RESEARCH CONTRIBUTIONS IN DETAIL


PHILOSOPHY OF OUR RESEARCH


DESIGN, SYNTHESIS AND APPLICATIONS OF MOLECULES HAVING THREE PROXIMAL FUNCTIONAL GROUPS

Bond forming and bond cleavage reactions play the most fundamental role in the ocean of organic chemistry and functional groups are the key players in these reactions. Each functional group has distinct properties and reaction profile. Proximity of functional groups in a molecule creates a unique avenue for reactivity pattern. Thus if two functional groups in a molecule are in proximity, such a molecule shows additional or even entirely different properties besides that of individual functional group present. Such uniqueness is not possible if these two functional groups are several atoms or groups apart.


INSIGHT:

Since the proximal presence of two functional groups in a molecule provides a highly divergent and different reaction profile, we envisioned that the molecules containing three proximal functional groups (Fig.1) will not only provide a unique reaction domain but also lead to new concepts in organic synthesis. However literature survey clearly reveals that there are no well established methodologies for the synthesis of such molecules.


OBJECTIVES:

1) To develop simple and facile strategies for synthesis of diverse classes of molecules containing three functional groups in proximity via one-pot C-C bond forming reaction. 2) To understand the chemistry and properties and to explore the applications of such diverse classes of molecules, containing three functional groups in proximity, in organic synthesis.


TOWARDS DEVELOPMENT OF BAYLIS-HILLMAN REACTION

For more information see Chimia 2013, 67, 8-16.

ORIGIN

Since my post-graduation (M.Sc.) days (1970-1972) at Department of Chemistry, Banaras Hindu University (BHU) I was fascinated by the Diels-Alder reaction because of its high and diverse levels of applications in organic synthesis. During that time we had excellent teachers who had tremendous influence on my thinking about organic chemistry. Professor Gurbakhsh Singh (who did Ph. D. at Harvard with Professor R. B. Woodward) was one such teacher whose brilliant teachings clearly indicated that there is a need to discover/uncover many more new reactions and synthetic strategies, although there are many name and unnamed reactions, to meet the challenges arising from continuous developments. It was also very clear from his thought provoking lectures that discovering/ developing new useful organic reaction(s) will not only be extremely difficult but also be the most challenging research endeavors that need several years of hard work and dedicated efforts. During that time, the molecule which had great impact on my chemistry understanding was methyl vinyl ketone (MVK) (Fig. 2) because of its high reactivity and versatility (aldol reaction at C-1; 1,2-addition at C-2; Michael reaction at C-4; and as diene for Diels-Alder reaction). One question used to bother me: Why there was no reaction known at C-3 of MVK as shown in Fig. 2 ? One day I asked Professor Gurbakhsh Singh the same question after his lecture. He smiled and told me that this aspect was not studied till then and performing any reaction at C-3 of MVK would, in fact, be challenging and useful endeavor. It was indeed a very interesting answer.



After my M. Sc., I joined the research group of Professor Gurbakhsh Singh for Ph. D. program at BHU. During those days I also had an opportunity of having excellent senior colleagues. In the beginning of my Ph. D. days, I started looking into patents through Chemical Abstracts based on the suggestion of a senior colleague with a view to originate ideas for research work. At that time, I came across a brilliant and highly promising patent by Baylis and Hillman (1972) (I used to write interesting reactions in my library note book and thus this patent information was noted down).1 This patent describes the coupling reaction between α-position of acrylates / acrylonitrile/ methyl vinyl ketone/ acrylamide with aldehydes under the influence of a tertiary amine providing multifunctional molecules. This patent impressed me very much. I started keeping track of any research work in the literature related to this patent. After obtaining my Ph. D. degree I joined the research group of Professor Herbert C. Brown at Purdue University for three years, that is, during 1980-1983 as a post doctoral fellow.

