Intramolecular Cyclization of 3,3-Diarylpropenylamides of Electron-Deficient Alkenes: Stereoselective Synthesis of Functionalized Hexahydrobenzo[f]isoindoles

Article abstract of DOI:10.1002/ejoc.201801508

Intramolecular Diels–Alder reactions of various 3,3-diarylpropenylamides of electron-deficient alkenes to give hexahydrobenzo[f]isoindoles were investigated. Reaction of 1,1,2-ethenetricarboxylic acid 1,1-diethyl ester with 3,3-diaryl-2-propen-1-amines under the amide formation conditions gave the tricyclic compounds in sequential processes involving intramolecular Diels–Alder reaction. The reaction gave cis- and trans-fused tricyclic compounds selectively, depending on the substituents on the benzene ring, reaction temperature and solvent. In the reaction with dissymmetrically substituted 3,3-diaryl-2-propen-1-amines, trans-substituted aryl group reacted mainly as a styrene component. Amides of electron-deficient alkenic carboxylic acids such as fumarate do not undergo cyclization at room temperature sequentially and the reaction on heating gave trans-fused hexahydrobenzo[f]isoindoles. The origin of the observed stereoselectivity has been examined by the DFT calculations.

Full text of DOI:10.1002/ejoc.201801508

A Journal of
Accepted Article
Title: Intramolecular Cyclization of 3,3-Diarylpropenylamides of
Electron-deficient Alkenes: Stereoselective Synthesis of
Functionalized Hexahydrobenzo[f]isoindoles
Authors: Hirotaka Sugiura, Shoko Yamazaki, Kakeru Go, and Akiya
Ogawa
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801508
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801508
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201801508
Intramolecular Cyclization of 3,3-Diarylpropenylamides of Electron-deficient Alkenes:
Stereoselective Synthesis of Functionalized Hexahydrobenzo[f]isoindoles
a
b
b
a
Hirotaka Sugiura, Prof. Dr. Shoko Yamazaki,* Kakeru Go, and Prof. Dr. Akiya Ogawa
aDepartment of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture
b
University, Gakuen-cho 1-1, Nakaku, Sakai, Osaka 599-8531, Japan, Department of
Chemistry, Nara University of Education, Takabatake-cho, Nara 630-8528, Japan,
yamazaks@nara-edu.ac.jp
http://mailsrv.nara-edu.ac.jp/~yamazaks
Graphical Abstract
X1
E1
HO C
E2
+
2
R
1
2
E /E =
CO Et/CO Et,
N
X2
H
2
2
H/CO Me, H/CF3
2
CF /CF3
E1
3
E2
O
H
H
HOBt
EDCI
Et N
X2
R N
3
X1
Abstract: Intramolecular Diels–Alder reactions of various 3,3-diarylpropenylamides of
electron-deficient alkenes to give hexahydrobenzo[f]isoindoles were investigated. Reaction of
1,1,2-ethenetricarboxylic acid 1,1-diethyl ester with 3,3-diaryl-2-propen-1-amines under the
amide formation conditions gave the tricyclic compounds in sequential processes involving
intramolecular Diels-Alder reaction. The reaction gave cis- and trans-fused tricyclic
compounds selectively, depending on the substituents on the benzene ring, reaction
temperature and solvent. In the reaction with dissymmetrically substituted 3,3-diaryl-2-
propen-1-amines, E-substituted aryl group reacted mainly as a styrene component. Amides of
electron-deficient alkenic carboxylic acids such as fumarate do not undergo cyclization at room
1
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
temperature sequentially and the reaction on heating gave trans-fused
hexahydrobenzo[f]isoindoles. The origin of the observed stereoselectivity has been examined
by the DFT calculations.
Introduction
The intramolecular [4+2] cycloaddition (Diels-Alder) reaction between alkenes and
dienes is a powerful tool for the facile construction of multicyclic skeletons. 1 Vinyl
heteroaromatic moieties such as vinyl pyrroles, thiophenes, furans, 2 imidazoles, 3 and
4
benzothiophens have been extensively used as dienes in the intramolecular Diels-Alder
reaction. The intramolecular Diels-Alder reaction of vinyl benzene (styrene) as a diene requires
relatively harsh conditions, because of involving dearomatization of benzene ring.5
The inter- and intramolecular reactions of styrenes diversely undergo [2+2]
cycloadditions 6 , 7 and [4+2] cycloadditions as dienophile components. 8 , 9 Limited
intermolecular [4+2] cycloadditions of styrenes as dienes were also reported.10 In addition to
the cycloaddition reactions of styrenes, the inter- and intramolecular reactions of diarylethenes
were studied.5c,11 Furthermore, one of the important selectivities of the intramolecular Diels-
Alder reaction in general is formation of trans or cis fused ring,1b,12 and the investigation on
the stereoselectivity of the intramolecular [4+2] cycloaddition of styrenes with various
substituents is of considerable interest.5c,5k
Recently, we have reported intramolecular [2+2] and [4+2] cycloaddition reactions of
1
,1,2-ethenetricarboxylic acid 1,1-diethyl ester 1 with E-cinnamylamines under the amide
formation conditions in sequential processes (Scheme 1).13 Reaction of E-cinnamylamines
without substituent on benzene ring and with halogens and OMe on para position at room
temperature gave cyclobutane-fused pyrrolidines as major products via [2+2] cycloaddition.
On the other hand, reaction of 1,1,2-ethenetricarboxylic acid 1,1-diethyl ester 1 and E-
cinnamylamines bearing electron-withdrawing groups under the amide formation conditions
gave trans-fused hexahydrobenzo[f]isoindoles via [4+2] cycloaddition as major products.
2
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
ref. 13
5
4
X
3
EtO C CO Et
6
2
2
EtO C CO Et
EDCI
2
2
5
4
X
3
1
2
HOBt
O
6
+
HO C
2
Et N
3
N
1
2
R
HN
R
CO Et
O
2
X = H, 4-F, 4-Cl, 4-Br
-OCH3
H
H
CO Et
2
4
R N
X
X = 2-NO , 2-NO -5-F,
2
2
4
4
4
-NO , 4-CN,
2
EtO C CO Et
2
2
-CO Me, 4-CO Et,
O
2
2
H
-CF3
R N
X
H
This work
E1 E2
HO C
X1
E1 E2
X2
HOBt
EDCI
Et N
3
O
R
+
2
R
N
N
X2
1
2
E /E =
CO Et/CO Et,
H
2
2
H/CO Me, H/CF
2
3
X1
CF /CF
3
3
E1
E2
O
H
H
[
4+2]
X2
H-shift
X2
Y
R N
X1
X1
Scheme 1
In this work, the sequential amide formation/[4+2] cycloaddition/H-shift reactions of
electron deficient alkenyl carboxylic acids with Z-cinnamyl amines and various 3,3-diaryl-2-
propen-1-amines have been studied. This reaction proceeds to give tricyclic compounds,
functionalized hexahydrobenzo[f]isoindoles. Some biologically active compounds such as
podophyllotoxin14 (Y=O) and 4-phenylbenzo[f]isoindoles15 (Y=N) have the skeletons of the
[4+2] cycloaddition products of 3,3-diaryl-2-propen-1-amines, shown in Scheme 1. In order to
3
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
understand the factors to control cis and trans-fused stereochemistry in the present results,
DFT calculations have been carried out.
Results and Discussion
We have previously reported that reactions of 1,1,2-ethenetricarboxylic acid 1,1-
diethyl ester 1 and E-cinnamylamines bearing p-H, halogen and MeO groups in the presence
of EDCI/HOBt/Et N at room temperature gave cyclobutane-fused pyrrolidines as major
3
products.13 The products may be formed via amide formation/intramolecular [2+2]
cycloaddition. First, reaction with Z-cinnamylamines has been examined. Reaction with benzyl
or cyclohexylmethyl cinnamylamines 2a,b (Z:E = ca. 5:1) in the presence of EDCI/HOBt/Et N
3
in THF at room temperature gave a complex mixture and the possible [2+2] cycloadducts were
not detected. Intramolecular [2+2] cycloaddition reaction path for possible intermediate Z-
amide was examined by DFT calculations according to the previously reported [2+2]
1
3
cycloaddition path of E-amide. The cyclobutane ring formation path is less stable than that
of E-amide, probably because of the steric effect of Ph group.16 The reaction at 80-110 C
gave [4+2] cycloadducts, cis-fused tricyclic compounds 3a,b as major products (eq 1, Table
1
). The cis-fused stereochemistry of 3a,b was determined by NOEs in C
6
6
D .
EtO C
EDCI
HOBt
2
O
CO Et
2
EtO C CO Et
H
2
2
+
Et N
3
R N
HN
R
HO C
2

1
2
H
2
0-23 h
(eq 1)
3
Table 1. Reactions of 1,1,2-ethenetricarboxylic acid 1,1-diethyl ester 1 and Z-cinnamylamines
2
Entry 2
R
Solvent Temp. Product 3 Yield (%)
a
b
1
2
3
4
5
6
2a CH
2
2
2
2
2
2
Ph
Ph
Ph
THF
r.t.
-
a
2a CH
Benzene 80C 3a
62
58
-
a
2a CH
Toluene 110 C 3a
a
b
2b CH
Cyclohexyl THF
r.t.
a
2b CH
Cyclohexyl Benzene 80 C 3b
Cyclohexyl Toluene 110 C 3b
50
61
a
2b CH
4
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
a
b
Z:E = 5:1. A complex mixture.
Next, the reaction of 1 and 3,3-diaryl-2-propenylamines 4 in the presence of the amide
condensation reagents has been examined (eq 2, Table 2). The influence of the second aromatic
ring to stereochemistry by both steric and electronic effects is of mechanistic and synthetic
interests.
The 3,3-diaryl-2-propen-1-amines 4 were prepared from the corresponding alcohols.17
The reaction of 1 and N-benzyl 3,3-diphenyl-2-propen-1-amine 4a with EDCI/HOBt/Et N in
3
THF at room temperature gave a complex mixture. However, the reaction in DMF gave trans-
fused hexahydrobenzo[f]isoindole 5a-trans in 52% yield via [4+2] cycloaddition.
Interestingly, the reaction of 4a,b in benzene or toluene at 80 or 110 C gave cis-fused
hexahydrobenzo[f]isoindoles 5a,b-cis as major products. Similarly, the reaction of N-benzyl-
3
,3-bis(4-fluorophenyl)-2-propenylamine 4c in DMF at room temperature gave trans-fused
tricyclic product 5c-trans in 53% yield and the reaction of 4c in benzene or toluene at 80 or
10 C gave cis-fused product 5c-cis in 87 and 98% yields, respectively. On the other hand,
1
reaction of 1 and 4,4'-dichloro and 3,3'-di(trifluoromethyl) derivatives 4d,e in THF, DMF and
benzene at room temperature, 80 and 110 C gave trans-fused tricyclic products 5d,e-trans in
high yields. Product 5e-trans from 3,3'-CF
3
substituted amine substrate 4e was obtained as a
single regioisomer (3,3'-CF ). The reaction of 1 and 4,4'-dimethyl derivative 4f in DMF gave
3
a complex mixture at room temperature and the reaction in DMF, benzene and toluene at 80
and 110 C gave cis-fused tricyclic product 5f-cis selectively. The relative configurations of 5
were determined by NOEs in CDCl
3
or C
g gave a complex mixture in THF, DMF, benzene and toluene at room temperature, 80 and
10 C.
Thus, the reaction with 3,3-diaryl-2-propen-1-amines gave cis- and trans-fused tricyclic
6
D
6
. The reaction of 1 and 4,4'-dimethoxy derivative
4
1
compounds selectively, depending on the substituents on the benzene ring, reaction
temperature and solvent.
