A Convenient One-Pot Synthesis of Substituted 1,1-Dicyanocyclopropanes from Sulfonium Salts, Malononitrile, and Carbonyl Compounds

Abstract

The three-component reaction of sulfonium salts 1, malononitrile 3, and aldehydes 2 in the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM][PF₆]) or in EtOH in the presence of Et₃N is a convenient one-pot method for synthesis of substituted 1,1-dicyanocyclopropanes (7 and 9). The reaction of compounds 1-3 occurs stereoselectively to form substituted trans-cyclopropanes (7), whose structures were confirmed by the data of physicochemical methods, including X-ray diffraction analysis. The yield of cyclopropanes produced by the reaction in the ionic ­liquid is 8-21% higher than that in EtOH.

Key words

cyclopropanes - sulfonium ylides - multicomponent - ionic liquid - spiroheterocycles

References

• 1 Yanovskaya LA. Dombrovskii VA. Khusid AK. Cyclopropanes with Functional Groups   Nauka; Moscow: 1980.  in Russian
• 2a The Chemistry of the Cyclopropyl Group   Rappoport Z. Wiley; New York: 1987. 
• 2b Wong HNC. Hon M.-Y. Tse G.-W. Yip Y.-C. Chem. Rev.  1989,  89:  165 
• 2c Salaiin J. Chem. Rev.  1989,  89:  1247 
• 2d Carbocyclic Three- and Four-Membered Ring Compounds, Houben-Weyl   Vol. E1:  de Meijere A. Thieme; Stutgart: 1996.  p.7a-7c  
• 3a Zefirov NS. Kazimirchik IV. Lukin KA. Cyclopropanation of Dichlorocarbene to Olefins   Nauka; Moscow: 1985. in Russian
• 3b Doyle MP. Protopopova MN. Tetrahedron  1998,  54:  7919 
• 3c Nefedov OM. Ioffe AI. Menchikov LG. The Chemistry of Carbenes   Khimiya; Moscow: 1990. in Russian
• 4a Shestopalov AM. Sharanin Yu A. Litvinov VP. Nefedov OM. Zh. Org. Khim.  1989,  25:  1111 
• 4b Shestopalov AM. Litvinov VP. Rodinovskaya LA. Sharanin Yu A.. Izv. Acad. Nauk. SSSR, Ser. Khim.  1991,  1:  146 
• 4c Litvinov VP. Shestopalov AM. Zh. Org. Khim.  1997,  33:  975 
• 4d Trost BM. Melvin LS. Sulfur Ylides   Academic Press; New York: 1975. 
• 4e Li A.-H. Dai L.-X. Aggarwal VK. Chem. Rev.  1997,  97:  2341 
• 4f Samet AV. Shestopalov AM. Semenov VV. Izv. Russ. Akad. Nauk, Ser. Khim.  1998,  6:  1262 
• 4g Freeman F. Chem. Rev.  1980,  80:  329 
• 4h Magdisieva NN. Usp. Khim.  1988,  57:  281 
• 5 Kojima S. Fujtomo K. Shiuohara Y. Shimizu M. Ohkata K. Tetrahedron Lett.  2000,  41:  9847 
• 6a Mehnert CP. Dispenziere NC. Cook RA. Chem. Commun.  2002,  1610 
• 6b Mehnert CP, and Dispenziere NC. inventors; WO  03/002502. 
• 7a Dell’Anna MM. Gallo V. Mastrorilli P. Nobile CF. Romanazzi G. Suranna GP. Chem. Commun.  2002,  434 
• 7b Hagiwara H. Sayuri T. Okabe T. Hoshi T. Suzuki T. Suzuki H. Shimizu K. Kitayama Y. Green Chem.  2002,  4:  461 
• 7c Morrison DW. Forbes DC. Davis JH. Tetrahedron Lett.  2001,  42:  6053 
• 8a Hangarge RV. Jarikote DV. Shingare MS. Green Chem.  2002,  4:  266 
• 8b Kryshtal GV. Zhdankina GM. Zlotin SG. Mendeleev Commun.  2002,  176 
• 12 Gunther H. ¹H NMR Spectroscopy   John Wiley Sons; New York: 1980. 

