An efficient synthesis of 4,6-dihydrospiro[azepino[4,3,2-cd]indole-3, 3′-indoline]-2′,5(1H)-diones via multi-component reaction

Article abstract of DOI:10.1016/j.tet.2013.12.010

A facile and efficient one-pot three-component synthesis of spiroazepinoindolones has been developed. Using DMF as solvent without any additional acid or metal catalysts, the three-component reaction of readily available isatins, indolamines, and Meldrum's acid affords a new class of spiroheterocycles in moderate yield.

Full text of DOI:10.1016/j.tet.2013.12.010

Tetrahedron 70 (2014) 578e582
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Tetrahedron
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An efficient synthesis of 4,6-dihydrospiro[azepino[4,3,2-cd]indole-
3,30-indoline]-20,5(1H)-diones via multi-component reaction
*
Bin Zou , Chun Chen, Seh Yong Leong, Mei Ding, Paul W. Smith
Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 October 2013
Received in revised form 20 November 2013
Accepted 2 December 2013
Available online 7 December 2013
A facile and efficient one-pot three-component synthesis of spiroazepinoindolones has been developed.
Using DMF as solvent without any additional acid or metal catalysts, the three-component reaction of
readily available isatins, indolamines, and Meldrum’s acid affords a new class of spiroheterocycles in
moderate yield.
Ó 2013 Published by Elsevier Ltd.
Keywords:
Spiroazepinoindolone/spirooxindole
Isatin
Indolamine
Meldrum’s acid
Multi-component reaction
1. Introduction
Spirooxindole is a common feature in not only various natural
alkaloids,1e3 but also pharmaceutically interesting drugs (Fig. 1).4e6
Due to the synthetic challenge of this unique structure and broad
biological activities, spirooxindole-derivatives have received in-
creasing attention from both academic and industrial chemists.7e10
Since developing spirooxindole NITD609 to clinical trials for the
treatment of malaria,6 we are continuously interested in exploring
spirooxindole-derivatives as drug lead compounds. Recently,
a
number of groups have reported the synthesis of new
spirooxindole-skeletonsvia multi-component reactions(MCRs).11e14
Herein, we report an efficient synthesis of novel spi-
a
roazepinoindolone template by three-component reaction of readily
available isatins, indolamines, and Meldrum’s acid (Scheme 1).
Fig. 1. Selected examples of natural products and pharmaceutical drugs/leads with
spirooxindole moiety.
2. Results and discussion
Intrigued by acetic acid promoted condensation of 5-
aminopyrazole, isatin, and Meldrum’s acid reported by Krayush-
kin,15 we considered 1H-indole-4-amine 2 as an alternative com-
ponent to 5-aminopyrazole. With this idea in mind, we tested the
reaction by heating the three starting materials 5-Cl-isatin 1, 1H-
indole-4-amine 2, and Meldrum’s acid 3 in acetic acid for 2 h
* Corresponding author. Tel.: þ65 67222921; fax: þ65 67222918; e-mail address:
Scheme 1. Synthesis of 50-chloro-4,6-dihydrospiro[azepino[4,3,2-cd]indole-3,30-indo-
line]-20,5(1H)-dione 4.
bin.zou@novartis.com (B. Zou).
0040-4020/$ e see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2013.12.010

B. Zou et al. / Tetrahedron 70 (2014) 578e582
579
(Scheme 1). To our delight, the desired product 4 was isolated, al-
though the yield was low (Table 1, entry 1). The structure of the
compound 4 was further confirmed by 1H NMR, 13C NMR, COSY,
NOESY, HMBC, and HSQC data analysis (see Supplementary data).
Our effort was next directed to optimize the reaction conditions
and improve the yield. Some selected conditions attempted are
summarized in Table 1. When the reaction was conducted under
Table 1
Optimization of the reaction conditions
Entry
Conditionsa
Yieldb (%)
1
2
3
4
5
6
7
8
9
AcOH, 120 ꢀC, 2 h
5
8
8
0
0
0
AcOH, 120 ꢀC, microwave, 30 min
10 mol % NaCl/water, reflux, 12 h
InCl3 (0.2e1.0 equiv), CH2Cl2, 0e40 ꢀC, 4 h
TfOH (2e20 equiv), CH2Cl2, 0e40 ꢀC, 4 h
TFA/CH2Cl2 (1:1), 40 ꢀC, 1.5 h
p-TsOH (1e10 equiv), toluene, reflux, 2 h
MeOH, reflux, 1.5 h
NRc
38
28
55
DMSO, 120 ꢀC, 1.5 h
DMF, 120 ꢀC, 2 h
10
a
The molar ratio of three starting materials is 1:1:1 (0.38 mmol).
Isolated yield by preparative HPLC, product purity is >95%.
