Intramolecular [2 + 2] and [4 + 2] Cycloaddition Reactions of Cinnamylamides of Ethenetricarboxylate in Sequential Processes

Article abstract of DOI:10.1021/acs.joc.6b01947

Intramolecular [2 + 2] and [4 + 2] cycloaddition reactions of cinnamylamides of ethenetricarboxylate in sequential processes have been studied. Reaction of 1,1-diethyl 2-hydrogen ethenetricarboxylate and trans-cinnamylamines in the presence of EDCI/HOBt/Et₃N led to pyrrolidine products in one pot, via intramolecular [2 + 2], [4 + 2], and some other cyclizations. The types of the products depend on the substituents on the benzene ring and the reaction conditions. Reaction of cinnamylamines without substituents on the benzene ring and with halogens and OMe on the para position at room temperature gave cyclobutane-fused pyrrolidines as major products via [2 + 2] cycloaddition. The reaction at 80 °C in 1,2-dichloroethane gave δ-lactone fused pyrrolidines as major products, probably via ring-opening of the cyclobutanes. Interestingly, reaction of 1,1-diethyl 2-hydrogen ethenetricarboxylate and cinnamylamines bearing electron-withdrawing groups such as NO₂, CN, CO₂Me, CO₂Et, and CF₃ on ortho and para positions in the presence of EDCI/HOBt/Et₃N at room temperature or at 60-80 °C gave tetrahydrobenz[f]isoindolines via [4 + 2] cycloaddition as major products. DFT studies have been performed to explained the observed [2 + 2]/[4 + 2] selectivity.

Full text of DOI:10.1021/acs.joc.6b01947

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Article
Intramolecular [2+2] and [4+2] Cycloaddition Reactions of
Cinnamylamides of Ethenetricarboxylate in Sequential Processes
Shoko Yamazaki, Hirotaka Sugiura, Shinnosuke Ohashi,
Keisuke Ishizuka, Rina Saimu, Yuji Mikata, and Akiya Ogawa
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01947 • Publication Date (Web): 10 Oct 2016
Downloaded from http://pubs.acs.org on October 11, 2016
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Intramolecular [2+2] and [4+2] Cycloaddition Reactions of Cinnamylamides of
Ethenetricarboxylate in Sequential Processes
a
a,b
a
a
Shoko Yamazaki,* Hirotaka Sugiura, Shinnosuke Ohashi, Keisuke Ishizuka, Rina
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a
c
b
Saimu, Yuji Mikata, and Akiya Ogawa
a
Department of Chemistry, Nara University of Education, Takabatake-cho, Nara 630-8528,
b
Japan, Department of Applied Chemistry, Graduate School of Engineering, Osaka
c
Prefecture University, Gakuen-cho 1-1, Nakaku, Sakai, Osaka 599-8531, Japan, KYOUSEI
c
Science Center, Nara Women's University, Nara 630-8506, Japan, KYOUSEI Science
Center, Nara Women's University, Nara 630-8506, Japan
yamazaks@nara-edu.ac.jp
Graphical Abstract
CO Et
O
2
X = H, 4-F, 4-Cl, 4-Br
4-OCH3
H
H
5
4
CO Et
X
3
2
EtO C CO
Et
5
6
2
2
R N
EtO C CO
Et
EDCI
HOBt
2
2
4
X
3
1
2
O
6
+
HO C
2
Et N
3
X
N
1
2
X = 2-NO , 2-NO -5-F,
, 4-CN,
-CO Me, 4-CO Et,
2
2
R
HN
R
4-NO
2
EtO C CO Et
2
2
4
O
2
2
H
4-CF3
R N
X
H
Abstract: Intramolecular [2+2] and [4+2] cycloaddition reactions of cinnamylamides of
ethenetricarboxylate in sequential processes have been studied. Reaction of 1,1ꢀdiethyl
2
ꢀhydrogen ethenetricarboxylate and transꢀcinnamylamines in the presence of
EDCI/HOBt/Et N led to pyrrolidine products in one pot, via intramolecular [2+2], [4+2] and
3
some other cyclizations. The types of the products depend on the substituents on benzene
ring and the reaction conditions. Reaction of cinnamylamines without substituent on benzene
ring and with halogens and OMe on para position at room temperature gave
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4
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5
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5
5
5
5
5
5
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cyclobutaneꢀfused pyrrolidines as major products via [2+2] cycloaddition. The reaction at
8
0 °C in 1,2ꢀdichloroethane gave δꢀlactone fused pyrrolidines as major products, probably
via ring–opening of the cyclobutanes. Interestingly, reaction of 1,1ꢀdiethyl 2ꢀhydrogen
ethenetricarboxylate and cinnamylamines bearing electronꢀwithdrawing groups such as NO
2
,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
0
1
2
3
4
5
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8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
2 2 3 3
CN, CO Me, CO Et, CF on ortho and para positions in the presence of EDCI/HOBt/Et N at
room temperature or at 60ꢀ80 °C gave tetrahydrobenz[f]isoindolines via [4+2] cycloaddition
as major products. The DFT studies have been performed to explained the observed
[
2+2]/[4+2] selectivity.
Introduction
Sequential reactions allow multiple bond formation in oneꢀpot and thus lead to high
1
efficiency. The intramolecular cycloaddition reactions are used for formation of various
2
3
multicyclic systems. Intramolecular photochemical, thermal and catalyzed [2+2]
4
cycloadditions have been reported. The reaction gives cyclobutaneꢀfused cyclic skeletons.
The reaction of substrates bearing styrene moiety also gave intramolecular [2+2]
2
a,4b
cycloadducts.
The intramolecular [4+2] cycloaddition (DielsꢀAlder reaction) between alkenes and
5
dienes leads to facile formation of multicyclic skeletons. Furan is effectively utilized as
diene moiety in intramolecular DielsꢀAlder reaction. Vinyl heterocycles such as vinyl
6
6a
7
8
furans, pyrroles, imidazoles, and benzothiophens have also been used as dienes. The
intramolecular DielsꢀAlder reaction of vinyl benzene (styrene) as a diene requires relatively
9
high temperature because of involving dearomatization of benzene ring.
Thus, styrenes work as alkene or diene components in intramolecular [2+2] or [4+2]
cycloadditions with electronꢀdeficient alkenes. The both reactions may be useful for the
construction of multicyclic skeletons and the question is how to control the selectivity.
Ethenetricarboxylate derivatives have been employed as highly electrophilic C=C
1
0
components in various bondꢀforming reactions. Ethenetricarboxylates allow the facile
derivatization at 2ꢀcarboxyl group. Snider and Roush reported in FeCl ꢀpromoted
3
1
1
intramolecular reactions of alkenyl ethenetricarboxylates to give chlorinated γꢀlactones.
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Recently, we have developed Lewis acid (MX
n
)ꢀpromoted cyclization/halogenation of
alkenyl ethenetricarboxylates to give 3,4ꢀtrans fiveꢀmembred rings stereoselectively with
1
2
high generality ((a) in Scheme 1). 2ꢀAlkenyl amides of ethenetricarboxylates also undergo
12c
facile intramolecular ene reactions (b). In addition, reaction of 1,1ꢀdiethyl 2ꢀhydrogen
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ethenetricarboxylate 1 and 2ꢀfurylmethylamines in the presence of EDCI/HOBt/Et N at room
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temperature led directly to intramolecular DielsꢀAlder adducts (c).
EtO C CO
Et
EtO C CO Et
2
2
1) MXn
2
2
H
H
X
R
O
O
2
) H O
(a)
2
R
Y
Y
X = Cl, Br, I
MX = TiCl , TiBr ,
H
Y = O, NR'
R = H, Me, Et
n
4
4
AlCl , AlBr , FeCl , ZnI
3
3
3
2
EtO C CO
Et
2
EtO C CO
Et
2
2
2
80 °C
(b)
O
N
O
N
Ph
Ph
Et N
HOBt
EDCI
3
EtO C
CO Et
2
2
H
N
+
O
HO C
R
2
1
EtO C
CO Et
2
2
EtO C
2
EtO C
O
R
2
O
H
O
(c)
O
N
N
R
Scheme 1
It is of interest to examine the reaction of the highly electrophilic
ethenetricarboxylates bearing arylꢀsubstituted alkenyl groups as an extension of the alkene
moiety and to examine the selectivity of styrenes. In this work, sequential intramolecular
reactions of 1,1ꢀdiethyl 2ꢀhydrogen ethenetricarboxylate 1 with transꢀcinnamylamines 2
under the amide formation conditions have been studied (Scheme 2). Reaction of 1 and 2 in
3
the presence of EDCI/HOBt/Et N led to pyrrolidine products in one pot, via intramolecular
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2
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4
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5
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[
2+2], [4+2] and some other cyclizations. The types of the products depend on the
substituents on benzene ring and the reaction conditions.
