Phase managed organic synthesis 2. A new polymer assisted synthesis of acid anhydrides.

Tetrahedron Letters,Vol.27,No.41,pp Printed in Great Britain

0040-&39/86 $3.00 + .OO Perqamon Journals Ltd.

4933-4936,1986

PHASE MANAGED ORGANIC SYNTHJBJS 2.

A NEW POLYMER

ASSLSTED SYNTRIBXS OF ACID ANHYDRIDRS.

Wilmer K. Fife* and Zhi-dq Deputment

Zhang

of Chemistry

Indiana University-Purdue

University

Wianaplis.

IN

at Jndianapolis

46223

Abstract:

A solid-phase copolymer of 4-vinylpyridine is shown to be a highly effective reagent/ catalyst for the synthesis of acid anhydrides from mixtures containing equimolar quantities of carboxylic acids and acid chlorides. The process may be carried out in batch or column mode. Acid anhydrides

They are frequently

are among the preferred

peptides.

Therefore,

wide variety

of these substances.

and convenience

of processes

contains a relatively transacylation

a large

reactive

acid derivative of synthetic

thesis,%6

for

of applications

polymeric

work,9

polymer-bound

the

polymeric

esters,

of the experimental reagents/catalysts,

of this potentially

Only a few investigations

of amides,

and

have been developed that furnish a

important

of polymer-bound available

methodology

anhydrides

reagents/catalysts

DCC, 5 have not been readily

simplicity the literature have been

used in anhydride or have

to

exhibited

synother

limitations.

During

solid-phase formation chloride

example

use solid-phase

used in organic synthesis.

for preparation

procedures

Despite general acknowledgement

reported.z-4 Prior to our recent serious

classes of reagents

number that

small number

reactions.z-8

the most important

our investigation co-polymer

‘)

phase techniques

of 4-vinylpyridinelo(P4-VP)

of acid anhydrides and a carboxylic

of multiple

in organic synthesis,

is an extremely

in solutions that contain approximately

acid, Eq. l., Table 1. 0 0

The reaction

effective equimolar

we discovered

reagent/catalyst quantities

that a for the

of an acid

may be carried out conventionally

in a

P4-VP

R

Cl

+

R'

HCH2C1*,

-HCl

round-bottom flask with stirring or the P4-VP can be loosely packed in a column and reaction effected by passing a solution of the reactants in dichloromethane over the solid reactant/catalyst.11

4933

4934

Table 1.

Reactants

Synthesis of Anhydride@

Reaction

Anhydridesb Composition,c

Temp. OC

Yield

Time, Min.

%

Mole %

Mixed Anhydrides R = Ph Ph Ph CH3 Ph Ph Ph CH3(CH2)4

Ph CH3tCH2)lo Ph Ph CH3CH20 (CH3)2CHCH20 PhCH20 Ph Ph 2-CH3Ph 4-CH30Ph Ph Ph Symmetric Anhydrides CH$CH2)10 2-CH3Ph 4-CH3Ph

R = CH3

64.8d

o.a2e

0.09

0.09

80.0 86.4 84.9 97.8 82.6 91.5 94.6 91.6 90.6 84.5 97.7 80.3 90.4 75.5 90.5 91.3 89.8 95.2 97.6 95.6

0.73e 0.74e 0.75e 0.80 0.69 0.76e

CH2=CH CH2=C(CH3) Ph Ph Ph 2-CH3Ph 4-CH3Ph 4-CH3Ph Ph 4-N02Ph 3,5-(N02)2Ph

rtl5 rt/5 O/60 o/15 O/l 0 o/10 o/10 o/10 o/210 O/60 o/90 O/60 o/30 rt/30 o/30 W240 rt/180 rt/240 rt/60 rt/120 rt/60

l.ooe 0.41eJ l.ood 0.96e,f o.goe*f 1.00 0.97 1.00 1.00e 1.00e 1.00e 1.00e 0.95e 0.92

0.12 0.12 0.09 0.04 0.12 0.16 0 0.39 0 0 0.02 0 0.03 0 0 0 0 0 0 0

0.15 0.14 0.16 0.16 0.19 0.08 0 0.20 0 0.04 0.08 0 0 0 0 0 0 0 0.05 0.08

CQ(CHz)lo 2-CH3Ph 4-CH3Ph

rt/60 rt/360 rt/l80

87.2 90.ae 93.2e

1.00 1.00 1.00

CH3 CH3 PChH312CH (CH313C CH3(CH2)4 Ph CH3(CH2)1

o

Ph

aReaction mixtures containing 0.005 mole acid chloride, 0.006 mole carboxylic acid, 3.0 equiv P4-VP, and 25 mL dichloromethane were stirred to complete reaction (no acid chloride). The dichloromethane solution was separated by filtration, washed with 10% aqueous potassium carbonate, dried over anhydrous potassium carbonate and rotary evaporated to obtain the product. bproduct identity was established by comparison of melting point, lH-NMR, and/or IR data with published values except where noted otherwise. cProduct composition was estimated by integration of NMR spectra. dReaction catalyzed by 1.6 equiv PQ-VP was incomplete. Product mixture contained 23.3% unreacted benzoyl chloride. CMass spectral analysis showed the appropriate molecular ion. fNo published data are available for this compound.

