Diastereoselective cycloreductions and cycloadditions catalyzed by Co(dpm)2-silane (dpm = 2,2,6,6-tetramethylheptane-3,5-dionate): Mechanism and partitioning of hydrometallative versus anion radical pathways

Article abstract of DOI:10.1021/ja020223k

In the presence of phenylsilane and 5 mol % cobalt(II) bis(2,2,6,6-tetramethylheptane-3,5-dionate), aryl-substituted monoenone monoaldehydes and bis(enones) undergo reductive cyclization to afford synaldol and anti-Michael products, respectively. For both

Full text of DOI:10.1021/ja020223k

Published on Web 07/23/2002
Diastereoselective Cycloreductions and Cycloadditions
Catalyzed by Co(dpm)2-Silane (dpm )
2,2,6,6-tetramethylheptane-3,5-dionate): Mechanism and
Partitioning of Hydrometallative versus Anion Radical
Pathways
Long-Cheng Wang,† Hye-Young Jang,† Yeonsuk Roh,† Vincent Lynch,†
Arthur J. Schultz,‡ Xiaoping Wang,‡ and Michael J. Krische*,†
Contribution from the Department of Chemistry and Biochemistry, UniVersity of Texas at Austin,
Austin, Texas 78712, and Intense Pulsed Neutron Source, Argonne National Laboratory,
Argonne, Illinois 60439-4814
Received February 13, 2002
Abstract: In the presence of phenylsilane and 5 mol % cobalt(II) bis(2,2,6,6-tetramethylheptane-3,5-dionate),
aryl-substituted monoenone monoaldehydes and bis(enones) undergo reductive cyclization to afford syn-
aldol and anti-Michael products, respectively. For both aldol and Michael cycloreductions, five- and six-
membered ring formation occurs in good yield with high levels of diastereoselectivity. Cycloreduction of
monoenone monoaldehyde 1a in the presence of d3-phenylsilane reveals incorporation of a single deuterium
at the enone â-position as an equimolar mixture of epimers, inferring rapid isomerization of the kinetically
formed cobalt enolate prior to cyclization. The deuterated product was characterized by single-crystal neutron
diffraction analysis. For bis(enone) substrates, modulation of the silane source enables partitioning of the
competitive Michael cycloreduction and [2 + 2] cycloaddition manifolds. A study of para-substituted
acetophenone-derived bis(enones) reveals that substrate electronic features also direct partitioning of
cycloreduction and cycloaddition manifolds. Further mechanistic insight is obtained through examination
of the effects of enone geometry on product stereochemistry and electrochemical studies involving cathodic
reduction of bis(enone) substrates. The collective experiments reveal competitive enone reduction pathways.
Enone hydrometalation produces metallo-enolates en route to aldol and Michael cycloreduction products,
that is, products derived from coupling at the R-position of the enone. Electron-transfer-mediated enone
reduction produces metallo-oxy-π-allyls en route to [2 + 2] cycloadducts and, under Ni catalysis, homoaldol
cycloreduction products, that is, products derived from coupling at the â-position of the enone. The
convergent outcome of the metal-catalyzed and electrochemically induced transformations suggests the
proposed oxy-π-allyl intermediates embody character consistent with the mesomeric metal-complexed anion
radicals.
Introduction
condensation of unmodified ketone and aldehyde partners are
remarkable as they approach this ideal.3 Nevertheless, current
The aldol and Michael reactions represent classical methods
of stereogenic carbon-carbon bond formation whereby an
enolate nucleophile undergoes addition to an electron-deficient
π-unsaturated partner. To adequately address the issues of
selectivity posed by these transformations, considerable effort
has been applied toward the development of stereoselective
catalytic processes that yield formal aldol and Michael prod-
ucts.1,2 The ideal aldol or Michael reaction would involve the
condensation of unmodified nucleophilic and electrophilic
partners to yield adducts that embody control of both relative
and absolute stereochemistry. For the aldol reaction, recently
described enantioselective catalytic systems promoting the direct
catalytic systems fail to address the fundamental issue of
(1) For selected reviews on catalytic enantioselective aldol reactions, see: (a)
Machajewski, T. D.; Wong, C.-H.; Lerner, R. A. Angew. Chem., Int. Ed.
