Enantioselective vinylogous aldol/lactonization cascade reaction between β,γ-unsaturated amides and trifluoromethyl ketones: Facile access to chiral trifluoromethyl dihydropyranones

Article abstract of DOI:10.1039/d0ob01746a

An efficient asymmetric vinylogous aldol/lactonization cascade reaction between β,γ-unsaturated amides and trifluoromethyl ketones has been developed. Using a chiral cyclohexanediamine-based tertiary amine-thiourea catalyst, optically active trifluoromethyl dihydropyranones have been constructed in moderate-to-excellent yields (up to 99%) with excellent stereoselectivities (96-> 99.5% ee). This journal is

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Enantioselective vinylogous aldol/lactonization cascade reaction
between β,γ‐unsaturated amides and trifluoromethyl ketones:
facile access to chiral trifluoromethyl dihydropyranones
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Jun‐Hao Fu, Zhen‐Guo Zhang, Xue‐Ying Zhou, Chun‐Wei Fu, Feng Sha, Xin‐Yan Wu*
An efficient asymmetric vinylogous aldol/lactonization cascade
reaction between β,γ‐unsaturated amides and trifluoromethyl
ketones has been developed. Using chiral cyclohexanediamine‐
based tertiary amine‐thiourea catalyst, optically active
trifluoromethyl dihydropyranones have been constructed in
moderate‐to‐excellent yields (up to 99%) and excellent
stereoselectivities (96‐>99.5% ee).
Fluorinated compounds are ubiquitous in pharmaceuticals and
agrochemicals.1 In particular, trifluoromethyl‐containing
compounds are important because the CF3 group can improve
the metabolic stability, lipophilicity and selectivity of bioactive
molecules.2 Therefore, the development of efficient and flexible
methods to construct trifluoromethyl‐substituted compounds
has received much attention from academia.3,4 Among these
Figure 1. Examples of bioactive structures containing CF3 group
b
co‐workers7 developed another approach to afford these
products via an enantioselective formal oxa‐Diels‐Alder
reaction
between
α
,
β‐unsaturated
aldehydes
and
trifluoromethyl ketones. Subsequently, cascade reactions
between cyclic nucleophiles and trifluoromethyl ketones were
compounds,
increasingly popular as chiral building blocks for
pharmaceuticals and drug candidates (Figure
).5 Asymmetric
additions to trifluoromethyl aldehydes and ketones are
straightforward and convenient approaches to obtain chiral
α‐trifluoromethyl alcohols have proven to be
c
e
f
reported by Chi’s,7 Connon’s7 and Bencivenni’s group.7 In
1
addition, direct AVA reaction of trifluoromethyl ketones has
been developed by Jiang, Bencivenni and Han.7
d,g,h
α
‐
trifluoromethyl alcohols and their derivatives.5 With the success
in asymmetric vinylogous aldol (AVA) reaction,6 trifluoromethyl
ketones as electrophiles have been explored in AVA reactions
to produce a variety of products with CF3 group. However, the
Due to their relatively low reactivity comparing to
aldehydes, ketones and acyl chlorides, the enantioselective
vinylogous aldol reactions between acyclic unsaturated amides
‐
11
and trifluoromethyl ketones has been much less developed.9
With our continuing interest in the AVA‐based tandem
reaction,9a‐c herein, we report an asymmetric vinylogous aldol/
lactonization cascade reaction of β,γ‐unsaturated amides and
use of
such as
aldehydes, alkylidene oxindoles and
γ‐nucleophiles are limited to highly reactive compounds
α
,
β‐unsaturated acyl chlorides,
α
,
β‐unsaturated
α
,
β
‐ or
β
,
γ
‐unsaturated
a
ketones (Figure 2).7 In 2011, Ye and co‐workers7 reported a
trifluoromethyl ketones to construct chiral
ones bearing CF3 groups.
5
,6
‐dihydropyran‐
2
‐
cascade reaction involving an AVA process between
α,β‐
Our study began with the model reaction between β,γ
‐
unsaturated acyl chlorides and trifluoromethyl ketones,
producing trifluoromethyl‐containing 5,6‐dihydropyran‐2‐ones,
which are building blocks of bioactive compounds.8 Chi and
unsaturated amide 1a and trifluoromethyl acetophenone 2a.
