excess or when the products are easily separable.5,6 An exception
to this rule exists when one of the carbonyl partners is a
diarylketone. McMurry found that the cross-coupled products
predominated if a diaryl ketone was coupled with an equimolar
amount of aryl, aliphatic ketones or aldehydes.6 McMurry also
described the mechanistic basis for selectivity by postulating
that the diaryl ketone first rapidly formed a dianion quantatively
and then added to the saturated ketone. This type of cross
coupling has already been used as the key step in the synthesis
of the antitumor agent tamoxifen,7 its analogues,7 and the
antihistamine drug loratadine.8
Insights into the General and Efficient Cross
McMurry Reactions between Ketones
Xin-Fang Duan,* Jing Zeng, Jia-Wei Lu¨, and
Zhan-Bin Zhang
Department of Chemistry, Beijing Normal UniVersity,
Beijing, 100875, China
xinfangduan@Vip.163.com
ReceiVed August 7, 2006
The few successful cross McMurry reactions were signifi-
cantly dependent upon the structural differences between the
two reactants, namely, (a) molecular weight allowing for
products to be more separable and (b) reduction potential as
diaryl ketones formed a dianion rapidly and quantatively.
Obviously such strict structural requirements have limited the
scope of the cross McMurry couplings. For this reason, other
types of cross couplings such as diaryl ketones with diaryl
ketones, aryl ketones with aryl ketones, and aryl ketones with
aliphatic ketones remain a challenge. In this paper we report
the results of our study on these cross couplings.
The selective cross McMurry couplings of diaryl or aryl
ketones with various substituted ketones were achieved in
53-94% isolated yields. It is believed that the strong affinity
of the substituents to the low-valent titanium surface plays
an important role in regards to moderating selectivity.
Through the introduction of such substituents followed by
their removal post McMurry coupling, structurally similar
ketones can be effectively cross-coupled.
Our research is based on the premise that the coupling
reaction occurs on the surface of the titanium and the difference
of the affinity of reactants to the titanium surface should affect
the outcome. To test this premise, we first chose two homo-
couplings and two mixed couplings: homocoupling of ben-
zophenone (1a); homocoupling of 4, 4′-dimorpholinylbenzophe-
none (1b); cross coupling of 1a with 1c and cross coupling of
1a with 1b (Table 1, entries 1-4). The reactions were carried
out using the TiCl4-Zn-Py system.7 For the cross couplings,
the two carbonyl compounds were charged in equimolar
amounts. It was observed that in the presence of the morpholinyl
groups, both the homo- and cross couplings were remarkably
retarded. Their cross reaction (entry 6) resulted in a selective
cross coupling with an isolated yield of 56%. On the contrary,
the coupling of 1a and 1c (entry 3) resulted in a nearly statistical
mixture of the possible products. These results indicate that the
morpholinyl group significantly influences the reductive cou-
pling and enhances the selective cross coupling over homocou-
pling. In light of the more rapid consumption of 1a during the
reaction, the mole ratio of 1a to 1b was raised from 1:1 to 1.2:
1. As a result, the isolated yield of the cross-coupling product
increased to 73% (Table 1, entry 7). Encouraged by these results,
we carried out a variety of cross couplings between 1a and 1b-
The reductive coupling of carbonyl compounds to produce
olefins through low valent titanium, known as the McMurry
reaction,1 has acquired great importance in organic synthesis.
The broad interest in the reaction is expressed by a number of
reviews outlining the synthetic applications and mechanism.2
The couplings are particularly prominent in (a) preparations of
sterically hindered alkenes through homocouplings and (b)
construction of cycloalkenes with ring sizes ranging from 3 to
72 via intramolecular couplings.3 The utility of this coupling
reaction is highlighted as the key step in numerous syntheses
of natural products.4
There are, however, remarkably few recorded examples of
the cross McMurry couplings between two different carbonyl
compounds. It is generally believed that this kind of cross
coupling will generate a roughly statistical mixture of the
possible coupling products. For synthetic purposes, such mixed
couplings are useful when conducted with one component in
(5) (a) Reddy, S. M.; Duraisamy, M.; Walborsky, H. M. J. Org. Chem.
1986, 51, 2361. (b) Paquette, L. A.; Yan, T.-H.; Wells, G. J. J. Org. Chem.
1984, 49, 3610.
(6) McMurry, J. E.; Krepski, L. R. J. Org. Chem. 1976, 41, 3929.
(7) (a) Castedo, L.; Saa, J. M.; Suau, R.; Tojo, G. Tetrahedron Lett,
1983, 24, 5419. (b) Gauthier, S.; Mailhot, J.; Labrie, F. J. Org. Chem. 1996,
61, 3890. (c) Meegan, M. J.; Hughes, R. B.; Lloyd, D. G.; Williams, D. C.;
Zisterer, D. M. J. Med. Chem. 2001, 44, 1072. (d) Detsi, A.; Koufaki, M.;
Calogeropoulou, T. J. Org. Chem. 2002, 67, 4608. (e) Yu, D. D.; Forman,
B. M. J. Org. Chem. 2003, 68, 9489. (f) Top, S.; Vessie, A.; Leclercq, G.;
Quivy, J.; Tang, J.; Vaissermann, J.; Huche, M.; Jaouen, G. Chem.sEur.
J. 2003, 9, 5223. (g) Uddin, J.; Rao, P. N. P.; Knaus, E. E. Synlett 2004,
513. (h) Pigeon, P.; Top, S.; Vessieres, A.; Huche, M.; Hillard, E. A.;
Salomon, E.; Jaouen, G. J. Med. Chem. 2005, 48, 2814.
(1) (a) McMurry, J. E.; Felming, M. P. J. Am. Chem. Soc. 1974, 96,
4708. (b) Mukaiyama, T.; Sato, T.; Hanna, J. Chem. Lett. 1973, 1041.
(2) (a) Ephritikhine, M. Chem. Commun. 1998, 2549. (b) Furstner, A.;
Bogdanovic, B. Angew. Chem., Int. Ed. Engl. 1996, 35, 2442. (c) McMurry,
J. E. Chem. ReV. 1989, 89, 1513. (d) Lenoir, D. Synthesis 1989, 883. (e)
Kahn, B. E.; Rieke, R. D. Chem. ReV. 1988, 88, 733.
(3) (a) For the construction of 36-membered cyclic compounds, see
Eguchi, T.; Terachi, T.; Kakinuma, K. Chem. Commun. 1994, 137. (b) For
72-membered cyclic compounds, see Eguchi, T.; Ibaragi, K.; Kakinuma,
K. J. Org. Chem. 1998, 63, 2689.
(4) Furstner, A.; Bogdanovic, B. Angew. Chem., Int. Ed. Engl. 1996,
35, 2445.
(8) (a) Alberto, S.; Pelayo, C.; Gloria, R.; Bosch, Onrubia, J.; Carmen,
M. U.S. Patent 6084100, 2000. (b) Jackson, W. P. WO 9838166, 1998.
10.1021/jo061644d CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/23/2006
J. Org. Chem. 2006, 71, 9873-9876
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