A One-Pot Multicomponent Coupling Reaction for the Stereocontrolled Synthesis of Allyl-Substituted Cyclopropanes

Abstract

Allyl-substituted cyclopropanes can be efficiently ­synthesized in a stereoselective manner from alkynes and 2-haloacrylate in a one-pot process.

Key words

one-pot reaction - multicomponent - 2-bromoacrylate - alkynes - allyl-substituted cyclopropanes

References

• 1a Harada T. Katsuhira T. Hattori K. Oku A. J. Org. Chem.  1993,  58:  2958 
• 1b The Chemistry of the Cyclopropyl Group   Patai S. Rappoport Z. Wiley; New York: 1987. 
• 1c Hoveyda AH. Evans DA. Fu GC. Chem. Rev.  1993,  93:  1370 
• 1d Doyle MP. Forbes DC. Chem. Rev.  1998,  98:  911 
• 1e Li AH. Dai LX. Aggarwal VK. Chem. Rev.  1997,  97:  2341 
• 1f Suzuki ND. Kondakov Y. Kageyama M. Kotora M. Hara R. Takahashi T. Tetrahedron  1995,  51:  4519 
• 2 Yachi K. Shinokubo H. Oshima K. Angew. Chem. Int. Ed.  1998,  37:  2515 
• 3 Chen H. Deng M.-Z. J. Org. Chem.  2000,  65:  4444 
• 4a Wakefield BJ. Organolithium Method   Academic Press; London: 1988. 
• 4b Wakefield BJ. Organomagnesium Methods in Organic Synthesis   Academic Press; London: 1995. 
• For the preparation of cyclopropylmetal compounds by carbometalation of cyclopropene, see:
• 5a Stoll AT. Negishi E. Tetrahedron Lett.  1985,  26:  5671 
• 5b Nakamura E. Isaka M. Matsuzawa S. J. Am. Chem. Soc.  1988,  110:  1297 
• 5c Isaka M. Nakamura E. J. Am. Chem. Soc.  1990,  112:  7428 
• 5d Isaka M. Ejiri S. Nakamura E. Tetrahedron  1992,  48:  2047 
• 6a Boron: Imai T. Mineta H. Nishida S. J. Org. Chem.  1990,  55:  4986 
• 6b Fontani P. Carboni B. Vaultier M. Mass G. Synthesis  1991,  605 
• 6c Wang X.-Z. Deng M.-Z. J. Chem. Soc., Perkin. Trans. 1  1996,  2663 
• 6d Hildebrand JP. Marsden SP. Synlett  1996,  893 
• 6e Pietruszka J. Widenmeyer M. Synlett  1997,  977 
• 6f Aluminum: Zweifel G. Clark GM. Whitney CC. J. Am. Chem. Soc.  1971,  93:  1305 
• 6g Silicon: Hirabayashi K. Mori A. Hiyama T. Tetrahedron Lett.  1997,  38:  461 
• 6h

  Zinc: see references 1a,2.

