Gold-Catalyzed Selective 6-exo-dig and 7-endo-dig Cyclizations of Alkyn-Tethered Indoles to Prepare Rutaecarpine Derivatives

Article abstract of DOI:10.1021/acs.joc.7b02956

An efficient method to synthesize rutaecarpine derivatives via the gold-catalyzed selective cyclization of alkyn-tethered indoles under mild conditions is described. The alkyn-tethered indole can undergo 6-exo-dig cyclization by oxidation and sequential gold catalysis, while it goes through 7-endo-dig cyclization by gold catalysis and sequential oxidation. Substrate scope studies reveal that the selectivity of cyclization was controlled by the substrates with sp³ and sp² hybridization of carbon at the 2 position in quinazolinone. Furthermore, the rutaecarpine scaffold was prepared in 67% yield at gram scale easily in four steps from isatoic anhydride.

Full text of DOI:10.1021/acs.joc.7b02956

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Gold-Catalyzed Selective 6-exo-dig and 7-endo-dig Cyclizations of
Alkyn-Tethered Indoles To Prepare Rutaecarpine Derivatives
Xiang-Fei Kong,†,‡ Feng Zhan,† Guo-Xue He,† Cheng-Xue Pan,† Chen-Xi Gu,† Ke Lu,†
Dong-Liang Mo,*,† and Gui-Fa Su*,†
†State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of
China, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin 541004, China
‡College of Chemistry and Bioengineering, Guilin University of Technology, 12 Jian Gan Road, Guilin 541004, China
S
* Supporting Information
ABSTRACT: An efficient method to synthesize rutaecarpine derivatives via the gold-catalyzed selective cyclization of alkyn-
tethered indoles under mild conditions is described. The alkyn-tethered indole can undergo 6-exo-dig cyclization by oxidation and
sequential gold catalysis, while it goes through 7-endo-dig cyclization by gold catalysis and sequential oxidation. Substrate scope
studies reveal that the selectivity of cyclization was controlled by the substrates with sp3 and sp2 hybridization of carbon at the 2
position in quinazolinone. Furthermore, the rutaecarpine scaffold was prepared in 67% yield at gram scale easily in four steps
from isatoic anhydride.
INTRODUCTION
■
Rutaecarpine and its derivatives are one important family of
quinazolinone alkaloids (Figure 1)1 and exhibit a wide range of
interesting biological activities, such as vasorelaxing, cytotoxity,
antiobesity, antiplatelet aggregation, and cyclooxygenase-2
inhibitory activity.2
From the structure of rutaecarpine and its derivatives, it
shows that the core scaffolds are constituted of A, B, C, D, and
E rings. A variety of synthetic endeavors have been devoted to
synthesize these natural or unnatural products.3,4 Among them,
the construction of a C ring is important for the synthesis of
rutaecarpine because it connects two important pharmaco-
phores of quinazolinone and indole. Many synthetic routes to
the construction of a C ring have been developed to prepare
rutaecarpine in the past decade. In 2007, Bowman and Weaver
group reported a radical cyclization of 2-bromoindole precursor
Figure 1. Rutaecarpine and its derivatives.
to afford rutaecarpine in 15% yield (Scheme 1A).5 In 2015,
Bannister and co-worker developed a general strategy of
was developed by the Pan and Liu group, which featured an
sequential Sonagashira reaction and Larock indole synthesis
elegant construction of the characteristic B/C rings in a one-pot
reaction to provide 2-quinazoline-substituted indole precursor,
which then underwent intramolecular substitution to give
rutaecarpine in 81% yield in 7 days (Scheme 1B).6 In 2015, an
Received: November 21, 2017
efficient cascade strategy to construct rutacarpine derivatives
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b02956
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Scheme 1. Strategies for the Construction of the C Ring of Rutaecarpine
a
Table 1. Optimization of 6-exo-dig Cylization Conditions
b
entry
cat.
amount (% mol)
solvent
3a (%)
1
AuCl3
AuCl3
AuCl3
AuCl3
AuCl3
AuCl3
AuCl
5
5
5
5
5
5
5
5
5
5
5
5
1
MeOH
DMSO
THF
38
55
38
85
89
90
85
10
70
22
0
2
3
4
MeCN
toluene
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
5
6
7
8
AuPPh3Cl
AuPPh3Cl/AgOTf
Pd(OAc)2
CuI
9
10
11
12
13
14
AgNO3
0
AuCl3
87
44
AuCl3
0.1
a
b
Reaction conditions: 2a (0.2 mmol), solvent (2 mL), 25 °C, 0.5 h. Isolated yield.
reaction (Scheme 1C).7 Although most of these methods were
accomplished to access rutaecarpines, they suffered from some
drawbacks, such as using toxic tin reagents, long reaction time,
high temperature, lack of gram-scale preparation, and use of
unavailable starting materials, which limited the further
modification and application of rutaecarpines. Therefore, a
green, efficient, and simple strategy to prepare rutaecarpine
derivatives from readily available materials is desirable.
B
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ab c
, ,
Table 2. Scope of Forming 6-exo-dig Product 3
a
b
c
Reaction conditions: 2 (0.2 mmol), AuCl3 (0.01 mmol, 5 mol %), DCM (2 mL), 25 °C, 0.5 h. Isolated yield. Thirty-three percent of 2j was
recovered.
Transition-metal-catalyzed cyclization has served as an
efficient strategy to construct cyclic compounds in recent
years, especially using gold catalysts.8 Various gold catalysts
have been considered to activate C−C triple bonds and
undergo cyclization reactions smoothly with diverse nucleo-
philes under mild reaction conditions, such as the O atom,9 N
atom,10 or C atom11 served as a nucleophile. Gold-catalyzed 6-
exo-dig, 6-endo-dig, or 7-endo-dig cyclization of indole substrates
has been reported previously,12 but few reports have showed
that 6-exo-dig and 7-endo-dig cyclizations could be selectively
achieved in one reaction. Our current research efforts are
focusing on the synthesis of quinazolinone and the studies of its
bioactivity.13 It was envisioned that selective cyclization of
alkyn-tethered indoles would be a direct strategy to access
rutaecarpine derivatives through retro-synthetic analysis
(Scheme 1D). Herein, we reported gold-catalyzed selective 6-
exo-dig and 7-endo-dig cyclizations of alkyn-tethered indoles to
afford two types of rutaecarpine derivatives from readily
available materials.
DCM was the best solvent, providing product 3a in 90% yield
compared to MeOH, DMSO, THF, MeCN, and toluene
(Table 1, entries 1−6). Other Au (I) catalysts were also tested.
AuCl could give product 3a in 85% yield, while AuPPh3Cl
afforded product 3a in only 10% yield (Table 1, entries 7 and
8). Adding AgOTf to AuPPh3Cl improved the yield of 3a to
70% (Table 1, entry 9). Using Pd(OAc)2 as catalyst resulted in
product 3a in 22% yield (Table 1, entry 10). Product 3a was
not observed when CuI or AgNO3 was used as catalyst (Table
1, entries 11 and 12). Product 3a was also obtained in 87%
yield though reducing the amount of AuCl3 to 1 mol % (Table
1, entry 13). However, further lowering the amount of AuCl3 to
0.1 mol %, the yield of 3a was sharply dropped to 44% (Table
1, entry 14). Addition of DDQ with AuCl3 in a one-pot
reaction from substrate 1a gave a lower yield of 3a
accompanied by other complex mixtures. Therefore, the
optimal conditions for preparing 6-exo-dig cyclization product
3a were initially oxidation of 1a by DDQ in methanol and
sequential 5 mol % of AuCl3 in DCM at room temperature
(Table 1, entry 6).
Next, we set out to explore the generality of this catalytic
system for 6-exo-dig cyclization. The scope with respect to
various alkyn-tethered indole 2 was examined (Table 2). A
variety of substituents (R1, R2, R3, R4) in compound 2 were well
tolerated and delivered to product 3 in uniformly high
efficiency. The R1 group at the 5, 6, or 7 position of the aryl
ring in quinazolinone bearing electron-donating groups or
electron-withdrawing groups furnished product 3 from
moderate to excellent yields (3a−h). Product 3i could be
RESULTS AND DISCUSSION
■
Initially, to probe the possible cyclization strategy alkyn-
tethered indole 2a was prepared in 95% yield by oxidation of 1a
in methanol with DDQ. When 2a was treated with 5 mol % of
AuCl3 in MeOH at room temperature, the desired 6-exo-dig
cyclization product 3a was afforded in 38% yield. However, 7-
endo-dig cyclization product was not observed under this
condition (Table 1, entry 1). Solvent screening showed that
C
DOI: 10.1021/acs.joc.7b02956
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Scheme 2. Observation of Forming 7-endo-dig Product 5a
a b c d e
, , , ,
Table 3. Scope of Forming 7-endo-dig Product 5
a
b
c
d
Reaction conditions: 1 (0.3 mmol), AuCl3 (5 mol %), DCM (3 mL), 25 °C, 1.5−3 h. Isolated yield. AuCl3 (15 mol %). AuCl3 (15 mol %), ran
e
with 2o. Ran with 2p.
afforded in 81% yield when an N-protecting group (R2) was
presented with a Bn group, which will facilitate more
applications by a deprotection procedure. However, substrate
2j with an N−H group only provided product 3j without
isomerization in 26% yield, and substrate 2j was recovered in
33% yield. When the R3 group in the indole moiety was a
methyl, bromo, or chloro group, the corresponding products
were afforded in excellent yields (3k−m). The structure of
compound 3 was confirmed by X-ray diffraction analysis of
product 3k.14 The alkynyl moiety was also evaluated. When R4
was a methyl or TMS substituent, desired product 3n or 3p was
obtained in 32% and 10% yield, respectively. A lower yield of
product 3p was obtained because product 3a was also observed
by deprotection of the TMS group. However, product 3o was
not observed when the R4 group is a phenyl group. When the
indole moiety was replaced by an N-methyl pyrrole, the desired
product 3q was obtained in 89% yield.
purification of compound 4a, compound 4a was finally oxidized
with DDQ, and product 5a, which was purified easily by flash
chromatography, was obtained in 99% yield. Treatment of
substrate 1a with AuCl3 until the reaction was completed and
then adding DQQ directly in one flask provided product 5a in
47% yield.
