Enantioselective synthesis of β-substituted cyclic ketones via cobalt-catalyzed asymmetric reductive coupling of alkynes with alkenes

Article abstract of DOI:10.1021/ja201827j

A CoI₂/(R)-BINAP, Zn, ZnI₂, H₂O system efficiently catalyzes the intermolecular asymmetric reductive coupling of alkynes with cyclic enones to afford highly regioand enantioselective β-alkenyl cyclic ketones. A possible mechanism that involves the formation of a cobaltacyclopentene intermediate from the alkyne and cyclic enone is proposed.

Full text of DOI:10.1021/ja201827j

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Enantioselective Synthesis of β-Substituted Cyclic Ketones via
Cobalt-Catalyzed Asymmetric Reductive Coupling of Alkynes
with Alkenes
Chu-Hung Wei, Subramaniyan Mannathan, and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
S Supporting Information
b
(R)-BINAP (5.0 mol %) as the ligand, Zn (1.10 mmol) as the
ABSTRACT: A CoI2/(R)-BINAP, Zn, ZnI2, H2O system
efficiently catalyzes the intermolecular asymmetric reductive
coupling of alkynes with cyclic enones to afford highly regio-
and enantioselective β-alkenyl cyclic ketones. A possible
mechanism that involves the formation of a cobaltacyclo-
pentene intermediate from the alkyne and cyclic enone is
proposed.
reducing agent, ZnI2 (0.20 mmol) as the Lewis acid, H2O (0.80
mmol) as the proton source, and 1,4-dioxane as the solvent at
room temperature for 24 h afforded the enantioselective reduc-
tive coupling product 3a in 67% yield with 92% ee. The absolute
configuration of 3a was determined to be S by comparison of the
13C NMR data for the ketal derivatives prepared from the
reaction of (2R,3R)-butane-2,3-diol with 3a and a racemic
mixture of 3a (see the Supporting Information).6 Control
experiments revealed that the asymmetric catalytic reaction did
not proceed in the absence of either CoI2/(R)-BINAP or Zn and
ZnI2. The reductive coupling product 3a obtained is highly
stereo- and regioselective: the two phenyl groups of the 1a
moiety are cis to each other, and the carbonÀcarbon bond
formed in the product is between the β-carbon of 2a and an
alkyne carbon of 1a.
To optimize the catalytic conditions, we surveyed various
chiral bidentate phosphine ligands using 1a and 2a as model
substrates in the presence of CoI2 (5.0 mol %), Zn (1.10 mmol),
ZnI2 (0.20 mmol), and H2O (0.80 mmol) at room temperature
with CH3CN as the solvent (Table 1). Among them, chiral
ligands such as (R)-Prophos (L1), (S,S)-Chiraphos (L2), and (S,
S)-BDPP (L3) afforded the reductive coupling product 3a in
moderate ee, whereas with (R,R)-DIOP (L4), both the conver-
sion and enantioselectivity were low. Improved results were
observed using (R)-BINAP (L5) and (R)-QUINAP (L6), with
81 and 74% ee, respectively. The chiral BINAP derivatives (R)-
H8-BINAP (L7) and (S)-Tol-BINAP (L8) were also active but
provided 3a in only 63 and 61% ee, respectively. The solvent
greatly influences the ee and yield of the reaction: 1,4-dioxane was
found to be the best, affording the product in 67% yield with 92%
ee, whereas THF, toluene, DCE, DME, EA, and DCM were
totally inactive. Other cobalt salts, including CoBr2/(R)-BINAP
and CoCl2/(R)-BINAP, were slightly less active and selective,
affording 3a in 49 and 54% yield with 81 and 87% ee, respectively.
To explore the scope of the present enantioselective reductive
coupling, the reactions of various alkynes with 2a were examined
under the optimized reaction conditions (Table 2, entries 2À5).
Thus, di-p-tolylacetylene (1b) gave reductive coupling product
3b in 71% yield and 93% ee (entry 2). In a similar manner, di-p-
chlorophenylacetylene (1c) afforded the expected product 3c in
72% yield with 96% ee (entry 3). The S configuration of product
3c was confirmed by single-crystal structure analysis of its oxime
derivative (Figure 1; also see the Supporting Information).
ransition-metal-catalyzed asymmetric carbonÀcarbon bond
T
formation by uniting readily available π components is an
atom- and step-economical method in organic synthesis.1,2
Among such reactions, asymmetric reductive coupling involving
alkynes as substrates is a competent method for the synthesis of
highly regio-, stereo-, and enantioselective substituted alkenes.3
Various types of π components, such as aldehyde, imine, epoxide,
and ketone, have been employed in the enantioselective coupling
with alkynes using nickel,3aÀj rhodium,3kÀm and iridium3n,o
complexes as catalysts. In this context, the asymmetric reductive
coupling of alkynes with alkenes remains less explored,4 despite
the fact that its racemic variants have been well-studied by
Montgomery’s group,4dÀg Jang and Krische,4h Reichard and
Micalizio,4i and our group.5a,b In 1998, Sato and Urabe reported
a stoichiometric reaction of titanium alkoxide-mediated diaster-
eoselective cyclization of enynols,4a but the catalytic intramolecu-
lar asymmetric reductive coupling of 1,6-enynes was demonstrated
by Krische and co-workers4b using chirally modified cationic
rhodium complexes as precatalysts and hydrogen as the reducing
agent. Previously, Ikeda’s group also reported a related intermo-
lecular three-component asymmetric alkylative coupling reaction
of cyclic enones, alkynes, and dimethylzinc in the synthesis of
enantioselective β-substituted cyclic ketones using Ni/oxazoline
as the catalyst.4c
Our continuing interest in the coupling reactions of π
