Efficient synthesis of SCF3-substituted tryptanthrins by a radical tandem cyclization

Article abstract of DOI:10.1039/d0ob00233j

Herein, we report a new, efficient and atom-economical strategy for the synthesis of SCF₃-substituted tryptanthrin derivatives. These previously unreported derivatives were obtained by means of a radical tandem cyclization. The reaction was triggered by addition of a SCF₃ radical to a carbon-carbon double bond and involved the formation of a C(sp³)-SCF₃ bond, a C(sp²)-C bond, and a C(sp²)-N bond. This method has mild conditions and a wide range of substrates which is particularly useful for the preparation of substituted indolquinazoline derivatives that widely exist in many natural products, but are not easy to obtain by conventional approaches.

Full text of DOI:10.1039/d0ob00233j

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DOI: 10.1039/D0OB00233J
ARTICLE
Efficient Synthesis of SCF3-Substituted Tryptanthrins by a Radical
Tandem Cyclization
Jincheng Guo,#a Yanan Hao,#a Gang Li,a Ziwen Wang,*ab Yuxiu Liu,*a Yongqiang Li,a and Qingmin
Received 00th January 20xx,
Accepted 00th January 20xx
Wang*a
DOI: 10.1039/x0xx00000x
Herein, we report a new, efficient and atom-economical strategy for the synthesis of SCF3-substituted tryptanthrin
derivatives. These previously unreported derivatives were obtained by means of a radical tandem cyclization. The reaction
was triggered by addition of SCF3 radical to a carbon–carbon double bond and involved the formation of a C(sp3)–SCF3 bond,
a C(sp2)–C bond, and a C(sp2)–N bond. This method has a mild condition and a wide range of substrates which is particularly
useful for the preparation of substituted indolquinazoline derivatives that widely exists in many natural products, but are
not easy to obtain in conventional approaches.
moderate. Tryptanthrin analogues can also be synthesized via aldol
reactions between tryptanthrin and various ketones6a,7 (Figure 2d),
and reactions of primary amines with the C6 carbonyl group of
tryptanthrin afford Schiff base analogues6b (Figure 2e). Although
significant achievements have been made for the synthesis of
tryptanthrin derivatives, mild and efficient synthetic approaches for
synthesis of C6 substituted tryptanthrin derivatives remain to be
further developed.
Introduction
The alkaloid tryptanthrin consists of a quinazoline ring fused to an
indole moiety with carbonyl groups at the 6- and 12-positions (Figure
1). This compound can be isolated from Polygonum tinctorium Lour,
Strobilanthes cusia, and Isatis tinctoria,1 which are sources of blue
dyes and were also used to treat cuts, infections, and hemorrhoids in
ancient China. In addition, tryptanthrin has recently been found to
have a broad spectrum of biological activities, including antitumor
activity,2 antifungal activity,3 and antituberculotic activity.4
Therefore, a large number of tryptanthrin derivatives, both naturally
occurring and chemically synthesized, have been studied. These
derivatives can be divided into two main types: one type containing
various substituents on the two benzene rings5 and a second type in
which the C6 carbonyl group has been replaced by some other
functional group6 (Figure 1). It was found that the C6 substituted
tryptamine showed better biological activity.
O
N
R
R
N
9
10
O
O
1
4
11
N
8
2
3
12
6
7
N
5
O
O
N
N
N
R
or
Tryptanthrin derivatives are generally prepared by reactions of
substituted isatoic anhydrides and isatins5c (Figure 2a), but the
necessary substituted isatoic anhydrides are not always easy to
prepare. Another approach involves oxone-induced dimerization of
indole-3-carbaldehydes5b (Figure 2b), but this method can be used
only with indoles bearing a halogen atom at the 5-position of the aryl
ring. In addition, Wang et al. reported a copper-catalyzed synthesis
of tryptanthrins from substituted indoles5e (Figure 2c); however, the
process is operationally complicated, and the yields are only
O
N
N
R
HO
Figure 1. Structure of tryptanthrin and the two main types of derivatives.
Organofluorine chemistry has been garnering increasing attention
because of its applications in drug development, pesticide chemistry,
and materials technology.8 In particular, various research groups
have recently focused on the trifluoromethylthio group (CF3S) owing
to its electronic properties, high stability, and lipophilicity.9 This
functional group has been shown to improve the membrane
permeability and bioavailability of molecules containing it.10 Various
trifluoromethylthiolation reagents have been reported, and the use
a. State Key Laboratory of Elemento-Organic Chemistry, Research Institute of
Elemento-Organic Chemistry, College of Chemistry, Collaborative Innovation
Center of Chemical Science and Engineering (Tianjin), Nankai University Tianjin
300071 (China).E-mail: wangqm@nankai.edu.cn; E-mail: liuyuxiu@nankai.edu.cn
b. Tianjin Key Laboratory of Structure and Performance for Functional Molecules,
College of Chemistry, Tianjin Normal University, Tianjin 300387 (P. R. China). E-
mail: hxxywzw@tjnu.edu.cn
# Guo and Hao contributed equally to this work.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
of AgSCF3 is
a straightforward method for accomplishing
trifluoromethylthiolation/cyclization reactions via radical,11
anionic,12 and cationic pathways.13 Nevertheless, methods for direct
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construction of common heterocyclic scaffolds while simultaneously (entries 4–8); these experiments revealed that 1.5 equiv of K2S2O8
View Article Online
DOI: 10.1039/D0OB00233J
incorporating a trifluoromethylthio group would be highly desirable. was optimal. Screening of various solvents—other polar organic
solvents (acetonitrile, DMF, acetone), a chlorinated solvent (DCE),
N-Acyl cyanamide could be used as an effective radical acceptor for
ethers (THF, dioxane), and toluene (entries 9–15)—showed no
heterocycles synthesis.14 Inspired by this and as the continuation of
improvement relative to DMSO.
our efforts in heterocycles synthesis,15 we synthesized a series of
trifluoromethylthio-substituted tryptanthrin derivatives by means of
Table 1. Optimization of the reaction conditions.[a]
a
single-step
protocol
involving
a
direct
O
N
trifluoromethylthiolation/cyclization cascade reaction (Figure 2f).
