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University of Groningen
Carbon-carbon bond formations using organolithium reagentsHeijnen, Dorus
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Chapter 7 : Oxygen Activated, Palladium
Nanoparticle Catalyzed, Ultrafast Cross-Coupling
of Organolithium Reagents and its Application in
Nuclear Medicine
Part of this chapter was published in : D. Heijnen, F. Tosi, C. Vila, M. C. A. Stuart,
P. H. Elsinga, W. Szymanski and B. L. Feringa. Angew.Chem. Int. Ed. 2017, 56,
3354-3359
Abstract : The discovery of an ultrafast cross-coupling of alkyl- and aryllithium reagents with a range
of aryl bromides is described in this chapter. The essential role of molecular oxygen to form the
active palladium catalyst was established; palladium nanoparticles that are highly active in cross-
coupling reactions with reaction times ranging from 5 s to 5 min are thus generated in situ. High
selectivities were observed for a range of heterocycles and functional groups as well as for an
expanded scope of organolithium reagents. The applicability of this method was showcased by the
synthesis of the [11C]-labeled PET tracer Celecoxib.
7.1 Introduction
Transition-metal-catalyzed cross-couplings of organometallic reagents have found
widespread application in the synthesis of pharmaceutical products and organic materials,
including the formation of important functionalized heterocycles.[1] Despite their prominent
role in the modern synthetic repertoire, it remains of considerable interest to shorten
reaction times, apply milder conditions, use less expensive starting materials, reduce catalyst
loadings and trace residual metals in the desired product, and to minimize the amount of
toxic waste. We have recently reported the direct cross-coupling of alkyl-, alkenyl-, and
aryllithium reagents with a wide range of (pseudo)halogenated aryl and alkenyl electrophiles
catalyzed by either palladium or nickel complexes.[2] These organolithium-based methods
typically show cross-coupling with enhanced speed (<1h), operate at mild temperatures (in
most cases room temperature), and produce lighter and less toxic stoichiometric waste (LiX).
Reactions with excellent chemoselectivity were initially achieved by slow addition of the
highly reactive lithium reagent.[2] Typically, commercially available unaltered complexes
were employed, including Pd/PEPPSI, Pd(PtBu3)2 (C1), or Pd/dba/XPhos, which are also
prominent catalysts in closely related transformations, such as Negishi or Suzuki cross-
coupling reactions.[3]
We envisioned that the exceptional reactivity and versatility of organolithium
reagents could be taken advantage of in developing a fast cross-coupling that proceeds
under ambient conditions, especially in light of the major current interest and important
advances in fast cross-coupling reactions under mild conditions.[4] To the best of our
knowledge, the very recently published procedure by the group of Schoenebeck, based on
the use of Grignard and organozinc reagents (Figure 7.1) stands out in terms of short
reaction times.[5]
Figure 7.110 Recent fast cross-coupling reactions
Herein, we present the discovery of an ultrafast cross-coupling with organolithium reagents.
In stark contrast to the common practice of rigorously excluding oxygen when working with
such extremely reactive organometallic reagents, we have found that molecular oxygen is
essential to form the active catalyst. Under our conditions, rapid C-C bond formation occurs
within seconds to minutes at room temperature while catalyst speciation studies point to
the involvement of 2-3 nm large Pd nanoparticles. Using this new procedure, chemoselective
cross-coupling reactions with organolithium reagents now include an expanded range of
heterocycles, functional groups, and organolithium compounds. Furthermore, it provides a
versatile method for isotope labeling, that is, for introducing -CD3 labels and short-lived 11C
radioisotopes (t½(11C)=20.3min) for PET imaging.
7.2 Oxygen activation
In preliminary experiments, we used the cross-coupling of methyllithium and 1-
bromonaphthalene in the presence of Pd(PtBu3)2 (C1, 5 mol %) at room temperature to test
whether very short reaction times with full conversion would be possible (Scheme 7.1)
Under presumably identical conditions, we were puzzled to observe greatly varying results.
Scheme 7.1 Optimization of fast cross-coupling
After eliminating many potential causes (variations in the concentration of the reagents,
light, temperature, the presence of salts, water, or trace metal impurities), we established
that minute traces of air were essential for catalyst activation. Samples briefly purged with
dry oxygen prior to MeLi addition always gave complete and chemoselective conversion into
1-methylnaphthalene. The lack of reactivity observed after adding degassed water or when
employing strictly oxygen-free conditions supported the notion that the presence of oxygen
greatly enhanced the catalytic activity of the system, leading to optimized reaction
conditions with catalyst C1 after short oxygen purging, and allowing for catalyst oxidation for
10 min.
7.3 Scope
Under the optimized conditions, an extended range of organolithium and aryl bromide
reagents, compared to our previously reported method,[2] underwent highly selective
coupling, providing excellent yields in 2-5 min at room temperature (Table 7.1). Substrates
from the naphthalene (2a-3f) and anthracene families (4a) gave good yields with near-
perfect selectivity when coupled with a variety of commercially available organolithium
reagents.
Gratifyingly, identical results were achieved with both electron-poor and electron-rich
substrates (5a-8a). Unwanted side reactions were suppressed with near-perfect selectivity
for C-Br over C-Cl in aromatic and aliphatic substrates with competitive coupling possibilities
(9a-11a), while aryl bromides 12a-15a, including CF3-substituted analogue 16a, gave
selectivities similar to those of the naphthalene substrates.[6] Remarkably, the fast coupling
of RLi can even be used when an epoxide functional group is present at a temperature as
low as -10°C, where the expected epoxide ring opening by the organolithium reagent is
effectively suppressed, to provide the desired coupling product 17a. Importantly, alcohols
18a-20a, including an unprotected phenol, provided the corresponding products in good
yields, albeit with a larger excess of organolithium reagent. Novel substrates were also found
amongst heterocycles 21a-26a.
The direct lithiation of inexpensive, commercially available ferrocene is well described in the
literature,[7] and the corresponding nucleophile provides an alternative to the less available
and costly boron or halide derivatives to yield 27a and 28a. Finally, aryllithium reagents
synthesized via lithium--halogen exchange (e.g., 3-anisyllithium) also proved to be suitable
coupling partners, providing biaryl 29a.
Table 7.1 Fast cross-coupling of (hetero)aryl bromides with organolithium reagents.
Reaction conditions: Substrate : 0.6 mmol in 4 ml toluene, 5 mol% catalyst, 4 ml oxygen, 1.5 eq (0.9 mmol)
organolithium reagent. All reactions were carried out at rt. Yields refer to isolated yields after column
chromatography unless noted otherwise. a) Reaction performed at 0 °C; b) Performed with 2.5 eq of
organolithium at 40 °C; c) Conversion determined by GCMS analysis; d) Reaction performed with 1 eq of n-BuLi
at -10 °C; e) Reaction performed with 2.5 eq of organolithium reagent.
The reaction time of the coupling between nBuLi and 1-bromonaphthalene could be reduced
to just 5s at room temperature with 5 mol% of the precatalyst, giving full conversion and a
turnover frequency of 14×103h-1 (Table 7.2 entry 1), provided that an excess of oxygen was
present with respect to Pd complex C1. With a catalyst loading of 0.05 %, we were able to
fully convert 1 on gram scale in just 10 min. On the other hand, by reducing the rate of
addition of nBuLi, we were able to use a catalyst loading as low as 0.025 mol % (entry 2-5). A
slightly higher catalyst loading was necessary for the coupling of 4-bromoanisole (entry 6).
Table 7.2 Screening of catalyst loading
Entry C1 (mol%) Addition time Conv.
1 5 5 sec Full
2 0.5 2 min Full
3 0.05 10 min Full
4 0.025 10 min 40
5 0.025 30 min Full
6 0.05a 30 min Full
All experiments were conducted at rt in toluene (0.15 M initial concentration of the substrate), entries 1 and 2
were conducted on 0.3 mmol scale, entries 3-6 on a 12 mmol (2.5 g) scale. Conversions were determined by
GCMS analysis. a) 4-Br-anisole was used as substrate.