No reaction.
b
c
microwave conditions, the yield of desired compound 4 was mar-
ginally increased (entry 2). NaCl was reported as catalyst in aqueous
conditions for MCRs by a few groups.16,17 However, when similar
reported conditions were applied to our reaction, the yield of
compound 4 remained very low (entry 3). Then, we began to in-
vestigate the acid effect on this reaction. When Lewis acid InCl3
(0.2e1.0 equiv) was used as catalyst,18 the reaction was not clean
and no desired product was isolated, despite lowering the tem-
perature to 0 ꢀC (entry 4). Similar results were found when stronger
acid TfOH (2e20 equiv) in DCM and TFA/DCM (1:1) were used
(entries 5 and 6). When weaker acid p-TsOH was employed, the
reaction did not occur (entry 7). We noticed that starting materials
were insoluble in toluene, which we assumed to be the reason why
there was no reaction under these conditions. Therefore, we in-
vestigated solvent effects. Gratifyingly, without adding any acid or
catalyst, polar solvents, such as MeOH and DMSO, gave much
higher yield of 4 (entries 8 and 9). Further optimization led to the
best solvent DMF, which provided product 4 in moderate yield
(55%, entry 10).19
With the optimized conditions in hand, we investigated the
substrate scope of this reaction. As shown in Fig. 2, the method-
ology is apparently applicable to a range of substituted isatins.
When 5-, 6- or 7-Cl substituted isatins were tested in the optimal
reaction conditions, products 4, 6, and 7 were isolated in 55, 24, and
26% yields, respectively. Interestingly, when 4-Cl substituted isatin
was used as substrate, starting materials remained intact and hence
no desired product 5a was isolated. Furthermore, there was no
reaction when either 4-Br or 4-F isatin was used. We believe that
the steric hindrance with larger substitutions at 4-position of the
isatin prevents the 3-ketone accessibility for condensation (see
proposed mechanism in Scheme 2). Then, electronic effects at the
5-position of the isatin were investigated. Compared to un-
a
Reaction conditions: DMF, 120 oC, 2 h. The molar ratio of three starting
materials is 1:1:1 (0.38 mmol).
b Isolated yield by preparative HPLC, product purity is >95%.
Fig. 2. Spiroazepinoindolones formation using substituted isatins.
and 64% yields, respectively). These results can be rationalized that
electron-withdrawing groups increase the electrophilicity of isatin
3-ketone and hence the condensation step with the other nucleo-
philic components is easier to be triggered. Lastly, N-methyl isatin
provided desired product 15 in moderate yield (53%) as well, which
suggests that substitution on the isatin nitrogen is tolerated for this
reaction.
Next, substituted aminoindoles as substrates were investigated
to form the spiroazepinoindolones. Due to limited commercially
available substituted aminoindoles, a few 6-substituted amino-
indoles were employed in the reaction conditions. As shown in
Fig. 3, electron-donating groups (i-Pre and MeOe) gave reasonable
yields (compounds 16 and 17 with 19 and 33% yields, respectively).
However, electron-withdrawing groups afforded significantly
lower yields. For example, 6-fluoro-indolamine gave compound 18
in only 8% yield and 6-Cl/CF3-indolamines prohibited the reaction
completely (no compounds 19 and 20 formed). We suspect that the
strong electron-withdrawing groups decrease the nucleophilicity
of the indoleamine. As a result, the indoleamine is not nucleophilic
enough to be involved in the condensation or addition with the
other components (see proposed mechanism in Scheme 2).
A plausible mechanism for this transformation to form the
spiroazepinoindolones is proposed as shown in Scheme 2. 5-Cl-
isatin 1 can be either condensed with Meldrum’s acid 3 to afford
substituted isatin (compound
8 with 27% yield), electron-
donating groups (Mee, t-Bue, and MeOe) afforded lower yields
(compounds 9, 10, and 11 with 23, 20, and 17% isolated yields, re-
spectively); In contrast, electron-withdrawing group (Fe, NO2e,
and CNe) gave higher yields (compounds 12,13, and 14 with 56, 63,

580
B. Zou et al. / Tetrahedron 70 (2014) 578e582
either aromatized to form intermediate D, which is further con-
verted to compound 4 via path b; or eliminated of CO2 and acetone
to give E, which is aromatized to afford spiroazepinoindolone 4
(path a).
3. Conclusion
A direct and efficient one-pot, three-component condensation
reaction of readily available isatins, indolamines, and Meldrum’s
acid to give a novel spiroazepinoindolone template, has been de-
veloped. Without additional acid or catalyst, this reaction is envi-
ronmentally benign and atom-economic. Using this established
methodology, a new class of spiro-heterocyclic compounds is ac-
cessible for further biological evaluations.
