N-Heterocyclic carbene-catalysed intermolecular Stetter reactions of acetaldehyde

Article abstract of DOI:10.1039/c0ob01178a

A facile method for the intermolecular Stetter reaction of various Michael acceptors with acetaldehyde as a biomimetic acylanion source was realized using N-heterocyclic carbene catalysis. This catalytic system has also been applied to the enantioselective Stetter reaction and resulted in moderate to good enantioselectivities for the corresponding Stetter products.

Full text of DOI:10.1039/c0ob01178a

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N-Heterocyclic carbene-catalysed intermolecular Stetter reactions of
acetaldehyde†
Sun Min Kim,‡a Ming Yu Jin,‡b Mi Jin Kim,b Yan Cui,a Young Sug Kim,a Liqiu Zhang,a Choong Eui Song,a,b
Do Hyun Ryu*b and Jung Woon Yang*a
Received 15th December 2010, Accepted 27th January 2011
DOI: 10.1039/c0ob01178a
A facile method for the intermolecular Stetter reaction of vari-
ous Michael acceptors with acetaldehyde as a biomimetic acy-
lanion source was realized using N-heterocyclic carbene catal-
ysis. This catalytic system has also been applied to the enan-
tioselective Stetter reaction and resulted in moderate to good
enantioselectivities for the corresponding Stetter products.
reaction,7 the acylanion equivalent is derived from pyruvate via
decarboxylation catalysed by pyruvate decarboxylase (PDC), one
of the thiamine diphosphate (ThDP)-dependent enzymes. Indeed,
this concept has recently been applied to the enzymatic Stetter
reaction.5f
In the search for a more efficient method of generating
acylanion, we have found that acetaldehyde could be employed
as a surrogate for the combination of pyruvate with ThDP-
dependent enzymes, resulting in the substantial benefit of eliminat-
ing carbon dioxide emission in an environmentally benign process
(Scheme 1).
Introduction
N-Heterocyclic carbene (NHC) catalysis is a highly dynamic and
rapidly growing area of asymmetric organocatalysis research.1
The Stetter reaction is a well-defined umpolung process in which
NHCs have been successfully applied to the construction of
1,4-dicarbonyl compounds and related derivatives, such as 1,4-
diketones, 1,4-ketoesters, and 1,4-ketonitriles, depending on the
particular Michael acceptors.2 After the initial discovery of a
chiral NHC-catalysed intramolecular asymmetric Stetter reaction
by the Enders group in 1996,3 several groups have extensively in-
vestigated the asymmetric version of the intramolecular reaction,4
and recently, the Rovis group has reported significant improve-
ments in enantioselectivity with triazolium salts derived from 2-
aminoindanol.4a On the other hand, despite a steadily growing
interest in the enantioselective intermolecular Stetter reaction,5 the
reaction of trans-chalcone derivatives with unmodified aldehydes
remains challenging in terms of enantioselectivity. Until now, a
single example of such a reaction has been reported with moderate
to good enantioselectivities (56–78% ee),5e but an enzymatic Stetter
reaction has recently been reported that proceeds in abysmally low
yield but with high enantioselectivity.5f
Scheme 1 Generation of an acylanion equivalent from acetaldehyde
without the emission of CO2 (g).
Herein, we describe NHC-catalysed intermolecular nonasym-
metric and asymmetric Stetter reactions of acetaldehyde with
a variety of Michael acceptors. To the best of our knowledge,
acetaldehyde has not previously been used as an acylanion source
in this reaction.
Results and discussion
In our initial studies, we examined the reaction of trans-chalcone
3a with acetaldehyde at room temperature using either thiazolium
1 or triazolium 2 precatalyst with Cs2CO3 (Table 1).
A quick screen of reaction parameters (e.g. catalyst and solvent)
allowed us to determine that good conversions could be achieved
in the presence of 10 mol% of thiazolium salt 1 and Cs2CO3 in dry
THF at room temperature for 24 h (Table 1, entry 1).
