Aromatization of enamines promoted by a catalytic amount of Pd/C. Synthesis of aromatic amines

Article abstract of DOI:10.1021/ol026184z

(Matrix presented) Aromatic amines were obtained efficiently from enamines by using a catalytic amount of Pd/C in the presence of nitrobenzene and 4 A molecular sieves in refluxing toluene.

Full text of DOI:10.1021/ol026184z

ORGANIC
LETTERS
2002
Vol. 4, No. 15
2557-2559
Aromatization of Enamines Promoted by
a Catalytic Amount of Pd/C. Synthesis
of Aromatic Amines
Janine Cossy* and Damien Belotti
Laboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin,
75231 Paris Cedex 05, France
janine.cossy@espci.fr
Received May 14, 2002
ABSTRACT
Aromatic amines were obtained efficiently from enamines by using a catalytic amount of Pd/C in the presence of nitrobenzene and 4 Å
molecular sieves in refluxing toluene.
Aromatic amines are important synthetic intermediates that
play a central role in many areas such as polymers,1
photography,2 and medicine.3 Despite the simplicity of the
arylamine structure, the synthesis of these compounds is often
difficult. Procedures employing electrophilic aromatic sub-
stitution (SE1 mechanism) that involve nitration followed by
reduction4 or direct amination5 are incompatible with many
functional groups and often require protection and depro-
tection steps. Aromatic amines can also be obtained by
nucleophilic aromatic substitution under strongly basic
conditions (SNAr,6 benzyne,7 or SRN18 mechanisms). Aryl-
alkylamines are typically prepared by reductive amination,
which involves formation of an imine from an arylamine
and subsequent reduction of the imine. However, this process
requires an excess of the arylamine, and the reductions are
sluggish.9-12 Starting in 1983, palladium-catalyzed amination
of aromatic halides has become the most prevalent method
for arylamine synthesis.13 Aromatic triflates can also be
aminated by this process.13a Recently, it has been shown that
aromatic amines can also be synthesized by reaction of
cyclohexanone enolate with nitroarenes14 or from enamines
by using 3 equiv of a TiCl4/Et3N reagent system15 or 2 equiv
of a PdII complex.16
(1) (a) D’Aproano, G.; Schiavon, G.; Zotti, G.; Leclerc, M. Chem. Mater.
1995, 7, 33.
(2) Loutfy, R. O.; Hsiao, C. K.; Kazmaier, P. M. Photogr. Sci. Eng.
1983, 27, 5.
Here, we would like to report that aromatic amines can
be obtained by dehydrogenation of enamines with a catalytic
(3) Negwer, M. Organic Chemical Drugs and their Synonyms, 7th ed.;
Akademie Verlag GmbH: Berlin, 1994.
(4) Olah, G. A.; Malhotra, R.; Narang, S. C. Nitration: Methods and
Mechanisms; VCH: New York, 1989. (b) Olah, G. A.; Ernst, T. D. J. Org.
Chem. 1989, 54, 1203.
(5) (a) Kovacic, P.; Russell, R. L.; Bennett, R. P. J. Am. Chem. Soc.
1964, 86, 1588 and references therein. (b) Olah, G. A.; Ernst, T. D. J. Org.
Chem. 1989, 54, 1203.
(6) (a) Ibata, T.; Isogami, Y.; Toyoda, J. Chem. Lett. 1987, 1187. (b)
Chiacchiera, S. M.; Singh, J. O.; Anunziata, J. D.; Silber, J. J. J. Chem.
Soc., Perkin Trans. 2 1987, 987. (c) Pardisi, C. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
4, Chapter 2.1.
(9) Smith, M. B.; March, J. AdVanced Organic Chemistry, 5th ed.;
Wiley: New York, 2001.
(10) Gribble, G. W.; Lord, P. D.; Skotnicki, J.; Dietz, S. E.; Eaton, J.
T.; Johnson, J. L. J. Am. Chem. Soc. 1974, 96, 7812.
(11) Marcini, P.; Liso, G.; Reho, A. J. Org. Chem. 1975, 40, 3453.
(12) Lane, C. F. Synthesis 1975, 135.
(13) (a) Hartwig, J. Angew. Chem. 1998, 37, 2046 and references therein.
(b) Alcazar-Roman, L. M.; Hartwig, J. F.; Rheingold, A. L.; Liable-Sands,
L. M.; Guzei, I. A. J. Am. Chem. Soc. 2000, 122, 4618. (c) Alcazar-Roman,
L. M.; Harwig, J. F. J. Am. Chem. Soc. 2001, 123, 12905. (d) Wolfe, J. P.;
Buchwald, S. L. J. Org. Chem. 1996, 61, 1133. (e) Klapars, A.; Antilla, J.
C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727.
(14) Moskalev, N.; Makosza, M. J. Chem. Soc., Chem. Commun. 2001,
1248.
(7) Kessar, S. V. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, Chapter 2.3.
(8) (a) Norris, R. K. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, Chapter 2.2. (b) Kim,
J. K.; Bunnett, J. F. J. Am. Chem. Soc. 1970, 92, 7463.
(15) Srinivas, G.; Periasamy, M. Tetrahedron Lett. 2002, 43, 2785.
(16) Ishikaura, T.; Uedo, E.; Tani, R.; Saito, S. J. Org. Chem. 2001, 66,
186.
10.1021/ol026184z CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/22/2002

