One-pot synthesis of spirofluorenyl- and spiroindeno[1,2-b]indolyl oxindoles via sequential inter- and intramolecular Friedel-Crafts reactions

Article abstract of DOI:10.1016/j.tetlet.2015.11.080

Various spirofluorenyl oxindoles and spiroindeno[1,2-b]indolyl oxindoles were synthesized in good yields in one-pot reaction by TiCl₄-catalyzed sequential inter- and intramolecular Friedel-Crafts reactions of isatins with meta-arylphenols and 2

Full text of DOI:10.1016/j.tetlet.2015.11.080

Accepted Manuscript
One-pot synthesis of spirofluorenyl- and spiroindeno[1,2-b]indolyl oxindoles
via sequential inter- and intramolecular Friedel-Crafts reactions
Jin Woo Lim, Hye Ran Moon, Su Yeon Kim, Jae Nyoung Kim
PII:
S0040-4039(15)30388-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.11.080
TETL 47020
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 October 2015
20 November 2015
25 November 2015
Please cite this article as: Lim, J.W., Moon, H.R., Kim, S.Y., Kim, J.N., One-pot synthesis of spirofluorenyl- and
spiroindeno[1,2-b]indolyl oxindoles via sequential inter- and intramolecular Friedel-Crafts reactions, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.11.080
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1
Tetrahedron Letters
One-pot synthesis of spirofluorenyl- and spiroindeno[1,2-b]indolyl oxindoles via
sequential inter- and intramolecular Friedel-Crafts reactions
Jin Woo Lim, Hye Ran Moon, Su Yeon Kim, Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Various spirofluorenyl oxindoles and spiroindeno[1,2-b]indolyl oxindoles were synthesized in
good yields in one-pot reaction by TiCl4-catalyzed sequential inter- and intramolecular Friedel-
Crafts reactions of isatins with meta-arylphenols and 2-arylindoles in 1,2-dichloroethane.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Spirofluorenyl oxindoles
Spiroindeno[1,2-b]indolyl oxindoles
Friedel-Crafts reactions
meta-Arylphenols
2-Arylindoles
———
 Corresponding author. Tel.: +82-62-530-3381; fax: +82-62-530-3389; E-mail address: kimjn@chonnam.ac.kr (J.N. Kim)

2
Tetrahedron
The oxindole framework bearing a spirocyclic quaternary
carbocycle-containing spirooxindoles has also been reported such
as spirocyclopentadienyl-, spiroindenyl-, and spirofluorenyl
oxindoles.2
stereocenter at the C3 position is a significant privileged
heterocyclic scaffold, appears in a plethora of natural and
synthetic compounds.1-3 The synthesis of five-membered
Scheme 1. (1) known process, (2) synthetic rationale of spirofluorenyl oxindole, (3) synthesis of spirofluorenyl oxindole 3a.

3
Table 1. Synthesis of spirofluorenyl oxindoles from meta-arylphenols.a,b
aConditions: isatin (0.5 mmol), phenol (0.5 mmol), ClCH2CH2Cl (2.0 mL), TiCl4 (1.0 mmol), reflux, 2 h.
b1a: isatin; 1b: 5-chloroisatin; 1c: 5-methylisatin; 1d: 5-nitroisatin; 1e: 5-methoxyisatin; 1f: N-methylisatin.
2a: 2-benzyl-4,5-diphenylphenol; 2b: 2-benzyl-4,5-di(p-methoxyphenyl)phenol; 2c: 2-benzyl-4-methyl-5-phenylphenol;
2d: 2-benzyl-3-methoxy-5-phenylphenol; 2e: 2-methyl-3-methoxy-5-phenylphenol; 2f: 2-acetyl-3-methoxy-5-phenylphenol.
