Copper(II)-catalyzed carbon-carbon triple bond cleavage of internal alkynes for the synthesis of annulated indolizines

Article abstract of DOI:10.1021/jo500456d

Cleavage of C≡C bond in butynedioates via copper(II)-catalyzed reaction has been achieved, leading to the synthesis of benzo[f]pyrido[1,2-a] indole-6,11-diones in high yields by one-pot three-component reactions. In this unprecedented C≡C bond cleavage reaction of internal alkynes, both fragments from the alkyne are successively incorporated into the products.

Full text of DOI:10.1021/jo500456d

Article
pubs.acs.org/joc
Copper(II)-Catalyzed Carbon−Carbon Triple Bond Cleavage of
Internal Alkynes for the Synthesis of Annulated Indolizines
Jinwei Sun,† Fuyao Wang,† Huayou Hu,‡ Xiangshan Wang,† Hui Wu,† and Yun Liu*,†
†Jiangsu Key Laboratory of Green Synthetic for Functional Materials and School of Chemistry and Chemical Engineering, Jiangsu
Normal University, Xuzhou 221116, Jiangsu, PR China
‡Jiangsu Key Laboratory for Chemistry of Low-Dimensional Materials, School of Chemistry and Chemical Engineering, Huaiyin
Normal University, Huaian 223300, Jiangsu, PR China
S
* Supporting Information
ABSTRACT: Cleavage of CC bond in butynedioates via
copper(II)-catalyzed reaction has been achieved, leading to the
synthesis of benzo[f ]pyrido[1,2-a]indole-6,11-diones in high
yields by one-pot three-component reactions. In this
unprecedented CC bond cleavage reaction of internal
alkynes, both fragments from the alkyne are successively
incorporated into the products.
butynedioate 3a (1.0 mmol) in acetonitrile in the presence of
catalytic amount of hydrated copper(II) chloride (0.3 mmol)
under an oxygen atmosphere of 1 atm. Interestingly, heating
the reaction mixture at 80 °C for 16 h did not generate the [4 +
2] cycloaddition product via the nucleophilic addition of the
zwitterion I to the naphthoquinone pyridinium salt II7c
followed by 6-endo-trig cyclization as shown in Scheme 1, but
gave the benzo[f ]pyrido[1,2-a]indole-6,11-dione product 4a in
83% yield (Scheme 1). This indicates that carbon−carbon triple
bond of butynedioate has been cleaved efficiently under this
condition.
Encouraged by this promising result, we attempted to
optimize the reaction conditions including solvent, the kind and
amount of copper(II) salts, and reaction temperature. We first
studied the influence of solvents and found DMF was a
superior solvent (entries 1−7, Table 1). Regarding the
copper(II) salts, hydrated copper(II) chloride proved to be
the most promising (entry 7−11, Table 1). Decreasing the
amount of copper chloride to 0.2 equiv led to a lower yield
(entry 12, Table 1). Without copper(II) catalyst, no desired
product was generated (entry 13, Table 1). When the reaction
was carried out in the air instead of oxygen, 1.0 equiv of
hydrated copper(II) chloride was needed to give the product in
high yield (Table 1, entry 14). We finally optimized the
reaction temperature with DMF as solvent and found the yield
decreased with the lowering of the temperature (entry 15,
Table 1). Therefore, the optimal reaction conditions should be
heating the reactants in DMF at 80 °C under 1 atm O2 in the
presence of 30 mol % hydrated copper(II) chloride.
INTRODUCTION
■
Carbon−carbon bond cleavage reactions have attracted
considerable attention because of both fundamental scientific
interest and potential utility in organic synthesis.1 Over the past
decades, various useful processes involving C−C single and
double bonds cleavage have been developed.2 In contrast, the
cleavage of C−C triple bond is much less reported and
remained one of the most challenging subjects in modern
synthetic organic chemistry.3 Most studies on alkyne cleavage
have focused on stoichiometric organometallic reactions, such
as alkyne ligand scission on metal complexes4 and oxidative
cleavage.5 Except for metathesis of alkynes, examples for the
metal-catalyzed C−C triple bond cleavage reactions are rare,
and the limited reports usually used expensive and toxic
transition metals such as rhodium, ruthenium, gold, or
palladium.6 Following our interest in copper(II)-catalyzed
aerobic reactions,7 we herein report the first example of
copper(II)-catalyzed cleavage of C−C triple bond of internal
alkyne under aerobic oxidation condition, which leads to an
efficient access to benzo[f ]pyrido[1,2-a]indole-6,11-diones.
Indolizines have received much attention in recent years for
their various pharmaceutical applications as antituberculosis
agents,8 PLA2 inhibitors,9 histamine H3 receptor antagonists,10
5-HT3 receptor antagonists,11 MPtpA/MPtpB phosphatases
inhibitors,12 TRPV1 antagonist,13 and 15-lipoxygenase inhib-
itors.14 As a class of benzo- annulated indolizines, benzo[f]-
pyrido[1,2-a]indole-6,11-diones are important synthetic target
molecules. Although a few synthetic routes for this class of
compounds have been developed,7c,15 there is still great
demand to find new synthetic method using easily obtained
substrates with high yields.
With the optimized conditions in hand, we then evaluated
the scope of our procedure, applying various butynedioates 3 to
react with naphthoquinone 1 and pyridines 2a. Under the
RESULTS AND DISCUSSION
■
Our investigation started with the reactions of 1,4-naphthoqui-
none 1 (1.0 mmol), pyridine 2a (3.0 mmol), and dimethyl
Received: February 25, 2014
Published: April 8, 2014
© 2014 American Chemical Society
3992
dx.doi.org/10.1021/jo500456d | J. Org. Chem. 2014, 79, 3992−3998

The Journal of Organic Chemistry
Article
Scheme 1. Formation of Product 4a
a
Table 1. Optimization of the Reaction Conditions
Table 2. Reactions of Pyridine 2a and 1,4-Naphthoquinone 1
with Different Butynedioates 3
a
b
entry
solvent
copper (equiv)
temp (°C)
yield (%)
1
CH3CN
C6H6
CuCl2 (0.3)
CuCl2 (0.3)
CuCl2 (0.3)
CuCl2 (0.3)
CuCl2 (0.3)
CuCl2 (0.3)
CuCl2 (0.3)
CuBr2 (0.3)
Cu(OTf)2 (0.3)
Cu(OAc)2 (0.3)
Cu(SO4)2 (0.3)
CuCl2 (0.2)
None
reflux
reflux
80
83
32
45
48
38
88
93
85
86
83
75
72
0
b
entry
3, R
product
yield (%)
2
1
2
3
4
5
6
3a, R = CH3
4a
4b
4c
4d
4e
4f
93
92
85
90
87
85
3
toluene
dioxane
C2H5OH
DMF
3b, R = C2H5
4
80
3c, R = (CH2)2CH3
3d, R = CH(CH3)2
3e, R = C(CH3)3
3f, R = (CH2)3CH3
5
reflux
100
80
6
7
DMF
8
DMF
80
a
Reagents and conditions: Under 1 atm of O2, a mixture of pyridine
(3.0 mmol), butynedioate (1.0 mmol), naphthoquinone (1.0 mmol)
and hydrated copper chloride (0.3 mmol) was heated in DMF at 80
9
DMF
80
10
11
12
13
14
15
DMF
80
DMF
80
b
°C for 16 h. Isolated yields.
