N-Heterocyclic Carbene/Lewis Acid Dual Catalysis for the Divergent Construction of Enantiopure Bridged Lactones and Fused Indenes

Article abstract of DOI:10.1021/acs.joc.6b02329

The chiral triazole carbene and Ti(OPr-i)₄ cocatalyzed reaction between α,β-unsaturated aldehydes and 2-(aroylvinyl)benzaldehydes was systematically studied. A divergence in reaction pathways was observed under different reaction conditions. In benzene solvent and at ambient temperature, the reaction produced 4,5-dihydro-1,4-methanobenzo[c]oxepin-3-ones, the bridged caprolactones, as the major products in moderate yields with excellent enantioselectivity. The same reaction in dichloroethane and at 50 °C, however, gave 2,8-dihydrocyclopenta[a]indenes as the major products in most cases. The application of the method developed was demonstrated by the transformation of the bridged lactone products into enantiopure 4-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acids.

Full text of DOI:10.1021/acs.joc.6b02329

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Article
An N-Heterocyclic Carbene/Lewis Acid Dual Catalysis for the Divergent
Construction of Enantiopure Bridged Lactones and Fused Indenes
Zhan-Yong Wang, Ya-Li Ding, Shi-Ning Li, and Ying Cheng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02329 • Publication Date (Web): 04 Nov 2016
Downloaded from http://pubs.acs.org on November 4, 2016
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An N-Heterocyclic Carbene/Lewis Acid Dual Catalysis for the
Divergent Construction of Enantiopure Bridged Lactones and
Fused Indenes
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Zhan-Yong Wang, Ya-Li Ding, Shi-Ning Li and Ying Cheng*
College of Chemistry, Beijing Normal University, Beijing 100875, China
E-mail: ycheng2@bnu.edu.cn
Abstract:
The chiral triazole carbene and Ti(OPr-i)
4
co-catalyzed reaction between
-unsaturated aldehydes and 2-(aroylvinyl)benzaldehydes was systematically studied.
A divergence in reaction pathways was observed under different reaction conditions. In
benzene solvent and at ambient temperature, the reaction produced
4
,5-dihydro-1,4-methanobenzo[c]oxepin-3-ones, the bridged caprolactones, as the major
products in moderate yields with excellent enantioselectivity. The same reaction in
o
dichloroethane and at 50 C, however, gave 2,8-dihydrocyclopenta[a]indenes as the
major products in most cases. The application of the method developed was demonstrated
by the transformation of the bridged lactone products into enantiopure
4
-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acids.
Introduction
The development of new strategies for the stereoselective construction of
multifunctional cyclic systems has been attracting increasing interest from organic
chemists. In the past decades, the N-heterocyclic carbene catalysis has been developed
into a powerful protocol for the synthesis of a wide range of carbocyclic and heterocyclic
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compounds.1,2 Recently, the combination of NHC and acid catalysis emerges as a
3
powerful strategy to expand the capabilities of NHC catalysis. The cooperative catalysis
of N-heterocyclic carbenes and acids is able to enhance the reactivity of substrates
including those even previously inactive reaction partners, and to improve
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enantioselectivity or/and diastereoselectivity 4
.
,5
Under the cooperative catalysis of
chiral NHC and Lewis or Brønsted acid catalysts, various ,-unsaturated aldehydes
undergo diverse reactions to afford five- and six-membered carbocyclic and heterocyclic
compounds in enantioselective fashion.4, 5 For example, the chiral triazole carbene and
Ti(OPr-i)
4
co-catalyzed dimerization of -unsaturated aldehydes and the
reactions between-unsaturated aldehydes and-unsaturated ketones permit
efficient synthesis of substituted cyclopentanes or cyclopentenes with excellent
enantioselectivity.4a,4b On the other hand, under the dual catalysis of chiral triazole
carbene and LiCl or chiral phosphoric acid, the alkenyl aldehydes or alkynyl
aldehydes underwent formal [3+2] cycloaddition with the C=O bond of -carbonyl
ketones
including
-ketoesters
and
in
isatins
good yields
to
produce
with high
-butyrolactonesor-lactone-spiro-oxindoles
stereoselectivities.4 Similarly, the [3+2] cycloaddition of -unsaturated aldehydes
to the C=N bond of -unsaturated imines or hydrazones catalyzed by the chiral
triazole carbene and Lewis or Brønsted acid has been reported to generate
c,5a
4
f, 5b
enantiopure-butyrolactam derivatives.
-bromoenals with isatins catalyzed by chiral NHC/Lewis acid and the reaction of enals
with trifluoromethyl ketones catalyzed by a combination of NHC, Lewis acid and
oxidant underwent [4+2] cycloadditions, leading to the formation of
-lactone-spiro-oxindolesor-lactone derivatives.4e, 4gAlthough many NHC-catalyzed
Furthermore, both the reaction of

-

reactions have been employed successfully in the synthesis of mono-, fused- and
spiro-heterocycles or carbocycles, to the best of our knowledge, the construction of
bridged cyclic compounds by NHC catalysis is very rare.6
We have been interested for many years in the development of new NHC-catalyzed
reactions for the divergent synthesis of complex molecules based on the same starting
7
materials. We were delighted to discover very recently that the NHC catalysts
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combined with Lewis acid are capable regulating reaction pathways under varied
conditions, transforming therefore the same reactants into diverse products.8 For
instance, while the triazole carbene-catalyzed dimerization of 2-formylcinnamates
underwent benzoin condensation followed by intramolecular oxa-Michael addition to
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afford isochromeno[4,3-c]isochromene products, the triazole carbene and Ti(OPr-i)
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co-catalyzed dimerization of 2-formylcinnamates proceeded through a completely
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a
different route to furnish the formation of isochromenone derivatives. On the other hand,
while chiral triazole carbenes catalyzed an intramolecular cyclization reaction of
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2
-aroylvinylcinnamaldehydes, a combination of chiral triazole carbene and Ti(OPr-i)
4
catalyzed the intermolecular dimerization under the same reaction conditions.8b To
generalize the concept and strategy of the cooperative NHC/Lewis acid catalyzed
divergent synthesis, we undertook the current study of the reaction between

-unsaturated aldehydes and 2-(aroylvinyl)benzaldehydes, the formyl-bearing
-unsaturated ketones. Conceivably, various reactions would take place between these

functionalized reactants. Herein we reported chiral triazole carbene/Ti(OPr-i)
4
co-catalyzed two distinct reactions, yielding 1,4-methanobenzo[c]oxepin-3-one and
2,8-dihydrocyclopenta[a]indene derivatives.
Results and Discussion
We commenced our study by investigating the reaction between cinnamaldehyde 1a
and 2-(benzoylvinyl)benzaldehyde 2a. In dry dichloromethane and at ambient
o
temperature (about 20-25 C), no reaction between 1a and 2a took place in the presence of
a chiral triazolium precatalyst 3a (10 mol%) and DBU (20 mol%). Addition of one
equivalent of Ti(OPr-i)
4
as a co-catalyst, however, led to the formation of a bridged
namely
caprolactone,
5
1
-(benzoylmethyl)-10-phenyl-4,5-dihydro-1,4-methanobenzo[c]oxepin-3-one 4a, and
,3-diphenyl-2,8-dihydrocyclopenta[a]indene 5a in 21% and 8% yield, respectively
(Table 1, entries 1 and 2). To improve the synthetic efficiency, other chiral carbenes were
tested. Unfortunately, in the presence of Ti(OPr-i) , the variation of a serial of chiral
4
triazoliumsalts 3b-3f as NHC precatalysts did not result in the high yields of products 4
and 5 (Table 1, entries 3-7). On the other hand, however, the addition of one equivalent
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of isopropanol as an additive in the 3a/Ti(OPr-i)
4
-catalyzed reaction slightly increased
the yields of 4a and 5a to 29% and 13%, respectively (Table 1, entry 8). To further
promote the reaction of 1a with 2a, the reaction temperature was then elevated to the
boiling point of dichloromethane. Pleasingly, the formation of the bridged lactone 4a in
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1% yield with 96% ee, along with the formation of 38% yield of fused indene 5a (4a:5a
1:1) was observed (Table 1, entry 9). In refluxing DCM, the increase of the loading of
i-PrOH to 200 mol% or of DBU to 50 mol% did not benefit to the formation of either 4a
or 5a (Table 1, entries 10 and 11). The use of other Lewis acids, such as Mg(OBu-t)
Mg(OTf) , Sc(OTf) and LiCl, did not facilitate the reaction. The replacement of DBU by
other bases including AcONa, K CO , Cs CO , NaH, t-BuOK and DMAP all led to
diminished yields of both the major product 4a and the total yields of 4a and 5a (Table 1,
entries 12-17). Therefore, the combination of chiral triazolium salt 3a, DBU, Ti(OPr-i)
~
2
,
2
3
2
3
2
3
4
and i-PrOH was chosen as a cooperative catalytic system for further optimization. The
o
reaction of 1a with 2a was then examined in a number of solvents at 50 C. It was found
that the reactions in chloroform, THF, acetone and acetonitrile gave even worse results
than that in dichloromethane (Table 1, entries 18-21). Delightfully, both the chemical
yield of product 4a and the selectivity of 4a over 5a were improved when toluene and
benzene were utilized as solvents. The bridged lactone 4a was isolated in 50% and 57%
yields, along with 18% and 15% yields of 5a, respectively. Moreover, the enantiomeric
excess values of 98% and 99% were obtained for product 4a (Table 1, entries 22 and
23). Interestingly, the reaction in 1,2-dichloroethane reversed the selectivity between 4a
o
and 5a, affording 4a and 5a in 33% and 41% yields at 50 C (Table 1, entry 24).To
further improve the chemical yield and the selectivity, other reaction parameters were
further optimized in benzene and 1,2-dichloroethane, respectively. In benzene solvent,
o
while an elevating reaction temperature as 80 C marginally affected the formation of
both 4a and 5a, the reaction at ambient temperature was found to significantly increase
the selectivity, leading to the formation of 4a in 60% (>99% ee) and 5a only in 5% yields,
respectively (Table 1, entries 25 and 26). The increase of the loading of carbene
precatalyst 3a to 20 mol% or Ti(OPr-i) to 150 mol% in benzene has a negligible effect to
4
the production of 4a (55%-57%), but led to a slightly increased yield of 5a (12%-18%)
o
(Table 1, entries 27 and 28). In the case of reaction in 1,2-dichloroethane and at 50 C,
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the reaction catalyzed by 10 mol% of carbene and 150 mol% of Ti(OPr-i) produced 50%
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yield of 5a and 33% yield of 4a (99% ee) (Table 1, entry 29). When the carbene catalyst
3a was loaded to 20 mol% or Ti(OPr-i) to 200 mol%, or the reaction temperature was
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increased to the boiling point of 1,2-dichloroethane, no dramatic effect was observed in
terms of efficiency and selectivity (Table 1, entries 30-32). In order to synthesize
selectively the 2,8-dihydrocyclopenta[a]indene 5a, some achiral triazolium, imidazolium,
imidazolinium and thiazolium salts were also employed as the carbene precatalysts.
Disappointingly, none of them acted as an efficient promoter for the reaction between 1a
and 2a.
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Table 1. Optimization of reaction conditions.
Entry
3
Base
mol%)
LA (mol%) Additive
(mol%)
Sol.
Temp.
( C)
T.