X
EtO C CO Et
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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0
1
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0
1
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0
1
2
3
4
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8
9
0
EtO C CO
Et
2
2
EDCI
HOBt
b
X
+
O
a
HO C
2
Et N
3
N
1
HN
R
R
2
a [2+2]
b [4+2]
other pyrrolidine formations
Scheme 2
Results and Discussion
Reaction of cinnamylamines with pꢀH, halogen and MeO groups: [2+2] Cycloaddition
Reactions of 1,1ꢀdiethyl 2ꢀhydrogen ethenetricarboxylate 1 and transꢀcinnamylamines
3
(X = H) 2aꢀc in the presence of EDCI/HOBt/Et N have been examined first. It was found
that the reaction gave cyclobutaneꢀfused pyrrolidines 3aꢀc in 41ꢀ51% yield as isolable major
products (eq 1, Table 1). The products may be formed via amide formation/intramolecular
[
2 6 4 3
2+2] cycloaddition. Reaction of RHNCH ꢀCH=CHꢀC H ꢀX (X = 4ꢀhalogen, 4ꢀOCH ) 2dꢀi
also gave cyclobutaneꢀfused pyrrolidines 3dꢀi in 39ꢀ51% yield as isolable major products.
The relative configuration of 3 was determined as shown in eq 1 by NOESY experiment
(NOEs between C5ꢀH and C1ꢀH, ArꢀH, etc).
X
CO Et
O
2
H
EtO C CO Et
EDCI
HOBt
2
2
CO Et
2
2
1
7
(eq 1)
+
R N
3
HO C
5 6
2
Et N
3
4
H
1
THF
r.t.
HN
R
X
3
2a-i
20 h
X = H, F, Cl, Br, OCH3
Table 1. Reactions of 1,1ꢀdiethyl ethenetricarboxylate 1 and cinnamylamines 2
Entry 2
R
X
H
Product 3 Yield (%)
1
2
2a CH
2
Ph
3a
3b
43
51
2b CH Cyclohexyl H
2
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3
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2c CH C H ꢀ4ꢀCF H
3c
3d
3e
3f
41
42
39
51
40
40
48
2
6
4
3
2d CH CH=CH2
H
2
2
3
4
5
6
2e CH
2
Ph
F
2f CH CH CH
F
2
2
2
2
2
3
2g CH
2h CH
2i CH
Ph
Ph
Ph
Cl
Br
OCH
3g
3h
3i
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3
The intermediate amide A was not observed under the reaction conditions of amide
formation (Scheme 3). The amide undergoes the first CꢀC bond formation to give a
zwitterꢀionic intermediate B, which is stabilized by phenyl group. The second CꢀC bond
formation proceeds, affording a highly strained cyclobutaneꢀfused bicyclic compound 3.
X
EtO C CO
Et
2
2
X
EtO C CO Et
EDCI
HOBt
2
2
O
+
HO C
2
Et N
3
N
R
R
1
N
A
H
2
CO Et
2
CO Et
O
O
2
H
H
CO Et
2
[2+2]
CO Et
2
R N
R N
H
H
X
B
X = H, F, Cl, Br
OCH
3
X
3
Scheme 3
1
4
When the reaction of 1 and 2a was carried out at 80 °C in 1,2ꢀdichloroethane or in
α,α,αꢀtrifluorotoluene, δꢀlactoneꢀfused pyrrolidine 4a was obtained as a major product in 69
and 50% yields, respectively (eq 2, Table 2). The reaction of 1 and 2b,eꢀi at 80 °C in
1,2ꢀdichloroethane gave δꢀlactoneꢀfused pyrrolidines 4b,eꢀi as major products. The relative
configuration of 4 was determined as shown in eq 2 by NOEs.
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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
X
CO Et
2
O
1
H
O
EtO C CO
Et
7
2
2
EDCI
HOBt
7
a
6
R N
3a
2
O5
+
(eq 2)
3
4
HO C
H
2
Et N
3
1
ClCH CH Cl
HN
R
2
2
0
1
2
3
4
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9
0
1
2
3
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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
2
80 °C
20 h
4
X
Table 2. Reactions of 1,1ꢀdiethyl ethenetricarboxylate 1 and cinnamylamines 2
Entry 2 Solvent
R
X
H
H
Product 4 Yield (%)
a
1
2
3
4
5
6
7
8
9
2a ClCH
2a C ꢀCF
2b ClCH
2
CH
2
Cl CH
CH
2
2
2
2
2
2
2
2
2
2
Ph
Ph
4a
4a
4b
4e
4f
69
50
75
55
38
53
31
41
6
H
5
3
a
Cl CH
Cyclohexyl H
2
CH
2
a
2e ClCH CH Cl CH
Ph
CH
Ph
Ph
Ph
F
2
2
2
2
2
2
2
2
a
2f ClCH
2g ClCH
2h ClCH
CH
CH
CH
Cl CH
2
CH
3
F
a
Cl CH
Cl
Br
OCH
H
4g
4h
a
Cl CH
a
2i ClCH CH Cl CH
3
4i
b
2
2
2
2
2
2
a
2c ClCH
2d ClCH
CH
CH
Cl CH
C
6
H
4
ꢀ4ꢀCF
3
a
b
10
Cl CH
CH=CH
2
H
a
14
b
The byproducts were removed by column chromatography.
Complex mixtures
containing 4 and small amounts of 3.
Formation of 4 from 3 under the reaction conditions is likely. The reaction conditions
may produce a small amount of HCl from EDCI and also along with formation of the
1
4
byproducts BtOCH
HCl was next examined (eq 3). After examining various ringꢀopening conditions, the reaction
of cyclobutane 3a with 1 equiv of HCl/Ether and 1 equiv of H O in ClCH CH Cl at 80 °C for
0 h was found to give 4a efficiently in 70% yield (Table 3, entry 1). The reaction of 3a with
equiv of HCl/H O in THF at room temperature gave the mixture of alcohol 5a and 4a
2 2 2 2
CH Cl and BtOCH CH OBt. Reaction of cyclobutane products 3 with
2
2
2
2
1
2
(
entry 2). Treatment of alcohol 5a with with 1 equiv of HCl/Ether in CH
temperature overnight gave 4a quantitatively. On the other hand, the reaction of 4 with 1
equiv of HCl/Ether in CH Cl or HCl/AcOEt at room temperature gave Clꢀadduct 6 as a
2 2
Cl at room
2
2
single diastereomer along with 4 (entries 3ꢀ5). The stereochemistries of 5a and 6a,c,d could
be deduced as follows. The 3,4ꢀcis stereochemistries of 5a and 6a,c,d were determined by
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NOEs. Preferred conformations of 5a and 6a,c,d may be as depicted in eq 3 from the
coupling constants and consideration of steric effects, respectively. The coupling constant
between CH(OH)Ph and C4ꢀH of 5a (J = 10.9 Hz) and those between CHClPh and C4ꢀH of
6a,c,d (J = 4.3ꢀ4.7 Hz) suggest the configurations of the side chains as shown. The similarity
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in the coupling constant between CHOHPh and C4ꢀH of 5a and that between C4ꢀH and
C3aꢀH of 4a (J = 11.3 Hz) supports the assignment of the configuration of 5a.
CO Et
CO Et
2
O
2
O
H
H
H
H
CO Et
O
2
HCl
0 h
R N
R N
3a
(eq 3)
O
2
4
3
4
CO Et
CO Et
2
2
O
2
O
2
H
H
CO Et
CO Et
2
2
3
4
3
4
R N
OH
H
R N
1
1
5
5
H
H
H
Cl
5
6
J = 4.3-4.7 Hz
H4
H
4
OH
H3
CH(CO Et)2
H
5
5
H3
H
H
H
CH(CO Et)
2
N
2
2
H
N
O
Cl O
H
PhH C
R
2
J = 10.9 Hz
5a
6a,c,d
Table 3. Ringꢀopening reactions of cyclobutaneꢀfused pyrrolidines 3
Entry 3
R
Condition
Product (Yield)
1
3a CH
2
Ph
Ph
1 equiv 1M HCl/Ether, 1 equiv H O 4a (70%)
2
ClCH
2
CH
2
Cl 80 °C
O, THF, r.t.
2
3
4
5
3a CH
2
1 equiv 1M HCl/H
2
5a (42%) 4a (47%)
3a CH Ph
1 equiv 1M HCl/Ether, CH Cl , r.t. 6a (60%) 4a (27%)
2
2
2
3c CH
3d CH
2
2
C
6
H
4
ꢀ4ꢀCF
3
1 equiv 1M HCl/AcOEt, r.t.
6c (62%) 4c (18%)
CH=CH
2
1 equiv 1M HCl/Ether, CH
2
Cl
2
, r.t. 6d (53%) 4d (18%)
+
Thus, δꢀlactone 4 may form from cyclobutane 3 via intermiediate BꢀH and alcohol 5,
followed by transesterification (Scheme 4). Formation of 5 may proceed in two steps and
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7
8
9
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
formation of Clꢀadducts 6 may proceed in one step ring opening based on their suggested
stereochemistries.
H
EtO
H
EtO
H
OH
O
ring-
opening
O
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
CO Et
2
H+
CO Et
2
3
R N
H
R N
H
H
B-H+
Cl-attack
ring-opening
Cl
-H+
+
H O
2
-H
CO Et
CO Et
2
2
O
H
O
H
CO Et
CO Et
2
2
R N
R N
OH
H
H
H
Cl
H
H
H
6
5
4
-
EtOH
Scheme 4
Reaction of cinnamylamines with o,pꢀelectronꢀwithdrawing groups: [4+2] cycloaddition
Next, the reaction of 1,1ꢀdiethyl 2ꢀhydrogen ethenetricarboxylate 1 and
cinnamylamines bearing electronꢀwithdrawing groups on ortho and para positions in the
presence of the amide condensation reagents was examined. Interestingly, reaction of 1 and
RHNCH
2
ꢀCH=CHꢀC
6 4 2 2 2 3
H ꢀX (X = 2, or 4ꢀNO , CN, CO Me, CO Et, CF ) 2jꢀr with
EDCI/HOBt/Et
3
N at room temperature, 60 and 80 °C gave tetrahydrobenz[f]isoindolines 7 as
major products via [4+2] cycloaddition (eq 4, Table 4 and Table S1 of Supporting
Information). The transꢀfused pyrrolidine stereochemistry of 7 was determined by NOEs (in
C
6
D
6
, CD
3
CN, or (CD
3
2
) CO, for some products).
