One-pot synthesis of amides and esters from 2,2,2-trihaloethyl esters using phosphorus(III) reagents

Full text of DOI:10.1021/jo9823700

1430
J . Org. Chem. 1999, 64, 1430-1431
Communications
amide (HMPT) was selected to determine the optimal
reaction conditions (Table 1). The tribromoethyl ester pro-
vides a softer, more reactive halogen electrophile than its
trichloroethyl ester counterpart, and HMPT was chosen for
its high nucleophilicity.6 Treatment of 1a with 1.2 equiv of
HMPT, 1 equiv of butylamine, and 2.5 equiv of triethylamine
in THF at 0 °C provided 2 in 36% yield (entry 1). Use of
benzene as a nonpolar solvent gave a similar yield (entry
2), while more polar solvents such as acetonitrile (entry 3)
or dimethylformamide (DMF, entry 4) facilitated the reac-
tion, with DMF providing the best yield. Lowering the
reaction temperature improved the yield of 2 to 83% (entry
5). Small amounts of 2,2-dibromoethyl benzoate and N,N-
dimethylbenzamide were isolated byproducts in these reac-
tions.
Investigation of the choice of reductant and electrophile
revealed the combination of HMPT and tribromoethyl
protecting group to be the most effective for amide synthesis
(Table 2). The reaction of HMPT with 1a proceeded rapidly
at -55 °C (entry 1). The use of tributylphosphine slowed
the reaction and provided 2 in reduced yield (entry 2).
Decreasing the nucleophilicity of the phosphorus reagent by
using triphenylphosphine markedly slowed the reaction at
room temperature (entry 3), resulting in a 24% yield of 2
after 48 h. This yield is similar to that of the corresponding
control experiment conducted in the absence of phosphine
(entry 4). Heating the triphenylphosphine reactions pro-
duced yields only marginally higher than controls. Use of
the trichloroethyl ester necessitated the use of higher
temperatures to afford complete consumption of starting
material, and lower yields were obtained (entries 5 and 6).
Using the optimized conditions, secondary and tertiary
amides of aromatic and aliphatic acids as well as a protected
alanylalanine dipeptide have been synthesized from the
corresponding tribromoethyl esters (Table 3).
Modification of the amide synthesis conditions allowed for
the synthesis of esters using this strategy. Initial attempts
to effect the transesterification of trihaloethyl esters by
addition of HMPT to tribromoethyl esters failed to produce
the desired products. The use of PBu3 as phosphine reagent
gave the ester products, albeit in low yield (Table 4, entry
1). Addition of 2 equiv of the acylation catalyst 4-(N,N-
dimethylamino)pyridine (DMAP)7 markedly improved yields
in both HMPT- and tributylphosphine-induced reactions. In
contrast to the amidation reactions, tributylphosphine pro-
vided yields of ester products superior to those obtained with
HMPT. Substantial amounts of N,N-dimethylamide products
were observed when HMPT was used as reductant, presum-
ably resulting from attack on activated acyl intermediates
by dimethylamine liberated by the alcoholysis of HMPT.8
In support of this theory, HMPT underwent methanolysis
On e-P ot Syn th esis of Am id es a n d Ester s fr om
2,2,2-Tr ih a loeth yl Ester s Usin g
P h osp h or u s(III) Rea gen ts
J eremy J . Hans, Russell W. Driver, and
Steven D. Burke*
Department of Chemistry, University of WisconsinsMadison,
1101 University Avenue, Madison, Wisconsin 53706-1369
Received December 3, 1998
The synthesis of amides and esters from carboxylic acid
derivatives is a transformation of general synthetic interest.
Preparation of complex amides and esters from protected
carboxylic acids is generally achieved by carboxylic acid
deprotection followed by formation of an activated acyl
species and treatment with an amine or alcohol nucleophile.
Such a deprotection/condensation protocol requires two or
more steps and can be attended by difficulties in working
with the free carboxylic acid intermediate.
The 2,2,2-trichloroethyl group is a useful protecting group
for carboxylic acids,1 and the 2,2,2-tribromoethyl group has
also been used in this capacity.2 The removal of trihaloethyl
esters has been accomplished with a variety of reductive
methods, the most popular being treatment with zinc. The
use of phosphorus(III) compounds for the reductive cleavage
of trichloroethyl-protected phosphotriesters has also been
reported,3 presumably involving formation of an electrophilic
phosphonium species in addition to liberation of the dialkyl
phosphate anion and 1,1-dichloroethylene. Although phos-
phonium salts have long been used to activate carboxylate
functional groups in condensation reactions,4,5 in situ forma-
tion of these species by reduction of trihaloethyl esters to
effect condensation reactions has not been exploited. Herein
we report amidation or transesterification of trihaloethyl
esters using phosphorus(III) compounds, as generalized in
eq 1. This one-pot deprotection, activation, and condensation
sequence provides an operationally simple method for the
title transformations.