(h)
Yield
ee of
Yield
o
(
of 4a 4a
of 5a
(
mol%)
b
a
(
%)a
(%)
(%)
1
2
3
4
5
3a
10%)
3a
(10%)
3b
10%)
3c
10%)
3d
10%)
3e
10%)
3f
(10%)
3a
10%)
3a
10%)
3a
DBU
no
no
no
no
no
no
DCM
DCM
DCM
DCM
DCM
rt
rt
rt
rt
rt
48
48
48
48
48
–
–
>99
99
–
(
(20%)
DBU
(20%)
DBU
(20%)
DBU
(20%)
DBU
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
4
4
4
4
21
13
8
10
trace
8
(
(
trace
11
–
–91
(20%)
(
(
6
7
8
9
DBU
(20%)
DBU
(20%)
DBU
(20%)
DBU
(20%)
DBU
(20%)
DBU
(50%)
NaOAc
(20%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
4
4
4
4
4
4
4
4
no
no
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
rt
48
48
48
12
12
12
24
24
trace
trace
29
–
–
trace
trace
13
rt
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(200%)
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(100%)
rt
97
96
87
98
97
ND
(
(
(
(
reflux
reflux
reflux
reflux
reflux
41
38
1
0
1
37
33
10%)
3a
10%)
3a
(10%)
1
32
22
12
30
3
1
3
3a
10%)
K
2
CO
3
10
trace
(
(20%)
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5
5
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5
5
5
5
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1
4
3a
(10%)
3a
(10%)
3a
NaH
(20%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
Ti(OPr-i)
(100%)
4
4
4
4
4
4
4
4
4
4
4
4
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(100%)
i-PrOH
(100%)
DCM
DCM
DCM
DCM
reflux
reflux
reflux
reflux
50
24
24
24
48
24
12
12
12
12
12
12
12
12
12
12
12
12
12
12
23
mess
14
90
–
15
mess
4
15
Cs
2
CO
3
(20%)
i-BuOK
(20%)
DMAP
(20%)
DBU
(20%)
DBU
(20%)
DBU
(20%)
DBU
(20%)
DBU
(20%)
DBU
(20%)
DBU
(20%)
DBU
(20%)
DBU
(20%)
DBU
(20%)
DBU
(20%)
DBU
(20%)
DBU
(20%)
DBU
(20%)
DBU
1
1
1
6
7
8
98
ND
99
98
82
–
(
(
(
10%)
3a
10%)
3a
10%)
3a
5
20
12
5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CHCl
3
29
19
20
THF
50
12
(10%)
3a
CH
3
CN
50
22
9
(
(
(
10%)
3a
10%)
3a
10%)
2
2
2
1
2
3
acetone
toluene
benzene
DCE
50
trace
50
trace
18
15
41
18
5
50
98
99
99
98
99
3a
(10%)
3a
50
57
24
50
33
(10%)
2
2
2
5
6
7
3a
benzene
benzene
benzene
benzene
DCE
reflux
rt
56
(
10%)
3a
4
60
(10%)
3a
4
rt
57
12
16
50
48
52
44
(20%)
28
3a
(10%)
3a
Ti(OPr-i)
(150%)
Ti(OPr-i)
(150%)
Ti(OPr-i)
(200%)
Ti(OPr-i)
(150%)
Ti(OPr-i)
4
rt
55
2
3
3
3
9
0
1
2
4
50
33
99
99
99
99
(10%)
3a
4
DCE
50
34
(10%)
3a
4
DCE
50
30
(20%)
3a
(20%)
4
DCE
reflux
34
(20%)
(150%)
aIsolated yields. Determined by HPLC analysis on a AD-H column.
b
Under the optimized conditions for the selective formation of the bridged lactone 4a,
the substrate scopes were surveyed by employing different substituted cinnamaldehydes 1
and 2-(aroylvinyl)benzaldehydes 2.The catalytic reaction was found to tolerate both
electron-donating and electron-withdrawing groups of both reactants. The electronic
nature and substitution pattern of substituents influenced, however, the reactivity and
selective formation of two products. For example, under the catalysis of a combination of
chiral triazoliumsalt 3a (10 mol%), DBU (20 mol%),Ti(OPr-i) (100 mol%) and i-PrOH
4
o
(100 mol%) in benzene at room temperature (about 20-25 C), the presence of an
electron-withdrawn group (p-Br, p-Cl, m-Cl, o-Cl, or p-Ac) on the phenyl ring of
cinnamaldehydes was beneficial to the reactions of 1b-1f with 2a, furnishing the
formation of the corresponding lactones 4b-4f in 53%-62% yields with 99%− >99% ee.
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The by-products 5b-5f were found in very low yields (4%-10%) (Table 2, entries 1-6). In
contrast, when the cinnamaldehyde 1g or 1h was substituted by an electron-donating
p-methyl or p-methoxy group, the reaction with 2a became less efficient and led to the
lower yield of product 4g (49%) or 4h (28%), although enantioselectivity remained
excellent (Table 2, entries 7 and 8). An improved yield was achieved for 4h (43%
yield, >99% ee) by increasing the loading of catalyst 3a to 20 mol% and reaction
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
temperature to 50 C, albeit the yield of by-product 5h was also increased (Table 2, entry
8). The move of the methoxy group from para- to ortho-position of cinnamaldehyde
resulted in the formation of product 4i in a higher yield (47%) than that of 4h under the
same conditions (Table 2, entries 8 and 9). The substituent effect of
2
-(aroylvinyl)benzaldehydes 2 on the reaction summarized in Table 2 indicated a
favorable effect of an electron-donating group. This has been examplified by the
reactions of 2-(benzoylvinyl)-5-methyl- (2c) and
-(benzoylvinyl)-5-methoxybenzaldehyde 2d, which reacted efficiently with
cinnamaldehyde 1a to give products 4k and 4l in 64% and 70% yields (99%->99% ee)
Table 2, entries 11 and 12). The reaction of 2-(benzoylvinyl)-5-fluorobenzaldehyde 2b
with 1a only produced 41% yield of 4j (Table 2, entry 10). Similarly, the
2
(
2
2
-(benzoylvinyl)-4-methylbenzaldehyde
2f
and
-(benzoylvinyl)-4-methoxybenzaldehyde 2g gave much better yields of the
corresponding products 4 than the 2-(benzoylvinyl)-4-fluorobenzaldehyde 2e in the
reaction
with
1a
(Table
2,
entries
13-15).
In
comparison
to
2
2
2
-((p-bromobenzoyl)vinyl)benzaldehyde 2h that only formed 48% yield of product 4p,
-((p-methylbenzoyl)vinyl)benzaldehyde
2i
and
-((p-methoxybenzoyl)vinyl)benzaldehyde 2j also afforded higher yields of products 4q
(69%) and 4r (78%) in the reaction with cinnamaldehyde 1a (Table 2, entries 16-18). It
was worth noting that, although the substituents of both substrates influenced the
reactivity of reaction and the selectivity between product 4 and 5, the stereoselectivity
was not affected, as all products 4 being isolated as a sole diastereomer with 99%− >99%
ee. In addition, the unconsumed cinnamaldehydes 1 that were excess to substrates 2 and
the minor dimeric products of reactants 2 were also detected in the reactions.
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 2. The chiral NHC/Ti(OPr-i)
4
-catalyzed reaction of -unsaturated aldehydes 1 with
2-(aroylvinyl)benzaldehydes 2 in benzene at ambient temperature.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
entry
1
R1
2
R2
R3
R4
Time
h)
yield of
4 (%)
ee of 4
(%)
yield of
5 (%)
a
b
a
(
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
H
4-Br
4-Cl
2-Cl
3-Cl
4-Ac
4-Me
4-OMe
2a
2a
2a
2a
2a
2a
2a
2a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
12
12
12
12
12
12
12
12
4a: 60
4b: 53
4c: 55
4d: 62
4e: 58
4f: 60
4g: 49
4h: 28/
99
99
99
>99
>99
>99
>99
>99
5a: 5
5b: 10
5c: 8
5d: 7
5e: 4
5f: 10
5g: 15
5h: 11/
1g
1h
c
c,d
c
c,d
34 /43
19 /22
9
1i
2-OMe
2a
2b
2c
2d
2e
H
F
H
H
H
H
F
H
H
H
H
H
12
12
12
12
24
4i: 47
4j: 41
4k: 64
4l: 70
99
>99
99
>99
99
5i: 14
trace
5k: 6
5l: 8
5m:
1
1
0
1
1a
1a
1a
1a
H
H
H
H
Me
OMe
H
1
1
2
3
4m:
2/25
c
c
2
29/30
5n:
22/26
5o:
1
4
1a
1a
H
H
2f
H
H
Me
H
H
24
24
4n:
45/52
>99
>99
c
c
15
2g
OMe
4o:
1/61
c
c
5
24/28
1
1
1
6
7
8
1a
1a
1a
H
H
H
2h
2i
2j
H
H
H
H
H
H
Br
Me
OMe
12
12
12
4p: 48
4q: 69
4r: 78
>99
>99
>99
5p: 6
5q: 9
5r: 8
a
b
Isolated yields. Determined by HPLC analysis on a AD-H or AS-H column.The details of HPLC
separation conditions for each product 4 have been listed in Supporting Information.
0 mol% of catalyst 3a was used.
The reaction was carried out at 50 C.
c
2
d
o
In order to synthesize the cyclopenta[a]indene products 5, the reactions between enals
o
1
and 2-(aroylvinyl)benzaldehydes 2 were then carried out in 1,2-dichloroethane at 50 C
under the catalysis of a combination of 3a (10 mol%), DBU (20 mol%), Ti(OPr-i) (150
4
mol%) and i-PrOH (100 mol%). Since cyclopenta[a]indane derivatives 5 are achiral
compounds, the racemic catalyst 3a was used in these reactions. It was found that, while
o
reacting in 1,2-dichloroethane at 50 C, the substituents of substrates strongly influenced
the selectivity in the formation of products 4 and 5. Although most of the reactions
examined produced fused indenes 5 as the major products, the selectivity between 5 and
4 appeared in general less satisfactory. Even in a few cases, compounds 4 were isolated
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as the major products. For example, all reactions of 2-(benzoylvinyl)benzaldehyde 2a
with cinnamaldehydes 1 attached by different substituents including H, 4-Br, 4-Cl, 4-Me,
4-OMe and 2-OMe groups produced the corresponding cyclopenta[a]indanes 5 as major
products in 38%-50% yields, along with the bridged cyclic lactones 4 in 11%-33% yields
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
Table 3, entries 1-6). Compounds 5k and 5m-5o were also obtained as the major
products in 40-62% yields from the reaction of cinnamaldehyde 1a with
2-(benzoylvinyl)benzaldehydes 2c and 2e-2g, which contained a 5-Me, 4-F, 4-Me or
4-OMe group (Table 3, entries 8, 10-12). However, the 5-F and 5-OMe substituted
2
-(benzoylvinyl)benzaldehydes 2b and 2d reacted with 1a to give 5 in 15%-26% yields
and 4 in 25%-41% yields (Table 3, entries 7 and 9). When 2-(aroylvinyl)benzaldehydes
h-2j were substituted by different aroyl groups, the electron-deficient 4-bromobenzoyl
group was benifical to the formation of product 5, while the electron-rich
-methylbenzoyl- and 4-methoxybenzoyl groups favored to the formation of 4 (Table 3,
2
4
entries 13-15). Although lots of efforts have been made to improve the yields of fused
indenes 5 by varying the catalytic system, reaction conditions or sequence of mixing
substrates and catalysts, no significant improvement were obtained. Finally, the reactions
of 1a with 2b, 2d, and 2j that produced the corresponding indenes 5 in very low yields
(15-26%) were repeated under the catalysis of a larger amount of catalysts [3a (20 mol%),
DBU (50 mol%), Ti(OPr-i) (200 mol%) and i-PrOH (200 mol%)] in refluxing
4
dichloroethane. Under these conditions, the yields of products 5j, 5l and 5r were slightly
increased to 20-37% (Table 3, entries 7, 9, 15).
Table 3. The NHC/Ti(OPr-
)
i 4
-catalyzed reaction of -unsaturated aldehydes
1
with
o
2
-(aroylvinyl)benzaldehydes 2 in dichloroethane at 50 C.
entry
1
R1
2
R2
R3
R4
Time
h)
yield of
5 (%)
yield of 4
(%)
a
a
(
1
2
3
4
1a
1b
1c
1g
H
2a
2a
2a
2a
H
H
H
H
H
H
H
H
H
H
H
H
12
12
12
12
5a: 50
5b: 38
5c: 42
5g: 48
4a: 33
4b: 18
4c: 15
4g: 22
4-Br
4-Cl
4-Me
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
6
7
8
9
1h
1i
4-OMe
2-OMe
2a
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
H
F
Me
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
12
12
12
12
12
12
12
12
12
12
12
5h: 40
5i: 40
5j: 15/20
5k: 52
5l: 26/37
5m: 40
5n: 62
5o: 62
5p: 43
5q: 36
5r: 19/24
4h:11
4i: 29
b
b
b
b
1a
1a
1a
1a
1a
1a
1a
1a
1a
H
H
H
H
H
H
H
H
H
4j: 25/30
4k: 33
4l: 41/34
4m: 10
4n: 20
4o: 18
4p: 22
4q:43
4r: 59/49
1
0
F
1
1
2
3
4
Me
OMe
H
H
H
1
1
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Br
Me
OMe
b
b
15
2j
H
a
b
Isolated yields. The reaction was carried out under the catalysis of a combination of 3a (20 mol %),
DBU (50 mol%), Ti(OPr-i) (200 mol%) and i-PrOH (200 mol%) in refluxing dichloroethane.