DMF
80
DMF
80
To further extend the utility of this reaction, we have
investigated the reactions of isoquinoline 6 with butynedioates
3 and 1,4-naphthoquinone 1 for the synthesis of further
annulated derivatives 7. As expected, when naphthoquinone 1
(1.0 mmol) was heated with isoquinoline 6 (3.0 mmol),
butynedioate 3 (3.0 mmol) and hydrated copper(II) chloride
(0.3 mmol) under the optimized conditions, the corresponding
products 7a−7e were obtained in excellent yields (Table 4).
For a better understanding of the reaction mechanism, two
control experiments were performed as shown in Scheme 3.
First, when N-(2,7-dihydroxynaphthyl)-pyridinium chloride 8
(1.0 mmol)16 was used as a substrate to react with pyridine 2a
(3.0 mmol) and butynedioate 3a (1.0 mmol) by heating in
DMF at 80 °C in O2 atmosphere in the presence of 30 mol %
copper(II) chloride, 4a was generated in 90% yield (eq 1,
Scheme 3). Meanwhile, this reaction cannot take place in the
absence of CuCl2 under otherwise the same conditions. Second,
heating pyridinium salt 9 (1.0 mmol) with naphthoquinone 1
(1.0 mmol) and pyridine 2a (3.0 mmol) in DMF at 80 °C in
O2 atmosphere in the presence of 30 mol % copper(II) chloride
also led to the generation of 4a in 92% yield (eq 1, Scheme 3).
These results reveal that the pyridinium salt II7c generated in
situ from naphthoquinone and pyridine under the action of
CuCl2 is a key intermediate in the reaction.
c
DMF
CuCl2 (1.0)
80
92
65
DMF
CuCl2 (0.3)
60
a
Reagents and conditions: Under 1 atm of O2, a mixture of
naphthoquinone (1.0 mmol), pyridine (3.0 mmol), butynedioate
(1.0 mmol), and hydrated copper(II) chloride was heated in solvent
for 16 h. Isolated yields. Heated in the air.
b
c
optimized reaction conditions, reactions of different alkyl
butynedioates 3a−3f (1.0 mmol) with pyridine 2a (1.0 mmol)
and naphthoquinone 1 (1.0 mmol) are found to afford the
corresponding products 4a−4f in excellent yields (entry 1−7,
Table 2). All products are fully characterized by analytical and
spectral (NMR and HRMS) data. Moreover, the structure of 4e
was unambiguously established by X-ray crystallography (see
Supporting Information).
Next, the scope of this reaction was extended to various
substituted pyridines. 4-Substituted pyridines 2b−2f also
proved to be efficient substrates in this reaction. Pyridine
with either EWG group (CO2Et, CO2Me, CN) or EDG group
(OMe, t-Bu) reacted with butynedioate smoothly, yielding the
desired products 5a−5s in 73−96% yields (Table 3).
We also tried to use 3-bromopyridine 2g to accomplish this
reaction under the optimal conditions and found that two
isomers 5t and 5u were formed simultaneously (Scheme 2).
When 2-bromo pyridine was used as a substrate in this reaction,
no desired product was formed, probably because of the steric
effect.
On the basis of the above experimental results, a possible
mechanism for this reaction is suggested in Scheme 4. The
reaction proceeded via two pathways. In the first, nucleophilic
addition of pyridine to dimethyl butynedioate gave zwitterion
3993
dx.doi.org/10.1021/jo500456d | J. Org. Chem. 2014, 79, 3992−3998

The Journal of Organic Chemistry
Article
both pieces of fragments from butynedioates participated in the
reaction, further confirming our proposed mechanism.
Table 3. Reaction of Pyridine 2b−2f, Terminal Alkynes 3,
a
and 1,4-Naphthoquinone 1
CONCLUSION
■
In conclusion, we have reported a novel copper(II)-catalyzed
reaction to cleave carbon−carbon triple bond of internal
alkynes for the synthesis of benzo[f]pyrido[1,2-a]indole-6,11-
diones. In this process, the two carbon atoms in the original
CC bond, together with their substituents, are fully
employed and incorporated into the products successively,
leading to a perfect atomic economy of the entire synthesis.
Further advantages of this synthesis include mild reaction
condition, high product yields, and broad substrate scope. This
protocol supplied an unprecedented avenue for the cleavage of
carbon−carbon triple bond and may be further applied to
synthesize other heterocyclic compounds. Studies toward
elucidating the reaction mechanism and developing further
applications of this type of CC triple bond cleavage reactions
are currently underway in our laboratory.
b
entry
2, R′
3, R
product yield (%)
1
2b, R′ = CO2Me
2b, R′ = CO2Me
2b, R′ = CO2Me
2b, R′ = CO2Me
2c, R′ = CO2Et
2c, R′ = CO2Et
2c, R′ = CO2Et
2c, R′ = CO2Et
2d, R′ = CN
3a, R = CH3
5a
5b
5c
5d
5e
5f
92
91
88
89
96
95
92
87
81
77
73
95
89
87
86
91
88
87
85
2
3b, R = C2H5
3
3c, R = (CH2)2CH3
3d, R = CH(CH3)2
3a, R = CH3
4
5
6
3b, R = C2H5
7
3d, R = CH(CH3)2
3e, R = C(CH3)3
3a, R = CH3
5g
5h
5i
8
9
10
11
12
13
14
15
16
17
18
19
2d, R′ = CN
2d, R′ = CN
3b, R = C2H5
5j
3d, R = CH(CH3)2
3a, R = CH3
5k
5l
2e, R′ = OMe
2e, R′ = OMe
2e, R′ = OMe
2e, R′ = OMe
2f, R′ = C(CH3)3
2f, R′ = C(CH3)3
2f, R′ = C(CH3)3
2f, R′ = C(CH3)3
EXPERIMENTAL SECTION
■
General Methods. Melting points are uncorrected. 1H NMR
spectra were measured at 400 MHz with CDCl3 as solvent. The
chemical shifts (δ) are reported in parts per million relative to the
residual deuterated solvent signal, and coupling constants (J) are given
in Hertz. 13C NMR spectra were measured at 100 MHz with CDCl3 as
solvent. HRMS (ESI) data were obtained in the electron impact (EI)
(70 eV) mode.
