XtalFluor-E, an efficient coupling reagent for amidation of carboxylic acids

Article abstract of DOI:10.1021/ol400045d

Amides were produced from carboxylic acids and amines by using XtalFluor-E as an activator. Even poorly reactive carboxylic acids can be transformed to amides. In addition, optically active amines and/or carboxylic acids were not epimerized/racemized during the process.

Full text of DOI:10.1021/ol400045d

ORGANIC
LETTERS
2013
Vol. 15, No. 4
902–905
XtalFluor-E, an Efficient Coupling Reagent
for Amidation of Carboxylic Acids
†
Aurelie Orliac, Domingo Gomez Pardo,* Agnes Bombrun, and Janine Cossy*
,†
‡
,†
ꢀ
ꢁ
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin,
75231 Paris Cedex 05, France, and Merck Serono S. A., Chemistry Department,
9 Chemin des Mines, 1202 Geneva, Switzerland
domingo.gomez-pardo@espci.fr; janine.cossy@espci.fr
Received January 7, 2013
ABSTRACT
Amides were produced from carboxylic acids and amines by using XtalFluor-E as an activator. Even poorly reactive carboxylic acids can be
transformed to amides. In addition, optically active amines and/or carboxylic acids were not epimerized/racemized during the process.
The conversion of carboxylic acids to the corresponding
amides is an important transformation.1 It has been re-
ported by three leading pharmaceutical companies that
the production of an amide bond was required in the syn-
thesis of 65% of the drug candidates surveyed.2 Numerous
synthetic methods have been developed to synthesize
amides from carboxylic acids and amines using various
reactive coupling reagents.1,3 Despite the variety of cou-
pling reagents, the reaction conditions can be drastic
(requiring elevated temperatures), the workup can be
problematic, and epimerization/racemization of the sub-
strates can occur, particularly when DCC is used. It is of
interest to develop alternative conditions and/or to find
new coupling reagents which are efficient and mild, which
do not induce epimerization/racemization of optically
active substrates and for which the workup is easy.
Herein, we would like to report that XtalFluor-E4ꢀ6
[(F2SNEt2)BF4] can be utilized as a reactive coupling
reagent to produce amides from carboxylic acids and
amines under mild conditions (THF, 0 °C to rt) and with
aneasyworkup(Na2CO3, H2O). Thiscoupling reagent has
been used to couple optically active substrates without
epimerization/racemization.
Our optimization of the reaction conditions involved us
studying the amidation of octan-1-oic acid 1 with benzyl-
amine 2. The best conditions for obtaining amide 3
entailed us using 1.5 equiv of XtalFluor-E and 2 equiv of
benzylamine, at 0 °C to rt for 4 h and at a concentration
of 6 ꢁ 10ꢀ2 mol/L which allowed the isolation of amide
3 in 96% yield (Table 1, entry 4). It is worth pointing out
that 1.1 equiv or 1.5 equiv of amine can be used as well as
1.05 equiv of XtalFluor-E. However, the yield in 3 is not
as good as with 1.5 equiv of XtalFluor-E and 2 equiv of 2
(Table 1, entries 1ꢀ3). Furthermore, increasing the number
of equivalents of benzylamine (5 equiv) did not increase the
yield of 3 (88%) (Table 1, entry 6).7
† ESPCI ParisTech.
‡ Merck Serono.
(1) (a) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61,
10827–10852. (b) Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606–
ꢀ
631. (c) Joullie, M. M.; Lassen, K. M. ARKIVOC 2010, 189–250.
The reaction is general, and the results are reported in
Table 2. XtalFluor-E can be utilized to transform aromatic
(d) El-Faham, A.; Albericio, F. Chem. Rev. 2011, 111, 6557–6602.
(2) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org.
Biomol. Chem. 2006, 4, 2337–2347.
(3) (a) Lee, K. S.; Kim, K. D. Synth. Commun. 2011, 41, 3497–3500
and references cited. (b) Luo, Q.-L.; Lv, L.; Tan, J.-P.; Nan, W.; Hui, Q.
Eur. J. Org. Chem. 2011, 6916–6922 and references cited. (c) Tian, J.;
Gao, W.-C.; Zhou, D.-M.; Zhang, C. Org. Lett. 2012, 14, 3020–3023.
(4) (a) Beaulieu, F.; Beauregard, L.-P.; Courchesne, G.; Couturier,
M.; LaFlamme, F.; L’Heureux, A. Org. Lett. 2009, 11, 5050–5053.
(b) L’Heureux, A.; Beaulieu, F.; Bennett, C.; Bill, D. R.; Clayton, S.;
LaFlamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier, M.
J. Org. Chem. 2010, 75, 3401–3411.
(5) Cochi, A.; Gomez Pardo, D.; Cossy, J. Org. Lett. 2011, 13, 4442–
4445. Cochi, A.; Gomez Pardo, D.; Cossy J. Eur. J. Org. Chem. 2012,
2023–2040.
(6) (a) Pouliot, M.-F.; Angers, L.; Hamel, J.-D.; Paquin, J.-F. Org.
ꢀ
Biomol. Chem. 2012, 10, 988–993. (b) Pouliot, M.-F.; Mahe, O.; Hamel,
J.-D.; Desroches, J.; Paquin, J.-F. Org. Lett. 2012, 14, 5428–5431.
(7) It is worth pointing out that N,N-diethylamide 8 was formed in
the reaction medium and the amount of 8 depends on the conditions.
r
10.1021/ol400045d
Published on Web 02/05/2013
2013 American Chemical Society

