Mild one-pot conversion of carboxylic acids to amides or esters with Ph3P/trichloroisocyanuric acid

Article abstract of DOI:10.1016/j.tetlet.2005.06.127

The reaction of trichloroisocyanuric acid (TCICA) and triphenylphosphine in the presence of a carboxylic acid results in the in situ formation of the corresponding acid chloride under mild conditions. Subsequent addition of amines or alcohols, in the presence of a tertiary amine affords the corresponding amides, or esters, in good to excellent yields. The methodology was applied to the synthesis of a dipeptide.

Full text of DOI:10.1016/j.tetlet.2005.06.127

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5945–5947
Mild one-pot conversion of carboxylic acids to amides or esters
with Ph3P/trichloroisocyanuric acid
*
´
Rogerio da C. Rodrigues, Igor M. A. Barros and Edson L. S. Lima
´ ´ ˆ ´
Universidade Federal do Rio de Janeiro, Instituto de Quımica, Departamento de Quımica Organica, Cidade Universitaria,
21945-970 Rio de Janeiro, RJ, Brazil
Received 29 March 2005; revised 20 June 2005; accepted 22 June 2005
Available online 14 July 2005
Abstract—The reaction of trichloroisocyanuric acid (TCICA) and triphenylphosphine in the presence of a carboxylic acid results in
the in situ formation of the corresponding acid chloride under mild conditions. Subsequent addition of amines or alcohols, in the
presence of a tertiary amine affords the corresponding amides, or esters, in good to excellent yields. The methodology was applied to
the synthesis of a dipeptide.
Ó 2005 Elsevier Ltd. All rights reserved.
The activation of carboxylic acids and their subsequent
conversion to esters or amides is a key transformation in
organic synthesis. In spite of the host of protocols devel-
oped to that end, invariably there is a commitment
between functional group compatibility and the cost of
the reagents employed to activate the carboxylic acid.
This scenario is particularly critical for substrates bear-
ing acid-sensitive functional groups. Thus a mild, cost-
effective alternative for acylations would find ample
application.
native method for obtention of the respective acid chlo-
rides from carboxylic acids by combination of Ph3P and
CCl3CN. Subsequent addition of primary amines
resulted in the obtention of secondary amides in high
yield.4
In the course of our studies, we have found that carboxy-
lic acids can be converted to the respective acid chlorides
under very mild conditions by simply mixing Ph3P and
TCICA in CH2Cl2 at 0 °C. Subsequent addition of
amines or alcohols, in the presence of a tertiary amine,
affords the corresponding amides or esters in a one-pot
procedure.
Acid chlorides are valuable intermediates in organic syn-
thesis and are generally prepared by the reaction of car-
boxylic acids with reagents such as thionyl chloride,
PCl3, PCl5, and oxalyl chloride, among others.1 However,
such protocols cannot be applied to acid-sensitive com-
pounds due to the vigorous conditions required and the
formation of strong acids (HCl) during the process.
Our initial experiments used a ratio of 1:1:0.3 of the
RCOOH–Ph3P–TCICA. However, under these condi-
tions the reactions were slow and afforded poor yields.
Significant improvement was observed when using ratio
1:1:1. Accordingly, the carboxylic acid was added to a
mixture of Ph3P and TCICA in DCM at 0 °C, and the
resulting suspension was allowed to warm to rt. After
45 min, triethylamine and the amine or alcohol of inter-
est were added, and the reaction mixture was stirred for
an additional 1–2 h.
It is known that the treatment of alcohols with the chlo-
rine or bromine triphenylphosphine adduct leads to the
formation of the corresponding halides in good to high
yield.2 Recently, Hiegel et al. showed that Ph3P treated
with trichloroisocyanuric acid (TCICA) in warm or
refluxing anhydrous CH3CN can convert alcohols to
the respective halides, 1,3-diketones to b-chloro-a,b-
insaturated ketones, an acid to an ester and a primary
amide to a nitrile group.3 Jang et al. developed an alter-
In order to illustrate the scope of this method, some
amides and esters were prepared as shown in Table 1.5
An important example that demonstrates the efficiency
of this method was the synthesis of the (Z)-N,N-
diethyl-2-methyl-2-butenamide (entry 2). This amide
*
Corresponding author. Tel.: +55 21 2562 7256; e-mail: edson@
iq.ufrj.br
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.127

