Ring-Closing Enyne Metathesis (RCEYM) for the Synthesis of Cyclic Sulfoximines

Abstract

Heterocyclic sulfoximines have been synthesized by RCEYM reactions starting from N-alkynyl-S-alkenyl sulfoximines in up to 79% yield. The products can be converted to tricyclic derivatives by a domino Diels-Alder/aromatization reaction sequence.

Key words

enynes - heterocycles - ring-closing metathesis - sulfoximines - tricycles

References and Notes

• Reviews:
• 1a Worch C. Mayer AC. Bolm C. In Organosulfur Chemistry in Asymmetric Synthesis   Toru T. Bolm C. Wiley-VCH; Weinheim: 2008.  p.209 
• 1b Bolm C. In Asymmetric Synthesis with Chemical and Biological Methods   Enders D. Jaeger K.-E. Wiley-VCH; Weinheim: 2007.  p.149 
• 1c Hais H.-J. Heteroat. Chem.  2007,  18:  472 
• 1d Okamura H. Bolm C. Chem. Lett.  2004,  33:  482 
• 1e Harmata M. Chemtracts  2003,  16:  660 
• 1f Reggelin M. Zur C. Synthesis  2000,  1 
• 2 Bolm C. Müller D. Dalhoff C. Hackenberger CPR. Weinhold E. Bioorg. Med. Chem. Lett.  2003,  13:  3207 ; and references therein
• 3a Williams TR. Cram DJ. J. Am. Chem. Soc.  1971,  93:  7333 
• 3b Williams TR. Cram D. J. Org. Chem.  1973,  38:  20 
• 3c Schaffner-Sabba K. Tomaselli H. Henrici B. Renfroe HB. J. Org. Chem.  1977,  42:  952 
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• For overviews on metathesis reactions affording sulfur-containing heterocycles, see:
• 4a Karsch S. Freitag D. Schwab P. Metz P. Synthesis  2004,  1696 
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• For other olefin metathesis reactions with sulfoximine-based substrates, see:
• 6a Lejkowski M. Gais H.-J. Banerjee P. Vermeeren C. J. Am. Chem. Soc.  2006,  128:  15378 
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9

Sonogashira Coupling
A mixture of 3a (0.286 mmol, 1.0 equiv), PhI (0.858 mmol, 3.0 equiv), [Pd(PPh₃)₂Cl₂] (0.029 mmol, 10 mol%), CuI (0.057 mmol, 20 mol%), and Ph₃P (0.029 mmol, 10 mol%) was dissolved in dry Et₃N-DMF (5.71 mL/2.86 mL, 2:1) and stirred under Ar at 70 ˚C for 4 h. After workup (CH₂Cl₂, brine) and column chromatography [silica gel, pentane-EtOAc (3:1)] 3h was obtained as orange oil (0.181 mmol, 63%).

10

Silylation
A soln of 3a (0.715 mmol, 1.0 equiv) in dry THF (10 mL) was cooled to -78 ˚C. n-BuLi in hexane (0.787 mmol, 1.1 equiv) was added dropwise via syringe. After 30 min at this temperature, TESCl (1.431 mmol, 2.0 equiv) was added slowly. After stirring for 1 h at -78 ˚C, the reaction was quenched with brine. After workup (Et₂O, brine) and column chromatography [silica gel, pentane-EtOAc (6:1)] 3i was obtained as colorless oil (0.526 mmol, 74%).

11

The RCEYM reactions were performed under argon using standard Schlenk techniques. N(H)- and N-alkynyl sulfoximines (7a-c and 3a-i) were synthesized according to literature procedures [8] [¹²] and used as racemates.
Ring-Closing Enyne Metathesis Reactions - Typical Procedure for the Synthesis of 9c
A dried Schlenk flask was charged with doubly unsaturated sulfoximine 3c and dry toluene (0.01 M). After heating to 120 ˚C under argon, the catalyst (Grubbs II, 10 mol%) was added under vigorous stirring in one batch. The dark brown reaction mixture was refluxed for 15 min. After cooling to r.t., the mixture was concentrated in vacuo. The residue was subjected to column chromatography [silica gel, pentane-EtOAc (3:1)], which afforded 9c as a light brownish oil in 79% yield. ^¹H NMR (400 MHz, CDCl₃): δ = 8.07-8.04 (m, 2 H_arom.), 7.62-7.57 (m, 1 H_arom.), 7.55-7.49 (m, 2 H_arom.), 5.91-5.84 (m, 1 H), 5.06 (br s, 1 H), 4.92 (br s, 1 H), 4.43 (d, 1 H, J = 16.5 Hz), 3.97 (d, 1 H, J = 16.5 Hz), 3.56 (ddd, 1 H, J = 13.5, 9.6, 1.9 Hz), 3.09 (ddd, 1 H, J = 13.3, 9.6, 1.9 Hz), 2.80-2.69 (m, 1 H), 2.64-2.54 (m, 1 H), 2.27 (q, 2 H, J = 7.4 Hz), 1.08 (t, 3 H, J = 7.4 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 150.3, 146.5, 138.8, 133.0, 128.9, 128.0, 123.4, 110.0, 55.6, 42.8, 27.2, 22.1, 13.2. IR (CHCl₃): 2965, 2846, 1447, 1231, 1135, 887, 754, 688 cm^-¹. MS (EI): m/z (%) = 261.1 (16) [M]⁺, 246.1 (4) [M - CH₃]⁺. HRMS (EI): m/z calcd for C₁₅H₁₉NOS: 261.1187; found: 261.1186.



Diels-Alder Reactions - Typical Procecure for the Synthesis of 12c
To a soln of 9c in toluene (0.032 M) was added p-benzo-quinone (5 equiv). The reaction mixture was refluxed at 120 ˚C for 3 h. After cooling to r.t., the yellowish solution was concentrated in vacuo and subjected to column chromat-ography [silica gel, pentane-EtOAc (2:1)]. Tricyclic product 12c was obtained as a yellow solid in 85% yield. ^¹H NMR (400 MHz, CDCl₃): δ = 7.98 (m, 3 H_arom.), 7.62-7.57 (m, 1 H_arom.), 7.53-7.47 (m, 3 H_arom.), 6.90 (d, 1 H, J = 10.4 Hz), 6.86 (d, 1 H, J = 10.2 Hz), 4.96 (d, 1 H, J = 15.1 Hz), 4.59 (d, 1 H, J = 14.8 Hz), 4.54 (ddd, 1 H, J = 14.8, 7.7, 1.1 Hz), 3.81-3.71 (m, 2 H), 3.05-2.93 (m, 3 H), 1.33 (t, 3 H, J = 7.7 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 187.5, 184.8, 150.1, 147.7, 141.9, 140.5, 139.0, 136.8, 133.2, 131.5, 129.0, 128.4, 127.6, 126.9, 55.4, 40.3, 28.0, 23.0, 15.7. IR (KBr): 3441, 2967, 1657, 1578, 1308, 1117, 844, 783 cm^-¹. MS (CI): m/z (%) = 365.8 (100) [M + H]⁺, 240.4 (86) [M - C₆H₅SO]⁺. HRMS (EI): m/z calcd for C₂₁H₁₉NO₃SC₆H₅SO: 240.1019; found: 240.1010.