7.4 Active catalyst investigation
Focusing on the crucial role of molecular oxygen, we observed that the catalyst solution
turned red upon purging with O2, suggesting that Pd(PtBu3)2 (C1) was converted into the
active catalyst. Many d10 metal complexes are known to rapidly interact with O2 to form
stable η2-peroxo complexes; however, C1 has not been reported as one of them.[8] The
reason for its stability towards O2 was attributed to the extreme bulkiness of the ligands,
which shield the Pd and hence hamper its oxidation. Therefore, the sterically hindered C1
complex needs prolonged oxygen exposure at room temperature to ensure complete
oxidation. To investigate whether known peroxo complexes could be excluded as possible
catalysts, we tested the η2-peroxo derivatives of Pd(PCy3)2 and Pd(PPh3)2,[5] which did not
show any catalytic activity (see the experimental section). Extensive 1H and 31PNMR studies
with catalytically inactive C1 prior to and after exposure to oxygen revealed the formation of
free PtBu3 (see Experimental Section), phosphine oxides, and (yet unidentified) oxidized Pd
species (C1ox) upon reaction with O2.[9,10]
The hypothesis that the monoligated [Pd(PtBu3)] complex, arising from dissociation of one
phosphine from the starting complex, acted as the active catalyst was excluded on the basis
of the lack of reactivity with aryl chlorides and inhibition experiments by adding an excess of
PtBu3 (up to 10 equiv, see Experimental Section), which had no effect on the outcome of the
cross-coupling, suggesting a different active species.[5,11,12]
We were able to isolate the oxidized form (C1ox) of C1 by washing the residue of the
oxidation step with acetonitrile (see Experimental Section). Addition of 4-bromoanisole to
C1ox at room temperature showed no change at all by NMR analysis, which led to the
conclusion that up until the addition of the organolithium reagent, no reaction is taking
place.[13] Given the fast cross-coupling and the lack of any reaction between C1 or C1ox and
the electrophile, we next tested whether the organolithium reagent initiates the catalytic
cycle by generation of the active Pd species. Upon stoichiometric addition of nBuLi to a
[D8]toluene solution of C1ox, some of the Pd species were reduced to form again catalytically
inactive C1, and stoichiometry indicates the formation of another Pd0 species, presumably
the active catalyst (see below). Important information came from independent experiments
with the bridged dinuclear PdI complex C2 (Scheme 7.1), which is also a catalyst precursor in
our cross-coupling. Oxidation of C2 occurs within seconds at room temperature, although we
found that the product C2ox arising from this reaction was not consistent with the one
described in the literature (see the Supporting Information).[14] Both C2 and C2ox gave full
conversion in cross-couplings with RLi reagents. The oxidation of C2 and subsequent
reduction of C2ox by nBuLi was studied in detail by 31P NMR spectroscopy (Figure 7.2),
showing, much to our surprise, partial formation of mononuclear complex C1, which we
knew to be catalytically inactive.
Figure 7.2 31
P-NMR Spectra of C2 in tol-d8 (a), after O2 exposure (b,c), and n-BuLi addition (d)
The lithium reagent promotes reduction from PdI to Pd0 and the formation of both
Pd(PtBu3)2 (C1) and Pd0, which becomes evident from the observed stoichiometry (NMR
analysis, see the Supporting Information) of the complexes and ligands (Scheme 7.2).
Scheme 7.2 Reduction of C2 with R-Li
Following the cross-coupling reaction of 4-bromoanisole by NMR spectroscopy, we also
observed the in situ formation of the bridged complex C2 from C1ox after RLi addition (in
accordance with previous observations by Schoenebeck using Grignard reagents),[5] for
which we suggest the stoichiometry shown in Scheme 7.3.
Scheme 7.3 Schematic in situ formation of C2 from C1ox
The combined results of the RLi addition experiments with C1ox, C2, and C2ox, which clearly
showed reduction in all cases, led to the hypothesis that a common active species, that is, Pd
nanoparticles (PdNPs), are formed in situ. TEM measurements were carried out to
investigate the presence of nanoparticles in samples of C1 and C1ox prior to RLi addition, but
in neither case, any PdNPs were observed. Studying the effect of the addition of the lithium
reagent to C1ox, we clearly observed PdNPs with dimensions of 2—3 nm (Figure 7.3).
Figure 7.3 TEM image and corresponding EDX spectrum of PdNPs
In a highly informative set of experiments, under optimized cross-coupling conditions and
with all previously mentioned precatalysts (C1ox, C2, and C2ox), samples were taken both
during and at the end of the reaction, and analyzed by TEM for the in situ formation of
nanoparticles (Figure 7.3). We were pleased to see the formation of nanoparticles in all
cases where product was formed. Energy-dispersive X-ray analysis (EDX)[15] revealed the
elemental compositions of the samples, and clearly showed an increase in the Pd/P ratio
with respect to catalytically inactive complexes, supporting the formation of PdNPs. Isolation
of these nanoparticles was successful by centrifugation and repeated washing with toluene,
and the absence of homogeneous Pd complexes was confirmed by 1H and 31P NMR
spectroscopy. Fast cross-coupling reactions of organolithium reagents with the isolated
nanoparticles were successful, strongly supporting the involvement of PdNPs as the active
catalyst.
Scheme 7.4 Proposed catalyst activation pathway
Based on the experimental data, the catalyst activation pathway shown in Scheme 7.4 is
proposed. PdNPs are known to be formed from PdII sources under reductive conditions.[16] In
our system, O2 reacts first with the Pd0 complex, thereby oxidizing it to C1ox (Scheme 7.4a)
which is then in situ reduced to highly active Pd0 nanoparticles by means of the
organolithium reagent, either directly (b) or via C2/C2ox. The striking difference of the novel
catalytic system presented here, compared to other PdNP-catalyzed cross-coupling
reactions,[17] is the ultrafast cross-coupling of organolithium reagents, which can be
explained by the in situ formation of numerous small (2-3 nm) Pd nanoparticles.
7.5 Application in the coupling of 11C and the synthesis of Celecoxib
The benefits of the ultrafast coupling presented here can best be exploited in reactions
where time restrictions are crucial. Therefore, we focused on the cross-coupling of
[11C]methyllithium (t½(11C)=20 min) for PET labeling.[1,18,19] Such a method would be
complementary to the more often used electrophilic quenching of a nucleophilic drug
precursor with [11C]iodomethane. The presence of several nucleophilic sites in specific
precursors often results in undesired (overalkylated) side products. We selected the
synthesis of [11C]celecoxib to illustrate the usefulness of our method (Scheme 7.5).[20,21]
Scheme 7.5 Synthesis of radiolabelled Celecoxib
Initially, we explored the reaction of commercially available MeLi and celecoxib precursor
30. Having isolated the target 31 in excellent yield (91 %), we used in situ generated MeLi,
prepared from MeI in both a stoichiometric and a substoichiometric (0.1 equiv) ratio with
respect to nBuLi.[18] Gratifyingly, we were able to isolate the corresponding product by
preparative HPLC in good yield (85 %) with respect to the MeI starting material.
With a representative result for the radiolabeling based on the use of substoichiometric MeI
in hand, the synthesis of [11C]celecoxib (31*; coupling time 2 min, total preparation time
including HPLC purification <15 min) was pursued. The final decay-corrected radiochemical
yield for 31* was found to be 65 % (average of three runs).
For further application in isotope labelling, we considered the direct incorporation of the -
CD3 moiety in organic compounds. The use of deuterated MeI is desirable from a cost
perspective, and its use with a range of electrophiles has recently been shown by Hu et al.[22]
Since the reported procedure requires a large excess of the costly CD3I (3.5 eq) we
anticipated that our method using in situ generated CD3Li could provide a viable alternative
(Scheme 7.6). As we had already converted unlabeled MeI into MeLi, as well as the [11C]-
analogue using n-BuLi and successfully applied it in cross-coupling, an identical experimental
setup for CD3I was used. Much to our surprise, no CD3-incorporation could be observed in
either a cross-coupling reaction, or electrophilic quench with benzaldehyde.[23,24] Switching
to tBuLi gave the desired CD3Li, which coupled readily with 2-Br-naphthalene to provide 2a-
d3 in 65 % yield, establishing a new method for the incorporation of the -CD3 moiety.