• 7 Dulayymi JRA. Baird MS. Boiesov IG. Tveresovsky V. Rubin M. Tetrahedron Lett.  1996,  38:  461 
• 8a Jung ME. Light LA. Tetrahedron Lett.  1982,  23:  3861 
• 8b Shinokubo H. Miki H. Yokoo K. Utimoto K. Tetrahedron  1995,  51:  11681 
• 9a Kubota K. Nakamura M. Nakamura E. J. Am. Chem. Soc.  1993,  115:  5867 
• 9b Nakamura M. Arai M. Nakamura E. J. Am. Chem. Soc.  1995,  117:  1179 
• 9c Kubota K. Mori S. Nakamura M. Nakamura E. J. Am. Chem. Soc.  1998,  120:  13334 
• 9d Nakamura M. Hirai A. Nakamura E. J. Am. Chem. Soc.  2000,  122:  978 
• 9e Nakamura M. Inoue T. Sato A. Nakamura E. Org. Lett.  2000,  2:  2193 
• 9f Nakamura M. Inoue T. Nakamura E. J. Organomet. Chem.  2001,  624:  300 
• 9g Nakamura M. Isobe H. Nakamura E. Chem. Rev.  2003,  103:  1295 
• 10a Araki S. Nakano H. Subburaj K. Hirashita T. Shibutani K. Yamamura H. Kawai M. Butsugan Y. Tetrahedron Lett.  1998,  39:  6327 
• 10b Richey HG. Bension RM. J. Org. Chem.  1980,  45:  5036 
• 10c Nesmeyanova OA. Rudashevskaya TY. Dyachenka AI. Savitova SF. Nefedov OM. Synthesis  1982,  296 
• 11a Chen C. Xi C. Jiang Y. Hong X. Tetrahedron Lett.  2004,  45:  6067 
• 11b Xi C. Chen C. Lin J. Hong X. Org. Lett.  2005,  7:  347 
• 12 Conjugate addition is often used in the formation of cyclic compound, see: Perlmutter P. Conjugate Addition Reactions in Organic Synthesis, In Tetrahedron Organic Chemistry Series 9   Pergamon Press; Oxford: 1992. 
• 13 Sato F. Ishikawa H. Sato M. Tetrahedron Lett.  1981,  22:  85 
• 14a Kawakami Y. Tsuruta T. Tetrahedron Lett.  1971,  12:  1173 
• 14b Tsuruta T. Kawakawi Y. Tetrahedron  1973,  29:  1173 
• 15a Takahashi T. Aoyagi K. Hara R. Suzuki N. J. Chem. Soc., Chem. Commun.  1993,  1042 
• 15b Takahashi T. Aoyagi K. Kondakov DY. J. Chem. Soc., Chem. Commun.  1994,  747 
• 16 Takahashi T. Kageyama M. Denisov N. Negishi E. Tetrahedron Lett.  1993,  34:  687 

17

Typical Procedure for Allyl-Substituted Cyclopropanes. Preparation of 1-Bromo-2-(2-ethylpent-2-enyl)cyclo-propane-1,2-dicarboxylic Acid Dimethyl Ester (4a).
To a mixture of Cp₂TiCl₂ (0.05 mmol, 15 mg) and 3-hexyne (1.0 mmol, 115 µL) in Et₂O (3.0 mL) was added i-BuMgBr (1.1 mmol, 1.0 M in Et₂O) at -78 °C. Then the mixture was warmed to r.t. and stirred for 1 h. Before CuCl (0.1 mmol, 10 mg) and methyl 2-bromo-acrylate (2.0 mmol, 230 µL) were added, the mixture was cooled to -30 °C using ice-salt bath and maintained at the same temperature for 1 h. After an additional 1 h, the suspension was quenched with 3 N HCl and aqueous layers were extracted with 15 mL of Et₂O for 3 times. The combined organic layers were dried over Na₂SO₄. The solvent was evaporated and the product was purified by column chromatography with petroleum ether-Et₂O = 10:1 as elution to afford the title compound 4a as a colorless liquid (193 mg, 58% isolated yield). ¹H NMR (SiMe₄, CDCl₃): δ = 0.89-0.98 (m, 6 H), 1.40 (d, J = 6.5 Hz, 1 H), 1.95-2.05 (m, 4 H), 2.37 (d, J = 15.0 Hz, 1 H), 2.47 (d, J = 6.5 Hz, 1 H), 2.87 (d, J = 15.0 Hz, 1 H), 3.63 (s, 3 H), 3.74 (s, 3 H), 5.22 (t, J = 7.2 Hz, 1 H). ¹³C NMR (SiMe₄, CDCl₃): δ = 13.02, 14.47, 20.76, 22.95, 27.41, 36.83, 37.46, 40.26, 52.28, 53.45, 128.94, 136.17, 168.05, 169.67. HRMS: m/z calcd for C₁₄H₂₁BrO₄: 332.0623, 334.0603; found: 332.0628, 334.0610.

