Asymmetric catalytic reductive coupling of 1,3-enynes and aromatic aldehydes

Article abstract of DOI:10.1002/adsc.200505175

Nickel-catalyzed reductive coupling reactions of 1,3-enynes and aromatic aldehydes efficiently afford conjugated dienols in excellent regioselectivity and modest enantioselectivity when conducted in the presence of catalytic amounts of a monodentate, P-chiral ferrocenyl phosphine ligand. 1-(Trimethylsilyl)-substituted enynes are shown to be effective coupling partners in these reactions, and the dienol products thus formed readily undergo protiodesilylation under mild conditions.

Full text of DOI:10.1002/adsc.200505175

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DOI: 10.1002/adsc.200505175
Asymmetric Catalytic Reductive Coupling of1,3-Enynes and
Aromatic Aldehydes
Karen M. Miller, Elizabeth A. Colby, Katrina S. Woodin, Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Fax: (þ1)-617-324-0253, e-mail: tfj@mit.edu
Received: April 24, 2005; Accepted: August 8, 2005
Dedicated to Professor Günther Wilke on the occasion of his 80th birthday.
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
À ꢀ À
Abstract: Nickel-catalyzed reductive coupling reac-
tions of 1,3-enynes and aromaticaldehydes efficient-
ly afford conjugated dienols in excellent regioselec-
tivity and modest enantioselectivity when conducted
in the presence of catalytic amounts of a monoden-
tate, P-chiral ferrocenyl phosphine ligand. 1-(Trime-
thylsilyl)-substituted enynes are shown to be effec-
tive coupling partners in these reactions, and the di-
enol products thus formed readily undergo protiode-
silylation under mild conditions.
alkynes (Ar C C R) and aldehydes are highly enan-
tioselective when (þ)-neomenthyldiphenylphosphine
(NMDPP) is employed as a chiral ligand (Scheme 1).[16]
We have also described a class of P-chiral, monodentate
ferrocenyl phosphines (e.g., 1a, 1b; Figure 1) that are ef-
ficient promoters of related couplings of aliphatic inter-
nal alkynes (Alkyl C C Alkyl’) and aldehydes,[17] and
À ꢀ À
of multi-component coupling reactions of alkynes,
imines, and organoboron reagents.[18]
Reductive coupling reactions of 2-methyl-1-hexen-3-
yne and benzaldehyde in the presence of catalytic
amounts of Ni(cod)2 and (þ)-NMDPP, and a stoichio-
metricquantity of triethylborane (Et 3B), afforded dien-
ol 2a in low yield and low enantioselectivity, but with
high regioselectivity (Table 1, entry 1). Ferrocenylphos-
phine 1a maintained this high regioselectivity but en-
hanced both the efficacy and enantioselectivity of the
Keywords: allylicaolchols; asymmetricactalysis;
À
C C bond formation; nickel; reductive coupling
1,3-Dienes are important and versatile intermediates in transformation (entry 2). ortho-Isopropylphenyl-substi-
organicsynthesis. They are able participants in an array
of cycloaddition reactions, most notably the Diels–Al-
der reaction,[1–3] and there are a variety of efficient
methods for preparing them.[4] Many of these, such as
olefination reactions,[5,6] cross-couplings,[7,8] alkene/
enyne metathesis,[9] and other transformations,[10] facili-
tate convergent synthesis because they simultaneously
construct a new carbon-carbon bond. Recently, our lab-
oratory[11] and others[12] reported a new strategy for the
synthesis of 1,3-dienes via transition metal-catalyzed re-
ductive coupling reactions of 1,3-enynes and aldehydes.
Scheme 1. Asymmetric, nickel-catalyzed reductive coupling
of arylalkynes and aldehydes.
In addition to forming a new carbon-carbon bond, these
methods also generate a stereogeniccenter, [13] allowing
for efficient construction of chiral 1,3-dienes that have
been widely employed in diastereoselective Diels–Al-
der reactions.[14,15] We now report the first enantioselec-
tive examples of catalytic reductive coupling reactions
of 1,3-enynes, promoted by sub-stoichiometric amounts
of a monodentate, P-chiral ferrocenyl phosphine ligand.
Previous work from our laboratory has shown that
nickel-catalyzed reductive couplings of aryl-substituted Figure 1.
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Karen M. Miller et al.
