Dimethylchloromethyleneammonium Chloride

(1; X = Cl)

[3724-43-4]  · C3H7Cl2N  · Dimethylchloromethyleneammonium Chloride  · (MW 128.01) (2; X = PO2Cl2)

[21382-90-1]  · C3H7Cl3NO2P  · Dimethylchloromethyleneammonium Dichlorophosphate  · (MW 226.43)

(formylation of arenes,1-3 heterocycles,1-3 and alkenes;2,3 conversion of alcohols into chlorides,4 and carboxylic acids into acid chlorides;5 preparation of b-chlorovinyl aldehydes,3,6 cyclic b-chloro-a,b-unsaturated ketones,7 and the conversion of acyclic precursors into ring systems8)

Alternate Names: Vilsmeier reagent; Arnold's reagent.

Physical Data: (1) mp 132 °C (dec).

Solubility: fairly sol polar solvents.

Form Supplied in: the chloride (1) is a white hygroscopic powder and is commercially available. The dichlorophosphate (2) is made in situ.

Preparative Methods: Thionyl Chloride,4b Oxalyl Chloride,5 or Phosgene is added slowly to N,N-Dimethylformamide, with cooling, to give the chloride (1) (eq 1). A solvent (typically dichloromethane,5 chloroform, or 1,1,2-trichloroethylene)9 may be used, and is advisable for large scale preparations.

The most commonly used Vilsmeier reagent is that formed by adding Phosphorus Oxychloride to DMF, to give dimethylchloromethyleneammonium dichlorophosphate (2).9 Reagent (2) is more reactive than reagent (1). Recent reports suggest that DMF-Pyrophosphoryl Chloride (P2O3Cl4) gives an even more reactive iminium intermediate (eq 2) than either salt (1) or salt (2).10

Handling, Storage, and Precautions: the chloride (1) is hygroscopic. DMF is an irritant and is harmful by skin absorption. The halogenating agents (thionyl chloride, phosgene, phosphorus oxychloride, etc.) are all corrosive and lachrymatory. Use in a fume hood.

Conversion of Alcohols into Chlorides.

Reagent (1) has been used to convert alcohols into chlorides in moderate to high yields.4 An alternative Vilsmeier reagent derived from N,N-diphenylbenzamide-oxalyl chloride has been used for the same transformation. Sensitive groups, such as acetals, are not affected by the reaction conditions (eq 3) and the yields are high.11

Conversion of Carboxylic Acids to Acid Chlorides.

Reagent (1) has been used to convert a wide variety of carboxylic acids into acid chlorides.5 A catalytic quantity of DMF may be used; thus isobutyric acid is converted into isobutyroyl chloride (89%) upon treatment with DMF (3 mol %) and phosgene.5c

Formylation of Arenes and Heterocyclic Systems.

Reagent (2) is the most commonly used Vilsmeier reagent for formylation of arenes and heterocycles. The subject has been extensively reviewed.1-3 The formylation process is general for all activated aromatic systems (e.g. pyrene, anthracene, azulene, ferrocene, and N,N-dimethylaniline)12a and electron-rich heterocyclic systems (e.g. thiophenes, indoles,12b furans, and pyrroles (eq 4)).12c Formylations continue to be regularly reported in the literature.13 However, simple aromatic hydrocarbons such as benzene and toluene do not react with Vilsmeier reagents, although the adduct formed from DMF-Trifluoroacetic Anhydride has been used to formylate some unactivated aromatic hydrocarbons, e.g. naphthalene (50%) and 1,3,5-trimethylbenzene (60%).14 DMF-P2O3Cl4 has been reported to be a good formylating agent.10 The time and temperature of the reaction, and the stoichiometry of the reagent, can be crucial to the outcome of the reaction.

Formylation of Alkenes.

Activated alkenes, e.g. styrene, undergo formylation by DMF-POCl3, usually giving a,b-unsaturated aldehydes in high yields.3,15 1-Aryl-1,3-butadienes are similarly formylated.16 Simple alkenes can give complex products as a result of a series of reactions. Thus isobutene affords a trimethinium salt after repeated iminoalkylation (eq 5).17 However, by using N-formylmorpholine (NFM)-POCl3, alkenes have been successfully monoformylated (eqs 6 and 7).18

Depending upon the reaction conditions and the structure of the alkene, isomerization of the carbon-carbon double bond may occur prior to formylation (eq 8).19

Silyl enol ethers react with DMF-POCl3 to give a-formyl carboxylic esters.20

Reaction of Carbonyl Compounds with DMF-POCl3.

