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Org. Synth. 1970, 50, 52
DOI: 10.15227/orgsyn.050.0052
2,4-DIMETHOXYBENZONITRILE
[Benzonitrile, 2,4-dimethoxy-]
Submitted by G. Lohaus1
Checked by Jurgen K. Weise and Richard E. Benson.
1. Procedure
Caution! Chlorosulfonyl isocyanate is a highly corrosive, irritating compound. This reaction should be carried out in an efficient hood.
A 1-l., round-bottomed flask equipped with a stirrer, a thermometer, a dropping funnel, and a reflux condenser to which is attached a drying tube containing calcium chloride, is charged with 138 g. (131 ml., 1.00 mole) of resorcinol dimethyl ether and 200 ml. of dichloromethane. The solution is stirred, and a solution of 150 g. (1.06 moles) of chlorosulfonyl isocyanate (Note 1) in 100 ml. of dichloromethane is added with stirring at 15–20° over a 25-minute period. The amide N-sulfonyl chloride separates as a crystalline solid, and the mixture is stirred for an hour at room temperature. The resulting mixture is cooled to 10–12° (Note 2) and 154 g. (2.1 moles) of N,N-dimethylformamide (Note 3) is added over a period of 5 minutes. The cooling bath is removed and the temperature gradually rises to about 30°, then falls. After 1 hour the crystals dissolve and the reaction mixture is poured onto 200 g. of ice. After the ice has melted, dichloromethane (150 ml.) is added, the mixture is shaken, and the organic layer is separated. The aqueous layer is extracted with 100 ml. of dichloromethane, and the organic phases are combined and washed with 100 ml. of water. The dichloromethane is removed by distillation, giving a white solid that is triturated with 250 ml. of cold water, recovered by filtration, and dried, yielding 155–157 g. (95–96%) of 2,4-dimethoxybenzonitrile, m.p. 91°. GC using a Chromosorb W column with 10% butadiene sulfone as the stationary phase indicates that the product has a purity of 98%. The IR spectrum shows absorption at 2220 cm.−1 attributable to the cyano group.
2. Notes
1. Chlorosulfonyl isocyanate may be prepared as described in Org. Synth., Coll. Vol. 5, 226 (1973); it is available from Farbwerke Hoechst AG. The checkers found it necessary to distill the product before use.
2. A less pure product is obtained if the temperature is allowed to rise at this phase of the reaction.
3. Other amides also can be used, but N,N-dimethylformamide generally is preferred, especially because of its low molecular weight, high solvent power, and miscibility with water. In addition, it is readily available.
3. Discussion
This procedure2 is an example of a broadly applicable, simple method for introducing the cyano substituent into compounds that readily undergo electrophilic substitution. The method is characterized by mild reaction conditions, a simple workup procedure, and, in most cases, good yields. Although the method has two steps, the reaction generally can be carried out without isolation of the intermediate chlorosulfonamide. An indication of its scope is given in Table I.2 Additional examples of the substitution reaction of chlorosulfonyl isocyanate with aromatic and heterocyclic compounds and with olefins, yielding carboxylic acid amide N-sulfonyl chlorides are reported.2,3,4,5,6
TABLE I
NITRILES2 PREPARED FROM ClSO2NCO

Reactant

Product

Yield, %


67

20

66

86

84

81

95

89


Other procedures for the preparation of 2,4-dimethoxybenzonitrile include the reaction of 2,4-dimethoxybenzamide with thionyl chloride,3 the action of acetic anhydride on 2,4-dimethoxybenzaldoxime,7 the reaction of diazotized 2,4-dimethoxyaniline with potassium copper cyanide,8 and the action of cyanogen bromide on resorcinol dimethyl ether in the presence of aluminum chloride.9

References and Notes
  1. Hoechst AG., Frankfurt/Main-Höchst, Germany.
  2. G. Lohaus, Chem. Ber., 100, 2719 (1967).
  3. F. Effenberger, R. Gleiter, L. Heider, and R. Niess, Chem. Ber., 101, 502 (1968).
  4. R. Graf, Ann. Chem., 661, 111 (1963).
  5. M. Seefelder, Chem. Ber., 96, 3243 (1963).
  6. R. Graf, Angew. Chem., 80, 179 (1968) [Angew. Chem., Int. Ed. Engl., 7, 172 (1968)].
  7. H. Baganz and I. Paproth, Naturwissenschaften, 40, 341 (1953).
  8. E. Späth, K. Klager, and C. Schlösser, Ber. Dtsch. Chem. Ges., 64, 2203 (1931).
  9. P. Karrer, A. Rebmann, and E. Zeller, Helv. Chim. Acta, 3, 261 (1920).

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

butadiene sulfone

acetic anhydride (108-24-7)

thionyl chloride (7719-09-7)

aluminum chloride (3495-54-3)

dichloromethane (75-09-2)

Cyanogen bromide (506-68-3)

N,N-dimethylformamide (68-12-2)

CHLOROSULFONYL ISOCYANATE (1189-71-5)

2,4-DIMETHOXYBENZONITRILE,
Benzonitrile, 2,4-dimethoxy- (4107-65-7)

resorcinol dimethyl ether (151-10-0)

2,4-dimethoxybenzamide

2,4-dimethoxybenzaldoxime

2,4-dimethoxyaniline (2735-04-8)

potassium copper cyanide