4
The structures of products 4 and 5 were elucidated on the basis of spectroscopic data.
The NMR spectra and mass data indicated that products 4 were 1+1 adducts of
cinnamaldehydes 1 and 2-(aroylvinyl)benzaldehydes 2. The products 5 were constructed
from 1+1 addition of cinnamaldehydes 1 and 2-(aroylvinyl)benzaldehydes 2 with the loss
of a CO
2
and a H O molecule. To determine the structures and especially the
2
stereochemistry of products beyond doubt, single crystals were cultivated. X-ray
diffraction studies confirmed unambiguously that the product 4b was
(
1S,4S,5R,10S)-5-(benzoylmethyl)-10-(p-bromophenyl)-4,5-dihydro-1,4-methanobenzo[c
]
oxepin-3-one,
and
the
products
5p
was
1
-(p-bromophenyl)-3-phenyl-2,8-dihydrocyclopenta[a]indene (See single crystal
structures of 4b and 5p in Supporting Information).
To account for the
formations
of
(
1S,4S,5R,10S)-5-(aroylmethyl)-10-aryl-4,5-dihydro-1,4-methanobenzo[c]oxepin-3-ones
4
and 1,3-diaryl-2,8-dihydrocyclopenta[a]indenes 5, two distinct cascade pathways were
proposed for the reaction of enals 1 and 2-(aroylvinyl)benzaldehydes 2. As illustrated in
Scheme 1, the nucleophilic addition of the homoenolates 6 derived from the enals 1 and
NHC catalyst to the Ti-activated aldehyde group of 2-(aroylvinyl)benzaldehydes 2 yields
an alcohol anion 7 that was coordinated with isopropoxytitanium. To avoid the steric
hindrance of the indene ring, the NHC-substituted homoenolates 6 approach
preferentially to the si-face of aldehyde, leading to the formation of two S-configured
chiral carbon centers of 7. The isopropanol additive might facilitate the disassociation of
the coordination between hydroxyl groups and titanium (IV) to generate the free alcohol
intermediates 8 from 7. An intramolecular Michael addition of enolates to the enone
species of 8, which also occurs preferentially to the si-face of C=C bond, gives rise to the
1
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9
(
1R,2S,3S,4S)-4-hydroxy-1-(aroylmethyl)-3-aryltetrahydronaphthalene-2-carbonylimidaz
olium intermediates 9 (Scheme 1, pathway A). Finally, the intramolecular lactonization
reaction
of
9
furnishes
the
formation
of
(1S,4S,5R,10S)-5-(aroylmethyl)-10-aryl-4,5-dihydro-1,4-methanobenzo[c]oxepin-3-ones
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
.
The formation of 2,8-dihydrocyclopenta[a]indenes
5
from enals
1
and
2-(aroylvinyl)benzaldehydes 2 is more intriguing than the formation of 4. Since reaction
intermediates could not been isolated, the reaction of 1a with 2a in DCE was monitored
by HPLC-MS to detect the intermediates. During the process of the reaction, the
+
HPLC-MS spectra indicated a compound having a molecule weight of [M + H] =
3
25.1603 (ESI MS) in the reaction mixture, which was in agreement with the weight of
(1a+2a-CO ). Scheidt and co-workers have reported a NHC/Lewis acid-catalyzed
reaction between enals and enones to form cyclopentenes via a decarboxylation of
2
4
a

-hydroxycarbonyl triazoium intermediates. Based on these messages, the mechanism
for the formation of fused indenes 5 was proposed as indicated in Scheme 1. Plausibly,
instead of the 1,4-addition of enolates to the enone species of intermediates 8 in the
formation of lactones 4, the enolates 8 undergo a 1,2-addition to the carbonyl groups of
enone
-(5,8-dihydroxy-5,6,7,8-tetrahydrobenzo[8]annulene-7-carbonyl)triazoium salts 10
Scheme 1, pathway B). A intramolecular acylation and decarboxylation cascade affords
species
to
form
the
5
(
the 5,6-dihydrobenzo[8]annulen-5-ols 12 (Calculated MS for 12 (M + H) = 325.1592.)
via the -lactone intermediates 11. A Lewis acid-promoted dehydroxyl of 12 gives the
transient tetrahydrobenzo[8]annulene carbocations 13, which isomerizes into the fused
indene carbocations 14. A base-catalyzed deprotonation of 14 yields the
dihydrocyclopenta[a]indenes
15.
Under
the
reaction
conditions,
the
dihydrocyclopenta[a]indenes 15 isomerize into products 5 via a [1,5]-H sigmatropic
1
0
7b,7d, 11
rearrangement and a base-promoted [1,3]-hydrogen shift.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme
1.
The
proposed
mechanisms
for
the
formation
of
(1S,4S,5R,10S)-5-(aroylmethyl)-10-aryl-4,5-dihydro-1,4-methanobenzo[c]oxepin-3-ones
4
and
1,3-diaryl-2,8-dihydrocyclopenta[a]indenes 5.
The 4,5-dihydro-1,4-methanobenzo[c]oxepin-3-one structure, a bridged lactone of
4
-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid, occurs in some biological or
pharmaceutical active molecules,12,13 such as neopodophyllotoxin that has been used in
clinical antitumor agents.14 The 4,5-dihydro-1,4-methanobenzo[c]oxepin-3-ones and
12
4
-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid derivatives have also been
used as the key intermediates in the total synthesis of various biological active natural
and unnatural compounds.15 Moreover, a large number of molecules of medicinal
importance possess 1,2,3,4-tetrahydronaphthalene moiety.16 We thought that the
transformation of the resulting bridged lactones 4 would provide a direct approach to
enantiomerically pure 1,2,3,4-tetrahydronaphthalene derivatives. To extend the
application of the reaction between cinnamaldehydes 1 and 2-(aroylvinyl)benzaldehydes
2, the hydrolysis or alcoholysis of compounds 4a and 4r was conducted with 5% aqueous
NaOH in THF or MeONa in methanol at ambient temperature. These reactions produced
1
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1
-(aroylmethyl)-3-aryl-4-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acids 18a
and 18r or the methyl carboxylates 19a and 19r, respectively, in 70-82% yields with
98-99% ee (Scheme 2).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Hydrolysis and alcoholysis of products 4.
Conclusion
In summary, we have studied the cooperative chiral NHC/Lewis acid catalyzed
reaction
between
cinnamaldehydes
and
2-(aroylvinyl)benzaldehydes.The
(1S,4S,5R,10S)-5-(aroylmethyl)-10-aryl-4,5-dihydro-1,4-methanobenzo[c]oxepin-3-ones,
a type of bridged caprolactones, were obtained in moderate yields with excellent
enantioselectivity. Meanwhile, in most cases, the selective syntheses of
4
,5-dihydro-1,4-methanobenzo[c]oxepin-3-ones and 2,8-dihydrocyclopenta[a]indenes
have been achieved by varying reaction conditions. The transformation of the bridged
lactone products to the enantiopure 1,2,3,4-tetrahydronaphthalene derivatives extend the
application of the reaction between cinnamaldehydes and 2-(aroylvinyl)benzaldehydes.
Thus, this work developed novel and simple methods for highly enantioselective
constructions
of
chiral
4,5-dihydro-1,4-methanobenzo[c]oxepin-3-ones
and
1
,2,3,4-tetrahydronaphthalene derivatives, both have potential application in the
syntheses of pharmaceutically important molecules.
Experimental Section
General
procedure
for
the
enantioselective
synthesis
of
(1S,4S,5R,10S)-5-(aroylmethyl)-10-aryl-4,5-dihydro-1,4-methanobenzo[c]oxepin-3-o
nes
4
from the
-unsaturated aldehydes
1
with
2
-(aroylvinyl)benzaldehydes 2 in benzene at ambient temperature.
Under
nitrogen
atmosphere,
cinnamaldehydes
(0.5
1
(1
mmol),
mmol),
2-(aroylvinyl)benzaldehydes 2
1
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
-)-N-mesityl-indeno[2,1-b]triazolo[4,3-d][1,4]oxazinium salt 3a (18.4 mg, 0.05 mmol),
Ti(OPr-i) (150 μl, 0.5 mmol) and i-PrOH (38.3 μl, 0.5 mmol) were mixed in dry benzene
4
(10 mL). The resulting mixture was stirred for 5 min, and DBU (15 μl, 0.1 mmol) was
added using a microsyringe. The reaction mixture was then stirred at room temperature
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
(20-25 C) for 12-24 h. After removal of the solvent, the residue was chromatographyed
on a silica gel column eluting with a mixture of petroleum ether and ethyl acetate (PE:EA
from 20:1 to10:1) to give the products 4 in 28-78% and 5 in 4-29% yields.
(1S,4S,5R,10S)-5-(Benzoylmethyl)-10-phenyl-4,5-dihydro-1,4-methanobenzo[c]oxepi
2
0
n-3-one 4a: white solid, 110 mg, 60%, ee 99%, []
D
= -101.8 (c = 0.50, CH
16-217 C; IR v (KBr, cm ) 1771, 1683; H NMR (400 MHz, CDCl ) δ (ppm) 8.01 (d, J
7.3 Hz, 2H), 7.59 (t, J = 7.4 Hz,1H), 7.48 (t, J = 7.7 Hz, 2H),7.38 (dd, J = 7.2, 2.5 Hz,
2
Cl
2
), mp
o
-1
1
2
3
=
1H), 7.21-7.26 (m, 4H), 7.16 (t, J = 7.1 Hz,1H),7.09 (d, J = 7.9 Hz, 2H), 7.04-7.07 (m,
1H), 5.67 (d, J = 4.7 Hz, 1H), 4.25 (t, J = 4.9 Hz,1H), 3.95-4.00 (m, 1H), 3.69 (dd, J =
1
3
1
8.7, 9.6 Hz, 1H), 3.58 (t, J = 4.6 Hz,1H), 3.37 (dd, J = 18.6, 3.6 Hz, 1H); C NMR (100
MHz, CDCl ) δ (ppm) 198.4, 176.7, 136.8, 136.7, 134.2, 134.1, 133.4, 129.9, 128.8,
28.7, 128.5, 128.2, 127.8, 127.6, 127.0, 126.9, 80.9, 47.3, 44.6, 42.4, 30.7; HRMS
3
1
+
(TOF-ESI): [M + H] calcd for C25
H
21
O
3
: 369.1491; found: 369.1487.
(1S,4S,5R,10S)-5-(Benzoylmethyl)-10-(p-bromophenyl)-4,5-dihydro-1,4-methanob
2
0
enzo[c]oxepin-3-one 4b: white solid, 119 mg, 53%, ee 99%, []
D
= -52.5 (c = 0.50,
), mp 231-232 C; IR v (KBr, cm ) 1769, 1684; H NMR (400 MHz, CDCl ) δ
ppm) 7.94 (d, J = 7.4 Hz, 2H), 7.52 (t, J = 7.3 Hz,1H), 7.41 (t, J = 7.8 Hz, 2H),
7.28-7.30 (m, 3H), 7.15-7.22 (m, 2H), 7.00 (d, J = 7.3 Hz, 1H), 6.90 (d, J = 8.1 Hz, 2H),
o
-1
1
CH
2
Cl
2
3
(
5
9
.56 (d, J = 4.7 Hz, 1H), 4.10 (t, J = 4.8 Hz,1H), 3.82-3.86 (m, 1H), 3.62 (dd, J = 18.7,
13
.8 Hz, 1H), 3.48 (t, J = 4.6 Hz,1H), 3.31 (dd, J = 18.7, 3.4 Hz, 1H); C NMR (100 MHz,
CDCl ) δ (ppm) 198.3, 176.3, 136.7, 136.5, 133.8, 133.5, 133.3, 131.7, 130.1, 129.5,
3
128.7, 128.2, 127.7, 127.2, 121.0, 80.5, 46.9, 44.4, 42.3, 30.7; HRMS (TOF-ESI): [M +
+
H] calcd for C25
H
20
3
O Br: 447.0596; found: 447.0591.
