[75-44-5]  · CCl2O  · Phosgene  · (MW 98.91)

(chlorinating agent;2 carbonylating agent; dehydrating agent;1 with DMF forms a chloromethyleniminium salt, used in formylation reactions3)

Alternate Name: carbonyl chloride.

Physical Data: mp -118 °C; bp 8.3 °C; d 1.381 g cm-3.

Solubility: slightly sol H2O (dec); sol toluene, chloroform.

Form Supplied in: liquefied gas in cylinders; solution in toluene.

Purification: chlorine is an impurity which can be detected by bubbling through mercury (gives discoloration) and removed by bubbling through two wash bottles containing cottonseed oil.

Handling, Storage, and Precautions: highly toxic gas; avoid contact or inhalation; there may be a delay of several hours before symptoms of exposure develop (pulmonary edema); keep container tightly closed and well-ventilated; excess phosgene should be vented into a water-fed scrubbing tower. Use in a fume hood.

Reactions with Carboxylic Acids, Alcohols, and Amines.

Phosgene reacts with carboxylic acids to give anhydrides, with liberation of carbon dioxide.4 This has been used to activate acids to attack from nucleophiles, e.g. in esterification,5 lactonization,6 and thiolation.7 For example, acids can be protected as 3-butenyl esters using phosgene and Pyridine,5 followed by addition of 3-buten-1-ol (eq 1).

The ester is removed under mild conditions by ozonolysis and b-elimination of the resulting aldehyde. In contrast, reaction with acids in the presence of a variety of catalysts (including Imidazole, 1,8-Diazabicyclo[5.4.0]undec-7-ene, and 1,3-Dicyclohexylcarbodiimide) cleanly affords the corresponding acid chloride.2 N,N-Dimethylformamide has also been used as a catalyst (eq 2).8

Phosgene reacts with alcohols to give chloroformates,9,1b and with secondary amines to give chloroformamides10 (it reacts preferentially with the latter).11 The formation of a chloroformate is the first step in the Barton oxidation of primary alcohols to aldehydes,12 which is followed by complex formation with Dimethyl Sulfoxide and elimination by base (eq 3),12b a mechanism closely related to that of the Swern and Moffatt oxidations.13

There are many examples of further displacement of the chloroformate in an intramolecular or intermolecular sense by suitably disposed second nucleophiles (e.g. hydroxy, amino, thio, or acid groups), resulting in carbonates (eq 4),14 ureas (eq 5),15 carbamates,11,16 dithiocarbonates (eq 6),17 etc.

The reaction of phosgene with primary amines initially forms chloroformamides which on heating above 50 °C eliminate HCl to give isocyanates. This useful reaction constitutes a general method for isocyanate synthesis (eq 7).18

With tertiary amines, phosgene-amine complexes can be formed.1a Warming results in decomposition to an N,N-dialkylchloroformamide by elimination of alkyl chloride.19 This has been utilized for the mild and high yielding deprotection of N-methyl amines (eq 8).20 a-Chloroethyl chloroformate, prepared from phosgene and Acetaldehyde, has also been used for this purpose.21

Reactions with Amides and Thioamides.

The action of phosgene on amides (and thioamides) initially gives dehydration to a chloromethyleneiminium chloride (eq 9). Primary amides react further, losing HCl to form nitriles in the presence of a base such as pyridine22 (this can also be accomplished by the Vilsmeier-Haack reagent generated using phosgene - see below). Secondary formamides are converted to isocyanides in the presence of Triethylamine or pyridine (eq 10).23 N-Formyl enamines also form isocyanides (eq 11);24 1,4-Diazabicyclo[2.2.2]octane is claimed to be a more efficient base due to the avoidance of azeotrope formation with the low boiling vinyl isocyanide products. Other secondary amides lose HCl to give imidoyl chlorides, which can undergo further reaction, e.g. to form pyrroles (eq 12)25 and oxazolones (eq 13).26