The reaction of isatin (1a) and electron-rich arenes such as
phenol and naphthol provides 3-aryl-3-hydroxy-2-oxindoles.4,5
presence of H2SO4 (2.0 equiv), a trace amount of 3a was formed
along with many intractable side products. The use of AlCl3 (2.0
A
selective C-C bond formation occurred at the ortho-position of
phenol or naphthol due to stabilizing hydrogen bonding effect
between the phenolic OH and the carbonyl group of oxindole
(Eq. 1, Scheme 1).4a-f We reasoned out a phenol derivative
bearing an aryl group at the meta-position could be used for the
synthesis of spirofluorenyl oxindole via sequential inter- and a
following intramolecular Friedel-Crafts reactions,6 as shown in
Eq. 2. Since the three positions (positions 2, 4 and 6) of meta-
arylphenol can react with isatin, the two positions (positions 4
and 6) of meta-arylphenol should be blocked with a substituent in
order to synthesize spirofluorenyl oxindole.7 As shown in Eq. 3,
meta-arylphenols such as 2-benzyl-4,5-diphenylphenol (2a)
could be used for this purpose. The reaction of 1a and 2a in the
presence of suitable acid catalyst would provide an intermediate
I, and a subsequent intramolecular Friedel-Crafts reaction under
the same reaction condition could form 3a.
equiv) in AcOH showed a similar result with that of
H2SO4/AcOH. To our delight, 3a was formed in a reasonable
yield (63%) by using TiCl4 (2.0 equiv) in 1,2-dichloroethane
(reflux, 2 h).4d,e,5 The yield of 3a decreased slightly by using
lesser amount of TiCl4 (1.2-1.5 equiv.), and the use of Ti(OiPr)4
showed completely no reaction.
Encouraged by the successful result, various meta-arylphenols
2b-f were prepared according to the reported methods,8 and the
syntheses of spirooxindoles were examined. The results are
summarized in Table 1. The reactions of isatins 1b-1f and 2a
afforded the corresponding spirooxindoles 3b-3f in good yields
(60-79%).9 The reactions of 1a and meta-arylphenols 2b-2e
afforded 3g-3j in moderate to good yields (55-76%). However,
the reaction of 1a and the phenol 2f, bearing an ortho-acetyl
moiety, failed completely. A preferential intramolecular chelation
of titanium phenolate with acetyl group would be the reason for
the failure, as shown in Table 1.
Phenol 2a was synthesized via [4+2] annulation protocol from
Morita-Baylis-Hillman (MBH) adducts according to the reported
method.8a At the outset of our experiment, the reaction of 1a and
2a was examined in refluxing AcOH; however, no reaction was
observed. When we carried out the reaction in AcOH in the
The mechanism for the formation of 3a could be proposed, as
shown in Scheme 1. Thermalization of phenol 2a and TiCl4
afforded titanium phenolate [TiCl3(OAr)].10 The coordination
between the oxygen atom of isatin and [TiCl3(OAr)] makes close
Scheme 2. Synthesis of spirooxindole 5a bearing indeno[1,2-b]indole moiety.

4
Tetrahedron
the two reaction centers, ortho-position of phenol and the 3-
position of isatin. Thus, the first intermolecular Friedel-Crafts
type bond-formation occurs readily to form I. A subsequent
the corresponding spirooxindoles 5f-5i in reasonable yields (52-
60%). It is interesting to note that the intramolecular Friedel-
Crafts cyclization occurred selectively at the 1-position of
Table 2. Synthesis of spirooxindoles from 2-arylindoles.a,b
aConditions: isatins (0.6 mmol), indoles (0.5 mmol), TiCl4 (1.0 mmol), ClCH2CH2Cl (25 mL), reflux, 2 h.
b4a: 2-phenylindole; 4b: 2-(4-chlorophenyl)indole; 4c: 2-(2-naphthyl)indole; 4d: 2-(2-thienyl)indole; 4e: N-methyl-2-phenylindole.
intramolecular Friedel-Crafts cyclization of I proceeds readily
under the same reaction condition to afford 3a, thus I cannot be
isolated.
naphthalene ring during the synthesis of 5g. The formation of a
regioisomeric product was not observed. The selective Friedel-
Crafts reaction is due to a small loss of resonance energy of the
naphthalene ring during the Friedel-Crafts reaction.17 The
reaction of 1f and 4e also gave 5j in a similar yield (56%).
