Morita-Baylis-Hillman
Alkylation of Unsaturated Thioesters

Marie E. Krafft; Kimberly A. Seibert; Thomas F. N. Haxell

doi:10.1055/s-0030-1258777

LETTER

Morita-Baylis-Hillman Alkylation of Unsaturated Thioesters

Marie E. Krafft*, Kimberly A. Seibert, Thomas F. N. Haxell
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Fl 32306-4390, USA
Fax: +1(850)6447409; e-Mail: mek@chem.fsu.edu;

Abstract

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Abstract

The Morita-Baylis-Hillman alkylation reaction with unsaturated thioesters is described. Five- and six-membered rings are formed with ease and in excellent yields. The method is high yielding with either stoichiometric or catalytic amounts of tributylphosphine.

Key words

cyclization - alkylation - thioesters - organocatalysis - Morita-Baylis-Hillman reaction

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Referenzen

References and Notes

1a Singh V. Batra S. Tetrahedron 2008, 64: 4511

1b Basavaiah D. Rao AJ. Satyanarayana T. Chem. Rev. 2003, 103: 81

2a Kaaoka T. Iwama H. Kinoshita H. Tsujiyama Y. Iwamura T. Watanabe S. Synlett 1999, 197

2b Kataoka T. Kinoshita H. Iwama T. Tsujiyama S.-I. Iwamura T. Watanabe S.-I. Muraoka O. Tanabe G. Tetrahedron 2000, 56: 4725

3a Black GP. Dinon F. Fratucello S. Murphy PJ. Nielsen M. Williams HL. Walshe NDA. Tetrahedron Lett. 1997, 38: 8561

3b Dinon F. Richards E. Murphy PJ. Hibbs DE. Hursthouse MB. Malic KMA. Tetrahedron Lett. 1999, 40: 3279

3c Richards EL. Murphy PJ. Dinon F. Fratucello S. Brown PM. Gelbrich T. Hursthouse MB. Tetrahedron 2001, 57: 7771

3d Des Mazery R. Pullez M. Lopéz F. Harutyunyan SR. Minnaare AJ. Feringa BL. J. Am. Chem. Soc. 2005, 127: 9966

4 Yost JM. Zhou G. Coltart DM. Org. Lett. 2006, 8: 1503

5 Keck GE. Welch DS. Org. Lett. 2002, 4: 3687

6 Agapiou K. Krische MJ. Org. Lett. 2003, 5: 1737

7 Krafft ME. Seibert KA. Haxell TFN. Hirosawa C. Chem. Commun. 2005, 5772

8 Krafft ME. Haxell TFN. J. Am. Chem. Soc. 2005, 127: 10168

9 Krafft ME. Haxell TFN. Seibert KA. Abboud KA. J. Am. Chem. Soc. 2006, 128: 4174

10 Krafft ME. Seibert KA. Synlett 2006, 3334

11a

Compound 2: ^¹H NMR (500 MHz, CDCl₃): δ = 6.83 (td, J = 7.0, 15.5 Hz, 1 H), 6.16 (td, J = 1.3, 15.5 Hz, 1 H), 3.41 (t, J = 6.6 Hz, 2 H), 2.95 (q, J = 7.5 Hz, 2 H), 2.38 (ddt, J = 1.3, 7.0, 7.0 Hz, 2 H), 2.03 (tt, J = 6.6, 7.0 Hz, 2 H), 1.28 (t, J = 7.1 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 189.6, 142.4, 129.5, 32.4, 30.6, 30.2, 23.0, 14.6. HRMS (FAB+): m/z [M + Na] calcd for C₈H₁₃BrOSNa: 259.9766; found: 258.9768. FTIR (neat): 2965, 2960, 2872, 1667, 1633, 1436, 1265, 1026, 970 cm^-¹. Anal. Calcd for C₈H₁₃OBrS: C, 40.52; H, 5.53. Found: C, 40.13; H, 5.53.

