A practical and one-pot procedure for the synthesis of 3-amino-2- cyclohexen-1-one from 3-aminophenol

Article abstract of DOI:10.1021/op0497761

A simple, totally catalytic, and environmentally benign process for the synthesis of 3-amino-2-cyclohexen-1-one using 10% Pd/C-catalyzed hydrogenation has been developed.

Full text of DOI:10.1021/op0497761

Organic Process Research & Development 2005, 9, 219−220
A Practical and One-Pot Procedure for the Synthesis of
-Amino-2-cyclohexen-1-one from 3-Aminophenol
3
Hironao Sajiki,* Takashi Ikawa, and Kosaku Hirota
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical UniVersity, Mitahora-higashi, Gifu 502-8585, Japan
Abstract:
(Scheme 1). The first type of applicable methods is conden-
sation of relatively expensive 1,3-cyclohexandione (2) with
ammonia or ammonium acetate under refluxing conditions
with azeotropic removal of water using hazardous sol-
A simple, totally catalytic, and environmentally benign process
for the synthesis of 3-amino-2-cyclohexen-1-one using 10%
Pd/C-catalyzed hydrogenation has been developed.
6
,17-24
vents such as benzene.
These procedures usually re-
quire a large excess of ammonia or ammonium acetate. The
second type of methods entails two-step procedures, viz.,
the Pd/C-catalyzed hydrogenation of 1,3-phenylenediamine
3
-Amino-2-cyclohexen-1-one (1), a cyclic enaminone, is
a useful intermediate in organic synthesis as a synthon for
the construction of biologically active compounds (such as
dopamine autoreceptor agonists, acetylcholinesterase inhibi-
tors, oxytocin antagonists, anticonvulsants, and KATP chan-
nel openers ) and functionally interesting heterocyclic com-
pounds (such as pyridines or quinolines,
sesquiterpenes, tetrahydro-1,3-oxazines, and angucycili-
none 5-aza-analogues ). The generally and industrially em-
ployed synthetic methods for the preparation of 1,3-amino-
-cyclohexen-1-one (1) are classified into three categories
1
(
3) and subsequent hydrolysis of the resulting 3-amino-2-
25
2
3
4
cyclohexen-1-imine (4) under strong basic conditions. The
5
third type of methods is the intramolocular cyclization of
6
-13
14
5
-oxohexanenitrile (5) under drastic (high heat and strong
azaazulenes,
2
6
1
5
16
basic) conditions; however, these methods involve some
problems such as the relatively low selectivity of the
cyclization and the cost of the substrate (5). Since environ-
mentally benign synthetic procedures have been the focus
of attention in recent years, development of an entirely
catalytic, selective, mild, inexpensive, and new synthetic
method of 1 to overcome all the problems of conventional
17
2
*
To whom correspondence should be addressed. E-mail: sajiki@
gifu-pu.ac.jp. Telephone: 81-58-237-3931 (ext. 225). Fax: 81-58-237-5979.
1) Caprathe, B. W.; Jaen, J. C.; Wise, L. D.; Heffner, T. G.; Pugsley, T. A.;
Meltzer, L. T.; Parvez, M. J. Med. Chem. 1991, 34, 2736-2746.
2) Gatta, F.; Del Giudice, M. R.; Pomponi, M.; Marta, M. Heterocycles 1992,
(
(
(
6
,17-26
methods
is an important goal.
We have recently developed a selective and reductive
mono-N-alkylation method of amines using nitriles as an
alkylating reagent under Pd/C- or Rh/C-catalysed hydrogena-
3
4, 991-1004.
3) Bell, I. M.; Erb, J. M.; Freidinger, R. M.; Gallicchio, S. N.; Guare, J. P.;
Guidotti, M. T.; Halpin, R. A.; Hobbs, D. W.; Homnick, C. F.; Kuo, M.
S.; Lis, E. V.; Mathre, D. J.; Michelson, S. R.; Pawluczyk, J. M.; Pettibone,
D. J.; Reiss, D. R.; Vickers, S.; Williams, P. D.; Woyden, C. J. J. Med.
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Med. Chem. 1999, 7, 2415-2425.
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Buckner, S. A.; Cassidy, C.; Chen, Y.; Coghlan, M. J.; Daza, A. V.; Drizin,
