Diphenylcarbamoyl Chloride

[83-01-2]  · C13H10ClNO  · Diphenylcarbamoyl Chloride  · (MW 231.69)

(acylating agent in Friedel-Crafts reactions;1 acylating agent for amines,2 amino acids,3 thiols,2 phenols,4 and carboxylic acid salts;5 protecting group in oligonucleotide synthesis6)

Alternate Name: DPC-Cl.

Physical Data: mp 85 °C.

Solubility: sol most common solvents.

Form Supplied in: white to off-white powder; widely available.

Handling, Storage, and Precautions: incompatible with strong oxidizing agents and strong bases; corrosive; moisture sensitive. Unlike dimethyl-, diethyl-, and methylphenylcarbamoyl chloride, it is not carcinogenic.

Acylating Agent in Friedel-Crafts Reactions.1

Diphenylcarbamoyl chloride can be used to introduce a carboxylic group into an aromatic compound. Friedel-Crafts acylation in ethylene chloride in the presence of Aluminum Chloride as catalyst gives a diphenylamide. Alkyl- or alkoxy-substituted benzenes are readily acylated, whereas fluoro or chloro derivatives are unreactive. With the exception of the sterically hindered amides obtained from mesitylene, durene, and pentamethylbenzene, the resultant diphenylamides are readily hydrolyzed by alkali (NaOH in 85% aq. EtOH or DMSO) to the parent carboxylic acids (eq 1).7

Acylating Agent for Amines, Amino Acids, Thiols, Phenols, and Carboxylic Acid Salts.

DPC-Cl reacts readily with primary and secondary aliphatic or cyclic amines,2 and with the a-amino group of a wide variety of amino acids,3 to give tri- or tetrasubstituted ureas (eq 2). In the case of amino acids, some racemization takes place on longer exposure to the basic conditions.3

Reactions with thiols2 can be carried out in aq. EtOH under basic conditions (NaHCO3), to give good yields of N,N-diphenylthiocarbamates. Other carbamoyl derivatives such as dimethyl- and dibutylcarbamoyl chloride are not as useful because they are too unstable to basic conditions in water.2 Imidazole in acetone or EtOH can be converted into its DPC derivative using an excess of imidazole as the base.2 O-Methylhydroxylamine reacts readily with DPC-Cl in THF to give N-methoxy-N,N-diphenylurea in 62% yield.8 The reaction of 5-methylene-1,3-thiazolidine-2-thione with DPC-Cl traps only the aromatic thiazole tautomer, giving the S-substitution product (eq 3).9

Phenols can be acylated by DPC-Cl in acetone4 in the presence of Potassium Carbonate or in pyridine to give N,N-diphenylcarbamates.10 Carboxylic N,N-diphenylcarbamic anhydrides have been isolated from the reaction of carboxylate salts with 1-(N,N-diphenylcarbamoyl)pyridinium chloride, prepared from DPC-Cl and pyridine, in aqueous or ethanolic solutions. In the presence of amino groups the reaction under these conditions is chemoselective and no carbamate is formed. These mixed anhydrides are stable, crystalline derivatives and are very reactive in acylation reactions (eq 4).5

The DPC group has been introduced in many pharmaceutical products. Hence the toxicity and tumor affinity of 5-fluorouracil have been modified by reacting it with DPC-Cl in DMA in the presence of Sodium Hydride to give the 1-DPC derivative (eq 5).11 When excess DPC-Cl is employed in the presence of K2CO3, the 1,3-disubstituted derivative is also produced. Treatment of an 85/15 endo/exo mixture of bicyclo[2.2.1]hept-5-en-2-ylmethylamine obtained by Diels-Alder reaction with DPC-Cl, followed by crystallization, gives a 74% yield of pure endo product. This product can then be condensed with a sulfonamide to give a sulfamylurea, which is a highly potent hypoglycemic agent (eq 6).12

Protecting Group in Oligonucleotide Synthesis.

The lactam function of the guanine residue is subject to side-reaction during oligonucleotide synthesis. It can be protected according to a widely used procedure originally devised by Kamimura et al.5,13 Treatment of the amino-protected oligonucleotide with DPC-Cl in dry pyridine containing Triethylamine or Diisopropylethylamine gives, after silica gel chromatography, the corresponding O6-(diphenylcarbamoyl)guanosine in excellent yield (eq 7).5 DPC-Cl is superior to dimethyl- and dimethylthiocarbamoyl chloride for this purpose. In addition to the successful protection of the guanine residue, introduction of DPC improves the solubility and chromatographic properties of the resultant derivatives. Deprotection occurs in conc. ammonia-MeOH (9:1, v/v) over 3 h at 60 °C, which are the conventional conditions for deprotection of the exo-amino acyl groups of other nucleoside bases.5 Modified deoxyguanosines14 are protected in the same way. Stannylation of the guanosine followed by electrophilic attack of the DPC-Cl at the stannyl intermediate has been reported.15 In the case of 2-aza-2-inosine, N1-acylation instead of O6-acylation occurs.16

1. (a) FF 1967, 1, 337. (b) FF 1969, 2, 177.
2. Rivett, D. E.; Wilshire, J. F. AJC 1966, 19, 165.
3. Rivett, D. E.; Wilshire, J. F. AJC 1965, 18, 1667.
4. Schmidt, B.; Hoffmann, H. M. R. CB 1992, 125, 1501.
5. Shepard, K. L.; Halczenko, W. JHC 1979, 16, 321.
6. (a) Kamimura, T.; Tsuchiya, M.; Koura, K.; Sekine, M.; Hata, T. TL 1983, 24, 2775. (b) Kamimura, T.; Tsuchiya, M.; Urakami, K.; Koura, K.; Sekine, M.; Shinozaki, K.; Miura, K.; Hata, T. JACS 1984, 106, 4552.
7. Wilshire, J. F. AJC 1967, 20, 575.
8. Perronnet, J.; Demoute, J. P. G 1982, 112, 507.
9. Hanefeld, W.; Bercin, E. LA 1985, 58.
10. Sabie, R.; Fillion, H.; Daudon, M.; Pinatel, H. SC 1990, 20, 1713.
11. Ozaki, S.; Ike, Y.; Mizuno, H.; Ishikawa, K; Mori, H. BCJ 1977, 50, 2406.
12. Kuhla, D. E.; Sarges, R.; Barth, W. E. JHC 1978, 15, 565.
13. Kamaike, K.; Hasegawa, Y.; Ishido, Y. Nucleosides, Nucleotides 1988, 7, 37 (CA 1988, 109, 170 777v).
14. Roelen, H. C.; Saris, C. P.; Brugghe, H. F.; Van den Elst, H.; Westra, J. G.; Van der Marel, G. A.; Van Boom, J. H. Nucleic Acids Res. 1991, 19, 4361 (CA 1991, 115, 232 760u).
15. Tanimura, H.; Sekine, M.; Hata, T. TL 1986, 27, 4047.
16. Fernandez-Forner, D.; Eritja, R.; Bardella, F.; Ruiz-Perez, C.; Solans, X.; Giralt, E.; Pedroso, E. T 1991, 47, 8917.

Cécile Pasquier

University of Neuchâtel, Switzerland

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