Efficient synthesis of α-ketoamides via 2-acyl-5-aminooxazoles by reacting acyl chlorides and α-isocyanoacetamides

Article abstract of DOI:10.1021/ol902894p

"Chemical equation presented" Acyl chlorides and α-isocyanoacetamides undergo an efficient reaction in dichloromethane in the presence of triethylamine to give 2-acyl5-aminooxazoles. Subsequent acid hydrolysis of the 5-aminooxazole moiety leads to α-ketoamides in good overall yields.

Full text of DOI:10.1021/ol902894p

ORGANIC
LETTERS
2010
Vol. 12, No. 4
820-823
Efficient Synthesis of r-Ketoamides via
2-Acyl-5-aminooxazoles by Reacting
Acyl Chlorides and
r-Isocyanoacetamides
Riccardo Mossetti,† Tracey Pirali,*,† Gian Cesare Tron,† and Jieping Zhu‡
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche,
UniVersita` degli Studi del Piemonte Orientale “A. AVogadro”, Via BoVio 6,
28100 NoVara, Italy, and Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-YVette Cedex, France
pirali@pharm.unipmn.it
Received December 16, 2009
ABSTRACT
Acyl chlorides and r-isocyanoacetamides undergo an efficient reaction in dichloromethane in the presence of triethylamine to give 2-acyl-
5-aminooxazoles. Subsequent acid hydrolysis of the 5-aminooxazole moiety leads to r-ketoamides in good overall yields.
R-Ketoamides1 represent a privileged scaffold in medicinal
chemistry, and this structural motif can be found in natural
products such as the immunosuppressant drugs FK-506
and rapamycin.2 In addition, R-ketoamides are used as
serine or cysteine protease inhibitors;3 the higher elec-
trophilicity of the R-keto group makes the inhibition of
proteases possible, thanks to the formation of a covalent
hemiketal or hemithioketal adduct with the -OH or -SH
group of serine or cysteine protease, respectively.
over the past decades.4 Among these methodologies, the
use of isocyanides as reacting partner to generate R-ke-
toamides dates back to 1961, when Ugi reported that
R-ketoimidoyl chlorides (3), obtained by condensation
between acyl chlorides (1) and isocyanides (2), could be
converted upon hydrolysis into R-ketoamides (4) (Scheme
1).5
Further syntheses of R-ketoamides using isocyanides were
encouraged by a renewed interest in this synthon as a pivotal
For these reasons, a vast array of synthetic procedures
for the preparation of R-ketoamides have been developed
(4) See the following for examples. (a) Oxidation of R-aminoamides:
Buckley, T. F.; Rapoport, H. J. Am. Chem. Soc. 1982, 104, 4446–4450. (b)
Oxidation of R-hydroxyamides: Ocain, T. D.; Rich, D. H. J. Med. Chem.
1992, 35, 451–456. (c) Oxidation of acyl cyanophosphoranes followed by
amidation: Wasserman, H. H.; Ho, W. B. J. Org. Chem. 1994, 59, 4364–
4366. (d) Amidation of ketoacids: Li, Z.; Ortega-Vulain, A. C.; Patil, G. S.;
Chu, D. L.; Foreman, J. E.; Eveleth, D. D.; Powers, J. C. J. Med. Chem.
1996, 39, 4089–4098. (e) Ring opening and hydrolysis of azetidinones: Kim,
S. K.; Nuss, J. M. Tetrahedron Lett. 1999, 40, 1827–1830. (f) Oxidation of
R-cyanoketones: Yang, Z.; Zhang, Z.; Meanwell, N. A.; Kadow, J. F.; Wang,
T. Org. Lett. 2002, 4, 1103–1105. (g) Amidation of R-keto esters: Bihovsky,
R.; Tao, M.; Mallamo, J. P.; Wells, G. J. Bioorg. Med. Chem. Lett. 2004,
14, 1035–1038. (h) Oxidation of ynamides: Al-Rashid, Z. F.; Johnson, W. L.;
Hsung, R. P.; Wei, Y.; Yao, P. Y.; Liu, R.; Zhao, K. J. Org. Chem. 2008,
73, 8780–8784.
† Universita` degli Studi del Piemonte Orientale “A. Avogadro”.
‡ Institut de Chimie des Substances Naturelles.
(1) For recent reviews, see: (a) Dugave, C. Curr. Org. Chem. 2002, 6,
1397–1431. (b) Wang, X. J.; Etzkorn, F. A. Biopolymers 2006, 84, 125–
146.
(2) (a) Swindells, D.; C, N.; White, P. S.; Findlay, J. A. Can. J. Chem.
1978, 56, 2491–2492. (b) Tanaka, H.; Kuroda, A.; Marusawa, H.; Hatanaka,
H.; Kino, T.; Goto, T.; Hashimoto, M.; Taga, T. J. Am. Chem. Soc. 1987,
109, 5031–5033. (c) Schreiber, S. L. Science 1991, 251, 283–287.
(3) (a) Mehdi, S. Bioorg. Chem. 1993, 21, 249–259. (b) Edwards, P. D.;
Bernstein, P. R. Med. Res. ReV. 1994, 14, 127–194. (c) Gante, J. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1699–1720. (d) Otto, H. H.; Schirmeister,
T. Chem. ReV. 1997, 97, 133–171.
(5) (a) Nef, J. U. Justus Liebigs Ann. Chem. 1892, 270, 267–335. (b)
Ugi, I.; Fetzer, U. Chem. Ber. 1961, 94, 1116–1121.
10.1021/ol902894p  2010 American Chemical Society
Published on Web 01/20/2010