5
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
X 4
3
EtO C
CO Et
2
2
Et N
HOBt
EDCI
3
2
1
+
HO C
1'
'
2
R
N
X
1
H
20 h
2
4
'
3
'
4
EtO C
EtO C
2
2
CO Et
CO Et
2
O
2
O
H
H
4
'
4
'
X
'
X
R N
R
N
3
3
'
1'
1
'
2'
H
2
'
H
1
1
2
2
3
X
(eq 2)
3
5-cis
5
-trans
4
X
4
Table 2. Reactions of 1,1,2-ethenetricarboxylic acid 1,1-diethyl ester 1 and 3,3-diaryl-2-
propen-1-amines 4
Entry 4a
X
R
Solvent Temp. Product Yield (%)
b
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
4a H
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Ph
Ph
Ph
THF
DMFc
r.t.
r.t.
-
4a H
5a-trans 52
4a H
Benzene 80 C 5a-cis
48d
55d
4b H
Cyclohexyl Benzene 80 C 5b-cis
e
4c 4,4’-F
4c 4,4’-F
4c 4,4’-F
4c 4,4’-F
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
THF
DMFc
r.t.
r.t.
-
5c-trans 53
Benzene 80 C 5c-cis
Toluene 110 C 5c-cis
87
98
4d 4,4’-Cl CH
4d 4,4’-Cl CH
4d 4,4’-Cl CH
THF
DMFf
r.t.
r.t.
5d-trans 89
5d-trans 93
0
1
2
3
4
5
6
Benzene 80 C 5d-trans 67
4e 3,3’-CF
4e 3,3’-CF
4e 3,3’-CF
3
3
3
CH
CH
CH
THF
DMFf
r.t.
r.t.
5e-trans 99
5e-trans 93
Benzene 80 C 5e-trans 93
4f 4,4’-Me CH
4f 4,4’-Me CH
Toluene 110 C 5f-cis
DMF 110 C 5f-cis
48g
55
a
b
c
The reaction of 4g (X = 4,4'-OMe) gave a complex mixture. A complex mixture. The
d
reaction in DMF at 80 or 110 C gave a mixture of 5-cis and 5-trans. The reaction in toluene
e
at 110 C gave 5-cis in lower yields (5a-cis 32%, 5b-cis 26%) and a complex mixture. A
f
mixture containing 5c-trans. The reaction in DMF at 80 or 110 C also gave 5-trans in 89-
6
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
g
9
5% yields. The reaction in benzene at 80 C gave 5f-cis in lower yield (17%) and a complex
mixture.
To obtain some insights into the mechanism, the reactions with dissymmetrically
substituted 3,3-diaryl-2-propen-1-amines have been studied (eq 3, Table 3). Reaction of 1 with
(
Z) and (E)-3-(2- or 4-chlorophenyl)-3-phenyl-2-propen-1-amines 4h-j in the presence of
EDCI/HOBt/Et N at room temperature gave trans-fused hexahydrobenzo[f]isoindoles 5h,i,j-
3
trans stereoselectively in 30-86% yield (entries 1,2,5,6,11). At higher temperature in benzene
or toluene, cis-fused hexahydrobenzo[f]isoindoles 5h,i,j-cis were also formed (entries
3
,4,8,9,13,14). Reaction of 1 with (Z)-3-(4-nitrophenyl)-3-phenyl-2-propen-1-amine 4k in the
presence of EDCI/HOBt/Et N at 110 °C gave trans-fused hexahydrobenzo[f]isoindoles 5k-
3
trans as a major product in 55% yield. Highly electron-deficient NO group on phenyl group
2
may decrease the [4+2] cycloaddition reaction rate. Thus, E-substituted aryl group reacted
selectively as a styrene component.
X1
4
3
EtO C
CO Et
2
2
Et N
HOBt
EDCI
3
2
+
1
HO C
2
1
'
'
Ph
N
H
X2
1
2
4
'
3
'
4h-k
EtO C
2
EtO C
CO Et
2
O
2
CO Et
O
2
H
H
X2
X2
N
N
Ph
H
Ph
H
(eq 3)
5-trans
X1
5-cis
X1
Table 3. Reactions of 1,1,2-ethenetricarboxylic acid 1,1-diethyl ester 1 and dissymmetrically
substituted 3,3-diaryl-2-propen-1-amines 4h-k
Entry 4 X1
X2 Solvent Temp. 5-trans (Yield %) 5-cis (Yield %)
1
2
4h 2-Cl
4h 2-Cl
H
H
THF
r.t.
r.t.
5h-trans (30)
5h-trans (33)
DMF
7
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
a
a
5h-cis (32)a
5h-cis (56)a
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
4h 2-Cl
4h 2-Cl
4i 4-Cl
4i 4-Cl
4i 4-Cl
4i 4-Cl
4i 4-Cl
4j H
H
H
H
H
H
H
H
Benzene 80 C 5h-trans (18)
Toluene 110 C 5h-trans (28)
THF
DMF
DMF
r.t.
r.t.
5i-trans (59)
5i-trans (72)
80 C 5i-trans (58)
a
5i-cis (27)a
5i-cis (39)a
Benzene 80 C 5i-trans (48)
a
Toluene 110 C 5i-trans (5)
0
1
2
3
4
5
6
7
8
4'-Cl THF
4'-Cl DMF
4'-Cl DMF
r.t.
r.t.
5j-trans (-)b
4j H
5j-trans (86)
4j H
80 C 5j-trans (71)
a
5j-cis (18)a
5j-cis (31)a
4j H
4'-Cl Benzene 80 C 5j-trans (61)
4'-Cl Toluene 110 C 5j-trans (47)
a
4j H
4k 4-NO
4k 4-NO
4k 4-NO
4k 4-NO
2
2
2
2
H
H
H
H
THF
r.t.
r.t.
5k-trans (32)c
5k-trans (34)c
DMF
Toluene 110 C 5k-trans (55)
d
DMF
110 C 5k-trans (36)
a
1
b
The yields were calculated by H NMR. A complex mixture containing a small amount of
c
5
j-trans. A complex mixture containing unidentified compounds was formed along with 5k-
d
trans. A small amount of possible phenyl epimer of 5k-trans was also formed but could not
be purified.
Next the reactions of other electron-deficient alkenes 6 with carboxyl group and 3,3-
diaryl-2-propen-1-amines 4 were carried out in order to examine the generality of the reaction
(
eq 4, Table 4). Reaction of β-substituted (CO
2
Me, CF
3
, bisCF ) α,β-unsaturated carboxylic
3
acids 6a-c and 3,3-diaryl-2-propen-1-amines (Ar=Ph, C
at room temperature gave the corresponding amides 7.18 On the other hand, the reaction of
a,c and 4a, 6a-c and 4d on heating (at 60-160 C) gave trans-fused tricyclic compounds 8 as
major products.
6
H
4
-4-Cl) 4a,d with EDCI/HOBt/Et N
3
6
8
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
X
HOBt
EDCI
E1
E2
+
Et N
3
HO C
2
Ph
N
20 h
6
H
X
4
E1 E2
E1
X
E2
O
H
H
X
O
N
N
Ph
Ph
(
eq 4)
7
8
X
X
Table 4. Reactions of electron-deficient alkenes 6 and 3,3-diaryl-2-propen-1-amines 4.
Entry 6 E1 E2
X Solvent Temp. Product Yield (%)
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
6a H CO
2
Me 4a H THF
r.t.
7aa
ca. 77
47
6a H CO
2
Me 4a H Toluene 110 C 8a
6b H CF
6b H CF
6b H CF
3
4a H THF
r.t.
7b
c
89
3
4a H Xylene 140 C
-
b
c
3
3
3
3
4a H Toluene 160 C
-
6c CF
6c CF
6c CF
3
3
3
CF
CF
CF
4a H THF
r.t.
7ca
ca. 39
37
4a H Benzene 80 C 8c
4a H Toluene 110 C 8c
48
6a H CO
6a H CO
6a H CO
6a H CO
2
2
2
2
Me 4d Cl THF
Me 4d Cl THF
r.t.
7da
ca. 86
80
0
1
2
3
4
5
6
7
8
9
60 C 8d
Me 4d Cl Benzene 80 C 8d
Me 4d Cl Toluene 110 C 8d
75
69
6b H CF
6b H CF
6b H CF
6b H CF
3
4d Cl THF
r.t.
7e
77
3
4d Cl Toluene 110 C 7e
4d Cl Xylene 140 C 8e
67
3
3
3
3
3
27
b
4d Cl Toluene 160 C 8e
38
6c CF
6c CF
6c CF
3
3
3
CF
CF
CF
4d Cl THF
r.t.
7fa
ca. 57
53
4d Cl Benzene 80 C 8f
4d Cl Toluene 110 C 8f
45
a
b
Products 7a,c,d,f are unstable and decompose to give complex mixtures gradually. In a
c
closed vessel. A complex mixture.
9
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
Transformation of the amides 7 to the tricyclic compounds 8 was also examined. Thermal
reaction of 7a,c,d,f with and without acid or base gave 8 in 21-88% yield (eq 5, Table 5).
E1 E2
E1
X
E2
O

H
H
X
O
with or without
HCl or Et N
N
3
N
Ph
Ph
(
eq 5)
7
8
X
X
Table 5. Transformation of amides 7 to hexahydrobenzo[f]isoindoles 8.
Entry 7 E1 E2
X Solvent Additive
Me H Toluene none
Temp. Product Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
7a H CO
7a H CO
7a H CO
2
2
2
110 C 8a
21
67
83
0b
a
Me H Toluene HCl (1 equiv) 110 C 8a
Me H Toluene Et N (1 equiv) 110 C 8a
H Toluene none 110 C 8b
H Toluene HCl (1 equiv) 110 C 8b
3
7b H CF
7b H CF
7b H CF
3
a
0b
0b
3
3
3
H Toluene Et
H Toluene Et
3
3
3
N (1 equiv) 110 C 8b
N (1 equiv) 110 C 8c
N (1 equiv) 60 C 8d
7c CF
3
CF
55
88
0b
7d H CO
2
Me Cl THF
Et
7e H CF
7e H CF
7e H CF
3
Cl Toluene none
110 C 8e
a
0b
0
1
2
3
Cl Toluene HCl (1 equiv) 110 C 8e
0b
3
3
Cl Toluene Et
3
3
N (1 equiv) 110 C 8e
N (1 equiv) 110 C 8f
7f CF
3
CF
Cl Toluene Et
87
a
b
1
M HCl in ether was added. No reaction.
