Intramolecular Arylation of Tertiary Enamides through Pd(OAc)2-Catalyzed Dehydrogenative Cross-Coupling Reaction: Construction of Fused N-Heterocyclic Scaffolds and Synthesis of Isoindolobenzazepine Alkaloids

Article abstract of DOI:10.1021/acs.joc.9b00010

Pd(OAc)₂-catalyzed intramolecular dehydrogenative cross-coupling reaction between tertiary enamides, which were derived from the condensation of 2-arylethylamines and methyl o-acetylbenzoate, and arenes enabled synthesis of 7,8-dihydro-5H-benzo

Full text of DOI:10.1021/acs.joc.9b00010

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Article
Intramolecular Arylation of Tertiary Enamides through Pd(OAc)2-catalyzed
Dehydrogenative Cross-coupling Reaction: Construction of Fused N-
Heterocyclic Scaffolds and Synthesis of Isoindoloben-zazepine Alkaloids
Wenju Zhu, Shuo Tong, Jieping Zhu, and Mei-Xiang Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00010 • Publication Date (Web): 08 Feb 2019
Downloaded from http://pubs.acs.org on February 9, 2019
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The Journal of Organic Chemistry
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Intramolecular Arylation of Tertiary Enamides through Pd(OAc)2-
catalyzed Dehydrogenative Cross-coupling Reaction: Construction of
Fused
N-Heterocyclic
Scaffolds
and
Synthesis
of
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Isoindolobenzazepine Alkaloids
1
,2
2,*
3
2,*
Wenju Zhu, Shuo Tong, Jieping Zhu, Mei-Xiang Wang
1
State Key Laboratory of Separation Membranes and Membrane Processes, School of Chemistry and Chemical Engineering
Tianjin Polytechnic University, Tianjin, 300387, China
2
MOE Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology, Department of Chemistry, Tsinghua
University, Beijing 100084, China
3
Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, EPFL-SB-ISIC-LSPN, BCH
5
304, 1015 Lausanne, Switzerland
H
H
O
Pd(OAc) (20 mol%)
2
Cu(OAc) (2.0 equiv)
2
N
R1
R2
N
o
R2
DMSO, 80 C
R1
X
O atmosphere
2
O
tertiary enamides
X
O
H CO
3
N
H CO
3
N
H CO
3
O
H CO
3
OCH3
OCH3
HO
O
(+/-)-chilenamine (X = H)
(+/-)-lennoxamine (X,X = O)
palmanine
2
ABSTRACT: Pd(OAc) -catalyzed intramolecular dehydrogenative cross-coupling reaction between tertiary enamides, which were
derived from the condensation of 2-arylethylamines and methyl o-acetylbenzoate, and arenes enabled synthesis of 7,8-dihydro-5H-
benzo[4,5]azepino[2,1-a]isoindol-5-one derivatives under mild conditions. The synthetic method was applied in the total synthesis
of aporhoeadane alkaloids palmanine, lennoxamine and chilenamine in only three or four steps.
INTRODUCTION
Enamines are powerful synthetic intermediates and find wide
applications in organic synthesis. When one of the N-alkyl groups
of an enamine is replaced by an electron-withdrawing group such
as an acyl, tertiary enamides are generated. In comparison to
conventional enamines, tertiary enamides have long been
recognized as chemically stable species because of the electron-
designed Lewis acid and phosphoric acid catalyzed intramolecular
and intermolecular reactions of tertiary enamides with electrophiles
provide unique and powerful methods for the synthesis of diverse
nitrogenous heterocycles which are not easily obtained by other
1
3-9
means For example, using tertiary enamides as synthons, various
4
b,5a,5b,5e,7c
4b,5c,6,7a,7b,8,9a,9b
4a,4c
five-,
six-
and eight-membered
N-
heterocycles are readily constructed under very mild conditions.
Very recently, intramolecular condensation between tertiary
enamides and aldehydes led to the facile synthesis of seven-
membered 2,3-dihydro-1H-azepine and 1H-azepin-2(3H)-one
2
3
withdrawing effect of N-acyl group. However, we envisioned that
tertiary enamides would be a type of shelf-stable nucleophiles with
tunable reactivity based on the cross-conjugational system
comprising carbon-carbon double bond, lone-pair electrons on
nitrogen atom and carbonyl group (C=C-N-C=O). The enabled
regulation of the cross-conjugation system by means of electronic
and steric effects of the substituents attached on the enamide
segment (C=C-N-C=O), for instance, would enhance the
delocalization of the lone-pair electrons of nitrogen into the carbon-
carbon-double bone, reviving therefore the nucleophilicity of the
5d
derivatives. To further explore the reactivity of stable tertiary
enamides, and also to develop their synthetic applications, we
undertook the current study. We report herein an efficient and rapid
construction of the 2,3-dihydro-1H-benzo[d]azepine, the seven-
membered heterocyclic core embedded in 7,8-dihydro-5H-
benzo[4,5]azepino[2,1-a]isoindol-5-one from intramolecular
dehydrogenative cross-coupling of tertiary enamides with arenes.
The method has been successfully employed in the total synthesis
of aporhoeadane alkaloids palmanine, lennoxamine and
chilenamine.
3
tertiary enamides. We have demonstrated in recent years that
tertiary enamides behave indeed as nucleophiles to react with
4
5
6
7
8
epoxides, carbonyls, imines, nitriliums and alkynes. The
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Scheme 1. Exploring tertiary enamides as versatile synthons in
organic synthesis
lead to the improvement of the efficiency of the catalytic reaction
(Supporting information).
1
2
3
4
5
6
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
nucleophilic
addition reactions
5- to 8-membered
N-heterocyclic compounds
O
R
Table 1. Optimization of Reaction Conditions
privious work
H
H
N
R'
Conditionsa
O
N
intramolecular
dehydrogenative
cross-coupling reaction
Pd(OAc)2 (20 mol%)
N
N
tertiary
enamides
DMSO (c 0.1 M)
O2 atmosphere
O
O
1a
2
a
this work
o
2a (%)b
Entry
[Oxi]
Additive (eq)
T ( C)
t (h)
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
X
X
1c
2
--
--
--
--
120
120
120
120
120
120
120
120
150
100
80
3
68
tr
H3CO
H3CO
H3CO
N
N
24
24
24
24
24
24
24
11
13
11
38
36
36
24
11
11
11
12
H3CO
OCH3
O
HO
palmanine
3
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
2
2
2
--
12
22
18
41
tr
(
(
+/-)-chilenamine (X = H)
+/-)-lennoxamine (X,X = O)
O
OCH3
4
AcOH (1.5)
TfOH (1.5)
PivOH (1.5)
Both
7,8,13,13a-tetrahydro-5H-benzo[4,5]azepino[2,1-
a]isoindole and 7,8,13,13a-tetrahydro-5H-benzo[4,5]azepino[2,1-
a]isoindol-5-one scaffolds are found in aporhoeadane alkaloids
such as chilenamine, chileninone, lennoxamine, palmanine and
Interesting fused heterocyclic structures with
sometimes dense functional groups have prompted a myriad of
different synthetic approaches. As summarized by Leonard in a
5
6
10
pictoamine.
7
K
2
3
CO (2.0)
8
Py (2.0)
tr
1
1
review
among all synthetic methods reported, late-stage
9
PivOH (1.5)
PivOH (1.5)
PivOH (1.5)
PivOH (1.5)
PivOH (1.5)
PivOH (1.5)
PivOH (1.5)
PivOH (1.5)
PivOH (3.0)
PivOH (5.0)
PivOH (3.0)
16
51
61
40
46
48
32
64
66
61
57
formation of five-membered isoindoline or isoindolinone ring and
seven-membered azepine ring, and concurrent construction of the
fused five/seven ring system are the most popular strategies by
means of various C-C and C-N bond forming protocols. Very
recently, intramolecular Suzuki-Miyaura cross-coupling reaction
and nucleophilic substitution reaction were applied respectively by
Yudin and Yao to assemble the azepine ring, accomplishing the
synthesis of 7,8,13,13a-tetrahydro- and 7,8-dihydro-5H-
benzo[4,5]azepino[2,1-a]isoindol-5-ones. Inspired by burgeoning
dehydrogenative cross-coupling reactions, the more atom-
10
11
Cu(OAc)2
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
2
2
2
2
2
1
2
60
1
2
13
13d
80
4e
1
80
5f
1
80
14
economic and environmentally benign processes, we focused on
Palladium-catalyzed direct intramolecular arylation of tertiary
16g
80
1
5
enamides. The salient advantage of this design is a one-step
access to complexed fused heterocyclic compounds and key
intermediates of aporhoeadane alkaloids from tertiary enamides
which were prepared conveniently from the condensation of 2-
arylethylamines and methyl o-acetylbenzoate. It is worth
addressing that although intramolecular arylations of enamines
through 6-membered palladacycle intermediates are known in the
1
7
80
18
80
19h
80
a
Reaction conditions: 1a (0.2 mmol), Pd(OAc)
2
(0.2 equiv),
b
c
Cu(OAc)
1.0 equiv); Air atmosphere;
equiv); Pd(OAc) (0.3 equiv) h 1a (8 mmol) under otherwise
2
2
(2.0 equiv), DMSO (2 mL); Isolated yield; Pd(OAc)
2
1
6
synthesis of indole derivatives, the catalytic C-H bond activation
d
e
f
(
N
2
atmosphere; Pd(OAc)
2
(0.1
process which proceeds via an 8-membered palladacycle (Scheme
) is very rare and challenging. To our knowledge, no
dehydrogenative cross-coupling reactions have ever been used in
the synthesis of aporhoeadane alkaloids and their analogs.
g
1
7
1
identical conditions, 2a 57% yield, 1.13g.
