Access to Indole-Fused Polyheterocycles via Pd-Catalyzed Base-Free Intramolecular Cross Dehydrogenative Coupling

Article abstract of DOI:10.1021/acs.joc.6b02160

A base-free process to access indole-fused polyheterocycles via a highly efficient and atom-economic palladium-catalyzed intramolecular cross dehydrogenetive coupling (CDC) reaction of 4-aniline substituted coumarins, quinolinones, and pyrones has been developed. A wide range of indolo[3,2-c]coumarins, indolo[3,2-c]quinolinones, and indolo[3,2-c]pyrones can be facilely afforded in good to excellent yields (up to 99%).

Full text of DOI:10.1021/acs.joc.6b02160

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Note
Access to Indole-Fused Polyheterocycles via Pd-Catalyzed
Base-Free Intramolecular Cross Dehydrogenative Coupling
Chao Cheng, Wen-Wen Chen, Bin Xu, and Ming-Hua Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02160 • Publication Date (Web): 21 Oct 2016
Downloaded from http://pubs.acs.org on October 22, 2016
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Access to Indole-Fused Polyheterocycles via Pd-Catalyzed Base-
Free Intramolecular Cross Dehydrogenative Coupling
Chao Cheng,a,b Wen-Wen Chen,*,a Bin Xub and Ming-Hua Xu*,a
aState Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai 201203, China
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bDepartment of Chemistry, Innovative Drug Research Center, Shanghai University,
Shanghai 200444, China
E-mail: wenwen@simm.ac.cn, xumh@simm.ac.cn
Abstract
A base-free process to access indole-fused polyheterocycles via a highly efficient and
atom-economic palladium-catalyzed intramolecular cross dehydrogenetive coupling
(CDC) reaction of 4-aniline substituted coumarins, quinolinones and pyrones has been
developed. A wide range of indolo[3,2-c]coumarins, indolo[3,2-c]quinolinones and
indolo[3,2-c]pyrones can be facilely afforded in good to excellent yields (up to 99%).
Indole and coumarin skeletons are recognized as two important classes of structural
motifs distributed in a number of natural products which exhibit a broad range of
biological and pharmaceutical activities. Design of new molecules by combination of
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different pharmacophores is of great interest in medicinal chemistry and drug discovery.
Indolo[3,2-c]coumarin with fused cyclic ring system containing both indole and
coumarin components belongs to an intriguing family of structurally unique
polyheterocycles having interesting biological profile such as anti-tumor angiogenesis
and estrogenic activity.1 Accordingly, there have been significant interests in
developing useful methodologies for construction of this fused polycyclic skeleton.
Among them, the most conventional method is the intramolecular thermal cyclization
of 4-azido-3-aryl coumarins to form the indole ring under harsh reaction conditions
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o
(150 C), which inevitably requires the use of highly toxic NaN3 to synthesize the
cyclization precursor (Scheme 1, right cutoff a).2 Alternatively, 4-nitro-3-aryl
coumarins can be employed as substrates for reductive cyclization via microwave-
o
assisted Cadogan reaction at high temperature (200 C) (Scheme 1, left cutoff a).3 In
recent years, several new methods mediated by transition-metal salts or complexes have
been successfully developed. For example, Hong reported an intramolecular Heck
cyclization approach to construct the indole ring from pre-bromo-functionalized 4-
aniline coumarins utilizing a special cobalt-sandwich diphosphine chelated palladium
catalyst (cutoff b).4 Thasana and co-workers disclosed a Cu(I)-mediated microwave-
assisted intramolecular lactonization method capable of producing indolo[3,2-
c]coumarins (cutoff c),5 while Larock et al. developed a Pd-catalyzed lactonization via
CO insertion using an acetoxy group as the nucleophile (cutoff d).6 Most recently, an
efficient Pd-catalyzed intramolecular oxidative C-H/C-H coupling protocol was
realized by Lan and You with indole-3-carboxylates as reaction substrates (cutoff e).7
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While these methods are useful for synthesis of valuable indolo[3,2-c]coumarins, they
mainly rely on the manipulation of prefunctionalized substrate and overall require
multi-step transformations. Moreover, most of them suffer from harsh reaction
conditions, limited substrate scope, poor functional-group compatibility and require
protection of indole NH. From the perspective of atom-economy and step-efficiency,
an ideal synthesis would involve an efficient ring construction via direct C-H coupling
without prefunctionalization and N-protection.
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In the past few years, the cross dehydrogenative coupling (CDC) protocol has
received considerable attention as it allows C-C bond formation by directly connecting
two different C-H bonds.8 Recently, we reported the development of a Pd-catalyzed
efficient intramolecular CDC approach for facile construction of coumestans from
readily available 4-aryloxy coumarins.9 Our preliminary study indicates that this
strategy is also applicable for the synthesis of indolo[3,2-c]coumarins, however, the
reaction yield varies depending on the substitution pattern of substrates. Continuing our
interest in the nitrogen-containing polyheterocycles10 for a drug discovery program, we
envisioned to develop a more general synthetic approach toward structurally diverse
indole-fused polycyclic motifs. Herein we disclose our success on the improvement of
this promising intramolecular CDC reaction to construct indolo[3,2-c]coumarins with
a very broad substrate scope in excellent yields. Notably, this method also provides
efficient access to other interesting units including indole-quinolinones and indole-
pyrones (Scheme 1).
