Highlights of Schmidt Reaction in the Last Ten Years

Transcription

1 ighlights of Schmidt eaction in the Last Ten Years Dendrobates histrionicus Jack Liu ov. 18, 2003

2 Introduction Classical Schmidt reaction of aldehydes and carboxylic acids Classical Schmidt reaction of ketones Inter- and intramolecular Schmidt reaction with ketones using alkyl azides Total Synthesis of alkaloid 251F Inter- and intramolecular Schmidt reaction of carbocations using alkyl azides Formal Synthesis of gephyrotoxin Conclusion

3 ow it all began 3 2 S 4 2 " " " " Et 2 C " " Et 2 C " " Schmidt reaction: insertion of into carbonyl group Schmidt, K. F. Z. Angew. Chem. 1923, 36, 511. Schmidt, K. F. Ber. 1924, 57, 704.

4 Migration of Carbon to an Electron Deficient eteroatom Br ofmann Br - ' Wolff 2 ' 2 Ac Lossen Curtius Schmidt 2 2 Ac ML n ' Beckmann 2 ' Schmidt 2 CAr ' Baeyer-Villager ' ' ' ML n 2 ArC 2 -

5 Schmidt eaction of Aldehydes a 3 (2.3 equiv) 2 S 4 (5.4 equiv) benzene, o C 59% Cl a 3 (2.3 equiv) 2 S 4 (5.4 equiv) benzene, o C Cl 48% Schmidt reaction of aldehydes results in formamides McEwen, W. E. et al. J. Am. Chem. Soc. 1952, 74, 1168.

6 Schmidt eaction of Carboxylic Acids C 2 a 3, 2 S 4, CCl 3, 40 o C, 1 h 2 C 2 a 3, 2 S 4, CCl 3, 40 o C, 1 h % Drawback: ne carbon lost; not atom economic Schmidt reaction of carboxylic acids results in amines with loss of carboxyl group Datta, S. K. et al. J. Chem. Soc (C) 1970, 2058.

7 Acid Promoted Schmidt eaction of Ketones Smith, P. A. S. in Molecular earrangements Part I. de Mayo, P. ed. ew York: Wiley, p. 512.

8 Studies on Migratory Aptitude Electronic Effect X a 3 (3 equiv) 2 S 4 (3.6 equiv) Cl 3 CC 2, o C X A X B X A:B 2 51:49 Cl 49:41 54:56 61:39 52:48 o clear correlation between migratory aptitude and electronic nature of aryl group Smith, P. A. S. et al. J. Am. Chem. Soc. 1950, 72, 3718.

9 Studies on Migratory Aptitude Steric Effect a 3 (3 equiv) 2 S 4 (3.6 equiv) Cl 3 CC 2, o C A B Et i-pr t-bu A:B 95:5 85:1 51:4 5 0: yield (%) Larger substituent has greater migratory aptitude Smith, P. A. S. et al. J. Am. Chem. Soc. 1950, 72, 3718.

10 rigin of Selectivity 2 3, 2 S L S L L S 3, major 2 L S 2 L S minor Migrating substituent is proposed to be antiperiplanar to azido group Smith, P. A. S. in Molecular earrangements Part I. de Mayo, P. ed. ew York: Wiley, p

11 Intermolecular Schmidt eaction of Ketones with Alkyl Azides Acid Effect TiCl 4 (2.5 equiv), C 2 Cl 2, 0 o C to rt 3 85% 15% Tf (1.1 equiv), C 2 Cl 2, 0 o C to rt 3 79% Schmidt favored when TiCl 4 used, Mannich favored when Tf used Aubé, J. et al. J. Am. Chem. Soc. 2000, 122, 7226.

12 Proposed chanism of Mannich eaction 3 2 rigin of Mannich side-reaction: generation of iminium ion in situ Aubé, J. et al. J. Am. Chem. Soc. 2000, 122, 7226.

13 entr y 1 Substitution Effect of Cyclohexanones substrat e conditions TiCl 4 (3.5 equiv), Bn 3 88% product(s), yield t-bu TiCl 4 (3.5 equiv), Bn 3 TiCl 4 (3.5 equiv), Bn 3 TiCl 4 (3.5 equiv), Bn 3 TiCl 4 (3.5 equiv), Bn 3 t-bu 65% 52% 100% 44% 35% 11% Aubé, J. et al. J. Am. Chem. Soc. 2000, 122, 7226.

14 Substrate Scope Cyclic Ketones entr y substrat e azide product(s), yield entr y substrat e azide product(s), yield 1 n- ex 3 n-ex 51% 4 n- ex 3 100% n-ex 2 n- ex 3 n-ex 5 Bn 3 < 5% 93% 3 n- ex 3 n-ex n-ex 32% 8% 6 Bn 3 33% Aubé, J. et al. J. Am. Chem. Soc. 2000, 122, 7226.

15 Behavior of 3-Pentanone 3 TiCl 4 (2.5 equiv), C 2 Cl 2, 0 o C to rt 62% 3 Tf (1.1 equiv), C 2 Cl 2, 0 o C to rt 84% Acyclic ketones give exclusively Mannich product Aubé, J. et al. J. Am. Chem. Soc. 2000, 122, 7226.

