Regioselective Synthesis of Indolo[1,2-c]quinazolines and 11H-Indolo[3,2-c]quinolines via Copper-Catalyzed Cascade Reactions of 2-(2-Bromoaryl)-1H-indoles with Aldehydes and Aqueous Ammonia

Article abstract of DOI:10.1021/acs.joc.5b02076

Highly selective and convenient synthesis of indolo[1,2-c]quinazolines and 11H-indolo[3,2-c]quinolines through copper-catalyzed one-pot cascade reactions of 2-(2-bromoaryl)-1H-indoles with aldehydes and aqueous ammonia has been achieved. Notably, the regioselectivity was easily controlled by tuning the reaction conditions. Compared with literature methods, the present protocol features easily controlled selectivity, readily available starting materials, good functional group tolerance, and simple operation procedures.

Full text of DOI:10.1021/acs.joc.5b02076

Article
pubs.acs.org/joc
Regioselective Synthesis of Indolo[1,2‑c]quinazolines and
11H‑Indolo[3,2‑c]quinolines via Copper-Catalyzed Cascade Reactions
of 2‑(2-Bromoaryl)‑1H‑indoles with Aldehydes and Aqueous
Ammonia
Shenghai Guo,* Li Tao, Wenwen Zhang, Xinying Zhang, and Xuesen Fan*
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, P. R. China
S
* Supporting Information
ABSTRACT: Highly selective and convenient synthesis of indolo[1,2-c]quinazolines and 11H-indolo[3,2-c]quinolines through
copper-catalyzed one-pot cascade reactions of 2-(2-bromoaryl)-1H-indoles with aldehydes and aqueous ammonia has been
achieved. Notably, the regioselectivity was easily controlled by tuning the reaction conditions. Compared with literature methods,
the present protocol features easily controlled selectivity, readily available starting materials, good functional group tolerance, and
simple operation procedures.
sequence, limited substrate scope, or harsh reaction conditions.
Therefore, the development of simple, practical, and general
synthetic methods for the selective synthesis of indolo[1,2-
c]quinazoline and 11H-indolo[3,2-c]quinoline derivatives from
the same starting materials is highly desirable.
INTRODUCTION
■
Indoloquinazolines and indoloquinolines have attracted much
attention since they are frequently found in natural products
and synthetic compounds with a broad spectrum of biological
activities (Figure 1).1 For example, indolo[1,2-c]quinazolines
exhibit potent antibacterial and antifungal activities.2 Mean-
while, 11H-indolo[3,2-c]quinolines have been used as promis-
ing antimalarial and anticancer drug candidates,3 selective
protein kinase DYRK1A inhibitors,4 and DNA intercalator5 for
inhibiting DNA replication, transcription, and/or topoisomer-
ase activities.
In view of their importance, several synthetic routes have
been developed for the preparation of indolo[1,2-c]quinazoline
and 11H-indolo[3,2-c]quinoline derivatives. For example, the
synthesis of indolo[1,2-c]quinazolines has been achieved
through cyclocondensation of 2-(2-aminoaryl)indoles with
aldehydes, acyl cyanides, or nitriles,2,6 and copper-catalyzed
tandem reactions of 2-(2-bromoaryl)indoles with benzylamines,
amino acids, or amidines.7 Meanwhile, palladium-catalyzed
isocyanide insertion reactions of 2-(2-aminoaryl)indoles,8 gold-
catalyzed cyclizations of acyclic alkynes,9 and aza-Wittig
reactions of isocyanates with imino-phosphoranes10 have been
utilized for the preparation of 11H-indolo[3,2-c]quinoline
derivatives. Although these existing synthetic routes are quite
effective, they are only suitable for the preparation of either
indolo[1,2-c]quinazolines or 11H-indolo[3,2-c]quinolines. In
addition, most of them still suffer from expensive or difficult-to-
obtain starting materials or reagents, a multistep reaction
On the other hand, copper-catalyzed cross-coupling reaction
of aryl halides with amines or aqueous ammonia turned out to
be a powerful tool for the construction of aromatic C(sp2)−N
bonds.11 Recently, by employing copper-catalyzed aromatic
C(sp2)−N bond formation reaction as a key step, we have
developed a series of practical and efficient synthetic routes
toward various bioactive N-fused heterocyclic compounds.12 As
a continuation of our study in this aspect, we disclose herein a
convenient synthesis of indolo[1,2-c]quinazoline and 11H-
indolo[3,2-c]quinoline derivatives through copper-catalyzed
one-pot two-step cascade reactions of 2-(2-bromoaryl)-1H-
indoles with aldehydes and aqueous ammonia. Interestingly,
highly selective synthesis of the above-mentioned two classes of
indole-fused heterocycles from the same starting materials was
easily accomplished by simply tuning the reaction conditions.
Now, we would like to report the details of these trans-
formations.
Received: September 4, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.joc.5b02076
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Figure 1. Selective compounds containing a indoloquinazoline or indoloquinoline scaffold.
a
Table 1. Optimization Study for the Synthesis of 4a
b
yield (%)
entry
catalyst
CuI
base
ligand
solvent
DMSO
T (°C)
4a
5a
1
2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
K3PO4
tBuOK
DABCO
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
60
65
52
57
56
62
50
51
56
5
4
4
3
3
6
5
6
CuCl
CuBr
Cu(OAc)2
CuCl2
CuI
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
3
4
5
6
7
CuI
8
CuI
9
CuI
10
11
12
13
14
15
16
17
18
19
20
21
22
CuI
CuI
L-proline
DMEDA
1,10-phen
DMAP
75
59
59
66
55
52
52
4
4
6
3
2
6
6
CuI
CuI
CuI
CuI
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
CuI
DMAC
NMP
CuI
CuI
1,4-dioxane
toluene
DMSO
DMSO
DMSO
CuI
CuI
43
55
60
6
3
8
CuI
80
CuI
120
a
The reactions were run with (1) 1a (0.4 mmol), 2a (0.8 mmol), aqueous ammonia (26%, 0.4 mL), catalyst (0.04 mmol), base (0.8 mmol), ligand
b
(0.08 mmol), solvent (1.5 mL), T (°C), N2, 12 h; (2) T (°C), air, 8 h. Isolated yield.
investigated. It was found that K2CO3 provided the highest
RESULTS AND DISCUSSION
■
yield of 4a (entries 1 and 6−10). Screening of different ligands
revealed that L-proline was the most efficient (entries 1 and
11−14). Next, several solvents, such as DMF, DMAC, NMP,
1,4-dioxane, and toluene, were also tried as the reaction
medium, and all of them were found to be less effective than
DMSO (entries 11 and 15−19). Moreover, it was observed that
decreasing or increasing the reaction temperature from 100 °C
resulted in decreased yields of 4a (entries 11 and 20−22).
With the optimized reaction conditions (Table 1, entry 11)
in hand, we then studied the scope and generality of this new
method for the preparation of indolo[1,2-c]quinazolines (4),
and the results are shown in Table 2. First, the reactions of
different aldehydes (2) with 2-(2-bromophenyl)-1H-indole
(1a) and aqueous ammonia were investigated. It was found
that aryl-substituted aldehydes with either electron-donating
groups including methyl and methoxyl or electron-withdrawing
groups such as trifluoromethyl, fluoro, bromo, and chloro on
Initially, 2-(2-bromophenyl)-1H-indole (1a) was treated with
benzaldehyde (2a) and aqueous ammonia in the presence of
CuI and K2CO3 in DMSO at 100 °C under a nitrogen
atmosphere. TLC analysis showed that 1a was consumed
completely in 12 h to give 6-phenyl-5,6-dihydroindolo[1,2-
c]quinazoline (3a). Subsequent treatment of the resulting
mixture at 100 °C for 8 h under air afforded the desired 6-
phenylindolo[1,2-c]quinazoline (4a) in a total yield of 65%.
Meanwhile, 6-phenyl-11H-indolo[3,2-c]quinoline (5a) as an
unexpected byproduct was also isolated in 5% yield (Table 1,
entry 1). To improve the efficiency, we commenced to optimize
the reaction parameters (Table 1). First, five different copper
catalysts were screened by using K2CO3 as base and DMSO as
solvent (entries 1−5). Among them, CuI proved to be optimal
for the formation of 4a. With CuI as catalyst, the effect of
inorganic and organic bases on this cascade reaction was also
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ab
,
Table 2. Scope for the Synthesis of Indolo[1,2-c]quinazolines (4)
a
Reaction conditions: (1) 1 (0.4 mmol), 2 (0.8 mmol), aqueous ammonia (26%, 0.4 mL), CuI (0.04 mmol), K2CO3 (0.8 mmol), L-proline (0.08
b
c
mmol), DMSO (1.5 mL), 100 °C, N2, 12 h; (2) 100 °C, air, 8 h. Isolated yields are shown. An unknown byproduct was formed.
the aryl ring at different positions were well tolerated with the
reaction conditions to provide the desired 6-aryl substituted
indolo[1,2-c]quinazolines 4a−4j in moderate to good yields.