This method is particularly useful for the preparation of substituted
indolquinazoline derivatives which widely exists in many natural
products, but are not easy to obtain in conventional approaches.
a) Synthesis using substituted isatins and isatoic anhydrides
O
oxidant
solvent
N
N
AgSCF3
+
air, 60 ℃,16 h
N
SCF3
2a
1a
R2
O
O
O
entry
1
oxidant (equiv)
K2S2O8 (2.0)
solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CH3CN
DMF
yield (%)[b]
92
Et3N
N
R1
O
R2
O
+
R1
N
toluene
N
N
H
O
H
O
95 (86[c])
84
b) Synthesis using oxone-induced dimerization of indole-3-carbaldehydes
2
K2S2O8 (1.5)
O
CHO
R
4 eq. oxone
R
3
K2S2O8 (1.0)
R
N
CH3CN/H2O 2:1
r.t. 16/72 h
N
N
H
4
benzoyl peroxide (1.5)
PhI(OAc)2 (1.5)
Ce(SO4)2 (1.5)
(NH4)2S2O8 (1.5)
Na2S2O8 (1.5)
K2S2O8 (1.5)
NR
O
R = F, Cl, Br, CH3
5
trace
trace
79
c) Copper-catalyzed synthesis of tryptanthrin from substituted indoles (Wang' work)
R1
O
O
6
CuI, O2
N
R2
O
R2
R1
+
N
N
NMP, 80 ℃
16 h
N
7
H
H
O
8
81
d) Synthesis of tryptanthrin derivatives by aldol reaction
O
9
66
O
N
Et2NH
N
N
10
11
12
13
14
15
K2S2O8 (1.5)
17
N
different types of ketones
R
O
HO
K2S2O8 (1.5)
DCE
NR
e) Synthesis of Schiff base analogues of tryptanthrin
K2S2O8 (1.5)
THF
NR
O
N
O
CH3OH
RNH2
N
K2S2O8 (1.5)
dioxane
toluene
acetone
NR
N
N
N
reflux 2 h
R
O
K2S2O8 (1.5)
NR
this work
f) Synthesis of tryptanthrin derivatives by radical cascade cyclization (
)
K2S2O8 (1.5)
NR
O
O
[a]
Reaction conditions: 1a (0.2 mmol), AgSCF3 (0.24 mmol, 1.2 equiv), oxidant
SCF3
N
N
(1.0–2.0 equiv), 2 mL solvent, at 60 °C under air for 16 h. Determined by 1H
NMR spectroscopy with CH2Br2 as an internal standard. [c] Isolated yield. NR = no
reaction.
[b]
condition
N
N
SCF3
Figure 2. Previously reported strategies for the synthesis of tryptanthrin
derivatives and our new approach to the synthesis of trifluoromethylthio-
substituted tryptanthrins.
With the optimized conditions in hand (Table 1, entry 2), we explored
the generality of the protocol by carrying out reactions of various
substrates 1. We began by evaluating the effects of substituents on
the phenyl ring attached to the carbonyl group (Scheme 1).
Substrates with an electron-withdrawing group (1b–1e) or an
electron-donating group (1f–1h, 1k) in the para position afforded the
corresponding products in 70–86% yields. Comparison of the yields
of methyl-substituted products 2f, 2i, and 2j indicated that the
position of the methyl group had little effect; however, when the
methyl substituent was in the meta position of the phenyl ring, there
were two sites at which the ring could undergo attack by the imine
radical generated during the reaction, so two regioisomers, 2i-1 and
Results and discussion
We set out to obtain trifluoromethylthio-substituted tryptanthrin 2a
from N-acylcyanamide 1a (0.2 mmol) by reaction with AgSCF3 (1.2
equiv) and K2S2O8 (2.0 equiv) in DMSO under air at 60 °C for 16 h; and
we were pleased to find that these conditions did in fact afford 2a, in
1
a yield of 92% as indicated by H NMR spectroscopy (Table 1, entry
1). Subsequently, we evaluated the effects of decreasing the amount
of oxidant (entries 2 and 3) and changing the oxidant to benzoyl
peroxide, iodobenzene diacetate, ceric sulfate, or a peroxosulphate
2 | J. Name., 2012, 00, 1-3
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2i-2, were obtained in a 1:2.5 ratio. Replacing the phenyl group with groups had a negligible effect on the yields (2m, 2n), but a substrate
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DOI: 10.1039/D0OB00233J
naphthyl group also gave the desired product (2l) in good yield (72%). with two electron-donating methoxy groups did not afford the
corresponding product (2o). Furthermore, when the 2-
phenylpropene moiety of the substrate was replaced with an alkyl
chain bearing a terminal olefin, 2p was obtained in 81% yield.
K2S2O8
O
O
(1.5 equiv)
N
R1
AgSCF3
+
N
R1
DMSO
60 ℃, air
16 h
(1.2 equiv)
N
N
1
Finally, we investigated the effects of the R3 substituent on the
carbon–carbon double bond (Scheme 3). When the substituent was
an isopropyl group, the yield of 2q was only 57%; but products with
a long-chain alkyl group (2s), a cycloalkyl group (2r), or an aryl group
(2t–2x) could be obtained in 80–84% yields. However, when R3 was
a hydrogen atom, none of the desired product (2y) was detected; the
double bond of 1y may have oxidized or polymerized.
