Palladium Catalyzed Synthetic Transformations of Diazabicyclic olefins

using Catechols

1. Introduction

Palladium has become the most versatile transition metal in metal-catalyzed reactions,

particularly those involving carbon-carbon bond formation.1Their real synthetic utility lies

in the wide range of organic transformations promoted by these catalysts, and in the

specificity and functional group tolerance shown in most of these processes. They permit

unconventional transformations and therefore give a wide range of starting materials for the

synthetic chemist to use.

Palladium has two stable oxidation states, a +2 and a zerovalent state, each with its

own chemistry. Palladium (II) complexes are electrophilic and tend to react with electron

rich organic molecules, particularly arenes and alkenes. Palladium (II) catalysts are used in

both catalytic and stoichiometric quantities.

Palladium (0) complexes are strong nucleophiles and strong bases. These catalysts are

most commonly used to promote reactions involving acetates, halides and triflates, and

are used only in catalytic quantities.

The diazabicyclic alkene 3 is easily accessible by the Diels-Alder reaction of

cyclopentadiene 1 with dialkyl azodicarboxylate 2 (Scheme 1.1).2 Even though symmetrical,

bi- and polycyclic hydrazines have been known for a long time, there are only few reports on

their desymmetrization as well as ring opening.

Scheme 1.1These azabicyclic alkenes exhibit diverse reactivity patterns due to the presence of

following characteristics (Figure 1). (1) The strained double bond of this diaza analogue of

norbornene should be very reactive towards electrophiles. (2) Ring fragmentations, via

nitrogen-nitrogen bond reduction, carbon-carbon oxidative cleavage, ring-opening metathesis

or allylic carbon-nitrogen cleavage are also expected to be thermodynamically favourable (3)

Skeletal rearrangements involving carbocationic intermediates, typically observed in the

norbornene series, could also be observed with this cycloadducts.3

Figure 1 General reactivity pattern of meso bicyclic hydrazines

The combination of all these transformations should provide a useful synthetic arsenal

for a large-scale elaboration of various functionalized amino-, diamino- or

hydrazinocyclopentanes, potentially valuable scaffolds for target- or diversity-oriented

synthesis of biologically active compounds. This report focuses on the palladium and

catalyzed synthetic transformations of bicyclic hydrazines designed for the synthesis of

carbocycles and heterocycles.

Hydroarylation Reactions

The chemistry of bicyclic hydrazines gained much attention after Kaufmann’s report on

the hydroarylation reactions. The reductive arylation of bicyclic alkenes using palladium

catalysts have been well studied, but there were no reports on the hydroarylation of 2,3-

diazabicyclic alkenes. Kaufmann et al. have carried out coupling reactions on the 2,3-

diazabicyclo[2.2.1]hept-5-enes 3a with different organic halides. Its reaction with aryl or β-

styryl halides in the presence of an in situ generated palladium catalyst afforded exclusively

the exo-configurated hydroarylation and hydrovinylation products in good yields. They

observed the formation of very small amount of a side product, which was formed by the N-

N bond cleavage (Scheme 1.2).4

NN

E

EElectrophilic additionsC-C bond cleavage

Allylic Fragmentation

N-N bond cleavage

C-N bond cleavage

Scheme 1.2The reductive cleavage of N-N bond of the hydroarylated product 7 with lithium in

liquid ammonia afforded the synthetically interesting cis-1,3-diaminocyclopentane derivative

8 (Scheme 1.3).

Scheme 1.3They also reported the palladium catalyzed domino coupling of aryl halide 4 and

phenylacetylene 9 onto the bicyclic alkene 3a which resulted in the formation of a bis

coupled product 10.5 In this case, they did not observe the formation of the ring opened

product (Scheme 1.4).

