7916
J. Org. Chem. 1993,58, 7916-7917 Scheme I
Condensation of Arylacetonitriles with Glyoxylic Acid. Facile Synthesis of Arylmaleic Acid Derivatives
II
ArCH2CN
W. D. Dean**+ and D. M. Blum American Cyanamid Company, Medical Research Division, Chemical Process Research and Development Department, Pearl River, New York 10965 Received March 5, 1993 (Revised Manuscript Received September 14,1993)
During a synthetic program aimed at the preparation of certain CNS agenta, we required an efficient route to arylmaleic acid derivatives for use as intermediates in the large-scale preparation of arylmaleimides and arylmaleic anhydrides. Of the numerous literature procedures for the preparation of these compounds,l* the most general and direct method appeared to be the Meerwein arylation of maleimides' or dialkylmaleates.2 In our hands, this method was used in the initial phases of our program to prepare several arylmaleimides. However, since we were ultimately interested in the preparation of kilogram quantities of materials, we found that several factors precluded scale-up of this reaction. In particular, the maleimides used in these reactions were quite expensive and the arylations were always accompanied by a substantial amount of aryl coupling to form biphenyls. Another method that we explored for the preparation of these arylmaleic acid derivatives involved Wittig reaction of aroyl cyanides with (carbalkoxymethy1ene)triphenylpho~phoranes.~ In our hands, reaction of commercially available benzoyl cyanide with (carbethoxymethy1ene)triphenylphosphorane using the literature procedure4 gave ethyl 3-cyano-3-phenylpropenoateas a 2.5:l mixture of ZEisomers. This ratio could be improved to ca. 1O:l Z E by treatment of the mixture with thiophenol in refluxing toluene. The desired 2-cyano ester could be cyclized in hot formic acid to phenyl~naleimide.~ Despite its overall efficiency, this method was abandoned due to the lack of availability of the desired aroyl cyanides. We had felt that condensations of readily available arylacetonitriles with glyoxylic acid might provide an easy alternate route to 3-aryl-3-cyanopropenoates.Glyoxylic acid has been shown to condense readily with ketones under acidic'l or basic conditions12to provide acylacrylic acids or hydroxyacetic acids, respectively,but the reactions of arylacetonitriles with glyoxylic acid have not been reported. Initially, these condensations were studied using an aqueous sodium hydroxidemethanolreaction medium. Under these conditions, a t room temperature, the corresponding sodium (Z)-3-aryl-3-cyanopropenoates were isolated in good yield. Actually, more consistent results were t Present address: Department of Medicinal Chemistry, Alcon Laboratories, Fort Worth, TX 76134. (1) Rondestvedt, C. S., Jr.; Vogl, 0. J. Am. Chem. SOC.1965,77,2313. (2) Taylor, G.C.; Strojny, E. J. J. Am. Chem. SOC.1954, 76, 1872. (3) Rondeatvedt, C. S., Jr.; Filby, A. H. J. Org. Chem. 1964, 19, 119. (4) Kalvoda, L. Collect. Czech. Chem. Commun. 1976, 41, 2034. (5) Hein, D. W. J. Am. Chem. SOC.1966, 77, 2797. (6) (a) Hill, R. K. J. Org. Chem. 1961, 25,4795. (b) Lopworth, A.; McRae, J. A. J. Chem. SOC.1992,121, 1699. (7) Dean, W. D. Unpublished results. (8) Neber, P. W. Ann. 1930, 478, 197. (9) Casella, L. D. B.P. 870106, 1938. (10) Hoch, 3. Comp. Rend. 1965,261, 4132. (11)Reigh-Rohmig, P.: Raninger, F.; Woerther, E.; Kloimstein, E. Ger. Offenr2, 614,825, 1977. (12) Pettit, G.R.; Green, B.; Dunn, G.L. J. Org. Chem. 1970,35,1367.
-
0
K2C03
HCC02H
+
MeOH rl or reflux
1
25% HCI
A'\
NGC
,c=c,/H
- /H
t
C02K
H 0 2 C /"'C ' O2H
rl
B
2
HC02H
2 H2S04
-
Ar.