3b, R = C2H5
5m
5n
5o
5p
5q
5r
5s
3d, R = CH(CH3)2
3e, R = C(CH3)3
3a, R = CH3
3b, R = C2H5
3c, R = (CH2)2CH3
3d, R = CH(CH3)2
General Experimental Procedures of 4. Pyridine 2a (3.0
mmol), 1,4-naphthaquionone 1 (1.0 mmol), butynedioates 3 (1.0
mmol), and hydrated copper(II) chloride (0.3 mmol) were mixed in
15 mL of DMF and heated at 80 °C for 16 h under 1 atm of O2. After
completion of the reaction, the reaction mixture was allowed to cool to
room temperature. Chromatographic separation (ethyl acetate/
petroleum ether, 1:6) of the reaction mixture after removal of the
solvent gave product 4.
Methyl 6,11-dioxo-6,11-dihydrobenzo[f]pyrido[1,2-a]indole-12-
carboxylate (4a). Red solid: yield 283 mg (93%); mp 190−191 °C;
1H NMR (400 MHz, CDCl3) δ 3.98 (s, 3H), 7.08 (t, J = 6.8 Hz, 1H),
7.34 (t, J = 8.0 Hz, 1H), 7.62−7.64 (m, 2H), 8.07−8.12 (m, 2H), 8.20
(d, J = 9.2 Hz, 1H), 9.69 (d, J = 6.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 179.9, 174.7, 163.4, 139.3, 133.8, 133.3, 133.1, 132.9, 128.1,
127.9, 127.6, 126.9, 125.7, 122.1, 120.6, 117.1, 105.1, 51.7; HRMS
(ESI) m/z [M + Na]+ calcd for C18H11NO4Na 328.0586, found
328.0586.
Ethyl 6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-a]indole-12-
carboxylate (4b). Red solid: yield 292 mg (92%); mp 156−158 °C;
1H NMR (400 MHz, CDCl3) δ 1.50 (t, J = 7.2 Hz, 3H), 4.51 (q, J =
7.2 Hz, 2H), 7.17 (d, J = 7.2 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.69−
7.72 (m, 2H), 8.20−8.23 (m, 2H), 8.30 (d, J = 9.2 Hz, 1H), 9.83 (d, J
= 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 180.3, 175.2, 163.3,
139.6, 134.2, 133.8, 133.7, 133.4, 133.2, 128.2, 127.8, 127.3, 126.0,
122.4, 120.9, 117.3, 106.1, 61.0, 14.4; HRMS (ESI) m/z [M + Na]+
calcd for C19H13NO4Na 342.0742, found 342.0740.
a
Reagents and conditions: Under 1 atm of O2, the mixture of
substituted pyridine 2b−2f (3.0 mmol), butynedioates 3 (1.0 mmol),
naphthoquinone 1 (1.0 mmol) and hydrated copper chloride (0.3
b
mmol) was heated in DMF at 80 °C for 16 h. Isolated yields.
I,17 which reacted with intermediate II to yield III. Subsequent
5-exo-trig cyclization in III followed by proton transfer led to
IV. Product 4a was finally formed by β-elimination in IV with
the loss of a pyridinium salt (path a, Scheme 4). The
pyridinium salt was then deprotonated to give the pyridinium
ylide V, which could also react with intermediate II to give 4a
as shown in path b, Scheme 4. The Cu2+ salt can be regenerated
by oxygen oxidation.
In order to further clarify the mechanism, we used less than
stoichiometric dimethyl butynedioate 3a (0.6 mmol) to react
with naphthoquinone 1 (1.0 mmol) and pyridine 2a (3.0
mmol) by heating in DMF at 80 °C for 24 h in the presence of
30 mol % copper(II) chloride under the O2 atmosphere. As
expected, naphthoquinone could be consumed completely and
the desired product 4a was formed in 86% yield. Similarly,
when less than stoichiometric diethyl butynedioate 3b (0.6
mmol) was used to react with naphthoquinone 1 (1.0 mmol)
and pyridine 2a (3.0 mmol) under the same conditions, 4b was
obtained in 84% yield (Scheme 5). These results showed that
Propyl 6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-a]indole-12-
carboxylate (4c). Red solid: yield 284 mg (85%); mp 133−135 °C;
Scheme 2. Formation of Two Isomers
3994
dx.doi.org/10.1021/jo500456d | J. Org. Chem. 2014, 79, 3992−3998

The Journal of Organic Chemistry
Article
a
Table 4. Reaction of Isoquinoline 6, Butynedioate 3, and 1,4-Naphthoquinone 1
b
entry
3, R
product
yield (%)
1
2
3
4
5
3a, R = CH3
7a
7b
7c
7d
7e
93
91
89
88
85
3b, R = CH2CH3
3c, R = (CH2)2CH3
3d, R = CH(CH3)2
3e, R = C(CH3)3
a
Reagents and conditions: Under 1 atm of O2, the mixture of isoquinoline 6 (3.0 mmol), butynedioate 3 (1.0 mmol), naphthoquinone 1 (1.0
b
mmol), and hydrated copper chloride (0.3 mmol) was heated in DMF at 80 °C for 16 h. Isolated yields.
Scheme 3. Control Experiment
Scheme 4. Proposed Mechanism
1H NMR (400 MHz, CDCl3) δ 1.11 (t, J = 7.2 Hz, 3H), 1.88−1.93
(m, 2H), 4.41 (t, J = 6.8 Hz, 2H), 7.14 (td, J = 6.8, 1.2 Hz, 1H), 7.39−
7.43 (m, 1H), 7.68−7.71 (m, 2H), 8.18−8.22 (m, 2H), 8.29 (d, J = 8.8
Hz, 1H), 9.81 (dt, J = 6.8, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
3995
dx.doi.org/10.1021/jo500456d | J. Org. Chem. 2014, 79, 3992−3998

The Journal of Organic Chemistry
Article
9.83 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 179.9, 175.7,
164.7, 162.9, 138.0, 134.2, 133.7, 133.6, 133.5, 129.0, 128.4, 127.7,
127.5, 126.3, 123.4, 116.2, 109.1, 61.5, 52.9, 14.3; HRMS (ESI) m/z
[M + Na]+ calcd for C21H15NO6Na 400.0797, found 400.0789.
12-Propyl 2-methyl 6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-
a]indole-2,12-dicarboxylate (5c). Red solid: yield 345 mg (88%); mp
188−190 °C; 1H NMR (400 MHz, CDCl3) δ 1.13 (t, J = 7.2 Hz, 3H),
1.90−1.95 (m, 2H), 4.00 (s, 3H), 4.46 (t, J = 6.8 Hz, 2H), 7.69 (dd, J
= 7.2, 1.6 Hz, 1H), 7.74−7.76 (m, 2H), 8.24−8.27 (m, 2H), 8.99 (s,
1H), 9.85 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 179.8,
175.7, 164.7, 162.9, 138.1, 134.2, 133.7, 133.6, 129.1, 128.4, 127.7,
127.5, 126.3, 123.4, 116.1, 109.1, 67.1, 52.9, 22.1, 10.7; HRMS (ESI)
m/z [M + Na]+ calcd for C22H17NO6Na 414.0954, found 414.0947.