I was surprised to note that no publication appeared in the literature having any relation with this fascinating patent for almost a decade (during 1972-1981). I saw the first publication in the year 1982 by Drewes and Emslie from South Africa, on the application of patent of Baylis and Hillman.2 This paper describes an interesting DABCO catalyzed reaction between ethyl acrylate and acetaldehyde to provide the corresponding adduct which was subsequently transformed into integerrinecic acid (Scheme 1).2




In the subsequent year (1983), Hoffmann and Rabe (from Germany) published two back to back papers on the coupling of methyl and t-butyl acrylates with aldehydes using DABCO as catalyst.3 One such resulting adduct thus obtained via the reaction of acetaldehyde with t-butyl acrylate was elegantly used for the synthesis of mikanecic acid (Scheme 2).3a




After being fascinated by Baylis and Hillman patent, I checked the literature thoroughly to see whether there was anything known before this. I noticed three interesting reports: (1) A patent by Rauhut and Currier on trialkyl-phosphine catalyzed dimerization of alkyl acrylates to provide dialkyl 2-methylene-glutarate derivatives in the year 1963 (one example is given in Eq. 1),4 (2) Two brilliant publications in the year 1968 by Morita and coworkers who reported tricyclohexylphosphine catalyzed reaction between aldehydes and acrylates to provide 2-methylene-3-hydroxyalkanoates. (Eq. 2).5



VISION AND AIM

Based on the above-mentioned Baylis-Hillman patent (actually buried in the literature) information and a few other related reports, we envisioned in the year 1984 that the patent by Baylis and Hillman will not only have a great potential as a novel three component C-C bond forming reaction (see Fig. 3) but also create challenging opportunities toward discovering new directions in organic chemistry in the years to come. Having envisioned the great potential of Baylis-Hillman patent as shown in Fig.3 we surmised that this reaction would address and fit best into the philosophy of our research. This reaction would provide molecules with three proximal functional groups via atom-economical formation of C-C-bond. These molecules with three proximal functional groups can be viewed in six different possible ways (Fig.4) and thus chemistry of these molecules can be designed and executed. In addition, this class of molecules can serve as a source of various reactive species which will offer new avenues in synthetic and mechanistic chemistry (Fig.5). On the basis of the above-mentioned insight we also believed that this reaction will prove to be as useful and popular as the well known Diels-Alder reaction. Thus our aim is to work in this direction, and make this reaction if possible, more useful and popular than the Diels-Alder reaction.






We therefore initiated a major long term research program in the year 1984 at the School of Chemistry, University of Hyderabad in this direction towards understanding as well as expanding the potential and scope of this reaction. While we were working in this direction an interesting report appeared from Perlmutter and Teo describing the coupling between acrylates and aldimine derivatives to produce the corresponding allyl amine derivatives.6 In fact we have been working for the past 33 + years and contributed significantly to the growth of this reaction.

Fundamental Contributions Towards Development of Baylis-Hillman Reaction

Our research group has contributed significantly for the growth of the Baylis-Hillman reaction in terms of all the three essential components.7- 31 Some of these developments are presented in Figures 6-28. Our group has also reported the application of chiral acrylates as activated alkenes in the asymmetric Baylis-Hillman reaction (Fig. 25).25 Our group has also demonstrated use of a chiral catalyst in asymmetric Baylis-Hillman reaction. Quinidine catalyzed Baylis-Hillman reaction between acrylonitrile and aldehydes provides the resulting adducts up to 20% enantiomeric purities. (Fig.26).25b Although the enantioselectivities are not high, this study demonstrates the applications of chiral catalysts and also indicates that design of appropriate catalysts would provide high enantioselectivities.



























Fundamental Contributions Towards Development of Baylis-Hillman adducts as valuable substrates in organic synthesis

The present levels of enormous popularity, growth, and importance of the Baylis-Hillman reaction can be largely attributed to the high versatility and extensive synthetic applications of the Baylis-Hillman adducts that contain a minimum of three functional groups in close proximity. We have used these adducts as valuable substrates in various organic transformations (Fig. 29-32).32-73 We have developed several stereo-selective synthetic methodologies using the Baylis-Hillman adducts, thus demonstrating the importance of these adducts as a valuable source for diverse organic transformations.32-73 Our research group also successfully employed the Baylis-Hillman adducts for the synthesis of several molecules of biological importance/relevance32-73 [representative compounds (1-59) are listed in Figs. 30 and 31]. We continue to have a long term research program on the Baylis-Hillman reaction with the main objective of developing this fascinating reaction as an operationally simple, convenient, useful, and powerful synthetic tool for carbon-carbon bond formation in order to provide an easy means of assembling carbon frameworks. The present day Baylis-Hillman reaction is presented in Scheme 32.

