1. 6 th J-NOST CONFERENCE DATE: 30.01.2011 VENUE: DST Auditorium UNIVERSITY OF HYDERABAD DATE: 30.01.2011 VENUE: DST Auditorium UNIVERSITY OF HYDERABAD DISCOVERY OF SOLID STATE MELT REACTION FOR THE DOMINO PROCESS DISCOVERY OF SOLID STATE MELT REACTION FOR THE DOMINO PROCESS by D. KANNAN Dr. M. BAKTHADOSS RESEARCH LABORATORY RESEARCH SCHOLAR DEPARTMENT OF ORGANIC CHEMISTRY UNIVERSITY OF MADRAS GUINDY CAMPUS, CHENNAI – 600 025 by D. KANNAN Dr. M. BAKTHADOSS RESEARCH LABORATORY RESEARCH SCHOLAR DEPARTMENT OF ORGANIC CHEMISTRY UNIVERSITY OF MADRAS GUINDY CAMPUS, CHENNAI – 600 025

2. Org. Lett. 2009, 11, 4466-4469 Damodharan Kannan, Manickam Bakthadoss* SOLID STATE MELT REACTION FOR THE DOMINO PROCESS: HIGHLY EFFICIENT SYNTHESIS OF FUSED TETRACYCLIC CHROMENOPYRAN PYRIMIDINEDIONES USING BAYLIS-HILLMAN DERIVATIVES

3. Domino The name was chosen from the game where one puts up several domino pieces in one row and in agreement with the time-resolved succession of reactions, if one knocks over the first domino, all the others follow without changing the conditions. The name was chosen from the game where one puts up several domino pieces in one row and in agreement with the time-resolved succession of reactions, if one knocks over the first domino, all the others follow without changing the conditions. Domino reaction Domino reaction a process involving two or more bond-forming transformations take place under the same reaction conditions without adding additional reagents and catalysts, the subsequent reactions result as a consequence of the functionality formed in the previous step. a process involving two or more bond-forming transformations take place under the same reaction conditions without adding additional reagents and catalysts, the subsequent reactions result as a consequence of the functionality formed in the previous step. Domino reactions Domino reactions very attractive very attractive a useful strategy which minimizes the reaction steps to achieve the target complex organic compounds with high yields. a useful strategy which minimizes the reaction steps to achieve the target complex organic compounds with high yields. Domino reaction 3

4. Domino Knoevenagel–hetero-Diels-Alder reaction 4 The domino Knoevenagel–hetero-Diels–Alder reaction:  powerful sequential transformation has been proven to be a valuable method for the construction of annulated dihydropyrans  The intramolecular variety of the reaction has gained much popularity ‘two component reaction’ putting together a 1,3-dicarbonyl compound and an aldehyde containing a dienophile moiety.  Synthesis of several natural products. The domino Knoevenagel–hetero-Diels–Alder reaction:  powerful sequential transformation has been proven to be a valuable method for the construction of annulated dihydropyrans  The intramolecular variety of the reaction has gained much popularity ‘two component reaction’ putting together a 1,3-dicarbonyl compound and an aldehyde containing a dienophile moiety.  Synthesis of several natural products. Tietze, L. F. Chem. Rev. 1996, 96, 115-136

5.  The Baylis-Hillman reaction, atom-economic carbon-carbon bond-forming reaction between the activated alkenes (alkynes) and carbon electrophiles in the presence of a tertiary amine base, which affords a highly functionalized product.  The Baylis-Hillman adducts have been widely used as intermediates for the synthesis of some useful compounds which have both synthetic and biological applications  The Baylis-Hillman reaction, atom-economic carbon-carbon bond-forming reaction between the activated alkenes (alkynes) and carbon electrophiles in the presence of a tertiary amine base, which affords a highly functionalized product.  The Baylis-Hillman adducts have been widely used as intermediates for the synthesis of some useful compounds which have both synthetic and biological applications BAYLIS – HILLMAN REACTION 5 Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110, 5447–5674