0
reflux
4
obtained by treatment of the arylacetonitriles 1 with 1.52.0 equiv of glyoxylic acid hydrate in methanol using potassium carbonate as the base. Use of these conditions smoothly provided the potassium (Z)-3-aryl-3-cyanopropenoates 2 (Scheme I). Data for these reactions are reported in Table I. In general, arylacetonitriles containing electron-withdrawing groups (entries b-d) reacted readily at room temperature while phenylacetonitrile and nitriles with electron-donating groups reacted best at reflux. In all cases, the products 2 precipitated from the reaction mixtures and could be freed from inorganic impurities by suspension in cold water. It is interesting to note that all of the condensations examined resulted in the formation of a single geometric isomer as evidenced by NMR. Also, the CN stretch in the IR spectra of these producta showed a shift from ca. 22502260 cm-l of the arylacetonitriles to ca. 2220 cm-l which suggesteda conjugated nitrile. These products were shown to be the desired 2 isomers by their cyclization in hot formic acid to the known arylmaleic anhydrides 4 in good yield (Table 11). In an effort to prepare the corresponding (Z)-arylcyanopropenoic acids, several compounds 2 were stirred at room temperature with 25 5% aqueous HCl which resulted in the isolation of the corresponding arylmaleic acids 3 (Table 111). The structures of these acids were confirmed by NMR and by their conversion to the anhydrides 4 with acetic anhydride. Our work has demonstrated that arylacetonitriles and glyoxylic acid condense under mild conditions, providing intermediates that can easily be converted to various useful arylmaleic acid derivatives. The ease of the reaction sequence as well as the high availability of the starting arylacetonitriles makes our route an attractive alternative to published procedures for the large-scale synthesis of these derivatives. Experimental Section Arylacetonitriles and glyoxylic acid were obtained commerc i d y from Aldrich Chemical Co. and were used without prior purification. NMR spectra were recorded on a Nicolet NT-300 or a General Electric QE-300spectrometer. Infrared spectra
0022-3263/93/1968-7916$04.00/0 0 1993 American Chemical Society
J. Org. Chem., Vol. 58, No. 27, 1993 7917
Notes Table I
,c=c NEC
/H 'C02K
2
86 94 92 92 63 93 26
calcd 56.72 245 252-253 41.40 252-253 48.88 42.87 252 58.64 242 230(dec) 58.64 199-200 38.81'
found 56.94 41.14 48.58 42.83 58.31 58.33 39.03
Anal. H calcd found 2.86 3.08 1.74 1.49 2.05 1.86 1.44 1.34 3.58 3.39 3.58 3.56 3.01 2.79
73
257 (dec) 66.87
66.45
3.51
C
Ar
N calcd found
3.83
NMR (ppm) DMSO-&
6.61 4.83 5.70 5.00 6.22 6.22 3.48
6.66 4.81 5.69 4.81 6.10 6.19 3.41
7.75 (m, 5H), 7.28 (br s,lH) 7.55 (d, 2H, J = 8.0 Hz), 7.63 (d, 2H), 7.25 ( 8 , W 7.5 (d, 2H, J = 8.7 Hz), 7.65 (d, 2H), 7.2 (8,lI-I) 7.9 (s,lH),7.70 (m, 2H), 7.3 (s,lH) 7.5 (d, 2H, J = 8.3 Hz), 7.25 (d, 2H), 7.04 (8, lH), 2.4 (s,3H) 7.3-7.6 (m, 4H), 7.15 (s,lH), 2.4 (8,3H) 6.99 (8, H), 6.65 (s,2H), 3.85 (8, 6H), 3.80 (8,3H)
4.87
4.87
8.20-7.45 (m, 9H), 7.05 (s,lH)
Microanalysis of cesium salt. Table I1 Ar
o
b
0
4
yield
Ar
(%I
mp ("(2)
lit, mp ("C)
NMR (ppm) CDCls
(a)CeHa (b) 4BrC& (C) 4-clc& (d) 3,4-CLCBHs (e) 4-MeC& (0 3-MeC& (e) 3,4,5-(MeO)sC&? (h) 4PhC&b
