Preparation of 3,3-Diaryloxindoles by superacid-induced condensations of isatins and aromatics with a combinatorial approach

Article abstract of DOI:10.1021/jo980588g

3,3-Diaryloxidoles are prepared in high yields (62-99%) by reaction of isatin or substituted isatins with aromatics in triflic acid. The reaction shows a significant dependence on acid strength which suggests the formation of diprotonated, superelectrophi

Full text of DOI:10.1021/jo980588g

J . Org. Chem. 1998, 63, 4481-4484
4481
P r ep a r a tion of 3,3-Dia r yloxin d oles by Su p er a cid -In d u ced
Con d en sa tion s of Isa tin s a n d Ar om a tics w ith a Com bin a tor ia l
Ap p r oa ch
Douglas A. Klumpp,*,† Ka Yeun Yeung,† G. K. Surya Prakash,‡ and George A. Olah*,‡
Department of Chemistry, California State Polytechnic University, Pomona, California, 91768, and Loker
Hydrocarbon Research Institute, University of Southern California, Los Angeles, California, 90089-1661
Received March 31, 1998
3,3-Diaryloxidoles are prepared in high yields (62-99%) by reaction of isatin or substituted isatins
with aromatics in triflic acid. The reaction shows a significant dependence on acid strength which
suggests the formation of diprotonated, superelectrophilic intermediates. Reaction of isatin, benzene,
and acid systems of varying strength (composed of CF3SO3H and CF3CO2H) showed that the acid
strength must be more acidic than Ho ) -11.5 for complete conversion to product. Reaction of
isatins with mixtures of aromatics allows for the preparation of libraries of 3,3-diaryloxindole
products by combinatorial synthesis.
In tr od u ction
prepared by reacting isatin and 4-methylisatin, respec-
tively, with phenol in sulfuric acid.3 These conversions
are presumably the result of protolytic activation of the
isatin carbonyl group and electrophilic attack on the
phenol ring.
In continuation of our studies on superelectrophilic
activation in superacids, we wish report a general
synthetic route to 3,3-diaryloxindoles from isatins in
superacidic triflic acid (CF3SO3H, TfOH), the synthesis
of modest sized libraries of 3,3-diaryloxindoles from
isatins, and studies of the electrophilic chemistry of
substituted isatins. Oxindole derivatives are known to
possess a variety of biological activity.1 The 3,3-diaryl-
oxindoles have been shown to possess antibacterial,
antiprotozoal, and antiinflammatory activities.2 Com-
pounds 1 and 2 have been used as laxatives.3
Recently Shudo and co-workers described the conver-
sion of some 1,2-diketones to the R,R-diphenyl ketones
from benzene and TfOH.8 For example, 2,3-butanedione
was converted in 95% yield to 3,3-diphenyl-2-butanone
from TfOH and benzene. It was suggested that the
protonation of the 1,2-diketone generated highly reactive,
or superelectrophilic, dicationic intermediates. The di-
cationic intermediates were sufficiently electrophilic to
condense with aromatics of moderate reactivity such as
benzene. Apart from these results of Shudo et al., our
own studies have indicated that protosolvation of
carbonyl groups in superacids may generate superelec-
trophilic intermediates.9 Because the superelectrophiles
often show enhanced and unique reactivity, superelec-
trophilic activation is a useful strategy toward the
synthesis of condensed aromatic products.10 It seemed
plausible that the 1,2-dicarbonyl group of isatin might
form a superelectrophilic species in superacidic solution,
leading to condensation products.
Oxindole derivatives have been prepared by the reac-
tion of N-aryl-R-chloro-R,R-diarylacetimidoyl chlorides in
sulfuric acid,4 by the reaction of isatins with Grignard
reagents,5 by the reaction of isatin with diphenylurea and
AlCl3,6 and other routes.7 Compounds 1 and 2 are
Resu lts a n d Discu ssion
We studied the reaction of isatin in TfOH with benzene
and found that 3,3-diphenyloxindole (3a ) was produced
† California State Polytechnic University.
‡ University of Southern California.
(1) (a) Hubacher, M. H.; Doernberg, S.; Horner, A. J . Am Pharm.