11b

Compound 3: ^¹H NMR (500 MHz, CDCl₃): δ = 6.83 (td, J = 7.1, 15.4 Hz, 1 H), 6.16 (td, J = 1.3, 5.4 Hz, 1 H), 3.41 (t, J = 6.7 Hz, 2 H), 2.95 (t, J = 7.3 Hz, 2 H), 2.37 (ddt, J = 1.3, 7.1, 7.1 Hz, 2 H), 2.03 (tt, J = 6.7, 7.1 Hz, 2 H), 1.59 (tt, J = 7.3, 7.3 Hz, 2 H), 1.41 (qt, J = 7.3, 7.3 Hz, 2 H), 0.92 (t, J = 7.3 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 189.4, 142.2, 129.5, 32.3, 31.4, 30.6, 30.1, 28.2, 21.7, 13.4. HRMS (FAB+): m/z [M + Na] calcd for C₁₀H₁₇OBrNa: 287.00813; found: 287.00812. FTIR (neat): 2959, 2930, 2872, 1671, 1632 cm^-¹. Anal. Calcd for C₁₀H₁₇OBr: C, 45.29; H, 6.46. Found: C, 45.57; H, 6.57.

11c

Compound 4: ^¹H NMR (500 MHz, CDCl₃): δ = 6.75 (td, J = 7.1, 15.5 Hz, 1 H), 6.06 (td, J = 1.3, 15.5 Hz, 1 H), 3.41 (t, J = 6.6 Hz, 2 H), 2.34 (tdd, J = 1.3, 7.1, 7.1 Hz, 2 H), 2.01 (tt, J = 6.6, 7.1 Hz, 2 H), 1.50 (s, 9 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 190.4, 141.4, 130.3, 47.9, 32.5, 30.7, 30.2, 29.8. HRMS (FAB+): m/z [M + Na] calcd for C₁₀H₁₇OBrSNa: 287.00825; found: 287.00812. FTIR (neat): 2962, 1667, 1630, 1454, 1363, 968 cm^-¹. Anal. Calcd for C₁₀H₁₇OBrS: C, 45.29; H, 6.46. Found: C, 45.54; H, 6.50.

11d

Compound 5: Treatment of bromide 2 (237 mg, 1 mmol), with tributylphosphine (0.23 mL, 1 mmol) in t-BuOH (2 mL) followed by addition of KOH (56 mg, 1 mmol) and BnEt₃NCl (23 mg, 0.1 mmol) in CH₂Cl₂-H₂O (10 mL, 1:1) yielded enone 5 in 99% yield (155 mg). ^¹H NMR (500 MHz, CDCl₃): δ = 6.79 (tt, J = 2.2, 2.4 Hz, 1 H), 2.93 (q, J = 7.4 Hz, 2 H), 2.62 (dtt, J = 2.2, 2.3, 7.6 Hz, 2 H), 2.51 (tdt, J = 2.3, 2.4, 7.6 Hz, 2 H), 1.96 (tt, J = 7.6, 7.6 Hz, 2 H), 1.27 (t, J = 7.4 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 188.9, 144.0, 141.4, 33.2, 31.0, 22.8, 22.7, 13.4. HRMS (CI+): m/z [M + H] calcd for C₈H₁₃OS: 157.06899; found: 157.06872. FTIR (neat): 2957, 2871, 1655, 1459, 1154 cm^-¹. Anal. Calcd for C₈H₁₂OS: C, 61.50; H, 7.74. Found: C, 61.03; H, 7.65.

11e

Compound 6: ^¹H NMR (500 MHz, CDCl₃): δ = 6.80 (tt, J = 2.1, 2.3 Hz, 1 H), 2.93 (t, J = 7.4 Hz, 2 H), 2.62 (dtt, J = 2.1, 2.2, 7.6 Hz, 2 H) 2.51 (tdt, J = 2.2, 2.3, 7.6 Hz, 2 H), 1.96 (tt, J = 7.6, 7.6 Hz, 2 H), 1.58 (m, 2 H), 1.41 (tq, J = 7.4, 7.4 Hz, 2 H), 0.94 (t, J = 7.4 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 189.1, 144.1, 141.5, 33.4, 31.7, 31.2, 28.1, 22.9, 22.0, 13.6. HRMS (CI+): m/z [M⁺] calcd for C₁₀H₁₆OS: 185.0999; found: 185.1000. FTIR (neat): 2958, 2930, 1655, 1613, 1156 cm^-¹. Anal. Calcd for C₁₀H₁₆OS: C, 65.17; H, 8.75. Found: C, 64.82; H, 8.87.