The reaction was carried out in toluene at 25 oC with 10 mol%
R2
O
Me
O
CHO
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of
Chemistry & Molecular Engineering, East China University of Science and
Technology, Shanghai 200237, P, R, China. E‐mail: xinyanwu@ecust.edu.cn; Tel:
+86 21 64252011
Me
H
O
Me
Cl
R1
R
Me
X
N
R
O
R
O
R
O
(X = N, O, S)
Chi and Song, 2013
Boc
Bencivenni, 2018
Ye, 2011
Connon, 2016
Chi, 2012
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Figure
2. Nucleophiles using for asymmetric vinylogous aldol/lactonization
cascade reactions of trifluoromethyl ketones in literatures
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Table 2. Optimization of reaction conditions a
of chiral bifunctional organocatalyst (Table 1). It was observed
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DOI: 10.1039/D0OB01746A
that
corresponding
tertiary amine catalysts used. As described previously,9a,9b α
β
,
γ
‐unsaturated amide
1a was easily transformed to the
O
O
α
,
β‐unsaturated amide in the presence of the
O
10 mol%
C4
O
+
Ph
N
,
β‐
Solvent, 2 d
CF3
Ph
Ph
CF3
N
Ph
unsaturated amides are unreactive under the vinylogous aldol
condition. To improve the chemical yield, we sought to
decrease the reaction temperature in order to prevent the
1a
2a
3aa
Entry
1
Solvent
Additive
Temp. (oC)
Yield (%)b
44
Ee (%)c
99
ndd
nd
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
generation of
carried out with
obtained with an improved yield and retained enantioselectivity
(entry vs entry 10, entry vs entry 11).
A survey of solvents indicated that CH2Cl2 and EtOAc were
α
,
β
C
‐unsaturated amide. When the reaction was
Toluene
CH2Cl2
EtOAc
p‐xylene
o‐xylene
m‐xylene
mesitylene
tBuPh
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
0
0
4
and aa was
C
5
in toluene at 0 oC, product
3
2
trace
trace
56
3
0
4
0
4
5
5
0
52
6
0
57
not suitable for this cascade reaction, and the
amide isomerized to the corresponding
amide completely (Table , entries and
β
,
β
γ
‐unsaturated
‐unsaturated
7
0
52
1
a
α
,
8
0
64
2
2
3
). Therefore, we
9
EtPh
iPrPh
0
44
turned our attention to aromatic solvents. Although
isomerization still existed, a moderate conversion rate of the
raw material to final product was observed. Among the toluene
homologues screened, tert‐butylbenzene provided the highest
chemical yield, and a 99% ee was achieved for all the aromatic
10
11
12
13
14
15
16
17
18
19e
20f
21g
22h
23i
0
51
CF3Ph
0
36
tBuPh
-15
-30
-15
-15
-15
-15
-15
-15
-15
-15
-15
-15
65
tBuPh
60
tBuPh
10 mg 4Å MS
20 mg 4Å MS
30 mg 4Å MS
20 mg 3Å MS
20 mg 5Å MS
20 mg 4Å MS
20 mg 4Å MS
20 mg 4Å MS
20 mg 4Å MS
20 mg 4Å MS
83
tBuPh
90
solvents used (Entries 4‐11).
tBuPh
88
Table
1. Screening of the chiral organocatalysts for the vinylogous
tBuPh
85
aldol/cyclization cascade reaction a
tBuPh
88
tBuPh
80
tBuPh
65
tBuPh
67
tBuPh
40
tBuPh
72
aUnless stated otherwise, the reactions were performed with 0.3 mmol β,γ‐
unsaturated amide 1a, 0.2 mmol trifluoromethyl acetophenone 2a and catalyst C4
c
in 1 mL solvent, the reaction time was 2 days. bIsolated yields. Determined by
HPLC analysis using chiral stationary phase. dNot determined. eThe amount of t‐
BuPh was 0.67 mL (0.3 M). fThe amount of t‐BuPh was 2 mL (0.1 M). gThe catalyst
loading was 5 mol%. hThe catalyst loading was 2 mol%. i0.2 mmol H2O was added.
