Diastereoselective intermolecular cobalt-catalyzed reductive aldol reactions of α,β-unsaturated amides with ketones

Article abstract of DOI:10.1021/ol701980e

Under cobalt catalysis, diethylzinc mediates the conjugate reduction of αβ-unsaturated amides to produce ethylzinc enolates that react with ketones in situ to produce tertiary alcohol-containing aldol products with up to >19:1 diastereoselectivity.

Full text of DOI:10.1021/ol701980e

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4367-4370
Diastereoselective Intermolecular
Cobalt-Catalyzed Reductive Aldol
Reactions of
with Ketones
r,â-Unsaturated Amides
Ralph J. R. Lumby, Pekka M. Joensuu, and Hon Wai Lam*
School of Chemistry, UniVersity of Edinburgh, Joseph Black Building,
The King’s Buildings, West Mains Road, Edinburgh EH9 3JJ, United Kingdom
h.lam@ed.ac.uk
Received August 13, 2007
ABSTRACT
Under cobalt catalysis, diethylzinc mediates the conjugate reduction of
r,â-unsaturated amides to produce ethylzinc enolates that react with
ketones in situ to produce tertiary alcohol-containing aldol products with up to >19:1 diastereoselectivity.
Zinc enolates are an important class of reagents for or-
ganic synthesis, readily reacting with a range of electro-
philes,1-3 and exhibiting lower basicity and greater functional
group compatibility compared to their alkali metal counter-
parts. There are several common methods to access zinc
enolates using stoichiometric zinc sources.4,5
The first method involves the transmetalation of an alkali
metal enolate with a zinc halide, which necessitates the use
of strong alkali metal amide bases at low temperatures in a
prior enolization step that may be accompanied by regiose-
lectivity problems when more than one site of enolization is
available.
of this method are the use of milder, less basic conditions,
often complete regioselectivity, and the ability to have the
electrophile present in situ. The utility of this methodology
is evidenced by the Reformatsky reaction and its variants,
(3) For the use of zinc enolates in palladium-catalyzed R-arylations,
see: (a) Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2006,
128, 4976-4985. (b) Hama, T.; Liu, X.; Culkin, D. A.; Hartwig, J. F. J.
Am. Chem. Soc. 2003, 125, 11176-11177. (c) Bentz, E.; Moloney, M. G.;
Westaway, S. M. Tetrahedron Lett. 2004, 40, 7395-7397.
(4) For other recent methods of stoichiometric zinc enolate formation
not discussed above, see: (a) Ikeda, Z.; Hirayama, T.; Matsubara, S. Angew.
Chem., Int. Ed. 2006, 45, 8200-8203. (b) Hlavinka, M. L.; Hagadorn, J.
R. Organometallics 2007, 16, 4105-4108. (c) Hlavinka, M. L.; Hagadorn,
J. R. Tetrahedron Lett. 2006, 47, 5049-5053. (d) Hlavinka, M. L.; Greco,
J. F.; Hagadorn, J. R. Chem. Commun. 2005, 5304-5306.
(5) For selected examples of catalytic zinc enolate generation using
substoichiometric quantities of chiral bimetallic zinc complexes, see: (a)
Matsunaga, S.; Yoshida, T.; Morimoto, H.; Kumagai, N.; Shibasaki, M. J.
Am. Chem. Soc. 2004, 126, 8777-8785. (b) Harada, S.; Kumagai, N.;
Kinoshita, T.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125,
2582-2590. (c) Kumagai, N.; Matsunaga, S.; Kinoshita, T.; Harada, S.;
Okada, S.; Sakamoto, S.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc.
2003, 125, 2169-2178. (d) Trost, B. M.; Hisaindee, S. Org. Lett. 2006, 8,
6003-6005. (e) Trost, B. M.; Jaratjaroonphong, J.; Reutrakul, V. J. Am.
Chem. Soc. 2006, 128, 2778-2779. (f) Trost, B. M.; Shin, S.; Sclafani, J.
A. J. Am. Chem. Soc. 2005, 127, 8602-8603. (g) Trost, B. M.; Ito, H.;
Silcoff, E. R. J. Am. Chem. Soc. 2001, 123, 3367-3368. (h) Trost, B. M.;
Ito, H. J. Am. Chem. Soc. 2000, 122, 12003-12004.
The second method involves the reaction of a suitable zinc
source (zinc powder, organozinc reagents) with an R-halo-
carbonyl compound, with or without catalysis.1 Advantages
(1) For the reaction of zinc enolates with aldehydes and ketones, see:
(a) Reformatsky, S. Chem. Ber. 1887, 20, 1210-1211. For reviews of the
Reformatsky reaction, see: (b) Fu¨rstner, A. Synthesis 1989, 571-590. (c)
Ocampo, R.; Dolbier, W. R., Jr. Tetrahedron 2004, 60, 9325-9374. (d)
Cozzi, P. G. Angew. Chem., Int. Ed. 2007, 46, 2568-2571.
(2) For selected examples of the reaction of zinc enolates with imines,
see: (a) Gilman, H.; Speeter, M. J. Am. Chem. Soc. 1943, 65, 2255-2256.
(b) Adrian, J. C., Jr.; Snapper, M. L. J. Org. Chem. 2003, 68, 2143-2150.
(c) Cozzi, P. G.; Rivalta, E. Angew. Chem., Int. Ed. 2005, 44, 3600-3603.
10.1021/ol701980e CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/15/2007

