LETTER
Heteroaryl-N-difluoromethyltrimethylsilanes
377
g (18.4 mmol) of Me3SiCl. At the end of the exothermic
lactones are presently under investigation in our laborato-
ries.
(40 °C) reaction, the mixture was heated at 40 °C for 5 h. After
removal of NMP and the excess of Me3SiCl at reduced
pressure till dryness, the residue was extracted with boiling
hexane (3 20 mL). The combined hexane solutions of 3b
were concentrated to 10 mL and the product was recrystallized
from hexane under cooling till -30 °C. 3b: colorless crystals,
yield 2.0 g (75%) (relative to compound 2b); mp 95-96 C; 1H
NMR = 0.1 (s, CH3), 7.2 7.7 (m, 7 H); 19F NMR = -80.6
(CF2); 13C NMR = -3.7 (CH3), 118.1 (CH), 124.4 (t,
JCF = 287.1 Hz), 128.3-147.9 (m, Ar); Calcd for C13H16N2F2Si:
C 58.62, H 6.05, F 14.27; Found: C 58.72, H 5.98, F 14.3.
Imidazole-1-yl-difluoromethyltrimethylsilane 3a, yield 85%,
bp 25 C/ 0.005 Torr; 1H NMR = 0.1 (CH3), 6.9 (dd,
Acknowledgement
The financial support of Deutsche Forschungsgemeinschaft to A. A.
K. is gratefully acknowledged.
References and Notes
(1) Tozer M. J.; Herpin, T. F., Tetrahedron 1996, 52, 8619 and
references cited therein; Filler, R.; Kobayashi Y.;
Yagupolskii, L., Organofluorine Compounds in Medicinal
Chemistry and Biomedical Applications, Elsevier:
Amsterdam, 1993.
3JHH = 2.2, 4JHH = 1.0 Hz, CH), 6.9 (brs, CH), 7.6 (brs, CH); 19
NMR = -88.1 (CF2); 13C NMR
5.2 (CH3), 108.2 (t,
CF = 250.6 Hz, CF2), 114.9 (CH), 129.8 (CH), 133.4 (CH);
HRMS calcd for C7H12N2F2Si 190.0738; Found 190.0738.
F
=
J
(2) Lefebvre, O.; Brigaud, T.; Portella, C. Tetrahedron 1999, 55,
7233, and references cited therein.
2-Methyl-benzimidazole-1-yl-difluoromethyltrimethylsilane
(3) Burton D. J.; Yang, Z.-Y., Tetrahedron 1992, 48, 189; Qiu
W.; Burton, D. J., Tetrahedron Lett 1996, 37, 2745.
(4) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757.
(5) Burkholder, C.; Dolbier, W. R. Jr.; Médebielle, M. J. Org.
Chem. 1998, 63, 5385.
(6) Burkholder, C.; Dolbier, W. R. Jr.; Médebielle, M.
Tetrahedron. Lett. 1998, 39, 8853.
(7) Clavel, Ph.; Biran, C.; Bordeau M.; Roques, N.; Trévin, S.,
Tetrahedron Lett. 2000, 41 8763.
3c: yield 82%, 1H NMR = 2.6 (t, 5JFH = 2.5 Hz, CH3), 7.2-7.7
(m, Ar); 19F NMR
=
86.5 (s, CF2); 13C NMR = -1.4 (s,
CH3), 16.5 (t, 4JCF = 4.4 Hz, CH3), 113.9 (t, JCF = 326.1 Hz,
CF2Br), 115.0 (t, 3JCF = 5.3 Hz, C-CH3), 116.7-147.2 (m, Ar);
HRMS calcd for C12H16N2F2Si: 254.1051; Found: 254.1055
(13) Ruppert, I.; Schlich, K.; Volbach, W., Tetrahedron. Lett.
1989, 42, 429.
(14) Grobe, J.; Hegge, J. Synlett 1995, 641.
(15) (a) Typical procedure for anionic heteroaryl-N-
difluoromethylation of cyclohexanone:
(8) Yagupolskii, L. M.; Fedyuk, D. V., Tetrahedron. Lett. 2000,
41, 2265.
1-(1,1-difluoro-1-cyclohexanol-1-yl-methyl)-2-phenyl-
imidazole 7b: To a stirred mixture of 3.0 g (11.3 mmol) 3b and
2.2 g (22.6 mmol) cyclohexanone in 7 mL monoglyme was
added 1.0 g (11.3 mmol) anhydrous tetramethylammonium
fluoride at 0 °C. The mixture was stirred for 10 min at 0 °C
and then allowed to warm up to ambient temperature within 10
min. After stirring for 1 h at 20 °C, the mixture was poured
into 20 mL water. The product was extracted with 3 30 mL
CHCl3, the combined organic phases were washed once with
water (30 mL) and dried over magnesium sulfate and
recrystallized. 7b: yield 2.54 g (77%); mp 115 117 C (from
CHCl3/hexane); 1H NMR (CDCl3) = 1.0 1.4 (m, CH2), 7.0
(brs, OH), 5.6 7.7 (m, Ar); 19F NMR (CDCl3) = - 89.3 (s,
CF2); 13C NMR (CDCl3) = 21.0 30.6 (m, CH2), 74.4 (t, 2JCF
28.6 Hz, C(OH)), 122.2 (t, JCF 269.8 Hz, CF2), 118.4 147.7
(m, Ar); HRMS calcd for C16H18ON2F2: 292.1389; Found:
292.1387.
