Catalytic enantioselective conjugate addition of trimethylsilylacetylene to 2-cyclohexen-1-one

Article abstract of DOI:10.1021/ol048623v

(Chemical Equation Presented) The first example of catalytic asymmetric conjugate addition of TMS-acetylene to a cyclic α,β-enone has been accomplished using the chiral bisoxazoline-Ni complex 9 as catalyst and dimethylalumino TMS-acetylide and 2-cyclohex

Full text of DOI:10.1021/ol048623v

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3385-3388
Catalytic Enantioselective Conjugate
Addition of Trimethylsilylacetylene to
2-Cyclohexen-1-one
Young-Shin Kwak and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received July 16, 2004
ABSTRACT
The first example of catalytic asymmetric conjugate addition of TMS-acetylene to a cyclic r,â-enone has been accomplished using the chiral
bisoxazoline-Ni complex 9 as catalyst and dimethylalumino TMS-acetylide and 2-cyclohexen-1-one as reactants.
The conjugate addition of alkynyl groups to cyclic R,â-
unsaturated ketones has been an elusive synthetic challenge.
Organocuprates, the most commonly used reagents for 1,4-
addition of alkyl and alkenyl groups to R,â-enones, cannot
be employed in â-alkynylation reactions because of the
inertness that arises from copper’s strong binding to alkynyl
ligands.1 Indeed, the strength of the sp-carbon-Cu(I) bond
has allowed alkynyl groups to serve as nontransferable
ligands in mixed cuprate reagents.2 â-Alkynylated ketones
have previously been accessed indirectly from â-stannyl
alkenyl cuprates3 rather than directly except for the special
case of acyclic R,â-enones, which undergo reaction with
ethynyl boranes, alanes, or boronates.4 This method is strictly
limited to acyclic enones capable of adapting an s-cis
conformation that can lead to reaction by way of a cyclic
transition state. For the substrates fixed in an s-trans
conformation, such as 2-cyclohexen-1-one, the enantiose-
lective conjugate addition of alkynyl groups has remained
as an unmet challenge.
Two methods have been reported for the nonenantiose-
lectiVe conjugate addition of alkynyl groups to cyclic R,â-
enones, one using organozinc reagents5 and the other
organoaluminum acetylides in the presence of a blood red
Ni(I) catalyst generated in situ by a reduction of Ni(acac)2
with an equimolar amount of DIBAL-H.6 Following up on
the latter approach we have investigated the asymmetric
conjugate addition of alkynyl groups to cyclic R,â-enones
in the presence of a chiral Ni catalyst using trimethylsilyl-
acetylene and 2-cyclohexenone as a test case.
We chose to start with a Ni(II) complex 2 possessing one
acetylacetonate and one (S,S)-bisoxazoline ligand 1, as shown
in Figure 1. Complex 2 was prepared by reaction of Ni-
(acac)2 with 1 equiv of the C2-symmetric bisoxazoline 1.
Complex 2 so made was obtained as a dark-purple solid that
was stable to air and moisture at room temperature and pure
(1) House, H. O.; Fischer, W. F., Jr. J. Org. Chem. 1969, 34, 3615.
(2) Corey, E. J.; Beames, D. J. J. Am. Chem. Soc. 1972, 94, 7210.
(3) Corey, E. J.; Wallenberg, R. H. J. Am. Chem. Soc. 1974, 96, 5581.
(4) (a) Hooz, J.; Layton, R. B. J. Am. Chem. Soc. 1971, 93, 7320. (b)
Pappo, R.; Collins, P. W. Tetrahedron Lett. 1972, 2627. (c) Collins, P. W.;
Dajani, E. Z.; Bruhn, M. S.; Brown, C. H.; Palmer, J. R.; Pappo, R.
Tetrahedron Lett. 1975, 16, 4217. (d) Bruhn, M.; Brown, C. H.; Collins, P.
W.; Palmer, J. R.; Dajai, E. Z.; Pappo, R. Tetrahedron Lett. 1976, 17, 235.
(e) Sinclair, J. A.; Molander, G. A.; Brown, H. C. J. Am. Chem. Soc. 1977,
99, 954. (f) Chong, J. M.; Shen, L.; Taylor, N. J. J. Am. Chem. Soc. 2000,
122, 1822.
1
by H NMR analysis. It was used directly without further
purification.
(5) Kim, S.; Lee, J. M. Tetrahedron Lett. 1990, 31, 7627.
(6) (a) Schwartz, J.; Carr, D. B.; Hansen, R. T.; Dayrit, F. M. J. Org.
Chem. 1980, 45, 3053. (b) Hansen, R. T.; Carr, D. B.; Schwartz, J. J. Am.
Chem. Soc. 1978, 100, 2244.
10.1021/ol048623v CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/13/2004