6. Synthesis of Fused Tetracyclic Chromenopyran pyrimidinediones Using Baylis-Hillman Derivatives 6

7. 7 Synthesis of complex heterocyclic compounds is very challenging in the field of organic chemistry and synthesized by a multistep reaction sequence. Recently domino reactions have become very attractive to achieve the target complex organic compounds with high yields. The domino Knoevenagel intramolecular hetero-Diels-Alder reaction is one of the most powerful synthetic routes for the synthesis of various heterocycles and natural products Flurry of activity in the synthesis of pyrimidine derivatives due to their proven biological activity and medicinal utility The Baylis-Hillman adducts and their derivatives are useful intermediates for the synthesis of many natural products and biologically active molecules Introduction

8. To the best of our knowledge, Baylis-Hillman derivatives have not been utilized for the domino Knoevenagel intramolecular hetero-Diels-Alder reaction.  Generally domino Knoevenagel intramolecular hetero-Diels-Alder reactions are carried out with catalyst, solvent or microwave irradiation. We envisaged that this intramolecular hetero-Diels-Alder reaction can be conducted without the above mentioned essential reaction components/conditions which are very important criteria in green synthesis.  In continuation of our interest in the field of Baylis-Hillman chemistry, we discovered a novel SOLID STATE MELT REACTION (SSMR) via a domino process for the synthesis of complex tetracyclic chromenopyran pyrimidinedione frameworks in a highly stereoselective and stereospecific fashion using Baylis-Hillman derivatives  Thus new routes for the synthesis of these complex tetracyclic chromenopyran pyrimidinedione frameworks have attracted considerable attention in search for a rapid entry to these heterocycles and their diverse biological properties. To the best of our knowledge, Baylis-Hillman derivatives have not been utilized for the domino Knoevenagel intramolecular hetero-Diels-Alder reaction.  Generally domino Knoevenagel intramolecular hetero-Diels-Alder reactions are carried out with catalyst, solvent or microwave irradiation. We envisaged that this intramolecular hetero-Diels-Alder reaction can be conducted without the above mentioned essential reaction components/conditions which are very important criteria in green synthesis.  In continuation of our interest in the field of Baylis-Hillman chemistry, we discovered a novel SOLID STATE MELT REACTION (SSMR) via a domino process for the synthesis of complex tetracyclic chromenopyran pyrimidinedione frameworks in a highly stereoselective and stereospecific fashion using Baylis-Hillman derivatives  Thus new routes for the synthesis of these complex tetracyclic chromenopyran pyrimidinedione frameworks have attracted considerable attention in search for a rapid entry to these heterocycles and their diverse biological properties. 8

9. Retrosynthetic Strategy for the Synthesis of Tetracyclic Frameworks 9

10. S.NoCatalyst (20 mol%) Temperature (°C) SolventTime (h) Product (%) 3a4a 1EDDA110Toluene657- 2AlCl 3 110Toluene6-- 3BF 3 (OEt) 2 110Toluene6-- 4CAN110Toluene629- 5-110Toluene624- 6-100-157- 7-120-186- 8-140-17221 9-160-12372 10-180-1-98 Table 1. Optimization for the formation of Tetracyclic Compound using various catalysts and conditions 10

11. Synthesis of Fused Tetracyclic Chromenopyran pyrimidinediones using Baylis-Hillman Derivatives Synthesis of Fused Tetracyclic Chromenopyran pyrimidinediones using Baylis-Hillman Derivatives 11 Org. Lett. 2009, 11, 4466-4469

12. Synthesis of Tetracyclic Chromenopyran Pyrimidinediones Using N, N-Dimethylbarbituric acid and Baylis-Hillman Derivatives with ester group (1a-j) Synthesis of Tetracyclic Chromenopyran Pyrimidinediones Using N, N-Dimethylbarbituric acid and Baylis-Hillman Derivatives with ester group (1a-j) 12

13. S.NoSubstrate RProductTime (h)Yield (%) 11a H4a198 21b 2-Me4b196 31c 4-Me4c198 41d 4-Et4d197 51e 4- i Pr4e198 61f 4-OMe4f197 71g 2-Cl4g195 81h 3-Cl4h193 91i 4-Cl4i196 101j 2-NO 2 4j192 Table 2. Synthesis of Tetracyclic Chromenopyran Pyrimidinediones Using N,N-Dimethylbarbituric acid and Baylis-Hillman Derivatives (1a-j). Table 2. Synthesis of Tetracyclic Chromenopyran Pyrimidinediones Using N,N-Dimethylbarbituric acid and Baylis-Hillman Derivatives (1a-j). 13

