N-heterocyclic carbene catalysed asymmetric cross-benzoin reactions of heteroaromatic aldehydes with trifluoromethyl ketones

Article abstract of DOI:10.1039/c0cc02013c

A new triazolium salt derived N-heterocyclic carbene catalyses an asymmetric cross-benzoin-type reaction of heteroaromatic aldehydes and various trifluoromethyl ketones in good to excellent yields (69-96%) and moderate to good enantioselectivities (ee = 39-85%). Up to 99% ee can be achieved by recrystallisation.

Full text of DOI:10.1039/c0cc02013c

View Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
N-heterocyclic carbene catalysed asymmetric cross-benzoin reactions
of heteroaromatic aldehydes with trifluoromethyl ketonesw
´
Dieter Enders,* Andre Grossmann, Jeanne Fronert and Gerhard Raabe
Received 22nd June 2010, Accepted 12th July 2010
DOI: 10.1039/c0cc02013c
A new triazolium salt derived N-heterocyclic carbene cata-
lyses an asymmetric cross-benzoin-type reaction of hetero-
aromatic aldehydes and various trifluoromethyl ketones in good
to excellent yields (69–96%) and moderate to good enantio-
selectivities (ee = 39–85%). Up to 99% ee can be achieved by
recrystallisation.
Demir et al.10e demonstrated independently that acylsilanes
and acylphosphonates are suitable substrates for the aldehyde
ketone cross-coupling. Unfortunately, so far chiral phosphates
have proved to be inactive in the reaction of such acylsilanes
with ketones. To the best of our knowledge the only example
of an asymmetric intermolecular cross coupling of aldehydes
and ketones has been carried out enzymatically by Muller
¨
et al.11 Since the corresponding a-hydroxy ketones bearing a
quaternary centre are important motifs in natural products,12
the development of the asymmetric version of this reaction
would be an important tool in synthetic organic chemistry.
Very recently, we have published the direct NHC-catalysed
reaction of aromatic aldehydes with an excess of trifluoro-
acetophenone derivatives affording the corresponding products
in good to excellent yields.13 Unfortunately, as we attempted to
apply enantiopure catalysts the yield dropped dramatically with
selectivities close to zero. Now we present triazolium derived
catalysts successfully promoting this reaction in good to excellent
yields and moderate to good enantioselectivities.
Since the first report of Liebig and Wohler1 about the self-
¨
condensation of benzaldehyde to benzoin in the presence of
cyanide there has been a lot of effort devoted towards the
development of an asymmetric version of this reaction.2 The
introduction of N-heterocyclic salts as catalyst precursors led
to a breakthrough in this area.3 Nowadays there are several
successful catalysts in the case of the reaction of two identical
aldehydes, yet the cross-benzoin condensation is still a
challenge.4
Initial studies on the cross-benzoin reaction were published
by Stetter and Dambkes in 1977.5 These showed that in a
¨
mixture of different aldehydes using a thiazolium salt-derived
catalyst the thermodynamic product was formed reversibly.
For certain combinations of aldehydes a very high chemo-
We reexamined the reaction of furfural and trifluoroaceto-
phenone using the salts 4–9 as catalyst precursors (Scheme 1).
They were chosen as they have successfully been employed in
the benzoin condensation (64b, 93) or in the Stetter reaction
(414a, 814b). In addition, we prepared new derivatives of these
triazolium salts to tune the electronic and steric properties.
The best results were observed with triazolium salt 5 yielding
a-hydroxy ketone 3a in 84% yield and 77% ee. Significantly,
no excess of ketone was necessary when an equivalent of
selectivity was achieved. A decade later Lopez-Calahorra et al.
´
added reactive iminium salts as acceptor molecules to the
aldehydes to selectively form a-aminoketones,6 with cross-
aza-benzoin type reaction under kinetic control. Murry et al.
and Scheidt et al. continued this method using acyl- and
phosphinoylimines to obtain the corresponding products in
high yields.7 Their work led Miller et al. to develop an
asymmetric version of the reaction using a thiazolium derived
catalyst with a synthetic tripeptide backbone.8
Hunig’s base was used instead of DBU.13a
¨
Then we turned our attention to the optimisation of the
reaction conditions (Table 1). Hence trifluoroacetophenone
and the ketone with the thienyl moiety were reacted with
furfural. The results indicated a strong temperature dependence
with regard to yield but only gave a slight increase in selectivity
with decreased temperature. Both the higher catalyst loading and
an excess of ketone accelerated the reaction at the cost of
selectivity. Therefore, we combined low temperature, 10% cata-
lyst loading and an excess of ketone to achieve optimal results in
terms of both yield and enantioselectivity. Interestingly, the
process of changing the conditions as outlined above affected
the less reactive thienyl ketone strongly.
