Dimethylcarbamoyl Chloride

(1; X = Cl)

[79-44-7]  · C3H6ClNO  · Dimethylcarbamoyl Chloride  · (MW 107.55) (2; X = F)

[431-14-1]  · C3H6FNO  · Dimethylcarbamoyl Fluoride  · (MW 91.10)

(convenient source of the dimethylaminocarbonyl unit; introduction of carbamates as directing groups)

Alternate Names: DMC-Cl; dimethylcarbamic chloride; dimethylcarbamyl chloride; N,N-dimethylaminocarbonyl chloride.

Physical Data: (1) bp 165-167 °C; bp 55-57 °C/11 mmHg; d 1.678 g cm-3. (2) bp 54-56 °C/51 mmHg.

Form Supplied in: both halides are colorless liquids; the chloride is widely available; the fluoride is not commercially available.

Handling, Storage, and Precautions: the liquid chloride decomposes on exposure to moist air or water and is usually kept under argon or nitrogen. Distillation at reduced pressure is recommended to prevent decomposition. It is a powerful lachrymator and a confirmed carcinogen and mutagen. Extreme care should be taken to avoid inhalation or skin contact. When heated to decomposition, toxic fumes containing CO, HCl, and NOx are emitted. Use in a fume hood.

Source of the Dimethylaminocarbonyl Unit.

The chemistry of dimethylcarbamoyl chloride (DMC-Cl) parallels that of acid chlorides in that the chloride can be replaced by other nucleophiles.1,2 However, these reactions are generally not as facile as their acid halide counterparts. Some reactions proceed via a trace equilibrium component, the more reactive dimethylaminoacylium ion (Me2+N=C=O Cl-). As a consequence, DMC-Cl is both less reactive and less selective than acid halides when reacted with substrates containing more than one nucleophilic site.3,4 Reaction of DMC-Cl with alcohols (phenols), amines, and thiols affords the respective carbamates, ureas, and thiocarbamates (eq 1), which classically exhibit significant bioactivities.5 Thus many important pharmaceuticals and especially agricultural biocides contain the DMC unit.5,6 In these acylations, pyridine often is the preferred acid scavenger.7 Like acid chlorides, DMC-Cl activates imine functions in the synthesis of heterocycles (eq 2).8

Dimethylamides are available by heating DMC-Cl with alkali carboxylates.9 Presumably an intermediate carbamic carboxylic anhydride loses CO2. Aryl carboxamides also have been made from DMC-Cl by Friedel-Crafts acylation of arenes.10 By including a hydrolysis step, this is a general route to aromatic carboxylic acids. Alkynylamides are available by a palladium-catalyzed condensation of terminal alkynes with DMC-Cl (eq 3).11 Conjugated aldehydes react with carbamoyl chlorides to form dienyl carbamates (eq 4), which have been used as dienes in the Diels-Alder reaction.4,12 After formation of the Diels-Alder adduct, the carbamate can be converted to the allylic alcohol by Lithium Aluminum Hydride reduction.12


The reagent also has been used to dehydrate primary amides to nitriles.13 Tetramethylformamidinium chloride is formed by the condensation of DMF with DMC-Cl.14 This is the key intermediate in the synthesis of Tris(dimethylamino)methane,15 a reagent used to introduce enamine functions in compounds containing activated methylene groups (eq 5).16

Carbamates as Directing Groups.

Deprotonation of aryl and many heteroaromatic carbamates with RLi/TMEDA occurs regioselectively at the ortho site. Subsequent treatment of the lithiated intermediates with electrophiles has yielded an enormous variety of ortho-substituted products in excellent yield (eq 6).17 In an extension of this reaction the product is treated with a Grignard reagent in the presence of Ni0 catalyst to replace the carbamate function. This latter reaction also works well without the prior ortho substitution step (eq 7).18 Allylic and benzylic carbamates undergo similar substitution (eq 8)19 and a-lithiation of O-vinyl carbamates recently has been demonstrated (eq 9).20 In these processes, N,N-diethyl- and N,N-diisopropylcarbamates generally react more cleanly (also, in eq 8, the ratio of a to g products is 5:95 with the NEt2 reactant).17-20 With lithioallyl N,N-diisopropylcarbamates, regio- and stereoselective homoaldol type additions have even been achieved via titanates.19

The DMC-Cl derived carbamates of cyclic allylic and homoallylic alcohols are epoxidized with m-Chloroperbenzoic Acid with high syn stereoselectivity (eq 10).21 The carbamate function has also been used to direct the stereochemical course of Grignard additions to ketones by a chelation control mechanism (eq 11).12 In the reaction depicted the diastereofacial selectivity is 100%; the product (R2 = -(CH2)2CH=CMe2) is an intermediate on the route12 to the sesquiterpene hernandulcin, which is over 1000 times sweeter than sucrose.22

Dimethylcarbamoyl Fluoride.

The reagent is prepared directly from DMC-Cl by halide exchange; IR (CCl4) 1800 cm-1; 1H NMR (CDCl3) d 2.95 (s). While an equilibrium process is involved, the thermodynamics overwhelmingly favor the acyl fluoride. Many fluoride sources have been utilized.23 However, in the most efficient preparation (95% yield), DMC-Cl is stirred neat with Potassium Fluoride activated by 4 mol % 18-Crown-6 at rt (reaction monitored by IR).24 Alternatively, an acetonitrile suspension of DMC-Cl and KF-CaF2 is stirred at 50 °C for 24 h.25