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2
3
4
5
6
7
8
9
5
4
X
3
EtO C CO Et
2
2
EtO C CO
Et
EDCI
HOBt
O
1
2
2
H
8
9
2
7
+
9a
(eq 4)
R 2N 3a
X
6
HO C
2
Et N
3
3
H 4
5
1
18-20 h
HN
R
7
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
2j-r
X = 2, or 4-NO , CN,
2
CO Me, CO Et, CF
2
2
3
a
Table 4. Reactions of 1,1ꢀdiethyl ethenetricarboxylate 1 and cinnamylamines 2jꢀr
2
X
Solvent Temp. R
7
Yield X
3
Yield
Entry
(%)
(%)
1
2
3
4
5
6
7
8
9
2j 2ꢀNO2
THF
r.t.
CH Ph
7j (75)
5ꢀNO2
2
2k 2ꢀNO
2l 2ꢀNO
2m 2ꢀNO
2
2
2
benzene 80 °C CH
2
2
2
Cyclohexyl 7k (73)
5ꢀNO
5ꢀNO
5ꢀNO
2
2
2
THF
ꢀ5ꢀF THF
THF
r.t.
r.t.
CH
CH
CH=CH
Ph
2
7l (74)
7m (78)
7n (68)
7o (75)
7p (71)
7q (57)
7r (51)
ꢀ8ꢀF
2n 4ꢀNO2
2o 4ꢀCN
60 °C CH Ph
7ꢀNO2
7ꢀCN
2
THF
r.t.
r.t.
r.t.
CH
CH
CH
2
2
2
Ph
Ph
Ph
b
b
2p 4ꢀCO
2q 4ꢀCO
2
2
Me THF
Et THF
7ꢀCO
2
2
Me
Et
7ꢀCO
2r 4ꢀCF3
Benzene 80 °C CH Ph
7ꢀCF3
3r (6)
2
CO Et
O
2
H
CO Et
2
PhH C N
2
H
CF3
3r
a
The best conditions for each compounds are shown in Table 4 and the other conditions are
b
described in Table S1 of Supporting Information. A small amount of cyclobutaneꢀfused
pyrrolidine 3 was detected but could not be isolated.
Formation of the zwitterꢀionic intermediate B corresponding to that in Scheme 3 may
be strongly destabilized by the resonance and inductive effects of ortho and para
electronꢀwithdrawing group on the benzene ring (Scheme 5). Instead, the interaction between
a styrene moiety and an alkene moiety of ethenetricarboxylate may lead to the intramolecular
DielsꢀAlder adduct C. The 1,3ꢀH transfer isomerization of C to the products 7 may proceed
+
by a stepwise process via intermediate DꢀH .
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8
9
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
EtO C
2
H
CO Et
2
O
EtO C
CO Et
NO2
O
CO Et
2
2
2
H
H
CO Et
[2+2]
2
N
O
R
H
B
R N
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
N
R
EtO C
2
O N
A
2
NO2
CO Et O
2
H
O
O
3
N
[
4+2]
N
R
H
EtO C
2
EtO C
CO Et
2
EtO C
2
O
2
CO Et
2
O
CO Et
O
2
H
H
H+
H
H
-H+
H
R N
R
N
R
N
H
H
H
NO2
H H
NO2
NO2
C
7
D-H+
Scheme 5
Reaction of cinnamylamines with mꢀCF
3
and F groups: [2+2] and/or [4+2]
cycloaddition
It is interesting to examine the chemoselectivity of the metaꢀelectronꢀwithdrawing
groups. Reaction of 1 and benzyl cinnamylamine (X = 3ꢀCF ) 2s with EDCI/HOBt/Et N at
3
3
room temperature gave tetrahydrobenz[f]isoindoline 7s in 53% and cyclobutaneꢀfused
pyrrolidine 3s in 24% yields, respectively (eq 5, Table 5 and Table S2 of Supporting
Information). The reaction of 1 and cinnamylamine (X = 3,5ꢀdiCF
cyclobutaneꢀfused pyrrolidine 3t as an isolable product in 13ꢀ30% yield and product 7 was
not formed. One metaꢀCF worked as an electronꢀwithdrawing group by the inductive effect
and the reaction preferred [4+2] adduct 7s to [2+2] adduct 3s. [4+2] adduct 7s was obtained
regioselectively. Cinnamylamine with two metaꢀCF groups 2t only gave cyclobutane 3t,
3
) 2t at 60 °C gave
3
3
3
probably because steric hindrance of metaꢀCF group interferes [4+2] cycloaddition (Scheme
6).
1
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5
6
7
8
9
Although the reaction of cinnamylamines with 4ꢀF group 2e,f gave cyclobutanes 3e,f
regioselectively (Table 1), reaction of 1 and cinnamylamine with 3ꢀF group 2u gave a
mixture of 6ꢀFꢀ and 8ꢀFꢀregioisomers of 7u and cyclobutaneꢀfused pyrrolidine 3u. F
substituents destabilize B by inductive effect with high electronegativity, but paraꢀF
stabilizes benzylic cation intermediate B by resonance effect (Scheme 6). The steric
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
hindrance of F is smaller than CF , therefore both 6ꢀFꢀ and 8ꢀFꢀregioisomers of 7u may be
3
formed.
3
Thus, the reaction of 1 and cinnamylamines with metaꢀCF and F groups 2s,t,u gave
[
2+2] and/or [4+2] cycloadducts.
5
4
X
EtO C CO Et
2
2
EtO C CO
Et
2
EDCI
HOBt
2
3
O
1
H
8
9
7
(eq 5)
+
2
C N 3a 9a
X
HO C
Et N
THF
PhH
2
2
3
2
6
3
1
H 4
5
18-20 h
HN
CH Ph
2
7
2
CO Et
O
2
H
CO Et
2
2
1
7
PhH C N
2
5
'
3
5
H
6
4
X
2
'
4'
3
3
'
a
Table 5. Reactions of 1,1ꢀdiethyl ethenetricarboxylate 1 and cinnamylamines 2sꢀu
Entry 2
X
Solvent Temp. 7 Yield (%)
X
3 Yield (%)
X
b
1
2
3
2s 3ꢀCF
2t 3,5ꢀdiCF3 THF
2u 3ꢀF THF
3
THF
r.t.
7s (53)
6ꢀCF
3
3s (24%)
3'ꢀCF
3
60 °C
r.t.
3t (30%)
3u (29%)
3',5'ꢀdiCF3
3'ꢀF
6ꢀFꢀ7u,
8ꢀFꢀ7u
6ꢀF,
8ꢀF
c
(2.5:1, 37)
a
The best conditions for each compounds are shown in Table 5 and the other conditions are
b
described in Table S2 of Supporting Information. Reaction for 1 h at room temperature
gave a complex mixture possibly containing intermediate amide A which could not be
c
isolated. 6ꢀFꢀ7u and 8ꢀFꢀ7u could not separated by column chromatography. The ratio was
1
determined by H NMR.
1
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8
9
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
EtO C
CO Et
EtO
2
C
N
CO Et
2
EtO C
CO Et
2
2
2
2
F
CF3
O
O
O
N
+
N
PhH C
PhH C
F
2
PhH C
CF3
2
2
A for 2t
A for 2u
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
EtO C
2
H
EtO C
2
CO Et
2
H
CO Et
2
O
O
N
F
N
PhH C
2
H
PhH C
H
2
F
B for 2u
B for 2e
destabilized by
inductive effect
stabilized by
resonance effect
Scheme 6
Reaction of cinnamylamines with mꢀnitro group: Stereoselective formation of
HOBtꢀincorporated pyrrolidines
Reaction of cinnamylamines with metaꢀNO
the inductive effect of a strong electronꢀwithdrawing group. Unexpectedly, reaction of 1 and
cinnamylamines (X = 3ꢀNO ) 2vꢀw with EDCI/HOBt/Et N at room temperature, 60 °C and
80 °C gave HOBtꢀincorporated 3,4ꢀtransꢀpyrrolidines 8vꢀw as single diastereomers in
2
group was carried out as examination of
2
3
5
3ꢀ75% yield selectively. The structure of 8w was determined by Xꢀray analysis (Figure S1
1
5
of Supporting Information).
CO Et
2
O
EtO C CO
Et
2
EDCI
HOBt
H
2
R
N
CO Et
R N 2
3
H
2
+
H
(
eq 6)
HO C
1
2
Et N
3
4
5
1
18 h
H
NO2
O
N
2v-w
NO2
N
N
8
v-w
single diastereomers
Table 6. Reactions of 1,1ꢀdiethyl ethenetricarboxylate 1 and cinnamylamines 2vꢀw
Entry 2 Solvent Temp. 8 Yield (%)
R
1
2
3
2v CH
2v CH
2v CH
2
2
2
Ph
Ph
Ph
THF
THF
r.t.