Scheme 1.4Later reports from the same group have shown that sterically more hindered and more

rigid tri- and tetracyclic substrates affords the hydroarylated products along with 3,4-

disubstituted cyclopentenes as minor product 14, the latter being formed via the C-N bond

cleavage (Scheme 1.5).4

Scheme 1.5

Under the optimized conditions the ring opened product 14 was obtained in 46% yield

(NaF/DMSO/65 0C). It is interesting to note that under the same set of reaction conditions,

the bicyclic substrates 3 afforded 3,5-disubstituted cyclopentenes while the tri- and tetracyclic

substrates gave 3,4-disubstituted cyclopentenes along with the hydroarylated products. This

was the first report on the formation of 3,4-disubstituted cyclopentenes from tri- and

tetracyclic hydrazines. In the case of tricyclic substrate, the low yields of the products were

explained on the basis of the low stability of the starting material under basic conditions.

Attempts to increase the yield of both products by changing the solvent and base used were

not very much successful.

Rearrangements Involving Allylic Cations

The thermal and/or acid catalyzed fragmentation of bicyclic hydrazines has been

intensively investigated.6 A [3,3]-sigmatropic rearrangement has been proposed to explain the

stereoselective formation of compound 17 from the corresponding bicyclic hydrazine

(Scheme 1.6). The bicyclic hydrazine 3 do not rearrange under similar thermal conditions.

This transformation is also dramatically accelerated by acids.6d The preference for a concerted

pathway instead of a two-step process has been assessed by kinetic studies.6a

Scheme 1.6Micouin et al. explored the acid catalyzed ring opening of N,N-benzyloxy-2,3-

diazabicyclo[2.2.1]heptanes, as the ring opening of these substrates by cleavage of the C-N

bond has only been scarcely investigated and has not been exploited for synthetic purposes.

To evaluate the fragmentation ability of bicyclic hydrazine 3d, they investigated its acid

catalyzed rearrangement to carbazate 19 (Scheme 1.7).7

Scheme 1.7

The structure of the rearranged product 19 have recently been reassigned by Lautens and

co-workers with the help of X-ray crystallography to be the [5.5]bicyclic systems 20.8 This

correct structural assignment rules out a concerted [3,3]-sigmatropic pathway for this

transformation which can be conducted on a large scale using sulfuric acid in trifluoroethanol

(Scheme 1.8).

Scheme 1.8

Reactions with Organotin Reagents

The pioneering report on the ring opening of bicyclic hydrazines with organotin

reagents, came from our group in 2005.9 The studies commenced with an attempt to carry out

a domino Heck-Stille coupling10 on 2,3-diazabicyclo[2.2.1]hept-5-ene 3a with aryl iodide 21

and organostannanes 22. Contrary to our expectation of a bis-coupled product, the reaction

afforded allylated hydrazinocyclopentene 24 in 48% yields. The reaction is outlined in

scheme 1.9.

Scheme 1.9

The role of iodine as promoter, facilitating the formation of the ring opened product was

proved by carrying out the reaction with catalytic amount of molecular iodine instead of aryl

iodide. Other Lewis acids were also found to promote this transformation, scandium triflate

giving the better results (Scheme 1.10).

Scheme 1.10

Our efforts in this area proved that this methodology can be used for introducing variety

of substituents to the cyclopentenic core. Thus we were successful in the desymmetrization of

meso bicyclic hydrazines using vinyl, phenyl, furyl and thienyl stannanes. It was interesting

to note that both bi and tricyclic hydrazines gave similar type of products under the same

reaction conditions (Scheme 1.11).11

Scheme 1.11

The possibility of introducing heteroatom substituents in the cyclopentenic core

inspired us to evaluate the reactivity of azidostannane 31 with bicyclic hydrazines. As

expected the reaction afforded 3-azido-4-hydrazinocyclopentene 32 in excellent yield

(Scheme 1.12).12 It is noteworthy that these compounds show remarkable similarity towards

vicinal diamines and hence can be used for the synthesis of bisarmed receptors and chiral

auxiliaries.

Scheme 1.12

Palladium mediated synthesis of cyclopenetene annulated benzofuran by the reaction of

azabicyclic olefins with 2-Iodophenol:

There are so many reports on palladium catalyzed annulations of different o-

functionalized aryl halides with unsaturated substrates.13,14 In 1998, Catellani M. reported the

formation of norbornane annulated benzofuran by the palladium catalyzed reaction of

iodophenol with norbornene.15 But the reactivity of these bicentered nucleophiles with

heterobicyclic substrates have not been studied at all. The reactivity of azabicyclic alkenes,

have been extensively investigated with monocentered nucleophiles.16,17 These investigations

resulted in the formation of either 3,4- or 3,5-disubstituted cyclopentenes. The easy

availability and well documented reactivity of various o-functionalized aryl halides prompted

us to investigate the reactivity of these bicentered nucleophiles towards azabicyclic olefins

under palladium catalysis (Scheme 1.13).