Scheme 7.6 Cross-coupling of MeLi-d3
7.6 Conclusions and outlook
In conclusion, a novel procedure for the rapid palladium-catalyzed coupling of alkyl-
and aryllithium reagents has been developed, with a crucial role for O2 in generating the
active catalyst. Systematic studies towards the active catalyst species revealed the formation
of palladium nanoparticles for all three active precatalysts upon addition of the
organolithium reagent, which facilitates rapid cross-couplings with a range of aryl bromides
at room temperature. The application of this novel method was showcased in the coupling
of [11C]methyllithium in less than two minutes with a decay-corrected yield of 65 % as a key
step in the synthesis of the PET tracer celecoxib.
Acknowledgements
This work described in this chapter was carried out together with Filippo Tosi. Initial studies were
peformed by Dr. Carlos Vila.
7.7 Experimental section General methods:
All reactions were carried out under a nitrogen atmosphere using oven dried glassware and using
standard Schlenk techniques unless noted otherwise. THF and toluene were dried using an SPS-
system. White colored Pd[P(tBu)3]2, was purchased from Strem chemicals and stored under nitrogen
at -25 ºC. Pure [PdBrP(tBu)3]2 was purchased from Strem chemicals, used in a glovebox and stored at
-35 ºC. All alkyllithium reagents and aryl bromides were purchased from Aldrich or TCI and used
without further purification, unless noted otherwise.
Chromatography: Merck silica gel type 9385 230-400 mesh, TLC: Merck silica gel 60, 0.25 mm, or
Grace-Reveleris purification system with Grace cartridges. Components were visualized by UV and
cerium/molybdenum or potassium permanganate staining. Progress and conversion of the reaction
were determined by GC-MS (GC, HP6890: MS HP5973) with an HP1 or HP5 column (Agilent
Technologies, Palo Alto, CA). PREP-HPLC was perfomed on a Grace-reveleris PREP with a 5 u Denali C-
18 (15 cm, 10 mm id). Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or a
LTQ Orbitrap XL (ESI+). 1H- and 13C-NMR were recorded on a Varian AMX400 (400 and 100.59 MHz,
respectively) or a 600 MHz (600 and 125 MHz, respectively) using CDCl3 as solvent, unless noted
otherwise. Chemical shift values are reported in ppm with the solvent resonance as the internal
standard (CHCl3: 7.26 for 1H, 77.0 for 13C) unless noted otherwise. Data are reported as follows:
chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet),
coupling constants (Hz), and integration.
Samples for TEM and cryo-TEM were analized on graphene grids (Graphene Supermarket). For cryo-
TEM analysis, the grids were vitrified in liquid nitrogen (Vitrobot, FEI, Eindhoven, The Netherlands)
and transferred to a Tecnai T20 cryo-electron microscope operating at 200 kV. EDX analysis was
performed with a EDX Oxford xmax instrument, and the elemental ratio was calculated via INCA
software.
General Procedures for the oxygen activated cross-coupling of organolithium reagents with aryl
bromides
Method A: General procedure for the cross-coupling with organolithium reagents.
In a dry Schlenk flask Pd(PtBu3)2 (5 mol%, 0.03 mmol, 15,3 mg) and the aryl bromide (0.6 mmol) were
dissolved in 4 mL of dry toluene at room temperature. The mixture was slowly purged with 10 ml of
pure oxygen and stirred for 1 min, upon which the color changed from slightly yellow to dark orange.
The corresponding alkyl or aryllithium reagent (1.5 eq) was diluted with toluene to reach 2.0 mL; this
solution was added over 2 min (alkyl) or 5 min (aryl) by the use of a syringe pump After the addition
was completed, the reaction was quenched with 0.5 mL of MeOH, and Celite was added to the
reaction mixture. The solvent was evaporated under reduced pressure to afford the crude product
on Celite which was purified by column chromatography.
Method B: General procedure for the cross-coupling with organolithium reagents at lower
temperature
In a dry Schlenk flask Pd(PtBu3)2 (5 mol%, 0.03 mmol, 15,3 mg) and the aryl bromide (0.6 mmol) were
dissolved in 4 mL of dry toluene at room temperature. The mixture was slowly purged with 10 ml of
pure oxygen and stirred for 1 min at rt, upon which the color changed from slightly yellow to dark
orange. Then, the reaction vessel was cooled to the corresponding temperature by means of an ice
batch. The corresponding alkyl or aryllithium reagent (1.5 eq) was diluted with toluene to reach 2.0
mL; this solution was added over 2 min (alkyl) or 5 min (aryl) by the use of a syringe pump. After the
addition was completed, the reaction was quenched with 0.5 mL of MeOH, and Celite was added to
the reaction mixture. The solvent was evaporated under reduced pressure to afford the crude
product on Celite which was purified by column chromatography.
Method C: General procedure for the cross-coupling with alkyllithium reagents in the presence of
acidic groups
In a dry Schlenk flask Pd(PtBu3)2 (5 mol%, 0.03 mmol, 15,3 mg) and the aryl bromide (0.6 mmol) were
dissolved in 4 mL of dry toluene at room temperature. The mixture was slowly purged with 10 ml of
pure oxygen and stirred for 1 min, upon which the color changed from slightly yellow to dark orange.
The corresponding alkyl or aryllithium reagent (1.5 eq) was diluted with toluene to reach 4.0 mL; this
solution was added over 2 min (alkyl) or 5 min (aryl) by the use of a syringe pump After the addition
was completed, the reaction was quenched with 0.5 mL of MeOH, and Celite was added to the
reaction mixture. The solvent was evaporated under reduced pressure to afford the crude product
on Celite which was purified by column chromatography.