Assoc. 1953, 42, 23. (b) Gazit, A.; Osherov, N.; Posner, I.; Yaish, P.;
Poradosu, E.; Gilon, C.; Levitzki, A. J . Med. Chem. 1991, 34, 1896. (c)
Dilber, S.; Saban, M.; J elaca, J .; Gelineo, A.; Arsenijevic, L.; Bogavac,
M. Pharmazie 1989, 44, 649. (d) Ram, V. J .; Mishra, L.; Pandey, H.
N.; Vlietnick, A. J . J . Heterocyclic Chem. 1986, 23, 1367.
(2) (a) J oshi, K. C.; Pathak, V. N.; J ain, S. K. Pharmazie 1980, 35,
677. (b) Bolotov, V. V.; Drugovina, V. V.; Yakovleva, L. V.; Bereznya-
kova, A. I. Khim.-Farm. Zh. 1982, 16, 58. (c) William, C. E., U.S. Patent
3,558,653, 1971. (d) Pajouhesh, H.; Parsons, R.; Popp, F. D. J . Pharm.
Sci. 1983, 72, 318. (e) Popp, F. D. J . Heterocyclic Chem. 1984, 21, 1367.
(3) Garrido, F.; Ibanez, J .; Gonalons, E.; Giraldez, A. Eur. J . Med.
Chem. 1975, 10, 143.
(7) (a) Stanek, J . Chem. Listy 1943, 37, 161. (b) Sarel, S.; Klug, J .
T.; Breaer, E.; Angel, F. D. Tetrahedron Lett. 1964, 1553. (c) Flemming,
I.; Loreto, M. A.; Wallace, I. H. M.; Michael, J . P. J . Chem. Soc., Perkin
Trans. 1 1986, 349.
(8) Yamazaki, T.; Saito, S.-i.; Ohwada, T.; Shudo, K. Tetrahedron
Lett. 1995, 36, 5749.
(9) (a) Olah, G. A.; Rasul, G.; York, C. T.; Prakash, G. K. S. J . Am.
Chem. Soc. 1995, 117, 11211. (b) Klumpp, D. A.; Baek, D. N.; Prakash,
G. K. S.; Olah, G. A. J . Org. Chem. 1997, 62, 6667. (c) See, also: Saito,
S.; Sato, Y.; Ohwada, T.; Shudo, K. J . Am. Chem. Soc. 1994, 116, 2312.
(d) Suzuki, T.; Ohwada, T.; Shudo, K. J . Am. Chem. Soc. 1997, 119,
6774.
(10) (a) Olah, G. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 2, 767.
(b) Yato, M.; Ohwada, T.; Shudo, K. J . Am. Chem. Soc. 1991, 113, 691
c) Berrier, C.; Gesson, J . P.; J acquesy, J . C.; Renoux, A. Tetrahedron
1984, 40, 4973. (d) Olah, G. A.; Klumpp, D. A.; Neyer, G.; Wang, Q.
Synthesis 1996, 321. (e) Olah, G. A.; Wang, Q.; Neyer, G. Synthesis
1994, 276.
(4) Seno, M.; Shiraishi, S.; Suzuki, Y.; Asahara, T. Bull. Chem. Soc.
J pn. 1978, 51, 1413.
(5) (a) Sarel, S.; Klug, J . T. Israel J . Chem. 1964, 2, 143. (b) Witkop,
B.; Arvid, E. K. J . Am. Chem. Soc. 1951, 73, 5664.
(6) Franklin, D. P. Ger. Patent 2258505 1973.
S0022-3263(98)00588-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/05/1998

4482 J . Org. Chem., Vol. 63, No. 13, 1998
Klumpp et al.