I.; Fey, T. A.; Fitzgerald, M.; Gopalakrishnan, M.; Gregg, R. J.; Henry, R.
F.; Holladay, M. W.; King, L. L.; Kort, M. E.; Kym, P. R.; Milicic, I.;
Tang, R.; Turner, S. C.; Whiteaker, K. L.; Yi, L.; Zhang, H.; Sullivan, J.
P. J. Med. Chem. 2004, 47, 3163-3179. (b) Carroll, W. A.; Agrios, K. A.;
Altenbach, R. J.; Buckner, S. A.; Chen, Y.; Coghlan, M. J.; Daza, A. V.;
Drizin, I.; Gopalakrishnan, M.; Henry, R. F.; Kort, M. E.; Kym, P. R.;
Milicic, I.; Smith, J. C.; Tang, R.; Turner, S. C.; Whiteaker, K. L.; Zhang,
H.; Sullivan, J. P. J. Med. Chem. 2004, 47, 3180-3192.
2
7
tion conditions (Scheme 2). During our efforts to extend
2
7
the applicability of the mono-N-alkylation, we observed
that an unexpected reduction of an aromatic ring was pro-
ceeded by the use of 3-aminophenol (6) as a substrate, and
the expected 3-ethylaminophenol (7) and unexpected 3-ethyl-
amino-2-cyclohexen-1-one (8) and 1 were obtained as a
mixture (Scheme 3). This led us to test whether the
hydrogenation conditions without MeCN can produce only
the reduced products, 3-amino-2-cyclohexen-1-one (1). We
now disclose that the 10% Pd/C-catalyzed hydrogenation of
(
(
3-aminophenol (6) in MeOH is quite efficient in the synthesis
(
(
(
6) Zymalkowski, F.; Rimek, J. Naturwissenschaften 1960, 47, 83.
7) Nitta, M.; Soeda, H.; Iino, Y. Bull. Chem. Soc. Jpn. 1990, 63, 932-934.
8) Fern a´ ndez, M.; Cuesta, E.; Avenda n˜ o, C. Heterocycles 1994, 38, 2615-
of 1.
(18) Dubas-Sluyter, M. A. T.; Speckamp, W. N.; Huisman, H. O. Recueil 1972,
91, 157-160.
2
620.
(
9) Mulamba, T.; Boukili-Garr e´ , R. E.; S e´ raphin, D.; No e´ , E.; Charlet-Fagn e` re,
C.; H e´ nin, J.; Laronze, J.; Sapi, J.; Barret, R.; Laronze, J.-Y.; L e´ vy, J.
Heterocycles 1995, 41, 29-36.
(19) Iida, H.; Yuasa, Y.; Kibayashi, C. Synthesis 1982, 471-472.
(20) Baraldi, P. G.; Simoni, D.; Manfredini, S. Synthesis 1983, 902-903.
(21) Montes, I. F.; Burger, U. Tetrahedron Lett. 1996, 37, 1007-1010.
(22) Huang, Y.; Hartmann, R. W. Synth. Commun. 1998, 28, 1197-1200.
(23) Lin, Y.-L.; Wu, C.-S.; Lin, S.-W.; Huang, J.-L.; Sun, Y.-S.; Yang, D.-Y.
Bioorg. Med. Chem. 2002, 10, 685-690.
(
(
(
10) Singh, K.; Singh, J.; Singh, H. Tetrahedron 1998, 54, 935-942.
11) Pyrko, A. N. Chem. Heterocycl. Compd. 1999, 35, 688-694.
12) (a) Miyabara, H.; Takayasu, T.; Nitta, M. Heterocycles 1999, 51, 983-
987. (b) Miyabara, H.; Takayasu, T.; Nitta, M. J. Chem. Soc., Perkin Trans.
(24) Quite recently, Arcadi et al. reported a mild condensation method of 1,3-
1
1999, 3199-3205.
4
cyclohexandione (2) with ammonia using NaAuCl as a catalyst, although
(
(
(
13) Albright, J. D.; Du, X. J. Heterocycl. Chem. 2000, 37, 41-46.
14) Nitta, M.; Mori, S.; Iino, Y. Heterocycles 1991, 32, 23-28.
15) Amougay, A.; Pete, J.-P.; Piva, O. Tetrahedron Lett. 1992, 33, 7347-
chromatographic purification processes were required to obtain the pure
product, see: Arcadi, A.; Bianchi, G.; Giuseppe, S. D.; Marinelli, F. Green
Chem. 2003, 5, 64-67.
7
350.
(25) (a) Jacobson, S. E. U.S. Patent 5,149,874, 1992. (b) Iimuro, S. Pat. Appl.
No. JP 1987-135451, 1987.
(26) (a) Kiso, Y.; Saeki, K. Pat. Appl. No. EP 1978-300885, 1978. (b) Cherubim,
M.; AboDagga, F. Pat. Appl. No. JP 1973-34859, 1973.
(27) Sajiki, H.; Ikawa, T.; Hirota, K. Org. Lett. 2004, 6, 4977-4980.
(
(
16) Bartoli, G.; Cimarelli, C.; Palmieri, G. J. Chem. Soc., Perkin Trans. 1 1994,
5
37-543.
17) Collet, S. C.; R e´ mi, J.-F.; Cariou, C.; Laib, S.; Guingant, A. Y.; Vu, N.
Q.; Dujardin, G. Tetrahedron Lett. 2004, 45, 4911-4915.
1
0.1021/op0497761 CCC: $30.25 © 2005 American Chemical Society
Vol. 9, No. 2, 2005 / Organic Process Research & Development
•
219
Published on Web 02/08/2005