No obvious electronic and steric effects of these functional
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Scheme 1. One-Pot Two-Step Synthesis of 5a from 1a, 2a, and Aqueous Ammonia
a b
,
Table 3. Scope for the Synthesis of 11H-Indolo[3,2-c]quinolines (5)
a
Reaction conditions: (1) 1 (0.4 mmol), 2 (0.8 mmol), aqueous ammonia (26%, 0.4 mL), CuI (0.04 mmol), K2CO3 (0.8 mmol), L-proline (0.08
b
mmol), DMSO (1.5 mL), 100 °C, N2, 12 h; (2) HCl (6 M), 120 °C, air, 8 h. Isolated yields are shown.
groups were observed. 1-Naphthaldehyde and thiophene-2-
carbaldehyde also underwent this cascade reaction smoothly to
deliver the corresponding products 4k and 4l in 60% and 53%
yields, respectively. In addition, with cinnamaldehyde and
butyraldehyde, 6-alkenyl and 6-alkyl substituted indolo[1,2-
c]quinazolines 4m and 4n were obtained in 56% and 35%
yields. More interestingly, paraformaldehyde proved to be also
compatible to generate 6-unsubstituted indolo[1,2-c]-
quinazoline 4o, albeit in a lower yield. Second, several 2-(2-
bromoaryl)-1H-indoles (1) were tried, and the results indicated
that 1 bearing different R1 and R2 groups reacted with various
aldehydes (2) and aqueous ammonia smoothly to afford 4p−4x
in 45%−89% yields.
Having established an efficient synthesis of indolo[1,2-
c]quinazolines (4) from the one-pot cascade reaction of 2-(2-
bromoaryl)-1H-indoles (1) with aldehydes (2) and aqueous
ammonia, we were then interested in whether 11H-indolo[3,2-
c]quinolines (5) could also be preferentially synthesized from
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Scheme 2. Control Experiments
Scheme 3. Plausible Mechanisms for Formation of 4a and 5a
the same starting materials under different reaction conditions.
For this purpose, 6-phenyl-5,6-dihydroindolo[1,2-c]quinazoline
(3a) was prepared and then subjected to various reaction
conditions. After several trials,13 we were pleased to find that
treating 3a with aqueous HCl and CuI in DMSO at 120 °C
under air could afford 5a in 94% yield. It is worth to be noted
that, under these conditions, the formation of 4a was not
observed. These results indicated that the pH value of the
reaction system played a vital role in determining the direction
of the transformation of 3a. To be specific, 3a could be
selectively converted into 4a under basic conditions, as shown
in Table 1. In contrast, treating 3a under acidic conditions
could afford 5a in an exclusive manner. On the basis of these
results, we continued our study by exploring the possibility of
developing a one-pot two-step synthesis of 5a directly from 1a,
2a, and aqueous ammonia. Thus, 1a was first treated with 2a
and aqueous ammonia in the presence of CuI, K2CO3, and L-
proline under N2 at 100 °C for 12 h. Then, hydrochloric acid
was added to the reaction vessel to adjust the pH value of the
reaction system to a range of 5−6, and the resulting mixture
was stirred at 120 °C for 8 h under air. It was observed that the
envisioned one-pot two-step cascade reaction proceeded
smoothly to provide 5a in a total yield of 81% (Scheme 1).
Next, the substrate scope for the synthesis of 11H-
indolo[3,2-c]quinolines (5) was studied in detail. As demon-
strated in Table 3, various aldehydes 2 and indoles 1 took part
in this cascade reaction to give the desired 11H-indolo[3,2-
c]quinolines 5a−5o in modest to good yields. For aldehydes 2,
it was found that aryl- and alkenyl-substituted aldehydes usually
gave the corresponding products in yields higher than alkyl-
substituted aldehydes. Moreover, it is worth noting that 6-
unsubstituted 11H-indolo[3,2-c]quinoline 5i, which can be
E
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1
purchased from commercial sources and used as received. H and 13
C
successfully utilized in the synthesis of the alkaloid
isocryptolepine (Figure 1) by regioselective N-methylation
reaction,3a,c,14 could also be obtained by using paraformalde-
hyde as a substrate. For indoles 1, different R1 and R2 groups
showed a slight influence on the outcome of this cascade
reaction.
NMR spectra were recorded at 400 and 100 MHz, respectively. High-
resolution mass spectra (HRMS) were collected in ESI mode by using
a MicrOTOF mass spectrometer. All reactions were monitored by
thin-layer chromatography (TLC) using silica gel plates (silica gel 60
F254 0.25 mm), and components were visualized by observation
under UV light (254 and 365 nm).
To explore the reaction mechanism for the regioselective
synthesis of indole-fused heterocycles 4 and 5, several control
experiments were performed, and the results are shown in
Scheme 2. First, treatment of a mixture of 1a, 2a, and aqueous
ammonia by using CuI as catalyst, L-proline as ligand, and
K2CO3 as base under N2 afforded the key intermediate 3a in
80% yield (Scheme 2, eq 1). Second, copper-catalyzed cross-
coupling reaction of 1a with aqueous ammonia at 100 °C under
a nitrogen atmosphere gave 2-(2-aminophenyl)-1H-indole (6)
in 60% yield. The following cyclocondensation of 6 with
benzaldehyde (2a) under N2 afforded 3a in 82% yield (Scheme
2, eq 2). Third, treating a mixture of 3a, CuI, and K2CO3 at 100
°C for 8 h under air could afford 4a (78%) together with 5a
(2%). On the other hand, treatment of 3a with CuI and HCl at
120 °C for 8 h under air gave rise to 5a in 94% yield (Scheme
2, eq 3). Finally, treatment of 3a with HCl at 120 °C for 1 h
under N2 afforded intermediate 7 in 85% yield. Next, 7 was
oxidized by air under the catalysis of CuI to deliver 5a in 97%
yield (Scheme 2, eq 4).
General Procedure for the Synthesis of Indolo[1,2-c]-
quinazolines 4. To a tube containing a solution of 2-(2-
bromoaryl)-1H-indole 1 (0.4 mmol) in DMSO (1.5 mL) were
added K2CO3 (0.8 mmol), CuI (0.04 mmol), L-proline (0.08 mmol),
aldehyde 2 (0.8 mmol), and 26% aqueous ammonia (0.4 mL) under a
nitrogen atmosphere. Then, the tube was sealed, and the mixture was
stirred at 100 °C for 12 h. Next, the resulting mixture was opened to
air and stirred at 100 °C for another 8 h. After being cooled to room
temperature, the reaction was quenched with saturated NH4Cl and
extracted with ethyl acetate. The combined organic layer was washed
with H2O and brine, and then dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure and the residue was
purified by chromatography on silica gel to afford the desired
indolo[1,2-c]quinazoline 4.
6-Phenylindolo[1,2-c]quinazoline (4a).7c Petroleum ether/ethyl
acetate (15:1) as eluent; yellow solid (88 mg, 75%), mp 195−197 °C.
1H NMR (CDCl3, 400 MHz) δ 6.48 (d, J = 8.8 Hz, 1H), 7.00 (t, J =
8.0 Hz, 1H), 7.28 (s, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.49−7.58 (m,
2H), 7.62−7.70 (m, 5H), 7.78 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 6.8 Hz,
1H), 8.11 (dd, J = 0.8, 7.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ
95.8, 115.0, 120.55, 120.60, 121.6, 122.8, 123.5, 127.5, 127.9, 128.3,
129.2, 129.4, 130.4, 130.5, 131.7, 135.2, 135.9, 139.2, 149.4. MS (ESI)
m/z 295 [M + H]+.
Based on the above results and previous studies,12 plausible
mechanisms for the formation of 4a and 5a are illustrated in
Scheme 3. First, copper-catalyzed amination of 2-(2-bromo-
phenyl)-1H-indole (1a) with aqueous ammonia via intermedi-
ates I and II affords 2-(2-aminophenyl)-1H-indole (6).
Subsequent condensation of 6 with benzaldehyde (2a) gives
rise to an imine intermediate III, which then undergoes an
intramolecular N-nucleophilic addition under basic conditions
to deliver the key intermediate 3a. With the promotion of CuI
and K2CO3, 3a could be oxidized by air to afford 4a as a major
product. As for the formation of 5a, it is proposed that, under
acidic conditions, an addition of H+ to the 3-position of the
indole-ring of 3a affords intermediate V, which then undergoes
a ring-opening process to deliver VI. Rearomatization of VI,
followed by intramolecular C-nucleophilic addition, gives
intermediate 7. Subsequent oxidative aromatization of 7 in
the presence of air and CuI generates 5a.