48 81 77 71 31 31 21 76
120-121 156-157 146-148 114.5-116 109-110 89-90 150-151 (toluene) 194.5-196 (chloroform)
119 156d 146e 115-116f 108-111e 88-906
8.1-7.95 (m, 2H), 7.6 (m, 3H), 7.10 (m, 1H) 7.88 (d, 2H, J = 8.7 Hz), 7.68 (d, 2H), 7.05 (s,lH) 7.95 (d, 2H, J = 8.8 Hz), 7.5 (d, 2H), 7.08 (e, 1H) 8.25-7.75 (m, 3H), 7.01 (s,lH) 7.9 (d, 2H, J = 8 Hz), 7.3 (s,2H), 6.95 (s,lH) 7.8-7.3 (m, 4H), 7.05 (8, lH), 2.95 (e, 3H) 7.20 (s,2H), 6.90 (8, lH), 3.95 (s,9H) 8.15 (d, 2H), 7.90 (d, 2H), 7.79 (s,2H), 7.75 (8, lH), 7.6-7.4 (m, 3H)
d
Calcd: C, 59.09; H, 4.58. Found C, 58.84; H, 4.41. bAnal. Calcd: C, 76.79; H, 4.03. Found C, 76.47; H, 4.15. 'Reference 2. "Anal. Reference 8. e Reference 1. f Reference 9.8 Reference 10. Table I11
c=c HO&'
/H \CO,H
Anal. yield Ar (%) 4-BrC& 91 4-C1CaHA 85 59 3-Me&& 61 4-MeC&
C mp(OC) 152-154 145-147 108-110 118-120
calcd 44.31 53.00 64.07 64.07
H
halogen
found calcd found calcd found NMR (ppm) DMSO-cf6 44.13 2.60 2.34 29.48 29.56 11.4 (br s,2H), 7.68 (d, 2H, J = 8 Hz),7.53 (d, 2H), 6.23 (s,lH) 52.73 3.11 3.09 15.64 15.56 13.2 (br s,2H), 7.63 (d, 2H, J = 8.5 Hz), 7.55 (d, 2H), 6.4 (s,lH) 7.2-7.4 (m, 4H), 6.3 (8, lH), 2.38 (s.3H) 64.09 4.89 4.93 11.2 (s,2H), 7.48 (d, 2H, J = 8.3 Hz), 7.28 (d, 2H), 6.2 (e, lH), 64.15 4.89 4.64 2.33 (s,3H)
were recorded on a Nicolet 205 X B FTIR spectrophotometer as KBr pellets. Combustion analyses of all new compounds were performed by the Analytical Department, American Cyanamid Company, Pearl River, NY. General Procedure for the Condensation of Arylacetonitriles (lb-d) with Glyoxylic Acid. A mixture of 0.05 mol of the appropriate arylacetonitrile 1 (b-d), 0.075 mol of glyoxylic acid hydrate, and 0.127 mol of potassium carbonate in 100 mL of methanol was stirred a t room temperature for 3-5 h. The resulting thick solid precipitate wae filtered and washed with dichloromethane. This solid was suspended in 500 mL of cold water, stirred overnight, and then filtered and air driedto provide the corresponding potassium (2)-3-aryl-3-cyanopropenoates 2 (b-d). Normallythese materials were sufficientlypure for further transformations; however, analytically pure 2 could be obtained by recrystallization from water. Condensation of Arylacetonitriles (la,-h) w i t h Glyoxylic Acid. These reactions were performed as described above
except these mixtures were heated at reflux 2-24 h. The products 2a,e-h were isolated by filtration upon cooling of the reaction mixture. Cyclization of Potassium (Z)-3-Aryl-3-cyanopropenoates 2 t o Arylmaleic Anhydrides 4. The potassium (Z)-3-aryl-3cyanopropenoates 2 (0.094 mol) were dissolved in ca. 200 mL of 88%formic acid containing 15mL of concentrated sulfuric acid. These mixtures were heated a t reflux for 2-3 h and then cooled and poured into ice water. The resulting solids were filtered, washed with water, and air dried to provide the arylmaleic anhydrides 4. These products were normally of sufficient purity for use in subsequent transformations. Preparation of Arylmaleic Acids 3. The potassium (2)3-aryl-3-cyanopropenoates(0.012 mol) were suspended in 100 mL of 3 N HC1 and stirred at room temperature overnight. The solids were collected by filtration, washed with water, and air dried to give the arylmaleic acids, in moat cases analytically pure.