Next, the substrate concentration, reaction temperature,
catalyst loading and additive concentration were optimized to
further improve the chemical yield of the cascade reaction
(Table 2, entries 12‐23). When the temperature was lowered
from
entry
0
8
oC to ‐15 oC, similar results were obtained (entry 12 vs
). However, a decreased yield was obtained at ‐30 oC
(entry 13). To our delight, the chemical yield could be
remarkably improved to 90% with 99% ee in the presence of 4Å
molecular sieves (entry 15). The concentration of substrate
2a
influenced the reaction. When the concentration of was
2
a
changed from 0.2 M to 0.1 M or 0.3 M, the yield substantially
decreased (entries 19 and 20 vs entry 15). The reduction of the
catalyst loading led to a decrease of yield (entries 21 and 22 vs
entry 15). The results suggest that the catalyst loading has a
significant impact on the reaction rate of the vinylogous
aldol/lactonization cascade reaction. To test the role of 4Å
aUnless stated otherwise, the reactions were performed with 0.3 mmol β,γ‐
unsaturated amide 1a, 0.2 mmol trifluoromethyl acetophenone 2a and 0.02 mmol
of the organocatalyst in 1 mL toluene at 25 oC. The yields refer to isolated yields,
and the ee values were determined by HPLC analysis using chiral stationary phase.
bThe reaction was performed at 0 oC.
molecular sieves in the cascade reaction, 1 equivalent of water
was added to the reaction system. As a result, the yield
decreased dramatically probably due to the water absorption of
4Å molecular sieves, thereby lowering their catalytic activity.
The optimal result was achieved by using 10 mol% tertiary
amine‐thiourea C4 as chiral catalyst, tert‐butylbenzene as
2 | J. Name., 2012, 00, 1‐3
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Table
3
.
Substrate scope of the enantioselective vinylogous
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DOI: 10.1039/D0OB01746A
aldol/lactonization cascade reactiona
Entry
R1
R2
Time (d)
Yield (%)b
Ee (%)c
1
2
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4‐FC6H4
4‐ClC6H4
3‐ClC6H4
2‐ClC6H4
4‐BrC6H4
4‐MeC6H4
(E)‐C6H5CH=CH
Et
2
3
2
2
3
2
3
2
4
3
2
3
3
3
3
3
3
7
90 (3aa)
82 (3ab)
99 (3ac)
99 (3ad)
28 (3ae)
95 (3af)
60 (3ag)
88 (3ah)
22 (3ai)
61 (3ba)
84 (3ca)
80 (3da)
79 (3ea)
92 (3fa)
99 (3ga)
83 (3ha)
51 (3ia)
57 (3ja)
99
>99.5
99
3
4
98
5
>99.5
99
6
7
>99.5
99
8
9
99
10
11
12
13
14
15
16
17
18d
4‐MeC6H4
4‐FC6H4
3‐ClC6H4
4‐ClC6H4
4‐CF3C6H4
3,4‐Cl2C6H3
2‐thienyl
1‐naphthyl
nBu
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
99
>99.5
99
Scheme 1. Proposed reaction pathway
>99.5
>99.5
>99.5
>99.5
96
amide is less reactive, and a 20 mol% catalyst was required to
proceed the reaction under the optimal reaction condition
(entry 18). Allylic amide provided vinylogous aldol adduct in 57
%
C6H5
99
yield and 73% ee, while and γ‐phenyl β,γ‐unsaturated amide
was unreactive under the typical reaction conditions.
To determine the absolute configuration, we compared
aUnless stated otherwise, the reactions were performed with 0.3 mmol β,γ‐
unsaturated amides 1, 0.2 mmol trifluoromethyl ketones 2 and 0.02 mmol chiral
catalyst C4 in 1 mL t‐BuPh at ‐15 oC. bIsolated yields. cDetermined by HPLC analysis
using chiral stationary phase. dThe loading of catalyst C4 was 20 mol%.
the HPLC trace and optical rotation value of product
3
aa with
those of the R‐product described in Chi's report.7 As a result,
we determined the absolute configuration to be S. The absolute
configuration of other products was assigned by analogy.
According to our experimental results and the related
literatures,7f,9a,9b,12 a possible mechanism for this cascade
b
solvent, and 4Å molecular sieves as an additive (20 mg for 0.2
mmol scale) at ‐15 oC.