6-p-Tolylindolo[1,2-c]quinazoline (4b).7c Petroleum ether/ethyl
acetate (20:1) as eluent; yellow solid (78 mg, 63%), mp 157−159 °C.
1H NMR (CDCl3, 400 MHz) δ 2.55 (s, 3H), 6.61 (d, J = 8.8 Hz, 1H),
7.03 (t, J = 8.0 Hz, 1H), 7.26 (s, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.44 (d,
J = 8.0 Hz, 2H), 7.47−7.55 (m, 2H), 7.59 (d, J = 7.6 Hz, 2H), 7.78 (d,
J = 7.6 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 8.09 (d, J = 7.2 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ 21.7, 95.8, 115.1, 120.5, 120.6, 121.5,
122.7, 123.5, 127.3, 127.9, 128.2, 129.1, 129.9, 130.4, 131.8, 133.1,
135.3, 139.3, 140.6, 149.6. MS (ESI) m/z 309 [M + H]+.
6-(4-Methoxyphenyl)indolo[1,2-c]quinazoline (4c).16a Petroleum
ether/ethyl acetate (15:1) as eluent; yellow solid (90 mg, 69%), mp
174−176 °C. 1H NMR (CDCl3, 400 MHz) δ 3.95 (s, 3H), 6.65 (d, J =
8.0 Hz, 1H), 7.01−7.05 (m, 1H), 7.11−7.14 (m, 2H), 7.26 (s, 1H),
7.30−7.34 (m, 1H), 7.47−7.56 (m, 2H), 7.61−7.64 (m, 2H), 7.78 (d, J
= 8.0 Hz, 1H), 7.85 (dd, J = 0.8, 7.6 Hz, 1H), 8.10 (dd, J = 1.6, 7.6 Hz,
1H); 13C NMR (CDCl3, 100 MHz) δ 55.5, 95.8, 114.6, 115.1, 120.5,
121.5, 122.7, 123.5, 127.3, 127.7, 128.2, 129.1, 129.9, 130.4, 131.8,
135.4, 139.2, 149.4, 161.2 (one 13C signal was not observed). HRMS
(ESI) calcd for C22H17N2O [M + H]+ 325.1335, found 325.1347.
6-(3,4-Dimethoxyphenyl)indolo[1,2-c]quinazoline (4d). Petrole-
um ether/ethyl acetate (5:1) as eluent; yellow solid (79 mg, 56%), mp
CONCLUSION
■
In conclusion, we have developed an efficient and general
strategy for the selective synthesis of indolo[1,2-c]quinazoline
and 11H-indolo[3,2-c]quinoline derivatives via copper-cata-
lyzed one-pot sequential reactions of 2-(2-bromoaryl)-1H-
indoles, aldehydes, and aqueous ammonia. In addition,
plausible reaction mechanisms for the formation of indolo-
[1,2-c]quinazolines and 11H-indolo[3,2-c]quinolines are sug-
gested based on the control experimental results. Compared
with the literature procedures, the present synthetic route
exhibits high efficiency and regioselectivity, readily obtainable
starting materials, and operational simplicity. Further applica-
tion of this novel method in the synthesis of bioactive
compounds embedding the indolo[1,2-c]quinazoline or 11H-
indolo[3,2-c]quinoline skeleton is currently underway in our
laboratory.
1
183−185 °C. H NMR (CDCl3, 400 MHz) δ 3.88 (s, 3H), 4.02 (s,
3H), 6.63 (d, J = 8.8 Hz, 1H), 7.01−7.05 (m, 1H), 7.08 (d, J = 8.4 Hz,
1H), 7.18 (d, J = 2.0 Hz, 1H), 7.25−7.26 (m, 1H), 7.27 (s, 1H), 7.32
(t, J = 7.6 Hz, 1H), 7.48−7.56 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.85
(d, J = 7.6 Hz, 1H), 8.10 (dd, J = 1.2, 7.6 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ 56.1, 56.2, 95.9, 111.2, 111.6, 115.2, 120.50, 120.52,
121.2, 121.6, 122.7, 123.5, 127.4, 127.7, 128.2, 129.1, 130.4, 131.7,
135.3, 139.1, 149.2, 149.6, 150.7. HRMS (ESI) calcd for C23H19N2O2
[M + H]+ 355.1441, found 355.1459.
6-(4-(Trifluoromethyl)phenyl)indolo[1,2-c]quinazoline (4e). Pe-
troleum ether/ethyl acetate (15:1) as eluent; yellow solid (59 mg,
1
41%), mp 202−204 °C. H NMR (CDCl3, 400 MHz) δ 6.52 (d, J =
8.4 Hz, 1H), 7.03−7.07 (m, 1H), 7.28 (s, 1H), 7.35 (t, J = 7.6 Hz,
1H), 7.51−7.59 (m, 2H), 7.79−7.85 (m, 4H), 7.90 (d, J = 8.0 Hz,
2H), 8.09−8.12 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 96.2, 114.5,
120.6, 120.8, 121.9, 122.8, 123.8, 123.9 (q, J = 270.3 Hz, 1C), 126.3
(q, J = 3.3 Hz, 2C), 127.87, 127.91, 129.0, 129.3, 130.5, 131.3, 132.5
(q, J = 33 Hz, 1C), 135.1, 138.9, 139.3, 147.8. HRMS (ESI) calcd for
C22H14F3N2 [M + H]+ 363.1104, found 363.1105.
EXPERIMENTAL SECTION
■
General Methods. 2-(2-Bromoaryl)-1H-indoles 1 were prepared
by the Fischer indole synthesis.15 Other reagents and solvents were
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6-(4-Fluorophenyl)indolo[1,2-c]quinazoline (4f).7c Petroleum
ether/ethyl acetate (30:1) as eluent; yellow solid (79 mg, 63%), mp
217−219 °C. 1H NMR (CDCl3, 400 MHz) δ 6.54 (d, J = 8.8 Hz, 1H),
7.05 (t, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.29−7.35 (m, 3H), 7.47−7.56
(m, 2H), 7.65−7.68 (m, 2H), 7.77 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 8.0
Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ
96.0, 114.8, 116.5 (d, J = 22.1 Hz, 2C), 120.5, 120.7, 121.6, 122.8,
123.6, 127.6, 127.8, 129.2, 130.5, 130.6 (d, J = 8.4 Hz, 2C), 131.6,
132.1 (d, J = 3.8 Hz, 1C), 135.2, 139.0, 148.4, 163.9 (d, J = 249.2 Hz,
1C). MS (ESI) m/z 313 [M + H]+.
6-(4-Bromophenyl)indolo[1,2-c]quinazoline (4g). Petroleum
ether/ethyl acetate (40:1) as eluent; yellow solid (47 mg, 31%), mp
204−206 °C. 1H NMR (CDCl3, 400 MHz) δ 6.61 (d, J = 8.8 Hz, 1H),
7.06 (t, J = 8.0 Hz, 1H), 7.26 (s, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.49−
7.58 (m, 4H), 7.75−7.83 (m, 4H), 8.09 (d, J = 7.2 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ 96.0, 114.7, 120.6, 120.7, 121.7, 122.8, 123.7,
124.9, 127.7, 127.9, 129.2, 130.1, 130.4, 131.4, 132.5, 134.8, 135.2,
139.0, 148.2. HRMS (ESI) calcd for C21H14BrN2 [M + H]+ 373.0335,
found 373.0364.
1H), 7.41−7.56 (m, 6H), 7.68−7.74 (m, 3H), 7.83 (d, J = 8.0 Hz,
1H), 7.88 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 16.0 Hz, 1H), 8.05 (t, J =
8.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 95.6, 115.0, 120.3, 120.9,
121.2, 122.2, 122.7, 123.6, 127.1, 127.4, 127.8, 129.06, 129.13, 129.7,
130.6, 131.6, 135.1, 135.6, 138.9, 139.8, 147.7. MS (ESI) m/z 321 [M
+ H]+.
6-Propylindolo[1,2-c]quinazoline (4n).7b Petroleum ether/ethyl
acetate (20:1) as eluent; yellow solid (36 mg, 35%), mp 95−97 °C. 1H
NMR (CDCl3, 400 MHz) δ 1.23 (t, J = 7.6 Hz, 3H), 2.04−2.11 (m,
2H), 3.40 (t, J = 7.6 Hz, 2H), 7.23 (s, 1H), 7.38−7.48 (m, 3H), 7.53
(t, J = 7.6 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 7.2 Hz, 1H),
7.99 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ 13.8, 19.6, 38.6, 95.6, 115.0, 120.3, 120.8, 122.2, 122.6,
123.3, 126.8, 127.0, 129.0, 130.6, 131.2, 135.2, 138.6, 151.6. MS (ESI)
m/z 261 [M + H]+.