(1S,4S,5R,10S)-5-(Benzoylmethyl)-10-(p-chlorophenyl)-4,5-dihydro-1,4-methanobe
20
nzo[c]oxepin-3-one 4c: white solid, 111 mg, 55%, ee 99%, []
D
= -77.1 (c = 0.50,
) δ
(ppm) 8.01 (d, J = 7.6 Hz, 2H), 7.59 (t, J = 7.3 Hz,1H), 7.48 (t, J = 7.6 Hz, 2H), 7.37 (d, J
o
-1
1
CH
2
Cl
2
), mp 214-215 C; IR v (KBr, cm ) 1768, 1685; H NMR (400 MHz, CDCl
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=
6.6 Hz, 1H), 7.24-7.29(m, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 7.3 Hz, 1H), 7.03
(
d, J = 8.2 Hz, 2H), 5.63 (d, J = 4.6 Hz, 1H), 4.19 (t, J = 4.7 Hz,1H),3.90-3.93 (m, 1H),
3.69 (dd, J = 18.6, 9.7 Hz, 1H), 3.55 (t, J = 4.6 Hz,1H), 3.38 (dd, J = 18.6, 3.3 Hz, 1H);
13C NMR (100 MHz, CDCl
) δ (ppm) 198.2, 176.2, 136.7, 136.5, 133.8, 133.5, 132.9,
32.8, 130.1, 129.1, 128.8, 128.73, 128.70, 128.1, 127.7, 127.2, 80.6, 46.8, 44.5, 42.3,
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
+
0.7; HRMS (TOF-ESI): [M + Na] calcd for C25
H
19
O
3
ClNa: 425.0914; found: 425.0913.
(1S,4S,5R,10S)-5-(Benzoylmethyl)-10-(o-chlorophenyl)-4,5-dihydro-1,4-methanobe
2
0
nzo[c]oxepin-3-one 4d: white solid, 125 mg, 62%, ee >99%, []
D
= -189.2 (c = 0.50,
), mp 173-174 C; IR v (KBr, cm ) 1772, 1684; H NMR (400 MHz, CDCl ) δ
ppm) 8.00 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H),
o
-1
1
CH
2
Cl
2
3
(
7
.38-7.44 (m, 2H), 7.28-7.33 (m, 2H), 7.14 (t, J = 7.6 Hz,1H), 7.11 (d, J = 8.0 Hz, 1H),
6.91 (t, J = 7.5 Hz,1H), 6.63 (d, J = 7.8 Hz, 1H), 5.62 (d, J = 4.3 Hz, 1H), 4.31 (t, J = 4.6
Hz,1H), 3.87 (t, J = 4.5 Hz,1H), 3.70-3.73 (m, 1H), 3.65 (dd, J = 17.8, 8.4 Hz, 1H), 3.35
1
3
(dd, J = 17.6, 3.4 Hz, 1H); C NMR (100 MHz, CDCl
3
) δ (ppm) 197.9, 176.3, 137.1,
1
1
36.6, 134.5, 134.1, 133.3, 131.9, 130.2, 130.1, 129.1, 128.6, 128.5, 128.3, 128.1, 127.7,
+
27.3, 126.3, 80.4, 46.5, 44.6, 42.6, 30.9; HRMS (TOF-ESI): [M + H] calcd for
Cl: 403.1101; found: 403.1096.
1S,4S,5R,10S)-5-(Benzoylmethyl)-10-(m-chlorophenyl)-4,5-dihydro-1,4-methanob
C
25
H
20
O
3
(
2
0
enzo[c]oxepin-3-one 4e: white solid, 117 mg, 58%, ee >99%, []
D
= -75.6 (c = 0.50,
), mp 233-234 C; IR v (KBr, cm ) 1766, 1685; H NMR (400 MHz, CDCl ) δ
ppm) 8.01 (d, J = 7.6 Hz, 2H), 7.59 (t, J = 7.3 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.39 (d,
J = 7.7 Hz, 1H), 7.23-7.30 (m, 2H), 7.13-7.20 (m, 2H), 7.08 (d, J = 7.2 Hz, 1H), 7.04 (s,
H), 7.01 (d, J = 7.1 Hz, 1H), 5.64 (d, J = 4.6 Hz, 1H), 4.20 (t, J = 4.6 Hz,1H), 3.94-3.97
o
-1
1
CH
2
Cl
2
3
(
1
(m, 1H), 3.68 (dd, J = 18.7, 9.6 Hz, 1H), 3.57 (t, J = 4.7 Hz,1H), 3.38 (dd, J = 18.7, 3.4
13
Hz, 1H); C NMR (100 MHz, CDCl
3
) δ (ppm) 198.1, 176.0, 136.6, 136.4, 136.2, 134.3,
133.5, 133.3, 130.0, 129.7, 128.62, 128.57, 128.0, 127.9, 127.6, 127.2, 127.1, 125.8, 80.3,
+
4
6.9, 44.3, 42.2, 30.5; HRMS (TOF-ESI): [M + H] calcd for C25
H
20
O Cl: 403.1095;
3
found: 403.1094.
(1S,4S,5R,10S)-10-(p-Acetylphenyl)-5-(benzoylmethyl)-4,5-dihydro-1,4-methanobe
2
0
nzo[c]oxepin-3-one 4f: white solid, 123 mg, 60%, ee >99%, []
D
= -57.9 (c = 0.50,
o
-1
1
CH
2
Cl
2
), mp 225-226 C; IR v (KBr, cm ) 1774, 1682; H NMR (400 MHz, CDCl ) δ
3
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2
2
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4
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4
4
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5
5
5
5
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6
(
ppm) 8.01 (d, J = 7.4 Hz, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.60 (t, J = 7.3 Hz,1H), 7.49 (t, J
=
7.6 Hz, 2H), 7.40 (dd, J = 8.7, 2.6 Hz, 1H), 7.25-7.28 (m, 2H), 7.21 (d, J = 8.0 Hz, 2H),
7.06 (d, J = 8.0 Hz, 1H), 5.70 (d, J = 4.6 Hz, 1H), 4.27 (t, J = 4.9 Hz,1H), 3.91-3.94 (m,
1
1
1
H), 3.70 (dd, J = 18.7, 9.7 Hz, 1H), 3.62 (t, J = 4.6 Hz,1H), 3.37 (dd, J = 18.6, 3.4 Hz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
H), 2.53 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 198.2, 197.4, 176.1, 139.7,
3
36.7, 136.5, 135.8, 133.8, 133.5, 130.2, 128.8, 128.7, 128.5, 128.1, 128.0, 127.7, 127.2,
+
80.5, 47.4, 44.4, 42.3, 30.8, 26.5; HRMS (TOF-ESI): [M + Na] calcd for C27
433.1410; found: 433.1412.
H
22
4
O Na:
(1S,4S,5R,10S)-5-(Benzoylmethyl)-10-(p-methylphenyl)-4,5-dihydro-1,4-methanob
20
enzo[c]oxepin-3-one 4g: white solid, 94 mg, 49%, ee >99%, []
D
= -80.1 (c = 0.50,
) δ
o
-1
1
CH
2
Cl
2
), mp 188-189 C; IR v (KBr, cm ) 1772, 1683; H NMR (400 MHz, CDCl
3
(ppm) 8.02 (d, J = 7.4 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.38 (dd,
J = 8.6, 2.1 Hz, 1H), 7.21-7.26 (m, 2H), 7.02-7.07 (m, 3H), 6.97 (d, J = 8.0 Hz, 2H), 5.65
(d, J = 4.7 Hz, 1H), 4.21 (t, J = 4.8 Hz,1H), 3.95-4.00 (m, 1H), 3.69 (dd, J = 18.7, 9.6 Hz,
13
1
H), 3.55 (t, J = 4.6 Hz,1H), 3.37 (dd, J = 18.7, 3.6 Hz, 1H), 2.24 (s, 3H); C NMR (100
MHz, CDCl ) δ (ppm) 198.2, 176.7, 136.7, 136.4, 134.0, 133.3, 131.0, 129.7, 129.1,
3
128.58, 128.55, 128.0, 127.5, 127.4, 126.8, 80.8, 46.9, 44.6, 42.2, 30.5, 20.9; HRMS
+
(TOF-ESI): [M + H] calcd for C26
H
23
3
O : 383.1647; found: 383.1644.
(1S,4S,5R,10S)-5-(Benzoylmethyl)-10-(p-methoxyphenyl)-4,5-dihydro-1,4-methano
benzo[c]oxepin-3-one 4h: white solid, 56 mg, 28% (43% from the reaction catalyzed by
o
20
o
2
0 mol% of 3a at 50 C), ee >99%, []
D
= -79.3 (c = 0.50, CH
v (KBr, cm ) 1772, 1682; H NMR (400 MHz, CDCl ) δ (ppm) 8.02 (d, J = 7.2 Hz, 2H),
.59 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.37 (dd, J = 7.1, 2.0 Hz, 1H),
2
Cl ), mp 210-211 C; IR
2
-1
1
3
7
7
2
.21-7.28(m, 2H), 7.07 (d, J = 7.3 Hz, 1H), 7.00 (d, J = 8.3 Hz, 2H), 6.76 (d, J = 8.7 Hz,
H), 5.63 (d, J = 4.6 Hz, 1H), 4.19 (t, J = 4.9 Hz,1H), 3.94-3.98 (m, 1H), 3.73 (s, 3H),
3.69 (dd, J = 18.7, 9.6 Hz, 1H), 3.52 (t, J = 4.5 Hz,1H), 3.38 (dd, J = 18.7, 3.6 Hz, 1H);
13C NMR (100 MHz, CDCl
) δ (ppm) 198.2, 176.7, 158.1, 136.67, 136.66, 134.0, 133.3,
29.8, 128.7, 128.6, 128.0, 127.4, 126.9, 126.0, 113.8, 80.9, 55.0, 46.6, 44.8, 42.2, 30.5;
3
1
+
HRMS (TOF-ESI): [M + H] calcd for C26
H
23
O
4
: 399.1596; found: 399.1591.
(1S,4S,5R,10S)-5-(Benzoylmethyl)-10-(o-methoxyphenyl)-4,5-dihydro-1,4-methano
2
0
benzo[c]oxepin-3-one 4i: white solid, 94 mg, 47%, ee 99%, []
D
= -90.1 (c = 0.50,
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o
-1
1
CH
2
Cl
2
), mp 134-135 C; IR v (KBr, cm ) 1770, 1684; H NMR (400 MHz, CDCl ) δ
3
(
ppm) 8.01 (d, J = 7.1 Hz, 2H),7.58 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H),
7.36-7.38 (m, 1H), 7.23-7.27 (m, 2H), 7.16 (td, J = 7.7, 1.2 Hz, 1H), 7.06 (dd, J = 6.6, 2.2
Hz, 1H), 6.84 (d, J = 7.7 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.69 (t, J = 7.4 Hz, 1H), 5.71
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
d, J = 4.4 Hz, 1H), 4.18 (t, J = 4.8 Hz,1H), 3.88 (s, 3H), 3.82-3.86 (m, 1H), 3.73 (td, J =
13
4
.9, 0.9 Hz, 1H), 3.67 (dd, J = 18.5, 8.9 Hz, 1H), 3.33 (dd, J = 18.4, 4.0 Hz, 1H); C
NMR (100 MHz, CDCl ) δ (ppm) 198.2, 177.3, 157.8, 137.1, 136.8, 134.5, 133.2, 129.6,
3
128.7, 128.5, 128.33, 128.25, 128.0, 127.5, 126.7, 122.4, 120.0, 110.3, 81.2, 55.1, 44.73,
+
4
3
4.66, 42.6, 30.9; HRMS (TOF-ESI): [M + H] calcd for C26
99.1592.
H
23
4
O : 399.1590; found:
(1S,4S,5R,10S)-5-(Benzoylmethyl)-8-fluoro-10-phenyl-4,5-dihydro-1,4-methanobe
2
0
nzo[c]oxepin-3-one 4j: white solid, 79 mg, 41%, ee >99%, []
D
= -65.8 (c = 0.50,
o
-1
1
CH
2
Cl
2
), mp 171-172 C; IR v (KBr, cm ) 1773, 1683; H NMR (400 MHz, CDCl ) δ
3
(ppm) 8.01 (d, J = 7.2 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H),
7
1
.24-7.27 (m, 2H), 7.18 (t, J = 7.3 Hz, 1H), 7.08-7.13 (m, 3H), 7.03 (dd, J = 8.5, 5.3 Hz,
H), 6.94 (td, J = 8.5, 2.7 Hz, 1H), 5.62 (d, J = 4.4 Hz, 1H), 4.24 (t, J = 4.8 Hz,1H),
3.92-3.97 (m, 1H), 3.68 (dd, J = 18.7, 9.5 Hz, 1H), 3.58 (t, J = 4.5 Hz,1H), 3.33 (dd, J =
1
3
1
2
8.6, 3.7 Hz, 1H); C NMR (100 MHz, CDCl
3
) δ (ppm) 198.0, 176.2, 160.9 (d, JC-F =
46 Hz), 136.5, 135.9 (d, JC-F = 6 Hz), 133.7, 133.4, 132.1 (d, JC-F = 3 Hz), 129.4 (d, JC-F
=
8 Hz), 128.6, 128.5, 128.0, 127.5, 127.0, 116.7 (d, JC-F = 21 Hz), 115.4 (d, JC-F = 22
+
Hz), 80.0, 47.1, 44.3, 42.3, 30.1; HRMS (TOF-ESI): [M + H] calcd for C25
H
20
3
O F:
3
87.1390; found: 387.1389.
