Synergistic catalysis: Enantioselective addition of Alkylbenzoxazoles to Enals

Article abstract of DOI:10.1002/chem.201404565

A novel catalytic enantioselective methodology based on synergistic catalysis is reported. The strategy involves: 1) the metal-Lewis-acid activation of alkylazaarenes, and 2) the secondary-amine activation of enals. Consequently, highly functionalized chiral alkylazaarenes were obtained in good yields and with reasonable stereoselectivity.

Full text of DOI:10.1002/chem.201404565

DOI: 10.1002/chem.201404565
Communication
&
Synergistic Catalysis
Synergistic Catalysis: Enantioselective Addition of
Alkylbenzoxazoles to Enals
[
a]
Marta Meazza, Victor Ceban, Mateusz B. Pitak, Simon J. Coles, and Ramon Rios*
and co-workers in 2006. They developed the direct a-allylic
Abstract: A novel catalytic enantioselective methodology
based on synergistic catalysis is reported. The strategy
involves: 1) the metal-Lewis-acid activation of alkylaza-
arenes, and 2) the secondary-amine activation of enals.
Consequently, highly functionalized chiral alkylazaarenes
were obtained in good yields and with reasonable stereo-
selectivity.
alkylation of unactivated aldehydes with allyl acetates using
[4]
both enamine and Pd catalysis. Later, Zhang reported an effi-
cient asymmetric variant using Cordova’s synergistic strategy
and Pd catalysts bearing C -symmetrical chiral metallocene li-
2
[5]
gands. MacMillan and Sibi reported examples of asymmetric
synergistic catalysis based on enamine catalysis and metal-
[6]
bonded electrophiles. In this area, List also reported his
research efforts joining phosphoric acid derivatives and tran-
sition-metal catalysts with excellent results in allylation, Over-
[7]
In Nature, the concurrent activation of nucleophiles and elec-
trophiles using different catalysts is prevalent. For example, in
enzymatic processes, several amino acid residues activate
nucleophiles and electrophiles simultaneously to facilitate che-
mical reactions. This dual activation is known as synergistic
man rearrangement and epoxidation reactions. On the other
hand, synergistic catalysis using a,b-unsaturated carbonyl com-
pounds has attracted much interest recently. The pioneering
works of Cordova in b-silylation or b-borylation using iminium
and transition-metal activation demonstrated the importance
[
1]
[8]
catalysis.
of this approach.
The concept of activating the nucleophile and electrophile
of a reaction simultaneously has been used for a long time in
organic synthesis. The most common approach in organocatal-
[
2]
ysis has been the use of bifunctional catalysts such as tertiary
amine/thiourea catalysts that activate the nucleophiles and
electrophiles via Brønsted base and hydrogen-bond donor in-
[
3]
teractions, respectively. Bifunctional catalysts have several ad-
vantages such as a well-ordered transition state; however,
there are several disadvantages such as the necessity to syn-
thesize a new catalyst each time one of the subunits needs to
be modified. In contrast, synergistic catalysis allows optimizing
each catalyst almost independently from the other co-catalyst
and, in principle, allows the use of several sources of chirality
in each of the co-catalysts, thus improving the stereo-
selectivity.
Recently, in asymmetric synthesis, the use of two catalysts
and two catalytic cycles, working in concert to create a single
new bond, has emerged as a powerful strategy for developing
new reactions. This concurrent activation of both the nucleo-
phile and electrophile using different catalysts enhanced the
chemical reactivity and allowed the synthesis of difficult scaf-
folds (Figure 1). One of the first examples in asymmetric syn-
thesis based on synergistic catalysis was reported by Cordova
Figure 1. Proposed mechanism.
Recently, our research group became interested in develop-
ing new methodologies for the synthesis of chiral azaarenes.
Despite the fact that alkylbenzoxazoles are an interesting class
of heterocycles because of their importance in agro- and me-
dicinal chemistry, only a few enantioselective methodologies
have been developed for their synthesis. Recently, Lam and
co-workers reported the addition of alkylazaarenes to nitro-
styrenes catalyzed by Pd-bisoxazoline complexes to afford
[
a] M. Meazza, V. Ceban, Dr. M. B. Pitak, Prof. Dr. S. J. Coles, Prof. Dr. R. Rios
Faculty of Natural and Environmental Sciences
University of Southampton
Highfield Campus, Southampton, SO17 1BJ (UK)
E-mail: R.Rios-Torres@southampton.ac.uk
Homepage: www.riosresearchgroup.com
[9]
excellent results. Recently, we reported the addition of alkyl-
benzoxazoles to Morita–Baylis–Hillman (MBH) carbonates,
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404565.
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Communication
based on a synergistic approach, in a highly diastereoselective
Cu salts did not afford the desired product (Table 1, entries 6–
9). Moreover, the addition of the base was crucial as the reac-
[
10]
manner.
Based on these previous studies and our own experience in
tion did not proceed in the absence of a base; 50 mol% Et N
3
[
11]
organocatalysis, we envisioned that the metal activation of
benzoxazoles would work in concordance with enantio-
selective organocatalytic processes in order to build a new
CÀC bond in an enantioselective manner.
was found to be the optimal base. The reaction had some dis-
advantages: the reaction time was crucial; higher reaction
times resulted in lower stereoselectivity. Thus, we assumed
that the reaction suffers from an epimerization process, afford-
ing racemic mixtures. Temperature also had a pivotal impor-
tance. To accelerate the reaction, heating was required; howev-
er, high temperatures resulted in low diastereoselectivity. After
extensive study of the reaction conditions, the best result was
obtained using acetonitrile as the solvent at 358C, 20 mol%
amine catalyst, 5 mol% Pd(OAc) , and 50 mol% Et N. We
In this study, we report the first example of enantioselective
alkylazaarene addition to enals using synergistic catalysis. This
catalytic enantioselective methodology affords highly function-
alized chiral alkylazaarenes and may potentially lead to the de-
velopment of new scaffolds of interest in the agrochemical
and pharmaceutical industries.
2
3
We focused our research efforts on the combination of the
metal-Lewis-acid activation of alkylazaarenes and the secon-
dary-amine activation of enals. The proposed mechanism is
shown in Figure 1.
tested several diphenylprolinol derivatives as the secondary
amine; the tert-butyldimethylsilyl derivatives afforded better
stereoselectivity when used with ACN as the solvent (Table 1,
entry 15).
As shown in Figure 1, we envi-
sioned that the metal Lewis
[a]
acids would interact with the al-
kylbenzoxazole (compound 1)
by coordinating to the nitrogen
of 1, thus increasing the acidity
of the a-carbon of 1. After treat-
ing the metallated alkylbenzoxa-
zole (compound 5) with a base,
Table 1. Optimization.
a
nucleophile (compound 6),
suitable to react with the elec-
trophile (enal), was obtained.
The enal reacts with the secon-
dary amine (organocatalyst) to
form the corresponding activat-
ed iminium form (compound 7).
The S catalyst efficiently shields
one face of the enal. After the
addition, the hydrolysis of com-
pound 8 affords 4 and releases
the catalyst, thus completing the
second catalytic cycle.
[
a]
[b]
[c]
[c]
Entry
Solvent
CHCl
EtOAc
toluene
DMSO
ACN
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
ACN
Metal
T [8C]
Yield [%]
d.r.
–
ee [%]
ee [%]
[
[
[
d]
d]
d]
1
2
3
4
5
6
7
8
9
3
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
CuOTf
Yb(Otf)
Cu(OAc)
Ni(OAc)
AgOAc
–
2
2
2
2
2
40
40
40
40
40
40
40
40
40
40
40
35
35
35
n.r.
32
n.r.
72
–
–
2:1
53
–
rac.
rac.
–
47
–
rac.
rac.
–
–
[d]
1.2:1
1.3:1
[
[
[
[
d]
d]
d]
d]
85
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
80
–
–
–
–
–
–
3
-
–
–
–
–
–
–
–
2
[d]
[
3
d]
d]
e]
10
[
[
12
13
14
15
–
–
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
1.2:1
61
–
88
19
–
68
First, we investigated the reac-
tion of enal 2a with 2-ethyl-6-ni-
trobenzoxazole (1a) in the pres-
ence of different metal Lewis
acids, solvents, and organic
Lewis bases. We selected com-
pound 1a because the presence
[f]
trace
84
[f,g]
1.3:1
[
a] Yields are the sum of pure isolated diastereomers; [b] d.r. calculated from the crude NMR comparing the al-
dehyde signals; [c] ee were determined by chiral HPLC analysis on the isolated products; [d] I as catalyst; [e] II
as catalyst; [f] III as catalyst; [g] reaction time 14 h.