which are still widely practiced in synthesis today.1 However,
the use of R-halocarbonyls compounds as zinc enolate pre-
cursors is not without limitations. Although simple R-halo-
carbonyls are readily available, more complex substrates
require the installation of the halide in a separate step, which
may pose problems when sensitive functional groups are
present.
ketones10 in situ to furnish tertiary alcohol-containing aldol
products.
Our studies commenced with the reactions of a range of
ketones with commercially available N,N-dimethylacrylamide
(4) (Table 1) and 4-acryloylmorpholine (7) (Table 2). Under
A third method to prepare zinc enolates is via the cata-
lytic conjugate addition of organozinc reagents to an R,â-
unsaturated carbonyl compound.6 Although this method may
benefit from the advantages of chemically robust, readily
available precursors and high regioselectivity of enolate
formation under mild conditions, the R,â-unsaturated car-
bonyl compounds that may be employed are often restricted
to enones. More synthetically versatile but less reactive R,â-
unsaturated carboxylic acid derivatives remain challenging
substrates for catalytic organozinc conjugate additions.7
Furthermore, this method necessitates the formation of a
carbon-carbon bond and often a new stereogenic center.
Although desired in some cases, other synthetic applications
may not require this increase in complexity. Therefore, the
development of an analogous method that results in the
formation of a carbon-hydrogen bond using R,â-unsaturated
carboxylic acid derivatives should be of utility.
Table 1. Cobalt-Catalyzed Reductive Aldol Reactions of
N,N-Dimethylacrylamide (4) with Representative Ketonesa
entry
R
product(s)
drb
5:1
yield(s) (%)c
1
2
3
4
5
6
7
8
Ph
5a
75
2-MePh
4-MePh
4-MeOPh
2-BrPh
5b
5c
5d
5e
9:1
5.5:1
6:1
68
79
84
56
7:1
4-BrPh
2-naphthyl
2-furyl
5f, 6f
5g
5h, 6h
3.5:1
5:1
2.5:1
73 (15)
78
66 (25)
We recently reported a method for the generation of zinc
enolates that meets these criteria.8 In the presence of a sub-
stoichiometric quantity of a cobalt salt, diethylzinc mediates
the conjugate reduction of R,â-unsaturated amides 1 to form
ethylzinc enolates 2 that participate in high-yielding diaste-
reoselective aldol cyclizations with tethered ketone elec-
trophiles (Scheme 1). Herein, we report that the Co/Et2Zn
a Reactions were conducted using 1.0 mmol of 4 and 1.1 mmol of ketone
in THF (10 mL) and hexane (2 mL) for 1-29 h. b Determined by 1H NMR
analysis of the unpurified reaction mixtures. c Isolated yield of major
diastereomer; numbers in parentheses refer to yields of minor diastereomers
if isolated.
conditions similar to those employed in our previous study,8
amides 4 and 7 underwent smooth reductive aldol reactions
with a range of acetophenone derivatives containing sub-
stituents of varying electronic properties to provide the
corresponding aldol products with up to 9:1 diastereomeric
ratio and 85% isolated yield of the major diastereomer (Table
1, entries 1-6, and Table 2, entries 1-3). The beneficial
effect of ortho-substitution in the acetophenone on the
diastereoselectivity of the reaction should be noted (Table
1, entries 2 and 5, and Table 2, entry 2). Reactions with
