Asymmetric intermolecular Stetter reactions catalyzed by a novel triazolium derived N-heterocyclic carbene

Article abstract of DOI:10.1039/b809913h

The asymmetric intermolecular Stetter reaction is catalyzed by a novel triazolium salt derived N-heterocyclic carbene leading to 1,4-diketones in moderate to excellent yields (49-98%) and moderate to good enantioselectivities (56-78% ee), which could be enhanced by one recrystallization to excellent levels (90-99% ee). The Royal Society of Chemistry.

Full text of DOI:10.1039/b809913h

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Asymmetric intermolecular Stetter reactions catalyzed by a novel
triazolium derived N-heterocyclic carbenew
Dieter Enders,* Jianwei Han and Alexander Henseler
Received (in Cambridge, UK) 11th June 2008, Accepted 2nd July 2008
First published as an Advance Article on the web 25th July 2008
DOI: 10.1039/b809913h
The asymmetric intermolecular Stetter reaction is catalyzed by a
novel triazolium salt derived N-heterocyclic carbene leading to 1,4-
diketones in moderate to excellent yields (49–98%) and moderate
to good enantioselectivities (56–78% ee), which could be enhanced
by one recrystallization to excellent levels (90–99% ee).
benzoin condensation,9 were tested but failed to catalyze this
transformation. We thus turned our attention to the prepara-
tion of a new carbene catalyst. Thiazolium salt 5 is one of the
most commonly used precatalysts for the intermolecular Stetter
reaction. A striking difference is that 5 contains an N-benzyl
substituent, whereas the triazolium salts 6–8 bear N-phenyl
substituents. Therefore, we synthesized precatalyst 9 with an
N-benzyl group.10 To our delight, compound 9 readily pro-
moted this transformation and the Stetter product 3 was
formed in good yield (73%). This indicated that the
N-substituent has a dramatic impact on the activity of triazo-
lium-based catalysts in the intermolecular Stetter reaction.
Although the precatalyst 9 was active, it gave low levels of
asymmetric induction (20% ee). In order to improve the en-
antioselectivity the reaction parameters were varied (Scheme 2).
Bases such as Et3N, i-Pr2NEt, KOt-Bu and KHMDS resulted in
no reaction or only trace amounts of the Stetter product
(Table 1, entries 2–5). Gratifyingly, when K2CO3 was used as
the base, precatalyst 9 afforded the Stetter product in good yield
Within the rapidly expanding field of organocatalysis,
N-heterocyclic carbenes (NHCs) have received considerable
attention due to their capability of catalysing a broad range of
synthetic transformations.1 The intrinsic ability of NHCs to
invert the classical reactivity (Umpolung) of certain functional
groups is unique in organic chemistry and is used in the Stetter
reaction, the catalytic nucleophilic acylation of a Michael
acceptor.2
Since a new stereocenter is usually generated within the
Stetter product, attention has been paid to the development of
enantioselective versions of this reaction. The first report
concerning an asymmetric intramolecular Stetter reaction
was published by our research group3 and later Rovis and
co-workers made improvements to the method.4 They also
extended the reaction scope to products with quaternary
stereocenters,5 investigated the use of aldehydic substrates
with pre-existing stereocenters6 and developed a diastereo-
and enantioselective variant involving a,b-disubstituted
Michael acceptors.7 However the asymmetric intermolecular
Stetter reaction is much less studied. A first enantioselective
version was published in 1993 by our research group.8 The
chiral thiazolium precatalyst 4 promoted the reaction of
n-butanal with chalcone providing the corresponding 1,4-di-
ketone in 30% yield an 40% ee. Herein, we report the
application of a novel chiral triazolium salt as a carbene
precatalyst in the enantioselective intermolecular Stetter reac-
tion leading to practical enantiomeric excesses.
We started our investigation by screening different chiral
triazolium based precatalysts 6–8, previously developed in our
group (Scheme 1). As the test reaction, benzaldehyde (1)
and chalcone (2) were exposed to catalytic quantities of
triazolium salt 6 and DBU. Interestingly, no reaction was
observed even though this precatalyst was effective in the
intramolecular Stetter reaction.3 Next, triazolium salts 7 and
8, initially developed for the asymmetric intramolecular
Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany.
E-mail: enders@rwth-aachen.de; Fax: +49-241-8092-127
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b809913h
Scheme 1 Precatalysts tested in the intermolecular Stetter reaction.
Chem. Commun., 2008, 3989–3991 | 3989
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Scheme
reaction.
2
Optimization studies for the intermolecular Stetter
Scheme 3 Enantioselective intermolecular Stetter reactions under
optimized conditions.
and improved enantioselectivity (73% yield, 51% ee, entry 6).
