Gold-catalyzed hydrosilyloxylation driving tandem aldol and Mannich reactions

Article abstract of DOI:10.1021/ol301660f

The chemoselective formation of an enolate from alkyne in the presence of a carbonyl and imine group was realized, which constructed a variety of structural motifs under exceedingly mild reaction conditions in a tandem process. Reaction driving tandem hyd

Full text of DOI:10.1021/ol301660f

ORGANIC
LETTERS
2012
Vol. 14, No. 15
3912–3915
Gold-Catalyzed Hydrosilyloxylation
Driving Tandem Aldol and Mannich
Reactions
Dongjin Kang, Sangjune Park, Taekyu Ryu, and Phil Ho Lee*
Department of Chemistry, Kangwon National University, Chuncheon 200-701, Republic
of Korea
phlee@kangwon.ac.kr
Received June 18, 2012
ABSTRACT
The chemoselective formation of an enolate from alkyne in the presence of a carbonyl and imine group was realized, which constructed a variety of
structural motifs under exceedingly mild reaction conditions in a tandem process. Reaction driving tandem hydrosilyloxylation/aldol reactions
was achieved through the formation of enol silyl ethers catalytically generated in situ from readily available alkynes. These reactions were
expanded to obtain β-amino enol silyl ethers in good yields via the tandem hydrosilyloxylation/isomerization/Mannich reaction.
The aldol1 and Mannich reactions2 are well-recognized
as two of the most important carbonÀcarbon bond-
forming reactions in organic synthesis. Most of these
processes critically depend on the activation of the alde-
hydes or ketones by converting them into enolates or their
derivatives such as enol silyl ethers. Accordingly, synthetic
methods based on this approach have been extensively
investigated over the past decades.3 In general, enolates
and enols can be prepared from the corresponding carbo-
nyl compounds by deprotonation with more than stoichio-
metric amounts of bases.1
However, this method is not compatible with sensitive
functional groups that are commonly employed in organic
synthesis. Therefore, enol silyl ethers and their derivatives
must be prepared separately prior to the addition of certain
electrophiles having sensitive functional groups in the next
step. This indicates that the chemoselective formation of
an enolate from one carbonyl group in the presence of
another is highly challenging. We thus have long been
interested in developing a synthetic method of enol silyl
ethers and their derivatives from readily available non-
carbonyl precursors without the use of bases.4 To date,
a variety of synthetic methods of enolates from alkynyl
(1) Reviews of the aldol reaction: (a) Evans, D. A.; Nelson, J. V.;
Taber, T. R. Top. Stereochem. 1982, 13, 1. (b) Heathcock, C. H.
Asymmetric Synth. 1984, 3, 111. (c) Braun, M. Angew. Chem., Int. Ed.
1987, 26, 24. (d) Heathcock, C. H. In Comprehensive Organic Synthesis;
Heathcock, C. H., Ed.; Pergamon Press: New York, 1991; Vol. 2, p 181. (e)
Kim, B. M.; Williams, S. F.; Masamune, S. In Comprehensive Organic
Synthesis; Heathcock, C. H., Ed.; Pergamon Press: New York, 1991; Vol. 2, p
239. (f) Paterson, I. In Comprehensive Organic Synthesis; Heathcock,
C. H., Ed.; Pergamon Press: New York, 1991; Vol. 2, p 301. (g) Franklin,
A. S.; Paterson, I. Contemp. Org. Synth. 1994, 1, 317. (h) Cowden, C. J.;
Paterson, I. Org. React. 1997, 51, 1.
(2) Reviews of the Mannich reaction: (a) Kleinmann, E. F. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
New York, 1991; Vol. 2, Chapter 4.1. (b) Arend, M.; Westermann, B.;
Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044. (c) Denmark, S. E.;
Nicaise, O. J.-C. In Comprehensive Asymmetric Catalysis; Jacobsen,
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R.; Evans, D. A. Modern Aldol Reactions, Vols. 1À2; Mahrwald, R.,
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r
10.1021/ol301660f
Published on Web 07/24/2012
2012 American Chemical Society

