Direct one-pot synthesis of naphthoxindoles from 4-bromooxindoles by Suzuki-Miyaura coupling and aldol condensation reactions

Article abstract of DOI:10.1002/ejoc.201301242

An efficient one-pot synthesis of naphthoxindoles by using 4-bromoindolin-2-ones and 2-formylphenylboronic acids has been developed. The coupling reaction proceeds in good to excellent yields under microwave irradiation through a Suzuki-Miyaura coupling a

Full text of DOI:10.1002/ejoc.201301242

FULL PAPER
DOI: 10.1002/ejoc.201301242
Direct One-Pot Synthesis of Naphthoxindoles from 4-Bromooxindoles by
Suzuki–Miyaura Coupling and Aldol Condensation Reactions
Kyeong-Yong Park,[a,b] Bum Tae Kim,[a] and Jung-Nyoung Heo*[a,b]
Keywords: Nitrogen heterocycles / Cross-coupling / C–C coupling / Aldol reactions / Palladium / Microwave chemistry
An efficient one-pot synthesis of naphthoxindoles by using
4-bromoindolin-2-ones and 2-formylphenylboronic acids has
been developed. The coupling reaction proceeds in good to
excellent yields under microwave irradiation through a
Suzuki–Miyaura coupling and an aldol condensation cascade
reaction. In addition, this protocol permits the facile construc-
tion of naphthoxindoles through an expanded scope of sub-
strates.
Introduction
Polycyclic compounds that contain an oxindole moiety
are important to the search for new biologically active
agents for the pharmaceutical and agrochemical indus-
tries.[1] Naturally occurring oxindoles include aristolactams
1, anhydrohapaloxindole A (2), and prioline (3, see Fig-
ure 1). The aristolactams are a large family of compounds
that exhibit various bioactivities, which include antitumor
effects against human cancer cell lines.[2] Anhydrohapalox-
indole A (2) was isolated from a cultured strain of a terres-
trial blue-green alga.[3] Prioline (3) was isolated from the
roots of a species of Salvia, a genus whose plants are used
in Chinese folk medicine for the treatment of tonsillitis,
pharyngitis, pulmonary tuberculosis, and bacillary dysen-
tery.[4] Of particular interest is sunitinib (4), which is a
highly active receptor tyrosine kinase inhibitor that is used
in the treatment of advanced renal cell carcinoma and gas-
trointestinal stromal tumors.[5]
As part of a drug discovery program for the synthesis of
unusual heterocycles,[6] we became interested in heteroaro-
matic scaffolds that contain oxindole, particularly naph-
thoxindoles (i.e., 5). The synthesis of these compounds
would provide access to a new ring system with highly di-
versified options for substitution. Reports of syntheses of
naphthoxindoles are limited. For example, Felpin and co-
workers reported a linear three-step sequence that employed
a complete palladium-catalyzed Heck coupling, C–H aryl-
ation, and reductive cyclization reactions.[7] In addition, Li
and co-workers employed a Diels–Alder reaction between
Figure 1. Natural and pharmaceutical compounds that contain the
oxindole core.
arynes and methyleneindolinones to obtain naphthox-
indoles.[8] However, a simple, rapid, and convergent method
is needed to construct this tetracyclic ring system. Herein,
we describe a generalized synthetic method for naphthox-
indole that is tolerant of various substituents and functional
groups.
Results and Discussion
Recently, we disclosed the total synthesis of aristolactam
derivatives by employing Suzuki–Miyaura coupling and
aldol condensation cascade reactions.[6a] This protocol is
highly efficient for furnishing aristolactams 1 through the
one-pot reaction of 4-bromoisoindolin-1-ones 6 with 2-
formylphenylboronic acid (7a) under microwave irradiation
(see Figure 2, A). The design of a new synthetic approach
toward naphthoxindoles 5 began by the simple replacement
of isoindolin-1-one 6 with oxindole 9 (see Figure 2, B). We
anticipated that the aldol condensation would be ac-
[a] Medicinal Chemistry Research Center, Korea Research
Institute of Chemical Technology,
141 Gajeong-ro, Daejeon 305-600, Republic of Korea
E-mail: heojn@krict.re.kr
http://www.krict.re.kr
[b] Graduate School of New Drug Discovery and Development,
Chungnam National University,
99 Daehak-ro, Daejeon 305-764, Republic of Korea
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301242.
164
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 164–170

One-Pot Synthesis of Naphthoxindoles
celerated by the presence of the more acidic C-3 methylene a reliable Pd catalytic system that employed microwave irra-
protons of oxindole 9. Microwave irradiation was used to diation (MW) included Pd(PPh3)4 (5 mol-%), K2CO3
facilitate the rapid construction of a wide range of (3 equiv.), and toluene/EtOH (2:1) at 150 °C for 10 min.
naphthoxindole libraries.[9]
Next, we explored the compatibility of the N-substituent
of 4-bromooxindole under the optimized conditions. The
proton at N-1 of 9b tolerated the conditions of this coupling
reaction, and the corresponding product 5b was produced,
but the yield was lower (see Table 1, Entry 7). We hypothe-
sized that the facile N–H proton abstraction (pKa ≈ 18.2)
from 4-bromooxindole 9b caused the transformation to be
less effective under basic conditions.[11] The para-meth-
oxybenzyl (PMB) group of 9c tolerated the coupling reac-
tion, and an excellent product yield was obtained (see
Table 1, Entry 8).
With the suitable reaction conditions in hand, a variety
of substituted 2-formylphenylboronic acids and heteroaryl-
boronic acids were coupled with 4-bromooxindole 9a under
microwave irradiation (see Scheme 1). The reaction pro-
ceeded smoothly and afforded excellent yields with both
Figure 2. One-pot synthesis by Suzuki–Miyaura coupling and aldol
condensation reactions.