Secondary thioureas can be dehydrated to carbodiimides (eq 14).27

Tertiary amides give stable chloromethyleneiminium chlorides. A particularly important example is the complex formed between phosgene and DMF (known as the Vilsmeier-Haack reagent), which is a versatile formylating agent.3 An identical or equivalent species can be generated with Oxalyl Chloride, Thionyl Chloride, or Phosphorus Oxychloride, and these are perhaps preferred in view of phosgene's toxicity. However, the Vilsmeier reagent generated from phosgene is claimed to be a more efficient reagent for the dehydration of primary amides to nitriles.28

Tertiary amides (and thioamides)29 with an a-proton react instead to give chloro enamines.30 These can undergo nucleophilic substitution (eq 15).30,31 Chloro enamines are also intermediates in synthetically useful dehydrogenation reactions, using Pyridine N-Oxide or DMSO as oxidant (eq 16).32 Tertiary ureas and thioureas form related adducts which have been utilized in the synthesis of hindered guanidine bases by further reaction with amines (eq 17).33

Phosgene Equivalents.

In recent years, Bis(trichloromethyl) Carbonate (triphosgene) has been introduced as a crystalline phosgene source;34 similarly, Trichloromethyl Chloroformate (diphosgene) has been used as a liquid equivalent35 (bp 128 °C, d15 1.65 g mL-1). They have the advantages of much easier manipulation (particularly for small-scale work), safer transport and storage, and they are less susceptible to hydrolysis. Triphosgene has so far been shown to perform several reactions undergone by phosgene itself, e.g. carbonylation36 and Barton oxidation.37 Diphosgene generates phosgene slowly at elevated temperatures, or rapidly in the presence of a charcoal catalyst;38 it is also effective in several of the reactions of phosgene, including N-carboxyanhydride formation38 and the conversion of amino alcohols to oxazolidinones,39 where it has been recommended for large-scale use.

Related Reagents.

Dimethyl Sulfoxide-Phosgene.