(1S,4S,5R,10S)-5-(Benzoylmethyl)-8-methyl-10-phenyl-4,5-dihydro-1,4-methanobe
20
nzo[c]oxepin-3-one 4k: white solid, 122 mg, 64%, ee 99%, []
D
= -106.3 (c = 0.50,
) δ
(ppm) 8.01 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.24 (t, J
7.7 Hz, 2H), 7.19 (s, 1H), 7.17 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 8.0 Hz, 2H), 7.05 (dd,
o
-1
1
CH
2
Cl
2
), mp 215-216 C; IR v (KBr, cm ) 1772, 1683; H NMR (400 MHz, CDCl
3
=
J= 7.9, 1.1 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 5.62 (d, J = 4.6 Hz, 1H), 4.23 (t, J = 5.0
Hz,1H), 3.90-3.95 (m, 1H),3.66 (dd, J = 18.6, 9.7 Hz, 1H), 3.56 (t, J = 4.9 Hz,1H), 3.35
13
(dd, J = 18.6, 3.6 Hz, 1H), 2.34 (s, 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 198.4,
176.7, 136.7, 136.6, 134.2, 133.8, 133.31,133.25, 130.5, 129.2, 128.5, 128.4, 128.0, 127.6,
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5
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5
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+
1
27.3, 126.7, 80.9, 47.3, 44.6, 42.2, 30.3, 20.8; HRMS (TOF-ESI): [M + H] calcd for
C
26
H
23
O
3
: 383.1641; found: 383.1641.
(1S,4S,5R,10S)-5-(Benzoylmethyl)-8-methoxy-10-phenyl-4,5-dihydro-1,4-methano
2
0
benzo[c]oxepin-3-one 4l: white solid, 139 mg, 70%, ee >99%, []
D
= -142.4 (c = 0.50,
) δ
ppm) 8.02 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.24 (t, J
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
-1
1
CH
2
Cl
2
), mp 214-215 C; IR v (KBr, cm ) 1771, 1683; H NMR (400 MHz, CDCl
3
(
=
7.6 Hz, 2H), 7.17 (t, J = 7.1 Hz, 1H), 7.10 (d, J = 7.9 Hz, 2H), 6.97 (d, J = 8.6 Hz, 1H),
6.92 (d, J = 2.7 Hz, 1H), 6.78 (dd, J = 8.6, 2.7 Hz, 1H), 5.60 (d, J = 4.5 Hz, 1H), 4.22 (t, J
4.9 Hz,1H), 3.87-3.91 (m, 1H), 3.82 (s, 3H), 3.65 (dd, J = 18.6, 9.6 Hz, 1H), 3.56 (t, J =
=
1
3
4
1
.5 Hz,1H), 3.33 (dd, J = 18.6, 3.7 Hz, 1H); C NMR (100 MHz, CDCl ) δ (ppm) 198.4,
3
76.6, 158.1, 136.7, 135.1, 134.1, 133.3, 128.7, 128.6, 128.4, 128.1, 128.0, 127.6, 126.8,
+
115.1, 114.0, 80.8, 55.3, 47.3, 44.6, 42.2, 30.0; HRMS (TOF-ESI): [M + H] calcd for
C
26
H
23
O
4
: 399.1596; found: 399.1592.
1S,4S,5R,10S)-5-(Benzoylmethyl)-7-fluoro-10-phenyl-4,5-dihydro-1,4-methanobe
nzo[c]oxepin-3-one 4m: white solid, 42 mg, 22% (25% from the reaction catalyzed by
(
20
o
2
0 mol% of 3a), ee 99%, []
D
= -85.0 (c = 0.55, CH
cm ) 1770, 1683; H NMR (400 MHz, CDCl ) δ (ppm) 8.01 (d, J = 7.7 Hz, 2H), 7.60 (t,
J = 7.4 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.37 (dd, J = 8.3, 5.8 Hz, 1H), 7.23-7.27 (m,
H), 7.18 (t, J = 7.2 Hz, 1H),7.08 (d, J = 7.3 Hz, 2H), 6.93 (td, J = 8.2, 1.9 Hz, 1H), 6.77
d, J = 9.8 Hz, 1H), 5.68 (d, J = 4.7 Hz, 1H), 4.25 (t, J = 4.8 Hz,1H), 3.95-3.98 (m, 1H),
.71 (dd, J = 18.7, 9.6 Hz, 1H), 3.58 (t, J = 4.8 Hz,1H), 3.30 (dd, J = 18.7, 3.6 Hz, 1H);
13C NMR (100 MHz, CDCl
) δ (ppm) 197.8, 176.2, 163.3 (d, JC-F = 247 Hz), 139.3 (d,
C-F = 7 Hz), 136.4, 133.8, 133.4, 130.3 (d, JC-F = 9 Hz), 130.0 (d, JC-F = 4 Hz), 128.6,
2
Cl
2
), mp 194-195 C; IR v (KBr,
-1
1
3
2
(
3
3
J
1
4
28.5, 128.0, 127.6, 126.9, 114.8 (d, JC-F = 23 Hz), 114.0 (d, JC-F = 22 Hz), 79.9, 47.1,
+
4.1, 42.1, 30.7; HRMS (TOF-ESI): [M + H] calcd for C25
H
20
O F: 387.1396; found:
3
387.1393.
1S,4S,5R,10S)-5-(Benzoylmethyl)-7-methyl-10-phenyl-4,5-dihydro-1,4-methanobe
nzo[c]oxepin-3-one 4n: white solid, 86 mg, 45% (52% from the reaction catalyzed by 20
(
20
o
mol% of 3a), ee >99%, []
D
= -109.6 (c = 0.50, CH
cm ) 1769, 1682; H NMR (400 MHz, CDCl ) δ (ppm) 8.02 (d, J = 7.4 Hz, 2H), 7.59 (t,
J = 7.3 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.22-7.27 (m, 3H), 7.16 (t, J = 7.1 Hz, 1H), 7.10
2
Cl
2
), mp 250-251 C; IR v (KBr,
-1
1
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(
d, J = 7.7 Hz, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.86 (s, 1H), 5.65 (d, J = 4.7 Hz, 1H), 4.22
t, J = 4.9 Hz,1H), 3.91-3.96 (m, 1H), 3.70 (dd, J = 18.7, 9.8 Hz, 1H), 3.57 (t, J = 4.7
(
1
3
Hz,1H), 3.37 (dd, J = 18.7, 3.4 Hz, 1H), 2.23 (s, 3H); C NMR (100 MHz, CDCl
3
) δ
(ppm) 198.3, 176.7, 139.6, 136.7, 136.3, 134.3, 133.3, 131.0, 128.6, 128.5, 128.4, 128.1,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
28.0, 127.7, 127.6, 126.7, 80.6, 47.3, 44.5, 42.2, 30.5, 21.3; HRMS (TOF-ESI): [M +
+
H] calcd for C26
H
23
3
O : 383.1647; found: 383.1644.
(1S,4S,5R,10S)-5-(Benzoylmethyl)-7-methoxy-10-phenyl-4,5-dihydro-1,4-methano
benzo[c]oxepin-3-one 4o: white solid, 101 mg, 51% (61% from the reaction catalyzed by
2
0
o
2
0 mol% of 3a), ee >99%, []
D
= -120.5 (c = 0.55, CH
2
Cl
2
), mp 189-190 C; IR v (KBr,
-1
1
cm ) 1768, 1683; H NMR (400 MHz, CDCl ) δ (ppm) 8.02 (d, J = 8.0 Hz, 2H), 7.59 (t,
3
J = 7.3 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.30 (d, J = 8.3 Hz, 1H), 7.23 (t, J = 7.6 Hz, 2H),
7.17 (t, J = 7.2 Hz, 1H), 7.09 (d, J = 7.6 Hz, 2H), 6.74 (dd, J = 8.3, 2.0 Hz, 1H), 6.57 (s,
1H), 5.65 (d, J = 4.8 Hz, 1H), 4.22 (t, J = 4.9 Hz,1H), 3.92-3.96 (m, 1H), 3.71 (dd, J =
1
8.6, 9.7 Hz, 1H), 3.70 (s, 3H), 3.55 (t, J = 4.9 Hz,1H), 3.34 (dd, J = 18.6, 3.6 Hz, 1H);
13C NMR (100 MHz, CDCl
) δ (ppm) 198.2, 176.8, 160.5, 138.1, 136.6, 134.3, 133.3,
29.8, 128.6, 128.4, 128.0, 127.7, 126.7, 126.4, 113.5, 111.8, 80.5, 55.0, 47.3, 44.4, 42.3,
3
1
+
30.8; HRMS (TOF-ESI): [M + H] calcd for C26
H
23
O
4
: 399.1590; found: 399.1590.
(1S,4S,5R,10S)-5-((p-Bromobenzoyl)methyl)-10-phenyl-4,5-dihydro-1,4-methanob
2
0
enzo[c]oxepin-3-one 4p: white solid, 107 mg, 48%, ee >99%, []
D
= -46.7 (c = 0.50,
), mp 195-196 C; IR v (KBr, cm ) 1771, 1684; H NMR (400 MHz, CDCl ) δ
ppm) 7.86 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.38 (dd, J = 8.6, 2.7 Hz, 1H),
o
-1
1
CH
2
Cl
2
3
(
7.20-7.25 (m, 4H), 7.15 (t, J = 7.3 Hz,1H), 7.07 (d, J = 7.4 Hz, 2H), 7.03 (dd, J = 8.3, 2.0
Hz, 1H), 5.66 (d, J = 4.8 Hz, 1H), 4.23 (t, J = 4.9 Hz,1H), 3.96-3.92 (m, 1H), 3.63 (dd, J
13
=
18.6, 9.8 Hz, 1H), 3.55 (t, J = 5.0 Hz,1H), 3.30 (dd, J = 18.6, 3.6 Hz, 1H); C NMR
(100 MHz, CDCl ) δ (ppm) 197.2, 176.5, 136.3, 135.4, 134.0, 133.9, 131.9, 129.8, 129.5,
3
128.7, 128.5, 128.4, 127.6, 127.4, 127.0, 126.8, 80.7, 47.2, 44.4, 42.2, 30.5; HRMS
+
(TOF-ESI): [M + H] calcd for C25
H
20
3
O Br: 447.0596; found: 447.0591.
(1S,4S,5R,10S)-5-((p-Methylbenzoyl)methyl)-10-phenyl-4,5-dihydro-1,4-methanob
20
enzo[c]oxepin-3-one 4q: white solid, 132 mg, 69%, ee >99%, []
D
= -73.6 (c = 0.50,
), mp 204-205 C; IR v (KBr, cm ) 1766, 1679; H NMR (400 MHz, CDCl ) δ
(ppm) 7.92 (d, J = 8.1 Hz, 2H), 7.38 (dd, J = 8.5, 2.3 Hz, 1H), 7.27 (d, J = 8.3 Hz, 2H),
o
-1
1
CH
2
Cl
2
3
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
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5
5
5
5
5
5
5
5
5
5
6
7
1
.21-7.24 (m, 4H), 7.15 (t, J = 7.1 Hz, 1H), 7.09 (d, J = 7.8 Hz, 2H), 7.05 (d, J = 7.7 Hz,
H), 5.66 (d, J = 4.7 Hz, 1H), 4.23 (t, J = 4.9 Hz,1H), 3.95-4.00 (m, 1H), 3.66 (dd, J =
18.6, 9.6 Hz, 1H), 3.57 (t, J = 4.7 Hz,1H), 3.34 (dd, J = 18.5, 3.6 Hz, 1H), 2.42 (s, 3H);
13C NMR (100 MHz, CDCl
) δ (ppm) 197.9, 176.7, 144.3, 136.9, 134.4, 134.3, 134.1,
29.9, 129.4, 128.7, 128.5, 128.3, 127.8, 127.6, 127.0, 126.9, 80.9, 47.4, 44.7, 42.2, 30.7,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
+
1.7; HRMS (TOF-ESI): [M + H] calcd for C26
H
23
O
3
: 383.1647; found: 383.1642.