Theoretical study
In order to understand the reaction mechanism of the cycloadditions and find the factors
to control cis and trans-fused stereochemistry, a theoretical study was carried out by DFT
calculation. Some theoretical studies on cis and trans-fused stereoselectivity of intramolecular
Diels-Alder reactions have been reported.10c-f The selectivity varies depending on the steric
and electronic effects of linkers and substituents.
The reaction mechanism was examined using B3LYP/6-31G* 19 , 20 calculations
including the PCM 21 solvent effect (solvent=THF). TS geometry was characterized by
1
0
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
vibrational analysis, which checked whether the obtained geometry has single imaginary
‡
frequencies ( ). From TSs, reaction paths were traced by the intrinsic reaction coordinate
(
IRC) method22 to obtain the energy-minimum geometries. ΔE (sum of electronic and zero-
point energies) for Schemes 2-4 were refined by single-point calculations of RB3LYP/6-
11+G(d,p) SCRF = (PCM, solvent = THF).
4+2] Cycloadditions without acid catalyst for Z-cinnamyl amide models were
3
[
calculated and the concerted path to 3a,9a-cis-fused and 8a,9a-trans [4+2] cycloadduct DZM
was obtained and is shown in Scheme 2. The path to give 3a,9a-trans-fused and 8a,9a-cis
cycloadduct could not be obtained because of the steric hindrance. Intermolecular proton
transfer of DZM possibly leads to rearomatized product 3M. A plausible mechanism involving
stepwise proton transfer via CO
2
R groups (R = Me in the model) could be included as shown
in Scheme 2.
TSZa
MeO C CO Me
2
2
MeO C CO Me
‡
2
2
E =+21.46
kcal/mol]
O
1
H
H
8
9
7
6
O
9
a 8a
N
3a
2
N
3
H 4
5

E=+2.78

E=0
kcal/mol]
kcal/mol]
DZM
AZM
H
O
OMe
H
O
MeO C CO Me
MeO
O
2
2
O
H
H
+
H+
H
N
N
H
H
H
H
O H
O
MeO C
2
CO Me
2
MeO
O
O
H
OMe -H+
H
N
N
H
H

E=-28.14
kcal/mol]
3
M
1
1
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
Scheme 2. [4+2] Cycloaddition path for Z-cinnamyl amide. ΔE’s (sum of electronic and zero-
point energies) by B3LYP/6-311+G(d,p) SCRF = (PCM, solvent = THF) // B3LYP/6-31G*
SCRF = (PCM, solvent = THF) relative to AZM are shown.23 The optimized structure of 3M
was obtained in the previous work.13
Next, the cis and trans-fused stereoselectivity for reaction of diaryl propenyl amides in
the [4+2] cycloaddition path has been examined by DFT calculations (Scheme 3). For
formation of trans-fused [4+2] cycloadduct CM1-trans, the asynchronous and concerted path
for X = H was obtained. For formation of cis-fused [4+2] cycloadduct CM2-cis, stepwise path
via zwitterionic intermediate BM2-cis was obtained.24 The activation energy TSa (+21.47
kcal/mol) leading to CM1-trans is lower than TSb (+22.51 kcal/mol) and TSc (+24.06
kcal/mol) leading to CM2-cis. However, the cycloadduct CM2-cis (+5.96 kcal/mol) is more
stable than CM1-trans (+11.03 kcal/mol). The stability of CM2-cis may be partially attributed
to 8a,9a-cis (1,3-diequatorial-like) conformation of the cyclohexene ring. At higher
temperature, the reaction leads to the more stable [4+2] cycloadduct CM2-cis. The path
reacting with Z-phenyl group (via AM3 → BM3-cis → CM3-cis) was also calculated.
However, the path to give CM3-cis with 8a,9a-trans stereochemistry is unfavorable. The paths
reacting with Z-phenyl group to give 3a,9a-trans stereochemistry could not be obtained
because of the steric hindrance, similar to the result of Z-cinnamyl amide. Thus, the reaction
paths at E-substituted phenyl group of diphenyl propenyl substrates as a diene moiety were
preferentially obtained for both trans and cis-fused products by the DFT calculations. This is
in agreement with the experimental results of reactions of dissymmetrically substituted diaryl-
2
-propen-1-amines 4h-k.
The reaction at room temperature proceeds favorably to give CM1-trans and the use of
polar solvent such as DMF facilitates the stepwise protonation-deprotonation and leads to the
trans-fused rearomatized product 5M-trans.
1
2
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
MeO C
2
MeO C CO Me
CO Me
MeO C CO Me
2
2
O
2
2
2
MeO C CO
Me
H
O
H
2
2
X
O
TSa'
H
H
TSa
X
Me
X
O
N
N
N
N
[
X=H; +21.47
H+ shift
[X=Me; +15.15
kcal/mol]
H
H
kcal/mol]
X=Cl; +22.26
kcal/mol]
X=Me; +19.88
kcal/mol]
H
[
AM1
[
Me
BM1-trans
[X=Me; +15.37 kcal/mol]
5M-trans
[

X=H,Cl,Me;
E = 0
kcal/mol]
CM1-trans
X
X
X
[
[
[
X=H; -19.64 kcal/mol]
X=Cl; -18.71 kcal/mol]
X=Me; -19.46 kcal/mol]
[
[
X=H; +11.03 kcal/mol]
X=Cl; +11.40 kcal/mol]
[X=Me; +10.75 kcal/mol]
X
MeO C CO Me
MeO
2
C
MeO C
TSc
2
2
CO Me
2
TSb
2
O
MeO C
O
CO Me
2
O
H
2
H
H
H
X
X
X
MeO C
N
2
N
N
[
X=H; +24.06
kcal/mol]
X=Cl; +25.42
kcal/mol]
X=Me; +22.63
kcal/mol]
N
O
+
H
H
H
shift
AM2
H
[
X
[
[
[
[
X=H; -0.48 kcal/mol]
X=Cl; +4.05 kcal/mol]
X=Me; -0.34 kcal/mol]
[
X=H; +22.51
kcal/mol]
BM2-cis
5M-cis
X
X
CM2-cis
X
[
X=Cl; +24.14 [X=H; +22.19 kcal/mol]
[X=Cl; +23.83 kcal/mol]
X=Me; +21.02 [X=Me; +19.82 kcal/mol]
[X=H; +5.95 kcal/mol]
[X=Cl; +6.33 kcal/mol]
[X=Me; +5.64 kcal/mol]
[X=H; -15.00 kcal/mol]
[X=Cl; -14.14 kcal/mol]
[X=Me; -14.96 kcal/mol]
kcal/mol]
[
kcal/mol]
[X=H]
MeO C CO
Me
TSd
X=H; +23.43 O
kcal/mol]
TSe
MeO C CO Me
2
2
2
2
MeO C
2
[
CO
2
Me [X=H; +26.04
kcal/mol]
O
H
H
H
O
N
N
N
H
H
AM3
CM3-cis
[X=H; +7.10 kcal/mol]
BM3-cis
[
X=H; -0.26 kcal/mol]
[X=H; +23.84 kcal/mol]
Scheme 3. [4 + 2] Cycloaddition reaction paths for model compounds of diaryl propenyl
amides. ΔE’s (sum of electronic and zero-point energies) by B3LYP/6-311+G(d,p) SCRF =
(
PCM, solvent = THF) // B3LYP/6-31G* SCRF = (PCM, solvent = THF) relative to AM1 are
shown. The 3D-structures of intermediates and transition states are shown in Supporting
Information.
The 1,3-H shift may not be a concerted process, 25 and the possible stepwise
+
26
protonation-deprotonation (H 1,3-shift) is also considered to play an important role to cis
and trans fused stereoselectivity in these cases. Selective formation of the stereochemistry at
the 4-aryl group may arise from the protonation from less hindered side (cis to adjacent H).
The result is in agreement with predominant formation of 10a in the [4+2] cycloaddition
reaction of N-allyl-N-diphenylallyl amide 9 at 180 °C for 6 days reported by Oppolzer et al.
5
c
(
eq 6). Intramolecular [4+2] cycloaddition of styrenes with [1,3]-hydrogen shift assisted di-
t-butylhydroxytoluene at 160 °C was also reported and radical intermediates were postulated.5j
1
3
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
180 C
6
d
N
O
o-dichloro-
benzene
CF3
ref. 5c
9
H
H
H
H
O
O
N
N
4
F3C
F3C
(eq 6)
10a (38%)
10b (10%)
The reaction of 4,4'-chlorophenyl and 4,4'-methylphenyl substrate models (X = Cl, Me)
were also calculated. In the reaction of 4,4'-methylphenyl substrate model (X = Me), the path
via intermediate BM1-trans was obtained.
+
The stepwise H 1,3-shift of CM2-cis (X = H and Me) by catalytic acid in situ leads to
rearomatized 5M-cis. The path through TSb with partial ionic character and zwitterionic
intermediate BM2-cis (X = Cl) is less stable than those of (X = H and Me) because of
destabilization by electron-withdrawing chloro-substituents.
The observed difference on cis- and trans-fused selectivity by substituents in eq 2 and
2
7
Table 2 may be correlated to the Hammet constants . (p-Me, -0.07) gave cis-fused
product. (H, 0, p-F, 0.06) gave cis and trans-fused products depending on the reaction
conditions. Positive values of (p-Cl, 0.23, m-CF , 0.43) only gave trans-fused
3
cycloadducts.Larger negative value of  (p-OMe, -0.27) gave a complex mixture, probably
because of the formation of the byproducts. The selective formation of trans-fused ring of
mono-NO
2
-substituted 5k-trans (eq 3, Table 3) may be attributed to the destabilization of the
-substituted substrates.
cation intermediate BM2-cis similar to bis-Cl and CF
3
Diels–Alder reactions of furan with halogen substituents have been found to increase
rates and yields. 28 Nitrofurans also undergo intramolecular Diels–Alder reactions more
rapidly and in higher yield than non-nitrated furans.29 Further study for the effects of the
1
4
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
electron-withdrawing groups to styrene moiety as dienes in the Diels-Alder reaction is under
investigation.
Next, the [4+2] cycloaddition reaction path of less reactive methyl (2E)-4-amino-4-
oxo-2-butenoates 7 has been examined (Scheme 4). For 7M, the models of 7a,d, the concerted
paths lead to both cis and trans adducts. The activation energies of TSFa and TSFb for 7M
leading to cycloadducts CMF-trans and CMF-cis are substantially higher than those of TSa,
TSb, and TSc in Scheme 3. The path with lower activation barrier TSFa may give trans-[4+2]
cycloadduct CMF-trans and the final stable aromatic ring-reproduced product 8M-trans by the
+
stepwise protonation-deprotonation (H 1,3-shift) under the reaction conditions.
The reaction of less reactive amides 7a,c,d,f with HCl or Et N has been shown to give
3
the cyclized products. The 1,3-H shift under thermal conditions without acid or base for 7a
may proceed intermolecularly as well. The [4+2] cycloaddition may be reversible and the
catalysts accelerate the 1,3-H shift step.