Ta ble 1. Rea ction of Isa tin s w ith Ar om a tics in Tr iflic
Acid , CF 3SO3H
R
R′
R′′
product
% yielda
H
H
H
H
H
H
F
Cl
NO2
H
H
H
H
H
H
H
H
H
H
CH3
(CH2)8CH3
Cl
3a
3b
3c
3d
3e
3f
3g
3h
3i
99
95
62
99
71
70
87
82
99
84
95
F
propyl-3-(4-pyridyl)
H
H
H
H
H
H
CH3
Ph
3j
3k
H
a
Isolated yields.
quantitatively (eq 1, R ) R′ ) R" ) H). The condensation
of isatin with substituted aromatics such as alkylben-
zenes or chlorobenzene also proceeds in high yield (Table
1), but strongly deactivated aromatics such as nitroben-
zene did not react with isatin in TfOH. N-Substituted
and aromatic ring-substituted isatins give high yields of
the 3,3-diaryloxindoles (3g-k ) from TfOH. In all of the
conversions, electrophilic activation occurred only at the
carbonyl at the 3-position. The carbonyl at the 2-position
is unreactive and this may be due to stabilization by the
indole nitrogen. For alkyl- and halogen-substituted
aromatics, the electrophilic attack is highly regioselective.
1H NMR analysis of the crude products shows only
products resulting from para attack.
F igu r e 1. Product mixture from the reaction of N-methyli-
satin, N-phenylisatin, toluene, ethylbenzene, 1-phenylpropane,
and 1-phenylbutane, in triflic acid (peaks are labeled as N-R,
R′, and R′′, from eq 2).12
When isatins are reacted with mixtures of aromatic
substrates, it is also possible to prepare libraries of 3,3-
diaryloxindoles from combinatorial synthesis.11 From
TfOH, N-methylisatin, and the aromatics toluene, eth-
ylbenzene, 1-phenylpropane, and 1-phenyl-butane, a
mixture is formed containing 10 products by GC-MS
analysis. The 10 peaks correspond to the 10 possible 3,3-
diaryloxindoles from electrophilic attack on two aromat-
ics, giving the products. GC-MS analysis shows ten GC
peaks having respective molecular ion signals of m/z )
327, 341, 355, 355, 369, 369, 383, 383, 397, 411. If one
also considers the possiblity of enantiomeric products
which have two different aryl groups in the 3-position of
oxindole, then a total of 15 products may be produced
from the combinatorial synthesis of N-methylisatin with
TfOH and the four aromatic substrates. When the same
four alkylaromatics are reacted with both N-methylisatin
and N-phenylisatin in TfOH (eq 2), the library of 3,3-
diaryloxindoles increases to 20 products (not including
enantiomeric stereoisomers).12 The product mixture from
this reaction is shown in Figure 1. All of the expected
products are found in the GC-MS analysis, although the
two GC peaks are unresolved which correspond to N-
methylisatin + ethylbenzene, ethylbenzene (m/z ) 355)
and N-methylisatin + toluene, 1-phenylpropane (m/z )
355). GC-MS analysis shows roughly two groupings of
peaks, those arising from the N-methylisatin and those
arising from the N-phenylisatin.
When H2SO4 is used instead of TfOH, the condensation
reaction is less effective. Isatin reacts with benzene in
H2SO4, but the yield of 3a is just 25%. In the much
weaker acid CF3CO2H, isatin does not react at all with
benzene. To examine the effects of acid strength on the
electrophilic chemistry, isatin was reacted with benzene
in varying ratios of TfOH:CF3CO2H mixtures.9c Complete
conversion of isatin to 3a is seen only in media more
acidic than Ho ) -11.5 (Table 2).13 Incomplete conver-
sions result in only unreacted starting material and
product 3a . No monoarylated product is observed. When
5-fluoroisatin, 5-chloroisatin, and 5-nitroisatin, are in-
dividually reacted with benzene in the TfOH:CF3CO2H
mixtures, complete conversion to the 3,3-diphenyloxin-
doles is seen in media of acid strengths of Ho ) -11.5,
(11) For a collection of reviews on combinatorial synthesis, see: Acc.
Chem. Res. 1996, 29, 9 (3), 114-170.
(12) Reaction conditions: 40 mg of 1-methylisatin, 70 mg of 1-
phenylisatin, and 4 mL of TfOH were combined and 0. 2 mL of toluene,
0.23 mL of ethylbenzene, 0.26 mL of 1-phenylpropane, and 0.29 mL of
1-phenylbutane were simultaneously added, and the reaction was
stirred for 12 h. Products were poured into water and extracted into
CHCl3. Analysis was done on an HP 5890 II GC-MS with a DB-5
capillary column.
