Additionally, 4-aryl-4-cyano-2-carbomethoxycyclohexanone in-
termediates have found synthetic utility in the preparation of
non-natural products, such as phosphodiesterase 4 (PDE4)
inhibitors 67 and 7.8 Advantageously, numerous diverse benzylic
nitriles and esters are commercially available, allowing for the
rapid synthesis of a variety of 4-aryl-4-cyano-2-carbomethoxy-
cyclohexanone and 4-aryl-2,4-biscarbomethoxycyclohexanone
intermediates, which can be especially valuable in the discovery
of medicinal chemistry agents. For example, 4,4-disubstituted
cyclohexanones 8, resulting from decarboxylation of 1, have
been used as a nucleus for the preparation of biologically active
hypotensive9 and analgesic10 agents, as well as calcium channel
antagonists.11
An Efficient and Scalable One-Pot Double
Michael Addition-Dieckmann Condensation for
the Synthesis of 4,4-Disubstituted Cyclohexane
â-Keto Esters
Michael R. DeGraffenreid, Sarah Bennett, Sebastien Caille,†
Felix Gonzalez-Lopez de Turiso, Randall W. Hungate,
Lisa D. Julian,* Jacob A. Kaizerman, Dustin L. McMinn,
Yosup Rew, Daqing Sun, Xuelei Yan, and Jay P. Powers*,‡
Department of Medicinal Chemistry, Amgen Incorporated, 1120
Veterans BouleVard, South San Francisco, California 94080
Despite the wide applicability that these intermediates have
found in the preparation of biologically active molecules, we
were unable to identify a general and operationally simple
synthesis of this class of intermediates. The most commonly
used method in the literature for the synthesis of 4-aryl-4-cyano-
2-carbomethoxycyclohexanones involves a two-step procedure,
initially reported by Irie and co-workers (Scheme 1).12 In this
reaction sequence, arylacetonitrile 9 undergoes a double Michael
addition reaction with methyl acrylate in the presence of benzyl-
(trimethyl) ammoniumhydroxide (Triton B) to afford the diester
12. Subsequently, in a separate step, diester 12 is treated with
95% sodium hydride (although a few cases have been reported
which replace the sodium hydride with potassium tert-butoxide)
to effect the Dieckmann cyclization providing the 4-aryl-4-
cyano-2-carbomethoxycyclohexanone 1.9,10 In our hands, we
found this reaction sequence to be problematic, particularly on
a larger scale. In the first step, the Triton B addition was found
to be extremely vigorous, requiring long addition times.
Additionally, the sodium hydride promoted Dieckmann con-
densation was often unpredictable with a variable induction
period which led to poor reproducibility and significant issues
of lab safety, especially when conducted on a larger scale.
Although a more recent report describes a one-pot transforma-
tion for the double Michael addition-Dieckmann cyclization of
the parent unsubstituted phenylacetonitrile and phenylacetate
promoted by Na2Fe(CO)4 or sodium methoxide, this method
affords the 4-phenyl-4-cyano-2-carbomethoxycyclohexanone
and 4-phenyl-2,4-biscarboalkoxycyclohexanone products in only
moderate yields (56 and 52%, respectively).13 Due to the
limitations with existing approaches, we set out to investigate
an improved method to effect the double Michael addition-
Dieckmann condensation reaction sequence. This effort has
ReceiVed June 6, 2007
A simple, scalable, and efficient one-pot methodology for
the synthesis of 4,4-disubstituted cyclohexane â-keto esters
from benzylic nitriles or esters and methyl acrylate promoted
by potassium tert-butoxide is described. The process relies
on a tandem double Michael addition-Dieckmann condensa-
tion reaction, which results in the formation of three discrete
carbon-carbon bonds in a single pot, including a quaternary
center. The method allows for the convenient and rapid
synthesis of a variety of 4-aryl-4-cyano-2-carbomethoxycy-
clohexanone and 4-aryl-2,4-biscarbomethoxycyclohexanone
building blocks for use in natural products synthesis and
medicinal chemistry.