amount of 10% Pd/C (0.05 equiv of Pd0), in the presence of
nitrobenzene and 4 Å molecular sieves in refluxing toluene
(Scheme 1).
morpholinoenamines, derived from substituted cyclo-
hexanones such as 4-tert-butyl-, 2-methyl-, 3-methyl-,
3,5-dimethyl-, 2,3-dimethyl-, and 2-ethoxycarbonylcyclo-
hexanone, were transformed to the corresponding substituted
aniline derivatives in yields between 30% and 82% (Table
1, entries 2-7).
Scheme 1
It is worth noting that lower yields of aniline derivatives
were obtained when the cyclohexenamines were substituted
at C-2 or disubstituted. In addition, the present method can
be applied to enamines prepared from cyclohexanone and
pyrrolidine, N-methyl-N-cyclohexylamine, or N,N-dipro-
pylamine. In each case, the enamines 8-10 were transformed
to the corresponding aniline derivatives 18-20 in yields
greater than 60% (Table, entries 8-10).
The pyrrolidinoenamine of 2-decalone, compound 21,
afforded a 1:1 mixture of compounds 22 and 23 in 46% yield.
An increase of the number of equivalents of nitrobenzene
(2.2 equiv) and the amount of molecular sieves, as well as
the reflux time, slightly improved the yield, but the product
ratio remained the same (Scheme 2).
When enamine 1 was subjected to these conditions for
4 h, the aniline derivative 11 was isolated in 86% yield after
purification by flash chromatography on silica gel (Table 1,
entry 1). The aromatization reaction is general. A variety of
Table 1. Aromatization of Enamines
Scheme 2
It is worth noting that treatment of 1 with 10% Pd/C
(5 mol % of Pd0) in the presence of 4 Å molecular sieves in
refluxing toluene, but without nitrobenzene, produced a
40/60 mixture of 11 and morpholinocyclohexane 24 in
quantitative yield (Scheme 3). This result shows that in the
absence of nitrobenzene enamine 1 acts as the hydrogen
acceptor and is reduced during the aromatization.
A plausible mechanism for this reaction is outlined in
Scheme 4. When palladium(0) reacts with enamine a, a
Scheme 3
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Org. Lett., Vol. 4, No. 15, 2002

In summary, we have developed a general, experimentally
simple,17 and inexpensive Pd0 catalyst system for the
synthesis of substituted anilines. This process, catalytic in
palladium zero, provides efficient access to synthetically
useful aromatic amines.
Scheme 4
Supporting Information Available: References for
spectroscopic data for compounds 11-20 and 22-24.
This material is available free of charge via Internet at
http://pubs.acs.org.
OL026184Z
dehydrogenation9 takes place to produce diene b and
palladium dihydride (“PdH2”). The hydrogenation of ni-
trobenzene by PdH2 effects the regeneration of Pd0. The
water that is liberated in this process is adsorbed on the
molecular sieves, thus preventing hydrolysis of the enamine.
Intermediate b can be aromatized to c by Pd/C, which is
transformed to PdH2 and again regenerated by hydrogenation
of nitrobenzene.
(17) Experimental procedure: To a solution of enamine (5 mmol)18 in
dry toluene (20 mL) were added 4 Å molecular sieves (1.5 g), dry
nitrobenzene (0.57 mL, 5.5 mmol), and 10% Pd/C (0.27 g, 0.25 mmol of
Pd0). The resulting black mixture was stirred and refluxed for 4-12 h (GC/
MS monitoring). After cooling to room temperature, the suspension was
filtered through Celite, which was washed with AcOEt. The solvent was
evaporated in vacuo, and the residue was purified by flash chromatography
on silica gel to give the aromatic amine.
(18) Hu¨nig, S.; Lu¨cke, E.; Brenninger, W. Organic Syntheses; Wiley:
New York, 1973; Collect. Vol. V, pp 808-809.
Org. Lett., Vol. 4, No. 15, 2002
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