Domino Oxidative Cyclization of 2-Aminoacetophenones for the One-Pot Synthesis of Tryptanthrin Derivatives

Article abstract of DOI:10.1002/ejoc.201501079

A new CuI/DMSO-mediated oxidative domino process has been developed for the synthesis of tryptanthrin derivatives. This is the first example of the synthesis of tryptanthrin derivatives directly from 2-aminoaryl methyl ketones and isatoic anhydrides through copper-promoted oxidative functionalization. A new DMSO/CuI-catalysed oxidative domino process has been developed for the one-pot synthesis of tryptanthrin derivatives.

Full text of DOI:10.1002/ejoc.201501079

FULL PAPER
DOI: 10.1002/ejoc.201501079
Domino Oxidative Cyclization of 2-Aminoacetophenones for the One-Pot
Synthesis of Tryptanthrin Derivatives
[a]
[a,b]
[a]
[a]
B. V. Subba Reddy,* D. Maheswara Reddy,
G. Niranjan Reddy, M. Ramana Reddy,
[b]
and V. Krishna Reddy
Keywords: Synthetic methods / Indolo[2,1-b]quinazolines / 2-Aminoacetophenone / Isatoic anhydride / Nitrogen
heterocycles
A new CuI/DMSO-mediated oxidative domino process has
been developed for the synthesis of tryptanthrin derivatives.
This is the first example of the synthesis of tryptanthrin deriv-
atives directly from 2-aminoaryl methyl ketones and isatoic
anhydrides through copper-promoted oxidative functionali-
zation.
Introduction
3
The direct C–H-bond functionalization of sp -CH3
groups is a versatile synthetic strategy for the construction
[1]
of C–C and C–N bonds. It proceeds through the acti-
3
2
vation of sp - or sp -C–H bonds by a metal species, fol-
lowed by oxidative addition.[ Recently, much effort has
been directed towards the development of sp -C–H-bond
2]
3
amidation through oxidative C–H/N–H cross-coupling re-
[
3]
I
actions. Recently, the use of Cu salts for oxidative C–H-
bond functionalization has received much attention due to
the low cost, negligible toxicity, ready availability, and
broad substrate tolerance of these salts.[
Figure 1. Biologically active quinazolinone natural products.
4]
The indolo[2,1-b]quinazoline core is found in many bio-
logically active natural products, including the asperlicins,
the benzomalvins, the circumdatins, tryptanthrin, phai-
Due to the scarcity of natural tryptanthrin, and to its
unique biological activity, several synthetic methods have
been developed for the synthesis of tryptanthrin derivatives
[
5]
tanthrins A–E, methylisatoid, candidine, etc. (Figure 1).
Compounds containing this moiety have been found to
[
11]
(Scheme 1).
The condensation of isatoic anhydride with
have a broad spectrum of biological activities.[
5–7]
Tryp-
tanthrin, a naturally occurring indolo[2,1-b]quinazoline al-
kaloid, was isolated from the indigo plant Strobilanthes cu-
[
8]
sia (Acanthaceae).
It shows remarkable cytotoxicity
against various cancer cell lines, including human breast
carcinoma (MCF-7), lung carcinoma (NCI-H460), and cen-
[5]
tral nervous system carcinoma (SF-268). It also shows po-
tent antimicrobial and antileishmanial activity.[ Recently,
tryptanthrin derivatives have been reported to act as potent
antitubercular agents.[
9]
10]
[
[
a] Natural Product Chemistry, CSIR – Indian Institute of
Chemical Technology,
Tarnaka, Hyderabad 500607, India
E-mail: basireddy@iict.res.in
www.iictindia.org
b] Department of Chemistry, Sri Krishnadevaraya University,
Anantapuram 515001, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201501079.
Scheme 1. Previous approaches. NMP = N-methylpyrrolidine;
DMAP = 4-(dimethylamino)pyridine.
