[758-16-7]  · C3H7NS  · N,N-Dimethylthioformamide  · (MW 89.18)

(Vilsmeier reagent for formylation of aliphatic, aromatic, and heteroaromatic systems; acyl anion equivalent; thiolysis of alkyl, aryl, and acyl halides; conversion of oximes into nitriles; reduction of sulfoxides; formation of some sulfur heterocycles and formamidines)

Alternate Name: TDMF.

Physical Data: bp 58-60 °C/1 mmHg; d 1.047 g cm-3; nD20 1.5760; fp 99 °C.

Solubility: sol THF, ethyl acetate, toluene, DMF; may react with some halogenated solvents.

Form Supplied in: yellow to colorless liquid.

Analysis of Reagent Purity: characterized by 1H and 13C NMR spectroscopy.2

Preparative Methods: various methods have been reported3 for the preparation of TDMF. As with other thioamides, it is best obtained by treatment of the parent amide with a suitable thionating reagent (see also 2,4-Bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-Disulfide) (eq 1).3d More recently, efficient conversion has been effected using Phosphorus(V) Sulfide that has been activated using solid Sodium Carbonate (eq 2).3a

Purification: distillation under reduced pressure.

Handling, Storage, and Precautions: can be stored for long periods of time at rt if kept sealed under inert atmosphere and out of direct contact with light; use in a fume hood.

Acyl Anion Equivalent.1c-e

TDMF can be readily deprotonated at low temperature to give a nucleophilic acylating reagent directly, and thus it serves as an acyl anion equivalent.4 However, due to the thermal instability of the anion, very low temperatures and rapid trapping of the incipient anion are required. Moderate to good yields have been obtained in this manner in reactions where ketones or aldehydes serve as electrophiles (eq 3).4e Recent protocols alleviate the need for precise low temperature control and provide for comparable yields by requiring admixing of the TDMF and electrophile followed by slow addition of the mixture to a chilled solution of Lithium Diisopropylamide (-78 °C).4a,b


TDMF is a very effective formylating reagent5 (see also Dimethylchloromethyleneammonium Chloride), providing intermediate enamines in good yields in situations where other more traditional reagent combinations, such as DMF/acetic anhydride, fail (eq 4).5c

Recently, TDMF has shown potential as a formylating reagent, yielding enaminones using a modified protocol of the Eschenmoser coupling of thioamides (eq 5).5a,1b

Preparation of Thiols.

Thiols can be obtained in excellent yield from the methanolysis of the adduct formed between an organic halide and TDMF (eq 6).6

Thiopyran Generation.

TDMF undergoes a Diels-Alder reaction with an electron-deficient diene with concomitant loss of the dimethylamino group to yield a 2H-thiopyran (eq 7).7

Thiirane Generation.

Thiiranes can be obtained in good to excellent yields from treatment of the corresponding epoxides with TDMF in the presence of a strong acid (eq 8).8

Reduction of Sulfoxides.

Thioformamidium ions, formed from the combination of TDMF and an alkyl halide, serve as excellent reagents for the reduction of sulfoxides (eq 9).9

Preparation of Nitriles.

Thioformamidium ions have also been used to convert oximes to nitriles (eq 10).10

Reaction with Amines.

TDMF reacts with primary amines (aryl and alkyl) to yield formamidines (eq 11),11 whereas upon heating TDMF in the presence of a secondary amine, the dimethylamino group is readily displaced by an amines of higher molecular weight, thereby leading to alternative thioformamide derivatives.4c,12

Related Reagents.

Acetic Anhydride; N,N-Dimethylformamide; Potassium Thiocyanate; Thiourea; Tris(methylthio)methane.