The 4,4-disubstituted cyclohexanone structural unit has served
as a useful synthetic intermediate in a wide range of applications.
For example, 4-aryl-4-cyano-2-carbomethoxycyclohexanones (1,
Figure 1) have been employed in the synthesis of natural
products such as the Amaryllidaceae alkaloids1 lycoramine (2)2
and analogs of the anticholinesterase galanthamine (3),3 and the
Sceletium alkaloids4 mesembrine (4)5 and tortuosamine (5).6
* To whom correspondence should be addressed. Phone: 650-244-2581.
Fax: 650-837-9369.
(7) Christensen, S. B.; Guider, A.; Forster, C. J.; Gleason, J. G.; Bender,
P. E.; Karpinski, J. M.; DeWolf, W. E., Jr.; Barnette, M. S.; Underwood,
D. C.; Griswold, D. E.; Cieslinski, L. B.; Burman, M.; Bochnowicz, S.;
Osborn, R. R.; Manning, C. D.; Grous, M.; Hillegas, L. M.; Bartus, J. O.;
Ryan, M. D.; Eggleston, D. S.; Haltiwanger, R. C.; Torphy, T. J. J. Med.
Chem. 1998, 41, 821.
† Department of Small Molecule Process Development, Amgen Inc., One
Amgen Center Drive, Thousand Oaks, CA 91320.
‡ Current Address: Department of Medicinal Chemistry, ChemoCentryx, Inc.,
850 Maude Avenue, Mountain View, CA 94043.
(1) Hoshino, O. In The Alkaloids; Cordell, G. A., Ed.; Academic Press:
New York, 1998; Vol. 51, pp 323-424.
(2) Hazama, N.; Irie, H.; Mizutani, T.; Shingu, T.; Takada, M.; Uyeo,
S.; Yoshitake, A. J. Chem. Soc. C 1968, 2947.
(8) Thomas, A.; Balasubramanian, G.; Gharat, L. A.; Mohite, J. R.;
Lingam, V. S. P. R.; Lakdawala, A. D.; Karunakaran, U.; Verma, R. PCT
Int. Appl. WO-016596, 2004.
(3) Uyeo, S.; Shirai, H.; Koshiro, A.; Yashiro, T, Kagei, K. Chem. Pharm.
Bull. 1966, 14, 1033.
(4) Jeffs, P. M. In The Alkaloids; Rodrigo, R. G. A., Ed.; Academic
Press: New York, 1981; Vol. 19, pp 1-80.
(5) Chavan, S. P.; Khobragade, D. A.; Pathak, A. B.; Kalkote, U. R.
Tetrahedron Lett. 2004, 45, 5263.
(9) Lednicer, D.; Emmert, D. E.; Rudzik, A. D.; Graham, B. E. J. Med.
Chem. 1975, 18, 593.
(10) Lednicer, D.; VonVoigtlander, P. F.; Emmert, D. E. J. Med. Chem.
1980, 23, 424.
(11) Dei, S.; Romanelli, N.; Scapecchi, S.; Teodori, E.; Chiarini, A.;
Gualtieri, F. J. Med. Chem. 1991, 34, 2219.
(6) (a) Koyama, J.; Sugita, T.; Suzuta, Y. Heterocycles 1981, 16, 969.
(b) Nomura, K.; Adachi, J.; Hanai, M.; Nakayama, S.; Mitsuhashi, K. Chem.
Pharm. Bull. 1974, 22, 1386.
(12) Irie, H.; Tsuda, Y.; Uyeo, S. J. Chem. Soc. 1959, 1446.
(13) Periasamy, M.; Reddy, M. R.; Radhakrishnan, U.; Devasagayaraj,
A. J. Org. Chem. 1993, 58, 4997.
10.1021/jo071202h CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/14/2007
J. Org. Chem. 2007, 72, 7455-7458
7455