Dimethylcarbamoyl chloride

Dimethylcarbamoyl chloride
Identifiers
79-44-7
ECHA InfoCard 100.001.099
PubChem 6598
Properties
C3H6ClNO
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Dimethylcarbamoyl chloride is a reagent for transferring a dimethylcarbonyl group to alcoholic or phenolic hydroxyl groups forming dimethyl carbamates, usually having pharmacological or pesticidal activities. Because of its high toxicity and its carcinogenic properties shown in animal experiments and presumably also in humans,[1] dimethylcarbamoyl chloride can only be used under stringent safety precautions.

Production and occurrence

The production of dimethylcarbamoyl chloride from phosgene and dimethylamine (DMA) was reported as early as 1879 (reported as "Dimethylharnstoffchlorid" - dimethylurea chloride).[2]

Dimethylcarbamoyl chloride can be produced in high yields (90%) at 275 °C by reacting phosgene with gaseous dimethylamine in a flow reactor.[3] To suppress the formation of ureas excessive phosgene is used (in a 3:1 ratio).

The reaction can also be carried out at the laboratory scale with diphosgene or triphosgene and a aqueous dimethylamine solution in the two-phase system benzene+xylene/water in a stirred reactor with sodium hydroxide as an acid scavenger. However, considerably lower yields (56%) are achieved due to the hydrolysis sensitivity of dimethylcarbamoyl chloride .[4]

Dimethylcarbamoyl chloride is also formed (together with methyl chloride) when reacting phosgene with trimethylamine.[5]

A more recent process is based on dimethylamine chloride, which is converted practically quantitatively to dimethylcarbamoyl chloride on a palladium catalyst under pressure with carbon monoxide at room temperature.[6]

Dicarbamoyl chloride can also be formed in small amounts (0-20 ppm) from dimethylformamide (DMF) in the Vilsmeier-Haack reaction[7] or when DMF is used as a catalyst in the reaction of carboxylic acids with thionyl chloride to the corresponding carboxylic acid chlorides.[8]

The tendency towards dicarbamoyl chloride formation depends on the chlorination reagent (thionyl chloride> oxalyl chloride> phosphorus oxychloride) and is higher in the presence of a base. However, dicarbamoyl chloride hydrolyses very quickly to dimethylamine, hydrochloric acid and carbon dioxide (with a half-life of about 6 minutes at 0 °C) so that less than 3 ppm of dicarbamoyl chloride are found in the Vilsmeier product after aqueous work-up.[9]

Properties

Dimethylcarbamoyl chloride is a clear, colorless, corrosive and flammable liquid with a pungent odor and a tear-penetrating effect, which decomposes rapidly in water.[10] Because of its unpleasant, toxic, mutagenic and carcinogenic properties[11][12] it has to be used under extreme precautions.

Dimethylcarbamoyl chloride behaves like an acid chloride whose chlorine atom can be exchanged for other nucleophiles. Therefore, it reacts with alcohols, phenols and oximes to the corresponding N, N-dimethylcarbamates, with thiols to thiolourethanes, with amines and hydroxylamine to substituted ureas, and with imidazoles and triazoles to carbamoylazoles.[13]

Dimethylcarbamoyl chloride is less reactive and less selective to substrates with multiple nucleophilic centers than conventional acid chlorides.

Unsaturated conjugated aldehydes such as (2E)-butenal react with dimethylcarbamoyl chloride forming dienyl carbamates, which can be used as dienes in Diels-Alder reactions.[14]

Alkali metal carboxylates react with dimethylcarbamoyl chloride forming the corresponding dimethylamides. Dimethylcarbamoyl chloride reacts with anhydrous sodium carbonate[15] or with excess dimethylamine to tetramethylurea.[16]

The reaction of dimethylcarbamoyl chloride with DMF forms tetramethylformamidinium[17] chloride which is a major intermediate in the preparation of tris(dimethylamino)methane, a reagent for the introduction of enamine functions in conjunction with activated methylene groups[18] and the preparation of amidines.[19]

Dimethylcarbamoyl chloride is a starting material for the insecticide class of the dimethyl carbamates[20] which act as inhibitors of acetylcholinesterase, including dimetilane,[21] and the related compounds isolane, pirimicarb and triazamate.

The quaternary ammonium compounds neostigmine[22] finds pharmaceutical applications as acetylcholinesterase inhibitors. It is obtained from 3-dimethylaminophenol and dimethylcarbamoyl chloride and subsequent quaternization with methyl bromide or dimethyl sulfate[23]

and pyridostigmine, which is obtainable from 3-hydroxypyridine and dimethylcarbamoyl chloride and subsequent reaction with methyl bromide.[24]

Dimethylcarbamoyl chloride is also used in the synthesis of the benzodiazepine camazepam.[25]