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Table 1. Catalytic, asymmetric reductive coupling of 2-methyl-1-hexen-3-yne and aromatic aldehydes.[a]
Entry
R
Ligand
Yield [%],[b] Regioselectivity[c]
ee [%][d]
1
2
3
4
5
Ph
“
“
o-Me
p-Me
p-OMe
p-Cl
p-CF3
p-(COMe)
p-(CO2Me)
1-naphthyl
2-naphthyl
NMDPP
16 (>95: 5)
61 (>95: 5)
66 (>95: 5)
71 (>95: 5)
73 (>95: 5)
66 (>95: 5)
54 (>95: 5)
62 (>95: 5)
55 (>95: 5)
65 (>95: 5)
52 (>95: 5)
47 (>95: 5)
8
36
56[e]
54
56
56
55
50
56
53
48
58
1a
1b
“
“
“
“
“
“
“
6
7[f]
8[f]
9[f]
10[f]
11
12
“
“
[a]
Experimental conditions: To Ni(cod)2 (0.05 mmol) and 1b (0.1 mmol) at room temperature were added EtOAc(0.5 mL),
Et3B (1.0 mmol), the aldehyde (1.0 mmol), and 2-methyl-1-hexen-3-yne (0.5 mmol). The reaction mixture was stirred for
3 h at room temperature unless otherwise noted.
[b]
[c]
[d]
[e]
[f]
Yield of isolated product.
1
Determined by H NMR.
Determined by HPLC analysis using Chiralcel OJ or Chiralpak AD-H column.
Absolute configuration of the major enantiomer determined to be (R) via Mosherꢁs ester analysis.
Reaction was conducted at 358C.[19]
tuted-ferrocenylphosphine 1b provided even higher lev- tivity (entries 6–9), and in every case the enantioselec-
els of both reactivity and enantioselectivity (entry 3). A tivity surpassed that of the corresponding vinyl-substi-
variety of aromatic aldehydes undergo reductive cou- tuted enyne (entries 2–5).
pling with 2-methyl-1-hexen-3-yne under these condi-
While the 1-(trimethylsilyl)-substituted enynes inves-
tions in excellent regioselectivity and modest enantiose- tigated underwent coupling in low enantioselectivity
lectivity. Both electron-donating (entries 4–6, 11–12) (Table 2, entries 5 and 10), they are nevertheless worthy
and electron-withdrawing[19] (entries 7–10) substituents of note as they provide access to synthetically-versatile
are tolerated, and aromaticketones and esters are also
compatible (entries 9 and 10).
silyl-substituted conjugated dienes.[21] We have found
that alkenylsilanes 7a and 11a are readily protiodesily-
In our previously reported investigations,[11] we found lated under mild conditions to afford dienols 7b and
that related coupling reactions of 1,3-enynes proceeded 11b, respectively (Scheme 2). This two-step sequence af-
in excellent regioselectivity, regardless of the substitu- fords an efficient route to functionalized 1,3-butadiene
tion pattern on the alkene or the size or nature of the and isoprene units, respectively.[22] These products
other alkyne substituent. The same was found to be also correspond to the dienols expected from reductive
À
true in reactions promoted by ferrocenylphosphine 1b, coupling reactions of terminal enynes (H Cꢀ
and a variety of vinyl-substituted enynes provided a sin-
gle dienol regioisomer with moderate enantioselectivity
À
(Table 2, entries 1–5), even when this required C C
bond formation to occur adjacent to sterically-demand-
ing tert-butyl[20] (entry 4) and trimethylsilyl (entry 5)
groups.
To further investigate this pronounced directing ef-
fect, we synthesized a series of isopropenyl-substituted
alkynes that we had not previously investigated in nick-
el-catalyzed reductive coupling reactions. As in the case
of their vinyl-substituted counterparts, all coupling reac-
tions of these enynes proceeded in excellent regioselec- Scheme 2. Protiodesilylation of alkenylsilanes.
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Reductive Coupling of 1,3-Enynes and Aromatic Aldehydes
Table 2. Catalytic, asymmetric reductive coupling reactions of 1,3-enynes with benzaldehyde.[a]
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Entry
R1
R2
Yield [%],[b] Regioselectivity[c]
ee [%][d]
1[e]
2
H
“
“
“
“
Me
“
“
n-hex
Cy
Ph
t-Bu
SiMe3
Cy
Ph
t-Bu
SiMe3
66 (>95: 5)
70 (>95: 5)
58 (>95: 5)
66 (>95: 5)
53 (>95: 5)
77 (>95: 5)
42 (>95: 5)
64 (>95: 5)
69 (>95: 5)
32
42
44
33
14
55[h]
54
52
28
3
4[f]
5[e]
6[g]
7
8[f]
9
“
[a]
Experimental conditions: To Ni(cod)2 (0.05 mmol) and 1b (0.1 mmol) at room temperature were added EtOAc(0.5 mL),
Et3B (1.0 mmol), benzaldehyde (1.0 mmol), and the enyne (0.5 mmol). The reaction mixture was stirred for 3 h at room
temperature unless otherwise noted.