8018
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 8018–8022

Domino Oxidative Cyclization of 2-Aminoacetophenones
isatin in the presence of base under heating conditions is Table 1. Screening of substrates for the formation of 3a.
one of the more direct of these methods.[ An alternative
12]
approach involves the coupling of ortho-aminobenzoic acid
with isatin using SOCl2.[ Eguchi et al. reported the syn-
13]
thesis of tryptanthrin from 2-azidobenzoyl chloride through
an intramolecular aza-Wittig reaction using triethyl-
[
14]
amine.
tanthrin from isatin using POCl3.
Bergman et al. reported the formation of tryp-
[15]
However, many of
these methods involve step-by-step synthetic strategies.
Therefore, the development of a one-pot strategy for the
synthesis of tryptanthrin derivatives would be desirable, es-
pecially for the generation of diversified scaffolds.
Results and Discussion
Following on from our interest in quinazolinone alka-
[
16]
loids, in this paper, we report a new strategy for the syn-
thesis of tryptanthrin derivatives from acetophenone and
isatoic anhydride using CuI/DMSO under aerobic condi-
tions. We first prepared N-(2-acetylphenyl)-2-aminobenz-
amide (A) from isatoic anhydride (1) and 2-aminoaceto-
phenone (2) in a single step (see Supporting Information).
Substrate (A) was then heated at 100 °C in the presence of [a] Reaction was carried out using CuI (10 mol-%) in DMSO at
100 °C.
CuI (10 mol-%) in DMSO under pure oxygen (Scheme 2).
Table 2. Optimizing the conditions for the formation of 3a.[a]
Entry
Catalyst
AlCl
ZnCl
FeCl
InCl
Cu(OAc)
CuOTf
Cu(OTf)2
CuI
Amount [mol-%]
Time [h]
Yield [%]
a
b
c
d
e
f
g
h
i
3
10
10
10
10
10
10
10
10
30
10
12
10
12
12
10
12
12
12
10
12
0
0
0
0
25
20
30
40
50
75
45
Scheme 2. Oxidative cyclization of A to give tryptanthrin.
2
3
3
The expected product, tryptanthrin (3a), was obtained in
only 40% yield after 12 h. It was purified by flash column
chromatography on silica gel, and characterized by NMR
and IR spectroscopy and mass spectrometry.
2
CuI
CuI
I
2
Encouraged by this result, we next tried to develop a one-
step synthesis of tryptanthrin from commercially available
precursors. Accordingly, we carried out the condensation of
j
k
150
150
[
a] A mixture of isatoic anhydride (1) (0.5 mmol), 2-aminoaceto-
2-aminoacetophenone (2) with different substrates, includ-
phenone (2) (0.6 mmol) and CuI (1.5 equiv.) in DMSO (5 mL) was
stirred at 100 °C under oxygen.
ing isatoic anhydride, 2-aminobenzoic acid, 2-amino-N-
methoxy-N-methylbenzamide, and isatin, under similar
conditions (Table 1).
The condensation of 2-aminoacetophenone (2) with
isatoic anhydride gave the desired product (i.e., 3a) in 40%
To try to further improve the yield of 3a, the reaction
yield (Table 1, Entry a). To optimize the conditions, various was carried out at different temperatures. The maximum
catalysts were then screened, and the results are presented conversion was achieved using 1.5 equiv. of CuI at 100 °C
in Table 2. None of the catalysts tested gave the desired in DMSO (Table 2, Entry j). It is noteworthy that the prod-
product except for copper salts and iodine (Table 2, En- uct was obtained in low yield (35%) when the reaction was
tries a–d). Of the various copper salts tested, CuI was found run under nitrogen. The scope of this process was further
to be superior in terms of yield. Therefore, the reaction was evaluated with respect to substituted isatoic anhydrides
tested with different amounts of CuI (Table 2, Entries h–j). such as 6-methyl and 4-chloro derivatives, which were pre-
Indeed, the yield was improved from 50 to 75% by increas- pared according to a reported procedure.[17] In all cases,
ing the amount of CuI to 1.5 equiv. (Table 2, Entry j). In the the corresponding tryptanthrin derivatives were obtained in
absence of a catalyst, the reaction did not give the desired good yields (Table 3). The method was also found to work
product. To our surprise, an I /DMSO system also gave the well with 2-aminoaryl methyl ketones bearing different sub-
2
product (i.e., 3a), albeit in low yield (Table 2, Entry k).
stituents on the aromatic ring (Table 3).