8v (53)
60 °C 8v (62)
benzene 80 °C 8v (55)
1
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9
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6
2w CH
2w CH
2w CH
2
2
2
Cyclohexyl THF
Cyclohexyl THF
r.t.
8w (75)
60 °C 8w (61)
Cyclohexyl benzene 80 °C 8w (61)
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
Stereospecific formation of 8vꢀw is proposed as shown in Scheme 7. Formation of the
zwitterꢀionic intermediate B may be destabilized by the inductive effect of meta NO group
2
on the benzene ring. Instead, the OꢀC bond formation and CꢀC bond formation from A
occurred concertedly to lead to cyclized products 8vꢀw. Intermolecular HOBt nucleophilic
attack from outside leading to 3,4ꢀtrans cyclized product 8vꢀw is proposed by steric reason.
EtO C
2
EtO C
CO Et
2
2
H
CO Et
2
O
O
N
N
R
R
H
NO2
A
B
O N
2
CO Et
2
O
H
EtO C
CO Et
2
2
CO Et
2
R N
H
δ+
O
R
δ-
δ+
H
N
O
N
NO2
NO2
N
N
HOBt
8
Scheme 7
2
Reaction of cinnamylamines with pꢀNMe group: Formation of HOBtꢀincorporated
pyrrolidines
Reaction of cinnamylamine (X = 4ꢀNMe
2
group) 2x as a strong electronꢀdonating
group in para position was also examined. The reaction of 1 and 2x with EDCI/HOBt/Et
3
N
at room temperature or 60 °C for 1 h to 18 h gave HOBtꢀincorporated pyrrolidine 9 as ca. 2:1
diastereomer mixture in 34ꢀ60% yield and as an isolable product (eq 7). The
1
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7
8
9
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
3
,4ꢀtransꢀstereochemistry of 9 was deduced by the absence of NOE's between C3ꢀH and
C4ꢀH and between CH(CO
2
Et)
2
and CH(Ar)O.
NMe2
CO Et
2
O
2
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
H
EtO C CO
Et
2
CO Et
2
(eq 7)
2
EDCI
HOBt
3
4
PhH C N
2
1
+
NMe2
5
HO C
H
2
Et N
THF
3
O
1
N N
HN
CH Ph
2x
N
2
9
dr = ca. 2:1
r.t. 1 h (34%)
r.t. 18 h (60%)
60 °C 18 h (56%)
Formation of 9 could be explained by the intervention of the strongly stabilized
zwitterꢀionic intermediate transꢀB by the resonance effect of para NMe group (Scheme 8).
2
TransꢀB is a 3,4ꢀtrans isomer of intermediate B. The stabilized zwitterꢀionic intermediates B
may cause isomerization to sterically more stable intermediate transꢀB. Stepwise nucleophilic
attack of HOBt to zwitterꢀionic intermediate transꢀB gives product 9 with loss of
stereochemistry at the side chain, 4ꢀCH(OBt)C
6
4
H ꢀ4ꢀNMe
2
.
EtO C
2
EtO C
CO Et
2
2
H
CO Et
2
O
O
N
N
H
NMe2
Ph
Ph
NMe2
A
B
CO Et
2
O
EtO C
H
2
CO Et
2
H
CO Et
2
O
N
3
Ph
4
N
H
H
Ph
trans-B
HOBt
NMe
2
NMe2
9
Scheme 8
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7
8
9
1
6
The difference on reactivity may be related to the Hammet constants σ. For [2+2]
cycloaddition, σ ranges from ꢀ0.27 (pꢀOMe) to +0.23 (pꢀCl, pꢀBr). For [4+2] cycloaddition,
p
σ
p
ranges from +0.78 (pꢀNO
2+2] and [4+2] mixtures. Large negative value σ
σ +0.71 (mꢀNO ) gave exceptional results, respectively.
2
) to +0.45 (pꢀCO
2
Et). σ
m
+0.45 (mꢀCF
3
) and +0.34 (mꢀF) gave
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
[
p
ꢀ0.83 (pꢀNMe
2
) and large positive value
m
2
Reaction of other electronꢀdeficient olefins and cinnamylamines with oꢀNO
4+2] cycloaddition
In order to examine the effects of electronꢀwithdrawing group in [4+2] cycloaddition
2
group:
[
of styrene moiety and the generality of the reaction, the reactions of other electronꢀdeficient
olefins with carboxyl group and cinnamylamines without substituents 2aꢀb and with oꢀNO2
group 2jꢀk were carried out. Reaction of monomethyl maleate 10 and 2aꢀb,2jꢀk with
3
EDCI/HOBt/Et N at room temperature gave amides 11aꢀb,11jꢀk as isolable products along
with the corresponding trans isomers 13 (eq 8, Table 7). Formation of byproducts 13 may
arise from partial isomerization of 10 to 12 under the reaction conditions. Reaction of
monomethyl fumarate 12 and 2aꢀb, 2jꢀk gave amides 13aꢀb, 13jꢀk, respectively (eq 9, Table
7).
MeO C
2
HOBt
EDCI
X
MeO C
2
R
O
Et N
+
3
(eq 8)
N
H
HOOC
N
R
THF
r.t.
X
10
2
a,b,j,k
1
8 h
11a,b,j,k
R = CH Ph, CH Cyclohexyl
2
2
R = CH Ph, CH Cyclohexyl
X = H, NO2
2
2
X = H, NO2
CO Me
2
HOBt
EDCI
X
CO Me
2
R
O
+
Et
3
N
(eq 9)
N
HOOC
H
N
THF
r.t.
18 h
X
2a,b,j,k
R
12
R = CH Ph, CH Cyclohexyl
2
2
1
3a,b,j,k
X = H, NO2
R = CH Ph, CH Cyclohexyl
2
2
X = H, NO2
1
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8
9
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
Table 7. Reactions of 10/12 and cinnamylamines 2
Entry 10/12 2
R
X
H
Yield (%) Isolated byproduct
a
b
1
2
3
4
5
6
7
10
10
10
10
12
12
12
12
2a CH
2b CH
2
2
Ph
11a (40)
11b (18) 13b (35)
2ꢀNO 11j (40) 13j (11)
Cyclohexyl H
2j CH Ph
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
2
2
2k CH
2a CH
2b CH
2
2
2
Cyclohexyl 2ꢀNO
Ph
Cyclohexyl H
2
11k (31) 13k (39)
a
H
13a (89)
a
13b (61)
a
2j CH Ph
2ꢀNO 13j (72)
2
2
8
a
2 2
2k CH Cyclohexyl 2ꢀNO 13k (63)
b
A small amount of impurity could not be removed. 13a could be formed but not
confirmed.
Compound 11jꢀk gradually change to 14jꢀk at room temperature. Heating 11jꢀk at 80
C in ClCH CH Cl for 18 h gave 14jꢀk via [4+2] cycloaddition/Hꢀtransfer (eq 10, Table 8).
On the other hand, heating 11aꢀb at 80 °C in ClCH CH Cl for 18 h gave complex mixtures.
Heating trans isomer 13k at 80 °C in ClCH CH Cl for 18 h did not change. The reaction of
°
2
2
2
2
2
2
1
3jꢀk at 110 °C in toluene for 18 h gave 14jꢀk as isolable products (eq 11, Table 8). Reaction
of 13aꢀb at 80 °C in ClCH CH Cl for 18 h gave remained starting materials, and the reaction
at 110 °C in toluene for 18 h gave complex mixtures. The stereochemistries of 14j,k and
5j,k were determined by NOE's. The pyrrolidine ring junction is trans. Thermal [4+2]
2
2
1
cycloaddition reaction of 11j,k and 13j,k underwent stereospecifically and the products
retained the original cis and trans stereochemistries of C=C double bonds.
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9
MeO C
2
CO Me
O
1
2
H
8
9
8
0 °C
7
6
O
9a
R 2N 3a
3
(eq 10)
N
R
ClCH CH Cl
X
2
8 h
2
4
5
H
1
X
1
1a,b,j,k
14
R = CH Ph, CH Cyclohexyl
2
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
X = H, NO2
CO Me
2
CO Me
O
1
2
R N
2
H
8
9
1
10 °C
O
7
6
9a
3
a
(eq 11)
N
toluene
8 h
3
5
X
4
R
H
1
X
1
3a,b,j,k
15
R = CH Ph, CH Cyclohexyl
2
2
X = H, NO2
Table 8. Thermal reactions of 11/13
Entry 11/13 R
X
H
Temp. Yield (%)
a
1
2
3
4
5
6
7
8
a
11a CH
11b CH
2
2
2
Ph
80 °C 14a (0)
a
Cyclohexyl H
Ph 2ꢀNO
80 °C 14b (0)
11j
CH
2
80 °C 14j (33)
11k CH Cyclohexyl 2ꢀNO 80 °C 14k (55)
2
2
2
2
2
a
13a CH
13b CH
Ph
Cyclohexyl H
Ph 2ꢀNO
H
110 °C 15a (0)
a
110 °C 15b (0)
110 °C 15j (31)
13j
CH
2
13k CH Cyclohexyl 2ꢀNO 110 °C 15k (46)
2
2
Complex mixtures.