To our delight, addition of a Brønsted acid greatly improved the
transformation (Table 1, entry 4-6). For instance, the presence of
pivalic acid (PivOH) (1.5 equiv) resulted in the formation of 2a in
44% (Table 1, entry 6). Basic reaction condition using either
potassium carbonate and pyridine had a detrimental effect on
catalysis (Table 1, entry 7-8). Notably, temperature played a crucial
role in the conversion of 1a into 2a. As indicted by the results
compiled in Table 1, the optimal temperature is 80 C (Table 1,
entry 11 vs entry 6, 9, 10, and 12). Oxygen atmosphere was
beneficial to facilitate the reaction since reactions slowed down
RESULTS AND DISCUSSION
We initiated our investigation with evaluating the intramolecular
sp -H/Carene-H corss coupling reaction using 3-methylene-2-
phenethylisoindolin-1-one 1a as a model substrate. In the presence
of a stoichiometric amount of Pd(OAc) , the reaction of 1a under
atmosphere delivered the desired 7,8-dihydro-5H-
benzo[4,5]azepino[2,1-a]isoindol-5-one 2a in 68% yield (Table 1,
entry 1). However, only a trace amount of 2a was obtained when
2
C
2
o
O
2
Pd(OAc)
implying that O
Pd(0) to Pd(II). A chemical yield of 12% was obtained after
Cu(OAc) was added as a terminal oxidant (Table 1, entry 3).
2
was used as a catalyst (20 mol%) (Table 1, entry 2),
dramatically under air or N atmosphere (entry 13-14). Increase a
2
2
was probably not an effective oxidant to reoxidize
catalyst loading to 30 mol% did not significantly increase the
formation of 2a whereas a lower catalyst loading (15 mol%) caused
the erosion of the chemical yield of the product (Table 1, entry 15-
16). Finally, product 2a was synthesized in 66% yield with the use
of 3.0 equiv of PivOH (Table 1, entry 17-18). Overall, the optimum
conditions at this stage are comprised of heating a solution of 1a
2
Unfortunately, further optimization of reaction conditions by
screening reaction media, palladium salts and the oxidants did not
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The Journal of Organic Chemistry
with Pd(OAc)
PivOH (3.0 equiv) in DMSO under O
2
(0.2 equiv or 1.0 equiv), Cu(OAc)
2
(2.0 equiv) and
similarly from the reaction of benzo[d][1,3]dioxole-bearing
substrate 1l, N-2-(3,4-dimethoxyphenethyl)-3-
1
2
3
4
5
6
7
8
9
2
, from which product 2a was
produced in 66-68% yield. Finally, performing the reaction of 1a
methyleneisoindolin-1-one 1k underwent cross-coupling reaction
to afford product 2k exclusively. It should be noted that, in some
cases, the use of one equivalent of Pd(OAc) under otherwise
2
identical conditions increased only slightly the chemical yields of
products.
(8 mmol) provided 2a in 57% yield (1.13g, Table 1, entry 19).
Table 2. Scope of the reaction
R2
H
H
To account for the formation of fused heterocycles, the catalytic
arylation proceeds most probably through palladation of tertiary
enamides owing to their nucleophilicity to form enamide-palladium
conditionsa
R1
R1
R2
N
N
1
8
species. The following intramolecular C-H activation and
carbopalladation gives rise to the formation of an 8-membered
palladacycle intermediate which undergoes reductive elimination
affording the final product 2 alone with the release of Pd(0).
Oxidation of Pd(0) by Cu(II) ion regenerates Pd(II) which enters
into the next catalytic cycle (Supporting Information).
O
O
N
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
OMe
Cl
OMe
Cl
N
N
Scheme 2. Total synthesis of lennoxamine 7, chilenamine 8 and
palmanine 12.
O
O
O
2
a, 66% (68%)b
2b, 62%
2c, 49%
O
OMe
R
O
R = OMe, 2e, 61% (69%)b
O
Me
R = Me, 2f, 68%
Me
CO Me
O
R = F, 2g, 58% (63%)b
R = CF3, 2h, 52%
+
a
N
MeO
2
N
N
O
NH2
O
O
OMe
MeO
O
O
OMe
3
4
5
2d, 50%
O
F
O
O
F
O
N
O
b or c
MeO
Me
d
+
N
N
O
N
+
N
N
O
O
MeO
X
X
i, 55% (57%)b
2j, 52% (49%)b
2j', 9% (16%)b
MeO
MeO
2
O
OMe
O
OMe
lennoxamine 7, X, X = O
e
OMe
OMe
O
O
O
O
6'
6
chilenamine 8, X = H
OMe
OMe
O
+
N
N
N
Me
MeO
a
+
O
O
O
MeO
2
CO Me
NH2
MeO
2l', 11% (12%)b
OMe
N
2k, 76%
2l, 51% (55%)b
MeO
3
9
OMe
OMe
O
10
a
A mixture of 1 (0.2 mmol), Pd(OAc)
2
(0.2 equiv), Cu(OAc)
2
o
OMe
(
2.0 equiv) and PivOH (3.0 eq) was heated at 80 C in DMSO (2
mL) under oxygen atmosphere. One equivalent Pd(OAc)
used under otherwise identical conditions.
OMe
OMe
b
2
was
O
b
f
HO
N
N
With the optimized conditions in hand, the generality of
Pd(OAc) -catalyzed intramolecular dehydrogenative arylation of
MeO
MeO
O
O
OMe
MeO
2
tertiary enamides was examined. Gratifyingly, all substrates tested
underwent cyclization reaction smoothly to afford a variety of 7,8-
dihydro-5H-benzo[4,5]azepino[2,1-a]isoindol-5-one derivatives in
moderate to good yields (Table 2). The nature of and the
substitution pattern of a substituent on benzene ring of 2-methyl-3-
methyleneisoindolin-1-one unit had a marginal effect on the
reaction, as substrates 1a-d gave the corresponding fused
heterocyclic ring products 2a-d in 49-66% yields. On the other side,
the presence of electron-donating group(s) on the arene moiety
appeared slightly favorable to the dehydrogenative cross-coupling
reaction. Only one regioisomeric product was yielded from the
reaction of the substrates which contain a para-substituted aryl (1e-
11
palmanine 12
a
Conditions: TsOH (0.05 equiv), toluene, Dean-Stark, reflux, 20 h,
b
5
, 73%, 20 h, 10, 67%; Pd(OAc)
2
(0.2 equiv), Cu(OAc)
2
(2.0
o
equiv), PivOH (3.0 equiv), DMSO, 80 C, O
14%, 6’, 54%, 5.5 h, 11, 73%;
trichloropropane, 80 C, 14 h, 6, 47%, 6’ trace; H
4
10% m/m), EtOAc, rt, 24 h, 7, 96%; LiAlH (5.0 equiv), THF,
2
atmosphere, 9 h, 6,
c
Pd(OAc)
2
(1.0 equiv),
2
(1 atm), Pd/C
o
d
e
(
8
o
f
0 C, 8, 93%; m-CPBA (2.5 equiv), THF, rt, 2 h, 12 43%.
To demonstrate the synthetic utility of the method developed,
total synthesis of natural products lennoxamine, chilenamine and
palmanine was conducted. As illustrated in Scheme 2, one-step
condensation of methyl 2-acetylbenzoate 3 with amines 4 and 9
produced tertiary enamides 5 and 10, respectively, in 73% and 67%
yields. Under the aforementioned optimal catalytic reaction
conditions, intramolecular arylation of enamide 10 afforded a good
1
h) or an ortho-methylphenyl (1i). When a fluorine atom was
introduced into the meta position of arene, the reaction of 1i
produced a mixture of regioisomers 2j and 2j’ in a total of 61%
yield, with a ratio of 2j over 2j’ being 5.8 : 1. Interestingly, when a
pair of regioisomers 2l (51%) and 2l’ (11%) were also generated
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J = 2.3 Hz, 1H), 4.01-3.97 (m, 2H), 2.97 (t, J = 8.0 Hz, 2H); 13C{ H}
NMR (100 MHz, CDCl ) δ 166.8, 141.5, 138.4, 136.2, 133.8, 131.8,
129.3, 129.2, 128.7, 128.5 126.5, 123.1, 122.9, 119.8, 88.5, 40.9,
1
yield of 11 regioselectively while the reaction of 5 gave a pair of
regioisomers 6 and 6’ in 68% yield. Unfortunately, the undesired
angularly fused heterocyclic ring compound 6’, which structure
was unambiguously determined by single crystal X-ray diffraction
analysis (see Supporting Information for detail), was obtained as a
1
2
3
4
5
6
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
−
1
34.5; IR (KBr, cm ): ν 1699, 1644, 1396. HRMS (ESI) m/z： [M
+ H] Calcd for C H NO 250.1226; Found: 250.1228.