At the same time there were several developments in the
cross coupling of two different aldehydes or aldehydes
with ketones. Both Suzuki et al. and our group discovered
independently the asymmetric intramolecular benzoin conden-
sation between aldehydes and ketones by employing different
tetracyclic triazolium salts as catalyst precursors to promote
this reaction in a highly enantioselective manner.9 Meanwhile,
a breakthrough in the intermolecular reaction came with the
introduction of the cyanide catalysed reaction of acylsilanes
with aldehydes by Johnson et al.10 Later they showed that the
replacement of the cyanide catalyst by a chiral phosphate led
to high ee values.10b Furthermore, Tarr and Johnson10d and
The absolute configuration of the a-hydroxy ketones 3 given
as (S) could not be unambiguously determined by X-ray
analysis (Fig. 1) because of a large standard deviation of the
Flack parameter16 and is based on CD-measurements and
theoretical calculations.17 We propose the transition state
given in Fig. 2. Using DFT methods Hawkes and Yates18
calculated that the configuration of the enolamine should be
E due to steric and stereoelectronic interactions. Dudding and
Houk19 predicted that the aromatic moieties of the aldehyde
Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany.
E-mail: enders@rwth-aachen.de; Fax: +49-241-809-2127;
Tel: +49-241-809-4676
w Electronic supplementary information (ESI) available: Experimental
details and characterization data. CCDC 781144. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c0cc02013c
ꢀc
This journal is The Royal Society of Chemistry 2010
6282 | Chem. Commun., 2010, 46, 6282–6284

View Online
Fig. 1 ORTEP plot of 3a determined by X-ray analysis.15
Scheme 1 Catalyst screening result of the reaction between furfural
(1a) and trifluoroacetophenone (2a).
Fig. 2 Proposed transition state.
Table 1 Optimisation studies of the reaction conditionsa
well as moderate to good enantioselectivities were achieved,
with electron-poor ketones performing better than their electron-
rich or heteroaromatic counterparts. By prolonging the reaction
time however, this disadvantage could be somewhat diminished.
Table
2 Examination of the substrate scope under optimised
Temperature/ Yieldb
(%)
conditionsa
Substrate Catalyst
ratio
3
R
loading (%) 1C
eec (%)
a
a
a
a
b
b
b
Ph
Ph
Ph
Ph
1 : 1
1 : 1
1 : 1
1 : 2
10
20
10
10
10
10
10
0
22
22
0
22
22
0
61
83
84
86
47
62
71
78
70
77
78
51
49
61
2-Thienyl 1 : 1
2-Thienyl 1 : 2
2-Thienyl 1 : 2
3
R1
R2
Yieldb (%) eec (%)
a
All reactions were performed on a 1 mmol scale in 1 mL THF for
b
c
24 h. Yield of isolated 3. Determined by HPLC analysis on a chiral
a
2-Furyl
2-Furyl
2-Furyl
2-Furyl
2-Furyl
2-Furyl
2-Furyl
2-Thienyl
2-(5-Me-Furyl)
2-(4,5-Di-Me-Furyl)
Ph
2-Thienyl
4-MeOC6H4 69
4-BrC6H4
4-ClC6H4
4-CF3C6H4
2-Furyl
4-BrC6H4
Ph
86 (43)
71
78 (99)
61
82
b
stationary phase.
cd
d
89 (49)
73 (99)
73 (81)
52 (96)
39
e
f
90 (46)
96 (41)
86
and the triazole must turn out of plane to avoid the dis-
favoured steric interactions. In our case the backside was
blocked by the sterically demanding silyl protecting group
attached to the triazole catalyst. Thus, the ketone should
approach from the opposite side. In their theoretical study
Houk et al. also discussed attractive interactions with the
aromatic moiety of the approaching molecule and the
developing iminium charge during C–C bond formation.