Scheme 1. Synthetic Routes of Indolo[3,2-c]coumarins through Different Cutoffs.
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Previous work:
N3
O
NO2
O
R2
R2
cutoff a
e
R1
R1
O
O
PPh3 or P(EtO)3
MW, 200 o
EtOH, 150 oC
60-89%
cutoff a
a
C
R2
71-92%
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O
R3
N
R2
H
cutoff b
cutoff e
O
HN
cat. [Pd], DABCO
cat. [Pd], [O]
R1
Br
b
dioxane, 100 o
73-79%
C
base, DMA, 120 oC
52-86%
d
R1
R2
R = Me, Bn
N
O
O
R
O
O
c
R2 = H. Me
[Cu], base
MW, 200-300 oC
63-81%
cat. [Pd], base
CO (1 atm), 60-80 o
75%
C
cutoff c
cutoff d
COOR
I
AcO
N
N
X
Me
Me
R = H, Me; X = Cl, Br
This work:
H
No prefunctionalization
R2
R2
HN
X
N-Protecting free
HN
cat. Pd(OAc)2
air or AgOAc
R1
H
O
Base-free conditions
R1
AcOH, 100 o
C
Broad substrate scope, high yield
Atom- and step-economy
O
X
up to 99% yield
X = O, NH
Although the previous standard conditions for synthesis of coumestans, with
Pd(OAc)2 as the catalyst, AgOAc as the oxidant, CsOAc as the additive, and PivOH as
the solvent, is applicable to the intramolecular dehydrogenative coupling of 4-aniline
coumarin 1a to provide indolo[3,2-c]coumarin 2a (Table 1, entry 1), the yields for other
substituted substrates are less satisfactory. To improve the reaction generality, we thus
commenced our further optimization studies to determine the influence of various
reaction parameters. The results are summarized in Table 1. Intriguingly, the reaction
proceeded smoothly under similar conditions in the absence of CsOAc, giving
indolo[3,2-c]coumarin 2a in a comparable 91% yield (entry 2). To our knowledge, base
is typically essential in the CDC reactions,11 and such avoidable use of base additive
has rarely been reported.12 To our delight, changing the solvent from PivOH to
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inexpensive AcOH could lead to a further increase of the reaction yield to 95% (entry
3). Unfortunately, lowering the amount of AgOAc oxidant (1.5 equiv) or the loading of
palladium catalyst (5 mol%) resulted in much lower conversions (entries 4 and 5).
Replacing AgOAc with other oxidants such as K2S2O8 and Cu(OAc)2 failed to furnish
better results, only providing moderate yields (entries 6 and 7). Notably, we were very
pleased to find that air could be employed as effective oxidant in promoting the reaction.
Under an air balloon with no use of any other oxidant, the desired product 2a was
obtained in 86% yield after 48 h (entry 8). Most gratifyingly, the reaction could be
greatly accelerated and the yield could be significantly improved to 95% with increase
of the catalyst loading to 15 mol % (entry 9).
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Table 1. Optimization Studies.a
entry
1
oxidant
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
K2S2O8
Cu(OAc)2
air
base
solvent T (h) yield (%)b
CsOAc PivOH
6
92
91
95
72d
72d
86
84
86
95
2
--
--
--
--
--
--
--
--
PivOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
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10
24
24
24
24
48
28
3
4c
5e
6f
7f
8
9g
air
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aReaction conditions: 1a (0.20 mmol), Pd(OAc)2 (10 mol %), oxidant (2 equiv) and
base (2 equiv) in 1.0 mL of solvent at 100 °C unless otherwise noted. bIsolated yields.
c1.5 equiv of AgOAc. dNMR yield. e5 mol % of Pd(OAc)2. f3 equiv of oxidant. g15 mol %
of Pd(OAc)2.
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With these optimized conditions in hand, we set out to evaluate the substrate scope
of the reaction (Scheme 2). The substituents on the aniline moiety were first
investigated. Substrates with electron-donating (Me, OMe) or electron-withdrawing (F)
groups at the C2´, C3´, C4´, C5´ positions all underwent efficient intramolecular
dehydrogenative coupling under the air conditions (Method A), giving the
corresponding indolo[3,2-c]coumarin products 2b-2n in mostly excellent yields.
Although the presence of a meta-substituent would lead to a mixture of two
regioisomers (2i and 2j, 2k and 2l, 2m and 2n) with a preference for the less hindered
products (2i, 2k, and 2m), the total yields remain high (91-95% yield).13 However, the
use of the same conditions for substrate with a methyl group at the C6 position led to a
dramatic drop in product yield (2o, 17%), suggesting a significant impact of substitution
on the coumarin moiety. Fortunately, we found that the transformation proceeded well
in the presence of AgOAc under the conditions shown in entry 3 of Table 1 (Method
B), giving 2o in 95% yield. Moreover, the reaction time could be shortened to 12 h. As
illustrated in Scheme 2, a variety of substituents were well tolerated, regardless of their
position on the phenyl ring of coumarin. The desired products 2p-2v could be easily
accessed in satisfactory yields (86-99%). Notably, compounds 1p and 1r bearing
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substituents on both the aniline and coumarin moieties were found to be equally suitable
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substrates, furnishing products 2p and 2r in 94% and 87% yields.
