Amide formation in one pot from carboxylic acids and amines via carboxyl and sulfinyl mixed anhydrides

Article abstract of DOI:10.1021/ol401053y

An efficient method has been developed for the preparation of yet unknown acyclic mixed anhydrides of carboxylic and sulfinic acids. Sterically hindered 2-methylbut-3-ene-2-sulfinyl carboxylates add primary and secondary amines preferentially onto the carbonyl moieties realizing a new method for the one-pot preparation of carboxamides. It uses 1:1 mixtures of carboxylic acids and amines without a base, requires no excess of reagents, and liberates only volatile coproducts. Protected di- and tripeptides have been prepared in solution without epimerization by application of this method.

Full text of DOI:10.1021/ol401053y

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Amide Formation in One Pot from
Carboxylic Acids and Amines via
Carboxyl and Sulfinyl Mixed Anhydrides
ꢀ
ꢀ
Bartosz K. Zambron, Srinivas R. Dubbaka, Dean Markovic, Elena Moreno-Clavijo, and
Pierre Vogel*
Laboratory of Glycochemistry and Asymmetric Synthesis, Swiss Federal Institute of
Technology (EPFL), CH 1015 Lausanne, Switzerland
Pierre.Vogel@epfl.ch
Received April 17, 2013
ABSTRACT
An efficient method has been developed for the preparation of yet unknown acyclic mixed anhydrides of carboxylic and sulfinic acids. Sterically
hindered 2-methylbut-3-ene-2-sulfinyl carboxylates add primary and secondary amines preferentially onto the carbonyl moieties realizing a new method
for the one-pot preparation of carboxamides. It uses 1:1 mixtures of carboxylic acids and amines without a base, requires no excess of reagents, and
liberates only volatile coproducts. Protected di- and tripeptides have been prepared in solution without epimerization by application of this method.
Amide formation from carboxylic acids and amines is a
fundamental reaction in organic, polymer, and medicinal
chemistry for which a lot of research is still pursued.1 The
main challenge is to find smooth reaction conditions that
require neither heating nor strong bases or acids in order to
avoid R-epimerization of the resulting carboxamides and
require no excess of reagents. A classical method for acyl
group transfers onto free amines is the use of carboxylic
mixed anhydrides,2 including acyloxyborates and boronates3
and sulfonyl carboxylates.4 Acyclic mixed anhydrides of
sulfinic and carboxylic acids (sulfinyl carboxylates)
are unstable compounds that have not yet been isolated,5
and their reactions with amines have not yet been re-
ported. However, cyclic sulfinyl carboxylates such as 1,2-
oxathiolane-5-ones6 have been reported to add alcohols
and amines preferentially onto their carbonyl moiety
generating the corresponding carboxylic esters and car-
boxamides, respectively.7 Amides can be obtained directly
from carboxylic acids using thionyl chloride in di-
methylacetamide in the absence of base.8 Recently, Cossy
and co-workers reported XtalFluor-E to be an excellent
coupling reagent for the amidification of carboxylic acids,
which in some cases generate mixtures containing the
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10.1021/ol401053y
XXXX American Chemical Society