4. Experimental section
4.1. General
All materials and reagents used were of the best commercially
available grade and used without further purification. 1H NMR and
13C NMR spectra were determined on a Bruker Ultrashield 400 MHz
spectrometer. LCeMS analysis were performed using Waters Acq-
uity UPLC using the following conditions: Acquity UPLC BEH C-18
a
Reaction conditions: DMF, 120 oC, 2 h. The molar ratio of three starting
materials is 1:1:1 (0.38 mmol).
b Isolated yield by preparative HPLC, product purity is >95%.
column, 1.7
mm, 2.1ꢁ50 mm; mobile phase system of 0.1% formic
Fig. 3. Spiroazepinoindolones formation using substituted indoleamines.
acid/acetonitrile and a gradient of 5e95% acetonitrile; run time of
2.0 min; with wavelength detection of 254 and 214 nm and flow
rate of 1.0 mL/min coupled with MS waters ZQ 2000; processing
software: Masslynx V4.1; or Agilent UHPLC 1290 using the fol-
lowing conditions: Acquity UPLC BEH C-18 column, 1.7
mm,
2.1ꢁ50 mm; mobile phase system of 0.1% formic acid/acetonitrile
and a gradient of 2e98% acetonitrile; run time of 2.0 min; with
wavelength detection of 254 and 214 nm and flow rate of 1.0 mL/
min coupled with mass spec: ABSciex API 3200; processing soft-
ware: LP Analyst V1.6.1. Purifications were performed using Waters
PrepLC Systems using the following conditions: Atlantis prep C-18
OBD 5
m
m 19ꢁ150 mm column; mobile phase system of 0.1% formic
acid/acetonitrile and a gradient of 5e95% acetonitrile; run time of
30e40 min; with wavelength detection of 254 and 214 nm and flow
rate of 20 mL/min. Melting points were measured on BUCHI B-540
€
apparatus. IR spectrums were obtained on a JASCO FT/IR-4100
spectrometer. In the 13C NMR spectrums of compounds 7, 9, 10,
and 11, one carbon peak is not observed due to overlap with the
solvent peak.
4.2. General procedure for spiroazepinoindolones
The solution of isatin (380
mmol), 1H-indole-4-amine (380
mmol,
1.0 equiv), and Meldrum’s acid (380
m
mol, 1.0 equiv) in DMF
(4.0 ml) was heated to 120 ꢀC for 2 h. The reaction mixture was
cooled down to room temperature and concentrated to remove the
solvents. The crude residue was subjected to reverse phase pre-
parative HPLC to provide pure products.
4.2.1. 50-Chloro-4,6-dihydrospiro[azepino[4,3,2-cd]indole-3,30-indo-
line]-20,5(1H)-dione (4). General procedure was followed, light pink
Scheme 2. Proposed mechanism for formation of spiroazepinoindolone 4.
solid, mp: 287e289 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d ppm: 11.15
(br s, 1H, NH), 10.66 (br s, 1H, NH), 10.42 (s, 1H, NH), 7.33e7.28 (m,
2H, ArH), 7.23 (d, J¼2.0 Hz, 1H, ArH), 6.95 (d, J¼8.5 Hz, 1H, ArH),
6.91 (d, J¼8.5 Hz,1H, ArH), 6.88 (br s,1H, ArH), 6.23 (d, J¼8.5 Hz,1H,
oxoindolylidene A followed by addition of indoleamine 2 to give
intermediate C (path a) or condensed first with indoleamine 2 to
form oxoindolylidene B20 followed by addition of Meldrum’s acid 3
to give the intermediate D (path b).15 Subsequently, intra-molecular
condensation of intermediate D and elimination of CO2 and acetone
afford spiroazepinoindolone 4 (path b). Intermediate C can be
ArH), 3.04 (d, J¼15.8 Hz, 1H, CH2), 2.69 (d, J¼15.8 Hz, 1H, CH2); 13
C
NMR (100 MHz, DMSO-d6)
d ppm: 178.9, 167.7, 140.5, 136.4, 135.5,
130.7, 128.4, 125.9, 125.0, 123.8, 118.7, 117.3, 111.3, 111.1, 106.0, 99.0,
51.1, 38.7; ESIMS m/z 338.0 [MþH]þ; IR (film) 3369, 3259, 1704,

B. Zou et al. / Tetrahedron 70 (2014) 578e582
581
1674, 1483, 1358 cmꢂ1; HRMS calcd for C18H13ClN3O2 [MþH]þ
brown solid, mp: 248e250 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d ppm: 11.12 (s, 1H, NH), 10.37 (s, 1H, NH), 10.33 (s, 1H, NH), 7.28 (t,
338.0691; found 338.0690.
J¼2.8 Hz, 1H, ArH), 6.93e6.79 (m, 5H, ArH), 6.24 (d, J¼8.5 Hz, 1H,
4.2.2. 60-Chloro-4,6-dihydrospiro[azepino[4,3,2-cd]indole-3,30-indo-
ArH), 3.65 (s, 3H, OCH3), 2.99 (d, J¼16.1 Hz, 1H, CH2), 2.64 (d,
line]-20,5(1H)-dione (6). General procedure was followed, light
J¼16.1 Hz, 1H, CH2); 13C NMR (100 MHz, DMSO-d6)
d ppm: 179.2,
brown solid, mp: 302e305 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d
ppm:
167.9, 155.1, 136.3, 134.8, 134.7, 130.7, 124.8, 119.0, 117.3, 112.9, 111.7,
11.14 (br s,1H, NH),10.69 (br s,1H, NH),10.42 (s,1H, NH), 7.29 (br s,1H,
ArH), 7.18 (d, J¼7.8 Hz,1H, ArH), 7.08e7.00 (m,1H, ArH), 6.95 (br s,1H,
ArH), 6.93e6.85 (m, 2H, ArH), 6.23 (d, J¼8.3 Hz, 1H, ArH), 2.98 (d,
J¼15.8 Hz, 1H, CH2), 2.69 (d, J¼15.8 Hz, 1H, CH2); 13C NMR (100 MHz,
110.8, 110.1, 105.8, 98.9, 55.4, 51.2; ESIMS m/z 334.1 [MþH]þ; IR
(film) 3274, 1678, 1491, 1350, 1199 cmꢂ1
; HRMS calcd for
C19H16N4O4 334.1186; found 334.1186.