After a variety of conditions were tested, we investigated the
scope for the formation of 7-endo-dig product 5. As shown in
Table 3, various alkyn-tethered indole 1 could convert to 7-
endo-dig product 5 in moderate yields accompanied by minor 6-
exo-dig product 3 by gold catalysis and sequential oxidation
with DDQ in a one-pot reaction. When the R4 group was
presented with a phenyl group, the desired product 5o was
obtained in 70% yield and 6-exo-dig cyclization product 3o was
not observed. The reversed selectivity for 5o might be caused
by the conjugated effect of the phenyl group to the alkynyl
group. Although there were two products 3 and 5 obtained
under these conditions, the two products could be separated
easily by flash column chromatography. This also provided a
new entry to access the 7-endo-dig cyclization products for
further studies in pharmaceuticals.
Although the 7-endo-dig cyclization product was not observed
during optimization for substrate 2a, when compound 1a was
treated with AuCl3 in DCM at room temperature, a 7-endo-dig
cyclization product 4a was obtained in 53% yield as a major
isomer accompanied by 6-exo-dig cyclization product 3a in 18%
yield as a minor isomer (Scheme 2). Due to the stability and
During identification of the structure for compound 5, we
found that the protons of the methylene group adjacent to
D
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Scheme 3. Studies of Variable-Temperature H NMR for Compound 5d in CDCl3
Article
1
nitrogen in compound 5 appeared as broad resonances while
compounds 5n and 5o showed sharp multiplets. To understand
better the structure of the seven-membered ring in compound
5, a variable-temperature NMR study of compound 5d in
CDCl3 was further studied (Scheme 3). The variable-temper-
for the formation of the selective cyclized products 3a and 5a
from alkyn-tethered indoles (Scheme 4).
In the presence of the gold catalyst, substrate 2a would give
intermediate A. This intermediate A would further undergo 6-
exo-dig cyclization to give intermediate B and finally afforded
product 3a via protodeauration and isomerization which could
be supported by isolation of product 3j in Table 2 (Scheme
4A). In the same manner, substrate 1 would give intermediate
E by activation of gold catalyst and subsequent 7-endo-dig
cyclization. Then intermediate E undergoes protodeauration to
provide intermediate 4a. Compound 4a was oxidized by DDQ
to give product 5a (Scheme 4B). The selectivity of 6-exo-dig
and 7-endo-dig cyclization perhaps correlates with the hybrid-
ization of the carbon at the 2 position in quinazolinone. The
planarity of sp2 hybridization is favorable to undergo 6-exo-dig
cyclization, while sp3 hybridization is favorable to undergo 7-
endo-dig cyclization.
1
ature H NMR experiment for 5d revealed that the protons of
the methylene group adjacent to nitrogen in compound 5
appear as 2 resonances separated by 2 ppm (5.689 and 3.617
ppm). The two protons are broad single peaks at 25 °C, while
they appear as sharp multiplets below 25 °C. It suggests that
the 7-membered ring is in two slowly interconverting
conformers, which was further confirmed by the X-ray structure
of compound 5d (Figure 2).15 The X-ray structure of 5d shows
that the 7-membered ring is a twist ring so that the two
conformers might be interconverted as the temperature.
On the basis of the experimental results and the
literature,11f,12c a plausible reaction mechanism was proposed
To illustrate this new protocol for rapid synthesis of
rutaecarpine scaffolds, a gram-scale preparation of 3a from
the commercial material isatoic anhydride was performed
(Scheme 5). When 1.3 g of isatoic anhydride was used as
starting material, followed with aminolysis, condensation,
oxidation, and gold-catalyzed 6-exo-dig cyclization procedure,
the desired product 3a was obtained in 67% yield (0.9 g) in
four steps. This efficient gram-scale preparation of a
rutaecarpine derivative will enable more potent application of
these compounds in pharmaceuticals.
Figure 2. X-ray structure of compound 5d.
E
DOI: 10.1021/acs.joc.7b02956
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Scheme 4. Plausible Mechanisms for the Formation of 3a and 5a
Scheme 5. Gram-Scale Preparation of Compound 3a
CONCLUSIONS
EXPERIMENTAL SECTION
■
■
General Methods. All reactions were carried out at room
temperature. All commercially available reagents and solvents were
used as received without further purification. Analytical thin layer
In summary, we developed an efficient and practical synthetic
method for the formation of two types of rutaecarpine scaffolds
in moderate to excellent yields from alkyn-tethered indoles.
The alkyn-tethered indole can undergo 6-exo-dig cyclization by
oxidation and sequential gold catalysis, while it goes through 7-
endo-dig cyclization under gold catalysis and sequential
oxidation. The rutaecarpine derivative could be prepared in
gram scale easily in good yield in four steps from isatoic
anhydride.
chromatography (TLC) was performed on silica gel plates (GF254
)
and was visualized with a UV lamp (254 nm). Flash column
chromatography was performed on silica gel (200−400 mesh).
Melting points were recorded on a digital microscopic melting
apparatus and uncorrected. Infrared (IR) spectra were recorded on a
PerkinElmer spectrometer (FTIR-Spectrum TWO) with KBr pellet,
and only major peaks are reported in cm−1. High-resolution mass
spectra (HRMS) were performed using ESI (electrospray ionization)
1
mode and a TOF (time-of-flight) mass analyzer. H NMR spectra
were recorded in CDCl3 or a mixture of chloroform-d and methanol-d4
F
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(v/v = 10/1) on a 400, 500, or 600 MHz NMR spectrometer (Bruker).
13C NMR spectra were proton decoupled and recorded in CDCl3 or a
mixture of chloroform-d and methanol-d4 (v/v = 10/1) on a 100, 125,
7.47 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 4.62 (s, 3H), 2.76 (s,
3H). 13C NMR (125 MHz, CDCl3 + CD3OD) δ 157.9, 146.4, 142.6,
141.8, 140.8, 135.9, 128.7, 128.1, 126.8, 122.4, 122.0, 121.5, 121.1,
120.3, 117.4, 115.8, 110.4, 87.8, 33.0, 18.0. IR (KBr) 3056, 2915, 1686,
1570, 1470, 1326, 1280, 1137, 817, 729 cm−1. HRMS (ESI) m/z calcd
for C20H15IN3O [M + H]+ 440.0260, found 440.0253.
2-Fluoro-8,13-dimethylindolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-
5(13H)-one (3g). Pale yellow crystalline; 0.060 g, 90% yield. Mp:
262−263 °C. 1H NMR (500 MHz, CDCl3) δ 8.41−8.36 (m, 2H), 8.10
(d, J = 8.0 Hz, 1H), 7.54 (d, J = 6.0 Hz, 2H), 7.34−7.32 (m, 2H), 7.07
(d, J = 8.0 Hz, 1H), 4.60 (s, 3H), 2.74 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 166.6 (J = 252.0 Hz), 158.4, 149.0, 141.9, 141.3, 130.2 (d, J
= 11.0 Hz), 127.8, 126.8, 122.5, 121.5, 121.0, 119.8, 115.9, 113.9 (d, J
= 24.0 Hz), 112.7, 111.0 (d, J = 21.0 Hz), 110.4, 33.1, 18.0. 19F NMR
(376 MHz, CDCl3) δ − 103.6. IR (KBr) 3100, 2923, 1680, 1542,
1455, 1327, 1275, 1149, 726 cm−1. HRMS (ESI) m/z calcd for
C20H15FN3O [M + H]+ 332.1199, found 332.1172.
4-Chloro-8,13-dimethylindolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-
5(13H)-one (3h). Pale yellow crystalline; 0.063 g, 90% yield. Mp:
293−294 °C. 1H NMR (500 MHz, CDCl3) δ 8.53 (s, 1H), 8.18 (d, J =
8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.64−7.59 (m, 3H), 7.41 (d, J =
8.0 Hz, 1H), 7.37−7.34 (m, 1H), 4.68 (s, 3H), 2.82 (s, 3H). 13C NMR
(125 MHz, CDCl3) δ 157.1, 149.6, 142.0, 141.0, 134.4, 133.1, 128.1,
126.9, 126.8, 126.2, 122.5, 122.4, 121.6, 121.0, 119.9, 116.0, 113.1,
110.4, 33.0, 18.1. IR (KBr) 3057, 2922, 1684, 1527, 1470, 1325, 1281,
1164, 803, 727 cm−1. HRMS (ESI) m/z calcd for C20H15ClN3O [M +
H]+ 348.0904, found 348.0908.
13-Benzyl-8-methylindolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-5-
(13H)-one (3i). Pale yellow crystalline; 0.063 g, 81% yield. Mp: 284−
285 °C. 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.46 (d, J = 8.0
Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.77−7.70 (m, 2H), 7.58 (d, J = 8.0
Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.33 (t, J =
8.0 Hz, 1H), 7.24−7.21 (m, 4H), 7.19−7.17 (m, 1H), 6.62 (s, 2H),
2.84 (s, 3H). 13C NMR (100 MHz, CDCl3 + CD3OD) δ 159.7, 147.5,
141.7, 140.4, 138.7, 134.5, 128.7, 128.0, 127.3, 127.2, 127.1, 126.9,
124.8, 122.6, 122.3, 122.2, 121.4, 121.2, 120.1, 116.3, 116.1, 111.3,
49.0, 18.2. IR (KBr) 3059, 1673, 1539, 1458, 1326, 1253, 1149, 729
cm−1. HRMS (ESI) m/z calcd for C26H20N3O [M + H]+ 390.1606,
found 390.1616.