[b]
[c]
[d]
[e]
[f]
Yield of isolated product.
1
Determined by H NMR.
Determined by HPLC analysis using Chiralcel OJ, OD, or Chiralpak AD-H column.
Reaction was conducted at 08C.
Reaction was conducted at 658C.[19]
[g]
[h]
Reaction was conducted at 388C.[19]
Absolute configuration of the major enantiomer determined to be (R) via Mosherꢁs ester analysis.
À
¼
After stirring an additional 5 min, the enyne (0.5 mmol) was
added. The reaction mixture was stirred for 3 h at room tem-
perature, at which point the septum was removed and the mix-
ture was stirred for 30 min open to air to promote oxidation of
the catalyst. The crude mixture was purified by flash chroma-
tography on silica gel using a solvent gradient (hexanes:ethyl
acetate; 50:1 to 10:1).
C CR2 CR2), which are typically not effective coupling
partners.
In summary, we have described a catalytic, enantiose-
lective reductive coupling of 1,3-enynes and aldehydes
promoted by a P-chiral ferrocenyl monophosphine li-
gand that affords conjugated dienols in very high regio-
selectivity and modest enantioselectivity. A variety of
aromaticaldehydes serve as coupling partners, and nov-
el enyne substitution was investigated. Trimethylsilyl-
substituted dienols obtained via reductive coupling un-
dergo protiodesilylation under mild conditions, increas-
ing the scope of synthetically-useful 1,3-dienes that can
be accessed using this methodology.
Standard Procedure for the Protiodesilylation of
Dienyl Alcohols 3a and 4a
A solution of the dienol (0.3 mmol) in THF (3 mL) was cooled
to 08C. Tetrabutylammoniumfluoride (1–2.5 equivs.) was add-
ed dropwise via syringe and the solution was stirred at 08C until
consumption of the alkenylsilane was evident by TLC analysis
(0.2–1.0 h). H2O was added (2 mL) and the mixture was parti-
tioned between EtOAc(15 mL) and brine (10 mL). The layers
were separated and the aqueous phase was extracted with
EtOAc(3 ꢁ20 mL). The combined organic layers were washed
with brine (1ꢁ30 mL), dried over MgSO4, filtered and concen-
trated. The crude residue was purified by flash chromatogra-
phy on silica gel using a solvent gradient (hexanes:ethyl ace-
tate; 93:7 to 90:10).
Experimental Section
Standard Procedure for the Catalytic Asymmetric
Reductive Coupling of1,3-Enynes and Aldehydes
In a glovebox, Ni(cod)2 (14 mg, 0.5 mmol), and 1b (42 mg,
0.1 mmol) were placed into a 10 mL oven-dried, single-necked,
round-bottom flask, which was then sealed with a rubber sep-
tum. The flask was removed from the glovebox, placed under
argon, and ethyl acetate (0.5 mL) was added via syringe, fol-
lowed immediately by Et3B (0.15 mL, 1.0 mmol). The resulting
solution was stirred 5 min at ambient temperature, and then
the aldehyde (1.0 mmol) was added dropwise via microsyringe.
Acknowledgements
E. A. C. thanks Bristol-Myers Squibb for a Graduate Fellow-
ship in Synthetic Organic Chemistry, and K. S. W. thanks MIT
for a Donald OꢀBrien Fellowship. Additional support for this
Adv. Synth. Catal. 2005, 347, 1533 – 1536
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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Karen M. Miller et al.
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work was provided by the National Institute of General Medical
Sciences (GM-063755). We also thank the NIGMS (GM-
072566), NSF (CAREER CHE-0134704), Amgen, Boehring-
er-Ingelheim, Bristol Myers-Squibb, GlaxoSmithKline, John-
son & Johnson, Merck Research Laboratories, Pfizer, the Sloan
Foundation, Wyeth, and the Deshpande Center (MIT) for gen-
erous financial support. We are grateful to Dr. Li Li for obtain-
ing mass spectrometric data for all compounds (MIT Depart-
ment of Chemistry Instrumentation Facility, which is supported
in part by the NSF [CHE-9809061 and DBI-9729592) and the
NIH (1S10RR13886-01)].
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[19] In certain cases, coupling reactions conducted at 23 0C
resulted in the formation of small amounts of allene-con-
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(Table 2) and heating was required to eliminate their for-
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et al. to be the exclusive product of addition reactions
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À
bond-forming reaction of a tert-alkyl–CꢀC R alkyne
that proceeds with this regioselectivity has been reported
(see ref.[11]).
[21] Review: T.-Y. Luh, K.-T. Wong, Synthesis 1993, 349.
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