ketones containing naphthyl and furyl substituents were
successful (Table 1, entries 7-8, and Table 2, entries 4-5),
Scheme 1. Cobalt-Catalyzed Reductive Aldol Cyclization
system is able to promote the corresponding intermolecular
reductive aldol reactions9 of R,â-unsaturated amides with
(8) Lam, H. W.; Joensuu, P. M.; Murray, G. J.; Fordyce, E. A. F.; Prieto,
O.; Luebbers, T. Org. Lett. 2006, 8, 3729-3732.
(6) For an early report, see: (a) Kitamura, M.; Miki, T.; Nakano, K.;
Noyori, R. Tetrahedron Lett. 1996, 37, 5141-5144. For selected examples
of sequential catalytic asymmetric conjugate addition-electrophilic trapping
reactions using organozinc reagents, see: (b) Feringa, B. L.; Pineschi, M.;
Arnold, L. A.; Imbos, R.; de Vries, A. H. M. Angew. Chem., Int. Ed. 1997,
36, 2620-2623. (c) Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B.
L. J. Org. Chem. 2002, 67, 7244-7254. (d) Naasz, R.; Arnold, L. A.;
Pineschi, M.; Keller, E.; Feringa, B. L. J. Am. Chem. Soc. 1999, 121, 1104-
1105. (e) Alexakis, A.; Trevitt, G. P.; Bernardinelli, G. J. Am. Chem. Soc.
2001, 123, 4358-4359. (f) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H.
J. Am. Chem. Soc. 2001, 123, 755-756. (g) Mizutani, H.; Degrado, S. J.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 779-781. (h) Agapiou, K.;
Cauble, D. F.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 4528-4529.
(7) For recent examples of catalytic enantioselective conjugate additions
of organozinc reagents to R,â-unsaturated carboxylic acid derivatives, see:
(a) Brown, M. K.; Degrado, S. J.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2005, 44, 5306-5310. (b) Hird, A. W.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2003, 42, 1276-1279. (c) Schuppan, J.; Minaard, A. J.; Feringa,
B. L. Chem. Commun. 2004, 792-793.
(9) For cobalt-catalyzed reductive aldol reactions, see: (a) Isayama, S.;
Mukaiyama, T. Chem. Lett. 1989, 2005-2008. (b) Wang, L.-C.; Jang,
H.-Y.; Roh, Y.; Lynch, V.; Schultz, A. J.; Wang, X.; Krische, M. J. J. Am.
Chem. Soc. 2002, 124, 9448-9453. For reductive aldol reactions catalyzed
by other metals, see references cited within: (c) Ngai, M.-Y.; Kong, J.-R.;
Krische, M. J. J. Org. Chem. 2006, 72, 1063-1072. For relevant reviews,
see: (d) Nishiyama, H.; Shiomi, T. Top. Curr. Chem. 2007, 279, 105-
137. (e) Jang, H.-Y.; Krische, M. J. Eur. J. Org. Chem. 2004, 3953-3958.
(f) Jang, H.-Y.; Krische, M. J. Acc. Chem. Res. 2004, 37, 653-661. (g)
Huddleston, R. R.; Krische, M. J. Synlett 2003, 12-21. (h) Chiu, P. Synthesis
2004, 2210-2215. (i) Motherwell, W. B. Pure Appl. Chem. 2002, 74, 135-
142.
(10) For catalytic enantioselective reductive aldol reactions with ketones,
see: (a) Lam, H. W.; Joensuu, P. M. Org. Lett. 2005, 7, 4225-4228. (b)
Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew. Chem., Int.
Ed. 2006, 45, 1292-1297. (c) Zhao, D.; Oisaki, K.; Kanai, M.; Shibasaki,
M. Tetrahedron Lett. 2006, 47, 1403-1407. (d) Zhao, D.; Oisaki, K.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 14440-14441. (e) Shiomi,
T.; Nishiyama, H. Org. Lett. 2007, 9, 1651-1654.
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Org. Lett., Vol. 9, No. 21, 2007