The conversion of 2,2,2-tribromoethyl benzoate (1a ) to
N-butylbenzamide (2) using hexamethylphosphorous tri-
(4) (a) Hruby, V. J .; Barstow, L. E. J . Org. Chem. 1971, 36, 1305. (b)
Yamada, S.; Takeuchi, Y. Tetrahedron Lett. 1971, 3595. (c) Castro, B.;
Dormoy, J .-R. Bull. Soc. Chim. Fr. 1971, 3034. (d) Castro, B.; Dormoy J . R.
Tetrahedron Lett. 1972, 4747. (e) Castro, B.; Dormoy, J .-R.; Evin, G.; Selve,
C. Tetrahedron Lett. 1975, 1219. (f) Coste, J .; Le-Nguyen, D.; Castro, B.
Tetrahedron Lett. 1990, 31, 205. (g) Coste, J .; Fre´rot, E.; J ouin P. J . Org.
Chem. 1994, 59, 2437.
(5) (a) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801. (b) Kim, M.
H.; Patel, D. V. Tetrahedron Lett. 1994, 35, 5603. (c) Coste, J .; Campagne,
J .-M. Tetrahedron Lett. 1995, 36, 4253.
* To whom correspondence should be addressed. Tel: (608) 262-4941.
Fax: (608) 265-4534. E-mail: burke@chem.wisc.edu.
(1) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991. (b) Woodward, R. B.; Heusler,
K.; Gosteli, J .; Naegeli, P.; Oppolzer, W.; Ramage, R.; Ranganathan, S.;
Vorbruggen, H. J . Am. Chem. Soc. 1966, 88, 852.
(2) (a) Stark, W. M.; Hawker, C. J .; Hart, G. J .; Philippides, A.; Petersen,
P. M.; Lewis, J . D.; Leeper, F. J .; Battersby, A. R. J . Chem. Soc., Perkin
Trans. 1 1993, 23, 2875. (b) Weiguny, J .; Schafer, H. J . Liebigs Ann. Chem.
1994, 225.
(3) (a) Letsinger, R. L.; Groody, E. P.; Tanaka, T. J . Am. Chem. Soc. 1982,
104, 6805. (b) Letsinger, R. L.; Groody, E. P.; Lander, N.; Tanaka, T.
Tetrahedron 1984, 40, 137.
(6) Castro, B. R. Org. React. 1983, 29, 1.
(7) (a) Ho¨fle, G.; Steglich, W.; Vorbrueggen, H. Angew. Chem., Int. Ed.
Engl. 1978, 17, 569. (b) Scriven, E. F. V. Chem. Soc. Rev. 1983, 12, 129. (c)
Hassner, A. In Encyclopedia of Reagents for Organic Synthesis; Paquette,
L. A., Ed.; Wiley: Chichester, 1995; p 2022.
10.1021/jo9823700 CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/17/1999

Communications
Ta ble 1. In itia l Stu d ies of Am id e F or m a tion
J . Org. Chem., Vol. 64, No. 5, 1999 1431
Ta ble 4. Syn th esis of Ester s fr om Tr ih a loeth yl Ester s
entry
solvent
T (°C)
% yield of 2a
1
2
3
4
5
THF
0
0
0
0
-55
36
35
70
75
83
entry trihaloethyl ester
alcohol (R′OH) product % yielda
benzene
CH3CN
DMF
1
2
1a
1a
1a
1a
1a
1a
3
CH3O(CH2)2OH
CH3O(CH2)2OH
BuOH
8a
8a
8b
8c
8d
8e
9a
9b
9c
9d
9e
8f
21b
69
81
77
62
61
74
65
70
63
65
11
44d
3
DMF
4
BnOH
a
Isolated yields.
5
2-pentanol
(-)-menthol
CH3O(CH2)2OH
BuOH
6
Ta ble 2. Effect of P h osp h or u s Nu cleop h ile a n d Ha logen
on th e Syn th esis of 2
7
8
3
9
3
BnOH
10
11
12
13
3
2-pentanol
(-)-menthol
t-BuOHc
3
1a
1b
CH3O(CH2)2OH
8a
a
b
Isolated yields. Reaction conducted in the absence of DMAP.
c 1:1 DMF/t-BuOH was used as solvent. Reaction temperature
d
entry
X
phosphorus rgt
T (°C)
time (h) % yield of 2a
) 100 °C.