In summary, the reactions of various meta-arylphenols and 2-
arylindoles with isatins provided spirofluorenyl- and
spiroindeno[1,2-b]indolyl oxindoles in the presence of TiCl4 in
moderate to good yields in one-pot reaction. The reaction
proceeds via a consecutive inter- and intramolecular Friedel-
Crafts reactions.
Spirooxindoles bearing an indole moiety has been received
special attention due to their abundance in natural and synthetic
drug candidates.11 The reaction of indole and isatin has been
studied extensively.12-14 3,3-Diindolyl-2-oxindole derivatives
were obtained as major products in the presence of an acid
catalyst.12 The synthesis of 3-hydroxy-3-indolyl-2-oxindole has
also been reported in
a
few reports;13 however, mono-
indolylization of isatin with 2-arylindoles has not been reported,
to the best of our knowledge.14 In these respects, we were not
confident with the successful synthesis of spiroindeno[1,2-
b]indolyl oxindole 5a; however, we decided to examine the
synthesis of 5a due to importance of spirooxindoles bearing an
indole moiety.11
As shown in Scheme 2, desired spiroindeno[1,2-b]indolyl
oxindole 5a was obtained in moderate yield (34%) by the
reaction of 1a and 2-phenylindole (4a), under the same reaction
condition for the synthesis of 3, to our delight. However, the
formation of 3,3-diindolyl derivative 6,12c,14 albeit in low yield
(18%), lowers the yield of 5a. Spirooxindole 5a must be formed
by an intramolecular Friedel-Crafts reaction of intermediate II,
while 6 could be produced by intermolecular Friedel-Crafts
reaction between II and 4a. Thus, we presumed that the
formation of 6 could be reduced by carrying out the reaction in
dilution conditions. As expected, the yield of 5a increased to
51% in 0.05 M concentration and further improved to 54% in
0.02 M concentration.15,16
Encouraged by the successful synthesis of spiroindeno[1,2-
b]indolyl oxindole, the reactions of some representative isatins
1a-1f and 2-arylindoles 4a-4e were examined. The results are
summarized in Table 2. The reactions of 1b-1d and 1f with 4a
afforded the corresponding spirooxindoles 5b-5e in moderate
yields (47-58%). The reactions of 1a with 2-(4-
chlorophenyl)indole (4b), 2-(2-naphthyl)indole (4c), 2-(2-
thienyl)indole (4d), and N-methyl-2-phenylindole (4e) afforded
Acknowledgments
This research was supported by Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (2014R1A1A2053606). Spectroscopic data were
obtained from the Korea Basic Science Institute, Gwangju
branch.
References and notes
1.
For leading reviews on spirooxindoles, see: (a) Yu, B.; Yu, D.-Q.;
Liu, H.-M. Eur. J. Med. Chem. 2015, 97, 673; (b) Santos, M. M.
M. Tetrahedron 2014, 70, 9735; (c) Cheng, D.; Ishihara, Y.; Tan,
B.; Barbas, C. F., III. ACS Catal. 2014, 4, 743; (d) Hong, L.;
Wang, R. Adv. Synth. Catal. 2013, 355, 1023; (e) Singh, G. S.;
Desta, Z. Y. Chem Rev. 2012, 112, 6104; (f) Ball-Jones, N. R.;
Badillo, J. J.; Franz, A. K. Org. Biomol. Chem. 2012, 10, 5165; (g)
Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003; (h) Marti, C.;
Carreira, E. M. Eur. J. Org. Chem. 2003, 2209.
2.
For
similar
spirocyclopentadienyl-,
spiroindenyl-,
and
spirofluorenyl oxindoles, see: (a) Peng, J.; Ran, G.-Y.; Du, W.;
Chen, Y.-C. Synthesis 2015, 47, 2538; (b) Peng, J.; Huang, X.;
Jiang, L.; Cui, H.-L.; Chen, Y.-C. Org. Lett. 2011, 13, 4584; (c)
Basavaiah, D.; Reddy, K. R. Org. Lett. 2007, 9, 57; (d) Saito, T.;
Sonoki, Y.; Otani, T.; Kutsumura, N. Org. Biomol. Chem. 2014,
12, 8398; (e) Trosien, S.; Schollmeyer, D.; Waldvogel, S. R.