On the basis of our previous work, this reaction was op-
timized by using 4-bromooxindole 9a[10] and 2-formylphen-
ylboronic acid (7a) as the coupling partners in a Pd system
under microwave irradiation (see Table 1). Using our pre-
viously reported conditions, the desired naphthoxindole 5a
was obtained in 74% yield. Decreasing the irradiation tem-
perature to 130 or 110 °C led to incomplete conversion with
yields of 68 and 63%, respectively (see Table 1, Entries 2
and 3). Various inorganic bases, including K3PO4, K2CO3,
and Na2CO3, were examined (see Table 1, Entries 4–6). The
most effective one was K2CO3, which afforded a 93% yield
(see Table 1, Entry 5). The optimized conditions to provide
Table 1. Optimization of the one-pot naphthoxindole procedure.[a]
Entry
R
Base
Temp.
[°C]
Product
%
Yield[b]
1
2
3
4
5
6
7
8
CH3
CH3
CH3
CH3
CH3
CH3
H
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
K2CO3
Na2CO3
K2CO3
K2CO3
150
130
110
150
150
150
150
150
5a
5a
5a
5a
5a
5a
5b
5c
74
68
63
85
93
25
76
88
Scheme 1. The scope of substituted 2-formylphenylboronic acids and
heteroarylboronic acid. Reagents and conditions: oxindole 9a
(0.5 mmol), the boronic acid (0.6 mmol), Pd(PPh3)4 (5 mol-%),
PMB
[a] Reagents and conditions: oxindole 9 (0.5 mmol), boronic acid
7a (0.6 mmol), Pd(PPh3)4 (5 mol-%), base (1.5 mmol), toluene/ K2CO3 (1.5 mmol), toluene/EtOH (2:1, 3 mL), MW, 150 °C, 10 min.
EtOH (2:1, 3 mL), microwave irradiation, 10 min. [b] Isolated yield. [a] 2-Acetylphenylboronic acid (7k) was used as a coupling partner.
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165

K.-Y. Park, B. T. Kim, J.-N. Heo
FULL PAPER
electron-rich and electron-deficient substituents on the phenylacetamide (see Scheme 3). The conversion of toluene
phenylboronic acids 7d–7h to give compounds 5d–5h. How- 15 into phenylacetonitrile 16 was accomplished through a
ever, the 1,3-dioxolyl-substituted phenylboronic acid 7i was two-step sequence that consisted of benzylic bromination
less effective and gave a 42% yield for naphthoxindole 5i.
Naphthoxindole 5j was also obtained by coupling 9a with
a thiophenylboronic acid 7j, but the product was produced
in a slightly lower yield, potentially from the poisoning of
the Pd catalyst. This protocol was compatible with 2-acetyl-
phenylboronic acid 7k, which contains a less reactive ketone
moiety, and afforded 6-methylnaphthoxindole 5k in moder-
ate yield.[6b]
Encouraged by these results, we further investigated the
scope of the reaction by employing other substituted 4-
bromooxindoles, which included those with fluoro, methyl,
and methoxy groups. Substituted 4-bromooxindoles 14a,
14b, and 14c were readily prepared by following modified
literature methods. The 5-methyl- and 7-fluoro-substituted
4-bromooxindoles 14a and 14b, respectively, were obtained
in good yield in four steps through an acid-catalyzed
Scheme 3. Preparation of 4-bromo-6-methoxy-1-methylindolin-2-
Friedel–Crafts cyclization of
a hydroxyimine and a
one (14c, NBS = N-bromosuccinimide, HBTU = O-(benzotriazol-
1-yl)-N,N,NЈ,NЈ-tetramethyluronium hexafluorophosphate, DIPEA
= N,N-diisopropylethylamine, acac = acetylacetonate, NMP = N-
methylpyrrolidone).
Wolff–Kishner reduction (see Scheme 2). The key interme-
diate isatins 12a and 12b were obtained in two steps from
the corresponding anilines 10a and 10b through a coupling
reaction with CCl3CH(OH)2 and Friedel–Crafts cyclization
of the resulting hydroxyimines 11a and 11b, respectively.[12]
Methylation of isatins 12a and 12b by treatment with CH3I
afforded the N-methylated isatins 13a and 13b in good
yields.[13] Finally, a Wolff–Kishner reduction in the presence
of hydrazine provided the desired 4-bromooxindoles 14a
and 14b.[10b]
Scheme 2. Preparation of substituted 4-bromoindolin-2-ones 14a
and 14b (DMF = N,N-dimethylformamide).
We envisioned the alternative approach to the targeted 6-
methoxy-substituted 4-bromooxindole 14c to occur through
a Cu-catalyzed Ullmann-type cyclization of a 2-bromo- Scheme 4. The scope of substituted oxindoles.
166 Eur. J. Org. Chem. 2014, 164–170
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

One-Pot Synthesis of Naphthoxindoles
(s, 1 H), 8.79 (d, J = 8.0 Hz, 1 H), 8.51 (s, 1 H), 8.33 (d, J = 7.9 Hz,
1 H), 8.23 (d, J = 8.4 Hz, 1 H), 7.86 (t, J = 7.0, 8.2 Hz, 1 H), 7.75
(t, J = 7.6 Hz, 1 H), 7.62 (t, J = 7.8 Hz, 1 H), 7.08 (d, J = 7.3 Hz,
1 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 168.9, 139.0,
133.6, 132.4, 131.9, 129.8, 129.7, 127.7, 126.9, 126.8, 125.9, 124.2,
122.5, 115.9, 107.1 ppm. HRMS (EI): calcd. for C15H9NO [M]+
219.0684; found 219.0684.
followed by nitrile substitution of the resulting benzyl
bromide. The acid-catalyzed hydrolysis of 16 and condensa-
tion of the resulting carboxylic acid by treatment with
methylamine gave amide 18 in good yield. Finally, the intra-
molecular formation of a five-membered lactam ring
through the Cu-catalyzed amidation reaction reported by
van den Hoogenband and co-workers produced 4-bromo-
oxindole 14c in 53% yield.[14]
4-(4-Methoxybenzyl)naphtho[3,2,1-cd]indol-5(4H)-one (5c): Yellow
1
solid (88% yield); m.p. 173 °C. H NMR (300 MHz, [D6]DMSO):
The scope of the reaction of the substituted 4-bromoox-
indoles (i.e., 14a, 14b, and 14c) was evaluated with respect
to 2-formylphenylboronic acids 7a, 7d, 7f, and 7g (see
Scheme 4). The one-pot reaction was compatible with vari-
ous electron-withdrawing and electron-donating substitu-
ents on the substrates. Notably, the Suzuki–Miyaura cou-
pling reaction tolerated the steric hindrance from the
methyl group in 4-bromooxindole 14a to provide 5l–5n in
excellent yields.