of an electron-withdrawing group in the benzoxazole ring in-
creases the acidity of the a-CH, thus making the compound
more reactive. Moreover, the final aldehyde products decom-
pose very fast; therefore, we subjected the aldehydes in situ to
a Wittig reaction that affords bench-stable compounds. As
shown in Table 1, the best solvent for the reaction was EtOAc,
affording the final products in moderate conversions and with
With the optimized reaction conditions in hand, we investi-
gated the substrate scope of the reaction with respect to enal
derivatives. As shown in Scheme 1, the reactions afforded the
corresponding products in good yields and with good enantio-
selectivity when different aromatic enals were used (3aa–3ah).
In contrast, the reactions of aliphatic enals afforded complex
mixtures due to their decomposition (3ai). However, in almost
all the examples, the diastereoselectivity of the reaction was
very low. Better results were obtained with 4-halogen-substi-
tuted cinnamaldehydes. For example, the fluoro derivative,
3ac, was obtained in 81% yield and with 1.1:1 d.r. and 86 and
reasonable stereoselectivity. Instead, CH CN or DMSO gave
3
higher conversions but almost racemic compounds (Table 1,
entries 1–5). After screening several metals, it resulted that
only Pd(OAc) afforded the final products, while Ag, Yb, Ni, or
2
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9
9% ee. Compounds 3ad and 3ae (Cl and Br derivatives, re-
zole ring. We also investigated the reaction with other func-
tional groups in the benzoxazole ring. The simple benzoxazole
was unreactive under the reaction conditions (3ga), probably
because of the low acidity of the alkyl azaarenes. Next, we in-
vestigated the effect of the substituent in the alkyl position.
Our results confirm that larger substituents could be used such
as n-butyl. The reaction afforded the final product, 3ce, in
a good yield and enantioselectivity with moderate diastereose-
lectivity. Remarkably, The reaction with 4-methyl pyridines
(3 fe), gave longer reaction times (more than 72 h) when cata-
lyst III was used. For this reason catalyst II was used instead
giving good yields and very
spectively) were obtained in similar yields and stereoselectivi-
ties. Electron-withdrawing groups in the aromatic ring resulted
in similar yields and stereoselectivities in the 4-nitro substitut-
ed compound (3af) but lower enantioselectivity when 4-cyano
cinnamaldehyde was used (3ag). It should be noted that in
some examples the use of catalyst III gave longer reaction
times (more than 48 h) which render worse yields due the de-
composition of the formed aldehyde. In order to shorten the
reaction times catalyst II was used in these examples (3af)
with good overall results in terms of yield and stereoselectivity.
good stereoselectivities, while 3-
nitro-6-methylpyridine was un-
reactive (3ga). During the prepa-
ration of this paper, Wang and
co-workers reported the reaction
of 3-nitro-4-methylpyridines with
enals catalyzed by only a secon-
dary amine in DMSO as the sol-
vent. However, when the reac-
tion was conducted under our
conditions but without Pd(OAc)2,
it failed to afford the addition
product. This clearly indicates
that synergistic catalysis was
needed in our case.
In the case of benzoxazoles,
our study shows the necessity of
a
strong electron-withdrawing
group on the heteroarene.
The absolute configuration of
the compounds was determined
by comparing the optical rota-
tion of compound 4 fc (remarka-
bly the aldehydes products de-
rived from pyridines are stable in
the reaction conditions and after
isolation, in contrast with the
compounds derived from ben-
zoxazoles) with that of a com-
pound previously reported by
Scheme 1. Scope of the reaction with several enals. a) DIPEA as a base, b) reaction conducted at 308C; c) II as cat-
alyst.
[12]
Wang (Scheme 3).
lute configuration was consistent
with the mechanism proposed for the iminium activation with
The abso-
Next, we investigated the substrate scope of the reaction
with respect to benzoxazole derivatives. As shown in
Scheme 2, the presence of electron-withdrawing groups in the
azaarene ring was crucial for the reactivity. In order to generate
more complex scaffolds that can be further modified we chose
azaarene 1b bearing a Cl atom close to the nitro. We were
very pleased to confirm that the reaction produces the final
compound 3be with excellent yields, good d.r. and excellent
ee in the major diastereomer. Compound 3de, bearing a nitro
group at 3-position of the benzoxazole ring, was obtained in
moderate yields and with moderate-to-low stereoselectivity.
