Cobalt-mediated [3 + 2]-annulation reaction of alkenes with α,β-unsaturated ketones and imines

Article abstract of DOI:10.1021/ol901542n

Image Presented The utility of cobalt dinitrosyl complexes for the [3 + 2] annulation of alkenes with unsaturated enones and ketimines has been demonstrated. Reaction of a series of cobalt dinitrosyl/alkene adducts with conjugate acceptors in the presence of Sc(OTf)₃/LHMDS formed two new C-C bonds at the carbons α to the nitrosyl groups of the substrate, leading to unusual tri- and tetracycles. Retrocycloaddition of these products in the presence of norbornadiene yielded functionalized tetrasubstituted bicyclic olefins.

Full text of DOI:10.1021/ol901542n

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3698-3700
Cobalt-Mediated [3 + 2]-Annulation
Reaction of Alkenes with
r,ꢀ-Unsaturated Ketones and Imines
Jennifer M. Schomaker, F. Dean Toste,* and Robert G. Bergman*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
rbergman@berkeley.edu; fdtoste@berkeley.edu
Received July 7, 2009
ABSTRACT
The utility of cobalt dinitrosyl complexes for the [3 + 2] annulation of alkenes with unsaturated enones and ketimines has been demonstrated.
Reaction of a series of cobalt dinitrosyl/alkene adducts with conjugate acceptors in the presence of Sc(OTf)3/LHMDS formed two new C-C
bonds at the carbons r to the nitrosyl groups of the substrate, leading to unusual tri- and tetracycles. Retrocycloaddition of these products
in the presence of norbornadiene yielded functionalized tetrasubstituted bicyclic olefins.
Vinyl anion synthons (e.g., A in eq 1) provide versatile
partners for the formation of new carbon-carbon bonds at
alkenyl centers.1 In contrast, the generation of the corre-
sponding dianion equivalent B, which would allow for the
one-pot formation of two carbon-carbon bonds on adjacent
carbons of the alkene substrate, is a much more challenging
task.2 We recently reported that in the presence of base,
cobalt dinitrosyl/alkene adducts behaved as vinyl anion (A)
equivalents and were capable of Lewis acid-mediated
conjugate addition reactions to enones (eq 1).3,4 Thermal
retrocyclization of these alkylated intermediates produced
organic products in which the unactivated alkene C-H bond
had been functionalized. Herein, we report that sequential
deprotonation of these cobalt complexes provides access to
vinyl dianion equivalents (B, eq 2), allowing for the overall
[3 + 2]-annulation reaction of alkenes with enones.
(1) For selected references, see: (a) Trost, B. M.; Imi, K.; Davies, I. W.
J. Am. Chem. Soc. 1995, 117, 5371–5372. (b) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2006, 128 (17), 5604–5605. (c) Trost,
B. M., Fleming, I., Eds.; ComprehensiVe Organic Synthesis; Pergamon Press:
Oxford, 1991; Vol. 1, Part 1.
(2) For examples of metal-promoted 1,3-additions to enals see: Herath,
A.; Montgomery, J. J. Am. Chem. Soc. 2006, 128, 14030, and references
therein. For other selected references on vinyl dianion equivalents, see: (a)
Lightfoot, A. P.; Maw, G.; Thirsk, C.; Twiddle, S. J. R.; Whiting, A.
Tetrahedron Lett. 2003, 44, 7645. (b) Chambert, S.; De´sire´, J.; De´cout, J.
Synthesis 2002, 16, 2319.
(3) Schomaker, J. M.; Boyd, W. C.; Stewart, I. C.; Toste, F. D.; Bergman,
R. G. J. Am. Chem. Soc. 2008, 130, 3777
.
(4) First reported examples of cobalt dinitrosyl and dinitrosoalkane
complexes: (a) Brunner, H. J. Organomet. Chem. 1968, 12, 517. (b) Brunner,
H.; Loskot, S. Angew. Chem., Int. Ed. Engl. 1971, 10, 515. (c) Brunner,
H.; Loskot, S. J. Organomet. Chem. 1973, 61, 401
.
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butylsulfinyl ketimines7 6 proved to be viable electrophiles
in the annulation reaction, yielding tertiary amines 8, 9, and
12 in 54-69% yield and modest diastereoselectivity (up to
2.6:1 dr). An additional benefit imparted by the use of a chiral
auxiliary was the ability to separate the product diastereo-
mers.
Treatment of the tetrahydrofuran-containing cobalt dini-
trosoalkane adduct 1 with 2-cyclohexen-1-one 2 in the
presence of 1.0 equiv of Sc(OTf)3 and 2.1 equiv of LHMDS
gave a 2.6:1 mixture of the polycyclic tertiary alcohol 3 and
the Michael adduct 4.5 Both compounds were isolated and
their structures confirmed by X-ray diffraction (Scheme 1).
Scheme 1. Annulation Reaction of Cobalt Complex 1
The strained cobalt dinitrosoalkane complexes synthesized
by this simple conjugate addition/aldol annulation reaction
serve as useful precursors for a number of synthetic building
blocks (eq 5). For example, treatment of the tricyclic fused-
ring product 3 with norbornadiene under microwave condi-
tions gave the expected tetrasubstituted bicyclic olefin 13 in
72% yield.8 Alternatively, the syn-1,2-diamine 14 could be
prepared by treatment of 3 with LiAlH4. Since both nitrogen-
bearing carbons are fully substituted, epimerization at these
carbons is not possible and the stereochemistry installed by
means of the [3 + 2] annulation reaction remains intact.
Given that cobalt complex 1 was prepared from 2,5-
dihydrofuran, the sequence leading to 13 illustrated in eqs 2
and 5 constitutes the overall [3 + 2]-annulation of this alkene
with 2-cyclohexen-1-one. Therefore, the cobalt dinitrosoal-
kane complex 1 was treated with several enones to determine
the scope of the new cobalt-mediated annulation reaction
(eq 6). Several acyclic conjugate acceptors underwent the
first step of the sequence in 44-58% yield. In contrast to
our previous work using cobalt dinitrosoalkanes, R,ꢀ-
unsaturated aldehydes were now viable substrates for the
annulation reaction, giving rise to secondary alcohols 15 and
16. Unsaturated methyl ketones also underwent successful
annulation with 1 to yield the tertiary alcohols 17 and 18.9
Moreover, the thermal retrocycloaddition liberated the newly
We were pleased to find that the annulation reaction was
not limited to the tetrahydrofuran-containing complex 1.
Cobalt dinitrosopyrrolidine (5) and cyclobutane (10) com-
plexes also underwent reaction with 2 to furnish the [3 + 2]
annulated adducts 76 and 11 respectively (eqs 3 and 4). We
thus turned our attention to the use of R,ꢀ-unsaturated
ketimines, which were not previously amenable to nucleo-
philic attack by anionic cobalt dinitrosoalkane species, as
partners in the annulation reaction. Unsaturated N-tert-
(5) 2-Cyclopenten-1-one afforded only the conjugate addition product,
and 2-cyclohepten-1-one gave a 22% yield of fused-ring product and 48%
of the acyclic product (see Supporting Information).
(6) Structure confirmed by X-ray structure analysis (see Supporting
Information).
(7) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119,
9913.
(8) (a) Becker, P. N.; Bergman, R. G. Organometallics 1983, 2, 787.
(b) Becker, P. N.; Bergman, R. G. J. Am. Chem. Soc. 1983, 105, 2985.
(9) Reaction of 18 with LiAlH4 furnished the corresponding diamine in
66% yield (see Supporting Information for details).
Org. Lett., Vol. 11, No. 16, 2009
3699