Table 1. Optimization of the Reaction Conditions for the
Amidation of Octan-1-oic Acid by Benzylamine
Table 2. Generalization: Amidation of Various Carboxylic Acids
2
XtalFluor-E
(equiv)
temp
yield
entry
(equiv)
(°C)
time
4 h
of 3a
1
2
3
4
5
6
7
1.1
1.5
1.6
2
1.05
1.05
1.5
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C
66%
71%
76%
96%
89%
88%
76%
4 h
4 h
1.5
4 h
2
1.5
30 min
30 min
4 h
5
1.5
1.5b
0 °C
0 °C to rt
2
a XtalFluor-E was added to a mixture of octan-1-oic acid and
benzylamine. b XtalFluor-M was used instead of XtalFluor-E.
and heteroaromatic carboxylic acids 4aꢀ4c to the corre-
sponding amides 5aꢀ5c in yields comprised between 53%
and 82% (Table2, entries 1ꢀ3). Sensitive acids suchasbut-
3-enoic acid 4d were transformed into amide 5d (88%),
when treated with benzylamine, without formation of
the corresponding conjugated amide (Table 2, entry 4).
In addition, sterically hindered carboxylic acids such as 4e
and 4f were converted to 5e and 5f in excellent yields
(86% and 84% respectively) (Table 2, entries 5ꢀ6). In
the case of deactivated acids such as 4g and 4h, amides 5g
and 5h were isolated in 67% and 52% yield respectively
(Table 2, entries 7ꢀ8).
Furthermore, optically active carboxylic acids 4i and 4j
were converted to the corresponding amides 5i and 5j in
91%ꢀ97% and 52%ꢀ67% yields respectively without
any racemization of the carboxylic acids8 (Table 2, entries
9ꢀ10). In addition, unprotected L-pyroglutamic acid was
converted to 5k in 84% yield (Table 2, entry 11).
a Isolated yields. b Amide 5g was isolated after 30 min. c 1.1 equiv of
XtalFluor-E and 2 equiv of benzylamine were used.
corresponding amide 7i was isolated in 74% yield with an
excellent enantiomeric excess (ee >99%)8 (Table 3, entry 9).
One limitation was observed with sterically hindered
primary amines as 6j was converted to amide 7j in only 8%
yield. Here, the major product formed was diethylamide 8
(ratio 7j:8 = 13:87) (Table 3, entry 10). XtalFluor-E can
also induce a coupling reaction between carboxylic acid 1
and different secondary amines 6kꢀ6m to produce the
corresponding amides 7kꢀ7m in good yields (62ꢀ98%)
(Table 3, entries 11ꢀ13). However, as previously observed,
sterically hindered secondary amines such as 6n were not
reactive and diethylamide 8 was formed instead in 89%
yield (Table 3, entry 14).
A diversity of primary and secondary amines can be
utilized for the amidation of carboxylic acids. The results
are summarized in Table 3. Primary amines such as 6aꢀ6d
led to the corresponding amides in good yields (up to 97%
yield) (Table 3, entries 1ꢀ4). We have to point out that
N-tosylamides are not reactive under these conditions,
with N-tosyl-1,2-diaminoethane 6d leading only to 7d in
94% yield (Table 3, entry 4). Various anilines also engaged
in the coupling process with 6eꢀ6g were transformed into
the corresponding amides 7eꢀ7g in yields varying from
53% to 74% (Table 3, entries 5ꢀ7). Alkyl amines were more
reactive than anilines, with octanoic acid 1 being converted
to 7h and 7h0 in 62% yield, in a ratio of 91:9, using aniline
6h (Table 3, entry 8). When an optically active primary
amine such as 6i was coupled with carboxylic acid 1, the
When sterically hindered or desactivated amines were
used, diethylamide 8 was the major product and this side
product constitutes a limit for the amidation of carboxylic
acids using XtalFluor-E as the activating agent.
When the amidation of octan-1-oic acid 1 was studied
with dibenzylamine using XtalFluor-E as the activating
(8) The ee’s were determined by SFC (Daicel chiralcel AD-H column,
P = 100 bar, flow = 5 mL/min).
Org. Lett., Vol. 15, No. 4, 2013
903