Method D: General procedure for the cross-coupling with alkyllithium reagents for large scale and
low catalyst loading
In a dry Schlenk flask Pd(PtBu3)2 (0,025 - 5 mol%) and the aryl bromide (0.6 -12 mmol) were dissolved
in dry toluene (4 – 80 ml) at room temperature. The mixture was slowly purged with 20 ml of pure
oxygen and stirred overnight to ensure complete oxidation of the precatalyst, upon which the color
changed from slightly yellow to (dark) orange. In view of safety, excess oxygen was removed from
the headspace by 2-3 careful vacuum/nitrogen cycles for the large scale reactions. The corresponding
commercial alkyllithium (1.5 eq.) reagent was diluted with toluene (2 - 25 ml); this solution was
added by the use of a syringe pump (2 – 30 min). After the addition was completed, the reaction was
quenched with MeOH, and conversion checked by GCMS analysis
Experimental data of compounds 2a-29a:
2-methylnaphthalene (2a): Synthesized according to Method A. [68 mg, 80% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.8
Hz, 1H), 7.80 (dd, J = 8.1, 4.1 Hz, 2H), 7.66 (s, 1H), 7.53-7.43 (m, 2H), 7.37 (d, J = 8.3 Hz, 1H), 2.57 (s,
3H) ppm. 13C NMR (100 MHz, CDCl3) δ 135.5, 133.7, 131.7, 128.1, 127.7, 127.6, 127.3, 126.9, 125.9,
124.5, 21.7 ppm. The physical data were identical in all respects to those previously reported. 1
2-phenylnaphthalene (2b): Synthesized according to Method A. [95 mg, 78% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3)) δ 8.10 (s, 1H),
7.99 – 7.89 (m, 3H), 7.80 (td, J = 8.6, 8.1, 1.3 Hz, 3H), 7.59 – 7.50 (m, 4H), 7.47 – 7.40 (m, 1H). 13C
NMR (101 MHz, CDCl3) δ 141.25, 138.69, 133.82, 132.75, 128.98, 128.54, 128.33, 127.77, 127.56,
127.47, 126.41, 126.05, 125.93, 125.72. The physical data were identical in all respects to those
previously reported. 2
2-butylnaphthalene (2c): Synthesized according to Method A. [101 mg, 91% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3)) δ 7.97 – 7.83
(m, 3H), 7.71 (s, 1H), 7.61 – 7.47 (m, 2H), 7.43 (d, J = 8.4 Hz, 1H), 2.88 (t, J = 7.7 Hz, 2H), 1.80 (p, J =
7.6 Hz, 2H), 1.61 – 1.37 (m, 2H), 1.07 (t, J = 8.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 143.15, 136.42,
134.70, 130.47, 130.34, 130.20, 130.15, 129.04, 128.54, 127.72, 38.57, 36.30, 25.17, 16.76. The
physical data were identical in all respects to those previously reported. 1
2-(sec-butyl)naphthalene (2d): Synthesized according to Method A. [97 mg, 88% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3)) δ 7.96 – 7.82
(m, 3H), 7.71 – 7.68 (m, 1H), 7.58 – 7.46 (m, 2H), 7.43 (dd, J = 8.5, 1.8 Hz, 1H), 2.85 (h, J = 7.0 Hz, 1H),
1.85 – 1.71 (m, 2H), 1.42 (d, J = 7.0 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
147.82, 134.92, 130.61, 130.56, 130.30, 130.27, 128.61, 128.49, 127.93, 127.74, 44.56, 33.79, 24.62,
15.04.The physical data were identical in all respects to those previously reported. 3
trimethyl(naphthalen-2-ylmethyl)silane (2e): Synthesized according to Method A. [120 mg, 93%
yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz,
CDCl3)) δ 7.82 (dt, J = 7.7, 1.1 Hz, 1H), 7.79 – 7.73 (m, 2H), 7.49 – 7.38 (m, 3H), 7.21 (dd, J = 8.3, 1.8
Hz, 1H), 2.30 (s, 2H), 0.07 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 140.95, 136.53, 133.69, 130.58, 130.26,
130.18, 129.67, 128.42, 127.82, 127.00, 30.06, 0.89. The physical data were identical in all respects to
those previously reported. 4
2-(methyl-d3)naphthalene (2e-d3) Synthesized according to Method A. [57 mg, 65% yield].
Preparation of methyllithium-d3: MeI-d3 (1,5 eq. 0,9 mmol, 56 ul) was added dropwise to a stirred
solution of tBuLi (2.2 eq. 2 mmol in Hexane) in THF (1 ml) at -78 °C. The reaction mixture was allowed
to reach room temperature, diluted with toluene (up to 5 mL) and used as such. 1H NMR (400 MHz,
CDCl3) δ 7.77 (d, J = 7.5 Hz, 1H), 7.73 (ddd, J = 54.1, 8.5, 4.4 Hz, 2H), 7.59 (s, 1H), 7.40 (d, J = 264.2 Hz,
2H), 7.29 (dd, J = 8.4, 1.7 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 135.45, 133.80, 131.85, 128.23,
128.02, 127.81, 127.73, 127.36, 126.98, 125.98, 125.07, 21.02 (d, J = 19.9 Hz). The physical data were
identical in all respects to those previously reported.5
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(4) Heijnen, D.; Hornillos, V.; Corbet, B. P.; Giannerini, M.; Feringa, B. L. Org. Lett., 2015, 17 (9),
pp 2262–2265.
(5) Ka Young Lee, Jeong Eun Na, Mi Jung Lee Jae, Nyoung Kim, Tetrahedron Lett, 2004, 45, 5977–
5981
1-methylnaphthalene (3a): Synthesized according to Method A. [72 mg, 84% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.3
Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.60-7.52 (m, 2H), 7.45 – 7.40 (m, 1H), 7.37 (d,
J = 6.9 Hz, 1H), 2.75 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 134.3, 133.6, 132.6, 128.6, 126.6, 126.4,
125.7, 125.6, 125.6, 124.1, 19.4 ppm. The physical data were identical in all respects to those
previously reported.1
1-phenylnaphthalene (3b): Synthesized according to Method A. [92 mg, 75% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane) 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 9.5
Hz, 2H), 7.88 (d, J = 7.5 Hz, 1H), 7.58 – 7.49 (m, 6H), 7.49 – 7.42 (m, 3H). 13C NMR (101 MHz, CDCl3) δ
140.74, 140.24, 133.77, 131.60, 130.05, 128.23, 128.22, 127.60, 127.20, 126.89, 126.00, 125.98,
125.73, 125.34. The physical data were identical in all respects to those previously reported.2
1-butylnaphthalene (3c): Synthesized according to Method A. [98 mg, 89% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane) 1H NMR (400 MHz, CDCl3) δ 8.17 (d, 1H),
8.00 – 7.92 (m, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.66 – 7.53 (m, 2H), 7.50 (dd, J = 8.1, 7.0 Hz, 1H), 7.42 (d,
J = 7.0, 1.2 Hz, 1H), 3.18 (t, 2H), 1.85 (tt, J = 7.8, 6.5 Hz, 2H), 1.57 (h, J = 7.4 Hz, 2H), 1.09 (t, J = 7.4 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 139.07, 133.99, 132.02, 128.84, 127.98 (naphthalene), 126.49,
125.95, 125.91 (naphthalene), 125.70, 125.62, 125.44, 124.01, 33.13, 32.94, 23.01, 14.15. The
product was obtained with traces of naphthalene.1
1-(sec-butyl)naphthalene (3d): Synthesized according to Method A. [67 mg, 61% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane) 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.4
Hz, 1H), 7.90 (dd, J = 8.5, 5.5 Hz, 2H (+ naphthalene)), 7.75 (d, J = 8.1 Hz, 1H), 7.59 – 7.40 (m, 4H (+
naphthalene)), 3.57 (h, J = 6.9 Hz, 1H), 1.91 (dq, J = 14.0, 7.4 Hz, 1H), 1.78 (dq, J = 13.6, 7.3 Hz, 1H),
1.43 (d, J = 6.9 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 143.75, 133.97, 131.83,
128.97, 126.22, 125.64, 125.62, 125.22, 123.30, 122.49, 35.34, 30.62, 21.27, 12.34.The physical data
were identical in all respects to those previously reported.1
trimethyl(naphthalen-1-ylmethyl)silane (3e): Synthesized according to Method A. [125 mg, 98%
yield] Colorless oil obtained after column chromatography (SiO2, n-pentane) 1H NMR (400 MHz,
CDCl3) δ 8.05 – 7.98 (m, 1H), 7.93 – 7.85 (m, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.57 – 7.47 (m, 2H), 7.47 –
7.38 (m, 1H), 7.23 (d, J = 7.1 Hz, 1H), 2.65 (s, 2H), 0.10 – 0.05 (s, 9H). 13C NMR (101 MHz, CDCl3) δ
139.95, 136.69, 134.43, 131.32, 128.22, 128.08, 127.98, 127.70, 127.50, 127.38, 26.19, 1.56. The
physical data were identical in all respects to those previously reported. 4
2-(naphthalen-1-yl)thiophene (3f) Synthesized according to Method A. [77 mg, 61% yield] Colorless
oil obtained after column chromatography (SiO2, n-pentane ) 1H NMR (400 MHz, CDCl3) δ 8.26 – 8.19
(m, 1H), 7.91 – 7.87 (m, 1H), 7.85 (dt, J = 8.2, 1.1 Hz, 1H), 7.57 (dd, J = 7.1, 1.3 Hz, 1H), 7.53 – 7.45 (m,
3H), 7.42 (dd, J = 5.1, 1.2 Hz, 1H), 7.24 (dd, J = 3.5, 1.2 Hz, 1H), 7.18 (dd, J = 5.1, 3.5 Hz, 1H). 13C NMR
(101 MHz, CDCl3) δ 141.77, 133.85, 132.44, 131.87, 128.41, 128.34, 128.22, 127.40, 127.29, 126.46,
126.02, 125.77, 125.64, 125.26.2
9-methylanthracene (4a): Synthesized according to Method A. [112 mg, 97% yield] White solid
obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H),
8.30 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.1 Hz, 2H), 7.54-7.46 (m, 4H), 3.11 (s, 3H) ppm. 13C NMR (100
MHz, CDCl3) δ 131.5, 130.1, 130.0, 129.1, 125.3, 125.2, 124.8, 124.7, 13.9 ppm. Data was consistent
with commercially available product.