formed cyclopentenols (19-22) in greater than 90% yield
in most cases. Notably, aliphatic enones and those conjugated
to an aromatic or heteroaromatic group underwent the both
steps of the sequence with equal efficiency.
is formed by a tandem reaction involving deprotonation of
an R-nitrosyl hydrogen and formation of initial diastereo-
meric Michael adducts 26a and 26b. Both diastereomers are
susceptible to further deprotonation at the remaining R-NO
hydrogen leading to diastereomeric anions 27a and 27b. In
27a, the carbanion is in close proximity to the carbonyl
group; therefore, rapid ring closure ensues, affording 3 in
58% yield. In contrast, the anion of 27b cannot readily
approach the carbonyl moiety, and therefore 27b6 leads to 4
in 22% yield on protonation during workup. To explore this
hypothesis, we subjected compound 26b to further treatment
with base and Lewis acid and found that it does not undergo
cyclization.
In conclusion, we have demonstrated a facile [3 +
2]-annulation reaction of cobalt dinitrosoalkane complexes
with R,ꢀ-unsaturated carbonyls and ketimines that leads to
unusual tri- and tetracyclic ring systems. The cycloannulated
tetrasubstituted olefins can be prepared by a thermally
induced olefin exchange reaction of the fused-ring product
with norbornadiene. Diamines are also accessible via a
LiAlH4 reduction of the aforementioned complexes. Future
work will focus on the identification of other difunctionalized
electrophiles that undergo the annulation reactions. Efforts
to develop enantioselective, cobalt-catalyzed variants are
ongoing and will be reported in due course.
Additionally, the two-step synthesis of aminated cyclo-
pentenes can be achieved using R,ꢀ-unsaturated imines as
electrophiles. For example, the use of the N-tert-butylsul-
Scheme 2. Proposed Mechanism for the Annulation Reaction
Acknowledgment. The authors wish to thank the Jonathan
Ellman group at the University of California, Berkeley for a
generous donation of (R)- and (S)-tert-butanesulfinamines.
R.G.B. acknowledges NIH grant GM 25459 for financial
support. F.D.T. acknowledges support from the Director,
Office of Science of the U.S. Department of Energy under
Contract No. DE-AC02-05CH11231. J.M.S. acknowledges
support from a Ruth Kirschstein postdoctoral fellowship
(NIH grant GM F32GM080059) and W. Christopher Boyd
for useful discussions. Dr. Fred Hollander of the CHEXRAY
Facility at the University of California, Berkeley is thanked
for the acquisition of X-ray crystal structures.
Supporting Information Available: Experimental pro-
cedures and spectral information are available for all
new compounds. X-ray crystal structure data are available
for compounds 3, 4 and 7. This material is available free of
charge via the Internet at http://pubs.acs.org.
famide imine 23, derived from cis-4-(2-furyl)-3-buten-2-one,
allowed for the preparation of enantiomerically pure tertiary
amine 25, after separation of the diastereomers of 24 (eq 7).
A proposed mechanistic pathway is outlined in Scheme 2
for the formation of annulated adduct 3. We postulate that 3
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Org. Lett., Vol. 11, No. 16, 2009