2000, 39, 1352. (b) Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res.
2000, 33, 432. (c) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357.
(d) Carreira, E. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. III, p 1.
(e) Braun, M. In StereoselectiVe Synthesis, Methods of Organic Chemistry
(Houben-Weyl), ed. E21; Helmchen, G., Hoffman, R., Mulzer, J., Schau-
mann, E., Eds.; Thieme: Stuttgart, 1996; Vol. 3, p 1730.
(2) For selected reviews on catalytic enantioselective Michael reactions, see:
(a) Yamaguchi, M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. III, p
1121. (b) Krause, N.; Hoffman-Ro¨der, A. Synthesis 2001, 171.
(3) For selected examples of direct catalytic enantioselective aldol reactions,
see: (a) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki,
M. J. Am. Chem. Soc. 1999, 121, 4168. (b) List, B.; Lerner, R. A.; Barbas,
C. F., III. J. Am. Chem. Soc. 2000, 122, 2395. (c) Trost, B. M.; Ito, H. J.
Am. Chem. Soc. 2000, 122, 12003. (d) Yoshikawa, N.; Kumagai, N.;
Matsunaga, S.; Moll, G.; Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am.
Chem. Soc. 2001, 123, 2466. (e) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am.
Chem. Soc. 2001, 123, 3367.
* To whom correspondence should be addressed. E-mail: mkrische@
mail.utexas.edu.
† University of Texas at Austin.
‡ Argonne National Laboratory.
9
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J. AM. CHEM. SOC. 2002, 124, 9448-9453
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Hydrometallative versus Anion Radical Pathways
A R T I C L E S
regioselective enolate formation and thus require symmetric
ketone partners, ketones possessing a single set of acidic
hydrogens or the use of hydroxy-directing groups. Enantio-
selective catalytic systems for direct Michael reaction exhibit
similar restrictions in scope.4,5
exceptionally high levels of syn- and anti-diastereoselectivity,
respectively, and are viable for both five- and six-membered
ring formations. An ancillary study describes a related metal-
catalyzed [2 + 2] cycloaddition whereby bis(enones) are
transformed to diastereomerically pure bicyclo[3.2.0] ring
systems (Scheme 1, eq 3).15 In this account, studies pertaining
to the mechanism and partitioning of these catalytic cyclore-
ductions and cycloadditions are presented.
An alternative strategy toward catalytic stereoselective aldol
and Michael processes involves the use of latent enolates. Enol
derivatives are most commonly employed in this capacity.1,2
However, as for the direct enantioselective catalytic aldol and
Michael reactions, regioselective enolate generation is again
problematic vis-a`-vis preparation of enol derivatives from
unsymmetrical ketone precursors. Additionally, the chemical
lability of enol derivatives detracts from their utility.
Scheme 1
As demonstrated in seminal studies by Stork, nucleophilic
activation of enones via conjugate reduction enables regio-
selective enolate formation from chemically robust precursors.6
The development of selective catalytic systems for the nucleo-
philic activation of enones, which are suited to a range of
electrophilic partners, constitutes a largely unresolved method-
ological challenge.7 It was not until 1987 that the first catalytic
enone-aldehyde coupling, or “reductive aldol” process, was
described, which employed a Rh(III) precatalyst.8a A second
Rh-based catalyst system was described in 1990.8b Transition
metals other than rhodium catalyze the reductive aldol reaction.