Scheme 1
.
Formation of R-Ketoimidoyl Chloride and Its
Scheme 2. Synthesis of 2-Acyl-5-aminooxazole 5a and Its
Subsequent Hydrolysis
Subsequent Acid Hydrolysis to R-Ketoamides 6a
substrate in multicomponent reactions, and in recent years
novel synthetic strategies exploiting the isocyanides emerged
from the literature.6 Despite these new methodologies, the
coupling between acyl chlorides and isocyanides to generate
R-ketoamides remains the most practical transformation.
Nevertheless, formation and hydrolysis of the key intermedi-
ate R-ketoimidoyl chloride are known to be problematic,
requiring several hours of heating.4b Even though the use of
microwave conditions has reduced the reaction time,7 this
methodology is impaired by low yields and harsh experi-
mental conditions that are not always compatible with
functionalized substrates. In light of this, a general and
straighforward methodology to rapidly prepare structurally
diverse R-ketoamides is still demanded.
In connection with our ongoing study on the reactivity of
R-isocyanoacetamides,8 we report herein their reaction with
acyl chlorides as a novel and reliable methodology to provide
access to R-ketoamides.
With the use of hexanoyl chloride 1a and R-isocyanoac-
etamide 2a as test substrates, 2-acyl-5-aminooxazole 5a9 was
isolated in very good yields, which upon acid hydrolysis led
to the R-ketoamide 6a in 61% yield (Scheme 2).
was added dropwise to a mixture of R-isocyanoacetamide
2a (1 equiv) and TEA (1 equiv) in dichloromethane under a
nitrogen atmosphere. The reaction was stirred at room
temperature for 1 h. After workup and column chromatog-
raphy, the 2-acyl-5-aminooxazole 5a was dissolved in THF,
and HCl 37% (100 µL/0.100 mmol) was added dropwise at
0 °C.10 The reaction was stirred at room temperature for 1 h,
worked up, and purified by column cromatography to give
the R-ketoamide 6a.
2-Acyl-5-aminooxazole 5a came with the formation of the
enol ester byproduct 7 (as a single geometrical isomer), due
to the reaction of the enolate ion with a second molecule of
acyl chloride (Scheme 2). Up to 45% yield of 7 was isolated
when the reaction was carried out in toluene under otherwise
identical conditions. However, by performing the reaction
in dichloromethane and by adding dropwise a solution of
acyl chloride in dichloromethane, the formation of 7 was
reduced to a minimum with concurrent increase in the yield
of the desired 2-acyl-5-aminooxazole.
The generality of this novel transformation was demon-
strated by applying the procedure to various acyl chlorides
and R-isocyanoacetamides. The R-isocyanoacetamides
2b,d,e,g were prepared by solventless aminolysis of methyl
isocyanoacetate with a primary or secondary amine as
reported by Do¨mling,11 and the subsequent alkylation in the
presence of cesium hydroxide12 gave rise to the R-substituted
R-isocyanoacetamides 2a,c,f (Scheme 3).
The following optimized experimental procedure was used:
A solution of acyl chloride 1a (1 equiv) in dichloromethane
(6) (a) El Ka¨ım, L.; Pinot-Pe´rigord, E. Tetrahedron 1998, 54, 3799–
3806. (b) Nakamura, M.; Inoue, J.; Yamada, T. Bioorg. Med. Chem. Lett.
2000, 10, 2807–2810. (c) Banfi, L.; Guanti, G.; Riva, R. Chem. Commun.
2000, 985–986. (d) Xu, P.; Lin, W.; Zhou, X. Synthesis 2002, 1017–1026.
(e) Grassot, J. M.; Masson, G.; Zhu, J. Angew. Chem., Int. Ed. 2008, 47,
947–950. (f) Faggi, C.; Neo, A. G.; Marcaccini, S.; Menchi, G.; Revuelta,
J. Tetrahedron Lett. 2008, 49, 2099–2102.
(7) Chen, J. J.; Deshpande, S. V. Tetrahedron Lett. 2003, 44, 8873–
8876.
(8) Selected examples: (a) Zhao, G.; Sun, X.; Bienayme`, H.; Zhu, J.
J. Am. Chem. Soc. 2001, 123, 6700–6701. (b) Janvier, P.; Bois-Choussy,
M.; Bienayme`, H.; Zhu, J. Angew. Chem., Int. Ed. 2003, 42, 811–814. (c)
Tron, G. C.; Zhu, J. Synlett 2005, 532–534. (d) Bonne, D.; Dekhane, M.;
Zhu, J. Org. Lett. 2005, 7, 5285–5288. (e) Pirali, T.; Tron, G. C.; Zhu, J.
Org. Lett. 2006, 8, 4145–4148. (f) Bughin, C.; Zhao, G.; Bienayme`, H.;
Zhu, J. Chem.sEur. J. 2006, 12, 1174–1184. (g) Wang, S.; Wang, M.-X.;
Wang, D.-X.; Zhu, J. Eur. J. Org. Chem. 2007, 407, 6–4080. (h) Pirali, T.;
Tron, G. C.; Masson, G.; Zhu, J. Org. Lett. 2007, 9, 5275–5278.
(9) Other oxazoles syntheses starting from isocyanides and acyl chlorides
are described in literature. See for example: (a) Suzuki, M.; Iwasaki, T.;
Matsumoto, K.; Okumura, K. Synth. Commun. 1972, 2, 237–242. (b)
Schro¨der, R.; Scho¨llkopf, U.; Blume, E.; Hoppe, I. Liebigs Ann. Chem.
1975, 533–546. (c) Huang, W.-S.; Zhang, Y.-X.; Yuan, C.-Y. Synth.
Commun. 1996, 26, 1149–1154. (d) dos Santos, A.; El Kau´m, L.; Grimaud,
L.; Ronserray, C. Chem. Commun. 2009, 3907–3909. (e) El Kau´m, L.;
Grimaud, L.; Schiltz, A. Tetrahedron Lett. 2009, 50, 5235–5237.
(10) Better yields were obtained by using 37% HCl (1 h, 61% for 6a),
instead of trifluoroacetic acid (32 h, 55% for 6a).
Scheme 3. Synthesis of R-Isocyanoacetamides Building Blocks
Five commercially available acyl chlorides, 1a-e, and
seven easily accessible R-isocyanoacetamides, 2a-g, were
used as starting materials (Figure 1).
(11) Do¨mling, A.; Beck, B.; Fuchs, T.; Yazback, A. J. Comb. Chem.
2006, 8, 872–880.
(12) Housseman, C.; Zhu, J. Synlett 2006, 11, 1777–1779.
Org. Lett., Vol. 12, No. 4, 2010
821