-(4-methoxyphenethyl)-5-chloro-3-methyleneisoindolin-1-
+
1
7
16
1
9
major product. However, slight modification of the conditions
Supporting Information) by using one equivalent of Pd(OAc) and
,2,3-trichloropropane as reaction media, the targeted isomer 6 was
2
(
2
o
f
one (1b): (1.03g, 73% yield) yellow solid, mp.125-126 C; R =
1
1
0
.60 (EtOAc/petroleum ether = 1/3); H NMR (400 MHz, CDCl
δ 7.79 (dd, J = 1.8, 0.4 Hz, 1H), 7.60 (dd, J = 8.1, 0.5 Hz, 1H), 7.53
dd, J = 8.1, 1.9 Hz, 1H), 7.18 – 7.12 (m, 2H), 6.86 – 6.80 (m, 2H),
5.17 (d, J = 2.5 Hz, 1H), 4.85 (d, J = 2.6 Hz, 1H), 3.98 – 3.91 (m,
3
)
synthesized predominantly in an acceptable yield. Catalytic
hydrogenation of the carbon-carbon double bond of 6 provided
lennoxamine 7 in a nearly quantitative yield. Further reduction of
(
lactam 7 with LiAlH
4
in THF yielded efficiently chilenamine 8 in
1
3
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2H), 3.78 (d, J = 1.4 Hz, 3H), 2.91 (dd, J = 8.6, 6.9 Hz, 2H); C{ H}
NMR (100 MHz, CDCl ) δ 165.9, 158.3, 140.7, 138.3, 137.8, 130.4,
29.8, 129.7, 127.7, 124.3, 120.3, 114.0, 89.7, 55.2, 41.35, 33.5; IR
9
3% yield. The synthesis of palmanine 12 was accomplished from
3
the treatment of 12 with m-CPBA. The structure of palmanine 12
1
(
was confirmed for the first time by X-ray crystallography (see
−
1
KBr, cm ): ν 2932, 1712, 1645, 1513, 1249, 1126. HRMS (ESI)
1
9
Supporting Information for detail).
+
m/z: [M + H] Calcd for C18
2
H17ClNO 314.0942; Found: 314.0938.
In summary, we have developed
a
2
Pd(OAc) -catalyzed
2
-(4-methoxyphenethyl)-6-chloro-3-methyleneisoindolin-1-
intramolecular arylation of tertiary enamides through an oxidative
dehydrogenative cross-coupling process. This reaction enabled
one-step construction of isoindolobenzazepine fused heterocyclic
ring structure. The developed synthetic method was applied
successfully in the step-economic total synthesis of aporhoeadane
alkaloids palmanine, lennoxamine and chilenamine.
o
one (1c): (1.03g, 73% yield) white solid, mp.115-116 C; R
EtOAc/petroleum ether = 1/3); H NMR (400 MHz, CDCl
3
f
= 0.56
) δ 7.79
dd, J = 1.8, 0.4 Hz, 1H), 7.60 (dd, J = 8.1, 0.5 Hz, 1H), 7.53 (dd,
J = 8.1, 1.9 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz,
H), 5.17 (d, J = 2.5 Hz, 1H), 4.85 (d, J = 2.6 Hz, 1H), 3.95 (dd, J
5.5, 4.0 Hz, 2H), 3.79 (s, 3H), 2.89 - 2.93 (m, 2H); C{ H} NMR
) δ 165.6, 158.35, 140.9, 135.7, 134.5, 132.0,
30.9, 130.3, 129.7, 123.3, 121.1, 114.0, 89.4, 55.2, 41.4, 33.6; IR
1
(
(
2
=
1
3
1
(100 MHz, CDCl
3
1
(
EXPERIMENTAL SECTION
−1
KBr, cm ): ν 2930, 1705, 1645, 1513, 1240, 817. HRMS (ESI)
General Information. Reagents and solvents were purchased
from commercial sources and preserved under argon. More
sensitive compounds were stored in a desiccator or glove-box if
required. Reagents were used without further purification unless
otherwise noted. All reactions were performed under nitrogen or
oxygen and stirring unless otherwise noted. When needed oven
dried glassware was used (T°>100 °C) or under vacuum with a heat
gun (T°>200 °C). Anhydrous solvents were purified and dried
following standard procedures. Flash column chromatography was
performed using Silicycle SiliaFlash® P60 200-300 mesh. TLC
analysis was performed on pre-coated, glass-backed silica gel
plates. TLC’s were revealed by UV fluorescence (254 nm) then one
+
m/z: [M + H] Calcd for C18
2
H17ClNO 314.0942; Found: 314.0938.
2
-(4-methoxyphenethyl)-5-methyl-3-methyleneisoindolin-1-
o
one (1d): (1.0g, 68% yield) white solid, mp.91-92 C; R
(EtOAc/petroleum ether = 1/3); H NMR (400 MHz, CDCl
f
= 0.50
) δ 7.70
1
3
(
d, J = 7.7 Hz, 1H), 7.47 (dd, J = 1.3, 0.6 Hz, 1H), 7.32 – 7.27 (m,
H), 7.21 – 7.13 (m, 2H), 6.86 – 6.79 (m, 2H), 5.14 (d, J = 2.3 Hz,
H), 4.77 (d, J = 2.3 Hz, 1H), 3.98 – 3.85 (m, 2H), 3.78 (s, 3H),
1
1
2
1
3
1
3
.95 – 2.83 (m, 2H), 2.48 (s, 3H); C{ H} NMR (100 MHz, CDCl )
δ 167.0, 158.3, 142.5, 141.8, 136.7, 130.7, 130.4, 129.75, 126.9,
−1
1
22.9, 120.2, 114.0, 88.1, 55.2, 41.15, 33.6, 21.95; IR (KBr, cm ):
ν 2928, 1701, 1635, 1510, 1395, 1246, 1035, 818. HRMS (ESI) m/z:
+
[M + H] Calcd for C19
2-(4-Methoxyphenethyl)-3-methyleneisoindolin-1-one (1e):
(1.04 g, 75% yield) colorless oil, R = 0.44 (EtOAc/petroleum ether
3
= 1/3); H NMR (400 MHz, CDCl ) δ 7.82 (d, J = 7.8 Hz, 1H), 7.68
2
H20NO 294.1489; Found: 294.1484.
4
of the following: KMnO , phosphomolybdic acid, ninhydrin,
pancaldi, p-anisaldehyde, vanillin. Melting points were
uncorrected. The H NMR and 13C{ H} NMR spectra were
1
1
f
1
1
recorded on a JEOL ECX-400 400 MHz spectrometers. H NMR
chemical shifts were reported relative to residual CDCl
3
(7.26 ppm).
C{ H} NMR chemical shifts were reported relative to the central
line of CDCl (77.16 ppm). Abbreviations are used in the
(d, J = 7.8 Hz, 1H), 7.57 (td, J = 7.6, 1.1 Hz, 1H), 7.49 (td, J = 7.3,
0.9 Hz, 1H), 7.18 - 7.15 (m, 2H), 6.84 - 6.82 (m, 2H), 5.18 (d, J =
2.3 Hz, 1H), 4.82 (d, J = 2.3 Hz, 1H), 3.97 - 3.93 (m, 2H), 3.77 (d,
1
3
1
3
13
1
description of NMR data as follows: chemical shift (δ, ppm),
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd =
doublet of doublets, m = multiplet), coupling constant (J, Hz). The
high resolution mass spectra (HRMS) were recorded on a GCT-MS
Micromass UK spectrometer or a microTOF-Q spectrometer.
Infrared spectra were recorded using a PerkinElmer Spectrum 100
FT-IR spectrometer with KBr pellets in the 4000-400 cm−1 region.
J = 5.0 Hz, 3H), 2.91 (t, J = 7.8 Hz, 2H); C{ H} NMR (100 MHz,
CDCl ) δ 166.9, 158.2, 141.6, 136.3, 133.8, 131.8, 130.5, 129.7,
129.4, 129.3, 123.1, 123.0, 119.8, 113.9, 88.6, 55.2, 41.2, 33.6; IR
3
−
1
+
(KBr, cm ): ν 1712, 1514. HRMS (ESI) m/z: [M + H] Calcd for
280.1332 ; Found: 280.1333.
-Methylene-2-(4-methylphenethyl)isoindolin-1-one
18 2
C H18NO
3
(1f):
= 0.59
) δ 7.83
o
(
1.02 g, 73% yield) yellow solid, mp. 86-87 C; R
f
(EtOAc/petroleum ether = 1/3); H NMR (400 MHz, CDCl
3
1
General procedure for the synthesis of substrate 1. A solution
of aniline (5.0 mmol), 2-acetylbenzoic acid (5.0 mmol) and
TsOH·H O (43 mg, 0.25 mmol, 0.05 equiv) in toluene (10 mL) was
2
held at reflux for 12 h using a Dean–Stark apparatus. After being
cooled to room temperature, the solvent was evaporated in vacuo
and the residue was diluted in EtOAc (100 mL). The organic phase
was washed with 1.0 M NaOH (20 mL), brine (20 mL) and dried
(d, J = 7.3 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.3 Hz,
1H), 7.49 (t, J = 7.6 Hz, 1H), 7.17 - 7.11 (m, 4H), 5.20 (d, J = 2.3
Hz, 1H), 4.85 (d, J = 2.3 Hz, 1H), 3.98 (t, J = 7.8 Hz, 2H), 2.94 (t,
1
3
1
J = 7.8 Hz, 2H), 2.33 (s, 3H); C{ H} NMR (100 MHz, CDCl
3
) δ
166.8, 141.6, 136.3, 136.0, 135.3, 131.8, 129.4, 129.3, 129.2, 128.6,
−
1
123.0, 119.8, 88.5, 41.0, 34.0, 21.0; IR (KBr, cm ): ν 1703, 1638,
+
over anhydrous Na
purified by column chromatography to give the final product 1.
