The Thiazolium-Catalyzed Sila-Stetter Reaction: Conjugate Addition of Acylsilanes to Unsaturated Esters and Ketones

Article abstract of DOI:10.1021/ja0318380

A new acyl anion addition reaction between acylsilanes and α,β-unsaturated conjugate acceptors promoted by a nucleophilic organic catalyst has been disclosed. The 1,4-dicarbonyl products produced in this reaction are highly useful synthons. Neutral carbenes (or zwitterions) generated in situ from commercial thiazolium salts are used as effective catalysts for the reaction which is in contrast to established anionic catalysts typically employed to promote the required Brook rearrangement (1,2-silyl shift from carbon to oxygen) involved in the reported reaction. This process successfully utilizes acylsilanes as tunable acyl anion progenitors and is tolerant of a wide range of structural diversity on the acylsilane or the conjugate acceptor. Copyright

Full text of DOI:10.1021/ja0318380

Published on Web 02/10/2004
The Thiazolium-Catalyzed Sila-Stetter Reaction: Conjugate Addition of
Acylsilanes to Unsaturated Esters and Ketones
Anita E. Mattson, Ashwin R. Bharadwaj, and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, EVanston, Illinois 60208
Received December 19, 2003; E-mail: scheidt@northwestern.edu
The inversions of normal reactivity patterns (umpolung) are
powerful strategies in organic synthesis that provide unconventional
access to important materials.1 A prominent class of umpolung
reactions employs organic catalysts (thiazolium salts) to induce
aldehydes to undergo nucleophilic addition reactions.2 Typically,
this aldehyde nucleophile is added either to another aldehyde
(benzoin condensation)3 or to a conjugate acceptor. This second
process, or Stetter reaction, is an efficient method to generate useful
1,4-dicarbonyl compounds.4 However, the Stetter reaction is
significantly limited by the high reactivity of the aldehyde, which
results in large amounts of self-condensation, or benzoin, products.5
We envisioned acylsilanes as unconventional acyl anion precursors
accessible via the addition of a neutral Lewis base catalyst. This
strategy generates an acyl anion nucleophile that adds selectively
to the conjugate acceptor over remaining acylsilane, thus completely
avoiding benzoin product formation. Herein, we report the realiza-
tion of this new general approach employing acylsilanes (1),
conjugate acceptors (2), and thiazolium salts (4) as the nucleophilic
catalyst precursors (eq 1).
Table 1. Effect of Reaction Conditions on the
Thiazolium-Catalyzed Addition of Acylsilane 1a to Chalcone (2a)a
b
entry
base
solvent
mol% 4
equiv of i-PrOH
yield (%)c
1
2
3
4
5
6
7
8
9
DBU
NEt3
THF
THF
THF
CH2Cl2
PhCH3
THF
THF
THF
100
100
100
100
100
30
50
30
10
0
0
0
71
40
0
KOt-Bu
DBU
DBU
DBU
DBU
DBU
DBU
0
0
39
0
0
43
78
77
44
4.0
4.0
4.0
THF
a All reactions were performed at reflux temperature in the solvent
indicated. b Equivalents relative to chalcone (2a). c Isolated yield after
chromatographic purification.
Table 2. Catalytic Sila-Stetter Reactions with Acylsilane 1a and
â-Aryl Unsaturated Phenyl Ketones (2)a
The use of acylsilanes6 as acyl anion precursors typically involves
the addition of highly charged, potentially toxic catalysts such as
cyanide and fluoride anions.7 These approaches ensure significant
charge density on the oxygen of the resulting tetrahedral intermedi-
ate to promote a 1,2-silyl group shift (Brook rearrangement) and
render the acylsilane carbon nucleophilic.8 However, to our
knowledge, Brook rearrangements have not been previously induced
with neutral Lewis basic species, such as carbenes. Specifically,
the use of thiazolium salts in the presence of an appropriate base
to generate the desired carbene (or zwitterionic) catalyst in situ is
an appealing, yet uncharted, platform for the development of
acylsilanes as tunable acyl anion equivalents with appropriate
conjugate acceptors.
1
2
entry
R
R
yield (%)b
product
1
2
3
4
5
6
7
8
9
Ph
Ph
4-ClPh
4-OMePh
Ph
82
80
72
66
74
68
84
75
77
50c
6
7
8
9
10
11
12
13
14
15
1-Napth
4-BrPh
4-ClPh
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2-ClPh
4-MePh
3-OMePh
4-OMePh
4-HOPh
10
a All reactions were performed at 0.8 M at 70 °C for 12-24 h. See
Supporting Information for details. b Isolated yield after chromatographic
purification. c Based on 70% conversion.