Having established the optimal protocol for the reaction,
the substrate scope of the cascade reaction was examined
reaction is illustrated in Scheme 1. Initially, reaction partners
and are synergistically activated by the bifunctional catalyst
C4 to form the hydrogen bonding species , which then
undergoes vinylogous aldol reaction through Re face attack of
dienolates to trifluoromethyl ketone to form S‐configurated
1
(Table
ketones used, providing excellent enantioselectivities (98‐>99.5
ee, entries ). The acetophenones bearing electron‐
withdrawing groups gave a better yield than those with
electron‐rich substituents (entries and vs entry ).
However, ‐chloro substituted trifluoromethyl acetophenone
produced a low yield (28%), probably due to a steric effect
(entry ). The cinnamenyl analogue also provided high yield and
excellent enantioselectivity (entry ). However, the
trifluoromethyl alkyl ketones were low reactive. Only 22% yield
was obtained for ‐trifluorobutan‐ ‐one (entry ), while
‐trifluoropropan‐ ‐one was unreactive under the typical
reaction conditions.
Next, the substrate scope of
investigated (entries 10 18). Both electron‐withdrawing and
electron‐donating substituents on β‐phenyl afforded the
corresponding products in 99% or >99.5% ee. The electron‐
deficient substrates provided good‐to‐excellent yields (79 99%)
than those with electron‐rich substituents (entries 11 15 vs
3). The reaction tolerated all of the trifluoromethyl
2
%
A
1‐9
2
‐
4
6
7
intermediate
the desired product
reaction of intermediate
amide , which could not act as a prenucleophile to perform the
B
. Finally, the lactonization of intermediate
and regenerate catalyst C4. The side
is the formation of α,β‐unsaturated
B give
2
3
2
e
A
5
D
8
vinylogous reaction.
1
,
1
,
1
2
9
1
,
1
,
1
2
Conclusions
In conclusion, we have developed a highly enantioselective
β,γ‐unsaturated amides was
vinylogous aldol/lactonization cascade reaction between
unsaturated amides and trifluoromethyl ketones. In the
presence of 10 mol% tertiary amine‐thiourea , the cascade
reaction was achieved in excellent enantioselectivities
96‐>99.5% ee) with up to 99% yield. This approach might prove
β,γ‐
‐
C
4
3
‐
‐
(
useful for the construction of biologically active trifluoromethyl
dihydropyranones.
entry 10). Good yield and high enantioselectivity was also
obtained for the heterocyclic substrate (entry 16). However,
allyl pyrazoleamide with a fused‐ring gave a relatively lower
yield (51% with 96% ee, entry 17). The β‐butyl β,γ‐unsaturated
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(e) C. Cornaggia, S. Gundala, F. Manoni, N. Gopalasetty and
Conflicts of interest
There are no conflicts of interest to declare.
View Article Online
S. J. Connon, Org. Biomol. Chem., 2016D,O1I4: ,103.0104309;/(Df0)OS.BC01r7o4t6tiA,
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Chem., 2018, 83, 12440; (g) S. Crotti, G. Belletti, N. Di Iorio, E.
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Acknowledgment
8
9
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annulation reactions using β,γ‐unsaturated amides as γ‐
nucleophiles, see: (a) T.‐Z. Li, Y. Jiang, Y.‐Q. Guan, F. Sha and
X.‐Y. Wu, Chem. Commun., 2014, 50, 10790; (b) Y. Jiang, J.‐H.
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We are grateful for the financial support by the Natural Science
Foundation of Shanghai (19ZR1412300), Shanghai Pujiang
Program (18PJD010) and the Fundamental Research Funds for
the Central Universities (222201814019).
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Enantioselective vinylogous aldol/lactonization cascade reaction
between β,γ-unsaturated amides and trifluoromethyl ketones: facile
access to chiral trifluoromethyl dihydropyranones
Jun-Hao Fu, Zhen-Guo Zhang, Xue-Ying Zhou, Chun-Wei Fu, Feng Sha, Xin-Yan Wu*
β,γ-Unsaturated amides have been firstly employed to react with trifluoromethyl ketones, and chiral
ɑ,β-unsaturated δ-lactones bearing trifluoromethyl group have been constructed conveniently.
CF3
S
O
N
N
H
CF3
H
N
O
R1
N
(10 mol%)
N
O
+
4Å MS, tBuPh, -15 o
C
CF3
R2
R1
O
up to 99% yield
96->99.5% ee
R2
CF3