N-heterocyclic carbene-initiated α-acylvinyl anion reactivity: Additions of α-hydroxypropargylsilanes to aldehydes

Article abstract of DOI:10.1021/ol0710515

Highly substituted α,β-unsaturated ketones are prepared by the N-heterocyclic carbene-initiated addition of α-hydroxypropargylsilanes to aldehydes. This strategy serves as a highly efficient alternative to the standard Morita-Baylis-Hillman (MBH) approach

Full text of DOI:10.1021/ol0710515

ORGANIC
LETTERS
2007
Vol. 9, No. 13
2581-2584
N-Heterocyclic Carbene-Initiated
-Acylvinyl Anion Reactivity: Additions
of -Hydroxypropargylsilanes to
r
r
Aldehydes
Troy E. Reynolds, Charlotte A. Stern, and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, EVanston, Illinois 60208
scheidt@northwestern.edu
Received May 5, 2007
ABSTRACT
Highly substituted
r,
â
-unsaturated ketones are prepared by the N-heterocyclic carbene-initiated addition of
r
-hydroxypropargylsilanes to
aldehydes. This strategy serves as a highly efficient alternative to the standard Morita
−
Baylis−Hillman (MBH) approaches for these types of
compounds. In contrast to the MBH reaction, different substitution in the
â
-position of the product (R1) can be accommodated in moderate
to excellent yields with a high degree of control over the resulting alkene.
The Morita-Baylis-Hillman (MBH) reaction is an efficient
reaction that generates highly functionalized compounds by
employing R-acylvinyl anion reactivity.1 Significant advances
in the MBH reaction have been made recently, including
mechanistic studies as well as asymmetric and intramolecular
variants.2,3 Despite this progress, the intermolecular MBH
reaction has intrinsic limitations. In particular, the â-sub-
stituents of the activated alkene starting materials (e.g., ethyl
acrylate, vinyl ketones) are almost always hydrogen atoms.
Recently, we reported the scandium(III)-catalyzed addition
of silyloxyallenes to aldehydes as a valuable alternative to
the MBH and other R-acylvinyl anion processes (Option I,
Figure 1).4-6 These reactions proceed under very mild
conditions (10 mol % Sc(OTf)3) and accommodate a wide
scope of â-substitution with excellent yields and a high
degree of control over the resulting alkene geometry. Also,
enantioenriched products could be synthesized by the (-)-
(4) Reynolds, T. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem.
Soc. 2006, 128, 15382-15383.
(5) For reports of silyloxyallenes, see: (a) Merault, G.; Bourgeoi, P.;
Dunogues, J.; Duffaut, N. J. Organomet. Chem. 1974, 76, 17-27. (b)
Fleming, I.; Perry, D. A. Tetrahedron 1981, 37, 4027-4034. (c) Kato, M.;
Kuwajima, I. Bull. Chem. Soc. Jpn. 1984, 57, 827-830. (d) Reich, H. J.;
Eisenhart, E. K.; Olson, R. E.; Kelly, M. J. J. Am. Chem. Soc. 1986, 108,
7791-7800. (e) Stergiades, I. A.; Tius, M. A. J. Org. Chem. 1999, 64,
7547-7551. (f) Li, G.; Wei, H. X.; Phelps, B. S.; Purkiss, D. W.; Kim, S.
H. Org. Lett. 2001, 3, 823-826. (g) Yoshizawa, K.; Shioiri, T. Tetrahedron
Lett. 2006, 47, 757-761.
(1) For a review of the MBH reaction, see: Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. ReV. 2003, 103, 811-891. For mechanistic studies,
see: (a) Aggarwal, V. K.; Fulford, S. Y.; Lloyd-Jones, G. C. Angew. Chem.,
Int. Ed. 2005, 44, 1706-1708. (b) Price, K. E.; Broadwater, S. J.; Walker,
B. J.; McQuade, D. T. J. Org. Chem. 2005, 70, 3980-3987. (c) Krafft, M.
E.; Haxell, T. F. N.; Seibert, K. A.; Abboud, K. A. J. Am. Chem. Soc.
2006, 128, 4174-4175.
