Advanced
Cross-Coupling Reaction of 2-halo1-methyl-1H-imidazo[4,5-b]pyridine Offers a New Synthetic Route to Mutagenic Heterocyclic Amine-PHIP and DMIP
Cross-Coupling Reaction of 2-halo1-methyl-1H-imidazo[4,5-b]pyridine Offers a New Synthetic Route to Mutagenic Heterocyclic Amine-PHIP and DMIP
Journal of the Korean Chemical Society. 2013. Jun, 57(3): 361-364
Copyright © 2013, Korea Chemical Society
  • Received : November 27, 2012
  • Accepted : April 09, 2013
  • Published : June 20, 2013
Download
PDF
e-PUB
PubReader
PPT
Export by style
Article
Author
Metrics
Cited by
TagCloud
About the Authors
Ayyiliath M. Sajith
Organic Chemistry Division, School of Chemical Sciences, Kasargod Govt. College, Kannur University, Kasargod, India.
Arayambath Muralidharan
Organic Chemistry Division, School of Chemical Sciences, Nehru Arts and Science College, Kannur University, Kannur, India
Ranjith P. Karuvalam
Organic Chemistry Division, School of Chemical Sciences, Kannur University Payannur Campus, India
Karickal R. Haridas
Organic Chemistry Division, School of Chemical Sciences, Kannur University Payannur Campus, India

Abstract
A modified synthetic approach to the synthesis of heterocyclic food mutagens, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PHIP) and 2-amino-1,6-dimethylimidazo[4,5-b]pyridine (DMIP) is reported. This route highlights an optimized palladium catalysed Buchwald cross-coupling of 2-halo-1-methyl-imidazo[4,5-b]pyridine with benzophenoneimine followed by acidic hydrolysis to yield compound 7 . Using finely tailored conditions, Suzuki cross-coupling reactions with highly efficient catalytic systems were performed as the final step on 8 to introduce the aryl group and methyl group on the heterocyclic core.
Keywords
INTRODUCTION
Imidazo pyridine derived structures are an important class of heterocycles that have been widely studied for biological activity. 1 They can be considered as structural analogs of purines and are of potential medicinal relevance. 2 These data stimulated our studies towards synthesis and medicinal chemistry applications 3 5 of this heterocyclic core. 6 9
A series of mutagenic and carcinogenic heterocyclic amines has been identified from cooked meat and fish. Most abundant of these heterocyclic amine is 2-amino-1- methyl-6-phenyl imidazo[4,5-b]pyridine 10 and 2-amino- 1,6-dimethylimidazo[4,5-b]pyridine. These amines are believed to form covalent DNA adducts 11 resulting in genetic mutations in animal and human models and is suspected to be responsible for various types of cancer such as prostate, breast and colon on humans. Hence, chemical standards of these mutagens needs to be made for biological assays to assess the risk associated with their consumption.
Nowadays, microwave assisted organic synthesis (MAOS) 12 plays a key role in drug development. One of the most widely studied reactions in microwave reactors is Palladium- catalysed reactions which usually takes hours and days to for completion. Rapid lead generation and optimization has recently been facilitated by the emergence of MAOS 12 and the technique is today one of the major tool for the medicinal chemist. MAOS can facilitate the discovery of new reactions and reduce cycle time in optimization of reactions. In addition, it serves to expand the chemical space in compound library synthesis.
RESULTS AND DISCUSSION
As a part of our ongoing research on Imidazo[4,5- b]pyridine based structures, 8 we were interested in developing an expedient and flexible synthesis of PHIP and DMIP, that would be useful in making isotope labelled and metabolites of 9 and 10 . Different approaches for the synthesis of these potential food mutagens are available in literature. 13 - 16 In this paper we report an alternative approach to the synthesis of these amines. Our method relies upon the synthesis of 2-halo-1-methyl-imidazo[4,5-b]pyridine derivative, 6 as outlined in 1 , which provides an easy handle for incorporating various functionalities at the second position of this heterocyclic core. This halo intermediate was efficiently synthesized starting from 3-amino-2- nitro pyridine. The first step involves the diazotisation reaction of 1 to yield the fluoro intermediate in 65% yield, which was displaced by methyl amine in THF at RT to get compound 3. Compound 3 was reduced by Fe/AcOH to yield the diamine derivative which was treated with formic acid and trimethylorthoformate to access the Imidazo[4,5- b]pyridine core 5 .
PPT Slide
Lager Image
Synthesis of Bromo intermediate.
Metallation reactions of 5 with different bases (n-BuLi, t-BuLi, LDA) were explored to find an optimum condition for the synthesis of the halo intermediate 6 . The chloro intermediate was synthesized according to the procedure mentioned in reference 8. Tertiary butyl lithium was found to be a better choice of base to yield compound 6 in high yields. With n-BuLi we observed n-Butylated product as a competing side product along with the required product. Once the halo intermediate 6 is synthesized, it could be used as an effective handle for preparing novel analogs based on the core structure which can lead to much more diverse molecules which are prone to have potential biological importance.
