CaSH Organocatalysis: Enantioselective Friedel-Crafts Alkylation of Indoles with α,β-Unsaturated Aldehydes

Abstract

Enantioselective Friedel-Crafts alkylation of indole with α,β-unsaturated aldehyde was catalyzed by camphor sulfonyl hydrazine (CaSH) with good enantioselectivity (81-88%).

Key words

camphor sulfonyl hydrazine (CaSH) - organocatalysis - indole alkylation - α,β-unsaturated aldehydes

References and Notes

• 1a Ahrendt KA. Borths CJ. MacMillan DWC. J. Am. Chem. Soc.  2000,  122:  4243 
• 1b A similar term ‘organic catalysis’ first appeared in the German literature: Langenbeck W. Fortschr. Chem. Forsch.  1966,  6:  301 
• 2a Eder U. Sauer G. Wiechert R. Angew. Chem., Int. Ed. Engl.  1971,  10:  496 
• 2b Hajos ZG. Parrish DR. J. Org. Chem.  1974,  39:  1615 
• 3a Alessandro D. Alessandro M. Angew. Chem. Int. Ed.  2008,  47:  4638 
• 3b List B. Chem. Rev.  2007,  107:  5413 
• 3c Dalko PI. Moisan L. Angew. Chem. Int. Ed.  2004,  43:  5138 
• 3d France S. Guerin DJ. Miller SJ. Lectka T. Chem. Rev.  2003,  103:  2985 
• 3e Dalko PI. Moisan L. Angew. Chem. Int. Ed.  2001,  40:  3726 
• 4a Notz W. Tanaka F. Barbas CF. Acc. Chem. Res.  2004,  37:  580 
• 4b Taylor MS. Jacobsen EN. Angew. Chem. Int. Ed.  2006,  45:  1520 
• 5 Poulsen TB. Jørgensen KA. Chem. Rev.  2008,  108:  2903 
• 6a Bandini M. Molloni A. Umani-Ronchi A. Angew. Chem. Int. Ed.  2004,  43:  550 
• 6b Austin JF. Kim S.-G. Sinz CJ. Xiao W.-J. MacMillan DWC. Proc. Natl. Acad. Sci. U.S.A.  2004,  101:  5482 
• 7a Erkkilä A. Majander I. Pihko PM. Chem. Rev.  2007,  107:  5416 
• 7b Mukherjee S. Yang JW. Hoffmann S. List B. Chem. Rev.  2007,  107:  5471 
• 7c Juhl K. Jørgensen KA. . Angew. Chem. Int. Ed.  2003,  42:  1498 
• 7d Seayad J. List B. Org. Biomol. Chem.  2005,  3:  719 
• 7e Northrup AB. MacMillan DWC. J. Am. Chem. Soc.  2002,  124:  2458 
• 8a Austin JF. MacMillan DWC. J. Am. Chem. Soc.  2002,  124:  1172 
• 8b Paras NA. MacMillan DWC.
  J. Am. Chem. Soc.  2001,  123:  4370 
• 8c Paras NA. MacMillan DWC. J. Am. Chem. Soc.  2002,  124:  7894 
• 8d Huang Y. Walji AM. MacMillan DWC. J. Am. Chem. Soc.  2005,  127:  15051 
• 9a King HD. Meng Z. Denhart D. Mattson R. Kimura R. Wu D. Gao Q. Macor JE. Org. Lett.  2005,  7:  3437 
• 9b Li C.-F. Liu H. Liao J. Cao Y.-J. Liu X.-P. Xiao W.-J. Org. Lett.  2007,  9:  1847 
• 10a Chen W. Du W. Chen YC. Org. Biomol. Chem.  2007,  5:  816 
• 10b Bartoli G. Bosco M. Melchiorre P. Org. Lett.  2007,  9:  1403 
• 11a Sander EG. Jencks WP. J. Am. Chem. Soc.  1968,  90:  6154 
• 11b Cavill JL. Elliott RL. Evans G. Jones IL. Platts JA. Ruda AM. Tomkinson NCO. Tetrahedron  2006,  62:  410 
• 12a Cavill JL. Peters JU. Tomkinson NCO. Chem. Commun.  2003,  728 
• 12b Gupta RR. Kumar M. Gupta V. Heterocyclic Chemistry   Vol. 3:  Springer; Heidelberg: 1999. 
• 12c Lemay M. Ogilvie WW. Org. Lett.  2005,  7:  4141 
• 12d Lemay M. Ogilvie WW. J. Org. Chem.  2006,  71:  4663 
• 12e Lemay M. Aumand L. Ogilvie WW. Adv. Synth. Catal.  2007,  349:  441 
• 13a He H. Pei B.-J. Chou H.-H. Tian T. Chan W.-W. Lee AW.-M. Org. Lett.  2008,  10:  2421 
• 13b Langlois Y. Petit A. Remy P. Scherrmann MC. Kouklovsky C. Tetrahedron Lett.  2008,  49:  5576 
• 13c Chen L.-Y. He H. Pei B.-J. Chan WH. Lee AWM. Synthesis  2009, 1573

