Notizen 1059
Unusual Grignard Reaction of a-Arylcinnamonitriles [1]
Mahavir Prashad, M. Seth, and A. P. Bhaduri Division of Medicinal Chemistry,
Central Drug Research Institute, Lucknow-226001, India
Z. Naturforsch. 33b, 1059-1060 (1978);
received May 22, 1978
Grignard Reaction, Alkylmagnesium Halide, Dialkylation
Reaction of a-arylcinnamonitriles with excess of alkylmagnesium halide yielded predominant- ly the erythro isomer of a,/S-dialkyl-a,/3-diaryl- propionitriles. PMR spectra of the diastereo- isomers have been described.
Grignard reaction of a-arylcinnamonitrile deriva- tives have been shown by earlier workers [2-5] to yield the conventional ^-substituted product but the simultaneous alkylation of a- and carbon atoms appears to have not been reported so far.
This communication describes this unusual ob- servation made during the syntheses of a,/?-dialkyl- a,/?-diarylpropionitriles.
Reaction of a-arylcinnamonitriles with excess of alkylmagnesium halides in dry ether yielded the desired a,/5-dialkyl-a,/3-diarylpropionitriles and the evidence for their structure could be obtained, when a,ß-dimethyl-a,/?-diphenylpropionitrile, synthesized by an unambiguous method [5] was found to be identical with the product obtained by the reaction described in this communication. The stereo- chemical assignment of erythro and threo isomers were made on the basis of the observation made by Wawzonek et al. [5]. In general the reaction yielded predominantly the erythro isomer which could be
Requests for reprints should be sent to Dr. A. P.
Bhaduri, Medicinal Chemistry Division, C.D.R.I., Lucknow-226001, India.
easily purified by crystallisation from hexane and the threo isomer obtained in very poor yields purified by column chromatography over silica gel.
The dominance of the erythro isomer makes the synthesis very highly stereoselective. The reaction has been successfully carried out with various substituents on the phenyl ring and with different
alkyl-magnesium halides. The general method of preparation is described and the diastereoisomers obtained are listed in the Table (see next side).
General method for the preparation of a,ß-dialkyl- a.ß-diarylpropionitriles (1-9)
To a solution of alkylmagnesium halide (0.09 mol) in dry ether (120 ml) was added substituted a-aryl cinnamonitrile (0.03 mol) in portions under stirring at room temperature (24 °C). The resulting mixture in most of the cases was refluxed for 6 h and when butylmagnesium bromide was used as the Grignard reagent, the time of reflux was increased to 18 h.
The reaction mixture was then carefully decomposed with 6 N hydrochloric acid (50 ml) at 0 °C under stirring. The organic layer was separated, washed with water and dried over anhydrous sodium sulphate. The residue obtained after the removal of the solvent crystallized in case of 4-7 from hexane to yield the pure erythro isomer. The filtrate obtained after crystallization was chromatographed over silica gel using hexane as the eluant to yield first the threo isomer followed by a small amount of erythro isomer. In rest of the cases the two diastereo- isomers were separated by similar chromatography of the residue obtained after the removal of the ether.
[1] C.D.R.I. Communication No. 2409. [4] Th. Eicher and S. Böhm, Chem. Ber. 107, 2186 [2] S. Wawzonek, J. Am. Chem. Soc. 68, 1157 (1946). (1974).
[3] H. R. Henze and L. R. Swett, J. Am. Chem. Soc. [5] S. Wawzonek, E. M. Smolin and J. E. Durham,
73, 4918 (1951). Org. Magn. Reson. 6, 547 (1974).
1060 Notizen Table. Physical and analytical data of a,)S-dialkyl-a,/S-diarylpropionitriles.
Elemental Diagnostic XH NMR signals0 Analyses Product0
1
R X i
2 3 X2
4
Yield [ % ] 5
m.p.
