Larock Indole synthesis

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1 Larock ndole synthesis CE 676 ilamber Mate 12/08/2016 Dr. Totah

2 Discovery and development Utility and scope The reaction Advantages and limitations Application 2

3 ndole Discovery Benzene ring Pyrrole ring (nitrogen containg ring) ndole nucleus Fig. 1 ndole aromatic heterocyclic organic compound. Which has a fused bicyclic structure. Benzene ring fused to a pyrrole ring is a better description for indole. n early 1800 s, indole chemistry started with the blue dye, ndigo. ndigo can be converted to oxindole. n 1866 Adolf Baeyer reduced oxindole to indole using zinc dust and then he proposed a formula for indole in n 19 th century, study of indole became extensive after finding out that, indole is present in many important alkaloids including tryptophan. Baeyer, A.; Emmerling, A. Synthese des ndols [Synthesis of indole]. Berichte der Deutschen Chemischen Gesellschaft. 1869, 2,

4 Scope and utility Dyes and pigments Fungicides and herbicides Animal / veterinary medicines Over the counter drugs and other drugs Flavor enhancements and perfumes Top eterocycl Chem 2011, 26, Molecules 2013, 18,

5 Dr. Richard Larock B.S., University of California 1967 Ph.D., Purdue University 1972 Postdoctoral fellow, arvard University, Dr. E. J. Corey Distinguished Professor Emeritus of Chemistry, owa State University More than 373 publications and 5 books Ac Ph Ph Ph Ph PhC CPh Ac PdCl 2 MeC CMe Ac C C Me Me Me Me Me R equiv R 2 R 3 Fig. 2 5% Pd(OAc)2 5 Base, 5% PPh 3 1 equiv MCl (M = n-bu 4, Li) 100 C, DMF R 1 R 3 R 2 Richard C. Larock, Eul Kgun Yum. J. Am. Chem. Soc., 1991, 113 (17), Fig. 3

6 Catalytic cycle Pd (OAc)2 L 2 Pd 0 L 2 R R L Cl - L 2 PdCl - R. Reduction of Pd(OAc) 2 to Pd(0) V R S. Co-ordination of ligands to Pd. V. Oxidative addition Co-ordination of alkyne to Pd Cl L Pd L R L R R S Cl R L Pd L V. itrogen displacement and ring formation -L V. Reductive elimination V base - Cl R L R L Pd R S R L V R S Fig. 4 R. C. Larock, E. K. Yum, and M. D. Refvik J. Org. Chem., 1998, 63 (22),

7 Optimization of reaction conditions KOAc C 2 K 2 CO C LiCl or Li 1 equiv PPh 3 not necessary + 3 n-pr n-pr 5% Pd(OAc)2 LiX 5 Base DMF 20 hr Fig. 5 n-pr n-pr 7

8 Silylalkynes 2 + Me 3 Si SiMe 3 5% Pd(OAc)2 5 Base DMF 100 C SiMe 3 54% Fig. 6 Ac SiMe 3 Ac X Desilylation by acylation, protonolysis, halogenation, or the eck reaction Me Me provides a convenient entry into variously substituted indoles X = (1. AlCl3, 2. 2 O; 87%); Br (BS, 70%); E-C CCOC 3 (2CCCOC 3, Pd(OAc)2; 50%) Fig. 7 8

9 Selectivity The process is highly chemoselective as well as regioselective. S C C Pd L Favored Over L C C S Pd Fig. 8 The bulky or large group ends up close to itrogen atom on the indole ring C C 3 C CMe 2 O 5% Pd(OAc)2 5 Base DMF 100 C MeC CMe 2 O C Fig. 9 9

10 Reaction with hydroxyalkyl groups 2 + OMe 2 C CMe 2 O CMe 2 O CMe 2 O Fig. 10 R R Pd O C n Fig. 11 R Pd R O C n 5% Pd(OAc)2 Ac + 5 Base Me (C2)nO DMF 100 C Me Fig. 12 (C2)nOAc 10

