A facile one-carbon homologation of aryl aldehydes to amides.

Article abstract of DOI:10.1021/ol025608m

The easily accessible 2-aryl-1,1-dibromo-1-alkenes can be converted to amides under unusually mild conditions in good to excellent yields. Both electron-donating and electron-withdrawing substitutions on the aromatic rings are tolerated, and the reaction works well with hindered alkylamines. This simple homologation could find broad applications. [reaction: see text]

Full text of DOI:10.1021/ol025608m

ORGANIC
LETTERS
2002
Vol. 4, No. 8
1315-1317
A Facile One-Carbon Homologation of
Aryl Aldehydes to Amides
,†
Wang Shen* and Aaron Kunzer‡
Sunesis Pharmaceuticals, 341 Oyster Point BouleVard,
South San Francisco, California 94080, and D04N6, AP10, Abbott Laboratories,
100 Abbott Park Road, Abbott Park, Illinois 60064
wshen@sunesis.com
Received January 23, 2002
ABSTRACT
The easily accessible 2-aryl-1,1-dibromo-1-alkenes can be converted to amides under unusually mild conditions in good to excellent yields.
Both electron-donating and electron-withdrawing substitutions on the aromatic rings are tolerated, and the reaction works well with hindered
alkylamines. This simple homologation could find broad applications.
Homologation of carbonyl compounds by one carbon has
been highly useful in organic and medicinal chemistry. The
mild conditions used in Arndt-Eistert-Wolff rearrangement
have led to a wide range of applications for the homologation
of carboxylic acids.1 On the contrary, even though one-carbon
homologation of aldehydes2 to carboxylic acid derivatives
offers an attractive alternative, the actual process is difficult
and has found only limited applications. These homologation
methods have relied on the intermediacy of R-heteroatom-
substituted enamines,3 R-heteroatom-substituted nitriles,4
ketene acetals5 and ketene thioacetal derivatives.6 Syntheses
of these intermediates and subsequent conversions to car-
boxylic acid derivatives often require harsh conditions that
may not be compatible with many functional groups present
in the molecules.
During our investigation of the of 1,1-dibromo-1-alkenes,7,8
amide 2 was isolated unexpectedly as the major product from
the homocoupling reaction when bis(tricyclohexylphosphine)-
palladium chloride was used as the catalyst (Scheme 1).8c
Scheme 1
† Sunesis Pharmaceuticals.
‡ Abbott Laboratories.
(1) Review: Gill, G. R. In ComprehensiVe Organic Synthesis; Trost, B.
M., Flemming, I, Eds.; Pergamon: Oxford, 1991; Vol. 3, p 887.
(2) Selected reviews on one-carbon homologation of aldehyde to
aldehyde: (a) (via vinyl thioether) Gro¨bel, B.; Seebach, D. Synthesis 1977,
357. (b) (via vinyl ether) Maercker, A. Org. React. 1965, 14, 270.
(3) Gross, H.; Costisella, B. Angew. Chem., Int. Engl. Ed. 1968, 7, 391.
(4) (a) Takahashi, K.; Masuda, T.; Ogura, K.; Iida, H. Synthesis 1983,
1043. (b) Takahashi, K.; Shibasaki, K.; Ogura, K.; Iida, H. J. Org. Chem.
1983, 48, 3566. (c) Dinizo, S. E.; Freerksen, R. W.; Pabst, W. E.; Watt, D.
S. J. Am. Chem. Soc. 1977, 99, 182.
Presumably, the water necessary for the transformation was
introduced from the solvent or other source since the
formation of diyne does not require anhydrous condiditions.
It is also known that tertiary amines could be converted to
(5) Van Schaik, T. A. M.; Henzen, A. V.; van der Gen, A. Tetrahedron
Lett. 1983, 24, 1303.
(6) (a) Ogura, K.; Tsuchihashi, G. Tetrahedron Lett. 1972, 1383. (b)
Jones, P. F.; Lappert, M. F. J. Chem. Soc., Chem. Commun. 1972, 526. (c)
Carey, F. A.; Court, S. J. Org. Chem. 1972, 37, 1926. (d) Funk, R.; Novak,
P. M.; Abelman, M. M. Tetrahedron Lett. 1988, 29, 1493. (e) Seebach, D.;
Grobel, B. T.; Beck, A. K.; Braun, M.; Geiss, K. H. Angew. Chem., Int.
Engl. Ed. 1972, 11, 443. (f) Kruse, C. G.; Broekhof, N. L. J. M.; Wijsman,
A.; van der Gen, A. Tetrahedron Lett. 1977, 885.
(7) Preparation: (a) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972,
3769. (b) Ramirez, F.; Desai, N. B.; McKelvie, N. J. Am. Chem. Soc. 1962,
84, 1745.
(8) (a) Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873. (b) Wang,
L.; Shen, W. Tetrahedron Lett. 1998, 39, 7625. (c) Shen, W.; Thomas, S.
A. Org. Lett. 2000, 2, 2857. (d) Shen, W. SynLett 2000, 737.
10.1021/ol025608m CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/21/2002