Having identified appropriate conditions, the general applicabil-
ity of the system was thoroughly investigated, and representative
results are summarized in Table 2. The thiazolium precatalyst
1 was applicable to a broad range of electron-deficient alkenes
(e.g. trans-chalcones 3a–g,8 methyl vinyl ketone 3h, and diethyl
fumarate 3i) as Michael acceptors. In most cases, various trans-
chalcone derivatives with either electron-withdrawing or electron-
donating substituents on the aromatic ring gave the corresponding
Given the importance of acetaldehyde as a simple nucleophile in
asymmetric organocatalysis,6 we hypothesized that acetaldehyde
could be used as an acylanion source in the Stetter reaction. Gen-
erally, in the enzymatic asymmetric cross-benzoin condensation
aDepartment of Energy Science, Sungkyunkwan University, Suwon 440-746,
Korea. E-mail: jwyang@skku.edu; Fax: +82-31-299-4279; Tel: +82-31-299-
4276
bDepartment of Chemistry, Sungkyunkwan University, Suwon 440-746,
Korea. E-mail: dhryu@skku.edu; Fax: +82-31-290-5976; Tel: +82-31-290-
5931
† Electronic supplementary information (ESI) available: Experimental
procedures, characterizations for all new compounds, and chiral HPLC
analysis for compound 5. See DOI: 10.1039/c0ob01178a
‡ These authors contributed equally to this work.
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Table 1 Screening parameters for optimization of the Stetter reactiona
Table 3 Optimization of the reaction conditionsa
Entry
Catalyst
Solvent [M]
Yield (%)b
1
2
3
4
5
6
7
8
9
1
THF [0.5 M]
THF [0.5 M]
THF [0.5 M]
THF [0.5 M]
THF [0.5 M]
CHCl3 [0.5 M]
CH2Cl2 [0.5 M]
PhMe [0.5 M]
Et2O [0.5 M]
99
—
7
—
40
52
50
35
97
2a
2b
2c
2d
1
Entry
Catalyst
Base
Solvent [M]
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
5
6
7a
7b
7a
7a
7a
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DBU
Cs2CO3
Cs2CO3
THF [0.5]
THF [0.5]
THF [0.5]
THF [0.5]
THF [0.5]
PhCH3 [0.5]
CHCl3 [0.5]
NR
NR
80
7
76
45
44
—
—
62
—
56
54
60
1
1
1
a General conditions: trans-chalcone 3a (0.5 mmol), acetaldehyde (5
mmol), 1–2 (10 mol%), Cs2CO3 (10 mol%), THF (1 mL), RT, 24 h.
b Isolated yield.
a General conditions: 3e (0.5 mmol), acetaldehyde (5 mmol), 5–7 (10
mol%), Cs2CO3 (10 mol%), THF (1 mL), 20 ◦C, 24 h. b Isolated yield.
c The enantioselectivity was determined by HPLC analysis using a chiralcel
OJ-H column with n-hexane–iPrOH (92 : 8) as eluent.
Table 2 NHC-catalysed intermolecular Stetter reaction of acetaldehyde
with a variety of Michael acceptorsa
initiated these studies by combining a p-chloro-substituted trans-
chalcone derivative 3e as the model substrate with acetaldehyde
in the presence of 10 mol% of NHC precatalysts 5–7 and base in
THF at room temperature.
No reaction took place when NHC precatalyst 5 or 6
were employed (Table 3, entries 1–2). In contrast, the use of
chiral cis-2-aminoindanol-derived triazolium salt 7a bearing a
N-pentafluorophenyl substituent on the triazole ring provided
the Stetter product in 80% yield and 62% ee (Table 3, en-
try 3). It is notable that the achiral bicyclic triazolium salts
2 had low catalytic activity in the non-asymmetric reaction
(Table 1, entries 2–5).
To optimize the enantioselectivity, we investigated the effect
of subtle electronic differences on the reactivity and stability
of catalyst 7. Switching the N-substituents on the bicyclic tri-
azole ring of precatalyst 7 from pentafluorophenyl to mesityl
7b, led to a dramatic decrease in catalytic performance and
enantioselectivity (Table 3, entry 4). In further experiments,
other reaction parameters (e.g. solvent and base), influencing
the reaction were investigated employing precatalyst 7a, and the
results are summarized in Table 3. Variations of the base or solvent
had a negligible effect on enantioselectivity (Table 3, entries 5–7).
Representative examples of other Michael acceptors re-
acting with acetaldehyde catalysed by 7a with Cs2CO3 in
THF or chloroform at 20 ◦C for 24 h, are summarized in
Table 4.
