Baylis hilman

Baylis hilman

1. BY Dr . Gurumeet.C.Wadhawa DEPARTMENT OF CHEMISTRY K. B. P . College,Vashi,Navimumbai Baylis-Hilman reaction

2. Introduction Two most fundamental reactions in synthetic organic chemistry functional group transformations Carbon-carbon bond formation Friedel-Crafts reaction Grignard reaction Diels-Alder reaction Wittig reaction Heck reaction Suzuki coupling Grubb’s RCM Some C-C bond forming reactions are- Morita-Baylis-Hillman Aldol reaction Reformatsky reaction Claisen rearrangements O Aldol 1,2-Addition 1, 4 - a d d i t io n Baylis Hillman Diels-Alder Five possible ways of constructing C-C bonds with MVK 3

3. Baylis-Hilman reaction It is a carbon-carbon bond forming reaction between the a-position of an activated alkene and an aldehyde or a carbon electrophile in presence of a nucleophilic catalyst such as tertiary amine and phosphine gives a densely functionalized product, if aldehyde as the electrophile is used functionalized allyl alcohol will the product. This reaction is also known as the Morita- Baylis -Hillman reaction or MBH. DABCO (1,4-Diazabicyclo[2,2,2]octane) is one of the most frequently used tertiary amine catalyst for this reaction. In addition nucleophilic amines such as DMAP (4-Dimethylamino pyridine) and DBU (1,8-Diazabicyclo [5,4,0]undec-7-ene) as well as phosphines have been found to successfully catalyze this reaction.

4. Advantages 1) It is an atom economic coupling reaction of easily prepared starting material. 2) Reaction of a pro- chiral electrophile generates a chiral centre therefore an asymmetric synthesis is possible. 3) Reaction products usually contain multiple functionalities in proximity so that a varity of further transformations are possible. 4) It can employ a nucleophilic organocatalytic system without the use of heavy metal under mild conditions.

5. Limitations Because of there is a great extent of variability in reaction substrates, it is often challenging to develop reaction conditions suitable for certain combination of substrates. The MBH reaction of an aryl vinyl ketone with an aldehyde is not straightforward, since the reactive aryl vinyl ketones readily adds first to another molecule of aryl vinyl ketone via Michael addition, then the adduct adds to the aldehyde to form a double MBH adduct.

6. 2 8 Hill, J. S.; Isaacs, N. S.; J. Phys. Org. Chem. 1990 , 3 , 285 Hill and Isaacs Mechanism Based on pressure dependence, rate, and kinetic isotope effect (KIE) data . ESMS and Tandem mass spectrometry. No α-proton cleavage occurs in the rate-determining step (RDS). Addition of the enolate to the aldehyde was the RDS. Ph R 3 N O Me O O R 3 N O Me O O Me O P h OMe O H O NR 3 Proposed RDS Int 1 Int 2 P h H O

7. Robiette, R.; Aggarwal, V. K.; Harvey, J. N.; J. Am. Chem. Soc ., 2007 , 129 , 15513 Mechanism of MBH reaction – based on computational method O O Me Alcohol catalyzed TS 1 NMe 3 O O Me O P h O H OMe Me 3 N Int 2 O 3 Me N Ph O O Me H O P h Hemi 1 O OM e Ph Me 3 N O H O P h RD S TS3-hemi O Me N P h O O M e O H P h 3 Hemi 2 O O P h O Ph O Ph O O Me O H Ph Hemi 3 Non-alcohol catalyzed O P h O H OMe MeO H Me 3 N Int 2 -MeOH TS 2-MeOH Ph O M e 3 N HOMe Me N COOM e O Ph H O M e H 3 TS 3 - M eO H R D S P h O OH O M e H O M e Me 3 N Int-MeOH O H O Me O Ph 2 9 Ph C H O Ph C H O I n t .1

8. Hindered bases with high p K a Higher the p K a of the conjugate acid of the amine higher the rate of reaction. (leading to increased concentrations of the intermediate ammonium enolate) e.g.; Quinuclidine (highest p K a), DBU. Improvement of reaction rate Important landmarks Hydrogen-bonding additives or solvents help the proton-transfer step. e.g.; MeOH/ t -BuOH/H 2 O Lewis acids with alcohol-based ligands The Lewis acid-alcohol complex results in increased acidity of the OH groups, which promotes proton-transfer events. 3

9. 3 1 XH Y ` R R * Three functional groups Via the functional group manipulation develop opportunities in organic synthesis Chiral center For asymmetric version offers challenge to develop efficient catalyst Intra-molecular version Offers challenges to design and synthesize novel class of substrates with several combinations of activated olefinic and electrophilic groups thereby leading to develop various cyclic frameworks of synthetic importance X= O, NR Y= Electron withdrawing group Offers challenge to develop novel activated alkenes , electrophiles and catalyst

10. 3 2 Pfizer, Pregabalin, Drugs Future , 2002 , 27 , 426 M e H M e O NC + DBU, DBP M e M e N C O H M e M e N C O Ac P y O E t NC M e O M e K OH O K NC M e O M e O t-BuNH 3 NC O M e Me H C l t-BuNH 2 P d( O A c ) 2 Ph 3 P CO, EtOH Chiral (R,R)-Rh catalyst H 2 Chiral (R,R)-Rh catalyst H 2 N C N C O K O M e Me O M e Me O t-BuNH 3 sponge Ni catalyst KOH, H 2 O H H 2 N M e O M e Pregabalin ( Lyrica ) Used in: Fibromyalagia spinal cord injury Neuropathic pain Baylis Hillman reaction AcCl, / Ac 2 O ( S )-3-(aminomethyl)-5-methylhexanoic acid Synthesis for Pregabalin