Eur. J. Org. Chem. 2015, 8018–8022
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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B. V. S. Reddy et al.
FULL PAPER
Table 3. Domino cyclization of isatoic anhydride (1) (0.5 mmol), 2- is proposed to proceed through the formation of amide A.
aminoacetophenone (2) (0.6 mmol) and CuI (1.5 equiv.) in DMSO
(5 mL) at 100 °C under oxygen.
Copper-mediated aerobic oxidation of A can generate acyl-
[4b]
iminium ion B.
by oxidative aromatization would give tryptanthrin 3
Scheme 3).
Subsequent cyclization of B followed
(
Scheme 3. Possible reaction mechanism.
Finally, we attempted the synthesis of tryptanthrin from
2-aminoacetophenone (2) without the use of isatoic an-
hydride. To our delight, the desired product, tryptanthrin
(3a), was isolated in 70% yield when 2-aminoacetophenone
(2) was heated in DMSO at 100 °C in the presence of CuI
(1.5 equiv.) under oxygen (Scheme 4).
Scheme 4. Formation of 3a from 2-aminoacetophenone (2).
We examined the substrate scope, by testing the method
with 5-chloro- and 5-bromo-2-aminoacetophenones. How-
ever, these substrates failed to undergo self-condensation to
give the expected tryptanthrin derivatives under similar
conditions. Instead, the corresponding isatins were isolated
in low yields (20–30%). This is due to the intrinsic low reac-
tivity of these substrates compared to 2-aminoacetophen-
one.
Based on previous observations,[18] we also propose a
similar mechanism for this transformation (Scheme 5). To
study the reaction pathway, 2-aminoacetophenone (2) was
treated with CuI (1.5 equiv.) in the presence of pivalic acid
[
18e]
(1.0 equiv.) under oxygen at 100 °C for 12 h.
To our sur-
prise, no tryptanthrin was formed, and instead isatin was
isolated in 60% yield. These results indicate that the reac-
tion proceeds through the formation of isatin from 2-
[
18]
aminoacetophenone (2).
Subsequent hydrolysis of isatin
[
a] All the products were characterized by NMR spectroscopy and
generates the α-oxocarboxylic acid, which can then undergo
copper-catalysed decarboxylative coupling with another
molecule of 2-aminoacetophenone (2) to give amide A.[
mass spectrometry. [b] Yield refers to pure products after
chromatography.
4b]
Based on the above results, we propose a possible mecha- As shown in Scheme 3, A can undergo a series of transfor-
nism for this reaction, as shown in Scheme 3. The reaction mations to give the desired tryptanthrin (3a).
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Eur. J. Org. Chem. 2015, 8018–8022

Domino Oxidative Cyclization of 2-Aminoacetophenones
product was purified by silica gel column chromatography (100–
00 mesh) with ethyl acetate/hexane as eluent to give pure N-(2-
2
1
acetylphenyl)-2-aminobenzamide (A).
CDCl ): δ = 12.5 (br. s, 1 H), 8.89 (d, J = 7.9 Hz, 1 H), 7.96 (d, J
6.5 Hz, 1 H), 7.79 (d, J = 8.0 Hz, 1 H), 7.61 (t, J = 7.1 Hz, 1 H),
.29–7.26 (m, 1 H), 7.15 (t, J = 7.1 Hz, 1 H), 6.81–6.71 (m, 1 H),
H
NMR (500 MHz,
3
=
7
5
1
3
3
.79 (br. s, 2 H), 2.72 (s, 3 H) ppm. C NMR (125 MHz, CDCl ):
δ = 203.9, 168.6, 149.9, 141.5, 135.1, 132.9, 131.8, 130.9, 128.8,
27.8, 122.2, 120.7, 117.5, 116.9, 23.7 ppm. MS (ESI): m/z = 255
1
+
15 2 2
[M + H] . HRMS (ESI): calcd. for C15H N O 255.1133; found
255.1128.
