An Improved Synthesis of Carbamates

DECEMBER,1963 AN IMPROVEDSYNTHESIS OF CARBAMATES 342 1 tion, extraction with methylene chloride, and removal of the sol- (V), m.p. 223-224". The reaction mixture had a strong odor of vent a small amount of white solid. This solid was recrystallized mesitol, but no attempt was made to isolate it. twive from hexane to yield white needles of a-t-butoxy-a-mesityl- 2-Mesity1-lj3-indandionewith Diphenyliodonium Chloride .- acetophenone-0-carboxylic acid, m.p. llE~116~. To a solution of 84.8 mg. (0.76 mmole) of potassium t-butoxide in Anal. Calcd. for CZZHZ~~O~:C, 74.55; H, 7.39; mol. wt., 20 ml. of t-butyl alcohol there was added with stirring 200 mg. 354.43. Found: C, 74.50; H, 7.36; mol. wt., 392 and 311. (0.76 mmole) of l' and 243 mg. (0.76 mmole) of diphenyliodo- Removal of the &Butyl Group in Compound VI.-A solution of nium chloride. The orange solution was refluxed overnight, dur- 250 mg. of VI in 15 ml. of dioxane and 5 ml. of 6 N hydrochloric ing which time it turned a light yellow, and all the iodonium cation acid was heated on a steam bath for 2 hr. During this time the was consumed. The solvent was removed, and the residue was solution was reduced to half the volume, with formation of light chromatographed on a 100-g. Florid column. The ether eluate ivory colored needles. The mixture was diluted with 25 ml. of yielded a yellow oil which after two distillations at 180-200' water, the solid was collected and chromatographed on silica gel. (0.05 mm.) gave 188 mg. (0.55 mmole, 73%) of a yellow glass of The ether eluate on removal of the solvent gave white crystals of 2-mesityl-3-phenoxy-1-indenone (IX). A small sample of this 2-hydroxy-2-mesityl-1,3-indandione(VIII), which was purified glass was crystallized from isopropyl alcohol to give a pale yellow by two sublimations at 15&175' (0.05 mm.) to yield white solid, m.p. 70.2-71 O; ultraviolet absorption maximum, 246 needles, m.p. 198-199". mp (ernm 42,200). The infrared spectrum showed a hydroxyl band at 3500 cm.-', Anal. Calcd. for C24H2002: C, 84.68; H, 5.92. Found: C, carbonyl bands at 1710 and 1640 cm.-', the latter arising from 84.94; H, 6.06. hydrogen bonding of one of the carbonyl groups with the hy- The infrared spectrum of this compound was similar to that of droxyl group. Other bands in the spectrum included a C-0 compound VII. stretching at 1100 cm. -l, characteristic of tertiary alcohols, along with CHI and mesityl absorption. The acetone eluate from the chromatography column yielded Anal. Calcd. for CI8HleOa: C, 77.12; H, 5.76. Found: C, 30 mg. of unchanged starting material. 76.99; H, 5.86. When the reaction was run with sodium &butoxide as the base, Hydrolysis of 2-Mesityl-3-mesityloxy-1 -indenone .-A solution the reaction time was shortened to 0.5 hr., with otherwise identi- of 885 mg. (2.32 mmoles) of IT1 in 25 ml. of dioxane and 25 ml. of cal results. 6 AT hydrochloric acid was refluxed for 3 days with stirring. The Hydrolysis of Z-Mesity1-3-phenoxy-l-indenone.-Asolution of mixture was then concentrated to about 20 ml., diluted with 50 50 mg. of IX in 3 ml. of isopropyl alcohol and 3 ml. of 3 N hydro- ml. of methylene chloride, and extracted five times with 1 N chloric acid was heated on a steam bath for 3 hr. The mixture sodium hydroxide. The organic layer contained unchanged was concentrated to ca. 3 ml. by solvent removal; an odor of starting material. The red aqueous phase on acidification, ex- phenol was detected. The mixture was diluted with 5 ml. Of traction with methylene chloride, and removal of solvent water, and the gummy solid formed was collected. Trituration yielded after trituration of the residue with ether 245 mg. (0.93 with ether gave an ivory solid, m.p. 219-222', whose infrared mmole, 407,) of pale yellow needles of 2-mesityl-1 ,3-indandione spectrum was identical with that of 2-mesityl-l,3-indandione(V). An Improved Synthesis of Carbamates HERiYARD LOEVAND MINERVA F. KORMENDY Research and Development Division, Smith Kline and French Laboratories, Philadelphia, Pennsylvania Received March 18, 1963 A simple synthesis of the hitherto difficultly prepared carbamates of tertiary alcohols has been developed, The method also has been found applicable to the synthesis of the carbamates of other alcohols (including steroids, as well as primary and secondary alcohols), polyols, phenols, mono- and polythiols, and oximes. Stereo- isomeric (syn and anti) ketoximes were converted to the corresponding stereoisomeric oxime carbamates. The preparation of any of these involves simply stirring the substrate, sodium cyanate, and trifluoroacetic acid in an inert solvent for several hours at room temperature. Although the carbamates of primary and secondary oxime, etc.) with sodium cyanate and trifluoroacetic alcohols, and the X-substituted carbamates of tertiary acid in certain solvents at room temperature. alcohols are relatively easily prepared,' the synthesis Although the reaction of alcohols with cyanic acid of unsubstituted carbamates of tertiary alcohols is had been presumed always to give allophonates,2 45 generally quite difficult, owing to the ease of dehydra- Werner6 reported a 56% yield of urethan from the re- tion and rearrangement of the al~ohols.