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Scheme 2. Substrate Scope of 4-Ayrlamino Coumarins.a
3'
4'
R2
2'
R2
5'
HN
Method A: Pd(OAc)2 (15 mol %), air, AcOH, 100 o
C
HN
6'
5
8
6
R1
Method B: Pd(OAc)2 (10 mol %), AgOAc (2 equiv), AcOH, 100 o
C
R1
7
O
O
O
O
1
2
Me
MeO
HN
Me
HN
O
HN
HN
O
Me
O
O
O
O
O
O
2a
2b
2c
2d
Method A: 93%, 24 h
Method A: 95%, 28 h
Method B: 95%, 10 h
Method A: 99%, 24 h
Method A: 96%, 24 h
OMe
HN
HN
OMe
F
HN
HN
OMe
O
O
O
O
O
O
O
O
2e
2f
2g
Method A: 92%, 28 h
2h
Method A: 91%, 24 h
Method A: 90%, 24 h
Method A: 76%, 50 h
Method B: 71%, 30 h
Me
OMe
+
F
HN
HN
HN
HN
HN
HN
+
+
Me
OMe
F
O
O
O
O
O
O
O
O
O
O
O
O
2i
2j
2k
2l
2m
2n
7.5 : 1
Method A: 91%, 28 h
2.4 : 1
Method A: 95%, 24 h
2.1 : 1
Method A: 92%, 28 h
Method B: 93%, 18 h
Me
MeO
HN
HN
HN
HN
Me
F
Me
Me
O
O
O
O
O
O
O
O
Me
2o
2p
Method B: 94%, 12 h
2q
2r
Method A: 17%, 48 h
Method B: 95%, 12 h
Method B: 99%, 23 h
Method B: 87%, 12 h
HN
HN
Me
HN
HN
Me
O
O
Me
O
O
MeO
O
O
F
O
O
Me
2s
Method B: 94%, 26 h
2t
Method B: 86%, 19 h
2u
Method B: 88%, 12 h
2v
Method B: 96%, 26 h
Reaction conditions for Method A: (0.20 mmol) and Pd(OAc)2 (15 mol %) in 1.0 mL of AcOH at 100 oC; Method B: (0.20
a
1
1
mmol), Pd(OAc)2 (10 mol %) and AgOAc (0.40 mmol, 2 equiv) in 1.0 mL of AcOH at 100 oC.
To demonstrate the synthetic generality of this intramolecular dehydrogenative
coupling protocol, we next turned our attention to the construction of other indole-fused
polycyclic ring system. Indolo[3,2-c]quinolinones14 and indolo[3,2-c]pyrones15 are
important scaffolds that often exhibit interesting bioactivities, they also serve as useful
building blocks for natural products syntheses.16 The key strategies for the synthesis of
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indolo[3,2-c]quinolinones include the use of Fischer indolization14a to construct the
indole ring, and intramolecular arylation,17 Heck cyclization18 or lactamization19 to
assemble the quinolinone ring. In contrast, the synthetic approaches for indolo[3,2-
c]pyrones are much less documented and only limited to the way of pyrone ring
formation.15,20 Not surprisingly, most of these existing protocols for indolo[3,2-
c]quinolinones and indolo[3,2-c]pyrones rely on the prefunctionalized substrates and
offer limited scope. Inspired by the above success, we anticipated that this CDC strategy
may be equally applicable to the synthesis of indolo[3,2-c]quinolinones and indolo[3,2-
c]pyrones.
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To our delight, the reactions of readily available 4-aniline quinolinones 3 in the
presence of AgOAc under the above latter conditions led to the formation of indolo[3,2-
c]quinolinone products 4a-f in very good yields (87-97%) (Scheme 3). Substrates with
different substitution patterns on the benzene rings of both the aniline and quinolinone
moieties can be efficiently converted into the corresponding products 4b-f. In particular,
the chloro-substituent on either ring was tolerated (4c and 4e), leaving a space for
further structural elaboration. It is also worth noting that protecting-group-free
synthesis is challenging and direct access to such N-unprotected indolo[3,2-
c]quinolinones are difficult using existing methods.16b,17,18,21
Scheme 3. Synthesis of Indolo[3,2-c]quinolinones.a
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Similarly, 4-aniline pyrone can be subjected to efficient intramolecular cross
dehydrogenative coupling (6a, 85% yield) under the palladium/AgOAc catalytic
system (Scheme 4). The variant of substituents such as Me, OMe, F and Ph on both the
aniline and pyrone moieties can tolerate the reaction conditions well. Pleasingly, a
range of high value, tricyclic indolo[3,2-c]pyrone products (6b-6f) can be easily
prepared in good yields (76-94%).
Scheme 4. Synthesis of Indolo[3,2-c]pyrones.a
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In summary, we have developed an efficient Pd-catalyzed intramolecular cross
dehydrogenative coupling reaction of readily available anilines for the direct synthesis
of indole-fused polyheterocycles. The base-free mild catalytic system is capable of
tolerating a broad scope of diversely substituted substrate, allowing facile access to a
variety of biologically valuable N-unprotected indolo[3,2-c]coumarins, indolo[3,2-
c]quinolinones and indolo[3,2-c]pyrones in good to excellent yields (up to 99%). This
protocol is thus practical and attractive, we expect that this work would facilitate
biological and drug discovery studies of indole-based polyheterocycles.