Co(II)-,8c Pd(0)-,8d and Cu(I)-based8e catalyst systems are
known. The scope of the Rh-based catalyst system has been
extended to include diastereoselective8f and enantioselective
variants.8g Finally, an enantioselective Ir-based catalyst has been
described.8h To the best of our knowledge, analogous catalytic
reductive Michael processes are unknown, as existing methods
for metal-catalyzed enone hydrodimerization primarily afford
products of â,â-coupling.9,10
Mechanism
The interaction of silane with Co(dpm)2 is a key feature of
the cycloreduction mechanism. Tetrahedral d7-metal complexes
such as Co(dpm)216 are known to participate in single electron
oxidative addition.17 Disproportionation of Co(II) is also well
documented.18 Thus, formation of the hydrido-metal intermedi-
ates required for initiation of the catalytic cycle via enone
hydrometalation may arise through (A) single electron oxidative
addition of silane, with subsequent reductive elimination to
produce Co(I), followed by two-electron oxidative addition to
silane or (B) disproportionation followed by two-electron
oxidative addition of silane to Co(I). The latter pathway is
supported by HRMS analysis of Co(dpm)2 in the presence and
absence of PhMeSiH2, which in the former case reveals an
intense signal consistent with the mass of Co(dpm)3. Direct
oxidative addition of silane to Co(II) is unlikely as the resulting
Co(IV) intermediate represents an unstable oxidation state
(Scheme 2).19
Despite a wealth of research on catalytic aldol and Michael
processes, metal-catalyzed aldol and Michael cyclizations remain
undeveloped.11-13 Recently, a catalytic method for aldol and
Michael cycloreduction was reported from our labs (Scheme 1,
eqs 1 and 2, respectively).14 These catalytic reactions exhibit
(4) For selected examples of direct catalytic enantioselective Michael reactions,
see: (a) Kumagai, N.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2001, 3,
4251. (b) Zhang, F.-Y.; Corey, E. J. Org. Lett. 2000, 2, 1097. (c) List, B.;
Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423. (d) Betancort, J. M.;
Sakthivel, K.; Thayumanavan, R.; Barbas, C. F., III. Tetrahedron Lett. 2001,
42, 4441.
Scheme 2
(5) The majority of catalytic enantioselective Michael reactions require use of
preformed enol derivatives or â-dicarbonyl nucleophiles: (a) Narasaka,
K.; Soai, K.; Mukaiyama, T. Chem. Lett. 1974, 1223. (b) Sasai, H.; Arai,
T.; Satow, Y.; Houk, K. N.; Shibasaki, M. J. Am. Chem. Soc. 1995, 117,
6194. (c) Zhang, F.-U.; Corey, E. J. Org. Lett. 2001, 3, 639. (d) Evans, D.
A.; Scheidt, K. A.; Johnston, J. N.; Willis, M. C. J. Am. Chem. Soc. 2001,
123, 4480.
(6) (a) Stork, G.; Rosen, P.; Goldman, N. L. J. Am. Chem. Soc. 1961, 83,
2965. (b) Stork, G.; Rosen, P.; Goldman, N.; Coombs, R. V.; Tsuji, J. J.
Am. Chem. Soc. 1965, 87, 275.
(7) For a review, see: Huddleston, R. R.; Krische, M. J. Synlett 2002, in press.
(8) For catalytic reductive aldol processes, see: (a) Revis, A.; Hilty, T. K.
Tetrahedron Lett. 1987, 28, 4809. (b) Matsuda, I.; Takahashi, K.; Sato, S.
Tetrahedron Lett. 1990, 31, 5331. (c) Isayama, S.; Mukaiyama, T. Chem.
Lett. 1989, 2005. (d) Kiyooka, S.; Shimizu, A.; Torii, S. Tetrahedron Lett.
1998, 39, 5237. (e) Ooi, T.; Doda, K.; Sakai, D.; Maruoka, K. Tetrahedron
Lett. 1999, 40, 2133. (f) Taylor, S. J.; Morken, J. P. J. Am. Chem. Soc.
1999, 121, 12202. (g) Taylor, S. J.; Duffey, M. O.; Morken, J. P. J. Am.
Chem. Soc. 2000, 122, 4528. (h) Zhao, C.-X.; Duffey, M. O.; Taylor, S.
J.; Morken, J. P. Org. Lett. 2001, 3, 1829.
(9) For a review on the metal-catalyzed dimerization of electron-deficient
alkenes, see: Tembe, G. L.; Bandyopadhyay, A. R.; Ganeshpure, P. A.;
Satish, S. Catal. ReV.-Sci. Eng. 1996, 38, 299.