14

Aldehyde 3 (R^¹ = Me): ^¹H NMR (400 MHz, CDCl₃): δ = 9.75 (s, 1 H), 7.63 (d, J = 8.0 Hz, 1 H), 7.31 (m, 1 H), 7.26 (m, 1 H), 7.14 (m, 1 H), 6.84 (s, 1 H), 3.75 (s, 3 H), 3.68 (m, 1 H), 2.87 (m, 1 H), 2.71 (m, 1 H), 1.43 (d, J = 6.8 Hz, 3 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 203.1, 137.4, 126.8, 125.4, 121.9, 119.3, 119.0, 109.6, 51.2, 32.9, 26.1, 21.9 ppm.
Alcohol 4 was obtained by NaBH₄ reduction. Alcohol 4 (R^¹ = Me): ^¹H NMR (400 MHz, CDCl₃): δ = 7.64 (dd, J = 8.0, 0.8 Hz, 1 H), 7.30 (dd, J = 7.2, 0.8 Hz, 1 H), 7.23 (m, 1 H), 7.10 (m, 1 H), 6.85 (s, 1 H), 3.75 (s, 3 H), 3.66 (m, 1 H), 3.22 (m, 1 H), 2.06 (m, 1 H), 1.96 (m, 1 H), 1.40 (d, J = 6.8 Hz, 3 H) ppm.

15

General Experimental Procedure for CaSH 1 Catalyzed Friedel-Crafts Reaction of Indoles with α,β-Unsaturated Aldehydes
TFA (0.15 mmol) was added to a solution of CaSH 1 (0.15 mmol) in toluene (1 mL). The solution was stirred for 20 min and then cooled to -40 ˚C. The α,β-unsaturated aldehyde (1.5 mmol) was then added. After stirring for another 20 min, the N-substituted indole (0.5 mmol) was added. The reaction was stirred until complete consumption of the indoles as determined by TLC. MeOH (2 mL) was added to the reaction mixture followed by NaBH₄ (3.0 mmol). The mixture was warmed to 0 ˚C and stirred for 20 min. The reaction was quenched by H₂O and extracted with EtOAc. The organic solution was dried over anhyd Na₂SO₄. The product 6 was purified by silica gel chromatography (PE-EtOAc, 4:1). The ee was determined by chiral HPLC (Chiracel AD-H) of the alcohol 6 (5% i-PrOH in hexane
as eluent, 1 mL min^-¹).