1. (a) Babad, H.; Zeiler, A. G. CRV 1973, 73, 75. (b) Fieser, L. F.; Fieser, M. FF 1967, 1, 856; 1969, 2, 328; 1972, 3, 225; 1974, 4, 157; 1975, 5, 532; 1979, 7, 289; 1990, 15, 265.
2. Hauser, C. F.; Theiling, L. F. JOC 1974, 39, 1134.
3. Marson, C. M. T 1992, 48, 3659.
4. Rinderknecht, H.; Guterstein, M. OSC 1973, 5, 822.
5. Barrett, A. G. M.; Lebold, S. A.; Zhang, X. TL 1989, 30, 7317.
6. Wehrmeister, H. L.; Robertson, D. E. JOC 1968, 33, 4173.
7. Bates, G. S.; Diakur, J; Masumune, S. TL 1976, 4423.
8. Ulrich, H.; Richter, R. JOC 1973, 38, 2557.
9. (a) Matzner, M.; Kurkjy, R. P.; Cottner, R. J. CRV 1964, 64, 645. (b) Kevill, D. N. In The Chemistry of Acyl Halides; Patai, S, Ed.; Wiley: New York, 1972; p 381. (c) Samsel, E. G.; Norton, J. R. JACS 1984, 106, 5505.
10. (a) Marley, H.; Wright, S. H. B.; Preston, P. N. JCS(P1) 1989, 1727. (b) Goerdeler, J.; Bartsch, H-J. CB 1985, 118, 2294.
11. Hall, H. K., Jr; El-Shekeil, A. JOC 1980, 45, 5325.
12. (a) Barton, D. H. R.; Garner, B. J.; Wightman, R. H. JCS(P1) 1964, 1855. (b) Epstein, W. W.; Sweat, F. W. CR 1967, 67, 247. (c) Finch, N.; Fitt, J. J.; Hsu, I. H. S. JOC 1975, 40, 206.
13. Mancuso, A. J.; Swern, D. S 1981, 165.
14. (a) Ona, H.; Uyeo, S. TL 1984, 25, 2237. (b) Krespan, C. G.; Smart, B. E. JOC 1986, 51, 320. (c) Das, J.; Vu, T.; Harris, D. N.; Ogletree, M. L. JMC 1988, 31, 930. (d) Nishiyama, T.; Yamaguchi, H.; Yamada, F. JHC 1990, 27, 143.
15. (a) Confalone, P. N.; Lollar, E. D.; Pizzolato, G. JACS 1978, 100, 6291. (b) Henning, R.; Lattrell, R.; Garhards, H. J.; Leven, M. JMC 1987, 30, 814. (c) Cram, D. J.; Dicker, I. B.; Lauer, M.; Knobler, C. B.; Trueblood, K. N. JACS 1984, 106, 7150.
16. (a) Gelb. M. H.; Abeles, R. H. JMC 1986, 5, 585. (b) Uff, B. C.; Joshi, B. L.; Popp, F. D. JSC(P1) 1986, 2295.
17. Rasheed, K.; Warkentin, J. D. JHC 1981, 18, 1581.
18. (a) Richter, R.; Ulrich, H. In The Chemistry of Cyanates and their Derivatives; Patai, S., Ed.; Wiley: New York, 1977; Part 2, p 619. (b) Butler, D. E.; Alexander, S. M. JHC 1982, 19, 1173. (c) Weisenfeld, R. B. JOC 1986, 51, 2434.
19. Cooley, J. H.; Evain, E. J. S 1989, 1.
20. Banholzer, R.; Heusner, A.; Schulz, W. LA 1975, 2227.
21. (a) Olofson, R. A.; Martz, J. T.; Senet, J-P.; Piteau, M.; Malfroot, T. JOC 1984, 49, 2081. (b) Olofson, R. A.; Abbott, D. E. JOC 1984, 49, 2795.
22. Ficken, G. E.; France, H.; Linstead, R. P. JCS 1954, 3731.
23. Bentley, P. H.; Clayton, J. P.; Boles, M. O.; Girven, R. J. JCS(P1) 1979, 2455.
24. Barton, D. H. R.; Bowles, T.; Husinec, S.; Forbes, J. E.; Llobera, A.; Porter, A. E. A.; Zard, S. Z. TL 1988, 29, 3343.
25. Engel, N.; Steglich, W. AG(E) 1978, 17, 676.
26. Miyoshi, M. BCJ 1973, 46, 212.
27. Groziak, M. P.; Townsend, L. B. JOC 1986, 51, 1277.
28. Bargar, T.; Riley, C. M. SC 1980, 10, 479.
29. Dietliker, K.; Heimgartner, H. HCA 1983, 66, 262.
30. (a) Henriet, M.; Houtekie, M.; Techy, B.; Touillaux, R.; Ghosez, L. TL 1980, 21, 223. (b) Bernard, C.; Ghosez, L. CC 1980, 940.
31. Toye, J.; Ghosez, L. JACS 1975, 97, 2276.
32. Da Costa, R.; Gillard, M.; Falmagne, J. B.; Ghosez, L. JACS 1979, 101, 4381.
33. Barton, D. H. R.; Elliott, J. D.; Gero, S. D. JCS(P1) 1982, 2085.
34. Eckert, H.; Forster, B. AG(E) 1987, 26, 894.
35. Kurita, K.; Iwakura, Y. OSC 1988, 6, 715.
36. Burk, R. M.; Roof, M. B. TL 1993, 34, 395.
37. Palomo, C.; Cossio, F. P.; Ontario, J. M.; Odriozola, J. M. JOC 1991, 56, 5948.
38. Katakai, R.; Iizuka, Y. JOC 1985, 50, 715.
39. Pridgen, L. N.; Prol, J.; Alexander, B.; Gillyard, L. JOC 1989, 54, 3231.

Peter Hamley

Fisons Pharmaceuticals, Loughborough, UK

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