11f Compound 7: Kishimoto N. Fujimoto T. Yamamoto I. J. Org. Chem. 1999, 64: 5988

11g

Compound 8: ^¹H NMR (500 MHz, CDCl₃): δ = 6.86 (td, J = 6.9, 15.4 Hz, 1 H), 6.12 (td, J = 1.5, 15.4 Hz, 1 H), 3.41 (t, J = 6.6 Hz, 2 H), 2.95 (q, J = 7.3 Hz, 2 H), 2.23 (dtd, J = 1.5, 7.1, 7.1 Hz, 2 H), 1.89 (tt, J = 6.6, 7.1 Hz, 2 H), 1.64 (tt, J = 7.1, 7.1 Hz, 2 H), 1.28 (t, J = 7.3 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 189.7, 143.9, 129.0, 33.0, 31.9, 31.0, 26.3, 22.9, 14.7. HRMS (FAB+): m/z [M + Na] calcd for C₉H₁₅OBrSNa: 272.9927; found: 272.9925. FTIR (neat): 2930, 1670, 1632, 1451, 1265, 969 cm^-¹. Anal. Calcd for C₉H₁₅OBrS: C, 43.03; H, 6.02. Found: C, 43.36; H, 5.98.

11h Compound 9: Schaumann E. Mergardt B. J. Chem. Soc., Perkin Trans. 1: Organic and Bioorganic Chem. 1989, 1361

11i

Compound 10: ^¹H NMR (500 MHz, CDCl₃): δ = 6.70 (td, J = 7.8, 15.4 Hz, 1 H), 6.15 (td, J = 1.2, 15.4 Hz, 1 H), 4.23 (ABq, J = 7.1, 7.1 Hz, 2 H), 4.22 (ABq, J = 7.1, 7.1 Hz, 2 H), 3.36 (t, J = 8.2 Hz, 2 H), 2.94 (q, J = 7.4 Hz, 2 H) 2.77 (dd, J = 1.2, 7.8 Hz, 2 H), 2.45 (t, J = 8.2 Hz, 2 H), 1.28 (t, J = 7.4 Hz, 3 H), 1.27 (t, J = 7.1 Hz, 6 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 189.3, 169.5, 137.5, 132.2, 61.9, 57.2, 36.7, 36.2, 26.6, 23.1, 14.6, 13.9. HRMS (FAB+): m/z [M + Na] calcd for C₁₅H₂₃O₅BrSNa: 417.0340; found: 417.0347. FTIR (neat): 2980, 2934, 1730, 1671, 1633, 1443, 1261 cm^-¹. Anal. Calcd for C₁₅H₂₃O₅BrS: C, 45.57; H, 5.86. Found: C, 45.47; H, 5.95.

11j

Compound 11: ^¹H NMR (500 MHz, CDCl₃): δ = 6.89 (tt, J = 1.8, 4.0 Hz, 1 H), 4.19 (ABq, J = 7.1, 7.1 Hz, 2 H), 4.19 (ABq, J = 7.1, 7.1 Hz, 2 H), 2.91 (q, J = 7.4 Hz, 2 H), 2.76 (td, J = 2.4, 4.0 Hz, 2 H), 2.39 (dtt, J = 1.8, 2.4, 6.4 Hz, 2 H), 2.18 (t, J = 6.4 Hz, 2 H), 1.26 (t, J = 7.4 Hz, 3 H), 1.25 (t, J = 7.1 Hz, 6 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 192.0, 170.7, 137.0, 134.2, 61.5, 52.4, 30.9, 27.0, 22.9, 21.2, 14.7, 13.9. HRMS (CI+): m/z [M + H] calcd for C₁₅H₂₃O₅S: 315.1262; found: 315.1266. FTIR (neat): 2957, 2930, 2871, 1655, 1156 cm^-¹. Anal. Calcd for C₁₅H₂₂O₅S: C, 57.30; H, 7.05. Found: C, 57.34; H, 7.07.