δ = 8.78 (d, J = 8.0 Hz, 1 H), 8.59 (s, 1 H), 8.33 (d, J = 8.0 Hz, 1
H), 8.25 (d, J = 8.5 Hz, 1 H), 7.86 (t, J = 7.5 Hz, 1 H), 7.75 (t, J
= 7.4 Hz, 1 H), 7.61 (t, J = 7.8 Hz, 1 H), 7.34 (d, J = 9.0 Hz, 2 H),
7.17 (d, J = 7.4 Hz, 1 H), 6.86 (d, J = 8.5 Hz, 2 H), 5.05 (s, 2 H),
3.67 (s, 3 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 167.1,
159.0, 139.4, 133.5, 132.4, 131.9, 130.0, 129.7, 129.6, 129.4 (2),
127.8, 127.6, 126.7, 124.7, 124.2, 121.2, 116.7, 114.5 (2), 107.1, 55.5,
43.1 ppm. HRMS (EI): calcd. for C23H17NO2 [M]+ 339.1259; found
339.1251.
4,9-Dimethylnaphtho[3,2,1-cd]indol-5(4H)-one (5d): Yellow solid
(94% yield); m.p. 218 °C. 1H NMR (300 MHz, [D6]DMSO): δ =
8.61 (s, 1 H), 8.50 (s, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 8.20 (d, J =
8.3 Hz, 1 H), 7.66 (t, J = 7.7, 8.0 Hz, 1 H), 7.59 (d, J = 8.2 Hz, 1
H), 7.22 (d, J = 7.3 Hz, 1 H), 3.38 (s, 3 H), 2.61 (s, 3 H) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 166.7, 139.9, 139.6, 131.7, 131.5,
131.0, 129.0, 128.9, 126.7, 125.7, 123.6, 123.4, 120.9, 116.0, 105.8,
26.3, 21.6 ppm. HRMS (EI): calcd. for C17H13NO [M]+ 247.0997;
found 247.0994.
Conclusions
In summary, we have developed a one-pot method that
proceeds through Suzuki–Miyaura coupling and aldol con-
densation reactions to synthesize naphthoxindoles in good
to excellent yields. This reaction employs 4-bromooxindoles
and 2-formylphenylboronic acids as coupling partners un-
der microwave irradiation. In addition, the substituted ox-
indoles were prepared either by a Friedel–Crafts cyclization
and Wolff–Kishner reduction of an isatin or by a Cu-cata-
lyzed amidation of a 2-bromophenylacetamide. Further
studies that are aimed at evaluating the bioactivities of these
new naphthoxindoles, particularly against human cancer
cell lines, are being pursued.
9-Methoxy-4-methylnaphtho[3,2,1-cd]indol-5(4H)-one (5e): Yellow
1
solid (91% yield); m.p. 197 °C. H NMR (300 MHz, [D6]DMSO):
δ = 8.46 (s, 1 H), 8.31 (d, J = 8.0 Hz, 1 H), 8.22 (d, J = 9.0 Hz, 1
H), 8.18 (d, J = 2.5 Hz, 1 H), 7.63 (t, J = 8.3, 7.4 Hz, 1 H), 7.37
(dd, J = 2.6, 8.8 Hz, 1 H), 7.20 (d, J = 7.2 Hz, 1 H), 4.01 (s, 3 H),
3.37 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 166.8,
160.4, 139.8, 133.5, 133.4, 128.5, 127.5, 126.7, 125.5, 122.0, 121.2,
117.7, 116.4, 105.8, 104.9, 55.8, 26.2 ppm. HRMS (EI): calcd. for
C17H13NO2 [M]+ 263.0946; found 263.0942.
Experimental Section
9-Fluoro-4-methylnaphtho[3,2,1-cd]indol-5(4H)-one (5f): Yellow so-
lid (87% yield); m.p. 232 °C. H NMR (300 MHz, [D6]DMSO): δ
1
General Procedure for the Direct One-Pot Synthesis of Naphthox-
= 8.60 (dd, J = 2.6, 10.6 Hz, 1 H), 8.5 (s, 1 H), 8.39 (dd, J = 6.0,
8.9 Hz, 1 H), 8.27 (d, J = 8.0 Hz, 1 H), 7.68–7.61 (m, 2 H), 7.24
(d, J = 7.3 Hz, 1 H), 3.37 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 166.5, 162.4 (J = 246.8 Hz), 139.9, 134.5 (J = 9.0 Hz),
133.3 (J = 9.7 Hz), 129.9, 129.2, 126.3, 125.6 (J = 4.5 Hz), 124.0 (J
= 3.0 Hz), 121.0, 116.4, 116.3 (J = 24.0 Hz), 109.0 (J = 21.7 Hz),
106.3, 26.3 ppm. HRMS (EI): calcd. for C16H10FNO [M]+
251.0746; found 251.0755.
indoles: To a thick-walled borosilicate glass vial (3 mL) were se-
quentially added oxindole
9 (0.5 mmol), the boronic acid
(0.6 mmol), Pd(PPh3)4 (5 mol-%), and K2CO3 (1.5 mmol). The
mixture was suspended in toluene/EtOH (2:1, 3 mL). The reaction
vial was sealed and then placed into a microwave reactor and irra-
diated at 150 °C for 10 min. (Usually, the average microwave power
ranged from 60 to 80 W, and the internal pressure was 6–8 bars.)