After considerable experimentation with the acyl addition reaction
of acylsilane 1a and chalcone (2a), we identified THF and DBU
as the optimal solvent and base, respectively, in the presence of
stoichiometric amounts of commercially available 4 (Table 1, eq
2).9 Initially, the use of thiazolium salts without an alcohol or
catalyst loading below 100 mol % afforded significantly reduced
yields of 5 (entry 6),10 and we postulated that the hydroxyl moiety
plays an important role in the reaction. Gratifyingly, straightforward
addition of 4 equiv of 2-propanol allows for the reduction of catalyst
to 30 mol % without impacting the yield (entry 8).
the R,â-unsaturated system. Additionally, moderate to high yields
are observed for the 1,4-dicarbonyl products when aryl substituents
with electron-withdrawing groups are employed (entries 1, 4-6).
Notably, the reaction proceeds moderately with an unprotected
phenol (entry 10).
The influence of acylsilane structure on the reaction has also
been investigated (Table 3, eq 4). The placement of a substituent
on the phenyl ring of benzoyltrimethylsilane (entries 2 and 3) or
the use of a dimethylphenylsilyl group (entry 4) affords high yields
of 1,4-dicarbonyl products. Remarkably, enolizable alkyl acylsilanes
such as 1e and 1f are functional acyl anion precursors without a
deleterious effect on conversion or yield (entries 5 and 6).
With the optimal solvent/base combination and alcohol additive,
the scope of the reaction was examined (Table 2, eq 3). The reaction
is tolerant of electron-donating aryl substituents on either side of
9
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J. AM. CHEM. SOC. 2004, 126, 2314-2315
10.1021/ja0318380 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Influence of Acylsilane Structure on Acyl Anion
Scheme 1. Proposed Catalytic Cycle for Thiazolium-Catalyzed
Acylsilane Additions to R,â-Unsaturated Ketones
Reactiona
1
2
entry
acylsilane
R
R
yield (%)b
product
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Ph
CH3
CH3
CH3
Ph
Ph
Ph
77
82
70
61
70
63
5
4-ClPh
4-CH3Ph
Ph
CH3
cyclohexyl
16
17
5
18
19
the scope of the Stetter reaction by utilizing acylsilanes as tunable
acyl anion progenitors. In addition, remarkably mild carbenes have
been employed as new and effective nucleophilic catalysts for 1,2-
silyl (Brook) rearrangements. Further development of this reaction
and studies regarding the reaction mechanism are being pursued
and will be reported in due course.
a All reactions were performed at 0.8 M for 12 h at 70 °C. See Supporting
Information for details. b Isolated yield after chromatographic purification.
Acknowledgment. This work has been supported by North-
western University. We thank Prof. Thomas Meade and Alisha
Taylor (NU) for assistance with shared instrumentation and Wacker
Biochem Co. for kindly supplying organosilanes. We also thank
Dr. Jared Shaw (ICCB/Harvard University) for helpful discussions.
The scope of this new sila-Stetter reaction has been further
examined by employing various classes of R,â-unsaturated carbonyl
electrophiles (Table 4, eq 5). Utilizing either reactive diethyl
fumarate (entry 1) or dimethyl maleate (entry 2) affords the desired
tricarbonyl products. Remarkably, using highly reactive methyl
vinyl ketone and ethyl acrylate as substrates produces dicarbonyls
22 and 23 cleanly (entries 3 and 4). Use of the more reactive
4-chlorobenzoyltrimethylsilane (1b) allows for the incorporation
of nonbisaryl R,â-unsaturated ketones as substrates (entries 5 and
6), although why these reactions stall is under investigation.11
Supporting Information Available: Experimental procedures and
spectral data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239-258. (b)
Fernandez, R.; Lassaletta, J. M. Synlett 2000, 1228-1240. (c) Eisch, J. J.
J. Organomet. Chem. 1995, 500, 101-115.
Table 4. Catalytic Sila-Stetter Reactions with R,â-Unsaturated
Carbonyl Electrophilesa
(2) (a) Ukai, T.; Tanaka, R.; Dokawa, T. J. Pharm. Soc. Jpn. 1943, 63, 296-
300. (b) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726.
(3) Stetter, H.; Kuhlmann, H. In Organic Reactions; Paquette, L. A., Ed.;
Wiley and Sons: New York, 1991; Vol. 40.
(4) (a) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639-712. (b) Stetter,
H.; Kuhlmann, H. Chem. Ber. 1976, 109, 2890-2896.