(1S,4S,5R,10S)-5-((p-Methoxybenzoyl)methyl)-10-phenyl-4,5-dihydro-1,4-methano
2
0
benzo[c]oxepin-3-one 4r: white solid, 155 mg, 78%, ee >99%, []
D
= -66.5 (c = 0.55,
), mp 154-155 C; IR v (KBr, cm )1772, 1673; H NMR (400 MHz, CDCl ) δ
ppm) 8.00 (d, J = 8.9 Hz, 2H), 7.37 (dd, J = 7.2, 2.4 Hz, 1H), 7.20-7.24 (m, 4H), 7.15 (t,
o
-1
1
CH
2
Cl
2
3
(
J = 7.1 Hz, 1H), 7.08 (d, J = 7.9 Hz, 2H), 7.06 (dd, J = 8.4, 2.1 Hz, 1H), 6.95 (d, J = 8.9
Hz, 2H), 5.66 (d, J = 4.6 Hz, 1H), 4.23 (t, J = 4.9 Hz,1H), 3.95-4.00 (m, 1H), 3.87 (s, 3H),
3.64 (dd, J = 18.4, 9.6 Hz, 1H), 3.56 (t, J = 4.6 Hz,1H), 3.31 (dd, J = 18.3, 3.7 Hz, 1H);
13C NMR (100 MHz, CDCl
) δ (ppm) 196.8, 176.7, 163.8, 136.9, 134.3, 134.1, 130.5,
3
1
29.9, 128.7, 128.5, 127.8, 127.7, 127.0, 126.9, 113.9, 80.9, 55.5, 47.4, 44.7, 41.9, 30.8;
+
HRMS (TOF-ESI): [M + H] calcd for C26
General procedure for
,3-daryl-2,8-dihydrocyclopenta[a]indenes
H
23
4
O : 399.1596; found: 399.1594.
the
preparation
and
of
1
5
5
racemic
-(aroylmethyl)-10-aryl-4,5-dihydro-1,4-methanobenzo[c]oxepin-3-ones 4 from the
reaction of -unsaturated aldehydes 1 with 2-(aroylvinyl)benzaldehydes 2 in
o
dichloroethane at 50 C.
Under nitrogen atmosphere, cinnamaldehydes 1 (1 mmol), 2-(aroylvinyl)benzaldehydes
2
(0.5 mmol), racemic N-mesityl-indeno[2,1-b]triazolo[4,3-d][1,4]oxazinium salt 3a
(18.4 mg, 0.05 mmol), Ti(OPr-i) (225μl, 0.75 mmol) and i-PrOH (38.3 μl, 0.5 mmol)
4
were mixed in dry dichloroethane (10 mL). The resulting mixture was stirred for 5 min,
and DBU (15 μl, 0.1mmol) was added using a microsyringe. The reaction mixture was
o
then stirred at 50 C for 12 h. After removal of the solvent, the residue was
chromatographyed on a silica gel column eluting with a mixture of petroleum ether and
ethyl
acetate
(PE:EA
from
20:1
to
10:1)
to
give
the
1
,3-daryl-2,8-dihydrocyclopenta[a]indenes 5 in 15-62% and racemic 4 in 10-59% yields.
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,3-Diphenyl-2,8-dihydrocyclopenta[a]indene 5a: yellow solid, 77 mg, 50%, mp
o
o
17
-1
1
1
64-165 C (174 C ); IR v (KBr, cm ) 1596, 1495; H NMR (400 MHz, CDCl
3
) δ
(ppm) 7.88 (d, J = 7.4 Hz, 1H), 7.62 (d, J = 7.2 Hz, 2H), 7.50 (d, J = 7.5 Hz, 2H),
7
2
1
.35-7.39 (m, 3H), 7.33 (t, J = 8.0 Hz, 2H), 7.20-7.24 (m, 2H), 7.12-7.17 (m, 2H), 4.13 (s,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
H), 3.90 (s, 2H); C NMR (100 MHz, CDCl ) δ (ppm) 149.4, 147.7, 147.2, 137.2,
3
36.3, 136.2, 133.1, 132.8, 128.7, 128.6, 128.0, 127.4, 126.8, 126.7, 126.0, 125.97, 125.6,
-
122.7, 49.5, 32.7; HRMS [TOF-(-APCI)]: [M - H] calcd for C24
305.1335.
H17: 305.1335; found:
3
-(p-Bromophenyl)-1-phenyl-2,8-dihydrocyclopenta[a]indene 5b: yellow solid, 73
o
-1
1
mg, 38%, mp 183-184 C; IR v (KBr, cm ) 1599, 1497, 1488; H NMR (400 MHz,
CDCl ) δ (ppm) 7.89 (d, J = 7.5 Hz, 1H), 7.57-7.53 (m, 6H), 7.47 (d, J = 7.4 Hz, 1H),
7.40 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 7.26-7.21 (m, 2H), 4.17 (s, 2H), 3.96 (s,
3
1
3
2
1
3
H); C NMR (100 MHz, CDCl ) δ (ppm) 149.6, 148.4, 147.1, 136.2, 136.1, 135.9,
3
33.1, 131.7, 131.5, 128.9, 128.7, 128.3, 126.8, 126.2, 126.1, 125.7, 122.6, 120.3, 49.4,
-
2.6; HRMS [TOF-(-APCI)]: [M - H] calcd for C24
H16Br: 383.0440; found: 383.0443.
3-(p-Chlorophenyl)-1-phenyl-2,8-dihydrocyclopenta[a]indene 5c: yellow solid, 71
o
-1
1
mg, 42%, mp 190-191 C; IR v (KBr, cm ) 1599, 1494; H NMR (400 MHz, CDCl
ppm) 7.88 (d, J = 7.5 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 7.7 Hz, 2H), 7.45 (d,
J = 7.3 Hz, 1H), 7.38-7.42 (m, 4H), 7.30 (t, J = 7.3 Hz, 1H), 7.21-7.26 (m, 2H), 4.14 (s,
3
) δ
(
13
2
H), 3.93 (s, 2H); C NMR (100 MHz, CDCl ) δ (ppm) 149.5, 148.3, 147.1, 136.1,
3
135.9, 135.6, 133.1, 132.2, 131.5, 128.71, 128.69, 128.5, 128.2, 126.8, 126.12, 126.09,
-
1
25.6, 122.6, 49.4, 32.6; HRMS [TOF-(-APCI)]: [M - H] calcd for C24
H16Cl: 339.0946;
found: 339.0943.
-(p-Methylphenyl)-1-phenyl-2,8-dihydrocyclopenta[a]indene 5g: yellow solid, 77
3
o
-1
1
mg, 48%, mp 151-152 C; IR v (KBr, cm ) 1595, 1510, 1495; H NMR (400 MHz,
CDCl ) δ (ppm) 7.95 (d, J = 7.4 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H),7.56 (d, J = 10.2 Hz,
H), 7.45 (d, J = 7.2 Hz, 1H), 7.40 (t, J = 7.4 Hz, 2H), 7.19-7.30 (m, 5H), 4.17 (s, 2H),
3
2
3
1
13
.95 (s, 2H), 2.42 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 149.3, 147.24, 147.18,
3
36.6, 136.4, 136.3, 134.3, 133.3, 132.3, 129.3, 128.7, 127.9, 127.3, 126.7, 126.0, 125.9,
-
125.6, 122.7, 49.5, 32.7, 21.3; HRMS [TOF-(-APCI)]: [M - H] calcd for C25
19
H :
3
19.1492; found: 319.1491.
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-(p-Methoxyphenyl)-1-phenyl-2,8-dihydrocyclopenta[a]indene 5h: yellow solid,
o
-1
1
6
8 mg, 40%, mp 170-171 C; IR v (KBr, cm ) 1601, 1510, 1495; H NMR (400 MHz,
CDCl ) δ (ppm) 7.88 (d, J = 7.2 Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 7.7 Hz,
H), 7.39 (d, J =7.3Hz, 1H), 7.25-7.15 (m, 3H), 6.95 (d, J = 8.5 Hz, 2H), 4.07 (s, 2H),
3
2
3
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
.87 (s, 2H), 3.84 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 158.6, 149.3, 147.3,
3
46.5, 136.5, 136.4, 133.0, 131.9, 129.9, 128.7, 128.6, 127.7, 126.7, 126.0, 125.8, 125.5,
-
122.5, 114.0, 55.4, 49.5, 32.7; HRMS [TOF-(-APCI)]: [M - H] calcd for C25
335.1441; found: 335.1443.
H19O:
3
-(o-Methoxyphenyl)-1-phenyl-2,8-dihydrocyclopenta[a]indene 5i: yellow solid, 67
o
-1
1
mg, 40%, mp 139-140 C; IR v (KBr, cm ) 1595, 1572, 1491, 1462; H NMR (400 MHz,
CDCl ) δ (ppm) 7.53-7.56 (m, 3H), 7.49 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 7.4 Hz, 1H),
7.36 (t, J = 7.4 Hz, 2H), 7.29 (t, J = 7.7 Hz, 1H), 7.13-7.23 (m, 3H), 6.96-7.02 (m, 2H),
3
1
3
4
1
1
.27 (s, 2H), 3.93 (s, 2H), 3.82 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 156.7,
3
49.2, 149.1, 146.4, 136.6, 136.5, 133.2, 130.2, 129.7, 128.6, 128.4, 127.7, 126.5, 126.3,
25.8, 125.72, 125.65, 123.3, 120.5, 111.1, 55.3, 50.4, 32.7; HRMS [TOF-(-APCI)]: [M -
-
H] calcd for C25
H
19O: 335.1441; found: 335.1443.
-Fluoro-1,3-diphenyl-2,8-dihydrocyclopenta[a]indene 5j: yellow solid, 26 mg, 15%
20% from the reaction catalyzed by a combination of 3a (20 mol %), DBU (50 mol%),
Ti(OPr-i) (200 mol%) and i-PrOH (200 mol%) in refluxing dichloroethane.), mp
5
(
4
o
-1
1
1
68-169 C; IR v (KBr, cm ) 1595, 1493, 1468; H NMR (400 MHz, CDCl
7.89 (dd, J = 8.5, 5.4 Hz, 1H), 7.65 (d, J = 7.2 Hz, 2H), 7.54 (d, J = 7.6 Hz, 2H), 7.45 (t, J
7.5 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 7.22 (t, J = 7.4 Hz, 1H),
.14 (dd, J = 8.8, 2.1 Hz, 1H), 6.94 (td, J = 8.8, 2.4 Hz, 1H), 4.19 (s, 2H), 3.95 (s, 2H);
13C NMR (100 MHz, CDCl
) δ (ppm) 162.6 (d, JC-F = 246 Hz), 151.8, 151.7, 146.8,
146.5, 137.0, 136.1, 133.0, 132.4 (d, JC-F = 2 Hz), 132.2 (d, JC-F = 2 Hz), 128.7, 128.6,
3
) δ (ppm)
=
7
3
1
2
3
27.2, 126.8, 126.1, 125.6, 123.7 (d, JC-F = 9 Hz), 113.9 (d, JC-F = 23 Hz), 113.0 (d, JC-F =
-
2 Hz), 49.4, 32.8; HRMS [TOF-(-APCI)]: [M - H] calcd for C24
23.1241.
H16F: 323.1241; found:
5
-Methyl-1,3-diphenyl-2,8-dihydrocyclopenta[a]indene 5k: yellow solid, 84 mg,
o
-1
1
52%, mp 154-155 C; IR v (KBr, cm ) 1596, 1496; H NMR (400 MHz, CDCl
3
) δ (ppm)
7
.85 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.5 Hz, 2H), 7.56 (d, J = 7.7 Hz, 2H), 7.45 (t, J =
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.6 Hz, 2H), 7.40 (t, J = 7.8 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.26 (s, 1H), 7.22 (t, J =
1
3
.4 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 4.18 (s, 2H), 3.91 (s, 2H), 2.41 (s, 3H); C NMR
) δ (ppm) 149.8, 147.7, 147.5, 138.1, 137.4, 136.4, 133.6, 132.6, 131.9,
28.6, 128.5, 127.6, 127.3, 126.64, 126.56, 125.9, 125.6, 122.5, 49.3, 32.6, 21.6; HRMS
(100 MHz, CDCl
3
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-
[
TOF-(-APCI)]: [M-H] calcd for C25
-Methoxy-1,3-diphenyl-2,8-dihydrocyclopenta[a]indene 5l: yellow solid, 44 mg, 26%
(37% from the reaction catalyzed by a combination of 3a (20 mol %), DBU (50 mol%),
Ti(OPr-i) (200 mol%) and i-PrOH (200 mol%) in refluxing dichloroethane.), mp
H19: 319.1492; found: 319.1493.
