Samarium Diiodide in the Synthesis of Medium-Sized Rings - Carbocycles and Heterocycles by Intramolecular Addition of Samarium Ketyls to Alkynes

Abstract

A series of alkynyl-substituted ketones and aldehydes was subjected to samarium diiodide in the presence of HMPA to study the scope and limitations of their ketyl-alkyne coupling. Seven- and eight-membered heterocycles such as 4, 6, 8, 25, 27, 29, 33, and 35 could be isolated in moderate to good yields. Other ­cyclization products were isolated in low yields only. The efficacy of the reductive cyclization strongly depends on the substitution pattern and the presence of heteroatoms and/or benzene rings in the spacer between the alkyne and carbonyl group. First subsequent transformations of azocine 29 leading to enone 38 or epoxide 39 demonstrate the synthetic potential of this method.

Key words

alkynes - 8-endo-dig-cyclizations - ketyl radicals - medium-sized rings - samarium diiodide

References

• 1 Nicolaou KC. Dai W.-M. Guy RK. Angew. Chem., Int. Ed. Engl.  1994,  33:  15 ; Angew. Chem. 1994, 106, 38
• 2 Nicolaou KC. Pfefferkorn J. Xu J. Winssinger N. Ohshima T. Kim S. Hosokawa S. Vourloumis D. van Delft F. Li T. Chem. Pharm. Bull.  1999,  47:  1199 
• Selected examples:
• 3a Trost BM. Ameriks MK. Org. Lett.  2004,  6:  1745 
• 3b Papaioannou N. Blank JT. Miller SJ. J. Org. Chem.  2003,  68:  2728 
• 3c Fellows IM. Kaelin DE. Martin SF. J. Am. Chem. Soc.  2000,  122:  10781 
• 3d Ducray R. Ciufolini MA. Angew. Chem. Int. Ed.  2002,  41:  4688 ; Angew. Chem. 2002, 114, 4882
• Selected reviews on syntheses of medium-sized rings:
• 4a Yet L. Chem. Rev.  2000,  100:  2963 
• 4b Mehta G. Singh V. Chem. Rev.  1999,  99:  881 
• 4c Yet L. Tetrahedron  1999,  55:  9349 
• 4d Hoberg JO. Tetrahedron  1998,  54:  12631 
• 4e Rousseau G. Tetrahedron  1995,  51:  2777 
• 4f Roxburgh CJ. Tetrahedron  1993,  49:  10749 
• 4g Petasis NA. Patane MA. Tetrahedron  1992,  48:  5757 
• 4h Evans PA. Holmes AB. Tetrahedron  1991,  47:  9131 
• First applications of this powerful one-electron transfer reagent to organic synthesis:
• 5a Namy J.-L. Girard P. Kagan HB. Nouv. J. Chim.  1977,  1:  5 
• 5b Girard P. Namy JL. Kagan HB. J. Am. Chem. Soc.  1980,  102:  2693 
• Selected reviews on samarium diiodide-mediated reactions:
• 6a Edmonds DJ. Johnston D. Procter DJ. Chem. Rev.  2004,  104:  3371 
• 6b Kagan HB. Tetrahedron  2003,  59:  10351 
• 6c Banik BK. Eur. J. Org. Chem.  2002,  2431 
• 6d Steel PG. J. Chem. Soc., Perkin Trans. 1  2001,  2727 
• 6e Hölemann A. Synlett  2002,  1497 
• 6f Krief A. Laval A.-M. Chem. Rev.  1999,  99:  745 
• 6g Molander GA. Harris CR. Tetrahedron  1998,  54:  3321 
• 6h Khan FA. Zimmer R. J. Prakt. Chem.  1997,  339:  101 
• 6i Molander GA. Harris CR. Chem. Rev.  1996,  96:  307 
• 6j Kagan HB. New J. Chem.  1990,  14:  453 
• 6k Kagan HB. Namy JL. Tetrahedron  1986,  42:  6573 
• 6l Also see ref. 16
• Selected references:
• 7a Sono M. Nakashiba Y. Nakashima K. Tori M. J. Org. Chem.  2000,  65:  3099 
• 7b Molander GA. McKie JA. J. Org. Chem.  1995,  60:  872 
• 7c Molander GA. McKie JA. J. Org. Chem.  1994,  59:  3186 
• 7d Molander GA. Kenny C. J. Am. Chem. Soc.  1989,  111:  8236 
• 7e Enholm EJ. Trivellas A. Tetrahedron Lett.  1989,  30:  1063 
• 7f Formation of 8-membered O-heterocycles has recently been reported during a study of SmI₂-induced cyclizations of methylenecyclo-propyl ketones: Underwood JJ. Hollingworth GJ. Horton PN. Hursthouse MB. Kilburn JD. Tetrahedron Lett.  2004,  45:  2223 
• 8a Molander GA. McKie JA. J. Org. Chem.  1992,  57:  3132 
• 8b Molander GA. Acc. Chem. Res.  1998,  31:  603 
• 8c Monovich LG. Le Huérou Y. Rönn M. Molander GA. J. Am. Chem. Soc.  2000,  122:  52 
• 8d Molander GA. George KM. Monovich LG. J. Org. Chem.  2003,  68:  9533 
• 9 Khan FA. Czerwonka R. Zimmer R. Reissig H.-U. Synlett  1997,  995 
• 10a Shim SC. Hwang J.-T. Kang H.-Y. Chang MH. Tetrahedron Lett.  1990,  31:  4765 
• 10b Anies C. Lallemand J.-Y. Pancrazi A. Tetrahedron Lett.  1996,  37:  5523 
• 10c Baldwin JE. MacKenzie Turner SC. Moloney MG. Tetrahedron  1994,  50:  9425 
• 11a Dinesh CU. Reissig H.-U. Angew. Chem. Int. Ed.  1999,  38:  789 ; Angew. Chem. 1999, 111, 874
• 11b Nandanan E. Dinesh CU. Reissig H.-U. Tetrahedron  2000,  56:  4267 
• 12 Hölemann A. Dissertation   Freie Universität Berlin; Germany: 2004. 
• 14a Inanaga I. Ishikawa M. Yamaguchi M. Chem. Lett.  1987,  1485 
• 14b Shabangi M. Flowers RA. Tetrahedron Lett.  1997,  38:  1137 
• 14c Prasad E. Flowers RA. J. Am. Chem. Soc.  2002,  124:  6895 , and references cited therein
• 16 Berndt M. Gross S. Hölemann A. Reissig H.-U. Synlett  2004,  422 
• 17a The relative configuration of the hydroxyl group and alkyl chain was determined by regarding the chemical shift of the proton at C-1. See: Kobayashi Y. Takahisa E. Nakano M. Watatani K. Tetrahedron  1997,  53:  1627 
• 17b