1-methoxy-4-methylbenzene (5a): Synthesized according to Method A. [50 mg, 67% yield] Colorless
oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). 1H NMR (400 MHz, CDCl3) δ
7.10 (d, J = 8.1 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 3.80 (s, 3H), 2.31 (s, 3H) ppm. 13C NMR (100 MHz,
CDCl3) δ 157.4, 129.9, 129.8, 113.7, 55.3, 20.5 ppm. Data was consistent with commercially available
product.
4-methoxy-1,1'-biphenyl (5b): Synthesized according to Method A. [105 mg, 95% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane/ether 100:1). 1H NMR (400 MHz, CDCl3) δ
7.59 (td, J = 8.7, 1.8 Hz, 4H), 7.46 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H),
3.88 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.16, 140.84, 133.78, 128.76, 128.18, 126.76, 126.69,
114.22, 55.35. The physical data were identical in all respects to those previously reported.1
1-butyl-4-methoxybenzene (5c): Synthesized according to Method A. [79 mg, 80% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane/ether 100:1). 1H NMR (400 MHz, CDCl3) δ
7.13 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 3.81 (s, 3H), 2.58 (t, J = 7.7 Hz, 2H), 1.66 – 1.53 (m,
2H), 1.38 (dq, J = 14.6, 7.3 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 157.54,
134.95, 129.21, 113.58, 55.18, 34.70, 33.91, 22.29, 13.95. The physical data were identical in all
respects to those previously reported.1
1-secbutyl-4-methoxybenzene (5d): Synthesized according to Method A. [75 mg, 76% yield]
Colorless oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). 1H NMR (400
MHz, CDCl3) δ 7.13 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 3.82 (s, 3H), 2.58 (q, J = 7.0 Hz, 1H), 1.60
(p, J = 7.3 Hz, 2H), 1.25 (d, J = 7.0 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 157.61,
139.74, 127.82, 113.56, 55.16, 40.80, 31.32, 22.03, 12.23. The physical data were identical in all
respects to those previously reported.1
(4-methoxybenzyl)trimethylsilane (5e): Synthesized according to Method A. [114 mg, 98% yield]
Colorless oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). 1H NMR (400
MHz, CDCl3) δ 6.94 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H), 2.03 (s, 2H), 0.01 (s, 9H). 13C
NMR (101 MHz, CDCl3) δ 156.49, 132.31, 128.80, 113.64, 55.20, 25.70, -1.91. The physical data were
identical in all respects to those previously reported 4
1-methoxy-3-methylbenzene (6a): Synthesized according to Method A. [51 mg, 69% yield] Colorless
oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). 1H NMR (400 MHz, CDCl3) δ
7.18 (t, J = 7.7 Hz, 1H), 6.78 (d, J = 7.4 Hz, 1H), 6.75-6.70 (m, 2H), 3.80 (s, 3H), 2.35 (s, 3H) ppm. 13C
NMR (100 MHz, CDCl3) δ 159.5, 139.5, 129.2, 121.5, 114.7, 110.7, 55.1, 21.6 ppm. Data was
consistent with commercially available product.
1-methoxy-3-methylbenzene (6b): Synthesized according to Method A. [79 mg, 72% yield] Colorless
oil obtained after column chromatography (SiO2, n-pentane/ether 100:1) 1H NMR (400 MHz, CDCl3) δ
7.65 (d, J = 7.1 Hz, 2H), 7.49 (t, J = 7.5 Hz, 2H), 7.40 (td, J = 7.6, 3.2 Hz, 2H), 7.24 (d, J = 9.1 Hz, 1H),
7.19 (d, J = 1.8 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 3.90 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.07,
142.88, 141.22, 129.86, 128.84, 127.52, 127.31, 119.79, 113.03, 112.79, 55.38.6
N,N,4-trimethylaniline (7a): Synthesized according to Method A. [71 mg, 88% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane/ether 100:1). 1H NMR (400 MHz, CDCl3) δ
7.10 (d, J = 8.2 Hz, 2H), 6.74 (d, J = 8.6 Hz, 2H), 2.94 (s, 6H), 2.31 (s, 3H) ppm. 13C NMR (100 MHz,
CDCl3) δ 148.8, 129.6, 126.2, 113.3, 41.1, 20.3 ppm. The physical data were identical in all respects to
those previously reported.7
N,N-dimethyl-[1,1'-biphenyl]-4-amine (7b): Synthesized according to Method A. [102 mg, 86% yield]
Colorless oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). 1H NMR (400
MHz, CDCl3) δ 7.65 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.9 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.34 (t, J = 6.8 Hz,
1H), 6.88 (d, J = 8.8 Hz, 2H), 3.05 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 150.01, 141.28, 129.27, 128.72,
127.76, 126.35, 126.05, 112.83, 40.64. The physical data were identical in all respects to those
previously reported.2
4-butyl-N,N-dimethylaniline (7c): Synthesized according to Method A. [90 mg, 85% yield] Colorless
oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). 1H NMR (400 MHz, CDCl3) δ
7.13 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 2.97 (s, 6H), 2.59 (t, J = 7.5 Hz, 2H), 1.67 – 1.57 (m,
2H), 1.42 (dq, J = 14.6, 7.3 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 148.95,
131.26, 129.00, 113.04, 41.02, 34.66, 34.07, 22.44, 14.08.The physical data were identical in all
respects to those previously reported.1
(6) Jin Yang, Lei, Wang, Dalton Trans., 2012, 41, 12031-12037
(7) Chen, W.-X.; Shao, L.-X. J. Org. Chem., 2012, 77, 9236.
4-(sec-butyl)-N,N-dimethylaniline (7d): Synthesized according to Method A. [85 mg, 80% yield]
Colorless oil obtained after column chromatography (SiO2, n-pentane/Ether 100:1). 1H NMR (400
MHz, CDCl3) δ 7.11 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 2.95 (s, 6H), 2.55 (h, J = 7.0 Hz, 1H), 1.75
– 1.46 (m, 2H), 1.25 (d, J = 7.0 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 148.99,
135.98, 127.57, 112.90, 40.94, 40.64, 31.38, 22.04, 12.37. HRMS [M+H|: 178.1596 Found :
178.1589.
N,N-dimethyl-4-((trimethylsilyl)methyl)aniline (7e): Synthesized according to Method A. [119 mg,
96% yield] Colorless oil obtained after column chromatography (SiO2, n-pentane/Ether 100:1). 1H
NMR (400 MHz, CDCl3) δ 6.95 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 8.7 Hz, 2H), 2.94 (s, 6H), 2.03 (s, 2H), 0.04
(s, 9H). 13C NMR (101 MHz, CDCl3) δ 147.92, 128.75 (2x), 113.43, 41.24, 25.49, -1.72. HRMS [M+H|:
Exact Mass: 208,1522 Found 208,1516.