corresponding N,N-diethyl carboxamides.9 We report a new
one-pot procedure for the synthesis of carboxamides that
combine carboxylic acids with primary and secondary
amines via acyclic sulfinyl carboxylates at room temperature.
This method that does not require any base has been applied
to the solution synthesis of protected di- and tripeptides.
We have found that carboxylic acids can be converted
under neutral conditions into their trimethylsilyl esters
quantitatively at 20 °C (<15 min) by reaction with 1 equiv
of trimethylsilyl 2-methylprop-2-ene-1-sulfinate (1).10 The
coproducts are volatile isobutylene and SO2 that result
from a quick retro-ene reaction of 2-methylprop-2-ene-1-
sulfinic acid at 20°C.11 Using 3-phenylpropionic acid (2) in
MeCN, ester 3 is obtained quantitatively. It is not isolated
but reacted (70 °C, 2 h) directly with 1 equiv of 2-methyl-
prop-2-ene-1-sulfinyl fluoride (5) to generate the corre-
sponding acylic sulfinyl carboxylates 6 and volatile TMSF
as a coproduct. Reagent 5 was prepared by reaction of 1
with SOCl2 that produces 2-methylprop-2-ene-1-sulfinyl
chloride (4) which was then reacted with KF (2 equiv) and
dibenzo-18-crown-6 (5 mol %).12 Reactions of 6 at 20 °C
with aniline (7a, 5 min), pyrrolidine (7b, 5 min), isopro-
panol (7c, 15 min), phenol (7d, 12 h), thiophenol (7e, 5 min),
(2-methylallyl)trimethyl silane (7f, 3 h), and 1-trimethylsi-
lyloxystyrene (7g, 12 h) generated products 8aꢀ8g (in 65 to
99% yield) by S-attack exclusively (Scheme 1).
We reasoned that a mixed anhydride bulkier than 6
about the sulfinyl moiety might divert the nucleophilic
attack to the carbonyl group rather than to the sulfinyl
moiety. Thus, silyl ester 3 was reacted with 1 equiv of
2-methylbut-3-ene-2-sulfinyl fluoride (12) to give mixed
anhydride 13 (Scheme 2). Reagent 12 was obtained in the
following way: 3-methylbut-2-en-1-yl chloride (9) was
reacted with Mg (I2 cat.), TMSCl in THF at ꢀ60 °C to
generate prenyltrimethylsilane (62%).13 The latter under-
went a sila-ene reaction with SO2 (saturated solution in
toluene at 20 °C)14 that is catalyzed by (CF3SO2)2NH.
It provided trimethylsilyl 2-methylbut-3-ene-2-sulfinate
(10, 75%) which was then reacted with SOCl2 (0ꢀ20 °C)
to yield the corresponding sulfinyl chloride 11 (85%).15
The latter was displaced with KF (MeCN, dibenzo-18-
crown-6, cat.) to give sulfinyl fluoride 12 (81%, after
distillation). The conversion of silyl ester 3 into mixed
anhydride 13 with 12 was a slow reaction at 70 °C and was
accompanied by decomposition. Pyridine, DMAP, Et3N,
Pd(PPh3)4, CsF, and KF (þ dibenzo-18-crown-6) in
MeCN catalyzed the reaction at 20 °C producing a mixture
of the desired mixed anhydride 13 and of undesired
symmetrical carboxylic anhydride (PhCH2CH2CO)2O.
However, with 10% KBr at 70 °C, or better, with CaBr2,
Bu4NBr, KI, Bu4NI, and Me3SI at 20 °C, a 1:1 mixture
of 3 þ 12 produced pure 13. For the moment the most
efficient catalyst is Me3SþIꢀ (20 °C, 2h). Aniline (7a)
reacted (20 °C 1 h) with 13 containing 20% Me3SþIꢀ
giving a 9:1 mixture of carboxylic acid 2 and carboxamide
14a (Scheme 2).
Scheme 1. Preparation of the Mixed Anhydride of
3-Phenylpropionic Acid and 2-Methylprop-2-ene-1-sulfinic
Acid and Its Reaction with Common Nucleophilesa
Scheme 2. Iodide-Catalyzed Preparation of Mixed Anhydride
of 3-Phenylpropionic Acid and of 2-Methylbut-3-ene-2-sulfinic
Acid and Its Reaction with Aniline in the Presence of an Iodide
a The sulfinyl addition is preferred for all nucleophiles.
All the catalysts applied above are nucleophiles able
to add to the sulfinyl fluoride 12 (Scheme 3)16 and to
(9) Orliac, A.; Gomez Pardo, D.; Bombrun, A.; Cossy, J. Org. Lett.
2013, 15, 902–905.
(10) Huang, X.; Craita, C.; Awad, L.; Vogel, P. Chem. Commun.
ꢀ ꢀ
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ꢁ
G.; Dunogues, J. J. Organomet. Chem. 1985, 281, 149–162.
(14) (a) Bouchez, L.; Vogel, P. Synthesis 2002, 225–231. (b) Vogel, P.;
Turks, M.; Bouchez, L.; Markovic, D.; Varela-Alvarez, A.; Sordo, J. A.
Acc. Chem. Res. 2007, 40, 931–942.
(15) (a) Stirling, C. J. M. Int. J. Sulfur Chem., Part B 1971, 6, 277–320.
(b) Braverman, S.; Cherlinsky, M.; Levinger, S. Science of Synthesis;
Thieme Chemistry: Stuttgart, 2007; Vol. 39, pp 187ꢀ243.
2005, 1297–1299.
(11) (a) Masilamani, D.; Rogic, M. M. J. Am. Chem. Soc. 1978,
100, 4634–4635. (b) Varela-Alvarez, A.; Markovic, D.; Vogel, P.; Sordo,
J. A. J. Am. Chem. Soc. 2009, 131, 9547–9561.
(12) See Supporting Information for details.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Possible Mechanism for the Nucleophile-Catalyzed
Formation of Mixed Anhydride and for Its Sulfinyl Transfer
to Amines
Scheme 4. One-Pot Conversion of Carboxylic Acids and Amines
into Their Carboxamides at 20 °C (Yield after Purification)
equilibrate with the corresponding sulfinyl intermediates
15. This liberates the fluoride anion which attacks the silyl
ester 3 forming the 3-phenylpropionate anion that adds
on its turn to the sulfinyl intermediate 15 generating the
mixed anhydride 13. The iodide anion (as well as bromide
anion and tertiary amines) is responsible for the preferred
S-addition of aniline (7a). The high affinity of the nucleo-
philic catalysts for sulfur brings 13 to equilibrate with
intermediates of type 15 and liberation of the carboxylate
anion (Scheme 3). Thus, aniline (7a) reacts preferentially
with 15 rather than with the mixed anhydride 13, produ-
cing carboxylic acid 2 and the corresponding sulfinylamide
16a as a major product. In order to avoid this we ex-
changed the nuꢀcleophilic iodide anion by the non-
nucleophilic BF4 anion by precipitation of AgI with
AgBF4. Under these conditions 13 reacted (20 °C, 6 h) with
1 equiv of aniline giving pure carboxamide 14a17 in 91%
yield. Thus, a one-pot method that converts carboxylic acid
2 and aniline (7a) into amide 14a at 20 °C was uncovered.
The method was then applied to the synthesis of amides
collected in Scheme 4. They combine aniline (7a), pyrroli-
dine (7b), benzylamine (16a), tert-butyl esters of L-alanine
(17b), L-valine (17c), L-proline (17d) with 3-phenylpropio-
nic acid (2), hexanoic acid (18), cyclopentanecarboxylic
acid (19), 3-methylbutyric acid (20), and benzoic acid (21).
In general the yield is the highest for the least bulky amines
and carboxylic acids. The reaction conducted with pivalic
acid did not give the expected amide. We verified that
carboxamides 14a and 14b did not result from the reac-
tion of carboxylic acid 2 with sulfinylamides 16a and
CH2dCH-CMe2-SO(1-pyrrolidinyl) (16b) (1:1 mixtures
in MeCN at 20 °C with 10% Me3SI þ AgBF4), re-
spectively. Isopropanol (7c), phenol (7d), thiophenol (7e),
1-trimethylsilyloxystyrene (7f), and (2-methylallyl)tri-
methylsilane (7g) mixed with anhydride 13 reacted very
slowly at 20ꢀ70 °C. The reactions produced carboxylic
acid 2, thus indicating preferred S-addition again. They
were accompanied by decomposition.
Combining benzylcarbamates of L-alanine (30b), L-va-
line (30c), and L-proline (30d) with tert-butyl esters of the
same R-amino acids afforded the pure protected dipeptides
31c, 32b, 33c, 33b, and 33c shown in Scheme 5. NMR
studies (elaborated in the Supporting Information)
showed that no epimerization had occurred during their
preparation. Treatment of tert-butyl ester 32c with 1 equiv
of silyl sulfinate 1inthepresenceof10%TMSOTf(20°C, 1 h)
resulted in the formation of the desired trimethylsilyl ester
(one-pot direct tert-butyl/TMS exchange, probably
through E1-elimination of isobutylene and silylation of the
intermediate carboxylic acid). Without isolation, the latter
(16) (a) Tillett, J. G. Chem. Rev. 1976, 76, 747–772. (b) Norton, S. H.;
Bachrach, S. M.; Hayes, J. M. J. Org. Chem. 2005, 70, 5896–5902.
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9366.
Org. Lett., Vol. XX, No. XX, XXXX
C