This subject has been extensively reviewed.21 Methyl and methylene ketones are the most studied classes of compound; they afford b-chlorovinyl aldehydes (b-CVAs) when allowed to react with DMF-POCl3 (eq 9). Acyclic, cyclic, heterocyclic, and benzo-fused ketones all give b-CVAs, which have proved to be useful intermediates in organic synthesis.3 The chlorine atom is readily displaced by nucleophiles and the aldehyde can then be transformed by means of condensations, reaction with Grignard reagents, or Wittig reagents. Condensations involving the aldehyde group, followed by base-catalyzed cyclization, allows the formation of a wide variety of heterocycles, e.g. thiophenes, isoxazoles (eq 10), pyrimidines (eq 10), and pyrazoles.3,22 More than 50 different ring systems have been synthesized using Vilsmeier methodology.22

b-CVAs can be hydrogenated to give saturated aldehydes, allowing the introduction of an aldehyde b with respect to the original ketone function (eq 11).23

b-CVAs have been used as dienophiles in Diels-Alder reactions.24 Treatment of b-CVAs with strong aqueous base affords alkynes.25 The chlorine atom can be removed using Zinc in ethanol,26a or hydrogen over Palladium on Carbon in the presence of Triethylamine,26b giving a,b-unsaturated aldehydes.

Reaction of 1,3-Diketones.

Salt (1) reacts with cyclic 1,3-diketones, giving b-chloro-a,b-unsaturated ketones.7 Cyclic 1,3-diketones can give bis-b-CVAs upon treatment with reagent (2).27 2,4-Pentanedione gave 2,4-dichlorobenzaldehyde on reaction with DMF-POCl3 (eq 12),28 and 2,4-dichloro-1,3-benzene dicarbaldehyde on reaction with the adduct from NFM-POCl3 (eq 13).27b

Epoxidation of Alkenes.

When reagent (1) is treated with Hydrogen Peroxide the reagent (3) is formed, which is capable of epoxidizing alkenes.29 However, the selectivity of reagent (3) is poor, and chlorinated products are also obtained. The yields and selectivity are improved by reacting alkenes with the intermediate (4), obtained from N-methylpyrrolidine-POCl3 and H2O2.30 Little chlorination of the alkene was noted and no Baeyer-Villiger products were identified from ketone-containing substrates. Acetals are not cleaved under the reaction conditions. Epoxidation occurs at the most substituted carbon-carbon double bond (eq 14).30

Cyclizations under Vilsmeier Conditions.

A large number of substrates undergo cyclization in the presence of DMF-POCl3 and other Vilsmeier reagents.8 The outcome of the reaction often depends upon the reaction time and temperature, and the nature of the Vilsmeier species. For example, benzylacetamides give quinolines and related systems; the nature of the product depends upon the conditions used (eq 15).31

2-Hydroxyacetophenones give 3-formylchromones.32 Aryl benzyl ketones have been converted into 2-aryl-1,3-dichloroindenes.33 Alkylidenemalononitriles give 2-chloro-3-cyanopyridines.34 Unsaturated alcohols may undergo dehydration prior to formylation and cyclization (eq 16).35

Related Reagents.

Dimethylbromomethyleneammonium Bromide; N,N-Dimethylformamide; Formyl Chloride; N-Methyl-N-phenyl(chloromethylene)ammonium Phosphorochloridate.