(2) Selected examples of enantioselective MBH: (a) Brzezinski, L. J.;
Rafel, S.; Leahy, J. W. J. Am. Chem. Soc. 1997, 119, 4317-4318. (b)
Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem.
Soc. 1999, 121, 10219-10220. (c) McDougal, N. T.; Schaus, S. E. J. Am.
Chem. Soc. 2003, 125, 12094-12095.
(6) For alternative approaches to R-acylvinyl anion equivalents, see: (a)
Sato, Y.; Takeuchi, S. Synthesis 1983, 734-735. (b) Marino, J. P.;
Linderman, R. J. J. Org. Chem. 1983, 48, 4621-4628. (c) Tsuda, T.;
Yoshida, T.; Saegusa, T. J. Org. Chem. 1988, 53, 1037-1040. (d)
Ramachandran, P. V.; Rudd, M. T.; Burghardt, T. E.; Reddy, M. V. R. J.
Org. Chem. 2003, 68, 9310-9316. (e) Gudimalla, N.; Frohlich, R.; Hoppe,
D. Org. Lett. 2004, 6, 4005-4008. (f) Xue, S.; He, L.; Han, K. Z.; Liu, Y.
K.; Guo, Q. X. Synlett 2005, 1247-1250. (g) Trost, B. M.; Oi, S. J. Am.
Chem. Soc. 2001, 123, 1230-1231. (h) Trost, B. M.; Chung, C. K. J. Am.
Chem. Soc. 2006, 128, 10358-10359.
(3) (a) Wang, L. C.; Luis, A. L.; Agaplou, K.; Jang, H. J.; Krische, M.
J. J. Am. Chem. Soc. 2002, 124, 2402-2403. (b) Frank, S. A.; Mergott, D.
J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404-2405. (c) Krafft, M.
E.; Haxell, T. F. N. J. Am. Chem. Soc. 2005, 127, 10168-10169.
10.1021/ol0710515 CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/01/2007

resulting solution was then cooled to -78 °C and followed
by addition of benzaldehyde and a substoichiometric amount
of Lewis base. At the onset of these studies, we performed
a limited survey of nucleophilic species. For example,
fluoride sources (20 mol % tetrabutylammonium difluoro-
triphenylsilicate, 27% yield) and potassium tert-butoxide (20
mol %, 20% yield) generated the desired product, but both
these classes of anions afforded poor yields with virtually
no catalyst turnover.9 While a potential solution to increase
the yields of this reaction was simply to add more fluoride
or potassium alkoxide, we were compelled to identify a
promoter that could be effective in amounts less than 1 equiv.
We reasoned that the cations associated with the fluoride or
alkoxides might be complicating the desired transformation
and looked to find zwitterionic nucleophilic molecules that
would avoid these possibilities. Gratifyingly, 20 mol % of
N-heterocyclic carbene (NHC) 2 catalyzes the addition to
benzaldehyde in an 80% yield and 1:20 E:Z ratio for the
new alkene (Scheme 1).10,11
Figure 1. Silyloxyallene addition strategies.
Scheme 1. NHC-Initiated Addition of
R-Hydroxypropargylsilane
(salen)Cr(III)-catalyzed additon of racemic silyloxyallenes.4
One aspect of the transformation is the prerequisite of
preparing the silyloxyallenes in a separate step through the
Kuwajima-Reich rearrangement of the R-hydroxypropar-
gylsilane precursors.7 Herein, we present an alternative
single-flask approach starting directly from the propargyl-
silanes, thus further enhancing the applicability of this
unconventional R-acylvinyl addition reaction (Option II,
Figure 1).
Our current interests include the development of reactions
employing Lewis base activation to efficiently access
unconventional reactivity. Several transformations from our
laboratory, including acyl anion additions, homoenolate
reactions, alkyne additions, disilylations of activated alkenes,
and hydroacylations of ketones have been facilitated by the
use of Lewis bases.8 Given our strong interest in the
combination of Lewis basic promoters/catalysts, we reasoned
that Lewis bases may activate silyloxyallenes toward addi-
tion. In particular, they should be more compatible with the
rearrangement conditions (substoichiometric n-BuLi, THF)
of the R-hydroxypropargylsilanes to the allenes and facilitate
a single flask procedure.