carboxylic anhydride. Subsequent addition of 30% AgBF4
and then amines 17b and 17c afforded tripeptides 34 (78%)
and 35 (77%), respectively. The syntheses of these tripep-
tides were not accompanied by epimerization as confirmed
by 1H and 13C NMR studies.
Scheme 5. Preparation of Di- and Tripeptidesa
An efficient method has been developed for the pre-
paration of acyclic mixed anhydrides of carboxylic and
sulfinic acids (sulfinyl carboxylates) at room temperature.
Unless the sulfinyl moiety is sterically hindered, common
nucleophiles add to it preferentially. In the presence of
Me3SþBF4ꢀ, 2-methylbut-2-ene-1-sulfinyl carboxylates
add primary and secondary amines preferentially onto
their carboxyl moieties realizing a new method for the
preparation of carboxamides that uses 1:1 mixtures of
reactants and requires neither a base nor excesses of
reagents. Since the coproducts are volatile, workup to
isolate pure amides is simplified. The method has been
applied to the solution synthesis of protected di- and
tripeptides. Further development of the method will con-
centrate on the search for catalysts of the amine addition
to the carboxyl group of the sulfinyl carboxylates.
Acknowledgment. This work was supported financially
by the Swiss National Science Foundation, the SCIEX
program (Switzerland), and the European PANACREAS
FP7 project. We gratefully acknowledge the IV Plan
´
Propio de Investigacıon of the University of Seville for a
grant to E.M-C for her stay at the EPFL.
Supporting Information Available. Experimental pro-
1
cedures, characterizations, data and H and 13C NMR
a Conditions: See Scheme 4 and text.
spectra of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
was reacted with the sulfinyl fluoride 12 and 30% Me3SI
to generate in situ the corresponding mixed sulfinyl
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX