N-Heterocyclic Carbene Catalyzed Highly Chemoselective Intermolecular Crossed Acyloin Condensation of Aromatic Aldehydes with Trifluoroacetaldehyde Ethyl Hemiacetal

Article abstract of DOI:10.1021/ol502581b

A highly chemoselective intermolecular crossed acyloin condensation between aromatic aldehydes and trifluoroacetaldehyde ethyl hemiacetal has been developed under mild reaction conditions using N-heterocyclic carbene as a catalyst. A wide range of aromatic aldehydes bearing electron-withdrawing and -donating substituents underwent a smooth transformation to their corresponding trifluoromethyl containing acyloin derivatives in moderate to good yields. (Figure Presented).

Full text of DOI:10.1021/ol502581b

Letter
pubs.acs.org/OrgLett
N‑Heterocyclic Carbene Catalyzed Highly Chemoselective
Intermolecular Crossed Acyloin Condensation of Aromatic
Aldehydes with Trifluoroacetaldehyde Ethyl Hemiacetal
Bandaru T. Ramanjaneyulu, Sriram Mahesh, and Ramasamy Vijaya Anand*
Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Sector 81, Knowledge City, S.
A. S. Nagar, Manauli (PO), Punjab − 140306, India
S
* Supporting Information
ABSTRACT: A highly chemoselective intermolecular crossed
acyloin condensation between aromatic aldehydes and
trifluoroacetaldehyde ethyl hemiacetal has been developed
under mild reaction conditions using N-heterocyclic carbene as
a catalyst. A wide range of aromatic aldehydes bearing
electron-withdrawing and -donating substituents underwent a
smooth transformation to their corresponding trifluoromethyl
containing acyloin derivatives in moderate to good yields.
he distinctive reactivity of N-heterocyclic carbenes
Later, Glorius developed a competent approach for the highly
T(NHCs) has been well investigated for the intermolecular chemoselective hydroxymethylation of aldehydes.7 Muller and
̈
co-workers reported an enantioselective cross-benzoin reaction
through enzymatic cross-coupling of aromatic aldehydes using
ThDP-dependent benzaldehyde lyase (BAL).8 Independent
reports by Glorius9 as well as Zeitler and Connon10 display that
high levels of chemoselectivity could be achieved by
introducing a substitution, especially chloro or bromo, at the
ortho position of aromatic aldehydes. Yang’s group has
demonstrated that the choice of NHC is the crucial factor for
switching the regioselectivity in crossed acyloin condensation.11
Recently, Gravel reported a highly chemoselective cross-
benzoin reaction using morpholinone or piperidinone derived
triazolium NHC as a catalyst.12 The Scheidt group has
developed fluoride mediated desilylative coupling of O-silyl
thiazolium carbinols with aliphatic aldehydes leading to crossed
acyloins.13
homodimerization of aldehydes (Benzoin and acyloin con-
densation).1 Nevertheless, the intermolecular cross benzoin or
acyloin condensations remain challenging due to a mismatch
between the reactivity of aldehyde and the coupling partner
(usually another aldehyde). Choosing the right coupling
partner is a crucial task in the crossed acyloin reaction;
otherwise, the reaction would lead to four different acyloins
including two homodimerized products (Scheme 1).
Scheme 1. General Crossed Acyloin Condensation
In addition, Enders’ group has developed an NHC catalyzed
chemoselective cross-benzoin reaction of aldehydes with
trifluoromethyl ketones.14 Johnson’s group reported a
regiospecific cross silyl benzoin reaction using trimethysilyl
ketones as donors.15 Apart from these methods, a few other
protocols were also reported for the chemoselective cross-
benzoin-type reaction, where α-keto esters16 or imines17 were
used as acceptors.
While working on NHC catalyzed transformations, we
envisioned that the chemoselectivity in the intermolecular
crossed acyloin/benzoin reaction could be enhanced if an
“aldehyde equivalent” is used as a coupling partner instead of
another aldehyde. Herein we report a highly chemoselective
intermolecular crossed acyloin reaction of aromatic aldehydes
using trifluoroacetaldehyde ethyl hemiacetal [CF3CH(OH)-
In order to execute the cross-benzoin/acyloin reaction
chemoselectively, the coupling partner must be chosen in
such a way that it must not react with the NHC, and at the
same time its reactivity toward Breslow intermediate2 must be
more than that of the aldehyde. In line with this concept, many
successful reports have appeared in the literature for the
asymmetric intramolecular benzoin reaction1,3 as well as the
inter-/intramolecular Stetter reaction.1,4 However, only a
handful of reports are available for the intermolecular crossed
acyloin type reactions. The first intermolecular crossed acyloin
condensation was reported by the Stetter group.5 This seminal
report was followed by Inoue’s contribution, which deals with
the cross coupling of aliphatic aldehydes with formaldehyde.6
Received: September 1, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502581b | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
OEt] as an aldehyde equivalent (coupling partner). Although
CF3CH(OH)OEt has been reconnoitered as an aldehyde
equivalent in a few other transformations,18 it has not been
explored yet in acyloin condensation. We were particularly
interested in CF3CH(OH)OEt because, unlike other hemi-
acetals, it is highly stable and commercially available (as 90%
aq. solution). Moreover, this hemiacetal introduces the
trifluoromethyl group in the acyloin product, which could be
easily transformed to pharmaceutically important trifluoro-
methyl containing heterocycles or drugs.19
a better understanding of this observation, an experiment was
carried out in which CF3CH(OH)OEt was subjected to self-
acyloin condensation using 11 as a catalyst followed by
esterification with p-nitrobenzoyl chloride under basic con-
