Diphenylphosphinic Chloride

[1499-21-4]  · C12H10ClOP  · Diphenylphosphinic Chloride  · (MW 236.64)

(agent for acid activation,1 alkylphosphine oxide formation,2 and amine protection3)

Alternate Name: chlorodiphenylphosphine oxide.

Physical Data: bp 222 °C/16 mmHg; d 1.240 g cm-3.

Form Supplied in: colorless liquid; widely available.

Handling, Storage, and Precautions: handle only in a chemical fume hood, wear chemical-resistant gloves and safety goggles, do not breathe vapor, and avoid contact with eyes or skin. Store in a flammable storage cabinet under nitrogen. Contact with water generates hydrogen chloride gas.

Acid Activation.

Chlorodiphenylphosphine oxide has been utilized for the activation of acids via in situ formation of the diphenylphosphinic (DPP) mixed anhydrides. These anhydrides are superior to carbon-based mixed anhydrides because they do not suffer from disproportionation to symmetrical anhydrides.1 Also, nucleophiles prefer to attack at carbon rather than phosphorus, solving the regioselectivity problem associated with carbon-based mixed anhydrides.4 Additionally, diphenylphosphinic mixed anhydrides are more electrophilic. Finally, diphenylphosphinic mixed anhydrides form rapidly allowing shorter activation times.

Diphenylphosphinic mixed anhydrides have been utilized to form peptide bonds.5 Peptides are easier to isolate by this method than by employing 1,3-Dicyclohexylcarbodiimide. These anhydrides are the method of choice for the formation of amides of 2-alkenoic acids (eq 1).6 Carbodiimide and acyl carbonate methods proved to be inferior. Primary amines result in better yields than secondary amines. This activation protocol can be employed to form thiol esters.7 b-Amino acids are readily converted to b-lactams with chlorodiphenylphosphine oxide (eq 2).8 Secondary amines work best. This activation protocol has been utilized to convert acids to amines via a Curtius rearrangement (eq 3).9 Phenols have been generated from diene acids, presumably via base-induced elimination of diphenylphosphinic acid from the mixed anhydrides to form ketenes which spontaneously cyclize (eq 4).10 Acids have been converted to ketones via activation followed by reaction with organometallic reagents (eq 5).11

Phosphine Oxides.

This reagent reacts with organometallic reagents to form phosphine oxides.2 Alkyl phosphonates have been converted to diphenylvinylphosphine oxides via trapping of the a-lithioalkylphosphonate with diphenylchlorophosphine oxide, deprotonation, and reaction with aldehydes (eq 6).12 Organometallic reagents have been converted to 1,3-dienes utilizing Ph2P(O)Cl and carbonyl compounds (eq 7).13

Thiol Esters and Ketones.

The Dpp mixed anhydrides react with thiols to yield thiol esters (eq 8)7 and undergo carbon-acylation reactions with both Grignard reagents and diethyl sodiomalonate in good yields (eq 9).14

Protection of Amino Groups.

In the presence of N-methylmorpholine, Ph2POCl reacts with amino acid esters in CH2Cl2 at 0 °C in 1.5-2 h to give N-diphenylphosphinyl (Dpp) amino acid esters (65-80%), which are then hydrolyzed under mild alkaline conditions to give N-Dpp amino acids (eq 10).3,4 Since Ph2POCl hydrolyzes extremely quickly under aqueous conditions, it is not possible to prepare N-Dpp amino acids directly.

The Dpp derivatives are slightly more acid-labile than the Boc derivatives and are cleaved by HOAc-HCOOH-H2O (7:1:2) (24 h), 1 M HCl in H2O-dioxane (2:1) (3 h), TFA-CH2Cl2 (1:1) (40 min), and 95% TFA (10 min). Selective cleavage of the Dpp group in the presence of a t-butyl ester and a phenyl ester is possible.

Amination.

Ph2POCl reacts with Hydroxylamine to yield O-(diphenylphosphinyl)hydroxylamine.15 This reagent aminates stabilized carbanions and Grignard reagents in moderate yields (eq 11).16 Electrophilic N-amination of imide sodium salts is also possible using this reagent (eq 12).17

Diphenylphosphinamide18 and 1-diphenylphosphinyl-2,2-dimethylaziridine,19 which are derived from Ph2POCl, react with Grignard reagents to give high yields of primary amines and moderate yields of a,a-dimethylarylalkylamines, respectively.


1. Jackson, A. G.; Kenner, G. W.; Moore, G. A.; Ramage, R.; Thorpe, W. D. TL 1976, 3627.
2. Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.; Kumobayashi, H.; Taketomi, T.; Akutagawa, S.; Noyori, R. JOC 1986, 51, 629.
3. (a) Kenner, G. W.; Moore, G. A.; Ramage, R. TL 1976, 3623. (b) Ramage, R.; Atrash, B.; Hopton, D.; Parrott, M. J. JCS(P1) 1985, 1217.
4. Ramage, R.; Atrash, B.; Hopton, D.; Parrott, M. J. JCS(P1) 1985, 1617.
5. Ramage, R.; Hopton, D.; Parrott, M. J.; Richardson, R. S.; Kenner, G. W.; Moore, G. A. JCS(P1) 1985, 461.
6. Bernasconi, S.; Comini, A.; Corbella, A.; Gariboldi, P.; Sisti, M. S 1980, 385.
7. Horiki, K. SC 1977, 7, 251.
8. Kim, S.; Lee, P. H.; Lee, T. A. CC 1988, 1242.
9. (a) Armstrong, V. W.; Coulton, S.; Ramage, R. TL 1976, 4311. (b) Ramage, R.; Armstrong, V. W.; Coulton, S. T 1981, 37, Supplement No. 1, 157.
10. Clinch, K.; Marquez, C. J.; Parrott, M. J.; Ramage, R. T 1989, 45, 239.
11. Soai, K.; Ookawa, A. CC 1986, 412.
12. (a) Savignac, P.; Teulade, M.-P.; Aboujaoude, E. E.; Collignon, N. SC 1987, 17, 1559. (b) Aboujaoude, E. E.; Lietje, S.; Collignon, N. TL 1985, 26, 4435.
13. Davidson, A. H.; Warren, S. CC 1975, 148.
14. Kende, A. S.; Scholz, D.; Schneider, J. SC 1978, 59.
15. (a) Harger, M. J. P. CC 1979, 768. (b) Harger, M. J. P. JCS(P1) 1981, 3284.
16. (a) Colvin, E. W.; Kirby, G. W.; Wilson, A. C. TL 1982, 23, 3835. (b) Boche, G.; Bernheim, M.; Schrott, W. TL 1982, 23, 5399.
17. Klotzer, W.; Stadlwieser, J.; Raneburger, J. OS 1985, 64, 96.
18. Zwierzak, A.; Slusarska, E. S 1979, 691.
19. Buchowiecki, W.; Grosman-Zjawiona, Z.; Zjawiony, J. TL 1985, 26, 1245.

David N. Deaton

Glaxo Research Institute, Research Triangle Park, NC, USA

Sunggak Kim

Korea Advanced Institute of Science and Technology, Taejon, Korea



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