Synthesis 2013, 45, 1160.

5
3.
4.
For our recent synthesis of spirooxindoles, see: (a) Kim, K. H.;
Moon, H. R.; Lee, J.; Kim, J. N. Adv. Synth. Catal. 2015, 357,
701; (b) Kim, K. H.; Moon, H. R.; Lee, J.; Kim, J.; Kim, J. N.
Adv. Synth. Catal. 2015, 357, 1532.
128.04, 128.26, 128.75, 131.67, 132.59, 133.13, 139.34, 140.60,
142.42, 143.73, 146.61, 149.07, 176.88; ESIMS m/z 404 [M+H]+.
Anal. Calcd for C28H21NO2: C, 83.35; H, 5.25; N, 3.47. Found: C,
83.46; H, 5.11; N, 3.45.
o
For the reaction of isatin with phenol derivatives, see: (a) Kaur, J.;
Kumar, A.; Chimni, S. S. Tetrahedron Lett. 2014, 55, 2138; (b)
Kaur, J.; Kumar, A.; Chimni, S. S. RSC Adv. 2014, 4, 62367; (c)
Ramachary, D. B.; Reddy, G. B.; Mondal, R. Tetrahedron Lett.
2007, 48, 7618; (d) Nicolaou, K. C.; Rao, P. B.; Hao, J.; Reddy,
M. V.; Rassias, G.; Huang, X.; Chen, D. Y.-K.; Snyder, S. A.
Angew. Chem. Int. Ed. 2003, 42, 1753; (e) Nicolaou, K. C.; Hao,
J.; Reddy, M. V.; Rao, P. B.; Rassias, G.; Snyder, S. A.; Huang,
X.; Chen, D. Y.-K.; Brenzovich, W. E.; Giuseppone, N.;
Giannakakou, P.; O’Brate, A. J. Am. Chem. Soc. 2004, 126,
12897; (f) Mai, C.-K.; Sammons, M. F.; Sammakia, T. Angew.
Chem. Int. Ed. 2010, 49, 2397; (g) Hewawasam, P.; Erway, M.
Tetrahedron Lett. 1998, 39, 3981; (h) Chowdhury, S.; Chafeev,
M.; Liu, S.; Sun, J.; Raina, V.; Chui, R.; Young, W.; Kwan, R.;
Fu, J.; Cadieux, J. A. Bioorg. Med. Chem. Lett. 2011, 21, 3676.
For Friedel-Crafts type ortho-alkylation of phenols with ketones
via a chelation-controlled transition state, see: (a) Casiraghi, G.;
Bigi, F.; Casnati, G.; Sartori, G.; Soncini, P.; Fava, G. G.;
Belicchi, M. F. J. Org. Chem. 1988, 53, 1779; (b) Casiraghi, G.;
Sartori, G.; Casnati, G.; Bigi, F. J. Chem. Soc., Perkin Trans. 1
1983, 1649; (c) Citterio, A.; Gandolfi, M.; Piccolo, O.; Filippini,
L.; Tinucci, L.; Valoti, E. Synthesis 1984, 760; (d) Piccolo, O.;
Filippini, L.; Tinucci, L.; Valoti, E.; Citterio, A. J. Chem. Res. (S)
1985, 258; (e) Vetica, F.; Pelosi, A.; Gambacorta, A.; Loreto, M.
A.; Miceli, M.; Gasperi, T. Eur. J. Org. Chem. 2014, 1899.
For sequential inter- and intramolecular Friedel-Crafts reactions,
see: (a) Park, B. R.; Kim, S. H.; Kim, Y. M.; Kim, J. N.