Further possible stabilising effects are p-stacking between the
aromatic residues in the Breslow intermediate and the hydrogen
bond between the reacting substrates.20
gd
hd
i
93
94 (62)
90
65
84 (99)
85
jd
kd
l
Ph
2-(5-(4-ClC6H4)-Furyl) Ph
2-Pyridyl
75 (50)
73
85
62 (94)
62
67
Ph
Ph
Ph
md 2-Benzofuryl
nd
2-Pyrryl
85 (41)
45 (93)
a
All reactions were performed on a 1 mmol scale in 1 mL THF under
b
optimised conditions. Yield of isolated 3; values in parentheses
c
indicate yield after crystallisation. Determined by HPLC analysis
on a chiral stationary phase; values in parentheses indicate ee after
d
crystallisation. Reaction time was prolonged to 48 h.
Finally, we tested various substrates to determine the scope
of the reaction (Table 2). Good to excellent yields (69–96%) as
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 6282–6284 | 6283

View Online
Notes and references
1 J. Liebig and F. Wohler, Ann. Pharm., 1832, 3, 249.
¨
2 For recent reviews on NHC catalysis, see: (a) D. Enders,
O. Niemeier and A. Henseler, Chem. Rev., 2007, 107, 5606;
(b) D. Enders and T. Balensiefer, Acc. Chem. Res., 2004, 37, 534;
(c) N. Marion, S. Dı
2007, 119, 3046 (Angew. Chem., Int. Ed., 2007, 46, 2988);
(d) P. Hoyos, J. Sinisterra, F. Molinari, A. R. Alcantara and
P. D. Marıa, Acc. Chem. Res., 2010, 43, 288.
es-Gonzalez and S. P. Nolan, Angew. Chem.,
´ ´
´
´
3 D. Enders and U. Kallfass, Angew. Chem., 2002, 114, 1822 (Angew.
Chem., Int. Ed., 2002, 41, 1743).
4 (a) Y. Ma, S. Wei, J. Wu, F. Yang, B. Liu, J. Lan, S. Yang and
J. You, Adv. Synth. Catal., 2008, 350, 2645; (b) L. Baragwanath,
C. A. Rose, K. Zeitler and S. J. Connon, J. Org. Chem., 2009, 74,
9214.
5 H. Stetter and G. Dambkes, Synthesis, 1977, 403.
¨
6 J. Castells, F. Lopez-Calahorra, M. Bassedas and P. Urrios,
´
Synthesis, 1988, 314.
Fig. 3 Direct observation of the reaction progress via 1H-NMR-
spectroscopy. The reaction was performed using 0.5 mmol aldehyde,
0.65 mmol ketone, 0.5 mmol i-Pr2NEt and 0.01 mmol catalyst 5 in
1 mL THF-d8 at room temperature.
7 (a) J. A. Murry, D. E. Frantz, A. Soheili, R. Tillyer, E. J. J.
Grabowski and P. J. Reider, J. Am. Chem. Soc., 2001, 123, 9696;
(b) A. E. Mattson and K. A. Scheidt, Org. Lett., 2004, 6,
4363.
The enantioselectivities ranged between 39 and 85%. There
appeared to be no obvious correlation between the substitu-
ents and the enantioselectivity, perhaps indicating a more
complicated relationship dictated by a number of steric or
stereoelectronic effects. Serendipitously, a number of products
crystallised as either enantiopure compounds (Table 1, 3a, 3d,
3e, 3f, 3i) or as racemates (3k, 3n). Thus, by crystallisation
some of the compounds could be isolated as a single
enantiomer.
8 S. M. Mennen, J. D. Gipson, Y. R. Kim and S. J. Miller, J. Am.
Chem. Soc., 2005, 127, 1654.
9 (a) Y. Hachisu, J. W. Bode and K. Suzuki, J. Am. Chem. Soc.,
2003, 125, 8432; (b) Y. Hachisu, J. W. Bode and K. Suzuki, Adv.
Synth. Catal., 2004, 346, 1097; (c) D. Enders and O. Niemeier,
Synlett, 2004, 2111; (d) D. Enders, O. Niemeier and T. Balensiefer,
Angew. Chem., 2006, 118, 1491 (Angew. Chem., Int. Ed., 2006, 45,
1463); (e) H. Takikawa, Y. Hachisu, J. W. Bode and K. Suzuki,
Angew. Chem., 2006, 118, 3572 (Angew. Chem., Int. Ed., 2006, 45,
3492).