Entry
Substrateb
Productc
Yield (%)d
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
4a
4b
4c
4d
4e
4f
4g
4h
4i
96
98
97
65
99
99
80
95
40
a General conditions: 3 (0.5 mmol), acetaldehyde (5 mmol), 1 (10 mol%),
Cs2CO3 (10 mol%), THF (1 mL), RT, 24 h. b Substrates 3 were prepared
and characterized as described in ref. 8. c Products 4 were obtained and
characterized as described in the ESI.† d Isolated yield.
conjugate addition products in excellent yields (from 80% to 99%)
compared to the parent system (Table 2, entries 1–3 and 5–7). An
unsubstituted a,b-unsaturated ketone, methyl vinyl ketone 3h, was
also a competent coupling partner in the reaction (Table 2, entry
8). Notably, the electron-donating para-methyl substituted trans-
chalcone derivative 3d and diethyl fumarate substrate 3i provided
the target products in moderate yields (Table 2, entries 4 and 9).
After identifying an efficient and practical set of conditions for
the Stetter reaction with acetaldehdye as the biomimetic acylanion
source, we focused our effort on obtaining asymmetric induction
in a model reaction using chiral NHC precatalysts and bases. We
In most cases, the corresponding Stetter adducts were ob-
tained in satisfactory chemical yields (up to 85%) within ac-
ceptable reaction times. The highest enantioselectivity (76%)
was obtained for substrate 3b, bearing the 2-naphthyl group
(Table 4, entry 2).
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Table 4 NHC-catalysed intermolecular asymmetric Stetter reaction of
Chem., Int. Ed., 2005, 44, 7506; (c) J. S. Johnson, Angew. Chem., Int. Ed.,
2004, 43, 1326.
acetaldehyde with a variety of Michael acceptorsa
2 (a) H. Stetter and M. Schreckenberg, Angew. Chem., Int. Ed. Engl.,
1973, 12, 81; (b) H. Stetter and H. Kuhlmann, Org. React., 1991, 40,
407; (c) D. Enders and T. Balensiefer, Acc. Chem. Res., 2004, 37, 534;
(d) M. Christmann, Angew. Chem., Int. Ed., 2005, 44, 2632; (e) D. Enders,
O. Niemeier and A. Henseler, Chem. Rev., 2007, 107, 5606; (f) T. Rovis,
Chem. Lett., 2008, 37, 2.
3 D. Enders, K. Breuer, J. Runsink and J. H. Teles, Helv. Chim. Acta, 1996,
79, 1899.
4 (a) M. S. Kerr, J. Read de Alaniz and T. Rovis, J. Am. Chem. Soc., 2002,
124, 10298; (b) M. S. Kerr and T. Rovis, Synlett, 2003, 1934; (c) M. S.
Kerr and T. Rovis, J. Am. Chem. Soc., 2004, 126, 8876; (d) J. Read de
Alaniz and T. Rovis, J. Am. Chem. Soc., 2005, 127, 6284; (e) M. S. Kerr,
J. Read de Alaniz and T. Rovis, J. Org. Chem., 2005, 70, 5725; (f) N.
T. Reynolds and T. Rovis, Tetrahedron, 2005, 61, 6368; (g) J. L. Moore,
M. S. Kerr and T. Rovis, Tetrahedron, 2006, 62, 11477; (h) Q. Liu and
T. Rovis, J. Am. Chem. Soc., 2006, 128, 2552; (i) Q. Liu and T. Rovis,
Org. Process Res. Dev., 2007, 11, 598; (j) J. Read de Alaniz, M. S. Kerr,
J. L. Moore and T. Rovis, J. Org. Chem., 2008, 73, 2033; (k) A. Orellana
and T. Rovis, Chem. Commun., 2008, 730; (l) J. Pesch, K. Harms and T.
Bach, Eur. J. Org. Chem., 2004, 2025; (m) S. M. Mennen, J. T. Blank, M.
B. Tran-Dube´, J. E. Imbriglio and S. J. Miller, Chem. Commun., 2005,
195; (n) Y. Matsumoto and K. Tomioka, Tetrahedron Lett., 2006, 47,
5843.
Entry
Substrate
Product
Solvent
Yield (%)b
ee (%)c
1
2
3
4
5
3a
3b
3e
3f
8ad
8b
8e
8f
THF
THF
THF
CHCl3
THF
42
62
78
85
43
57
76
62
60
58
3g
8g
a General conditions: 3 (0.5 mmol), acetaldehyde (5 mmol), 7a (10 mol%),
Cs2CO3 (10 mol%), THF (1 mL), 20 ◦C, 24 h. b Isolated yield. c Determined
by HPLC analysis using a chiral column. d The absolute configurations
were determined as described in ref. 5f.