DMSO-d6)
d
ppm: 179.2, 167.7, 143.1, 136.4, 132.7, 132.4, 130.7, 125.2,
4.2.8. 50-Fluoro-4,6-dihydrospiro[azepino[4,3,2-cd]indole-3,30-indo-
124.9,121.8,118.7,117.3,111.1,109.8,105.9, 99.0, 50.6, 38.8; ESIMS m/z
line]-20,5(1H)-dione (12). General procedure was followed, brown
338.0 [MþH]þ; IR (film) 3316, 1674, 1491, 1354 cmꢂ1; HRMS calcd for
solid, mp: 257e258 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d ppm: 11.14
C
18H13ClN3O2 [MþH]þ 338.0691; found 338.0691.
(br s, 1H, NH), 10.53 (br s, 1H, NH), 10.40 (s, 1H, NH), 7.29 (t,
J¼2.8 Hz, 1H, ArH), 7.14e7.04 (m, 2H, ArH), 6.96e6.85 (m, 3H, ArH),
6.22 (d, J¼8.5 Hz, 1H, ArH), 3.06 (d, J¼15.8 Hz, 1H, CH2), 2.65 (d,
4.2.3. 70-Chloro-4,6-dihydrospiro[azepino[4,3,2-cd]indole-3,30-indo-
line]-20,5(1H)-dione (7). General procedure was followed, brown
J¼15.8 Hz, 1H, CH2); 13C NMR (100 MHz, DMSO-d6)
d ppm: 179.2,
solid, mp: 345e347 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d
ppm: 11.14 (br
167.7, 158.2 (d, JCeF¼236 Hz), 137.9, 136.5, 135.1 (d, JCeF¼8 Hz),
130.8, 125.0, 118.8, 117.3, 114.8 (d, JCeF¼23 Hz), 111.6 (d, JCeF¼24 Hz),
111.1, 110.6 (d, JCeF¼9 Hz), 105.9, 99.0, 51.3, 38.8; ESIMS m/z 322.1
[MþH]þ; IR (film) 3365, 3263, 1670, 1491, 1362 cmꢂ1; HRMS calcd
for C18H13FN3O4 322.0986; found 322.0986.
s,1H, NH), 10.96 (br s,1H, NH),10.43 (s,1H, NH), 7.32 (d, J¼7.8 Hz,1H,
ArH), 7.29 (t, J¼2.5 Hz,1H, ArH), 7.15 (d, J¼7.3 Hz,1H, ArH), 7.04e6.98
(m,1H, ArH), 6.94e6.87 (m, 2H, ArH), 6.24 (d, J¼8.5 Hz,1H, ArH), 3.00
(d, J¼15.8 Hz, 1H, CH2), 2.74 (d, J¼15.8 Hz, 1H, CH2); 13C NMR
(100 MHz, DMSO-d6)
d ppm: 179.2, 167.7, 139.3, 136.4, 135.4, 130.7,
128.5, 125.0, 123.5, 122.4, 118.8, 117.3, 114.0, 111.1, 106.0, 99.0, 51.7;
4.2.9. 50-Nitro-4,6-dihydrospiro[azepino[4,3,2-cd]indole-3,30-indo-
ESIMS m/z 338.2 [MþH]þ; IR (film) 3678, 2980,1714,1620,1054cmꢂ1
;
line]-20,5(1H)-dione (13). General procedure was followed, yellow
HRMS calcd for C18H13ClN3O2 [MþH]þ 338.0691; found 338.0691.