boronic acid,5 allylic alkoxide,6 allylic alcohols,7 and vinyl
metals8 were reported.9 An addition reaction of silanols
to enynes to produce 1,3-silyloxydienes was reported.10
Recently, Gaunt et al. reported a scandium-catalyzed
tandem hydrosilyloxylation/aldol reaction with an acti-
vated alkyne.11 We envisioned that an aldol or a Mannich
reaction upon the catalytic formation of enol silyl ethers
from alkynes would be an attractive tandem process12 to
give a variety of structural motifs. To the best of our
knowledge, no example of a hydrosilyloxylation/aldol
and hydrosilyloxylation/Mannich tandem process has
been described, and encouraged by recent advances in
tandem processes we decided to explore such a sequence.
Herein, we report the Au-catalyzed13 tandem hydro-
silyloxylation/aldol and hydrosilyloxylation/Mannich re-
action starting from readily available alkynes in one pot
under extremely mild conditions.
Table 1. Optimization of Intramolecular Hydrosilyloxylationa
entry
cat. (mol %)
AuCl3/AgOTf
time (h)
yield (%)
1
12
0.6
1
23b
40
2
Ph3PAuCl/AgOTf
Ph3PAuCl/AgPF6
Ph3PAuCl/AgAsF6
Ph3PAuCl/AgSbF6
Ph3PAuCl/AgBF4
Ph3PAuCl/AgNTf2
(C6F5)3PAuCl/AgNTf2
(C6F5)3PAuCl/AgOTf
(C6F5)3PAuCl/AgOTf
AgOTf
3
39
4
0.3
12
12
2
36
5
14 (66)c
13 (64)c
57
6
7
8
0.5
0.17
0.5
3
43
9
88
10
11
12
86d
0e
To find out the mosteffective catalyst for the cyclization,
an initial study was carried out with 1a in DCE (Table 1)
and a wide range of gold catalysts along with silver salts
TfOH
24
0e
a Au and Ag catalyst (5 mol % each) was used unless otherwise noted.
b AgOTf (15 mol %) was used. c Recovery yield of 1a. d (C6F5)3PAuCl
(1 mol %) and AgOTf (1 mol %) were used. e AgOTf and TfOH
(5 mol %) were used.
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Varma, R. S.; Li, C.-J. Org. Lett. 2003, 5, 657. (d) Cuperly, D.; Petrignet,
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J.; Crevisy, C.; Gree, R. Chem.;Eur. J. 2006, 12, 3261. (e) Petrignet, J.;
and protic acids were examined. A gold catalyst system of
(C6F5)3PAuCl/AgOTf (1 mol % each) turned out to be the
most effective to selectively provide an
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Roisnel, T.; Gree, R. Tetrahedron Lett. 2006, 47, 7745. (f) Petrignet, J.;
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6-endo addition product 2a in 86% yield in DCE (0.25 M)
at room temperature within 30 min without detection of a
5-exo addition product (entry 10). It is noteworthy that
high dilution conditions are not necessary in the present
intramolecular cyclization.10,14 AgOTf and triflic acid
(5 mol % each) were totally ineffective (entries 11 and 12).
In addition, the effects of disubstituents tethered to silicon on
cyclization were next examined. Under the optimized reac-
tion conditions, the alkynyl silanol 1b having a dimethyl
group on the silicon atom was converted to an enol silyl ether
2b in 58% yield along with disiloxane in 26% yield (eq 1).
When an alkynyl silanol 1c bearing a sterically bulky diiso-
propyl group on silicon was treated with the gold catalyst, the
corresponding disiloxane was not observed as anticipated
while the cyclization (2c, 60% yield) was not complete (eq 2).
With this newly developed protocol in hand, we sub-
sequently examined a variety of alkynyl silanols for the
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under high dilution (0.05 M in fluorobenzene) conditions.
Org. Lett., Vol. 14, No. 15, 2012
3913

