Tetrahedron Letters,Vol.29,No.45,pp 5763-5764,1988 oo40-4039/88 $3.00 + .Oo Printed in Great Britain Pergamon Press plc

DIBENZYL PHOSPHOROFLUORIDATE, A NEW PHOSPHORYLATING AGENT

Yutaka Watanabe, Nobuyuki Hyodo, and Shoichiro Ozaki*

Department of Resources Chemistry, Faculty of Engineering,

Ehime University, Matsuyama 790, Japan

Abstract: The first synthesis of dibenzyl phosphorofluoridate and its utility as a phosphorylating agent are described.

Dibenzyl phosphorofluoridate l_ has not been reported so far whereas many

synthetic methods are known and various phosphoric acid fluorides and their

related phosphorus compounds are recorded." In this communication, we wish to

report an easy synthesis of L and its utility as a phosphorylating agent.')

During our investigation on polyphosphorylation,3) pyrophosphate 2 was

found to react quite smoothly with cesium fluoride in acetonitrile at room

temperature to afford phosphorofluoridate 1 in 80% yield. Fluoridate _l_ was

also prepared in 90% yield by the reactiorof dibenzyl phosphate 3 with 2-

fluoropyridinium salt 4." Both methods have not been known whze J was

employed for the synzesis of carboxylic acid fluorides.5' The present

procedures may provide rapid and effective synthetic methods of fluorides of

phosphoric acid diesters. Dibenzyl phosphorofluoridate J is fairly stable and

purified by silica gel column chromatography. Distillation of c?, is also

possible (bp about 150 C/O.2 mmHg) whereas J decomposes by prolonged heating.

Contrary to these facts, preparation and purification of analogous dibenzyl

phosphorochloridate 5_ which has been frequently employed for phosphorylation

of alcoholss' are quite difficult. Therefore, chloridateAis not satisfactory

when restricted quantity ofziis required.

P CsF ?

Me TsO-~ ?

1 W-0 ,Pl *O - (BnO) ,P-F ( (BnO),POH

2 3 (Bn=benzyl)

Utility of dibenzyl phosphorofluoridate & as a phosphorylating agent was

investigated and J (1.4 equiv, used without purification) was found to react

with primary alcohols activated by cesium fluoride (3.0 equiv) in acetonitrile

at room temperature to afford the corresponding triesters 5 (Table 1). The

reaction with secondary alcohols was so sluggish that the primary hydroxyl

group reacted selectively with L. On the other hand, phenols and the anomeric

hydroxyl of glucose derivative reacted extremely smoothly with 1 in the

presence of CsF. The high reactivity of the phenolic hydroxyl was utzized for

the selective introduction of the dibenzyl phosphoryl group on the phenol

moiety without protection of the primary hydroxyl. Since combination of cesium

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Table 1. Synthesis of dibenzyl phosphate derivatives

F1 Base

c1 ROH + (BnO),P-F p ROP(OBn),

r-t. 6

ROH Base Solv. Time,h Yield,%

o-ClC,H,CH,OH CsF CH,CN 18 quant.

N-(2-hydroxyethyl)phthalimide CsF CH,CN 20 82

1,2-0-isopropylideneglycerol CsF CH,CN 21 87

m-(CH,)C,H,OH CsF CH,CN 1.5 86

CsF CH,CN 6.0 76 (a//?=2/3)

OBn

P- (HO)C,H+ (CH,) ,OH

CH,CH(OH) (CH,) ,OH

CH, (CH,) ITOH CH,CH(OH) (CH,),CH,

Bnq Qd _

CsF CH,CN 3.0 62"' (82)b'

CsF CH,CN 20 53"'

DBU CH,Cl, 20 96

n-BuLi THF 4.5d' 80

R1=H, R2=Bn n-BuLi THF

R'=(-& R*=H n-BuLi THF OBn

80"'

69"' (83)b'

a) The phenolic hydroxyl group was phosphorylated. b) Yield based on recovered diol. c) The primary hydroxyl group was phosphorylated and no diphosphate observed. d) The reaction temperature was 0 C. e) Diphosphate was obtained.

fluoride and acetonitrile is essential, an alcohol which is insoluble in the

solvent was phosphorylated by employment of DBU in place of CsF in an

appropriate solvent. Thus, stearyl alcohol was treated in methylene chloride

to afford the ester in 96% yield. Secondary alcohols were phosphorylated with

1 after generation of the lithium alkoxides by butyllithium. N

In conclusion, synthetically useful dibenzyl phosphoric triesters?' were

conveniently prepared by the use of dibenzyl phosphorofluoridate 1.

Acknowledgment: This work was partly supported by The Naito Foundation. We wish to thank Advanced Instrumentation Center for Chemical Analysis, Ehime University, for the high-field NMR and combustion analyses.

References I .

2.

3.

54: 6.

G. M. Kosolapoff and L. Maier, "Organic Phosphorus Compounds," Wiley- Interscience, John Wiley & Sons, New York (1973), Vol. 6, Chap. 15; W. Dabkowski! F. Cramer, and J. Michalski, Tetrahedron Lett., 3, 3561 (1987) A nucleoside phosphorofluoridate was used for the formation of internucleo- tidic bond: R. von Tigerstrom and M. Smith, Science, 167, 1266 (1970). Y. Watanabe, H. Nakahira, M. Bunya, and S. Ozaki, Tetrahedron Lett., 28, 4179 (1987).

7.

T. Mukaiyama, Angew. Chem., Int. Ed. Engl., u, 707 (1979). T. Mukaiyama and T. Tanaka, Chem. Lett., 1976. 303. Ez;;nt utilization: M. Inage, H. Chaki! S. Kusumoto, and T. Shiba, Chem.

Lps2, 1281; T. Takahashi, C. Shimizu, S. Nakamoto, K. Ikeda, and K. Achiw:, Chem. Pharm. Bull., 33, 1760 (1985). J. W. Perich and R. B. Johns, Tetrahedron Lett., 28, 101 (1987); K.-L. Yu and B. Fraser-Reid, ibid., 2, 979 (1988).

(Received in Japan 29 July 1988)