solid, mp: 361e363 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d ppm: 11.10
(br s, 2H, NH), 10.45 (s, 1H, NH), 8.17 (dd, J¼8.6, 2.4 Hz, 1H, ArH),
8.01 (d, J¼2.3 Hz, 1H, ArH), 7.25 (t, J¼2.8 Hz, 1H, ArH), 7.08 (d,
J¼8.8 Hz, 1H, ArH), 6.89e6.81 (m, 2H, ArH), 6.19 (d, J¼8.3 Hz, 1H,
ArH), 3.11 (d, J¼16.1 Hz, 1H, CH2), 2.70 (d, J¼16.1 Hz, 1H, CH2); 13C
4.2.4. 4,6-Dihydrospiro[azepino[4,3,2-cd]indole-3,30-indoline]-
20,5(1H)-dione (8). General procedure was followed, brown solid,
mp: 321e324 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d ppm: 11.12 (br s,1H,
NH),10.54 (s,1H, NH),10.41 (s,1H, NH), 7.29 (t, J¼2.8 Hz,1H, ArH), 7.25
(td, J¼7.6, 1.2 Hz, 1H, ArH), 7.17 (d, J¼7.0 Hz, 1H, ArH), 7.00e6.92 (m,
2H, ArH), 6.91e6.87 (m, 2H, ArH), 6.26 (d, J¼8.5 Hz, 1H, ArH), 2.92 (d,
J¼15.8 Hz, 1H, CH2), 2.70 (d, J¼15.8 Hz, 1H, CH2); 13C NMR (100 MHz,
NMR (100 MHz, DMSO-d6) d ppm: 179.6, 167.6, 148.2, 142.5, 136.6,
134.4, 130.9, 125.9, 125.2, 119.4, 118.6, 117.4, 110.5, 110.1, 106.1, 99.1,
50.9, 38.3; ESIMS m/z 349.2 [MþH]þ; IR (film) 3674, 3712, 2980,
1339,1060,1011 cmꢂ1; HRMS calcd for C18H13N4O4 349.0931; found
349.0931.
DMSO-d6)
d ppm: 179.3, 167.9, 141.4, 136.3, 133.6, 130.7, 128.4, 124.8,
123.6,122.0,118.9,117.3,111.7,109.7,105.8, 98.9, 50.8, 39.2; ESIMS m/z
304.2 [MþH]þ; IR (film) 3346, 3274, 1670, 1469, 1358 cmꢂ1; HRMS
calcd for C18H14N3O2 [MþH]þ 304.1081; found 304.1080.
4.2.10. 20,5-Dioxo-1,4,5,6-tetrahydrospiro[azepino[4,3,2-cd]indole-
3,30-indoline]-50-carbonitrile (14). General procedure was followed,
light brown solid, mp: 354e356 ꢀC; 1H NMR (400 MHz, DMSO-d6)
4.2.5. 50-Methyl-4,6-dihydrospiro[azepino[4,3,2-cd]indole-3,30-indo-
d ppm: 11.10 (br s, 1H, NH), 10.95 (br s, 1H, NH), 10.35 (s, 1H, NH),
line]-20,5(1H)-dione (9). General procedure was followed, brown
7.69 (dd, J¼8.0, 1.8 Hz, 1H, ArH), 7.57 (d, J¼1.5 Hz, 1H, ArH), 7.23 (t,
J¼2.8 Hz, 1H, ArH), 7.03 (d, J¼8.2 Hz, 1H, ArH), 6.86e6.80 (m, 2H,
ArH), 6.11 (d, J¼8.2 Hz,1H, ArH), 3.07 (d, J¼16.1 Hz,1H, CH2), 2.61 (d,
solid, mp: 318e321 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d ppm: 11.12
(br s, 1H, NH), 10.46 (s, 1H, NH), 10.40 (s, 1H, NH), 7.29 (t, J¼2.6 Hz,
1H, ArH), 7.04 (d, J¼8.0 Hz, 1H, ArH), 6.97 (d, J¼2.0 Hz, 1H, ArH),
6.93e6.87 (m, 2H, ArH), 6.83 (d, J¼7.8 Hz, 1H, ArH), 6.28 (d,
J¼8.2 Hz, 1H, ArH), 2.84 (d, J¼15.8 Hz, 1H, CH2), 2.72 (d, J¼15.8 Hz,
J¼16.1 Hz, 1H, CH2); 13C NMR (100 MHz, DMSO-d6)
d ppm: 179.2,
167.6, 146.3, 136.5, 134.5, 133.9, 130.9, 127.5, 125.1, 119.2, 118.6, 117.4,
110.7, 110.5, 106.0, 104.0, 99.0, 50.6, 38.4; ESIMS m/z 329.1 [MþH]þ;
IR (film) 3369, 1715, 1666, 1613, 1483, 1377 cmꢂ1; HRMS calcd for
1H, CH2), 2.20 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6)
d ppm:
179.3, 167.9, 138.8, 136.3, 133.8, 130.9, 130.6, 128.7, 124.9, 124.1,
119.0, 117.3, 111.9, 109.6, 105.9, 99.0, 50.9, 20.7; ESIMS m/z 318.1
[MþH]þ; IR (film) 3316, 1674, 1491, 1354 cmꢂ1; HRMS calcd for
C19H13N4O2 329.1033; found 329.1033.
4.2.11. 50-Chloro-10-methyl-4,6-dihydrospiro[azepino[4,3,2-cd]in-
dole-3,30-indoline]-20,5(1H)-dione (15). General procedure was fol-
lowed, brown solid, mp: 296e298 ꢀC; 1H NMR (400 MHz, DMSO-
C
19H16N3O2 [MþH]þ 318.1237; found 318.1237.