(13) The Ho value is that of the starting acid. During the reaction,
the acidity decreases due to the protonation of starting materials and
products.

Superacid-Induced Condensations
J . Org. Chem., Vol. 63, No. 13, 1998 4483
Ta ble 2. Resu lts fr om th e Rea ction of Isa tin , C6H6, a n d
CF 3SO3H:CF 3CO2H Acid System s
3,3-Bis(4-(1-n on yl)p h en yl)oxin d ole, 3c. Isatin (0.2 g,
1.36 mmol) gave 3c (0.43 g, 0.8 mmol, 62%) after column
chromatograhpy (9:1, hexanes:Et2O) as a waxy solid: mp 65-
68 °C (CHCl3); 1H NMR (300 MHz, CDCl3) δ ) 0.88 (t, J ) 6.9
Hz, 6H), 1.26 (m, 24H), 1.58 (m, 4H), 2.56 (t, J ) 7.5 Hz, 4H),
6.95 (d, J ) 8.1 Hz, 1H), 7.04 (t, J ) 7.8 Hz, 1H), 7.10 (d, J )
8.1 Hz, 4H), 7.19 (t, J ) 6.9 Hz, 4H), 7.20-7.32 (m, 2H), 9.05
(s, 1H); 13C NMR (125 MHz, CDCl3) δ ) 14.1, 22.6, 29.3, 29.4,
29.5, 29.5, 31.3, 31.9, 35.5, 62.5, 110.3, 122.6, 126.2, 128.0,
Ho
CF3SO3H:CF3CO2H (w/w)
isatin:3a
-14.1
-12.5
-11.5
-10.6
-9.0
100:0
0:100
0:100
0:100
10:90
80:20
100:0
72.8:27.2
43.5:56.5
22.1:77.9
5.0:95.0
0:100
-2.7
128.2, 128.4, 134.0, 138.8, 140.2, 142.0, 180.5; HRMS C38H51
NO calcd 537.3960, found 537.3970.
-
a
Reaction conditions: 0.05 g of isatin, 1.0 mL of acid, and 1.0
mL of C6H6 at 25 °C for 12 h.
3,3-Bis(4-ch lor op h en yl)oxin d ole, 3d . Isatin (0.1 g, 0.68
mmol) gave 3d (0.238 g, 0.67 mmol, 99%) as a white solid: mp
180-184 °C (CHCl3); 1H NMR (300 MHz, CDCl3) δ ) 6.96 (d,
J ) 7.5 Hz, 1H), 7.10 (t, J ) 7.5 Hz, 1H), 7.18 (m, 1H), 7.23
(d, J ) 8.7 Hz, 14H), 7.26-7.39 (m, 6H), 9.68 (s, 1H); 13C NMR
(125 MHz, CDCl3) δ ) 62.0, 110.9, 123.1, 125.9, 128.8, 129.7,
132.7, 133.7, 139.7, 140.2, 180.0; HRMS C20H13Cl2NO calcd
353.0374, found 353.0371. Anal. Calcd for C20H13Cl2NO: C,
67.81; H, 3.70; N, 3.95. Found: C, 67.61; H, 3.74; N, 3.86.
3,3-Bis(4-flu or op h en yl)oxin d ole, 3e. Isatin (0.1 g, 0.68
mmol) gave 3e (0.153 g, 0.48 mmol, 71%) as a white solid: mp
Ho ) -10.6, and Ho ) -9, respectively. Thus, substitu-
tion of isatin by electron-withdrawing groups tends to
enhance the electrophilic character of the protonated
isatins.
These results show that strongly acidic media is
required to completely convert the isatins to 3,3-di-
phenyloxindoles. A significant dependence on acid
strength is also seen when isatin is reacted with chlo-
robenzene. Isatin and TfOH with chlorobenzene pro-
duces 3d in 99% yield, while from H2SO4 and chloroben-
zene, 3d is produced in 2% yield. The requirement for
superacidic media is consistent with the formation of
protosolvated, dicationic intermediates. Diprotonated
isatin (or substituted isatins) would only be formed in
superacidic media and would exhibit superelectrophilic
chemistry. The present results obtained with isatins and
Shudo’s earlier studies of 1,2-diketones indicate that
adjacent carbonyl groups form highly reactive electro-
philes in superacidic TfOH.