The low yield can be attributed to the steric effects, causing
difficulty in the coordination of the Lewis acid to the benzoxa-
[13]
the diphenylprolinol catalysts.
The relative configuration of compounds 3 and 4 was ascer-
tained by the X-ray diffraction analysis of a single crystal of the
minor diastereomer of 3af. The minor diastereomer of the
addition product possessed an S,R relative configuration
(Figure 2).
In summary, we have developed a new methodology for the
synthesis of chiral azaarene derivatives based on the concept
of synergistic catalysis. Two different catalytic cycles: 1) the
metal-Lewis-acid activation of azaarenes, and 2) secondary-
amine activation of enals worked in concordance to afford the
final products in good yields and with moderate-to-excellent
Chem. Eur. J. 2014, 20, 1 – 6
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Experimental Section
In a vial were added, in this se-
quence: the organic catalyst
(
20 mol%equiv), a,b-unsaturated
aldehyde (2 equiv), azaarene
1 equiv), Pd(OAc)2 (5 mol%equiv)
(
and CH CN (1 mL). To the crude so-
3
lution was finally added TEA
(50 mol%equiv). The reaction mix-
ture was stirred at the temperature
and time reported in Table 1 and
then concentrated in vacuo. In
a vial were then added the crude
obtained after the first reaction, an
excess of methyl triphenylphos-
phoranylidene acetate (>3 equiv)
and DCM as solvent. The reaction
mixture was stirred at RT for 48 h
and then concentrated in vacuo.
The crude product was purified by
flash column chromatography
(
hexane/EtOAc) to obtain the de-
Scheme 2. Scope of the reaction with several azaarenes: a) II as a catalyst.
sired product.
Single-crystal X-ray diffraction
data of 3af were collected at
1
00 K on Rigaku AFC12 goniome-
ter equipped with an enhanced
sensitivity (HG) Saturn 724+ de-
tector mounted at the window of
an FR-E+ Superbright MoKa rotat-
ing anode generator with HF Vari-
[15]
max optics. Unit-cell parameters
were refined against all data. An
empirical absorption correction
was carried out using CrystalClear
Scheme 3. Synthesis of 4 fc.
[16]
software. The crystal structure of
af was solved by charge flipping
3
[17]
2
methods and refined on Fo by
full-matrix least-squares refine-
ments using programs of the
[18]
SHELX-2013 software. All nonhy-
drogen atoms were refined with
anisotropic displacement parame-
ters. All hydrogen atoms were
added at calculated positions and
refined using a riding model with
isotropic displacement parameters
based on the equivalent isotropic
displacement parameter (U ) of
eq
the parent atom.
[
14]
Figure 2. X-ray structure of compound 3af. The displacement ellipsoids are drawn at the 50% probability level.
Acknowledgements
V.C., M.M. and R.R. acknowledge
the European Regional Develop-
ment Fund (ERDF) for co-financing the AI-CHEM-Chem project
No. 4061) through the INTERREG IV A France (Channel)–Eng-
enantioselectivity and low diastereoselectivity. The mechanistic
studies, synthetic applications, and development of new
organocascade reactions based on this concept are currently
ongoing in our laboratory.
(
land cross-border cooperation programme. We thank India
Willans for her assistance in the synthesis of the starting mate-
rials.
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Communication
[
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· iminium catalysis · Michael
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H
19
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3
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604 unique reflections (Rint =0.0895), 4448 reflections with F >2s,
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4
[
2
Received: July 24, 2014
Published online on && &&, 0000
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Communication
COMMUNICATION
In good company: A novel catalytic
enantioselective methodology based on
synergistic catalysis is reported. The
strategy involves: 1) the metal-Lewis-
acid activation of alkylazaarenes, and 2)
the secondary-amine activation of enals
(see scheme). Consequently, highly
functionalized chiral alkylazaarenes were
obtained in good yields and with
reasonable stereoselectivity.
&
Synergistic Catalysis
M. Meazza, V. Ceban, M. B. Pitak,
S. J. Coles, R. Rios*
&
& – &&
Synergistic Catalysis: Enantioselective
Addition of Alkylbenzoxazoles to
Enals
&
&
Chem. Eur. J. 2014, 20, 1 – 6
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6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!