1
5
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European Journal of Organic Chemistry
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CO Me
CO Me
2
2
CO Me
2
O
X
H
H
O
H
H
H
X
TSFa
X=H;
X
O
N
N
[
N
+
H shift
+27.85
kcal/mol]
[X=Cl;
+
27.32
7
M1
X=H,Cl;
E = 0
kcal/mol]
kcal/mol]
X
[

X
X
CMF-trans
8M-trans
[X=H; -23.12
kcal/mol]
[
X=H; +7.33
kcal/mol]
[X=Cl; -23.30
[X=Cl; +6.71
kcal/mol]
kcal/mol]
CO Me
CO Me
2
2
CO Me
2
O
O
H
H
H
H
H
X
O
X
TSFb
X
N
N
N
+
H shift
[
X=H;
30.44
kcal/mol]
X=Cl;
30.38
kcal/mol]
+
X
M-cis
X
8
X
CMF-cis
X=H; +3.82
kcal/mol]
X=Cl; +3.44
kcal/mol]
[
+
7
M2
X=H; +3.98
kcal/mol]
X=Cl; +3.97
kcal/mol]
[
[X=H; -19.61
kcal/mol]
[X=Cl; -19.50
kcal/mol]
[
[
[
Scheme 4. [4 + 2] Cycloaddition reaction paths for the models of 7a,d. ΔE’s (sum of electronic
and zero-point energies) by B3LYP/6-311+G(d,p) SCRF = (PCM, solvent = THF) // B3LYP/6-
3
1G* SCRF = (PCM, solvent = THF) are shown. The 3D-structures of intermediates and
transition states are shown in Supporting Information.
Conclusions
In summary, intramolecular Diels–Alder reactions of various 3,3-
diarylpropenylamides of electron-deficient alkenes to give hexahydrobenzo[f]isoindoles were
investigated. Reaction of 1,1,2-ethenetricarboxylic acid 1,1-diethyl ester with 3,3-
diarylpropenylamines or Z-cinnamyl amines under the amide formation conditions gave the
tricyclic compounds in sequential processes involving intramolecular Diels-Alder reaction.
When the electron-withdrawing substituents (positive values of Hammet constants) are
present on benzene ring, the [4+2] cycloaddition proceeds in trans-fused manner. When the
1
6
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
substituents such as H and F ( near 0) are present, the reaction gives cis and trans-fused
products depending on the reaction conditions. When the substituents (slightly negative values
of ) are present, the reaction gives cis-fused product. These processes are controlled by the
substituents on the benzene ring, reaction temperature and solvent. Reaction of electron-
deficient alkenic carboxylic acids such as fumarate and 3,3-diaryl-2-propen-1-amines under
the amide formation conditions at room temperature gave the corresponding amides, and the
reaction on heating gave trans-fused hexahydrobenzo[f]isoindoles. The origin of observed
stereoselectivity of the fused rings has been examined by the DFT calculations.
Experimental Section
1
13
General Methods. H Chemical shifts are reported in ppm relative to Me
4
Si. C Chemical
(77.1 ppm). F Chemical shifts are reported in
. C multiplicities were determined by DEPT and HSQC. Mass spectra
1
9
shifts are reported in ppm relative to CDCl
3
1
3
ppm relative to CFCl
3
were recorded at an ionizing voltage of 70 eV by EI, FAB or ESI. Mass analyzer type used for
EI and FAB is double-focusing and that for ESI is TOF in the HRMS measurements. All
reactions were carried out under a nitrogen atmosphere. Column chromatography was
performed on silica gel (75-150 m).
1
,1,2-Ethenetricarboxylic acid 1,1-diethyl ester 1 was prepared according to the literature.30
Z)-Cinnamyl alcohol 31 was prepared by hydrogenation of 3-phenyl-2-propyn-1-ol with
Lindlar catalyst in methanol.
Z)-Cinnamyl bromide32 was prepared by reaction of (Z)-cinnamyl alcohol with PBr
and
(
(
3
pyridine in ether and used without further purification. Z-Cinnamylamines 2a-b were prepared
by reaction of benzylamine or cyclohexylamine (2 equiv) with (Z)-cinnamyl bromide in ether
according to the literature procedure.33
(
Z)-Benzyl cinnamylamine (2a): Z:E = 5:1 (2.4 mmol scale, 274 mg, 51%); R = 0.1 (hexane-
f
1
ether = 1 : 1); colorless oil; H NMR (400 MHz, CDCl
3
) δ (ppm) For a major isomer, 1.68 (bs,
1H), 3.55 (dd, J = 6.6, 1.9 Hz, 2H), 3.77 (s, 2H), 5.65 (dt, J = 11.6, 6.6 Hz, 1H), 6.53 (d, J =
1
7
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
1
1.6 Hz, 1H), 7.19-7.37 (m, 10H). Selected NOEs are between  5.65 (=C-H) and  6.53 (=C-
1
3
H).; C NMR (100.6 MHz, CDCl
26.93 (CH), 127.01 (CH), 128.19 (CH), 128.27 (CH), 128.41 (CH), 128.80 (CH), 130.78
CH), 130.94 (CH), 137.07 (C), 140.04 (C); IR (neat) 3313, 3024, 2831, 1599, 1494, 1453,
3
) δ (ppm) For a major isomer, 46.99 (CH
2
), 53.53 (CH
2
),
1
(
-1
+
1
115, 1028 cm ; MS (EI) m/z 223 (M , 35), 222 (17), 132 (100%); HRMS (EI) m/z 223.1372
(
(
calcd for C16
H
17N 223.1361).
Z)-Cinnamyl cyclohexylmethylamine (2b): Z:E = 5:1 (20 mmol scale, 2.24 g, 49%); R =
f
1
0
.4 (hexane-ether = 1 : 4); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) For a major
isomer, 0.834-0.957 (m, 2H), 1.08-1.29 (m, 3H), 1.36-1.48 (m, 1H), 1.62-1.77 (m, 5H), 2.43
d, J = 6.6 Hz, 2H), 3.50 (dd, J = 6.5, 1.9 Hz, 2H), 5.76 (dt, J = 11.7, 6.5 Hz, 1H), 6.49 (d, J =
(
1
1.7 Hz, 1H), 7.16-7.37 (m, 5H). Selected NOEs are between  5.76 (=C-H) and  6.49 (=C-
1
3
H) and between  3.50 (CH
2
) and  7.16-7.37 (Ph).; C NMR (100.6 MHz, CDCl
3
) δ (ppm)
), 56.48
For a major isomer, 26.03 (CH
2
), 26.66 (CH ), 31.45 (CH ), 38.01 (CH), 47.92 (CH
2
2
2
(
CH
neat) 3323, 3023, 2923, 1600, 1494, 1447, 1124 cm ; MS (EI) m/z 229 (M , 9.3), 146 (19),
17 (100%); HRMS (EI) m/z 229.1836 (calcd for C16 23N 229.1830).
2
), 126.76 (CH), 128.08 (CH), 128.74 (CH), 130.14 (CH), 131.56 (CH), 137.18 (C); IR
-1
+
(
1
H
Typical experimental procedure for eq 1 (eq 1, Table 1, entry 2). To a solution of 1,1,2-
ethenetricarboxylic acid 1,1-diethyl ester (1) (prepared from 1,1-diethyl 2-tert-butyl
3
0
ethenetricarboxylate (272 mg, 1 mmol) upon treatment with CF
3
CO
2
H (4 mL)) in benzene
(
0.7 mL) were added Z-benzyl cinnamylamine (2a) (223 mg, 1 mmol) in benzene (0.7 mL),
Et
3
N (0.14 mL, 102 mg, 1 mmol), HOBt (1-hydroxybenzotriazole) (270 mg, 2 mmol) and
EDCI (1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride) (199 mg, 1.04
mmol) at 0 °C. The reaction mixture was stirred for 1 h at 0 °C, and then heated at 80 °C and
stirred for 20 h. The reaction mixture was diluted with CH
with saturated aqueous NaHCO solution, 2M aqueous citric acid, saturated aqueous NaHCO
and water, dried (Na SO ), and evaporated in vacuo. The residue was purified by column
chromatography over silica gel eluting with hexane-Et O to give 3a (261 mg, 62%).
2
Cl . The organic phase was washed
2
3
3
2
4
2
1
8
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
1
3
a: R
f
= 0.5 (hexane-ether = 1 : 4); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 1.17
(
t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H), 2.34 (dd, J = 17.4, 11.1 Hz, 1H), 2.86-2.98 (m,
3
1
H), 3.49 (dd, J = 8.5, 8.5 Hz, 1H), 3.59 (d, J = 11.1 Hz, 1H), 4.07-4.26 (m, 2H), 4.27 (d, J =
4.7 Hz, 1H), 4.35-4.40 (m, 2H), 4.67 (d, J = 14.7 Hz, 1H), 7.08 (d, J = 7.2 Hz, 1H), 7.15-7.18
1
3
(
(
(
(
(
m, 2H), 7.20-7.30 (m, 5H), 7.53 (dd, J = 7.7, 1.3 Hz, 1H); C NMR (100.6 MHz, CDCl
3
) δ
ppm) 13.80 (CH
3
), 13.99 (CH
3
), 29.05 (CH), 33.21 (CH
2
), 46.85 (CH
2
), 48.41 (CH), 52.48
CH ), 60.72 (C), 61.72 (CH
2
2
), 62.29 (CH ), 126.96 (CH), 127.34 (CH), 127.77 (CH), 127.82
2
CH), 127.97 (CH), 128.22 (CH), 128.49 (CH), 135.36 (C), 136.14 (C), 136.35 (C), 168.81
1
C), 169.88 (C), 172.77 (C); H NMR (400 MHz, C
6
D ) δ (ppm) 0.843 (t, J = 7.1 Hz, 3H),
6
0
6
9
1
.949 (t, J = 7.1 Hz, 3H), 2.09 (dd, J = 14.8, 8.6 Hz, 1H), 2.35 (ddddd, J = 11.5, 9.0, 8.6, 7.2,
.4 Hz, 1H), 2.50 (dd, J = 14.8, 7.2 Hz, 1H), 2.58 (dd, J = 9.0 Hz, 6.4 Hz, 1H), 2.88 (dd, J =
.0, 9.0 Hz, 1H), 3.62 (d, J = 11.5 Hz, 1H), 3.81-3.89 (m, 1H), 4.01-4.17 (m, 3H), 4.17 (d, J =
4.8 Hz, 1H), 4.35 (d, J = 14.8 Hz, 1H), 6.78 (d, J = 7.0 Hz, 1H), 6.93-7.08 (m, 7H), 7.83 (dd,
J = 7.8, 1.0 Hz, 1H). Selected NOEs are between  2.35 (C3a-H) and  3.62 (C9a-H), 2.88
13
(
C3-HH) and 2.50 (C4-HH). Atom numbering is shown in Supporting Information.; C NMR
100.6 MHz, C ) δ (ppm) 13.85 (CH ), 13.95 (CH ), 29.30 (CH), 33.24 (CH ), 46.94 (CH ),
(
6
D
6
3
3
2
2
4
1
1
2

3
8.68 (CH), 52.21 (CH
2
), 61.08 (C), 61.61 (CH
2
), 62.17 (CH ), 127.13 (CH), 127.38 (CH),
2
27.89 (CH), 128.24 (CH), 128.49 (CH), 128.66 (CH), 128.73 (CH), 136.15 (C), 136.78 (C),
37.29 (C), 168.87 (C), 169.95 (C), 172.26 (C). Selected HMBC correlations are between 
.35 (C4-HH), 2.50 (C4-HH), 2.58 (C3-HH), 2.88 (C3-HH), 3.62 (C9a-H) and  29.30 (C3a),
2.58 (C3-HH), 2.88 (C3-HH), 3.62 (C9a-H), 6.78 (C5-H) and  33.24 (C4), and between 
.62 (C9a-H) and  61.08 (C9).; IR (neat) 2980, 1734, 1689, 1485, 1444, 1247, 1096, 1031
-1
+
cm ; MS (EI) m/z 421 (M , 45), 347 (8.4), 303 (14), 301 (12), 91 (100%); HRMS (EI) m/z
4
21.1906 (calcd for C25
H
27NO 421.1889).
