Ni(II)-catalyzed enantioselective conjugate addition of acetylenes to α,β-enones

Article abstract of DOI:10.1021/ol902643w

(Figure presented) Alkynylaluminum reagents undergo enantloselective conjugate addition to cyclic α,β-enones In the presence of chiral bisphosphine complexes of NI(II).

Full text of DOI:10.1021/ol902643w

ORGANIC
LETTERS
2010
Vol. 12, No. 2
300-302
Ni(II)-Catalyzed Enantioselective
Conjugate Addition of Acetylenes to
r,ꢀ-Enones
Oleg V. Larionov and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received November 16, 2009
ABSTRACT
Alkynylaluminum reagents undergo enantioselective conjugate addition to cyclic r,ꢀ-enones in the presence of chiral bisphosphine complexes
of Ni(II).
In 2004, we reported a catalytic enantioselective conjugate
addition of a terminal acetylene to an R,ꢀ-unsaturated enone,
Scheme 1
as illustrated in Scheme 1.1 The key to the success of this
method was the use of the chiral Ni(II) catalyst 1. One
significant finding from this research was that the Ni(I)
cyanobisoxazoline complex corresponding to 1 was much
less effective since its use led to very low yields and poor
enantioselectivity.
In the meantime, T. Hayashi and his group at Kyoto
University have described the use of chiral bisphosphine
Rh(I) catalysts (5 mol %) to effect asymmetric conjugate
addition of trialkylsilylacetylenes to R,ꢀ-enones.2
More recently, we returned to the less expensive Ni-based
catalytic system to develop other catalysts and to obtain a
better understanding of the mechanistic pathway of Ni(II)-
catalyzed alkynylation of R,ꢀ-enones.
The focus of the present work has been the use of chiral
preliminary experiments that although the Ni(0) complex
Ni(COD)2 (COD ) 1,5-cyclooctadiene) catalyzes the rapid
and efficient conjugate addition of alkynyldimethylaluminum
reagents3 to R,ꢀ-enones Ni(0) complexes with chiral bis-
phosphines or chiral bicyclo[2.2.1]heptadienes are not ef-
fective catalysts.
bisphosphine Ni(II) complexes as catalysts. We found in
(1) Kwak, Y.-S.; Corey, E. J. Org. Lett. 2004, 6, 3385–3388.
(2) (a) Nishimura, T.; Tokuji, S.; Sawano, T.; Hayashi, T. Org. Lett.
2009, 11, 3222–3225. (b) Nishimura, T.; Guo, X.-X.; Uchiyama, M.; Katoh,
T.; Hayashi, T. J. Am. Chem. Soc. 2008, 130, 1576–1577. (c) Nishimura,
T.; Katoh, T.; Takatsu, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc.
2007, 129, 14158–14159.
(3) Alkynyldialkylaluminum reagents were prepared from the corre-
sponding alkynyllithium and dialkylaluminum chloride. In line with the
observation made in the previous study (ref 1), the exact 1:1 stoichiometry
of the reagents is necessary to achieve high yields of the conjugate addition
products.
10.1021/ol902643w  2010 American Chemical Society
Published on Web 12/15/2009

