A New Approach to Activation of Hydroxy Compounds Using

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A New Approach to Activation of Hydroxy Compounds Using Pentacoordinated Spirophosphoranes J. I. G. CADOGAN B. P. Research Centre, Chertsey Road, Sunbury-on-Thames, Middlesex, TW16 7LN, England I. GOSNEY, D. RANDLES, and S. YASLAK Department of Chemistry, University of Edinburgh West Mains Road, Edinburgh, EH9 3JJ, Scotland

There are several examples in the literature of activation of hydroxy compounds by various organophosphorus compounds. For example, in the presence of pyridine, n-butyltriphenoxyphosphonium bromide (1) activates carboxylic acids towards reaction with amines or phenols to give, respectively, amides or esters (1). Such condensation reactions are also promoted by certain trivalent phosphorus compounds, e.g. triphenyl phosphite (2) or diphenyl ethylphosphonite (3), or to a lesser extent by phosphonate esters, e.g. diphenyl n-butylphosphonate (3). "Bates' reagent," μ-oxobis[tris(dimethylamino)phosphonium] bis-tetra-f1uoroborate (2) may also be used to activate the carboxyl function towards amide bond formation during peptide synthesis (4) and to bring about the Beckmann rearrangement of ketoximes (5). We wish to report a new approach to condensation reactions of hydroxy compounds related to the Ritter reaction, the Beckmann rearrangement and peptide formation based on easily accessible pentaco-ordinate spirophosphoranes of the type (3) (6 - 9). Thus, reaction of equimolar amounts of 2-phenyl-2,2' spirobis(1,3,2-benzodioxaphosphole) (3a) (6) and benzhydrol under anhydrous conditions in boiling acetonitrile gave N-benzhydrylacetamide (40%), bis(benzhydryl)ether (30%) and 2-phenyl-1,3, 2-benzodioxaphosphole (4) which was identified by spectroscopic comparison with an authentic sample prepared from phenylphosphonic dichloride and catechol (10). The formation of N-benzhydrylacetamide from benzhydrol and acetonitrile constitutes a Ritter reaction (11) which, in this case, is accomplished under extraordinarily mild, and above all neutral conditions. Usually, such reactions are carried out in 0097-6156/81/0171-0041$05.00/0 © 1981 American Chemical Society In Phosphorus Chemistry; Quin, L., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.


42

PHOSPHORUS CHEMISTRY

concentrated sulphuric acid. The formation of the by-product, bis(benzhydryl) ether, may be inhibited and the yield of Ritter product greatly increased (to 84%) by slow addition of the alcohol to an excess of the phosphorane (3a) in boiling acetonitrile, other phosphoranes giving similar results. Re action as in Scheme 1 is assumed, whereby the f i r s t step (step A) involves nucleophilic substitution of benzhydrol for one of the catechol oxygens i n the phosphorane (3a) to give the phosphorane intermediate (5). This activates the alcohol toward nucleophilic attack by either the solvent, acetonitrile (step Β ) , or another molecule of benzhydrol (step C) to give, respectively, N-benzhydrylacetamide or bis(benzhydryl) ether. Nucleophilic attack on the intermediate (5) has a direct analogy in the reaction shown in Scheme 2, in which the phosphorane (6) acts as a powerful methylating agent towards carboxylic acids and phenols (12J. Equimolar quantities of benzhydrol and the phosphorane (3a) were also reacted in dimethyl sulphoxide solution. Apart from bis(benzhydryl) ether (18%) and catechol monobenzhydryl ether (39%), a small amount of benzophenone (17%) was obtained. It was shown that, in the absence of phosphorane, benzhydrol is not oxidised to benzophenone by dimethyl sulphoxide. Reaction similar to that outlined in Scheme 1 is a l i k e l y p o s s i b i l i t y . Again, the alcohol is activated by reaction with the phosphorane toward nucleophilic attack, in this case by dimethyl sulphoxide. Significantly, oxidation of alcohols by dimethyl sulphoxide is usually carried out using the Pfitzner-Moffatt reagent (dicyclohexylcarbodiimide and anhydrous phosphoric acid in dimethyl sulphoxide) (13) whereas the reaction using the phosphorane (3a) is carried out under neutral conditions. Unfortunately, however, attempts to improve the y i e l d of benzophenone have hitherto fai led. Pentaco-ordinate spirophosphoranes of the type (3) are also capable of activating N-hydroxy functional groups towards Beckmann-type rearrangements. In a typical experiment, reaction of acetophenone oxime in boiling acetonitrile for several days in the presence of phosphorane (3a) afforded acetoacetanilide in 70% y i e l d . Here again, the conditions employed are much milder than the usual conditions required for the Beckmann rearrangement (e.g. phosphorus pentachloride, concentrated sulphuric acid, polyphosphoric acid), and are comparable to the conditions re quired using Bates' reagent (5.). Preliminary results show that pentaco-ordinate phosphoranes are practical reagents for the formation of the peptide link. Thus, application of the phosphorane (3b) (7) in the stringent Izumiya test (14)

In Phosphorus Chemistry; Quin, L., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.

8.

CADOGEN E T A L .

Activation

Scheme

L

of Hydroxy

43

Compounds

R = Ph CH. 2


(A)

ι

Me ^ acid workup



44

PHOSPHORUS CHEMISTRY

Scheme

2.

(Pho) PBu 3

n

R=MeC=

O; 2,4,6-trimeth

ylbenzoyl; Ph.

Br"

0) (Me N) P 2

3

/ 0 > X

P(NMe )3 2

2BF "

(3) a:R = Ph b:R = H ;

4

W

c:R=CI .d:R=PhO



8.

CADOGEN E T A L .

Activation

of Hydroxy

Compounds

45

Table 1. Degree of racemisation(l5) as measured by the Izumiya test. Coupling agent

Conditions Yield % Racemisation% 20° 14days 60°, Iday

3

Ν - m e t h y l morpholine (NMM)-THF

20

50-60

23

60°7days

50-60

21

40°7days

50-60

12

40°4days

50-60

11

Iday

(Me N) P-0-P(NMe ) Et N 2BF " Ν MM DMF,20°(4_) poly Hunig base + HOBt 2

3

2

4

3

18

50-60

100°

Et N-THF

30

3

43 16 9

A New Approach to Activation of Hydroxy Compounds Using

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