There normally is little advantage in using DMC-F in place of the chloride as an acylating agent. An exception is the reaction of trimethylsilyl (TMS) protected anions which undergo electrophilic carbodesilyations in the presence of a catalytic amount of naked F-. This scheme has been used to stereospecifically convert enol silyl ethers to vinyl carbamates (eq 12).26 The O-acylation is catalyzed by PhCH2+NBu3 F- (BTAF) and has been performed with enol silyl ethers from aldehydes and aliphatic, aromatic, and conjugated ketones.26 A similar process has been utilized to obtain the hindered pyrazolecarboxylic acid from 1-methylpyrazole (eq 13).27 The greater acidity of HC(5) accounts for the success of the first step of this synthesis (for H/D exchange in NaOMe/MeOD at 139 °C, the relative rate constants (k2) are HC(3) = 1, HC(4) = 2, HC(5) = 1500).28

1. MOC 1983, E4.
2. For other kinds of nucleophilic additions to DMC-Cl see: (a) Gaiffe, A.; Jaques, A. CR(C) 1971, 272, 410. (b) Somlo, T. Ger. Offen. 2 206 366 (CA 1972, 77, 151 532r). (c) Thieme, P.; Patsch, M.; König, H. LA 1972, 764, 94. (d) Seebach, D.; Weller, T.; Protschuk, G.; Bech, A. K.; Hoekstra, M. S. HCA 1981, 64, 716. (e) Barbot, F.; Miginiac, P. BSF(2) 1983, 41.
3. Wancowicz, D. J. Dissertation, Pennsylvania State University, 1976.
4. De Cusati, P. F.; Olofson, R. A. TL 1990, 31, 1405.
5. (a) Kuhr, R. J.; Dorough, W. Carbamate Insecticides, Chemistry, Biochemistry, and Toxicity; CRC: Cleveland, 1976. (b) The Pesticide Manual; 8th ed.; Worthing, C. R., Ed.; British Crop Protection Council: Croydon, England, 1987.
6. (a) Baille, A. C. Pestic. Sci. 1981, 12, 7. (b) Hansen, K. T.; Bundgaard, H.; Faarup, P. Eur. Patent Appl. 331 130 (CA 1990, 112, 118 677k). (c) Jacobson, R. M.; Nguyen, L. T. Eur. Patent Appl. 338 685 (CA 1990, 112, 178 991t).
7. (a) Apparao, S.; Schmidt, R. R. S 1987, 896. (b) Ponaras, A. A.; Zaim, &OOuml;. JOC 1987, 52, 5630.
8. (a) Venkov, A. P.; Lukanov, L. K. S 1989, 59. (b) Duarte, F. F.; Popp, F. D. H 1991, 32, 723.
9. (a) Lawson, J. K., Jr.; Croom, J. A. T. JOC 1963, 28, 232. (b) Grega, E.; Gribovszki, P.; Marosvolgyi, S.; Zoltan, P.; Szilagyi, G.; Szita, I.; Tarr, C.; Tasi, L. S. Afr. Pat. 74 00 572 (CA 1975, 83, 96 777w).
10. Ivanova, V. M.; Nemleva, S. A.; Seina, Z. N.; Kaminskaya, E. G.; Gitis, S. S.; Kaminskii, A. Y. JOU 1967, 3, 141.
11. (a) Tohda, Y.; Sonogashira, K.; Hagihara, N. S 1977, 777. (b) Hartke, K.; Gerber, H.-D.; Roesrath, U. LA 1991, 903 and refs. therein.
12. De Cusati, P. F.; Olofson, R. A. TL 1990, 31, 1409.
13. Weisz, I.; Otvos, L. Hung. Patent 33 998 (CA 1985, 103, 141 483s).
14. Arnold, Z. CCC 1959, 24, 760.
15. Meerwein, H.; Florian, W.; Schön, N.; Stopp, G. LA 1961, 641, 1.
16. (a) Bredereck, H.; Effenberger, F.; Brendle, Th. AG(E) 1966, 5, 132. (b) Martin, S. F.; Moore, D. R. TL 1976, 4459. (c) Wasserman, H. H.; Ives, J. L. JOC 1985, 50, 3573. (d) Schuda, P. F.; Ebner, C. B.; Morgan, T. M. TL 1986, 27, 2567.
17. Snieckus, V. CRV 1990, 90, 879 and refs. therein.
18. Sengupta, S.; Leite, M.; Raslan, D. S.; Quesnelle, C.; Snieckus, V. JOC 1992, 57, 4066.
19. Hanko, R.; Rabe, K.; Dally, R.; Hoppe, D. AG(E) 1991, 30, 1690 and several refs. to the publications of D. Hoppe therein.
20. (a) Sengupta, S.; Snieckus, V. JOC 1990, 55, 5680. (b) Tsukazaki, M.; Snieckus, V. TL 1993, 34, 411.
21. Kocovsky, P. TL 1988, 29, 2475.
22. Compadre, C. M.; Hussain, R. A.; Lopez de Compadre, R. L.; Pezzuto, J. M.; Kinghorn, A. D. J. Agric. Food Chem. 1987, 35, 273.
23. (a) Fawcett, F. S.; Tullock, C. W.; Coffman, D. D. JACS 1962, 84, 4275. (b) Olah, G. A.; Nishimura, J.; Kreienbühl, P. JACS 1973, 95, 7672. (c) Dmowski, W.; Kaminski, M. JFC 1983, 23, 207.
24. Cuomo, J.; Olofson, R. A. JOC 1979, 44, 1016.
25. Ichihara, J.; Matsuo, T.; Hanafusa, T.; Ando, T. CC 1986, 793.
26. Cuomo, J.; Olofson, R. A. TL 1980, 819.
27. Effenberger, F.; Krebs, A. JOC 1984, 49, 4687.
28. Kohn, H. L. Dissertation, Pennsylvania State University, 1971 (Diss. Abstr. Int. B. 1972, 33, 89).

Charles B. Kreutzberger & Roy A. Olofson

The Pennsylvania State University, University Park, PA, USA

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