Experimental section
General Information. NMR spectra were recorded on spectrometers (300 MHz for 1H
and 125 MHz or 150 MHz for 13C) . Chemical shifts are reported in δ ppm referenced
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1
to chloroform-d (δ 7.26) DMSO-d (δ 2.5) for H NMR and chloroform-d (δ 77.16)
6
7
8
9
DMSO-d (δ 39.52) for 13C NMR. HRMS were recorded on a Q-TOF mass spectrometer
with ESI resource or Magnetic Sector for EI. Melting point determinations were
performed by the open capillary method. The substrates 1,22a 322b and 522c were prepared
following the literature procedure, and their NMR spectra copies can be found in the
supporting information.
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General Procedures for intramolecular CDC reaction to access indole-fused
polyheterocycles 2, 4 and 6.
Method A: Compound 1 (0.2 mmol, 1.0 equiv) and Pd(OAc)2 (6.7 mg, 0.03 mmol, 15
mol %) were combined in AcOH (1.0 mL) under air (balloon). Then the reaction
o
mixture was heated to 100 C for 24-50 h with the progress monitored by TLC
(CH2Cl2/MeOH = 100/1 as the mobile phase). When completed, the reaction mixture
was cooled to room temperature and diluted with CH2Cl2. Then excess NaHCO3(aq.)
was added to neutralize AcOH. After stirring the mixture for 10 min, the residue was
washed with aqueous NaHCO3. The isolated organic layer was dried over Na2SO4.
After removal of solvent, the residue was purified by silica gel column chromatography
with CH2Cl2/MeOH as the eluent (80/1 to 40/1) to give desired product 2.
Method B: To a 10 mL reaction tube was added compound 1/3/5 (0.2 mmol, 1.0 equiv),
Pd(OAc)2 (4.5 mg, 0.02 mmol, 10 mol %), AgOAc (66.4 mg, 0.4 mmol, 2 equiv) and
o
AcOH (1.0 mL). Then the reaction mixture was heated to 100 C for 5-26 h with the
progress monitored by TLC (CH2Cl2/MeOH = 100/1 as the mobile phase for substrate
1; CH2Cl2/MeOH = 40/1 as the mobile phase for substrates 3 and 5). The work-up
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procedure is the same as Method A. CH2Cl2/MeOH was used as the eluent (80/1 to 40/1)
for silica gel column chromatography to give desired products 2, 4 and 6.
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Chromeno[4,3-b]indol-6(11H)-one (2a).23 Light yellow solid, 43.2 mg, 95%;
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mp >300 C; H NMR (300 MHz, DMSO) δ 13.02 (s, 1H), 8.21 (d, J = 7.6 Hz, 1H),
8.05 (d, J = 7.8 Hz, 1H), 7.69-7.60 (m, 2H), 7.55-7.31 (m, 4H).
10-Methylchromeno[4,3-b]indol-6(11H)-one (2b). Light yellow solid, 49.2 mg, 99%;
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mp >300 C; H NMR (300 MHz, DMSO) δ 12.58 (s, 1H), 8.44 (d, J = 7.8 Hz, 1H),
7.88 (d, J = 7.9 Hz, 1H), 7.66-7.46 (m, 3H), 7.27-7.20 (m, 2H), 2.64 (s, 3H); 13C NMR
(125 MHz, DMSO) δ 157.9, 152.6, 141.6, 137.3, 130.7, 125.4, 124.2, 124.1, 123.1,
122.5, 122.1, 117.7, 117.2, 113.3, 100.5, 17.0; HRMS (EI): m/z calcd for C16H11NO2
[M]+: 249.0790; found: 249.0794.
10-Methoxychromeno[4,3-b]indol-6(11H)-one (2c).9 Light yellow solid, 51.1 mg,
96%; mp 285-287oC; 1H NMR (300 MHz, DMSO) δ 13.11 (s, 1H), 8.48 (d, J = 7.6 Hz,
1H), 7.64-7.50 (m, 3H), 7.51 (d, J = 8.0 Hz, 1H), 7.27 (dd, J = 7.5, 6 Hz, 1H), 7.01 (d,
J = 7.9 Hz, 1H), 4.04 (s, 3H);13C NMR (125 MHz, DMSO) δ 158.0, 152.6, 146.4, 141.3,
130.7, 127.8, 125.7, 124.3, 123.3, 123.2, 117.1, 113.4, 112.6, 105.5, 100.6, 55.5;
HRMS (ESI): m/z [M-H]- calcd for C16H10NO3: 264.0666; found: 264.0663.
7,9-Dimethylchromeno[4,3-b]indol-6(11H)-one (2d).9 Yellow solid, 48.9 mg, 93%.
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mp >300 C; H NMR (300 MHz, DMSO) δ 12.84 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H),
7.62-7.41 (m, 3H), 7.22 (s, 1H), 6.89 (s, 1H), 2.89 (s, 3H), 2.42 (s, 3H); 13C NMR (125
MHz, DMSO) δ 157.7, 152.4, 141.6, 138.7, 134.5, 131.3, 130.4, 125.8, 124.0, 122.4,
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121.5, 116.7, 113.0, 109.6, 100.6, 21.6, 21.1; HRMS (ESI): m/z [M-H]- calcd for
C17H12NO2: 262.0874; found: 262.0868.
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7,9-Dimethoxychromeno[4,3-b]indol-6(11H)-one (2e). Light yellow solid, 53.6 mg,
91%; mp 290-292 oC; 1H NMR (300 MHz, DMSO) δ 12.81 (s, 1H), 8.11 (d, J = 7.5 Hz,
1H), 7.57-7.38 (m, 3H), 6.67 (d, J = 1.4 Hz, 1H), 6.41 (s, 1H), 3.87 (s, 3H), 3.85 (s,
3H); 13C NMR (125 MHz, DMSO) δ 159.1, 156.0, 154.6, 152.3, 140.4, 140.1, 129.9,
123.9, 122.0, 116.6, 112.9, 108.4, 100.3, 94.3, 87.7, 55.6, 55.4; HRMS (EI): m/z calcd
for C17H13NO4 [M]+: 295.0845; found: 295.0844.