(10) For examples of cobalt-catalyzed acrylate and enone hydrodimerization,
see: (a) Kanai, H.; Okada, M. Chem. Lett. 1975, 167. (b) Kanai, H.; Ishii,
K. Bull. Chem. Soc. Jpn. 1981, 54, 1015. (c) Kanai, H. J. Mol. Catal. 1981,
12, 231.
In principle, σ-bond metathesis of silane to Co(dpm)2 may
account for the formation of hydrido-metal intermediates.
Mechanisms involving σ-bond metathesis have been proposed
for the Ti-catalyzed cycloreduction of 1,5-enones and 1,5-enals
9
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A R T I C L E S
Wang et al.
Figure 1. Structure of deuterio-1b determined by single-crystal neutron diffraction. The two equimolar epimers are disordered on the same crystallographic
site. Atoms are drawn at their 50% probability level. Left: syn,syn-epimer. Right: syn,anti-epimer. Atom colors: H, orange; D, green; C, blue; O, red.30
Table 1. Site Occupancies of H and D Atoms at the â-Position As Determined by Neutron Diffraction of Monocrystalline Deuterio-1b30
atom
occupancy
total occupancy
total H/D ratio
site H/D ratio
0.908(9) (syn)
1.049(9) (anti)
D syn/anti ratio
0.518(8) (syn)
0.482(8) (anti)
H-syn
H-anti
D-syn
D-anti
0.476(6)
0.512(6)
0.524(6)
0.488(6)
0.988(9)
0.976(9)
1.012(9)
conducted in the presence of silane.20,21 This mechanistic motif
is well recognized for catalytic reactions of early transition
metals, actinides, and lanthanides.22 More recently, σ-bond
metathesis pathways have been proposed for catalytic reactions
of late transition metals with silanes and boranes.23
process,25 which (although subject to debate26) is the commonly
accepted mechanism for alkene hydrosilylation.
Scheme 3
Given the preceding discussion, a catalytic mechanism
predicated on a Co(I)-Co(III) cycle is proposed as a working
model (Scheme 3). Oxidative addition of silane to LnCo(I)
affords hydrido-cobalt species I. Hydrometalation of the enone
provides cobalt enolate II, which undergoes carbonyl addition
to the appendant aldehyde to provide cobalt-alkoxide III.
Oxygen-silicon reductive elimination liberates the aldol product
in the form of the silyl ether and regenerates LnCo(I) to com-
plete the catalytic cycle. An analogous catalytic cycle is
envisioned for the related Michael cycloreduction. Evolution
of elemental hydrogen is observed throughout the reaction
suggesting competitive dehydrogenative coupling of silane.24
The proposed mechanism bears similarity to the Chalk-Harrod
A related mechanistic possibility involves oxygen-silicon
reductive elimination at the stage of the cobalt enolate II
followed by condensation of the resulting silyl enol ether with
the appendant aldehyde. This pathway is observed for the
intermolecular Rh-catalyzed reductive aldol reaction utilizing
dichloromethylsilane as terminal reductant.8h Here, the inter-
mediate enol silane was isolated and exposed to benzaldehyde
in the absence of catalyst to provide the syn-aldol product.27
For the cycloreductions reported herein, this pathway is unlikely.
While the spontaneous aldol condensation of trichlorosilyl enol
ethers and related ketene acetals has been reported,28 aliphatic
enol silanes covalently appended to aldehydes and capable of
five-membered ring formation do not spontaneously react.29
Deuterium labeling studies employing d3-phenylsilane support
the proposed mechanism. Exposure of 1a to d3-phenylsilane
under standard conditions results in the formation of the
monodeuterated aldol cycloreduction product deuterio-1b as an
equimolar mixture of stereoisomers (Figure 1). The stereochem-
ical assignment deuterio-1b was established by 1H NMR
analysis and single-crystal neutron diffraction analysis, the latter
enabling a precise assessment of the site occupancy of deuterium
(11) Aldol cyclizations have been catalyzed by antibodies and chiral amines:
(a) List, B.; Lerner, R. A.; Barbas, C. F., III. Org. Lett. 1999, 1, 59. (b)
Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10,
496. (c) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (d)
Agami, C.; Platzer, N.; Sevestre, H. Bull. Soc. Chim. Fr. 1987, 2, 358. (e)
Eder, U.; Weichert, R.; Sauer, G. German Patent DE 2014757, Oct. 7, 1971.