SCF3
2
O
N
O
O
N
N
N
N
Cl
Br
N
F
SCF3
SCF3
SCF3
2d
70%
2b
2c
86%
84%
K2S2O8
O
O
O
O
O
(1.5 equiv)
N
AgSCF3
+
N
N
N
N
DMSO
60 ℃, air
16 h
(1.2 equiv)
N
R3
NC
N
N
O
N
R3
N
1
SCF3
2
SCF3
SCF3
SCF3
2e
2f
84%
84%
2g
80%
O
O
O
N
N
O
N
N
O
N
N
N
O
N
N
N
SCF3
N
N
SCF3
SCF3
SCF3
SCF3
SCF3
2s
84%
N
2q
2r
82%
57%
2i-1
2i-2
23%
57%
2h
76%
O
O
N
O
N
N
N
SCF3
O
SCF3
O
N
N
O
SCF3
N
N
N
N
N
Cl
F
2t
80%
SCF3
SCF3
SCF3
2v
83%
2u
82%
2k
82%
2j
85%
2l
72%
O
N
O
N
O
Scheme 1. Synthesis of trifluoromethylthio-substituted tryptanthrins 2b–2l.
Unless otherwise noted, all reactions were performed with 1 (0.2 mmol, 1 equiv),
AgSCF3 (1.2 equiv), and K2S2O8 (1.5 equiv) in DMSO (2 mL) at 60 °C under air
for 16 h. Isolated yields are given.
N
N
N
H
N
SCF3
SCF3
SCF3
2y
0%
R2
K2S2O8
R2
O
Br
O
(1.5 equiv)
2w
80%
N
AgSCF3
2x
84%
+
N
DMSO
60 ℃, air
16 h
(1.2 equiv)
N
N
SCF3
Scheme 3. Synthesis of trifluoromethylthio-substituted tryptanthrins 2q–2x. The
2
1
reaction conditions are described in Scheme 1.
Cl
O
K2S2O8
O
Cl
O
(1.5 equiv)
O
N
O
N
O
N
AgSCF3
(1.2 equiv)
Cl
Br
O
+
N
DMSO
60 oC, air
16 h
N
N
N
N
Cl
SCF3
N
N
1z
2z
84%
SCF3
SCF3
SCF3
2m
2n
2o
82%
60%
0%
O
K2S2O8
O
(1.5 equiv)
N
O
N
TEMPO
AgSCF3
(1.2 equiv)
+
+
N
N
DMSO
60 oC. air
16 h
(2.0 equiv)
N
SCF3
N
1a
2aa
0%
SCF3
2p
81%
Scheme 4. Mechanistic experiments.
Scheme 2. Synthesis of trifluoromethylthio-substituted tryptanthrins 2m–2p. The
reaction conditions are described in Scheme 1.
Two control experiments were conducted to probe the reaction
mechanism (Scheme 4). When an N-acylcyanamide with a chlorine
atom at each of the two ortho positions of the phenyl ring attached
to the carbonyl carbon was subjected to the standard conditions, a
Next, we explored the effects of substituents on the phenyl ring
attached to the amide nitrogen (Scheme 2). Electron-withdrawing
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J. Name., 2013, 00, 1-3 | 3
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product 2z generated by the loss of one of the chlorine atoms was The combined organic extracts were washed with brine (40 mL),
View Article Online
DOI: 10.1039/D0OB00233J
obtained in 84% yield, a result that rules out a mechanism involving dried over Na2SO4, and concentrated in vacuo. The residue was
cyclization of an imine cation. Specifically, the addition of the radical directly used to determine yield by 1H NMR spectroscopy with CH2Br2
scavenger TEMPO completely inhibited the reaction. We recovered as an internal standard.
1a with 96% yield. The corresponding product 2aa and the directing
trapping product between TEMPO and SCF3 radical were not
observed based on 1H NMR and HRMS.
General procedures for the synthesis of 2a–2x.
To a 25 mL over-dried shrek tube was added 1 (0.2 mmol, 1.0 equiv)
AgSCF3 (0.24 mmol, 1.2 equiv), K2S2O8 (0.3 mmol, 1.5 equiv) and 2.0
On the basis of the above-described experiments and relevant
mL DMSO. The reaction mixture was stirred rapidly at 60 oC for 16 h.
literature precedents, a plausible mechanism is depicted in Scheme
The mixture was diluted with brine (40 mL), and extracted with EA
5. First, oxidation of AgSCF3 by K2S2O8 gives the SCF3 radical, which
(40 mL × 3). The combined organic extracts were washed with brine
(40 mL), dried over Na2SO4, and concentrated in vacuo. The residue
was purified by flash chromatography on silica gel using the PE/EA
system to afford the desired products 2a–2x.
adds to the carbon–carbon double bond of substrate 1a to give
benzyl radical intermediate A. Intermediate A undergoes subsequent
5-exo-dig cyclization to generate imine radical intermediate B, and
then 6-endo-tig cyclization affords phenyl radical intermediate C.
Finally, oxidation of C produces cationic intermediate D, which
undergoes deprotonation to generate 2a.
6-Methyl-6-(((trifluoromethyl)thio)methyl)indolo[2,1-b]quinazolin-
12(6H)-one (2a). White solid, 86% yield, mp: 97-98 ℃, 1H NMR (400
MHz, CDCl3) δ 8.62 (d, J = 8.0 Hz, 1H), 8.43 (d, J = 7.9 Hz, 1H), 7.79 (d,
J = 3.7 Hz, 2H), 7.57 – 7.45 (m, 3H), 7.37 (t, J = 7.5 Hz, 1H), 3.61 (q, J
= 12.9 Hz, 2H), 1.76 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.2, 159.8,
147.3, 139.3, 134.5, 133.1, 130.4 (q, J = 307.8 Hz), 129.6, 127.5,
127.2, 126.9, 126.8, 123.0, 121.6, 117.4, 48.7, 38.60 (q, J = 2.0 Hz),
25.1. HRMS (ESI) calcd for C18H14F3N2OS [M+H]+ 363.0773, found
363.0776.
