(X = Cl)

[26189-59-3]  · C6H12ClN  · 1-Chloro-N,N,2-trimethylpropenylamine  · (MW 133.62) (X = F)

[65560-29-4]  · C6H12FN  · 1-Fluoro-N,N,2-trimethylpropenylamine  · (MW 117.17) (X = Br)

[73630-93-0]  · C6H12BrN  · 1-Bromo-N,N,2-trimethylpropenylamine  · (MW 178.07) (X = I)

[65560-41-0]  · C6H12IN  · 1-Iodo-N,N,2-trimethylpropenylamine  · (MW 225.07)

(mild halogenation of alcohols and acids under neutral conditions;2 conversion of N-protected amino acids into peptides without racemization;3 coupling of acids and allylic alcohols with organometallics;9 [2 + 2] cycloaddition synthons, more reactive than dimethylketene1b,4,5)

Alternate Name: tetramethyl-a-chloroenamine; TMCE

Physical Data: X = Cl: bp 129-130 °C (760 mmHg), d 1.01 g cm-3; X = F: bp 89-92 °C (760 mmHg); X = Br: bp 42-45 °C (15 mmHg); X = I: bp 61-63 °C (9 mmHg), d 1.55 g cm-3.

Solubility: very sol most organic solvents; reacts instantaneously with H2O, alcohols, and protic solvents.

Preparative Methods: 1-chloro-N,N,2-trimethylpropenylamine is conveniently prepared by the reaction of N,N,2-trimethylpropanamide with Phosgene followed by dehydrochlorination of the intermediate a-chloroiminium chloride (eq 1).1a,6 Recent unpublished results of our laboratory have shown that Phosphorus Oxychloride or di- or triphosgene can also be used for the preparation of TMCE.

The corresponding 1-fluoro-, 1-bromo- and 1-iodo-N,N,2-trimethylpropenylamines (tetramethyl-a-fluoro-, -bromo-, and -iodoenamines; TMFE, TMBE, and TMIE) are readily prepared from TMCE by halogen exchange (eq 2).1a,7

Analysis of Reagent Purity: IR, 1H NMR, elemental analysis.6

Handling, Storage, and Precautions: 1-chloro-, 1-fluoro-, and 1-bromo-N,N,2-propenylamines are thermally stable. They must be transferred in the absence of moisture and stored under nitrogen in sealed tubes. In spite of these precautions, light precipitates sometimes may form. 1-Iodo-N,N,2-trimethylpropenylamine is less stable and should be used when freshly prepared.

Halogenation Reactions.

1-Chloro-, 1-bromo- and 1-iodo-N,N,2-trimethylpropenylamines are mild reagents which transform alcohols into the corresponding halides (eqs 3-6).2b The reaction proceeds under neutral conditions, thus allowing the presence of acid-sensitive functional groups. The reaction occurs with inversion of configuration (eq 4). Secondary allylic and propargylic alcohols give some rearranged halides (eqs 5 and 6), but their formation seems to occur after the halogenation step.

The halogenation reaction has been applied to the modification of various furanose and pyranose hemiacetals (eqs 7 and 8).8

The reaction of 1-fluoro-N,N,2-trimethylpropenylamine with alcohols usually gives a mixture of products.2b In some cases a bulkier derivative has been successfully used to transform alcohols into fluorides (eqs 9 and 10).2b,8

All the 1-halo-N,N,2-trimethylpropenylamines rapidly convert acids into acid halides (eqs 11 and 12).2a Since the only byproduct is the relatively inert N,N,2-trimethylpropanamide, the isolation of the acid halide will often be unnecessary. This method has been applied in peptide synthesis; no racemization was observed (eq 13).3

Coupling Reactions.

1-Chloro-N,N,2-trimethylpropenylamine is an excellent reagent for the coupling of carboxylic acids (eq 14) or allylic alcohols (eq 15) with organometallic compounds.9

[2 + 2] Cycloadditions.