(5) Tethering the aldehyde to the conjugate acceptor (intramolecular reaction)
or significant excess of aldehyde can alleviate the problem of benzoin
formation in the Stetter reaction, see: (a) Trost, B. M.; Shuey, C. D.;
Dininno, F.; McElvain, S. S. J. Am. Chem. Soc. 1979, 101, 1284-1285.
(b) Ciganek, E. Synthesis 1995, 1311-1314. (c) Enders, D.; Breuer, K.;
Runsink, J.; Teles, J. H. HelV. Chim. Acta 1996, 79, 1899-1902. (d) Kerr,
M. S.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298-
10299. (e) Raghavan, S.; Anuradha, K. Tetrahedron Lett. 2002, 43, 5181-
5183.
(6) For reviews on acylsilanes and their chemistry, see: (a) Ricci, A.;
Degl’Innocenti, A. Synthesis 1989, 647-660. (b) Page, P. C. B.; Klair,
S. S.; Rosenthal, S. Chem. Soc. ReV. 1990, 19, 147-195. (c) Cirillo, P.
F.; Panek, J. S. Org. Prep. Proced. Int. 1992, 24, 553-582.
(7) (a) Schinzer, D.; Heathcock, C. H. Tetrahedron Lett 1981, 22, 1881-
1884. (b) Degl’Innocenti, A.; Ricci, A.; Mordini, A.; Reginato, G.; Colotta,
V. Gazz. Chim. Ital. 1987, 117, 645-648. (c) Degl’Innocenti, A.; Pike,
S.; Walton, D. R. M.; Seconi, G.; Ricci, A.; Fiorenza, M. J. Chem. Soc.,
Chem. Commun. 1980, 1201-1202. (d) Xin, L. H.; Johnson, J. S. Angew.
Chem., Int. Ed. 2003, 42, 2534-2536.
(8) (a) Brook, A. G. Acc. Chem. Res. 1974, 7, 77-84 and references therein.
(b) Moser, W. H. Tetrahedron 2001, 57, 2065-2084.
(9) Control experiments omitting either DBU (1,8-diazoabicyclo-[5.4.0]-
undecane) or 4 resulted in no product formation.
(10) Thiazolium salts such as 3-benzyl-4,5-dimethylthiazolium bromide afford
no product when exogenous alcohols were omitted from the reaction.
(11) The use of benzoyltrimethylsilane (1a) for these reactions results in
significantly reduced conversion. This observation is under investigation.
(12) For mechanistic investigations of thiazolium salts as catalysts, see: (a)
Breslow, R.; Schmuck, C. Tetrahedron Lett. 1996, 37, 8241-8242. (b)
Chen, Y. T.; Barletta, G. L.; Haghjoo, K.; Cheng, J. T.; Jordan, F. J.
Org. Chem. 1994, 59, 7714-7722 and references therein.
(13) The use of 3-octanol in the reaction affords 3-trimethylsilyloxyoctane
(observed by gas chromatography), thus implicating the alcohol as the
ultimate silyl acceptor. See Supporting Information for details.
(14) Replacing 1a with PhCHO affords mainly benzoin and only 20-30% of
5.
1
2
3
entry
R
R
R
Ar
yield (%)b
product
1
2
3
4
5
6
EtO2C
H
H
OEt
OCH3
OEt
CH3
CH3
t-Bu
Ph
Ph
Ph
Ph
65
72
72
20
21
22
23
24
25
CH3O2C
H
H
H
H
H
H
75
Ph
Ph
4-ClPh
4-ClPh
63c
48d
a All reactions were performed at 0.8 M at 70 °C for 2-12 h. b Isolated
yield after purification. c 64% conversion. d 59% conversion.
A plausible catalytic cycle for this reaction is depicted in Scheme
1.12 The carbene (or zwitterion) catalyst (I) addition to the acylsilane
promotes a Brook rearrangement that affords silylated intermediate
II. The alcohol additive present in the reaction desilylates II, which
produces intermediate III.13 Under normal thiazolium-catalyzed
benzoin or Stetter reactions, this nucleophilic intermediate can
intercept another aldehyde. However, due to the attenuated elec-
trophilicity of the acylsilane (relative to an aldehyde), the reaction
proceeds via the preferred 1,4-addition manifold to produce IV.14
Formation of the aryl ketone expels the carbene catalyst and affords
the desired dicarbonyl compounds 5-25.
In conclusion, we have disclosed a new silyl variant of the Stetter
reaction between acylsilanes and R,â-unsaturated conjugate accep-
tors promoted by an organic catalyst. This catalytic process rapidly
accesses useful 1,4-dicarbonyl products and significantly increases
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