O
N
O
optimal conditions
N
N
N
SCF3
H+
1 a
2 a
SCF3
AgSCF3
O
O
N
2-
-
SO42-+SO4
S2O8
N
N
N
3-Fluoro-6-methyl-6-(((trifluoromethyl)thio)methyl)indolo[2,1-
b]quinazolin-12(6H)-one (2b). White solid, 86% yield, mp: 106-107
H
SCF3
D
SCF3
A
1
℃, H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 8.0 Hz, 1H), 8.45 – 8.39
5-exo-d
(m, 1H), 7.53 – 7.35 (m, 4H), 7.30 – 7.21 (m, 1H), 3.60 (q, J = 12.9 Hz,
2H), 1.75 (s, 4H). 13C NMR (100 MHz, CDCl3) δ 166.5 (d, J = 254.8 Hz),
162.6, 159.1, 149.5 (d, J = 13.1 Hz), 139.2, 133.0, 130.3 (q, J = 306.7
Hz), 129.7, 129.6 (d, J = 10.7 Hz), 126.9, 123.0, 118.2, 117.4, 115.8 (d,
J = 23.3 Hz), 113.1 (d, J = 22.2 Hz), 48.9, 38.5 (q, J = 2.0 Hz), 25.0.
HRMS (ESI) calcd for C18H14F4N2OS [M+H]+ 381.0679, found
381.0675.
[O]
ig
O
N
O
N
N
N
H
SCF3
SCF3
B
C
6-endo-trig
Scheme 5. Proposed reaction mechanism.
3-Chloro-6-methyl-6-(((trifluoromethyl)thio)methyl)indolo[2,1-
b]quinazolin-12(6H)-one (2c). White solid, 84% yield, mp: 140-141 ℃,
1H NMR (400 MHz, CDCl3) δ 8.60 (t, J = 6.6 Hz, 1H), 8.35 (d, J = 8.5 Hz,
1H), 7.79 (d, J = 1.9 Hz, 1H), 7.55 – 7.44 (m, 3H), 7.43 – 7.36 (m, 1H),
3.60 (q, J = 12.9 Hz, 2H), 1.74 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
162.5, 159.3, 148.2, 139.1, 133.0, 130.5, 130.3, 130.2 (q, J = 306.7
Hz), 129.7, 129.2, 128.3, 127.0, 123.0, 120.4, 117.4, 48.9, 38.5(q, J =
2.0 Hz), 25.0. HRMS (ESI) calcd for C18H13ClF3N2OS [M+H]+ 397.0384,
found 397.0384.
Experimental
General Experimental Details. Reagents were purchased from
commercial sources and were used as received. H and 13C Nuclear
1
Magnetic Resonance (NMR) spectra were recorded on Bruker Avance
400 Ultrashield NMR spectrometers. Chemical shifts (δ) were given
in parts per million (ppm) and were measured downfield from
internal tetramethylsilane. High-resolution mass spectrometry
(HRMS) data were obtained on an FTICR-MS instrument (Ionspec 7.0
T). The melting points were determined on an X-4 microscope
melting point apparatus and are uncorrected. Conversion was
monitored by thin layer chromatography (TLC). Flash column
chromatography was performed over silica gel (100-200 mesh). The
preparation of substrates 1 can be seen in Supporting Information.
3-Bromo-6-methyl-6-(((trifluoromethyl)thio)methyl)indolo[2,1-
b]quinazolin-12(6H)-one (2d). White solid, 70% yield, mp: 159-161
℃, 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 8.1 Hz, 1H), 8.28 (d, J = 8.5
Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.65 (dd, J = 8.5, 1.9 Hz, 1H), 7.56 –
7.44 (m, 2H), 7.39 (t, J = 7.5 Hz, 1H), 3.59 (q, J = 12.9 Hz, 2H), 1.74 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 162.5, 159.3, 148.2, 139.1, 133.0,
130.5, 130.3, 130.2 (q, J = 306.7 Hz), 129.7, 129.2, 128.3, 127.0,
123.0, 120.4, 117.4, 48.9, 38.5(q, J = 2.0 Hz), 25.0. HRMS (ESI) calcd
for C18H13BrF3N2OS [M+H]+ 440.9879, found 440.9872.
General procedures for the condition optimization.
To a 25 mL over-dried shrek tube was added 1a (52.4 mg, 0.2 mmol,
1.0 equiv), AgSCF3 (50.4 mg, 0.24 mmol, 1.2 equiv), corresponding
oxidant (1.0–2.0 equiv) and 2.0 mL corresponding solvent. The
reaction mixture was stirred rapidly at 60 oC for 16 h. The mixture
was diluted with brine (40 mL), and extracted with EA (40 mL × 3).
6-Methyl-12-oxo-6-(((trifluoromethyl)thio)methyl)-6,12-
dihydroindolo[2,1-b]quinazoline-3-carbonitrile (2e). White solid,
1
84% yield, mp: 127-128 ℃, H NMR (400 MHz, CDCl3) δ 8.59 (d, J =
8.0 Hz, 1H), 8.52 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 0.9 Hz, 1H), 7.78 – 7.70
4 | J. Name., 2012, 00, 1-3
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13
(m, 1H), 7.60 – 7.38 (m, 3H), 3.62 (q, J = 13.1 Hz, 2H), 1.76 (s, 3H). 13
C
1H), 3.58 (q, J = 12.8 Hz, 2H), 2.98 (s, 3H), 1.73 (s, 3H). C NMR (100
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NMR (100 MHz, CDCl3) δ 163.2, 158.5, 147.2, 138.8, 133.0, 132.2, MHz, CDCl3) δ 160.8, 160.7, 148.9, 141.7, 13D9O.6I,: 1103.310.63,91/D303O.2B,0103203.30J,
130.2 (q, J = 306.7 Hz), 129.9, 129.0, 128.2, 127.4, 124.6, 123.1, 129.5, 126.5, 125.8, 122.0, 120.0, 117.4, 48.4, 38.5 (q, J = 2.0 Hz),
117.8, 117.6, 117.5, 49.2, 38.4 (q, J = 1.8 Hz), 25.0. HRMS (ESI) calcd 25.0, 23.4. HRMS (ESI) calcd for C19H16F3N2OS [M+H]+ 377.0930,
for C19H13F3N3OS [M+H]+ 388.0726, found 388.0719.
found 377.0935.