TMCE is a source of tetramethylketeniminium chloride.1a This highly electrophilic intermediate can be trapped by Schiff bases to generate azetidiniminium salts which readily hydrolyze to b-lactams (eq 16).1b,5a This has been developed into a general method to produce b-lactams from tertiary amides (eqs 17 and 18).5c,5d

With the less nucleophilic carbon-carbon multiple bonds, cycloaddition will only occur in the presence of a Lewis acid which displaces the equilibrium toward the cumulene form (eq 19).1a,4 AgBF4, ZnCl2, AlCl3, and SnCl4 have been successfully used, but the combination of TMCE with Zinc Chloride is the most convenient in many cases.4b Thus tetramethylketeniminium salts, which are most often generated in situ, behave as highly reactive equivalents of dimethylketene for the preparation of cyclobutanones and cyclobutenones. Indeed, the cyclobutane- and cyclobuteneiminium salts intermediates are readily hydrolyzed (eqs 20-23).

The reaction has been extended to other 2-substituted 1-chloro-N,N-dialkylvinylamines.10 An asymmetric version of the cycloaddition has been described (eq 24).11

Miscellaneous Reactions.

Reaction of 1-chloro-N,N,2-trialkylpropenylamines with azide ion gives 2-amino-1-azirines; these three-membered ring amidines are useful intermediates for the synthesis of pyridines.12 1-Chloro-N,N,2-trialkylpropenylamines react readily with electron-rich aromatics in electrophilic substitutions, without the need of an acid catalyst.13 The corresponding a-metalated vinylamines give nucleophilic aminoalkenylation reactions.14 TMCE reacts with potassium cyanide to yield 1-cyano-N,N,2-trimethylpropenylamine, a synthetic intermediate for the preparation of a-diketones.15 TMCE is smoothly converted to N,N-dimethylmethacrylamide in the presence of Pyridine N-Oxide and Triethylamine; this reaction has been applied successfully to the preparation of various a,b-unsaturated amides.16 1-Phosphonato enamines have been obtained by treatment of TMCE with trialkyl phosphites.17 The reaction of metal carbonyl anions with TMCE has been described; this leads to the formation of new transition metal organometallic compounds with novel structural features.18

