Superacid-promoted reactions of α-ketoamides and related systems

Article abstract of DOI:10.1021/jo801208m

(Chemical Equation Presented) The superacid-promoted reactions of α-hydroxy and α-ketoamides have been studied. Ionization of these compounds leads to varied aryl-substituted oxyindole products. In some cases, electrocyclization can lead to substituted fl

Full text of DOI:10.1021/jo801208m

Superacid-Promoted Reactions of r-Ketoamides and Related
Systems
Kiran Kumar Solingapuram Sai,† Pierre M. Esteves,‡ Eduardo Tanoue da Penha,‡ and
Douglas A. Klumpp*,†
Department of Chemistry and Biochemistry, Northern Illinois UniVersity, DeKalb, Illinois 60115, and
Instituto de Quimica, UniVersidade Federal do Rio de Janeiro, Cidade UniVersitaria, CT Bloco A,
21949-900, Rio de Janeiro-RJ, Brazil
dklumpp@niu.edu
ReceiVed June 4, 2008
The superacid-promoted reactions of R-hydroxy and R-ketoamides have been studied. Ionization of these
compounds leads to varied aryl-substituted oxyindole products. In some cases, electrocyclization can
lead to substituted fluorene products. Dicationic, superelectrophilic intermediates are proposed as
intermediates leading to the products from R-hydroxy and R-ketoamides.
Introduction
Substituted oxyindoles are known to have a variety of
biological activities. The aryl-substituted oxyindole substructure
is present in natural products and in several potent therapeutic
agents, such as anticancer drugs (1),1 cardiovascular drugs (2),2
and laxatives (3).3 The aryl-substituted oxyindoles may be
prepared by a number of synthetic routes,4 including the
condensation of isatins with arenes in an acid-promoted conver-
sion.5 The cyclizations of mandelic and benzilic acid derivatives
(i.e., 4) have also been studied, and in H2SO4-catalyzed
reactions, for example, the aryl-substituted oxyindoles are
produced (eq 1).6
† Northern Illinois University.
‡ Universidade Federal do Rio de Janeiro.
(1) Uddin, M. K.; Reignier, S. G.; Coulter, T.; Montalbetti, C.; Graanas, C.;
Butcher, S.; Krog-Jensen, C.; Felding, J. Bioorg. Med. Chem. Lett. 2007, 17,
2854–2857.
(2) Neel, D. A.; Brown, M. L.; Lander, P. A.; Grese, T. A.; Defauw, J. M.;
Doti, R. A.; Fields, T.; Kelley, S. A.; Smith, S.; Zimmerman, K. M.; Steinberg,
M. I.; Jadhav, P. K. Bioorg. Med. Chem. Lett. 2005, 15, 2553–2557.
(3) Garrido, F.; Ibanez, J.; Gonalons, E.; Giraldez, A. Eur. J. Med. Chem.
1975, 10, 143–146.
(4) (a) Sarel, S.; Klug, J. T.; Breaer, E.; Angel, F. D. Tetrahedron Lett. 1964,
1553. (b) Flemming, I.; Loreto, M. A.; Wallace, I. H. M.; Michael, J. P. J. Chem.
Soc., Perkin Trans. 1 1986, 349. (c) Seno, M.; Shiraishi, S.; Suzuki, Y.; Asahara,
T. Bull. Chem. Soc. Jpn. 1978, 51, 1413–1417. (d) Liu, K. G.; Robichaud, A. J.
Tetrahedron Lett. 2007, 48, 461–463. (e) Barker, M. W.; Sung, H.-S. J. Het-
erocycl. Chem. 1977, 14, 521–522. (f) Lee, S.; Hartwig, J. F. J. Org. Chem.
2001, 66, 3402–3415.
Recently, we described our studies of the superacid-promoted
cyclizations of ꢀ-ketoamides to quinolin-2-ones (Knorr cycliza-
tion).7 Experimental and theoretical evidence strongly suggested
the involvement of diprotonated, superelectrophilic intermediates
(6) Bolotov, V. V.; Drugovina, V. V.; Petyunin, P. A.; Spetsivtseva, Z. S.;
Drogovoz, S. M. Khim. Farm. Zh. 1979, 13 (11), 45–49. (b) Petyunin, P. A.;
Bezuglyi, P. O. Farm. Zh. (KieV) 1973, 28 (3), 23–26.