3,6-Dimethyl-6-(((trifluoromethyl)thio)methyl)indolo[2,1-
6-Methyl-3-phenyl-6-(((trifluoromethyl)thio)methyl)indolo[2,1-
b]quinazolin-12(6H)-one (2f). White solid, 84% yield, mp: 131-132 ℃, b]quinazolin-12(6H)-one (2k). White solid, 82% yield, mp: 122-123
1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.1 Hz, 1H), 8.31 (d, J = 8.1 Hz, ℃, 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 8.0 Hz, 1H), 8.50 (d, J = 8.3
1H), 7.59 (s, 1H), 7.52 – 7.44 (m, 2H), 7.40 – 7.35 (m, 2H), 3.59 (q, J = Hz, 1H), 8.05 (d, J = 1.5 Hz, 1H), 7.82 (dd, J = 8.3, 1.6 Hz, 1H), 7.77 (d,
12.8 Hz, 2H), 2.54 (s, 3H), 1.74 (s, 3H). 13C NMR (100 MHz, CDCl3) δ J = 7.3 Hz, 2H), 7.57 – 7.39 (m, 6H), 3.65 (dd, J = 28.2, 12.9 Hz, 2H),
161.2, 159.9, 147.4, 145.6, 139.4, 133.1, 129.6, 128.7, 127.4, 126.8, 1.80 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.6, 159.7, 147.7, 147.4,
126.6, 123.0, 119.1, 117.3, 48.6, 38.62 (q, J = 1.6 Hz), 25.1, 21.9. 139.5, 139.4, 133.1, 130.4 (d, J = 306.6 Hz), 129.7, 129.1, 128.6,
HRMS (ESI) calcd for C19H16F3N2OS [M+H]+ 377.0930, found 127.5, 127.5, 126.7, 126.2, 125.6, 123.0, 120.3, 117.4, 48.7, 38.6 (q,
377.0932.
J = 1.6 Hz), 25.1. HRMS (ESI) calcd for C24H18F3N2OS [M+H]+ 439.1086,
found 439.1089.
3-Methoxy-6-methyl-6-(((trifluoromethyl)thio)methyl)indolo[2,1-
b]quinazolin-12(6H)-one (2g). White solid, 82% yield, mp: 137-138 8-Methyl-8-(((trifluoromethyl)thio)methyl)benzo[f]indolo[2,1-
℃, 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 8.8 b]quinazolin-14(8H)-one (2l). White solid, 72% yield, mp: 111-112 ℃,
Hz, 1H), 7.58 – 7.43 (m, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H NMR (400 MHz, CDCl3) δ 10.06 (d, J = 8.6 Hz, 1H), 8.79 (d, J = 8.0
1H), 7.12 (dd, J = 8.8, 2.4 Hz, 1H), 3.97 (s, 3H), 3.61 (q, J = 12.9 Hz, Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.83 – 7.73
2H), 1.77 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.8, 162.0, 159.5, (m, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.58 – 7.44 (m, 2H), 7.38 (t, J = 7.4 Hz,
149.6, 139.5, 130.4 (q, J = 306.8 Hz), 133.0, 129.6, 128.4, 126.5, 1H), 3.63 (q, J = 12.9 Hz, 2H), 1.78 (s, 3H). 13C NMR (100 MHz, CDCl3)
122.9, 117.3, 117.0, 114.9, 108.5, 55.8, 48.6, 38.6 (q, J = 1.2 Hz), 25.0. δ 160.5, 149.6, 139.8, 135.9, 133.6, 132.2, 131.3, 130.4 (q, J = 306.6
HRMS (ESI) calcd for C19H16F3N2O2S [M+H]+ 393.0879, found Hz), 129.7, 128.8, 128.4, 127.2, 126.9, 126.8, 126.2, 123.0, 118.0,
393.0881.
115.0 48.8, 38.4 (q, J = 1.6 Hz), 24.8. HRMS (ESI) calcd for
C22H16F3N2OS [M+H]+ 413.0930, found 413.0930.
3-(Tert-butyl)-6-methyl-6-(((trifluoromethyl)thio)methyl)indolo[2,1-
b]quinazolin-12(6H)-one (2h). White solid, 86% yield, mp: 140-141 8-Chloro-6-methyl-6-(((trifluoromethyl)thio)methyl)indolo[2,1-
℃, 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 8.4 b]quinazolin-12(6H)-one (2m). White solid, 82% yield, mp: 188-189
Hz, 1H), 7.78 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.56 – 7.43 (m, 2H), 7.36 ℃, 1H NMR (400 MHz, CDCl3) δ 8.44 (dd, J = 38.2, 7.2 Hz, 2H), 7.92 –
(t, J = 7.5 Hz, 1H), 3.60 (q, J = 12.8 Hz, 2H), 1.75 (s, 3H), 1.43 (s, 9H). 7.39 (m, 5H), 3.58 (dd, J = 33.7, 12.8 Hz, 2H), 1.75 (s, 3H). 13C NMR
13C NMR (100 MHz, CDCl3) δ 161.2, 159.8, 158.7, 147.3, 139.4, 133.1, (100 MHz, CDCl3) δ 160.4, 159.6, 147.2, 138.3, 135.3, 134.6, 132.7,
130.4 (q, J = 306.8 Hz), 129.6, 126.6, 126.5, 125.3, 123.8, 123.0, 130.2 (q, J = 307.1 Hz), 127.6, 127.4, 126.9, 126.4, 121.4, 119.9,
119.0, 117.3, 48.6, 38.6(q, J = 1.6 Hz), 35.5, 31.1, 25.1. HRMS (ESI) 118.8, 48.8, 38.4 (q, J = 1.6 Hz), 24.9. HRMS (ESI) calcd for
calcd for C22H22F3N2OS [M+H]+ 419.1399, found 419.1401.