18

1-Bromo-2-(2-butylhept-2-enyl)cyclopropane-1,2-dicarboxylic Acid Dimethyl Ester (4b).
Colorless liquid (237 mg, 61% isolated yield). ¹H NMR (SiMe₄, CDCl₃): δ = 0.81-0.88 (m, 6 H), 1.15-1.27 (m, 9 H), 1.90-1.96 (m, 4 H), 2.30-2.37 (m, 2 H), 2.77 (d, J = 15.0 Hz, 1 H), 3.54 (s, 3 H), 3.65 (s, 3 H), 5.18 (t, J = 7.2 Hz, 1 H). ¹³C NMR (SiMe₄, CDCl₃): δ = 13.70, 13.74, 21.95, 22.39, 27.06, 27.13, 29.51, 30.17, 31.81, 36.37, 37.29, 40.34, 51.98, 53.10, 127.48, 134.85, 167.67, 169.39. HRMS: m/z calcd for C₁₈H₂₉BrO₄: 388.1249, 390.1229; found: 388.1251, 390.1233.

19

Typical Procedure for the Reaction of Zirconacyclo-pentene with 2-Bromo-acrylate. Preparation of 1-Bromo-2-(3-ethyl-2-propylhex-2-enyl)cyclopropane-1,2-dicarboxylic Acid Dimethyl Ester (4c).
To a solution of Cp₂ZrCl₂ (1.2 mmol, 0.352 g) in THF (5.0 mL) was added EtMgBr (0.89 M in Et₂O, 2.40 mmol) at -78 °C and the mixture was stirred for 1 h. After addition of 4-octyne (1.0 mmol, 144 µL) the mixture was warmed up to 0 °C and stirred for 1 h. Before CuCl (1.0 mmol, 99 mg) and methyl 2-bromo-acrylate (2.0 mmol, 230 mL) were added, the mixture was cooled to -30 °C using ice-salt bath and maintained at the temperature for 1 h. The suspension was quenched with 3 N HCl and aqueous layers were extracted with Et₂O (3 × 15 mL). The combined organic layers were dried over Na₂SO₄. The solvent was evaporated and the product was purified by column chromatography with petroleum ether-Et₂O = 10:1 as eluent to afford 4c as a colorless liquid (245 mg, 63%). ¹H NMR (SiMe₄, CDCl₃): δ = 0.86-0.91 (m, 9 H), 1.28-1.37 (m, 6 H), 1.39 (d, J = 7.0 Hz, 1 H), 1.87 (q, J = 7.0 Hz, 2 H), 2.00-2.07 (m, 3 H), 2.19 (q, J = 7.5 Hz, 2 H), 2.48 (d, J = 6.5 Hz, 1 H), 3.17 (d, J = 14.5 Hz, 1 H), 3.57 (s, 3 H), 3.72 (s, 3 H). ¹³C NMR (SiMe₄, CDCl₃): δ = 13.65, 14.08, 14.33, 21.89, 22.29, 24.50, 28.72, 32.06, 33.52, 35.17, 36.93, 38.61, 52.15, 53.62, 128.18, 139.73, 168.41, 169.27. HRMS: m/z calcd for C₁₈H₂₉BrO₄: 388.1249, 390.1229; found: 388.1268, 390.1235.

20

1-Bromo-2-(2,3-diethylpent-2-enyl)cyclopropane-1,2-dicarboxylic Acid Dimethyl Ester (4d).
Colorless liquid (125 mg, 69% isolated yield). ¹H NMR (SiMe₄, CDCl₃): δ = 0.91-0.94 (m, 9 H), 1.42 (d, J = 6.5 Hz, 1 H), 1.92 (q, J = 7.5 Hz, 2 H), 2.02-2.12 (m, 3 H), 2.20 (q, J = 7.5 Hz, 2 H), 2.49 (d, J = 6.0 Hz, 1 H), 3.17 (d, J = 14.0 Hz, 1 H), 3.58 (s, 3 H), 3.73 (s, 3 H). ¹³C NMR (SiMe₄, CDCl₃): δ = 13.42, 13.53, 13.68, 22.97, 24.07 (2 C), 28.73, 34.91, 36.94, 38.63, 53.13, 53.63, 129.30, 140.56, 168.46, 169.31. HRMS: m/z calcd for C₁₆H₂₅BrO₄: 360.0936, 362.0916; found: 360.0940, 362.0923.