reaction diastereoselectivity (g9:1). Both linear and branched
alkyl groups were tolerated (entries 1-3), as were aromatic
(entries 4-5) and heteroaromatic (entry 6) substituents. With
alkyl-substituted morpholine amides 10a-10c, incomplete
conversions were observed using Co(acac)2‚2H2O as the
precatalyst, but the combination of CoCl2 and Cy2PPh
provided improved results (entries 1-3).8
Table 2. Cobalt-Catalyzed Reductive Aldol Reactions of
4-Acryloylmorpholine (7) with Representative Ketonesa
Unsaturated amide 12 provided an interesting regiochemi-
cal problem, because it contains an R,â-unsaturated amide
that also forms part of an R,â-unsaturated ester. It was
therefore of interest to observe whether conjugate reduction
would be successful, and if so, whether an amide enolate or
an ester enolate would result. In the event, reductive aldol
reaction of 12 with a range of methyl ketones provided
lactones 14a-14c in 62-68% yield as a result of the
intermediate zinc alkoxides 13 cyclizing onto the pendant
ethyl ester (Scheme 2). These experiments demonstrate that
entry
R1
R2
product(s)
drb
yield(s) (%)c
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
Et
Ph
8a
8b
8c
8d, 9d
8e, 9e
8f, 9f
8g, 9g
8h
5.5:1
9:1
6.5:1
4.5:1
3:1
1:1
1:1
6:1
na
80
84
85
82 (17)
72 (22)
33 (31)
35 (36)
75
2-MePh
4-MeOPh
2-naphthyl
2-furyl
i-Pr
i-Bu
Ph
Ph
Ph
8i
62
a Reactions were conducted using 1.0 mmol of 7 and 1.1 mmol of ketone
in THF (10 mL) and hexane (2 mL) for 3-7 h. b Determined by 1H NMR
analysis of the unpurified reaction mixtures. c Isolated yield of major
diastereomer; numbers in parentheses refer to yields of minor diastereomers
if isolated.
Scheme 2. Reductive Aldol Coupling of 12 with Various
Ketones Producing Lactones 14a-14c
as was reaction of 7 with propiophenone (Table 2, entry 8)
and benzophenone (Table 2, entry 9). Although aliphatic
ketones were also found to be competent substrates from a
reactivity standpoint, their reactions exhibit no diastereose-
lection (Table 2, entries 6-7).
Table 3 presents the results of reactions of a range of
â-substituted R,â-unsaturated morpholine amides with aceto-
conjugate reduction of 12 occurred to generate the morpho-
line amide enolate preferentially.11
The diastereochemical outcomes of these reactions12 are
consistent with the participation of Z-zinc enolates 15 and
chelated chairlike Zimmerman-Traxler transition states13 in
which the larger aromatic substituent of the ketone prefers
to reside in a less sterically hindered pseudoequatorial
position (as in 16; Scheme 3).
Table 3. Cobalt-Catalyzed Reductive Aldol Reactions of
Acetophenone with Representative R,â-Unsaturated Morpholine
Amidesa
Scheme 3. Model for Stereochemical Outcome
yield
(%)c
entry method
R
substrate product
drb
1
2
3
4
5
6
B
B
B
A
A
A
Me
i-Bu
CH2CH2Ph
Ph
2-naphthyl
2-furyl
10a
10b
10c
10d
10e
10f
11a
11b
11c
11d
11e
11f
>19:1 76
>19:1 85
16:1 81d
>19:1 71
10:1 74
9:1 84
In conclusion, zinc enolates generated through cobalt-
catalyzed conjugate reduction of R,â-unsaturated amides
a Reactions were conducted using 1.0 mmol of 10a-10f and 1.1 mmol
of acetophenone in THF (10 mL) and hexane (2 mL) for 2-6 h.
b Determined by 1H NMR analysis of the unpurified reaction mixtures.
c Isolated yield of major diastereomer. d Yield of a 16:1 inseparable mixture
of diastereomers.
(11) R,â-Unsaturated esters do undergo reductive aldol reactions with
ketones using Co/Et2Zn, but with low diastereoselectivities. For example,
methyl cinnamate reacts with acetophenone to produce a ca. 1:1 mixture
of diastereomers.
(12) The relative stereochemistry of the known compound 5a was
assigned by comparison with literature spectral data. The relative stereo-
chemistries of 5c, 8f, and 8g were determined by X-ray crystallography.
The stereochemistries of the remaining aldol products were assigned by
analogy. See the Supporting Information for details.
phenone. These data illustrate that substitution at the â-posi-
tion of the unsaturated amide has a beneficial impact on
Org. Lett., Vol. 9, No. 21, 2007
4369

using diethylzinc as the stoichiometric reductant undergo in
situ diastereoselective aldol reactions with ketones to provide
tertiary â-hydroxycarbonyl compounds. Further applications
of this methodology will be reported in due course.
providing high-resolution mass spectra. We thank Dr. Simon
Parsons, Dr. Anna Collins, and Fraser J. White at the School
of Chemistry, University of Edinburgh, for assistance with
X-ray crystallography.
Acknowledgment. Financial support was provided by the
EPSRC, Merck Sharp & Dohme, and the University of
Edinburgh. The EPSRC National Mass Spectrometry Service
Centre at the University of Wales, Swansea, is thanked for
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds
(PDF); crystallographic data in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
(13) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920-1923.
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