Indolo[1,2-c]quinazoline (4o).7b Petroleum ether/ethyl acetate
1
(10:1) as eluent; yellow solid (26 mg, 30%), mp 199−200 °C. H
NMR (CDCl3, 400 MHz) δ 7.14 (s, 1H), 7.40−7.47 (m, 2H), 7.50−
7.58 (m, 2H), 7.82−7.84 (m, 2H), 7.96 (d, J = 8.0 Hz, 1H), 8.06 (d, J
= 8.0 Hz, 1H), 9.06 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 94.9,
109.9, 121.0, 121.3, 122.4, 123.2, 124.2, 127.8, 128.0, 129.2, 129.8,
130.4, 132.8, 137.2, 139.1. MS (ESI) m/z 219 [M + H]+.
6-(4-Chlorophenyl)indolo[1,2-c]quinazoline (4h).7b Petroleum
ether/ethyl acetate (40:1) as eluent; yellow solid (79 mg, 60%), mp
201−203 °C. 1H NMR (CDCl3, 400 MHz) δ 6.60 (d, J = 8.0 Hz, 1H),
7.06 (t, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.47−
7.56 (m, 2H), 7.58−7.63 (m, 4H), 7.77 (d, J = 7.6 Hz, 1H), 7.83 (d, J
= 7.6 Hz, 1H), 8.06 (d, J = 7.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
δ 96.0, 114.8, 120.5, 120.7, 121.7, 122.8, 123.7, 127.6, 127.9, 129.2,
129.6, 129.9, 130.4, 131.4, 134.3, 135.2, 136.6, 139.0, 148.2. MS (ESI)
m/z 329 [M + H]+.
6-(3-Chlorophenyl)indolo[1,2-c]quinazoline (4i). Petroleum
ether/ethyl acetate (40:1) as eluent; yellow solid (73 mg, 55%), mp
167−169 °C. 1H NMR (CDCl3, 400 MHz) δ 6.56 (d, J = 8.8 Hz, 1H),
7.05 (t, J = 8.0 Hz, 1H), 7.25 (s, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.49−
7.56 (m, 4H), 7.65 (s, 1H), 7.71 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.84
(d, J = 7.2 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 100
MHz) δ 96.1, 114.7, 120.6, 120.7, 121.8, 122.8, 123.7, 126.6, 127.7,
127.9, 128.6, 129.2, 130.4, 130.6, 130.7, 131.4, 135.1, 135.4, 137.4,
138.9, 147.8. HRMS (ESI) calcd for C21H14ClN2 [M + H]+ 329.0840,
found 329.0862.
6-(2-Chlorophenyl)indolo[1,2-c]quinazoline (4j). Petroleum
ether/ethyl acetate (15:1) as eluent; yellow solid (82 mg, 62%), mp
119−121 °C. 1H NMR (CDCl3, 400 MHz) δ 6.37 (d, J = 8.0 Hz, 1H),
7.05 (t, J = 8.0 Hz, 1H), 7.31 (s, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.52−
7.66 (m, 6H), 7.80 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 8.14
(d, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 96.0, 113.4,
120.7, 120.8, 122.3, 122.9, 123.7, 127.8, 128.0, 129.2, 130.31, 130.32,
130.4, 131.3, 131.7, 133.4, 134.7, 135.2, 139.0, 146.7 (one 13C signal
was not observed). HRMS (ESI) calcd for C21H14ClN2 [M + H]+
329.0840, found 329.0862.
10-Chloro-6-phenylindolo[1,2-c]quinazoline (4p).7b Petroleum
ether/ethyl acetate (15:1) as eluent; yellow solid (79 mg, 60%), mp
205−207 °C. 1H NMR (CDCl3, 400 MHz) δ 6.34 (d, J = 8.8 Hz, 1H),
6.92 (d, J = 8.8 Hz, 1H), 7.19 (s, 1H), 7.51−7.58 (m, 2H), 7.60−7.65
(m, 5H), 7.71 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.0 Hz,
1H); 13C NMR (CDCl3, 100 MHz) δ 95.2, 115.9, 119.7, 120.2, 121.8,
122.9, 127.7, 127.9, 128.2, 129.3, 129.5, 129.6, 130.0, 130.7, 131.5,
135.4, 136.5, 139.1, 149.0. MS (ESI) m/z 329 [M + H]+.
10-Chloro-6-p-tolylindolo[1,2-c]quinazoline (4q). Petroleum
ether/ethyl acetate (15:1) as eluent; yellow solid (87 mg, 64%), mp
212−214 °C. 1H NMR (CDCl3, 400 MHz) δ 2.53 (s, 3H), 6.45 (d, J =
9.2 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H), 7.15 (s, 1H), 7.42 (d, J = 7.2 Hz,
2H), 7.48−7.57 (m, 4H), 7.69 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 8.06
(d, J = 7.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 21.7, 95.1, 116.0,
119.6, 120.1, 121.7, 122.8, 127.5, 127.9, 128.1, 129.2, 129.5, 130.0,
131.5, 132.6, 136.5, 139.3, 140.8, 149.1 (one 13C signal was not
observed). HRMS (ESI) calcd for C22H16ClN2 [M + H]+ 343.0997,
found 343.1018.
10-Chloro-6-(4-chlorophenyl)indolo[1,2-c]quinazoline (4r).7b Pe-
troleum ether/ethyl acetate (15:1) as eluent; yellow solid (110 mg,
1
76%), mp 244−246 °C. H NMR (CDCl3, 400 MHz) δ 6.49 (d, J =
9.2 Hz, 1H), 6.99 (d, J = 9.6 Hz, 1H), 7.20 (s, 1H), 7.51−7.62 (m,
6H), 7.73 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 7.2 Hz, 1H);
13C NMR (CDCl3, 100 MHz) δ 95.4, 115.6, 119.9, 120.2, 121.9, 122.9,
127.9, 128.0, 129.5, 129.67, 129.73, 129.78, 129.82, 131.5, 133.8,
136.5, 136.9, 139.0, 147.8. MS (ESI) m/z 364 [M + H]+.
10-Chloro-6-(thiophen-2-yl)indolo[1,2-c]quinazoline (4s).7b Pe-
troleum ether/ethyl acetate (15:1) as eluent; yellow solid (104 mg,
6-(Naphthalen-1-yl)indolo[1,2-c]quinazoline (4k). Petroleum
ether/ethyl acetate (20:1) as eluent; yellow solid (83 mg, 60%), mp
148−150 °C. 1H NMR (CDCl3, 400 MHz) δ 5.99 (d, J = 8.8 Hz, 1H),
6.79 (t, J = 8.0 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.33−7.37 (m, 2H),
7.51−7.64 (m, 4H), 7.71−7.80 (m, 3H), 7.95−7.97 (m, 1H), 8.02 (d, J
= 8.4 Hz, 1H), 8.16−8.22 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ
96.0, 114.6, 120.5, 120.8, 121.9, 122.9, 123.5, 124.7, 125.9, 126.7,
126.9, 127.6, 127.7, 128.1, 128.6, 129.2, 130.4, 130.6, 131.0, 131.3,
133.4, 133.8, 135.0, 139.3, 148.5. HRMS (ESI) calcd for C25H17N2 [M
+ H]+ 345.1386, found 345.1389.
1
78%), mp 234−236 °C. H NMR (DMSO-d6, 400 MHz) δ 6.59 (d, J
= 9.2 Hz, 1H), 7.12 (dd, J = 1.6, 9.2 Hz, 1H), 7.35 (t, J = 4.0 Hz, 1H),
7.55 (s, 1H), 7.58−7.63 (m, 3H), 7.75 (d, J = 7.2 Hz, 1H), 7.87 (s,
1H), 7.98 (d, J = 4.8 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H); 13C NMR
(DMSO-d6, 100 MHz) δ 96.3, 116.1, 120.1, 120.3, 121.9, 123.9, 128.0,
128.2, 128.6, 128.7, 130.0, 130.3, 130.4, 131.6, 135.3, 136.7, 139.1,
143.3 (one 13C signal was not observed). MS (ESI) m/z 335 [M +
H]+.
6-(Thiophen-2-yl)indolo[1,2-c]quinazoline (4l).7b Petroleum
ether/ethyl acetate (15:1) as eluent; yellow solid (64 mg, 53%), mp
10-Chloro-6-propylindolo[1,2-c]quinazoline (4t). Petroleum
ether/ethyl acetate (20:1) as eluent; yellow solid (53 mg, 45%), mp
124−126 °C. 1H NMR (CDCl3, 400 MHz) δ 1.21 (t, J = 7.6 Hz, 3H),
2.00−2.10 (m, 2H), 3.30 (t, J = 7.6 Hz, 2H), 7.10 (s, 1H), 7.31 (d, J =
9.6 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.75 (m,
2H), 7.86 (d, J = 9.6 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ 13.9, 19.4, 38.6, 94.8, 115.9, 119.9, 120.0, 122.2,
122.7, 127.0, 127.3, 129.0, 129.3, 129.5, 131.6, 136.5, 138.9, 150.8.