secondary amines in palladium-catalyzed reactions.9 This
observation led us to investigate the generality of this novel
new transformation. As one could have expected, the use of
secondary amine (piperidine)10 instead of tertiary ones and
addition of water to the reaction greatly facilitate the reaction.
The optimal amount of water was found to be about 25% in
the mixed solvent. Under these conditions, dibromide 1 is
transformed to the desired amide 3 within 1 h at 80 °C in
high yield. This transformation constitutes a novel two-step
homologation of aldehydes to carboxylic acid derivatives.
Furthermore, it compared very favorably with previously
reported similar reactions such as the hydrolyzation of 1,1-
dibromo-1-alkenes to carboxylic acids with concentrated
strong base (NaOH or KOH) at high temperature11 or the
hydrolyzation of 1,1-difluoro-1-alkenes with either mercury-
(II) acetate or concentrated sulfuric acid.12
Table 2. Conversion of 1,1-Dibromo-1-alkenes to Amidesa
Initially, we assumed that the transformation required
catalysis by palladium, as was observed in hydrolysis of 1,1-
dibromo-1-alkenes to the corresponding carboxylic acids.11
However, the transformation occurred smoothly in the
absence of a palladium catalyst. After a broad survey of
reaction conditions, we report here a facile and general two-
step homologation of aryl aldehydes to amides via 1,1-
dibromo-1-alkenes under very mild conditions in which many
functional groups could be tolerated. Further survey of the
reaction conditions is summarized in Table 1. Solvents play
Table 1. Optimization of Dibromoalkene 1 Conversion to
Amide 2a
entry
solvent
base
t [h]b
yield [%]c
1
2
3
4
5
6
7
toluene
MeCN
DME
i-PrOH
DMF
piperidine
piperidine
piperidine
piperidine
piperidine
96
18
24
22
1
10d
77
72
54
92
89
87
e
DMF
DMSO
Na2CO3
piperidine
1
1
a Reaction conditions: 1 (1.0 mmol), piperidine (5.0 mmol), solvent (3
mL), water (1 mL), 80 °C. b Reaction time is not optimized for those
reactions completed under 1 h. c Yields of isolated products. d Recovery
of 1 (50%). e Piperidine (1.1 mmol) and Na2CO3 (3.0 mmol) were used.
a Reaction conditions: 1,1-dibromo-1-alkene (1.0 mmol), amine (5.0
mmol), DMF (3 mL), water (1 mL). b Reaction time is not opimized for
those reactions completed within 2 h at 80 °C. c Yields of isolated products.
d Concentrated aqueous ammonium hydroxide (1 mL) was used in place of
water, and N,N-dimethyl amide (6%) was also isolated. e Recovered starting
material (23%).
an important role in the conversion of 1,1-dibromo-1-alkenes
to amides. While the reaction proceeds readily in highly
dipolar aprotic solvents such as DMF and DMSO, the
transformation requires a much longer time and results in
lower yields in moderately polar solvents such as 1,2-
dimethoxyethane (DME) and acetonitrile. The reaction
proceeds poorly in the protic solvent 2-propanol, and almost
no reaction occurs in nonpolar solvent toluene. In addition,
combination of slightly more than 1 equiv of piperidine with
sodium carbonate works well for the reaction.
More 1,1-dibromo-1-alkenes were subjected to the reaction
conditions with a variety of amines, as shown in Table 2.
(9) (a) Penalva, V.; Hassan, J.; Lavenot, L.; Gozzi, C.; Lemaire, M.
Tetrahedron Lett. 1998, 39, 2559. (b) Konopelski, J. P.; Chu, K. S.; Negrete,
G. R. J. Org. Chem. 1991, 56, 1355.
(10) Piperidine was used because of the availability of the chemical.
Diethylamine was found to give 2 in similar yield under identical conditions.
(11) Li, P.; Alper, H. J. Org. Chem. 1986, 51, 4354.
(12) (a) Hayahsi, S.; Nakai, T.; Ishikawa, N. Chem. Lett. 1980, 651. (b)
Hayahsi, S.; Nakai, T.; Ishikawa, N. Chem. Lett. 1980, 935. (c) Hayahsi,
S.; Nakai, T.; Ishikawa, N.; Burton, D. J.; Naae, D. G.; Kesling, H. S. Chem.
Lett. 1979, 983.
1316
Org. Lett., Vol. 4, No. 8, 2002

