N-Methyl-N-phenyl(chloromethylene)ammonium Phosphorochloridate

[80984-92-5]  · C8H9Cl3NO2P  · N-Methyl-N-phenyl(chloromethylene)ammonium Phosphorochloridate  · (MW 288.50)

(formylation of activated aromatic systems1,2 and alkenes2)

Alternate Name: N-methylformanilide-phosphorus oxychloride complex.

Physical Data: see N-Methylformanilide (MFA) and Phosphorus Oxychloride.

Form Supplied in: prepared in situ.

Preparative Method: POCl3 is slowly added to a small excess of MFA.3 A solvent may be added,4 typically 1,2-dichloroethane or 1,2-dichlorobenzene; MFA may also be used as the solvent in the reaction.

Handling, Storage, and Precautions: phosphorus oxychloride is corrosive and lachrymatory. N-Methylformanilide is toxic and harmful by absorption. The iminium salt reacts vigorously with water. Use in a fume hood.

Formylation of Arenes.

Simple unactivated aromatic systems do not react with most Vilsmeier reagents (the adduct from N,N-Dimethylformamide-Trifluoroacetic Anhydride has been reported to formylate unactivated systems;5) electron-rich aromatic systems undergo monoformylation with MFA-POCl3 in moderate to good yields.1 Thus anthracene gives 9-anthracenecarbaldehyde (eq 1);6 pyrene gives 3-pyrenecarbaldehyde (53%);7 and azulene gives 1-azulenecarbaldehyde (eq 2).8 Recent reports suggest that the adduct of Pyrophosphoryl Chloride (P2O3Cl4) and MFA is a more effective formylating agent. For example, formylation of anisole with MFA-P2O3Cl4 gives p-methoxybenzaldehyde in 72% yield, compared to only 34% with MFA-POCl3.9

Heterocyclic systems have been formylated in moderate to good yields using MFA-POCl3, e.g. thiophene (eq 3)3,10 and indole (eq 4).4 It is notable that poor yields of 3-indolecarbaldehyde (highest yield 37%) are obtained in the absence of a solvent.4

Formylation of Alkenes.

Styrene and several of its derivatives have been converted into the corresponding a,b-unsaturated aldehydes (eq 5).11 A series of 1,1-diarylethylenes have been similarly converted into a,b-unsaturated aldehydes (eq 6).12

Reaction with Ketones.

9-Anthraquinone is converted into 10-chloro-9-anthracenecarbaldehyde (eq 7).13 However, few examples of the synthesis of b-chlorovinyl aldehydes14 using MFA-POCl3 have been reported.15

Cyclizations under Vilsmeier Conditions.

Numerous cyclizations have been reported when DMF-POCl3 is used as the reagent, but few have been reported using MFA-POCl3.16 Hippuric acid is converted into a substituted isoxazole by the action of MFA-POCl3 (eq 8).17 An allylbenzene has been reported to give a dihydronaphthaldehyde (eq 9).18

Although the use of MFA-POCl3 in Vilsmeier reactions has been largely replaced by adducts formed from DMF-POCl3 (see Dimethylchloromethyleneammonium Chloride), MFA-POCl3 often gives aldehydes in higher yield and at lower temperatures than required for reactions with DMF-POCl3.1a,19 MFA-POCl3 is considered to be more reactive,19 but extensive decomposition occurs at high reaction temperatures. The cost and low molecular weight favors the use of DMF-POCl3.1a,19

1. (a) Minkin, V. I.; Dorofeenko, G. N. RCR 1960, 29, 599. (b) de Maheas, M. BSF 1962, 1989.
2. Jutz, C. Adv. Org. Chem. 1976, 9, 225.
3. Weston, A. R.; Michael, R. J. OSC 1963, 4, 915.
4. Shabica, A. C.; Howe, E. E.; Ziegler, J. B.; Tishler, M. JACS 1946, 68, 1156.
5. 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.
6. (a) Fieser, L. F.; Hartwell, J. L. JACS 1938, 60, 2555. (b) Fieser, L. F.; Hartwell, J. L.; Jones, J. E. OSC 1955, 3, 98.
7. Vollman, H.; Becker, H.; Correl, M.; Streeck, H. LA 1937, 531, 1.
8. Triebs, W.; Neupert, H.-J.; Hiebsch, J. CB 1959, 92, 141.
9. (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.
10. King, W. J.; Nord, F. F. JOC 1948, 13, 635.
11. Wizinger, R.; Coenen, M. L.; Bellfontaine, A. Ger. Patent 864 404, 1953 (CA 1958, 52, 18 322). (b) Wizinger, R.; Kölliker, P. HCA 1955, 38, 372.
12. Lorenz, R.; Wizinger, R. HCA 1945, 28, 600.
13. Kalischer, G; Scheyer, A.; Keller, K. Ger. Patent 514 415, 1927 (CA 1931, 25, 1536).
14. Pulst, M.; Weissenfels, M. ZC 1976, 16, 337.
15. Drewry, D. T.; Scrowston, R. M. JCS(C) 1969, 2750.
16. For a review see: Meth-Cohn, O; Tarnowski, B. Adv. Heterocycl. Chem. 1982, 31, 207.
17. Cornforth, J. W. Heterocycl. Compd. 1957, 5, 346.
18. Narasimhan, N. S.; Mukhopadhyay, T. TL 1979, 1341.
19. Campaigne, E.; Archer, W. L. JACS 1953, 75, 989.

Paul R. Giles & Charles M. Marson

University of Sheffield, UK

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