12-Isopropyl 2-methyl 6,11-dioxo-6,11-dihydrobenzo[f ]pyrido-
[1,2-a]indole-2,12-dicarboxylate (5d). Red solid: yield 348 mg
Scheme 5. Mechanism Confirmation
1
(89%); mp 209−211 °C; H NMR (400 MHz, CDCl3) δ 1.52 (d, J
= 6.8 Hz, 6H), 4.02 (s, 3H), 5.41−5.48 (m, 1H), 7.69 (dd, J = 7.6, 2.0
Hz, 1H), 7.74−7.77 (m, 2H), 8.25−8.28 (m, 2H), 8.98 (s, 1H), 9.84
(dd, J = 7.6, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):δ 179.8,
175.6, 164.7, 162.4, 137.9, 134.2, 133.7, 133.6, 133.5, 129.0, 128.3,
127.7, 127.6, 127.5, 126.3, 123.4, 116.0, 109.7, 69.2, 52.9, 21.9; HRMS
(ESI) m/z [M + Na]+ calcd for C22H17NO6Na 414.0954, found
414.0954.
12-Methyl 2-ethyl 6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-a]-
indole-2,12-dicarboxylate (5e). Yellow solid: yield 363 mg (96%);
mp 212−214 °C; 1H NMR (400 MHz, CDCl3) δ 1.45 (t, J = 7.2 Hz,
3H), 4.08 (s, 3H), 4.46 (q, J = 7.2 Hz, 2H), 7.68−7.75 (m, 3H), 8.22−
8.24 (m, 2H), 8.94 (s, 1H), 9.82 (d, J = 7.6 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 180.1, 175.8, 164.4, 163.6, 138.3, 134.3, 133.9, 133.8,
133.7, 129.1, 129.0, 127.8, 127.6, 126.4, 123.5, 123.3, 116.4, 108.6,
62.3, 52.5, 14.4; HRMS (ESI) m/z [M + Na]+ calcd for C21H15NO6Na
400.0797, found 400.0791.
Diethyl 6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-a]indole-
2,12-dicarboxylate (5f). Yellow solid: yield 371 mg (95%); mp
176−177 °C; 1H NMR (400 MHz, CDCl3) δ 1.45 (t, J = 7.2 Hz, 3H),
1.52 (t, J = 7.2 Hz, 3H), 4.45 (q, J = 7.2 Hz, 2H), 4.54 (q, J = 7.2 Hz,
2H), 7.67 (dd, J = 7.2, 1.6 Hz, 1H), 7.71−7.74 (m, 2H), 8.21−8.24
(m, 2H), 8.94 (s, 1H), 9.80 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 179.1, 174.9, 163.7, 162.2, 137.5, 133.6, 133.2, 133.1, 133.0,
128.4, 128.3, 127.2, 127.0, 125.7, 122.8, 122.7, 115.7, 108.4, 61.6, 60.9,
13.9; HRMS (ESI) m/z [M + Na]+ calcd for C22H17NO6Na 414.0954,
found 414.0959.
δ 180.2, 175.1, 163.4, 139.6, 134.2, 133.7, 133.4, 133.1, 128.7, 128.2,
127.8, 127.3, 126.0, 122.4, 120.9, 117.3, 106.0, 66.7, 21.2, 10.7; HRMS
(ESI) m/z [M + Na]+ calcd for C20H15NO4Na 356.0899, found
356.0897.
Isopropyl 6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-a]indole-
12-carboxylate (4d). Red solid: yield 299 mg (90%); mp 131−133
1
°C; H NMR (400 MHz, CDCl3) δ 1.49 (d, J = 6.0 Hz, 6H), 5.39−
5.42 (m, 1H), 7.16 (td, J = 7.2, 1.6 Hz, 1H), 7.40−7.44 (m, 1H),
7.69−7.73 (m, 2H), 8.21−8.24 (m, 2H), 8.28 (d, J = 9.2 Hz, 1H), 9.84
(d, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 179.8, 174.8,
162.4, 139.0, 133.9, 133.4, 133.0, 132.7, 128.3, 127.9, 127.3, 126.9,
125.6, 122.0, 120.5, 116.9, 106.3, 68.3, 21.7; HRMS (ESI) m/z [M +
Na]+ calcd for C20H15NO4Na 356.0899, found 356.0899.
tert-Butyl 6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-a]indole-
12-carboxylate (4e). Red solid: yield 301 mg (87%); mp 178−180
1
°C; H NMR (400 MHz, CDCl3) δ 1.71 (s, 9H), 7.13 (t, J = 7.2 Hz,
1H), 7.39 (t, J = 7.6 Hz, 1H), 7.68−7.73 (m, 2H), 8.20 (dd, J = 6.0, 2.0
Hz, 2H), 8.25 (d, J = 8.8 Hz, 1H), 9.81 (d, J = 7.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 180.2, 175.1, 162.6, 139.3, 134.3, 133.9, 133.3,
133.1, 128.6, 128.2, 127.5, 127.2, 126.0, 122.1, 120.8, 117.2, 108.1,
81.8, 28.4; HRMS (ESI) m/z [M + Na]+ calcd for C21H17NO4Na
370.1055, found 370.1055.
Butyl 6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-a]indole-12-
carboxylate (4f). Red solid: yield 294 mg (85%); mp 89−90 °C;
1H NMR (400 MHz, CDCl3) δ 1.02 (t, J = 7.6 Hz, 3H), 1.52−1.58
(m, 2H), 1.84−1.88 (m, 2H), 4.46 (t, J = 6.8 Hz, 2H), 7.16 (t, J = 6.8
Hz, 1H), 7.40−7.44 (m, 1H), 7.70−7.73 (m, 2H), 8.18−8.23 (m, 2H),
8.29 (d, J = 8.8 Hz, 1H), 9.82 (d, J = 7.2 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 180.5, 175.5, 163.7, 139.8, 134.5, 134.0, 133.7, 133.4,
129.0, 128.5, 128.1, 127.6, 126.3, 122.7, 121.2, 117.6, 106.3, 65.3, 31.1,
19.6, 14.1; HRMS (ESI) m/z [M + Na]+ calcd for C21H17NO4Na
370.1055, found 370.1053.
General Procedure for the Preparation of 5. Substituted
pyridine 2b−2g (3.0 mmol), 1,4-naphthaquionone 1 (1.0 mmol),
butynedioates 3 (1.0 mmol), and hydrated copper(II) chloride (0.3
mmol) were mixed in 15 mL of DMF and heated at 80 °C for 16 h
under 1 atm of O2. After completion of the reaction, the reaction
mixture was allowed to cool to room temperature. Chromatographic
separation (ethyl acetate/petroleum ether, 1:6) of the reaction mixture
after removal of the solvent gave product 5.