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8-Methoxychromeno[4,3-b]indol-6(11H)-one (2f). Yellow solid, 47.8 mg, 90%; mp
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298-299 C; H NMR (300 MHz, DMSO) δ 12.89 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H),
7.65-7.39 (m, 5H), 7.08-6.95 (m, 1H), 3.84 (s, 3H); 13C NMR (125 MHz, DMSO) δ
158.0, 155.6, 152.6, 141.7, 132.4, 130.6, 125.2, 124.3, 122.5, 117.2, 114.6, 113.3, 101.8,
99.8, 55.4; HRMS (ESI): m/z [M-H]- calcd for C16H10NO3: 264.0666; found: 264.0661.
8-Fluorochromeno[4,3-b]indol-6(11H)-one (2g).9 Light yellow solid, 46.6 mg, 92%;
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mp >300 C; H NMR (300 MHz, DMSO) δ 13.14 (s, 1H), 8.18 (d, J = 7.6 Hz, 1H),
7.64 (dd, J = 11.9, 8.7 Hz, 3H), 7.53 -7.44 (m, 2H), 7.25 (dd, J = 9.0, 9.0 Hz, 1H); 13C
NMR (125 MHz, DMSO) δ 158.5 (d, JCF = 235.0 Hz), 157.7, 152.8, 143.1, 134.3, 131.1,
125.0 (d, JCF = 11.3 Hz), 124.4, 122.8, 117.3, 113.8(d, JCF = 10.0 Hz), 113.0, 112.8 (d,
JCF = 25.0 Hz), 105.2 (d, JCF = 25.0 Hz), 100.1 (d, JCF = 3.8 Hz); HRMS (ESI): m/z [M-
H]- calcd for C15H7FNO2: 252.0466; found: 252.0459.
Benzo[g]chromeno[4,3-b]indol-6(13H)-one (2h). Light brown solid, 43.3 mg, 76%;
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mp >300 C; H NMR (300 MHz, DMSO) δ 13.47 (s, 1H), 8.62 (d, J = 8.3 Hz, 1H),
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8.42 (d, J = 7.7 Hz, 1H), 8.12 (dd, J = 16.8, 8.2 Hz, 2H), 7.83 (d, J = 8.7 Hz, 1H), 7.78-
7.73 (m, 1H), 7.67-7.51 (m, 4H); 13C NMR (125 MHz, DMSO) δ 158.1, 152.3, 139.8,
133.2, 131.0, 130.3, 128.8, 126.5, 125.4, 124.4, 123.3, 122.6, 121.5, 121.3, 120.6, 119.1,
117.2, 113.5, 101.7; HRMS (ESI): m/z [M-H]- calcd for C19H10NO2: 284.0717; found:
284.0711.
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9-Methylchromeno[4,3-b]indol-6(11H)-one (2i). Light yellow solid; mp >300 oC; 1H
NMR (300 MHz, DMSO) δ 12.86 (s, 1H), 8.19 (d, J = 7.7 Hz, 1H), 7.90 (d, J = 8.0 Hz,
1H), 7.61 (dd, J = 11.1, 3.8 Hz, 1H), 7.52-7.44 (m, 3H), 7.15 (d, J = 8.0 Hz, 1H), 2.48
(s, 3H); 13C NMR (150 MHz, DMSO) δ 157.9, 152.6, 141.5, 138.2, 134.4, 130.6, 124.3,
124.0, 122.6, 122.1, 119.9, 117.2, 113.3, 112.3, 100.0, 21.5; HRMS (EI): m/z calcd for
C16H11NO2 [M]+: 249.0790; found: 249.0785.
7-Methylchromeno[4,3-b]indol-6(11H)-one (2j). Light yellow solid; mp >300 oC; 1H
NMR (300 MHz, DMSO) δ 13.01 (s, 1H), 8.21 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 7.9 Hz,
1H), 7.52-7.44 (m, 3H), 7.31-7.26 (m, 1H), 7.06 (d, J = 7.4 Hz, 1H), 2.95 (s, 3H); 13C
NMR (150 MHz, DMSO) δ 157.8, 152.6, 142.1, 138.3, 131.8, 130.8, 125.1, 124.2,
124.1, 123.8, 122.6, 116.8, 112.9, 109.9, 100.7, 21.9; HRMS (EI): m/z calcd for
C16H11NO2 [M]+: 249.0790; found: 249.0785.
9-Methoxychromeno[4,3-b]indol-6(11H)-one (2k). Light yellow solid; mp >300 oC;
1H NMR (300 MHz, DMSO) δ 12.86 (s, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 8.6
Hz, 1H), 7.61-7.56 (m, 1H), 7.52-7.42 (m, 2H), 7.10 (s, 1H), 6.97 (d, J = 8.7 Hz, 1H),
3.86 (s, 3H); 13C NMR (125 MHz, DMSO) δ 157.9, 157.8, 152.4, 141.1, 139.0, 130.3,
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124.3, 122.3, 120.9, 118.1, 117.1, 113.3, 111.9, 100.2, 95.8, 55.5; HRMS (ESI): m/z
[M-H]- calcd for C16H10NO3: 264.0666; found: 264.0660.