16 Trends of Chemoselectivity Cl n Ti 2 Proposed key intermediate of TiCl 4 mediated Schmidt reaction good Schmidt substrates good Mannich substrates Good substrate for Schmidt reaction: not hindered and conformationally less flexible Aubé, J. et al. J. Am. Chem. Soc. 2000, 122, 7226.

17 Intramolecular Schmidt eaction of Ketones with an Alkyl Azide Tether 3 TFA, C 2 Cl 2, 10 min., rt 90% Intramolecular Schmidt reaction of ketones gives bicyclic amides Aubé, J. et al. J. Am. Chem. Soc. 1991, 113, 8965.

18 Substrate Scope entr y 1 substrate 3 conditions TFA, 40 min. product yield (%) TFA, 10 min TFA, 24 h TiCl 4, 16 h TFA, 20 min TFA 77 Aubé, J. et al. J. Am. Chem. Soc. 1991, 113, 8965.

19 Intramolecular Schmidt eaction of Ketones with in situ Tethering of ydroxyalkyl Azides 3 BF 3 Et X - - X - - Aubé, J. et al. J. Am. Chem. Soc. 1995, 117, Aubé, J. et al. Tetrahedron 1997, 53,

20 Intermolecular Schmidt eaction of Ketones with ydroxyalkyl Azides Substrate Scope entr y 1 substrate azide 3 product yield (%) Azides with longer carbon chain give no product. Aubé, J. et al. Tetrahedron 1997, 53,

21 BF 3 Et 2, C 2 Cl 2, 0 o C 2. a Effect of Subsitution by-product entry 1 yield (%) 95 A A:B:byproduct 55:45 B by-product 2 Et 94 57:43 3 i-pr 40 23:54: >95:5 i-pr :0:10 6 Br 51 83:0:17 Aubé, J. et al. J. rg. Chem. 2000, 65, 3771.

22 Proposed rigin of Selectivity 2 2 Disfavored when = i-pr A 2 2 B eversal of regioselectivity caused by steric interaction between i-pr and diazo group Aubé, J. et al. J. rg. Chem. 2000, 65, 3771.

23 Synthetic Utility Macrocyclic Lactames and Lactones n BF 3 Et 2, C 2 Cl 2, 0 o C 2. reflux, 73 h 3. base, time n A B n entry n bas e K K K time (h) yield A:B 68:0 88:0 51:19 entr y n base ac 3 ac 3 ac 3 time (h) yield A:B 27:43 26:64 30: K 30 50: ac :79 Lactams favoured when K used; lactones favoured when ac 3 used Aubé, J. et al. J. rg. Chem. 1999, 64, 4381.

24 rigin of Chemoselectivity K Work-Up p ~ 14 3 BF 3 Et 2 - X Aubé, J. et al. J. rg. Chem. 1999, 64, 4381.

25 rigin of Chemoselectivity ac 3 Work-Up p ~ 9 3 BF 3 Et 2-2 X - - X - pka ~ 11 Aubé, J. et al. J. rg. Chem. 1999, 64, 4381.

26 Asymmetric Intramolecular Schmidt eaction BF 3 Et 2, (3.5 equiv) C 2 Cl 2, -82 o C 2. K 1 A B 1 entr y t- Bu t- Bu t- Bu 1 P h P h 2 P h P h 3 P h P h A:B 93:7 95:5 89:11 90:10 60:40 60:40 yield (%) Aubé, J. et al. J. Am. Chem. Soc. 2003, 125, 7914.

27 Proposed rigin of Selectivity t-bu 3 equatorial addition of azide 2?? t-bu t-bu 2 t-bu major minor t-bu rigin of selectivity: phenyl group preferentially occupieds equatorial position Aubé, J. et al. J. Am. Chem. Soc. 2003, 125, 7914.

28 Scope of Chiral ydroxyalkyl Azide BF 3 Et 2, (3.5 equiv) C 2 Cl 2, -82 o C 2. K 1 A B 1 entr y t- Bu t- Bu t- Bu 1 P h P h 2 P h P h 3 P h P h A:B 93:7 95:5 89:11 90:10 60:40 60:40 yield (%) Aubé, J. et al. J. Am. Chem. Soc. 2003, 125, 7914.

29 Proposed Cation-p Interaction t-bu equatorial 3 Ar addition of azide 2 Ar?? t-bu t-bu 2 X Ar Ar t-bu t-bu Aryl group occupying axial position is proposed to be stabilized by cation-p interaction Aubé, J. et al. J. Am. Chem. Soc. 2003, 125,

30 Effect of Substituents on Aryl Group 3 1.BF 3 Et 2 2.K t-bu X t-bu A X X B t-bu entr y 1 X A:B 43:57 yield (%) : F 69: :24 86 Electron-withdrawing substituents increase diastereoselectivity Aubé, J. et al. J. Am. Chem. Soc. 2003, 125,

31 Another Asymmetric Schmidt eagent 3 1.BF 3 Et 2, (3.5 equiv) C 2 Cl 2, -82 o C 2. K 2? 2 entr y 1 2 t- Bu A:B 59:41 60:40 yield (%) A B rigin of low diastereoselectivity: one methyl group axial and the other equatorial Aubé, J. et al. J. Am. Chem. Soc. 2003, 125, 7914.