16

Spectroscopic Data of Products 6 (Table 2) Compound 6 (R^² = Me): ^¹H NMR (400 MHz, CDCl₃): δ = 7.74 (dd, J = 7.6, 0.8 Hz, 1 H), 7.33 (m, 4 H), 7.21 (m, 4 H), 6.96 (s, 1 H), 5.29 (s, 2 H), 3.30 (m, 2 H), 3.27 (m, 1 H), 2.08 (m, 1 H), 1.95 (m, 1H), 1.44 (d, J = 7.2 Hz, 3 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 138.0, 137.1, 129.0, 127.7, 127.6, 126.9, 124.6, 122.0, 121.1, 119.8, 119.1, 110.0, 61.7, 50.1, 40.6, 27.9, 22.1 ppm. HRMS (MALDI-TOF): m/z calcd for C₁₉H₂₂NO [M + H]⁺: 280.1696; found: 280.1695.
Compound 6 (R^² = Et): ^¹H NMR (400 MHz, CDCl₃): δ = 7.64 (d, J = 7.6, Hz, 1 H), 7.25 (m, 4 H), 7.14 (m, 1 H), 7.06 (m, 3 H) 6.88 (s, 1 H), 5.24 (s, 2 H), 3.56 (m, 2 H), 2.93 (m, 1 H), 1.98 (m, 2 H), 1.74 (m, 2H), 0.83 (t, J = 7.0 Hz, 3 H) ppm.
Compound 6 (R^² = Pr): ^¹H NMR (400 MHz, CDCl₃): δ = 7.69 (d, J = 8.0 Hz, 1 H), 7.33-7.24 (m, 4 H), 7.18 (m, 1 H), 7.17-7.06 (m, 3 H) 6.93 (s, 1 H), 5.29 (s, 2 H), 3.62 (m, 2 H), 3.05 (m, 1 H), 2.03 (m, 2 H), 1.18 (m, 2 H), 1.30 (m, 2 H), 0.88 (t, J = 7.2 Hz, 3 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 138.0, 137.1, 128.9, 127.8, 127.7, 126.7, 125.6, 121.8, 119.9, 119.0, 118.9, 110.0, 61.9, 50.0, 39.0, 38.9, 33.6, 21.0, 14.4 ppm.
Compound 6 (R^² = Bu): ^¹H NMR (400 MHz, CDCl₃): δ = 7.66 (d, J = 7.6 Hz, 1 H), 7.30-7.22 (m, 4 H), 7.14 (t, J = 7.6 Hz, 1 H), 7.09-7.03 (m, 3 H), 6.90 (s, 1 H), 5.27 (s, 2 H), 3.59 (m, 2 H), 3.01 (m, 1 H), 2.00 (m, 2 H), 1.78 (m, 2 H), 1.23 (m, 4 H), 0.83 (t, J = 7.2 Hz, 3 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 138.0, 137.1, 128.9, 127.8, 127.7, 126.7, 125.6, 121.8, 119.9, 119.0, 110.0, 61.9, 50.0, 39.0, 36.3, 33.8, 30.2, 23.0, 14.3 ppm.
Compound 6 (R^² = Ph): ^¹H NMR (400 MHz, CDCl₃): δ = 7.52 (m, 1 H), 7.38-7.07 (m, 12 H), 7.03 (m, 2 H), 5.30 (s, 2 H), 4.44 (t, J = 7.6 Hz, 1 H), 3.68 (m, 2 H), 2.48 (m, 1 H), 2.29 (m, 1 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 145.1, 138.0, 237.2, 129.0, 128.7, 128.1, 127.9, 127.8, 126.9, 126.4, 125.6, 122.1, 120.0, 119.3, 119.1, 109.9, 61.5, 50.2, 39.4, 39.0 ppm.
Compound 6 (R^² = 4-ClC₆H₄): ^¹H NMR (400 MHz, CDCl₃): δ = 7.41 (d, J = 8.0 Hz, 1 H), 7.33-7.22 (m, 8 H), 7.15 (m, 3 H), 7.01 (m, 2 H), 5.29 (s, 2 H), 4.40 (t, J = 7.6 Hz, 1 H), 3.64 (m, 2 H), 2.43 (m, 1 H), 2.22 (m, 1 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 143.6, 137.8, 137.2, 131.9, 129.4, 129.0, 128.7, 127.8, 127.6, 126.8, 125.5, 122.2, 119.8, 119.4, 118.5, 110.0, 61.2, 50.2, 38.8, 38.7 ppm.
Compound 6 (R^² = 4-BrC₆H₄): ^¹H NMR (400 MHz, CDCl₃): δ = 7.40 (m, 3 H), 7.37-7.18 (m, 6 H), 7.15-7.07 (m, 3 H), 6.99 (m, 2 H), 5.28 (s, 2 H), 4.38 (t, J = 8.0 Hz, 1 H), 3.62 (m, 2 H), 2.43 (m, 1 H), 2.22 (m, 1 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 144.1, 137.8, 137.2, 131.7, 129.8, 129.0, 127.8, 127.6, 126.8, 125.5, 122.2, 120.0, 119.8, 119.4, 118.4, 110.0, 61.2, 50.2, 38.8, 38.7 ppm.