A useful acylation method using trichloroacetonitrile and triphenylphosphine for solid phase organic synthesis

Article abstract of DOI:10.1016/S0040-4039(02)01241-8

A novel acylation procedure was developed for polymer supported synthesis, with in situ generated acyl chlorides using trichloroacetonitrile and triphenylphosphine.

Full text of DOI:10.1016/S0040-4039(02)01241-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6039–6041
A useful acylation method using trichloroacetonitrile and
triphenylphosphine for solid phase organic synthesis
Istva´n Va´go´* and Istva´n Greiner
Chemical Works of Gedeon Richter Ltd, Gyo¨mroi u´t 19-21, H-1103 Budapest, Hungary
Received 22 February 2002; revised 7 June 2002; accepted 24 June 2002
Abstract—A novel acylation procedure was developed for polymer supported synthesis, with in situ generated acyl chlorides using
trichloroacetonitrile and triphenylphosphine. © 2002 Published by Elsevier Science Ltd.
1. Introduction
Trichloroacetonitrile (TCA) and triphenylphosphine
(TPP) convert carboxylic acids to acyl chlorides mildly
and rapidly under acid free conditions.3 The application
of this method for solid phase chemistry seems advan-
tageous because the excess of reagents and the resulting
triphenylphosphine oxide by-product can be easily
removed by washing. To investigate the applicability of
this method we performed 40 experiments with two
different amines attached to two types of solid sup-
ports, using the two different acylation methods and
ten benzoic acids (Fig. 1).
In recent years solid phase organic synthesis has
become an important technique for the generation of
biologically active molecules. Acylation was one of the
first reactions performed on solid phase1 and is used
frequently in solid phase organic chemistry. Despite the
fact that there are many coupling agents and methods
for coupling carboxylic acids and amines,2 in some
cases there is a need to use acyl chlorides for amide
synthesis. Steric hindrance or low reactivity can hamper
acylation with coupling agents and in those cases using
acyl chlorides gives better results. Herein we report a
new solid phase acylation method that converts car-
boxylic acids to the corresponding acyl chlorides in situ,
in the acylation step, and can be easily employed simi-
lar to other coupling agents.
Two amines were used in the experiments: benzylamine
was attached to the sterically hindered bromo-(4-
methoxyphenyl)-methyl polystyrene4 (MAMP5) and
cyclohexylamine was attached to 2-(4-formyl-3-
methoxy)-phenoxyethyl polystyrene6 (FMPE). The
Figure 1. Reagents and conditions: (i) 4 equiv. TCA/TPP 10 h, rt; (ii) 4 equiv. HBTU 10 h, rt; (iii) 5% TFA/DCM, 1 h, rt; (iv)
25% TFA/DCM, 1 h, rt.
Keywords: solid phase synthesis; acylation; acyl chloride.
* Corresponding author. Tel.: +36-1-4314737; fax: +36-1-4326002; e-mail: vagoi@richter.hu
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01241-8

6040
I. Va´go´, I. Greiner / Tetrahedron Letters 43 (2002) 6039–6041
amines were attached to the polymers using standard
procedures.7,8 The loading of the resins were deter-
mined by Kjeldahl nitrogen analysis, and was equal to
the substitution data provided by the manufacturer.
effect on acylation, as in the case of cyclohexylamine
bound to the FMPE linker, the TCA/TPP and HBTU
methods gave comparable results in terms of purity and
isolated yields (Table 2).
Ten commercially available benzoic acid derivatives
were chosen for the experiments. Two acylation proto-
cols were used, TCA/TPP in DCM and for comparison
the commonly used O-benzotriazol-1-yl-N,N,N%,N%-tet-
ramethyluronium hexafluorophosphate9 (HBTU) cou-
pling agent. Subsequent cleavage with acid treatment
released the products from the resins. The purity of
products were determined by HPLC/MS analysis
(Tables 1 and 2).
3. Experimental
3.1. General procedure for acylation with TCA/TPP
To a mixture of 0.1 mmole of resin bound amine, 0.4
mmole of benzoic acid, 125 ml of triethylamine and 90
ml of trichloroacetonitrile in 1.5 ml of THF was added
0.25 g of triphenylphosphine in 1.5 ml of THF. The
suspension was shaken for 10 hours at room tempera-
ture. The resin was washed sequentially with 2×2 ml of
THF, MeOH, DMF, MeOH, and DCM.
2. Conclusions
In the case of benzylamine bound to the sterically
hindered benzhydryl-type MAMP linker (Table 1), no
acylated product could be isolated using HBTU as the
coupling agent. On the other hand, with the TCA/TPP
method, the desired products were obtained with high
to acceptable purity. When steric hindrance has no
Acknowledgements
The authors wish to thank Dr. Gyo¨rgyi Szendrei for
recording and evaluating the HPLC/MS data.
Table 1. Results of acylation of benzylamine bound to MAMP resin
Entry
Carboxylic acid
HBTU
Purityb (%)
TCA/TPP
Purityb (%)
Yielda (%)
Yielda (%)
1
2
3
4
5
6
7
8
9
Benzoic
0
0
0
0
0
0
0
0
0
0
–
–
–
–
–
–
–
–
–
–
59
19
46
24
16
57
15
43
84
41
87
84
97
92
81
99
87
74
88
98
2,3-Dichlorobenzoic
2,4-Dichlorobenzoic
2,5-Dichlorobenzoic
2,6-Difluorobenzoic
3-Chloro-6-methoxybenzoic
2-(2-Cyanophenylthio)benzoic
2-Bromo-5-methoxybenzoic
3-Cyanobenzoic
10
2-Chloro-5-methylthiobenzoic
a Isolated yields, without further purification.
b Determined by HPLC/MS.
Table 2. Results of acylation of cyclohexylamine bound to FMPE resin
Entry
Carboxylic acid
HBTU
Purityb (%)
TCA/TPP
Yielda (%)
Yielda (%)
Purityb (%)
1
2
3
4
5
6
7
8
9
Benzoic
65
50
65
66
57
50
70
66
40
78
99
99
95
100
81
99
93
81
99
99
98
33
26
95
77
63
60
22
100
94
99
99
83
94
91
99
99
98
92
95
2,3-Dichlorobenzoic
2,4-Dichlorobenzoic
2,5-Dichlorobenzoic
2,6-Difluorobenzoic
3-Chloro-6-methoxybenzoic
2-(2-Cyanophenylthio)benzoic
2-Bromo-5-methoxybenzoic
3-Cyanobenzoic
10
2-Chloro-5-methylthiobenzoic
a Isolated yields, without further purification.
b Determined by HPLC/MS.

I. Va´go´, I. Greiner / Tetrahedron Letters 43 (2002) 6039–6041
6041
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