HRMS (ESI) calcd for C18H16ClN2 [M + H]+ 295.0997, found
295.1025.
1
163−164 °C. H NMR (CDCl3, 400 MHz) δ 6.72−6.74 (m, 1H),
7.07−7.11 (m, 1H), 7.26−7.29 (m, 2H), 7.33−7.37 (m, 1H), 7.49−
7.57 (m, 3H), 7.65−7.66 (m, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.83−7.86
(m, 1H), 8.09−8.11 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 96.0,
114.8, 120.6, 120.7, 121.7, 122.7, 123.6, 127.5, 127.8, 128.0, 128.3,
129.1, 129.2, 130.4, 131.6, 135.3, 136.0, 139.0, 143.5. MS (ESI) m/z
301 [M + H]+.
(E)-6-Styrylindolo[1,2-c]quinazoline (4m).16a Petroleum ether/
ethyl acetate (40:1) as eluent; yellow solid (72 mg, 56%), mp 182−
2-Methoxy-6-phenylindolo[1,2-c]quinazoline (4u). Petroleum
ether/ethyl acetate (15:1) as eluent; yellow solid (91 mg, 70%), mp
1
184 °C. H NMR (CDCl3, 400 MHz) δ 7.21 (s, 1H), 7.34−7.38 (m,
G
DOI: 10.1021/acs.joc.5b02076
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
184−186 °C. 1H NMR (CDCl3, 400 MHz) δ 3.98 (s, 3H), 6.48 (d, J =
8.8 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 7.15 (dd, J = 2.4, 8.8 Hz, 1H),
7.25 (s, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.52 (d, J = 2.8 Hz, 1H), 7.59−
7.68 (m, 5H), 7.77−7.80 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ
55.7, 95.6, 104.9, 115.0, 117.3, 120.5, 121.45, 121.50, 123.3, 128.4,
129.3, 129.4, 130.2, 130.3, 131.7, 133.7, 135.2, 136.1, 147.3, 158.8.
HRMS (ESI) calcd for C22H17N2O [M + H]+ 325.1335, found
325.1365.
6-(4-Chlorophenyl)-2-methoxyindolo[1,2-c]quinazoline (4v). Pe-
troleum ether/ethyl acetate (15:1) as eluent; yellow solid (127 mg,
89%), mp 220−222 °C. 1H NMR (CDCl3, 400 MHz) δ 3.99 (s, 3H),
6.61 (d, J = 8.4 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 7.15 (dd, J = 2.4, 8.8
Hz, 1H), 7.26 (s, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 2.4 Hz,
1H), 7.60−7.66 (m, 4H), 7.76−7.81 (m, 2H); 13C NMR (CDCl3, 100
MHz) δ 55.7, 95.8, 104.9, 114.8, 117.4, 120.7, 121.5, 121.6, 123.5,
129.4, 129.6, 130.0, 130.3, 131.5, 133.5, 134.5, 135.1, 136.4, 146.1,
158.9. HRMS (ESI) calcd for C22H16ClN2O [M + H]+ 359.0946,
found 359.0978.
residue was purified by chromatography on silica gel to afford the
desired 11H-indolo[3,2-c]quinoline 5.
6-Phenyl-11H-indolo[3,2-c]quinoline (5a).9a Petroleum ether/
ethyl acetate (2:1) as eluent; white solid (95 mg, 81%), mp 248−
250 °C. 1H NMR (DMSO-d6, 400 MHz) δ 7.10−7.13 (m, 1H), 7.41−
7.45 (m, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.58−7.64 (m, 3H), 7.66−7.76
(m, 3H), 7.83 (dd, J = 1.2, 7.6 Hz, 2H), 8.13−8.15 (m, 1H), 8.59 (dd,
J = 1.2, 8.0 Hz, 1H), 12.92 (s, 1H); 13C NMR (DMSO-d6, 100 MHz)
δ 112.38, 112.43, 116.7, 120.7, 121.5, 122.2, 122.4, 125.8, 126.0, 128.8,
128.9, 129.28, 129.31, 129.8, 139.5, 141.2, 141.5, 145.4, 155.9. MS
(ESI) m/z 295 [M + H]+.
6-p-Tolyl-11H-indolo[3,2-c]quinoline (5b).9b Petroleum ether/
ethyl acetate (2:1) as eluent; white solid (80 mg, 65%), mp 282−
1
284 °C. H NMR (DMSO-d6, 400 MHz) δ 2.44 (s, 3H), 7.12 (t, J =
8.0 Hz, 1H), 7.39−7.44 (m, 3H), 7.59 (d, J = 7.6 Hz, 1H), 7.65−7.74
(m, 5H), 8.12 (d, J = 8.4 Hz, 1H), 8.57 (d, J = 8.0 Hz, 1H), 12.88 (s,
1H); 13C NMR (DMSO-d6, 100 MHz) δ 21.5, 112.3, 112.4, 116.7,
120.6, 121.6, 122.2, 122.4, 125.7, 125.9, 128.8, 129.29, 129.33, 129.8,
138.4, 138.7, 139.5, 141.5, 145.5, 156.0. MS (ESI) m/z 309 [M + H]+.
6-(4-Methoxyphenyl)-11H-indolo[3,2-c]quinoline (5c).9a Petrole-
um ether/ethyl acetate (1:1) as eluent; white solid (92 mg, 71%), mp
2-Chloro-6-phenylindolo[1,2-c]quinazoline (4w). Petroleum
ether/ethyl acetate (15:1) as eluent; yellow solid (97 mg, 74%), mp
1
243−245 °C. H NMR (DMSO-d6, 400 MHz) δ 6.29 (d, J = 8.8 Hz,
1
278−280 °C. H NMR (DMSO-d6, 400 MHz) δ 3.89 (s, 3H), 7.15−
1H), 7.00 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.59 (dd, J =
2.0, 8.4 Hz, 1H), 7.64−7.73 (m, 7H), 7.82 (d, J = 8.0 Hz, 1H), 8.45 (d,
J = 2.0 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 97.9, 114.8,
121.3, 122.2, 122.4, 123.1, 124.0, 128.6, 129.6, 129.69, 129.74, 130.3,
131.0, 131.6, 132.3, 133.9, 135.9, 137.9, 149.6. HRMS (ESI) calcd for
C21H14ClN2 [M + H]+ 329.0840, found 329.0861.
7.21 (m, 3H), 7.46 (t, J = 8.0 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.69−
7.83 (m, 5H), 8.13 (d, J = 8.4 Hz, 1H), 8.60 (d, J = 7.6 Hz, 1H), 13.17
(br s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 55.8, 112.5, 114.3,
116.7, 120.8, 121.7, 122.4, 122.5, 125.9, 126.0, 129.0, 129.8, 130.9,
133.6, 139.6, 141.6, 145.6, 155.8, 160.4 (one 13C signal was not
observed). MS (ESI) m/z 325 [M + H]+.
(E)-2-Chloro-6-styrylindolo[1,2-c]quinazoline (4x). Petroleum
ether/ethyl acetate (15:1) as eluent; yellow solid (113 mg, 80%),
mp 222−224 °C. 1H NMR (CDCl3, 400 MHz) δ 7.21 (s, 1H), 7.36−
7.51 (m, 6H), 7.69−7.75 (m, 4H), 7.84 (d, J = 8.0 Hz, 1H), 7.92 (d, J
= 15.6 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ 96.2, 115.0, 121.1, 121.4, 121.6, 122.2,
122.6, 123.7, 127.8, 129.0, 129.1, 129.3, 129.7, 130.4, 131.6, 132.4,
133.9, 135.5, 137.8, 139.7, 147.7. HRMS (ESI) calcd for C23H16ClN2
[M + H]+ 355.0997, found 355.1009.
6-(4-Chlorophenyl)-11H-indolo[3,2-c]quinoline (5d).9b Petroleum
ether/ethyl acetate (2:1) as eluent; white solid (79 mg, 60%), mp >
1
300 °C. H NMR (DMSO-d6, 400 MHz) δ 7.15 (t, J = 8.0 Hz, 1H),
7.43 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.65−7.75 (m, 5H),
7.85 (d, J = 8.4 Hz, 2H), 8.12 (d, J = 8.4 Hz, 1H), 8.56−8.58 (m, 1H),
12.92 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 112.2, 112.4, 116.7,
120.8, 121.4, 121.9, 122.4, 125.9, 126.2, 128.9, 129.0, 129.8, 131.2,
134.1, 139.5, 140.0, 141.5, 145.4, 154.5. MS (ESI) m/z 329 [M + H]+.