Scheme 1. Au-Catalyzed Intramolecular Hydrosilyloxylation
Scheme 2. Au-Catalyzed Intramolecular Hydrosilyloxylation/
Aldol Reactiona
a RCHO (2 equiv) was used. b(C6F5)3PAuCl and AgOTf (5 mol %
each) was used.
butyraldehyde with (C6F5)3PAuCl/AgOTf (1 mol % each)
in DCE (25 °C, 4 h) gave the aldol product 3a in 76%
yield (dr = 2.2:1) (eq 4). This indicates that the enolate was
catalytically generated in situ from alkyne in the presence
of aldehyde.
intramolecular hydrosilyloxylation (Scheme 1). Treat-
ment of alkynyl silanols (1d, 1e, 1f, and 1g) having
various substituents such as butyl, phenethyl, cyclo-
hexyl, and chloropropyl on sp-hybridized carbon with
(C6F5)3PAuCl/AgOTf (1 mol % each) provided the
desired enol silyl ethers (74À86% yields) at room tempera-
ture within 20 min. 4-Methylphenyl and 3-chlorophenyl-
substituted alkynyl silanols (1h and 1i) were efficiently cy-
clized to afford enol silyl ethers (2h and 2i) in 89% and 80%
yields, respectively. Electronic variation (methyl and fluoride
groups) on the phenyl ring possessing diphenylhydroxysilyl
and alkynyl groups did not much influence the cyclization
efficiency although a fluoride-substituted silanol (1l and 1m)
required a slightly longer reaction time.
We first examined the gold-catalyzed aldol reaction of
enol silyl ether with aldehyde to find reaction conditions
that tolerate both the catalytic generation of enol silyl ether
and the subsequent aldol reaction. When enol silyl ether
2a was treated with butyraldehyde under the optimized
reaction conditions, the corresponding aldol product 3a
was produced in 78% yield (dr = 2.2:1) in DCE at
room temperature after 4 h (eq 3).15 Encouraged by this
result, a one-pot tandem hydrosilyloxylation and aldol
reaction from alkyne and aldehyde was carefully investi-
gated. Gratifyingly, treatment of alkynyl silanol 1a and
Next, we explored the gold-catalyzed tandem intramo-
lecular hydrosilyloxylation and aldol reaction with a wide
range of alkynes and aldehydes in one pot (Scheme 2).
Fluorophenyl and methylphenyl silanol 1l and 1j having
a phenylethynyl group underwent the tandem hydrosily-
loxylation and aldol reaction to provide aldol products
3b (67%, dr = 5:1) and 3c (76%, dr = 2:1), respectively.
Although a tandem reaction of silanol 1d bearing hexyn-1-
yl with 2-bromobenzaldehyde gave 3db in 68% yield with
moderate diastereoselectivity (dr = 1.4:1), 4-nitrobenzal-
dehyde gave3da in 75% yield with high diastereoselectivity
(dr = 13:1). Under the optimized reaction conditions,
5-chloropentyn-1-yl-substituted silanol 1g was also suc-
cessfully subjected to the tandem intramolecular hydro-
silyloxylation and aldol reaction with butyraldehyde,
affording the desired aldol product 3ea and 3eb in 40%
yields, respectively. When a tandem reaction was carried
out with 1g and 2-nitrobenzaldehyde, the desired aldol
(15) Reaction of 2a with butanal did not produce aldol product 3a
without a gold catalyst. Reaction of 2a with butanal in the presence of
AgOTf (10 mol %) and (separately) TfOH (10 mol %) did not proceed.
3914
Org. Lett., Vol. 14, No. 15, 2012