Procedure for the Synthesis of Tryptanthrin from 2-Aminoaceto-
phenone (2): CuI (1.5 equiv.) was added to a stirred solution of 2-
aminoacetophenone (2) (0.6 mmol) in DMSO (5 mL) at 25 °C. The
resulting mixture was stirred at 100 °C under oxygen for the speci-
Scheme 5. Possible reaction mechanism.
Recently, the formation of isatin from 2-aminoaceto- fied time (Table 2). After TLC indicated that the reaction was com-
plete, the mixture was quenched with saturated NaHCO solution
(1.0 mL) and extracted with dichloromethane (2ϫ 5 mL). The
combined organic layers were washed with brine (3–5 mL), dried
3
phenone (2) has been reported through an oxidative func-
[
18]
tionalization.
However, the formation of tryptanthrin
from 2-aminoacetophenone (2) is an entirely new and at-
tractive strategy.
with anhydrous Na
crude product was purified by silica gel column chromatography
100–200 mesh) with ethyl acetate/hexane as eluent to give the pure
2 4
SO , and concentrated in vacuo. The resulting
(
tryptanthrin.
Conclusions
Indolo[2,1-b]quinazoline-6,12-dione (Tryptanthrin) (3a): Solid; m.p.
1
2
1
60–262 °C. H NMR (500 MHz, CDCl
3
): δ = 8.66 (d, J = 7.7 Hz,
We developed a new one-pot strategy for the synthesis of
tryptanthrin derivatives from 2-aminoaryl methyl ketones
and isatoic anhydrides. This domino process proceeds
through copper-mediated aerobic oxidation, imine forma-
tion, nucleophilic addition, and oxidative aromatization.
This method is applicable to a wide range of substrates, and
has a high functional-group tolerance. The method uses
readily available reagents, and is quite simple, convenient,
and practical.
H), 8.43 (d, J = 7.9 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.92 (d,
J = 7.5 Hz, 1 H), 7.85 (dt, J = 1.3, 7.4 Hz, 1 H), 7.79 (t, J = 7.7 Hz,
1
3
1
H), 7.67 (t, J = 7.7 Hz, 1 H), 7.43 (d, J = 7.5 Hz, 1 H) ppm.
C
3
NMR (125 MHz, CDCl ): δ = 181.8, 157.0, 145.7, 145.4, 137.4,
134.3, 130.0, 129.5, 126.8, 126.5, 124.7, 123.1, 121.3, 117.4 ppm.
+
8 2 2
MS (EI): m/z = 248 [M] . HRMS (EI): calcd. for C15H N O
248.0586; found 248.0586.
1
-Methylindolo[2,1-b]quinazoline-6,12-dione (3b): Solid; m.p.195–
1
3
197 °C. H NMR (300 MHz, CDCl ): δ = 8.65 (d, J = 7.8 Hz, 1
H), 7.93 (t, J = 7.2 Hz, 2 H), 7.80–7.75 (m, 2 H), 7.60–7.43 (m, 3
1
3
H), 2.5 (s, 3 H) ppm. C NMR (125 MHz, CDCl
3
): δ = 180.9,
Experimental Section
164.3, 156.8, 142.6, 138.1, 134.1, 133.2, 129.1, 126.8, 125.2, 121.9,
+
1
17.9, 23.0 ppm. MS (EI): m/z = 262 [M] . HRMS (EI): calcd. for
262.0742; found 262.0738.
-Bromoindolo[2,1-b]quinazoline-6,12-dione (3c): Solid; m.p. 290–
General Remarks: All solvents were dried according to standard
literature procedures. Reactions were carried out in oven-dried
round-bottomed flasks under oxygen. Crude products were puri-
fied by column chromatography on silica gel (60–120 or 100–
16 10 2 2
C H N O
8
2
7
1
92 °C. H NMR (500 MHz, CDCl
.68 (m, 2 H), 7.40 (t, J = 7.7 Hz, 1 H), 7.15 (s, 1 H) ppm.
): δ = 189.5, 155.5, 154.3, 137.5, 135.9,
34.9, 134.8, 131.0, 129.7, 125.5, 124.7, 113.9, 113.0, 112.7 ppm.