5
3
b: (1 mmol scale, toluene, 110 °C, 262 mg, 61%); R = 0.3 (hexane-ether = 1 : 4); pale yellow
f
1
oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 0.803-0.925 (m, 2H), 1.09-1.20 (m, 3H), 1.17 (t, J =
7
.0 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.43-1.70 (m, 6H), 2.40 (dd, J = 17.5, 11.0 Hz, 1H), 2.87
dd, J = 13.5, 6.7 Hz, 1H), 2.96-3.01 (m, 2H), 3.05 (dd, J = 9.0, 5.9 Hz, 1H), 3.30 (dd, J = 13.5,
.8 Hz, 1H), 3.55 (d, J = 10.7 Hz, 1H), 3.66 (dd, J = 9.0, 8.6 Hz, 1H), 4.08-4.26 (m, 2H), 4.34
(
7
1
9
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
13
(
q, J = 7.1 Hz, 2H), 7.11-7.13 (m, 1H), 7.20-7.28 (m, 2H), 7.54-7.57 (m, 1H); C NMR (100.6
MHz, CDCl
3
) δ (ppm) 13.83 (CH
9.17 (CH), 30.74 (CH ), 30.78 (CH
4.10 (CH ), 60.54 (C), 61.65 (CH
3
), 13.98 (CH
3
), 25.77 (CH
2
), 25.83 (CH
2
), 26.38 (CH
2
),
),
2
5
1
2
2
), 33.34 (CH ), 35.85 (CH), 48.52 (CH), 49.40 (CH
2
2
2
2
), 62.24 (CH
2
), 126.94 (CH), 127.71 (CH), 127.95 (CH),
1
27.97 (CH), 135.36 (C), 136.14 (C), 168.75 (C), 169.90 (C), 172.96 (C); H NMR (400 MHz,
C
6
D
6
) δ (ppm) 0.689-0.850 (m, 2H), 0.965-1.12 (m, 3H), 0.938 (t, J = 7.1 Hz, 3H), 0.993 (t, J
=
7.0 Hz, 3H), 1.36-1.45 (m, 2H), 1.49-1.63 (m, 4H), 2.26 (dd, J = 14.8, 8.2 Hz, 1H), 2.53
(
ddddd, J = 11.3, 8.8, 8.2, 7.0, 6.4 Hz, 1H), 2.69 (dd, J = 14.8, 7.0 Hz, 1H), 2.73 (dd, J = 9.0,
6.4 Hz, 1H), 2.90 (dd, J = 13.5, 6.8 Hz, 1H), 3.04 (dd, J = 9.0, 8.8 Hz, 1H), 3.12 (dd, J = 13.5,
7.2 Hz, 1H), 3.71 (d, J = 11.3 Hz, 1H), 3.91-3.99 (m, 1H), 4.07-4.24 (m, 3H), 6.92 (d, J = 7.4,
0.6 Hz, 1H), 7.05 (ddd, J = 7.6, 7.4, 1.2 Hz, 1H), 7.14 (ddd, J = 7.8, 7.6, 1.4 Hz, 1H), 8.01 (d,
J = 7.8 Hz, 1H). Selected NOEs are between  2.53 (C3a-H) and  3.71 (C9a-H), 3.04 (C3-
1
3
HH) and 2.69 (C4-HH).; C NMR (100.6 MHz, C
6
D
6
) δ (ppm) 13.85 (CH
3
), 13.90 (CH ),
3
2
4
1
1
6.15 (CH
2
), 26.70 (CH
2
), 29.43 (CH), 30.88 (CH
2
), 31.06 (CH
2
), 33.44 (CH
2
), 36.16 (CH),
8.76 (CH), 49.47 (CH
2
), 53.77 (CH ), 60.88 (C), 61.53 (CH
2
2
), 62.10 (CH
2
), 127.14 (CH),
27.76 (CH), 128.24 (CH), 128.98 (CH), 136.10 (C), 136.71 (C), 168.76 (C), 169.93 (C),
72.34 (C). Selected HMBC correlations are between  2.26 (C4-HH), 2.69 (C4-HH), 2.73
(C3-HH), 3.04 (C3-HH), 3.71 (C9a-H) and  29.30 (C3a),  2.58 (C3-HH), 2.88 (C3-HH),
3
.62 (C9a-H), 6.92 (C5-H) and  29.43 (C4), and between  3.62 (C9a-H) and  60.88 (C9).;
-1
IR (neat) 2925, 2852, 1733, 1690, 1485, 1448, 1366, 1236, 1118, 1095, 1035 cm ; MS (EI)
+
m/z 427 (M , 9.9), 345 (11), 117 (10), 84 (100%); HRMS (EI) m/z 427.2368 (calcd for
C
25
H
33NO 427.2359).
5
Arylpropenyl esters, ethyl 3,3-diphenylacrylate Xa (for 4a-b), ethyl 3,3-bis-(4-
fluorophenyl)acrylate Xc (for 4c), ethyl 3,3-bis-(4-chlorophenyl)acrylate Xd (for 4d), ethyl
3
,3-bis[3-(trifluoromethyl)phenyl]acrylate Xe (for 4e) and ethyl (2Z)-3-(2-chlorophenyl)-3-
phenylprop-2-enoate Xh (for 4h) and the corresponding alcohols, 3,3-diphenylprop-2-en-1-ol
Ya, 3,3-bis(4-fluorophenyl)prop-2-en-1-ol Yc, 3,3-bis(4-chlorophenyl)prop-2-en-1-ol Yd,
3
,3-bis[3-(trifluoromethyl)phenyl]prop-2-en-1-ol Ye, and 3-(2-chlorophenyl)-3-phenylprop-
2
0
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
17
2
-en-1-ol Yh were prepared according to the literature. Arylpropenyl esters Xf (for 4f), Xg
(
(
for 4g), Xi (for 4i ), Xj (for 4j), Xk (for 4k) and the corresponding alcohols Yf (for 4f), Yg
for 4g), Yi (for 4i ), Yk (for 4k) were prepared by the literature methods.17
The stereochemistry of ethyl 3-(2-chlorophenyl)-3-phenylprop-2-enoate Xh obtained as a
1
7
major product by the literature method was reported as E but it was found to be Z by the
1
observed NOE's in C
data.
6
D
6
. The H NMR spectra of Xh in CDCl
3
were in accord with the reported
(
2E)-3-(4-chlorophenyl)-3-phenylprop-2-en-1-ol (Yj) (for 4j) was prepared by the Suzuki
cross-coupling reaction of (E)-3-bromo-3-phenylprop-2-en-1-ol and 4-chlorophenylboronic
acid by the literature method.34
Ethyl 3,3-bis-(4-methylphenyl)acrylate (Xf): (2.7 mmol scale, 721 mg, 95%); R = 0.4 (hexane-
f
1
ether = 4 : 1); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 1.14 (t, J = 7.1 Hz, 3H),
2
.34 (s, 3H), 2.39 (s, 3H), 4.06 (q, J = 7.1 Hz, 2H), 6.30 (s, 1H), 7.08-7.12 (m, 4H), 7.17-7.20
1
3
(
m, 4H); C NMR (100.6 MHz, CDCl
3
) δ (ppm) 14.13 (CH
3
), 21.29 (CH
3
), 21.44 (CH ), 59.96
3
(
CH
2
), 116.22 (CH), 128.38 (CH), 128.59 (CH), 129.09 (CH), 129.21 (CH), 136.16 (C), 137.94
(
C), 138.34 (C), 139.61 (C), 156.94 (C), 166.31 (C); IR (neat) 2980, 1723, 1604, 1508, 1368,
-1
+
1
264, 1160, 1038 cm ; MS (EI) m/z 280 (M , 98), 235 (100%); HRMS (EI) m/z 280.1459
(
calcd for C19
H
20
O
2
280.1463).
Ethyl 3,3-bis-(4-methoxyphenyl)acrylate (Xg): (2.7 mmol scale, 537 mg, 64%); R = 0.4
f
1
(
hexane-ether = 1 : 1); colorless oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 1.16 (t, J = 7.1 Hz,
3
H), 3.81 (s, 3H), 3.84 (s, 3H), 4.07 (q, J = 7.1 Hz, 2H), 6.23 (s, 1H), 6.84 (d-like, J = 9.0 Hz,
H), 6.91 (d-like, J = 8.7 Hz, 2H), 7.15 (d-like, J = 8.7 Hz, 2H), 7.24 (d-like, J = 9.0 Hz, 2H);
) δ (ppm) 14.21 (CH ), 55.27 (CH ), 55.39 (CH ), 59.90 (CH ),
13.26 (CH), 113.74 (CH), 114.97 (CH), 130.04 (CH), 130.91 (CH), 131.33 (C), 133.89 (C),
56.43 (C), 159.71 (C), 160.79 (C), 166.50 (C); IR (neat) 2979, 2837, 1717, 1600, 1513, 1250,
2
13C NMR (100.6 MHz, CDCl
3
3
3
3
2
1
1
1
3
-1
+
174, 1149, 1034 cm ; MS (EI) m/z 312 (M , 100), 267 (33), 240 (49%); HRMS (EI) m/z
12.1357 (calcd for C19 312.1362).
H
20
O
4
2
1
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European Journal of Organic Chemistry
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1
Ethyl (2Z)-3-(2-chlorophenyl)-3-phenylprop-2-enoate (Xh): H NMR (400 MHz, C
6
D
6
) δ
(
ppm) 0.824 (t, J = 7.1 Hz, 3H), 3.88 (q, J = 7.1 Hz, 2H), 6.61 (s, 1H), 6.86 (ddd, J = 7.6, 7.5,
2
.0 Hz, 1H), 6.91 (ddd, J = 7.5, 7.4, 1.4 Hz, 1H), 6.95-7.03 (m, 5H), 7.18-7.20 (m, 2H), 7.24
(
dd, J = 7.6, 1.4 Hz, 1H). Selected NOEs are between  6.61 (C2-H) and  7.18-7.20 (2-H of
1
3
Ph).; C NMR (100.6 MHz, C
6
D
6
) δ (ppm) 13.99 (CH
CH), 127.67 (CH), 128.79 (CH), 129.05 (CH), 129.57 (CH), 130.62 (CH), 133.14 (C), 138.74
C), 139.06 (C), 153.03 (C), 164.89 (C).