Figure 1. Structures of acyl chlorides and R-isocyanoacetamides.
Figure 3. Synthesized R-ketoamides. The yields refer to the
hydrolysis of compounds 5a-l.
The 2-acyl-5-aminooxazoles 5a-l were obtained in good
to excellent yields (Figure 2). Subsequent hydrolysis of these
R-branched acyl chloride 1e afforded the oxazole in lower
yields. Both R-unsubstituted and R-substituted R-isocyanoac-
etamides participated in the reaction. It is remarkable that,
compared to the multicomponent reaction between aldehydes,
amines, and isocyanoacetamides,13 which leads to the
formation of a 5-aminooxazole and, after acid hydrolysis,
to a dipeptidic structure (Scheme 4), this new strategy works
Scheme 4
.
Previously Reported 3-CR between Aldehydes,
Amines, and R-Isocyanoacetamides13
well not only with tertiary R-isocyanoacetamides but also
with secondary ones (2d,g), leading to a marked peptido-
mimetic scaffold. The reason for this result can be tentatively
explained by assuming an increase in stability of the
aminooxazoles due to the presence of the electron-withdraw-
ing acyl group at the 2 position.
Figure 2. Synthesized 2-acyl-5-aminooxazoles.
intermediates gave the R-ketoamides 6a-l listed in Figure
3 in good yields.
Structural modifications of both components do not affect
the yield of the corresponding reactions, which are still
characterized by good overall efficiency. Aliphatic acyl
chlorides were found to be good substrates, whereas
From a mechanistic point of view, the reaction between
acyl chloride and R-isocyanoacetamide might pass through
(13) (a) Sun, X.; Janvier, P.; Zhao, G.; Bienayme´, H.; Zhu, J. Org. Lett.
2001, 3, 877–880. (b) Janvier, P.; Sun, X.; Bienayme´, H.; Zhu, J. J. Am.
Chem. Soc. 2002, 124, 2560–2567.
822
Org. Lett., Vol. 12, No. 4, 2010