4.2.6. 50-(tert-Butyl)-4,6-dihydrospiro[azepino[4,3,2-cd]indole-3,30-
d6)
d
ppm: 11.16 (br s, 1H, NH), 10.46 (s, 1H, NH), 7.43 (dd, J¼8.4,
indoline]-20,5(1H)-dione (10). General procedure was followed, yel-
1.9 Hz, 1H, ArH), 7.35e7.25 (m, 2H, ArH), 7.16 (d, J¼8.2 Hz, 1H, ArH),
6.94e6.86 (m, 2H, ArH), 6.19 (d, J¼8.2 Hz,1H, ArH), 3.17 (s, 3H, CH3),
3.06 (d, J¼15.8 Hz, 1H, CH2), 2.71 (d, J¼15.8 Hz, 1H, CH2); 13C NMR
low solid, mp: 347e348 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d ppm:
11.12 (s,1H, NH),10.42 (s,1H, NH),10.40 (s,1H, NH), 7.30e7.24 (m, 2H,
ArH), 7.23e7.21 (m, 1H, ArH), 6.90e6.83 (m, 3H, ArH), 6.23 (d,
J¼8.2 Hz,1H, ArH), 2.97 (d, J¼15.8 Hz,1H, CH2), 2.66 (d, J¼15.8 Hz,1H,
(100 MHz, DMSO-d6)
d ppm: 177.0, 167.7, 142.1, 136.5, 134.6, 130.8,
128.4, 126.6, 125.0, 123.5, 118.7, 117.3, 110.8, 110.4, 105.9, 99.0, 50.6,
CH2), 1.20 (s, 9H, t-Bu); 13C NMR (100 MHz, DMSO-d6)
d
ppm: 179.5,
38.6, 26.3; ESIMS m/z 352.4 [MþH]þ; IR (film) 3347, 1643, 1488,
168.1, 144.6, 139.0, 136.3, 133.2, 130.8, 124.9, 124.8, 120.5, 118.9, 117.3,
111.9, 109.1, 105.8, 98.9, 51.0, 34.1, 31.3, 30.9; ESIMS m/z 360.2
[MþH]þ; IR (film) 3407, 3339, 1685, 1594, 1492, 1356 cmꢂ1; HRMS
calcd for C22H22N3O2 [MþH]þ 360.1707; found 360.1706.
1356 cmꢂ1
352.0847.
; HRMS calcd for C19H15ClN3O2 352.0847; found
4.2.12. 50-Chloro-8-isopropyl-4,6-dihydrospiro[azepino[4,3,2-cd]in-
dole-3,30-indoline]-20,5(1H)-dione (16). General procedure was fol-
lowed, brown solid, mp: 226e230 ꢀC; 1H NMR (400 MHz, DMSO-
4.2.7. 50-Methoxy-4,6-dihydrospiro[azepino[4,3,2-cd]indole-3,30-in-
doline]-20,5(1H)-dione (11). General procedure was followed,
d6)
d
ppm: 11.03 (d, J¼2.01 Hz, 1H, NH), 10.67 (s, 1H, NH), 10.27 (s,

582
B. Zou et al. / Tetrahedron 70 (2014) 578e582
5. Zhao, Y.; Liu, L.; Sun, W.; Lu, J.; McEachern, D.; Li, X.; Yu, S.; Bernard, D.; Och-
senbein, P.; Ferey, V.; Carry, J.; Deschamps, J. R.; Sun, D.; Wang, S. J. Am. Chem.
Soc. 2013, 135, 7223e7234.
1H, NH), 7.30 (dd, J¼8.4, 2.1 Hz,1H, ArH), 7.11 (br s,1H, ArH), 6.95 (d,
J¼8.3 Hz, 1H, ArH), 6.93 (br s, 1H, ArH), 6.67 (d, J¼1.0 Hz, 1H, ArH),
6.56 (d, J¼2.3 Hz, 1H, ArH), 3.15 (d, J¼15.2 Hz, 1H, CH2), 2.99e2.86
(m, 1H, CH), 2.72 (d, J¼15.2 Hz, 1H, CH2), 1.24 (d, J¼7.0 Hz, 6H, CH3);
6. (a) Rottmann, M.; McNamara, C.; Yeung, B. K. S.; Lee, M. C. S.; Zou, B.; Russell, B.;
Seitz, P.; Plouffe, D. M.; Dharia, N. V.; Tan, J.; Cohen, S. B.; Spencer, K. R.;
ꢀ
ꢀ
13C NMR (100 MHz, DMSO-d6)
d ppm: 177.9, 169.1, 143.1, 140.3,
Gonzalez-Paez, G. E.; Lakshminarayana, S. B.; Goh, A.; Suwanarusk, R.; Jegla, T.;
Schmitt, E. K.; Beck, H.-P.; Brun, R.; Nosten, F.; Renia, L.; Dartois, V.; Keller, T. H.;
Fidock, D. A.; Winzeler, E. A.; Diagana, T. T. Science 2010, 329, 1175e1180; (b)
Yeung, B. K. S.; Zou, B.; Rottmann, M.; Lakshminarayana, S. B.; Ang, S. H.; Leong,
S. Y.; Tan, J.; Wong, J.; Keller-Maerki, S.; Fischli, C.; Goh, A.; Schmitt, E. K.;
Krastel, P.; Francotte, E.; Kuhen, K.; Plouffe, D.; Henson, K.; Wagner, T.; Winz-
eler, E. A.; Petersen, F.; Brun, R.; Dartois, V.; Diagana, T. T.; Keller, T. H. J. Med.