3
), 59.91 (CH
2
), 119.56 (CH), 126.54
(
(
Xi and Xj were obtained as a ca. 1:1 mixture. (20 mmol scale, 5.46 g, 95%). Xi (2.15 g, 38%)
was partially isolated by fractional crystallization of the mixture (from hexane). Xj (3:1 (Xj:Xi)
mixture) was obtained from the filtrates. The stereochemistries of Xi and Xj were assigned by
the NOE's of the corresponding alcohols Yi and Yj obtained by DIBAL-H reduction. The
spectral data for Yj obtained from Xj were in accord with those by the Suzuki cross-coupling
reaction.
Ethyl (2Z)-3-(4-chlorophenyl)-3-phenylprop-2-enoate (Xi): R
f
= 0.5 (hexane-ether = 4 : 1);
) δ (ppm) 1.16 (t, J = 7.1
1
colorless crystals; mp 67-68 C (hexane); H NMR (400 MHz, CDCl
3
Hz, 3H), 4.07 (q, J = 7.1 Hz, 2H), 6.37 (s, 1H), 7.15 (d-like, J = 8.4 Hz, 2H), 7.26-7.39 (m,
13
7
H); C NMR (100.6 MHz, CDCl
3
) δ (ppm) 14.12 (CH
3
), 60.27 (CH
2
), 117.92 (CH), 128.24
(
(
(
CH), 128.33 (CH), 128.56 (CH), 129.69 (CH), 130.69 (CH), 134.26 (C), 137.43 (C), 140.49
-1
C), 155.46 (C), 165.96 (C); IR (KBr) 2981, 1718, 1488, 1368, 1271, 1157, 1089 cm ; MS
+
+
EI) m/z 288 (M , 27), 286 (M , 81), 241 (100%); HRMS (EI) m/z 286.0759, 288.0732 (calcd
286.0761, 288.0731); Anal. Calcd for C17 : C, 71.20; H, 5.27. Found:
C, 71.27; H, 5.29.
for C17
H15ClO
2
H15ClO
2
Ethyl (2E)-3-(4-chlorophenyl)-3-phenylprop-2-enoate (Xj): R = 0.4 (hexane-ether = 4 : 1);
f
1
pale yellow oil; (Xj:Xi = 3:1) H NMR (400 MHz, CDCl
3
) δ (ppm) 1.10 (t, J = 7.1 Hz, 3H),
1
3
4
.04 (q, J = 7.1 Hz, 2H), 6.33 (s, 1H), 7.14-7.23 (m, 3H), 7.25-7.39 (m, 6H); C NMR (100.6
MHz, CDCl ) δ (ppm) 13.98 (CH ), 60.14 (CH ), 117.81 (CH), 128.00 (CH), 128.61 (CH),
29.08 (CH), 129.55 (CH), 130.62 (CH), 135.50 (C), 138.51 (C), 139.26 (C), 155.10 (C),
3
3
2
1
1
-1
65.86 (C); IR (neat) 2981, 1724, 1618, 1489, 1368, 1263, 1165, 1092 cm ; MS (EI) m/z 288
2
2
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
+
+
(
(
M , 27), 286 (M , 79), 241 (89), 214 (51), 178 (100%); HRMS (EI) m/z 286.0767, 288.0743
calcd for C17 286.0761, 288.0731).
H
15ClO
2
Ethyl (2Z)-3-(4-nitrophenyl)-3-phenylprop-2-enoate (Xk): (2.7 mmol scale, 424 mg, purified
by recrystalization, 52%); R
f
= 0.4 (hexane- AcOEt = 4 : 1); yellow crystals; mp 88.5-90.0 C
) δ (ppm) 1.17 (t, J = 7.1 Hz, 3H), 4.07 (d, J =
1
(
hexane-MeOH); H NMR (400 MHz, CDCl
3
7
.1 Hz, 2H), 6.48 (s, 1H), 7.24-7.27 (m, 2H), 7.33-7.43 (m, 5H), 8.27 (d-like, J = 8.8 Hz, 2H).
13
Selected NOEs are between  6.48 (C2-H) and  7.24-7.27 (2-H of Ph).; C NMR (100.6
MHz, CDCl ) δ (ppm) 14.12 (CH ), 60.54 (CH ), 118.62 (CH), 123.34 (CH), 128.08 (CH),
28.81 (CH), 130.08 (CH), 130.14 (CH), 139.24 (C), 146.13 (C), 147.57 (C), 154.50 (C),
65.49 (C). Selected HMBC correlations are between  6.48 (C2-H) and  139.24 (1-C of Ph),
3
3
2
1
1
and  7.24-7.27 (2-H of Ph) and  154.50 (C3).; IR (KBr) 2985, 1719, 1619, 1594, 1515, 1350,
-1
+
1
267, 1172, 1034 cm ; MS (EI) m/z 297 (M , 80), 252 (100%); HRMS (EI) m/z 297.1010
(
calcd for C17 297.1001).
H
15NO
4
3
,3-Bis(4-methylphenyl)prop-2-en-1-ol (Yf): (26 mmol scale, 5.915 g, 95%); colorless
1
crystals: mp 68.5-69.0 °C; H NMR (400 MHz, CDCl
3
) δ (ppm) 1.57 (bs, 1H), 2.33 (s, 3H),
2
7
.37 (s, 3H), 4.19 (d, J = 6.8 Hz, 2H), 6.17 (t, J = 6.8 Hz, 1H), 7.04 (d-like, J = 8.0 Hz, 2H),
1
3
.08 (d-like, J = 8.0 Hz, 2H), 7.13-7.17 (m, 4H); C NMR (100.6 MHz, CDCl ) δ (ppm) 21.15
3
(
CH
3
), 21.29 (CH
3
), 60.81 (CH
2
), 126.46 (CH), 127.62 (CH), 128.91 (CH), 129.72 (CH),
136.28 (C), 137.26 (C), 137.42 (C), 139.27 (C), 144.13 (C); IR (KBr) 3267, 2916, 1510, 1012
-1
+
cm ; MS (EI) m/z 238 (M , 60), 223 (68), 195 (100%); HRMS (EI) m/z 238.1361 (calcd for
18O 238.1358).
17
C H
3
,3-Bis(4-methoxyphenyl)prop-2-en-1-ol (Yg): (19.4 mmol scale, 5.26 g, 100%); R = 0.1
f
1
(
(
hexane-ether = 1 : 1); colorless oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 1.75 (bs, 1H), 3.79
s, 3H), 3.82 (s, 3H), 4.20 (d. J = 7.0 Hz, 2H), 6.09 (t, J = 7.0 Hz, 1H), 6.81 (d-like, J = 8.9 Hz,
H), 6.88 (d-like, J = 8.8 Hz, 2H), 7.07 (d-like, J = 8.8 Hz, 2H), 7.18 (d-like, J = 8.9 Hz, 2H);
13C NMR (100.6 MHz, CDCl
) δ (ppm) 55.29 (CH ), 55.31 (CH ), 60.81 (CH ), 113.54 (CH),
13.56 (CH), 125.46 (CH), 128.92 (CH), 131.01 (CH), 131.60 (C), 134.86 (C), 143.48 (C),
2
3
3
3
2
1
1
-1
59.01 (C), 159.24 (C); IR (neat) 3344, 2933, 2835, 1607, 1511, 1245, 1174, 1034 cm ; MS
2
3
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
+
(
EI) m/z 270 (M , 52), 242 (29), 227 (100), 135 (65%); HRMS (EI) m/z 270.1253 (calcd for
C
17
H
18
3
O 270.1256).
(
2Z)-3-(2-chlorophenyl)-3-phenylprop-2-en-1-ol (Yh): (11.4 mmol scale, 2.67 g, 96%); R =
f
1
0
4
.1 (hexane-ether = 1 : 1); colorless oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 1.55 (bs, 1H),
.03-4.08 (m, 2H), 6.44 (t, J = 6.8 Hz, 1H), 7.18-7.20 (m, 1H), 7.22-7.33 (m, 7H), 7.43-7.48
1
3
(
m, 1H); C NMR (100.6 MHz, CDCl
3
) δ (ppm) 60.99 (CH
27.83 (CH), 128.46 (CH), 128.60 (CH), 129.15 (CH), 129.82 (CH), 131.50 (CH), 133.61 (C),
37.75 (C), 139.66 (C), 140.79 (C); IR (neat) 3327, 3056, 2867, 1597, 1494, 1472, 1446, 1052,
2
), 126.58 (CH), 126.96 (CH),
1
1
1
2
-
1
+
+
035 cm ; MS (EI) m/z 246 (M , 11), 244 (M , 32), 209 (100%); HRMS (EI) m/z 244.0651,
1
46.0625 (calcd for C15
H13ClO 244.0655, 246.0625); H NMR (400 MHz, C
6
6
D ) δ (ppm) 0.43
(
(
bs, 1H), 3.93 (bs, 2H), 6.33-6.39 (m, 1H), 6.78-6.88 (m, 2H), 6.92-6.97 (m, 1H), 7.00-7.09
m, 3H), 7.19 (dd, J = 7.7, 1.5 Hz, 1H), 7.22-7.25 (m, 2H). Selected NOEs are between  6.33-
6
.39 (CH=CPh) and  7.22-7.25 (2'-H of CH=CPh) and between  3.93 (CH
2
) and  6.92-6.97
) δ (ppm) 60.75 (CH ), 126.82
CH), 126.90 (CH), 127.76 (CH), 128.65 (CH), 129.05 (CH), 129.89 (CH), 129.91 (CH),
31.77 (CH), 134.08 (C), 138.37 (C), 140.17 (C), 140.25 (C).
1
3
(
(
6-H of 2-chlorophenyl) in C
6
D
6
.; C NMR (100.6 MHz, C
D
6 6
2
1
(
2Z)-3-(4-chlorophenyl)-3-phenylprop-2-en-1-ol (Yi): (8.75 mmol scale, 2.37 g, 94%); R =
f
1
0
.4 (hexane-ether = 1 : 1); colorless crystals; mp 88.5-89.0 °C; H NMR (400 MHz, CDCl
3
) δ
(
ppm) 1.48 (bs, 1H), 4.20 (d, J = 6.8 Hz, 2H), 6.24 (t, J = 6.8 Hz, 1H), 7.11 (d-like, J = 8.6 Hz,
H), 7.22-7.32 (m, 5H), 7.35 (d-like, J = 8.6 Hz, 2H). Selected NOEs are between  4.20 (CH
2
2
)
1
3
and  7.11 (2-H of 4-chlorophenyl).; C NMR (100.6 MHz, CDCl
3
) δ (ppm) 60.66 (CH
2
),
1
1
27.88 (CH), 127.91 (CH), 128.02 (CH), 128.37 (CH), 128.57 (CH), 131.21 (CH), 133.67 (C),
-1
37.55 (C), 141.47 (C), 143.26 (C); IR (KBr) 3270, 2860, 1594, 1491, 1091, 1015 cm ; MS
+
+
(
EI) m/z 246 (M , 23), 244 (M , 70), 201 (100%); HRMS (EI) m/z 244.0647, 246.0615 (calcd
13ClO 244.0655, 246.0625).