12-Isopropyl 2-ethyl 6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-
a]indole-2,12-dicarboxylate (5g). Yellow solid: yield 374 mg (92%);
mp 180−182 °C; 1H NMR (400 MHz, CDCl3) δ 1.45 (t, J = 7.2 Hz,
3H), 1.51 (d, J = 6.4 Hz, 6H), 4.45 (q, J = 7.2 Hz, 2H), 5.42−5.46 (m,
1H), 7.68 (dd, J = 7.2, 1.6 Hz, 1H), 7.72−7.76 (m, 2H), 8.22−8.26
(m, 2H), 8.95 (s, 1H), 9.82 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 179.4, 175.3, 163.9, 161.9, 137.6, 133.9, 133.3, 133.2, 128.7,
128.3, 127.3, 127.1, 125.9, 122.9, 115.8, 109.3, 68.8, 61.7, 21.6, 13.9;
HRMS (ESI) m/z [M + Na]+ calcd for C23H19NO6Na 428.1110,
found 428.1101.
12-tert-Butyl 2-ethyl 6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-
a]indole-2,12-dicarboxylate (5h). Yellow solid: yield 366 mg (87%);
mp 198−199 °C; 1H NMR (400 MHz, CDCl3) δ 1.46 (t, J = 7.2 Hz,
3H), 1.74 (s, 9H), 4.47 (q, J = 7.2 Hz, 2H), 7.81−7.83 (m, 3H), 8.02−
8.22 (m, 2H), 8.97 (s, 1H), 9.83 (dd, J = 7.2, 0.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 179.7, 175.5, 164.3, 161.7, 143.5, 137.8, 133.5,
133.4, 130.9, 129.1, 128.5, 127.6, 127.4, 126.2, 123.3, 116.0, 111.0,
82.4, 62.0, 28.3, 14.3; HRMS (ESI) m/z [M + Na]+ calcd for
C24H21NO6Na 442.1267, found 442.1268.
Methyl 2-cyano-6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-a]-
indole-12-carboxylate (5i). Yellow solid: yield 267 mg (81%); mp
287−289 °C; 1H NMR (400 MHz, CDCl3) δ 4.13 (s, 3H), 7.19 (dd, J
= 7.6, 2.0 Hz, 1H), 7.77−7.79 (m, 2H), 8.25−8.28 (m, 2H), 9.03 (s,
1H), 9.38 (dd, J = 7.6, 0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
179.5, 175.9, 162.9, 136.9, 134.1, 134.0, 133.2, 129.1, 128.6, 127.7,
127.3, 126.4, 116.7, 110.5, 108.5, 52.6; HRMS (ESI) m/z [M + Na]+
calcd for C19H10N2O4Na 353.0538, found 353.0539.
Dimethyl 6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-a]indole-
2,12-dicarboxylate (5a). Yellow solid: yield 333 mg (92%); mp
1
224−225 °C; H NMR (400 MHz, CDCl3) δ 4.01 (s, 3H), 4.08 (s,
3H), 7.70 (dd, J = 7.2, 1.6 Hz, 1H), 7.74−7.77 (m, 2H), 8.24−8.26
(m, 2H), 8.97 (s, 1H), 9.85 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 179.9, 175.6, 164.7, 163.4, 138.1, 134.1, 133.7, 133.6, 128.9,
128.6, 127.7, 127.5, 126.3, 123.3, 116.2, 108.5, 52.9, 52.4; HRMS
(ESI) m/z [M + Na]+ calcd for C20H13NO6Na 386.0641, found
386.0632.
12-Ethyl 2-methyl 6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-
a]indole-2,12-dicarboxylate (5b). Yellow solid: yield 342 mg
1
(91%); mp 214−215 °C; H NMR (400 MHz, CDCl3) δ 1.52 (t, J
= 7.2 Hz, 3H), 4.00 (s, 3H), 4.55 (q, J = 7.2 Hz, 2H), 7.68 (dd, J = 7.2,
1.6 Hz, 1H), 7.74−7.76 (m, 2H), 8.24−8.26 (m, 2H), 8.97 (s, 1H),
Ethyl 2-cyano-6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-a]-
indole-12-carboxylate (5j). Yellow solid: yield 265 mg (77%); mp
3996
dx.doi.org/10.1021/jo500456d | J. Org. Chem. 2014, 79, 3992−3998

The Journal of Organic Chemistry
Article
225−226 °C; 1H NMR (400 MHz, CDCl3) δ 1.52 (t, J = 7.2 Hz, 3H),
4.55 (q, J = 7.2 Hz, 2H), 7.22 (dd, J = 7.2, 1.6 Hz, 1H), 7.76−7.78 (m,
2H), 8.23−8.27 (m, 2H), 8.70 (s, 1H), 9.88 (dd, J = 7.2, 0.8 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 179.3, 175.9, 162.4, 136.8, 134.1,
134.0, 133.9, 133.2, 129.1, 128.5, 127.7, 127.3, 126.4, 123.8, 116.7,
116.6, 110.3, 109.1, 61.7, 14.3; HRMS (ESI) m/z [M + Na]+ calcd for
C20H12N2O4Na 367.0695, found 367.0694.
Isopropyl 2-cyano-6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-
a]indole-12-carboxylate (5k). Yellow solid: yield 261 mg (73%);
mp 183−184 °C; 1H NMR (400 MHz, CDCl3) δ 1.50 (d, J = 6.4 Hz,
6H), 5.40−5.45 (m, 1H), 7.21 (dd, J = 7.2, 1.6 Hz, 1H), 7.75−7.79
(m, 2H), 8.23−8.27 (m, 2H), 8.67 (s, 1H), 9.87 (d, J = 7.2 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 179.0, 175.6, 161.6, 136.3, 133.8,
Propyl 2-tert-butyl-6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-
a]indole-12-carboxylate (5r). Red solid: yield 338 mg (87%); mp
139−141 °C; 1H NMR (400 MHz, CDCl3) δ 1.10 (t, J = 7.2 Hz, 3H),
1.38 (s, 9H), 1.68−1.92 (m, 2H), 4.39 (t, J = 6.8 Hz, 2H), 7.19 (dd, J
= 7.6, 2.0 Hz, 1H), 7.63−7.66 (m, 2H), 8.11−8.17 (m, 2H), 8.22 (d, J
= 1.2 Hz, 1H), 9.67 (dd, J = 7.6, 0.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 180.2, 174.8, 163.6, 152.3, 140.1, 134.3, 133.7, 133.3, 132.9,
129.0, 127.7, 127.2, 125.8, 122.1, 116.7, 115.5, 105.4, 66.6, 35.4, 30.3,
22.2, 10.7; HRMS (ESI) m/z [M + Na]+ calcd for C24H23NO4Na
412.1525, found 412.1527.