Figure 1. Preparation of the “mixed” Ni(II) catalyst 2.
Complex 2 was readily reduced by 1 equiv of DIBAL-H
in DCM at -40 °C to give a deep red solution of what is
probably a Ni(I) species. This complex was immediately
treated with dimethylaluminum TMS-acetylide followed by
2-cyclohexen-1-one (Figure 2). The alkynylated product 3
Figure 3. Possible catalytic cycle for the Ni(II)-catalyzed conjugate
addition of TMSCCAlMe2 to 2-cyclohexenone.
Figure 2. Ni(I)-catalyzed asymmetric conjugate addition of
TMSCCAlMe2 to 2-cyclohexenone.
examined by Schwartz’s group.6b They reported that Ni-
(acac)2 in the absence of DIBAL-H did not function as well
as Ni(I) in the 1,4-addition of dimethylaluminum acetylides.
Instead they obtained an equimolar amount (based on nickel)
of coupled diacetylene, which presumably resulted from a
double ligand exchange reaction of Ni(acac)2 with two
molecules of the aluminum acetylide followed by reductive
elimination to form lower valent Ni species. We considered
the possibility that the formation of diacetylene might be
reduced because the bisoxazoline ligand is bound to the
nickel more tightly than acetylacetonate so as to allow clean
formation of the required intermediate 4 without the forma-
tion of a bisalkynyl Ni(II) complex.
Our initial experiment on the Ni(II)-catalyzed conjugate
addition of TMS-acetylide to 2-cyclohexenone is summarized
in Figure 4. Catalyst 2 (10 mol % relative to 2-cyclohex-
enone) was added to the solution of dimethylaluminum TMS-
acetylide in diethyl ether (2 equiv relative to 2-cyclohex-
enone) at 0 °C. The Michael acceptor 2-cyclohexenone was
then added, and the mixture was stirred for 2 h at the same
temperature. The conjugate adduct 3 was isolated in 51%
yield7 and with 61% ee.
was isolated in 13% yield (13 mol % catalyst loading) and
shown by GC analysis (Cyclosil B) to have 65% enantio-
meric excess (ee). The absolute configuration of 3 was
established by desilylation (K2CO3-MeOH) and hydrogena-
tion (1 atm H2, Pd-C) to give the known levorotatory (S)-
3-ethyl cyclohexanone.
Despite substantial effort to optimize the conditions for
this Ni(I)-catalyzed reaction, we were unable to increase the
yield or the selectivity. These efforts led us to investigate
the possibility of using complex 2 directly without reduction,
which appeared to be reasonable since Ni(II)-catalyzed
conjugate addition of organozinc reagents to 2-cyclohex-
enones is well-known. Although, the application of Ni(II)
catalysis to 1,4-addition of alkynyl groups has not been
reported, to the best of our knowledge, a rational mechanistic
pathway for such a Ni(II)-catalyzed reaction can be envis-
aged, as is illustrated in Figure 3 for complex 2. This pathway
involves the carbometalation of the R,â-enone by intermedi-
ate 4 as a key step.
It is worth mentioning that Ni(II)-catalyzed 1,4-addition
of alkynyl groups to 2-cyclohexenone has been previously
3386
Org. Lett., Vol. 6, No. 19, 2004