Initial experiments with various classes of ligands indicated
that diphosphines of the BINAP family showed promise with
Ni(II) (Scheme 2). The complex of BINAP with NiBr2
with bulky aryl substituents on phosphorus atoms, were
prepared for this study in three steps from bistriflate 5
(Scheme 3). Palladium-catalyzed coupling4 of 5 with dia-
Scheme 2
Scheme 3. Synthesis of the Novel Bisphosphine Ligands 4b,c
produced the alkynylation product 3 with 7:1 enantioselec-
tivity (75% ee) but in only 26% yield. Since the nickel(II)
complexes of BINAP are only sparingly soluble in toluene,
the more soluble H8-BINAP (4a) was employed. This led to
an improvement in yield to 42% with a slight drop in
enantioselectivity (72% ee).
rylphosphine oxide 6 yielded the phosphine oxide 7, which
was reduced with trichlorosilane in the presence of triethy-
lamine in toluene. The monophosphines 8 were allowed to
react with the diarylphosphine-borane complexes 9 in the
presence of a nickel(II) catalyst to give the bisphosphines
4b (Ar ) 2-naphthyl) and 4c (Ar ) m-terphenyl) in yields
of 77% and 73%, respectively, over three steps. The
bisphosphines are crystalline, air-stable solids.
The catalytic performance of the nickel(II) complex of the
2-naphthyl analogue of H8-BINAP 4b proved to be similar
to that of the parent ligand, as only a moderate improvement
of enantioselectivity (84% ee) was observed. However, the
larger m-terphenyl ligand 4c proved to be very efficatious
since it afforded the conjugate addition product with 90%
ee (71% yield).
Other cyclic enones also undergo efficient alkynylation
catalyzed by the Ni(II) complex of the new terphenyl bispho-
sphine ligand 4c. Although cyclopentenone appeared to be
unsuitable for the reaction, larger cycloalkenones underwent
conjugate additions of alkynyl-diisobutylaluminum reagents to
form the corresponding ketones with 85-90% ee.
Ni(II) phosphine complexes are known to react with
acetylenes under basic conditions to give bis(phosphine)n-
ickel diacetylides.5 When Ni(BINAP)Br2 was treated with
2 equiv of phenylethynyllithium, a new peak in the 31P NMR
spectrum appeared at δ 40 ppm.
Experiments with other solvents showed that while the
use of more polar solvents, such as dichloromethane and
tetrahydrofuran, affords ketone 3 in higher yields the
enantioselectivity is diminished. Toluene emerged as the
solvent of choice for this process, the rate of which was very
slow in hexane, partly due to poor solubility of the catalyst.
The counterion in the nickel salt also influenced the reaction
outcome. Nickel acetate or triflate failed to catalyze the
reaction. The complex of nickel iodide with 4a proved to
be a very efficient catalyst; however, the overall yield of
the product 3 was lower than for the bromide, due to
condensation of the intermediate enolate with cyclohexenone.
This side reaction may be promoted by the high Lewis acidity
of dimethylaluminum iodide, which is formed from the
alkynylaluminum reagent. Nickel chloride, on the contrary,
performed better than the bromide and gave rise to the
conjugate addition product 3 in 64% yield and 72% ee.
The influence of the dialkylaluminum unit was studied
next. While dimethyl- and diethylaluminum reagents pro-
vided comparable results, diisobutyl(phenylethynyl)-alu-
minum, prepared from phenylethynyllithium and diisobuty-
laluminum chloride, produced ketone 3 with 75% ee. Use
of 2 mol % of the ligand H8-BINAP (4a) resulted in a further
increase of enantioselectivity (79% ee). The optimal tem-
perature was found to be -45 °C. Lower temperatures led
to very slow reaction, probably as a result of poor catalyst
solubility. On the other hand, experiments run at higher
temperatures afforded ketone 3 with lower enantiomeric
purity. In fact, nearly racemic product was obtained, when
the reaction was conducted at room temperature.
The same peak was present in the spectrum when Ni(BI-
NAP)Br2 was treated with dimethyl(phenylethynyl)-aluminum,
(4) Henschke, J. P.; Burk, M. J.; Malan, C. J.; Herzberg, D.; Peterson,
J. A.; Wildsmith, A. J.; Cobley, C. J.; Casy, G. AdV. Synth. Catal. 2003,
345, 300–307.
Further improvement in enantioselectivity was sought
through modification of the bisphosphine ligand. Two new
ligands, which contain the octahydrobinaphthalene backbone
(5) (a) Nast, R.; Beyer, A. J. Organomet. Chem. 1981, 204, 267–272.
(b) Masai, H.; Sonogashira, K.; Hagihara, N. J. Organomet. Chem. 1971,
26, 271–276.
Org. Lett., Vol. 12, No. 2, 2010
301