1
107-110 °C (CHCl3); H NMR (300 MHz, CDCl3) δ ) 7.20-
7.63 (m, 12H), 9.35 (s, 1H); 13C NMR (125 MHz, CDCl3) δ )
62.1, 111.2, 115.4 (d, J c-f ) 36 Hz), 123.4, 125.8, 128.7, 129.9
(d, J c-f ) 13 Hz), 133.3, 136.8 (d, J c-f ) 5 Hz), 139.9, 162.1 (d,
J c-f ) 411 Hz), 180.9; HRMS C20H13F2NO calcd 321.0965,
found 321.0967.
3,3-Bis[4-(3-(4-pyr idyl)pr opyl)ph en yl]oxin dole, 3f. Isat-
in (0.1 g, 0.68 mmol) gave 3f (0.247 g, 0.47 mmol, 70%) after
column chromatography (9:1, hexanes:Et2O) as a white solid:
mp 151-156 °C (CHCl3); 1H NMR (300 MHz, CDCl3) δ ) 1.90
(m, 4H), 2.60 (m, 8H), 6.92 (d, J ) 8.1 Hz, 1H), 7.00-7.32 (m,
15H), 8.47 (M 4H), 9.98 (s, 1H); 13C NMR (125 MHz, CDCl3) δ
) 31.3, 34.4, 34.6, 62.3, 110.0, 122.3, 123.7, 126.0, 127.9, 128.3,
133.7, 139.4, 140.7, 141.4, 149.4, 151.0, 179.9; HRMS-CIMS
C
36H34N3O (M + H+) calcd 524.2702, found 524.2695. Anal.
Con clu sion
Calcd for C36H33N3O: C, 82.57; H, 6.35; N, 8.02. Found: C,
82.69; H, 6.34; N, 8.76.
In summary, we have found that isatins react with
aromatics in TfOH to give 3,3-diaryloxindoles in high to
excellent yields. The reaction is highly regioselective in
para attack on alkyl- and halogen-substituted aromatics
and in condensation chemistry occurring exclusively at
the 3-carbonyl group of the isatins. Modestly sized
libraries of 3,3-diaryloxyindoles have been prepared from
mixtures of TfOH, aromatics, and isatins, using the
technique of combinatorial synthesis. Isatin is com-
pletely converted to the condensation product 5a only in
media more acidic than Ho ) -11.5. These results are
consistent with the formation of dicationic intermediates
leading to products.
3,3-Dip h en yl-5-flu or ooxin d ole, 3g. 5-Fluoroisatin (0.1 g,
0.61 mmol) gave 3g (0.160 g, 0.53 mmol, 78%) as a white
solid: mp 219-223 °C (CHCl3); 1H NMR (300 MHz, CDCl3) δ
) 6.84-7.08 (m, 3H), 7.20-7.36 (m, 10H), 8.44 (s, 1H); 13C
NMR (125 MHz, CDCl3) δ ) 63.6, 111.1 (d, J c-f ) 13 Hz), 113.9
(d, J c-f ) 42 Hz), 114.8 (d, J c-f ) 39 Hz), 127.6, 128.3, 128.6,
135.5 (d, J c-f ) 125 Hz), 141.0 (d, J c-f ) 400 Hz), 180.2; HRMS
C
20H14FNO calcd 303.1059, found 303.1052.
3,3-Dip h en yl-5-ch lor ooxin d ole, 3h . 5-Chloroisatin (0.1
g, 0.55 mmol) gave 3h (0.145 g, 0.46 mmol, 82%) as a white
solid: mp 207-210 °C (CHCl3); 1H NMR (300 MHz, CDCl3) δ
) 6.85 (d, J ) 8.1 Hz, 1H), 7.13-7.33 (m, 12H), 8.81 (s, 1H);
13C NMR (125 MHz, CDCl3) δ ) 62.5, 111.1, 126.7, 127.7,
128.3, 128.4, 128.7, 135.2, 136.5, 140.9, 149.0, 167.5; HRMS-
CIMS C20H18ClN2O (M + NH4+) calcd 337.1108, found 337.1109.