11 Limitations / Exceptions Ac + Me C 2 COC % Pd(OAc)2 5 Base DMF 100 C Me Ac + C 2C(OAc)C3 22 Me 23 Fig. 13 C 2 COC 3 Acetyl transfer can only be seen when the alcohol group ends up close to the nitrogen on the aniline system. Above is one of the exception Larock and coworkers reported. As per the regioselectivity, bulky group is found near the nitrogen in indole. (yield is very low but still exception is reported) 11

12 Reverse regioselectivity in Larock eteroannulation (C-glycosyl-iso-tryptophan) Boc (i) Boc COOMe (ii) Cu(C)Zn COOMe TF C O Boc COOMe BnO O 26 2, morpholine Ph (45 C, 24h) (86%) (i) - Zn, (C 2 Br) 2, TMS-Cl/TF (ii) - CuC. 2LiCl/TF BnO O 27 BnO 28 C-glucosyl-propargyl glycine Fig. 14 BnO Boc O COOMe R 4 Pd(OAc)2, Ph 3 P, n-bu 4 Cl, a 2 CO 3 / DMF Boc O BnO COOMe R Boc O BnO COOMe R 28 Fig. 15 Toshio ishikawa, Kyoko Wada & Minoru sobe Bioscience, Biotechnology, and Biochemistry, 2002, 66 (10), Pages

13 mportant application X 1 X TMS EtO OEt Pd(OAc)2 a 2 CO 3, LiCl 100 C, DMF X 1 EtO X TMS OEt Fig. 16 Synthesis of Optically Active Ring-A Substituted Tryptophans ndoleamine 2,3-dioxygenase inhibitor X 1 EtO X 2 TMS 33 OEt 1) 2 Cl, TF 6 hr, 25 C 2) 1 ao, EtO 1 hr, 55 C 80-83% Fig. 17 X 1 X COO Chunrong Ma; Xiaoxiang Liu; Shu Yu; Shuo Zhao; and James M. Cook. Tetrahedran Lett. 1999, 40 (4),

14 3-iodoindole synthesis R 1 R 2 Me R 3 C C cat. Pd/Cu R 1 R 2 Me R 3 R 2 2 C 2 Cl 2 R 1 R R 3 = Ph, n-c 6 13, t-bu,, etc. Fig. 18 D. Yue, T. Yao, R. C. Larock, J. Org. Chem., 2006, 71,

15 Conclusion ndole is an important moiety for synthesis. ndole nucleus can be found in alkaloid, natural products t s a important pharmacophore, and has a widespread variety of medical applications, fertilizers, dyes Richard Larock and coworkers had developed the facile way to synthesize the indole using 2-iodoaniline and simple or unsymmetric alkynes with the help of Pd as a catalyst. They tried to optimize reaction conditions and concluded following points, KOAc C, K 2 CO C, LiCl or Li 1 equiv, PPh 3 not necessary Catalytic cycle and mechanism Regioselectivity and chemoselectivity Some limitation and/or problems occurred 15

16 References Kaushik,.K.; Kaushik,.; Attri, P.; Kumar,.; Kim, C..; Verma, A.K.; Choi, E.. Biomedical mportance of ndoles. Molecules 2013, 18, Top eterocycl Chem 2011, 26, Molecules 2013, 18, Chunrong Ma; Xiaoxiang Liu; Shu Yu; Shuo Zhao; and James M. Cook. Concise synthesis of optically active ring-a substituted tryptophans. Tetrahedran Lett. 1999, 40 (4), Richard C. Larock, Eul Kgun Yum. J. Am. Chem. Soc., 1991, 113 (17), R. C. Larock, E. K. Yum, and M. D. Refvik J. Org. Chem., 1998, 63 (22), Toshio ishikawa, Kyoko Wada & Minoru sobe. Synthesis of ovel α-c-glycosylamino Acids and Reverse Regioselectivity in Larock's eteroannulation for the Synthesis of the ndole ucleus Bioscience, Biotechnology, and Biochemistry, 2002, 66 (10), Pages D. Yue, T. Yao, R. C. Larock, J. Org. Chem., 2006, 71,

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