tion of 1.6
,17-26
The waste disposal of the process was greatly
Scheme 1
diminished compared with those of conventional methods.
Experimental Section
Materials. Reagents and solvents were obtained from
commercial suppliers and were used without further purifica-
tion. The 10% Pd/C was from Aldrich; other reagents were
1
13
purchased from TCI or Wako. H and C NMR spectra were
recorded in CDCl at 400 and 100 MHz, respectively, on a
3
JEOL spectrometer. Chemical shifts are expressed in ppm
using TMS signal (f ) 0.00) as internal reference. Mass
spectrometry was performed on a JMS-SX 102A mass
spectrometer in electron ionization mode. GC analyses were
performed using a SHIMADZU GC-17A gas chromatogra-
phy (DB-624 column, 60 m × 0.25 mm, df ) 1.4 µm)
equipped with a flame ionization detector with helium as
the carrier gas. The following conditions were used in the
GC analysis: injector temperature 260 °C, 200 °C (hold 5
min) to 255 °C (hold 25 min) at 20 °C/min temperature
program. Thin-layer chromatography used 0.25 mm thick
silica gel 60 F254 plates (Art 5715, Merk) using UV light.
Scheme 2
Scheme 3
1
0% Pd/C-Catalyzed Hydrogenation of 3-Aminophe-
2
7
nol in MeOH in the Presence of MeCN. After two
vacuum/H cycles to remove air from the reaction tube, a
mixture of the 3-aminophenol (109 mg, 1.00 mmol), MeCN
216 µL, 5 mmol), 10% Pd/C (10.9 mg, 10 wt % of the
2
(
substrate) in MeOH was stirred at room temperature under
ambient pressure of hydrogen (balloon). The reaction was
filtered through a membrane filter (Millipore Dimex-13, 0.22
µm), and the filtrate was concentrated under reduced
pressure. The ratio of the 3-ethylamino phenol (7), 3-(ethyl-
Scheme 4
amino)-2-cyclohexen-1-one (8), and 3-amino-2-cyclohexen-
1
1
-one (1) was confirmed by H NMR of the crude mixture
in CDCl
Preparation of 3-Amino-2-cyclohexen-1-one (1). After
two vacuum/H cycles to remove air from the reaction tube,
3
.
2
a mixture of the 3-aminophenol (5.46 g, 50.0 mmol), 10%
Pd/C (546 mg, 10 wt % of the substrate) in MeOH (50 mL)
was stirred at 60 °C under ambient pressure of hydrogen
Our protocol (Scheme 4) consists of stirring 6 with
commercial 10% Pd/C (Aldrich, 10% of the weight of 1) in
MeOH under hydrogen atmosphere. Within 11 h stirring
at 60 °C the hydrogenation was complete by TLC and
GC-FID, while the hydrogenation at room temperature was
incomplete even after 32 h stirring. After the reaction mixture
was cooled to room temperature, the catalyst was filtered
through a Celite cake or a membrane filter (Millipore Dimex-
3, 0.22 µm), and the product (1) was isolated by simple
solvent evaporation. As shown in Scheme 4, the desired
-amino-2-cyclohexen-1-one (1) was prepared in 94% iso-
(balloon). The reaction was filtered through a Celite cake,
and the filtrate was concentrated under reduced pressure to
afford analytically pure 3-amino-2-cyclohexene-1-one (1)
1
(
(
5.23 g, 94% yield). R
400 MHz, DMSO-d
f
(CHCl
3
:MeOH ) 5:1) 0.31. H NMR
6
): δ 1.76 (m, 2H), 1.98 (t, J ) 6.3
Hz, 2H), 2.25 (t, J ) 6.3 Hz, 2H), 4.90 (s, 1H), 6.66 (brs,
1
3
NH
9
6
2
). C NMR (100 MHzs, DMSO-d
7.5, 35.9, 27.9, 21.5. MS (EI): 111 (34), 84 (84), 83 (55),
6 (100), 55 (23); GC 100.0, AUC, t ) 16.66 min.
6
): δ 194.3, 167.0,
1
3
R
lated yield from commercially available 6. Over-reduction
was not a problem, as the corresponding 3-aminocyclohexane
was never observed. The reaction is very clean, and no
chromatographic separation is required to obtain spectrally
pure 1.
In summary, a simple and totally catalytic process for the
synthesis of 3-amino-2-cyclohexen-1-one (1) has been
demonstrated. The mild and neutral conditions, quantitative
yield of 1, operational simplicity, easy availability, and low
cost of the reagents make this process a more useful and
practical alternative to the existing methods for the prepara-
Acknowledgment
This work was supported by the Research Foundation of
Gifu Pharmaceutical University.
Supporting Information Available
1
13
H and C NMR spectra and GC data and the GC chart
for the compound 1. This material is available free of charge
via the Internet at http://pubs.acs.org.
Received for review December 8, 2004.
OP0497761
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Vol. 9, No. 2, 2005 / Organic Process Research & Development