Stereoselective Lewis acid-catalyzed α-acylvinyl additions

Article abstract of DOI:10.1021/ja0653674

Silyloxyallenes derived from α-hydroxypropargylsilanes undergo efficient addition to aldehydes with catalytic amounts of Lewis acids. The allenes are accessed from the corresponding propargylsilanes in a base-catalyzed 1,2-Brook rearrangement/S_E

Full text of DOI:10.1021/ja0653674

Published on Web 11/10/2006
Stereoselective Lewis Acid-Catalyzed r-Acylvinyl Additions
Troy E. Reynolds, Ashwin R. Bharadwaj, and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road, EVanston, Illinois 60208
Received July 26, 2006; E-mail: scheidt@northwestern.edu
Table 1. Optimization of R-Acylvinyl Anion Additions
The development of atypical nucleophilic reagents provides
unconventional access to valuable molecules.1 A well-established
catalytic method to access unusual R-acylvinyl anion reactivity is
the Morita-Baylis-Hillman (MBH) reaction.2,3 Advances to render
this reaction enantioselective4 and intramolecular5 have been
recently reported, but the MBH process continues to be restricted
in scope and selectivity. Since the reaction involves a conjugate
addition of a catalytic nucleophile, the â-substituent (R1) is typically
a hydrogen atom. A potential alternative strategy to generate
R-acylvinyl anion reactivity is the use of silyloxyallenes prepared
from R-hydroxypropargylsilanes 1.6 Herein we report a stereo-
selective process for the addition of silyloxyallene 2 derived from
1 to carbonyl compounds catalyzed by Lewis acids (eq 1). This
sequence efficiently generates R,â-unsaturated carbonyl compounds
3 with control over alkene geometry and the stereochemistry of
the newly formed carbinol.
entry
Lewis acid
E:Za
yield (%)b
1
2
3
4
5
1 equiv of Et2O‚BF3
10 mol % of TMS-OTf
10 mol % of Cu(OTf)2
10 mol % of Zn(OTf)3
10 mol % of Sc(OTf)3
1:6
1:4
80
52
0
0
78
1:20
1
a Determined by 500 MHz H NMR spectroscopy. b Isolated yield.
process, 10 mol % of Sc(OTf)3 generates the desired R-acylvinyl
addition product 6 at low temperature with excellent selectivity for
the Z alkene isomer (1:20, E:Z).
In contrast to the MBH reaction, this process accommodates a
wide variety of â-substitution of the R-acylvinyl nucleophile and
also provides the products in greater than 90% yield (Table 2).
Aryl-, alkyl- (entries 1, 2, and 4), and trimethylsilyl (entry
3)-substituted silyloxyallenes are excellent substrates for this Lewis
acid-catalyzed reaction. A silyl-protected alcohol (entry 5) and a
tert-butyl group (entry 6) can also be incorporated into the products
without complications. Notably, the product alkene geometry for
these reactions is 20:1 favoring the Z isomer (except for R1 ) Me).
Racemic silyloxyallene 5 also adds to a variety of aromatic and
unbranched aliphatic aldehydes with excellent yields and alkene
selectivity (Table 3). Enolizable R-branched aldehydes afford
complex reaction mixtures, and further work with these substrates
is necessary. With 20 mol % of Sc(III), allene 5 smoothly adds to
pivaldehyde (entry 6), resulting in a 95% yield. A highly reactive
ketone does provide low yields under the current reaction conditions
(entry 8).
The conversions of R-hydroxypropargylsilanes into silyloxy-
allenes were pioneered independently by Kuwajima7 and Reich.8
Kuwajima demonstrated that racemic R-hydroxypropargylsilanes
undergo a base-catalyzed rearrangement to form silyloxyallenes 2.
In a related process, Reich converted acylsilanes into allenyl metal
reagents via a [1,2]-Brook rearrangement9 initiated by the addition
of alkynyl lithium reagents. The allenyl anions generated in situ
using Reich’s method have been used in alkylations, protonations,
and formylations. However, employing related neutral silyloxy-
allenes as nucleophiles has been limited to date, and the few
examples require harsh conditions or are limited to â-halo substitu-