N-Heterocyclic carbenes have become increasingly power-
ful in synthesis not only as ligands but also as reagents and
catalysts for several bond-forming transformations, including
benzoin condensations, Stetter reactions, homoenolate ad-
ditions, transesterifications, and acylations.12,13 The use of
an NHC to activate silicon reagents has only been observed
recently.14 Song and co-workers were the first to demonstrate
that N-heterocyclic carbenes effectively catalyze the addition
of TMSCF3 as well as TMSCN to carbonyl compounds in
high yields and with very low catalyst loadings.15 This
reactivity has also been reported with the NHC-catalyzed
ring-opening of aziridines with silylated nucleophiles.16 Most
(9) Pilcher, A. S.; Deshong, P. J. Org. Chem. 1996, 61, 6901-6905.
(10) Arduengo, A. J., III; Krafczyk, R.; Schmutzler, R.; Craig, H. A.;
Goerlich, J. R.; Marshall, W. J.; Unverzagt, M. Tetrahedron 1999, 55,
14523-14534.
Starting with R-hydroxypropargylsilane 1 in THF at 0 °C,
the allene was formed with use of 5 mol % of n-BuLi. The
(11) Attempts at using a single base to catalyze both the rearrangement
as well as the addition provided low yields of desired product.
(12) For reviews of N-heterocyclic carbenes as ligands, see: (a)
Herrmann, W. A.; Ofele, K.; Von Preysing, D.; Schneider, S. K. J.
Organomet. Chem. 2003, 687, 229-248. (b) Herrmann, W. A. Angew.
Chem., Int. Ed. 2002, 41, 1291.
(13) For reviews of N-heterocyclic carbenes as catalysts, see: (a) Enders,
D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534-541. (b) Nair, V.; Bindu,
S.; Sreekumar, V. Angew. Chem., Int. Ed. 2004, 43, 5130-5135. (c)
Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326-1328.
(14) (a) Song, J. J.; Tan, Z. L.; Reeves, J. T.; Gallou, F.; Yee, N. K.;
Senanayake, C. H. Org. Lett. 2005, 7, 2193-2196. (b) Song, J. J.; Gallou,
F.; Reeves, J. T.; Tan, Z. L.; Yee, N. K.; Senanayake, C. H. J. Org. Chem.
2006, 71, 1273-1276.
(7) (a) Kuwajima, I.; Kato, M. Tetrahedron Lett. 1980, 21, 623-626.
(b) Reich, H. J.; Olson, R. E.; Clark, M. C. J. Am. Chem. Soc. 1980, 102,
1423-1424.
(8) Acyl anion additions: (a) Mattson, A. E.; Bharadwaj, A. R.; Scheidt,
K. A. J. Am. Chem. Soc. 2004, 126, 2314-2315. (b) Myers, M. C.;
Bharadwaj, A. R.; Milgram, B. C.; Scheidt, K. A. J. Am. Chem. Soc. 2005,
127, 14675-14680. (c) Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.;
Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4932-4933. Homoenolate
addition: (d) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905-908.
Trialkoxysilylalkyne addition: (e) Lettan, R. B.; Scheidt, K. A. Org. Lett.
2005, 7, 3227-3230. Disilylation: (f) Clark, C. T.; Lake, J. F.; Scheidt, K.
A. J. Am. Chem. Soc. 2004, 126, 84-85. Hydroacylation: (g) Chan, A.;
Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4558-4559.
2582
Org. Lett., Vol. 9, No. 13, 2007

recently, Song and his colleagues have extended their
research to include carbene-catalyzed additions of silyl enol
ethers in Mukaiyama aldol reactions.17
Table 2. Addition of a-Hydroxypropargylsilanes to
Benzadehyde
With the optimized bond-forming conditions in hand for
this process, we set out to investigate the scope of the reaction
using 1 as the nucleophilic precursor (Table 1). Addition
Table 1. Addition of R-Hydroxypropargylsilane 1 to
Aldehydes
1
a Determined by 500 MHz H NMR spectroscopy. b Isolated yields.