Figure 4. Ni(II)-catalyzed conjugate addition of dimethylaluminum
TMS-acetylide to 2-cyclohexenone.
Figure 5.
5 h at 10 °C was required). The yields and enantioselectivity
also varied with solvent. Methyl-tert-butyl ether was found
to be distinctly superior to Et2O, THF, toluene, or mixtures
of these. Under optimal conditions, which involved the use
of 4 equiv of TMSCCAlMe2 in t-BuOMe at 0 °C for 45
min and 5 mol % of the R,R-catalyst 9 (prepared from ent-
1) with addition of 2-cyclohexenone over less than a min,
the R-conjugate addition product 10 was produced in 86%
yield and with 82-88% ee (Figure 5).8
We then examined the Ni(II)-catalyzed conjugate addition
with several other bisoxazolines (Table 1). This study showed
Table 1.
In contrast to the results described above using the
enantiomeric nickel complexes 2 and 9, we have not been
able to effect conjugate addition of TMS acetylene to
2-cyclohexenone using different variants of the recently
developed methodology for enantioselective rhodium-BI-
NAP-catalyzed conjugate addition of aryl groups to R,â-
enones.9 We believe that the enantioselective nickel-catalyzed
alkynylation exemplified herein deserves further investigation
to define fully the scope, mechanistic pathway, and optional
catalytic ligand. It is, nonetheless and as it stands, a practical
process with no current alternatives. Illustrative procedures
are given in refs 10-12.
entry
R1
R2
Ph
Ph
t-Bu
i-Pr
benzyl
1-naph
2-naph
Ph
Ph
Ph
X
yield (%)
ee (%)
1
2
3
4
5
6
7
8
Me
H
H
H
H
H
H
Me
Me
Me
Me
CN
51
48
46
47
43
44
45
54
45
41
33
61
44
0
5
9
17
27
14
10
0
CN
CN
CN
CN
CN
CN
Tf
(8) It is very important that the formation of TMSCCAlMe2 be complete
(ca. 5 h at 10 °C required) and that exact 1:1 stoichiometry of TMSCCLi
and Me2AlCl be used. Any excess of Me2AlCl catalyzes the conjugate
addition to form racemic â-ethynylated cyclohexanone. Any excess of
TMSCCLi rapidly destroys the catalyst. Using these optimal conditions the
rate of addition of 2-cyclohexanone is no longer critical and the ee of the
product falls in the 82-88% ee range.
(9) See: (a) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829.
(b) Shintani, Y.; Takunaga, N.; Doi, H.; Hayashi, T. J. Am. Chem. Soc.
2004, 126, 6240.
9
10
11
Ts
F
Ph
CO2Me
5
that 2 (R1 ) Me, R2 ) Ph, X ) CN) is the most selective
catalyst among those tested. Aromatic groups (particularly
phenyl) at R2 were superior to other appendages (entries
3-7). It is noteworthy that better results were obtained with
X ) CN than with other electron-withdrawing groups (entries
8-11). The reaction was also very sensitive to other
variables. The purity of TMSCCAlMe2, which was generated
in situ by reaction of TMSCCLi with Me2AlCl, was critical.
Any excess of either lithium acetylide or Me2AlCl led to 3
with lower yield and ee. Complete reaction of the lithium
acetylide with Me2AlCl is therefore essential (we found that
(10) Preparation of Cyanobisoxazoline ent-1 (R,R-Configuration). A
250-mL round-bottom flask was equipped with a Dean-Stark apparatus,
and 100 mL of dry xylenes was added under a nitrogen atmosphere. Then
2.1 g of (R)-1,1-dimethyl-2-amino-2-phenylethanol (12.7 mmol) and 0.96
mL of diethyl malonate (6.3 mmol) were added. The reaction mixture was
heated at reflux with magnetic stirring overnight, and 100 mg of dibutyltin
dichloride was added. Heating at reflux was continued with removal of
water by the Dean-Stark trap for 2 days at which time TLC analysis
(hexanes-ethyl acetate, 1:2) indicated completion of the reaction. Removal
of solvent by distillation gave a yellow syrup that was purified by column
chromatography (hexanes-ethyl acetate, 1:2) to provide 1.77 g (4.9 mmol,
78%) of the corresponding bisoxazoline. A solution of 800 mg (2.2 mmol)
of this bisoxazoline in 10 mL of anhydrous THF was stirred at -78 °C
under a nitrogen atmosphere and treated with tetramethylethylenediamine
(TMEDA) (0.3 mL, 2 mmol) and 1.6 mL (3.5 mmol) of n-BuLi in hexanes
at the same temperature. The resulting brown reaction mixture was stirred
for 1 h at -78 °C, and 635 mg (3.5 mmol) of tosyl cyanide was added in
one portion (the brown color faded immediately). The reaction mixture was
allowed to warm to 0 °C, stirred for 1 h, and then diluted with Et2O and
(7) The major contaminants in the crude product were formed by further
reactions of the aluminum enolate 8 with 2-cyclohexenone. The yield can
be improved (up to 68%) by slow addition of 2-cyclohexenone.
Org. Lett., Vol. 6, No. 19, 2004
3387