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9-Fluorochromeno[4,3-b]indol-6(11H)-one (2m). Light yellow solid; mp >300 oC;1H
NMR (300 MHz, DMSO) δ 13.25 (s, 1H), 8.22 (d, J = 7.7 Hz, 1H), 8.00 (dd, J = 8.5,
5.6 Hz, 1H), 7.70-7.57 (m, 1H), 7.54-7.47 (m, 3H), 7.23-7.16 (m, 1H); 13C NMR (150
MHz, DMSO) δ 160.4 (d, J CF = 238.5 Hz), 157.7, 152.6, 142.7, 138.2 (d, J CF = 13.5
Hz), 130.9, 124.5, 122.7, 121.4 (d, J CF = 10.5 Hz), 121.0, 117.3, 113.0, 110.8 (d, J CF
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= 24.0 Hz), 100.0, 99.2 (d, J
= 25.5 Hz); HRMS (ESI): m/z [M-H]- calcd for
CF
C15H7FNO2: 252.0466; found: 252.0461.
2-Methylchromeno[4,3-b]indol-6(11H)-one (2o). Yellow solid, 47.3 mg, 95%;
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mp >300 C; H NMR (300 MHz, DMSO) δ 12.94 (s, 1H), 8.02 (d, J = 7.7 Hz, 1H),
7.98 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.42-7.38 (m, 3H), 7.34-7.27 (m, 1H), 2.42 (s,
3H); 13C NMR (150 MHz, DMSO) δ 158.0, 150.9, 141.8, 137.8, 133.5, 131.6, 124.7,
124.4, 122.4, 122.3, 120.2, 116.9, 112.8, 112.4, 100.0, 20.6; HRMS (ESI): m/z [M-H]-
calcd for C16H10NO2: 248.0717; found: 248.0710.
10-Methoxy-2-methylchromeno[4,3-b]indol-6(11H)-one (2p). Light yellow solid,
52.5 mg, 94%; mp >300 oC; 1H NMR (300 MHz, DMSO) δ 12.98 (s, 1H), 8.28 (s, 1H),
7.60 (d, J = 7.9 Hz, 1H), 7.36 (s, 2H), 7.24 (dd, J = 7.5, 7.5 Hz, 1H), 6.97 (d, J = 7.9
Hz, 1H), 4.02 (s, 3H), 2.40 (s, 3H);13C NMR (150 MHz, DMSO) δ 158.1, 150.8, 146.4,
141.3, 133.4, 131.4, 127.7, 125.8, 123.2, 123.0, 116.8, 113.0, 112.5, 105.5, 100.5, 55.5,
20.6; HRMS (ESI): m/z [M-H]- calcd for C17H12NO3: 278.0823; found: 278.0824.
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2-Fluorochromeno[4,3-b]indol-6(11H)-one (2q). Light yellow solid, 50.4 mg, 99%;
mp >300 oC; 1H NMR (300 MHz, DMSO) δ 13.01 (s, 1H), 8.03 (dd, J = 11.3, 5.3 Hz,
2H), 7.69 (d, J = 8.1 Hz, 1H), 7.59 (dd, J = 9.1, 4.6 Hz, 1H), 7.52-7.41 (m, 2H), 7.38-
7.33 (m, 1H); 13C NMR (125 MHz, DMSO) δ 158.0 (d, JCF = 238.8 Hz), 157.6, 149.0,
140.9, 137.7, 125.0, 124.1, 122.5, 120.3, 119.2 (d, JCF = 8.8 Hz), 117.8 (d, JCF = 23.8
Hz), 114.0 (d, JCF = 10.0 Hz), 112.5, 108.3 (d, JCF = 26.3 Hz), 100.4; HRMS (ESI): m/z
[M-H]- calcd for C15H7FNO2: 252.0466; found: 252.0462.
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2,4,10-Trimethylchromeno[4,3-b]indol-6(11H)-one (2r). Light yellow solid, 48.4 mg,
87%; mp >300 oC; 1H NMR (300 MHz, DMSO) δ 12.43 (s, 1H), 8.08 (s, 1H), 7.86 (d,
J = 6.3 Hz, 1H), 7.29 (s, 1H), 7.25-7.20(m, 2H), 2.63 (s, 3H), 2.41 (s, 6H); 13C NMR
(125 MHz, DMSO) δ 158.0, 149.1, 142.0, 137.3, 132.7, 125.6, 125.3, 124.1, 122.4,
122.0, 120.4, 117.7, 112.6, 100.3, 20.5, 17.0, 15.7; HRMS (ESI): m/z [M-H]- calcd for
C18H14NO2: 276.1030; found: 276.1025.
2,4-Dimethylchromeno[4,3-b]indol-6(11H)-one (2s). Light yellow solid, 49.4 mg,
94%; mp >300 oC; 1H NMR (300 MHz, DMSO) δ 12.90 (s, 1H), 8.03 (d, J = 7.6 Hz,
1H), 7.83 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.43-7.38 (m, 1H), 7.35-7.29 (m, 2H), 2.41
(s, 3H), 2.40 (s, 3H); 13C NMR (125 MHz, DMSO) δ 157.9, 149.2, 142.2, 137.8, 132.8,
125.7, 124.6, 124.4, 122.2, 120.2, 112.0, 112.5, 112.3, 99.9, 20.5, 15.7; HRMS (ESI):
m/z [M-H]- calcd for C17H12NO2: 262.0874; found: 262.0868.