2Z)-3-(4-Nitrophenyl)-3-phenylprop-2-en-1-ol (Yk): (5 mmol scale, 854 mg, 88%); pale
for C15
H
(
1
yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 2.12 (bs, 1H), 4.19 (d, J = 6.9 Hz, 2H), 6.34
t, J = 6.9 Hz, 1H), 7.18-7.21 (m, 2H), 7.28-7.32 (m, 3H), 7.35 (d-like, J = 8.8 Hz, 2H), 8.21
d-like, J = 8.8 Hz, 2H). Selected NOEs are between  6.34 (CH=CPh) and  7.18-7.21 (2'-H
(
(
2
4
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
13
of CH=CPh) between  4.19 (CH ) and  7.35 (2-H of 4-nitrophenyl).; C NMR (100.6 MHz,
2
CDCl
3
) δ (ppm) 60.27 (CH
2
), 123.53 (CH), 127.56 (CH), 128.21 (CH), 128.51 (CH), 129.34
(CH), 130.75 (CH), 140.57 (C), 142.29 (C), 146.10 (C), 147.21 (C); IR (neat) 3359, 3078,
-1
+
1
520, 1347, 1107, 1014 cm ; MS (EI) m/z 255 (M , 100), 237 (79), 212 (61), 165 (78%);
HRMS (EI) m/z 255.0892 (calcd for C15
H13NO
3
255.0895).
Preparation of Yj. A mixture of Pd(OAc)
2
(22 mg, 0.1 mmol), PPh (52 mg, 0.2 mmol), 4-
3
chlorophenylboronic acid (2.4 mmol), KOH (224 mg, 4 mmol), MeOH (8 mL), and THF (8
mL) was heated at 60 °C overnight. After cooling to room temperature, the solution was taken
up in Et
2
O (30 mL) and the Et
2
O layer was washed with aq 1.0 M NaOH (10 mL) and brine (2
), filtered, concentrated under reduced pressure.
×
5mL). The organic layer was dried (MgSO
4
The crude material was purified by column chromatography on silica gel using hexane/ethyl
acetate as eluent. The E-configuration of the products was assigned by 2D-NOESY.
(
(
(
(
2E)-3-(4-chlorophenyl)-3-phenylprop-2-en-1-ol (Yj): (6.8 mmol scale, 1.49 g, 90%); R
f
= 0.3
) δ
1
hexane-AcOEt = 1 : 1); colorless crystals; mp 72.0-73.0 °C; H NMR (400 MHz, CDCl
3
ppm) 1.53 (bs, 1H), 4.21 (d, J = 6.8 Hz, 2H), 6.22 (t, J = 6.8 Hz, 1H), 7.12-7.15 (m, 2H), 7.18
d-like, J = 8.6 Hz, 2H), 7.25 (d-like, J = 8.6 Hz, 2H), 7.32-7.40 (m, 3H). Selected NOEs are
between  4.21 (CH
7.18 (2-H of 4-chlorophenyl).; C NMR (100.6 MHz, CDCl
CH), 127.97 (CH), 128.42 (CH), 128.95 (CH), 129.73 (CH), 133.57 (C), 138.64 (C), 140.33
2
) and  7.12-7.15 (2'-H of CH=CPh) and between  6.22 (CH=CAr) and
1
3

3
) δ (ppm) 60.71 (CH ), 127.88
2
(
(
(
-
1
+
C), 143.15 (C); IR (neat) 3261, 2848, 1488, 1092, 1010 cm ; MS (EI) m/z 246 (M , 22), 244
+
M , 67), 226 (37), 209 (61), 201 (100%); HRMS (EI) m/z 244.0651, 246.0625 (calcd for
15
C H13ClO 244.0655, 246.0625).
The 3,3-diaryl-2-propen-1-amines 4a-k were prepared from the corresponding alcohols Ya,
Yc-k. The corresponding bromides were prepared by reaction of the alcohols with PBr in
3
ether and used without further purification. The 3,3-diaryl-2-propen-1-amines 4a-k were
prepared by reaction of benzylamine (2 equiv) with the corresponding bromide in ether
according to the literature procedure.33
2
5
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
1
4
a: (1.5 mmol scale, 216 mg, 48%); R
f
= 0.1 (hexane-ether = 1 : 1); colorless oil; H NMR
(400 MHz, CDCl
3
) δ (ppm) 2.00 (bs, 1H), 3.35 (d, J = 7.0 Hz, 2H), 3.75 (s, 2H), 6.22 (t, J =
1
3
7
4
1
1
.0 Hz, 1H), 7.14-7.16 (m, 2H), 7.19-7.36 (m, 13H); C NMR (100.6 MHz, CDCl
8.02 (CH ), 53.43 (CH ), 127.05 (CH), 127.30 (CH), 127.34 (CH), 127.48 (CH), 128.19 (CH),
28.24 (CH), 128.26 (CH), 128.44 (CH), 129.81 (CH), 139.64 (C), 139.99 (C), 142.21 (C),
3
) δ (ppm)
2
2
-1
43.83 (C); IR (neat) 3330, 3026, 2836, 1598, 1495, 1443, 1114, 1073, 1028 cm ; MS (EI)
+
m/z 299 (M , 70), 298 (21), 222 (30), 208 (66), 132 (49), 91 (100%); HRMS (EI) m/z 299.1678
(
calcd for C22
H21N 299.1674).
4
6
1
=
b: (10 mmol scale, 1.31 g, 43%); R
f
= 0.1 (hexane-ether = 1 : 1); colorless crystals; mp 67.5-
1
8.5 C; H NMR (400 MHz, CDCl
3
) δ (ppm) 0.803-0.901 (m, 2H), 1.06-1.24 (m, 4H), 1.31-
.42 (m, 1H), 1.62-1.70 (m, 5H), 2.38 (d, J = 6.6 Hz, 2H), 3.27 (d, J = 6.8 Hz, 2H), 6.18 (t, J
1
3
6.8 Hz, 1H), 7.14-7.34 (m, 5H); C NMR (100.6 MHz, CDCl
3
) δ (ppm) 25.93 (CH ), 26.57
2
(
CH
2
), 31.29 (CH
2
), 37.80 (CH), 48.60 (CH
2
), 56.19 (CH ), 126.99 (CH), 127.20 (CH), 127.94
2
(
CH), 127.98 (CH), 128.04 (CH), 129.60 (CH), 139.61 (C), 142.06 (C), 142.96 (C); IR (neat)
-1
+
3
317, 3076, 2925, 2846, 1596, 1493, 1444, 1363, 1118 cm ; MS (EI) m/z 305 (M , 46), 302
(11), 222 (11), 193 (100%); HRMS (EI) m/z 305.2145 (calcd for C22
H27N 305.2143); Anal.
Calcd for C22
H27N: C, 86.51; H, 8.91; N, 4.59. Found: C, 86.35; H, 8.66; N, 4.49.
1
4
c: (2 mmol scale, 501 mg, 74%); R
f
= 0.4 (hexane-ether = 4 : 1); colorless oil; H NMR (400
MHz, CDCl ) δ (ppm) 1.60 (bs, 1H), 3.32 (d, J = 6.8 Hz, 2H), 3.75 (s, 2H), 6.13 (t, J = 6.8 Hz,
3
1
H), 6.92-6.98 (m, 2H), 7.01-7.06 (m, 2H), 7.07-7.12 (m, 2H), 7.14-7.19 (m, 2H), 7.21-7.32
1
3
(
m, 5H); C NMR (100.6 MHz, CDCl
FC = 21 Hz), 115.27 (CH, d, JFC = 21 Hz), 127.09 (CH), 127.90 (CH), 128.19 (CH), 128.47
CH), 129.03 (CH, d, JFC = 8.4 Hz), 131.39 (CH, d, JFC = 8.4 Hz), 135.28 (C, d, JFC = 3.1 Hz),
38.22 (C, d, JFC = 3.1 Hz), 140.06 (C), 141.63 (C), 162.13 (C, d, JFC = 247 Hz), 162.32 (C, d,
3
) δ (ppm) 48.00 (CH
2
), 53.59 (CH
2
), 115.10 (CH, d,
J
(
1
1
9
J
FC = 247 Hz); F NMR (376 MHz, CDCl
3
) δ (ppm) -115.14 (m), -114.68 (m); IR (neat) 3330,
-
1
+
3
1
4
028, 2835, 1601, 1508, 1453, 1224, 1159, 1095 cm ; MS (EI) m/z 335 (M , 94), 244 (70),
32 (67), 91 (100%); HRMS (EI) m/z 335.1482 (calcd for C22
H
19
F
2
N 335.1486).
1
d: (2.5 mmol scale, 446 mg, 48%); colorless oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 1.61
(
bs, 1H), 3.31 (d, J = 6.8 Hz, 2H), 3.73 (s, 2H), 6.17 (t, J = 6.8 Hz, 1H), 7.05 (d-like, J = 8.7
2
6
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
1
3
Hz, 2H), 7.11 (d-like, J = 8.7 Hz, 2H), 7.20-7.32 (m, 9H); C NMR (100.6 MHz, CDCl ) δ
3
(
ppm) 47.98 (CH
2
), 53.62 (CH
2
), 127.08 (CH), 128.15 (CH), 128.43 (CH), 128.47 (CH),
1
1
28.60 (CH), 128.69 (CH), 128.89 (CH), 131.10 (CH), 133.41 (C), 133.49 (C), 137.57 (C),
-1
40.09 (C), 140.29 (C), 141.37 (C); IR (neat) 3028, 2837, 1591, 1492, 1091, 1014 cm ; MS
+
+
(
EI) m/z 369 (M , 6.5), 367 (M , 10), 278 (7.3), 276 (10), 165 (60), 164 (58), 106 (100%);
HRMS (EI) m/z 367.0887, 369.0887 (calcd for C22 N 367.0895, 369.0865).
e: (1.9 mmol scale, 592 mg, 72%); R = 0.3 (hexane-ether = 1 : 4); pale yellow oil; H NMR
400 MHz, CDCl ) δ (ppm) 1.52 (bs, 1H), 3.34 (d, J = 6.8 Hz, 2H), 3.76 (s, 2H), 6.30 (t, J =
.8 Hz, 1H), 7.22-7.34 (m, 7H), 7.39 (dd, J = 7.7, 7.7 Hz, 1H), 7.41 (s, 1H), 7.47-7.53 (m, 3H),
H19Cl
2
1
4
f
(
3
6
7
1
1
3
.61 (d, J = 7.8 Hz, 1H); C NMR (100.6 MHz, CDCl
3
) δ (ppm) 47.98 (CH
2
), 53.75 (CH ),
2
23.96 (CH, q, JFC = 3.8 Hz), 124.08 (C, q, JFC = 272 Hz), 124.12 (C, q, JFC = 273 Hz), 124.37
(
CH, q, JFC = 3.8 Hz), 124.64 (CH, q, JFC = 3.8 Hz), 126.46 (CH, q, JFC = 3.8 Hz), 127.19
CH), 128.19 (CH), 128.53 (CH), 128.89 (CH), 129.05 (CH), 130.84 (CH), 130.92 (C, q, JFC
(
=
32 Hz), 130.96 (CH), 130.99 (C, q, JFC = 32 Hz), 133.17 (CH), 139.59 (C), 140.00 (C),
1
9
1
2
1
4
41.05 (C), 142.31 (C); F NMR (376 MHz, CDCl ) δ (ppm) -62.62, -62.69; IR (neat) 3030,
3
-1
+
836, 1608, 1589, 1495, 1331, 1168, 1125, 1074 cm ; MS (EI) m/z 435 (M , 24), 344 (18),
32 (33), 91 (100%); HRMS (EI) m/z 435.1418 (calcd for C24 N 435.1422).