In conclusion, the first example of an asymmetric conju-
gate addition of an alkynyl group to a cyclic R,â-enone has
been achieved with dimethylalumino TMS-acetylide, 2-cy-
clohexenone, and a catalytic amount of the chiral Ni(II)
complex 9 (or the enantiomer 2) in t-BuOMe under carefully
controlled conditions.
saturated NH4Cl solution. The organic layer was dried with MgSO4 and
concentrated in vacuo, and the residue was purified by column chroma-
tography (hexanes-ethyl acetate, 2:1) to provide 652 mg (1.68 mmol, 77%)
of the (R,R)-cyano-bisoxazoline ent-2.
OL048623V
(11) Preparation of Ni(II) Complex 9. A solution of 193 mg of
cyanobisoxazoline ent-1 in 2 mL of MeOH was stirred at 23 °C under a
nitrogen atmosphere. Then 154 mg of Ni(acac)2 was added in one portion;
an immediate color change from green to dark purple was observed. The
reaction mixture was then heated at reflux for 1 min and cooled to room
temperature. The reaction mixture was stirred for 12 h at ambient
temperature under a nitrogen atmosphere. The solvent was removed in
vacuo, and the remaining solid was dissolved in ethyl ether. Insoluble
material was removed by filtration, and the dark-purple filtrate was
concentrated in vacuo to provide analytically pure 9 as a dark-purple solid
(201 mg, 74%). 1H NMR (400 MHz, CDCl3): 7.41 (5H, bs), 7.27-7.31
(5H, t, J ) 7.3), 4.95 (1H, s), 4.05 (2H, s), 1.49 (6H, s), 1.38 (6H, s), 0.83
(6H, s). 13C NMR (100 MHz, CDCl3): 185.7, 167.6, 141.3, 128.4, 127.5,
127.0, 101.2, 87.2, 71.7, 28.8, 24.8, 24.1. FT-IR (thin film, cm-1): 2359.8,
2340.4, 1624.3, 1521.0, 1088.6.
same temperature for 30 min. It was then transferred via a cannula to a
solution of 1.9 mL of dimethylaluminium chloride (1.0 M solution in
hexanes) in 1 mL of tert-butylmethyl ether at 0 °C. Upon the addition a
slow precipitation of LiCl was observed. Then 5 mg of lithium iodide was
added, and the reaction mixture was stirred for 5 h at 10 °C. The reaction
mixture was cooled to 0 °C, and 20 mg (0.036 mmol, 5 mol %) of (R,R)-
Ni(II) catalyst 9 was added. Then 70 µL (0.7 mmol) of 2-cyclohexen-1-
one was added immediately. The reaction mixture was stirred at 0 °C for
45 min and monitored by TLC analysis (hexanes-ethyl acetate, 4:1). Ethyl
ether and 0.3 mL of saturated NaHCO3 solution were added, and the mixture
was stirred for 10 min at ambient temperature. The ether layer was dried
with MgSO4 and filtered through a pad of Celite. Concentration and
purification by column chromatography on silica gel (hexanes-ethyl acetate,
5:1) provided 116 mg (86%) of 10 as a colorless oil, [R]20 ) -0.266 (c
D
(12) Enantioselective Synthesis of 10 using Complex 9. A solution of
n-BuLi (1.1 mL, 2.5 M solution in hexanes) was added to 2 mL of anhydrous
t-BuOMe with stirring at -78 °C under nitrogen. Then 0.35 mL of TMS-
acetylene was added dropwise, and the reaction mixture was stirred at the
1, CHCl3). The enantiomeric purity (82% ee) was determined by GC analysis
using a chiral Cyclosil B column. (The oven temperature was 50 °C for 8
min at start and increased by 2 °C/min). The retention times of 10 and its
enantiomer 3 were 47.225 and 47.516 min.
3388
Org. Lett., Vol. 6, No. 19, 2004