1
or 150 MHz NMR spectrometer. The H and 13C chemical shifts are
referenced to signals at δ 0.00 (TMS). 1H NMR coupling constants (J)
are reported in Hertz (Hz), and multiplicities are indicated as follows:
s (singlet), d (doublet), t (triplet), and m (multiplet).
General Procedure for the Synthesis of Products 3a−3n,
3p−3q, and 5n−5p. To a stirred solution of compound 2 (0.2
mmol) in dichloromethane (2 mL) was added AuCl3 (0.003 g, 0.01
mmol) under an atmosphere of air, and then the reaction mixture was
stirred at room temperature for 0.5 h. After completion of the reaction
as monitored by TLC, the solvent was removed under vacuum. The
residue was purified by flash column chromatography (silica gel,
dichloromethane) to give product 3 or 5.
8,13-Dimethylindolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-5(13H)-
one (3a). Pale yellow crystalline; 0.056 g, 90% yield. Mp: 239−240 °C.
1H NMR (400 MHz, CDCl3) δ 8.35−8.33 (m, 1H), 8.30 (d, J = 0.8
Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.72−7.65 (m, 2H), 7.47−7.40 (m,
2H), 7.33 (t, J = 8.0 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 4.62 (s, 3H),
2.73 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 158.9, 147.1, 141.5,
140.4, 133.9, 127.9, 127.2, 126.7, 126.3, 124.3, 122.2, 121.5, 121.3,
120.8, 119.3, 115.9, 115.7, 110.1, 32.9, 17.9. IR (KBr) 3057, 2917,
1684, 1450, 1251, 1113, 759, 724 cm−1. HRMS (ESI) m/z calcd for
C20H16N3O [M + H]+ 314.1293, found 314.1288.
3-Methoxy-8,13-dimethylindolo[2′,3′:3,4]pyrido[2,1-b]-
quinazolin-5(13H)-one (3b). Pale yellow crystalline; 0.059 g, 85%
1
yield. Mp: 255−256 °C. H NMR (500 MHz, CDCl3 + CD3OD) δ
8.43 (s, 1H), 8.13 (d, J = 6.5 Hz, 1H), 7.74−7.69 (m, 2H), 7.55 (s,
2H), 7.43 (d, J = 6.5 Hz, 1H), 7.32 (s, 1H), 4.64 (s, 3H), 3.95 (s, 3H),
2.79 (s, 3H). 13C NMR (125 MHz, CDCl3 + CD3OD) δ 158.9, 156.8,
142.3, 141.4, 138.8, 128.5, 128.2, 126.1, 125.9, 122.0, 121.6, 120.8,
120.5, 119.9, 116.1, 115.4, 110.2, 104.8, 55.6, 32.8, 17.9. IR (KBr)
3102, 2939, 1671, 1496, 1329, 1160, 1032, 743 cm−1. HRMS (ESI) m/
z for C21H18N3O2 [M + H]+ 344.1399, found 344.1406.
3,8,13-Trimethylindolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-5(13H)-
one (3c). Pale yellow crystalline; 0.061 g, 93% yield. Mp: 258−259 °C.
1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 1.2 Hz, 1H), 8.07 (s, 1H),
8.00 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.50−7.44 (m, 3H),
7.26−7.22 (m, 1H), 4.53 (s, 3H), 2.66 (d, J = 0.8 Hz, 3H), 2.43 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 158.8, 145.1, 141.4, 139.8, 135.7,
134.3, 128.0, 126.5, 126.1, 122.1, 121.5, 121.0, 120.6, 119.2, 115.7,
115.6, 110.1, 32.8, 21.3, 17.9. IR (KBr) 3047, 2917, 1673, 1537, 1480,
1328, 1250, 818, 732 cm−1. HRMS (ESI) m/z calcd for C21H18N3O
[M + H]+ 328.1450, found 328.1455.
3-Chloro-8,13-dimethylindolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-
5(13H)-one (3d). Pale yellow crystalline; 0.038 g, 55% yield. Mp:
269−270 °C. 1H NMR (500 MHz, CDCl3) δ 8.41 (s, 1H), 8.32 (d, J =
8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.65−
7.63 (m, 1H), 7.55−7.52 (m, 2H), 7.32 (t, J = 7.1 Hz, 1H), 4.62 (s,
3H), 2.75 (s, 3H). 13C NMR (100 MHz, CDCl3 + CD3OD) δ 158.4,
145.8, 141.9, 140.6, 134.8, 129.9, 128.7, 128.1, 126.8, 126.1, 122.5,
121.9, 121.6, 121.2, 120.4, 116.5, 115.7, 110.4, 33.1, 18.1. IR (KBr)
3100, 2930, 1676, 1536, 1472, 1328, 1132, 729 cm−1. HRMS (ESI) m/
z calcd for C20H15ClN3O [M + H]+ 348.0904, found 348.0890.
3-Bromo-8,13-dimethylindolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-
5(13H)-one (3e). Pale yellow crystalline; 0.063 g, 80% yield. Mp: 268−
269 °C. 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J = 2.0 Hz, 1H), 8.42
(s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.79−7.77 (m, 1H), 7.60 (d, J = 8.0
Hz, 1H), 7.54 (t, J = 8.0 Hz, 2H), 7.33 (t, J = 8.0 Hz, 1H), 4.62 (s,
3H), 2.75 (s, 3H). 13C NMR (100 MHz, CDCl3 + CD3OD) δ 158.2,
146.0, 141.0, 140.7, 137.4, 129.5, 128.7, 128.1, 126.9, 122.5, 122.0,
121.6, 121.2, 120.5, 117.5, 116.9, 115.8, 110.5, 33.1, 18.0. IR (KBr)
3068, 2928, 1691, 1531, 1471, 1325, 1134, 821, 732 cm−1. HRMS
(ESI) m/z calcd for C20H15BrN3O [M + H]+ 392.0393, found
392.0388.
8-Methylene-8,13-dihydroindolo[2′,3′:3,4]pyrido[2,1-b]-
quinazolin-5(7H)-one (3j). Pale yellow crystalline; 0.016 g, 26% yield.
1
Mp: 230−231 °C. H NMR (400 MHz, CD3OD) δ 8.25−8.23 (m,
1H), 7.93 (d, J = 8.0 Hz, 1H), 7.84−7.80 (m, 1H), 7.78−7.76 (m,
1H), 7.55 (d, J = 8.0 Hz, 1H), 7.52−7.48 (m, 1H), 7.38−7.34 (m,
1H), 7.24−7.20 (m, 1H), 5.76 (t, J = 1.6 Hz, 1H), 5.43 (t, J = 1.6 Hz,
1H), 5.11 (t, J = 1.6 Hz, 2H) (the resonance of N−H was not
observed in CD3OD). 13C NMR (100 MHz, CDCl3) δ 160.1, 147.3,
143.8, 138.6, 134.4, 131.6, 127.8, 127.1, 126.7, 126.6, 125.9, 123.8,
121.8, 121.5, 120.8, 117.5, 112.3, 110.1, 48.2. IR (KBr) 3062, 1640,
1588, 1472, 1324, 1246, 870, 732 cm−1. HRMS (ESI) m/z calcd for
C19H14N3O [M + H]+ 300.1137, found 300.1133.
8,10,13-Trimethylindolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-5-
(13H)-one (3k). Pale yellow crystalline; 0.059 g, 90% yield. Mp: 287−
1
288 °C. H NMR (500 MHz, CDCl3) δ 8.45−8.44 (m, 2H), 7.88 (s,
1H), 7.83−7.77 (m, 2H), 7.45−7.40 (m, 2H), 7.36 (d, J = 8.0 Hz,
1H), 4.65 (s, 3H), 2.78 (s, 3H), 2.53 (s, 3H). 13C NMR (100 MHz,
CDCl3+ CD3OD) δ 159.2, 147.0, 140.4, 140.2, 134.1, 130.3, 128.2,
128.0, 127.0, 126.6, 124.3, 121.62, 121.57, 121.1, 119.9, 115.7, 115.3,
109.9, 32.9, 21.4, 17.9. IR (KBr) 3095, 2916, 1676, 1540, 1459, 1308,
1251, 1101, 763 cm−1. HRMS (ESI) m/z calcd for C21H18N3O [M +
H]+ 328.1450, found 328.1452.
10-Bromo-8,13-dimethylindolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-
5(13H)-one (3l). Pale yellow crystalline; 0.071 g, 90% yield. Mp: 313−
314 °C. 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.46 (d, J = 8.0
Hz, 1H), 8.26 (d, J = 1.6 Hz, 1H), 7.83−7.82 (m, 2H), 7.64−7.62 (m,
1H), 7.47−7.44 (m, 2H), 4.69 (s, 3H), 2.78 (s, 3H). 13C NMR (125
MHz, CDCl3 + CD3OD) δ 159.3, 147.1, 140.5, 140.2, 134.4, 129.3,
128.8, 127.1, 127.0, 124.9, 124.6, 123.0, 120.6, 119.4, 116.1, 116.0,
113.9, 111.8, 33.2, 17.8. IR (KBr) 3099, 2913, 1675, 1637, 1540, 1455,
3-Iodo-8,13-dimethylindolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-5-
(13H)-one (3f). Pale yellow crystalline; 0.068 g, 77% yield. Mp: 279−
1
280 °C. H NMR (500 MHz, CDCl3) δ 8.71 (s, 1H), 8.43 (s, 1H),
8.11 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.58−7.53 (m, 2H),
G
DOI: 10.1021/acs.joc.7b02956
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1304, 1226, 1106, 858, 761 cm−1. HRMS (ESI) m/z calcd for
C20H15BrN3O [M + H]+ 392.0393, found 392.0389.
(m, 1H), 0.26 (t, J = 3.2 Hz, 9H). 13C NMR (100 MHz, CDCl3) δ
160.8, 147.2, 147.0, 142.7, 139.1, 134.3, 133.5, 131.4, 127.09, 127.07
126.5, 125.1, 125.0, 122.5, 122.2, 120.7, 120.3, 110.4, 40.6, 32.8, 0.5. IR
(KBr) 3078, 2930, 1683, 1554, 1470, 1371, 1241, 1146, 843, 760 cm−1.