9

Typical Experimental Procedure: The synthesis was carried out using an intensely operating exhaust system. To a mix-ture of equimolar amounts (2 mmol) of the corresponding sulfonium salt 1, aldehyde 2 or ketone 8, and malononitrile 3 in [BMIM][PF₆] (3 mL) or EtOH (10 mL) was added Et₃N (0.33 mL, 2.3 mmol). The reaction mixture was stirred at ca 70 °C for 10 min and cooled to 20 °C, after which stirring was continued for 4-5 h. The precipitate that formed was filtered off and washed successively with 50% and 96% EtOH and hexane. After recrystallization from EtOH, cyclopropanes 7 and 9 were obtained (Table [1] ).

10

Procedure of Regeneration of the Ionic Liquid: The ionic liquid was successively washed with water, diethyl ether, acetone, and hexane, dried using a rotary evaporator under a reduced pressure, and used in further reactions.

11

Spectral Characteristics and Properties of (7a-e, 9a-c). IR spectra were recorded on a Perkin-Elmer 577 instrument in KBr pellets. ¹H NMR spectra were obtained using a Bruker AM-300 (300 MHz) spectrometer in DMSO-d ₆.
Trans -2-Benzoyl-1,1-dicyano-3-(4-methoxyphenyl)-cyclopropane (7a): mp 164-165 °C. IR: 1678 (C=O), 2248 (CN) cm^-1. ¹H NMR: δ = 6.80-8.30 (m, 9 H, C₆H₅, C₆H₄), 4.96 (d, ³ J = 7.9 Hz, 1 H, C²H), 3.99 (d, ³ J = 7.9 Hz, 1 H, C³H), 3.75 (s, 3 H, CH₃). Anal. Calcd for C₁₉H₁₄N₂O₂: C, 75.48; H, 4.67; N, 9.29. Found: C, 75.73; H, 4.83; N, 9.47.
Trans -2-Benzoyl-1,1-dicyano-3-(2-fluorophenyl)-cyclopropane (7b): mp 989-999 °C. IR: 1672 (C=O), 2251 (CN) cm^-1. ¹H NMR: δ = 7.24-8.40 (m, 9 H, C₆H₅, C₆H₄), 4.98 (d, ³ J = 8.4 Hz, 1 H, C²H), 4.00 (d, ³ J = 8.4 Hz, 1 H, C³H). Anal. Calcd for C₁₈H₁₁FN₂O: C, 74.47; H, 3.82; N, 9.65. Found: C, 74.18; H, 3.57; N, 9.32.
Trans -2-(1-Adamantoyl)-1,1-dicyano-3-(2,3,4-trimethoxyphenyl)cyclopropane (7c): mp 146-148 °C. IR: 1700 (C=O), 2258 (CN) cm^-1. ¹H NMR: δ = 7.10 (d, ³ J = 7.8 Hz, 1 H, C⁵H-phenyl), 6.82 (d, ³ J = 7.8 Hz, 1 H, C⁶H-phenyl), 4.42 (d, ³ J = 8.2 Hz, 1 H, C²H). 3.54 (d, ³ J = 8.2 Hz, 1 H, C³H), 2.08, 1.95, 1.74 (m, 15 H, Ad¹). Anal. Calcd for C₂₅H₂₈N₂O₄: C, 71.41; H, 6.71; N, 6.65. Found: C, 71.74; H, 6.87; N, 6.92.
Trans -2-(1-Adamantoyl)-1,1-dicyano-3-(3,4-difluoro-phenyl)cyclopropane (7d): mp 153-155 °C. IR: 1698 (C=O), 2256 (CN) cm^-1. ¹H NMR: δ = 7.80, 7.52 (m, 3 H, C₆H₃), 4.60 (d, ³ J = 8.3 Hz, 1 H, C²H), 3.56 (d, ³ J = 8.3 Hz, 1 H, C³H), 2.08, 1.94, 1.74 (m, 15 H, Ad¹). Anal. Calcd for C₂₂H₂₀F₂N₂O: C, 72.12; H, 5.50; N, 7.65. Found: C, 71.83; H, 5.24; N, 7.42.