Isopropyl 2-tert-butyl-6,11-dioxo-6,11-dihydrobenzo[f ]pyrido-
[1,2-a]indole-12-carboxylate (5s). Red solid: yield 332 mg (85%);
1
mp 106−108 °C; H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 1.49
(d, J = 6.4 Hz, 6H), 5.37−5.43 (m, 1H), 7.21 (dd, J = 7.2, 2.0 Hz, 1H),
7.67−7.71 (m, 2H), 8.18−8.23 (m, 3H), 9.72 (d, J = 7.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 180.5, 175.1, 163.1, 152.4, 140.1, 134.5,
134.0, 133.5, 133.2, 129.3, 127.9, 127.5, 126.1, 122.3, 116.9, 115.7,
106.2, 68.7, 35.6, 30.5, 22.4; HRMS (ESI) m/z [M + Na]+ calcd for
C24H23NO4Na 412.1525, found 412.1525.
133.6, 133.5, 133.0, 128.8, 128.2, 127.3, 127.0, 126.9, 126.1, 116.5,
116.2, 109.9, 109.4, 69.3, 21.6; HRMS (ESI) m/z [M + Na]+ calcd for
C21H14N2O4Na 381.0851, found 381.0839.
Methyl 2-methoxy-6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-
a]indole-12-carboxylate (5l). Red solid: yield 319 mg (95%); mp
1
242−243 °C; H NMR (400 MHz, CDCl3) δ 3.97 (s, 3H), 4.03 (s,
Ethyl 3-bromo-6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-a]-
indole-12-carboxylate (5t). Yellow solid: yield 131 mg (33%); mp
186−188 °C; 1H NMR (400 MHz, CDCl3) δ 1.50 (t, J = 7.2 Hz, 3H),
4.51 (q, J = 7.2 Hz, 2H), 7.48 (dd, J = 9.6, 1.6 Hz, 1H), 7.72−7.75 (m,
2H), 8.20−8.24 (m, 3H), 10.03 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 179.9, 175.4, 163.0, 137.7, 134.2, 133.6, 133.5, 133.4, 131.1,
128.4, 128.1, 127.5, 126.1, 122.3, 121.4, 112.8, 106.8, 61.2, 14.3;
HRMS (ESI) m/z [M + Na]+ calcd for C19H12BrNO4Na 419.9847,
found 419.9841.
Ethyl 1-bromo-6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-a]-
indole-12-carboxylate (5u). Red solid: yield 188 mg (47%); mp
260−262 °C; 1H NMR (400 MHz, CDCl3) δ 1.48 (t, J = 7.2 Hz, 3H),
4.56 (q, J = 7.2 Hz, 2H), 6.94 (t, J = 7.2 Hz, 1H), 7.50 (d, J = 7.2 Hz,
1H), 7.68−7.76 (m, 2H), 8.18 (d, J = 7.2 Hz, 1H), 8.22 (d, J = 8.0 Hz,
1H), 9.68 (d, J = 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 180.9,
174.8, 165.1, 134.7, 134.3, 133.6, 133.5, 129.8, 127.3, 127.2, 126.9,
121.2, 116.9, 114.0, 110.8, 62.7, 14.3; HRMS (ESI) m/z [M + Na]+
calcd for C19H12BrNO4Na 419.9847, found 419.9845.
General Procedure for the Preparation of 7. Isoquinoline 6
(3.0 mmol), 1,4-naphthaquionone 1 (1.0 mmol), butynedioates 3 (1.0
mmol), and hydrated copper(II) chloride (0.3 mmol) were mixed in
15 mL of DMF and heated at 80 °C for 16 h under 1 atm of O2. After
completion of the reaction, the reaction mixture was allowed to cool to
room temperature. Chromatographic separation (ethyl acetate/
petroleum ether, 1:6) of the reaction mixture after removal of the
solvent gave product 7.
3H), 6.84 (dd, J = 7.6, 2.4 Hz, 1H), 7.67−7.71 (m, 3H), 8.17−8.20
(m, 2H), 9.68 (d. J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
180.3, 174.6, 164.4, 159.7, 142.7, 134.0, 133.5, 133.3, 132.9, 129.4,
129.2, 127.1, 125.7, 122.0, 111.9, 102.9, 98.1, 55.8, 51.7; HRMS (ESI)
m/z [M + Na]+ calcd for C19H13NO5Na 358.0691, found 358.0683.
Ethyl 2-methoxy-6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-a]-
indole-12-carboxylate (5m). Red solid: yield 312 mg (89%); mp
183−185 °C; 1H NMR (400 MHz, CDCl3) δ 1.51 (t, J = 7.2 Hz, 3H),
3.96 (s, 3H), 4.50 (q, J = 7.2 Hz, 2H), 6.84 (dd, J = 7.6, 2.8 Hz, 1H),
7.67−7.72 (m, 3H), 8.17−8.21 (m, 2H), 9.68 (d, J = 7..6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 180.4, 174.7, 164.0, 159.7, 142.7, 134.2,
133.7, 133.4, 133.0, 129.5, 127.3, 125.8, 122.1, 112.0, 103.7, 98.2, 60.8,
55.9, 14.4; HRMS (ESI) m/z [M + Na]+ calcd for C20H15NO5Na
372.0848, found 372.0844.
Isopropyl 2-methoxy-6,11-dioxo-6,11-dihydrobenzo[f ]pyrido-
[1,2-a]indole-12-carboxylate (5n). Red solid: yield 316 mg (87%);
mp 172−174 °C; 1H NMR (400 MHz, CDCl3) δ 1.48 (d, J = 6.0 Hz,
6H), 3.95 (s, 3H), 5.34−5.40 (m, 1H), 6.83 (dd, J = 7.6, 2.8 Hz, 1H),
7.64−7.71 (m, 3H), 8.17−8.21 (m, 2H), 9.67 (d, J = 8.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 179.9, 174.3, 163.0, 159.2, 142.1, 133.9,
133.3, 132.9, 132.6, 129.1, 126.9, 125.4, 121.7, 111.5, 103.9, 97.8, 68.0,
55.4, 21.7; HRMS (ESI) m/z [M + Na]+ calcd for C21H17NO5Na
386.1004, found 386.1003.
t-Butyl 2-methoxy-6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-
a]indole-12-carboxylate (5o). Red solid: yield 325 mg (86%); mp
1
215−216 °C; H NMR (400 MHz, CDCl3) δ 1.71 (s, 9H), 3.92 (s,
3H), 6.76 (dd, J = 7.6, 1.8 Hz, 1H), 7.56 (d, J = 2.8 Hz, 1H), 7.62−
7.69 (m, 2H), 8.12−8.16 (m, 2H), 9.60 (d, J = 7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 180.1, 174.4, 162.9, 159.4, 142.2, 134.3, 133.7,
133.1, 132.8, 129.5, 129.4, 127.1, 125.7, 121.8, 111.7, 105.6, 98.1, 81.3,
55.8, 28.4; HRMS (ESI) m/z [M + Na]+ calcd for C22H19NO5Na
400.1161, found 400.1161.