HRMS (ESI) m/z calcd for C23H24N3OSi [M + H]+ 386.1683, found
386.1689.
General Procedure for the Synthesis of Compounds 5a, 5b,
5d−5f, and 5m. To a stirred solution of compound 1 (0.3 mmol) in
dichloromethane (3 mL) was added AuCl3 (14 mg, 0.045 mmol)
under an atmosphere of air, and then the reaction mixture was stirred
at room temperature for 1.5−3 h. When completion of the reaction
was noted by TLC, 2,3-dicyano-5,6-dichlorobenzoquinone (DDQ, 68
mg, 0.3 mmol) was added. The resultant reaction mixture was stirred
at room temperature for an additional 0.5 h (monitored by TLC).
Evaporation of solvent and purification of the residue on a silica gel
column using dichloromethane/petroleum ether (from 1/1 to 2/1) as
eluent afforded product 5.
14-Methyl-7,14-dihydro-5H-indolo[2′,3′:3,4]azepino[2,1-b]-
quinazolin-5-one (5a). White crystalline; 0.044 g, 47% yield. Mp:
184−185 °C. 1H NMR (500 MHz, CDCl3) δ 8.37 (d, J = 8.0 Hz, 1H),
7.78−7.72 (m, 3H), 7.51−7.44 (m, 3H), 7.33 (d, J = 9.5 Hz, 1H),
7.28−7.24 (m, 1H), 6.37−6.31 (m, 1H), 5.71 (s, 1H), 4.28 (s, 3H),
3.62 (s, 1H). 13C NMR (125 MHz, CDCl3) δ 161.1, 147.1, 139.5,
134.3, 131.9, 127.4, 127.1, 127.0, 126.4, 125.7, 124.8, 123.9, 121.0,
120.98, 120.0, 119.5, 110.4, 41.0, 33.2. IR (KBr) 3057, 2927, 1674,
1556, 1472, 1344, 1243, 1024, 745, 729 cm−1. HRMS (ESI) m/z calcd
for C20H16N3O [M + H]+ 314.1293, found 314.1303.
3-Methoxy-14-methyl-7,14-dihydro-5H-indolo[2′,3′:3,4]azepino-
[2,1-b]quinazolin-5-one (5b). White crystalline; 0.041 g, 40% yield.
Mp: 166−167 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.0 Hz,
1H), 7.72 (d, J = 2.8 Hz, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 8.0
Hz, 1H), 7.45−7.41 (m, 1H), 7.36−7.33 (m, 1H), 7.31 (d, J = 9.5 Hz,
1H), 7.26−7.22 (m, 1H), 6.35−6.29 (m, 1H), 5.71 (s, 1H), 4.22 (s,
3H), 3.94 (s, 3H), 3.63 (s, 1H). 13C NMR (100 MHz, CDCl3) δ
161.0, 158.1, 145.2, 142.1, 139.3, 132.3, 128.9, 127.4, 125.4, 124.84,
124.82, 123.5, 121.8, 120.8, 119.8, 118.6, 110.2, 106.0, 55.9, 41.0, 33.0.
IR (KBr) 3046, 2925, 1683, 1556, 1489, 1365, 1256, 1030, 829, 723
cm−1. HRMS (ESI) m/z calcd for C21H18N3O2 [M + H]+ 344.1399,
found 344.1396.
3-Chloro-14-methyl-7,14-dihydro-5H-indolo[2′,3′:3,4]azepino-
[2,1-b]quinazolin-5-one (5d). White crystalline; 0.054 g, 52% yield.
Mp: 232−233 °C. 1H NMR (500 MHz, CDCl3) δ 8.35−8.34 (m, 1H),
7.79 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 2.0 Hz, 2H), 7.53−7.48 (m, 2H),
7.37 (d, J = 9.5 Hz, 1H), 7.31−7.28 (m, 1H), 6.38−6.34 (m, 1H), 5.72
(s, 1H), 4.25 (s, 3H), 3.63 (s, 1H). 13C NMR (125 MHz, CDCl3) δ
160.2, 147.3, 145.8, 139.5, 134.7, 131.9, 131.7, 128.9, 127.5, 126.4,
125.9, 124.8, 123.7, 122.0, 121.1, 120.1, 119.6, 110.4, 41.2, 33.2. IR
(KBr) 3045, 2945, 1677, 1553, 1471, 1336, 1230, 825, 730 cm−1.
HRMS (ESI) m/z calcd for C20H15ClN3O [M + H]+ 348.0904, found
348.0896.
3-Bromo-14-methyl-7,14-dihydro-5H-indolo[2′,3′:3,4]azepino-
[2,1-b]quinazolin-5-one (5e). White crystalline; 0.056 g, 48% yield.
Mp: 236−237 °C. 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 2.3 Hz,
1H), 7.85−7.72 (m, 2H), 7.59 (d, J = 8.7 Hz, 1H), 7.52−7.41 (m,
2H), 7.33 (d, J = 9.5 Hz, 1H), 7.28−7.24 (m, 1H), 6.36−6.30 (m,
1H), 5.68 (s, 1H), 4.22 (s, 3H), 3.61 (s, 1H). 13C NMR (100 MHz,
CDCl3) δ 160.1, 147.4, 146.2, 139.4, 137.4, 131.8, 129.5, 129.1, 127.4,
125.8, 124.7, 123.7, 122.4, 121.0, 120.0, 119.5, 110.3, 41.1, 33.1. IR
(KBr) 3062, 2942, 1669, 1552, 1468, 1340, 1150, 828, 730 cm−1.
HRMS (ESI) m/z calcd for C20H15BrN3O [M + H]+ 392.0393, found
392.0388.
3-Iodo-14-methyl-7,14-dihydro-5H-indolo[2′,3′:3,4]azepino[2,1-
b]quinazolin-5-one (5f). White crystalline; 0.065 g, 49% yield. Mp:
160−161 °C. 1H NMR (500 MHz, CDCl3) δ 8.70 (d, J = 2.0 Hz, 1H),
8.01−7.98 (m, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.51−7.45 (m, 3H), 7.34
(d, J = 8.0 Hz, 1H), 7.30−7.25 (m, 1H), 6.36−6.31 (m, 1H), 5.68 (s,
1H), 4.23 (s, 3H), 3.63 (s, 1H). 13C NMR (125 MHz, CDCl3) δ
159.8, 147.6, 146.7, 142.9, 139.5, 135.9, 131.9, 129.1, 127.4, 125.9,
124.8, 123.7, 122.7, 121.1, 120.0, 119.6, 110.3, 90.2, 41.2, 33.1. IR
(KBr) 3056, 2922, 2852, 1678, 1589, 1468, 1338, 958, 780, 730 cm−1.
11-Chloro-8,13-dimethylindolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-
5(13H)-one (3m). Pale yellow crystalline; 0.061 g, 89% yield. Mp:
315−316 °C. 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.47 (d, J =
8.0 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.83−7.80 (m, 2H), 7.64−7.62
(m, 1H), 7.47−7.44 (m, 2H), 4.68 (s, 3H), 2.83 (s, 3H). 13C NMR
(125 MHz, CDCl3 + CD3OD) δ 159.3, 147.2, 140.5, 140.2, 134.4,
129.3, 128.8, 127.1, 126.9, 124.9, 124.6, 123.0, 120.6, 119.4, 116.1,
116.0, 113.9, 111.8, 33.2, 17.8. IR (KBr) 3078, 2928, 1693, 1539, 1454,
1325, 1251, 1111, 837, 763 cm−1. HRMS (ESI) m/z calcd for
C20H15ClN3O [M + H]+ 348.0904, found 348.0894.
8-Ethyl-13-methylindolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-5-
(13H)-one (3n). Pale yellow crystalline; 0.021 g, 32% yield. Mp: 171−
172 °C. 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.44 (d, J = 8.0
Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.78−7.77 (m, 2H), 7.55−7.53 (m,
2H), 7.43−7.40 (m, 1H), 7.34−7.31 (m, 1H), 4.66 (s, 3H), 3.20−3.15
(m, 2H), 1.49 (t, J = 8.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ
159.2, 147.2, 141.7, 140.7, 134.1, 128.5, 127.3, 126.8, 126.3, 125.4,
124.4, 122.6, 121.0, 120.9, 120.8, 116.0, 114.8, 110.3, 33.1, 24.8, 13.5.
IR (KBr) 3053, 2926, 1673, 1543, 1459, 1328, 1250, 1149, 733 cm−1.
HRMS (ESI) m/z calcd for C21H18N3O [M + H]+ 328.1450, found
328.1442.
8-(Trimethylsilyl)methyl-13-methylindolo[2′,3′:3,4]pyrido[2,1-b]-
quinazolin-5(13H)-one (3p). Pale yellow crystalline; 0.008 g, 10%
1
yield. Mp: 238−239 °C. H NMR (600 MHz, CDCl3) δ 8.46−8.44
(m, 1H), 8.37 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 7.9 Hz,
1H), 7.79−7.76 (m, 1H), 7.57−7.52 (m, 2H), 7.42−7.40 (m, 1H),
7.33−7.30 (m, 1H), 4.69 (s, 3H), 2.66 (s, 2H), 0.06 (s, 9H). 13C NMR
(150 MHz, CDCl3) δ 158.9, 147.1, 141.8, 140.2, 134.0, 128.5, 127.2,
126.7, 126.3, 124.3, 122.7, 121.7, 121.4, 120.6, 115.9, 114.2, 110.4,
33.2, 21.3, − 1.4. IR (KBr) 3051, 2930, 1673, 1459, 1321, 1251, 1149,
845, 733 cm−1. HRMS (ESI) m/z calcd for C23H24N3OSi [M + H]+
386.1683, found 386.1688.