5
4
o
-1
1
1
7
7
44-145 C; IR v (KBr, cm ) 1614, 1596, 1493; H NMR (400 MHz, CDCl ) δ (ppm)
3
.86 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 7.3 Hz, 2H), 7.52 (d, J = 7.6 Hz, 2H), 7.41 (t, J =
.6 Hz, 2H), 7.40 (t, J = 7.9 Hz, 2H), 7.26 (t, J = 7.4 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H),
6.96 (d, J = 2.1 Hz, 1H), 6.78 (dd, J = 8.5, 2.4 Hz, 1H), 4.14 (s, 2H), 3.89 (s, 2H), 3.83 (s,
1
3
3
1
4
H); C NMR (100 MHz, CDCl ) δ (ppm) 159.8, 151.6, 147.5, 147.2, 137.4, 136.4,
3
32.6, 130.4, 129.3, 128.7, 128.65, 127.1, 126.4, 125.9, 125.6, 123.6, 112.8, 111.1, 55.4,
-
9.1, 32.9; HRMS [TOF-(-APCI)]: [M-H] calcd for C25
H
19O: 335.1441; found:
335.1443.
-Fluoro-1,3-diphenyl-2,8-dihydrocyclopenta[a]indene 5m: yellow solid, 65 mg,
6
o
-1
1
4
0%, mp 147-148 C; IR v (KBr, cm ) 1597, 1493, 1470; H NMR (400 MHz, CDCl
ppm) 7.64 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 9.7 Hz, 1H), 7.55 (d, J = 7.6 Hz, 2H), 7.46 (t,
J = 7.5 Hz, 2H), 7.36-7.42 (m, 3H), 7.32 (t, J = 7.4 Hz, 1H), 7.22 (t, J = 7.3 Hz, 1H), 6.99
3
) δ
(
1
3
(t, J = 8.4 Hz, 1H), 4.20 (s, 2H), 3.92 (s, 2H); C NMR (100 MHz, CDCl
3
) δ (ppm)
1
62.0 (d, JC-F = 241 Hz), 147.3, 147.0, 146.9, 144.7 (d, JC-F = 2 Hz), 137.8, 137.7 (d, JC-F
=
5 Hz), 136.8, 136.1, 134.3, 133.0, 128.7, 127.3, 127.1, 126.7 (d, JC-F = 9 Hz), 126.1,
1
25.6, 114.9 (d, JC-F = 23 Hz), 109.5 (d, JC-F = 24 Hz), 49.5, 32.0; HRMS [TOF-(-APCI)]:
-
[M - H] calcd for C24
H16F: 323.1241; found: 323.1240.
6
-Methyl-1,3-diphenyl-2,8-dihydrocyclopenta[a]indene 5n: yellow solid, 100 mg,
o
-1
1
6
7
7
2%, mp 200-201 C; IR v (KBr, cm ) 1595, 1493; H NMR (400 MHz, CDCl ) δ (ppm)
3
.74 (s, 1H), 7.67 (d, J = 7.5 Hz, 2H), 7.54 (d, J = 7.6 Hz, 2H), 7.44 (t, J = 7.5 Hz, 2H),
.38 (t, J = 7.5 Hz, 2H), 7.27-7.33 (m, 2H), 7.19 (t, J = 7.2 Hz, 1H), 7.09 (d, J = 7.4 Hz,
13
1H), 4.16 (s, 2H), 3.88 (s, 2H), 2.34 (s, 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 147.7,
1
46.6, 137.3, 136.4, 136.29, 136.27, 132.8, 132.6, 129.0, 128.7, 128.6, 127.4, 126.7,
2
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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5
5
5
5
5
5
5
5
6
-
1
25.9, 125.63, 125.60, 123.2, 49.5, 32.3, 21.6; HRMS[TOF-(-APCI)]: [M - H] calcd for
19: 319.1492; found: 319.1491.
6-Methoxy-1,3-diphenyl-2,8-dihydrocyclopenta[a]indene 5o: yellow solid, 118 mg,
C H
25
o
-1
1
7
0%, mp 173-174 C; IR v (KBr, cm ) 1599, 1493, 1479; H NMR (400 MHz, CDCl
3
) δ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
ppm) 7.65 (d, J = 7.6 Hz, 2H), 7.53 (d, J = 7.7 Hz, 2H), 7.46 (d, J = 1.7 Hz, 1H), 7.42 (t,
J = 7.6 Hz, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.27 (t, J = 7.4 Hz, 1H),
7.19 (t, J = 7.3 Hz, 1H), 6.84 (dd, J = 8.3, 2.0 Hz, 1H), 4.15 (s, 2H), 3.85 (s, 2H), 3.77 (s,
1
3
3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 158.5, 147.9, 147.6, 141.5, 137.1, 137.0,
1
4
3
36.2, 133.0, 132.5, 128.5, 128.4, 127.2, 126.7, 126.2, 125.8, 125.5, 114.2, 107.8, 55.3,
-
9.2, 31.8; HRMS[TOF-(-APCI)]: [M - H] calcd for C25
35.1442.
H19O: 335.1441; found:
1-(p-Bromophenyl)-3-phenyl-2,8-dihydrocyclopenta[a]indene 5p: yellow solid, 82
o
-1
1
mg, 43%, mp 148-149 C; IR v (KBr, cm ) 1597, 1490; H NMR (400 MHz, CDCl
3
) δ
(
ppm) 7.94 (d, J = 7.4 Hz, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H),
7
.43-7.46 (m, 3H), 7.40 (d, J = 8.6 Hz, 2H), 7.27-7.33 (m, 2H), 7.24 (t, J = 7.2 Hz, 1H),
1
3
4.14 (s, 2H), 3.90 (s, 2H); C NMR (100 MHz, CDCl
3
) δ (ppm) 149.2, 148.0, 147.7,
1
1
37.0, 136.0, 135.2, 133.4, 131.7, 131.6, 128.6, 128.2, 127.3, 127.0, 126.9, 126.8, 126.0,
-
22.7, 119.5, 49.4, 32.6; HRMS [TOF-(-APCI)]: [M - H] calcd for C24H16Br: 383.0440;
found: 383.0441.
-(p-Methylphenyl)-3-phenyl-2,8-dihydrocyclopenta[a]indene 5q: yellow solid, 57
1
o
-1
1
mg, 36%, mp 132-133 C; IR v (KBr, cm ) 1595, 1512; H NMR (400 MHz, CDCl
3
) δ
(
ppm) 7.94 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 7.8 Hz, 2H), 7.41-7.40 (m, 5H), 7.27 (t, J =
8
2
.5 Hz, 2H), 7.23 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 4.15 (s, 2H), 3.91 (s, 2H),
13
.36 (s, 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 149.6, 147.8, 146.2, 137.3, 136.3,
135.7, 133.6, 132.8, 132.6, 129.4, 128.5, 128.0, 127.3, 126.69, 126.65, 126.0, 125.6,
-
1
22.7, 49.5, 32.6, 21.2; HRMS [TOF-(-APCI)]: [M - H] calcd for C25
H
19: 319.1492;
found: 319.1493.
-(p-Methoxyphenyl)-3-phenyl-2,8-dihydrocyclopenta[a]indene 5r: yellow solid, 31
mg, 19% (24% from the reaction catalyzed by a combination of 3a (20 mol %), DBU (50
1
mol%), Ti(OPr-i) (200 mol%) and i-PrOH (200 mol%) in refluxing dichloroethane.), mp
4
o
-1
1
1
66-167 C; IR v (KBr, cm ) 1601, 1510; H NMR (400 MHz, CDCl
3
) δ (ppm) 7.93 (d, J
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=
7.4 Hz, 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.41-7.46 (m,
3
H),7.22-7.30 (m, 3H), 6.95 (d, J = 8.3 Hz, 2H), 4.16 (s, 2H), 3.92 (s, 2H), 3.85 (s, 3H);
13C NMR (100 MHz, CDCl
) δ (ppm) 157.9, 149.6, 147.8, 145.0, 137.3, 136.3, 132.5,
32.1, 129.5, 128.5, 128.0, 127.3, 126.8, 126.7, 126.6, 126.0, 122.7, 114.2, 55.3, 49.5,
3
1
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-
2.5; HRMS [TOF-(-APCI)]: [M - H] calcd for C25H19O: 335.1441; found: 335.1440.
Hydrolysis
of
(
1S,4S,5R,10S)-5-(aroylmethyl)-10-aryl-4,5-dihydro-1,4-methanobenzo[c]oxepin-3-o
nes 4.
The 5-(aroylmethyl)-10-aryl-4,5-dihydro-1,4-methanobenzo[c]oxepin-3-ones 4 (0.25
mmol) and the aqueous solution of NaOH (5% w/w, 1.9 mL, 10 equiv.) were dissolved in
THF (5 mL). The resulting mixture was stirred at room temperature for14 h. The reaction
mixture was neutralized with aqueous solution of HCl (1% w/w) to pH ~ 5-6, and then
dichloromethane (10 mL) was added. The organic phase was separated using a separating
funnel, and the aqueous layer was extracted with dichloromethane (10×2 mL). The
combined organic solutionwas dried over anhydrous Na
2
SO . After removal of the
4
solvent, the residue was chromatographyed on a silica gel column eluting with a mixture
of petroleum ether, ethyl acetate and dichloromethane from PE:EA = 5:1 to
PE:EA:DCM= 1:1:1 to give the products 18 in 75-72% yields.
(1R,2S,3S,4S)-4-Hydroxy-1-(benzoylmethyl)-3-phenyl-1,2,3,4-tetrahydronaphthale
2
0
ne-2-carboxylate 18a: white solid, 73 mg, 75%, ee 99%, []
D
= +124.5 (c = 0.50,
COCD ) δ
ppm) 7.99 (dd, J = 7.5, 1.3 Hz, 2H), 7.57-7.61 (m, 2H), 7.49 (t, J = 7.4 Hz, 2H), 7.40 (d,
J = 7.3 Hz, 2H), 7.9 (t, J = 7.4 Hz, 2H), 7.17-7.22 (m, 4H), 4.84 (d, J = 8.8 Hz,1H), 4.21
o
-1
1
CH
2
Cl
2
), mp 98-99 C; IR v (KBr, cm ) 1708, 1686; H NMR (400 MHz, CD
3
3
(
(
dd, J = 11.0, 5.7 Hz,1H), 3.95 (dd, J = 18.1, 6.4 Hz, 1H), 3.48 (dd, J = 11.4, 4.7 Hz,1H),
1
3
3
.34-3.40 (m, 2H); C NMR (100 MHz, CDCl ) δ (ppm) 198.2, 176.4, 141.1, 138.9,
3
137.1, 136.9, 133.1, 128.8, 128.5, 128.12, 128.1, 128.0, 127.8, 127.3, 127.2,127.1, 74.3,
+
5
1.6, 48.0, 47.7, 43.6, 35.0; HRMS (FT-ESI): [M + Na] calcd for C25
H
22
O Na: 409.1410;
4
found: 409.1403.
(1R,2S,3S,4S)-4-hydroxy-1-((p-methoxybenzoyl)methyl)-3-phenyl-1,2,3,4-tetrahyd
2
0
ronaphthalene-2-carboxylate 18r: white solid, 85 mg, 82%, ee 99%, []
D
= +144.8 (c
o
-1
1
= 0.50, CH
2
Cl ), mp 93-94 C; IR v (KBr, cm ) 1708, 1675, 1600; H NMR (400 MHz,
2
2
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5
5
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CD
3
COCD
3
) δ (ppm) 10.55 (br, 1H), 7.97 (d, J = 8.9 Hz, 2H), 7.58 (d, J = 7.6 Hz,1H),
7
.39 (d, J = 7.3 Hz, 2H), 7.30 (t, J = 7.4 Hz, 2H), 7.18-7.25 (m, 3H), 6.99 (d, J = 8.9 Hz,
2H), 4.84 (d, J = 8.6 Hz,1H), 4.37 (brs, 1H), 4.19 (dd, J = 10.8, 5.7 Hz,1H), 3.87 (s, 3H),
1
3
3
.84 (dd, J = 17.9, 6.0 Hz, 1H), 3.48 (dd, J = 11.4, 4.7 Hz,1H), 3.30-3.39 (m, 2H); C
NMR (100 MHz, CDCl ) δ (ppm) 196.6, 175.7, 163.5,141.2, 138.9, 137.1, 130.4, 129.9,
28.9, 128.1, 127.9, 127.7, 127.4, 127.1, 126.9,113.7, 74.2, 55.4, 48.2, 47.8, 42.2, 35.0;
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
+
HRMS (MALDI-TOF): [M + K] calcd for C26
H
24
O K: 455.1255; found: 455.1284.