After cooling to room temperature, the mixture was treated with
EtOAc, and the resulting mixture was filtered through a short pad
of Celite. The solvents were removed with a rotary evaporator, and
the residue was purified by silica gel flash column chromatography
(EtOAc/hexanes) to afford the naphthoxindole product.
8-Methoxy-4-methylnaphtho[3,2,1-cd]indol-5(4H)-one (5g): Yellow
1
solid (93% yield), m.p. 163 °C. H NMR (300 MHz, [D6]DMSO):
δ = 8.68 (d, J = 9.0 Hz, 1 H), 8.44 (s, 1 H), 8.18 (d, J = 8.4 Hz, 1
H), 7.81 (d, J = 2.6 Hz, 1 H), 7.62 (t, J = 7.6, 8.0 Hz, 1 H), 7.47
(dd, J = 2.6, 8.9 Hz, 1 H), 7.15 (d, J = 7.2 Hz, 1 H), 3.92 (s, 3 H),
3.36 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 166.7,
158.2, 140.0, 134.7, 129.3, 126.1, 126.0, 125.7, 125.2, 125.1, 125.0,
119.8, 115.8, 112.0, 105.0, 55.5, 26.3 ppm. HRMS (EI): calcd. for
C17H13NO2 [M]+ 263.0946; found 263.0941.
4-Methylnaphtho[3,2,1-cd]indol-5(4H)-one (5a): Yellow solid (93%
yield); m.p. 148 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.79 (d,
J = 8.3 Hz, 1 H), 8.54 (s, 1 H), 8.31 (d, J = 8.1 Hz, 1 H), 8.26 (d,
J = 8.3 Hz, 1 H), 7.86 (t, J = 7.9, 7.4 Hz, 1 H), 7.75 (t, J = 7.6 Hz,
1 H), 7.67 (t, J = 7.9, 7.8 Hz, 1 H), 7.23 (d, J = 7.3 Hz, 1 H), 3.38
(s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 166.7, 140.0,
133.0, 131.9, 131.4, 129.4, 129.3, 127.3, 126.8, 126.0, 124.6, 123.8,
120.7, 116.1, 105.9, 26.3 ppm. HRMS (EI): calcd. for C16H11NO
[M]+ 233.0841; found 233.0845.
8-(Benzyloxy)-4-methylnaphtho[3,2,1-cd]indol-5(4H)-one (5h): Yel-
low solid (92% yield); m.p. 170 °C. 1H NMR (300 MHz, [D6]-
DMSO): δ = 8.70 (d, J = 8.7 Hz, 1 H), 8.40 (s, 1 H), 8.19 (d, J =
8.4 Hz, 1 H), 7.94 (d, J = 2.7 Hz, 1 H), 7.63 (t, J = 7.8, 7.8 Hz, 1
H), 7.57–7.51 (m, 3 H), 7.44–7.31 (m, 3 H), 7.16 (d, J = 7.3 Hz, 1
H), 5.27 (s, 2 H), 3.37 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]-
Naphtho[3,2,1-cd]indol-5(4H)-one (5b): Pale yellow solid (76%
yield); m.p. 233 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 10.86
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K.-Y. Park, B. T. Kim, J.-N. Heo
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DMSO): δ = 166.7, 157.3, 140.0, 136.6, 134.7, 129.4, 128.5 (2), 7.67 (s, 1 H), 4.04 (s, 3 H), 3.44 (s, 3 H) ppm. 13C NMR (75 MHz,
128.0 (2), 126.1, 126.0, 125.8, 125.3, 125.1, 120.1, 119.8, 115.8, CDCl3): δ = 168.5, 161.8, 141.6, 134.0, 131.9, 131.6, 128.5, 127.3,
113.3, 107.5, 105.1, 69.6, 26.3 ppm. HRMS (EI): calcd. for 127.0, 124.8, 124.3, 123.4, 117.3, 97.8, 95.6, 60.0, 26.5 ppm. HRMS
C23H17NO2 [M]+ 339.1259; found 339.1254.
(EI): calcd. for C17H13NO2 [M]+ 263.0946; found 263.0950.
4-Methyl-[1,3]dioxolo[4Ј,5Ј:6,7]naphtho[3,2,1-cd]indol-5(4H)-one
(5i): Yellow solid (42% yield); m.p. 238 °C. 1H NMR (300 MHz,
[D6]DMSO): δ = 8.37 (s, 1 H), 8.26 (s, 1 H), 8.17 (d, J = 8.0 Hz, 1
H), 7.73 (s, 1 H), 7.58 (t, J = 7.8, 7.9 Hz, 1 H), 7.14 (d, J = 7.2 Hz,
9-Fluoro-2-methoxy-4-methylnaphtho[3,2,1-cd]indol-5(4H)-one (5p):
Yellow solid (83% yield); m.p. 208 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.23 (s, 1 H), 8.14–8.07 (m, 2 H), 7.42 (dt, J = 8.3,
2.5 Hz, 1 H), 7.27 (s, 1 H), 6.68 (s, 1 H), 4.03 (s, 3 H), 3.44 (s, 3
1 H), 6.25 (s, 2 H), 3.35 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]- H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.2, 162.5 (J =
DMSO): δ = 166.8, 150.1, 147.8, 139.8, 129.6, 128.8, 128.6, 125.9,
125.8, 122.6, 120.5, 116.3, 108.2, 105.0, 102.2, 101.7, 26.2 ppm.
HRMS (EI): calcd. for C17H11NO3 [M]+ 277.0739; found 277.0742.
