Oxalyl Chloride-Dimethylformamide

(COCl)2

[79-37-8]  · C2Cl2O2  · Oxalyl Chloride-Dimethylformamide  · (MW 126.92) (DMF)

[68-12-2]  · C3H7NO  · Oxalyl Chloride-Dimethylformamide  · (MW 73.11)

(versatile agent combination for in situ generation of Vilsmeier reagent used in preparation of carboxylic acid chlorides and other acid derived products,1 phosphonic acid chlorides,2 b-chloro enones,3 ketoximes4 and formyl derivatives5)

Physical Data: see entries for Oxalyl Chloride and N,N-Dimethylformamide.

Form Supplied in: generated in situ under anhydrous conditions from oxalyl chloride and either catalytic or stoichiometric dimethylformamide, typically in halogenated solvents such as dichloromethane; acetonitrile, or hexane. The intermediate dimethylforminium chloride (DMFCl) can be isolated as a hygroscopic solid, mp 140 °C (see also Thionyl Chloride, Phosphorus Oxychloride).

Handling, Storage, and Precautions: (see also Oxalyl Chloride); reagent generated in situ under anhydrous conditions; corrosive, toxic. Oxalyl chloride should be used in the fume hood.

Synthesis of Carboxylic Acid Chlorides and Anhydrides.

Carboxylic acids, including amino acids,6 readily react with DMFCl generated in situ to produce acid chlorides on heating (eq 1).1 The procedure has been shown to be general, and may provide acid chlorides not available with oxalyl chloride alone.7,8

The mild reaction conditions employed enables the preparation of chlorides without disrupting chiral or other sensitive functionality. The use of hexane has been found particularly suitable for microscale preparation of high purity Mosher's acid chloride as it enables residual DMFCl to be filtered from solution (eq 2).9

DMFCl has been used to prepare carboxylic esters (eq 3),10 N-hydroxycarboxamides and O,N-dimethylcarboxamides,11 and a-hydroxycarboxamides (eq 4),12 via a one pot process.

A procedure using silyl esters, developed to allow synthesis of acid chlorides under neutral conditions, has been applied to a range of substrates (eq 5),13 including amino acid anhydrides.1

Reduction of the intermediate generated from a carboxylic acid and DMFCl provides aldehydes with Lithium Tri-t-butoxyaluminum Hydride,14 and alcohols with Sodium Borohydride,15 both in high yield and chemoselectivity.

Preparation of Phosphonic Acid Chlorides.

Disilyl esters of phosphonic acids react with oxalyl chloride-DMF to give the phosphonyl chlorides and silyl chlorides under mild conditions (eq 6).2 Prior treatment of an acid-sensitive phosphonate monoester with Trimethylsilyldiethylamine was used to minimize exposure to HCl (eq 7).16

A general process suitable for large scale synthesis of phosphonic acid dichlorides, which avoids the need for preforming silyl esters, has been reported (eq 8).17

b-Chloro (or Bromo) Enones.

Cyclic diketones in solution with DMF and dichloromethane react with oxalyl chloride (or bromide) to give b-halo enones in high yield (eq 9).3 The reported procedure reduces overall reaction time and avoids solubility problems.

Formylation.

Vilsmeier formylation reactions have been reviewed.1 Oxalyl chloride-dimethylformamide has found occasional use; one application has been preparation of a piperidine substituted dialdehyde (eq 10).5

Alkyl Chlorides.

N,N-Diphenylformamide is reported to be an improvement on DMF when used with oxalyl chloride to prepare primary and secondary alkyl chlorides from alcohols.18

Ketoximes.

Lithium salts of nitroalkanes react with DMFCl, preformed from oxalyl chloride and DMF, to give intermediates which on reaction with Grignard reagents give ketoximes on workup (eq 11).4


1. (a) Standler, P. A. HCA 1978, 61, 1675. (b) Marson, C. M. T 1992, 48, 3659.
2. Bhongle, N. N.; Notter, R. N.; Turcotte, J. G. SC 1987, 17, 1071.
3. Mewshaw, R. E. TL 1989, 30, 3753.
4. Fujisawa, T.; Kurita, Y.; Sata, T. CL 1983, 1537.
5. Reichardt, C.; Schagerer, K. AG(E) 1973, 12, 323.
6. Ookawa, A.; Soai, K.; JCS(P1) 1987, 1465.
7. (a) Bosshard H. H.; Mory, R.; Schmid, M.; Zollinger, H. HCA 1959, 42, 1653 (b) Borer, B. C.; Balogh, D. W. TL 1991, 32, 1039. (c) Buschmann, H.; Scharf, H-D. S 1988, 827.
8. Ireland, R. E.; Anderson, R. C.; Badoud, R.; Fitzsimmons, B. J.; McGarvey, G. J.; Thaisrivongs, S.; Wilcox, C. S. JACS 1983, 105, 1988.
9. Ward, D. E.; Rhee, C. K. TL 1991, 32, 7165.
10. Stetter, H.; Kogelnik, H-J. S 1986, 140.
11. (a) Nakonieczna, L.; Milewska, M.; Kolasa, T.; Chimiak, A. S 1985, 929 (b) Ward, J. S.; Merritt, L. JHC 1990, 27, 1709.
12. Kelly, S. E.; LaCour, T. G. SC 1992, 22 859.
13. (a) Wissner, A.; Grudzinskas, C. V. JOC 1978, 43, 3972 (b) Hausler, J.; Schmidt, U. CB 1974, 107, 145 (c) Mobashery, S; Johnston, M. JOC 1985, 50, 2200.
14. Fujisawa, T.; Mori, T.; Sato, T. CL 1983, 835.
15. Fujisawa T.; Toshiki, M.; Tsuge, S,; Sato, T. TL 1983, 24, 1543.
16. Biller, S. A.; Forster, C.; Gordon, E. M.; Harrity, T.; Scott, W.; Ciosek, C. P. JMC 1988, 31, 1869.
17. Rogers, R. S. TL 1992, 33, 7473.
18. Fujisawa, T.; Tida, S; Sato, T. CL 1984, 1173.

Roger Salmon

Zeneca Agrochemicals, Bracknell, UK



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