Both electron-donating (entries 9-11) and electron-with-
drawing (entries 1-4, 7, 13) substitutions on the aromatic
rings are tolerated, though the reactivity decreases as the
electron richness of 2-aryl substitution increases. The
substitution pattern has little impact on the yield. The reaction
also works with 2-alkenyl-1,1-dibromo-1-alkene (entry 15),
though the reaction time is longer and the yield is moderate.
Generally, when sterically hindered or less nucleophilic
amines are used, the reactions require longer time or higher
temperature (entries 1-3, 6) to complete. It is noteworthy
that the preparation of amides works for the poor nuleophile
ammonia and hindered diisopropylamine. Aniline alone or
in combination with sodium carbonate failed to react with
1,1-dibromo-1-alkenes.
examined. 1,1-Dichloro-1-alkene (7a)14 is far less reactive,
probably due to the stronger carbon-chlorine bond.15
However, we were surprised that 1,1-diiodo-1-alkene (7b)16
was also found to be less reactive than the corresponding
dibromoalkene 1.
In summary, a facile, mild, and general two-step homolo-
gation of aryl (alkenyl) aldehydes to the corresponding
amides via 1,1-dibromo-1-alkenes was developed. To the best
of our knowledge, the route reported here is the shortest and
most convenient one to prepare homologated amides from
aldehydes.17 This homologation could find a wide range of
applications in medicinal chemistry in particular, as amides
are one of the most common functional groups encountered.
A detailed mechanistic study, as well as further investigation
of the reaction, will be reported soon.
A number of 2-alkyl-1,1-dibromo-1-alkenes were exam-
ined under the reaction conditions.13 However, to our
disappointment, no corresponding amides were observed
even after prolonged heating. Only decomposition of 2-alkyl-
1,1-dibromoalkenes was observed. As shown in Scheme 2,
Acknowledgment. We thank Drs. Saul H. Rosenberg and
Michael Wendt for the support and help of this work and
Dr. Thomas Pagano for NMR structural determination of the
product in entry 15, Table 2.
Supporting Information Available: Detailed experi-
mental procedures and characterizations data (1H and 13C
spectra) for compounds 2 and 4 and products in Table 2.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 2
OL025608M
(13) 2-(2-Ethoxycarbonyl)cyclopropyl-, 2-cyclohexyl-, and 2-tert-butyl-
1,1-dibromoethenes were studied; see ref 8 for their preparation.
(14) (a) Paquette, L. A.; Wittenbrook, L. S. J. Am. Chem. Soc. 1968,
90, 6790. (b) Hazard, R.; Tallec, A. Bull. Soc. Chim. Fr. 1974, 121.
(15) Synthesis of indolidinone was achieved by treating the corresponding
2-(2-aminoaryl)-1,1-dichloroethene with sodium hydroxide and sulfuric acid
sequentially (one example, 46% isolated yield): Jpn. Kokai Tokkyo Koho,
JP 56115772, 1981.
(16) Gavina, F.; Luis, S. V.; Ferrer, P.; Costero, A. M.; Marco, J. A. J.
Chem. Soc., Chem. Commun. 1985, 296.
(17) During the preparation of this manuscript, pyrrolidine amide was
isolated as an unexpected product in the Sonogashira coupling of 2-aryl-
1,1-dibromoethene (only one example reported by the author): Lee, H. B.;
Huh, D. H.; Oh, J. S.; Min, G. H.; Kim, B. H.; Lee, D. H.; Hwang, J. K.;
Kim, Y. G. Tetrahedron 2001, 57, 8283.
monosubstitution at the 2-position of 1,1-dibromo-1-alkene
is essential for the reaction to proceed, as dibromoalkene 5
prepared from the corresponding ketone failed to convert to
the expected amide. Halogens other than bromine were also
Org. Lett., Vol. 4, No. 8, 2002
1317