again utilize enones as substrates and either dialkylzinc or
organoboron reagents as the organometallic, resulting in
carbocyclic products.4,5 Expansion of the scope of these
reactions to encompass other conjugate acceptors and orga-
nometallic reagents to result in a correspondingly broader
range of products, including valuable heterocyclic structures,
is a desirable objective. Herein, we report highly diastereo-
selective cobalt-catalyzed alkylative aldol cyclizations that
result in the formation of ꢀ-hydroxylactams containing three
contiguous stereogenic centers, using trialkylaluminums as
the organometallic reagents.
During our recent studies of cobalt-catalyzed reductive
aldol cyclizations, it was found that certain substrates
containing a ꢀ-unsubstituted R,ꢀ-unsaturated amide as the
conjugate acceptor furnished small quantities of alkylative
aldol products when triethylaluminum was used in place of
diethylzinc as the stoichiometric reductant.6a In addition,
during further studies of our nickel-catalyzed reductive aldol
cyclizations,7 we observed that with substrate 1a, the use of
Et3Al provided small quantities of the alkylative aldol product
2ab as a single diastereoisomer,8 in addition to the reductive
aldol product 3 (Table 1, entry 1).9 Collectively, these results
were of interest not only because of the highly diastereose-
lective formation of 2ab but also because, to our knowledge,
there haVe been no prior reports of conjugate addition of
trialkylaluminum reagents to R,ꢀ-unsaturated amides.10,11
Intrigued by these observations, we embarked upon a study
to identify conditions that would favor the formation of 2ab
over 3. The presence of bidentate (entry 2) or monodentate
(entry 3) phosphine ligands still provided 3 as the major
product, along with traces of unidentified side-products. The
use of nitrogen ligand 412 (entry 4) offered no improvement,
and our attention then returned to cobalt-based precatalysts.
Although the combination of CoCl2 and Cy2PPh6 was found
to increase the proportion of the desired product 2ab (entry
5), we were gratified to observe that Co(acac)2·2H2O along
with oxazoline 4 provided 2ab as the sole product (entry 6).
The same result was obtained in the absence of ligand 4
(entry 7), and therefore, these optimized conditions were
adopted for a study of the scope and limitation of the process
(Table 2).
Using Et3Al, substrates containing a range of aromatic
(Table 2, entries 2, 6, 9-10, 13, and 15-17) and heteroaro-
matic (entries 11 and 12) substituents at the ꢀ-carbon of the
R,ꢀ-unsaturated amide were found to undergo alkylative aldol
cyclization. A study of different substituents at the para-
position of the aromatic ring revealed that electron-donating
groups favored the reaction (entries 6 and 9) compared with
an electron-withdrawing chlorine atom (entry 10). However,
substrate 1g containing an o-methoxyphenyl substituent
provided the desired product 2g in 21% yield, along with
the reductive aldol product (28% yield) and recovered starting
material (16% yield) (entry 13). The higher trialkylaluminum
reagents n-Pr3Al and n-Hex3Al were accommodated (entries
3, 4 and 7, 8), but yields were lower using Me3Al (entries 1
and 5). Replacement of the methyl ketone with an ethyl
ketone was also tolerated (entries 15 and 16). In most of the
Table 1. Survey of Reaction Conditions for Cyclization of 1aa
(9) Certain substrates also provided varying degrees of alkylative aldol
cyclization using Ni(acac)2/Et2Zn; see ref 7.
entry
metal salt (10 mol %)
ligand (10 mol %)
2a/3c
(10) For nickel-catalyzed conjugate addition of trialkylaluminum reagents
to enones, see: (a) Jeffery, E. A.; Meisters, A.; Mole, T. J. Organomet.
Chem. 1974, 74, 365–371. (b) Bagnell, L.; Jeffery, E. A.; Meisters, A.;
Mole, T. Aust. J. Chem. 1975, 28, 801–815. (c) Ashby, E. C.; Heinsohn,
1
2
3
4
5
6
7
Ni(acac)2
Ni(acac)2
(PPh3)2NiBr2
Ni(acac)2
CoCl2
10:90
8:92d
rac-BINAP
<5:95d
4
5:95e
G. J. Org. Chem. 1974, 39, 3297–3299
.
