A direct intermolecular cross-benzoin type reaction: N-heterocyclic carbene-catalyzed coupling of aromatic aldehydes with trifluoromethyl ketones

Article abstract of DOI:10.1002/adsc.200900247

A direct intermolecular cross-benzointype condensation catalyzed by an N-heterocyclic carbene has been developed. The cross-coupling of commercially available aromatic aldehydes and trifluoromethyl ketones results in a-hydroxy-a-trifluoromethyl ketones be

Full text of DOI:10.1002/adsc.200900247

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DOI: 10.1002/adsc.200900247
A Direct Intermolecular Cross-Benzoin Type Reaction:
N-Heterocyclic Carbene-Catalyzed Coupling of Aromatic
Aldehydes with Trifluoromethyl Ketones
Dieter Endersa,* and Alexander Henselera
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax : (+49)-214-809-2127; e-mail: enders@rwth-aachen.de
Received: April 9, 2009; Revised: May 29, 2009; Published online: July 11, 2009
Abstract: A direct intermolecular cross-benzoin-
type condensation catalyzed by an N-heterocyclic
carbene has been developed. The cross-coupling of
commercially available aromatic aldehydes and tri-
fluoromethyl ketones results in a-hydroxy-a-tri-
fluoromethyl ketones bearing a quaternary stereo-
center with excellent chemoselectivity and good to
excellent yields.
et al. reported intermolecular cross-acyloin reactions
by fluoride-promoted addition of O-silylthiazolium
salts.[8] However, to the best of our knowledge, there
is no precedent for a direct organocatalytic intermo-
lecular coupling of aldehydes with ketones, which we
would like to report in this communication.
Based on our mechanistic proposal for the Stetter
reaction, which relies on a reversible formation of the
benzoin product prior to the Stetter product forma-
tion,[9] we envisaged to use benzoins as masked alde-
hyde equivalents.[10] To our delight, benzoin (1) in
combination with an excess of trifluoroacetophenone
(2) as reactive electrophilic ketone component led
chemoselectively to the crossed acyloin product 3 in
high yield, employing 20 mol% of the bicyclic triazoli-
um salt 4[11] as precatalyst in the presence of 20 mol%
Keywords: cross-benzoin reaction; N-heterocyclic
carbenes; organocatalysis; trifluoromethyl substitu-
tion; umpolung
In their pioneering and historic paper on the benzoyl DBU in THF at room temperature (Scheme 1).
compounds of 1832[1] Wçhler and Liebig not only
started the chemistry of aromatic compounds, such as
benzaldehyde, benzoic acid, benzoyl chloride and
benzamide, but also reported the cyanide-catalyzed
(bitter almond oil) formation of benzoin, which in a
sense can be seen as the start of organocatalysis.
Since these early days of organic chemistry, the cya-
nide- and later carbene-catalyzed coupling of two al-
dehyde molecules to form the corresponding a-hy-
droxy ketones (benzoin, acyloin) has been investigat-
ed extensively.[2]
Scheme 1. Intermolecular cross-benzoin test reaction.
Although significant progress has been made with
enantioselective and intramolecular versions in recent
years,[3] there still are limitations in the intermolecular
Since the crossed acyloin product 3 containing a
coupling of two different aldehydes and of aldehydes tertiary alcohol seemed to be energetically preferred
with ketones. In these cases the outcome is typically a relative to benzoin (1) a simpler and more practical
mixture of all possible symmetrical and unsymmetri- version of this concept would be to employ the alde-
cal acyloins, with the chemoselectivity strongly de- hyde component directly in this transformation
pending on the relative thermodynamic stability of (Scheme 2). Under the reaction conditions given
the corresponding products.[4] In order to overcome (10 mol% carbene precursor 4 and 10 mol% DBU), it
this problem several research groups have made ex- was indeed possible to obtain the cross-coupled prod-
cellent contributions by developing enzymatic ap- uct 3 in 64% yield beside 36% of the homo-coupled
proaches[5] or utilizing acylsilanes[6] and acylphospho- benzoin. By simply employing an excess of DBU the
nates[7] as acyl anion equivalents in cyanide-catalyzed formation of benzoin could be avoided and the cross-
transformations. In addition, very recently Scheidt coupling improved to 93% yield which may be due to
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1749