14-Methoxycarbonylbenz[5,6]indolo[2,1-a]isoquinoline-8,13-
1
dione (7a). Yellow solid: yield 329 mg (93%); mp 245−247 °C; H
NMR (400 MHz, CDCl3) δ 4.17 (s, 3H), 7.26−7.28 (m, 1H), 7.59−
7.62 (m, 2H), 7.69−7.74 (m, 3H), 8.17−8.24 (m, 3H), 9.41−9.44 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 180.5, 174.9, 166.9, 134.2,
133.6, 133.3, 133.1, 132.5, 129.3, 129.2, 128.8, 127.5, 126.7, 126.4,
124.2, 124.1, 124.0, 122.3, 117.3, 109.4, 53.2; HRMS (ESI) m/z [M +
Na]+ calcd for C22H13NO4Na 378.0742, found 378.0734.
Methyl 2-tert-butyl-6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-
a]indole-12-carboxylate (5p). Red solid: yield 328 mg (91%); mp
1
212−214 °C; H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 4.05 (s,
14-Ethoxycarbonylbenz[5,6]indolo[2,1-a]isoquinoline-8,13-dione
1
(7b). Yellow solid: yield 337 mg (91%); mp 238−240 °C; H NMR
3H), 7.24 (dd, J = 7.6, 2.0 Hz, 1H), 7.68−7.72 (m, 2H), 8.19−8.22
(m, 2H), 8.27 (s, 1H), 9.73 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 180.2, 174.6, 163.9, 152.2, 140.0, 133.9, 133.4, 133.1, 132.7,
128.5, 127.3, 126.9, 125.6, 121.7, 116.5, 115.1, 104.4, 51.6, 35.0, 29.9;
HRMS (ESI) m/z [M + Na]+ calcd for C22H19NO4Na 384.1212,
found 384.1216.
(400 MHz, CDCl3) δ 1.53 (t, J = 7.2 Hz, 3H), 4.67 (q, J = 7.2 Hz,
2H), 7.25 (d, J = 7.2 Hz, 1H), 7.57−7.59 (m, 2H), 7.68−7.71 (m,
3H), 8.16−8.25 (m, 3H), 9.39 (d, J = 7.6 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 180.8, 175.4, 166.8, 134.6, 133.9, 133.7, 133.4, 132.9,
129.7, 129.6, 129.2, 127.9, 127.1, 127.0, 126.8, 124.7, 124.6, 122.7,
117.6, 110.4, 62.7, 14.3; HRMS (ESI) m/z [M + Na]+ calcd for
C23H15NO4Na 392.0899, found 392.0889.
Ethyl 2-tert-butyl-6,11-dioxo-6,11-dihydrobenzo[f ]pyrido[1,2-a]-
indole-12-carboxylate (5q). Red solid: yield 330 mg (88%); mp 159−
1
160 °C; H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 1.51 (t, J = 7.2
14-Propoxycarbonylbenz[5,6]indolo[2,1-a]isoquinoline-8,13-
1
Hz, 3H), 4.52 (q, J = 7.2 Hz, 2H), 7.23 (d, J = 7.2 Hz, 1H), 7.70−7.72
(m, 2H), 8.21−8.26 (m, 3H), 9.74 (d, J = 7.2 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 180.4, 174.9, 163.5, 152.3, 140.1, 134.3, 133.8, 133.3,
133.0, 129.0, 127.7, 127.3, 125.9, 122.1, 116.8, 115.5, 105.3, 60.9, 35.4,
30.2, 14.4; HRMS (ESI) m/z [M + Na]+ calcd for C23H21NO4Na
398.1368, found 398.1372.
dione (7c). Yellow solid: yield 340 mg (89%); mp 228−229 °C; H
NMR (400 MHz, CDCl3) δ 1.07 (t, J = 7.2 Hz, 3H), 1.89−1.95 (m,
2H), 4.57 (t, J = 6.8 Hz, 2H), 7.30 (d, J = 7.2 Hz, 1H), 7.62−7.64 (m,
2H), 7.71−7.78 (m, 3H), 8.19−8.27 (m, 3H), 9.46 (d, J = 7.6 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 180.6, 175.2, 166.7, 134.4,
133.7, 133.5, 133.2, 132.6, 129.5, 129.4, 129.0, 127.7, 126.8, 126.6,
3997
dx.doi.org/10.1021/jo500456d | J. Org. Chem. 2014, 79, 3992−3998

The Journal of Organic Chemistry
Article
124.4, 124.3, 122.4, 117.4, 110.2, 68.1, 21.9, 10.5; HRMS (ESI) m/z
[M + Na]+ calcd for C24H17NO4Na 406.1055, found 406.1053.
14-Isopropoxycarbonylbenz[5,6]indolo[2,1-a]isoquinoline-8,13-
Am. Chem. Soc. 2003, 125, 9294. (d) Liu, Y.-H.; Song, F.-J.; Guo, S.-H.
J. Am. Chem. Soc. 2006, 128, 11332. (e) Wang, A.-Z.; Jiang, H.-F. J.
Am. Chem. Soc. 2008, 130, 5030. (f) Liu, Q.-L.; Chen, P.-H.; Liu, G.-S.
ACS Catal. 2013, 3, 178.
1
dione (7d). Yellow solid: yield 336 mg (88%); mp 261−263 °C; H
NMR (400 MHz, CDCl3) δ 1.55 (d, J = 6.4 Hz, 6H), 5.58−5.61 (m,
1H), 7.27 (d, J = 7.6 Hz, 1H), 7.59−7.62 (m, 2H), 7.69−7.75 (m,
3H), 8.19−8.29 (m, 3H), 9.42 (d, J = 7.6 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 180.3, 174.9, 165.8, 134.2, 133.4, 133.3, 132.9, 132.2,
129.2, 129.0, 128.6, 127.4, 126.6, 126.4, 126.3, 124.1, 122.1, 117.1,
110.5, 69.9, 21.5; HRMS (ESI) m/z [M + Na]+ calcd for
C24H17NO4Na 406.1055, found 406.1054.
(7) (a) Sun, J.-W.; Wang, X.-S.; Liu, Y. J. Org. Chem. 2013, 78, 10560.
(b) Liu, Y.; Hu, H.-Y.; Su, X.-B.; Sun, J.-W.; Cao, C.-S.; Shi, Y.-H. Eur.
J. Org. Chem. 2013, 2020. (c) Liu, Y.; Sun, J.-W. J. Org. Chem. 2012,
77, 1191.
