N,N-Dimethyl Dichlorophosphoramide

[677-43-0]  · C2H6Cl2NOP  · N,N-Dimethyl Dichlorophosphoramide  · (MW 161.96)

(electrophilic phosphorylating reagent used to convert vicinal diols to alkenes2,3 and to activate carboxylic acids and alcohols towards nucleophiles)

Alternate Names: (dimethylamido)phosphoryl dichloride; dimethylphosphoramidic dichloride; N,N-dimethylamidophosphorodichloridate.

Physical Data: bp 194-195 °C/760 mmHg; d 1.369 g cm-3.

Solubility: sol most organic solvents.

Form Supplied in: colorless liquid.

Preparative Method: obtained by treatment of Phosphorus Oxychloride with dimethylamine.1

Purification: fractional distillation.

Handling, Storage, and Precautions: very reactive towards water, alcohols, and amines.

Diol Elimination.

N,N-Dimethyl dichlorophosphoramide efficiently converts vicinal diols into cyclic phosphoramides. These cyclic phosphoramides, when treated with Lithium in ammonia, afford alkenes resulting primarily via syn elimination.2,3 The process occurs in high yield with cyclic diols to afford cis-alkenes contaminated with ~10% of the trans-isomer (eq 1). Yields, however, are typically much lower with cyclic trans-diols which afford trans-alkenes in 10- and 12-membered rings (eq 2); for a complete discussion on alternative methods, consult Block.4

Carboxylic Acid Activation.

Dimethyl dichlorophosphoramide readily phosphorylates carboxylic acids to give a mixed anhydride which reacts at carbon with a variety of nucleophiles. Upon heating the mixed anhydride, the dimethylamino group is transferred to produce tertiary amides.5 Alternatively, alcohols or thiols can be added to produce esters6 or thiol esters7 at 0-25 °C (eq 3).

Applications of this method in the synthesis of b-lactams have been reported via the closure of b-amino alcohols8 in high yield (eq 4) and the coupling of acetic acids with imines9 in low to moderate yields (eq 5).

Although yields are often quite good (eqs 1-5) these methods are rarely used instead of acid chloride or 1,3-Dicyclohexylcarbodiimide couplings.

Alcohol Activation.

Dimethyl dichlorophosphoramide also readily phosphorylates alcohols to produce an activated alcohol which undergoes displacement and elimination reactions. Primary, secondary, and tertiary alcohols are phosphorylated at rt. Upon heating the activated alcohol at ~80 °C for several hours, primary alcohols produce alkyl chlorides by an SN2 process, tertiary alcohols produce alkenes by elimination (trans elimination is slightly more facile than cis), and secondary alcohols produce mixtures of alkyl chlorides and alkenes (eq 6).10

The phosphorylated alcohols may be treated at rt with dimethylamine to produce a tetramethylphosphorodiamidate derivative. These derivatives can be treated with lithium/ethylamine to reductively cleave the carbon-oxygen bond and produce deoxygenation products (eq 7).11

Dimethyl dichlorophosphoramide phosphorylates a broad range of alcohols, but the production of alkenes and alkyl chlorides is of somewhat limited utility since the two processes are competitive with secondary alcohols and since trans and cis eliminations occur at comparable rates. The reductive deoxygenation, on the other hand, is quite efficient with a broad range of substrates.

1. Walsh, E. N.; Toy, A. D. F. Inorg. Synth. 1963, 7, 69.
2. Marshall, J. A.; Lewellyn, M. E. SC 1975, 5, 293.
3. Marshall, J. A.; Lewellyn, M. E. JOC 1977, 42, 1311.
4. Block, E. OR 1984, 30, 457.
5. Liu, H. J.; Chan, W. H.; Lee, S. P. SC 1979, 9, 31.
6. Liu, H. J.; Chan, W. H.; Lee, S. P. TL 1978, 4461.
7. Liu, H. J.; Lee, S. P.; Chan, W. H. SC 1979, 9, 91.
8. Palomo, C.; Aizpurua, J. M.; Urchegui, R.; Iturburu, M.; de Retana, A. O.; Cuevas, C. JOC 1991, 56, 2244.
9. Cossio, F. P.; Ganboa, I.; Garcia, J. M.; Lecea, B.; Palomo, C. TL 1987, 28, 1945.
10. Liu, H. J.; Chan, W. H.; Lee, S. P. CL 1978, 923.
11. Liu, H. J.; Lee, S. P.; Chan, W. H. CJC 1977, 55, 3797. John MontgomeryWayne State University, Detroit, MI, USA

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