[°C]
6
a Molecular formula 7
( C C I 4 )
ö ppm 8
Re-quired [ % ] 9
Found [ % ] 10 1 Eb CH3 H H 60 Oile C 1 7 H 1 7 N
(235.3) 3.03 (q, 1 H, CH), 1.72 (s, 3 H,
CH3) & 1.46 (d, 3 H, CH3) C 86.77 H 7.28 N 5.95
C 86.70 H 7.66 N 6.07 2 Eb CH3 H 2-C1 60 50--52 CivHieCIN
(269.9) 3.82 (q, 1 H, CH), 1.80 (s, 3 H,
CH3) & 1.46 (d, 3 H, CH3) C 75.64 H 5.92 N 5.18
C 76.25 H 6.10 N 5.30 3 E CH3 H 2,4-Cl2 64 85--86 Ci7H15C12N
(304.2) 3.78 (q, 1 H, CH), 1.82 (s, 3 H, CH3), 1.40 (d, 3 H, CH3) &
7.0-7.34 (m, Harom)
C 67.11 H 4.93 N 4.60
C 67.20 H 5.04 N 4.48 3 T CH3 H 2,4-Cl2 2 110-112 C 1 7 H 1 5 C I 2 N
(304.2) 3.85 (q, 1 H, CH), 1.44 (s, 3 H, CH3), 1.12 (d, 3 H, CH3) &
7.26-7.78 (m, 8 Harom)
C 67.11 H 4.93 N 4.60
C 67.02 H 5.08 N 4.45 4 E CH3 H 4-OMe 50 91--92 Ci8H19NO
(265.4) 3.7 (s, 3 H, OCH3), 3.08 (q, 1 H, C 81.48 CH), 1.78 (s, 3 H, CH3), 1.46 (d, H 7.22
3 H,CH3)& 6.6-7.95 (m, 9Harom) N 5.28 C 81.25 H 6.93 N 5.53 4 T CH3 H 4-OMe 1 Oil Ci8H I9N O
(265.4) 3.69 (s, 3 H, OCH3), 2.98 (q, 1 H, C 81.48 CH), 1.38 (s, 3 H, CH3), 1.15 (d, H 7.22 3 H, CH3) & 6.55-7.4 (m, N 5.28 9 Harom)
C 81.33 H 7.05 N 5.21 5 E CH3 H 3,4-Cl2 60 76--80 C 1 7 H 1 5 C I 2 N
(304.2) 3.08 (q, 1 H, CH), 1.82 (s, 3 H, CH3), 1.51 (d, 3 H, CH3) &
6.7-7.3 (m, 8 Harom)
C 67.11 H 4.93 N 4.60
C 67.00 H 5.05 N 4.69 5 T CH3 H 3,4-Cl2 2 100 -102 CI7H15C12N
(304.2) 3.0 (q, 1 H, CH), 1.46 (s, 3 H, CH3), 1.19 (d, 3 H, CH3) &
7.11-7.42 (m, 8 Harom)
C 67.11 H 4.93 N 4.60
C 67.08 H 5.23 N 4.55 6 E C2H5 H 2,4-Cl2 45 97--98 C 1 9 H 1 9 C I 2 N
(332.0) 3.6 (2d, 1 H, CH) & 6.86-7.34
(m, 8 Harom) C 68.73
H 5.72 N 4.21
C 68.40 H 5.75 N 4.13
6 T C 2 H 5 H 2,4-Cl2 2 Oil Ci9H19C12N
(332.0) 3.7 (2d, 1 H, CH) & 7.12-7.8
(m, 8 Harom) C 68.73
H 5.72 N 4.21
C 68.54 H 5.63 N 4.09 7 E C2H5 H 4-OMe 20 105 -106 C20H23NO
(293.4) 2.85 (2d, 1 H, CH), 3.78 (s, 3 H, OCH3) & 6.75-7.22 (m, 9 Harom)
C 81.87 H 7.90 N 4.77
C 81.63 H 7.71 N 4.83 7 T C2H5 H 4-OMe 5 Oil C2OH23NO
(293.4) 2.75 (2d, 1 H, CH), 3.68 (s, 3 H, C 81.87 OCH3) & 6.6-7.12 (m, 9 Harom) H 7.90
N 4.77 C 82.00 H 8.13 N 4.97
8 Eb C 4 H 9 H 2,4-(OMe)2 65 Oil C25H33N02
(379.5) 3.65 & 3.5 (2 S, 6 H, OCH3),
2.15 (2d, 1 H, CH) C 79.11 H 8.76 N 3.69
C 79.03 H 8.71 N 3.54
9 Eb C 4 H 9 4 - C 1 H 50 Oil C23H28CIN
(353.7) 2.82 (2d, 1 H, CH) & 6.8-7.35
(m, 9 Harom) C 78.09
H 7.91 N 3.95
C 77.50 H 8.32 N 2.80
a All melting points are uncorrected; b the threo isomer could not be separated from the available mixture;
c the NMR spectra were recorded on Perkin-Elmer (R-32) NMR Spectrometer (90 MHZ) using TMS as internal standard; d E and T stands for erythro and threo respectively; e lit. [5],