21

1-Bromo-2-[3-(2-d-ethyl)-2-propylhex-2-enyl]cyclo-propane-1,2-dicarboxylic Acid Dimethyl Ester (5).
Colorless liquid (127 mg, 70% isolated yield) ¹H NMR (SiMe₄, CDCl₃): δ = 0.87-0.91 (m, 8 H), 1.28-1.37 (m, 6 H), 1.39 (d, J = 7.0 Hz, 1 H), 1.87 (q, J = 7.0 Hz, 2 H), 2.00-2.07 (m, 3 H), 2.19 (q, J = 7.5 Hz, 2 H), 2.48 (d, J = 6.5 Hz, 1 H), 3.17 (d, J = 14.5 Hz, 1 H), 3.57 (s, 3 H), 3.72 (s, 3 H). ¹³C NMR (SiMe₄, CDCl₃): δ = 13.37 (t), 14.08, 14.33, 21.89, 22.29, 24.50, 28.72, 32.06, 33.52, 35.17, 36.93, 38.61, 52.15, 53.62, 128.18, 139.73, 168.41, 169.27. HRMS: m/z calcd for C₁₈H₂₈DBrO₄: 389.1311, 391.1290; found: 389.1316, 391.1293.

22

1-Bromo-2-(2-phenylpent-2-enyl)cyclopropane-1,2-dicarboxylic Acid Dimethyl Ester (4e).
Colorless liquid (284 mg, 72% isolated yield). ¹H NMR (SiMe₄, CDCl₃): δ = 1.04 (t, J = 7.5 Hz, 3 H), 2.14-2.24 (m, 3 H), 2.73 (d, J = 14.4 Hz, 1 H), 3.44 (s, 3 H), 3.67 (s, 3 H), 5.60 (t, J = 7.2 Hz, 3 H), 7.20-7.28 (m, 5 H). ¹³C NMR (SiMe₄, CDCl₃): δ = 14.41, 22.10, 27.89, 34.69, 38.04, 52.29, 53.67, 126.97, 127.39, 128.18, 135.05, 135.91, 143.14, 168.15, 169.22. HRMS: m/z calcd for C₁₈H₂₁BrO₄, 380.0623, 382.0603; found: 380.0621, 382.0605.

23

1-Bromo-2-(2,3-diphenylpent-2-enyl)cyclopropane-1,2-dicarboxylic Acid Dimethyl Ester (4f). Colorless liquid (204 mg, 45% isolated yield). ¹H NMR (SiMe₄, CDCl₃): δ = 0.94 (t, J = 7.0 Hz, 3 H), 1.20 (q, J = 7.0 Hz, 2 H), 1.84 (d, J = 3.5 Hz, 1 H), 2.06 (d, J = 7.0 Hz, 1 H), 2.45 (d, J = 7.0 Hz, 1 H), 2.71 (d, J = 14.0 Hz, 1 H), 3.57 (s, 3 H), 3.67 (s, 3 H), 6.87-6.91 (m, 4 H), 6.97-6.99 (m, 2 H), 7.01-7.05 (m, 4 H). ¹³C NMR (SiMe₄, CDCl₃,): δ = 13.01, 27.39, 27.61, 37.22, 37.42, 38.35, 52.10, 53.49, 125.78, 125.95, 127.44 (2 C), 129.54, 130.04, 133.00, 141.82, 142.34, 143.53, 168.09, 169.33. HRMS: m/z calcd for C₂₄H₂₅BrO₄: 456.0936, 458.0916; found: 456.0940, 458.0918.