4935

The

hydrogen

chloride

regeneration

is easily

produced

during

accomplished

reaction

remains

by treatment

bound to the P4-VP after

with aqueous

sodium

work-up.

Catnlyst

hydroxide

or tricthylaminc

procedure

for obtaining

in

dichloromethane. This variety

two-phase

subsequent acrylic bility

benzoic

reaction

successful

is believed

to follow

by carboxylate

8

+

the typical pyridine

brate

Eq.

to mixtures

sufficiently anhydrides,

transacylation

pathway

benzoic

the

8

of aliphatic 4.

and

Furthermore,

of the

two

a widr in

use

anhydridc,

synthetic

capn-

below,

Eqs. 2 and

ions, -1, which are readily

-&&+RLOAO

cl-

aromatic

mixtures

acids

shown

1-acylpyridinium

..

carboxylic

of carboxylic

acids acids

and two acid chlorides,15

are

known to undergo

and acid chlorides

Eq. 5.

Our results

readily

indicate

disproequili-

that

thr

0

OH

Cl

yields

chloride

direct

ions.12913

RLCl=

t

best

for

acetic

demonstrates

r-l

5)

pure

anhydride,

and form

,,x,

anhydrides

portionation,l4

and

of the mixed

benzoic

..

Mixed

convenient

>90%,

synthesis

and isobutylcarbonic

are known to acylate

to anhydrides

3)

an extremely generally

of the method.

Acid chlorides

converted

The

anhydride,

and scope

represents

in high yield,

reactions.

The 3.

method

of acid anhydrides

of alkylcarboxylic

and the arylcarboxylic

R’OH

arylcarboxylic acid,

Table

t

\

1.

anhydrides

are

usually

,w,,

obtained

by using the alkoyl

4936

Development anhydrides

and

is an area

application

of multiple

of continuing

interest

phase

techniques

in synthesis

and reactions

of acid

in our laboratory.

Acknowledgements: We gratefully thank

Gerald

(Merrill-Dow)

References

1.

acknowledge

Goe (Reilly)

and Ben Freiser

(Purdue

of Reilly

for

Tar & Chemical

helpful

discussions,

for mass spectral

Corporation.

and

Robert

WC

Barbuch

analyses.

and Footnotes:

Accounts

in “The Peptides:

Press,

drides,

Chem.

Academic Ethers

1969, 2, 296.

Analysis,

to applications

see: a) N. K. Mathur,

“Crown

Res.,

Synthesis,

New York, 1979, Vol. 1, Chpt.

an introduction

Chemistry”, Jr.,

support

(Reilly)

University)

b) J. Meienhofer

For

financial Sauers

al D. S. Tarbell,

Academic 2.

the

and Edward

reagents/catalysts

in the synthesis

“Polymers

and R. E. Williams,

as Acids

New York, 1980, p. 187 ff; bl L. J. Mathias

and Phase

Transfer

Catalysts

cds.

6, pp. 264-309.

of polymeric

C. K. Narang,

Press,

E. Gross and J. Meinhofer,

Biology”,

in Polymer

Science”,

of anhyin Organic

and C. E. Carrahcr,

Plenum

Press,

New York,

1984, p. 83. 3.

a) A. Akelah

and D. C. Sherrington,

b) A. Akelah, 4.

S. Boivin,

Synthesis,

P. Hemery,

Rev.,

Chem.

1981, 2,

557.

Bull. Sot.

Chim.

1981, 413. J.-P.

Senet

5.

N. M. Weinshenker

6.

J. A. Moore and J. J. Kennedy,

7.

M. Ralitsch,

8.

Y. Shai, K. A. Jacobson

and A. Patchornik,

9.

a) W. K. Fife and Z.-d.

Zhang,

Phase

Managed

Organic

Synthesis

b) W. K. Fife

Zhang,

Phase

Managed

Organic

Synthesis

10.

PI-VP

and C.-M.

and S. Boileau,

J. Ciccio,

and Z.-d.

- Reillex

copolymerized

425,

Shen, Tetrahedron J. Chem.

and J. Calzada,

Reilly

Tar

and cross-linked

Sot.

Rev.

Lett., Chem.

1972, 3281. Commun.,

Latinoam.

Quim.,

J. Am. Chem.

& Chemical

Fr., 1984, R-201. 1976, 1079.

1982, 13, 16.

Sot.,

Corporation,

1985, -107, 4249. 1, 1986, in press. 3, following Indianapolis,

with 25% 4:l divinylbenzene/4_ethylstyrene

article. is 4-vinylpyridinc and

contains

0.007

eq. pyridinelg. 11.

Representative

results

using column

methodology

in a related

study are reported

ing letter. 12.

R. K. Smalley

13.

a) A. R. Fersht

and W. P. Jencks,

J. Am. Chem.

b) A. R. Fersht

and W. P. Jencks,

ibid.,

and H. Suschitzky,

D. Hurd and M. F. Dull, ibid.,

14.

C.

15.

R. Adams (Received

and L. H. Ulich, in

USA 2 May

ibid., 1986)

J. Chem.

Sot.,

1964, 755. Sot.,

1970, 92, 5442.

1932, 54, 3427. 1920, 42, 599.

1970, 92, 5432.

in the follow-