Tetrahedron Lett. 2011, 52, 1700; (b) Lee, H. J.; Kim, T. H.; Kim,
J. N. Bull. Korean Chem. Soc. 2001, 22, 1063; (c) Basavaiah, D.;
Reddy, R. M. Tetrahedron Lett. 2001, 42, 3025; (d) Ramulu, B.
V.; Niharika, P.; Satyanarayana, G. Synthesis 2015, 26, 1255; (e)
Ramulu, B. V.; Reddy, A. G. K.; Satyanarayana, G. Synlett 2013,
24, 868; (f) Boiaryna, L.; Azizi, M. S.; Bouakher, A. E.; Picard,
B.; Taillier, C.; Othman, M.; Trabelsi-Ayadi, M.; Dalla, V. Org.
Lett. 2015, 17, 2130.
Compound 3i: 76%; pale yellow solid, mp 120-122 C; IR (KBr)
3321, 1695, 1492 cm-1; 1H NMR (DMSO-d6, 300 MHz)  3.87 (s,
3H), 3.93 (s, 2H), 6.46 (d, J = 7.5 Hz, 1H), 6.78 (t, J = 7.5 Hz,
1H), 6.88 (d, J = 7.5 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 7.05-7.13
(m, 3H), 7.13-7.22 (m, 5H), 7.38 (t, J = 7.5 Hz, 1H), 7.89 (d, J =
7.5 Hz, 1H), 8.75 (s, 1H), 10.74 (s, 1H); 13C NMR (DMSO-d6, 75
MHz)  28.21, 56.02, 61.91, 95.49, 109.48, 115.27, 120.34,
121.63, 122.59, 122.83, 124.81, 125.45, 127.42, 127.88, 127.93,
128.17, 131.46, 140.79, 141.73, 142.05, 143.67, 146.69, 151.77,
159.28, 176.94 (one carbon was overlapped); ESIMS m/z 420
[M+H]+. Anal. Calcd for C28H21NO3: C, 80.17; H, 5.05; N, 3.34.
Found: C, 80.34; H, 5.33; N, 3.19.
o
Compound 5a: 54%; white solid, mp 295-297 C; IR (KBr) 3275,
3171, 1674, 1277 cm-1; 1H NMR (DMSO-d6, 300 MHz)  6.53 (d,
J = 7.2 Hz, 1H), 6.77-6.84 (m, 2H), 6.89 (d, J = 7.2 Hz, 1H), 6.94
(d, J = 8.1 Hz, 1H), 7.02-7.17 (m, 3H), 7.26 (t, J = 7.2 Hz, 1H),
7.39 (t, J = 7.2 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 7.2
Hz, 1H), 10.92 (s, 1H), 11.86 (s, 1H); 13C NMR (DMSO-d6, 75
MHz)  58.18, 109.95, 112.82, 117.25, 118.42, 119.86, 121.44,
121.58, 122.02, 122.36, 123.27, 123.43, 125.95, 128.16, 128.56,
130.17, 135.59, 140.70, 143.41, 144.67, 150.41, 177.02; ESIMS
m/z 323 [M+H]+. Anal. Calcd for C22H14N2O: C, 81.97; H, 4.38;
N, 8.69. Found: C, 81.68; H, 4.64; N, 8.52.
5.
o
Compound 5h: 55%; white solid, mp 245-247 C; IR (KBr) 3280,
3179, 1688, 1517 cm-1; 1H NMR (DMSO-d6, 500 MHz)  6.39 (d,
J = 7.5 Hz, 1H), 6.82 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H),
6.89 (d, J = 5.5 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 7.01-7.08 (m,
3H), 7.22 (d, J = 5.5 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 10.69 (s,
1H), 11.48 (s, 1H); 13C NMR (DMSO-d6, 125 MHz)  58.43,
110.44, 117.81, 119.25, 120.44, 121.34, 121.91, 122.28, 122.49,
123.72, 124.06, 126.55, 129.05, 130.52, 135.70, 142.06, 143.85,
145.68, 150.89, 177.30; ESIMS m/z 329 [M+H]+. Anal. Calcd for
C20H12N2OS: C, 73.15; H, 3.68; N, 8.53. Found: C, 73.41; H, 3.80;
N, 8.59.