5 (a) Q. Liu, S. Perreault and T. Rovis, J. Am. Chem. Soc., 2008, 130, 14066;
(b) D. Enders and J. Han, Synthesis, 2008, 3864; (c) D. A. DiRocco, K.
M. Oberg, D. M. Dalton and T. Rovis, J. Am. Chem. Soc., 2009, 131,
10872; (d) Q. Liu and T. Rovis, Org. Lett., 2009, 11, 2856; (e) D. Enders,
J. Han and A. Henseler, Chem. Commun., 2008, 3989; (f) C. Dresen, M.
Richter, M. Pohl, S. Lu¨deke and M. Mu¨ller, Angew. Chem., Int. Ed.,
2010, 49, 6600.
6 (a) J. W. Yang, C. Chandler, M. Stadler, D. Kampen and B. List,
Nature, 2008, 452, 453; (b) Y. Hayashi, T. Itoh, S. Aratake and H.
Ishikawa, Angew. Chem., Int. Ed., 2008, 47, 2082; (c) P. Garc´ıa-Garc´ıa,
A. Lade´peˆche, R. Halder and B. List, Angew. Chem., Int. Ed., 2008,
47, 4719; (d) Y. Hayashi, T. Itoh, M. Ohkubo and H. Ishikawa, Angew.
Chem., Int. Ed., 2008, 47, 4722; (e) Y. Hayashi, T. Okano, T. Itoh, T.
Urushima, H. Ishikawa and T. Uchimaru, Angew. Chem., Int. Ed., 2008,
47, 9053; (f) Y. Hayashi, S. Samanta, T. Itoh and H. Ishikawa, Org.
Lett., 2008, 10, 5581; (g) T. Kano, Y. Yamaguchi and K. Maruoka,
Angew. Chem., Int. Ed., 2009, 48, 1838; (h) M. Y. Jin, S. M. Kim, H.
Han, D. H. Ryu and J. W. Yang, Org. Lett., 2011, 13, DOI: 10.1021/
ol102937w.
Conclusions
In summary, we have developed the NHC-catalysed non-
asymmetric intermolecular Stetter reaction of acetaldehyde as
a complementary method to the enzymatic generation of the
acylanion. These reactions were conducted with a variety of
Michael acceptors in the presence of N-heterocyclic carbene
catalysts, resulting in chemical yields above 95% in most cases. We
also conducted the asymmetric intermolecular Stetter reaction of
acetaldehyde with a variety of Michael acceptors in the presence
of cis-aminoindanol-based chiral NHC catalyst 7a to create 1,4-
diketones with moderate to good enantioselectivities (up to 76%
ee). Investigations to uncover a highly enantioselective variant of
this reaction is currently underway.
7 A. Cosp, C. Dresen, M. Pohl, L. Walter, C. Ro¨hr and M. Mu¨ller, Adv.
Synth. Catal., 2008, 350, 759.
Acknowledgements
8 (a) General procedure for the synthesis of trans-chalcone derivatives 3b, 3c,
3d, 3e, 3f , 3g, see: T. Narender and K. T. Papi Reddy, Tetrahedron Lett.,
2007, 48, 3177; (b) trans-Chalcone derivatives were characterized by 1H
NMR and 13C NMR spectra, and we are found to match previously
reported data: 3b,8c 3c,8d 3d,8e 3e,8f 3f, 8g3g,8f see: (c) B. C. Ranu and
R. Jana, J. Org. Chem., 2005, 70, 8621; (d) M.-L. Yao, M. S. Reddy, L.
Yong, I. Walfish, D. W. Blevins and G. W. Kabalka, Org. Lett., 2010, 12,
700; (e) W.-B. Yi and C. Cai, J. Fluorine Chem., 2009, 130, 484; (f) T.
Ishikawa, T. Mizuta, K. Hagiwara, T. Ailawa, T. Kudo and S. Saito,
J. Org. Chem., 2003, 68, 3702; (g) B. Xin, Y. Zhang and K. Cheng,
Synthesis, 2007, 1970.
This work was supported by the NRF WCU program (R31-
2008-000-10029-0) to J.W.Y. and C.E.S., the NRF grant (No.
2010-0023127) to J.W.Y., and the NRF Priority Research Centers
Program (No. 2010-0029698) to D.H.R.
Notes and references
1 For general reviews on NHC catalysis, see: (a) D. Enders, O. Niemeier
and A. Henseler, Chem. Rev., 2007, 107, 5606; (b) K. Zeitler, Angew.
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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2069–2071 | 2071
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