-Methylene-2-phenethylisoindolin-1-one (1a): (997 mg, 80%
2
SO
4
. After removal of solvents, the residue was
1393. HRMS (ESI) m/z: [M + H] Calcd for C18
Found: 264.1384.
H18NO 264.1383;
3
2-(4-Fluorophenethyl)-3-methyleneisoindolin-1-one
(1g):
= 0.40
) δ 7.81
o
o
yield) white solid, mp.85-86 C; R
1/5); H NMR (400 MHz, CDCl
f
= 0.44 (EtOAc/petroleum ether
) δ 7.82 (d, J = 7.3 Hz, 1H), 7.67
(949 mg, 71% yield) white solid, mp.71-72 C; R
f
1
1
=
3
(EtOAc/petroleum ether = 1/5); H NMR (400 MHz, CDCl
3
(d, J = 7.3 Hz, 1H), 7.56 (td, J = 7.6, 0.9 Hz, 1H), 7.48 (td, J = 7.3,
0.9 Hz, 1H), 7.31 - 7.20 (m, 5H), 5.18 (d, J = 2.3 Hz, 1H), 4.82 (d,
- 7.79 (m, 1H), 7.67 - 7.65 (m, 1H), 7.58 - 7.54 (m, 1H), 7.48 (t, J
= 7.3 Hz, 1H), 7.19 - 7.16 (2H), 6.95 (t, J = 8.7 Hz, 2H), 5.17 (d, J
ACS Paragon Plus Environment

Page 5 of 9
The Journal of Organic Chemistry
=
2.7 Hz, 1H), 4.79 (d, J = 2.3 Hz, 1H), 3.96 (t, J = 7.8 Hz, 2H),
General procedure for the synthesis of 2. Under oxygen
protection, Pd(OAc) (9.0 mg, 0.02 mmol), Cu(OAc) (80 mg, 0.40
1
3
1
1
2
3
4
5
6
7
8
9
2.94 (t, J = 7.8 Hz, 2H); C{ H} NMR (100 MHz, CDCl
3
) δ 166.8,
61.6 (d, J = 244.4 Hz), 141.5, 136.2, 134.1 (d, J = 3.2 Hz), 131.8,
30.2 (d, J = 7.9 Hz), 129.4, 129.1, 123.0, 119.8, 115.3 (d, J = 21.3
2
2
1
1
mmol), PivOH (68.8 μL, 0.60 mmol) was added to a mixture of
tertiary enamides 1 (0.20 mmol) in DMSO (2 mL). The resulting
1
9
1
o
Hz), 88.5, 40.9, 33.6; F{ H} NMR (376 MHz, CDCl
IR (KBr, cm ): ν 1702, 1645, 1509, 1396. HRMS (ESI) m/z: [M +
H] Calcd for C17
3
) δ -116.3;
mixture was stirred at 80 C for a period of time. After being cooled
−
1
to room temperature, EtOAc (30 mL) and water (30 mL) was added,
and filtrated with Celate, the aqueous layer was extracted with
EtOAc (3 × 20 mL). The combined organic extracts were washed
with water (5 × 20 mL), brine (20 mL) and dried over anhydrous
+
H15NOF 268.1132; Found: 268.1134.
3
-methylene-2-(4-(trifluoromethyl)phenethyl)isoindolin-1-
o
one (1h): (872 mg, 55% yield) white solid, mp. 86-87 C; R
f
= 0.35
1
2 4
Na SO . After removal of solvents in vacuo, the residue was
(EtOAc/petroleum ether = 1/5); H NMR (400 MHz, CDCl ) δ 7.80
3
purified by column chromatography (200–300 mesh) eluted with a
mixture of ethyl acetate and petroleum (1:20 to 1:5) to give the pure
product 2.
(d, J = 7.5 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.56 (td, J = 7.5, 1.1
Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.48 (td, J = 7.4, 0.9 Hz, 1H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
.34 (d, J = 8.0 Hz, 2H), 5.18 (d, J = 2.5 Hz, 1H), 4.79 (d, J = 2.5
1
3
1
Hz, 1H), 4.00 (t, J = 7.6 Hz, 2H), 3.03 (t, J = 7.6 Hz, 2H); C{ H}
NMR (100 MHz, CDCl ) δ 167.0, 142.7, 141.6, 136.3, 132.1, 129.6,
29.2, 129.0 (q, J = 32 Hz), 125.6 (q, J = 4 Hz), 124.3 (q, J = 271
7,8-Dihydro-5H-benzo[4,5]azepino[2,1-a]isoindol-5-one (2a):
o
3
(32.8 mg, 66% yield) yellow solid, mp.125-126 C; R
f
= 0.54
, 60 C)
1
o
1
(EtOAc/petroleum ether = 1/2); H NMR (400 MHz, CDCl
3
−1
Hz), 123.1, 120.0, 100.0, 88.6, 40.5, 34.4; IR (KBr, cm ): ν 3391,
1701, 1647, 1333, 1119, 1069, 772, 698. HRMS (ESI) m/z: [M +
H] Calcd for C18
δ 7.83 (d, J = 7.3 Hz, 1H), 7.76 (d, J = 6.9 Hz, 1H), 7.58 - 7.54 (m,
1H), 7.48 - 7.44 (m, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.27 - 7.23 (m,
1H), 7.20 - 7.17 (m, 2H), 6.58 (t, J = 1.8 Hz, 1H), 4.14 (s, 2H), 3.13
+
H
15NOF
3
318.1100; Found: 318.1111.
1
3
1
(
d, J = 4.1 Hz, 2H); C{ H} NMR (100 MHz, CDCl
3
) δ 165.9,
3-Methylene-2-(2-methylphenethyl)isoindolin-1-one
(1i):
= 0.59
) δ 7.71
o
139.6, 137.2, 134.9, 133.7, 131.7, 131.2, 129. 8, 128.8, 128.4, 127.6,
(909 mg, 69% yield) yellow solid, mp.62-63 C, R
f
−
1
1
127.0, 123.3, 119.1, 107.0, 41.6, 35.6; IR (KBr, cm ): ν 1714.
(EtOAc/petroleum ether = 1/2); H NMR (400 MHz, CDCl
3
+
HRMS (ESI) m/z: [M + H] Calcd for C17
48.1070.
2-chloro-11-methoxy-7,8-dihydro-5H-benzo [4,5] azepino
H14NO 248.1070; Found:
(d, J = 7.3 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.47 - 7.43 (m, 1H),
2
7
4
2
.39 - 7.35 (m, 1H), 7.09 - 7.02 (m, 4H), 5.08 (d, J = 2.3 Hz, 1H),
.73 (d, J = 2.3 Hz, 1H), 3.85 - 3.81 (m, 2H), 2.88 - 2.84 (m, 2H),
.31 (s, 3H); C{ H} NMR (100 MHz, CDCl
13
1
3
) δ 166.8, 141.6,
[2,1-a] isoindol-5-one (2b): (38.7 mg, 62% yield) yellow solid,
o
1
136.6, 136.2, 133.8, 131.7, 130.3, 129.34, 129.32, 129.2, 126.7,
126.1, 122.9, 119.8, 88.3, 39.7, 32.0, 19.2; IR (KBr, cm ): ν 1710,
mp.192-193 C, R
(400 MHz, CDCl
f
= 0.52 (EtOAc/petroleum ether = 1/3); H NMR
−
1
o
3
, 60 C) δ 7.81 – 7.69 (m, 2H), 7.48 – 7.39 (m,
+
1
2
643, 1396. HRMS (ESI) m/z: [M + H] Calcd for C18
64.1383; Found: 264.1383.
H
18NO
1H), 7.08 (d, J = 8.3 Hz, 1H), 6.91 (s, 1H), 6.81 – 6.74 (m, 1H),
6.50 (s, 1H), 4.10 (s, 2H), 3.83 (d, J = 2.3 Hz, 3H), 3.09 (s, 2H);
1
3
1
3
C{ H} NMR (100 MHz, CDCl ) δ 165.0, 158.6, 138.8, 138.2,
2
-(3-Fluorophenethyl)-3-methyleneisoindolin-1-one
(1j):
o
134.4, 134.2, 132.3, 131.0, 129.2, 126.8, 124.65, 119.6, 116.4,
(
1.08g, 81% yield): yellow solid, mp.75-76 C; R
f
= 0.68 (EtOAc /
petroleum ether = 1/2); H NMR (400 MHz, CDCl ) δ 7.82 (d, J =
.3 Hz, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.52 -
.48 (m, 1H), 7.27 - 7.22 (m, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.97 -
1
113.6, 108.0, 55.4, 42.1, 34.7; IR (KBr, cm−1): ν 2929, 1685, 1653,
3
+
1270, 1049. HRMS (ESI) m/z: [M + H] Calcd for C18
312.0786; Found: 312.0781.