components5aÀi and the related asymmetric syntheses5j prompted
us to explore a mild, convenient, and atom-economical method for
the synthesis of β-substituted cyclic enones with high enantios-
electivity. Herein we report that cobalt complexes can catalyze the
enantioselective intermolecular reductive coupling of alkynes and
cyclic enones with high regio- and stereoselectivity. This reaction
provides an excellent complement to the metal-catalyzed enantio-
selective addition reaction of organometallic reagents to unsatu-
rated carbonyl compounds.
Treatment of diphenylacetylene (1a) with 2-cyclohexenone
(2a) in the presence of CoI2 (5.0 mol %) as the catalyst,
Received: February 28, 2011
Published: April 15, 2011
r
2011 American Chemical Society
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Table 1. Influence of Chiral Ligandsa,b
Figure 1. ORTEP representation of the oxime derivative of 3c. Thermal
ellipsoids are set at 50% probability.
Scheme 1. Proposed Mechanism for the Enantioselective
Reductive Coupling of 1a and 2a
a Unless otherwise mentioned, each reaction was carriedout using1a (0.40
mmol) and 2a (0.60 mmol) in the presence of CoI2 (5.0 mol %), ligand
(L) (5.0 mol %), Zn (1.10 mmol), ZnI2 (0.20 mmol), and H2O (0.80
mmol) in CH3CN (0.80 mL) at rt for 24 h. b Isolated yields are shown.
c The reaction was carried out using 1,4-dioxane as the solvent.
Table 2. Results of Cobalt-Catalyzed Asymmetric Reductive
Coupling of Alkynes and Alkenesa
the corresponding products with high enantio-, regio- and stereo-
selectivities. Thus, 1-phenyl-1-propyne (1d) and 2-naphthyl-1-
propyne (1e) afforded 3d and 3e, respectively in good yields with
high ee values (entries 4 and 5). Similarly, electron-deficient
alkyne 1f nicely coupled with 2b to give 3h in 83% yield with 86%
ee (entry 8). It is noteworthy that the present reductive coupling
reaction is not suitable for terminal alkynes but instead leads to
facile homocyclotrimerization of the alkynes under the optimized
reaction conditions.
The present catalytic reaction was also successfully extended
to various types of cyclic enones (Table 2). Thus, 2-cyclopente-
none (2b) effectively coupled with 1c and 1a to give reductive
coupling products 3f and 3g, respectively, in 72À81% yield with
85À90% ee (entries 6 and 7). Similarly, 4,4-dimethyl-2-cyclo-
pentenone (2c) reacted with 1a and 1d to afford products 3i and
3j, respectively, in good yields with excellent ee values (92À95%)
(entries 9 and 10). 2-Cycloheptenone (2d) also underwent
asymmetric reductive coupling with alkynes 1a and 1d to provide
3k and 3l in good yields with 96 and 85% ee, respectively. In the
a Unless otherwise mentioned, each reaction was carried out using
alkyne 1 (0.40 mmol) and alkene 2 (0.60 mmol) in the presence of
CoI2 (5.0 mol %), (R)-BINAP (5.0 mol %), Zn (1.10 mmol), ZnI2 (0.20
mmol), and H2O (0.80 mmol) in 1,4-dioxane (0.80 mL) at rt for 24 h.
c
b Isolated yields. The reaction was carried out using CH3CN as the
solvent. d The reaction was carried out using ZnCl2 as the Lewis acid.
Under similar reaction conditions, unsymmetrical alkynes also
underwent the reductive coupling reaction effectively, providing
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COMMUNICATION
present catalytic asymmetric reaction, it appears that increasing
the ring size of the cyclic enone and the size of the substituent on
the alkyne lead to an increase in the ee of the product. For
example, the reactions of 1a with 2aÀd afforded the reductive
coupling products with enantioselectivites that increased with
the size of the cyclic enone ring. Furthermore, the ee values for
the coupling of cyclic 2-enones with diarylacetylenes 1aÀc were
higher than that with 1-phenyl-1-propyne 1d in most cases
(except for 3j).
A mechanism for this present catalytic reaction that accounts
for the absolute configuration of the product 3a is proposed in
Scheme 1. The reaction is likely initiated by the reduction of
Co(II)7a to Co(I) species 4 by Zn dust. Coordination of 1a at the
equatorial position and 2a with its si face at the axial position of
the Co(I) center to form 5 followed by oxidative cyclization then
gives cobaltacyclopentene intermediate 6.7b Protonation of 6
affords product 3a and a Co(III) species that is reduced by Zn
dust to regenerate Co(I).
In conclusion, we have successfully demonstrated an atom-
economical, cobalt-catalyzed enantioselective reductive coupling
of internal alkynes with cyclic enones. The catalytic reaction
proceeds with high regio- and stereoselectivity and provides
various β-substituted ketones in good yields with high ee values.
The reaction employs an air-stable, less expensive cobalt catalyst,
a mild reducing agent (Zn), and a simple hydrogen source
(water).
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’ ASSOCIATED CONTENT
S
Supporting Information. General experimental proce-
b
dures and characterization details. This material is available free
of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(6) Lemiꢀere, G. L.; Dommisse, R. A.; Lepoivre, J. A.; Alderweireldt,
F. C.; Hiemstra, H.; Wynberg, H.; Jones, J. B.; Toone, E. J. J. Am. Chem.
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120, 5579.
Corresponding Author
chcheng@mx.nthu.edu.tw
’ ACKNOWLEDGMENT
We thank the National Science Council of the Republic of
China (NSC 98-2119-M-007-002-MY3) for support of this
research.
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