An NHC-Catalyzed Cross-Benzoin-Esterification Sequential Reaction for the Synthesis of Trifluoromethyl-Substituted α,β-Unsaturated Esters

Article abstract of DOI:10.1055/s-0035-1561631

Efficient preparation of synthetically important CF₃-containing α,β-unsaturated esters is described using an NHC-catalyzed multicomponent reaction. This approach combines sequential NHC-mediated HOMO and LUMO activation to produce a C-C bond an

Full text of DOI:10.1055/s-0035-1561631

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
Q. Zhao et al.
Letter
Synlett
An NHC-Catalyzed Cross-Benzoin–Esterification Sequential Reac-
tion for the Synthesis of Trifluoromethyl-Substituted α,β-Unsatu-
rated Esters
Qian Zhaoa,1
Li-Ying Fengb,1
Wei Huanga
Xiang-Hong Hea
Cheng Peng*a
Bo Han*a,b
NHC
HOMO
NHC
LUMO
O
O
OH
OEt
O
O
R2
R1
2
+
+
R
H
R1
cross-
benzoin
F3C
H
esterification
CF3
O
Br
R1 = (hetero)aryl or cinnamyl
R2 = (hetero)aryl or alkyl
• sequential NHC-NHC catalysis
• C–C bond and C–O bond formation
• 23 examples, 38–82% yield
a State Key Laboratory Breeding Base of Systematic Research,
Development and Utilization of Chinese Medicine Resources,
Chengdu University of Traditional Chinese Medicine, 1166 Liutai
Avenue, Chengdu 611137, P. R. of China
pengchengchengdu@126.com
hanbo@cdutcm.edu.cn
b Department of Ultrasongraphy, Beijing Militray General Hospital
of PLA, No.5 Nanmencang, Beijing 100007, P. R. of China
Received: 02.03.2016
Accepted after revision: 13.04.2016
Published online:
om-based electrophiles to generate a diverse range of
synthetically valuable compounds. Prominent examples of
such reactions include benzoin condensation7 and the Stet-
ter reaction.8
DOI: 10.1055/s-0035-1561631; Art ID: st-2016-w0148-l
Abstract Efficient preparation of synthetically important CF3-contain-
ing α,β-unsaturated esters is described using an NHC-catalyzed multi-
component reaction. This approach combines sequential NHC-mediat-
ed HOMO and LUMO activation to produce a C–C bond and C–O bond
in a one-pot operation.
Well-established strategies
a) NHC-mediated HOMO activation: ref. 6–8
NHC
HOMO
O
E
OH
O
Key words organocatalytic reaction, multicomponent reaction, NHC
catalysis, trifluoromethylated compounds, cross-benzoin, esterification
R
H
R
NHC
OH
R
E
NHC
HOMO
E
O
E
O
R1
NHC
R1
NHC
R
H
Multicomponent one-pot reactions have developed
enormously in recent years and remain one of the hottest
areas in organic chemistry.2 The one-pot approach is often
much more efficient, faster, and less expensive than the tra-
ditional ‘stop-and-go’ approach.3 It also often avoids the
need to isolate reaction intermediates. The expanding ap-
plications of one-pot reactions mean that developing novel
catalytic systems for them remains an important goal.
One potentially useful catalyst class for one-pot reac-
tions are N-heterocyclic carbenes (NHC),4 first reported in
stable form by Arduengo et al. in 1991.5 NHC-mediated
HOMO activation already plays an important role in organic
synthesis: it reverses the polarity of the ipso position in sat-
urated aldehydes or the β-position in α,β-unsaturated alde-
hydes (Scheme 1, a).6 The resulting increase in HOMO ener-
gy can be exploited in reactions with carbon- and heteroat-
b) NHC-mediated LUMO activation: ref. 9–13
Nu1
Nu2
R
O
NHC
O
2-haloenals, enol esters, ynals,
LUMO
Nu1 Nu2
O
α,β-unsaturated acyl fluorides,
NHC
enals (with oxidative conditions)
R
R
Nu
Nu
Underexplored strategies
c) the combination of HOMO and LUMO activation: ref. 14
NHC
HOMO
NHC
LUMO
hydroxamic
esters
nitrosobenzenes & aldehydes & enals
multicomponent
one-pot reaction
Scheme 1 Synthetic strategies based on NHC-mediated HOMO and/or
LUMO activation
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
Q. Zhao et al.
Letter
Synlett
NHC can also catalyze reactions by reducing LUMO en-
ergy. This strategy has been exploited to generate α,β-un-
saturated acylazolium (Scheme 1, b) from 2-haloenals,9
enals (under oxidative conditions),10 enol esters,11 ynals,12
or α,β-unsaturated acyl fluorides.13 Several groups have
used NHC-mediated LUMO activation to achieve the [3+3]
annulation of α,β-unsaturated acylazoliums using 1,3-nu-
cleophiles; this approach has been used to synthesize many
important molecules.9–13
The ability of NHC to catalyze reactions via both HOMO
and LUMO activation raises the possibility that both activa-
tion modes might be harnessed in a single multicomponent
one-pot reaction. Indeed, Enders and co-workers reported
an NHC-catalyzed one-pot reaction involving an aza-benzo-
in-type reaction between nitrosobenzenes and various al-
dehydes followed by redox esterification, affording hy-
droxamic esters (Scheme 1, c).14 Our group aimed to build
on this success by developing one-pot reactions based on
NHC-mediated HOMO and LUMO activation that utilize
other types of aldehydes or aldehyde equivalents.
Our approach was to start from the system described by
Anand’s group, who achieved an NHC-catalyzed cross-ben-
zoin reaction of aromatic aldehydes with trifluoroacetalde-
hyde ethyl hemiacetal to afford trifluoromethyl-containing
acyloins.15 Drawing on our recent success in developing or-
ganocatalytic one-pot reactions to assemble multiple sub-
strates into synthetically important molecules,16 we won-
dered whether the trifluoromethylated acyloins could
serve as the basis for a one-pot reaction combining NHC-
mediated HOMO and LUMO activation.
Initial experiments were carried out with benzaldehyde
(1a) and CF3CH(OH)OEt (2) in the presence of triazolium
salt A and DBU in MeCN. Cross-benzoin condensation pro-
ceeded quickly. After most benzaldehyde (1a) was con-
sumed, we added α-bromocinnamic aldehyde (4a) directly
to the reaction mixture. To our gratification, the sequential
reaction proceeded smoothly to afford the desired product
5a (Table 1, entry 1). The [3+2] annulation product 6a, how-
ever, was not obtained. We then screened conditions to op-
timize the reaction (Table 1). We first tested various precat-
alysts (Table 1, entries 1–4), with precatalyst A showing the
Table 1 Optimization of Reaction Conditionsa
O
OH
OEt
O
OH
cat., base
solvent
CHO
Ph
Ph
Ph
+
+
F3C
Ph
H
CF3
3a
Br
4a
1a
2
O
Ph
O
O
+
F3C
Ph
O
Ph
CF3
O
O
5a
6a
N
N
BF4
BF4
Ph
N
N
N
N
Ph
cat. A
cat. B
S
Br
Cl
Mes
N
N
N
OH
Mes
Bn
cat. C
cat. D
We envisioned a two-step NHC-catalyzed sequential re-
action to synthesize trifluoromethyl-substituted α,β-unsat-
urated ester derivatives (Scheme 2). Synthesis of diverse
CF3-containing compounds is one of the most fascinating
areas of organofluorine chemistry, since the added CF3
groups can significantly improve the chemical, physical,
and biological properties of the parent compounds.17 Our
protocol began with a cross-benzoin condensation between
aromatic aldehyde 1 and CF3CH(OH)OEt (2). The resulting
trifluoromethylated α-hydroxyketone 3 would then partici-
pate as the nucleophile in the next step. Subsequent inter-
molecular esterification with an α,β-unsaturated acylazoli-
um intermediate would generate the final product 5.
Entry
Cat.
Base
Solvent
Time 1
(h)b
Time 2 Yield (%)d
(h)c
1
2
A
B
C
D
A
A
A
A
A
A
A
A
DBU
MeCN
MeCN
MeCN
MeCN
CH2Cl2
DMF
6
12
–
6
6
50
40
n.r.
n.r.
36
n.r.
30
60
n.r.
40
45
65
DBU
3
DBU
–
4
DBU
–
–
5
DBU
24
–
12
–
6
DBU
7
DBU
toluene
THF
12
6
8
8
DBU
6
9
Et3N
THF
–
–
10
11
12e
Cs2CO3
t-BuOK
DBU
THF
6
6
NHC
O
HOMO
OH
O
THF
6
6
OH
CF3
R1
+
R1
H
THF
2
2
cross-
benzoin
F3C
OEt
a Reaction conditions: Base (0.1 mmol) was added to a solution of benzal-
dehyde 1a (0.5 mmol), CF3CH(OH)OEt (2, 1.0 mmol), and precatalyst (0.05
mmol) in solvent (2 mL) at room temperature under argon. After benzalde-
hyde (1a) had been consumed based on TLC monitoring, α-bromocinnam-
ic aldehyde (4a, 0.3 mmol) was added.
1
2
3
NHC
LUMO
O
O
O
R2
R2
H
+
3
R1
b Time for step 1.
esterification
c Time for step 2.
Br
CF3
O
d Yield of the isolated product 5a.
4
5
e Reaction was performed at 60 °C, r.t. = 20–25 °C; n.r. = no reaction; DBU =
1,8-diazabicyclo [5.4.0]undec-7-ene.
Scheme 2 Synthetic strategy
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
Q. Zhao et al.
Letter
Synlett
best activity (Table 1, entry 1). Replacing MeCN with other
solvents substantially changed the yield (Table 1, entries 5–
8), with THF giving the highest yield (Table 1, entry 8). Re-
placing DBU with Et3N, Cs2CO3, or t-BuOK did not improve
yield (Table 1, entries 9–11). Increasing reaction tempera-
ture slightly improved yield (Table 1, entry 12).
Table 2 Substrate Scope under Optimized Conditionsa
CHO
O
R2
R2
O
OH
O
4
Br
cat. A, DBU
R1
+
R1
H
F3C
OEt
CF3
O
THF, 60 °C
1
2
5
With the optimized reaction conditions in hand, we
evaluated the substrate scope and limitations of the one-
pot sequential reaction (Table 2).18,19 We explored cross-
benzoin condensation of CF3CH(OH)OEt (2) with various al-
dehydes 1, followed by addition of α-bromo cinnamalde-
hyde (4a, Table 2, entries 2–11). Most electron-withdraw-
ing-group substitutions generated the desired unsaturated
ester in good yield (Table 2, entries 2–7), which varied in
the trend para > ortho ≈ meta. Using an aromatic aldehyde
carrying an electron-donating group gave the product 5h in
moderate yield (Table 2, entry 8). Heteroaromatic alde-
hydes and cinnamaldehyde also participated in the reaction
(Table 2, entries 9–11), generating the corresponding prod-
ucts 5i–k in slightly lower yield. This lower yield likely re-
flects the inefficient cross-benzoin condensation involving
heteroaromatic aldehydes or cinnamaldehyde. The aliphat-
ic aldehydes, such as 2-phenylacetaldehyde and 3-phenyl-
propanal, were also screened. Unfortunately, complex mix-
tures were obtained in the first cross-benzoin step, suggest-
ing that the one-pot reaction is compatible only with
(hetero)aromatic aldehydes and aromatic enals.
Next we examined various substitutions on the α-bro-
mocinnamic aldehyde in this tandem reaction (Table 2, en-
tries 12–21). Intriguingly, the position of the substitution
barely affected reaction efficiency, whereas the electronic
properties of substituents on the aromatic ring system
markedly affected it. In general, product yield was greater
with electron-poor enals (Table 2, entries 12–19) than with
electron-rich enals (Table 2, entries 20 and 21). The reac-
tion proceeded with 2-bromo-3-furanyl-acrylaldehyde, but
yield of the final product 5v was low (Table 2, entry 22). We
were pleased that even the less reactive α-bromocrotonal-
dehyde participated in the one-pot reaction, giving product
5w in moderate yield (Table 2, entry 23).
Entry
R1
R2
Time 1 + Time 2 Product Yield
(h)b
(%)c
1
2
Ph
Ph
2 + 2
5a
5b
5c
5d
5e
5f
65
74
80
73
82
70
76
58
50
53
55
67
70
73
66
71
72
75
63
60
54
38
51
3-ClC6H4
4-ClC6H4
3-BrC6H4
4-BrC6H4
2-FC6H4
4-FC6H4
Ph
2 + 2
2 + 2
2 + 2
2 + 2
4 + 2
4 + 2
4 + 2
8 + 2
8 + 2
4 + 2
2 + 1
2 + 1
2 + 1
2 + 1
2 + 1
2 + 1
2 + 1
2 + 1
2 + 4
2 + 4
2 + 8
2 + 4
3
Ph
4
Ph
5
Ph
6
Ph
7
Ph
5g
5h
5i
8
4-i-PrC6H4
Ph
9
2-furyl
2-thienyl
cinnamyl
Ph
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Ph
5j
Ph
5k
5l
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-FC6H4
3-FC6H4
3-BrC6H4
4-BrC6H4
4-O2NC6H4
4-MeC6H4
4-MeOC6H4
2-furyl
Me
Ph
5m
5n
5o
5p
5q
5r
Ph
Ph
Ph
Ph
Ph
Ph
5s
5t
Ph
Ph
5u
5v
5w
Ph
Ph
a Reaction conditions: Base (0.1 mmol) was added to a solution of aromatic
aldehyde 1 (0.5 mmol), CF3CH(OH)OEt (2, 1.0 mmol), and precatalyst A
(0.05 mmol) in THF (2 mL) at 60 °C under argon. After aldehyde 1 had been
consumed based on TLC monitoring, α-bromoenal 4 (0.3 mmol) was add-
ed.
b Time for step 1 and 2.
c Yield of the isolated product 5.
We propose a mechanism for this multicomponent one-
pot sequential reaction (Scheme 3). NHC-mediated HOMO
activation leads to transformation of the aromatic aldehyde
1 into the nucleophilic intermediate M1. Cross-benzoin
condensation between M1 and CF3CH(OH)OEt (2) generates
trifluoromethylated acyloin 3. Next, NHC-mediated LUMO
activation initiates intermolecular esterification of the elec-
trophilic α,β-unsaturated acylazolium intermediate M2
with nucleophilic α-hydroxyketone 3, affording the final
product 5. The same catalyst drives both the HOMO and
LUMO cycles.
building blocks. Treating 5a with thiourea in DMF at 150 °C
for 16 hours generated a high yield of the corresponding
multifunctionalized oxazole 7 bearing phenyl, trifluoro-
methyl, and styryl groups (Scheme 4).20
In conclusion, we have developed an NHC-catalyzed
multicomponent sequential reaction involving a cross-ben-
zoin–esterification relay to assemble aromatic aldehydes,
trifluoroacetaldehyde ethyl hemiacetal, and α-bromoenals
into synthetically important CF3-containing α,β-unsaturat-
ed esters in moderate to high yields of up to 82%. This pro-
cess combines, into a one-pot operation, sequential NHC-
mediated HOMO and LUMO activation leading to the pro-
To illustrate the synthetic utility of this one-pot reac-
tion, we showed that the CF3-containing unsaturated ester
5a is easily converted into other medicinally interesting
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
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Letter
Synlett
O
CHO
R2
R1
H
Br
1
4
Ph
N
HO
N
R1
N
N
N
NHC-HOMO
activation
NHC-LUMO
activation
N
N
Ph
R2
Ph
N
N
HO
M1
N
N
O
N
OH
OH
Ph
R2
O
CF3
F3C
OEt
R1
3
2
M2
R2
O
O
R1
CF3
O
5
Scheme 3 Proposed reaction mechanism
duction of C–C and C–O bonds. The α,β-unsaturated esters
produced using this approach are readily converted into bi-
ologically interesting oxazole scaffolds bearing multiple
functional groups. Further study of multicomponent one-
pot reactions involving consecutive NHC catalysis is under
way in our laboratory.
References and Notes
(1) These authors contributed equally.
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S
O
Ph
Ph
N
H2N
NH2
O
Ph
Ph
DMF, 150 °C
O
F3C
CF3
O
5a
7, 72% yield
Scheme 4 Synthetic transformation downstream of the one-pot reac-
tion
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The reaction was carried out with aromatic aldehyde 1 (0.5
mmol), CF3CH(OH)OEt (2, 1.0 mmol), precatalyst A (0.05 mmol,
13.7 mg), and DBU (0.1 mmol, 15 μL) in THF (2.0 mL) at 60 °C
under argon to afford the acyloin 3, after which α-bromoenal 4
(0.3 mmol) was added in one-pot. The reaction mixture was
stirred at 60 °C for a specified reaction time until the reaction
completed. Then the reaction mixture was concentrated, and
the residue was purified by flash chromatography on silica gel
(PE–EtOAc = 40:1) to give the final product.
(19) Analytical Data for Compound 5a
Obtained as a white solid in 65% yield (65.3 mg) for two steps
after flash chromatography; mp 58–60 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.03–8.01 (m, 2 H), 7.82 (d, J = 16.0 Hz, 2 H), 7.57–
7.51 (m, 4 H), 7.44–7.38 (m, 3 H), 6.57 (d, J = 16.0 Hz, 1 H), 6.45
(q, J = 6.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 188.6,
164.8, 148.2, 134.6, 133.7, 131.2, 129.0, 128.9, 128.5, 121.9 (d,
JCF = 280 Hz), 115.2, 70.9 (q, JCF = 31 Hz) ppm. ESI-HRMS: m/z
calcd for C18H13F3O3 + Na: 357.0714; found: 357.0717.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E