H15ClNO
2
7
7
6.89 (m, 2H), 5.18 (d, J = 2.7 Hz, 1H), 4.80 (d, J = 2.3 Hz, 1H),
3-chloro-11-methoxy-7,8-dihydro-5H-benzo [4,5] azepino
1
3
1
4.01 - 3.97 (m, 2H), 2.97 (t, J = 7.8 Hz, 2H); C{ H} NMR (100
MHz, CDCl ) δ 166.9, 162.9 (d, J = 246.1 Hz), 141.0 (d, J = 7.3
Hz), 140.9, 136.2, 131.9, 130.0 (d, J = 8.2 Hz), 129.5, 129.2, 124.45
[2,1-a] isoindol-5-one (2c): (30.6 mg, 49% yield) yellow solid,
o
1
3
mp.154-155 C, R
(400 MHz, CDCl
f
= 0.54 (EtOAc/petroleum ether = 1/3); H NMR
o
3
, 60 C) δ 7.81 (d, J = 1.9 Hz, 1H), 7.69 (d, J =
(
2
1
+
d, J = 2.6 Hz), 123.1, 119.9, 115.7 (d, J = 21.1 Hz), 113.5 (d, J =
8.2 Hz, 1H), 7.54 (dd, J = 8.2, 1.9 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H),
6.90 (d, J = 2.6 Hz, 1H), 6.77 (dd, J = 8.3, 2.6 Hz, 1H), 6.50 (s,
1
9
1
0.9 Hz), 88.5, 40.7, 34.2; F{ H} NMR (376 MHz, CDCl
3
) δ -
−1
13
1
13.2; IR (KBr, cm ): ν 1702, 1646, 1397. HRMS (ESI) m/z: [M
1H), 4.11 (s, 2H), 3.83 (s, 3H), 3.12 – 3.05 (m, 2H); C{ H} NMR
(100 MHz, CDCl ) δ 164.7, 158.6, 135.5, 135.1, 134.5, 134.4,
132.2, 131.9, 130.9, 129.9, 123.5, 120.5, 116.4, 113.4, 107.8, 55.4,
+
H] Calcd for C17
H
15NOF 268.1132; Found: 268.1131.
3
2
-(3,4-Dimethoxyphenethyl)-3-methyleneisoindolin-1-one
−
1
o
55.4, 42.15, 34.65; IR (KBr, cm ): ν 2931, 1691, 1648, 1273, 829.
(1k): (1.24 g, 80% yield) yellow solid, mp.109-110 C; R
(EtOAc/petroleum ether = 1/2); H NMR (400 MHz, CDCl
f
= 0.27
+
1
HRMS (ESI) m/z: [M + H] Calcd for C18
Found: 312.0782.
2
H15ClNO 312.0786;
3
) δ 7.80
(
7
d, J = 7.8 Hz, 1H), 7.65 (d, J = 7.3 Hz, 1H), 7.56 - 7.52 (m, 1H),
.48 - 7.44 (m, 1H), 6.77 (d, J = 0.9 Hz, 2H), 6.71 (s, 1H), 5.16 (d,
J = 2.3 Hz, 1H), 4.80 (d, J = 2.3 Hz, 1H), 3.98 - 3.94 (m, 2H), 3.83
11-methoxy-2-methyl-7,8-dihydro-5H-benzo [4,5] azepino
[2,1-a] isoindol-5-one (2d): (29.2 mg, 50% yield) yellow solid,
1
3
1
o
1
(
s, 3H), 3.76 (s, 3H), 2.92 - 2.88 (m, 2H); C{ H} NMR (100 MHz,
CDCl ) δ 166.8, 148.8, 147.6, 141.5, 136.2, 131.7, 131.0, 129.3,
129.2, 122.9, 120.6, 119.7, 111.9, 111.1, 88.6, 55.7, 55.6, 41.0, 33.9;
mp.158-159 C, R
(400 MHz, CDCl
f
= 0.40 (EtOAc/petroleum ether = 1/3); H NMR
o
3
3
, 60 C) δ 7.72 – 7.58 (m, 2H), 7.39 (d, J = 7.0
Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 6.89 (s, 1H), 6.74 (dd, J = 5.7,
2.5 Hz, 1H), 6.48 (d, J = 1.4 Hz, 1H), 4.10 (s, 2H), 3.92 – 3.72 (m,
−
1
+
IR (KBr, cm ): ν 1708, 1517, 1397. HRMS (ESI) m/z: [M + Na]
Calcd for C19 Na 332.1257; Found: 332.1256.
2-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-3-methyleneisoindolin-
1
0
1
3
1
H
19NO
3
3H), 3.07 (d, J = 3.5 Hz, 2H), 2.47 (d, J = 1.5 Hz, 3H); C{ H}
NMR (100 MHz, CDCl ) δ 166.2, 158.5, 139.3, 135.5, 135.0, 134.8,
132.8, 132.15, 130.8, 128.7, 123.6, 119.0, 116.1, 112.9, 106.2,
3
o
f
-one (1l): (1.13 g, 77% yield) white solid, mp.105-106 C; R =
−
1
1
55.35, 42.0, 34.8, 21.5; IR (KBr, cm ): ν 2923, 1689, 1653, 1502,
3
.36 (EtOAc/petroleum ether = 1/5); H NMR (400 MHz, CDCl )
+
1
2
273, 1122. HRMS (ESI) m/z: [M + H] Calcd for C19
92.1332; Found: 292.1327.
H18NO
2
δ 7.82 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.59 - 7.55 (m,
H), 7.51 - 7.47 (m, 1H), 6.74 - 6.67 (m, 3H), 5.92 (s, 2H), 5.18 (d,
J = 2.3 Hz, 1H), 4.82 (d, J = 2.3 Hz, 1H), 3.96 - 3.92 (m, 2H), 2.89
1
11-Methoxy-7,8-dihydro-5H-benzo [4,5] azepino [2,1-a]
13
1
(t, J = 7.8 Hz, 2H); C{ H} NMR (100 MHz, CDCl
3
) δ 166.9,
isoindol-5-one (2e): (33.9 mg, 61% yield) yellow solid, mp.146-
o
1
147.7, 146.2, 141.7, 136.3, 132.3, 131.8, 129.4, 129.3, 123.1, 121.7,
147 C; R
f
= 0.27 (EtOAc/petroleum ether = 1/4); H NMR (400
3
−
1
o
1
1
3
19.8, 109.2, 108.4, 100.9, 88.5, 41.2, 34.3; IR (KBr, cm ): ν 1714,
MHz, CDCl
, 60 C) δ 7.85 (d, J = 7.3 Hz, 1H), 7.78 (d, J = 7.3 Hz,
+
395. HRMS (ESI) m/z: [M + Na] Calcd for C18
16.0944; Found: 316.0940.
H
15NO
3
Na
1H), 7.58 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.3 Hz, 1H), 7.08 (d, J =
8.2 Hz, 1H), 6.92 (d, J = 2.7 Hz, 1H), 6.78 - 6.75 (m, 1H), 6.54 (s,
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The Journal of Organic Chemistry
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H), 4.13 (s, 2H), 3.84 (s, 3H), 3.09 (t, J = 4.8 Hz, 2H); 13C{ H}
NMR (100 MHz, CDCl ) δ 166.0, 158.5, 137.3, 135.3, 134.8, 132.2,
31.7, 130.8, 128.9, 128.4, 123.4, 119.2, 116.2, 113.1, 106.9, 55.3,
1
196 C, R
MHz, CDCl
o
= 0.22 (EtOAc/petroleum ether = 1/2); H NMR (400
3
1
1
f
o
1
2
3
4
5
6
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
, 60 C) δ 7.85 (d, J = 7.3 Hz, 1H), 7.75 (d, J = 7.3 Hz,
1
4
1H), 7.57 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.3 Hz, 1H), 6.89 (s, 1H),
6.71 (s, 1H), 6.52 (s, 1H), 4.15 (br, 2H), 3.92 (s, 3H), 3.91 (s, 3H),
3.10 (t, J = 4.8 Hz, 2H); C{ H} NMR (100 MHz, CDCl
48.4, 147.6, 137.3, 133.7, 133.0, 131.6, 128.5, 128.2, 126.2, 123.4,
18.9, 114.1, 113.1, 107.0, 56.0, 56.0, 41.8, 35.3; IR (KBr, cm ):
3
ν 1700. HRMS (ESI) m/z: [M + H] Calcd for C19H18NO 308.1281;
Found: 308.1281.
−
1
+
2.0, 34.7; IR (KBr, cm ): ν 1719. HRMS (ESI) m/z: [M + H]
278.1176; Found: 278.1171.
1-Methyl-7,8-dihydro-5H-benzo [4,5] azepino [2,1-a]
1
3
1
Calcd for C18
H
16NO
2
3
) δ 165.8,
1
1
1
−1
isoindol-5-one (2f): (35.6 mg, 68% yield): yellow solid, mp.106-
+
o
1
1
07 C; R
f
= 0.39 (EtOAc/petroleum ether = 1/4); H NMR (400
, 60 C) δ 7.86 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 7.8 Hz,
o
MHz, CDCl
3
1
H), 7.59 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.20 (s, 1H),
6,7-Dihydro-9H-[1,3]dioxolo [4'',5'':5',6'] benzo [1',2':4,5]
o
7.08 (d, J = 7.3 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.57 (s, 1H), 4.15
azepino [2,1-a] isoindol-9-one (2l): yellow solid, mp.201-202 C,
1
3
1
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(s, 2H), 3.12 (t, J = 4.8 Hz, 2H), 2.37 (s, 3H); C{ H} NMR (100
MHz, CDCl ) δ 166.0, 137.3, 136.8, 136.6, 134.9, 133.6, 131.9,
31.7, 129.8, 128.8, 128.5, 128.4, 123.4, 119.1, 107.2, 41.8, 35.2,
R
f
= 0.45 (EtOAc/petroleum ether = 1/2); H NMR (400 MHz,
o
3
CDCl
3
, 60 C) δ 7.84 (d, J = 7.3 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H),
1
2
7.56 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 6.67 (s, 1H), 6.23
−
1
+
13
1
0.9; IR (KBr, cm ): ν 1705. HRMS (ESI) m/z: [M + H] Calcd
16NO 262.1226; Found: 262.1223.