3,3-Dip h en yl-5-n itr ooxin d ole, 3i. 5-Nitroisatin (0.1 g,
0.52 mmol) gave 3i (0.17 g, 0.51 mmol, 99%) as a white solid:
mp 203-209 °C (CHCl3); 1H NMR (300 MHz, CDCl3) δ ) 7.02
(d, J ) 8.4 Hz, 1H), 7.15-7.40 (m, 11H), 8.13 (s, 1H), 8.19 (d,
J ) 8.4 Hz, 1H), 10.18 (s, 1H); 13C NMR (125 MHz, CDCl3) δ
) 63.1, 110.5, 122.0, 125.4, 128.1, 128.2, 128.8, 134.4, 140.0,
143.7, 146.1, 180.8; HRMS C20H14N2O3 calcd 330.1004, found
330.1003.
3,3-Dip h en yl-1-m eth yloxin d ole, 3j. 1-Methylisatin (0.1
g, 0.62 mmol) gave 3j (0.155 g, 0.52 mmol, 84%) as a white
solid: mp 169-173 °C (CHCl3); 1H NMR (300 MHz, CDCl3) δ
) 3.31 (s, 3H), 6.95 (d, J ) 7.8 Hz, 1H), 7.13 (d, J ) 7.8 Hz,
1H), 7.20-7.35 (m, 12H); 13C NMR (125 MHz, CDCl3) δ ) 26.5,
62.5, 108.5, 122.8, 126.0, 127.2, 128.2, 128.3, 128.4, 132.8,
141.8, 143.0, 177.5; HRMS C21H17NO calcd 299.1310, found
299.1315. Anal. Calcd for C21H17NO: C, 84.25; H, 5.72; N,
4.68. Found: C, 84.47; H, 5.80; N, 4.57.
Exp er im en ta l Section
Triflic acid was purchased from 3M Co. and distilled under
an Ar atmosphere. Isatin and substituted isatins were
purchased from Aldrich and used as received. 1H and 13C
NMR were recorded on a 300 MHz NMR instrument and mass
spectra were recorded with a mass selective detector. High-
resolution mass spectra were measured by the Southern
California Mass Spectrometry Facility at the University of
California at Riverside. Combustion anaylsis was done by
Galbraith Laboratories, Knoxville, TN.
Gen er a l Syn th etic P r oced u r e. Isatin (0.1 g, 0.68 mmol)
is combined with 2 mL of freshly distilled TfOH, and to this
mixture is added 1 mL of benzene. After stirring at 25 °C for
about 8 h, the product mixture is poured over severeal grams
of ice and the products are then extracted into either toluene
or chloroform. The organic solution is then washed with water
and then brine and dried with MgSO4. Concentration in vacuo
provides 3,3-diphenyloxindole as the sole product which may
be further purified by recrystallization from chloroform.
3,3-Dip h en yl-1-p h en yloxin d ole, 3k . 1-Phenylisatin (0.1
g, 0.45 mmol) gave 3j (0.154 g, 0.43 mmol, 95%) as a white
solid: mp 161-163 °C (CHCl3); 1H NMR (300 MHz, CDCl3) δ
) 6.95 (d, J ) 8.1 Hz, 1H), 7.16-7.60 (m, 18H); 13C NMR (125

4484 J . Org. Chem., Vol. 63, No. 13, 1998
Klumpp et al.
MHz, CDCl3) δ ) 62.6, 109.9, 123.3, 126.4, 126.8, 127.4, 128.1,
Grant from the California State Polytechnic University,
Pomona, is gratefully acknowledged (D.A.K.).
128.2, 128.5, 129.6, 132.7, 134.5, 142.0, 177.5; HRMS C26H19
NO calcd 361.1467, found 361.1456. Anal. Calcd for C26H19
-
-
NO: C, 86.40; H, 5.30; N, 3.88. Found: C, 86.27; H, 5.24; N,
3.86.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR for
products 3c-k (18 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
Ack n ow led gm en t. Support of the work by the
Loker Hydrocarbon Research Institute and the National
Science Foundation is gratefully acknowledged. Support
from the Research, Scholarship, and Creative Activities
J O980588G