14. 1 H-NMR spectrum of compound 4a 14

15. Figure 1. X-ray crystal structure of 4a 15

16. Synthesis of Tetracyclic Chromenopyran Pyrimidinediones Using Cyclohexane-1,3-dione and Baylis-Hillman Derivative 1a 16

17. Synthesis of Tetracyclic chromenopyran Pyrimidenedione Using 5,5-Dimethylcyclohexane-1,3-dione and Baylis-Hillman Derivative 1a Synthesis of Tetracyclic chromenopyran Pyrimidenedione Using 5,5-Dimethylcyclohexane-1,3-dione and Baylis-Hillman Derivative 1a 17

18. Synthesis of Tetracyclic chromenopyran Pyrimidenedione Using N,N-Dimethylbarbituric Acid and Baylis-Hillman Derivatives (11a-j). Synthesis of Tetracyclic chromenopyran Pyrimidenedione Using N,N-Dimethylbarbituric Acid and Baylis-Hillman Derivatives (11a-j). 18

19. S.NoSubstrateR1R1 ProductTime (h) Yield (%) 111a H13a197 211b 2-Me13b198 311c 4-Me13c198 411d 4-Et13d196 511e 4- i Pr13e195 611f 4-OMe13f198 711g 2-Cl13g194 811h 3-Cl13h192 911i 4-Cl13i193 1011j 2,4-Dichloro13j192 Table 3. Synthesis of Tetracyclic chromenopyran Pyrimidenedione Using N,N-Di-methylbarbituric Acid and Baylis-Hillman Derivatives (11a-j). 19

20. 1 H-NMR spectrum of compound 13a 20

21. Figure 2. X-ray crystal structure of 13a 21

22.  Successfully developed a simple and novel protocol for the facile synthesis of complex angularly substituted tetracyclic frameworks containing a chromenopyran pyrimidinedione ring system via a solid state melt reaction (SSMR) through a domino process using Baylis-Hillman derivatives.  Notable features: (a) catalyst and solvent is not required even for solid reactants (b) high stereoselective and stereospecific fashion (c) does not require any column chromatography purification (d) Excellent yields  The new [4+2] cycloaddition leads to a novel class of angularly substituted fused tetracyclic frameworks containing a chromenopyran pyrimidinediones, creating two rings, three contiguous stereogenic centres, one of them being a tetrasubstituted carbon center in a unique fashion.  This strategy opens new opportunities for the preparation of libraries of a wide variety of chromenopyran pyrimidinedione derivatives for biological screening.  Successfully developed a simple and novel protocol for the facile synthesis of complex angularly substituted tetracyclic frameworks containing a chromenopyran pyrimidinedione ring system via a solid state melt reaction (SSMR) through a domino process using Baylis-Hillman derivatives.  Notable features: (a) catalyst and solvent is not required even for solid reactants (b) high stereoselective and stereospecific fashion (c) does not require any column chromatography purification (d) Excellent yields  The new [4+2] cycloaddition leads to a novel class of angularly substituted fused tetracyclic frameworks containing a chromenopyran pyrimidinediones, creating two rings, three contiguous stereogenic centres, one of them being a tetrasubstituted carbon center in a unique fashion.  This strategy opens new opportunities for the preparation of libraries of a wide variety of chromenopyran pyrimidinedione derivatives for biological screening. CONCLUSION 22

23. Dr. M. BAKTHADOSS RESEARCH SUPERVISOR Department of Organic Chemistry University of Madras UGC-JRF and CSIR–SRF for Financial assistance UNIVERSITY OF MADRAS for Infrastructure facility J-NOST Organizing Committee UNIVERSITY OF HYDERABAD Dr. M. BAKTHADOSS RESEARCH SUPERVISOR Department of Organic Chemistry University of Madras UGC-JRF and CSIR–SRF for Financial assistance UNIVERSITY OF MADRAS for Infrastructure facility J-NOST Organizing Committee UNIVERSITY OF HYDERABAD Acknowledgement 23

24. THANK YOU 24

25. Synthesis of required precursors from Baylis – Hillman adducts 25

26. 26 1 H-NMR spectrum of intermediate 3a

27. 27 13 C-NMR spectrum of intermediate 3a

28. 13 C-NMR spectrum of compound 4a 28

29. 13 C-NMR spectrum of compound 13a 29