2-(p-tolyl)-1,3-dioxolane (8a): Synthesized according to Method A. [84 mg, 86% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane/Ether 100:1). 1H NMR (400 MHz, CDCl3) δ
7.38 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 5.80 (s, 1H), 4.27-3.94 (m, 4H), 2.37 (s, 3H) ppm. 13C
NMR (100 MHz, CDCl3) δ 139.0, 135.0, 129.0, 126.4, 103.8, 65.2, 21.3 ppm. The physical data were
identical in all respects to those previously reported.4
1,3-dichloro-5-methylbenzene (9a): Synthesized according to Method A. [62 mg, 64% yield]
Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ
7.17 (s, 1H), 7.06 (s, 2H), 2.31 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 141.1, 134.6, 127.5, 125.7,
21.0 ppm. The physical data were identical in all respects to those previously reported.20
1-butyl-4-(chloromethyl)benzene (10a) Synthesized according to Method B at 0ºC. [88mg, 80%
yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz,
CDCl3) δ 7.31 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 4.59 (s, 2H), 2.63 (t, J = 7.7 Hz, 2H), 1.66 –
1.55 (m, 2H), 1.37 (dq, J = 14.6, 7.3 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
145.99, 137.38, 131.45, 131.21, 48.98, 38.03, 36.20, 25.01, 16.60. The physical data were identical in
all respects to those previously reported.8
4-(chloromethyl)-1,1'-biphenyl (10b) Synthesized according to to Method B at 0ºC [121 mg, 100%
yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz,
CDCl3) δ 7.64 – 7.56 (m, 4H), 7.50 – 7.43 (m, 4H), 7.37 (d, J = 7.3 Hz, 1H), 4.65 (s, 2H). 13C NMR (101
MHz, CDCl3) δ 141.37, 140.47, 136.42, 129.04, 128.80, 127.52, 127.48, 127.11, 46.05. Data was
consistent with commercially available product.
(8) Youichi;, Y.; TakeshiI, Y.; Susumo, M.; Akiko, I. N-Phenyloxamide derivatives. US Patent US20070870741 20071011
1-chloro-4-(prop-1-en-2-yl)benzene (11a): Synthesized according to Method A. [66 mg, 72% yield]
Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ
7.40 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 5.36 (s, 1H), 5.20-5.04 (m, 1H), 2.14 (d, J = 0.6 Hz, 3H)
ppm. 13C NMR (100 MHz, CDCl3) δ 142.1, 139.6, 133.1, 128.3, 126.8, 113.0, 21.7 ppm. The physical
data were identical in all respects to those previously reported.9
2-methyl-1,1'-biphenyl (12a): Synthesized according to Method A. [95 mg, 94% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.50-7.44 (m,
2H), 7.43-7.37 (m, 3H), 7.35-7.29 (m, 4H), 2.35 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 142.0, 141.9,
135.4, 130.3, 129.8, 129.2, 128.1, 127.3, 126.8, 125.8, 20.5 ppm. The physical data were identical in
all respects to those previously reported.10
4,4'-dimethyl-1,1'-biphenyl (13a): Synthesized according to Method A with 2.5 eq organolithium at
40 °C. [90 mg, 83% yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H
NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 2.44 (s, 3H) ppm. 13C NMR
(100 MHz, CDCl3) δ 138.3, 136.7, 129.5, 126.8, 21.1 ppm. The physical data were identical in all
respects to those previously reported.11
(E)-prop-1-en-1-ylbenzene (14a): Synthesized according to Method A. [39 mg, 55% yield] Colorless
oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J =
8.5 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.20 (t, J = 7.1 Hz, 1H), 6.42 (dq, J = 15.8, 1.4 Hz, 1H), 6.25 (dq, J =
15.7, 6.5 Hz, 1H), 1.90 (dd, J = 6.5, 1.6 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 137.9, 131.0, 128.5,
126.7, 125.8, 125.7, 18.5 ppm. The physical data were identical in all respects to those previously
reported.12
(E)-1,2-diphenylethene (14b) Synthesized according to Method A. [77 mg, 71% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.0
Hz, 4H), 7.40 (t, J = 8.4 Hz, 4H), 7.31 (t, J = 7.1 Hz, 2H), 7.16 (s, 2H). 13C NMR (101 MHz, CDCl3) δ
137.34, 128.73, 128.71, 127.67, 126.55. Data was consistent with commercially available product.
(E)-2-styrylthiophene (14c) Synthesized according to Method A. [92 mg, 82% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.6
Hz, 2H), 7.40 (d, J = 7.0 Hz, 2H), 7.33 – 7.26 (m, 2H), 7.24 (d, J = 5.1 Hz, 1H), 7.12 (d, J = 3.6 Hz, 1H),
7.06 (dd, J = 5.1, 3.6 Hz, 1H), 7.00 (d, J = 16.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 142.92, 136.99,
128.76, 128.36, 127.66, 126.36, 126.20, 124.40, 121.83. The physical data were identical in all
respects to those previously reported 6
9) Tripathi, C. B.; Mukherjee, S. Angew. Chem. Int. Ed., 2013, 52, 8450.
10) Rajabi, F.; Thiel, W. R. Adv. Synth. Catal. 2014, 356, 1873 – 1877.
11) Zhou, Y.; You, W.; Smith, K. B.; Brown, M. K. Angew. Chem. Int. Ed., 2014, 53, 3475.
12) Gauthier, D.; Lindhardt, A. T.; Olsen, E. P. K.; Overgaard, J.; Skrydstrup, T. J. Am. Chem. Soc.,
2010, 132, 7998.
2-methyl-9H-fluorene (15a): Synthesized according to Method A. [102 mg, 95% yield] White solid
obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.5
Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.45-7.40 (m, 2H), 7.34 (td, J = 7.4 , 1.1 Hz,
1H), 7.25 (dd, J = 7.7, 0.6 Hz, 1H), 3.91 (s, 2H), 2.50 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 143.5,
143.1, 141.9, 139.1, 136.6, 127.6, 126.7, 126.3, 125.8, 125.0, 119.6, 119.6, 36.8, 21.7 ppm. The
physical data were identical in all respects to those previously reported.1
2-(4-butylphenyl)oxirane (17a) Synthesized according to to Method B at -10ºC. [61 mg, 58% yield]
Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ
7.22 – 7.13 (m, 4H), 3.84 (dd, J = 4.1, 2.6 Hz, 1H), 3.13 (dd, J = 5.5, 4.1 Hz, 1H), 2.82 (dd, J = 5.5, 2.6
Hz, 1H), 2.61 (t, J = 7.6 Hz, 2H), 1.66 – 1.51 (m, 2H), 1.35 (h, J = 7.3 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ 145.72, 137.36, 131.22, 128.12, 55.02, 53.73, 38.02, 36.26, 24.97, 16.59.The
physical data were identical in all respects to those previously reported.13
p-tolylmethanol (18a): Synthesized according to Method C. [65 mg, 88% yield] Colorless oil obtained
after column chromatography (SiO2, n-pentane/Ether 90:10). 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J =
7.9 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 4.63 (s, 2H), 2.36 (s, 3H), 1.90 (s, 1H) ppm. 13C NMR (100 MHz,
CDCl3) δ 137.9, 137.3, 129.2, 127.1, 65.2, 21.1 ppm. The physical data were identical in all respects to
those previously reported.14
(4-butylphenyl)methanol (18b): Synthesized according to Method C. [70 mg, 71% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane/Ether 90:10). 1H NMR (400 MHz, CDCl3) δ
7.27 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 4.62 (s, 2H), 2.69 – 2.57 (m, 2H), 2.12 (s, 1H), 1.71 –
1.53 (m, 2H), 1.38 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 142.47 , 138.24,
128.67, 127.19, 65.25, 35.44, 33.77, 22.44, 14.04. Data was consistent with commercially available
product.
2-(4-butylphenyl)ethan-1-ol (19a) Synthesized according to Method C. [56 mg, 52% yield] Colorless
oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J =
8.1 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 4.62 (s, 2H), 2.63 (t, J = 7.1 Hz, 2H), 2.12 (s, 1H), 1.70 – 1.54 (m,
2H), 1.38 (dq, J = 14.6, 7.3 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 145.05, 140.82,
131.25, 129.77, 67.82, 38.02, 41.44, 36.35, 25.01, 16.62. Exact Mass [M+H|: 179,1436 Found :
179,1430.