ditions (Scheme 2). Interestingly, in this case, the acyloin ester
Scheme 2. Control Experiment with CF3CH(OH)OEt
The optimization studies were carried out using p-
chlorobenzaldehyde (1) and a variety of NHC precursors
(7−11) under different reaction conditions (Table 1). Initially,
a
Table 1. Catalyst Screen and Optimization
12 was not observed; instead the acetal ester 13 was isolated in
55% yield. This experiment suggests that CF3CH(OH)OEt
does not decompose to trifluoroacetaldehyde under the
reaction conditions, which also explains why 5 and 6 were
not observed in any of the reaction conditions tried (Table
1).20
Having optimized conditions in hand (entry 5, Table 1), we
shifted our attention in evaluating the substrate scope. As
shown in Scheme 3, a wide range of aromatic aldehydes were
treated with CF3CH(OH)OEt under standard reaction
conditions. In all cases, the expected crossed acyloin adducts
were obtained in moderate to good yields with high levels of
chemoselectivity (>95:5). A general observation was that the
yields of products in the cases of electron-rich aldehydes (14b−
14d) were found to be a bit inferior when compared to those of
electron-poor aldehydes (14e−14i). Interestingly, in the cases
of halo- and dihalo-substituted aryl aldehydes, the desired
acyloin products (14k−14q) were obtained in good yields.
Even highly hindered aldehydes such as ortho-bromo
substituted aromatic aldehydes underwent smooth conversion
to the corresponding products in good yields (14r and 14s).
This methodology also worked very well for heteroaromatic
aldehydes as well (e.g., 14u−14x). In the case of aliphatic
aldehydes such as hydrocinnamaldehyde and phenylacetalde-
hyde, complex mixtures were obtained. But, cinnamaldehyde
was efficiently converted to the acyloin 14t in 66% yield. We
also tried to elaborate this methodology to other cyclic
hemiacetals (such as lactols and carbohydrate derivatives) as
well as acyclic acetals.21 Unfortunately, none of them reacted
with 1 under standard reaction conditions to give the crossed
acyloin products. In all those cases, only benzoin 4 was
observed.
time
[h]
yield
b
c
entry catalyst
base
solvent
THF
3:4
3 [%]
1
7
DBU
DBU
DBU
DBU
DBU
KtOBu
Cs2CO3
Et3N
24
15
15
24
4
>95:5
−
7
2
8
THF
0
3
9
THF
73:27
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
22
33
90
68
76
62
40
80
82
82
4
10
11
11
11
11
11
11
11
11
THF
5
THF
6
THF
6
7
THF
6
8
THF
8
9
DBU
DBU
DBU
DBU
DCM
DME
DMF
1,4-dioxane
26
10
10
12
10
11
12
a
Reaction conditions: 0.15 M of 1 in solvent. Use of 2 equiv of 2 with
b
respect to 1 was found to be optimal. Ratio determined by 1H NMR
c
analysis of the crude mixture after workup. Isolated yield. rt = 23−26
°C.
we carried out an experiment using 7 as a catalyst (entry 1) and
the anticipated crossed acyloin adduct 3 was formed only in 7%
yield. Indeed, this result was encouraging because the crossed
acyloin product 3 was formed in a chemoselective manner,
albeit the yield was quite low. Screening of other NHCs 9 and
10 did not give promising results, as a considerable amount of 4
was obtained and/or the yield of 3 was low (entries 3 and 4).
Intriguingly, when the reaction was performed using NHC 11
as a catalyst and DBU as a base, the desired crossed acyloin 3
was obtained in 90% yield with high chemoselectivity (entry 5).
Further optimization studies were performed using 11 as a
catalyst by altering the base or solvent (entries 6−12). But in all
those cases, the yield of the desired product was inferior when
compared to entry 5. A noteworthy observation was that the
other possible products 5 and 6 were not formed under the
reaction conditions. The acyloins 5 and 6 are possible only if
trifluoroacetaldehyde is produced during the reaction. To have
It is obvious from the outcome of the reaction that the
Breslow intermediate reacts with CF3CH(OH)OEt chemo-
selectively to deliver the crossed acyloin product. To under-
stand the reaction in detail, a few experiments were performed.
In a typical crossover experiment (Scheme 4), benzoin 15a was
treated with an excess of 2 under the standard reaction
conditions and the reaction was monitored by 1H NMR
spectroscopy, but the crossed acyloin product 14a was not
detected even after 2 days. This experiment clearly indicates
that benzoin 15a did not undergo a retro-benzoin reaction
under the reaction conditions. This result also suggests that the
formation of 15a is irreversible. In another experiment, the
1
standard reaction (Table 1, entry 5) was monitored by H
NMR spectroscopy. In this case, the formation of product 3
was observed prior (within 5 min) to the formation of 4. The
above experiments clearly show that the chemoselectivity
outcome of the reaction is controlled by kinetic factors.
B
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Organic Letters
Letter
a
using NHC as a catalyst. Further elaboration to an
enantioselective version will be the focus in the near future.
Also, detailed investigation to understand the mechanism is
currently underway.
Scheme 3. Substrate Scope
ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental procedures and characterization data of
the products. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: rvijayan@iisermohali.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the Department of Science
& Technology (DST), New Delhi for financial support and
IISER Mohali for providing infrastructure. The authors
sincerely thank Dr. Satya P. Singh (IISER Mohali) and Dr. P.
Balanarayan (IISER Mohali) for useful discussions. B.T.R. and
S.M. thank the CSIR, New Delhi and the UGC, New Delhi
respectively for a research fellowship. The NMR and HRMS
facilities at IISER Mohali are gratefully acknowledged.
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