(12) Hydride-mediated aldol and Michael cycloreductions have been de-
scribed: Suwa, T.; Nishino, K.; Miyatake, M.; Shibata, I.; Baba, A.
Tetrahedron Lett. 2000, 41, 3403.
(13) An intramolecular Mukaiyama-Michael addition has been reported: Jung,
M. E.; McCombs, C. A.; Takeda, Y.; Pan, Y.-G. J. Am. Chem. Soc. 1981,
103, 6677.
(14) Baik, T.-G.; Luiz, A. L.; Wang, L.-C.; Krische, M. J. J. Am. Chem. Soc.
2001, 123, 5112.
(15) Baik, T.-G.; Luiz, A. L.; Wang, L.-C.; Krische, M. J. J. Am. Chem. Soc.
2001, 123, 6716.
(16) Co(dpm)2 was characterized by single-crystal X-ray diffraction. See
Supporting Information for crystallographic data.
(17) Halpern, J. Acc. Chem. Res. 1970, 3, 386.
(18) Socol, S. M.; Verkade, J. G. Inorg. Chem. 1986, 25, 2658.
(19) Topich, J.; Halpern, J. Inorg. Chem. 1979, 18, 1339.
(20) (a) Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1995, 117, 6785.
(b) Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 3182.
(21) (a) Crowe, W. E.; Rachita, M. J. J. Am. Chem. Soc. 1995, 117, 6787. (b)
Crowe, W. E.; Vu, A. T. J. Am. Chem. Soc. 1996, 118, 1557.
(22) For reviews, see: (a) Folga, E.; Woo, T.; Ziegler, T. In Theoretical Aspects
of Homogeneous Catalysis; van Leeuwen, P. W. N. M., Morokuma, K.,
van Lenthe, J. H., Eds.; Kluwer: Dordrecht, The Netherlands, 1995; p 115
and references therein. (b) Arndtsen, B. A.; Bergman, R. G.; Mobley, T.
A.; Peterson, T. H. Acc. Chem. Res. 1995, 28, 154. (c) Crabtree, R. H.
Chem. ReV. 1995, 95, 987. (d) Jones, W. D. In SelectiVe Hydrocarbon
ActiVation; Davies, J. A., Watson, P. L., Greenberg, A., Liebman, J. F.,
Eds.; Wiley-VCH: Weinheim, Germany, 1990; pp 113-148.
(23) (a) Hartwig, J. F.; Bhandari, S.; Rablen, P. R. J. Am. Chem. Soc. 1994,
116, 1839. (b) Milet, A.; Dedieu, A.; Kapteijn, G.; van Koten, G. Inorg.
Chem. 1997, 36, 3223. (c) LaPointe, A. M.; Rix, F. C.; Brookhart, M. J.
Am. Chem. Soc. 1997, 119, 906. (d) Moritani, Y.; Appella, D. H.;
Jurkauskas, V.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 6797.
(24) Rosenberg, L.; Davis, C. W.; Yao, J. J. Am. Chem. Soc. 2001, 123, 5120
and references therein.
(25) Chalk, A. J.; Harrod, J. F. J. Am. Chem. Soc. 1965, 87, 16.
(26) (a) Chatani, N.; Kodama, T.; Kajikawa, Y.; Murakami, H.; Kakiuchi, F.;
Ikeda, S.-I.; Murai, S. Chem. Lett. 2000, 14. (b) Brookhart, M.; Grant, B.
E. J. Am. Chem. Soc. 1993, 115, 2151. (c) Bosnich, B. Acc. Chem. Res.
1998, 31, 667 and references therein.
(27) Zhao, C.-X.; Bass, J.; Morken, J. P. Org. Lett. 2001, 3, 2839.
(28) Denmark, S. E.; Wong, K. T.; Stavenger, R. A. J. Am. Chem. Soc. 1997,
119, 2333.
(29) (a) Enda, J.; Kuwajima, I. J. Am. Chem. Soc. 1985, 107, 5495. (b) Enda,
J.; Matsutani, T.; Kuwajima, I. Tetrahedron Lett. 1984, 25, 5307.
