Highly Substituted Dihydroindole Derivatives by Intermolecular Couplings of Samarium Ketyls and Indoles

Abstract

Samarium diiodide promoted intermolecular reductive couplings of ketones and aldehydes to 3-methoxycarbonyl-substituted indole derivatives afforded dihydroindoles in good yields and with excellent diastereoselectivities. Trapping of the intermediate samarium enolate with allyl iodide furnished tricyclic lactones with good efficacy, thus demonstrating the potential of this method for the construction of structurally complex indole derivatives by a three-component protocol.

indoles - radical reactions - samarium - ketyls - lactones

References and Notes

1a Somei M. Yamada F. Nat. Prod. Prep.  2005,  22:  73 

1b Joule JA. In Science of Synthesis (Houben-Weyl, Methods of Molecular Transformation)   Vol. 10:  Thoma J. Georg Thieme Verlag; Stuttgart: 2000.  p.361-652  

1c Bonjoch J. Bosch J. Alkaloids  1996,  48:  75 

1d Sundberg RJ. Indoles   Academic Press; London: 1996. 

1e Saxton JE. The Chemistry of Heterocyclic Compounds   Part IV, Vol. 25:  Academic Press; New York: 1994. 

1f Döpp H. Döpp U. Langer U. Gerding B. In Methoden der Organischen Chemie (Houben-Weyl)   Vol. E6b1:  Georg Thieme Verlag; Stuttgart: 1994.  p.546-848  

1g Döpp H. Döpp U. Langer U. Gerding B. In Methoden der Organischen Chemie (Houben-Weyl)   Vol. E6b2:  Georg Thieme Verlag; Stuttgart: 1994. 

1h Chadwick DJ. Jones RA. Sundberg RJ. Comprehensive Heterocyclic Chemistry   Vol. 4:  Pergamon; Oxford: 1984.  p.155-376  

For selected recent reviews on samarium-promoted chemistry:

2a Edmonds DJ. Johnston D. Procter DJ. Chem. Rev.  2004,  104:  3371 

2b Berndt M. Gross S. Hölemann A. Reissig H.-U. Synlett  2004,  422 

2c Kagan HB. Tetrahedron  2003,  59:  10351 

2d Molander GA. Harris CR. Tetrahedron  1998,  54:  3321 

3a Gross S. Reissig H.-U. Org. Lett.  2003,  5:  4305 

3b Gross S. Reissig H.-U. Synlett  2002,  2027 

3c Berndt M. Reissig H.-U. Synlett  2001,  1290 

3d Nandanan E. Dinesh CU. Reissig H.-U. Tetrahedron  2000,  56:  4267 

3e Dinesh CU. Reissig H.-U. Angew. Chem. Int. Ed.  1999,  38:  789 ; Angew. Chem. 1999, 111, 874

For related aryl carbonyl couplings, see:

4a Ohno H. Okumura M. Maeda SI. Iwasaki H. Wakayama R. Tanaka T. J. Org. Chem.  2003,  68:  7722 

4b Ohno H. Wakayama R. Maeda SI. Iwasaki H. Okumura M. Iwata C. Mikamiyama H. Tanaka T. J. Org. Chem.  2003,  68:  5909 

4c Shiue J.-S. Lin M.-H. Fang J.-M. J. Org. Chem.  1997,  62:  4643 

4d Schmalz H.-G. Siegel S. Bats JW. Angew. Chem., Int. Ed. Engl.  1995,  34:  2383 ; Angew. Chem. 1995, 107, 2597

5 A few inter- and intramolecular indole carbonyl coupling reactions mainly affording rearomatized products have been reported; however, different mechanisms were suggested: Lin S.-C. Yang F.-D. Shiue J.-S. Yang S.-M. Fang J.-M. J. Org. Chem.  1998,  63:  2909 

The use of HMPA as additive strongly raises the reducing ability of samarium diiodide and is required for many ketyl coupling reactions. See:

6a Flowers RA. Xu X. Timmons C. Li G. Eur. J. Org. Chem.  2004,  2988 

6b Prasard E. Flowers RA. J. Am. Chem. Soc.  2002,  124:  6895 

6c Inanaga J. Ishikawa M. Yamaguchi M. Chem. Lett.  1987,  1485 

7

Typical Procedure, Conversion of 3 into 5a. Samarium (335 mg, 2.23 mmol) and 1,2-diiodoethane (580 mg, 2.06 mmol) were suspended in freshly distilled anhyd THF (20 mL) under an argon atmosphere and stirred for 2 h at r.t. The reaction flask was then evacuated, purged with argon and HMPA (1.45 mL, 8.25 mmol) was added and stirred for 30 min. To the deep violet solution indole 3 (105 mg, 0.55 mmol), acetone (60 µL, 0.82 mmol) and phenol (155 mg, 1.65 mmol), dissolved in THF (5 mL), were added in one portion. After 30 min the mixture was quenched with 2 N solution of NaOH (15 mL), the organic layer was separated and the aqueous layer was extracted with Et₂O. The combined ether extracts were washed with brine, dried (MgSO₄), filtrated and evaporated. The resulting crude product was purified by flash chromatography on silica gel using a hexane-EtOAc mixture (8:2) to afford 5a (118 mg, 87%) as colorless oil. IR (KBr): ν = 3480 (OH), 3050, 3030 (ArH), 2975-2815 (CH), 1740 (CO), 1600, 1490 (C=C) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.18 (s, 3 H, CH₃), 1.29 (s, 3 H, CH₃), 1.95 (s_br, 1 H, OH), 3.00 (s, 3 H, NCH₃), 3.76 (d, J = 6.4 Hz, 1 H, 2-H), 3.77 (s, 3 H, OCH₃), 4.08 (d, J = 6.4 Hz, 1 H, 3-H), 6.60 (d, J = 8.0 Hz, 1 H, Ar), 6.74 (dt, J = 1.0, 7.5 Hz, 1 H, Ar), 7.14-7.18, 7.22-7.24 (2 m, 1 H each, Ar). ¹³C NMR (126 MHz, CDCl₃): δ = 25.1, 27.4 (2 q, CH₃), 41.1 (q, NCH₃), 49.1 (d, C-3), 52.4 (q, OCH₃), 73.0 (s, C-1′), 76.7 (d, C-2), 109.9, 118.9, 124.4 (3 d, Ar), 126.4 (s, Ar), 128.8 (d, Ar), 153.9 (s, Ar), 173.0 (s, CO). MS (EI, 80 eV, 40 °C): m/z (%) = 249 (16) [M]⁺, 234 (4) [M - CH₃]⁺, 190 (96) [M - CO₂CH₃]⁺, 158 (51), 131 (100) [M - CO₂CH₃ - C₂H₇O]⁺. Anal. Calcd for C₁₄H₁₉NO₃ (249.3): C, 67.45; H, 7.68; N, 5.62. Found: C, 66.74; H, 7.46; N, 5.66. HRMS (EI, 80 eV, 40 °C): m/z calcd for C₁₄H₁₉NO₃: 249.13649; found: 249.13634.