References

  1. ↑ R.P. Pohanish (2011) (in German), Sittig’s Handbook of Toxic and Hazardous Chemicals and Carcinogens, 6th Edition, Amsterdam: Elsevier, pp. 1045–1047, ISBN 978-1437778694
  2. ↑ W. Michler; C. Escherich (1879), "Ueber mehrfach substituirte Harnstoffe" (in German), Ber. Dtsch. Chem. Ges. 12 (1): pp. 1162–1164, doi:10.1002/cber.187901201303
  3. ↑ R.J. Slocombe; E.A. Hardy; J.H. Saunders; R.L. Jenkins (1950), "Phosgene derivatives. The preparation of isocyanates, carbamyl chlorides and cyanuric acid" (in German), J. Am. Chem. Soc. 72 (5): pp. 1888–1891, doi:10.1002/ja01161a009
  4. ↑ G. Karimipour; S. Kowkabi; A. Naghiha (2015), "New aminoporphyrins bearing urea derivative substituents: synthesis, characterization, antibacterial and antifungal activity" (in German), Braz. Arch. Biol. Technol. 58 (3), doi:10.1590/S1516-891320500024, http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-89132015000300431
  5. ↑ H. Babad; A.G. Zeiler (1973), "Chemistry of Phosgene" (in German), Chem. Rev. 73 (1): pp. 75–91, doi:10.1021/cr60281a005
  6. ↑ T. Saegusa; T. Tsuda; Y. Isegawa (1971), "Carbamoyl chloride formation from chloramine and carbon monoxide" (in German), J. Org. Chem. 36 (6): pp. 858–860, doi:10.1021/jo00805a033
  7. ↑ M. Stare; K. Laniewski; A. Westermark; M. Sjögren; W. Tian (2009), "Investigation on the formation and hydrolysis of N,N-dimethylcarbamoyl chloride (DMCC) in Vilsmeier reactions using /GC/MS as the analytical detection method" (in German), Org. Process Res. Dev. 13 (5): pp. 857–862, doi:10.1021/op900018f
  8. ↑ D. Levin (1997), "Potential toxicological concerns associated with carboxylic acid chlorination and other reactions" (in German), Org. Process Res. Dev. 1 (2): pp. 182, doi:10.1021/op970206t
  9. ↑ A. Queen (1967), "Kinetics of the hydrolysis of acyl chlorides in pure water" (in German), Canad. J. Chem. 45 (14): pp. 1619–1629, doi:10.1139/v67-264
  10. ↑ C.B. Kreutzberger; R.A. Olofson (2001), "Dimethylcarbamoyl Chloride" (in German), e-EROS Encyclopedia of Reagents for Organic Synthesis, doi:10.1002/047084289X.rd319
  11. ↑ P. Jäger; C.N. Rentzea; H. Kieczka (2014) (in German), Carbamates and Carbamoyl Chloride, in Ullmann’s Fine Chemicals, Weinheim: Wiley-VCH, pp. 57–58, ISBN 978-3-527-33477-3
  12. ↑ "Dimethylcarbamoyl Chloride, CAS No. 79-44-7" (PDF). Report on Carcinogens, Thirteenth Edition (in German). National Toxicology Program, Department of Health and Human Services. Retrieved 2016-09-25.
  13. ↑ C.B. Kreutzberger, R.A. Olofson (2007-02-01). "Dimethylcarbamoyl Chloride" (in German). John Wiley&Sons, Ltd. Retrieved 2016-09-27.
  14. ↑ P.F. De Cusati; R.A. Olofson (1990), "A simple synthesis of 1-(1,3-butadienyl)carbonates and carbamates" (in German), Tetrahedron Lett. 31 (10): pp. 1405–1408, doi:10.1016/S0040-4039(00)88817-6
  15. ↑ J.K. Lawson Jr.; J.A.T. Croom (1963), "Dimethylamides from alkali carboxylates and dimethylcarbamoyl chloride" (in German), J. Org. Chem. 28 (1): pp. 232–235, doi:10.1021/jo1036a513
  16. ↑ US 3597478, M.L. Weakly, "Preparation of tetramethylurea"
  17. ↑ Z. Arnold (1959), "The preparation of tetramethylformamidinium salts and their vinylogues" (in German), Coll. Czech. Chem. Commun. 24: pp. 760–765, doi:10.1135/cccc19590760
  18. ↑ H. Meerwein; W. Florian; N. Schön; G. Stopp (1961), "Über Säureamidacetale, Harnstoffacetale und Lactamacetale" (in German), Justus Liebigs Ann. Chem. 641 (1): pp. 1–39, doi:10.1002/jlac.19616410102
  19. ↑ H. Bredereck; F. Effenberger; Th. Brendle (1966), "Synthese und Reaktionen von Trisdimethylaminomethan" (in German), Angew. Chem. 78 (2): pp. 147–148, doi:10.1002/ange.19660780212
  20. ↑ "Compendium of Pesticide Common Names" (in German). Alan Wood. Retrieved 2016-09-27.
  21. ↑ US 3452043, T. Grauer, H. Urwyler, "Production of 1-N,N-dimethylcarbamoyl-5-methyl-3-N,N-dimethyl-carbamoyl-oxy-pyrazole"
  22. ↑ J.A. Aeschlimann; M. Reinert (1931), "Pharmacological action of some analogues of physostigmine" (in German), J. Pharmacol. Exp. Ther. 43 (3): pp. 413–444
  23. ↑ US 1905990, J.A. Aeschlimann, "Disubstituted carbamic acid esters of phenols containing a basic constituent"
  24. ↑ US 2572579, "Disubstituted carbamic acid esters of 3-hydroxy-1-alkyl-pyridinium salts"
  25. ↑ DOS 2448015, "Verfahren zur Herstellung des 3-N,N-Dimethylcarbamoyl-oxy-1-methyl-5-phenyl-7-chlor-1,3-dihydro-2H-1,4-benzodiazepin-2-on"
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