1,3-Dimethylchromeno[4,3-b]indol-6(11H)-one (2t). Light yellow solid, 45.3 mg,
86%; mp >300 oC; 1H NMR (300 MHz, DMSO) δ 11.79 (s, 1H), 8.06 (d, J = 7.5 Hz,
1H), 7.79 (d, J = 7.9 Hz, 1H), 7.41-7.30 (m, 2H), 7.16 (s, 1H), 7.04 (s, 1H), 2.84 (s,
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3H), 2.36 (s, 3H); 13C NMR (150 MHz, DMSO) δ 157.9, 153.5, 141.4, 140.4, 138.1,
133.9, 127.5, 124.3, 123.7, 122.4, 119.8, 115.4, 113.2, 110.1, 100.0, 22.0, 20.9; HRMS
(ESI): m/z [M-H]- calcd for C17H12NO2: 262.0874; found: 262.0866.
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3-Methoxychromeno[4,3-b]indol-6(11H)-one (2u).2a Light yellow solid, 46.8 mg,
88%; mp >300 oC; 1H NMR (300 MHz, DMSO) δ 12.84 (s, 1H), 8.10 (d, J = 8.6 Hz,
1H), 7.99 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.40-7.28 (m, 2H), 7.11-7.07
(m, 2H), 3.88 (s, 3H); 13C NMR (125 MHz, DMSO) δ 161.6, 158.0, 154.5, 142.6, 137.6,
124.5, 124.3, 123.7, 122.2, 119.9, 112.24, 112.20, 106.2, 101.6, 98.1, 55.8.
3-Fluorochromeno[4,3-b]indol-6(11H)-one (2v). Light yellow solid, 49.4 mg, 96%;
mp >300 oC; 1H NMR (300 MHz, DMSO) δ 13.04 (s, 1H), 8.28-8.23 (m, 1H), 8.03 (d,
J = 7.7 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 9.9 Hz, 1H), 7.45-7.32 (m, 3H);
13C NMR (125 MHz, DMSO) δ 163.0 (d, JCF = 246.3 Hz), 157.5, 153.8 (d, JCF = 13.8
Hz), 141.5, 137.6, 124.7, 124.5 (d, JCF = 11.3 Hz), 124.2, 122.4, 120.1, 112.4, 112.2 (d,
JCF = 22.5 Hz), 110.2, 104.8 (d, JCF = 26.3 Hz), 99.0; HRMS (EI): m/z calcd for
C15H8NFO2 [M]+: 253.0539; found: 253.0535.
5,11-Dihydro-6H-indolo[3,2-c]quinolin-6-one (4a).24 Light yellow solid, 45.2 mg,
97%; mp >300 oC; 1H NMR (300 MHz, DMSO) δ 12.55 (s, 1H), 11.42 (s, 1H), 8.20 (d,
J = 7.8 Hz, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.54-7.45 (m, 2H), 7.37 (dd, J = 7.7, 7.5 Hz,
1H), 7.28 (q, J = 7.9 Hz, 2H).
8-Methyl-5,11-dihydro-6H-indolo[3,2-c]quinolin-6-one (4b).25 Yellow solid, 43.9
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mg, 89%; mp >300 C; H NMR (300 MHz, DMSO) δ 12.41 (s, 1H), 11.38 (s, 1H),
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8.17 (d, J = 7.9 Hz, 1H), 8.01 (s, 1H), 7.51-7.43 (m, 3H), 7.27 (dd, J = 6.9, 6.9 Hz, 1H),
7.18 (d, J = 8.0 Hz, 1H), 2.47 (s, 3H).
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8-Chloro-5,11-dihydro-6H-indolo[3,2-c]quinolin-6-one (4c).25 Yellow solid, 46.7
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mg, 87%; mp >300 C; H NMR (300 MHz, DMSO) δ 12.74 (s, 1H), 11.50 (s, 1H),
8.19 (d, J = 7.9 Hz, 1H), 8.14 (s, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.56-7.46 (m, 2H), 7.38
(d, J = 8.6 Hz, 1H), 7.31 (dd, J = 7.4, 7.4 Hz, 1H).
2,3-Dimethoxy-5,11-dihydro-6H-indolo[3,2-c]quinolin-6-one (4d). Light gray solid,
55.8 mg, 94%; mp 282-285 oC; 1H NMR (300 MHz, DMSO) δ 11.19 (s, 1H), 8.15 (d,
J = 7.5 Hz, 1H), 7.77 (s, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.34-7.20 (m, 2H), 7.04 (s, 1H),
3.88 (s, 3H), 3.83 (s, 3H); 13C NMR (125 MHz, DMSO) δ 159.7, 150.8, 144.7, 141.4,
137.6, 133.3, 124.7, 123.4, 120.8, 120.4, 111.4, 105.0, 104.4, 103.9, 98.9, 55.8, 55.5;
HRMS (ESI): m/z [M+Na]+ calcd for C17H14N2NaO3: 317.0897; found: 317.0890.