3
): δ = 8.6–8.43 (m, 3 H), 7.76–
1
3
C
200 mesh). Spots on hin-layer chromatography plates were visual-
NMR (125 MHz, CDCl
1
3
ized by exposure to ultraviolet light and/or by exposure to iodine
vapours and/or by exposure to a methanolic acidic solution of p-
anisaldehyde followed by heating (Ͻ 1 min) on a hot plate (ca.
+
MS (EI): m/z = 325 [M] . HRMS (EI): calcd. for C15
25.9691; found 325.9697.
8-Bromo-3-chloroindolo[2,1-b]quinazoline-6,12-dione (3d): Solid;
7 2 2
H BrN O
3
2
50 °C). Organic solutions were concentrated using a rotary evapo-
1
13
rator at 35–40 °C. H and C (proton-decoupled) NMR spectra
were recorded in CDCl with a 200, 300, 400, or 500 MHz NMR m.p. 256–258 °C. H NMR (500 MHz, CDCl ): δ = 8.12 (d, J =
spectrometer. Chemical shifts (δ) are reported in parts per million
ppm) relative to tetramethylsilane, which was used as an internal
C
1
3
3
8.4 Hz, 1 H), 7.91 (d, J = 8.7 Hz, 1 H), 7.61–7.55 (m, 2 H), 7.45
1
3
(
(m, 1 H), 6.86 (s, 1 H), 6.62 (dd, J = 1.7, 8.7 Hz, 1 H) ppm.
standard. Coupling constants (J) are quoted in Hertz (Hz). Mass
spectra were recorded with a mass spectrometer using the electro-
spray ionization (ESI) or the atmospheric-pressure chemical ioniza-
tion (APCI) technique.
NMR (125 MHz, CDCl ): δ = 180.0, 146.4, 138.5, 136.3, 129.9,
3
128.7, 127.1, 124.9, 124.5, 115.1, 115.0, 113.8 ppm. MS (EI): m/z =
+
359 [M] . HRMS (EI): calcd. for C H BrClN O 359.9302; found
1
5
6
2
2
359.9305.
N-(2-Acetylphenyl)-2-aminobenzamide (A): Isatoic anhydride
8-Methylindolo[2,1-b]quinazoline-6,12-dione (3e): Solid; m.p. 281–
1
(0.5 mmol) and 2-aminoacetophenone (2) (0.6 mmol) were dis-
283 °C. H NMR (300 MHz, CDCl
3
): δ = 8.93 (dd, J = 8.2,
solved in DMF (5 mL) at 25 °C. The resulting mixture was stirred
under reflux for 1 h. After TLC indicated that the reaction was
13.9 Hz, 1 H), 8.64–8.51 (m, 1 H), 8.30–8.11 (m, 1 H), 7.88–7.37
1
3
(m, 2 H), 7.34–7.28 (m, 1 H), 3.02 (s, 3 H) ppm. C NMR
(125 MHz, CDCl ): δ = 181.8, 167.7, 147.9, 146.0, 143.7, 138.3,
134.5, 131.5, 129.6, 127.0, 126.5, 117.3, 116.8, 116.1, 25.2 ppm. MS
complete, the mixture was quenched with saturated NaHCO
3
solu-
3
tion (1.0 mL) and extracted with ethyl acetate (2–5 mL). The com-
bined organic layers were washed with brine (3–5 mL), dried with
+
10 2 2
(EI): m/z = 262 [M] . HRMS (EI): calcd. for C16H N O
anhydrous Na
2
SO
4
, and concentrated in vacuo. The resulting crude
262.0742; found 262.0746.
Eur. J. Org. Chem. 2015, 8018–8022
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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B. V. S. Reddy et al.
FULL PAPER
3
2
1
7
,8-Dichloroindolo[2,1-b]quinazoline-6,12-dione (3f): Solid; m.p.
[2] a) F. Collet, C. Lescot, P. Dauban, Chem. Soc. Rev. 2011, 40,
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194.