the ketene intermediate or via direct R-addition of the
isocyanide to the acyl chloride to give the R-ketoimidoyl
chloride. We therefore investigated the reaction starting from
the optically active (S)-2-phenylbutanoyl chloride (1e),
checking the stereochemistry of the product 5m by 1H NMR
in the presence of the chiral reagent Eu(tfc)3. A racemic
mixture was detected, suggesting that the reaction proceeds
through a ketene intermediate (Scheme 5).
Scheme 6
.
Proposed Mechanism for the Synthesis of
2-Acyl-5-aminooxazoles
Scheme 5. Reaction with (S)-2-Phenylbutanoyl Chloride
and R-isocyanoacetamides, two easily accessible starting
materials. This synthesis has clear advantages over the
previously reported methodologies: the entire sequence is
realized under mild and simple conditions. Besides efficiency,
the overall sequence displays versatility, providing R-ketoa-
mides with four potential points of diversity.
We believe that the synthesis reported herein can find
application in a number of fields in view of the medicinal
importance of this scaffold.
This conclusion is in accord with our experimental
observations. By reacting acyl chlorides and R-isocyanoac-
etamides without TEA, only the R-ketoimidoyl chloride was
formed; this intermediate could not be transformed to the
corresponding 2-acyl-5-aminooxazole as addition of the base
gave rise to a complex mixture. Moreover, when performing
the reaction between benzoyl chloride and 2d in the presence
of TEA at room temperature, only starting materials were
recovered.
A plausible reaction scenario is depicted in Scheme 6. Acyl
chloride 1 reacts with TEA forming the corresponding ketene
9. The isocyanide 2 attacks the electrophilic carbon atom to
produce the nitrilium ion 10. This latter intermediate cyclizes
and, after proton transfer, gives the 2-acyl-5-aminooxazole 5.
In conclusion, we documented a very straightforward two-
step synthesis of R-ketoamides starting from acyl chlorides
Acknowledgment. Financial support from Regione Pi-
emonte (Ricerca Sanitaria Finalizzata 2009 to TP) is grate-
fully acknowledged. We dedicate this paper to Prof. Aldo
Martelli (Universita` degli Studi del Piemonte Orientale,
Novara, Italy) on the occasion of his retirement.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL902894P
Org. Lett., Vol. 12, No. 4, 2010
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