1. Minkin, V. I.; Dorofeenko, G. N. RCR 1960, 29, 599.
2. de Maheas, M. BSF 1962, 1989.
3. Jutz, C. Adv. Org. Chem., 1976, 9, 225.
4. (a) Hepburn, D. R.; Hudson, H. R. JCS(P1) 1976, 754. (b) Dods, R. K.; Roth, J. S. TL 1969, 165; JOC 1969, 34, 1627. (c) Yoshihara, M; Eda, T.; Sakaki, K.; Maeshima, T. S 1980, 746.
5. (a) Fujisawa, T.; Sato, T. OS 1988, 66, 121. (b) Bossard, H. H.; Zollinger, H. AG 1959, 71, 375. (c) Eilingsfeld, H.; Seefelder, M.; Weidinger, H. AG 1960, 72, 836.
6. Pulst, M.; Weissenfels, M. ZC 1976, 16, 337.
7. Mewshaw, R. E. TL 1989, 30, 3753.
8. Meth-Cohn, O.; Tarnowski, B. Adv. Heterocycl. Chem. 1982, 31, 207.
9. Paquette, L. A.; Johnson, B. A.; Hinga, F. M. OSC 1973, 5, 215.
10. (a) Cheung, G. K.; Downie, I. M.; Earle, M. J., Heaney, H., Matough, M. F. S; Shuhaibar, K. F.; Thomas, D. SL 1992, 77. (b) Downie, I. M.; Earle, M. J., Heaney, H.; Shuhaibar, K. F. T 1993, 49, 4015.
11. Fujisawa, T.; Sato, T.; Iida, S. CL 1984, 1173.
12. (a) Campaigne, E.; Archer, W. L. OSC 1963, 4, 331. (b) James, P. N.; Synder, H. R.; OSC 1963, 4, 539. (c) Silverstein, R. M.; Ryskiewicz, E. E.; Willard, C. OSC 1963, 4, 831.
13. (a) Yokoyama, Y.; Okuyama, N.; Iwadate, S.; Momoi, T.; Murakami, Y.; JCS(P1) 1990, 1319. (b) Black, D. St. C.; Kumar, N.; Wong, L. C. H. S 1986, 474.
14. Martinez, A. G.; Alvarez, R. M.; Barcina, J. O.; de la Moya Cerero, S.; Vilar, E. T.; Fraile, A. G.; Hanack, M.; Subramanian, L. R. CC 1990, 1571.
15. Schmidle, C. J.; Barnett, P. G. JACS 1956, 78, 3209.
16. Jutz, C.; Heinicke, R. CB 1969, 102, 623.
17. Jutz, C.; Müller, W.; Müller, E. CB 1966, 99, 2479.
18. Katritzky, A. R.; Shcherbakova, I. V.; Tack, R. D.; Steel, P. J. CJC 1992, 70, 2040.
19. Grimwade, M. J.; Lester, M. G. T 1969, 25, 4535.
20. Reddy, C. P.; Tanimoto, S. S 1987, 575.
21. Marson, C. M. T 1992, 48, 3659.
22. Marson, C. M.; Giles, P. R. Synthesis using Vilsmeier Reagents; CRC: New York, 1994.
23. Virgilio, J. A.; Heilweil, E. OPP 1982, 14, 9.
24. Willard, P. G.; de Laszlo, S. E. JOC 1985, 50, 3738.
25. (a) Bodendorf, K; Mayer, R. CB 1965, 98, 3554. (b) Alexander, C; Feast, W. J. S 1992, 735.
26. (a) Hara, A.; Sekiya, M. CPB 1972, 20, 309. (b) Traas, P. C.; Takken, H. J.; Boelens, H. TL 1977, 2027.
27. (a) Katritzky, A. R.; Marson, C. M. TL 1985, 4715. (b) Katritzky, A. R.; Marson, C. M. JOC 1987, 52, 2726.
28. Holy, A.; Arnold, Z. CCC 1965, 30, 53.
29. Dulcere, J.-P.; Rodriguez, J. TL 1982, 1887.
30. Rodriguez, J.; Dulcere, J.-P. JOC 1991, 56, 469.
31. (a) Ahlbrecht, H.; Vonderheid, C. CB 1975, 108, 2300. (b) Chupp, J. P.; Metz, S. JHC 1979, 16, 65. (c) Hayes, R.; Meth-Cohn, O.; Tarnowski, B. JCR(S) 1980, 414. (d) Korodi, F.; Cziaky, Z. OPP 1990, 22, 579.
32. (a) Harnish, H. LA 1972, 765, 8. (b) Nohora, A; Umetani, T.; Sanno, Y. TL 1973, 1995. (c) Nohora, A; Umetani, T.; Sanno, Y. T 1974, 30, 3553.
33. Elliot, I. W.; Evans, S. L.; Kennedy, L. T.; Parrish, A. E. OPP 1989, 21, 368.
34. Sreenivasulu, M.; Rao, G. S. K. IJC(B) 1989, 28, 584.
35. (a) Rao, M. S. C.; Rao, G. S. K. IJC(B) 1988, 27, 660. (b) Rao, M. S. C.; Rao, G. S. K. IJC(B) 1988, 27, 213.

Paul R. Giles & Charles M. Marson

University of Sheffield, UK

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