(7) Sai, K. K. S.; Gilbert, T. M.; Klumpp, D. A. J. Org. Chem. 2007, 72,
9761–9764.
(5) Klumpp, D. A.; Yeung, K. Y.; Prakash, G. K. S.; Olah, G. A. J. Org.
Chem. 1998, 63, 4481–4484.
6506 J. Org. Chem. 2008, 73, 6506–6512
10.1021/jo801208m CCC: $40.75 2008 American Chemical Society
Published on Web 07/30/2008

Superacid-Promoted Reactions of R-Ketoamides
TABLE 1. Products and Yields from the Reactions of r-Ketoamides with CF3SO3H and C6H6 at 50 °Ca
a Reaction conditions: 0.1 mmol of R-ketoamide, 1 mL of C6H6, 23 mmol of CF3SO3H, 50 °C, 18 h.
leading to the cyclization products.8 The ꢀ-ketoamides are proto-
nated at the two carbonyl oxygens in superacid, giving dicationic
intermediates. A number of 1,2-dicarbonyl compounds have
likewise been shown to form diprotonated superelectrophilic species
in strongly acidic media.9 In this regard, we considered the
possibility that the 1,2-dicarbonyl groups of R-ketoamides could
form superelectrophiles capable of undergoing cyclizations to the
aryl-substituted oxyindoles. Herein, we report the results of these
studies, describing a new route to aryl-substituted oxyindoles and
proposing a superelectrophilic mechanism.
(22-26), the expected oxyindole products are not obtained from
CF3SO3H and benzene, but rather the R,ꢀ-unsaturated amides
(27-31; entries 9-13) are formed. Even with forcing conditions
(50 or 80 °C), only the R,ꢀ-unsaturated amides (or decomposition
products) are obtained. Although the stereochemistry of the double
bond has not been definitively established for products 29, 30, and
31, it assumed to be syn on the basis of structural studies of the
chlorobenzene product (32) from R-ketoamide 24 (eq 2). Strong
NOE enhancements are observed between the olefinic hydrogen
and the ortho-hydrogens in 32, while only a weak enhancement is
detected between the methyl group and the ortho-hydrogens.
Unsymmetrically substituted oxyindole products may be formed
by the reactions of R-ketoamides with varied arene nucleophiles,
as shown in the conversion with p-dimethoxybenzene (eq 3).
Likewise, reaction of the R-hydroxyamide (34) with superacid gives
7-isopropyl-3-phenylindolin-2-one (35, eq 4). In the case of the
naphthyl system (36), the cyclization does not produce the
5-member ring, but rather, cyclization to the benzo[de]quinolin-
2(3H)-one (37) is preferred (eq 5).
Results and Discussion
A series of R-ketoamides (7-14 and 22-26) are reacted with
C6H6 in the presence of CF3SO3H, and the aryl-substituted
oxyindoles (6 and 15-21) are formed in good to fair yields
(Table 1). The R-ketoamides are prepared by DCC-promoted
coupling reactions between the appropriate anilines and phenylg-
lyoxylic acid or other R-ketoacids.10 With the use of benzene in
the condensation reactions, the gem-diphenyl group is produced
(entries 1-8). With the alkyl- and benzyl-substituted R-ketoamides
(8) For a general reference on superelectrophiles, see: Olah, G. A.; Klumpp,
D. A. Superelectrophiles and Their Chemistry; Wiley & Sons: New York, 2008.
(9) (a) Yamazaki, T.; Saito, S.; Ohwada, T.; Shudo, K. Tetrahedron Lett
1995, 36, 5749–5752. (b) Klumpp, D. A.; Yeung, K. Y.; Prakash, G. K. S.;
Olah, G. A. Synlett 1998, 918–919. (c) Klumpp, D. A.; Zhang, Y.; Do, D.;
Kartika, R. Appl. Catal. A: Gen. 2008, 336, 128–132.