1,4-Dimethylpyrrolo[2″,3′:3,4]pyrido[2,1-b]quinazolin-7(1H)-one
(3q). Pale yellow crystalline; 0.047 g, 89% yield. Mp: 187−188 °C. 1H
NMR (400 MHz, CDCl3) δ 8.41 (d, J = 8.0 Hz, 1H), 8.34 (s, 1H),
7.75−7.67 (m, 2H), 7.38−7.32 (m, 1H), 7.10 (d, J = 2.8 Hz, 1H), 6.40
(d, J = 2.8 Hz, 1H), 4.44 (s, 3H), 2.41 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 159.4, 147.7, 140.8, 133.9, 132.3, 129.6, 127.3, 126.5, 123.7,
123.0, 118.4, 115.93, 115.91, 101.2, 37.9, 15.9. IR (KBr) 3056, 2920,
1674, 1544, 1461, 1309, 722 cm−1. HRMS (ESI) m/z calcd for
C16H14N3O [M + H]+ 264.1137, found 264.1135.
9,14-Dimethyl-7,14-dihydro-5H-indolo[2′,3′:3,4]azepino[2,1-b]-
quinazolin-5-one (5n). White crystalline; 0.028 g, 43% yield. Mp:
163−164 °C. 1H NMR (500 MHz, CDCl3) δ 8.37 (d, J = 8.0 Hz, 1H),
7.93 (d, J = 8.0 Hz, 1H), 7.77−7.73 (m, 2H), 7.52−7.44 (m, 3H), 7.24
(t, J = 8.0 Hz, 1H), 6.05 (t, J = 8.0 Hz, 1H), 5.61−5.56 (m, 1H), 4.18
(s, 3H), 3.57−3.52 (m, 1H), 2.44 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 160.9, 147.4, 147.0, 139.3, 138.1, 134.1, 132.0, 127.3, 127.0,
126.4, 125.0, 124.7, 122.2, 121.0, 120.8, 120.7, 120.6, 110.4, 40.3, 32.8,
21.7. IR (KBr) 3065, 2921, 1685, 1554, 1470, 1371, 1243, 767, 723
cm−1. HRMS (ESI) m/z calcd for C21H18N3O [M + H]+ 328.1450,
found 328.1444.
14-Methyl-9-phenyl-7,14-dihydro-5H-indolo[2′,3′:3,4]azepino-
[2,1-b]quinazolin-5-one (5o). White crystalline; 0.060 g, 70% yield.
Mp: 290−291 °C. 1H NMR (500 MHz, CDCl3) δ 8.37 (d, J = 8.0 Hz,
1H), 7.80−7.76 (m, 2H), 7.50−7.48 (m, 2H), 7.39−7.33 (m, 6H),
6.95 (t, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.36 (t, J = 8.0 Hz,
1H), 5.79−5.75 (m, 1H), 4.24 (s, 3H), 3.73−3.69 (m, 1H). 13C NMR
(125 MHz, CDCl3) δ 160.9, 147.3, 147.2, 143.0, 139.7, 139.2, 134.3,
133.4, 128.44, 128.41, 128.3, 127.3, 127.1, 126.6, 125.0, 124.9, 122.7,
121.4, 121.0, 120.5, 118.7, 110.2, 40.4, 32.8. IR (KBr) 3060, 2930,
1673, 1557, 1471, 1336, 1237, 1171, 754, 695 cm−1. HRMS (ESI) m/z
calcd for C26H20N3O [M + H]+ 390.1606, found 390.1600.
14-Methyl-9-trimethylsilyl-7,14-dihydro-5H-indolo[2′,3′:3,4]-
azepino[2,1-b]quinazolin-5-one (5p). Pale yellow crystalline; 0.010 g,
1
yield 13%. Mp: 233−235 °C. H NMR (400 MHz, CDCl3) δ 8.40−
8.38 (m, 1H), 7.84−7.76 (m, 3H), 7.51−7.41 (m, 3H), 7.25−7.21 (m,
1H), 6.63−6.58 (m, 1H), 5.70−5.65 (m, 1H), 4.17 (s, 3H), 3.57−3.52
H
DOI: 10.1021/acs.joc.7b02956
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
HRMS (ESI) m/z calcd for C20H15IN3O [M + H]+ 440.0254, found
440.0249.
120.2, 117.1, 116.5, 109.4, 105.1, 77.9, 72.1, 66.4, 32.8, 31.0. IR (KBr)
3235, 3078, 2909, 2123, 1635, 1496, 1230, 1143, 791, 733 cm−1.
HRMS (ESI) m/z calcd for C20H17ClN3O [M + H]+ 350.1060, found
350.1061.
12-Chloro-14-methyl-7,14-dihydro-5H-indolo[2′,3′:3,4]azepino-
[2,1-b]quinazolin-5-one (5m). White crystalline; 0.043 g, 41% yield.
Mp: 246−247 °C. 1H NMR (400 MHz, CDCl3) δ 8.37−8.35 (m, 1H),
7.78−7.72 (m, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.48−7.44 (m, 2H), 7.27
(d, J = 9.5 Hz, 1H), 7.23−7.20 (m, 1H), 6.38−6.32 (m, 1H), 5.68 (s,
1H), 4.20 (s, 3H), 3.64 (s, 1H). 13C NMR (100 MHz, CDCl3) δ
161.1, 147.2, 146.8, 139.7, 134.3, 132.7, 131.7, 127.3, 127.1, 126.9,
126.5, 124.5, 123.3, 121.8, 121.1, 121.0, 119.1, 110.3, 40.8, 33.3. IR
(KBr) 3076, 2939, 1691, 1556, 1467, 1329, 1236, 1067, 803, 770 cm−1.
HRMS (ESI) m/z calcd for C20H15ClN3O [M + H]+ 348.0904, found
348.0903.
Synthesis of Alkyn-Tethered Indole 1. The solution of 2-
aminobenzoic acid derivatives (5 mmol), triphosgene (0.50 g, 1.7
mmol) in THF (9 mL) was stirred at room temperature under an
atmosphere of air until 2-aminobenzoic acid derivative was consumed
completely (8−16 h, monitored by TLC). Then, water (90 mL) was
added to the mixture giving a white or gray precipitate. Filtration, the
solid was washed with ether, and then dried to give substituted isatoic
anhydride as solid. It was used directly for the next step.
To a stirred solution of substituted isatoic anhydride (2.5 mmol) in
DMF (4 mL) was added propynylamine derivative (3.77 mmol) at
room temperature under an atmosphere of air. The reaction was
completed over a period of 2−6 h. Then, the reaction mixture was
poured into water (40 mL). The aqueous layer was extracted with
dichloromethane (4 × 15 mL). After removal of the solvent under
vacuum, water (10 mL) was then added to give a white or gray
precipitate. Filtration, the solid was washed with petroleum ether, and
then dried to give alkynyl anilines as solid.
To a stirred mixture of alkynyl anilines (1.5 mmol), indole-2-
carboxaldehyde (1.65 mmol) and anhydrous magnesium sulfate (0.6 g,
5 mmol) in THF (5 mL) was added p-toluene sulfonic acid (0.077 g,
0.45 mmol) at 25 °C under an atmosphere of nitrogen. The resulting
mixture was allowed to stir at 25 °C for 8−12 h. After completion of
the reaction, as indicated by TLC, the solvent was removed under
reduced pressure. The crude product was purified by flash column
chromatography (silica gel, gradient eluent: dichloromethane/
petroleum ether = 3/1 to 6/1) to afford compound 1.
6-Bromo-2-(1-methy-1H-indol-2-yl)-3-(prop-2-yn-1-yl)-2,3-dihy-
droquinazolin-4(1H)-one (1e). White crystalline; 0.420 g, 68% yield.
Mp: 223−224 °C. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 2.4 Hz,
1H), 7.60 (d, J = 8.0 Hz, 1H), 7.41−7.39 (m, 1H), 7.36 (d, J = 8.0 Hz,
1H), 7.31−7.28 (m, 1H), 7.17−7.13 (m, 1H), 6.61 (s, 1H), 6.55 (d, J
= 8.0 Hz, 1H), 6.36 (s, 1H), 4.91−4.87 (m, 1H), 4.60 (s, 1H), 3.91 (s,
3H), 3.44−3.39 (m, 1H), 2.18 (t, J = 2.4 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ 162.6, 144.1, 138.8, 136.6, 133.2, 131.5, 126.5, 123.2,
121.3, 120.2, 117.4, 116.7, 112.1, 109.4, 105.1, 77.9, 72.1, 66.4, 32.8,
31.0. IR (KBr) 3234, 3061, 2907, 2115, 1634, 1495, 1231, 733 cm−1.
HRMS (ESI) m/z calcd for C20H16BrN3NaO [M + Na]+ 416.0374,
found 416.0393.
6-Iodo-2-(1-methyl-1H-indol-2-yl)-3-(prop-2-yn-1-yl)-2,3-dihy-
droquinazolin-4(1H)-one (1f). White crystalline; 0.260 g, 40% yield.
Mp: 208−209 °C. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 2.4 Hz,
1H), 7.60 (d, J = 8.0 Hz, 1H), 7.57−7.55 (m, 1H), 7.36 (d, J = 8.0 Hz,
1H), 7.31−7.27 (m, 1H), 7.16−7.12 (m, 1H), 6.61 (s, 1H), 6.43 (d, J
= 8.0 Hz, 1H), 6.35 (s, 1H), 4.90−4.61 (m, 1H), 4.61 (s, 1H), 3.89 (s,
3H), 3.41−3.36 (m, 1H), 2.17 (t, J = 2.4 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ 162.4, 144.7, 142.3, 138.8, 137.4, 133.2, 126.5, 123.2,
121.3, 120.2, 117.7, 117.0, 109.4, 105.1, 81.1, 77.9, 72.1, 66.3, 32.8,
31.0. IR (KBr) 3241, 3057, 2931, 2116, 1633, 1494, 1142, 735 cm−1.
HRMS (ESI) m/z calcd for C20H17IN3O [M + H]+ 442.0416, found
442.0408.