´
Rogerio da C. Rodrigues et al. / Tetrahedron Letters 46 (2005) 5945–5947
5946
Table 1. Conversion of carboxylic acids to amines and esters by TCICA/Ph3P
Entry
1
Amide
Yield (%)
96a
Entry
7
Ester
Yield (%)
96d
Boc
N
O
O
N
H
OBn
O2N
O
O
2
95b
8
95d
OEt
OTBS
N
O
O
H
N
3
4
85b
92a
9
53d
90d
N
OEt
O
O
O
O
10
O
N
H
O
OH
OEt
O
5
6
50b
85c
11
12
30d
65e
N
H
O
HO
O
O
O
O
O
(Et)2N
N(Et)2
O
4
4
a n-Propylamine (6.0 equiv) was used.
b Triethylamine (3.0 equiv) and corresponding amine (1.0 equiv).
c Triethylamine (3.0 equiv) and corresponding amine (2.0 equiv).
d Corresponding alcohol (1.0 equiv) and triethylamine (3.0 equiv).
e Corresponding alcohol (2.0 equiv) and triethylamine (3.0 equiv).
was obtained in 95% yield without isomerization (lit.6
49% yield, 12% additional of the (E)-isomer when using
SOCl2). An inexpensive amine can be used in excess in
place of the ad-mixture with Et3N (entry 1). a-Keto-
amides7 are versatile synthetic intermediates, and could
be efficiently prepared by using this method (entries 4
and 5). Some representative esters were also synthesized
(entries 7–12). Boc-L-proline gave the benzyl ester in
Cl
N
Cl
N
O
O
O
O
Cl
P
Ph
Ph
Ph
N
N
R
N
N
Ph3P
Cl
Cl
Cl
O
O
O
HO
96% yield (entry 7), no racemization was observed after
Amines
or
20
D
The TBS-protected lactate (entry 8) was prepared in
hydrogenolysis {½aꢀ ꢁ60.1 (c 2.0, AcOH) (lit.9 ꢁ60.3)}.
23
O
Alcohols
Et3N
Amides
+
Ph3P=O
or
Cl
R
Esters
good yield, with no detectable racemization {½aꢀ
D
ꢁ28.7 (c 1.16, CHCl3) (lit.10 ꢁ28.9)}, leading to the con-
clusion that the acylation does not involve ketene as
intermediate. In some instances however, the protection
of functional groups is not required to perform this
transformation efficiently (entries 9, 10, and 11), making
this protocol even more versatile. Finally, a dicarboxylic
acid afforded the corresponding diester (entry 12), as
well as the diamide (entry 6), both in good yields.8
Scheme 1. Proposed mechanism.
the carboxylic acid, yielding triphenylphosphine oxide
and the corresponding acyl chloride.
The demonstrated methodology was applied to the syn-
thesis of the important dipeptide Boc-L-Leu-L-Pro-OBn,
a common intermediate in the synthesis of the tamanda-
rin cyclic depsipeptides, important natural products with
immunosuppressive, antiviral, and antitumor activity.11
The ester Boc-L-Pro-OBn (entry 6) after removal of
The mechanism proposed for the generation of the acid
chloride is depicted in Scheme 1. Thus, the initial attack
at the halogen in TCICA by triphenylphosphine leads to
the halogen–phosphonium salt, which then reacts with
Cl
N
O
1 - Ph3P, CH2Cl2
OBn
0 0C - rt, 45 min
O
O
N
OH
NHBoc
+
O
N
N
2 - H-L-Pro-OBn.HCl / Et3N
1h - 2h
O
Cl
Cl
O
NHBoc
85%
Scheme 2. Synthesis of the dipeptide Boc-L-Leu-L-Pro-OBn.