The use of benzophenone imine as nucleophilic crosscoupling partner 17 in the Buchwald cross-coupling reactions aryl/heteroaryl halides with subsequent hydrolysis of the resultant imine permits the conversion of aryl/heteroaryl halides to their corresponding amine derivatives. Though many other ammonia equivalents 18 19 have been used to attain this goal, however, benzophenone imine remains the widely employed reagent in the presence of range of functional groups, with aryl/heteroaryl halides. In this paper we report the use of benzophenoneimine as the masking amine source for the synthesis of potential food mutagens PHIP and DMIP.
Effect of catalyst on the Buchwald couplingaof6aand6bwith benzophenoneimine
PPT Slide
Lager Image
aReaction conditions: 6a (0.5 mmol), benzophenoneimine (0.9 mmol), K3PO4 (3 mmol), Pd catalyst (5 mol %), Ligand (10 mol%), Dioxan, 120 oC microwave. After completion of the reaction as indicated by TLC, HCl was added to the reaction mixture and stirred at RT overnight. bYields correspond to isolated yields of 7. c6b was used as the halo intermediate instead of 6a.
Effect of base on the Buchwald couplingaof6aand6bwith benzophenoneimine
PPT Slide
Lager Image
aReaction conditions: 6 (0.5 mmol), benzophenoneimine (0.9 mmol), K3PO4 (3 mmol), Pd2(dba)3 catalyst (5 mol %), RuPhos (10 mol %), Dioxan, 120 oC microwave. After completion of the reaction as indicated by TLC, HCl was added to the reaction mixture and stirred at RT overnight. bYields correspond to isolated yields of 7. c6b was used as the halo intermediate instead of 6a.
Palladium catalysed Buchwald cross-coupling reactions were employed on the halo intermediate, (6a, and 6b) with benzophenoneimine followed by treating the crude reaction mixture in THF with HCl to get compound 7. Different palladium catalysts and ligands combinations were tried on this system to find an appropriate catalyst that would enhance the coupling ( 1 ). 2 shows the different bases that were explored in order to find an effective base that would enhance the coupling yield. From the table it is clear that K 3 PO 4 was found to be an effective base among all the bases explored. Surprisingly, Pd 2 (dba) 3 /RuPhos was found to give better conversions to product compared to other catalytic systems. A major problem encountered during this coupling reaction was the dehalogenation. It has been shown that increasing the catalytic activity of the palladium catalyst employed by using ligands which are sterically demanding and electronically rich, facilitates the coupling. Thus using Pd 2 (dba) 3 /Ru-Phos combination we could get 50% yield over two steps to yield the compound 7. Both the halo intermediates (Br, Cl) were found to be effective under Buchwald conditions and yielded the amine intermediate in reasonable yields, 1 . The use of the weak base K 3 PO 4 provides excellent functional group tolerance and was found to be superior in enhancing the yield. Bromination of 7 using Bromine/AcOH yielded the compound 8 in excellent yields. Finally, Suzuki coupling was employed on compound 8 to access the title compounds PHIP and DMIP. In the synthesis of DMIP, 3 , we found that adding water to the reaction mixture as employed for the synthesis of PHIP, 2 , yielded less product formation and hence non-aqueous conditions were employed for Suzuki coupling. Under these finely tailored conditions, Trimethyl boroxine was found to be more effective cross-coupling reagent compared to methyl boronic acid. Incomplete conversions and use of excess methyl boronic acids to drive the reactions to reasonable conversions were required when compared to trimethylboroxine. The use of trimethylboroxine in this cross-coupling reaction was instrumental in the synthesis of DMIP. 3 shows the effect of base in the Suzuki coupling reaction of 8 with Trimethyl boroxine. The use of highly efficient catalytic systems was required due to the possibility of catalyst deactivation that can be encountered while using hetero aromatic substrates as the cross-coupling partners, 4 . Both P(tBu) 3 and PCy 3 were found to be effective ligands along with Pd 2 (dba) 3 for the Suzuki cross-coupling reactions of 8 with trimethylboroxine. The use of S-Phos as a choice of ligand under aqueous conditions was required for better conversions of Suzuki coupled product, as the reaction under non aqueous conditions using phenyl boronic acid showed only traces of product formation. Since compounds 9 and 10 are known mutagens and suspected carcinogens, direct contact should be avoided.
PPT Slide
Lager Image
Synthesis of DMIP.
PPT Slide
Lager Image
Synthesis of PHIP.
4.
PPT Slide
Lager Image
Structures of the ligands used for screening the Buchwald reaction.
Effect of base on the Suzuki couplingaof8with Trimethyl boroxine
PPT Slide
Lager Image
aReaction conditions: 8 (1 equiv), Trimethyl boroxine (1.3 equiv), Base (3 equiv), Pd2(dba)3 catalyst (5 mol %), P(tBu)3 (10 mol %), Dioxan, 120 oC microwave.