2-(6-Chloro-1-methyl-1H-indol-2-yl)-3-(prop-2-yn-1-yl)-2,3-dihy-
droquinazolin-4(1H)-one (1m). White crystalline; 0.400 g, 77% yield.
Mp: 202−203 °C. 1H NMR (400 MHz, CDCl3) δ 8.02−8.00 (m, 1H),
7.47 (d, J = 8.0 Hz, 1H), 7.34−7.31 (m, 2H), 7.11−7.09 (m, 1H),
6.94−6.90 (m, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.59 (s, 1H), 6.35 (s,
1H), 4.92−4.85 (m, 1H), 4.56 (s, 1H), 3.89 (s, 3H), 3.44−3.39 (m,
1H), 2.30 (t, J = 2.4 Hz, 1H). 13C NMR (100 MHz, CDCl3
+
CD3OD) δ 168.4, 149.7, 143.0, 139.0, 138.2, 132.6, 132.4, 129.0,
125.9, 124.6, 123.3, 119.0, 113.3, 108.2, 81.7, 76.1, 69.9, 36.8, 34.8. IR
(KBr) 3289, 3064, 2935, 2125, 1634, 1513, 1341, 1158, 813, 757 cm−1.
HRMS (ESI) m/z calcd for C20H17ClN3O [M + H]+ 350.1060, found
350.1064.
2-(1-Methyl-1H-indol-2-yl)-3-(prop-2-yn-1-yl)-2,3-dihydroquina-
zolin-4(1H)-one (1a). White crystalline; 0.460 g, 90% yield. Mp: 186−
187 °C. 1H NMR (400 MHz, CDCl3) δ 8.00−7.97 (m, 1H), 7.59 (d, J
= 8.0 Hz, 1H), 7.36−7.28 (m, 3H), 7.15−7.11 (m, 1H), 6.90−6.86 (m,
1H), 6.65 (d, J = 8.0 Hz, 1H), 6.61 (s, 1H), 6.34 (s, 1H), 4.88−4.83
(m, 1H), 4.64 (s, 1H), 3.90 (s, 3H), 3.40−3.35 (m, 1H), 2.15 (t, J =
2.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 164.0, 145.5, 138.8,
134.0, 133.6, 129.0, 126.6, 123.0, 121.3, 120.1, 119.9, 115.8, 114.9,
109.4, 105.0, 78.3, 71.8, 66.7, 32.7, 31.1. IR (KBr) 3291, 3056, 2935,
2122, 1634, 1508, 1236, 1174, 755 cm−1. HRMS (ESI) m/z calcd for
C20H17N3NaO [M + Na]+ 338.1269, found 338.1280.
Synthesis of Compound 2. To a stirred solution of compound 1
(0.5 mmol) in methanol (5 mL) was added DDQ (0.125 g, 0.55
mmol) in portions at room temperature in air. The reaction mixture
was stirred for 0.5 h before the methanol was removed under reduced
pressure. The crude product was purified by flash column
chromatography (silica gel, gradient eluent: dichloromethane/
petroleum ether = 1/1 to 3/1) to afford the corresponding products 2.
2-(1-Methyl-1H-indol-2-yl)-3-(prop-2-yn-1-yl)quinazolin-4(3H)-
one (2a). White crystalline; 0.140 g, 87% yield. Mp: 194−195 °C. 1H
NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.0 Hz, 1H), 7.81−7.78 (m,
2H), 7.72 (d, J = 8.0 Hz, 1H), 7.58−7.54 (m, 1H), 7.44 (d, J = 8.0 Hz,
1H), 7.37 (t, J = 8.0 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.14 (s, 1H),
4.94 (d, J = 2.4 Hz, 2H), 3.89 (s, 3H), 2.34 (t, J = 2.4 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ 161.6, 148.0, 146.8, 138.2, 134.8, 131.0,
127.7, 127.1, 126.9, 123.9, 121.9, 120.8, 120.7, 110.1, 105.4, 78.4, 72.7,
36.2, 31.5. IR (KBr) 3059, 2947, 2126, 1692, 1515, 1242, 1170, 780,
721 cm−1. HRMS (ESI) m/z calcd for C20H16N3O [M + H]+
314.1293, found 314.1291.
6-Methoxy-2-(1-methyl-1H-indol-2-yl)-3-(prop-2-yn-1-yl)-
quinazolin-4(3H)-one (2b). White crystalline; 0.160 g, 93% yield. Mp:
176−177 °C. 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 3.0 Hz, 1H),
7.75−7.73 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.44−7.42 (m, 1H),
7.40−7.37 (m, 1H), 7.25−7.22 (m, 1H), 7.12 (s, 1H), 4.95 (d, J = 2.5
Hz, 2H), 3.99 (s, 3H), 3.89 (s, 3H), 2.36 (t, J = 2.5 Hz, 1H). 13C NMR
(125 MHz, CDCl3) δ 161.4, 159.2, 145.7, 141.4, 138.0, 131.1, 129.4,
127.0, 125.1, 123.7, 121.8, 121.6, 120.6, 110.1, 106.3, 105.1, 78.4, 72.6,
56.0, 36.3, 31.4. IR (KBr) 3057, 2926, 2246, 1673, 1555, 1470, 1242,
746 cm−1. HRMS (ESI) m/z calcd for C21H18N3O2 [M + H]+
344.1399, found 344.1413.
6-Methoxy-2-(1-methyl-1H-indol-2-yl)-3-(prop-2-yn-1-yl)-2,3-di-
hydroquinazolin-4(1H)-one (1b). White crystalline; 0.440 g, 84%
1
yield. Mp: 192−193 °C. H NMR (400 MHz, CDCl3) δ 7.58 (d, J =
8.0 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.35−7.33 (m, 1H), 7.29−7.25
(m, 1H), 7.14−7.10 (m, 1H), 6.95−6.92 (m, 1H), 6.64 (d, J = 8.0 Hz,
1H), 6.54 (s, 1H), 6.29 (s, 1H), 4.96−4.91 (m, 1H), 4.33 (s, 1H), 3.92
(s, 3H), 3.80 (s, 3H), 3.47−3.42 (m, 1H), 2.19 (t, J = 2.4 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ 164.0, 154.1, 139.1, 138.7, 133.9, 126.6,
122.9, 122.5, 121.2, 120.0, 117.8, 110.8, 109.4, 104.6, 78.4, 72.0, 66.6,
55.8, 32.9, 31.0. IR (KBr) 3224, 3062, 2942, 2837, 2116, 1640, 1504,
1285, 1139, 794, 734 cm−1. HRMS (ESI) m/z calcd for C21H20N3O2
[M + H]+ 346.1556, found 346.1566.
6-Chloro-2-(1-methyl-1H-indol-2-yl)-3-(prop-2-yn-1-yl)-2,3-dihy-
droquinazolin-4(1H)-one (1d). White crystalline; 0.370 g, 71% yield.
Mp: 219−220 °C. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 2.4 Hz,
1H), 7.62−7.58 (m, 1H), 7.37−7.34 (m, 0.8 Hz, 1H), 7.31−2.29 (m,
1H), 7.27−7.25 (m, 1H), 7.16−7.12 (m, 1H), 6.62−6.58 (m, 2H),
6.36 (s, 1H), 4.92−4.87 (m, 1H), 4.57 (s, 1H), 3.91 (s, 3H), 3.44−
3.39 (m, 1H), 2.18 (t, J = 2.4 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ 162.8, 143.7, 138.8, 133.9, 133.2, 128.5, 126.5, 125.3, 123.2, 121.3,
I
DOI: 10.1021/acs.joc.7b02956
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
6-Methyl-2-(1-methyl-1H-indol-2-yl)-3-(prop-2-yn-1-yl)-
quinazolin-4(3H)-one (2c). White crystalline; 0.150 g, 92% yield. Mp:
176−177 °C. 1H NMR (400 MHz, CDCl3) δ 8.21−8.20 (m, 1H), 7.74
(d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.65−7.63 (m, 1H),
7.46−7.44 (m, 1H), 7.40−7.36 (m, 1H), 7.25−7.21 (m, 1H), 7.13 (d, J
= 0.8 Hz, 1H), 4.95 (d, J = 2.4 Hz, 2H), 3.89 (s, 3H), 2.56 (s, 3H),
2.35 (t, J = 2.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 161.6, 147.2,
144.9, 138.2, 138.1, 136.3, 131.3, 127.6, 127.0, 126.5, 123.8, 121.8,
120.7, 120.6, 110.1, 105.2, 78.5, 72.6, 36.2, 31.5, 21.5. IR (KBr) 3054,
2930, 2120, 1698, 1576, 1199, 798, 727 cm−1. HRMS (ESI) m/z calcd
for C21H18N3O [M + H]+ 328.1450, found 328.1464.
3H), 6.89−6.88 (m, 2H), 5.59 (s, 2H), 4.43 (d, J = 2.4 Hz, 2H), 2.35
(t, J = 2.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 161.3, 148.0,
146.7, 138.0, 137.8, 134.7, 130.5, 128.6, 127.7, 127.61, 127.60, 127.0,
126.9, 126.8, 124.2, 122.0, 120.8, 120.7, 110.4, 106.6, 78.5, 72.8, 47.9,
36.2. IR (KBr) 3058, 2907, 2123, 1672, 1576, 1470, 1334, 1173, 779,
722 cm−1. HRMS (ESI) m/z calcd for C26H20N3O [M + H]+
390.1606, found 390.1616.
2-(1H-Indol-2-yl)-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one (2j).
