146.5, 147.3, 166.1, 172.5; HRMS (ESI-Orbitrap) m/z
Calcd for [M+H]+ C11H9NO5 236.0553; Found 236.0556.
4-Hydroxy-6-(thiophen-3-yl)-5,6-dihydro-2H-pyran-2-one (4g): The title compound was prepared
according to the General Procedure, and isolated as an off-white solid (230.3 mg, 47% yield). mp 118 - 119
oC;
1H NMR (500 MHz, CDCl3) 2.89 - 3.08 (m, 2H), 3.44 (d, J = 19.2 Hz, 1H), 3.61 (d, J = 19.2 Hz 1H),
5.78 - 5.84 (m, 1 H), 7.12 (dd, J = 5.0, 1.6 Hz, 1H), 7.32 - 7.36 (m, 1H), 7.42 (dd, J = 5.0, 2.8 Hz, 1H); 13
C
Chapter 5
107
NMR (125 MHz, CDCl3) 44.1, 47.0, 72.9, 123.0, 125.3, 127.7, 137.8, 166.8, 199.3; HRMS (ESI-Orbitrap)
m/z Calcd for [M+H]+ C9H8O3S 197.0267; Found 197.0266.
4-Hydroxy-6-[(E)-2-phenylethenyl]-5,6-dihydro-2H-pyran-2-one (4h): The title compound was prepared
according to the General Procedure, and isolated as an off-white solid (370.3 mg, 69% yield). mp 118 - 119
oC;
1H NMR (500 MHz, CDCl3) 2.74 (dd, J = 18.3, 9.8 Hz, 1H), 2.88 (dd, J = 18.3, 3.5 Hz, 1H), 3.50 (d, J =
19.2 Hz, 1H), 3.60 (d, J = 19.2 Hz, 1H), 5.34 (d, J = 1.6 Hz, 1H), 6.23 (dd, J = 15.8, 6.0 Hz, 1H), 6.71 - 6.81
(m, 1H), 7.28 - 7.44 (m, 5H); 13
C NMR (125 MHz, CDCl3) 43.5, 47.1, 75.4, 123.8, 126.8, 126.9, 128.8,
128.9, 134.3, 135.1, 166.8, 199.3; HRMS (ESI-Orbitrap) m/z Calcd for [M+H]+ C13H13O3 217.0859; Found
217.0860.
4-Hydroxy-6-(2-phenylethyl)-5,6-dihydro-2H-pyran-2-one (4i): The title compound was prepared
according to the General Procedure, and isolated as an off-white solid (366.0 mg, 59% yield). mp 100 - 101
oC;
1H NMR (500 MHz, CDCl3) 2.01 (dddd, J = 14.4, 8.9, 7.6, 4.1 Hz, 1H), 2.18 (m, 1H), 2.51 (dd, J = 18.3,
11.7 Hz, 1H), 2.69 (dd, J = 18.3, 2.5 Hz, 1H), 2.80 - 2.88 (m, 1H), 2.88 - 2.97 (m, 1H), 3.44 (d, J = 18.9 Hz,
1H), 3.55 (d, J = 18.6 Hz, 1H), 4.59 (m, 1H), 7.19 - 7.26 (m, 3H), 7.30 - 7.36 (m, 2H); 13
C NMR (125 MHz,
CDCl3)30.8, 36.2, 43.6, 47.1, 74.3, 126.5, 128.5, 128.8, 140.0, 167.1, 199.7; HRMS (ESI-Orbitrap) m/z
Calcd for [M+H]+ C13H15O3 219.1016; Found 219.1015.