We have written three major reviews 74-76 (Tetrahedron 1996, 52, 8001-8062; Chem. Rev. 2003, 103, 811-891; Chem. Rev. 2010, 110, 5447-5674) and four mini reviews 77-80 (Chem. Soc. Rev. 2007, 36, 1581 -1588; Chem. Soc. Rev. 2012, 41, 68-78; Chimia 2013, 67, 8-16; ARKIVOC 2016, 172-205) highlighting the salient features of development of BH reaction and future projections on this fascinating reaction. Our mini review in Chimia79 (Chimia 2013, 67, 8-16) describes accounts of our own work on the Baylis–Hillman reaction. Our research is now focused towards development of single component and multi-BH reactions.








References:

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  33. D. Basavaiah, K. Muthukumaran, B. Sreenivasulu Synthesis 2000, 545-548.
  34. D. Basavaiah, S. Pandiaraju Tetrahedron 1996, 52, 2261-2268.
  35. D. Basavaiah, N. Kumaragurubaran, K. Padmaja Synlett 1999, 1630-1632.
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  37. D. Basavaiah, S. Pandiaraju, K. Padmaja Synlett 1996, 393-395.
  38. D. Basavaiah, M. Krishnamacharyulu, R. S. Hyma, S. Pandiaraju Tetrahedron Lett. 1997, 38, 2141-2144.
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  40. D. Basavaiah, K Padmaja, T. Satyanarayana Synthesis 2000, 1662-1664.
  41. D. Basavaiah, M. Krishnamacharyulu, R. S. Hyma, P. K. S. Sarma, N. Kumaragurubaran J. Org. Chem. 1999, 64, 1197-1200.
  42. D. Basavaiah, S. Pandiaraju, P. K. S. Sarma Tetrahedron Lett. 1994, 35, 4227-4230.
  43. D. Basavaiah, K. Muthukumaran Tetrahedron 1998, 54, 4943-4948.
  44. D. Basavaiah, R. J. Reddy, J. S. Rao Tetrahedron Lett. 2006, 47, 73-77.
  45. D. Basavaiah, M. Bakthadoss, S. Pandiaraju Chem. Commun. 1998, 1639-1640
  46. D. Basavaiah, T. Satyanarayana Chem. Commun. 2004, 32-33.
  47. D. Basavaiah, D. S. Sharada, A. Veerendhar Tetrahedron Lett. 2004, 45, 3081-3083.
  48. D. Basavaiah, J. S. Rao, R. J. Reddy J. Org. Chem. 2004, 69, 7379-7382.
  49. D. Basavaiah, T. Satyanarayana Org. Lett. 2001, 3, 3619-3622.
  50. D. Basavaiah, K. Aravindu Org. Lett. 2007, 9, 2453-2456.
  51. D. Basavaiah, S. Roy Org. Lett. 2008, 10,1819-1822.
  52. D. Basavaiah, B. Devendar, K. Aravindu, A. Veerendhar Chem. Eur.J. 2010, 16, 2031-2035.
  53. D. Basavaiah, T. Satyanarayana Tetrahedron Lett. 2002, 43, 4301-4303.
  54. D. Basavaiah, D. V. Lenin Eur. J. Org. Chem. 2010, 5650-5658.
  55. D. Basavaiah, K. Aravindu, K. S. Kumar, K. R. Reddy Eur. J. Org. Chem. 2010, 1843-1848
  56. D. Basavaiah, K. R. Reddy Tetrahedron, 2010, 66, 1215-1219.
  57. D. Basavaiah, R. J. Reddy Org. Biomol. Chem. 2008, 6, 1034-1039.
  58. D. Basavaiah, N. Kumaragurubaran Tetrahedron Lett. 2001, 42, 477-479.
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  67. D. Basavaiah, D. M. Reddy Org. Biomol. Chem. 2012, 10, 8774-8777.
  68. D. Basavaiah, S. S. Badsara, B. C. Sahu Chem. Eur. J. 2013, 19, 2961-2965.
  69. D. Basavaiah, S. S. Badsara, G.Veeraraghavaiah Tetrahedron, 2013, 69, 7995-8001.
  70. D. Basavaiah, D. M. Reddy RSC Adv. 2014, 4, 23966-23970.
  71. D. Basavaiah, K. S. Kumar, K. Aravindu, B. Lingaiah RSC Adv. 2013, 3, 9629-9632.
  72. D.Basavaiah, S. Pal, G.Veeraraghavaiah, K. C. Bharadwaj Tetrahedron, 2015, 71, 4659-4664.
  73. D. Basavaiah, B. Lingaiah, G. Chandrashekar Reddy, B. C. Sahu Eur. J. Org. Chem. 2016, 2398-2403.