1
88–290 °C. H NMR (500 MHz, CDCl
3
): δ = 8.23 (d, J = 8.4 Hz,
H), 7.97 (d, J = 8.7 Hz, 1 H), 7.71–7.67 (m, 1 H), 7.56 (s, 1 H),
13
.52–7.50 (m, 1 H), 7.43 (dd, J = 1.9, 8.4 Hz, 1 H) ppm. C NMR
): δ = 181.1, 157.5, 157.0, 149.6, 146.6, 131.7,
30.4, 130.1, 129.3, 128.1, 127.7, 125.4, 116.7, 115.6 ppm. MS (EI):
[
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(75 MHz, CDCl
3
1
+
6 2 2 2
m/z = 315 [M] . HRMS (EI): calcd. for C15H Cl N O 315.9806;
found 315.9815.
8-Methoxyindolo[2,1-b]quinazoline-6,12-dione (3g): Solid; m.p. 278–
1
5, 378; f) X. Wu, Q. Gao, S. Liu, A. Wu, Org. Lett. 2014, 16,
1
2
3
80 °C. H NMR (300 MHz, CDCl ): δ = 8.53 (d, J = 8.7 Hz, 1
2888.
H), 8.43 (dd, J = 1.4, 8.1 Hz, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 7.85
dt, J = 1.8, 8.5 Hz, 1 H), 7.73–7.66 (m, 1 H), 7.39 (d, J = 3.9 Hz,
[
4] a) Q. Li, Y. Huang, T. Chen, Y. Zhou, Q. Xu, S.-F. Yin, L.-B.
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W. Gu, Z. Wu, W. Zhang, Chem. Rev. 2015, 115, 1622.
(
1
H), 7.32 (dd, J = 2.8, 8.8 Hz, 1 H), 3.90 (s, 3 H) ppm. 1 C NMR
3
(75 MHz, CDCl ): δ = 182.8, 158.1, 156.1, 146.1, 144.9, 139.9,
3
1
5
34.4, 130.2, 129.8, 127.0, 124.6, 123.5, 122.5, 118.8, 108.1, [5] C.-W. Jao, W.-C. Lin, Y.-T. Wu, P.-L. Wu, J. Nat. Prod. 2008,
+
71, 1275.
6.1 ppm. MS (EI): m/z = 278 [M] . HRMS (EI): calcd. for
278.0691; found 278.0695.
[
6] a) J. P. Michael, Nat. Prod. Rep. 2007, 24, 223; b) S. Eguchi,
Top. Heterocycl. Chem. 2006, 6, 113; c) A. M. Tucker, P.
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16 10 2 3
C H N O
8-Chloroindolo[2,1-b]quinazoline-6,12-dione (3h): Solid; m.p. 290–
1
292 °C. H NMR (300 MHz, CDCl
3
): δ = 8.53 (d, J = 8.7 Hz, 1
[7] a) L. A. Mitscher, W. R. Baker, Pure Appl. Chem. 1998, 70, 365;
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H), 8.37 (d, J = 7.7 Hz, 1 H), 7.97 (d, J = 8.0 Hz, 1 H), 7.84–7.79
13
(
m, 2 H), 7.71–7.60 (m, 2 H) ppm. C NMR (125 MHz, CDCl
δ = 181.1, 158.0, 157.0, 146.8, 144.6, 140.0, 134.9, 130.6, 130.3,
27.4, 125.1, 123.7, 122.8, 119.1, 108.3 ppm. MS (EI): m/z = 282
3
):
1
3
9, 59.
+
7 2 2
[M] . HRMS (EI): calcd. for C15H ClN O 282.0196; found
[
[
8] G. Honda, M. Tabata, Planta Med. 1979, 36, 85.
282.0197.
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8-Chloro-1-methylindolo[2,1-b]quinazoline-6,12-dione (3i): Solid;
1
m.p. 265–267 °C. H NMR (300 MHz, CDCl
8
1
3
): δ = 8.62 (d, J =
.6 Hz, 1 H), 7.89–7.85 (m, 1 H), 7.76–7.68 (m, 2 H), 7.57–7.54 (m,
H), 7.45 (d, J = 7.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl
):
10, 1979.
3
[
10] a) J. M. Hwang, T. Oh, T. Kaneko, A. M. Upton, S. G.