Dieter Enders and Alexander Henseler
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Scheme 2. NHC-catalyzed direct intermolecular cross-benzoin reaction.
the generation of more triazolylidene catalyst under phenone (2) leading to the tetrahedral intermediate 9.
these reaction conditions. Of note, a decrease of cata- An intramolecular proton transfer and elimination of
lyst loading (5 mol%) in combination with an excess the a-hydroxy-a-trifluoromethyl ketone 3 returns the
of DBU (10 mol%) resulted in a lower yield of a-hy- catalyst. Next we examined the substrate scope and
droxy-a-trifluoromethyl ketone 3 (63%). The reversi- various aromatic as well as heteroaromatic aldehydes
ble nature of the benzoin condensation under the 10 were tested for their reactivity with aromatic tri-
present reaction conditions (Scheme 1) and our previ- fluoromethyl ketones 11 (Scheme 4). As is shown in
ous mechanistic insights into the Stetter product for-
mation[9] led us to the assumption that two coupled
catalytic cycles are involved in this transformation
(Scheme 3).
Initially, benzoin (1) is formed rapidly and reversi-
bly prior to the formation of the cross-coupling prod-
uct 3. Next, initiated by a nucleophilic attack of the
NHC-catalyst 6 at the carbonyl function of benzoin,
the 1,2-adduct 7 is formed. This in turn eliminates
benzaldehyde (5) to result in the formation of the
Breslow intermediate 8, which attacks trifluoroaceto-
Scheme 4. Direct intermolecular cross-benzoin type reaction
under optimized conditions.
Table 1, the reaction works well for all tested sub-
strates, providing the crossed hydroxy ketones 12a–l
in good to excellent yields (64–99%). Aldehydes and
ketones bearing an electron-withdrawing group (en-
tries 2–6) gave slightly better yields (88–92%, except
entry 7[12]), than electron-rich aldehydes (entries 8–10)
(66–84%). Of note, heteroaromatic aldehydes such as
2-furfural and 2-thiophenaldehyde (entries 11 and 12)
resulted in excellent yields (91–99%).
In summary, we have developed a first NHC-orga-
nocatalyzed method for the direct cross-coupling of
aromatic aldehydes and trifluoromethyl ketones in
good to excellent yields. The resulting trifluorometh-
yl-substituted a-hydroxy ketones bearing a quaternary
stereocenter are useful synthetic building blocks and
valuable pharmaceutical intermediates. Extension of
the substrate scope as well as development of an
enantioselective version of this protocol are currently
being investigated in our laboratories.
Scheme 3. Coupled catalytic cycles in the formation of the
crossed benzoin-type products 3.
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A Direct Intermolecular Cross-Benzoin Type Reaction
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Table 1. Substrate scope for the direct intermolecular cross-
benzoin type reaction.
Experimental Section
General Procedure for the Intermolecular Crossed
Benzoin Reaction
Entry R1
R2
Ph
Ph
Product
Yield[a]
[%]
In a dry, argon-flushed Schlenk tube precatalyst 4 (27 mg,
0.1 mmol, 10 mol%), DBU (30 mg, 0.2 mmol, 20 mol%), al-
dehyde 10 (1 mmol) and trifluoromethyl ketone 11 (2 mmol)
were dissolved in absolute THF (3 mL). After stirring for
15 h at room temperature, the reaction mixture was loaded
directly on to a column and purified via flash chromatogra-
phy on silca gel (pentane/diethyl ether=9:1) to yield the
corresponding a-hydroxy-a-trifluoromethyl ketone 12 as a
colorless solid or yellow oil.
1
2
3
4
Ph
12a
12b
12c
12d
93
88
89
89
4-Cl-
C6H4
4-Cl-
C6H4
Ph
Ph
Acknowledgements
4-F-
C6H4
This work was supported by the Fonds der Chemischen In-
dustrie and the Deutsche Forschungsgemeinschaft (priority
program organocatalysis). We thank BASF AG for the dona-
tion of chemicals.
4-Cl-
C6H4
4-F-
C6H4
5
12e
90
References
4-CF3-
C6H4
6
7
8
9
Ph
Ph
Ph
Ph
Ph
12f
12g
12h
12i
92
64
81
84
66
[1] F. Wçhler, J. Liebig, Ann. Pharm. 1832, 3, 249–282.
[2] Reviews: a) D. Enders, O. Niemeier, A. Henseler,
Chem. Rev. 2007, 107, 5606–5655; b) D. Enders, T. Ba-
lensiefer, Acc. Chem. Res. 2004, 37, 534–541; minire-
views: c) T. Rovis, Chem. Lett. 2008, 2–7; d) N.
Marion, S. Diez-Gonzalez, S. P. Nolan, Angew. Chem.
2007, 119, 3046–3058; Angew. Chem. Int. Ed. 2007, 46,
2988–3000; highlights: e) M. Christmann, Angew.
Chem. 2005, 117, 2688–2690; Angew. Chem. Int. Ed.
2005, 44, 2632–2634; f) K. Zeitler, Angew. Chem. 2005,
117, 7674–7678; Angew. Chem. Int. Ed. 2005, 44, 7506–
7510; perspective: g) D. Enders, A. A. Narine, J. Org.
Chem. 2008, 73, 7857–7870.
[3] a) D. Enders, O. Niemeier, T. Balensiefer, Angew.
Chem. 2006, 118, 1491–1495; Angew. Chem. Int. Ed.
2006, 45, 1463–1467; b) D. Enders, O. Niemeier, G.
Raabe, Synlett 2006, 2431–2434; c) H. Takikawa, Y.
Hachisu, J. W. Bode, K. Suzuki, Angew. Chem. 2006,
118, 3572–3574; Angew. Chem. Int. Ed. 2006, 45, 3492–
3494; d) D. Enders, O. Niemeier, Synlett 2004, 2111–
2114; e) Y. Hachisu, J. W. Bode, K. Suzuki, Adv. Synth.
Catal. 2004, 346, 1097–1100; f) Y. Hachisu, J. W. Bode,
K. Suzuki, J. Am. Chem. Soc. 2003, 125, 8432–8433;
g) D. Enders, U. Kallfass, Angew. Chem. 2002, 114,
1822–1824; Angew. Chem. Int. Ed. 2002, 41, 1743–
1745.
2,4,6-F3-
C6H2
4-Me-
C6H4
4-MeO-
C6H4
4-Me2N-
C6H4
10
11
12j
2-furyl
Ph
Ph
12k
12l
99
91
2-thien-
yl
12
[a]
[4] a) R. Heck, A. P. Henderson, B. Kçhler, J. Rꢁtey, B. T.
Golding, Eur. J. Org. Chem. 2001, 2623–2627; b) H.
Stetter, G. Dꢂmbkes, Synthesis 1980, 309–310; H. Stet-
ter, G. Dꢂmbkes, Synthesis 1977, 403–404; c) W. S. Ide,
J. S. Buck, Org. React. 1948, 4, 269–304.
Yield of the isolated analytically pure product.
[5] a) P. Dunkelmann, D. Kolter-Jung, A. Nitsche, A. S.
Demir, P. Siegert, B. Lingen, M. Baumann, M. Pohl, M.
Mꢃller, J. Am. Chem. Soc. 2002, 124, 12084–12085;
b) A. S. Demir, O. Sesenoglu, E. Eren, B. Hosrik, M.
Adv. Synth. Catal. 2009, 351, 1749 – 1752
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1751