Furthermore, reaction of 4,4,4ꢀtrifluoroꢀ3ꢀ(trifluoromethyl)crotonic acid 16 and
cinnamylamine with oꢀNO group 2j was examined. Reaction of 16 and 2j with
2
3
EDCI/HOBt/Et N at room temperature gave amide 17 in 57% yield (Scheme 9). Thermal
reaction of 17 at 80 °C in ClCH
2 2
CH Cl for 22 h gave ca. 1:1 mixture of 17 and 18. Heating
17 at 110 °C in toluene for 20 h completed the conversion and 18 was obtained in 89% yield.
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9
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
F3C
CF
3
O N
HOBt
EDCI
Et N
3
2
F3C
CF
3
O
+
HOOC
N
THF
r.t.
20 h
NO2
PhH C
2
16
NH
O
17 (57%)
2
j
PhH C
2
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
F3C
H
CF
3
8
9
1
10 °C
1
7
6
2
9a
PhH C N 3a
2
toluene
0 h
3
5
4
2
H
NO2
1
8 (89%)
Scheme 9
Higher reactivity of 11 than that of 13 may arise from preferable steric overlap on the
transition states of [4+2] cycloaddition (Scheme 10). Much higher reactivity of
ethenetricarboxylate intermediates A compared to 11 and 13 may arise from activation of
C=C double bond by three electronꢀwithdrawing carbonyl groups. Lower reactivity of 17
than that of A could be due to the steric effect of CF
3
groups.
MeO
MeO C
2
O
O
O
R
N
N
O
NO2
NO2
R
13
11
EtO
F
EtO C
F3C
F
2
O
C
O
F
N
R
N
NO2
NO2
PhH C
2
A
1
7
Scheme 10
Finally, intermolecular reaction of ethenetricarboxylate triester 19 and
nitrophenylstyrene 20 was attempted in order to examine the effect of electronꢀdeficient
substituent on benzene ring to [4+2] cycloaddition of styrene as a diene component.
However, heating 19 and 20 at 80 °C in ClCH
2 2
CH Cl or 110 °C in toluene did not proceed
and only starting materials were recovered (eq 12).
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9
80 °C
2
EtO C CO Et
NO2 ClCH CH Cl
2
2
EtO C
CO
2
Et
2
2
NO2
EtO C
2
+
(
eq 12)
EtO C
2
or 110 °C
toluene
1
9
20
21
18 h
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
Additional comparison with the results in literatures is discussed as follows. The
difference in stability between A (in Scheme 13) and compound 22, the oxygen analogue of
A, is noteworthy (Scheme 11). Compound 22 was isolated, as reported by Snider and his
17
coworkers. Heating compound 22 at 85 °C or 115 °C led to an equilibrium mixture of 22
and hetero DielsꢀAlder adduct. They also reported that treatment of 22 with FeCl
3
underwent
intramolecular reactions to give chlorinated γꢀlactone ((a) in Scheme 3) with loss of
11
stereochemistry on the side chain. The difference in stability can be explained, similar to
12,13
the cyclization of other ethenetricarboxylate derivatives.
Triester 22 may be more stable
in sꢀcis conformation of O=C−O−CH as shown in Scheme 11, probably because of the steric
2
repulsion. In diester amide A (in Scheme 3), the energy differences of sꢀcis and sꢀtrans
2
conformations of O=C−NR−CH may be small. The facile intramolecular reaction of amide
probably originates from higher ratio of the reactive sꢀtrans conformer. Amideꢀtethered
alkylidene malonate 23 is also a stable compound and scandiumꢀcatalyzed [2+2] cyclization
5b
to produce cyclobutaneꢀfused pyrrolidine was reported. Higher reactivity of A compared to
3 may arise from the electronꢀwithdrawing effect of 2ꢀcarboxyl group and the steric effect
of the restricted rotation of the CꢀN amide bond.
2
MeO C CO
Me
MeO C CO
Me
2
2
F
2
2
O
O
N
Ns
Ns = 2-nitrophenylsulfonyl
22
23
Scheme 11
Theoretical study
1
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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
Understanding the detailed mechanism of the cycloadditions is important to find the
factor to control the selectivity. In order to explain the observed [2+2]/[4+2] selectivity, the
1
8,19
reaction mechanism was examined using B3LYP/6ꢀ31G*
calculations including the
2
0
PCM
solvent effect (solvent=THF). TS geometry was characterized by vibrational
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
analysis, which checked whether the obtained geometry has single imaginary frequencies
‡
(
ν ). From TSs, reaction paths were traced by the intrinsic reaction coordinate (IRC)
21
method to obtain the energyꢀminimum geometries. Relative Gibbs free energies are of
RB3LYP/6ꢀ31G* SCRF = (PCM, solvent = THF) (T = 298.15 K, P = 1 atm).
H
O
O
H
O
O
MeO
H
H
O
MeO
O
OMe
TS1
MeO
TS2
O
O
[
+5.05
kcal/mol]
O
[+2.51
OMe
H
kcal/mol]
OMe
N
N
N
H
[
ꢀG° = 0
H
kcal/mol]
[
-0.0 kcal/mol]
[-5.8 kcal/mol]
BM+H+
3M+H+
AM1+H+
TS5
[
+12.2
H
kcal/mol]
O
N
O
MeO
O
OMe
H
O
OMe
H
O
O H
O
MeO
O
MeO C
2
CO
H
2
Me
MeO
O
H
H
O
H
OMe
N
[
-0.2 kcal/mol]
N
N
+
AM2+H
H
H
H H
H
[
+7.4 kcal/mol]
[+1.9 kcal/mol]
[-24.5 kcal/mol]
cis-CM+H+
cis-7M+H+
TS3
cis-DM+H+
[+0.7
kcal/mol]
H
O
H
O
O
O
O H
MeO
TS4
MeO
MeO C CO Me
2
2
MeO
O
O
OMe
O
[+13.7
kcal/mol]
O
H
OMe
O
H
H
H
H
H
OMe
N
N
N
N
H
H
H
H H
H
[
-4.3 kcal/mol]
trans-BM+H
[
+11.0 kcal/mol]
[-0.4 kcal/mol]
[-23.9 kcal/mol]
+
CM+H+
DM+H+
7M+H+
Scheme 12. [2+2] and [4+2] cycloaddition reaction paths of protonated intermediate amides,
+
+
AM1+H and AM2+H . Gibbs free energies (T = 298.15 K, P = 1 atm) were obtained at the
+
RB3LYP/6ꢀ31G* SCRF = (PCM, solvent = THF) level and are relative to AM1+H .
2
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Possible [2+2] cycloaddition paths could not be obtained using the neutral model
systems. Alternatively, acidꢀcatalyzed intramolecular [2+2] cycloaddition reaction models for
+
AM1+H were calculated (Scheme 12). The protonated sixꢀmembered ring intermediates
+
22
with hydrogen bonding were assumed in models for AM1+H . The acid in situ, possibly
generating from EDCI (1ꢀ[3ꢀ(dimethylamino)propyl]ꢀ3ꢀethylcarbodiimide hydrochloride) or
starting material 1 may catalyze the cycloaddition reactions. Stepwise [2+2] cycloaddition
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
+
mechanism via benzylic cation intermediates BM+H leads to cyclobutaneꢀfused product
+
+
3
M+H . Stepwise [4+2] cycloaddition path via trans intermediate transꢀBM+H leading to
+
+
+
CM+H was also obtained. Intermolecular proton transfer of CM+H to DM+H possibly
+
leads to rearomatized product 7M+H . The path leading to the corresponding pyrrolidine
+
cisꢀfused product cisꢀ7M+H via TS5 was also calculated.
‡
The activation energies ꢀG of both TS4 and TS5 (13.7 and 12.2 kcal/mol) for [4+2]
cycloadditions are higher than that of TS1 (5.1 kcal/mol) for [2+2] cycloaddition. Thus, for
cinnamlyamine without electronꢀwithdrawing group, [2+2] cycloaddition is more favorable
than [4+2] cycloaddition.
Next, the effect of ortho electronꢀwithdrawing group to [4+2] cycloaddition was
examined. Acidꢀcatalyzed reaction of orthoꢀnitro models were first calculated and the results
were shown in Scheme 13. [2+2] cycloaddition path from unstable benzylic cation
+
+
intermediate BN+H could not be obtained. Alternatively, intermediate transꢀBN+H leads to
[
4+2] cycloaddition path.
2
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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
H
H
H
O
O
N
O
O
N
O
O
MeO
O
TS1N
+8.6
kcal/mol]
MeO
O
OMe
MeO
O
OMe
[
H
OMe
O N
2
[2+2]
N
NO2
NO2
H
[
ꢀG° = 0 kcal/mol]
1.700 Å
AN2+H+
[-2.1
kcal/mol]
AN1+H
[+9.2 kcal/mol]
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
BN+H+
+
TS3N
[+4.5
kcal/mol]
O H
H
O
O
O H
O
MeO
O
MeO
TS4N
[+15.5
kcal/mol]
MeO C CO Me
2
H
2
MeO
O
O
OMe
O
H
O
H
H
H
OMe
H
OMe
N
N
N
N
H
H
H
H H NO2
H
NO2
NO2
NO2
[
+6.2 kcal/mol]
[
+11.3 kcal/mol]
[
+1.9 kcal/mol]
[-22.8 kcal/mol]
+
+
CN+H
DN+H
+
trans-BN+H+
7jN+H
Scheme 13. Acidꢀcatalyzed reaction path of orthoꢀnitro models. Gibbs free energies are
+
relative to AN2+H .