6.
o
Compound 5i: 53%; white solid, mp 280-282 C; IR (KBr) 3255,
7.
8.
9.
Actually, the reaction of 3-phenylphenol and isatin (1a) under
optimized reaction conditions did not afford any trace amount of
spirooxindole. One of the three possible 3,3-diarylation products
was obtained selectively in moderate yield (52%, see
Supplementary data).
For synthesis of starting materials, see: (a) Kim, S. J.; Kim, S. H.;
Kim, K. H.; Kim, J. N. Bull. Korean Chem. Soc. 2008, 29, 876; (b)
Ramachary, D. B.; Kishor, M. J. Org. Chem. 2007, 72, 5056; (c)
Kim, J. M.; Lee, K. Y.; Kim, J. N. Bull. Korean Chem. Soc. 2003,
24, 1057.
3193, 1691, 1488 cm-1; 1H NMR (DMSO-d6, 300 MHz)  4.13 (s,
3H), 6.55 (d, J = 7.5 Hz, 1H), 6.79-6.87 (m, 2H), 6.94 (t, J = 7.5
Hz, 1H), 6.96 (d, J = 7.5 Hz, 1H), 7.07-7.21 (m, 3H), 7.27 (t, J =
7.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H),
7.87 (d, J = 7.5 Hz, 1H), 10.94 (s, 1H); 13C NMR (DMSO-d6, 75
MHz)  31.19, 57.97, 110.00, 110.94, 117.37, 118.83, 120.00,
120.88, 121.47, 121.83, 122.05, 123.29, 123.63, 126.11, 128.17,
128.62, 130.07, 135.26, 141.61, 143.41, 145.24, 150.44, 176.87;
ESIMS m/z 337 [M+H]+. Anal. Calcd for C23H16N2O: C, 82.12; H,
4.79; N, 8.33. Found: C, 82.03; H, 4.96; N, 8.16.
Typical procedure for the synthesis of 3a: To a stirred solution
of 1a (74 mg, 0.5 mmol) and 2a (168 mg, 0.5 mmol) in 1,2-
dichloroethane (1.5 mL) was added dropwise a solution of TiCl4
(190 mg, 1.0 mmol in 0.5 mL 1,2-dichloroethane) at room
temperature over 2 min, and the reaction mixture was heated to
reflux for 2 h. After the usual extractive aqueous workup and
column chromatographic purification process (hexanes/EtOAc,
2:1) compound 3a was obtained as a white solid, 147 mg (63%).
Other compounds were synthesized similarly, and the selected
spectroscopic data of 3a, 3h, 3i, 5a, 5h, and 5i are as follows.
10. (a) Nielson, A. J.; Schwerdtfeger, P.; Waters, J. M. J. Chem. Soc.,
Dalton Trans. 2000, 529; (b) Nielson, A. J.; Shen, C.;
Schwerdtfeger, P.; Waters, J. M. Eur. J. Inorg. Chem. 2005, 1343;
(c) Suttil, J. A.; McGuinness, D. S.; Pichler, M.; Gardiner, M. G.;
Morgan, D. H.; Evans, S. J. Dalton Trans. 2012, 41, 6625.
11. For examples of indole moiety-containing spirooxindoles, see: (a)
Zheng, H.; Liu, X.; Xu, C.; Xia, Y.; Lin, L. Feng, X. Angew.
Chem. Int. Ed. 2015, 54, 10958; (b) Reddy, B. V. S.; Swain, M.;
Reddy, S. M.; Yadav, J. S.; Sridhar, B. Eur. J. Org. Chem. 2014,
3313; (c) Shi, F.; Zhu, R.-Y.; Dai, W.; Wang, C.-S.; Tu, S.-J.