Further studies on the role of the solvent revealed that THF was
the most suitable (entries 6–12). Next, the alkali-cation of the
carbonate base was varied. While Li2CO3 resulted in no reac-
tion, Cs2CO3 led to an increased enantioselectivity with no
change in yield (72% yield, 62% ee, entry 14). Lowering the
reaction temperature to 0 1C allowed a further enhancement in
enantioselectivity at the cost of yield (65% yield, 66% ee, entry
15) and at ꢁ20 1C only benzoin condensation was observed.
Under the optimized conditions, a variety of aromatic
aldehydes and substituted Michael acceptors were examined
in the intermolecular asymmetric Stetter reaction (Scheme 3,
Table 2). In general, acylation of a,b-unsaturated ketones 11
occurred smoothly affording the corresponding 1,4-diketones
12 in moderate yields and good enantioselectivities. Electron-
rich aldehydes gave better asymmetric inductions than elec-
tron-deficient aldehydes and the highly reactive heteroaromatic
aldehyde 2-furfural reacted almost quantitatively and
with moderate enantioselectivity. Most importantly, the
enantiomeric excesses of several products could be increased
to excellent levels (90–99% ee) after a single recrystallization.
The absolute configuration of the 1,4-diketone 12a was
determined to be (R) by comparison of its optical rotation.11
This stereochemical outcome can be explained by the
following transition state models (Fig. 1).
Table 2 Substrate scope for the intermolecular Stetter reaction
12
R1
R2
R3
Yield (%)a
Ee (%)b,c
12a
12b
12c
12d
12e
12f
12g
12h
12i
a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MePh
4-ClPh
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
65 (40)
43 (31)
50 (32)
55
66 (499)
78 (499)
70 (98)
67d
4-MeC6H4
3-MeC6H4
4-ClC6H4
4-BrC6H4
2-Naphthyl
2-Furyl
Ph
68
56d
65 (41)
98
55
70 (90)
56e
64d
56 (94)
Ph
57 (21)
b
Value in brackets is the yield after recrystallization. The enantio-
meric excess was determined by HPLC with a chiral stationary phase
c
(Daicel Chiralpak AD). Value in brackets is the ee after recrystalli-
d
e
zation. The products were obtained as thick oil. Attempt to
recrystallize was unsuccessful.
Fig. 1 Proposed transition states.
Table 1 Conditions for the optimization studies
Entry
Base
Solvent
Yield (%)
Ee (%)a
1
2
3
4
5
6
7
8
DBU
Et3N
THF
THF
THF
THF
THF
THF
Et2O
DCM
DMF
DMSO
MeOH
PhCH3
THF
73
0
0
20
—
—
—
ND
51
15
0
52
33
9
31
—
62
66
i-Pr2NEt
KHMDS
KOt-Bu
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Li2CO3
Cs2CO3
Cs2CO3
0
Traces
73
39
42
55
50
60
67
0
9
10
11
12
13
14
15b
a
THF
THF
72
65
The enantiomeric excess was determined by HPLC with a chiral
b
stationary phase (Daicel Chiralpak AD). Reaction was performed at
0 1C for 6 h.
Fig. 2 Reaction control via gas chromatography.
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in fact, benzoin can serve as a masked benzaldehyde equiva-
lent in a carbene-catalysed cross-coupling of aldehydes with
unactivated imines.13
In summary a new chiral triazolium based carbene preca-
talyst was synthesized and successfully employed in the
asymmetric intermolecular Stetter reaction. The resulting 1,4-
diketones were obtained in moderate to excellent yields and
good enantioselectivities. For several Stetter products the
enantiomeric excess could be enhanced by a single recrystalli-
zation up to 99% ee. Examination of the reaction course
revealed new mechanistic insights about the formation of the
Stetter product.
Notes and references
z In addition the reaction course was monitored by HPLC removing
aliquots from the reaction mixture, revealing that insignificant race-
mization of the Stetter product 3 was taking place (10% over 24 h).
1 (a) T. Rovis, Chem. Lett., 2008, 37, 2; (b) D. Enders, O. Niemeier
and A. Henseler, Chem. Rev., 2007, 107, 5606; (c) N. Marion, S.
Diez-Gonzalez and S. P. Nolan, Angew. Chem., 2007, 119, 3046
(Angew. Chem., Int. Ed., 2007, 46, 2988); (d) K. Zeitler, Angew.
Chem., 2005, 117, 7674 (Angew. Chem., Int. Ed., 2005, 44, 7506);
(e) M. Christmann, Angew. Chem., 2005, 117, 2688 (Angew. Chem.,
Int. Ed., 2005, 44, 2632); (f) D. Enders and T. Balensiefer, Acc.