´
Rogerio da C. Rodrigues et al. / Tetrahedron Letters 46 (2005) 5945–5947
5947
9. Kurokawa, M.; Shindo, T.; Suzuki, M.; Nakajima, N.;
Ishihara, K.; Sugai, T. Tetrahedron: Asymmetry 2003, 14,
1323.
´
10. Li, W.; Ewing, W. R.; Harris, B. D.; Joullie, M. M. J. Am.
Chem. Soc. 1990, 112, 7659.
the Boc group, by treatment with 4.0 M HCl–EtOAc
was coupled in 85% yield using conditions analogous
to those previously described. No loss of the stereo-
20
chemical integrity was observed {½aꢀ ꢁ64.5 (c 2.0,
D
DCM) (lit.12 ꢁ64.7)} (Scheme 2).13,14
11. (a) Fenical, W.; Vervoort, H.; Epifanio, R. A. J. Org.
Chem. 2000, 65, 782; (b) Liang, B.; Portonovo, P.; Vera,
In summary, a convenient and practical method for the
preparation of amides and esters in good to excellent
yields, from readily available, inexpensive starting mate-
rials has been described.
´
M. D.; Xiao, D.; Joullie, M. M. Org. Lett. 1999, 1, 1319;
(c) Joullie, M. M.; Portonovo, P.; Liang, B.; Richard, D. J.
´
Tetrahedron Lett. 2000, 41, 9373.
´
12. Jou, G.; Gonzalez, I.; Albericio, F.; Williams, P. L.;
Giralt, E. J. Org. Chem. 1997, 62, 354.
13. Typical experimental procedure (1): To a solution of
triphenylphosphine (1.31 g, 4.99 mmol) and TCICA
(1.16 g, 4.99 mmol) in DCM, 30 mL at 0 °C was added
(0.500 g, 4.99 mmol) (Z)-2-methyl-2-butenoic acid in
portion. The solution was stirred for 45 min, diethylamine
(0.516 mL, 4.99 mmol) was added dropwise followed by
triethylamine (2.00 mL, 14.98 mmol). The ice bath was
removed and the solution was stirred for 1 h. The mixture
was filtered and the organic layer was washed with water
and dried over Na2SO4. The solution was then filtered on
a short column of silica gel with 10% EtOAc/hexanes and
the filtrate was concentrated in vacuo affording 2 in 95%
yield.6 1H NMR (CDCl3, 200 MHz): d 1.13 (6H, t,
J = 7.0 Hz, CH3); 1.59 (3H, dd, J = 7.0, 1.0 Hz, CH3),
1.76 (3H, d, J = 2.0 Hz, CH3); 3.31 (4H, q, J = 7.0 Hz,
CH2); 5.52 (1H, qq, J = 7.0, 1.5 Hz, CH).
14. Typical experimental procedure (2): To a solution of
triphenylphosphine (0.226 g, 0.86 mmol) and TCICA
(0.200 g, 0.86 mmol) in DCM, 4.3 mL at 0 °C was added
dropwise (0.200 g, 0.86 mmol) Boc-L-Leu in DCM,
4.6 mL. The solution was stirred for 30 min. H-Pro-L-
OBnÆHCl was added dropwise followed by triethylamine
(0.360 mL, 2.58 mmol). The ice bath was removed and the
solution was stirred for 2 h. The mixture was filtered and
the organic layer was washed with water and dried over
Na2SO4. The solution was then filtered on a short column
of silica gel with 5–10% EtOAc/hexanes and the filtrate
was concentrated in vacuo affording dipeptide Boc-L-Leu-
L-Pro-OBn in 85% yield.12 1H NMR (CDCl3, 200 MHz): d
0.86 (3H, d, J = 6.5 Hz, CH3); 0.88 (3H, d, J = 6.5, CH3),
1.45 (9H, s, CH3); 1.56–2.45 (6H, m, CH2, CH); 3.50–3.68
(2H, m, CH2); 4.38–4.54 (3H, m, CH2, CH); 5.10 (2H, d,
J = 12.3 Hz, CH2); 5.11 (1H, br, NH); 7.24 (5H, m, CH).
Acknowledgments
Financial support from CNPq and the Analytical Center
(IQ/UFRJ) are gratefully acknowledged. We also thank
Professor Simon John Garden for proofreading this
manuscript.
References and notes
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