Scheme 1.13

Palladium catalyzed annulation of azabicyclic olefin with 2 - iodobenzonitrile:

As a continuation of our interest in the metal catalyzed annulation process, we examined

the reactivity of o- functionalized aryl halides like o-iodobenzonitrile with the diazabicyclic

olefin. This reaction resulted in the formation of highly functionalized indanones (Scheme

1.14).

Scheme 1.14

Rhodium catalyzed reaction of azabicyclic olefin with ortho-functionalized

phenylboronic acid:

Rhodium catalyzed annulations using ortho functionalized phenyl boronic acids and

unsaturated compounds provide a versatile route to the construction of complex cyclic

systems. Murakami and co-workers reported the rhodium catalysed annulation reactions of 2-

formylphenylboronic acid and 2-cyanophenylboronic acid with alkynes and strained

alkenes.18,19 This prompted us to carry out the reaction of these ortho functionalized boronic

acids with heterobicyclic olefin under rhodium catalysis. These reactions afforded highly

functionalized indanone as the product (Scheme 1.15).

Scheme 1.15

2. Results and Discussion Synthesis of Azabicyclic Olefins

The azabicyclic olefins required for our investigations were prepared as per the literature

procedures. 2,3-Diazabicyclo[2.2.1]hept-5-enes 3(a-d) required for our studies were

synthesized by the Diels-Alder cycloaddition of cyclopentadiene with azodicarboxylate 2(a-

d) .

Scheme 2.1

Palladium catalyzed organic transformations of catechol and resorcinol

Substituted cyclopentenes are valuable synthetic intermediates in synthesis of bio

logically interestining molecules.20 Micouin and co-workers reported the stereo selective ring

opening of meso bicyclic hydrazines by phenol.21 The cleavage of fulvene-derived bicyclic

alkenes with phenol was reported from our group.22Apart from the above mentioned reports

there are not much efforts to check the reactivity of catechol and resorcinol with bicyclic

alkenes. Here we describe the ring opening reactions of bicyclic alkenes using catechol and

resorcinol, leading to the formation of substituted cyclopentenes with phenolic hydroxyl

group which will be an intermediate for the synthesis of cyclopentene appended

benzoquinones.

In an initial attempt, the bicyclic alkene, 3a was treated with catechol 38 in the

presence of Pd2(dba)3CHCl3, BINAP and K2CO3 in THF at room temperature. The reaction

afforded the product 39 in 10% yield (Scheme 2.2).

Scheme 2.2

The IR spectrum of the compound 39 showed the characteristic ester carbonyl absorption at

1705 cm-1. In the 1H NMR spectrum, peaks in the region δ 6.88-6.78 ppm were assigned to

the aromatic protons. -NH and –OH protons resonated in the region δ 6.40 and δ 5.88

respectively. The peak at δ 5.32 ppm corresponds to the proton on the carbon attached to the

oxygen. The proton on the carbon bearing the hydrazine moiety resonated in the region δ 5.32

– 5.21 ppm. The methylene protons of the cyclopentene ring appeared as two separate peaks

at δ 2.76-2.70 and 2.17 ppm. In the 13C NMR spectrum ester carbonyl carbons resonated at δ

156.8 and 155.64 ppm. The carbon attached to oxygen resonated at δ 81.44 ppm. All other

signals in 13C NMR spectra were in agreement with the proposed structure. The structure

assigned was further confirmed by low resolution mass spectral analysis which showed a

molecular ion peak at m/z =373.73.