[1,1'-biphenyl]-4-ol (20a) Synthesized according to Method C. [85 mg, 83% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane 1H NMR (400 MHz, CDCl3 + DMSO-d6) δ 8.99 (s,
1H), 7.49 – 7.42 (m, 2H), 7.40 – 7.28 (m, 4H), 7.23 – 7.15 (m, 1H), 6.89 – 6.78 (m, 2H). 13C NMR (101
MHz, CDCl3 + DMSO-d6) δ 157.03, 140.83, 131.85, 128.61, 127.84, 126.26, 117.40, 115.80. Data was
consistent with commercially available product.
(13) Maryanoff, B. E.; Mccomsey, D. F.; Gardocki, J. F.; Shank, R. P.; Costanzo, M. J.; Nortey, S.;
Schneider, C. R.; Setler, P. E. J. Med. Chem. 1987, 30, 1433–1454.
(14) Sutter, M.; Pehlivan, L.; Lafon, R.; Dayoub, W.; Raoul, Y.; Metay, E.; Lemaire, M. Green Chem.,
2013, 15, 3020
3-butylbenzo[b]thiophene (21b) Synthesized according to Method A. [96 mg, 84% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.5
Hz, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.48 – 7.35 (m, 2H), 7.11 (s, 1H), 2.90 (d, J = 6.7 Hz, 2H), 1.79 (ddd, J =
15.3, 8.2, 6.9 Hz, 2H), 1.49 (dt, J = 14.7, 7.4 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ 140.63, 139.28, 137.32, 124.17, 123.84, 122.97, 121.85, 120.92, 31.45, 28.41, 22.79, 14.10. The
physical data were identical in all respects to those previously reported. 15
4-butyldibenzo[b,d]furan (22a) Synthesized according to Method A. [116 mg, 86% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 8.00 (ddd, J =
7.7, 1.4, 0.7 Hz, 1H), 7.85 (dd, J = 5.4, 3.6 Hz, 1H), 7.66 (dt, J = 8.2, 0.8 Hz, 1H), 7.51 (ddd, J = 8.3, 7.3,
1.4 Hz, 1H), 7.39 (td, J = 7.5, 1.0 Hz, 1H), 7.35 – 7.30 (m, 2H), (3.06 (t, J = 7.5 Hz, 2H)), 1.99 – 1.75 (m,
2H), 1.52 (h, J = 7.4 Hz, 2H), 1.06 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 156.07, 154.85,
127.27, 127.16, 126.91, 124.72, 123.82, 122.72, 122.54, 120.70, 118.09, 111.71, 32.15, 29.70, 22.66,
14.07.
3-butylthiophene (23a) Synthesized according to Method A. [69 mg, 82% yield] Colorless oil
obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.26 (dd, J =
4.9, 2.9 Hz, 1H), 6.96 (dd, J = 8.1, 3.4 Hz, 2H), 2.67 (t, J = 7.7 Hz, 2H), 1.71 – 1.59 (m, 2H), 1.40 (h, J =
7.3 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 143.21, 128.30, 125.04, 119.78,
32.75, 30.00, 22.43, 13.96. The physical data were identical in all respects to those previously
reported. 16
3-butyl-1-(triisopropylsilyl)-1H-pyrrole (24a) Synthesized according to Method A. [117 mg, 70%
yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz,
CDCl3) δ 6.69 (t, J = 2.2 Hz, 1H), 6.52 (s, 1H), 6.15 (s, 1H), 2.49 (t, J = 7.7 Hz, 2H), 1.63 – 1.50 (m, 2H),
1.49 – 1.29 (m, 5H), 1.09 (d, J = 7.5 Hz, 18H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
126.37, 123.86, 120.98, 110.57, 33.24, 26.71, 22.53, 17.88, 14.02, 11.69. HRMS [M+H|: 280.2461
Found : 280.2455.
3-phenyl-1-(triisopropylsilyl)-1H-pyrrole (24b) Synthesized according to Method A. [151 mg, 84%
yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz,
Chloroform-d) δ 7.57 (dd, J = 8.2, 1.3 Hz, 2H), 7.34 (t, J = 7.7 Hz, 2H), 7.17 (t, J = 6.7 Hz, 1H), 7.08 (t, J =
1.8 Hz, 1H), 6.82 (t, J = 2.4 Hz, 1H), 6.63 (dd, J = 2.8, 1.5 Hz, 1H), 1.59 – 1.41 (m, 3H), 1.15 (d, J = 7.5
Hz, 18H). 13C NMR (101 MHz, Chloroform-d) δ 138.68, 131.19, 129.43, 127.93, 127.88, 127.82,
123.22, 111.27, 20.50, 14.35. HRMS [M+H|: 300.2148 Found : 300.2142.
(15) Cabiddu, S.; Cancellu, D.; Floris, C.; Gelli, G.; Melis, S. Synthesis. 1988, 1988, 888–890
(16) Tan, L.; Curtis, M. D.; Francis, A. H. Macromolecules 2002, 35, 4628–4635.
3-phenylfuran (25a) Synthesized according to Method A. [47 mg, 54% yield] Colorless oil obtained
after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.57 – 7.48
(m, 3H), 7.40 (t, J = 7.6 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 6.73 (s, 1H). 13C NMR (101 MHz, CDCl3) δ
143.67, 138.48, 132.41, 128.82, 127.01, 126.46, 125.88, 108.86.The physical data were identical in all
respects to those previously reported.17
1-methyl-5-phenyl-1H-indole (26a) Synthesized according to Method A. [50 mg, 40% yield] Colorless
oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H),
7.77 – 7.63 (m, 2H), 7.56 – 7.45 (m, 3H), 7.41 (d, J = 8.5 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 3.1
Hz, 1H), 6.58 (t, J = 2.5 Hz, 1H), 3.84 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 145.30, 132.17, 131.62,
131.32, 130.07, 128.92, 124.08, 122.09, 112.12, 103.99, 35.63. The physical data were identical in all
respects to those previously reported.18
1-(3-methoxyphenyl)naphthalene (27a) Synthesized according to Method A.
[75 mg, 40 % yield] Ferrocenyl lithium prepared according to literature procedure.7 Dark red oil
obtained after column chromatography (SiO2, n-pentane:DCM). 1H NMR (400 MHz, CDCl3) δ 8.59 –
8.53 (m, 1H), 7.89 (ddd, J = 8.2, 6.2, 2.5 Hz, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.54 – 7.45 (m, 3H), 4.68 (t, J
= 1.8 Hz, 2H), 4.42 (t, J = 1.8 Hz, 2H), 4.21 (s, 5H). 13C NMR (101 MHz, CDCl3) δ 136.07, 133.78, 131.91,
128.44, 127.99, 126.94, 126.02, 125.51, 125.46, 125.22, 87.09, 70.52, 69.64, 68.15. HRMS [M+H|:
313.0680 found 313.0625.
1-(3-methoxyphenyl)naphthalene (28a) Synthesized according to Method A
[35 mg, 20 % yield] Ferrocenyl lithium prepared according to literature procedure.7 Dark red oil
obtained after column chromatography (SiO2, n-pentane:DCM). 1H NMR (400 MHz, CDCl3 ) δ 7.41 (d, J
= 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.57 (t, J = 1.9 Hz, 2H), 4.27 (t, J = 1.9 Hz, 2H), 4.04 (s, 5H), 3.83
(s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.66, 133.92, 129.83, 116.48, 88.53, 72.10, 71.12, 68.77,
57.93. 8 HRMS Mass : 293.0551 Found : 293.0545.
1-(3-methoxyphenyl)naphthalene (29a) Synthesized according to Method B.
[122 mg, 87 % yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR
(400 MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 1H), 7.95 (dd, J = 17.5, 8.1 Hz, 2H), 7.67 – 7.41 (m, 5H), 7.18 (d,
J = 7.6 Hz, 1H), 7.14 (s, 1H), 7.06 (dd, J = 8.3, 2.1 Hz, 1H), 3.91 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
162.22, 144.91, 142.85, 136.51, 134.33, 131.97, 130.99, 130.43, 129.51, 128.79, 128.78, 128.51,
128.07, 125.32, 118.38, 115.61. The physical data were identical in all respects to those previously
reported.19
(17) Yu, J.; Liu, J.; Shi, G.; Shao, C.; Zhang, Y. Angew. Chem. Int. Ed. Engl. 2015, 54, 4079–4082
(18) Mesganaw, T.; Fine Nathel, N. F.; Garg, N. K. Org. Lett. 2012, 14, 2918–2921.