Concerted [4+2] cycloadditions without acid catalyst for cinnamyl and
orthoꢀnitrocinnamyl amide models were also calculated and the result is shown in Scheme
1
4. The concerted process of orthoꢀnitrocinnamyl amide (TSNa) is slightly energetically
favored over that of cinnamyl amide (TSa). Substitution of nitro group at one carbon away
from diene moiety may give little electronic effect to [4+2] cycloaddition. Thus, the [4+2]
cycloaddition occurs in either acidꢀcatalyzed path or concerted path under the oneꢀpot
reaction conditions.
The calculated results of the concerted path are also in agreement with observed
preferable formation of transꢀfused pyrrolidine ring to that of cisꢀfused pyrrolidine ring
(TSNa < TSNb). The experimental result is similar to reported intramolecular [4+2]
cycloaddition involving styrenes giving transꢀfused heterocyclic fiveꢀmembered rings
9
e,f
mainly.
The intramolecular [4+2] cycloaddition reaction may be governed by steric
requirement.
2
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7
8
9
O
N
O
TSa
+25.6
kcal/mol]
MeO C CO Me
2
2
MeO C CO Me
2
2
O
[
H
MeO
O
OMe
O
H
H
N
N
H
H
[-22.3 kcal/mol]
[
ꢀG° = 0 kcal/mol]
[+14.1 kcal/mol]
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
AM2
7M
CM
O
N
O
TSb
[+27.0
kcal/mol]
MeO C
MeO
O
OMe
MeO C CO Me
2
CO Me
2
2
2
O
H
O
H
H
N
N
H
H
[-0.7
[-22.1 kcal/mol]
[
+8.5 kcal/mol]
kcal/mol]
cis-7M
cis-CM
AM1
O
O
TSNa
MeO C CO Me
2
H
2
MeO C CO Me
2
H
2
O
[
+25.2
kcal/mol]
MeO
O
OMe
O
H
N
N
N
H
NO2
H
NO2
NO2
[
ꢀG° = 0 kcal/mol]
[
-23.2 kcal/mol]
[+11.5 kcal/mol]
AN2
7jN
CN
O
N
O
TSNb
MeO C
2
MeO
O
OMe
MeO C
CO Me
[+27.4
kcal/mol]
2
CO Me
2
2
O
H
O
H
H
N
N
NO2
H
H
NO2
NO2
[
-1.4 kcal/mol]
[-19.9 kcal/mol]
[+6.5 kcal/mol]
cis-7jN
AN1
cis-CN
Scheme 14. [4+2] cycloaddition reaction paths of AM2, AM1 and orthoꢀnitro models AN2,
AN1. Gibbs free energies are relative to AM2 and AN2, respectively.
These results suggest that electronꢀwithdrawing group on benzene ring destabilizes
[
2+2] cycloaddition path and alternatively [4+2] cycloaddition path proceeds. The [4+2]
cycloaddition of styrene moiety involves dearomatization and rearomatization. Acceleration
of dearomatization by nitroꢀsubstitution is reported in the reactions of C=C component of
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
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4
4
4
4
4
4
4
4
4
5
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5
5
5
5
5
5
5
5
6
2
3
benzene ring. However, whether there is any acceleration or not is unclear yet in the [4+2]
cycloaddition of electron deficient olefin by substitution of ortho NO
moiety as diene. Further mechanistic study is under investigation.
2
group to styrene
In summary, intramolecular [2+2] and [4+2] cycloaddition reactions of
cinnamylamides of ethenetricarboxylate in sequential processes have been studied. Reaction
of cinnamylamines without substituent on benzene ring and with halogens and OMe on para
position at room temperature gave cyclobutaneꢀfused pyrrolidines as major products via
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
[
2+2] cycloaddition. The reaction at 80 °C in 1.2ꢀdichloroethane gave δꢀlactoneꢀfused
pyrrolidines as major products, possibly via ring–opening of the cyclobutanes. Interestingly,
reaction of 1,1ꢀdiethyl 2ꢀhydrogen ethenetricarboxylate and cinnamylamines bearing
2 2 2 3
electronꢀwithdrawing groups such as NO , CN, CO Me, CO Et, CF on ortho and para
positions in the presence of EDCI/HOBt/Et N at room temperature or at 60ꢀ80 °C gave
3
tetrahydrobenz[f]isoindolines via [4+2] cycloaddition as major products. Diversity of the
reaction pattern depending on the substituents of benzene ring was found. Further
transformation of the highly functionalized heterocyclic products to useful compounds are
under investigation.
Experimental Section
1
13
4
General Methods. H Chemical shifts are reported in ppm relative to Me Si. C Chemical
1
9
shifts are reported in ppm relative to CDCl (77.1 ppm). F Chemical shifts are reported in
3
13
ppm relative to CFCl
3
. C mutiplicities were determined by DEPT and HSQC. Mass spectra
were recorded at an ionizing voltage of 70 eV by EI, FAB, CI or ESI. Mass analyzer type
used for EI, FAB and CI is doubleꢀfocusing 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 (75ꢀ150 ꢁm).
2
4
Ethenetricarboxylate 1 was prepared according to the literature. Cinnamylamines 2aꢀx
were prepared from the corresponding cinnamaldehydes and amines by reductive amination
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5 1
in methanol (for 2aꢀp, 2rꢀx) or ethanol (for 2q) according to the literature procedure.
H
2
6
NMR of 2a was in accord with the reported data.
5ꢀFluoroꢀ2ꢀnitrocinnamaldehyde
(90%),
4ꢀcyanocinnamaldehyde
(86%)
and
3
ꢀnitrocinnamaldehyde (47%) were prepared from the corresponding benzaldehydes and
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7
1
acetoaldehyde according to the literature procedure.
H
NMR spectra of
28
4
ꢀcyanocinnamaldehyde and 3ꢀnitrocinnamaldehyde were in accord with the reported data.
4
ꢀ(Methoxycarbonyl)cinnamaldehyde (59%) was prepared by the palladiumꢀcatalyzed
28 1
reaction of the corresponding aryl iodides with acrolein diethyl acetal. H NMR spectra of
29
4
ꢀ(methoxycarbonyl)cinnamaldehyde were in accord with the reported data.
4
ꢀ(Ethoxycarbonyl)cinnamaldehyde and 3ꢀfluorocinnamaldehyde were prepared according to
2
8
the
literature.
4ꢀ(Trifluoromethyl)cinnamaldehyde
(58%),
3
ꢀ(trifluoromethyl)cinnamaldehyde (56%), 3,5ꢀbis(trifluoromethyl)cinnamaldehyde (81%)
were prepared from the corresponding benzaldehydes and
formylmethylenetriphenylphosphorane according to the literature procedure. H NMR of
3
0 1
28
3ꢀ(trifluoromethyl)cinnamaldehyde was in accord with the reported data.
4ꢀ(Trifluoromethyl)cinnamaldehyde: (8.2 mmol scale, 0.951 g, 58%); R
f
= 0.6
1
(
hexaneꢀether = 1 : 1); pale yellow crystals; mp 60 °C; H NMR (400 MHz, CDCl
3
) δ (ppm)
6
1
3
.78 (dd, J = 16.0, 7.6 Hz, 1H), 7.52 (d, J = 16.0 Hz, 1H), 7.69 (s, 4H), 9.76 (d, J = 7.6 Hz,
1
3
H); C NMR (100.6 MHz, CDCl
3
) δ (ppm) 123.7 (C, q, JCF = 272 Hz), 126.0 (CH, q, JCF =
.8 Hz), 128.6 (CH), 130.5 (CH), 132.4 (C, q, JCF = 33 Hz), 137.3 (C, q, JCF = 1.5 Hz), 150.3
1
9
(
CH), 193.2 (CH); F NMR (376 MHz, CDCl ) δ (ppm) ꢀ63.05; IR (KBr) 2817, 2733, 1680,
3
ꢀ1
+
1
324, 1172, 1122, 1066 cm ; MS (EI) m/z 200 (M , 38), 199 (32), 151 (47), 131 (100%);
+
HRMS (EI) m/z M 200.0448 (calcd for C10
H
7
3
F O 200.0449).
3
,5ꢀBis(trifluoromethyl)cinnamaldehyde: (10 mmol scale, 2.17 g, 81%); R = 0.7
f
1
(
hexaneꢀether = 1 : 1); pale yellow crystals; mp 80ꢀ81 °C; H NMR (400 MHz, CDCl
3
) δ
(
ppm) 6.85 (dd, J = 16.1, 7.4 Hz, 1H), 7.56 (d, J = 16.1 Hz, 1H), 7.94 (s, 1H), 8.02 (d, J = 0.4
1
3
Hz, 2H), 9.80 (d, J = 7.4 Hz, 1H); C NMR (100.6 MHz, CDCl ) δ (ppm) 123.0 (C, q, J
=
CF
3
2
73 Hz), 124.2 (CH, q, JCF = 3.8 Hz), 128.1 (CH, q, JCF = 3.1 Hz), 131.5 (CH), 132.8 (C, q,
1
9
J
3
CF = 34 Hz), 136.2 (C), 148.1 (CH), 192.6 (CH); F NMR (376 MHz, CDCl ) δ (ppm)
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5
5
5
5
6
ꢀ
1
ꢀ
63.27; IR (KBr) 3088, 2834, 2749, 1696, 1379, 1279, 1178, 1123, 1107 cm ; MS (FAB)
+
+
+
5 6
m/z 269 ([M+H] ), 267 ([MꢀH] ); HRMS (FAB) m/z [MꢀH] 267.0245 (calcd for C11H F O
+
2
67.0245), [M+H] 269.0402 (calcd for C H F O 269.0401).