4-Methoxy-6-[(E)-2-phenylethenyl]-5,6-dihydro-2H-pyran-2-one ((±)-Kavain) (Scheme 3): To a 25 mL
round-bottom flask were added 4-Hydroxy-6-[(E)-2-phenylethenyl]-5,6-dihydro-2H-pyran-2-one (4h) (216.1
mg, 1.0 mmol), powdered potassium carbonate (276.4 mg, 2.0 mmol, 2.0 equiv), dimethyl sulfate (190 L, 2.0
mmol, 2.0 equiv) and acetone (2 mL). The reaction mixture was stirred at ambient temperature overnight
and then diluted with EtOAc (10 mL). The solution was washed with 0.5 N aq HCl (10 mL). The aqueous
layer was extracted with EtOAc (4 mL X 2). The combined organic layer was concentrated in vacuo to give
the crude solid. The crude solid was purified by flash chromatography (50% EtOAc/Hexane) to give the title
Chapter 5
108
compound as an off-white solid (178.8 mg, 78% yield). mp 145 - 146 oC;
1H NMR (500 MHz, CDCl3) 2.55
(dd, J = 17.2, 4.3 Hz, 1H), 2.67 (ddd, J = 17.0, 10.7, 1.6 Hz, 1H), 3.77 (s, 3H), 5.07 (dddd, J = 10.6, 6.2, 4.4,
1.6 Hz, 1H), 5.20 (d, J = 1.6 Hz, 1H), 6.23 - 6.30 (m, 1H), 6.71 - 6.77 (m, 1H), 7.26 - 7.30 (m, 1H), 7.31 -
7.36 (m, 2H), 7.37 - 7.41 (m, 2H); HRMS (ESI-Orbitrap) m/z Calcd for [M+H]+ C14H15O3 231.1016; Found
231.1015. Analysis of the spectroscopic data matched reported data.3e,4g
4-Methoxy-6-[(E)-2-(4-methoxyphenyl)ethenyl]-2H-pyran-2-one (Yangonin) (Scheme 4): To a 100 mL
round-bottom flask were added ethyl bromozincacetate (THF solution) (23.5 mL, ca. 12.5 mmol, 5 equiv),
TMEDA (0.75 mL, 5 mmol, 2.0 equiv) and 4-Methoxycinnamaldehyde (3j) (406.0 mg, 2.5 mmol, 1.0 equiv).
The yellow solution was warmed to 50 oC and stirred for 5 h. After cooling to ambient temperature, the
mixture was diluted with EtOAc (50 mL). The solution was successively washed with 20% aq citric acid (25
mL), 10% aq NaCl (25 mL), 5% aq NaHCO3 (25 mL) and water (25 mL). The organic layer was concentrated
in vacuo to give an orange oil. Methanol (2 mL) and powdered potassium carbonate (862.5 mg, 6.3 mmol, 2.5
equiv) were added to the oil, and the mixture was warmed to 50 oC and stirred for 3 h. After cooling to
ambient temperature, the mixture was concentrated in vacuo. Acetone (2 mL) and dimethyl sulfate (597 L,
6.3 mmol, 2.5 equiv) were added to the mixture, and the mixture was stirred at ambient temperature overnight.
The mixture was diluted with EtOAc (24 mL). The solution was neutralized with 0.5 mol/L aq HCl. The
aqueous layer was separated and washed with ethyl acetate (4 mL x 2). The combined organic layer was
concentrated in vacuo. THF (8 mL) and DDQ (483.2 mg, 2.2 mmol, 0.9 equiv) were added to the mixture, the
mixture was stirred reflux for 30 min (HPLC assay yield: 87%). After cooling to ambient temperature, the
mixture was concentrated in vacuo. Toluene (20 mL) was added to the mixture, and the mixture was warmed
to 100 oC and stirred for 1.5 h. After cooling to ambient temperature, the precipitates were filtered off. The
filtrate was concentrated in vacuo. The crude oil was purified by flash chromatography (EtOAc/Hexane) to
give the title compound as an orange solid (303.5 mg, 47% yield). mp 152 - 153 oC;
1H NMR (500 MHz,
CDCl3) 3.81 (s, 3H), 3.83 (s, 3H), 5.46 (d, J = 2.5 Hz, 1H), 5.89 (d, J = 2.2 Hz, 1H), 6.44 (d, J = 16.1 Hz,
Chapter 5
109
1H), 6.87 - 6.92 (m, 2H), 7.40 - 7.47 (m, 3H). HRMS (ESI-Orbitrap) m/z Calcd for [M+H]+ C14H15O3
259.0965; Found 259.0962. Analysis of the spectroscopic data matched reported data. 3e
Chapter 5
110
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Chapter 5
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Chapter 5
112
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Chapter 5
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J. Am. Chem. Soc. 1994, 116, 6989
15. Mors, W. B.; Gottlieb, O. R.; Djerassi, C. J. Am. Chem. Soc. 1957, 117, 4507.
Chapter 5
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16. For the pioneering works, see: (a) Huckin, S. N.; Weiler, L. Can. J. Chem. 1974, 52, 2157. (b) Huckin, S.