compound 3ec was isolated in 69% yield as a single
diastereomer.
Scheme 3. Plausible Mechanism of the Tandem Hydrosilylox-
ylation/Isomerization/Mannich Reaction
Encouraged by these tandem hydrosilyloxylation/
aldol reactions, we investigated a gold-catalyzed tandem
intramolecular hydrosilyloxylation/Mannich reaction
starting from alkynes and imines. Reaction of 1d with
(E)-N-benzylidene-4-methyl benzenesulfonamide (1.2 equiv)
in DCE at room temperature afforded unexpectedly 4a
and 4b, which are enol silyl ether forms of the Mannich
product, in 44% and 26% yields (dr = 1.7:1), respectively,
albeit requiring (C6F5)3PAuCl and AgOTf (5 mol %, each)
(eq 6).16 In addition, a silyl enol ether 2d was reacted
with imine to give the same result (eq 5).17 The structure
of diastereomer 4b was unambiguously determined by
spectroscopy and X-ray crystallography (Supporting
Information). The serendipitous introduction of an imine
moiety at the exo position indicates that isomerization of a
double bond of enol silyl ether occurred during the tandem
reaction.4a,18 A plausible reaction mechanism is shown in
Scheme 3. After initially generated 2d from 1d was iso-
merized to 5 by the present conditions, 5 was sequentially
reacted with imine to afford 6 and then deprotonation
finally furnished 4a and 4b. The selective introduction of
an imine moiety to the exo position could be explained by
the steric effect. These results might be supported by the
fact that nonisomerizable 2a generated in situ from 1a did
not react with imine under the optimized reaction condi-
tions. Alkynyl silanol 1g underwent a smooth gold-cata-
lyzed tandem hydrosilyloxylation/isomerization/Mannich
reaction in one pot to provide 4c and 4d in 40% and 31%
yields (dr = 1.3:1), respectively (eq 7). Enol silyl ether
generated in situ from the treatment of 1d with a gold
catalyst was sequentially subjected to bromine (1 equiv) at
À78 °C to furnish 4e in 80% yield via tandem hydrosily-
loxylation/isomerization/bromination (eq 8).
chemoselective formation of anenol silyl ether from alkyne
in the presence of a carbonyl and imine group, which opens
new opportunities for the invention of related transition
metal and Lewis acid catalyzed processes.
In conclusion, we have developed an extremely mild
tandem Au-catalyzed hydrosilyloxylation/aldol reaction
and hydrosilyloxylation/isomerization/Mannich reaction
through the formation of enol silyl ether catalytically
generated in situ from readily available alkynes in one
pot. When enol silyl ethers were treated with imine and
bromine, these moieties were selectively introduced at the
exo position viaisomerization of adoublebondof enolsilyl
ether. Key to the success of these tandem reactions is the
Acknowledgment. This work was supported by the CRI
(2012-0001245) and BRL program (2009-0087013) funded
by the National Research Foundation of Korea. We thank
Mr. H.-J. Park, Seoul National University, for performing
the X-ray crystallographic analyses and Dr. Sung Hong
Kim at the KBSI(Daegu) for obtaining the HRMS data. P.
H.L. thanks Prof. S. Kim, Nanyang Technological Uni-
versity, for helpful discussions.
(16) Alkynyl silanol 1d did not react with imine without a gold
catalyst. The use of (C6F5)3PAuCl and AgOTf (1 mol % each) gave 4a
and 4b in 50% yield.
(17) Reaction of 2d with imine in the presence of AgOTf (10 mol %)
did not proceed. Treatment of 2d with imine in the presence of TfOH
(10 mol %) gave the desired product 4a (43%) and 4b (43%), indicating
that a gold(I) catalyst is essential for intramolecular hydrosilyloxylation
and TfOH can assist sequential Mannich reaction.
Supporting Information Available. Experimental pro-
cedure, X-ray crystallographic data for 4b (CIF) and
spectral data (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(18) Lee, P. H.; Kang, D. J.; Choi, S. B.; Kim, S. Org. Lett. 2011, 13,
3470.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 15, 2012
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