(11) For copper-catalyzed conjugate addition of trialkylaluminum
reagents to enones or enals, see: (a) Westermann, J.; Nickisch, K. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1368–1370. (b) Kabbara, J.; Flemming, S.;
Nickisch, K.; Neh, H.; Westermann, J. Tetrahedron 1995, 51, 743–754.
For selected examples of asymmetric variants, see: (c) Takemoto, Y.;
Kuraoka, S.; Hamaue, N.; Iwata, C. Tetrahedron: Asymmetry 1996, 7, 993–
996. (d) Bennett, S. M. W.; Brown, S. M.; Cunningham, A.; Dennis, M. R.;
Muxworthy, J. P.; Oakley, M. A.; Woodward, S. Tetrahedron 2000, 56,
2847–2855. (e) Liang, L.; Chan, A. S. C. Tetrahedron: Asymmetry 2002,
13, 1393–1396. (f) Su, L.; Li, X.; Chan, W. L.; Jia, X.; Chan, A. S. C.
Tetrahedron: Asymmetry 2003, 14, 1865–1869. (g) Alexakis, A.; Albrow,
V.; Biswas, V.; d’Augustin, M.; Prieto, O.; Woodward, S. Chem. Commun.
2005, 2843–2845. (h) d’Augustin, M.; Palais, L.; Alexakis, A. Angew.
Chem., Int. Ed. 2005, 44, 1376–1378. (i) Fuchs, N.; d’Augustin, M.; Humam,
M.; Alexakis, A.; Taras, R.; Gladiali, S. Tetrahedron: Asymmetry 2005,
16, 3143–3146. (j) Li, K.; Alexakis, A. Angew. Chem., Int. Ed. 2006, 45,
7600–7603. (k) Vuagnoux-d’Augustin, M.; Alexakis, A. Tetrahedron Lett.
2007, 48, 7408–7412. For copper-catalyzed conjugate addition of Me3Al
to nitroalkenes, see: (l) Polet, D.; Alexakis, A. Tetrahedron Lett. 2005,
Cy2PPh
4
-
25:75
>95:5e
>95:5
Co(acac)2·2H2O
Co(acac)2·2H2O
a All reactions proceeded to >95% conversion. b dr ) (major isomer):
Σ(other isomers). c Determined by 1H NMR analysis of the unpurified
reaction mixture. d Small quantities of unidentified side-products were
observed. e No enantioselectivity was observed in the reaction. BINAP )
2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, acac ) acetonylacetonate.
(6) (a) Lam, H. W.; Joensuu, P. M.; Murray, G. J.; Fordyce, E. A. F.;
Prieto, O.; Luebbers, T. Org. Lett. 2006, 8, 3729–3732. For an intermoelcular
variant, see: (b) Lumby, R. J.; Joensuu, P. M.; Lam, H. W. Org. Lett.
2007, 9, 4367–4370.
(7) Joensuu, P. M.; Murray, G. J.; Fordyce, E. A. F.; Luebbers, T.; Lam,
H. W. J. Am. Chem. Soc. 2008, 130, 7328–7338.
46, 1529–1532
.
(8) The relative stereochemistries of 2ab and 2i (see Table 2) were
determined by X-ray crystallography. The stereochemistries of the remaining
products obtained in Table 2 were assigned by analogy. See the Supporting
Information for further details.
(12) Oxazoline ligands similar to 4 have been successfully applied in
enantioselective [2 + 2 + 2] cycloadditions using Ni(acac)2 as a precatalyst
in the presence of Me3Al. See: Ikeda, S.; Kondo, H.; Arii, T.; Odashima,
K. Chem. Commun. 2002, 2422–2423.
2940
Org. Lett., Vol. 10, No. 14, 2008