1. (a) COS 1991, 6, 419. (b) COS 1991, 2, 865. (c) Martin, S. F. S 1979, 633. (d) Gröbel, B. T.; Seebach, D. S 1977, 357. (e) Lever, O. W., Jr. T 1976, 32, 1943.
2. Fritz, H. G.; Hug, P.; Lawesson, S. O.; Logemann, E.; Pedersen, B. S.; Sauter, H.; Scheibye, S.; Winkler, T. BSB 1978, 87, 525.
3. (a) Brillon, D. SC 1990, 20, 3085. (b) Yde, B.; Yousif, N. M.; Pedersen, U.; Thomsen, I.; Lawesson, S. O. T 1984, 40, 2047. (c) Kantlehner, W.; Haug, E.; Farkas, M. LA 1982, 1582 (CA 1982, 97, 161 856b). (d) Scheibye, S.; Pedersen, B. S.; Lawesson, S. O. BSB 1978, 87, 229. (e) Pedersen, B. S.; Lawesson, S. O. BSB 1977, 86, 693. (f) Hirabayashi, T.; Inoue, K.; Yokota, K.; Ishii, Y. JOM 1975, 92, 139. (g) Perregaard, J.; Thomsen, I.; Lawesson, S. O. ACS(B) 1975, 29, 538. (h) Petermann, J.; Plieninger, H. T 1975, 31, 1209 (CA 1975, 83, 96 383q). (i) Scheeren, J. W.; Ooms, P. H. J.; Nivard, R. J. F. S 1973, 149. (j) Maier, L. AG(E) 1969, 8, 141. (k) Eilingsfeld, H.; Seefelder, M.; Weidinger, H. CB 1963, 96, 2671 (CA 1963, 59, 15 215d). (l) Walter, W.; Maerten, G. LA 1963, 669, 66 (CA 1964, 60, 5330e). (m) Witte, J.; Huisgen, R. CB 1958, 91, 1129. (n) de Benneville, P. I.; Strong, J. S.; Elkind, V. T. JOC 1956, 21, 772. (o) Westphal, K., Andersag, H. U.S. Patent 2 265 212, 1939 (CA 1942, 36, 1950). (p) Todd, A. R.; Bergel, F.; Karimullah, Keller, R. JCS 1937, 361. (q) Willstätter, R.; Wirth, T. CB 1909, 42, 1908 (CA 1909, 3, 2430).
4. (a) Creary, X.; Hatoum, H. N.; Barton, A.; Aldridge, T. E. JOC 1992, 57, 1887. (b) Ablenas, F. J.; George, B. E.; Maleki, M.; Jain, R.; Hopkinson, A. C.; Lee-Ruff, E. CJC 1987, 65, 1800. (c) Seebach, D.; Lubosch, W.; Enders, D. CB 1976, 109, 1309 (CA 1976, 85, 4640m). (d) Campaigne, E.; Skowronski, G.; Forsch, R. A.; Beckman, J. C. SC 1976, 6, 387. (e) Enders, D.; Seebach, D. AG(E) 1973, 12, 1014.
5. (a) Corsaro, A.; Perrini, G.; Testa, M. G.; Chiacchio, U. PS 1992, 71, 197. (b) Takido, T.; Tomizawa, N.; Tsukano, K.; Hayashi, T.; Itabashi, K. JHC 1992, 29, 841. (c) Reynolds, G. A.; Van Allan, J. A.; Seidel, A. K. JHC 1979, 16, 369. (d) Dingwall, J. G.; Ingram, A. S.; Reid, D. H.; Symon, J. D. JCS(P1) 1973, 2351. (e) Dingwall, J. G.; Reid, D. H.; Wade, K. JCS(C) 1969, 913.
6. (a) Kobayashi, Y.; Takido, T.; Itabashi, K. NKK 1986, 619. (b) Kobayashi, Y.; Itabashi, K. S 1985, 671. (c) Hibino, S.; Kubota, M.; Takido, T.; Itabashi, K. NKK 1985, 898. (d) Hosojima, S.; Takido, T.; Itabashi, K. Yuki Gosei Kagaku Kyokaishi 1984, 42, 170. (e) Hattori, K.; Takido, T.; Itabashi, K. NKK 1979, 101.
7. (a) Padwa, A.; Gareau, Y.; Harrison, B.; Rodriguez, A. JOC 1992, 57, 3540. (b) Padwa, A.; Harrison, B.; Murphree, S. S.; Yeske, P. E. JOC 1989, 54, 4232.
8. (a) Lie Ken Jie, M. S. F.; Zheng, Y. F. S 1988, 467. (b) Takido, T.; Kobayashi, Y.; Itabashi, K. S 1986, 779.
9. Nozaki, K.; Yoshihara, M.; Enomura, K.; Matsubara, Y.; Maeshima, T. PS 1985, 22, 131.
10. Ho, Tse-Lok; Wong, C. M. SC 1975, 5, 299.
11. Pettit, G.; Garson, L. R. CJC 1965, 43, 2640.
12. Mills, J. E. S 1986, 482.

Alexander G. Godfrey

Lilly Research Laboratories, Indianapolis, IN, USA

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