tion.10 With our interest in acylsilanes and unusual nucleophiles,11
we recognized that an efficient method to access R-acylvinyl anions
under mild conditions would significantly enhance the utility of
these unconventional reagents.12
With this selective bond-forming sequence in hand, we wished
to control the stereochemistry of the product through chirality
transfer from the propargylsilane (reagent control). Accordingly,
we have developed a catalytic asymmetric alkyne addition to
acylsilane 20 using tridentate Schiff base ligand 21 to access an
Table 2. Addition of Silyloxyallenes 2 to Benzaldehyde
Our strategy initially focused on the use of Lewis acids with
silyloxyallene 5 (Table 1). The controlled addition of alkynyl
Grignard reagents to acylsilanes furnishes the racemic propargyl-
silanes in high yields.13 The corresponding allene is obtained by
exposure of 4 to 5 mol % of n-BuLi and removal of THF in vacuo.14
Stoichiometric quantities of strong Lewis acids (BF3, entry 1) deliver
6 in good yield, favoring the Z alkene. In searching for a catalytic
variant, scandium(III) triflate emerged as the most efficient catalyst
for additions of silyloxyallene 5. Surprisingly, numerous other metal
triflate salts surveyed did not promote the reaction.15 In the optimal
entry
R
R1
E:Za
yield (%)b
1
2
3
4
5
6
7
Et
Me
Ph
1:4
99 (7)
Et
1:20
1:20
1:20
1:20
1:20
1:20
98 (8)
Et
SiMe3
98 (9)
Et
n-Bu
91 (10)
97 (11)
98 (12)
95 (13)
Et
CH2OTBDPS
t-Bu
Et
C3H5
n-Bu
a Determined by 500 MHz H NMR spectroscopy. b Isolated yield.
1
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J. AM. CHEM. SOC. 2006, 128, 15382-15383
10.1021/ja0653674 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Additions of Allene 5 to Aldehydes
resulting unsaturated ketone products can be controlled by a chiral
catalyst. Full development of the asymmetric addition of alkynes
to acylsilanes as well as the enantioselective Cr(III)-catalyzed
reactions with silyloxyallenes are underway and will be reported
in due course.
Acknowledgment. Financial support for this work has been
provided by Northwestern University, the NSF, and the PRF. K.A.S.
thanks Abbott, Amgen, 3M, and Boehringer Ingelheim for generous
research support. Wacker Chemical, FMCLithium, and BASF have
provided reagents for this work. We thank Dr. Jacob Janey (Merck)
for the kind gift of (-)-1,2-cis-aminoindanol.
Supporting Information Available: Experimental procedures and
spectral data for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
entry
R
R
′
E:Za
yield (%)b
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
H
H
1:20
1:20
1:20
1:20
1:20
1:20
1:20
1:20
91 (10)
96 (14)
97 (15)
98 (16)
78 (6)
4-Cl-Ph
4-MeO-Ph
2-Nap
PhCH2CH2
t-Bu
C3H5
95 (17)c
56 (18)
18 (19)c
Ph
COMe
a Determined by 1H NMR spectroscopy. b Isolated yield. c 20 mol % of
Sc(OTf)3.
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(13) See Supporting Information for details.
With substrate control proving unlikely, we examined chiral
catalysts for the addition of racemic silyloxyallenes (e.g., 23).
Gratifyingly, the use of (-)-(salen)Cr(III)-SbF6 with racemic
silyloxyallene 23 (1 equiv) and 2-chlorobenzaldehyde (1 equiv)
affords carbinol 24 in 92% ee, demonstrating that a chiral catalyst
can modulate the facial selectivity of both reagents with a high
level of control.19
(14) This 1,2-Brook process works in THF but not toluene or Et2O.
(15) 10 mol% of Sm(OTf)3, Yb(OTf)3, La(OTf)3, In(OTf)3, or Eu(OTf)3 as
the Lewis acid did not afford product.
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In summary, silyloxyallenes generated from acylsilanes undergo
scandium(III)-catalyzed R-acylvinyl additions to a variety of
aldehydes. A wide range of â-substitution on the allene is
accommodated with excellent yields and a high degree of control
over the new alkene geometry. The carbinol stereocenter of the
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