9
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Scheme 6. Mechanistic Rationale for the Competitive Formation of Michael Cycloreduction and [2 + 2] Cycloaddition Products
at the â-position (Table 1).30 Related deuterium labeling studies
on the Mn(dpm)3-phenylsilane catalyst system for enone
conjugate reduction also reveal incorporation of a single
deuterium at the â-position.31 The formation of deuterio-1b as
a 1:1 mixture of epimers suggests π-facial interconversion of
the kinetically formed metallo-enolate is faster than aldehyde
addition. Both isomerization and aldehyde addition are likely
to occur through the η1-haptomer of the enolate, as supported
by related studies involving Ni(II)-enolates (Scheme 4).32a
R- and â-coupled products are observed. Here, R-coupling is
represented by the formation of Michael cycloreduction product
3b, whereas â-coupling is represented by the formation of
[2 + 2] cycloadduct 3c. As previously demonstrated, these
competitive reaction manifolds may be partitioned as a function
of silane; phenylsilane promotes the Michael cycloreduction
pathway, while methylphenylsilane promotes the [2 + 2]
cycloaddition pathway.15 A mechanistic rationale for the
partitioning of the cycloreduction and cycloaddition pathways
is proposed in Scheme 6. In the presence of phenylsilane, facile
oxidative addition promotes the hydrometallative pathway en
route to Michael cycloreduction product 3b. However, in the
presence of methylphenylsilane, oxidative addition to the
secondary silicon center is retarded presumably due to crowding
of the incipient adduct, stabilizing LnCo(I) and promoting [2
+ 2] cycloaddition via intermediacy of a Co(III)-oxy-π-allyl.
The convergent stereochemical outcome observed for the
cycloaddition of 3a and iso-3a is consistent with the mechanism
outlined in Scheme 6. The proposed mechanism for cyclo-
addition invokes the intermediacy of a bis(Co(III)-enolate). As
suggested by the deuterium labeling experiment performed on
monoenone aldehyde 1a, Co(III)-enolates are subject to rapid
π-facial interconversion. Equilibration of the intermediate bis-
(Co-enolate) should favor the isomer in which the benzoyl
substituents reside on the convex face of the metallobicyclo ring
system. Reductive elimination then provides the cyclobutane
product that embodies a cis-stereochemical relationship between
the benzoyl moieties (Scheme 7). The cis-stereochemistry of
cycloadducts such as 3c does not represent the thermodynami-
cally preferred configuration. As previously described, exposure
of 3c to either Brønsted or Lewis acid catalysts at 30 °C results
in clean conversion to the corresponding trans-derivative.15
Scheme 4
Also consistent with the proposed mechanism (Scheme 3),
the stereochemical outcome of the aldol cycloreduction is
independent of alkene geometry.32 Both trans- and cis-
configured enones 1a and iso-1a provide the syn-aldol cyclo-
reduction product. The observed syn-diastereoselectivity is
accounted for on the basis of a Zimmerman-Traxler type
transition state.33 Coordination of the reacting partners in the
form of their higher haptomers results in chelates of normal
ring size. Z-Enolate formation is preferred on a steric basis, that
is, allylic 1,2 strain.34 A similar stereochemical model has been
proposed for related hydride-mediated aldol and Michael
cycloreductions (Scheme 5).12
Scheme 5
Scheme 7
Competitive r- and â-Coupling Manifolds. Upon exposure
of bis(enone) 3a to the Co(dpm)2-silane catalyst system, both
Co(II)-complexed anion radicals and Co(III)-oxy-π-allyls may
be viewed as mesomeric forms that result upon one-electron
versus two-electron reduction of the enone precursor, respec-
tively. As demonstrated by electrochemical studies performed
in collaboration with Bauld, cathodic reduction of bis(enones)
3a and 8a affords the very same [2 + 2] cycloadducts obtained
under Co-catalysis.15,35 These electrochemical studies establish
(30) See Supporting Information for detailed data pertaining to the structural
assignment of deuterio-2b by 1H NMR and neutron diffraction.