*~~The method action of ethanol in an aqueous solution of sodium cya- usually employed involves conversion of the alcohol to nate and hydrochloric acid. r\lcLamorez reported, a mixed carbonate using phenyl chloroformate, then however, that reaction of a tertiary alcohol with potas- treatment with liquid amm~nia.~,~ sium cyanate in acetic acid led to dehydration or rear- During the course of a study which necessitated the rangement and gave no carbamate. Moderate (ap- preparation of a number of carbamates of tertiary proximately 50%) yields of the carbamates of tertiary alcohols, we developed a simple method for their alcohols were described by llarshall,' employing in situ synthesis which has been found to be broadly applicable generation of cyanic acid from an anhydrous mixture not only to the synthesis of the carbamates of alcohols of sodium cyanate in trichloroacetic acid. (primary, secondary, and tertiary alcohols, steroids, polyols, and phenols), but also to the synthesis of the (4) W. J. Close and M. A. Spielman. J. Am. Chem. Sor., 76, 4055 (1953). carbamates of mono- and polythiols and oximes. (5) H. W. Blohrn and E. I. Becker, Chem. Rec., 61, 471 (1952), give a This method involves stirring the alcohol (mercaptan, comprehensive review of the synthesis of allophonates and point out the erratic results obtained by various investigators. (6) A. Werner, Sca. Proc. Roy. Dublin Soc., 24, 209 (1947); Chem. Abstr., (1) Houhen-Weyl, "Methoden der Organischen Chemie," Vol. VIII, 4th 41, 6533e (1947). Ed., Georg Thierne Verlag, Stuttgart, 1952, pp. 103, 115, 137. (7) P. G. Marshall, J. H. Barnes. and P. A. McCrea, U. S. Patent 2,814,637 (2) W. M. McLarnore, S. Y. P'An, and A. Bavley, J. 070. Chem., 20, (1957). The same procedure was later used by W. Stuehmer and S. Funke, 1379 (1955). U. S.Patent 2,878,158 (1859). and J. H. Barnes, et al., J. Pharm. Pharmarol.. (3) B. Melander. J. Med. Pharm. Chem., 1, 443 (1959). 18, 39 (1961). 3422 LOEVAND KORMENDY VOL. 28 On modifying this procedure we found that signifi- with mixtures of other products, probably mono- and cantly improved yields of carbamates were readily and dicarbamates. consistently obtained ; thus, the yield of t-butyl carba- Attempts were made to extend these reactions to the mate was raised to over 90%. preparation of carbamates from 1,l-(gem) diols and The compounds prepared by this procedure are dithiols. Dihydroxymalonic acid (mesoxalic acid hy- listed in Table I (pp. 3424 and 3425). drate) was recovered unchanged from the reaction The most significant factor leading to improved mixture, and biphenylglyoxal hydrate gave a high yields was substitution of trifluoroacetic for trichloro- melting, insoluble mixture of products.12 acetic acid. This beneficial effect does not appear to The only simple alcohols from which carbamates be solely related to increased acid strength, for hydro- could not be isolated were diphenylethylcarbinol chloric and methanesulfonic acids gave only truces (which gave 1,I-diphenylethylene) and trichloro- and of product when used in place of trifluoroacetic acid trifluoromethylcarbinols (these gave complex mixtures under the same conditio1m8 ofproducts). Another factor markedly influencing the yield was the Phenols easily gave the corresponding carbamates choice of solvent ; benzene and methylene chloride (8 and 9). gave markedly better yields than other inert solvents The carbamates of surprisingly few primary and such as ether, carbon tetrachloride, or tetrahydrofuran. secondary mercaptans, and of no tertiary mercaptans, Substitution of potassium cyanate for sodium cyanate are known. These (15-17) and the carbamate of a reduced the yield to less than 5%. 1,3-dithiol (18)13 were readily prepared. The odors of The reaction is generally over in less than two hours, the freshly prepared thiolcarbamates were not particu- and the crude yields of product are high (60 to goyo). larly unpleasant; however, on prolonged standing a In some instances, the final yield of analytically pure typical mercaptan odor developed. A gem-dithiol, product was low; this was generally due to losses 2,2-dimercapt0-1,3-diphenylpropane,'~did not react occurring during purification, as the result of the in- and was recovered unchanged from the reaction mixture. herent thermal or hydrolytic instability or volatility Oxime carbamates were first prepared by Conduche'5 of the products.

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