Fig: 1H NMR of compound 39

Fig: 1H NMR of compound 39 in D2O

Fig: 13C NMR of compound 39

Optimization Studies

Detailed optimization studies were carried out to find out the best condition for this

transformation. Poor result was obtained when THF was used as solvent. The yield of the

reaction was increased when LiCl was used as additive. The reaction did not work in other

catalysts like [Pd(allyl)Cl]2 and PdCl2. Prolonged reaction time decreased the yield. The best

result was obtained with the catalyst system Pd2(dba)3CHCl3, PPh3 and K2CO3 in toluene at 60 0C. The optimization studies are summarized in the following table.

Table 1. Optimization Studies

Generality of the methodology was proved by carrying out the reactions of different

bicyclic alkenes with resorcinol and substituted catechols under optimized condition. The

results are summarized in Table 2.

Table 2. Palladium catalyzed coupling of catechol and resorcinol with azabicyclic alkene

Reaction Conditions: alkene (1.0 equiv.), nucleophile (1.0 equiv.), catalyst (5 mol %),

base (1.0 equiv.), ligand ( 10 mol%), solvent (2 mL), 60 °C, 24 h.

Mechanistic Rationale

A plausible mechanism is illustrated for the reaction of catechol and resorcinol with bicyclic

alkenes involves two stages, the initial being the ring opening of bicyclic alkene. The first

step of catalytic cycle involves the formation of π–allyl palladium intermediate B by the

attack of Pd(O) the coordination of the phenolic oxygen atom to Pd(0) on the double bond

(allylic species), and subsequent oxidative addition to C-N bond leading to the ring opening.

In the second stage, the nucleophile attacks the π –allylpalladium species B there by forming

the intermediate C.

Proposed mechanism of the reaction

3. Conclusion

In summary, we have unraveled a facile method towards the synthesis of a new class

of disubstituted cyclopentenes with potent phenolic hydroxyl group. The widespread

occurrence and interesting biological activities of substituted cyclopentane derivatives in

nature make them important targets for synthesis.23 The product can also act as useful

intermediates in the modulation of heterocyclic substituents by multicomponent hydrazine–

based chemistry.

4. References:

1. Hegedus, L. S. organometallics in synthesis – A manual 1994, Wiley: New York,

chapter 5

2. Diels, O.; Blom, J. H.; Knoll, W. Justus Liebigs Ann. Chem. 1925, 443, 242.

3. (a) Brunner, H.; Kramler, K. Synthesis, 1991, 1121. (b) Namyslo, J. C.; Kaufmann, D.

E.; Eur. J. Org. Chem. 1998, 1997. (c) Brunel, J. M.; Hirlemann, M. H.; Heumann, A.;

Buono, G. Chem. Commun. 2000, 1869. (d) Bournaud, C.; Chung, F.; Luna, A. P.;

Pasco, M.; Errasti, G.; Lecourt, T.; Micouin L. Synthesis 2009, 869.

4. Yao, M.-L.; Adiwidjaja, G.; Kaufmann, D. E. Angew. Chem., Int. Ed. 2002, 41, 3375.

5. Storsberg, J.; Nandakumar, M. V.; Sankaranarayanan, S.; Kaufmann, D. E. Adv. Synth.

Catal. 2001, 343, 177.

6. (a) Mackay, D.; Campbell, J. A.; Jennison, C. P. R. Can. J. Chem. 1970, 48, 81. (b)

Campbell, J. A.; Mackay, D.; Sauer, T. D. Can. J. Chem. 1972, 50, 371. (c) Chung, C.

Y.-J.; Mackay, D.; Sauer, T. D. Can. J. Chem. 1972, 50, 3315. (d) Chung, C. Y.-J.;

Mackay, D.; Sauer, T. D. Can. J. Chem. 1972, 50, 1568.

7. Luna, A. P.; Cesario, M.; Bonin, M.; Micouin, L. Org. Lett. 2003, 5, 4771.

8. Martins, A.; Lemouzy, S.; Lautens, M. Org. Lett. 2009, 11, 181

9. Radhakrishnan, K. V.; Sajisha, V. S.; Anas, S.; Krishnan, K. S. Synlett 2005, 2273.

10. (a) Kosugi, M.; Kumura, T.; Oda, H.; Migita, T. Bull. Chem. Soc. Jpn. 1993, 66, 3522.

(b) Oda, H.; Ito, K.; Kosugi, M.; Migita, T. Chem. Lett. 1994, 1443.