11k

Compound 12: ^¹H NMR (500 MHz, CDCl₃): δ = 6.67 (td, J = 7.6, 15.3 Hz, 1 H), 6.15 (br d, J = 15.3 Hz, 1 H), 3.76 (s, 6 H), 3.35 (t, J = 8.2 Hz, 2 H), 2.94 (t, J = 7.3 Hz, 2 H), 2.78 (dd, J = 1.1, 7.6 Hz, 2 H), 2.46 (t, J = 8.2 Hz, 2 H), 1.58 (tt, J = 7.3, 7.3 Hz, 2 H), 1.40 (qt, J = 7.3, 7.3 Hz, 2 H), 0.92 (t, J = 7.3 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 189.2, 169.9, 137.0, 132.2, 57.3, 52.8, 36.6, 36.2, 31.4, 28.4, 26.5, 21.8, 13.5. HRMS (FAB+): m/z [M + Na] calcd for C₁₅H₂₃O₅BrSNa: 417.03409; found: 417.03472. FTIR (neat): 2956, 1734, 1670, 1437, 1264 cm^-¹. Anal. Calcd for C₁₅H₂₃O₅BrS: C, 45.57; H, 5.86. Found: C, 45.57; H, 6.17.

11l

Compound 13: ^¹H NMR (500 MHz, CDCl₃): δ = 6.91 (tt, J = 1.5, 4.0 Hz, 1 H), 3.73 (s, 6 H), 2.90 (t, J = 7.3 Hz, 2 H), 2.78 (td, J = 2.2, 4.0 Hz, 2 H), 2.38 (dtt, J = 1.5, 2.2, 6.4 Hz, 2 H), 2.19 (t, J = 6.4 Hz, 2 H), 1.56 (tt, J = 7.3, 7.4 Hz, 2 H), 1.39 (tq, J = 7.4, 7.4 Hz, 2 H), 0.92 (t, J = 7.4 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 192.1, 171.2, 137.2, 134.0, 52.8, 52.5, 31.6, 31.1, 28.3, 27.2, 22.0, 21.3, 13.6. HRMS (CI+): m/z [M + H] calcd for C₁₅H₂₃O₅S: 315.12677; found: 315.12662. FTIR (neat): 2955, 2872, 1736, 1651, 1257 cm^-¹. Anal. Calcd for C₁₅H₂₂O₅S: C, 57.30; H, 7.05. Found: C, 57.16; H, 7.20.

11m

Compound 14: ^¹H NMR (500 MHz, CDCl₃): δ = 6.59 (td, J = 7.6, 15.3 Hz, 1 H), 6.06 (td, J = 1.2, 15.3 Hz, 1 H), 3.76 (s, 6 H), 3.35 (t, J = 8.1 Hz, 2 H), 2.76 (dd, J = 1.2, 7.6 Hz, 2 H), 2.45 (t,
J = 8.1 Hz, 2 H), 1.49 (s, 9 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 189.7, 170.0, 136.0, 133.0, 57.3, 52.9, 48.2, 36.6, 36.1, 29.7, 26.6. HRMS (FAB+): m/z [M + Na] calcd for C₁₅H₂₃O₅BrSNa: 417.03471; found: 417.02472. FTIR (neat): 2956, 1734, 1667, 1631, 1435, 1264 cm^-¹. Anal. Calcd for C₁₅H₂₃O₅BrS: C, 45.57; H, 5.86. Found: C, 45.47; H, 5.95.

11n

Compound 15: ^¹H NMR (500 MHz, CDCl₃): δ = 6.86 (tt, J = 2.0, 4.4 Hz, 1 H), 3.73 (s, 6 H), 2.73 (td, J = 2.2, 4.0 Hz, 2 H), 2.32 (dtt, J = 2.2, 2.2, 6.4 Hz, 2 H), 2.16 (t, J = 6.4 Hz, 2 H), 1.47 (s, 9 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 193.0, 171.3, 138.0, 133.2, 52.9, 52.5, 47.6, 31.1, 29.9, 28.3, 27.3, 21.6. HRMS (CI+): m/z [M⁺] calcd for C₁₅H₂₂O₅S: 315.12718; found: 315.12662. FTIR (neat): 2954, 1735, 1645, 1257 cm^-¹. Anal. Calcd for C₁₅H₂₂O₅S: C, 57.30; H, 7.05. Found: C, 57.66; H, 7.21.