(8) Gundersen, L.-L.; Charnock, C.; Negussie, A. H.; Rise, F.; Teklu,
S. Eur. J. Pharm. Sci. 2007, 30, 26.
(9) Hagishita, S.; Yamada, M.; Shirahase, K.; Okada, T.; Murakami,
Y.; Ito, Y.; Matsuura, T.; Wada, M.; Kato, T.; Ueno, M.; Chikazawa, Y.;
Yamada, K.; Ono, T.; Teshirogi, I.; Ohtani, M. J. Med. Chem. 1996, 39,
3636.
(10) Chai, W.; Breitenbucher, J. G.; Kwok, A.; Li, X.; Wong, V.;
Carruthers, N. I.; Lovenberg, T. W.; Mazur, C.; Wilson, S. J.; Axe, F.
U.; Jones, T. K. Bioorg. Med. Chem. Lett. 2003, 13, 1767.
(11) Bermudez, J.; Fake, C. S.; Joiner, G. F.; Joiner, K. A.; Kim, F. D.;
Miner, W. D.; Sanger, G. J. J. Med. Chem. 1990, 33, 1924.
(12) Weide, T.; Arve, L.; Prinz, H.; Waldmann, H.; Kessler, H.
Bioorg. Med. Chem. Lett. 2006, 16, 59.
(13) Dorange, I.; Forsblom, R.; Macsari, I.; Svensson, M.; Bylund, J.;
Besidski, Y.; Blid, J.; Sohn, D.; Gravenfors, Y. Bioorg. Med. Chem. Lett.
2012, 22, 6888.
(14) Teklu, S.; Gundersen, L.-L.; Larsen, T.; Malterud, K. E.; Rise, F.
Bioorg. Med. Chem. 2005, 13, 3127.
(15) (a) Pratt, E. F.; Rice, R. G.; Luckenbaugh, R. W. J. Am. Chem.
Soc. 1957, 79, 1212. (b) Citterio, A.; Fochi, M.; Marion, A.; Mele, A.;
Sebastiano, R.; Delcanale, M. Heterocycles 1998, 48, 1993. (c) Liu, Y.;
Hu, H.-Y.; Liu, Q.-J.; Hu, H.-W.; Xu, J.-H. Tetrahedron 2007, 63, 2024.
(16) For the generation of 8, see: Schmidt, A.; Topp, M.; Mordhorst,
T.; Schneider, O. Tetrahedron 2007, 63, 1842.
14-tert-Butoxycarbonylbenz[5,6]indolo[2,1-a]isoquinoline-8,13-
1
dione (7e). Yellow solid: yield 339 mg (85%); mp 240−241 °C; H
NMR (400 MHz, CDCl3) δ 1.79 (s, 9H), 7.28 (d, J = 7.6 Hz, 1H),
7.61−7.65 (m, 2H), 7.70−7.77 (m, 3H), 8.21−8.26 (m, 2H), 8.35−
8.37 (m, 1H), 9.44 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 180.6, 175.2, 165.6, 134.5, 133.6, 133.5, 133.1, 132.2, 129.4, 129.2,
128.8, 127.6, 126.8, 126.5, 126.4, 124.5, 124.4, 122.1, 117.3, 112.1,
83.3, 28.0; HRMS (ESI) m/z [M + Na]+ calcd for C25H19NO4Na
420.1212, found 420.1205.
ASSOCIATED CONTENT
* Supporting Information
■
S
X-ray crystallographic structures and crystal data (CIF) on
compound 4e. 1H NMR and 13C NMR spectra for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: liu__yun3@sina.com.cn.
■
(17) For the generation of intermediate I, see for examples: (a) Nair,
V.; Pillai, A. N.; Menon, R. S.; Suresh, E. Org. Lett. 2005, 7, 1189.
(b) Nair, V.; Sreekanth, A. R.; Vinod, A. U. Org. Lett. 2001, 3, 3495.
(c) Asghari, S.; Habibi, A. K. Tetrahedron 2012, 68, 8890.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge National Natural Science
Foundation of China (NSFC 21172188, 21202058), and Open
Project Program of Jiangsu Province Key Laboratory of Green
Synthetic for Functional Materials (K201308) for financial
support of this work.
REFERENCES
■
(1) For selected reviews, see: (a) Jun, C. H. Chem. Soc. Rev. 2004, 33,
610. (b) Park, Y. J.; Park, J. W.; Jun, C. H. Acc. Chem. Res. 2008, 41,
222. (c) Murakami, M.; Matsuda, T. Chem. Commun. 2011, 47, 1100.
(2) See for examples: (a) Miyamoto, K.; Tada, N.; Ochiai, M. J. Am.
Chem. Soc. 2007, 129, 2772. (b) Seiser, T.; Roth, O. A.; Cramer, N.
Angew. Chem., Int. Ed. 2009, 48, 6320. (c) Najera, C.; Sansano, J. M.
Angew. Chem., Int. Ed. 2009, 48, 2452. (d) Seiser, T.; Cramer, N. J. Am.
Chem. Soc. 2010, 132, 5340. (e) Li, H.; Li, Y.; Zhang, X. S.; Chen, K.;
Wang, X.; Shi, Z. J. J. Am. Chem. Soc. 2011, 133, 15244.
(3) (a) For reviews, see: (a) Jennings, P. W.; Johnson, L. L. Chem.
Rev. 1994, 94, 2241. (b) Rybtchinski, B.; Milstein, D. Angew. Chem.,
Int. Ed. 1999, 38, 870. (c) Murakami, M.; Ito,Y. In Activation of
Unreactive Bonds and Organic Synthesis; Murai, S., Ed.; Springer: Berlin,
1999; p 97.
(4) (a) Cairns, G. A.; Carr, N.; Green, M.; Mahon, M. F. Chem.
Commun. 1996, 2431. (b) Chamberlin, R. L. M.; Rosenfeld, D. C.;
Wolczanski, P. T.; Lobkovsky, E. B. Organometallics 2002, 21, 2724.
(c) Adams, H.; Guio, L. V. Y.; Morris, M. J.; Spey, S. E. J. Chem. Soc.,
Dalton Trans. 2002, 2907.
(5) (a) Moriarty, R. M.; Penmasta, R.; Awasthi, A. K.; Prakash, I. J.
Org. Chem. 1988, 53, 6124. (b) Sawaki, Y.; Inoue, H.; Ogata, Y. Bull.
Chem. Soc. Jpn. 1983, 56, 1133.
(6) (a) Jun, C.-H.; Lee, H.; Moon, C.-W.; Hong, H.-S. J. Am. Chem.
Soc. 2001, 123, 8600. (b) Shimada, T.; Yamamoto, Y. J. Am. Chem. Soc.
2003, 125, 6646. (c) Datta, S.; Chang, C.-L.; Yeh, K.-L.; Liu, R.-S. J.
3998
dx.doi.org/10.1021/jo500456d | J. Org. Chem. 2014, 79, 3992−3998