Chem. Eur. J. 2014, 20, 2597; (d) Liu, Y.; Nappi, M.; Arceo, E.;
Vera, S.; Melchiorre, P. J. Am. Chem. Soc. 2011, 133, 15212; (e)
Dai, W.; Lu, H.; Li, X.; Shi, F.; Tu, S.-J. Chem. Eur. J. 2014, 20,
11382; (f) Hao, W.-J.; Wang, S.-Y.; Ji, S.-J. ACS Catal. 2013, 3,
2501; (g) Majumdar, K. C.; Ponra, S.; Nandi, R. K. Tetrahedron
Lett. 2012, 53, 1732; (h) Lian, Z.; Wei, Y.; Shi, M. Tetrahedron
2012, 68, 2401; (i) 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.; 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, 1175; (j) 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.; Winzeler, E. A.; Petersen, F.; Brun, R.;
Dartois, V.; Diagana, T. T.; Keller, T. H. J. Med. Chem. 2010, 53,
5155; (k) Badillo, J. J.; Silva-Garcia, A.; Shupe, B. H.; Fettinger,
o
Compound 3a: 63%; white solid, mp 144-146 C; IR (KBr) 3270,
1697, 1618, 1470 cm-1; 1H NMR (DMSO-d6, 300 MHz)  3.90 (d,
J = 15.3 Hz, 1H), 4.01 (d, J = 15.3 Hz, 1H), 6.56 (d, J = 7.2 Hz,
1H), 6.82 (t, J = 7.5 Hz, 1H), 6.85-6.92 (m, 3H), 7.02 (d, J = 7.8
Hz, 1H), 7.05-7.29 (m, 8H), 7.39-7.55 (m, 5H), 8.96 (s, 1H), 10.84
(s, 1H); 13C NMR (DMSO-d6, 75 MHz)  34.60, 61.90, 109.54,
121.70, 121.97, 122.74, 123.05, 125.96, 127.27, 127.43, 127.46,
128.00, 128.35, 128.56, 128.91, 128.97, 129.19, 131.41, 132.62,
132.65, 138.11, 140.19, 140.21, 141.38, 143.76, 146.79, 150.44,
176.76 (one carbon was overlapped); ESIMS m/z 466 [M+H]+.
Anal. Calcd for C33H23NO2: C, 85.14; H, 4.98; N, 3.01. Found: C,
85.02; H, 5.09; N, 2.93.
o
Compound 3h: 74%; pale yellow solid, mp 172-174 C; IR (KBr)
1
3261, 1697, 1275, 1260 cm-1; H NMR (DMSO-d6, 300 MHz) 
2.55 (s, 3H), 3.84 (d, J = 15.3 Hz, 1H), 3.95 (d, J = 15.3 Hz, 1H),
6.45 (d, J = 7.2 Hz, 1H), 6.78 (t, J = 7.2 Hz, 1H), 6.82-6.95 (m,
2H), 6.99 (d, J = 7.2 Hz, 1H), 7.20-7.32 (m, 7H), 7.39 (t, J = 7.2
Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 8.58 (s, 1H), 10.77 (s, 1H); 13C
NMR (DMSO-d6, 75 MHz)  19.59, 34.58, 62.03, 109.47, 121.65,
122.60, 122.73, 122.95, 123.62, 125.85, 126.83, 127.21, 127.87,

6
Tetrahedron
J. C.; Franz, A. K. Tetrahedron Lett. 2011, 52, 5550; (l) Duce, S.;
Chem. Int. Ed. 2010, 49, 744; (d) Shanthi, G.; Lakshmi, N. V.;
Perumal, P. T. Arkivoc 2009 (x) 121. (e) Kumar, V. P.; Reddy, V.
P.; Sridhar, R.; Srinivas, B.; Narender, M.; Rao, K. R. J. Org.
Chem. 2008, 73, 1646; (f) Kinthada, L. K.; Ghosh, S.; De, S.;
Bhunia, S.; Dey, D.; Bisai, A. Org. Biomol. Chem. 2013, 11, 6984.
14. For synthesis of 3,3-di(2-phenylindol-3-yl)-2-oxindole (6), see:
(a) Praveen, C.; Karthikeyan, K.; Perumal, P. T. Tetrahedron
2009, 65, 9244; (b) Praveen, C.; Sagayaraj, Y. W.; Perumal, P. T.