(31) Magnus, P.; Waring, M. J.; Scott, D. A. Tetrahedron Lett. 2000, 41, 9731.
(32) The stereochemical outcome of the Ni-catalyzed [2 + 2 + 2] cycloaddition
is also independent of enone geometry: (a) Amarasinghe, K. K. D.;
Chowdhury, S. K.; Heeg, M. J.; Montgomery, J. Organometallics 2001,
20, 370. (b) Seo, J.; Chui, H. M. P.; Heeg, M. J.; Montgomery, J. J. Am.
Chem. Soc. 1999, 121, 476.
(33) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920.
(34) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841 and references therein.
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A R T I C L E S
Wang et al.
the plausibility of Co(II)-complexed anion radicals as reactive
intermediates in the Co-catalyzed [2 + 2] cycloaddition. They
do not provide sufficient basis to exclude the intermediacy of
oxy-π-allyls. The reactive intermediates en route to â-coupled
products are perhaps best described as oxy-π-allyls that possess
anion radical character (Scheme 8).
tions performed under Co-catalysis. Under cathodic reduction
and cobalt catalysis, bis(benzoyl) derivative 3a yields [2 + 2]
cycloadducts, whereas bis(anisoyl) derivative 5a does not.
Additionally, as demonstrated by the electrochemically promoted
cycloaddition of mixed bis(enone) 8a, only a single benzoyl
moiety is required for both the electrochemically promoted and
the metal-catalyzed transformations.
Scheme 8
Thus, for the Co-catalyzed transformations, the requirement
of aroyl-substituted enones and the observed effects of enone
electronics on partitioning of the reaction manifolds likely relate
to the susceptibility of a given enone moiety to reduction by
LnCo(I). For bis(enones) that are more easily reduced, cyclo-
addition predominates. Upon introduction of electron-donating
groups, electron-transfer-mediated reduction is disfavored,
enabling competitive hydrometallative pathways. The results
obtained for heteroaromatic bis(enones) 6a and 7a are consistent
with this interpretation. Cycloaddition predominates for 2-furyl
substituted bis(enone) 6a, while under identical conditions
cycloreduction is exclusively observed for 2-(N-methylpyrrolyl)
substituted bis(enone) 7a (Scheme 10).
To further evaluate the plausibility of intermediates possessing
anion radical character, the electrochemically promoted35 and
Co-catalyzed cycloadditions of several electronically biased,
sterically unbiased bis(enone) substrates were compared. A
parallel outcome of the metal-catalyzed and electrochemically
promoted transformations would lend credence to mechanisms
involving reactive intermediates that embody anion radical
character (Scheme 9). For the Co-catalyzed process, cyclo-
addition predominates for phenyl-substituted bis(enone) 3a. In
contrast, bis(enone) 4a, which bears a single para-methoxy
substituent, yields roughly equal proportions of cycloreduction
and cycloaddition products.36 Cycloreduction represents the
exclusive reaction pathway for bis(enone) 5a, which incorporates
two para-methoxy substituents. These results suggest that
cycloaddition is disfavored for electron-rich enones because of
their diminished susceptibility to reduction. As borne out by
CV studies, the parent benzoyl-based enone reduces more easily
than the corresponding anisoyl derivative (peak reduction
potentials of -1.20 and -1.30 V, respectively).35 Finally, only
a single aroyl moiety should be required for anion radical
formation. Accordingly, mixed bis(enone) 8a, which incorpo-
rates a single benzoyl moiety, smoothly undergoes cycloaddition
(Scheme 9).
Scheme 10
On the basis of the observance of competitive R- and
â-coupling manifolds for bis(enone) substrates 3a-8a, analo-
gous R- and â-coupling pathways would be anticipated for
monoenone monoaldehydes 1a and 2a. Under Co-catalysis, aldol
cycloreduction products 1b and 2b are observed, that is, products
of “R-coupling”. Under Ni-catalysis, the very same substrates
provide products of homoaldol cycloreduction, that is, “â-
coupling” products (Scheme 11).37 The homoaldol cycloreduc-
Scheme 11
Scheme 9
tion products 1c and 2c obtained under Ni-catalysis may derive
from transition metal-complexed anion radical intermediates.