11
7 6
0
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0
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0
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9
0
5
ꢀFluoroꢀ2ꢀnitrocinnamaldehyde was prepared from 5ꢀfluoroꢀ2ꢀnitrobenzaldehyde and
28
acetoaldehyde according to the literature procedure.
5
ꢀFluoroꢀ2ꢀnitrocinnamaldehyde: (5.9 mmol scale, 1.04 g, 90%); colorless crystals; mp
1
1
39ꢀ140 °C; H NMR (400 MHz, CDCl
3
) δ (ppm) 6.61 (dd, J = 15.8, 7.6 Hz, 1H), 7.30 (ddd,
JCH = 9.1, 2.7 Hz, JFH = 7.0 Hz, 1H), 7.35 (dd, JCH = 2.7 Hz, JFH = 8.6 Hz, 1H), 8.06 (d, J =
1
3
1
5.8 Hz, 1H), 8.21 (dd, JCH = 9.1 Hz, JFH = 5.0 Hz, 1H), 9.80 (d, J = 7.6 Hz, 1H); C NMR
100.6 MHz, CDCl ) δ (ppm) 116.1 (CH, d, JCF = 25 Hz), 118.0 (CH, d, JCF = 23 Hz), 128.3
CH, d, JCF = 10 Hz), 133.42 (CH), 133.43 (C, d, JCF = 10 Hz), 144.1 (C), 146.2 (CH, d, JCF
(
(
3
1
9
= 1.5 Hz), 165.0 (C, d, JCF = 258 Hz), 192.7 (CH); F NMR (376 MHz, CDCl
3
) δ (ppm)
ꢀ101.91 (ddd, J = 8.6, 7.0, 5.0 Hz); IR (KBr) 3082, 2849, 1695, 1584, 1521, 1344, 1278,
ꢀ1
+
1119, 979 cm ; MS (EI) m/z 195 (M , 1.3), 166 (100), 145 (86), 120 (52), 110 (69%);
+
HRMS (EI) m/z M 195.0327 (calcd for C
9
H
6
FNO
3
195.0332).
Typical experimental procedure for preparation of cinnamylamines 2: A solution of
transꢀcinnamaldehyde (0.834 g, 10 mmol) and cyclohexylmethylamine (1.01 g, 8.9 mmol) in
methanol (6.8 mL) was heated under reflux for 30 min, followed by the portionwise addition
of NaBH (567 mg, 15 mmol) in iceꢀcooled bath. The mixture was stirred overnight at room
4
temperature. Excess sodium borohydride was quenched by the addition of acetone (3.7 mL)
The mixture was concentrated and the residue dissloved in CH
2 2
Cl and water. The organic
lawayer was washed with water, dried over Na SO and concentrated. The residue was
2
4
purified by column chromatography over silica gel eluting with hexaneꢀEt
2
O to give 2b (1.82
g, 89%).
1
Cinnamyl cyclohexylmethylamine (2b): R = 0.4 (hexaneꢀether = 2 : 1); pale yellow oil; H
f
NMR (400 MHz, CDCl
3
) δ (ppm) 0.863ꢀ0.963 (m, 2H), 1.10ꢀ1.30 (m, 3H), 1.42ꢀ1.52 (m,
2H), 1.64ꢀ1.77 (m, 5H), 2.47 (d, J = 6.6 Hz, 2H), 3.37 (dd, J = 6.3, 1.5 Hz, 2H), 6.29 (dt,
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5.9, 6.3 Hz, 1H), 6.51 (d, J = 15.9 Hz, 1H), 7.17ꢀ7.21 (m, 1H), 7.26ꢀ7.32 (m, 2H), 7.34ꢀ7.39
1
3
(m, 2H); C NMR (100.6 MHz, CDCl
3
) δ (ppm) 26.1 (CH
2 2 2
), 26.7 (CH ), 31.5 (CH ), 38.1
(CH), 52.1 (CH ), 56.3 (CH ), 126.2 (CH), 127.2 (CH), 128.5 (CH), 128.8 (CH), 131.0 (CH),
2
2
ꢀ1
1
37.2 (C); IR (neat) 3339, 3025, 2925, 2850, 1652, 1599, 1495, 1448, 1348, 1125, 966 cm ;
10
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57
58
59
60
+
+
MS (EI) m/z 229 (M , 17), 146 (26), 117 (100%); HRMS (EI) M 229.1832 (calcd for
C H N 229.1830).
16
23
Cinnamyl 4ꢀ(trifluoromethyl)benzylamine (2c): (8.9 mmol scale, 2.45 g, 95%); pale
1
yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 1.51 (bs, 1H), 3.42 (dd, J = 6.3, 1.5 Hz,
2
H), 3.88 (s, 2H), 6.29 (dt, J = 15.9, 6.3 Hz, 1H), 6.53 (d, J = 15.9 Hz, 1H), 7.20ꢀ7.24 (m,
H), 7.28ꢀ7.32 (m, 2H), 7.36ꢀ7.38 (m, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H);
1
1
3
C NMR (100.6 MHz, CDCl
3 2 2
) 51.3 (CH ), 52.7 (CH ), 124.3 (C, q, JCF = 272 Hz), 125.4
(
CH, q, JCF = 3.8 Hz), 126.3 (CH), 127.5 (CH), 128.1 (CH), 128.4 (CH), 128.6 (CH), 128.8
1
9
(C, q, JCF = 32 Hz), 131.7 (CH), 137.0 (C), 144.5 (C); F NMR (376 MHz, CDCl
3
) δ (ppm)
ꢀ62.38; IR (neat) 3313, 3027, 2827, 1619, 1495, 1449, 1418, 1329, 1164, 1120, 1066, 1018,
ꢀ1
+
+
967 cm ; MS (FAB) m/z 290 ([MꢀH] ); HRMS (FAB) [MꢀH] 290.1158 (calcd for
N 290.1157).
Allyl cinnamylamine (2d): (8.9 mmol scale, 1.48 g, 95%); pale yellow oil; H NMR (400
MHz, CDCl ) δ (ppm) 1.23 (bs, 1H), 3.30 (ddd, J = 6.0, 1.6, 1.4 Hz, 2H), 3.41 (dd, J = 6.3,
17 15 3
C H F
1
3
1
.5 Hz, 2H), 5.11 (ddt, J = 10.3, 1.6, 1.4 Hz, 1H), 5.20 (ddt, J = 17.1, 1.6, 1.6 Hz, 1H), 5.93
(
ddt, J = 17.1, 10.3, 6.0 Hz, 1H), 6.29 (dt, J = 15.8, 6.3 Hz, 1H), 6.52 (d, J = 15.8 Hz, 1H),
1
3
7
.19ꢀ7.23 (m, 1H), 7.27ꢀ7.32 (m, 2H), 7.35ꢀ7.38 (m, 2H); C NMR (100.6 MHz, CDCl ) δ
3
(ppm) 51.2 (CH
2 2 2
), 51.9 (CH ), 116.0 (CH ), 126.3 (CH), 127.4 (CH), 128.4 (CH), 128.6
(
CH), 131.4 (CH), 136.8 (CH), 137.1 (C); IR (neat) 3316, 3025, 2816, 1643, 1598, 1494,
ꢀ1
+
+
1
448, 1114, 967 cm ; MS (FAB) m/z 174 ([M+H] ); HRMS (FAB) m/z [M+H] 174.1285
+
(calcd for C12
H
16N 174.1283), [MꢀH] 172.1130 (calcd for C12
H
14N 172.1126).
f
Benzyl 4ꢀfluorocinnamylamine (2e): (6.9 mmol scale, 1.32 g, 79%); R = 0.4 (ether); pale
1
yellow oil; H NMR (400 MHz, CDCl ) δ (ppm) 1.70 (bs, 1H), 3.41 (dd, J = 6.3, 1.4 Hz,
3
2
H), 3.82 (s, 2H), 6.22 (dt, J = 15.8, 6.3 Hz, 1H), 6.49 (d, J = 15.8 Hz, 1H), 6.98 (ddꢀlike,
1
3
J
3
HH = 8.8 Hz, JFH = 8.8 Hz, 2H), 7.23ꢀ7.35 (m, 7H); C NMR (100.6 MHz, CDCl ) δ (ppm)
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1.1 (CH
2
), 53.4 (CH
2
), 115.4 (CH, d, JCF = 21 Hz), 127.1 (CH), 127.8 (CH, d, JCF = 7.7 Hz),
28.1 (CH, d, JCF = 1.5 Hz), 128.2 (CH), 128.5 (CH), 130.3 (CH), 132.8 (C, d, JCF = 3.1 Hz),
1
9
40.2 (C), 162.2 (C, d, JCF = 246 Hz); F NMR (376 MHz, CDCl ) δ (ppm) ꢀ114.86 (tt, J =
3
ꢀ1
.8, 5.7 Hz); IR (neat) 3312, 3028, 2819, 1602, 1508, 1453, 1228, 1158, 968 cm ; MS (EI)
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
+
+
m/z 241 (M , 21), 196 (11), 132 (38), 106 (35), 91 (100%); HRMS (EI) m/z M 241.1273
(calcd for C H FN 241.1267).