C18H13ClF3N2OS [M+H]+ 397.0384, found 397.0382.
2,6-Dimethyl-6-(((trifluoromethyl)thio)methyl)indolo[2,1-
8-Bromo-6-methyl-6-(((trifluoromethyl)thio)methyl)indolo[2,1-
b]quinazolin-12(6H)-one (2i-1). White solid, 23% yield, mp: 88-99 ℃, b]quinazolin-12(6H)-one (2n). White solid, 80% yield, mp: 175-176
1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 7.68 ℃, 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 8.5 Hz, 1H), 8.40 (d, J = 7.8
(d, J = 8.2 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.55 – 7.43 (m, 2H), 7.37 (t, Hz, 1H), 7.84 – 7.74 (m, 2H), 7.59 – 7.52 (m, 1H), 7.50 – 7.42 (m, 2H),
J = 7.4 Hz, 1H), 3.59 (q, J = 12.8 Hz, 2H), 2.53 (s, 3H), 1.74 (s, 3H). 13
C
3.59 (q, J = 13.1 Hz, 2H), 1.75 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
NMR (100 MHz, CDCl3) δ 160.3, 159.9, 145.3, 139.4, 137.4, 135.8, 160.6, 159.6, 147.2, 137.8, 135.0, 134.6, 132.3, 130.2 (q, J = 306.8
133.2, 130.4 (q, J = 306.6 Hz), 129.6, 127.3, 126.6, 126.4, 123.0, Hz),129.7, 127.6, 127.4, 126.9, 123.5, 121.4, 118.4, 48.8, 38.4(q, J =
121.3, 117.4, 48.5, 38.7 (q, J = 1.5 Hz), 25.0, 21.3. HRMS (ESI) calcd 1.6 Hz), 24.9. HRMS (ESI) calcd for C18H13BrF3N2OS [M+H]+ 440.9879,
for C19H16F3N2OS [M+H]+ 377.0930, found 377.0930.
found 440.9870.
4,6-Dimethyl-6-(((trifluoromethyl)thio)methyl)indolo[2,1-
3-Methyl-3-(((trifluoromethyl)thio)methyl)-2,3-dihydropyrrolo[2,1-
b]quinazolin-12(6H)-one (2i-2). White solid, 57% yield, mp: 129-130 b]quinazolin-9(1H)-one (2p). White solid, 81% yield, mp: 44-45 ℃, 1H
℃, 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 7.9 NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.0 Hz, 1H), 7.80 – 7.69 (m, 2H),
Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.54 – 7.32 (m, 4H), 3.59 (dd, J = 29.4, 7.49 (t, J = 7.4 Hz, 1H), 4.35 – 4.25 (m, 1H), 4.14 – 4.03 (m, 1H), 3.40
12.8 Hz, 2H), 2.68 (s, 3H), 1.75 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (dd, J = 40.1, 13.4 Hz, 2H), 2.49 – 2.39 (m, 1H), 2.20 – 2.12 (m, 1H),
160.2, 159.7, 145.8, 139.4, 136.2, 135.1, 133.4, 130.5 (q, J = 306.6 1.53 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.8, 160.8, 149.0, 134.28,
Hz), 129.6, 126.6, 124.5, 123.0, 121.5, 117.4, 48.6, 38.6 (q, J = 1.5 Hz), 130.7 (q, J = 306.0 Hz), 127.2, 126.6, 126.4, 120.9, 47.1, 43.2, 37.6 (q,
25.3, 17.4. HRMS (ESI) calcd for C19H16F3N2OS [M+H]+ 377.0930, J = 1.6 Hz), 31.7, 24.0. HRMS (ESI) calcd for C14H14F3N2OS [M+H]+
found 377.0928.
315.0773, found 315.0775.
1,6-Dimethyl-6-(((trifluoromethyl)thio)methyl)indolo[2,1-
6-Isopropyl-6-(((trifluoromethyl)thio)methyl)indolo[2,1-
b]quinazolin-12(6H)-one (2j). White solid, 85% yield, mp: 114-115 ℃, b]quinazolin-12(6H)-one (2q). White solid, 85% yield, mp: 96-97 ℃,
1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 4.4 Hz, 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 8.0 Hz, 1H), 8.47 (d, J = 8.0 Hz,
2H), 7.51 – 7.43 (m, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.28 (t, J = 4.3 Hz, 1H), 7.83 (d, J = 3.1 Hz, 2H), 7.63 – 7.51 (m, 2H), 7.47 (d, J = 7.2 Hz,
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Organic & Biomolecular Chemistry
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Journal Name
1H), 7.40 (t, J = 7.4 Hz, 1H), 3.76 (q, J = 12.3 Hz, 2H), 2.58 (dt, J = 13.6, 125.1, 121.4, 117.7, 55.6, 38.3 (q, J = 1.3 Hz). HRMS V(iEewSIA)rcticallecOdnflioner
6.8 Hz, 1H), 1.03 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H). 13C NMR C23H15ClF3N2OS [M+H]+ 459.0540, found 459D.0O5I3: 160..1039/D0OB00233J
(100 MHz, CDCl3) δ 160.5, 159.8, 147.2, 140.5, 134.4, 130.6, 130.4 (q,
J = 306.3 Hz), 129.6, 127.7, 127.1, 126.9, 126.4, 123.8, 121.5, 117.2,
6-(4-Bromophenyl)-6-(((trifluoromethyl)thio)methyl)indolo[2,1-
b]quinazolin-12(6H)-one (2w). White solid, 80% yield, mp: 160-161
56.0, 37.5, 36.2 (q, J = 1.5 Hz), 17.3. HRMS (ESI) calcd for
℃, 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 8.1 Hz, 1H), 8.41 (d, J = 7.9
C20H18F3N2OS [M+H]+ 391.1086, found 391.1085.