1-Fluoro-7,8-dihydro-5H-benzo[4,5]azepino[2,1-a]isoindol-
(s, 2H), 6.02 (s, 2H), 4.12 (br, 2H), 3.07 (t, J = 4.8 Hz, 2H); C{ H}
NMR (100 MHz, CDCl ) δ 166.0, 146.2, 145.9, 137.1, 135.7, 133.5,
31.8, 128.9, 128.4, 122.1, 119.4, 116.9, 107.2, 101.3, 98.6, 41.8,
for C18
H
3
1
1
−
1
+
o
35.3; IR (KBr, cm ): ν 1704. HRMS (ESI) m/z: [M + H] Calcd
292.0968; Found: 292.0969.
5
0
f
-one (2g): (30.9 mg, 58% yield) white solid, mp.137-138 C, R =
.33 (EtOAc/petroleum ether = 1/4); H NMR (400 MHz, CDCl ,
3
1
for C18H14NO
3
o
60 C) δ 7.85 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.59 (t,
J = 7.6 Hz, 1H), 7.51 - 7.47 (m, 1H), 7.12 (t, J = 6.9 Hz, 1H), 7.07
5
,6-Dihydro-8H-[1,3] dioxolo [4'',5'':4',5'] benzo [1',2':4,5]
o
azepino[2,1-a]isoindol-8-one (2l’): yellow solid, mp.214-215 C,
R = 0.38 (EtOAc/petroleum ether = 1/2); H NMR (400 MHz,
f
CDCl , 60 C) δ 7.85 (d, J = 7.3 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H),
3
-
(
7.04 (m, 1H), 6.91 - 6.86 (m, 1H), 6.49 (d, J = 1.1 Hz, 1H), 4.12
1
1
3
1
3
s, 2H), 3.11 (t, J = 3.9 Hz, 2H); C{ H} NMR (100 MHz, CDCl )
o
δ 166.0, 161.75 (d, J = 244.4 Hz), 137.1, 135.9, 135.7, 135.7 (d, J
8.0 Hz), 131.9, 131.26 (d, J = 8.0 Hz), 129.2, 128.4, 123.5, 119.3,
7.59 - 7.55 (m, 1H), 7.46 (d, J = 7.3 Hz, 1H), 6.84 (s, 1H), 6.69 (s,
1H), 6.47 (s, 1H), 5.97 (s, 2H), 4.12 (s, 2H), 3.07 (t, J = 4.8 Hz,
=
1
17.1 (d, J = 21.9 Hz), 114.1 (d, J = 21.2 Hz), 105.6, 41.7, 34.9;
1
3
1
1
9
1
−1
2H); C{ H} NMR (100 MHz, CDCl
3
) δ 165.8, 147.3, 146.7,
F{ H} NMR (376 MHz, CDCl
3
) δ -116.7; IR (KBr, cm ): ν 1699.
+
137.3, 134.4, 133.8, 131.7, 128.6, 128.3, 127.5, 123.4, 119.0, 110.6,
HRMS (ESI) m/z: [M + H] Calcd for C17
Found: 266.0973.
H13NOF 266.0976;
−
1
1
(
2
10.3, 106.9, 101.4, 41.9, 35.6; IR (KBr, cm ): ν 1718. HRMS
+
3
ESI) m/z: [M + H] Calcd for C18H14NO 292.0968; Found:
11-(trifluoromethyl)-7,8-dihydro-5H-benzo[4,5]azepino[2,1-
92.0969.
a]isoindol-5-one (2h): (32.8 mg, 52% yield) white solid, mp.202-
2
MHz, CDCl
7
7
o
1
2-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-6,7-dimethoxy-3-
methyleneisoindolin-1-one (5): A solution of 2.0 mol of 2-
(benzo[d][1,3]dioxol-5-yl)ethan-1-aminium 4, 2.0 mol of methyl
04 C, R
f
= 0.32 (EtOAc/petroleum ether = 1/5); H NMR (400
) δ 7.86 (d, J = 7.5 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H),
.65 - 7.61 (m, 2H), 7.54 - 7.50 (m, 1H), 7.44 (d, J = 7.8 Hz, 1H),
.30 (d, J = 7.8 Hz, 1H), 6.60 (s, 1H), 4.13 (br s, 2H), 3.20 (br s,
3
2
6-acetyl-2,3-dimethoxybenzoate 3 and TsOH·H O (17.2mg, 0.1
1
3
1
mmol) in 10 mL of toluene was held at reflux for 20 h using a
Dean–Stark apparatus. After being cooled to room temperature, the
solvent was evaporated in vacuo and the residue was purified by
column chromatography to give the final product (516 mg, yield:
2H); C{ H} NMR (100 MHz, CDCl
136.5, 134.8, 132.3, 130.5, 129.8 (q, J = 32 Hz), 129.5, 128.6, 127.8
3
) δ 166.1, 143.1, 137.2,
(q, J = 3 Hz), 124.2 (q, J = 271 Hz), 124.0 (q, J = 3 Hz), 123.8,
−
1
1
1
C
19.5, 105.3, 41.5, 35.8; IR (KBr, cm ): ν 3417, 1688, 1648, 1316,
o
+
73.1%) white solid, mp. 113-114 C, R
f
=0.59 (EtOAc/petroleum
169, 1103, 1079. HRMS (ESI) m/z: [M + H] Calcd for
1
ether 1/1); H NMR (400 MHz, CDCl
3
) δ 7.35 (d, J = 7.8 Hz, 1H),
18
H
13NOF
3
316.0944; Found: 316.0948.
7.09 (d, J = 8.2 Hz, 1H), 6.73 - 6.67 (m, 3H), 5.91 (s, 2H), 5.02 (d,
J = 2.3 Hz, 1H), 4.67 (d, J = 2.3 Hz, 1H), 4.09 (s, 3H), 3.91 (s, 3H),
9
-Methyl-7,8-dihydro-5H-benzo[4,5]azepino[2,1-a]isoindol-
o
5
=
-one (2i): (28.8 mg, 55% yield) yellow solid, mp.156-157 C; R
f
13
1
3
(
1
6
(
.87 (t, J = 8.0 Hz, 2H), 2.85 (t, J = 7.8 Hz, 2H); C{ H} NMR
1
0.32 (EtOAc/petroleum ether = 1/4); H NMR (400 MHz, CDCl
3
,
100 MHz, CDCl ) δ 164.9, 153.6, 147.7, 146.6, 146.1, 141.0,
3
o
60 C) δ 7.88 (d, J = 7.4 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.61 (t,
J = 7.8 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.28 (s, 1H), 7.20 - 7.13
32.3, 130.0, 121.7, 121.2, 116.2, 115.2, 109.2, 108.3, 100.8, 86.4,
−1
2.5, 56.7, 41.3, 34.1; IR (KBr, cm ): ν 1694, 1625, 1501. HRMS
(
m, 2H), 6.62 (s, 1H), 4.15 (s, 2H), 3.21 (s, 2H), 2.44 (s, 3H);
+
ESI) m/z: [M + H] Calcd for C20
H
20NO
5
354.1336; Found:
1
3
1
C{ H} NMR (100 MHz, CDCl
3
) δ 165.8, 138.2, 137.3, 135.8,
354.1329.
1
1
34.5, 134.3, 131.7, 129.8, 129.6, 128.7, 128.5, 126.6, 123.4, 119.1,
−
1
9,10-dimethoxy-5,6-dihydro-8H [1,3] dioxolo [4'',5'':4',5']
benzo [1',2':4,5] azepino[2,1-a]isoindol-8-one (6) and 10,11-
dimethoxy-6,7-dihydro-9H [1,3] dioxolo [4'',5'':5',6'] benzo
07.5, 41.6, 29.6, 20.7; IR (KBr, cm ): ν 1706. HRMS (ESI) m/z:
+
[M + H] Calcd for C18
H16NO 262.1226; Found: 262.1224.