1
White crystalline; 0.110 g, 72% yield, mp: 210−211 °C. H NMR
(500 MHz, CDCl3) δ 9.73 (s, 1H), 8.36−8.32 (m, 1H), 7.82−7.73 (m,
3H), 7.61 (s, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H),
7.21 (t, J = 7.5 Hz, 1H), 5.25 (d, J = 2.0 Hz, 2H), 2.54 (t, J = 2.0 Hz,
1H). 13C NMR (125 MHz, CDCl3) δ 161.7, 147.3, 147.0, 136.3, 134.8,
128.8, 128.4, 127.1, 127.05, 127.0, 125.3, 122.2, 120.8, 119.9, 111.5,
107.5, 78.4, 73.7, 35.7. IR (KBr) 3296, 3058, 2124, 1678, 1552, 1474,
1396, 1230, 771 cm−1. HRMS (ESI) m/z calcd for C19H14N3O [M +
H]+ 300.1137, found 300.1129.
6-Chloro-2-(1-methyl-1H-indol-2-yl)-3-(prop-2-yn-1-yl)-
quinazolin-4(3H)-one (2d). White crystalline; 0.140 g, 83% yield. Mp:
1
204−205 °C. H NMR (500 MHz, CDCl3) δ 8.33−8.32 (m, 1H),
7.73−7.68 (m, 3H), 7.43 (d, J = 8.0 Hz, 1H), 7.38−7.35 (m, 1H), 7.21
(t, J = 8.0 Hz, 1H), 7.15 (s, 1H), 4.93 (d, J = 2.5 Hz, 2H), 3.88 (s,
3H), 2.36 (t, J = 2.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 160.6,
148.2, 145.3, 138.2, 135.2, 133.5, 130.7, 129.3, 126.8, 126.4, 124.0,
121.9, 121.7, 120.7, 110.1, 105.6, 78.1, 72.9, 36.4, 31.5. IR (KBr) 3100,
2931, 2119, 1680, 1580, 1469, 1335, 1210, 831, 743 cm−1. HRMS
(ESI) m/z calcd for C20H15ClN3O [M + H]+ 348.0904, found
348.0898.
2-(1,5-Dimethyl-1H-indol-2-yl)-3-(prop-2-yn-1-yl)quinazolin-
4(3H)-one (2k). White crystalline; 0.140 g, 88% yield. Mp: 225−226
1
°C. H NMR (400 MHz, CDCl3) δ 8.40−8.37 (m, 1H), 7.83−7.77
(m, 2H), 7.57−7.53 (m, 1H), 7.50 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H),
7.20−7.18 (m, 1H), 7.06 (s, 1H), 4.93 (d, J = 2.4 Hz, 2H), 3.86 (s,
3H), 2.48 (s, 3H), 2.34 (t, J = 2.4 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 161.6, 148.1, 146.7, 136.8, 134.8, 130.9, 130.0, 127.7, 127.6,
127.1, 127.0, 125.7, 121.3, 120.7, 109.8, 105.0, 78.4, 72.6, 36.3, 31.5,
21.4. IR (KBr) 3061, 2915, 2127, 1697, 1582, 1471, 1340, 1170, 780,
728 cm−1. HRMS (ESI) m/z calcd for C21H18N3O [M + H]+
328.1450, found 328.1449.
6-Bromo-2-(1-methyl-1H-indol-2-yl)-3-(prop-2-yn-1-yl)-
quinazolin-4(3H)-one (2e). White crystalline; 0.160 g, 80% yield. Mp:
207−208 °C. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 2.0 Hz, 1H),
7.88−7.85 (m, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H),
7.44−7.42 (m, 1H), 7.39−7.35 (m, 1H), 7.23−7.19 (m, 1H), 7.16 (s,
1H), 4.94 (d, J = 2.4 Hz, 2H), 3.88 (s, 3H), 2.36 (t, J = 2.4 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 160.4, 148.4, 145.6, 138.3, 138.0,
130.7, 129.6, 129.5, 126.8, 124.0, 122.0, 121.9, 121.3, 120.8, 110.1,
105.7, 78.1, 73.0, 36.5, 31.5. IR (KBr) 3056, 2963, 2124, 1680, 1586,
1465, 1326, 1156, 753 cm−1. HRMS (ESI) m/z calcd for
C20H15BrN3O [M + H]+ 392.0398, found 392.0387.
2-(5-Bromo-1-methyl-1H-indol-2-yl)-3-(prop-2-yn-1-yl)-
quinazolin-4(3H)-one (2l). White crystalline; 0.170 g, 87% yield. Mp:
255−256 °C. 1H NMR (400 MHz, CDCl3) δ 8.40−8.38 (m, 1H), 7.90
(d, J = 8.0 Hz, 1H), 7.84−7.80 (m, 1H), 7.78−7.76 (m, 1H), 7.59−
7.55 (m, 1H), 7.45−7.43 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.06 (d, J
= 0.8 Hz, 1H), 4.91 (d, J = 2.4 Hz, 2H), 3.87 (s, 3H), 2.33 (t, J = 2.4
Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 161.4, 147.5, 146.6, 136.7,
134.9, 132.1, 128.4, 127.9, 127.7, 127.1, 126.8, 124.2, 120.8, 113.9,
111.6, 104.5, 78.2, 72.8, 36.1, 31.6. IR (KBr) 3071, 2962, 2124, 1694,
1584, 1468, 1170, 1100, 781, 722 cm−1. HRMS (ESI) m/z calcd for
C20H15BrN3O [M + H]+ 392.0398, found 392.0396.
2-(6-Chloro-1-methyl-1H-indol-2-yl)-3-(prop-2-yn-1-yl)-
quinazolin-4(3H)-one (2m). White crystalline; 0.150 g, 91% yield.
Mp: 225−226 °C. 1H NMR (400 MHz, CDCl3) δ 8.40−8.38 (m, 1H),
7.84−7.77 (m, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.59−7.55 (m, 1H), 7.43
(s, 1H), 7.19−7.16 (m, 1H), 7.11 (s, 1H), 4.93 (d, J = 2.4 Hz, 2H),
3.86 (s, 3H), 2.35 (t, J = 2.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ
160.4, 146.5, 145.6, 137.5, 133.9, 130.8, 128.9, 126.9, 126.6, 126.1,
124.4, 121.7, 120.5, 119.8, 109.1, 104.4, 77.2, 71.8, 35.1, 30.6. IR (KBr)
3058, 2959, 2125, 1690, 1582, 1470, 1283, 1065, 804, 771 cm−1.
HRMS (ESI) m/z calcd for C20H15ClN3O [M + H]+ 348.0904; found
348.0899.
3-(But-2-yn-1-yl)-2-(1-methyl-1H-indol-2-yl)quinazolin-4(3H)-one
(2n). White crystalline; 0.150 g, 93% yield. Mp: 159−160 °C. 1H
NMR (500 MHz, CDCl3) δ 8.39 (d, J = 8.0 Hz, 1H), 7.81−7.75 (m,
2H), 7.72 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0
Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.13 (s,
1H), 4.88 (d, J = 2.0 Hz, 2H), 3.88 (s, 3H), 1.82 (s, 3H). 13C NMR
(125 MHz, CDCl3) δ 161.6, 148.2, 146.8, 138.1, 134.6, 131.3, 127.6,
127.5, 127.0, 126.9, 123.7, 121.8, 120.9, 120.5, 110.0, 105.2, 80.5, 73.8,
36.6, 31.4, 3.6. IR (KBr) 3057, 2915, 2233, 1679, 1591, 1472, 1339,
1237, 781, 731 cm−1. HRMS (ESI) m/z calcd for C21H18N3O [M +
H]+ 328.1450, found 328.1441.
2-(1-Methyl-1H-indol-2-yl)-3-(3-phenylprop-2-yn-1-yl)-
quinazolin-4(3H)-one (2o). White crystalline; 0.180 g, 93% yield. Mp:
152−153 °C. 1H NMR (500 MHz, CDCl3) δ 8.40 (d, J = 8.0 Hz, 1H),
7.82−7.78 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.58−7.54 (m, 1H), 7.41
(d, J = 8.0 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.33−7.25 (m, 5H), 7.21
(t, J = 8.0 Hz, 1H), 7.15 (s, 1H), 5.18 (s, 2H), 3.87 (s, 3H). 13C NMR
(125 MHz, CDCl3) δ 161.5, 148.2, 146.7, 138.0, 134.7, 131.9, 131.3,
128.6, 128.3, 127.7, 127.1, 127.0, 123.7, 122.1, 121.8, 120.9, 120.6,
110.0, 105.1, 84.1, 83.7, 36.7, 31.4. IR (KBr) 3057, 2943, 2243, 1679,
6-Iodo-2-(1-methyl-1H-indol-2-yl)-3-(prop-2-yn-1-yl)quinazolin-
4(3H)-one (2f). White crystalline; 0.190 g, 88% yield. Mp: 205−206
1
°C. H NMR (500 MHz, CDCl3) δ 8.71 (d, J = 2.0 Hz, 1H), 8.06−
8.04 (m, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.43
(d, J = 8.0 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H),
7.16 (s, 1H), 4.93 (d, J = 2.0 Hz, 2H), 3.88 (s, 3H), 2.36 (t, J = 2.0 Hz,
1H). 13C NMR (125 MHz, CDCl3) δ 160.2, 148.5, 146.0, 143.6, 138.3,
135.9, 130.6, 129.4, 126.8, 124.1, 122.2, 121.9, 120.7, 110.1, 105.7,
92.2, 78.1, 72.9, 36.5, 31.5. IR (KBr) 3060, 2937, 2128, 1692, 1568,
1465, 1342, 827, 732 cm−1. HRMS (ESI) m/z calcd for C20H15IN3O
[M + H]+ 440.0260, found 440.0250.