indicating that nickel(bisphosphine) diacetylide may be the
Ni(II) reagent responsible for the conjugate addition to R,ꢀ-
enones. When this complex was treated with cyclohexenone
and the alkynylaluminum at -45 °C, formation of the ketone
3 with 72% ee was observed. Since the reaction requires the
presence of aluminum reagents to proceed, the dialkylaluminum
chloride formed during the ligand metathesis with Ni(BI-
NAP)Cl2 plays a crucial role as an enone activator. Electrophilic
attack by the R,ꢀ-enone-R2AlCl complex on the dialkynyl
Ni(II) partner can explain absolute stereochemical preference
summarized in Table 1.
bisphosphines being ligands of choice,6 we studied this
application of the new ligand 4c with diisobutylaluminum
hydride (DIBAL) as the hydrogen source.
Gratifyingly, when the isophorone (9) and 3-butylcyclo-
hex-2-eneone (10) were treated with DIBAL at -40 °C in
the presence of CuI, ligand 4c (10 mol %), and HMPA7 (6
equiv), rapid conjugate reduction ensued (Scheme 4). The
Scheme 4
.
CuI/4c-Catalyzed Conjugate Reduction of Enones by
DIBAL
Table 1. Nickel-Catalyzed Conjugate Additions of
Alkynylaluminum Reagents to Cyclic R,ꢀ-Enonesa
saturated ketones 11 (92% ee) and 12 (91%) were formed
in high yield.8 DIBAL has not been used previously in the
enantioselective conjugate reduction of R,ꢀ-enones. It is
known that in the absence of catalyst DIBAL effects 1,2-
addition to R,ꢀ-enones.7 Interestingly, virtually racemic
conjugate reduction product was formed in low yield (10%),
when BINAP was used as a ligand under otherwise identical
conditions.
In conclusion, the enantioselective conjugate addition
of alkynylaluminum reagents catalyzed by Ni(II) com-
plexes of bisphosphine 4c provides a new and efficient
synthesis of enantiomerically enriched cyclic 3-alkynylke-
tones, which are otherwise difficult or expensive to access.
The new bisphosphine 4c is a useful ligand for enanti-
oselective reduction of R,ꢀ-enones and probably other
applications in enantioselective catalysis.
Supporting Information Available: Experimental details
and compound characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL902643W
a Reactions were performed with 0.5 mmol of cyclic R,ꢀ-enone,
Ni(4c)Cl2 (8 mol %), 4c (2 mol %), and diisobutyl(phenylethynyl)aluminum
(1.4 mmol) in toluene at -45 °C for 6 h. Enantiomeric purity (ee) of the
products was determined by chiral HPLC.
(6) For recent reviews, see: (a) Deutsch, C.; Krause, N.; Lipshutz, B. H.
Chem. ReV. 2008, 108, 2916–2927. (b) Lipshutz, B. H. Modern Organo-
copper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim, 2002; pp
167-187. (c) Rendler, S.; Oestreich, M. Angew. Chem. 2007, 119, 504-510;
Angew. Chem., Int. Ed. 2007, 46, 498-504.
(7) The beneficial effect of hexamethylphosphoramide on nonenanti-
oselective CuMe-catalyzed conjugate enone reductions by DIBAL was first
observed by Saegusa et al.: Tsuda, T.; Hayashi, T.; Satomi, H.; Kawamoto,
T.; Saegusa, T. J. Org. Chem. 1986, 51, 537–540.
The bisphosphine 4c may also be a very useful ligand for
other catalytic transformations. Since copper(I)-catalyzed
conjugate reduction of enones has been described with chiral
(8) Less then 3% of the racemic alcohol arising form the uncatalyzed
1,2-reduction was formed.
302
Org. Lett., Vol. 12, No. 2, 2010