1
2-fluoro-7,8-dihydro-5H-benzo[4,5]azepino[2,1-a]isoindol-
[
1',2':4,5] azepino[2,1-a]isoindol-9-one (6’): Under oxygen
o
5
-one (2j): yellow solid, mp.155-156 C,
R
f
=
0.54
protection, Pd(OAc) (9.0 mg, 0.02 mmol), Cu(OAc) (80 mg, 0.40
2
2
1
o
(EtOAc/petroleum ether = 1/2); H NMR (400 MHz, CDCl
δ 7.84 (t, J = 8.5 Hz, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6
Hz, 1H), 7.18 - 7.13 (m, 1H), 7.03 - 6.95 (m, 2H), 6.87 (s, 1H), 4.16
3
, 60 C)
mmol), PivOH (68.8 μL, 0.60 mmol) was added to a mixture of
tertiary enamides 5 (71 mg, 0.20 mmol) in DMSO (2 mL). The
o
resulting mixture was stirred at 80 C for 9 h. After being cooled to
1
3
1
(s, 2H), 3.16 (J = 4.6 Hz, 2H); C{ H} NMR (100 MHz, CDCl
3
) δ
room temperature, EtOAc (30 mL) and water (30 mL) was added,
and filtered through a celite, the aqueous layer was extracted with
EtOAc (3 × 20 mL). The combined organic extracts were washed
with water (5 × 20 mL), brine (20 mL) and dried over anhydrous
1
1
1
3
66.0, 160.8 (d, J = 250.1 Hz), 141.9, 137.3, 136.1, 132.0, 129.1,
28.6 (d, J = 9.3 Hz), 128.4, 125.2 (d, J = 2.8 Hz), 123.4, 122.2,
22.1, 119.5, 113.8 (d, J = 22.8 Hz), 97.4 (d, J = 9.7 Hz), 41.6,
19
1
o
5.7; F{ H} NMR (376 MHz, CDCl
3
, 60 C) δ -116.1; IR (KBr,
2 4
Na SO . After removal of solvents in vacuo, the residue was
−
1
+
cm ): ν 1721. HRMS (ESI) m/z: [M + H] Calcd for C17
H
13NOF
purified by column chromatography (200–300 mesh) eluted with a
mixture of ethyl acetate and petroleum (1:20 to 1:5) to give the pure
product 6 (14% yield) and its regioisomer 6’ (54% yield).
2
66.0976; Found: 266.0975.
10,11-dimethoxy-7,8-dihydro-5H-benzo[4,5]azepino[2,1-a]
isoindol-5-one (2k): (46.8 mg, 76% yield) yellow solid, mp.195-
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1
9,10-dimethoxy-5,6-dihydro-8H [1,3] dioxolo [4'',5'':4',5']
1/2); H NMR (400 MHz, CDCl
3
) δ 7.34 (d, J = 8.2 Hz, 1H), 7.09
1
2
3
4
5
6
7
8
9
benzo [1',2':4,5] azepino[2,1-a]isoindol-8-one (6): yellow solid,
(d, J = 8.2 Hz, 1H), 6.79 (s, 2H), 6.74 (s, 1H), 5.02 (d, J = 2.3 Hz,
1H), 4.68 (d, J = 2.3 Hz, 1H), 4.08 (s, 3H), 3.91 (t, J = 7.8 Hz, 2H),
o
1
mp. 212-213 C, R
400 MHz, CDCl
f
= 0.46 (EtOAc/petroleum ether = 1/1); H NMR
, 60 C) δ 7.41 (d, J = 8.2 Hz, 1H), 7.13 (d, J =
o
13
1
(
3
3.91 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H), 2.91 - 2.87 (m, 2H); C{ H}
NMR (100 MHz, CDCl ) δ 164.9, 153.6, 148.9, 147.6, 146.6, 141.0,
8
4
.2 Hz, 1H), 6.80 (s, 1H), 6.66 (s, 1H), 6.32 (s, 1H), 5.95 (s, 2H),
.12 (s, 3H), 4.07 (s, 2H), 3.93 (s, 3H), 3.04 (t, J = 4.8 Hz, 2H);
3
131.1, 130.0, 121.2, 120.7, 116.2, 115.2, 112.0, 111.2, 86.5, 62.5,
13
1
−1
C{ H} NMR (100 MHz, CDCl
3
) δ 163.7, 152.9, 146.9, 146.9,
56.7, 55.9, 55.8, 41.2, 33.9; IR (KBr, cm ): ν 1702. HRMS (ESI)
+
1
46.6, 134.0, 133.3, 131.1, 127.8, 120.4, 116.4, 114.4, 110.3, 110.2,
m/z: [M + Na] Calcd for C21
H
23NO
5
Na 392.1468; Found:
−
1
105.0, 101.3, 62.5, 56.8, 41.9, 35.5; IR (KBr, cm ): ν 1700, 1498.
392.1467.
+
HRMS (ESI) m/z: [M + H] Calcd for C20
52.1173.
10,11-dimethoxy-6,7-dihydro-9H [1,3] dioxolo [4'',5'':5',6']
5
H18NO 352.1180; Found:
3
,4,10,11-tetramethoxy-7,8-dihydro-5H-benzo [4,5] azepino
[2,1-a] isoindol-5-one (11): Under oxygen protection, Pd(OAc)
(9.0 mg, 0.02 mmol), Cu(OAc) (80 mg, 0.40 mmol), PivOH (68.8
3
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
benzo [1',2':4,5] azepino[2,1-a]isoindol-9-one (6’): yellow solid,
μL, 0.60 mmol) was added to a mixture of tertiary enamides 10 (74
o
1
mp.193-194 C, R
400 MHz, CDCl
f
= 0.50 (EtOAc/petroleum ether = 1/1); H NMR
mg, 0.20 mmol) in DMSO (2 mL). The resulting mixture was
o
o
(
3
, 60 C) δ 7.44 (d, J = 8.2 Hz, 1H), 7.11 (d, J =
stirred at 80 C for 5.5 h. After being cooled to room temperature,
8
4
.2 Hz, 1H), 6.61 (s, 2H), 6.53 (s, 1H), 6.01 (s, 2H), 4.11 (s, 3H),
EtOAc (30 mL) and water (30 mL) was added, and filtered through
a celite, the aqueous layer was extracted with EtOAc (3 × 20 mL).
The combined organic extracts were washed with water (5 × 20
mL), brine (20 mL) and dried over anhydrous Na SO . After
2 4
removal of solvents in vacuo, the residue was purified by column
13
1
.07 (s, 2H), 3.92 (s, 3H), 3.05 (t, J = 4.8 Hz, 2H); C{ H} NMR
) δ 164.0, 153.3, 146.9, 145.9, 145.8, 135.4,
133.3, 130.8, 122.0, 120.5, 117.3, 116.3, 114.9, 106.8, 101.2, 96.6,
(100 MHz, CDCl
3
−
1
6
2.5, 56.7, 41.7, 35.3; IR (KBr, cm ): ν 1692, 1275. HRMS (ESI)
+
m/z: [M + H] Calcd for C20
H
18NO
5
352.1180; Found: 352.1173.
chromatography (200–300 mesh) eluted with a mixture of ethyl
acetate and petroleum (1:20 to 1:5) to give the pure product 11 (73%
Lennoxamine (7): A mixture of 6 (105.4 mg, 0.3 mmol) and
Pd/C (30 mg, 10 mol%) was placed in anhydrous EtOAc (9 mL)
under an atmosphere (via balloon) of H for 24 hours at room
2
o
yield). Yellow solid, mp.199-200 C; R
f
= 0.12 (EtOAc/petroleum
1
o
3
ether = 1/2). H NMR (400 MHz, CDCl , 60 C) δ 7.41 (d, J = 8.2
Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 6.84 (s, 1H), 6.68 (s, 1H), 6.36
(s, 1H), 4.11 (s, 3H), 4.11 - 4.08 (m, 2H), 3.92 (s, 3H), 3.90 (s, H),
temperature. Filtration of the mixture through Celite, the residue
was purified by column chromatography (200–300 mesh) eluted
with a mixture of EtOAc and petroleum (1:5 to 1:3) to give the pure
product Lennoxamine 7 (102 mg, 96% yield): white solid, mp.230-
1
3
1
3
.89 (s, 3H), 3.06 (t, J = 4.8 Hz, 2H); C{ H} NMR (100 MHz,
CDCl ) δ 163.7, 152.8, 148.1, 147.5, 146.8, 133.3, 132.6, 131.1,
126.5, 120.4, 116.3, 114.3, 113.7, 113.1, 105.0, 62.5, 56.7, 56.0,
3
o
1
2
31 C. H NMR (400 MHz, CDCl
3
) δ 7.16 (d, J = 7.8 Hz, 1H),
−
1
5
[
5.9, 41.7, 35.3; IR (KBr, cm ): ν 1697, 1689. HRMS (ESI) m/z:
7
.12 (d, J = 8.2 Hz, 1H), 6.77 (s, 1H), 6.70 (s, 1H), 5.95 (d, J = 2.8
+
M + Na] Calcd for C21
Palmanine (12): To a solution of 11 (36.7 mg, 0.1 mmol) in THF
(1 mL) was added m-CPBA (57 mg, 75%, 2.5 mmol). The reaction
5
H21NO Na 390.1312; Found: 390.1311.
Hz, 2H), 4.75 - 4.71 (m, 1H), 4.28 (d, J = 10.5 Hz, 1H), 4.10 (s,
3
2
H), 3.91 (s, 3H), 3.11 - 3.07 (m, 1H), 2.93 -2.87 (m, 2H), 2.85 -
.78 (m, 2H); C{ H} NMR (100 MHz, CDCl ) δ 165.2, 152.6,
3
13
1
147.2, 146.3, 146.1, 138.2, 134.8, 130.9, 124.2, 117.1, 116.2, 110.3,
mixture was stirred at room temperature for 2 h. Saturated Na
solution (10 mL) was added to quenched the reaction, then Na
2
SO
CO
3
−
1
101.0, 62.6, 60.1, 56.7, 42.7, 41.1, 35.9; IR (KBr, cm ): ν 1684,
2
3
+
1
493. HRMS (ESI) m/z: [M + H] Calcd for C20
Found: 354.1329.