Effect of catalytic system on the Suzuki couplinga of8with Trimethyl boroxine
PPT Slide
Lager Image
aReaction conditions: 8 (1 equiv), Trimethyl boroxine (1.3 equiv), Base (3 equiv), Pd2(dba)3 catalyst (5 mol %), Ligand (10 mol %), Dioxan, 120 oC microwave.
The efficiency with which the catalytically active, monoligated Pd(0) complex is formed before entering the catalytic cycle is the deciding factor in the selection of reaction protocol for palladium catalyzed amination reactions. If a Pd(II) salt such as Pd(OAC) 2 is used, reduction of Pd(II) to Pd(0) must occur before the cross-coupling reaction can take place. The need for reduction step to form Pd(0) can be avoided by using a stable Pd(0) complex as the Pd source. In many cases, Pd 2 (dba) 3 was found to be suitable and effective palladium source in conjunction with dialkylbiaryl phosphines for Buchwald cross-coupling reactions and in our Buchwald reaction protocol we can see that Pd 2 (dba) 3 along with RuPhos followed by acid hydrolysis provided better conversions to 7 ( 1 ). The most important advantages of this route to access these title compounds are safer reaction conditions compared to the other routes employed in the previous literature. Moreover, the conversion of 5 to 7 required higher temperatures and pressures in bomb calorimeter in previously reported methods. Here we employ a much safer and environmentally friendly method to access compound 7.
CONCLUSION
We have reported a new route to the synthesis of potential food mutagen, PHIP and DMIP (compounds 9 and 10). This route involves metallation reaction on 5 to yield compound 6 , which can be used as efficient intermediate for further derivatzation to yield novel analogs. Also optimised palladium catalysed Buchwald cross-coupling reaction was employed in this synthetic route which can be useful in synthesizing novel N-arylated Imidazo[4,5-b]pyridines.
Acknowledgements
The authors are thankful to organic chemistry division, School of Chemical Science department, Kannur University and the Head of chemistry department, Professor Gopalan, Govt. College Kasargod for providing facilities and good support for research work. And the publication cost of this paper was supported by the Korean Chemical Society.
References
Aridoss G. , Balasubramaniam S. , Parthiban P. , Kabilan S. 2006 Eur. J. Med. Chem. 41 268 -    DOI : 10.1016/j.ejmech.2005.10.014
Youssef A. F. , E1-Gendy M. A. , Aboutaleb N. A. E. , Ahmed S. H. 1982 Egypt. J. Pharm. Sci. 23 131 -
Cristalli G. , Vittori S. , Eleuteri A. , Volpini R. , Vamaioni E. , Lupidi G. , Mohmoud N. , Bevilacqua F. , Palu G. 1995 J. Med. Chem. 38 4019 -    DOI : 10.1021/jm00020a017
Temple C. , Rose J. D. , Combu R. N. , Rener G. A. 1987 J. Med. Chem. 30 1746 -    DOI : 10.1021/jm00393a011
Temple C. 1990 J. Med. Chem. 33 656 -    DOI : 10.1021/jm00164a030
Bukowski L. , Janowiec M. 1989 Pharmazie 44 267 -
Itoh T. , Mase T. 2005 Tetrahedron Lett 46 3573 -    DOI : 10.1016/j.tetlet.2005.03.053
Sajith A. M. , Muralidharan A. 2012 Tetrahedron Lett 53 1036 -    DOI : 10.1016/j.tetlet.2011.12.051
Doucet H. , Hierso J. 2007 Angew. Chem., Int. Ed. 46 834 -    DOI : 10.1002/anie.200602761
Felton J. S. , Knize M. G. , Shen N. H. , Lewis I. R. , Anderson B. D. , Happe J. , Hatch F. T. 1986 Carcinogenesis 7 1081 -    DOI : 10.1093/carcin/7.7.1081
Buonarati N. H. , Tucker J. V. , Minkler J. L. , Wu R. W. , Thompson L. H. , Felton J. S. 1991 Mutagenesis 6 253 - 259    DOI : 10.1093/mutage/6.4.253
Knize M. G. , Felton J. S. 1986 Heterocycles 24 1815 - 1819    DOI : 10.3987/R-1986-07-1815
Fabio S. B. , Tullio C. 1997 Tetrahedron Lett 38 7793 - 7796    DOI : 10.1016/f0040-4039(97)10039-9
Christopher J. C. , James E. B. , Mary J. T. 2002 ARKIVOC 90 - 96
Tominari C. , Akiko T. , Haruyuki Y. , Kenichi H. , Eiichi S. , SatoshI H. 1993 J. Org. Chem. 58 7952 - 7954    DOI : 10.1021/jo00079a055
Wolfe J. P. , Ahman J. , Sadighi J. P. , Singer R. A. , Buchwald S. L. 1997 Tetrahedron Lett 38 6367 - 6370    DOI : 10.1016/f0040-4039(97)01465-2
Lee S. , Jorgensen M. , Hartwig J. F. 2001 Org. Lett. 3 2729 - 2732    DOI : 10.1021/ol016333y
Huang X. H. , Buchwald S. L. 2001 Org. Lett. 3 3417 - 3419    DOI : 10.1021/ol0166808