249.0 Hz), 161.7, 141.6, 133.9 (J = 9.0 Hz), 133.2 (J = 9.0 Hz),
130.6, 126.7 (J = 4.5 Hz), 124.2 (J = 3.0 Hz), 123.6, 117.5, 116.3 (J
= 24.0 Hz), 108.5 (J = 21.7 Hz), 98.4, 95.4, 55.9, 26.5 ppm. HRMS
(EI): calcd. for C17H12FNO2 [M]+ 281.0852; found 281.0858.
4-Methylthieno[3Ј,4Ј:4,5]benzo[1,2,3-cd]indol-5(4H)-one (5j): Yellow
1
solid (63% yield); m.p. 138 °C. H NMR (300 MHz, [D6]DMSO):
2-Methoxy-4,9-dimethylnaphtho[3,2,1-cd]indol-5(4H)-one (5q): Yel-
1
δ = 8.66 (d, J = 3.0 Hz, 1 H), 8.51 (d, J = 3.1 Hz, 1 H), 8.26 (s, 1
low solid (86% yield); m.p. 194 °C. H NMR (300 MHz, CDCl3):
H), 7.91 (d, J = 8.1 Hz, 1 H), 7.56 (t, J = 7.7, 7.8 Hz, 1 H), 7.11 δ = 8.30 (s, 1 H), 8.22 (s, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.49 (d,
(d, J = 7.4 Hz, 1 H), 3.32 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]- J = 8.3 Hz, 1 H), 7.37 (s, 1 H), 6.65 (s, 1 H), 4.04 (s, 3 H), 3.43 (s,
DMSO): δ = 171.8, 145.2, 143.3, 140.1, 134.6, 131.9, 129.3, 129.0,
127.5, 123.8, 121.6, 111.0, 107.2, 31.5 ppm. HRMS (EI): calcd. for
C14H9NOS [M]+ 239.0405; found 239.0401.
3 H), 2.66 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.6,
161.6, 141.5, 138.8, 131.9, 131.7, 131.6, 128.9, 126.9, 124.2, 123.9,
123.1, 117.5, 97.7, 95.5, 56.0, 26.5, 22.1 ppm. HRMS (EI): calcd.
for C18H15NO2 [M]+ 277.1103; found 277.1098.
4,6-Dimethylnaphtho[3,2,1-cd]indol-5(4H)-one (5k): Yellow solid
(48% yield); m.p. 216 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 3-Fluoro-4-methylnaphtho[3,2,1-cd]indol-5(4H)-one (5r): Yellow so-
8.80 (d, J = 8.0 Hz, 1 H), 8.38 (d, J = 8.0 Hz, 1 H), 8.23 (d, J = lid (92% yield); m.p. 190 °C. 1H NMR (300 MHz, CDCl3): δ = 8.57
8.4 Hz, 1 H), 7.87 (t, J = 6.9, 8.0 Hz, 1 H), 7.79 (t, J = 7.6, 7.3 Hz,
(d, J = 8.0 Hz, 1 H), 8.45 (s, 1 H), 8.13 (d, J = 8.1 Hz, 1 H), 8.06
1 H), 7.60 (t, J = 7.7, 7.9 Hz, 1 H), 7.19 (d, J = 7.3 Hz, 1 H), 3.37 (dd, J = 3.3, 9.1 Hz, 1 H), 7.81 (t, J = 7.6, 7.8 Hz, 1 H), 7.68 (t, J
(s, 3 H), 3.06 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = = 7.6, 7.7 Hz, 1 H), 7.38 (t, J = 10.1, 10.0 Hz, 1 H), 3.65 (s, 3
167.5, 138.7, 138.6, 133.1, 131.2, 129.0, 128.2, 127.3, 127.1, 124.9,
124.0, 120.8, 120.3, 115.7, 105.5, 26.2, 12.9 ppm. HRMS (EI):
calcd. for C17H13NO [M]+ 247.0997; found 247.0999.
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.2, 144.5 (J =
246.0 Hz), 132.8, 131.9, 131.8, 129.4, 128.4, 127.0, 124.7 (J =
3.7 Hz), 124.1 J = (9.0 Hz), 123.8 (J = 6.7 Hz), 123.4 (J = 1.5 Hz),
123.2, 119.0 (J = 22.5 Hz), 117.8 (J = 6.7 Hz), 28.6 (J =
3.0 Hz) ppm. HRMS (EI): calcd. for C16H10FNO [M]+ 251.0746;
found 251.0760.
1,4-Dimethylnaphtho[3,2,1-cd]indol-5(4H)-one (5l): Yellow solid
(91% yield); m.p. 172 °C. 1H NMR (300 MHz, [D6]DMSO): δ =
8.91 (d, J = 8.0 Hz, 1 H), 8.53 (s, 1 H), 8.35 (d, J = 8.0 Hz, 1 H),
7.88 (t, J = 7.4, 7.6 Hz, 1 H), 7.76 (t, J = 7.6, 7.4 Hz, 1 H), 7.48
(d, J = 7.3 Hz, 1 H), 7.14 (d, J = 7.3 Hz, 1 H), 3.37 (s, 3 H), 3.00
(s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 171.7, 143.7,
139.1, 138.1, 137.7, 137.0, 134.5, 133.9, 132.5, 131.9, 131.8, 130.3,
3-Fluoro-8-methoxy-4-methylnaphtho[3,2,1-cd]indol-5(4H)-one (5s):
Yellow solid (85% yield); m.p. 206 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.44 (d, J = 10.0 Hz, 1 H), 8.34 (s, 1 H), 7.95 (dd, J
= 3.2, 9.0 Hz, 1 H), 7.44 (s, 1 H), 7.41–7.31 (m, 2 H), 4.00 (s, 3 H),
126.8, 111.2, 100.0, 31.4, 29.7 ppm. HRMS (EI): calcd. for 3.64 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.3, 158.3,
C17H13NO [M]+ 247.0997; found 247.1005.