Chilenamine (8): Under argon atmosphere, a mixture of 7 (70.6
mg, 0.2 mol) and LiAlH (38 mg, 1 mol) was placed in anhydrous
H
20NO
5
354.1336;
(10 mL) was added and the aqueous layer was extracted with
EtOAc (3 × 20 mL), washed with water (20 mL) and brine (20 mL),
dried with anhydrous Na SO . The solvent was evaporated in vacuo
2 4
and the residue was purified by flash silica gel chromatography to
afford Palmanine 12 (17 mg, 43% yield): white solid, mp. 200-201
4
o
THF (2 mL) in a seal tube for 8 hours at 80 C. The solution was
cooled to rt. The reaction mixture was quenched by pouring into
ice water (40 mL), extracted with diethyl ether (15 mL) three times.
The combined organic phases were washed with brine, dried over
o
1
C; R
f
= 0.21 (EtOAc/petroleum ether = 3/2); H NMR (400 MHz,
) δ 7.35 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.87 (s,
H), 6.67 (s, 1H), 4.28-4.23 (m, 1H), 4.15 (s, 1H), 4.02 (s, 3H),
.90 (s, 3H), 3.87 (s, 3H), 3.79 (s, 3H), 3.64-3.58 (m, 1H), 3.39 –
CDCl
3
1
3
3
1
1
2 4
anhydrous Na SO . After evaporation of the solvent, the residue
1
3
1
3
.31 (m, 2H); C{ H} NMR (100 MHz, CDCl ) δ 201.5, 166.2,
54.0, 152.7, 147.7, 146.1, 135.9, 132.8, 127.8, 122.6, 119.1, 116.2,
12.1, 111.9, 90.9, 62.4, 56.4, 56.0, 56.0, 38.0, 31.4; IR (KBr,
were purified by flash column chromatography on silica gel eluted
with a mixture of EtOAc and petroleum (1:5 to 1:3) to give the pure
product Chilenamine 8 (63 mg, 93% yield): yellow solid, mp.174-
−1
+
o
1
cm ): ν 1707. HRMS (ESI) m/z: [M + Na] Calcd for
Na 422.1210; Found: 422.1208.
1
75 C, R
MHz, CDCl
.76 (s, 1H), 6.67 (s, 1H), 5.92 (s, 2H), 4.39 (d, J = 12.8 Hz, 1H),
3.88 (s, 3H), 3.86 (s, 3H), 3.66 (d, J = 12.8 Hz, 1H), 3.39 - 3.30 (m,
f
= 0.16 (EtOAc/petroleum ether = 1/1); H NMR (400
3
21 7
C H21NO
) δ 6.90 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H),
6
ASSOCIATED CONTENT
Supporting Information
2
1
1
6
1
H), 3.16 – 3.04 (m, 3H), 2.79 - 2.73 (m, 1H), 2.64 (t, J = 11.5 Hz,
1
3
1
3
H); C{ H} NMR (100 MHz, CDCl ) δ 151.3, 145.7, 145.6,
The Supporting Information is available free of charge on the ACS
Publications website.
Reaction optimization
44.1, 137.4, 134.9, 133.9, 131.3, 116.0, 111.1, 110.6, 110.2, 100.8,
−
1
7.8, 60.3, 56.8, 56.2, 53.3, 40.8, 37.4, 29.7; IR (KBr, cm ): ν 1717,
+
4
474. HRMS (ESI) m/z: [M + H] Calcd for C20H22NO 340.1543;
Crystallographic data of 6’. 12
Spectroscopic data ( H, C{ H}, F{ H} spectra) of all new
conpounds (PDF)
Found:340.1536.
1
13
1
19
1
2
-(3,4-dimethoxyphenethyl)-6,7-dimethoxy-3-
methyleneisoindolin-1-one (10): A solution of 2.0 mol of 2-(3,4-
dimethoxyphenyl)ethan-1-amine 9 , 2.0 mol of methyl 6-acetyl-
AUTHOR INFORMATION
2
2,3-dimethoxybenzoate 3 and TsOH·H O (17.2 mg, 0.1 mmol) in
1
0 mL of toluene was held at reflux for 20 h using a Dean–Stark
Corresponding Author
apparatus. After being cooled to room temperature, the solvent was
evaporated in vacuo and the residue was purified by flash silica gel
chromatography to afford the product 10 (496.5 mg, yield: 67.2%).
* Email: tongshuo@mail.tsinghua.edu.cn
*
Email: wangmx@mail.tsinghua.edu.cn
o
f
White solid, mp. 117-118 C; R = 0.20 (EtOAc/petroleum ether =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 9
Notes
Substituted Pyridines from Cascade [1+5] Cycloaddition of Isonitriles
to N‑Formylmethyl-Substituted Enamides, Aerobic Oxidative
Aromatization, and Acyl Transfer Reaction. J. Am. Chem. Soc. 2013,
1
2
3
4
5
6
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
The authors declare no competing financial interest.
1
35, 4708. (b) Lei, C.-H.; Wang, D.-X.; Zhao, L.; Zhu, J.; Wang, M.-
X. Synthesis of Multifunctionalized 1,2,3,4-Tetrahydropyridines,
,3Dihydropyridin-4(1H)-ones, and Pyridines from Tandem Reactions
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (No.
2
2
1320102002, 91427301) for financial support.
Initiated by [5+1] Cycloaddition of N-Formylmethyl-Substituted
Enamides to Isocyanides: Mechanistic Insight and Synthetic
Application. Chem. -Eur. J. 2013, 19, 16981. (c) Lei, C.-H.; Wang, D.-
X.; Zhao, L.; Zhu, J.; Wang, M.-X. Functionalized Imidazoliniums
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Hydroxytetrahydropyridine Derivatives by Intramolecular Addition of
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The Journal of Organic Chemistry
2
3
2
Direct Arylation of Cyclic Enamides with Aryl Silanes by sp C-H
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Palladium-Catalyzed Through-Space C(sp )-H and C(sp )-H Bond
Activation by 1,4-Palladium Migration: Efficient Synthesis of
[3,4]Fused Oxindoles. Angew. Chem. Int. Ed. 2013, 52, 12385.
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Coupling for Medium-Ring Synthesis. J. Am. Chem. Soc. 2011, 133,
1209.
1
2
3
4
5
6
7
8
9
Characterization of
a
Cyclic Vinyl Palladium(II) Complex:
(18) The reaction mechanism may be complicated and we could not
exclude other reasonable pathways. For example, C-H activation on the
other arene may also be possible if the arene is an electron-rich one. If
this happened, oxidative addition of the arene to Pd(0) and subsequent
intramolecular carbopalladation could give two possible intermediates.
One is metal-7-endo intermediate, which may undergo β-H elimination
to give the final product. The other one is metal-6-exo intermediate,
which may go through rearrangement to furnish ring expansion. Koseki,
Y.; Kusano, S.; Sakata, H.; Nagasaka, T. A New Approach to
Isoindolobenzazepines via A Ring-Expansion of Isoindoloisoquinoline:
Synthesis of Lennoxamine and Chilenine. Tetrahedron Lett. 1999, 40,
2169.
Vinylpalladium Species as the Possible Intermediate in the Catalytic
Direct Olefination Reaction of Enamide. Chem. Sci. 2011, 2, 1822. (h)
Pankajakshan, S.; Xu, Y.-H.; Cheng, J. K.; Low, M. T.; Loh, T.-P.
Palladium-Catalyzed Direct C-H Arylation of Enamides with Simple
Arenes. Angew. Chem. Int. Ed. 2012, 51, 5701.
(16) For select examples of intramolecular C-H arylation of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
enamines, see: (a) Würtz, S.; Rakshit, S.; Neumann, J. J. Dröge, T.;
Glorius, F. Palladium-Catalyzed Oxidative Cyclization of N-Aryl
Enamines: From Anilines to Indoles. Angew. Chem. Int. Ed. 2008, 47,
7
230. (b) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N.
Indoles from Simple Anilines and Alkynes: Palladium-catalyzed C-H
Activation Using Dioxygen as the Oxidant. Angew. Chem. Int. Ed.
(19) CCDC 1873247 (6’) and CCDC 1873246 (12) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
2
009, 48, 4572. (c) Piou, T.; Neuville, L.; Zhu, J. Pd(II)-catalyzed
Intramolecular Aminopalladation/direct C-H Arylation under Aerobic
Conditions: Synthesis of Pyrrolo[1,2,-a]indoles. Tetrahedron 2013, 69,
4415. (d) Piou, T.; Bunescu, A.; Wang, Q.; Neuville, L.; Zhu, J.
TOC
H
H
O
Pd(OAc) (20 mol%)
2
Cu(OAc) (2.0 equiv)
2
N
R1
R2
N
o
R2
DMSO, 80 C
R1
X
O atmosphere
O
2
tertiary enamides
X
O
H CO
3
N
H CO
3
N
H CO
3
O
H CO
3
OCH3
HO
O
(+/-)-chilenamine (X = H)
OCH3
palmanine
(+/-)-lennoxamine (X,X = O)
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