Dieter Enders and Alexander Henseler
COMMUNICATIONS
Pohl, E. Janzen, D. Kolter, R. Feldmann, P. Dunkel-
mann, M. Mꢃller, Adv. Synth. Catal. 2002, 344, 96–103;
c) A. S. Demir, M. Pohl, E. Janzen, M. Mꢃller, J. Chem.
Soc. Perkin Trans. 1 2001, 633–635; d) T. Dꢃnnwald,
A. S. Demir, P. Siegert, M. Pohl, M. Mꢃller, Eur. J.
Org. Chem. 2000, 2161–2170.
2005, 347, 1207–1211; e) A. S. Demir, ꢄ. Reis, A. C¸ .
˘
Igdir, I. Esiringꢃ, S. Eymur, J. Org. Chem. 2005, 70,
10584–10587.
[8] A. K. Mathies, A. E. Mattson, K. A. Scheidt, Synlett
2009, 377–383.
[9] a) D. Enders, J. Han, A. Henseler, Chem. Commun.
2008, 3989–3991; b) Bode et al. also observed a reversi-
ble benzoin product formation prior to the actual trans-
formation see: P.-C. Chiang, J. Kaeobamrung, J. W.
Bode J. Am. Chem. Soc. 2007, 129, 3520–3521.
[10] G.-Q. Li, L.-X. Dai, S.-L. You, Chem. Commun. 2007,
852–854.
[11] N. T. Reynolds, J. Read deAlaniz, T. Rovis, J. Am.
Chem. Soc. 2004, 126, 9518–9519.
[12] Of note, the reaction seems to be sensitive to aldehydes
carrying a substituent in ortho-position. A reaction of
2-chlorobenzaldehyde with 2 afforded the correspond-
ing 1-(2-chlorophenyl)-3,3,3-trifluoro-2-hydroxy-2-phe-
nylpropan-1-one in 34% yield.
[6] a) X. Linghu, C. C. Bausch, J. S. Johnson, J. Am. Chem.
Soc. 2005, 127, 1833–1840; b) X. Linghu, J. R. Potnick,
J. S. Johnson, J. Am. Chem. Soc. 2004, 126, 3070–3071;
c) C. C. Bausch, J. S. Johnson, J. Org. Chem. 2004, 69,
4283–4285; d) J. S. Johnson, J. L. Xin, Angew. Chem.
2003, 115, 2638–2640; Angew. Chem. Int. Ed. 2003, 42,
2534–2536.
[7] a) A. S. Demir, I. Esiringꢃ, M. Gçllꢃ, ꢄ. Reis, J. Org.
Chem. 2009, 74, 2197–2199; b) A. S. Demir, B. Reis, ꢄ.
Reis, S. Eymꢃr, M. Gçllꢃ, S. Tural, G. Saglam, J. Org.
Chem. 2007, 72, 7439–7442; c) A. S. Demir, ꢄ. Reis, I.
Esiringꢃ, B. Reis, S. Baris, Tetrahedron 2007, 63, 160–
165; d) C. C. Bausch, J. S. Johnson, Adv. Synth. Catal.
1752
asc.wiley-vch.de
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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