Table 3. Generalization: Amidation with Primary and Secondary
Amines
Table 4. Optimization of the Coupling Conditions
HNBn2 XtalFluor-E
ratio yieldb
entry (equiv)
(equiv)
additives
9:8a
in 9
1
2
2
2
1.5
1.5
ꢀ
17:83
20:80
ꢀ
ꢀ
Et3N
(3 equiv)
DBU
3
4
5
2
2
2
1.5
1.5
1.5
20:80
ꢀ
(3 equiv)
Proton sponge 70:30
67%
ꢀ
(2 equiv)
Proton sponge
(3 equiv)
ꢀ
64:36
6
7
2
2
1.1
1.1
60:40
83:17
ꢀ
Proton sponge
(2 equiv)
ꢀ
68%
8
5
1.5
90:10
74%
a Ratio determined by 1H NMR of the crude. b Isolated yields.
Table 5. Amidation of Carboxylic Acids with Sterically Hin-
dered Amines and Anilines
a Ratio determined by 1H NMR of the crude. b Isolated yields.
Conditions: (A) 2 equiv of amine 6, (B) 2 equiv of amine 6 and 2 equiv
of proton sponge, (C) 5 equiv of amine 6, (D) 2 equiv of amine 6,
c = 6 ꢁ 10ꢀ3 mol/L.
amide 8 (Table 4). In order to avoid deprotonation of
the carboxylic acid by the valuable secondary amine
(dibenzylamine), the addition of a base such as Et3N or
DBU was examined. In both cases, the ratio of 9:8 was 20:80
in favor of 8 (Table 4, entries 2ꢀ3). However, when a proton
sponge such as 1,8-bis(dimethylamino)naphthalene (proton
sponge) (2 equiv) was used, the ratio of 9:8 increased to 70:30
(Table 4, entry 4) and a similar ratio was obtained by addition
of 3 equiv of proton sponge (64:36) (Table 4, entry 5). The use
a Isolated yields. b 1.1 equiv of XtalFluor-E and 5 equiv of amine
were used. c A mixture of 7j and 8 was obtained in a ratio 7j:8 = 13:87.
reagent, a mixture of the desired amide 9 and diethylamide
8 was obtained in a ratio of 17:83 in favor of the undesired
904
Org. Lett., Vol. 15, No. 4, 2013

of 1.1 equiv of XtalFluor-E improved the 9:8 ratio (83:17)
in favor of 9 without improvement of this yield (Table 4,
entry 7). The coupling reaction between octan-1-oic acid
and a large excess of dibenzylamine led to 9 in 74% yield.
The coupling reaction was also achieved between octan-
1-oic acidand aniline 6fusing 2 equivofproton spongeand
2 equiv of amine (conditions B), or 5 equiv of amine
(conditions C), improving the yield in amide 7f (Table 5,
entries 1). Amides 7k and 7o were obtained in good yield
(87ꢀ94%) even with sterically hindered secondary amines
6k and 6o using conditions B and C (Table 5, entries 2ꢀ3).
It is worth pointing out that realizing the reaction at
6 ꢁ 10ꢀ3 mol/L (conditions D) led to a mixture of amide 7o
and 8 in a ratio of 28:72 in favor of diethylamide 8.
acid to produce the undesired diethylamide D.6 The latter can
be the major product when the reaction is realized under high
dilution. To decrease the formation of the diethylamide,
either one must increase the number of equivalents of amine
(5 equiv) or use a proton sponge (2 equiv) in the presence of
2 equiv of amine.
Scheme 2. Proposed Mechanism for the Formation of Amides
XtalFluor-E was also used in the synthesis of a dipeptide.
Thus, N-Boc proline 10 was transformed to dipeptide 12
in 52% yield by using the optically active amine 11 with an
excellent diastereomeric excess (dr >98/2) (Scheme 1).
Scheme 1. Peptidic Coupling
In conclusion, we have shown that XtalFluor-E is an
efficient coupling reagent for the synthesis of amides from
carboxylic acids and amines without epimerization/race-
mization of the substrates.
From these results, it seems that different intermediates
may be involved in the amidation of carboxylic acids in-
duced by XtalFluor-E (Scheme 2). Treatment of a car-
boxylic acid by an amine or by a proton sponge should
produce a carboxylate intermediate that can react with
XtalFluor-E to produce intermediate A. This intermediate
can be attacked intermolecularly by an amine to produce
B, which should lead to the desired amide C. However, an
intramolecular process can take place in intermediate A as
the diethylamino group can attack the activated carboxylic
Acknowledgment. A.O. thanks Merck Serono S. A. for
a grant, and Merck Serono S. A. is gratefully acknowl-
edged for financial support.
Supporting Information Available. Experimental pro-
cedure, characterization data, and NMR spectra of com-
pounds 3, 5aꢀ5k, 7aꢀ7o, 8, 9, and 12. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
905