Chem. 2010, 53, 5155e5164; (c) Zou, B.; Yap, P.; Sonntag, L.-S.; Leong, S. Y.;
Yeung, B. K. S.; Keller, T. H. Molecules 2012, 17, 10131e10141.
137.8, 136.0, 130.3, 128.1, 125.8, 124.2, 120.0, 114.6, 113.1, 111.2, 106.5,
103.3, 48.1, 47.0, 33.7, 24.4, 24.3; ESIMS m/z 380.5 [MþH]þ; IR (film)
3713, 3674, 2972, 2871, 1058, 1012 cmꢂ1
; HRMS calcd for
C
21H19ClN3O2 380.1160; found 380.1159.
4.2.13. 50-Chloro-8-methoxy-4,6-dihydrospiro[azepino[4,3,2-cd]in-
dole-3,30-indoline]-20,5(1H)-dione (17). General procedure was fol-
lowed, brown solid, mp: 236e238 ꢀC; 1H NMR (400 MHz, DMSO-
7. (a) Edmondson, F.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N. J. Am. Chem.
Soc. 1999, 121, 2147e2155; (b) Sebahhar, P. R.; Williams, R. M. J. Am. Chem. Soc.
2000, 122, 5666e5667; (c) Yang, J.; Wearing, X. Z.; Quesne, P. W. L.; Deschamps,
J. R.; Cook, J. M. J. Nat. Prod. 2008, 71, 1431e1440; (d) Budovska, M.; Kutschy, P.;
Kozar, T.; Gondova, T.; Petrovaj, J. Tetrahedron 2013, 69, 1092e1104.
d6) d ppm: 11.08 (br s,1H, NH),10.87 (br s,1H, NH),10.35 (s, 1H, NH),
7.27e7.18 (m, 2H, ArH), 6.96 (d, J¼8.5 Hz, 1H, ArH), 6.64 (br s, 1H,
ArH), 6.44e6.41 (m, 1H, ArH), 6.40 (d, J¼2.5 Hz, 1H, ArH), 3.67 (s,
3H, CH3), 3.19 (d, J¼16.3 Hz, 1H, CH2), 2.49 (overlap with DMSO, 1H,
8. (a) Chen, X. H.; Wei, Q.; Luo, S. W.; Xiao, H.; Gong, L. Z. J. Am. Chem. Soc. 2009,
131, 13819e13825; (b) Trost, B. M.; Brennan, M. K. Synthesis 2009, 18,
3003e3025; (c) Labadie, S. S.; Parmer, C. Synth. Commun. 2011, 41, 1742e1751;
(d) Hong, S.; Jung, M.; Park, Y.; Ha, M. W.; Park, C.; Lee, M.; Park, H. Chem.dEur.
CH2); 13C NMR (100 MHz, DMSO-d6)
d ppm: 179.4, 167.5, 151.9,
ꢁ
J. 2013, 19, 9599e9605; (e) Moody, C. L.; Franckevicius, V.; Drouhin, P.; Klein, J.
138.24, 138.15, 134.0, 128.1, 125.5, 124.8, 124.7, 124.0, 117.4, 108.0,
107.1, 98.2, 87.8, 55.3, 51.0, 36.0; ESIMS m/z 368.1 [MþH]þ; IR (film)
2925, 2852, 1719, 1678, 1491 cmꢂ1; HRMS calcd for C19H15ClN3O3
368.0796; found 368.0795.
E. M. N.; Taylor, R. J. K. Tetrahedron Lett. 2012, 53, 1897e1899; (f) Ramachary, D.
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oorg. Med. Chem. 2006, 14, 2409e2417; (b) Rambabu, D.; Raja, G.; Sreenivas, B.
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Bioorg. Med. Chem. Lett. 2013, 23, 1351e1357; (c) Pitchaimani, P.; Kamaraj, B.;
Subbu, P.; Perumal, Y.; Dharmarajan, S. Eur. J. Med. Chem. 2010, 45, 5653e5661;
(d) Kia, Y.; Osman, H.; Kumar, R. S.; Murugaiyah, V.; Basiri, A.; Perumal, S.;
Razak, I. A. Bioorg. Med. Chem. Lett. 2013, 23, 2979e2983; (e) Tian, Y.; Nam, S.;
Liu, L.; Yakushijin, F.; Yakushijin, K.; Buettne, R.; Liang, W.; Yang, F.; Ma, Y.;
Horne, D. PLos One 2012, 7, e49306; (f) Antonchick, A. P.; Gerding-Reimers, C.;
Catarinella, M.; Schurmann, M.; Preut, H.; Ziegler, S.; Rauh, D.; Waldmann, H.