143.9 (J = 245.3 Hz), 134.3, 127.5, 126.2 125.2 (J = 4.5 Hz), 124.4,
123.9 (J = 8.2 Hz), 123.4 (J = 1.5 Hz), 122.8 (J = 6.0 Hz), 120.3,
119.1 (J = 22.5 Hz), 117.3 (J = 6.0 Hz), 111.3, 55.5, 28.5 (J =
3.0 Hz) ppm. HRMS (EI): calcd. for C17H12FNO2 [M]+ 281.0852;
found 281.0858.
9-Fluoro-1,4-dimethylnaphtho[3,2,1-cd]indol-5(4H)-one (5m): Yellow
1
solid (85% yield); m.p. 210 °C. H NMR (300 MHz, [D6]DMSO):
δ = 8.50 (s, 1 H), 8.45–8.37 (m, 2 H), 7.67 (t, J = 8.6, 8.7 Hz, 1 H),
7.44 (d, J = 7.0 Hz, 1 H), 7.13 (d, J = 7.4 Hz, 1 H), 3.35 (s, 3 H),
2.93 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 166.1, Preparation of isonitrosoacetanilides 11a and 11b: To a solution
161.7 (J = 244.5 Hz), 138.3, 134.7 (J = 9.8 Hz), 134.0 (J = 9.7 Hz),
131.5, 130.7, 128.6, 126.6, 124.5 (J = 4.5 Hz), 124.4 (J = 3.0 Hz),
chloral hydrate (3.2 g, 19.34 mmol) in H2O (20 mL) were added
Na2SO4 (6.46 g, 35.46 mmol), 3-bromoaniline 10a or 10b
121.7, 115.4 (J = 23.2 Hz), 111.7 (J = 24.0 Hz), 106.3, 26.0, (16.12 mmol) in a mixture of 37% HCl (1.3 mL) and water
23.8 ppm. HRMS (EI): calcd. for C17H12FNO [M]+ 265.0903; (60 mL), and
a
solution of hydroxylamine sulfate (9.53 g,
found 265.0903.
58.03 mmol) in water (20 mL). The resulting mixture was stirred at
100 °C for 1 h and then cooled to room temperature. The resulting
precipitate was collected by filtration, washed with water (3ϫ
100 mL), and then dried in vacuo to provide isonitrosoacetanilide
11a or 11b.
8-Methoxy-1,4-dimethylnaphtho[3,2,1-cd]indol-5(4H)-one (5n): Yel-
low solid (87% yield); m.p. 180 °C. 1H NMR (300 MHz, [D6]-
DMSO): δ = 8.80 (d, J = 10.0 Hz, 1 H), 8.44 (s, 1 H), 7.84 (s, 1
H), 7.49 (d, J = 9.2 Hz, 1 H), 7.44 (d, J = 6.7 Hz, 1 H), 7.07 (d, J
= 6.3 Hz, 1 H), 3.94 (s, 3 H), 3.35 (s, 3 H), 2.95 (s, 3 H) ppm. 13C (E)-N-(3-Bromo-4-methylphenyl)-2-(hydroxyimino)acetamide (11a):
NMR (75 MHz, [D6]DMSO): δ = 171.7, 162.5, 143.7, 141.0, 136.9,
133.3, 133.2, 132.3, 131.7, 130.7, 125.9, 125.8, 124.4, 118.0, 110.3,
60.6, 33.3, 29.6 ppm. HRMS (EI): calcd. for C18H15NO2 [M]+
277.110; found 247.1099.
(3.16 g, 76% yield). 1H NMR (300 MHz, [D6]DMSO): δ = 12.18
(s, 1 H), 10.23 (s, 1 H), 8.01 (d, J = 2.0 Hz, 1 H), 2.27 (s, 1 H),
7.59 (s, 1 H), 7.27 (d, J = 8.3 Hz, 1 H), 2.27 (s, 3 H) ppm. MS (EI):
m/z (%) = 258 (51) [M + 2]+, 256 (48) [M]+, 227 (19), 225 (22), 187
(31), 185 (32), 160 (92), 77 (100).
2-Methoxy-4-methylnaphtho[3,2,1-cd]indol-5(4H)-one (5o): Yellow
1
solid (89% yield); m.p. 152 °C. H NMR (300 MHz, CDCl3): δ = (E)-N-(5-Bromo-2-fluorophenyl)-2-(hydroxyimino)acetamide (11b):
8.54 (d, J = 8.0 Hz, 1 H), 8.26 (s, 1 H), 8.11 (d, J = 8.0 Hz, 1 H),
7.77 (t, J = 7.5 Hz, 1 H), 7.67 (t, J = 7.5 Hz, 1 H), 7.40 (s, 1 H),
(3.19 g, 76% yield), 1H NMR (300 MHz, [D6]DMSO): δ = 12.37
(s, 1 H), 9.95 (s, 1 H), 8.13–8.10 (m, 1 H), 7.75 (s, 1 H), 7.40–7.25
168
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 164–170

One-Pot Synthesis of Naphthoxindoles
(m, 2 H) ppm. MS (EI): m/z (%) = 261 (41) [M + 2]+, 259 (42)
= 9.0 Hz), 127.6 (J = 4.5 Hz), 125.3 (J = 6.8 Hz), 117.7 (J =
20.3 Hz), 113.4 (J = 3.0 Hz), 37.5 (J = 2.3 Hz), 28.7 (J =
5.3 Hz) ppm. MS (EI): m/z (%) = 244 (38) [M + 2]+, 242 (39)
[M]+, 215 (11), 213 (11), 136 (16), 135 (100).
[M]+, 216 (31), 214 (32), 190 (92), 188 (100), 162 (36), 160 (37).