N.; Weiler, L. Tetrahedron Lett. 1971, 50, 4835. (c) For a review see: Langer, P. Friberg. W. Chem. Rev.
2004, 104, 4125.
17. Mineno, M.; Sawai, Y.; Kanno, K.; Sawada, N.; Mizufune, H. J. Org. Chem. 2013, 78, 5843.
18. Hydrolysis of -ketoesters was hardly observed.
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List of publications
1. Rapid access to diverse -carbolines through sequential transition metal catalyzed amination and
direct C-H Arylation
Masahiro Mineno, Misayo Sera, Tsuyoshi Ueda, Masahiro Mizuno, Mitsuhisa Yamano, Hideya Mizufune,
Atsuhiko Zanka.
Tetrahedron 2014, 70, 5550.
(Chapter 2)
2. Integrated Cross-Coupling Strategy for -Carboline-Based Aurora B Kinase Inhibitor
Masahiro Mineno, Misayo Sera, Tsuyoshi Ueda, Hideya Mizufune, Atsuhiko Zanka, Colin O'Bryan, Jason
Brown, Nick Scorah.
J. Org. Chem. 2015, 80, 1564.
(Chapter 3)
3. Double Reformatsky Reaction: Divergent Synthesis of -Hydroxy--Ketoesters
Masahiro Mineno, Yasuhiro Sawai, Kazuaki Kanno, Naotaka Sawada, Hideya Mizufune.
J. Org. Chem. 2013, 78, 5843.
(Chapter 4)
4. A rapid and diverse construction of 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones through double
Reformatsky Reaction
Masahiro Mineno, Yasuhiro Sawai, Kazuaki Kanno, Naotaka Sawada, Hideya Mizufune.
Tetrahedron 2013, 69, 10921.
(Chapter 5)
116
Other publications
1. A General and Straightforward Route toward Diarylmethanes. Integrated Cross-Coupling Reactions
Using (2-Pyridyl)silylmethyl stannane as an Air-Stable, Storable, and Versatile Coupling Platform
Itami, K.; Mineno, M.; Kamei, T.; Yoshida, J.
Org. Lett. 2002, 4, 3635.
2. AgOAc catalyzed Aldehyde Allylation Using Allyldimethyl(2-pyridyl)silane
Itami, K.; Kamei, T.; Mineno. M.; Yoshida, J.
Chem. Lett. 2002, 1086.
3. Sequential Assembly Strategy for Tetrasubstituted Olefin Synthesis Using Vinyl 2-Pyrimidyl Sulfide as a
Platform
Itami, K.; Mineno, M.; Muraoka, N.; Yoshida, J.
J. Am. Chem. Soc. 2004, 126, 11778.
4. Rapid Synthesis of CDP-840 with 2-Pyrimidyl Vinyl Sulfide as a Platform
Muraoka, N.; Mineno, M.; Itami, K.; Yoshida, J.
J. Org. Chem. 2005, 70, 11778.
5. Iron-Catalyzed Cross-Coupling of Alkenyl Sulfides with Grignard Reagents
Itami, K.; Higashi, S.; Mineno, M.; Yoshida, J.
Org. Lett. 2005, 7, 1219.
117
List of patents
1. Alpha-Carboline Derivative and Methods for Preparation Thereof
Masahiro Mizuno, Hideya Mizufune, Misayo Sera, Masahiro Mineno, Tsuyoshi Ueda.
WO 2008016184.
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119
Acknowledgement
The author would like to express his sincerest gratitude to Professor Seiji Suga for his nice guidance,
valuable discussions, and warm encouragement throughout this work.
The studies presented in this thesis have been carried out during 2006-2012 at the Chemical Development
Laboratories, CMC Center, Takeda Pharmaceutical Company Limited. The author is greatly indebted to Dr.
Hideya Mizufune and Dr. Atsuhiko Zanka. The author would also like to express his acknowledgement to
Professor Jun-ichi Yoshida of Kyoto University and Professor Kenichiro Itami of Nagoya University.
Finally, the author expresses his deep appreciation to his parents, Kiyoshi Mineno and Taeko Mineno and
his wife, Rie Mineno, for their affectionate encouragement through this work.