8 To the best of our knowledge no related intermolecular additions of samarium ketyls to β-amino-substituted acrylates (the key substructure of 3 and 4) have been reported. For a few intramolecular examples see: MacDonald SJF. Mills K. Spooner JE. Upton RJ. Dowle MD. J. Chem. Soc., Perkin Trans. 1  1998,  3931 

9

Typical Procedure, Conversion of 3 into 8.
Indole 3 (60 mg, 0.317 mmol) and acetone (36 µL, 0.480 mmol), dissolved in THF (5 mL), were added in one portion to the solution of SmI₂ (Sm: 191 mg, 1.27 mmol; 1,2-diiodoethane: 335 mg, 1.19 mmol) and HMPA (830 µL, 4.77 mmol) freshly prepared as above. After 30 min, allyl iodide (0.29 mL, 3.17 mmol) was added and the mixture was quenched with saturated aqueous solution of NaHCO₃ (10 mL), the organic layer was separated and the aqueous layer was extracted with Et₂O. The combined ether extracts were washed with brine, dried (MgSO₄), filtrated and evaporated. The resulting crude product was purified by flash chromatography on silica gel using a hexane-EtOAc mixture (8:2) to provide 8 (67 mg, 82%) as colorless crystals; mp 67 °C (hexane). IR (KBr): ν = 3080, 3055 (ArH), 2980-2800 (CH), 1760 (CO), 1605, 1500 (C=C) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.31 (s, 3 H, CH₃), 1.49 (s, 3 H, CH₃), 2.68 (tdd, J = 1.1, 7.2, 14.1 Hz, 1 H, CH₂), 2.75 (tdd, J = 1.1, 7.2, 14.1 Hz, 1 H, CH₂), 2.91 (s, 3 H, NCH₃), 3.75 (s, 1 H, 3a-H), 5.10-5.16, 5.49-5.57 (2 m, 2 H, 1 H, CH₂=CH), 6.42 (d, J = 7.6 Hz, 1 H, Ar), 6.71 (dt, J = 1.0, 7.6 Hz, 1 H, Ar), 7.16 (dt, J = 1.3, 7.6 Hz, 1 H, Ar), 7.29 (ddd, J = 0.5, 1.3, 7.6 Hz, 1 H, Ar). ¹³C NMR (126 MHz, CDCl₃): δ = 23.5, 29.4 (2 q, CH₃), 35.8 (q, NCH₃), 41.8 (t, CH₂), 58.9 (s, C-8b), 76.4 (d, C-3a), 87.3 (s, C-3), 106.2, 118.1 (2 d, Ar), 119.6 (t, CH₂=), 123.7 (d, Ar), 126.6 (s, Ar), 129.5 (d, Ar), 132.8 (d, CH=), 150.8 (s, Ar), 176.6 (s, CO). MS (EI, 80 eV, 40 °C): m/z (%) = 257 (84) [M]⁺, 171 (100) [M - C₄H₆O₂]⁺, 158 (59), 144 (40). Anal. Calcd for C₁₆H₁₉NO₂ (257.3): C, 74.68; H, 7.44; N, 5.44. Found: C, 74.52; H, 7.23; N, 5.50.

10 O’Dell DK. Nicholas KM. Tetrahedron  2003,  59:  747 

11

We thank one of the reviewers of this manuscript for suggesting a speculative but plausible explanation for the observed diastereoselectivity: the approach of the ketyl to
C-2 is more favorable when the very bulky samarium alkoxy group is positioned anti with respect to C-3 bearing the fairly large methoxycarbonyl group; the smaller substituent of the ketyl then points to the indole ring, which is the hydrogen in the case of aldehydes or the phenyl group for acetophenone.

12a Inanaga J. Ujikawa O. Handa Y. Otsubo K. Yamaguchi M. J. Alloys Compd.  1993,  192:  197 

12b Fukuzawa S.-I. Nakanishi A. Fujinami T. Sakai S. J. Chem. Soc., Perkin Trans. 1  1988,  1669 

12c Otsubo K. Inanaga J. Yamaguchi M. Tetrahedron Lett.  1986,  27:  5763 

12d Fukuzawa S.-I. Nakanishi A. Fujinami T. Sakai S. J. Chem. Soc., Chem. Commun.  1986,  624