δ = 179.8, 169.8, 147.9, 145.7, 142.7, 137.5, 134.3, 133.5, 130.8,
Franzblau, Z. Ma, S.-N. Cho, P. Kim, J. Nat. Prod. 2013, 76,
1
2
2
30.1, 129.3, 128.7, 125.0, 122.8, 119.1, 23.6 ppm. MS (EI): m/z =
354; b) L. A. Mitscher, W. Baker, Med. Res. Rev. 1998, 18, 363.
+
96 [M] . HRMS (EI): calcd. for C16
96.0355.
9 2 2
H ClN O 296.0353; found
[
11] a) A. C. Nelson, E. S. Kalinowski, T. L. Jacobson, P. Grundt,
Tetrahedron Lett. 2013, 54, 6804; b) T. Abe, T. Itoh, T. Choshi,
S. Hibino, M. Ishikura, Tetrahedron Lett. 2014, 55, 5268; c)
S. D. Vaidya, N. P. Argade, Org. Lett. 2010, 12, 3716; d) W. R.
Bowman, M. R. J. Elsegood, T. Stein, G. W. Weaver, Org. Bio-
mol. Chem. 2007, 5, 103.
3
2
-Chloroindolo[2,1-b]quinazoline-6,12-dione (3j): Solid; m.p. 282–
1
3
84 °C. H NMR (300 MHz, CDCl ): δ = 8.59 (d, J = 8.0 Hz, 1
H), 8.36 (d, J = 8.4 Hz, 1 H), 8.15 (d, J = 8.4 Hz, 1 H), 8.03–8.00
m, 1 H), 7.92 (d, J = 7.5 Hz, 1 H), 7.80 (dt, J = 1.3, 8.0 Hz, 1 H),
(
[
12] a) J. Bergman, B. Egestad, J. O. Lindstrom, Tetrahedron Lett.
1977, 18, 2625; b) A. Kumar, V. D. Tripathi, P. Kumar, Green
Chem. 2011, 13, 51.
7
1
1
.64–7.58 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl
3
): δ = 171.6,
66.2, 145.2, 143.6, 139.2, 131.1, 129.8, 128.9, 128.8, 127.5, 126.8,
26.7, 122.5, 119.4 ppm. MS (EI): m/z = 282 [M] . HRMS (EI):
+
[13] a) K.-C. Jahng, S.-I. Kim, D.-H. Kim, C.-S. Seo, J.-K. Son, S.-
H. Lee, E.-S. Lee, Y. Jahng, Chem. Pharm. Bull. 2008, 56, 607;
b) J.-L. Liang, S.-E. Park, Y. Kwon, Y. Jahng, Bioorg. Med.
Chem. 2012, 20, 4962.
calcd. for C15
7 2 2
H ClN O 282.0196; found 282.0194.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of H and C NMR spectra.
1
13
[14] a) S. Eguchi, H. Takeuchi, Y. Matsushita, Heterocycles 1992,
33, 153; b) E.-S. Lee, J.-G. Park, Y. Jahng, Tetrahedron Lett.
2
003, 44, 1883.
Acknowledgments
[15] J. Bergman, J.-O. Lindstrom, U. Tilstam, Tetrahedron 1985, 41,
2879.
B. V. S. R. thanks the Council of Scientific and Industrial Research
[16] J. S. Yadav, B. V. S. Reddy, Tetrahedron Lett. 2002, 43, 1905.
[
17] D. P. Rotella, Z. Sun, Y. Zhu, J. Krupinski, R. Pongrac, L.
(CSIR), New Delhi for financial support as part of the XII five-
Seliger, D. Normandin, J. E. Macor, J. Med. Chem. 2000, 43,
year plan program under the title ORIGIN (CSC-0108).
1257.
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18] a) P.-C. Huang, P. Gandeepan, C.-H. Cheng, Chem. Commun.
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1] a) J. A. Labinger, J. E. Bercaw, Nature 2002, 417, 507; b) J.
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Ramirez, B. Zhao, Y. Shi, Chem. Soc. Rev. 2012, 41, 931; e) C.-
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Received: August 20, 2015
2012, 51, 8960; Angew. Chem. 2012, 124, 9092.
Published Online: November 16, 2015
8022
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 8018–8022