The role of the N-heterocyclic carbene in this reaction is
currently under investigation: two reaction pathways can be
envisaged (Scheme 2). The first possibility is that the
N-heterocyclic carbene acts in a catalytic capacity. In their
recent report, Song and co-workers invoke initial NHC
addition to the TMS enol ether, which subsequently activates
the silyloxy species to form a pentavalent silicon complex
analogous to other Lewis base-catalyzed Mukaiyama aldol
reactions.18 Support for this pathway includes the known
interaction of TMSI as well as polychlorosilanes with
N-heterocyclic carbenes to form stable adducts.19 However,
these experiments by Kuhn involved less sterically encum-
bered carbenes than 2.
A second possible mode of reactivity is an NHC-initiated
reaction in which the N-heterocyclic carbene interacts with
the aldehyde and not the silyloxy compound. A clear
possibility based on the known interactions of N-heterocyclic
carbenes with aldehydes13 is the initial addition of the
nucleophilic NHC 2 to the aldehyde to form an alkoxide
intermediate 14 devoid of an external cation,which can then
proceed to desilylate the silyloxyallene 1 via silyl transfer.20
This highly reactive “naked” allenolate would react readily
with a second equivalent of aldehyde to form the desired
1
a Determined by 500 MHz H NMR spectroscopy. b Isolated yields.
occurred readily to aromatic aldehydes (entries 1-4) in good
yields. The R-hydroxypropargylsilane 1 also added to
aliphatic aldehydes (entries 5 and 6) albeit in lower yields.
For all of the aldehydes, the E/Z selectivity of the reaction
was greater than 1:20 favoring the Z isomer.
An advantage of this reaction over the standard MBH
approaches is the tolerance of â-substitution of the alkene
on the product (Table 2). A wide range of R-hydroxypro-
pargylsilanes are tolerated including both alkyl (entry 1) and
aromatic (entry 2) substituted substrates. A trimethylsilyl
(entry 3), silyl protected alcohol (entry 4), and tert-butyl
(entry 5) group can also be accommodated. Moderate to
excellent yields were achieved as well as excellent E:Z
regiocontrol.
(15) Other NHC-catalyzed cyanation reactions: (a) Fukuda, Y.; Maeda,
Y.; Ishii, S.; Kondo, K.; Aoyama, T. Synthesis 2006, 589-590. (b) Fukuda,
Y.; Maeda, Y.; Kondo, K.; Aoyama, T. Chem. Pharm. Bull. 2006, 54, 397-
398. (c) Fukuda, Y.; Maeda, Y.; Kondo, K.; Aoyama, T. Synthesis 2006,
1937-1939. (d) Fukuda, Y.; Kondo, K.; Aoyama, T. Synthesis 2006, 2649-
2652. (e) Suzuki, Y.; Abu Bakar, M. D.; Muramatsu, K.; Sato, M.
Tetrahedron 2006, 62, 4227-4231. (f) Kano, T.; Sasaki, K.; Konishi, T.;
Mii, H.; Maruoka, K. Tetrahedron Lett. 2006, 47, 4615-4618.
(16) (a) Wu, J.; Sun, X.; Ye, S.; Sun, W. Tetrahedron Lett. 2006, 47,
4813-4816. (b) Sun, X.; Ye, S.; Wu, J. Eur. J. Org. Chem. 2006, 4797-
4798.
(18) See ref 17. For a recent review of the Mukaiyama aldol reaction
see: Mukaiyama, T. Angew. Chem., Int. Ed. 2004, 43, 5590.
(19) Kuhn, N.; Kratz, T.; Blaser, D.; Boese, R. Chem. Ber. 1995, 128,
245-250.
(20) (a) Noyori, R.; Nishida, I.; Sakata, J.; Nishizawa, M. J. Am. Chem.
Soc. 1980, 102, 1223. (b) Noyori, R.; Nishida, I.; Sakata, J. J. Am. Chem.
Soc. 1983, 105, 1598. (c) Nakamura, E.; Shimizu, M.; Kuwajima, I.; Sakata,
J.; Yokoyama, K.; Noyori, R. J. Org. Chem. 1983, 48, 932.
(17) Song, J. J.; Tan, Z. L.; Reeves, J. T.; Yee, N. K.; Senanayake, C.