10 (a) X. Linghu and J. S. Johnson, Angew. Chem., 2003, 115, 2638
(Angew. Chem., Int. Ed., 2003, 42, 2534); (b) X. Linghu,
J. R. Potnick and J. S. Johnson, J. Am. Chem. Soc., 2004, 126,
3070; (c) C. C. Bausch and J. S. Johnson, Adv. Synth. Catal., 2005,
347, 1207; (d) J. C. Tarr and J. S. Johnson, Org. Lett., 2009, 11,
In our previous report we postulated a mechanism for the
cross-benzoin reaction,13a which now we were able to observe
1
directly using H-NMR. Therefore, the reaction was carried
out in an NMR tube using 2 mol% catalyst 5 without stirring
to decrease the reaction rate. At the beginning of the reaction
furoin was observed far before the first cross product was
detected (Fig. 3). After approximately one hour the formation
of the intermediate was complete and the benzoin began to
react slowly with the ketone producing the cross product. This
corroborated previous observations that the formation of the
benzoin is thermodynamically controlled under the reported
conditions. Then we turned our attention to the second step of
this reaction. Several racemisation experiments were performed
to determine the character of the cross-benzoin formation. We
exposed enantiomerically pure 3a to a racemic catalyst under
the optimized reaction conditions for several days. If the second
step of this reaction had been reversible and under thermo-
dynamic control we would have achieved racemisation of 3a. In
fact the ee stayed at the initial value. Therefore, we state that the
product is irreversibly formed under kinetic control.
¨
˙ ˙
3870; (e) A. S. Demir, O. Reis, A. C¸ . Igdir, I. Esiringu and
¨
S. Eymur, J. Org. Chem., 2005, 70, 10584.
11 For enzymatically promoted benzoin condensations, see:
(a) H. Iding, T. Dunnwald, L. Greiner, A. Liese, M. Muller,
¨
P. Siegert, J. Grotzinger, A. S. Demir and M. Pohl, Chem.–Eur.
¨
¨
J., 2000, 6, 1483; (b) A. S. Demir, M. Pohl, E. Janzen and
M. Muller, J. Chem. Soc., Perkin Trans. 1, 2001, 633;
¨
(c) P. Dunkelmann, D. Kolter-Jung, A. Nitsche, A. S. Demir,
¨
P. Siegert, B. Lingen, M. Baumann, M. Pohl and M. Muller,
¨
J. Am. Chem. Soc., 2002, 124, 12084; (d) P. Lehwald, M. Richter,
C. Rohr, H. Liu and M. Muller, Angew. Chem., 2010, 122, 2439
¨
¨
(Angew. Chem., Int. Ed., 2010, 49, 2389).
12 R. Kourist, P. D. Marıa and U. T. Bornscheuer, ChemBioChem,
2008, 9, 491.
´
13 (a) D. Enders and A. Henseler, Adv. Synth. Catal., 2009, 351, 1749;
(b) D. Enders, A. Henseler and S. Lowins, Synthesis, 2009,
4125.
14 (a) J. R. Alaniz, M. S. Kerr, J. L. Moore and T. Rovis, J. Org.
Chem., 2008, 73, 2033; (b) D. Enders, J. Han and A. Henseler,
Chem. Commun., 2008, 3989.
15 CCDC 781144 contains the supplementary crystallographic data
for the compound 3a reported in this paper.
16 H. D. Flack, Acta Crystallogr., Sect. A, 1983, 39, 876.
17 G. Raabe and S. Wehrse, RWTH Aachen University, unpublished
results.
18 K. J. Hawkes and B. F. Yates, Eur. J. Org. Chem., 2008,
5563.
19 T. Dudding and K. N. Houk, Proc. Natl. Acad. Sci. U. S. A., 2004,
101, 5770.
20 For a recent review on interactions between aromatic com-
pounds, see: E. A. Meyer, R. K. Castellano and F. Diederich,
Angew. Chem., 2003, 115, 1244 (Angew. Chem., Int. Ed., 2003,
42, 1210).
In summary, we have synthesised a novel chiral triazolium salt
which is a potent catalyst precursor for the asymmetric cross-
benzoin reaction of aldehydes with ketones. Several hetero-
aromatic aldehydes successfully reacted with various aromatic
trifluoroketones in good to excellent yields and moderate to
good enantioselectivities which could be improved by crystalli-
sation. Direct observation of the reaction by NMR along with
racemisation experiments showed that the product is formed
under kinetic control.
ꢀc
This journal is The Royal Society of Chemistry 2010
6284 | Chem. Commun., 2010, 46, 6282–6284