Reviews from our group

  1. D. Basavaiah, P. D. Rao, R. S. Hyma Tetrahedron 1996, 52, 8001-8062.
  2. D. Basavaiah, A. J. Rao, T. Satyanarayana Chem. Rev. 2003, 103, 811-891.
  3. D. Basavaiah, B. S. Reddy, S. S. Badsara Chem. Rev. 2010, 110, 5447-5674
  4. D. Basavaiah, K. V. Rao, R. J. Reddy Chem. Soc. Rev. 2007, 36, 1581-1588.
  5. D. Basavaiah, G. Veeraraghavaiah Chem. Soc. Rev. 2012, 41, 68-78.
  6. D. Basavaiah, B. C. Sahu Chimia 2013, 67, 8-16.
  7. D. Basavaiah, G. C. Reddy ARKIVOC 2016, 172-205.

Selected reviews from other groups

  1. S. E.Drewes, G. H. P. Roos Tetrahedron 1988, 44, 4653-4670.
  2. E. Ciganek Organic Reactions; L. A. Paquette Ed; Wiley, New York: 1997, vol. 51, p 201-350.
  3. P.Langer Angew. Chem. Int. Ed., 2000, 39, 3049-3052.
  4. J. L Methot, W. R. Roush Adv. Synth. Catal. 2004, 346, 1035-1050.
  5. T. Kataoka, H. Kinoshita Eur. J. Org. Chem. 2005, 45-58.
  6. Y.-L Shi, M. Shi Org. Biomol. Chem. 2007, 5, 1499-1504.
  7. Y.-L Shi, M. Shi Eur. J. Org. Chem. 2007, 2905-2916.
  8. G. Masson, C. Housseman, J. Zhu Angew. Chem. Int. Ed. 2007, 46, 4614-4628.
  9. V. Singh, S. Batra Tetrahedron 2008, 64, 4511-4574.
  10. V. Declerck, J. Martinez, F. Lamaty Chem. Rev. 2009, 109, 1-48.
  11. C. E Aroyan, A. Dermenci, S.J. Miller Tetrahedron 2009, 65, 4069-4084.
  12. Y. Wei, M. Shi Acc. Chem. Res. 2010, 43, 1005-1018.
  13. T. Y. Liu, M. Xie, Y-C. Chen Chem. Soc. Rev. 2012, 41, 4101-4112.
  14. P.Xie, Y. Huang Eur. J. Org. Chem. 2013, 6213-6226.
  15. Y. Wei, M. Shi Chem. Rev., 2013, 113, 6659-6690.
  16. F.-L. Hu, M. Shi Org. Chem. Front. 2014, 1, 587-595.
  17. M. S. Santos, F. Coelho, C. G Lima-Junior, M.L. A. A. Vasconcellos Curr. Org. Synth. 2015, 12, 830-852.
  18. K. C. Bharadwaj RSC Adv. 2015, 5, 75923−75946.
  19. P. Xie, Y. Huang Org. Biomol. Chem. 2015, 13, 8578- 8595.
  20. H. Pellissier Tetrahedron 2017, 73, 2831-2861. etc.