(10) Tani, K.; Suwa, K.; Tanigawa, E.; Ise, T.; Yamagata, T.; Tatsuno, Y.;
Otsuka, S. J. Organomet. Chem. 1989, 370 (1-3), 203–221.
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Sai et al.
SCHEME 1. Proposed superelectrophilic mechanism for the preparation of oxyindole 6 from r-ketoamide 8 and C6H6 in
CF3SO3H
the yields of product 6 are proportional to acid strength and
good conversions are only observed in superacidic media.
In the superacid-promoted conversions of R-ketoamides to
oxyindoles, a mechanism is proposed which involves super-
electrophilic species (Scheme 1). Protonation of the amide
carbonyl leads to the carboxonium cation (38), which itself
should have no tendency to cyclize or react with benzene at
the ketone group. Partial or complete protonation at the ketone
gives the superelectrophilic species (39a or 39b), and cyclization
then leads to the carbenium-carboxonium dication (40, route
A). Dication 40 then reacts with benzene to give the final aryl-
substituted oxyindole (6). The proposed mechanism is also
consistent with the observed need for superacidic conditions.
Weaker acids such as H2SO4 and CF3CO2H are less capable of
protonating the monocationic species (38) and forming the
superelectrophile (39a or 39b). Based on the earlier results with
benzilic acid derivatives (eq 1), it is conceivable that the
R-ketoamides could initially react with benzene and then
undergo cyclization to the oxindole 6 (route B). However in
contrast to the earlier results from H2SO4-promoted reactions,
we have found that benzilic acid derivatives (4, 43, 44) do not
provide the oxyindoles from CF3SO3H, but rather the fluorene
ring system (i.e., 45-47) is produced (Scheme 2). None of the
expected aryl-substituted oxindoles are formed in reactions of
compounds 4, 43, or 44. This observation argues against the
involvement of either 41 or 42 in the formation of oxyindoles
(route B, Scheme 1).
The formation of products 6, 46, and 47 can be understood
in light of Shudo’s and Ohwada’s earlier studies of ester 48
and its superacid-promoted conversion to 50 (eq 6).13 In this
study, kinetic and spectroscopic evidence demonstrated the
involvement of superelectrophile 49 in a concerted, 4-π elec-
trocyclization leading to the fluorene ring system. It was
suggested that electrostatic repulsive effects lead to a significant
degree of charge delocalization into the phenyl rings (of dication
49) and this facilitates the 4-π electrocyclization. A similar
reaction is likely occurring in the case of 42 and the related
superelectrophiles from benzilic acid derivatives 43 and 44.
Although the condensation reactions (R-ketoamides to oxy-
indoles) have not been fully optimized, the effects of acid
strength and quantities have been studied. In the reaction of
R-ketoamide 8 with C6H6 (0.88 mmol 8, 2 mL C6H6, 50 °C,
14 h), product 6 may be obtained in yields of 80% or more
with as little as 5 mmol of CF3SO3H (7 equiv). When less
CF3SO3H or weaker Brønsted acids are used, the condensation
reaction is much less efficient. Even with a large excess of
concentrated sulfuric acid (86 equiv), product 6 can only be
isolated in 7% yield. Similar reactions of 8 with C6H6 in
phosphoric acid, or CF3CO2H, gave only unreacted starting
material 8. Likewise, solid acids (sulfated zirconia, montmo-
rillonite K10, or acidic alumina) exhibited no catalytic activity
in the condensation.11 Triflic acid (CF3SO3H, Ho -14.1) is 1000
times more strongly acidic than 98% H2SO4 (Ho -10), and it
is roughly 1011 times stronger than CF3CO2H (Ho -2.7).12 Thus,
(11) Commercial grade solid acid catalysts were used in these reactions:
compound 8 (0.1 g), benzene (3 mL), and the solid acid (1.0 g) were stirred at
50 °C for 12 h.
(12) Olah, G. A.; Prakash, G. K. S.; Sommer, J. In Superacids; Wiley: New
York, 1985.