1
2
3
4
5
6
Br
Br
Br
Br
Cl
Cl
HMPT
PBu3
PPh3
none
HMPT
PBu3
-55
0.5
1.2
48
48
4.5
3.5
83
benzoate ester when tert-butyl alcohol was used as cosolvent
(entry 12). As a control, treatment of 1a with 2-methoxy-
ethanol and DMAP in the absence of phosphine for 24 h at
room temperature produced no product by TLC analysis. As
with the amidation reactions, the use of the trichloroethyl
ester derivatives required higher temperatures for starting
material consumption and provided lower yields (entry 13).
The mechanism implied in eq 1, involving an acyloxy-
phosphonium intermediate,4b-d,g,5 is supported by the ob-
servation of 1,1-dibromoethylene by proton and carbon NMR
analysis of the crude distillates from reaction mixtures in
the conversion of 1a to 2 and 1a to 8a . Furthermore, 1H
NMR coupling constants for menthol-derived esters 8e and
9e revealed a retention of configuration at the carbinol
carbon. Thus, esterification does not proceed by a Mitsunobu-
type inversion in which the alcohol is activated by a
phosphonium species and then displaced by a carboxylate
anion.10 The beneficial effect of catalytic DMAP in transes-
terification reflects the lower nucleophilicity of alcohols,
relative to amines.
In summary, secondary and tertiary amides have been
synthesized in moderate to good yields from tribromoethyl
esters in one step by treatment with HMPT and amine.
Similarly, esters of primary and secondary alcohols have
been prepared from tribromoethyl esters by treatment with
tributylphosphine in the presence of DMAP. Trichloroethyl
carboxylates gave lower yields of ester and amide products
when subjected to these reaction conditions. This method
conveniently bypasses the free acid form of the substrate
and provides a direct and efficient method for the conversion
of protected carboxylic acids to esters or amides.
-55 f 0
25
rt
rt
rt
90
24b
17c
18
39
a
b
Isolated yields. 42% of 1a was recovered. c 66% of 1a was
recovered.
Ta ble 3. Op tim ized Con ver sion of Tr ibr om oeth yl Ester s
to Am id es
entry trihaloethyl ester
amine
HNEt2
HCl‚GlyOEt
BuNH2
HNEt2
HCl‚AlaOEt
product
% yielda
1
2
3
4
5
1a
1a
3
3
4
5a
5b
6a
6b
7
76
77
88
57
70
a
Isolated yields.
when subjected to similar reaction conditions in the absence
of tribromoethyl ester.9 The reduced nucleophilicity of alco-
hols relative to amines allows attack by dimethylamine to
become a competitive reaction pathway in the HMPT-
mediated transesterifications.
Esters of both primary and secondary alcohols were
produced in good yields using the tributylphosphine-DMAP
procedure (Table 4, entries 2-11). Acylation of tert-butyl
alcohol proved difficult, giving only 11% of the tert-butyl
Ack n ow led gm en t. This research was supported by
NIH Grant Nos. GM 28321 and CA74394. Additional
support from Merck and Pfizer is gratefully acknowledged.
The University of Wisconsin NMR facility receives financial
support from NSF (CHE-9208463) and NIH (1S10 RR0
8389-D1).
(8) (a) Petrov, K. A.; Nifant’ev, EÄ . E.; Lysenko, T. P.; Evdakov, V. P. Zh.
Obshch. Khim. 1961, 31, 2377. (b) Nifant’ev, EÄ . E.; Ivanova, N. L.; Fursenko,
I. V. Zh. Obshch. Khim. 1969, 39, 854. (c) Houalla, D.; Sanchez, M.; Wolf,
R. Bull. Soc. Chim. Fr. 1965, 2368.
(9) A solution of HMPT in DMF was treated with methanol (1.4 equiv),
DMAP (1 equiv), and 4-(N,N-dimethylamino)pyridinium trifluoroacetate
(DMAP‚TFA, 0.4 equiv). Phosphorus NMR analysis of an aliquot of this
reaction mixture after 10 min showed no HMPT resonance (122.7 ppm) and
two downfield resonances that correspond to MeOP(NMe2)2 (137.9 ppm) and
(MeO)2PNMe2 (147.6 ppm). This spectrum is similar to the 31P spectrum
obtained in the ethanolysis of HMPT (ref 8c).
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures, characterization data, and 1H and 13C NMR spectra for
compounds 1-9.
J O9823700
(10) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. Org. React. 1992,
43, 335.