Nat. Chem. 2010, 2, 735e740; (h) Vintonyak, V. V.; Warburg, K.; Over, B.; Hubel,
K.; Rauh, D.; Waldmann, H. Tetrahedron 2011, 67, 6713e6729.
10. For reviews, see: (a) Hong, L.; Wang, R. Adv. Synth. Catal. 2013, 355, 1023e1052;
(b) Ball-Jones, N. R.; Badillo, J. J.; Franz, A. K. Org. Biomol. Chem. 2012, 10,
5165e5181; (c) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104e6155; (d)
Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748e8758.
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(b) Chen, H.; Shi, D. Tetrahedron 2011, 67, 5686e5692; (c) Rad-Moghadam, K.;
Youseftabar-Miri, L. Tetrahedron 2011, 67, 5693e5699; (d) Balamurugan, K.;
Perumal, S.; Menendez, J. C. Tetrahedron 2011, 67, 3201e3208; (e) Quiroga, J.;
Portillo, S.; Perez, A.; Galvez, J.; Abonia, R.; Insuasty, B. Tetrahedron Lett. 2011, 52,
2664e2666; (f) Rajan, R.; Babu, B. P.; Kumar, A.; Paul, R. R.; Sinu, C. R.; Suresh,
E.; Nair, V. Synthesis 2012, 44, 417e422; (g) Bakthadoss, M.; Kannan, D.; Siva-
kumar, G. Synthesis 2012, 44, 793e799; (h) Yu, H.; Man-Man, W.; Hui, C.; Da-
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4.2.14. 50-Chloro-8-fluoro-4,6-dihydrospiro[azepino[4,3,2-cd]indole-
3,30-indoline]-20,5(1H)-dione (18). General procedure was followed,
brown solid, mp: 277e280 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d
ppm: 11.33 (br s, 1H, NH), 11.17 (s, 1H, NH), 10.47 (s, 1H, NH),
7.38e7.34 (m, 1H, ArH), 7.30 (dd, J¼8.6, 2.4 Hz, 1H, ArH), 7.00 (d,
J¼8.5 Hz, 1H, ArH), 6.85 (d, J¼10.5 Hz, 1H, ArH), 6.51 (br s, 1H, ArH),
6.50 (d, J¼2.3 Hz, 1H, ArH), 3.02 (d, J¼16.3 Hz, 1H, CH2), 2.70 (d,
J¼16.3 Hz, 1H, CH2); 13C NMR (100 MHz, DMSO-d6)
d ppm: 178.6,
166.9, 154.7 (d, JCeF¼235 Hz), 138.1, 137.3 (d, JCeF¼13 Hz), 134.4 (d,
JCeF¼11 Hz), 128.7, 126.0, 125.8, 124.9, 124.0, 117.7, 110.2, 106.0 (d,
JCeF¼22 Hz), 98.5, 91.4 (d, JCeF¼24 Hz), 50.7, 36.9; ESIMS m/z 356.5
[MþH]þ; IR (film) 3316, 2939, 1670, 1491, 1392, 1088 cmꢂ1; HRMS
calcd for C18H12ClFN3O2 356.0597; found 356.0597.
Acknowledgements
We thank all the chemists at Novartis Institute for Tropical
Diseases for providing support for doing this research. We also
12. (a) Niar, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.; Mathen, J. S.;
Balagopal, L. Acc. Chem. Res. 2003, 36, 899e907; (b) Nair, V.; Menon, R. S.;
Sreekanth, A.; Abhilash, N.; Biju, A. T. Acc. Chem. Res. 2006, 39, 520e530.
13. (a) Eckert, H. Molecules 2012, 17, 1074e1102; (b) Robert, W. A.; Andrew, P. C.;
Paul, A. T.; David, B.; Thomas, A. K. Acc. Chem. Res. 1996, 29, 123e131.
14. Paul, S.; Eelco, R.; Romano, V. A. O. Med. Chem. Commun. 2012, 3, 1189e1218.
15. Lichitsky, B. V.; Komogortsev, A. N.; Dudinov, A. A.; Krayushkin, M. M. Russ.
Chem. Bull., Int. Ed. 2009, 58, 1504e1508.
}
thank Prof. Dr. Fritz E. Kuhn for being co-supervisor of Ms. C.C. at
National University of Singapore.
Supplementary data
16. Dandia, A.; Laxkar, A. K.; Singh, R. Tetrahedron Lett. 2012, 53, 3012e3017.
17. Yan, S.; Jing, S.; Chao-Guo, Y. Tetrahedron Lett. 2012, 53, 3647e3649.
18. Li, Z.; Zhiming, L.; Renhua, F. Org. Lett. 2012, 14, 6076e6079.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.12.010.
19. Due to the poor solubility in organic solvents, such as CH2Cl2, EtOAc, and
MeOH, it was not possible to isolate the compounds with good purities by
normal phase column chromatography. So all the products described in this
paper were purified by preparative HPLC, with the>95% purities.
20. (a) Zhang, Y.; Wang, S.; Xu, X.; Jiang, R.; Ji, S. Org. Biomol. Chem. 2013, 11,
1933e1937; (b) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66e77.
References and notes
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