(19) Molander, G. A.; Beaumard, F. Org. Lett. 2010, 12, 4022–4025.
Synthesis of Celecoxib
Figure 1 Two-step synthesis of celecoxib precursor20
1-(4-bromophenyl)-4,4,4-trifluorobutane-1,3-dione : Synthesized according to reported procedure.20
1-(4-bromophenyl)ethan-1-one (1.6 g, 8 mmol) was dissolved in 8 mL of DMF under N2 atmosphere
and 60% NaH dispersion in oil (500 mg, 10 mmol) was added in three portions at 0°C. After stirring at
this temperature for 30 min, ethyl trifluoroacetate (1.2 mL, 10 mmol) was added and the reaction
mixture was stirred for 4 h. The reaction mixture was poured on to ice water, acidified with 2N
aqueous HCl and extracted with EtOAc. The combined organic layers were washed with water, dried
and the solvent evaporated under vacuum. The crude mixture was purified by column
chromatography (SiO2, n-pentane:ether 98:2). [2.17 g, 92% yield]. 1H NMR (400 MHz, CDCl3) δ 7.80
(d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 6.54 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 184.9, 177.4
(q, JC-F = 36.4 Hz), 132.4, 131.7, 129.3, 128.9, 117.0 (q, JC-F = 283.4 Hz), 92.3 (q, JC-F = 2.0 Hz) ppm. 19F
NMR (376 MHz, CDCl3) δ -76.51 (s, 3F). The physical data were identical in all respects to those
previously reported.21
4-(5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide (30): Synthesized
according to reported procedure.22 1-(4-bromophenyl)-4,4,4-trifluorobutane-1,3-dione (1.2 g, 4
mmol) and 4-hydrazinylbenzenesulfonamide hydrochloride (1.07 g, 4.8 mmol) were dissolved in 15
mL of EtOH and the mixture heated at reflux for 24 h. The solvent was evaporated under reduced
pressure and the crude product was purified by column chromatography (SiO2, n-pentane:EtOAc
65:35). [1.60 gram 90% yield]. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.5 Hz,
2H), 7.43 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.5 Hz, 2H), 6.77 (s, 1H), 5.33 (s, 2H) ppm. 13C NMR (100 MHz,
CDCl3) δ 144.2 (q, JC-F = 38.7 Hz), 144.0, 142.1, 141.8, 132.4, 130.3, 127.6, 127.4, 125.6, 124.1, 120.9
(q, JC-F = 269.3 Hz), 106.7 (q, JC-F = 1.6 Hz) ppm. 19F NMR (376 MHz, CDCl3) δ -62.43 (s, 3F).
(20) S. K. Singh, P. G. Reddy, K. S. Rao, B. B. Lohray, P. Misra, S. A. Rajjak, Y. K. Rao, A. Venkateswarlu,
Bioor. Med. Chem. Lett., 2004, 14, 499-504.
(21) S. Büttner, A. Riahi, I. Hussain, M. A. Yawer, M. Lubbe, A. Villiger, H. Reinke, C. Fischer, P. Langer,
Tetrahedron, 2009, 65, 2124-2135.
(22) J. Prabhakaran, V. J. Majo, N. R. Simpson, R. L. Van Heertum, J. J. Mann, J. S. D. Kumar, J. Label
Compd. Radiopharm., 2005, 48, 887-895.
4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide (31): In a dry Schlenk flask
Pd(PtBu3)2 (5 mol%, 0.05 mmol, 5.1 mg), and the aryl bromide (0.1 mmol, 44.5 mg) were dissolved in
1 mL of dry toluene , and 5 ml of O2 was bubbled through the reaction mixture with a syringe,
followed by stirring for 10 min. Methyllithium (0.19 mL, 3 eq, 1.6 M in diethyl ether) was diluted
with toluene to reach 1 mL; this solution was added over 2 min by the use of a syringe pump. After
the addition was completed, the reaction was quenched with 0.5 mL of MeOH. The solvent was
evaporated under reduced pressure to afford the crude product that was purified by column
chromatography. [35 mg, 91% yield]. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.7 Hz, 1H), 7.45 (d, J =
8.8 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.2 Hz, 2H), 6.73 (s, 1H), 5.25 (s, 2H), 2.37 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 145.3, 144.0 (q, JC-F = 38.8 Hz), 142.5, 141.4, 139.8, 129.7, 128.7, 127.5,
125.6, 125.5, 121.0 (q, JC-F = 269.1 Hz), 106.3 (q, JC-F = 1.7 Hz), 21.3 ppm. 19F NMR (376 MHz, CDCl3) δ -
62.42 (s, 3F). The physical data were identical in all respects to those previously reported.23
(23) Ji, G.Wang, X.; Zhang, S.; Xu, Y.; Ye, Y.n; Li, M.; Zhang, Y.; Wang, J. Chem. Commun., 2014, 50,
4361-4363.
General scheme [11C]-labelling experiments with 2-Br-Naphthalene and Precursor 30
[11C]-methyl iodide was trapped in a solution of n-BuLi in THF at -78 °C, and subsequently diluted
with toluene and allowed to reach rt. The solution was drawn back up in the syringe, and added to a
previously oxygenated mixture of Pd complex and substrate. In the case of the Celecoxib synthesis
(31*), the oxygenated mixture was first treated with 1.1 eq. of n-butyllithium to ensure complete
deprotonation of the sulfonamide, which would otherwise consume the prepared [11C]-MeLi. After
slow addition (2 min) of the organolithium reagents, the reaction was quenched with methanol, and
an aliquot of the crude mixture concentrated, dissolved in acetonitrile, and directly loaded onto a RP-
HPLC (eluent water:acetonitrile:trifluoroacetic acid 50:49:1). The total reaction time from the start of
[11C]-MeI trapping, lithium halogen exchange, cross coupling and injection on HPLC was less than 15
min.
Figure 2 [11C]-labelling experiments
Figure 3 [11C]-labelling experiments setup
Figure 4 Schematic representation of [11C]-labelling experiments
Method for [11C]-labelling experiments
The substrate was transferred to a dry nitrogen purged 20 ml vial equipped with a septum and a
stirring bar (vial A), and was further flushed with nitrogen through a septum for 5 min. In a separate,
dry conical 4 ml vial (vial B), 0.25 ml dry THF was cooled down to -78 ºC under a nitrogen
atmosphere. n-BuLi (0.9 eq. 0.18 ml) was added. The [11C]-MeI inlet needle was inserted in the THF-n-
BuLi mixture, and a carbosphere vent added. During the trapping procedure of the [11C]-MeI in vial B,
3 ml of dry toluene was added to the substrate in vial A, and the mixture purged with oxygen (10 ml).
n-BuLi (1.1 eq, 0.22 ml) was added to vial A prior to the coupling reaction to deprotonate the
sulfonamide. The activity of the trapped and converted MeI of vial B was measured, the solution was
diluted with 1 ml of toluene by means of a 2.5 ml syringe, and subsequently drawn up in the syringe.
The addition of the MeLi solution to vial A was executed by means of a syringe pump, and was
performed in 2 min. After the addition was complete, the reaction was quenched with 0.5 ml MeOH,
and the total activity measured. A sample was taken, and dried at 50 ºC under a stream of nitrogen.
The sample was taken up in 1.5 ml of eluent, its activity measured, and loaded onto a RP C-18 Denali
HPLC column. Finally, residual activity in the used syringe was measured. Peaks from the HPLC-run
were collected in vials, and their activity measured. The product was obtained by comparison with
retention time of the previously prepared (isolated/injected) product.