Preparation of 4-Bromoisatin 12a and 12b: Isonitrosoacetanilide 11a
or 11b (11.67 mmol) was added to concentrated sulfuric acid
(13 mL) that was rapidly stirred at 0 °C. The resulting solution was
stirred at 80 °C for 1 h and then cooled to room temperature. The
mixture was poured carefully onto crushed ice. The orange precipi-
tate was collected by filtration, washed with H2O and benzene, and
then purified by column chromatography on silica gel (MeOH/
CH2Cl2) to give 12a or 12b.
4-Bromo-5-methylisatin (12a): (2.20 g, 78% yield). 1H NMR
(300 MHz, [D6]DMSO): δ = 11.06 (s, 1 H), 7.49 (d, J = 8.0 Hz, 1
H), 6.78 (d, J = 7.9 Hz, 1 H), 2.26 (s, 3 H) ppm. MS (EI): m/z (%)
= 240 (41) [M + 2]+, 238 (41) [M]+, 212 (97), 210 (100), 185 (30),
183 (37).
2-(2,6-Dibromo-4-methoxyphenyl)acetonitrile (16)
1,3-dibromo-2-(bromomethyl)-5-methoxybenzene: To a solution of
2,6-dibromotoluene 15 (1.8 g, 6.43 mmol) in CCl4 (20 mL) were
added N-bromosuccinimide (2.29 g, 12.86 mmol) and benzoyl per-
oxide (0.16 g, 0.64 mmol). The reaction mixture was stirred at
90 °C for 12 h and then cooled to room temperature. The mixture
was diluted with H2O, and the resulting solution was extracted with
EtOAc (3ϫ 50 mL). The combined organic phases were washed
with brine, dried with Na2SO4, and concentrated to provide 1,3-
dibromo-2-(bromomethyl)-5-methoxybenzene (2.1 g) as
a pale
1
brown solid. H NMR (300 MHz, CDCl3): δ = 7.11 (s, 2 H), 4.82
(s, 2 H), 3.80 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.1,
128.2, 125.8 (2), 118.6 (2), 55.9, 34.3 ppm. MS (EI): m/z (%) = 357
(5) [M + 2]+, 355 (2) [M]+, 281 (49), 278 (100), 276 (53), 119 (19),
91 (20), 76 (29).
4-Bromo-7-fluoroisatin (12b): (2.47 g, 87% yield). 1H NMR
(300 MHz, [D6]DMSO): δ = 11.67 (s, 1 H), 7.48–7.41 (m, 1 H),
7.22–7.18 (m, 1 H) ppm. MS (EI): m/z (%) = 245 (36) [M + 2]+,
243 (32) [M]+, 217 (67), 215 (77), 190 (15), 188 (21), 108 (100).
2-(2,6-Dibromo-4-methoxyphenyl)acetonitrile (16): To a suspension
Preparation of 4-Bromo-1-methylisatin 13a and 13b: To a solution
of 4-bromoisatin 12a or 12b (8.75 mmol) in DMF (30 mL) were
added potassium carbonate (1.81 g, 13.12 mmol) and methyl iodide
(3.73 g, 26.24 mmol). The mixture was heated at 80 °C for 1 h. Af-
ter cooling to room temperature, the mixture was diluted with
CH2Cl2 and H2O. The biphasic layers were separated, and the
aqueous layer was extracted with CH2Cl2 (2ϫ). The combined or-
ganic layers were dried with Na2SO4 and concentrated to yield 4-
bromo-1-methylisatin 13a or 13b as an orange solid.
4-Bromo-1,5-dimethylisatin (13a): (1.89 g, 85% yield). 1H NMR
(300 MHz, [D6]DMSO): δ = 7.59 (d, J = 8.0 Hz, 1 H), 7.04 (d, J
= 8.0 Hz, 1 H), 3.09 (s, 3 H), 2.29 (s, 3 H) ppm. MS (EI): m/z (%)
= 254 (57) [M + 2]+, 252 (60) [M]+, 226 (48), 224 (49), 198 (53),
196 (55), 118 (100).
of
1,3-dibromo-2-(bromomethyl)-5-methoxybenzene
(2.0 g,
5.57 mmol) in EtOH/H2O (4:1 v/v, 40 mL) was added KCN (0.98 g,
15.05 mmol). The reaction mixture was stirred at 90 °C for 3 h. The
reaction was cooled to room temperature and then extracted with
EtOAc (3ϫ 50 mL). The aqueous layer was additionally extracted
with EtOAc (2ϫ). The combined organic phases were washed with
brine, dried with Na2SO4, and concentrated under reduced pres-
sure. The residue was purified by column chromatography on silica
gel (10% EtOAc/hexanes) to provide phenylacetonitrile 16 (1.6 g,
1
81% for 2 steps) as a white solid. H NMR (300 MHz, CDCl3): δ
= 7.15 (s, 2 H), 4.04 (s, 2 H), 3.81 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 160.1, 125.2, 122.0, 118.5 (2), 117.8, 115.9, 55.9,
25.0 ppm. MS (EI): m/z (%) = 304 (97) [M + 2]+, 302 (48) [M]+,
225 (98), 223 (100), 182 (12), 180 (11), 145 (14), 144 (35).
4-Bromo-7-fluoro-1-methylisatin (13b): (1.98 g, 88% yield). 1H
NMR (300 MHz, [D6]DMSO): δ = 7.54–7.47 (m, 1 H), 7.29–7.25
(m, 1 H), 3.27 (d, J = 3.1 Hz, 3 H) ppm. MS (EI): m/z (%) = 258
(41) [M + 2]+, 256 (52) [M]+, 230 (31), 228 (32), 202 (44), 200 (45),
122 (100).
2-(2,6-Dibromo-4-methoxyphenyl)acetic Acid (17): To a solution of
phenylacetonitrile 16 (1.5 g, 4.92 mmol) in acetic acid (5 mL) and
H2O (5 mL) was added dropwise concentrated sulfuric acid (5 mL).