Hz, 1H), 7.85 – 7.71 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.57 – 7.51 (m,
6-Cyclohexyl-6-(((trifluoromethyl)thio)methyl)indolo[2,1-
1H), 7.50 – 7.39 (m, 4H), 7.34 (d, J = 8.6 Hz, 2H), 4.06 (dd, J = 30.7,
b]quinazolin-12(6H)-one (2r). White solid, 82% yield, mp: 145-146 ℃, 12.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 159.8, 159.4, 147.1, 140.2,
1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 8.0 Hz, 1H), 8.47 (d, J = 7.9 Hz, 137.9, 134.6, 132.1, 130.9, 130.4, 128.8, 127.8, 127.5, 126.9, 126.9,
1H), 7.91 – 7.78 (m, 2H), 7.63 – 7.51 (m, 2H), 7.47 (d, J = 7.2 Hz, 1H), 125.1, 122.8, 121.4, 117.7, 100.0, 55.6, 38.2 (q, J = 1.5 Hz). HRMS (ESI)
7.40 (t, J = 7.5 Hz, 1H), 3.84 – 3.68 (m, 2H), 2.24 (t, J = 11.8 Hz, 1H), calcd for C23H15BrF3N2OS [M+H]+ 503.0335, found 503.0335.
1.79 (t, J = 12.0 Hz, 2H), 1.63 (s, 2H), 1.43 (d, J = 12.3 Hz, 1H), 1.30 –
6-(p-Tolyl)-6-(((trifluoromethyl)thio)methyl)indolo[2,1-b]quinazolin-
12(6H)-one (2x). White solid, 84% yield, mp: 126-127 ℃, H NMR
(400 MHz, CDCl3) δ 8.71 (d, J = 8.0 Hz, 1H), 8.40 (d, J = 7.8 Hz, 1H),
1.14 (m, 3H), 1.08 – 0.94 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 160.8,
1
159.8, 147.2, 140.5, 134.4, 131.0, 130.5 (q, J = 306.7 Hz), 129.5,
127.7, 127.1, 126.9, 126.4, 123.9, 121.4, 117.1, 56.2, 47.4, 35.9 (q, J
7.78 – 7.70 (m, 2H), 7.59 – 7.46 (m, 3H), 7.41 (t, J = 7.5 Hz, 1H), 7.32
= 1.1 Hz), 27.2, 26.4, 26.1, 25.9. HRMS (ESI) calcd for C23H22F3N2OS
(d, J = 8.2 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 4.10 (q, J = 12.4 Hz, 2H),
2.30 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 159.9, 147.3, 140.2, 138.4,
[M+H]+ 431.1339, found 431.1394.
6-Pentyl-6-(((trifluoromethyl)thio)methyl)indolo[2,1-b]quinazolin-
136.1, 134.4, 131.8, 130.4 (d, J = 306.9 Hz), 130.0, 129.7, 127.9,
12(6H)-one (2s). White solid, 80% yield, mp: 57-58 ℃, 1H NMR (400 127.2, 126.9, 126.8, 126.7, 125.2, 121.5, 117.5, 55.8, 38.2 (q, J = 1.5
MHz, CDCl3) δ 8.64 (d, J = 8.0 Hz, 1H), 8.44 (d, J = 7.9 Hz, 1H), 7.80 (d, Hz), 21.0. HRMS (ESI) calcd for C24H18F3N2OS [M+H]+ 439.1086, found
J = 3.7 Hz, 2H), 7.62 – 7.47 (m, 2H), 7.45 – 7.32 (m, 2H), 3.61 (dd, J = 439.1085.
32.1, 12.7 Hz, 2H), 2.37 – 2.20 (m, 1H), 2.13 – 1.97 (m, 1H), 1.12 (s,
Verify experiment (Scheme 4), preparation of 1-chloro-6-methyl-6-
(((trifluoromethyl)thio)methyl)indolo[2,1-b]quinazolin-12(6H)-one
(2z).
4H), 0.94 – 0.76 (m, 2H), 0.77 – 0.67 (m, 3H). 13C NMR (100 MHz,
CDCl3) δ 160.5, 159.8, 147.3, 140.2, 134.4, 131.6, 130.4 (q, J = 306.6
Hz), 129.6, 127.6, 127.1, 126.9, 126.7, 123.1, 121.5, 117.3, 53.1, 39.0,
To a 25 mL over-dried shrek tube was added 1z (83.4 mg, 0.2 mmol,
38.2(q, J = 1.6 Hz), 31.6, 29.7, 23.8, 22.1, 13.8. HRMS (ESI) calcd for
1.0 equiv), AgSCF3 (50.4 mg, 0.24 mmol, 1.2 equiv), K2S2O8 (81 mg,
C22H22F3N2OS [M+H]+ 419.1399, found 419.1398.
0.3 mmol, 1.5 equiv) and 2.0 mL DMSO. The reaction mixture was
6-Phenyl-6-(((trifluoromethyl)thio)methyl)indolo[2,1-b]quinazolin-
12(6H)-one (2t). White solid, 81% yield, mp: 41-43 ℃, 1H NMR (400
o
stirred rapidly at 60 C for 16 h. Compound 2z was isolated in 84%
yield, white solid, mp: 69-71 ℃. 1H NMR (400 MHz, CDCl3) δ 7.66 (d,
MHz, CDCl3) δ 8.71 (d, J = 8.1 Hz, 1H), 8.41 (d, J = 7.7 Hz, 1H), 7.79 –
J = 7.7 Hz, 1H), 7.54 – 7.40 (m, 3H), 7.36 (d, J = 7.1 Hz, 1H), 6.68 (d, J
7.73 (m, 2H), 7.61 – 7.48 (m, 3H), 7.47 – 7.40 (m, 3H), 7.37 – 7.27 (m,
= 7.0 Hz, 2H), 3.56 (s, 2H), 1.81 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