11. Dunn, et al; Organic Process Research & Development , 2003 , 3 7 3 , 244 Synthesis of Sampatrilat CO 2 Bu t + O 3-Quinuclidinol (0.25 eq) H 2 O, CH 3 CN, H O CO 2 Bu t C l 2 CO Bu t 2 SOCl (0.88 eq) Et 3 N (1.02eq) Py (0.1 eq) P h Et 3 N, 81% N P h H (S,S) (0.66 eq) H H (1.6eq) 2 N Ph Bu t O C P h C O 2 H (1.1 eq) LDA (2.2 eq) THF -30 to 20 O C CO 2 H N P h Ph Bu t O 2 C de > 98% N H CO 2 H O H HO 2 C H N NHSO 2 Me O H 2 N O Sampatrilat Baylis Hillman Reaction Vasopeptidase inhibitor Inhibits the angiotensin converting enzyme (ACE)

12. O H O N C H O M e OO C + O H OH O N COOMe DA B C O 88% O H O N COO M e DEAD, Ph 3 P AcOH, THF 77% C OO M e O A c OA c Dry HCl Et 2 O 99 % H 3 N Cl O N H O N N P h C OO H O DCC, HOBT, DMAP, CHCl 3 , 79% O N H O N O N Ph O N H O Me O O A c Baylis Hillman Reaction Potential Antimalarial Therapeutic Agents The antimalarial efficacy of compound is comparable to that of chloroquine with IC 50 6-8ng/mL against D-6 3 4 Zhu, S.; Hudson, T.H.; Kyle, D.E.; Lin, A.J.; J. Med. Chem. 2002, 45, 3491 Synthesis of Novel Pyrimidinyl Peptidomimetics

13. N O R 1 HN CH O N P h + C O OM e DABC O N O R 1 HN N Ph OH C O O Me Baylis Hillman reaction DEAD, Ph 3 P 4-(NO 2 )PhCOOH or PhCOOH or CH 3 COOH N O R 1 HN N P h COO Me OR 2 R 1 = PhCH 2 OCO, R 2 = 4-(NO 2 )PhCO R 1 = PhCH 2 OCO, R 2 = PhCO R 1 = PhCH 2 OCO, R 2 = CH 3 CO Anti-malarial compound 3 5 Zhu, S.; Hudson, T.H.; Kyle, D.E.; Lin, A. J. J. Med. Chem. 2002 , 45, 3491 Antimalarial Therapeutic Agents

14. H 3 C O O H + OCH 3 OCH 3 DABCO, 7 days, rt 90% O H O NBS, (CH 3 ) 2 S, O o C to rt, 24 h, 92% O OCH 3 Br O H COOH LiAlH 4 , THF O H CH 2 OH CH 3 I, acetone reflux 6h 50% CH 2 OH OCH 3 K 2 CO 3 , 95% C H O OCH 3 PCC, CH 2 Cl 2 1.5 h, rt,90% H H O Sn, (CH 3 CH 2 ) 2 O, HOAc, O p-(TsOH), C 6 H 6 , reflux 9h, 70% OCH 3 Baylis Hillman reaction 3 6 J. Bermejo et al , J. Med. Chem. 2002, 45, 2358 Synthesis of Antiproliferative Agent

15. Simplicity of this reaction in the easy construction of the carbon- carbon bond. Conclusions Morita Baylis Hillman adduct is an excellent source for various stereochemical transformation methodologies. Several natural products and biologically active molecules have also been synthesized using Morita Baylis Hillman strategy. 3 7

16. 3 9 T h a n k y o u

17. References 1. Baylis , A. B.; Hillman, M. E. D. Ger. Pat. 2,155,113, ( 1972). Both Anthony B. Baylis and Melville E. D. Hillman were chemists at Celanese Corp. USA. 2. Basavaiah , D.; Rao , P. D.; Hyma , R. S. Tetrahedron 1996, 52, 8001-8062 . (Review). 3. Ciganek , E. Org. React. 1997, 51, 201-350 . (Review). 4. Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 2402􀀐2403. 5. Frank, S. A.; Mergott , D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404-2405 . 6. Reddy, L. R.; Saravanan , P.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 6230-6231 . 7. Krishna, P. R.; Narsingam , M.; Kannan , V. Tetrahedron Lett . 2004, 45, 4773-4775 . 8. Sagar , R,; Pant, C. S.; Pathak , R.; Shaw, A. K. Tetrahedron 2004, 60, 11399-11406 . 9. Mi, X.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2005, 70, 2338-2341 . 10. Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680 - 3681 . 11. Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade , D. T. Org. Lett . 2005, 7, 147􀀐150. A novel mechanism involving a hemiacetal intermediate is proposed. 12. Limberakis , C. Morita– Baylis –Hillman Reaction. In Name Reactions for Homologations- Part I; Li, J. J., Ed.; Wiley: Hoboken, NJ, 2009, pp 350-380 . (Review). 13. Cheng, P.; Clive, D. L. J. J. Org. Chem. 2012, 77, 3348-3364 . 14. Chandrasoma , N.; Brown, N.; Brassfield , A.; Nerurkar , A.; Suarez, S.; Buszek , K. R. Tetrahedron Lett . 2013, 54, 913-917 .