6-(Naphthalen-1-yl)-11H-indolo[3,2-c]quinoline (5e). Petroleum
ether/ethyl acetate (2:1) as eluent; white solid (85 mg, 62%), mp
Typical Procedure for the Synthesis of the Intermediate 3a.
To a tube containing a solution of 2-(2-bromophenyl)-1H-indole 1a
(109 mg, 0.4 mmol) in DMSO (1.5 mL) were added K2CO3 (110 mg,
0.8 mmol), CuI (7.6 mg, 0.04 mmol), L-proline (9.2 mg, 0.08 mmol),
benzaldehyde 2a (81 μL, 0.8 mmol), and 26% aqueous ammonia (0.4
mL) under a nitrogen atmosphere. Then, the tube was sealed, and the
mixture was stirred at 100 °C for 12 h. After being cooled to room
temperature, the reaction was quenched with saturated NH4Cl and
extracted with ethyl acetate. The combined organic layer was washed
with H2O and brine, and then dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure and the residue was
purified by chromatography on silica gel, eluting with petroleum
ether/ethyl acetate (15:1), to afford 3a (95 mg) as a yellow solid in
1
298−300 °C. H NMR (DMSO-d6, 400 MHz) δ 6.40 (d, J = 8.0 Hz,
1H), 6.79−6.83 (m, 1H), 7.23−7.32 (m, 2H), 7.37 (d, J = 8.4 Hz,
1H), 7.46−7.51 (m, 1H), 7.66−7.79 (m, 5H), 8.06 (d, J = 8.4 Hz,
1H), 8.13−8.16 (m, 2H), 8.61 (dd, J = 1.2, 8.0 Hz, 1H), 13.00 (s, 1H);
13C NMR (DMSO-d6, 100 MHz) δ 112.3, 114.1, 116.9, 120.7, 120.9,
122.0, 122.5, 125.67, 125.74, 126.1, 126.3, 126.6, 126.8, 126.9, 128.8,
129.0, 129.1, 129.8, 131.4, 133.6, 138.5, 139.5, 140.9, 145.5, 155.0.
HRMS (ESI) calcd for C25H17N2 [M + H]+ 345.1386, found 345.1389.
6-(Thiophen-2-yl)-11H-indolo[3,2-c]quinoline (5f). Petroleum
ether/ethyl acetate (3:1) as eluent; white solid (80 mg, 66%), mp
1
245−246 °C. H NMR (DMSO-d6, 400 MHz) δ 7.21−7.25 (m, 1H),
1
7.32−7.35 (m, 1H), 7.46−7.50 (m, 1H), 7.65−7.69 (m, 1H), 7.72−
7.76 (m, 2H), 7.81−7.85 (m, 2H), 8.09 (d, J = 8.4 Hz, 2H), 8.55−8.58
(m, 1H), 12.95 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 112.0,
112.5, 116.7, 120.8, 121.6, 121.9, 122.4, 126.0, 126.1, 127.9, 128.5,
128.8, 129.1, 129.5, 139.6, 141.8, 143.9, 145.1, 149.3. HRMS (ESI)
calcd for C19H13N2S [M + H]+ 301.0794, found 301.0798.
80% yield (mp: 205−206 °C): H NMR (CDCl3, 400 MHz) δ 4.55
(br s, 1H), 6.65−6.68 (m, 2H), 6.85−6.93 (m, 3H), 7.00−7.12 (m,
3H), 7.21 (m, 2H), 7.26−7.29 (m, 3H), 7.63 (d, J = 8.0 Hz, 1H), 7.74
(d, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 68.7, 95.9, 110.0,
115.5, 116.2, 120.0, 120.3, 120.5, 121.6, 124.2, 126.1, 128.7, 129.0,
129.5, 133.7, 135.3, 138.8, 140.7 (one 13C signal was not observed).
HRMS (ESI) calcd for C21H16N2Na [M + Na]+ 319.1206, found
319.1205.
(E)-6-Styryl-11H-indolo[3,2-c]quinoline (5g). Petroleum ether/
ethyl acetate (2:1) as eluent; white solid (77 mg, 60%), mp 206−
208 °C. 1H NMR (DMSO-d6, 400 MHz) δ 7.37−7.43 (m, 2H), 7.46−
7.54 (m, 3H), 7.63 (t, J = 7.6 Hz, 1H), 7.71−7.76 (m, 2H), 7.92 (d, J =
7.6 Hz, 2H), 8.14−8.26 (m, 3H), 8.47−8.53 (m, 2H), 12.83 (s, 1H);
13C NMR (DMSO-d6, 100 MHz) δ 112.4, 113.1, 116.8, 121.3, 122.1,
122.4, 122.7, 125.6, 125.7, 125.8, 128.1, 129.0, 129.2, 129.4, 129.6,
135.5, 136.8, 139.5, 141.4, 145.5, 151.1. HRMS (ESI) calcd for
C23H17N2 [M + H]+ 321.1386, found 321.1391.
6-Propyl-11H-indolo[3,2-c]quinoline (5h). Petroleum ether/ethyl
acetate (1:1) as eluent; white solid (48 mg, 46%), mp 206−208 °C. 1H
NMR (DMSO-d6, 400 MHz) δ 1.08 (t, J = 7.2 Hz, 3H), 1.87−1.96
(m, 2H), 3.36 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 8.0 Hz, 1H), 7.48 (t, J =
8.0 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.67−7.74 (m, 2H), 8.05 (d, J =
8.4 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 8.49 (d, J = 8.0 Hz, 1H), 12.80
General Procedure for the Synthesis of 11H-Indolo[3,2-
c]quinolines 5. To a tube containing a solution of 2-(2-bromoaryl)-
1H-indole 1 (0.4 mmol) in DMSO (1.5 mL) were added K2CO3 (0.8
mmol), CuI (0.04 mmol), L-proline (0.08 mmol), aldehyde 2 (0.8
mmol), and 26% aqueous ammonia (0.4 mL) under a nitrogen
atmosphere. Then, the tube was sealed, and the mixture was stirred at
100 °C for 12 h. After the pH value of the resulting mixture was
adjusted to a range of 5−6 by addition of HCl (6 M, ca. 0.7 mL), the
tube was opened to air and the reaction mixture was stirred at 120 °C
for another 8 h. Upon completion, the reaction was quenched with
saturated NaHCO3 and extracted with CHCl3. The combined organic
layer was washed with H2O and brine, and then dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure and the
H
DOI: 10.1021/acs.joc.5b02076
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The Journal of Organic Chemistry
Article
(br s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 14.5, 21.6, 39.4, 112.4,
112.8, 116.6, 121.2, 121.9, 122.2, 122.3, 125.4, 125.5, 128.6, 128.9,
139.3, 140.8, 144.9, 158.3. HRMS (ESI) calcd for C18H17N2 [M + H]+
261.1386, found 261.1386.
Typical Procedure for the Synthesis of Compound 6. To a
tube containing a solution of 2-(2-bromophenyl)-1H-indole 1a (109
mg, 0.4 mmol) in DMSO (1.5 mL) were added K2CO3 (110 mg, 0.8
mmol), CuI (7.6 mg, 0.04 mmol), L-proline (9.2 mg, 0.08 mmol), and
26% aqueous ammonia (0.4 mL) under a nitrogen atmosphere. Then,
the tube was sealed, and the mixture was stirred at 100 °C for 1 h.
After being cooled to room temperature, the reaction was quenched
with saturated NH4Cl and extracted with ethyl acetate. The combined
organic layer was washed with H2O and brine, and then dried over
anhydrous Na2SO4. The solvent was removed under reduced pressure
and the residue was purified by chromatography on silica gel, eluting
with petroleum ether/ethyl acetate (8:1), to afford 6 (50 mg) as a
11H-Indolo[3,2-c]quinoline (5i).9a Petroleum ether/ethyl acetate
1
(1:1) as eluent; white solid (28 mg, 32%), mp > 300 °C. H NMR
(DMSO-d6, 400 MHz) δ 7.34 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz,
1H), 7.68−7.77 (m, 3H), 8.15 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 8.0 Hz,
1H), 8.55 (d, J = 7.2 Hz, 1H), 9.62 (s, 1H), 12.85 (br s, 1H); 13C
NMR (DMSO-d6, 100 MHz) δ 112.4, 114.7, 117.5, 120.6, 121.1,
122.3, 122.7, 126.1, 126.3, 128.6, 129.7, 139.3, 140.4, 145.1, 145.5. MS
(ESI) m/z 219 [M + H]+.