1. (a) Ghosez, L.; Marchand-Brynaert, J. In Advances in Organic Chemistry; Raphael, R. A.; Taylor, E. C.; Wynberg, H., Eds.; Interscience: New York, 1976; Part 1, pp 421-523. (b) Ghosez, L.; O'Donnell, M. J. Pericyclic Reactions; Marchand, A. P.; Lehr, R. C., Eds.; Academic: New York, 1977; Vol. 2, Chapter 2. (c) Ghosez, L. Medicinal Chemistry V; Elsevier: Amsterdam, 1977; pp 363-385. (d) Ghosez, L. Organic Synthesis Today and Tomorrow; Trost, B. M.; Hutchinson, C. R., Eds.; Pergamon: Oxford, 1981; pp 145-162. (e) Ghosez, L. New Synthetic Methodology and Functionally Interesting Compounds; Yoshida, Z., Ed.; Kodansha: Tokyo, 1986; pp 99-117.
2. (a) Devos, A.; Rémion, J.; Frisque-Hesbain, A.-M.; Colens, A.; Ghosez, L. CC 1979, 1180. (b) Munyemana, F.; Frisque-Hesbain, A.-M.; Devos, A.; Ghosez, L. TL 1989, 30, 3077. (c) Schmidt, U.; Werner, J. CC 1986, 996.
3. (a) Schmidt, U.; Lieberknecht, A.; Griesser, H.; Utz, R.; Beuttler, T.; Bartkowiak, F. S 1986, 361. (b) Schmidt, U.; Kroner, M.; Beutler, U. S 1988, 475.
4. (a) Marchand-Brynaert, J.; Ghosez, L. JACS 1972, 94, 2870. (b) Sidani, A.; Marchand-Brynaert, J.; Ghosez, L. AG(E) 1974, 13, 267. (c) Hoornaert, C.; Hesbain-Frisque, A.-M.; Ghosez, L. AG(E) 1975, 14, 569. (d) Heine, H.-G.; Hartmann, W. AG 1981, 93, 805. (e) Heine, H.-G.; Hartmann, W. S 1981, 706.
5. (a) De Poortere, M.; Marchand-Brynaert, J.; Ghosez, L. AG(E) 1974, 13, 267. (b) Marchand-Brynaert, J.; Moya-Portuguez, M.; Lesuisse, D.; Ghosez, L. CC 1980, 173. (c) Ghosez, L.; Bogdan, S.; Cérésiat, M.; Frydrych, C.; Marchand-Brynaert, J.; Moya-Portuguez, M.; Huber, I. PAC 1987, 59, 393. (d) Marchand-Brynaert, J.; Moya-Portuguez, M.; Huber, I.; Ghosez, L. CC 1983, 818.
6. (a) Haveaux, B.; Dekoker, A.; Rens, M.; Sidani, A. R.; Toye, J.; Ghosez, L. OS 1979, 59, 26. (b) Ghosez, L.; Koch, I. Swiss Pat. 681 623A, 1993.
7. (a) Colens, A.; Demuylder, M.; Téchy, B.; Ghosez, L. NJC 1977, 1, 369. (b) Colens, A.; Ghosez, L. NJC 1977, 1, 371.
8. (a) Ernst, B.; Winkler, T. TL 1989, 30, 3773. (b) Ernst, B.; De Mesmaeker, A.; Hoffmann, P.; Ernst, B. TL 1989, 30, 3773. (c) Ernst, B.; De Mesmaeker, A.; Wagner, B.; Winkler, T. TL 1990, 31, 6167. (d) Ernst, B. Eur. Pat. Appl. 373 118A2, 1990.
9. (a) Fujisawa, T.; Mori, T.; Higuchi, K.; Sato, T. CL 1983, 1791. (b) Fujisawa, T.; Iida, S.; Yukizaki, H.; Sato, T. TL 1983, 24, 5745. (c) Fujisawa, T.; Umezu, K.; Sato, T. CL 1985, 1453. (d) Fujisawa, T.; Sato, T. OS 1988, 66, 116.
10. (a) Falmagne, J.-B.; Escudero, J.; Taleb-Sahraoui, S.; Ghosez, L. AG(E) 1981, 20, 879. (b) Schmit, C.; Sahraoui-Taleb, S.; Differding, E.; Dehasse-De Lombaert, C.-G.; Ghosez, L. TL 1984, 25, 5043. (c) Génicot, C.; Gobeaux, B.; Ghosez, L. TL 1991, 31, 3827.
11. (a) Houge, C.; Frisque-Hesbain, A.-M.; Mockel, A.; Ghosez, L.; Declercq, J. P.; Germain, G.; Van Meerssche, M. JACS 1982, 104, 2920. (b) Saimoto, H.; Houge, C.; Hesbain-Frisque, A.-M.; Mockel, A.; Ghosez, L. TL 1983, 24, 2251. (c) Génicot, C.; Ghosez, L. TL 1992, 33, 7357. (d) Ghosez, L.; Génicot, C.; Gouverneur, V. PAC 1992, 64, 1849.
12. (a) Rens, M.; Ghosez, L. TL 1970, 3765. (b) Vittorelli, P.; Heimgartner, H.; Schmid, H.; Hoet, P.; Ghosez, L. T 1974, 30, 3737. (c) Demoulin, A.; Gorissen, H.; Hesbain-Frisque, A.-M.; Ghosez, L. JACS, 1975, 97, 4409.
13. Marchand-Brynaert, J.; Ghosez, L. JACS 1972, 94, 2869.
14. Wiaux-Zamar, C.; Dejonghe, J.-P.; Ghosez, L.; Normant, J.-F.; Villieras, J. AG(E) 1976, 15, 371.
15. Toye, J.; Ghosez, L. JACS 1975, 97, 2276.
16. Da Costa, R.; Gillard, M.; Falmagne, J.-B.; Ghosez, L. JACS 1979, 101, 4381.
17. Ahlbrecht, H.; Farnung, W. S 1977, 336.
18. (a) King, R. B.; Hodges, K. C. JACS 1974, 96, 1263. (b) King, R. B.; Hodges, K. C. JACS 1975, 97, 2702.

Léon Ghosez & Jacqueline Marchand-Brynaert

Université Catholique de Louvain, Louvain-la-Neuve, Belgium

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