  The diastereoselectivity in favor of the trans-isomer may be explained by assuming that the sterically demanding samarium-alkoxy group and the alkyl group are in equatorial positions in the transition state of cyclization.

• 20 Hölemann A. Brüdgam I. Hartl H. Reissig H.-U. Z. Kristallogr. NCS  2004,  219:  59 
• 21a Dudley GB. Danishefsky SJ. Org. Lett.  2001,  3:  2399 
• 21b Büchi G. Egger B. J. Org. Chem.  1971,  36:  2021 

13

Typical Procedure: Cyclization of 5 to 6. Samarium powder (0.361 g, 2.40 mmol) and 1,2-diiodoethane (0.620 g, 2.20 mmol) were suspended in freshly distilled anhyd THF (25 mL) under an argon atmosphere and stirred for 2 h at r.t. To the resulting dark blue solution HMPA (3.3 g, 18 mmol) was added. Alkynyl ketone 5 (0.230 g, 0.80 mmol) and
t-BuOH (0.150 g, 2.00 mmol) were dissolved in anhyd THF (15 mL) and then added to the deep violet solution. After 16 h at r.t., the mixture was quenched with sat. aq solution of NaHCO₃ (15 mL) and H₂O (10 mL), the organic layer was separated and the aqueous layer was extracted with Et₂O (3 × 15 mL). The combined organic extracts were washed with H₂O (15 mL) and brine (2 × 20 mL), dried with anhyd MgSO₄, filtered and evaporated. The resulting crude oil was purified by column chromatography on silica gel using n-hexane-EtOAc (5:1) as eluent. Compound 6 (0.181 g, 78%) was obtained as a colorless oil. Data for tert-butyl 5-hydroxy-5-methyl-5,6-dihydro-1-benzazocin-1(2H)-carboxylate (6): ¹H NMR (500 MHz, CDCl₃, 334 K): δ = 7.22-7.12 (m, 4 H, Ar), 5.49 (dd, J = 1.0, 12.4 Hz, 1 H, 4-H), 5.27 (td, J = 6.9, 12.4 Hz, 1 H, 3-H), AB part of the ABX system (δ_A = 4.31, δ_B = 4.22, J _AB = 15.3 Hz, J _AX = J _BX = 6.9 Hz, each 1 H, 2-H), 3.17 (d, J = 13.8 Hz, 1 H, 6-H), 2.84 (d, J = 13.8 Hz, 1 H, 6-H), 1.94 (br s, 1 H, OH), 1.44 (s, 3 H, 5-CH₃), 1.39 [s, 9 H, C(CH₃)₃]. ¹³C NMR (126 MHz, CDCl₃, 334 K): δ = 154.6 (s, CO), 141.8 (d, C-4), 140.3, 135.9 (2 s, Ar), 130.1, 129.0, 127.2, 126.8 (4 d, Ar), 121.4 (d, C-3), 80.3, 28.3 [s, q, C(CH₃)₃], 74.5 (s, C-5), 47.4 (t, C-2), 45.4 (t, C-6), 29.5 (q, 5-CH₃). IR (film): ν = 3450 (O-H), 3065-2930 (=C-H, C-H), 1695 (C=O), 1605-1495 (C=C) cm^-1. Anal. Calcd for C₁₇H₂₃NO₃ (289.4): C, 70.56; H, 8.01; N, 4.84. Found: C, 70.32; H, 8.04; N, 4.39.

15

Attempts to replace HMPA by less toxic co-solvents have so far not been successful in general. In individual examples, related additives (e.g. N-methylpyrrolidinone or other phosphoramide derivatives) were efficient but unfortunately, no rule has yet been recognized in which cases these additives are applicable. Berndt, M.; Gross, S.; Hölemann, A.; Reissig, H.-U. unpublished results.

18

The formation of allene 14 could not be mechanistically elucidated so far, but it can probably be explained by assuming a samarium(II) or samarium(III)-induced isomerization of the alkyne to an allene moiety.

19

The configuration of the double bond was unambiguously determined by NOESY spectroscopy.