The mesomerically related Ni(II)-trimethylsilyloxy-π-allyls,
obtained upon enal reduction in the presence of chlorotrimeth-
ylsilane, have been isolated and characterized via single-crystal
X-ray diffraction.38 Anion radical pathways are further supported
by reports of electrochemically induced homoaldol cycloreduc-
tions.39
The trends observed for the electrochemically promoted
cycloadditions bear striking similarities to the analogous reac-
(37) Montgomery, J.; Oblinger, E.; Savchenko, A. V. J. Am. Chem. Soc. 1997,
119, 4911.
(38) (a) Johnson, J. R.; Tully, P. S.; Mackenzie, P. B.; Sabat, M. J. Am. Chem.
Soc. 1991, 113, 6172. (b) Grisso, B. A.; Johnson, J. R.; Mackenzie, P. B.
J. Am. Chem. Soc. 1992, 114, 5160.
(35) Roh, Y.-S.; Jang, H.-Y.; Lynch, V.; Bauld, N. L.; Krische, M. J. Org. Lett.
2002, 4, 611.
(36) Compound 4b was obtained as a 1:1.2 ratio of constitutional isomers.
9
9452 J. AM. CHEM. SOC. VOL. 124, NO. 32, 2002

Hydrometallative versus Anion Radical Pathways
A R T I C L E S
Conclusion
S-cis-conformation. Additionally, it is possible that enone
hydrometalation does not occur through the canonical syn-
addition of a metal hydride. Hydrogen atom abstraction of the
metallo-anion radical at the â-position of the enone is also
plausible and would yield formal products of hydrometalation.
Beyond addressing such questions, future studies are aimed at
developing catalyst systems of enhanced substrate scope,
enantioselective catalytic systems, and the discovery of related
catalytic functional group interconversions.
The most significant aspect of these studies resides in the
observance of competitive enone reduction manifolds and the
inference of reactive intermediates possessing anion radical
character. Whereas enone hydrometalation enables catalytic
aldol and Michael cycloreduction pathways (i.e., products
derived from coupling at the â-position of the enone), electron
transfer results in the formation of [2 + 2] cycloadducts and,
under Ni-catalysis, homoaldol products (i.e., products derived
from coupling at the â-position of the enone). The viability of
anion radical pathways is underscored by the observance of
identical [2 + 2] cycloadducts and related homoaldol products
for both metal-catalyzed and electrochemically induced trans-
formations.35,39 Thus, for the formulation of mechanistic hy-
potheses accounting for the observance of â-coupling products
from enone substrates obtained in the presence of low valent
metals, it should be obligatory to consider the intermediacy of
transition metal anion radicals in addition to metallo-oxy-π-
allyls.
Acknowledgment. Acknowledgment is made to the Robert
A. Welch Foundation (F-1466), the NSF-CAREER program,
the Herman Frasch Foundation (535-HF02), the NIH (RO1
GM65149-01), donors of the Petroleum Research Fund admin-
istered by the ACS (34974-G1), and the Research Corporation
Cottrell Scholar Award (CS0927) for partial support of this
research. The work at Argonne National Laboratory was
supported by the U.S. Department of Energy, Basic Energy
Sciences-Materials Sciences, under contract no. W-31-109-ENG-
38.
Many mechanistic questions remain regarding these trans-
formations. For the Co-catalyzed cycloreductions, the superior
performance of aromatic versus aliphatic enone partners is not
wholly understood. In addition to electronic effects, aroyl
residues may facilitate hydrometalation by stabilizing the enone
Supporting Information Available: Experimental procedures
and spectral data (1H NMR, 13C NMR, IR, and HRMS) for all
new compounds. 2-Dimensional NMR spectra pertaining to
deuterio-1b. X-ray crystallographic data for 1b and Co(dpm)2.
Neutron diffraction data for deuterio-2b (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
(39) Little, R. D.; Fox, D. P.; Van Hijfte, L.; Dannecker, R.; Sowell, G.; Wolin,
R. L.; Moens, L.; Baizer, M. M. J. Org. Chem. 1988, 53, 2287.
JA020223K
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