The mixture was heated at 110 °C for 8 h, cooled to room tempera-
ture, and then poured onto crushed ice. The resulting white precipi-
tate was removed by filtration and then dissolved in CH2Cl2. The
resulting solution was extracted with NaOH (1 n solution). The
aqueous layer was acidified to pH ≈ 2 with HCl (1 n solution),
and the solution was extracted with CH2Cl2. The combined organic
phases were washed with brine, dried with Na2SO4, and concen-
trated in vacuo to provide phenylacetic acid 17 (1.32 g, 83%) as a
Preparation of 4-Bromo-1-methyloxindole 14a and 14b: To a solu-
tion of 4-bromo-1-methylisatin 13a or 13b (7.28 mmol) in ethanol
(48 mL) was added hydrazine hydrate (85%, 12 mL) under nitro-
gen. The mixture was stirred at 90 °C for 24 h. After cooling to
room temperature, the solution was concentrated. The residue was
diluted with H2O, and the resulting solution was extracted with
EtOAc. The combined organic phases were washed with H2O and
brine, dried with Na2SO4, and concentrated under reduced pres-
sure. The residue was purified by column chromatography on silica
gel (EtOAc/hexanes) to provide 4-bromo-1-methyloxindole 14a or
14b as a light yellow solid.
1
white solid. H NMR (300 MHz, [D6]DMSO): δ = 12.60 (s, 1 H),
7.26 (s, 2 H), 3.85 (s, 2 H), 3.78 (s, 3 H) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 170.4, 158.9, 126.4, 125.5 (2), 117.8 (2), 56.0,
41. ppm. MS (EI): m/z (%) = 323 (47) [M + 2]+, 321 (22) [M]+, 279
(100), 277 (55), 245 (41), 243 (39), 164 (12), 119 (13).
2-(2,6-Dibromo-4-methoxyphenyl)-N-methylacetamide (18): To
a
1
4-Bromo-1,5-dimethyloxindole (14a): (1.14 g, 65% yield), H NMR
solution of phenylacetic acid 17 (1.30 g, 3.92 mmol) in DMF
(10 mL) were added HBTU (3.71 g, 9.79 mmol), diisopropylethyl-
amine (2.09 mL, 12.04 mmol), and methylamine (0.38 g,
12.04 mmol). The reaction mixture was stirred at room temperature
for 3 h. The mixture was diluted with NH4Cl (1 n solution), and
the resulting solution was extracted with EtOAc (3ϫ 50 mL). The
combined organic phases were washed with brine, dried with
Na2SO4, and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (30% EtOAc/hex-
(300 MHz, CDCl3): δ = 7.15 (d, J = 7.0 Hz, 1 H), 6.67 (d, J =
7.9 Hz, 1 H), 3.48 (s, 2 H), 3.19 (s, 3 H), 2.38 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 173.9, 143.6, 131.4, 129.5, 125.9,
121.6, 106.7, 37.8, 26.4, 22.0 ppm. MS (EI): m/z (%) = 240 (64) [M
+ 2]+, 238 (65) [M]+, 211 (16), 209 (17), 160 (32), 132 (26), 131
(100).
4-Bromo-7-fluoro-1-methyloxindole (14b): (1.13 g, 64% yield). 1H
NMR (300 MHz, CDCl3): δ = 7.08 (dd, J = 8.9, 3.8 Hz, 1 H), 6.97–
6.90 (m, 1 H), 3.49 (s, 2 H), 3.41 (d, J = 3.4 Hz, 3 H) ppm. 13C anes) to provide acetamide 18 (1.26 g, 93%) as a white solid. 1H
NMR (75 MHz, CDCl3): δ = 173.1, 146.7 (J = 242.2 Hz), 132.7 (J
NMR (300 MHz, [D6]DMSO): δ = 7.79 (s, 1 H), 7.23 (s, 2 H), 3.77
Eur. J. Org. Chem. 2014, 164–170
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
169

K.-Y. Park, B. T. Kim, J.-N. Heo
FULL PAPER
(s, 3 H), 3.74 (s, 2 H), 2.57 (d, J = 4.0 Hz, 3 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 168.0, 158.7, 127.2, 125.8 (2), 117.7 (2),
55.9, 42.0, 25.7 ppm. MS (EI): m/z (%) = 335 (1) [M]+, 279 (51),
277 (22), 258 (100), 256 (96), 199 (16), 177 (16), 119 (14).
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4-Bromo-6-methoxy-1-methyloxindole (14c): A screw-capped test
tube was charged with acetamide 18 (1.25 g, 3.71 mmol), K2CO3
(2.56 g, 18.5 mmol), copper(I) chloride (37 mg, 0.37 mmol), and
acetylacetone (96 μL, 0.93 mmol). Anhydrous N-methyl-2-pyrrol-
idone (30 mL) was added by syringe. The reaction tube was evacu-
ated and then backfilled with nitrogen (3ϫ). The mixture was
heated at 90 °C for 1 h and then cooled to room temperature. The
reaction mixture was diluted with NH4Cl (1 n solution), and the
resulting solution was extracted with EtOAc (3ϫ 50 mL). The com-
bined organic phases were washed with brine, dried with Na2SO4,
and concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (20% EtOAc/hexanes) to
provide oxindole 14c (0.51 g, 53%) as a white solid. 1H NMR
(300 MHz, CDCl3): δ = 6.68 (s, 1 H), 6.35 (s, 1 H), 3.82 (s, 3 H),
3.41 (s, 2 H), 3.17 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
174.5, 160.7, 146.7, 118.9, 117.3, 109.1, 95.7, 55.8, 36.4, 26.5 ppm.
MS (EI): m/z (%) = 256 (57) [M + 2]+, 254 (57) [M]+, 176 (25), 148
(21), 147 (100), 133 (19), 132 (14).
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Supporting Information (see footnote on the first page of this arti-
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1
data and MS spectra as well as H and 13C NMR spectra.
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Acknowledgments
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Received: August 19, 2013
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Published Online: November 12, 2013
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