7-Fluoro-2-(1-methyl-1H-indol-2-yl)-3-(prop-2-yn-1-yl)-
quinazolin-4(3H)-one (2g). White crystalline; 0.150 g, 90% yield. Mp:
186−187 °C. 1H NMR (500 MHz, CDCl3) δ 8.40−8.37 (m, 1H), 7.72
(d, J = 8.0 Hz, 1H), 7.45−7.36 (m, 3H), 7.28−7.24 (m, 1H), 7.21 (t, J
= 8.0 Hz, 1H), 7.17 (s, 1H), 4.94 (d, J = 2.5 Hz, 2H), 3.90 (s, 3H),
2.37 (t, J = 2.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 166.7 (J =
253.6 Hz), 160.8, 149.3, 148.9, 138.3, 130.6, 129.8 (d, J = 10.6 Hz),
126.8, 124.1, 121.9, 120.7, 117.4, 116.5 (d, J = 23.5 Hz), 113.0 (d, J =
21.8 Hz), 110.1, 105.7, 78.2, 72.9, 36.4, 31.5. IR (KBr) 3046, 2941,
2126, 1693, 1568, 1471, 1339, 1272, 1146, 860, 721 cm−1. HRMS
(ESI) m/z for C20H15FN3O [M + H]+ 332.1199, found 332.1194.
5-Chloro-2-(1-methyl-1H-indol-2-yl)-3-(prop-2-yn-1-yl)-
quinazolin-4(3H)-one (2h). White crystalline; 0.140 g, 80% yield. Mp:
175−176 °C. 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 1H),
7.68−7.62 (m, 2H), 7.54−7.58 (m, 1H), 7.43 (d, J = 7.8 Hz, 1H),
7.38−7.36 (m, 1H), 7.23−7.20 (m, 1H), 7.18 (s, 1H), 4.91 (d, J = 2.5
Hz, 2H), 3.98 (s, 3H), 2.37 (t, J = 2.5 Hz, 1H). 13C NMR (125 MHz,
CDCl3) δ 159.6, 149.1, 148.8, 138.3, 134.6, 134.1, 130.6, 130.3, 126.9,
126.8, 124.1, 121.9, 120.7, 117.9, 110.1, 105.8, 78.3, 72.9, 36.5, 31.6. IR
(KBr) 3062, 2953, 2123, 1681, 1586, 1460, 1344, 1224, 810, 735 cm−1.
HRMS (ESI) m/z calcd for C20H15ClN3O [M + H]+ 348.0904, found
348.0914.
2-(1-Benzyl-1H-indol-2-yl)-3-(prop-2-yn-1-yl)quinazolin-4(3H)-
1
one (2i). White crystalline; 0.110 g, 58% yield. Mp: 124−125 °C. H
NMR (400 MHz, CDCl3) δ 8.34 (m, 1H), 7.81−7.70 (m, 3H), 7.55−
7.48 (m, 2H), 7.37−7.33 (m, 1H), 7.25−7.22 (m, 2H), 7.15−7.09 (m,
J
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1570, 1470, 1238, 1170, 754, 690 cm−1. HRMS (ESI) m/z calcd for
C26H20N3O [M + H]+ 390.1606, found 390.1618.
S.-F.; Yu, C.-H.; Pu, H.-F.; Hsu, J. M.; Chen, M.-J.; Wang, P. S. J. Cell.
Biochem. 2007, 101, 44. (f) He, Y.; Yao, P.-F.; Chen, S.-B.; Huang, Z.-
H.; Huang, S.-L.; Tan, J.-H.; Li, D.; Gu, L.-Q.; Huang, Z.-S. Eur. J. Med.
Chem. 2013, 63, 299. (g) Zhang, Y.-J.; Xu, J.-Y.; Zhang, Y.-K.; Jia, L.;
Liu, G.-H. J. Chem. Pharm. Res. 2015, 7, 93. (h) Li, Y.-Z.; Feng, T.-T.;
Liu, P.; Liu, C.; Wang, X.; Li, D.-S.; Li, N.; Chen, M.-H.; Xu, Y.-N.; Si,
S.-Y. ACS Med. Chem. Lett. 2014, 5, 884.
(3) For a review on the synthesis of rutaecarpines, see: Lee, S. H.;
Son, J.-K.; Jeong, B. S.; Jeong, T.-C.; Chang, H. W.; Lee, E.-S.; Jahng,
Y. Molecules 2008, 13, 272 and references cited therein.
(4) Some recent examples for the synthesis of rutaecarpines, see:
(a) Kokosi, J.; Szasz, G.; Hermecz, I. Tetrahedron Lett. 1992, 33, 2995.
(b) Harayama, T.; Hori, A.; Serban, G. Tetrahedron 2004, 60, 10645.
(c) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc. 2008,
130, 416. (d) Tseng, M.-C.; Cheng, H.-T.; Shen, M.-J.; Chu, Y.-H. Org.
Lett. 2011, 13, 4434. (e) Ramesh, S.; Nagarajan, R. Synthesis 2015, 47,
3573. (f) Kwon, S. H.; Seo, H.-A.; Cheon, C.-H. Org. Lett. 2016, 18,
5280. (g) Wen, L.-R.; Dou, Q.; Wang, Y.-C.; Zhang, J.-W.; Guo, W.-S.;
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2-(1-Methyl-1H-indol-2-yl)-3-(3-(trimethylsilyl)prop-2-ynyl)-
quinazolin-4(3H)-one (2p). White crystalline; 0.174 g, 90% yield. Mp:
1
136−137 °C. H NMR (400 MHz, CDCl3) δ 8.41−8.39 (m, 1H),
7.84−7.79 (m, 2H), 7.70 (d, J = 7.6 Hz, 1H), 7.59−7.54 (m, 1H),
7.45−7.43 (m, 1H), 7.39−7.34 (m, 1H), 7.23−7.19 (m, 1H), 7.14 (d, J
= 0.4 Hz, 1H), 4.96 (s, 2H), 3.89 (s, 3H), 0.13 (t, J = 3.6 Hz, 9H). 13C
NMR (100 MHz, CDCl3) δ 161.4, 148.2, 146.7, 138.0, 134.7, 127.6,
127.1, 127.0, 123.7, 121.7, 120.9, 120.5, 110.0, 105.3, 99.8, 89.5, 36.8,
31.4, − 0.3. IR (KBr) 3057, 2915, 2233, 1679, 1591, 1472, 1257, 841,
731 cm−1. HRMS (ESI) m/z calcd for C23H24N3OSi [M + H]+
386.1683, found 386.1689.
2-(1-Methyl-1H-pyrrol-2-yl)-3-(prop-2-yn-1-yl)quinazolin-4(3H)-
1
one (2q). White crystalline; 0.110 g, 83% yield, mp: 180−181 °C. H
NMR (400 MHz, CDCl3) δ 8.34−8.32 (m, 1H), 7.78−7.73 (m, 1H),
7.70 (d, J = 8.0 Hz, 1H), 7.50−7.46 (m, 1H), 6.94−6.93 (m, 1H),
6.85−6.83 (m, 1H), 6.26−6.25 (m, 1H), 4.96 (d, J = 2.4 Hz, 2H), 3.85
(s, 3H), 2.36 (t, J = 2.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ
161.9, 148.0, 147.0, 134.5, 127.2, 126.9, 126.8, 124.7, 120.2, 113.7,
108.2, 78.8, 72.4, 36.4, 35.8. IR (KBr) 3057, 2930, 2122, 1675, 1473,
1340, 1240, 958, 746 cm−1. HRMS (ESI) m/z calcd for C16H14N3O
[M + H]+ 264.1137, found 264.1128.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b02956.
■
(8) Recent reviews on gold catalysis, see: (a) Li, Y.; Li, W.; Zhang, J.
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S
Spectra of compounds 3, 5, 2 and 1 (PDF)
X-ray structure of compound 3k (CIF)
X-ray structure of compound 5d (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: moeastlight@mailbox.gxnu.edu.cn
*E-mail: gfysglgx@163.com
■
ORCID
Dong-Liang Mo: 0000-0002-4005-2249
Gui-Fa Su: 0000-0003-3128-2381
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21462008, 21562005), China Postdoc-
toral Science Foundation (2017M612869), Natural Science
Foundation of Guangxi (2015GXNSFCA139001,
2016GXNSFFA380005, 2017GXNSFDA198045), State Key
Laboratory for Chemistry and Molecular Engineering of
Medicinal Resources, Ministry of Science and Technology of
China (CMEMR2015-A05, CMEMR2014-A01), and “Overseas
100 Talents Program” of Guangxi Higher Education are greatly
appreciated.
(12) (a) Liu, Y.; Xu, W.; Wang, X. Org. Lett. 2010, 12, 1448.
(b) Nishiyama, D.; Ohara, A.; Chiba, H.; Kumagai, H.; Oishi, S.; Fujii,
N.; Ohno, H. Org. Lett. 2016, 18, 1670. (c) Zhang, L.; Wang, Y.; Yao,
Z.-J.; Wang, S.; Yu, Z.-Y. J. Am. Chem. Soc. 2015, 137, 13290.
(d) Guven, S.; Ozer, M. S.; Kaya, S.; Menges, N.; Balci, M. Org. Lett.
2015, 17, 2660.
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Pan, C.-X.; Su, G.-F. Eur. J. Med. Chem. 2015, 95, 377. (b) Shi, W.-M.;
Ma, X.-P.; Pan, C.-X.; Su, G.-F.; Mo, D.-L. J. Org. Chem. 2015, 80,
11175. (c) Zhang, G.-H.; Yuan, J.-M.; Qian, G.; Gu, C.-X.; Wei, K.;
Mo, D.-L.; Qin, J.-K.; Peng, Y.; Zhou, Z.-P.; Pan, C.-X.; Su, G.-F. J.
Med. Chem. 2017, 60, 6853.
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(14) CCDC: 1568829 (compound 3k) contains the supplementary
crystallographic data for this paper. These data can be obtained free of
K
DOI: 10.1021/acs.joc.7b02956
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The Journal of Organic Chemistry
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charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
(15) CCDC: 1568828 (compound 5d) contains the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
L
DOI: 10.1021/acs.joc.7b02956
J. Org. Chem. XXXX, XXX, XXX−XXX