8-Chloro-6-phenyl-11H-indolo[3,2-c]quinoline (5j). Petroleum
ether/ethyl acetate (3:1) as eluent; white solid (87 mg, 66%); mp >
300 °C. 1H NMR (DMSO-d6, 400 MHz) δ 7.37−7.42 (m, 2H), 7.61−
7.63 (m, 3H), 7.66−7.70 (m, 2H), 7.73−7.79 (m, 3H), 8.11 (d, J = 8.0
Hz, 1H), 8.53 (d, J = 7.6 Hz, 1H), 13.04 (s, 1H); 13C NMR (DMSO-
d6, 100 MHz) δ 111.7, 113.9, 116.6, 120.6, 122.4, 123.4, 124.9, 125.6,
126.3, 128.9, 129.2, 129.3, 129.5, 129.8, 137.9, 140.8, 142.2, 145.6,
155.8. HRMS (ESI) calcd for C21H14ClN2 [M + H]+ 329.0840, found
329.0840.
1
brown solid in 60% yield (mp: 146−148 °C): H NMR (CDCl3, 400
MHz)16b δ 4.12 (br s, 2H), 6.75 (s, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.89
(t, J = 7.6 Hz, 1H), 7.15−7.25 (m, 3H), 7.42 (t, J = 7.6 Hz, 2H), 7.67
(d, J = 8.0 Hz, 1H), 8.49 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ
101.6, 110.9, 116.6, 118.8, 119.1, 120.2, 120.5, 122.2, 128.9, 129.1,
129.3, 135.9, 136.2, 144.1. MS (ESI) m/z 209 [M + H]+.
Typical Procedure for the Selective Synthesis of Compound
5a from 3a. To a solution of compound 3a (89 mg, 0.3 mmol) in
DMSO (1 mL) were added CuI (5.7 mg, 0.03 mmol) and HCl (0.04
mL, 0.5 M) under air, and then the mixture was stirred at 120 °C for 8
h. Next, brine and CHCl3 were added into the reaction mixture. After
extraction, the combined organic layer was dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure and the
residue was purified by chromatography on silica gel, eluting with
petroleum ether/ethyl acetate (2:1), to afford 5a (83 mg) as a white
solid in 94% yield.
2-Methoxy-6-phenyl-11H-indolo[3,2-c]quinoline (5k). Petroleum
ether/ethyl acetate (2:1) as eluent; white solid (98 mg, 76%), mp
1
249−252 °C. H NMR (DMSO-d6, 400 MHz) δ 3.99 (s, 3H), 7.08−
7.12 (m, 1H), 7.37 (dd, J = 2.8, 9.2 Hz, 1H), 7.42 (t, J = 8.4 Hz, 1H),
7.51 (d, J = 8.4 Hz, 1H), 7.56−7.62 (m, 3H), 7.71 (d, J = 8.4 Hz, 1H),
7.80 (d, J = 8.0 Hz, 2H), 8.00−8.04 (m, 2H), 12.74 (s, 1H); 13C NMR
(DMSO-d6, 100 MHz) δ 56.0, 101.5, 112.3, 112.4, 117.3, 120.3, 120.5,
121.5, 122.1, 125.8, 128.8, 129.1, 129.3, 131.3, 139.5, 140.9, 141.1,
141.3, 153.4, 157.4. HRMS (ESI) calcd for C22H17N2O [M + H]+
325.1335, found 325.1323.
Typical Procedure for the Synthesis of Intermediate 7 from
3a. To a tube containing a solution of compound 3a (89 mg, 0.3
mmol) in DMSO (1 mL) was added HCl (0.04 mL, 0.5 M) under a
nitrogen atmosphere. Then, the tube was sealed, and the mixture was
stirred at 120 °C for 1 h. Next, brine and CHCl3 were added into the
reaction mixture. After extraction, the combined organic layer was
dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure and the residue was purified by flash chromatography
on silica gel, eluting with petroleum ether/dichloromethane (1:1), to
afford 7 (75.3 mg) as a light yellow solid in 85% yield (mp: 209−210
6-(4-Chlorophenyl)-2-methoxy-11H-indolo[3,2-c]quinoline (5l).
Petroleum ether/ethyl acetate (3:1) as eluent; white solid (88 mg,
61%), mp > 300 °C. 1H NMR (DMSO-d6, 400 MHz) δ 3.98 (s, 3H),
7.12−7.16 (m, 1H), 7.37 (dd, J = 2.8, 9.2 Hz, 1H), 7.41−7.45 (m,
1H), 7.53 (d, J = 8.4 Hz, 1H), 7.64−7.66 (m, 2H), 7.72 (d, J = 8.4 Hz,
1H), 7.82−7.84 (m, 2H), 7.99−8.03 (m, 2H), 12.77 (s, 1H); 13C
NMR (DMSO-d6, 100 MHz) δ 56.0, 101.5, 112.2, 112.4, 117.4, 120.4,
120.7, 121.5, 121.9, 125.9, 128.9, 131.2, 131.3, 133.9, 139.5, 140.0,
140.9, 141.1, 152.0, 157.5. HRMS (ESI) calcd for C22H16ClN2O [M +
H]+ 359.0946, found 359.0935.
1
°C): H NMR (CDCl3, 400 MHz) δ 4.35 (s, 1H), 6.23 (s, 1H), 6.55
(d, J = 8.0 Hz, 1H), 6.74 (dt, J = 0.8, 7.6 Hz, 1H), 6.92−6.98 (m, 2H),
7.04−7.08 (m, 1H), 7.10−7.15 (m, 1H), 7.27−7.32 (m, 2H), 7.33−
7.37 (m, 3H), 7.49−7.52 (m, 2H), 8.26 (s, 1H); 13C NMR (CDCl3,
100 MHz) δ 57.7, 109.5, 110.8, 113.1, 113.6, 117.3, 118.8, 120.0,
120.1, 122.2, 126.1, 127.4, 127.9, 128.70, 128.73, 130.6, 137.2, 143.2,
144.8. HRMS (ESI) calcd for C21H17N2 [M + H]+ 297.1386, found
297.1367.
2-Chloro-6-phenyl-11H-indolo[3,2-c]quinoline (5m). Petroleum
ether/ethyl acetate (3:1) as eluent; white solid (93 mg, 71%), mp >
1
300 °C. H NMR (DMSO-d6, 400 MHz) δ 7.13 (t, J = 7.2 Hz, 1H),
7.43−7.50 (m, 2H), 7.61−7.62 (m, 3H), 7.71−7.74 (m, 2H), 7.79−
7.81 (m, 2H), 8.11 (d, J = 8.8 Hz, 1H), 8.67 (d, J = 2.0 Hz, 1H), 12.94
(s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 112.5, 113.0, 117.5, 120.9,
121.6, 121.8, 126.2, 128.9, 129.2, 129.3, 129.5, 130.2, 131.9, 139.5,
140.5, 140.8, 143.8, 156.3 (one 13C signal was not observed). HRMS
(ESI) calcd for C21H14ClN2 [M + H]+ 329.0840, found 329.0833.
2-Chloro-6-(4-methoxyphenyl)-11H-indolo[3,2-c]quinoline (5n).
Petroleum ether/ethyl acetate (1:1) as eluent; white solid (72 mg,
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02076.
1
Table S1 and H and 13C NMR spectra of compounds
1
50%), mp 230−232 °C. H NMR (DMSO-d6, 400 MHz) δ 3.88 (s,
4a−4x, 3a, 5a−5o, 6, and 7 (PDF)
3H), 7.14−7.18 (m, 3H), 7.43−7.47 (m, 1H), 7.63 (d, J = 8.4 Hz,
1H), 7.71−7.74 (m, 2H), 7.76−7.80 (m, 2H), 8.09 (d, J = 8.8 Hz,
1H), 8.65 (d, J = 2.4 Hz, 1H), 12.91 (s, 1H); 13C NMR (DMSO-d6,
100 MHz) δ 55.7, 112.5, 112.9, 114.2, 117.4, 120.9, 121.4, 121.7,
121.9, 126.2, 129.1, 130.0, 130.8, 131.7, 133.0, 139.5, 140.5, 143.7,
156.1, 160.4. HRMS (ESI) calcd for C22H16ClN2O [M + H]+
359.0946, found 359.0946.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: shguo@htu.cn (S.G.).
*E-mail: xuesen.fan@htu.cn (X.F.).
■
Notes
(E)-2-Chloro-6-styryl-11H-indolo[3,2-c]quinoline (5o). Petroleum
ether/ethyl acetate (2:1) as eluent; white solid (75 mg, 53%), mp
The authors declare no competing financial interest.
1
286−288 °C. H NMR (DMSO-d6, 400 MHz) δ 7.40−7.54 (m, 5H),
ACKNOWLEDGMENTS
■
7.66−7.73 (m, 2H), 7.89 (d, J = 8.0 Hz, 2H), 8.07−8.14 (m, 3H), 8.43
(d, J = 8.4 Hz, 1H), 8.57 (s, 1H), 12.81 (s, 1H); 13C NMR (DMSO-d6,
100 MHz) δ 112.5, 113.5, 117.5, 121.48, 121.51, 121.8, 122.8, 125.3,
126.1, 128.1, 129.2, 129.36, 129.39, 129.7, 131.5, 135.9, 136.6, 139.5,
140.4, 143.7, 151.4. HRMS (ESI) calcd for C23H16ClN2 [M + H]+
355.0997, found 355.0988.