(13) (a) Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1989, 111, 34–40. (b)
Ohwada, T.; Suzuki, T.; Shudo, K. J. Am. Chem. Soc. 1998, 120, 4629–4637.
6508 J. Org. Chem. Vol. 73, No. 17, 2008

Superacid-Promoted Reactions of R-Ketoamides
SCHEME 2. Superacid-Promoted Reactions of Benzilic
Acid Derivatives 4, 43, and 45
Interestingly, the alkyl- and benzyl-substituted R-ketoamides
give the R,ꢀ-unsaturated amides (27-31) in reactions with
benzene in CF3SO3H (entries 9-13, Table 1), suggesting that
(in these systems) the initial electrophilic reaction is with
benzene, rather than the phenyl group in a cyclization step. This
may be due to high electrophilic reactivities of the O,O-
diprotonated intermediates from the alkyl-substituted R-ketoa-
mides (22-26). Presumably, the methyl, ethyl, and benzyl
groups are less capable of stabilizing the adjacent carboxonium
ion (compared to the phenyl group of superelectrophile 39), and
this results in an enhanced reactivity toward benzene and a
deactivation of the amidophenyl group (thus suppressing in-
tramolecular reaction). Under the reaction conditions, there was
little or no tendency for the R,ꢀ-unsaturated amides (27-31)
to react further with benzene or the adjacent phenyl group. In
contrast, the superelectrophilic reactivity of a number of R,ꢀ-
unsaturated amides has been previously demonstrated (eq 7).14
The sluggish reactivity of amides 27-31 may reflect a tendency
to form (primarily) monocationic species in CF3SO3H.
resonances at δ 157.5 and 186.7, respectively. The upfield shifts
of the carboxonium groups can be understood to involve charge
delocalization involving the amide nitrogen and the phenyl group
(keto). Charge-charge repulsive effects will lead to an increas-
ing contribution from the delocalized resonance forms, such as
39b′ (eq 8).16 Similar observations were made by Shudo and
Ohwada in their studies of protonated methyl benzoylformate:
with increasing acidity the benzoyl group is shifted upfield due
to charge delocalization in the dication 54 (Scheme 4).17 The
amide carboxonium ion resonance at δ 157.5 (from 8) is also
consistent with a dicationic species, as diprotonated oxamide
(55) exhibits a carboxonium resonance at δ 157.9 in magic acid
solution.18 Although the NMR data suggests the formation of
39 in superacidic media, it is not possible to determine the extent
of protonation.
In order to further gain insights into the chemistry of the
R-ketoamides, DFT calculations were done on the possible
monocationic and dicationic intermediates (Scheme 3).15 At the
MP2(FC)/6-311++G(d,p) level, the energies of the monopro-
tonated products from 8 were studied, and it was shown that
protonation at the amide carbonyl (i.e., 38) is favored by about
8 kcal ·mol-1 over protonation at the ketone. With the dipro-
tonated products, several structures were located at energy
minima, including 39b, 52, and 53. Among these structures,
39b is found to be the most stable superelectrophile, located
12 and 55 kcal·mol-1 below 52 and 53, respectively. If it is
assumed that cyclization of 8 requires protonation of the ketone
group, then these results are evidence for the involvement of
superelectrophile 39b or the protosolvated species 39a.
Compounds 8 and 4 were also studied using NMR spectros-
copy and stable ion conditions (superacidic solution and low
temperature; Table 2). Ionization of R-ketoamide 8 in
FSO3H-SbF5-SO2ClF leads to a significant downfield shift of
the phenyl ring carbons, and the two carbonyl 13C resonances
are shifted slightly upfield in the superacid (compared to CDCl3).
The protonated amide and ketone groups are assigned to the
In the case of compound 4, ionization in FSO3H-SbF5-
SO2ClF gives a 13C NMR spectrum with several notable features
(Table 2). The hydroxylic carbon resonance at δ 82.0 (CDCl3)
has disappeared and the phenyl ring carbons are (on the average)
shifted significantly downfield in the superacidic media. The
(15) Gaussian 03, Revision B.04: Frisch, M. J.; Trucks, G. W.; Schlegel,
H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.;
Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi,
J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson,
G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa,
J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo,
J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli,
C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.;
Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.;
Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.;
Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople,
J. A. Gaussian, Inc.: Wallingford, CT, 2004.
(16) Klumpp, D. A. Chem. Eur. J. 2008, 14, 2004–2015.