24

1-Bromo-2-(3-methyl-2-phenylpent-2-enyl)cyclo-propane-1,2-dicarboxylic Acid Dimethyl Ester (4g).
Colorless liquid (284 mg, 72% isolated yield). ¹H NMR (SiMe₄, CDCl₃): δ = 0.88 (s, 3 H), 1.06 (t, J = 7.5 Hz, 3 H), 1.40 (q, J = 6.5 Hz, 2 H), 1.59 (d, J = 4.0 Hz, 1 H), 2.08 (d, J = 3.5 Hz, 1 H), 2.37 (d, J = 3.5 Hz, 1 H), 2.47 (d, J = 14.5 Hz, 1 H), 3.57 (s, 3 H), 3.68 (s, 3 H), 7.06-7.08 (m, 2 H), 7.20-7.21 (m, 1 H), 7.22-7.30 (m, 2 H). ¹³C NMR (SiMe₄, CDCl₃,): δ = 13.06, 19.36, 26.72, 27.45, 37.29, 38.13, 38.30, 52.24, 53.48, 126.28, 128.00, 129.34, 136.93, 142.67, 168.15, 169.46. HRMS: m/z calcd for C₁₉H₂₃BrO₄: 394.0780, 396.0759; found: 394.0798, 396.0782.

25

1-Bromo-2-(2-naphthalen-1-ylpent-2-enyl)cyclo-propane-1,2-dicarboxylic Acid Dimethyl Ester (4h).
Colorless liquid (223 mg, 52% isolated yield). ¹H NMR (SiMe₄, CDCl₃): δ = 1.12 (t, J = 7.5 Hz, 3 H), 2.03 (d, J = 6.9 Hz, 1 H), 2.39 (m, 2 H), 2.78 (d, J = 6.9 Hz, 1 H), 3.66 (s, 3 H), 3.76 (s, 3 H), 5.63 (t, J = 7.2 Hz, 3 H), 7.38-7.92 (m, 7 H). ¹³C NMR (SiMe₄, CDCl₃): δ = 14.52, 21.76, 36.31, 36.44, 52.33, 53.54, 125.33, 125.59, 125.70, 125.89, 127.36, 128.41, 133.73, 134.20, 136.57, 141.00, 167.92, 169.53. HRMS: m/z calcd for C₂₂H₂₃BrO₄: 430.0780, 432.0759; found: 430.0766, 432.0743.

26

trans -1-Chloro-2-(2,3-diethylpent-2-enyl)cyclopropane-1,2-dicarbonitrile ( 4i).
¹H NMR (SiMe₄, CDCl₃): δ = 0.98-1.06 (m, 9 H), 1.94 (d, J = 7.5 Hz, 1 H), 2.05-2.19 (m, 7 H), 2.38 (d, J = 15.0 Hz, 1 H), 2.81 (d, J = 15.0 Hz, 1 H). ¹³C NMR (SiMe₄, CDCl₃): δ = 13.48, 13.49, 13.58, 23.91, 24.23, 24.73, 27.58, 30.07, 31.33, 33.35, 114.86, 116.00, 126.72, 143.66. HRMS:
m/z calcd for C₁₄H₁₉ClN₂: 250.1237, 252.1207; found: 250.1242, 252.1225.

27

cis -1-Chloro-2-(2,3-diethylpent-2-enyl)cyclopropane-1,2-dicarbonitrile (3i). ¹H NMR (SiMe₄, CDCl₃): δ = 0.94-1.05 (m, 9 H), 1.67 (d, J = 7.5 Hz, 1 H), 2.08-2.17 (m, 7 H), 2.32 (d, J = 15.0 Hz, 1 H), 2.35 (d, J = 7.5 Hz, 1 H), 2.81 (d, J = 15.0 Hz, 1 H). ¹³C NMR (SiMe₄, CDCl₃): δ = 13.36, 13.41, 13.47, 23.65, 24.12, 24.62, 25.18, 29.59, 31.05, 33.29, 115.36, 116.81, 126.56, 143.48. HRMS: m/z calcd for C₁₄H₁₉ClN₂: 250.1237, 252.1207; found: 250.1242, 252.1225.