11. Sajisha, V. S.; Mohanlal, S.; Anas, S.; Radhakrishnan, K. V. Tetrahedron 2006, 62,

3997.

12. Sajisha, V. S.; Radhakrishnan, K. V. Adv. Synth. Catal. 2006, 924.

13. (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689. (b) Larock, R. C.;

Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652.

14. Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K. K. C. J. Org. Chem. 1995, 60, 3270.

15. Catellani, M.; Rio, A. D. Russ. Chem. Bl., 1998, 47, 928.

16. (a) Storsberg, J.; Nandakumar, M. V.; Sankaranarayanan, S.; Kaufmann, D. E. Adv.

Synth. Catal. 2001, 343, 177; (b) Luna, A. P.; Cesario, M.; Bonin, M.; Micouin, L.

Org. Lett. 2003, 5, 4771; (c) Pineschi, M.; Moro, F. D.; Crotti P. F.; Macchia, F. Org.

Lett. 2005, 7, 3605; (d) Bournaud, C.; Falciola, C.; Lecourt, T.; Rosset, S.; Alexakis,

A.; Micouin, L. Org. Lett. 2006, 8, 3581; (e) Crotti, S.; Bertolini, F.; Macchia F.;

Pineschi, M. Chem. Commun. 2008, 3127; (f) Palais, L.; Mikhel, I. S.; Bournaud, C.;

Micouin, L.; Falciola, C. A.; Vuagnoux-d'Augustin, M.; Rosset, S.; Bernardinelli G.;

Alexakis, A. Angew. Chem. Int. Ed. 2007, 46, 7462; (g) Bournaud, C.; Chung, F.;

Luna, A. P.; Pasco, M.; Errasti, G.; Lecourt, T.; Micouin, L. Synthesis 2009, 869.

17. (a) Radhakrishnan, K. V.; Sajisha, V. S.; Anas S., Krishnan K. S., Synlett 2005,

2273; (b) Sajisha, V. S.; Mohanlal, S.; Anas, S.; Radhakrishnan, K. V. Tetrahedron

2006, 62, 3997; (c) Sajisha V. S.; Radhakrishnan, K. V. Adv. Synth. Catal. 2006, 348,

924; (d) John, J.; Sajisha, V. S.; Mohanlal S.; Radhakrishnan, K. V. Chem. Commun.

2006, 3510; (e) John, J.; Anas, S.; Sajisha, V. S.; Viji, S.; Radhakrishnan, K. V.

Tetrahedron Lett. 2007, 48, 7225. (f) Anas, S.; John, J.; Sajisha, V. S.; John, J.; Rajan,

R.; Suresh E.; Radhakrishnan, K. V. Org. Biomol. Chem., 2007, 5, 4010; (g) Anas, S.;

Sajisha, V. S.; John, J.; Joseph, N.; George, S. C.; Radhakrishnan, K. V. Tetrahedron

2008, 64, 9689.

18. Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2005, 7, 2229

19. Miura, T.; Murakami, M. Org. lett. 2005, 7, 3339 (a) Larock, R. C.; Yum, E. K. J. Am.

Chem. Soc. 1991, 113, 6689. (b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org.

Chem. 1998, 63, 7652.

20. (a) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515.

(b) Berecibar, A.; Grandjean, C.; Siriwardena, A. Chem. Rev. 1999, 99, 779.

21. Alejandro Pe´rez Luna,† Miche`le Cesario,‡ Martine Bonin,† and Laurent Micouin*, Org.

Lett, 2003, 5, 4771-4775.

22. (1) For reviews, see: (a) Bournaud, C.; Chung, F.; Luna, A. P.; Pasco,M.; Errasti,

G.; Lecourt, T.; Micouin, L. Synthesis 2009, 869–887. (b)Rayabarapu, D. K.;

Cheng, C.-H. Acc. Chem. Res. 2007, 40, 971–983. (c)Lautens, M.; Fagnou, K.;

Heibert, S. Acc. Chem. Res. 2003, 36, 48–58.

23. Trost, B. M.; Dong, L.; Schroeder, G. M. J. Am. Chem. Soc. 2005, 127, 10259.