H F
19 6
1
f: (2 mmol scale, 234 mg, 35%); R
) δ (ppm) 1.44 (bs, 1H), 2.31 (s, 3H), 2.37 (s, 3H), 3.35 (d, J = 6.8 Hz, 2H),
.74 (s, 2H), 6.14 (t, J = 6.8 Hz, 1H), 7.02-7.07 (m, 4H), 7.12-7.15 (m, 4H), 7.19-7.30 (m, 5H);
) δ (ppm) 21.13 (CH ), 21.31 (CH ), 48.24 (CH ), 53.59 (CH ),
26.73 (CH), 126.92 (CH), 127.41 (CH), 128.20 (CH), 128.40 (CH), 128.85 (CH), 129.72
CH), 136.83 (C), 136.85 (C), 136.99 (C), 139.69 (C), 140.41 (C), 143.38 (C); IR (neat) 3316,
f
= 0.2 (hexane-ether = 1 : 4); pale yellow oil; H NMR
(400 MHz, CDCl
3
3
13C NMR (100.6 MHz, CDCl
3
3
3
2
2
1
(
-
1
+
3
9
4
024, 2919, 1512, 1453, 1111 cm ; MS (EI) m/z 327 (M , 26), 236 (27), 195 (42), 119 (69),
1 (100%); HRMS (EI) m/z 327.1985 (calcd for C24 25N 327.1987).
g: (2.9 mmol scale, 365 mg, 35%); R = 0.2 (hexane-ether = 1 : 4); pale yellow oil; H NMR
) δ (ppm) 1.48 (bs, 1H), 3.35 (d, J = 7.0 Hz, 2H), 3.75 (s, 2H), 3.79 (s, 3H),
.84 (s, 3H), 6.07 (t, J = 7.0 Hz, 1H), 6.80 (d-like, J = 8.9 Hz, 2H), 6.87 (d-like, J = 8.8 Hz
H
1
f
(400 MHz, CDCl
3
3
2
1
3
H), 7.07 (d-like, J = 8.8 Hz, 2H), 7.17 (d-like, J = 8.9 Hz, 2H), 7.21-7.31 (m, 5H); C NMR
2
7
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
(100.6 MHz, CDCl
3
) δ (ppm) 48.26 (CH
2
), 53.62 (CH
2
), 55.31 (CH
3
), 55.33 (CH
3
), 113.51
(CH), 113.53 (CH), 125.76 (CH), 126.94 (CH), 128.22 (CH), 128.42 (CH), 128.68 (CH),
1
3
30.99 (CH), 132.20 (C), 135.32 (C), 140.41 (C), 142.69 (C), 158.77 (C), 159.01 (C); IR (neat)
-1
+
328, 2953, 2834, 1606, 1511, 1246, 1173, 1035 cm ; MS (EI) m/z 359 (M , 100), 268 (52%);
359.1887).
= 0.4 (hexane-ether = 1 : 4); pale yellow oil; H NMR
) δ (ppm) 1.49 (bs, 1H), 3.17-3.21 (m, 2H), 3.73 (s, 2H), 6.41 (t, J = 6.8 Hz,
HRMS (EI) m/z 359.1878 (calcd for C24
H25NO
2
1
4
h: (3.1 mmol scale, 515 mg, 50%); R
f
(400 MHz, CDCl
3
1
3
1
H), 7.14-7.16 (m, 1H), 7.17-7.29 (m, 12H), 7.41-7.44 (m, 1H); C NMR (100.6 MHz, CDCl )
3
δ (ppm) 48.27 (CH
28.08 (CH), 128.34 (CH), 128.37 (CH), 128.82 (CH), 129.00 (CH), 129.72 (CH), 131.49
CH), 133.73 (C), 138.22 (C), 139.99 (C), 140.25 (C), 140.35 (C); IR (neat) 3026, 2835, 1597,
2
), 53.59 (CH ), 126.35 (CH), 126.78 (CH), 126.91 (CH), 127.40 (CH),
2
1
(
-1
+
+
1
495, 1445, 1362, 1125, 1050 cm ; MS (EI) m/z 335 (M , 7.5), 333 (M , 18), 298 (42), 91
(
100%); HRMS (EI) m/z 333.1282, 335.1245 (calcd for C22
H20ClN 333.1284, 335.1255).
1
4
i: (3.5 mmol scale, 531 mg, 45%); R
f
= 0.5 (hexane-AcOEt = 1 : 4); pale yellow oil; H NMR
(400 MHz, CDCl
3
) δ (ppm) 1.59 (bs, 1H), 3.33 (d, J = 6.8 Hz, 2H), 3.75 (s, 2H), 6.21 (t, J =
6
3
4
1
.8 Hz, 1H), 7.08 (d-like, J = 8.4 Hz, 2H), 7.19-7.33 (m, 12H). Selected NOEs are between 
13
.33 (CH
8.01 (CH
28.49 (CH), 131.21 (CH), 133.25 (C), 138.08 (C), 140.14 (C), 141.82 (C), 142.55 (C); IR
2
-CH=) and  7.08 (2'-H of 4-chlorophenyl).; C NMR (100.6 MHz, CDCl
3
) δ (ppm)
2
), 53.59 (CH ), 127.09 (CH), 127.47 (CH), 127.55 (CH), 128.21 (CH), 128.31 (CH),
2
-1
+
(
neat) 3316, 3027, 2833, 1597, 1489, 1445, 1090, 1015 cm ; MS (EI) m/z 335 (M , 16), 333
+
(
M , 16), 242 (41), 132 (49), 91 (100%); HRMS (EI) m/z 333.1277, 335.1266 (calcd for
C
22
H
20ClN 333.1284, 335.1255).
j: (2.4 mmol scale, 805 mg, 41%); R
400 MHz, CDCl ) δ (ppm) 1.50 (bs, 1H), 3.34 (d, J = 6.8 Hz, 2H), 3.74 (s, 2H), 6.18 (t, J =
1
4
f
= 0.3 (hexane-AcOEt = 1 : 1); pale yellow oil; H NMR
(
3
1
3
6
4
1
1
.8 Hz, 1H), 7.11-7.16 (m, 4H), 7.20-7.37 (m, 10H); C NMR (100.6 MHz, CDCl
8.14 (CH ), 53.63 (CH ), 127.02 (CH), 127.51 (CH), 128.18 (CH), 128.32 (CH), 128.34 (CH),
28.45 (CH), 128.73 (CH), 129.74 (CH), 133.15 (C), 139.18 (C), 140.24 (C), 140.73 (C),
3
) δ (ppm)
2
2
-1
42.46 (C); IR (neat) 3323, 3027, 2836, 1599, 1488, 1453, 1442, 1092, 1012 cm ; MS (EI)
2
8
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European Journal of Organic Chemistry
10.1002/ejoc.201801508
+
+
m/z 335 (M , 23), 333 (M , 65), 242 (55), 132 (69), 91 (100%); HRMS (EI) m/z 333.1279,
3
35.1266 (calcd for C22
k: (2.6 mmol scale, 432 mg, 48%); R
) δ (ppm) 1.54 (bs, 1H), 3.31 (d, J = 7.0 Hz, 2H), 3.76 (s, 2H), 6.30 (t, J =
.0 Hz, 1H), 7.16-7.18 (m, 2H), 7.23-7.32 (m, 10H), 8.18 (d-like, J = 8.8 Hz, 2H). Selected
H
20ClN 333.1284, 335.1255).
1
4
f
= 0.2 (hexane-AcOEt = 1 : 4); pale yellow oil; H NMR
(400 MHz, CDCl
3
7
1
3
NOEs are between  6.30 (CH=CPh) and  7.16-7.18 (2-H of CH=CPh).; C NMR (100.6
MHz, CDCl ) δ (ppm) 47.78 (CH ), 53.53 (CH ), 123.48 (CH), 127.12 (CH), 127.41 (CH),
27.88 (CH), 128.13 (CH), 128.45 (CH), 129.69 (CH), 130.72 (CH), 139.88 (C), 140.94 (C),
3
2
2
1
1
-1
41.75 (C), 146.64 (C), 147.02 (C); IR (neat) 3026, 2838, 1598, 1516, 1346, 1107 cm ; MS
+
(
EI) m/z 344 (M , 31), 253 (22), 132 (35), 91 (100%); HRMS (EI) m/z 344.1521 (calcd for
C
22
H
20
N
2
2
O 344.1525).
Typical experimental procedure for eq 2 (Table 2, entry 2). To a solution of 1,1,2-
ethenetricarboxylic acid 1,1-diethyl ester (1) (prepared from 1,1-diethyl 2-tert-butyl
2
9
ethenetricarboxylate (136 mg, 0.5 mmol) upon treatment with CF
3
CO
2
H (2 mL)) in DMF
(
0.7 mL) were added N-benzyl 3,3-diphenyl-2-propen-1-amine (4a) (150 mg, 0.5 mmol) in
DMF (0.7 mL), Et N (0.07 mL, 51 mg, 0.5 mmol), HOBt (1-hydroxybenzotriazole) (135 mg,
3
1
mmol) and EDCI (1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride) (100
mg, 0.5 mmol) at 0 °C. The reaction mixture was stirred for 1 h at 0 °C, and was allowed to
warm to room temperature and stirred for 20 h. The reaction mixture was diluted with CH Cl
2
2
.
The organic phase was washed with saturated aqueous NaHCO
3
solution, 2M aqueous citric
acid, saturated aqueous NaHCO and water, dried (Na SO ), and evaporated in vacuo. The
3
2
4
residue was purified by column chromatography over silica gel eluting with hexane-Et O to
2
give 5a-trans (129 mg, 52%).
5
a-trans: R
f
= 0.4 (hexane-ether = 1 : 4); colorless crystals; mp 159.5-160 C (hexane-AcOEt);
) δ (ppm) 1.25 (t, J = 7.1 Hz, 3H), 1.38 (t, J = 7.1 Hz, 3H), 2.60
dd, J = 9.6, 9.0 Hz, 1H), 2.96 (dddd, J = 13.5, 9.6, 8.0, 6.3 Hz, 1H), 3.24 (dd, J = 9.0, 8.0 Hz,
1H NMR (400 MHz, CDCl
3
(
1
4
H), 3.48 (d, J = 13.5 Hz, 1H), 3.78 (d, J = 15.0 Hz, 1H), 4.16 (qd, J = 10.8, 7.1 Hz, 1H), 4.29-
.48 (m, 4H), 4.90 (d, J = 15.0 Hz, 1H), 6.90 (d, J = 6.8 Hz, 2H), 6.98 (d, J = 7.6 Hz, 1H),
2
9
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