Trans -2-(1-Adamantoyl)-1,1-dicyano-3-isopropyl)cyclo-propane (7e): mp 135-136 °C. IR: 1692 (C=O), 2258 (CN) cm^-1. ¹H NMR: δ = 3.88 (d, ³ J = 7.2 Hz, 1 H, C²H), 2.34 (dd, ³ J = 7.2 Hz, ³ J = 6.1 Hz, 1 H, C³H), 2.07, 1.92, 1.73 (m, 15 H, Ad¹). Anal. Calcd for C₁₉H₂₄N₂O: C, 76.99; H, 8.16; N, 9.45. Found: C, 76.78; H, 8.03; N, 9.43.
2-Benzoyl-6- tert -butyl-1,1-dicyanospiro[2.5]octane (9a): mp 137-138 °C. IR: 1672 (C=O), 2240 (CN) cm^-1. ¹H NMR: δ = 7.98, 7.74, 7.58 (m, 5 H, C₆H₅), 4.26 (s, 1,H, C²H), 2.26, 1.72, 1.56, 1.12 (m, 9 H, C₆H₉), 0.86 (s, 9 H, t-Bu). Anal. Calcd for C₂₁H₂₄N₂O: C, 78.72; H, 7.55; N, 8.74. Found: C, 79.12; H, 7.78; N, 8.93.
2-(1-Adamantoyl)-1,1-dicyano-6- tert -butoxycarbonyl-azaspiro[2.5]octane (9b): mp 229-230°C. IR: 1698 (C=O), 2244 (CN) cm^-1. ¹H NMR: δ = 3.86 (s, 1 H, C²H), 3.25-3.50 (m, 4 H, CH₂NCH₂), 1.66-2.08 [m, 19 H, Ad¹, (CH₂)₂], 1.43 (s, 9 H, t-Bu). Anal. Calcd for C₂₅H₃₃N₃O₃: C, 70.89; H, 7.85; N, 9.92. Found: C, 70.64; H, 7.62; N, 9.73.
2-(1-Adamantoyl)-1,1-dicyano-6-oxyspiro[2.5]octane (9c): mp 223-224 °C. IR: 1708 (C=O), 2248 (CN) cm^-1. ¹H NMR: δ = 3.86 (s, 1 H, C²H), 3.64-3.74, 3.52 (m, 4 H, CH₂OCH₂), 1.68-2.08 [m, 19 H, Ad¹, (CH₂)₂]. Anal. Calcd for C₂₀H₂₄N₂O₂: C, 74.05; H, 7.46; N, 8.63. Found: C, 73.86; H, 7.29; N, 8.46.

13

Compound 7a (C₁₉H₁₄N₂O₂) crystallized in a monoclinic system, space group C2/c, a = 19.879 (4), b = 12.089 (2),
c = 15.535(3) , β = 120.58(3)°, V = 3214(1) ³, d _calc = 1.250 g/cm³, Z = 4. The crystal lattice parameters and intensities of 2878 independent reflections were collected at 20 °C on a Siemens P3/PC diffractometer (MoK radiation, graphite monochromator, /2 scan mode to _max = 25°). The structure was solved by direct method and refined by full-matrix least squares. Non-hydrogen atoms were refined anisotropically. All hydrogen atoms were placed to the calculated positions. The final R factors were R = 0.0457 (2230 independent reflections) and R = 0.1357 (2796 independent reflections). All calculations were performed using the SHELXL97 program. Details of X-ray analysis including atom coordinates and their isotropic equivalent temperature parameters will be given in a full report.