16 16
f
4ꢀFluorocinnamyl propylamine (2f): (8.9 mmol scale, 1.24 g, 72%); R = 0.2 (ether); pale
1
yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 0.935 (t, J = 7.4 Hz, 3H), 1.31 (bs, 1H), 1.55
(tq, J = 7.4, 7.4 Hz, 2H), 2.62 (t, J = 7.4 Hz, 2H), 3.39 (dd, J = 6.3, 1.4 Hz, 2H), 6.22 (dt, J =
15.8, 6.3 Hz, 1H), 6.48 (d, J = 15.8 Hz, 1H), 6.98 (ddꢀlike, JHH = 8.8 Hz, JFH = 8.8 Hz, 2H),
1
3
3
7.32 (ddꢀlike, JHH = 8.8 Hz, JFH = 5.5 Hz, 2H); C NMR (100.6 MHz, CDCl ) δ (ppm) 11.8
(CH ), 23.3 (CH ), 51.5 (CH ), 51.9 (CH ), 115.4 (CH, d, J = 22 Hz), 127.7 (CH, d, JCF =
3 2 2 2 CF
7.7 Hz), 128.4 (CH, d, JCF = 2.3 Hz), 129.9 (CH), 133.4 (C, d, JCF = 3.1 Hz), 162.2 (C, d, JCF
1
9
3
= 246 Hz); F NMR (376 MHz, CDCl ) δ (ppm) ꢀ115.04 (tt, J = 8.8, 5.5 Hz); IR (neat) 3308,
ꢀ1
+
2961, 1602, 1508, 1458, 1228, 1158, 1128, 967 cm ; MS (EI) m/z 193 (M , 29), 164 (20),
+
135 (100%); HRMS (EI) m/z M 193.1272 (calcd for C12
H
16FN 193.1267).
f
Benzyl 4ꢀchlorocinnamylamine (2g): (4.5 mmol scale, 0.794 g, 68%); R = 0.3
1
(hexaneꢀether = 2 : 1); pale yellow oil; H NMR (400 MHz, CDCl ) δ (ppm) 1.62 (bs, 1H),
3
3
1
5
.42 (dd, J = 6.3, 1.3 Hz, 2H), 3.82 (s, 2H), 6.23 (dt, J = 15.8, 6.3 Hz, 1H), 6.45 (dt, J = 15.8,
1
3
.3 Hz, 1H), 7.23ꢀ7.28 (m, 5H), 7.32ꢀ7.33 (m, 4H); C NMR (100.6 MHz, CDCl
3
) δ (ppm)
1.1 (CH ), 53.4 (CH ), 127.1 (CH), 127.5 (CH), 128.2 (CH), 128.5 (CH), 128.7 (CH), 129.2
2
2
(CH), 130.1 (CH), 132.9 (C), 135.7 (C), 140.2 (C); IR (neat) 3311, 3027, 2818, 1491, 1453,
ꢀ1
+
+
1404, 1360, 1091, 1012, 968 cm ; MS (EI) m/z 259 (M , 9.1), 257 (M , 22), 166 (16), 132
+
(52), 91 (100%); HRMS (EI) m/z M 257.0971, 259.0980 (calcd for C H ClN 257.0971,
16
16
259.0942).
1
Benzyl 4ꢀbromocinnamylamine (2h): (4.5 mmol scale, 1.15 g, 85%); pale yellow oil; H
NMR (400 MHz, CDCl ) δ (ppm) 1.60 (bs, 1H), 3.40 (dd, J = 6.2, 1.5 Hz, 2H), 3.82 (s, 2H),
3
6.28 (dt, J = 15.9, 6.2 Hz, 1H), 6.46 (d, J = 15.9 Hz, 1H), 7.20 (dꢀlike, J = 8.5 Hz, 2H),
1
3
7.23ꢀ7.28 (m, 1H), 7.30ꢀ7.35 (m, 4H), 7.40 (dꢀlike, J = 8.5 Hz, 2H); C NMR (100.6 MHz,
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CDCl
3
) δ (ppm) 51.1 (CH
2 2
), 53.4 (CH ), 127.1 (CH), 127.8 (CH), 128.2 (CH), 128.5 (CH),
1
1
29.4 (CH), 130.1 (CH), 131.7 (CH), 136.1 (C), 140.1 (C); IR (neat) 3354, 3026, 2920, 2824,
ꢀ1
+
652, 1486, 1455, 1401, 1361, 1116, 1071, 1008, 967 cm ; MS (EI) m/z 303 (M , 4.5), 301
+
+
(
M , 4.5), 196 (19), 132 (18), 106 (54), 91 (100%); HRMS (EI) m/z M 301.0470, 303.0451
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
(
calcd for C16 16BrN 301.0466, 303.0446).
H
1
Benzyl 4ꢀmethoxycinnamylamine (2i): (8.9 mmol scale, 2.13 g, 94%); pale yellow oil; H
NMR (400 MHz, CDCl ) δ (ppm) 1.78 (bs, 1H), 3.40 (dd, J = 6.4, 1.0 Hz, 2H), 3.77 (s, 3H),
.82 (s, 2H), 6.17 (dt, J = 15.8, 6.4 Hz, 1H), 6.47 (d, J = 15.8 Hz, 1H), 6.83 (dꢀlike, J = 8.6
3
3
13
Hz, 2H), 7.22ꢀ7.34 (m, 7H); C NMR (100.6 MHz, CDCl ) δ (ppm) 51.3 (CH ), 53.3 (CH ),
3
2
2
5
3
5.3 (CH ), 114.0 (CH), 126.1 (CH), 127.0 (CH), 127.4 (CH), 128.2 (CH), 128.4 (CH), 129.9
(C), 131.0 (CH), 140.2 (C), 159.1 (C); IR (neat) 3313, 3028, 2932, 2834, 1607, 1511, 1453,
ꢀ1
+
1
249, 1174, 1107, 1034, 968 cm ; MS (EI) m/z 253 (M , 3.3), 196 (18), 162 (18), 106 (56),
+
91 (100%); HRMS (EI) m/z M 253.1471 (calcd for C17
H
19NO 253.1467).
f 2 2
Benzyl 2ꢀnitrocinnamylamine (2j): (8.9 mmol scale, 1.35 g, 56%); R = 0.4 (CH Cl ꢀether
1
= 1 : 4); yellow oil; H NMR (400 MHz, CDCl ) δ (ppm) 1.77 (bs, 1H), 3.47 (dd, J = 6.3, 1.6
3
Hz, 2H), 3.84 (s, 2H), 6.29 (dt, J = 15.6, 6.3 Hz, 1H), 7.01 (d, J = 15.6 Hz, 1H), 7.23ꢀ7.28
1
3
(m, 1H), 7.31ꢀ7.37 (m, 5H), 7.50ꢀ7.58 (m, 2H), 7.89 (dd, J = 8.2, 1.0 Hz, 1H); C NMR
(100.6 MHz, CDCl ) δ (ppm) 51.0 (CH ), 53.3 (CH ), 124.5 (CH), 126.5 (CH), 127.1 (CH),
3
2
2
1
27.9 (CH), 128.3 (CH), 128.5 (CH), 128.7 (CH), 132.8 (C), 133.0 (CH), 134.1 (CH), 140.0
(C), 147.8 (C); IR (neat) 3329, 3063, 3027, 2820, 1606, 1571, 1523, 1454, 1347, 1120, 966
ꢀ1
+
+
+
cm ; MS (EI) m/z 269 ([M+H] , 1.5), 268 (M , 0.7), 267 ([MꢀH] , 2.8), 250 (13), 146 (28),
+
1
20 (48), 91 (100%); HRMS (EI) m/z [M+H] 269.1284 (calcd for C16
H
17
N
2
O
2
269.1290),
+
+
M 268.1179 (calcd for C16
16 2 2 15 2 2
H N O 268.1212), [MꢀH] 267.1138 (calcd for C16H N O
2
67.1134).
f
Cyclohexylmethyl 2ꢀnitrocinnamylamine (2k): (8.9 mmol scale, 1.76 g, 72%); R = 0.4
1
(CH
2
Cl
2
ꢀether = 1 : 4); yellow oil; H NMR (400 MHz, CDCl
3
) δ (ppm) 0.891ꢀ0.981 (m,
2
H), 1.10ꢀ1.30 (m, 3H), 1.43ꢀ1.53 (m, 1H), 1.55 (bs, 1H), 1.65ꢀ1.78 (m, 5H), 2.50 (d, J = 6.6
Hz, 2H), 3.44 (dd, J = 6.2, 1.5 Hz, 2H), 6.30 (dt, J = 15.8, 6.2, 1H), 6.99 (d, J = 15.8 Hz,
1H), 7.35 (ddd, J = 8.2, 7.4, 1.2 Hz, 1H), 7.53 (ddd, J = 7.8, 7.4, 1.0 Hz, 1H), 7.60 (dd, J =
2
9
ACS Paragon Plus Environment