This work was financially supported by the National Natural
Science Foundation of China (Grants 21202040 and
21572047), Project Funded by China Postdoctoral Science
Foundation (2014M552007 and 2015T80771), the Program
for Innovative Research Team in Science and Technology in
I
DOI: 10.1021/acs.joc.5b02076
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The Journal of Organic Chemistry
Article
(14) (a) Uchuskin, M. G.; Pilipenko, A. S.; Serdyuk, O. V.; Trushkov,
I. V.; Butin, A. V. Org. Biomol. Chem. 2012, 10, 7262. (b) Gengan, R.
M.; Pandian, P.; Kumarsamy, C.; Mohan, P. S. Molecules 2010, 15,
3171. (c) Kumar, R. N.; Suresh, T.; Mohan, P. S. Tetrahedron Lett.
2002, 43, 3327.
(15) Liu, Y.; McWhorter, W. W. J. Am. Chem. Soc. 2003, 125, 4240.
(16) (a) Xu, M.; Xu, K.; Wang, S.; Yao, Z.-J. Tetrahedron Lett. 2013,
54, 4675. (b) Billimoria, A. D.; Cava, M. P. J. Org. Chem. 1994, 59,
6777.
University of Henan Province (15IRTSTHN003), and PCSIRT
(IRT1061).
REFERENCES
■
(1) (a) Blackman, A. J.; Hambley, T. W.; Picker, K.; Taylor, W. C.;
Thirasasana, N. Tetrahedron Lett. 1987, 28, 5561. (b) Pousset, J.-L.;
Martin, M.-T.; Jossang, A.; Bodo, B. Phytochemistry 1995, 39, 735.
(c) Van Miert, S.; Hostyn, S.; Maes, B. U. W.; Cimanga, K.; Brun, R.;
́ ̀
Kaiser, M.; Matyus, P.; Dommisse, R.; Lemiere, G.; Vlietinck, A.;
Pieters, L. J. Nat. Prod. 2005, 68, 674. (d) Chen, Y.-L.; Chung, C.-H.;
Chen, I.-L.; Chen, P.-H.; Jeng, H.-Y. Bioorg. Med. Chem. 2002, 10,
2705. (e) Lu, C.-M.; Chen, Y.-L.; Chen, H.-L.; Chen, C.-A.; Lu, P.-J.;
Yang, C.-N.; Tzeng, C.-C. Bioorg. Med. Chem. 2010, 18, 1948.
(2) (a) Rohini, R.; Reddy, P. M.; Shanker, K.; Hu, A.; Ravinder, V.
Eur. J. Med. Chem. 2010, 45, 1200. (b) Rohini, R.; Shanker, K.; Reddy,
P. M.; Sekhar, V. C.; Ravinder, V. Arch. Pharm. 2009, 342, 533.
(c) Rohini, R.; Reddy, P. M.; Shanker, K.; Hu, A.; Ravinder, V. J. Braz.
Chem. Soc. 2010, 21, 897.
(3) (a) Aroonkit, P.; Thongsornkleeb, C.; Tummatorn, J.; Krajangsri,
S.; Mungthin, M.; Ruchirawat, S. Eur. J. Med. Chem. 2015, 94, 56.
(b) Wang, N.; Wicht, K. J.; Imai, K.; Wang, M.-Q.; Ngoc, T. A.;
Kiguchi, R.; Kaiser, M.; Egan, T. J.; Inokuchi, T. Bioorg. Med. Chem.
2014, 22, 2629. (c) Whittell, L. R.; Batty, K. T.; Wong, R. P. M.;
Bolitho, E. M.; Fox, S. A.; Davis, T. M. E.; Murray, P. E. Bioorg. Med.
́
Chem. 2011, 19, 7519. (d) Wang, L.; Switalska, M.; Wang, N.; Du, Z.-
J.; Fukumoto, Y.; Diep, N. K.; Kiguchi, R.; Nokami, J.; Wietrzyk, J.;
́
Inokuchi, T. Molecules 2014, 19, 19021. (e) Wang, N.; Switalska, M.;
Wu, M.-Y.; Imai, K.; Ngoc, T. A.; Pang, C.-Q.; Wang, L.; Wietrzyk, J.;
Inokuchi, T. Eur. J. Med. Chem. 2014, 78, 314.
(4) Falke, H.; Chaikuad, A.; Becker, A.; Loaec, N.; Lozach, O.; Abu
̈
Jhaisha, S.; Becker, W.; Jones, P. G.; Preu, L.; Baumann, K.; Knapp, S.;
Meijer, L.; Kunick, C. J. Med. Chem. 2015, 58, 3131.
(5) Molina, A.; Vaquero, J. J.; Garcia-Navio, J. L.; Alvarez-Builla, J.; de
Pascual-Teresa, B.; Gago, F.; Rodrigo, M. M.; Ballesteros, M. J. Org.
Chem. 1996, 61, 5587.
(6) (a) Kiang, A. K.; Mann, F. G.; Prior, A. F.; Topham, A. J. Chem.
Soc. 1956, 1319. (b) Frer
Tetrahedron 2003, 59, 773.
̀ ́
e, S.; Thiery, V.; Bailly, C.; Besson, T.
(7) (a) Sang, P.; Xie, Y.; Zou, J.; Zhang, Y. Org. Lett. 2012, 14, 3894.
(b) Liu, Q.; Yang, H.; Jiang, Y.; Zhao, Y.; Fu, H. RSC Adv. 2013, 3,
15636. (c) Zhang, H.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H. Eur. J. Org.
Chem. 2012, 2012, 6798.
(8) (a) Wang, Y.; Zhu, Q. Adv. Synth. Catal. 2012, 354, 1902.
(b) Nanjo, T.; Yamamoto, S.; Tsukano, C.; Takemoto, Y. Org. Lett.
2013, 15, 3754.
(9) (a) Xu, M.; Hou, Q.; Wang, S.; Wang, H.; Yao, Z.-J. Synthesis
2011, 2011, 626. (b) Abbiati, G.; Arcadi, A.; Chiarini, M.; Marinelli, F.;
Pietropaolo, E.; Rossi, E. Org. Biomol. Chem. 2012, 10, 7801.
(c) Cacchi, S.; Fabrizi, G.; Pace, P.; Marinelli, F. Synlett 1999, 1999,
620.
(10) (a) Molina, P.; Alajarin, M.; Vidal, A. Tetrahedron 1990, 46,
1063. (b) Molina, P.; Alajarin, M.; Vidal, A. Tetrahedron Lett. 1989, 30,
2847.
(11) (a) Okano, K.; Tokuyama, H.; Fukuyama, T. Chem. Commun.
2014, 50, 13650. (b) Beletskaya, I. P.; Cheprakov, A. V. Organo-
metallics 2012, 31, 7753. (c) Wang, Y.; Ling, J.; Zhang, Y.; Zhang, A.;
Yao, Q. Eur. J. Org. Chem. 2015, 2015, 4153 and references cited
therein. (d) Wang, D.; Cai, Q.; Ding, K. Adv. Synth. Catal. 2009, 351,
1722. (e) Xia, N.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 337.
(12) (a) Guo, S.; Wang, J.; Fan, X.; Zhang, X.; Guo, D. J. Org. Chem.
2013, 78, 3262. (b) Fan, X.; Li, B.; Guo, S.; Wang, Y.; Zhang, X. Chem.
- Asian J. 2014, 9, 739. (c) Zhang, X.-Y.; Guo, X.-J.; Fan, X.-S. Chem. -
Asian J. 2015, 10, 106. (d) Fan, X.-S.; Zhang, J.; Li, B.; Zhang, X.-Y.
Chem. - Asian J. 2015, 10, 1281. (e) Li, B.; Guo, C.; Fan, X.; Zhang, J.;
Zhang, X. Tetrahedron Lett. 2014, 55, 5944. (f) Guo, S.; Li, Y.; Tao, L.;
Zhang, W.; Fan, X. RSC Adv. 2014, 4, 59289. (g) Guo, S.; Wang, J.; Li,
Y.; Fan, X. Tetrahedron 2014, 70, 2383. (h) Li, B.; Guo, S.; Zhang, J.;
Zhang, X.; Fan, X. J. Org. Chem. 2015, 80, 5444.
(13) For details, please see Table S1 in the Supporting Information.
J
DOI: 10.1021/acs.joc.5b02076
J. Org. Chem. XXXX, XXX, XXX−XXX