181.4, 179.0, 167.7, 146.5, 146.4, 136.1, 134.0, 130.4, 130.3 (q, J =
348.1 Hz) , 130.1 127.0, 124.4, 113.5, 45.1, 37.2 (q, J = 2.1 Hz), 24.5.
3H), 4.12 (dd, J = 40.4, 12.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ
160.0, 159.9, 147.3, 140.2, 139.0, 134.5, 131.9, 131.5, 130.1, 129.0,
128.4, 127.9, 127.3, 127.0, 126.9, 126.8, 125.2, 121.5, 117.6, 56.1,
HRMS (ESI) calcd for C18H13ClF3N2OS [M+H]+ 397.0348, found
38.2 (q, J = 1.6 Hz). HRMS (ESI) calcd for C23H16F3N2OS [M+H]+
397.0380.
425.0930, found 425.0934.
TEMPO were used as radical scavenger (Scheme 4).
6-(4-Fluorophenyl)-6-(((trifluoromethyl)thio)methyl)indolo[2,1-
To a 25 mL over-dried shrek tube was added 1a (52.4 mg, 0.2 mmol,
1.0 equiv), AgSCF3 (50.4 mg, 0.24 mmol, 1.2 equiv), TEMPO (62.5 mg,
0.4 mmol, 2.0 equiv), K2S2O8 (0.3 mmol, 1.5 equiv) and 2.0 mL DMSO.
The reaction mixture was stirred rapidly at 60 oC for 16 h. We
b]quinazolin-12(6H)-one (2u). White solid, 82% yield, mp: 91-92 ℃,
1H NMR (400 MHz, CDCl3) δ 8.76 – 8.67 (m, 1H), 8.42 (d, J = 7.7 Hz,
1H), 7.82 – 7.73 (m, 2H), 7.63 – 7.58 (m, 1H), 7.57 – 7.52 (m, 1H), 7.50
(d, J = 6.5 Hz, 1H), 7.47 – 7.44 (m, 1H), 7.44 – 7.38 (m, 2H), 7.35 – 7.28
recovered 1a with 96% yield. The corresponding product 2aa and the
(m, 2H), 4.07 (dd, J = 31.4, 12.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ
directing trapping product between TEMPO and SCF3 radical were
not observed based on 1H NMR and HRMS.
163.8, 161.3, 159.8 (d, J = 2.6 Hz), 147.2, 140.2, 134.5, 131.1, 130.3,
129.1, 129.0 (d, J = 8.2 Hz), 128.5, 127.8, 127.4, 126.9, 126.8, 125.2,
121.5, 117.7, 115.9 (d, J = 21.6 Hz), 55.5, 38.5 (q, J = 1.3 Hz). HRMS
(ESI) calcd for C23H15F4N2OS [M+H]+ 443.0836, found 443.0840.
Conclusions
6-(4-Chlorophenyl)-6-(((trifluoromethyl)thio)methyl)indolo[2,1-
In short, we used N-acylcyanamides as starting materials for the
b]quinazolin-12(6H)-one (2v). White solid, 83% yield, mp: 183-184
synthesis of previously unreported trifluoromethylthio-
℃, 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 8.1 Hz, 1H), 8.41 (d, J = 7.7
substituted tryptanthrin derivatives by means of a radical
Hz, 1H), 7.79 – 7.75 (m, 2H), 7.62 – 7.56 (m, 1H), 7.56 – 7.51 (m, 1H),
7.51 – 7.47 (m, 1H), 7.47 – 7.43 (m, 1H), 7.43 – 7.38 (m, 2H), 7.34 –
7.28 (m, 2H), 4.07 (dd, J = 31.4, 12.5 Hz, 2H). 13C NMR (100 MHz,
CDCl3) δ 159.8, 159.5, 147.1, 140.2, 137.4, 134.6, 134.5, 130.9, 130.3,
129.1, 128.5, 127.8, 127.4, 127.2 (q, J = 306.9 Hz), 126.9, 126.8,
trifluoromethylthiolation/cyclization
cascade.
This
transformation, which involves the formation of a C(sp3)–SCF3
bond, a C(sp2)–C bond, and a C(sp2)–N bond, proceeds smoothly
in moderate to excellent yields and represents a new strategy
for synthesis of tryptanthrin derivatives.
6 | J. Name., 2012, 00, 1-3
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Chem., 2017, 6, 445-448; d) M. Zhu, W. J. Fu, W. S. Guo, Y. F.
Conflicts of interest
There are no conflicts to declare.
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Tian, Z. Q. Wang, B. M. Ji, Org. Biomol. Chem., 2019, 17, 3374-
DOI: 10.1039/D0OB00233J
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Acknowledgements
This study was supported by Natural Science Fund of China
(21772145, 21732002, 21772104).
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This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB00233J
ARTICLE
Graphical Abstract
O
N
O
N
SCF3
condition
N
N
SCF3
Forming three chemical bonds in one step ;
24 substrates, 57%~86% isolated yield;
Mild condition, cheap catalyst
atom-economical strategy
An efficient strategy for synthesis of SCF3-substituted tryptanthrin derivatives was developed with AgSCF3/K2S2O8-promoted radical
trifluoromethylthiolation/cyclization cascade reaction as key step.
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DOI: 10.1039/D0OB00233J
Table of contents entry
O
N
O
N
SCF3
condition
N
N
SCF3
Forming three chemical bonds in one step ;
24 substrates, 57%~86% isolated yield;
Mild condition, cheap catalyst
atom-economical strategy
An efficient strategy for synthesis of SCF3-substituted tryptanthrin derivatives was developed with
AgSCF3/K2S2O8-promoted radical trifluoromethylthiolation/cyclization cascade reaction as key step.