11o

Compound 16: ^¹H NMR (500 MHz, CDCl₃): δ = 6.70 (dd, J = 8.2, 15.7 Hz, 1 H), 6.13 (dd, J = 1.0, 15.7 Hz, 1 H), 3.40 (ABt, J = 9.7, 6.5 Hz, 1 H), 3.33 (ABt, J = 9.7, 6.5 Hz, 1 H), 2.95 (q, J = 7.4 Hz, 2 H), 2.57 (m, 1 H), 1.94 (ABdt, J = 14.0, 7.0, 7.0 Hz, 1 H), 1.91 (ABdt, J = 14.0, 7.0, 7.0 Hz, 1 H), 1.28 (t, J = 7.4 Hz, 3 H), 1.10 (d, J = 6.8 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 189.6, 147.5, 127.9, 43.9, 38.2, 34.7, 30.9, 26.6, 25.8, 23.2, 22.9, 18.8, 14.6, 14.5, 14.4. HRMS (FAB+): m/z [M + Na] calcd for C₉H₁₅OBrNaS: 272.99276; found: 272.99247. FTIR (neat): 2965, 1670, 1631, 1453 cm^-¹. Anal. Calcd for C₉H₁₅OBrS: C, 43.03; H, 6.02. Found: C, 43.29; H, 6.23.

11p

Compound 18: ^¹H NMR (500 MHz, CDCl₃): δ = 6.98 (dd, J = 9.2, 15.5 Hz, 1 H), 6.23 (dd, J = 0.7, 15.5 Hz, 1 H), 3.25 (dd, J = 7.1, 10.0 Hz, 1 H), 3.14 (dd, J = 8.2, 10.0 Hz, 1 H), 2.96 (ABq, J = 15.0, 7.5 Hz, 1 H), 2.96 (ABq, J = 15.0, 7.5 Hz, 1 H), 2.78 (dddd, J = 4.0, 4.0, 8.0, 9.1 Hz, 1 H), 1.98 (ddddd, J = 4.0, 4.0, 7.1, 8.2, 10.8 Hz, 1 H), 1.3-1.75 (m, 7 H), 1.29 (t, J = 7.5 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 189.7, 143.1, 130.0, 42.6, 40.1, 36.6, 30.2, 27.2, 24.8, 23.1, 21.6, 14.7. HRMS (FAB+): m/z [M + Na] calcd for C₁₂H₁₉OBrSNa: 313.02361; found: 313.02377. FTIR (neat): 2930, 2856, 1670, 1628, 1449 cm^-¹. Anal. Calcd for C₁₂H₁₉OBrS: C, 49.49; H, 6.58. Found: C, 49.70; H, 6.53.

11q

Compound 19: HRMS (CI+): m/z [M + Na] calcd for C₁₂H₁₈OS: 211.1152; found: 211.1157. Anal. Calcd for C₁₂H₁₈OS: C, 68.52; H, 8.63. Found: C, 68.27; H, 8.67.

11r

Catalysis of Reactions of α,β-Unsaturated Thioesters in the MBH Reaction: General Procedure of the Catalytic MBH Alkylation Reaction of Thioesters: A solution of thioester 2 (237 mg, 1 mmol) in CH₂Cl₂-t-BuOH (1:1; 2 mL, 0.5 M), and H₂O (10 mL, 0.1 M) with BnEt₃NCl (23 mg, 0.1 mmol) and KOH (56 mg, 1 mmol) was treated with tributylphosphine (0.45 mL, 0.2 mmol). The reaction was stirred in a resealable tube until complete consumption of starting material as indicated by TLC. The organic layer was then extracted with CH₂Cl₂, dried over anhyd Na₂SO₄ and concentrated in vacuo. Purification via column chroma-tography gave the desired product 5 (152 mg, 97%).