32 Another Asymmetric Schmidt eagent 3 1.BF 3 Et 2, (3.5 equiv) C 2 Cl 2, -82 o C 2. K 2? 2 entr y 1 2 t- Bu A:B 98:2 94:6 yield (%) A B rigin of high diastereoselectivity: both methyl groups occupy equatorial position Aubé, J. et al. J. Am. Chem. Soc. 2003, 125, 7914.

33 Scope of Substrate entr y substrate azide products dr yield(%) : major minor 96:4 96 major minor : :40 57 Aubé, J. et al. J. Am. Chem. Soc. 2003, 125, 7914.

34 Total Synthesis of Alkaloid 251F 1. a/ /DMS Bn 2. Zn( 3 ) 2 2Pyr DEAD, P 3 2. ab % (2 steps) a:b = 4:1 Tf LiAl % (2 steps) 79% % Alkaloid 251F Aubé, J. et al. J. Am. Chem. Soc. 2002, 124, 9974.

35 Intermolecular Schmidt eaction of Carbocations with Alkyl Azides Ar acid 1 2 Ar 1 2 Ar Ar Ar Ar 1 2 Ar 2 aryl migration migration alkyl migration 1 2 Pearson, W.. et al. Tetrahedron Lett. 1992, 37, Pearson, W.. et al. J. rg. Chem. 1995, 60, 4960.

36 Substrate Scope Acyclic Benzylic Alcohols Ar n-bu 3, C 2 Cl 2, Tf (2 equiv) 2. ab 4 (6 equiv), Bu 1 2 Ar Bu Ar 1 2 Bu Ar 2 1 aryl migration migration alkyl migration A B C entr y Ar n- Pr 2 A:B:C 1:5.8:0 1:1.94:0 4.3:1: :2.5: 1 3.6:0:1 yield (%) Migratory aptitude is related to the ability to stabilize positive charge Pearson, W.. et al. J. rg. Chem. 1995, 60, 4960.

37 Substrate Scope Cyclic Benzylic Alcohols n-bu 3, C 2 Cl 2, Tf (2 equiv) 2. ab 4 (6 equiv), Bu 1 2 Bu 2 1 entr y 1 substrate Products, ratio Bu Bu 1:5.1 yield (%) 97 2 Bu Bu 1.1: Bu Bu 2.4:1 82 Aryl migration slightly favoured except for the case of cyclobutanol Pearson, W.. et al. J. rg. Chem. 1995, 60, 4960.

38 Intramolecular Schmidt eaction of Carbocations with Alkyl Azide Tether 3 1. Tf (2 equiv), benzene, 5 o C, 45 min. 2. ab 4 (4 equiv),, 10 h 1:1 79% isolated yield 3 1. g(tf) 2 (1 equiv), TF, rt, 15 min. 2. ab 4 (4 equiv), a, 2, 2 h 84% GC yield rcury promoted Schmidt reaction proceeds with much higher regioselectivity Pearson, W.. et al. J. Am. Chem. Soc. 1993, 22, Pearson, W.. et al. J. rg. Chem. 2000, 65, 8327.

39 Difference in Brønstead Acid and Lewis Acid Promoted Pathway gx 2 3 Xg more reactive carbocation Xg 2 Xg - 2 A spirocyclic intermediate generates two isomers in Brønstead acid promoted reaction Pearson, W.. et al. J. Am. Chem. Soc. 1993, 22, Pearson, W.. et al. J. rg. Chem. 2000, 65, 8327.

40 Formal Synthesis of Gephyrotoxin 3 Br Tf Br Br 1.L-Selectride 2.Bu 4 Ac 3.LiAl 4 Br 10% 45% gephyrotoxin Pearson, W.. et al. J. rg. Chem. 2000, 65, 7158.

41 Conclusion Alkyl azides can be used in Schmidt reaction in the present of a strong acid Intramolecular Schmidt reaction useful in synthesis of amides of different ring size Asymmetric Schmidt reaction achieved by employing chiral hydroxy azides Schmidt reaction of carbocations is promoted by acids; useful in synthesis of bicyclic heterocycles Much work needed to improve selectivity

42 Analysis of Selectivity 2 2 alkyl migration minor Tf Aryl migration favoured 2 aryl migration major

43 First alf of the Synthesis of Alkaloid 251F

44 Synthesis of Alkyl Azide Advanced Intermediate Pearson, W.. et al. J. rg. Chem. 2000, 65, 7158.

45 Ito Formal Synthesis of gephyrotoxin ydrogenation catalyst: 5% h on alumina Ito, Y. Tetrahedron Lett. 1983, 24, 2881.