1-(1,1-difluoro-1-cyclohexanol-1-yl-methyl)-3-methyl-
imidazolium triflate 9a: yield 47%; mp 212 214 C; 1H
NMR (CDCl3) = 3.9 (s, CH3), 4.8 (brs, CH), 5.4 (brs, OH),
7.4 (brs, CH), 7.6 (brs, CH), 9.2 (brs, CH); 19F NMR
(CDCl3) = -80.4 (s, CF3), 93.6 (s, CF2); 13C NMR
(CDCl3) = 27.2 36.1 (m, CH2), 85.4 (t, 2JCF 29.5 Hz,
C(OH)), 131.6 (t, JCF = 258.2Hz, CF2), 119.0 (CH), 137.1
(CH), 143.8 (CH); HRMS calcd for C11H17ON2F2+ 231.1317;
Found: 231.1315.
(9) Kolomeitsev, A.; Schoth, R.-M.; Lork, E.; Röschenthaler, G.-
V. Chem. Comm. 1996, 335.
(10) Kolomeitsev, A.; Bissky, G.; Médebielle, M. Röschenthaler,
G.-V. 16th International Symposium on Fluorine Chemistry,
Durham, July 16-21 2000, Abstract A17.
(11) Typical procedure for bromodifluoromethylation of
imidazole and benzimidazole derivatives (all reactions were
performed under nitrogen in carefully dried solvents):
1-Bromodifluoromethyl-imidazole 2a. To a solution of 5.0 g
(47.2 mmol) imidazolyl-potassium (synthetized from 3.2 g
(47.2 mmol) imidazole and 5.3 g (47.2 mmol) t-BuOK in
THF) in dried DMF (50 ml) under nitrogen dibromodi-
fluoromethane 29.7g (141.5 mmol) was added. The reaction
mixture was stirred for 48 h at ambient temperature. The
excess of dibromodifluoromethane was recycled by distilling
it into a cooled ( 20 °C) trap. The residue was diluted with
100 mL water. The product was extracted with petroleum
ether, the organic phase was washed three times with water
and dried over sodium sulfate. The product was isolated by
distillation at reduced pressure. 2a: bp 62 C/30 Torr, yield
8.0 g (85%). 1H NMR = 7.1 (dd, 3JHH = 2.2 Hz, 4JHH = 1.0
Hz, CH), 7.3 (m, CH), 7.9 (brs, CH); 19F NMR
= 28.9
(CF2); 13C NMR = 107.6 (t, JCF 306.7 Hz, CF2Br), 116.0
(CH), 130.9 (CH), 133.9 (CH); HRMS calcd for C4H3N2F2
79Br 195.9448, found 195.9450.
1-Bromodifluoromethyl-2-phenyl-imidazole 2b: bp 64 C/
0.005 Torr, yield (83%); 1H NMR = 7.1 (d, 3JHH = 2.0 Hz,
CH), 7.3 (m, CH), 7.4 7.6 (m, 5H); 19F NMR = -25.4 (s,
CF3); 13C NMR = 107.9 (t, JCF = 308.9 Hz, CF2Br), 115.4 (s,
C), 117.7 (s, CH), 128.0 (s, CH), 128.7-130.0 (m, Ar); Calcd
for C10H7N2F2Br: C 43.98, H 2.58, F 13.91; Found: C 44.51,
H 2.69, F 13.8.
(b) Typical procedure for anionic heteroaryl-N-
difluoromethylation of benzaldehyde:
1-(1,1-difluoro-2-phenyl-2-trimethylsiloxy-ethyl)-imidazole
5a: To a stirred mixture of 3.1 g (16.3 mmol) 3a and 1.73 g
(16.3mmol) benzaldehyde in monoglyme (20 mL) was added
ca. 2 mg of anhydrous tetramethylammonium fluoride at 0 °C.
The mixture was stirred for 10 min at 0 °C and then allowed
within 0.5 h to warm up to ambient temperature. After stirring
for 10 h at 20 °C, the solvent was evaporated under reduced
pressure. The residue was distilled in vacuo. 5a: yield 3.9 g
(80%); bp 84 86 C/ 0.005 Torr; 1H NMR (CDCl3) = 0.0
(s,CH3), 5.0 (brs, CH), 6.8 (brs, CH), 7.0 (brs, CH), 7.1 7.3
(12) Typical procedure for heteroaryl-N-
difluoromethyltrimethylsilanes preparation.
2-Phenyl-imidazole-1-yl-difluoromethyltrimethylsilane 3b,
method A: To a stirred suspension of 0.2 g (7.4 mmol)
aluminium powder (Fluka, purity >98%, 160 m) in 25 mL
NMP were added in one portion 2.7 g (10 mmol) of 2b and 2.0
Synlett 2001, No. 3, 374–378 ISSN 0936-5214 © Thieme Stuttgart · New York