H. Org. Lett. 2007, 9, 1013-1016.
Org. Lett., Vol. 9, No. 13, 2007
2583

and recrystallization of the resulting solid produced the
NHC-aldehyde adduct as a single product with chloride as
the counterion to the positively charged heterocycle (H14‚
Cl, Figure 2). The NHC-Si adduct was not detected or
recovered under the reaction conditions. This ORTEP
provides for the first time definitive, structural evidence for
the widely invoked addition of carbenes to aldehydes. Initial
experiments to determine if this adduct is a catalyst in the
reaction were inconclusive most likely due to the potential
reversibility of the addition. We believe this adduct to be
the more likely intermediate in the addition of silyloxyallenes
and aldehydes “catalyzed” by N-heterocyclic carbenes. We
reason that the aldehyde carbonyl carbon is significantly more
accessible to the NHC 2 than the silicon atom of the
silyloxyallene. An examination of space-filling depictions
of tetrasubstituted silyl species and a large, sterically
encumbered N-heterocyclic carbene such as 2 make a direct
interaction between the C2 carbon of the carbene and the
silicon atom highly tenuous.
Scheme 2. Proposed Mechanisms
In summary, we have developed a highly efficient single-
flask procedure for the addition of R-hydroxypropargylsilanes
to aldehydes. The reaction generates â-substituted unsaturated
ketone products in moderate to excellent yields with exquisite
control of the alkene geometry. The reaction pathway of this
process currently invokes the initial formation of a nucleo-
philic alkoxide resulting from the addition of a free N-
heterocyclic carbene to an aldehyde. This alkoxide promotes
a silyl group transfer to generate a reactive allenolate.
Structural evidence supporting the NHC-aldehyde adduct
as the initiator of the reaction has been reported. Further
investigations of the synthetic utility of silyloxyallenes and
this unique mode of silicon activation reported herein are
currently underway.
carbinol product (Figure 1). A similar model has been
proposed previously by both Aoyama et al. and Suzuki et
al. with cyanosilylations of carbonyl compounds.15
We lend support for the latter NHC-initiated mechanism
with the isolation and X-ray structure of the N-heterocyclic
carbene-aldehyde adduct (Figure 2). In an effort to elucidate
Acknowledgment. Support for this research has been
provided by the NIH (National Institute of General Medical
Sciences RO1 GM073072). K.A.S. thanks Abbott, Amgen,
Boerhinger-Ingelheim, and 3M for generous unrestricted
research support. FMCLithium, BASF, and Wacker Chemical
kindly provided reagents for these studies. Funding for the
NU Analytical Services Laboratory has been furnished in
part by the NSF (CHE-9871268).
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds, and a CIF
file for H14‚Cl. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL0710515
(21) Solvent, hydrogen atoms (including OH) were removed from
ORTEP for clarity. X-ray data for 14: C36H45Cl5N2O, MW ) 698.99, T )
153(2) K, λ ) 0.71073 Å, monoclinic space group, P2(1)/c, a ) 10.0917(8)
Å, b ) 15.981(12) Å, c ) 23.623(18) Å, â ) 95.076(1)°, V ) 3794.8(5)
Å3, Z ) 4, Dc ) 1.223 g/cm3, µ ) 0.411 mm-1, F(000) ) 415, crystal size
0.30 × 0.29 × 0.28 mm3, independent reflections 9255 [R(int) ) 0.0930],
reflections collected 35196, refinement method was full-matrix least-squares
on F2, goodness-of-fit on F2 was 0.976, final R indices [I > 2σ(I)] R1 )
0.0906, wR2 ) 0.2519, R indices (all data) R1 ) 0.1274, wR2 ) 0.2519,
largest diff. peak and hole 2.047 and -1.193 e Å-3. See the Supporting
Information for additional details.
Figure 2. ORTEP of NHC-aldehyde Adduct H14‚Cl.21
the role of the N-heterocyclic carbene in our reaction,
benzaldehyde (1 equiv), chlorodimethylphenylsilane (1 equiv),
and 2 (1 equiv) were combined in THF at -78 °C. After
warming, the removal of the solvent under reduced pressure
2584
Org. Lett., Vol. 9, No. 13, 2007