Tetrahedron Lett. 2009, 50, 644.
Pesciaioli, F.; Gramigna, L.; Bernardi, L.; Mazzanti, A.; Ricci, A.;
Bartoli, G.; Bencivenni, G. Adv. Synth. Catal. 2011, 353, 860.
12. For synthesis of 3,3-diindolyl-2-oxindoles, see: (a) Brahmachari,
G.; Banerjee, B. ACS Sustainable Chem. Eng. 2014, 2, 2802; (b)
Yu, J.; Shen, T.; Lin, Y.; Zhou, Y.; Song, Q. Synth. Commun.
2014, 44, 2029; (c) Reddy, B. V. S.; Rajeswari, N.; Sarangapani,
M.; Prashanthi, Y.; Ganji, R. J.; Addlagatta, A. Bioorg. Med.
Chem. Lett. 2012, 22, 2460; (d) Sarrafi, Y.; Alimohammadi, K.;
Sadatshahabi, M.; Norozipoor, N. Monatsh Chem. 2012, 143,
1519; (e) Praveen, C.; Ayyanar, A.; Perumal, P. T. Bioorg. Med.
Chem. Lett. 2011, 21, 4072; (f) Sharma, R. K.; Sharma, C. J. Mol.
Catal. A: Chem. 2010, 332, 53; (g) Paira, P.; Hazra, A.; Kumar,
S.; Paira, R.; Sahu, K. B.; Naskar, S.; Saha, P.; Mondal, S.; Maity,
A.; Banerjee, S.; Mondal, N. B. Bioorg. Med. Chem. Lett. 2009,
19, 4786; (h) Yadav, J. S.; SubbaReddy, B. V.; Gayathri, K. U.;
Meraj, S.; Prasad, A. R. Synthesis 2006, 4121; (i) Wang, S.-Y.; Ji,
S.-J. Tetrahedron 2006, 62, 1527; (j) Azizian, J.; Mohammadi, A.
A.; Karimi, N.; Mohammadizadeh, M. R.; Karimi, A. R. Catal.
Commun. 2006, 7, 752; (k) Kamal, A.; Srikanth, Y. V. V.; Khan,
M. N. A.; Shaik, T. B.; Ashraf, M. Bioorg. Med. Chem. Lett. 2010,
20, 5229.
15. When we reduced the amount of TiCl4, the formation of 6
increased. When we carried out the reaction with 2.0 equiv. of 1a
in order to reduce the amount of 6, the yield of 5a increased to
41% (c = 0.25 M). The use of other acid catalysts such as AlCl3,
InCl3, FeCl3, or SnCl4 was less effective than TiCl4. The use of
H2SO4 produced 6 as a major product.
16. In order to reduce the formation of 3,3-diindolyl derivative, isatin
was used in a slightly excess amount (1.2 equiv).
17. For regioselective cyclization of 2-naphthyl derivatives, see: (a)
Lim, J. W.; Kim, K. H.; Kim, S. H.; Kim, J. N. Tetrahedron Lett.
2012, 53, 5449; (b) Lim, J. W.; Kim, K. H.; Kim, S. H.; Kim, J. N.
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Kim, J. N. Bull. Korean Chem. Soc. 2015, 36, 1900; (d) Zhang, L.;
Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 10204.
13. For selected synthesis of 3-indolyl-3-hydroxyoxindoles, see: (a)
Prathima, P. S.; Rajesh, P.; Rao, J. V.; Kailash, U. S.; Sridhar, B.;
Rao, M. M. Eur. J. Med. Chem. 2014, 84, 155; (b) Chauhan, P.;
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Sahin, A. H.; Chang, T. W. Fettinger, J. C.; Franz, A. K. Angew.

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One-pot synthesis of spirofluorenyl- and
spiroindeno[1,2-b]indolyl oxindoles via
sequential inter- and intramolecular Friedel-
Crafts reactions
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Jin Woo Lim, Hye Ran Moon, Su Yeon Kim, Jae Nyoung Kim*