2-Chloro-5,11-dihydro-6H-indolo[3,2-c]quinolin-6-one (4e).26 Light yellow solid,
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52.0 mg, 96%; mp >300 C; H NMR (300 MHz, DMSO) δ 12.58 (s, 1H), 11.55 (s,
1H), 8.32 (s, 1H), 8.20 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.55 (dd, J = 8.8,
1.9 Hz, 1H), 7.48-7.37 (m, 2H), 7.28 (dd, J = 7.5, 7.5 Hz, 1H).
4-Methyl-5,11-dihydro-6H-indolo[3,2-c]quinolin-6-one (4f). Light green solid, 48.6
mg, 97%; mp>300 oC; 1H NMR (300 MHz, DMSO) δ 12.52 (s, 1H), 10.43 (s, 1H), 8.21
(d, J = 7.8 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.38 (dd, J = 8.7,
2.8 Hz, 2H), 7.25 (dd, J = 15.9, 7.8 Hz, 2H), 2.52 (s, 3H);13C NMR (125 MHz, DMSO)
δ 160.0, 141.2, 137.8, 136.3, 130.6, 124.4, 124.3, 124.0, 121.3, 121.0, 120.8, 120.1,
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found: 247.0875.
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253 oC; 1H NMR (300 MHz, DMSO) δ 12.13 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.52 (d,
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J = 7.7 Hz, 1H), 7.34-7.23 (m, 2H), 6.66 (s, 1H), 2.34 (s, 3H); C NMR (125 MHz,
DMSO) δ 159.9, 159.2, 146.1, 137.3, 124.0, 123.7, 121.9, 119.7, 112.1, 98.0, 95.3, 19.8;
HRMS (EI): m/z calcd for C12H9NO2 [M]+: 199.0633; found: 199.0632.
3,8-Dimethylpyrano[4,3-b]indol-1(5H)-one (6b). Yellow solid, 34.2 mg, 92%; mp
280-282 oC; 1H NMR (300 MHz, DMSO) δ 12.01 (s, 1H), 7.71 (s, 1H), 7.40 (d, J = 8.3
Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.62 (s, 1H), 2.43 (s, 3H), 2.33 (s, 3H); 13C NMR
(125 MHz, DMSO) δ 159.6, 159.2, 146.0, 135.5, 130.8, 125.3, 124.0, 119.5, 111.7,
97.7, 95.3, 21.1, 19.7; HRMS (EI): m/z calcd for C13H11NO2 [M]+: 213.0790; found:
213.0789.
8-Fluoro-3-methylpyrano[4,3-b]indol-1(5H)-one (6c). Yellow solid, 36.0 mg, 83%;
mp 279-280 oC; 1H NMR (300 MHz, DMSO) δ 12.21 (s, 1H), 7.56-7.50 (m, 2H), 7.19-
7.12 (m, 1H), 6.65 (s, 1H), 2.33 (s, 3H); 13C NMR (125 MHz, DMSO) δ 160.4, 158.3
(d, JCF = 234.3 Hz), 158.9, 147.2, 133.9, 124.5 (d, JCF = 11.0 Hz) , 113.3 (d, JCF = 9.5
Hz), 111.8 (d, JCF = 25.4 Hz), 104.8 (d, JCF = 24.6 Hz), 98.2 (d, JCF =4.1 Hz), 95.3, 19.8;
HRMS (EI): m/z calcd for C12H8FNO2 [M]+: 217.0539; found: 217.0538.
3,7,9-Trimethylpyrano[4,3-b]indol-1(5H)-one (6d). Yellow solid, 34.8 mg, 77%;
mp >300 oC; 1H NMR (300 MHz, DMSO) δ 11.97 (s, 1H), 7.08 (s, 1H), 6.81 (s, 1H),
6.56 (s, 1H), 2.84 (s, 3H), 2.37 (s, 3H), 2.30 (s, 3H); 13C NMR (125 MHz, DMSO) δ
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159.7, 146.6, 138.6, 134.1, 131.2, 125.6, 121.3, 109.8, 99.0, 95.5, 21.7, 21.5, 20.0;
HRMS (EI): m/z calcd for C14H13NO2 [M]+: 227.0946; found: 227.0948.
6-Methoxy-3-methylpyrano[4,3-b]indol-1(5H)-one (6e). Yellow solid, 34.8 mg, 76%;
mp 263-265 oC; 1H NMR (300 MHz, DMSO) δ 12.27 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H),
7.19 (dd, J = 7.8, 7.8 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 6.56 (s, 1H), 3.97 (s, 3H), 2.33
(s, 3H); 13C NMR (125 MHz, DMSO) δ 159.6, 159.3, 146.1, 145.6, 127.0, 125.1, 122.7,
112.2, 105.0, 98.5, 95.3, 55.4, 19.7; HRMS (EI): m/z calcd for C13H11NO3 [M]+:
229.0739; found: 229.0738.
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8-Methoxy-3-phenylpyrano[4,3-b]indol-1(5H)-one (6f).20a Light brown solid, 54.9
mg, 94%; mp >300 oC; 1H NMR (300 MHz, DMSO) δ 12.20 (s, 1H), 7.97 (d, J = 7.0
Hz, 2H), 7.57-7.48 (m, 4H), 7.44-7.41 (m, 2H), 6.99 (dd, J = 8.9, 1.9 Hz, 1H), 3.84 (s,
3H).
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website
at DOI: 10.1021/acs.joc.xxxxxxx.
1H and 13C NMR spectra of the substrates and products (PDF)
Acknowledgements
Financial support from the National Natural Science Foundation of China (21325209,
81402798, 81521005) and the Shanghai Municipal Committee of Science and
Technology (14xd1404400) is greatly acknowledged.
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