5
Alcoholysisof
(1S,4S,5R,10S)-5-(aroylmethyl)-10-aryl-4,5-dihydro-1,4-methanobenzo[c]oxepin-3-o
nes 4.
The 5-(aroylmethyl)-10-aryl-4,5-dihydro-1,4-methanobenzo[c]oxepin-3-ones 4 (0.25
mmol) and NaOMe (41 mg, 3 equiv.) were dissolved in methanol (10 mL). The resulting
mixture was stirred at room temperature for 12 h. The reaction was quenched by the
addition of saturated aqueous solution of NH Cl (5 mL), and then dichloromethane (20
4
mL) was added. The organic phase was separated and the aqueous layer was extracted
with dichloromethane (20×2 mL). The combined organic solution was dried over
anhydrous Na
2
SO . After removal of the solvent, the residue was chromatographyed on a
4
silica gel column eluting with a mixture of petroleum ether andethyl acetate (PE:EA
from10:1 to 5:1) to give the products 19 in 70-76% yields.
(1R,2S,3S,4S)-Methyl
4-hydroxy-1-(benzoylmethyl)-3-phenyl-1,2,3,4-tetrahydronaphthalene-2-carboxylate
2
0
1
9a: white solid, 82 mg, 76%, ee 99%, []
D
= +130.3 (c = 0.55, CH
2
Cl
2
), mp 136-137
o
-1
1
C; IR v (KBr, cm ) 1732, 1682; H NMR (400 MHz, CDCl
3
) δ (ppm) 7.93 (d, J = 7.5
Hz, 2H), 7.60 (d, J = 7.4 Hz,1H), 7.54 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H),
.24-7.36 (m, 7H), 7.20 (t, J = 7.2 Hz, 1H), 4.87 (d, J = 9.1 Hz,1H), 4.29-4.33 (m, 1H),
3.98 (dd, J = 18.4, 7.9 Hz, 1H), 3.50 (dd, J = 11.9, 4.9 Hz,1H), 3.31 (dd, J = 11.9, 9.2 Hz,
7
1
3
1
H), 3.29 (s, 3H), 3.18 (dd, J = 18.4, 3.8 Hz, 1H), 1.72 (brs, 1H); C NMR (100 MHz,
CDCl ) δ (ppm) 197.8, 172.8, 141.0, 139.2, 136.9, 133.0, 128.8, 128.6, 128.2, 128.1,
28.04, 128.0, 127.3, 127.2, 127.1,74.3, 51.6, 48.0, 47.7, 43.6, 35.0; HRMS (FT-ESI):
3
1
+
[M + Na] calcd for C26
H
24
4
O Na: 423.1567; found: 423.1563.
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(
1R,2S,3S,4S)-Methyl
4
-hydroxy-1-((p-methoxybenzoyl)methyl)-3-phenyl-1,2,3,4-tetrahydronaphthalene-2
2
0
-carboxylate 19r: white solid,75 mg, 70%, ee 98%, []
D
= +146.8 (c = 0.50, CH
) δ (ppm)
.92 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 7.4 Hz,1H), 7.24-7.36 (m, 7H), 7.21 (t, J = 7.4 Hz,
2
Cl ),
2
o
-1
1
mp 145-146 C; IR v (KBr, cm ) 1734, 1676, 1601; H NMR (400 MHz, CDCl
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
1
1
H), 6.90 (d, J = 8.9 Hz, 2H), 4.86 (d, J = 9.1 Hz,1H), 4.28-4.32 (m, 1H), 3.99 (dd, J =
8.2, 7.8 Hz, 1H), 3.85 (s, 3H), 3.49 (dd, J = 11.9, 5.0 Hz,1H), 3.31 (dd, J = 11.8, 9.1 Hz,
1
3
1H), 3.29 (s, 3H), 3.13 (dd, J = 18.1, 4.0 Hz, 1H), 1.80 (brs, 1H); C NMR (100 MHz,
CDCl ) δ (ppm) 196.3, 172.7, 163.5, 141.1, 139.4, 137.2, 130.3, 130.0, 128.8, 128.2,
28.1, 128.0, 127.3, 127.1, 127.0,113.7, 74.3, 55.4, 51.5, 48.1, 47.8, 43.1, 35.1; HRMS
3
1
+
(
FT-ESI): [M + Na] calcd for C27
H
26
O Na: 453.1673; found: 453.1668.
5
ASSOCIATED CONTENT
1
13
Supporting Information Available. The copies of H NMR and C NMR spectra of products 4, 5,
1
8 and 19, the copies of HPLC chromatographs for products 4, and single crystal data of 4b and 5p
(
CIF). These materials are available free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author：
E-mail: ycheng2@bnu.edu.cn
Notes：
The authors declare no competing financial interest.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 21372030).
Reference：
1
2
4
. Some reviews for NHCs organocatalysis: (a) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev.
007, 107, 5606-5655. (b) Marion, N.; Diez-Gonzalez, S.; Nolan, S. P. Angew. Chem. Int. Ed. 2007,
6, 2988-3000. (c) Grossmann, A.; Enders, D. Angew. Chem. Int. Ed. 2012, 51, 314-325.
2. Examples for the constructions of cyclic compounds by NHC-catalyzed reactions of enals: (a)
Lathrop, S. P.; Rovis, T. J. Am. Chem. Soc .2009, 131, 13628–13630. (b) Gao, Z.-H.; Chen, X.-Y.;
2
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Zhang, H.-M.; Ye, S. Chem. Commun., 2015, 51, 12040–12043. (c ) Chan, A.; Scheidt, K. A. J. Am.
Chem. Soc. 2007, 129, 5334-5335. (d) Rommel, M.; Fukuzumi, T.; Bode, J. W. J. Am. Chem. Soc.
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008, 130, 17266–17267. (e) Fang, X.; Jiang, K.; Xing, C.; Hao, L.; Chi,Y. R. Angew. Chem. Int. Ed.
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. A review for NHC/Lewis acid cooperative catalysis: Cohen, D. T.; Scheidt, K. A. Chem. Sci., 2012,
3, 53-57.
. Examples for the NHC/Lewis acid catalysis: (a) Cardinal-David, B.; Raup, D. E. A.; Scheidt, K. A.
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J. Am. Chem. Soc. 2010, 132, 5345-5347. (b) Cohen, D. T.; Cardinal-David, B.; Scheidt, K. A. Angew.
Chem. Int. Ed. 2011, 50, 1678–1682. (c) Dugal-Tessier, J.; O'Bryan, E. A.; Schroeder, T. B. H.;
Cohen, D. T.; Scheidt, K. A. Angew. Chem. Int. Ed. 2012, 51, 4963–4967. (d) Bera, S.; Samanta, R. C.;
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Lett. 2014, 16, 3632−3635. (h) Patil, N. T. Angew. Chem. Int. Ed. 2011, 50, 1759–1761.
5. The NHC/Brønsted acid catalysis: (a) Lee, A.; Scheidt, K. A. Angew. Chem. Int. Ed. 2014, 53,
7594–7598. (b) Zhao, X.; DiRocco, D. A.; Rovis, T.; J. Am. Chem. Soc. 2011, 133, 12466–12469. (c)
Li, J.-L.; Sahoo, B.; Daniliuc, C.-G.; Glorius, F. Angew. Chem. Int. Ed. 2014, 53, 10515–10519. (d)
Kato, T.; Matsuoka,S.; Suzuki,M.; J. Org. Chem. 2014, 79, 4484−4491.
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. (a) ElSohly, A. M.; Wespe, D. A.; Poore, T. J.; Snyder, S. A. Angew. Chem. Int. Ed. 2013, 52,
789–5794. (b) Boddaert, T.; Coquerel,Y.; Rodriguez, J. Chem. Eur. J. 2011, 17,2266–2271.
. (a) Cheng, Y.; Peng, J.-H.; Li, Y.-J.; Shi, X.-Y.; Tang, M.-S.; Tan, T.-Y. J. Org. Chem. 2011, 76,
1844-1851. (b) Zhao, Y.; Wang, Z.-T.; Cheng, Y. Adv. Synth. Catal. 2014, 356, 2580-2590. (c) Wang,
Z.-T.; Zhao, Y.; Wang, Z.-Y.; Cheng, Y. J. Org. Chem. 2015, 80, 1727–1734. (d) Mao, J.-H.; Wang,
Z.-T.; Wang, Z.-Y.; Cheng, Y. J. Org. Chem. 2015, 80, 6350-6359.
8. (a) Dang, H.-Y.; Wang, Z.-T.; Cheng, Y. Org. Lett. 2014, 16, 5520-5523. (b) Wang, Z.-Y.; Ding,
Y.-L.; Wang, G.; Cheng, Y. Chem. Commun. 2016, 52, 788–791. (c) Wang, G.; Wang, Z.-Y.; Niu,
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. (a) Phillips, E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. A. Angew. Chem. Int. Ed. 2007, 46,
107–3110. (b) Li, Y.; Wang, X.-Q.; Zheng, C.; You, S.-L. Chem. Commun. 2009, 5823–5825.
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0. Examples for 1,5-H sigmatropic rearrangements: (a) Flamini, A.; Fares, V.; Capobianchi, A.;
Valentini, V. J. Chem. Soc. Perkin Trans. 1 2001, 3069-3072. (b) Alajarin, M.; Sanchez-Andrada,
P.; Lopez-Leonardo, C.; Alvarez, A. J. Org. Chem. 2005, 70, 7617-7623.
11. Examples for 1,3-H shifts: (a) Wei, H.; Li, Y.; Xiao, K.; Cheng, B.; Wang, H.; Hu, L.; Zhai,
H. Org. Lett. 2015, 17, 5974-5977. (b) Karmakar, R.; Mamidipalli, P.; Salzman, R. M.; Hong, S.;
Yun, S. Y.; Guo, W.; Xia, Y.; Lee, D. Org. Lett. 2016, 18, 3530-3533.
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2. Examples for the synthesis of neopodophyllotoxin: (a) Charlton, J. L.; Koh, K. J. Org. Chem. 1992,
57, 1514-1516. (b) Renz, J.; Kuhn, M.; Wartburg, A. Justus Liebigs Ann. Chem. 1965, 681, 207-224.
c) Rajapaksa, D.; Rodrigo, R. J. Am. Chem. Soc. 1981, 103, 6208-6209.
(
13. (a) Schwarz, J. S. P.; Weisenborn, F. L.; Neidleman, S. L.; Kinney, R. W. U.S.
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4. Some examples: (a) Sun, Z. CN Pat., 2007, CN 1887262 A, 20070103. (b) Gao, H. Sun, Z. CN
Pat., 2007, CN 1887262 A, 20070103. (c) Gao, H. CN Pat., 2006, CN 1846676 A, 20061018.
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5. Some examples: (a) Roulland, E.; Bertounesque, E.; Huelb, C.; Monnereta, C. Tetrahedron Lett.
000, 416769-6773. (b) Forsey, S. P.; Rajapaksa, D.; Taylor, N. J.; Rodrigo, R. J. Org. Chem. 1989,
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Hathaway, B. A.; Nichols, D. E.; Nichols, M. B.; Yim, G. K. W. J.Med. Chem. 1982, 25, 535-538.
6. Some examples: (a) Cimetiere, B.; Dubuffet, T.; Landras, C.; Descombes, J.-J.; Simonet, S.;
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Verbeuren, T. J.; Lavielle, G. Bioorg. Med. Chem. Lett. 1998, 8, 1381-1386. (b) Stutz, A.;
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M.; Dumas, J.-P.; Bardou, M.; Rochette, L.; Advenier, C.; Giudicelli, J.-F. Eur. J. Pharmacol. 1998,
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