Chem. Res., 2004, 37, 534.
Scheme 4 Catalytic cycle for the formation of the Stetter product.
2 (a) H. Stetter, Angew. Chem., 1976, 88, 695 (Angew. Chem., Int.
Ed., 1976, 15, 639); (b) H. Stetter and H. Kuhlmann, Org. React.,
1991, 40, 407.
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) J. Read de Alaniz, M. S. Kerr, J. L. Moore
and T. Rovis, J. Org. Chem., 2008, 73, 2033.
Assuming that the silyl branch of the catalyst blocks the
Si-face of the Breslow intermediate, the 1,4-addition would
occur at its less hindered Re-face. The chalcone then reacts
from its Si-face to give the observed (R)-configured Stetter
product.
Under the Stetter reaction conditions used here, self-
condensation of the aldehyde component always took place.
To investigate the role of this competing pathway, the reaction
course was monitored by gas chromatography (Fig. 2).z Inter-
estingly, in the early stage of the reaction when no chalcone
had been consumed, significant conversion (480%) of ben-
zaldehyde had already occurred to form its benzoin product.
As the reaction progressed, the disappearance of the benzoin
product strongly correlated with the consumption of chalcone.
Based on these observations, we propose that the Stetter
product forms as a result of two coupled catalytic reactions
(Scheme 4). Initially, a rapid carbene-catalyzed benzoin con-
densation occurs prior to Stetter product formation.12 Next,
the desired 1,4-diketone is formed in a subsequent catalytic
cycle initiated by the nucleophilic attack of catalyst 13 at the
carbonyl function of benzoin product 14. Elimination of
benzaldehyde (1) from the 1,2-adduct 15 results in the forma-
tion of the Breslow intermediate 16, which in turn attacks
chalcone (2) leading to the tetrahedral intermediate 17. In-
tramolecular proton transfer and elimination of the 1,4-dike-
tone 3 returns the catalyst. This mechanistic proposal is in
agreement with the literature. Stetter and Kuhlmann described
the carbene-catalyzed benzoin condensation as highly rever-
sible2 and a recent study by You and co-workers revealed that,
5 (a) M. S. Kerr and T. Rovis, J. Am. Chem. Soc., 2004, 126, 8876;
(b) J. Moore, M. S. Kerr and T. Rovis, Tetrahedron, 2006, 62,
11477.
6 N. T. Reynolds and T. Rovis, Tetrahedron, 2005, 61, 6368.
7 J. Read de Alaniz and T. Rovis, J. Am. Chem. Soc., 2005, 127,
6284.
8 (a) D. Enders, in Stereoselective Synthesis, ed. E. Ottow, K.
Schollkopf and B.-G. Schulz, Springer-Verlag, Heidelberg,
¨
Germany, 1993, p. 63; (b) D. Enders, B. Blockstiegel, H. Dyker,
U. Jegelka, H. Kipphardt, D. Kownatka, H. Kuhlmann, D.
Mannes, J. Tiebes and K. Papadopoulos, in Dechema-Monogra-
phies, ed. T. Anke and U. Onken, VCH, Weinheim, Germany,
1993, vol. 129, p. 209; (c) for asymmetric intermolecular metallo-
phosphite catalyzed Stetter reactions, see: M. R. Nahm, J. R.
Potnick, P. S. White and J. S. Johnson, J. Am. Chem. Soc., 2006,
128, 2751; (d) M. R. Nahm, X. Linghu, J. R. Potnick, C. M. Yates,
P. S. White and J. S. Johnson, Angew. Chem., 2005, 117, 2423
(Angew. Chem., Int. Ed., 2005, 44, 2377).
9 (a) D. Enders, O. Niemeier and T. Balensiefer, Angew. Chem.,
2006, 118, 1491 (Angew. Chem., Int. Ed., 2006, 45, 1463); (b) D.
Enders, O. Niemeier and G. Raabe, Synlett, 2006, 2431; (c) H.
Takikawa, H. Hachisu, J. W. Bode and K. Suzuki, Angew. Chem.,
2006, 118, 3572 (Angew. Chem., Int. Ed., 2006, 45, 3492); (d) D.
Enders and O. Niemeier, Synlett, 2004, 2111; (e) Y. Hachisu, J. W.
Bode and K. Suzuki, Adv. Synth. Catal., 2004, 346, 1097.
10 For the synthesis of precatalyst 9 see ESIw.
11 G. Blay, I. Fernandez, B. Monje, C. M. Munoz, J. R. Pedro and C.
Vila, Tetrahedron, 2006, 62, 9174.
12 R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719.
13 G. Q. Li, L. X. Dai and S. L. You, Chem. Commun., 2007, 852.
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