(17) (a) Ohwada, T.; Shudo, K. J. Org. Chem. 1989, 54, 5227–5237. (b)
See also: Olah, G. A.; Westerman, P. W. J. Org. Chem. 1973, 38, 1986–1992.
(18) Olah, G. A.; Bausch, J.; Rasul, G.; George, H.; Prakash, G. K. S. J. Am.
Chem. Soc. 1993, 115, 8060–8065.
(14) (a) Koltunov, K. Y.; Walspurger, S.; Sommer, J. Chem. Commun. 2004,
1754–1755. (b) Koltunov, K. Y.; Walspurger, S.; Sommer, J. Eur. J. Org. Chem.
2004, 4039–4047.
J. Org. Chem. Vol. 73, No. 17, 2008 6509

Sai et al.
SCHEME 3. Calculated Relative Stabilities of Plausible Monocationic (38 and 51) and Dicationic Intermediates (39b, 52, and
53; MP2/6-311++G(d,p) level)
SCHEME 4. 13C NMR Data from the Ionizations of Benzoyl Formate and Oxamide in Superacids17,18
SCHEME 5. Calculated 13C NMR Chemical Shift Values for Dications 39b and 42 (GIAO-B3LYP/6-311++G(d,p)//B3LYP/
6-31+G(d) Level)
number of 13C resonances also increases from 10 signals in
compound 4 to 13 signals from the ionized product in superacid.
It is not presently clear if these signals arise from a static species
or a mixture of equilibrating products, including dication 42.
When the solution of 4 in FSO3H-SbF5-SO2ClF is carefully
quenched at low temperature, the starting material is recovered.
If the same solution is warmed to room temperature and then
quenched, only decomposition products are obtained. Interest-
ingly, Shudo and Ohwada observed that the R-hydroxyester 48
and related systems tend to form superelectrophiles that are too
reactive for direct observation by low temperature NMR (i.e.,
49).13
TABLE 2. 13C NMR Spectral Data from Ionizations of
Compounds 8 and 4 in FSO3H-SbF5-SO2ClF and Data from
CDCl3 Solution
For comparison, the calculated 13C chemical shifted of
superelectrophiles 39b and 42 were also determined (Scheme
5). Geometry optimizations of dications 39b and 42 were done
using DFT calculations at the B3LYP/6-31+G(d) level.15 The
calculated NMR shifts were then determined (relative to
tetramethylsilane) from the optimized structures at the GIAO-
B3LYP/6-311++G(d,p) level. For dication 39b, the calculated
gas-phase 13C NMR shifts are in reasonably good agreement
with the experimentally determined values. For example, the
calculated 13C resonances for the keto and amido carboxonium
ions are δ 179 and 162, respectively, while compound 8 in
FSO3H-SbF5-SO2ClF solution exhibits resonances at δ 186.7
and 157.5. The calculations also show deshielded aromatic ring
carbons, likely a consequence of charge delocalization in 39b.
In the case of dication 42, there are similarities between the
calculated 13C NMR and the spectrum obtained from ionization
of 4 in FSO3H-SbF5-SO2ClF solution. However, even with
comparison to the computed spectrum, it is not clear if com-
6510 J. Org. Chem. Vol. 73, No. 17, 2008

Superacid-Promoted Reactions of R-Ketoamides
63.1, 32.8, 29.4, 25.5; EI MS (low res) 325 (M+), 296, 248, 220,
165; HRMS calcd for C23H19NO: 325.1467, found 325.1467.
7-Isopropyl-3,3-diphenyl-1,3-dihydroindol-2-one (18): yellow
solid; mp 225-229 °C; 1H NMR (CDCl3) δ 9.24 (s, 1H), 7.35-7.28
(m, 10 H), 7.18 (d, 2H, J ) 7 Hz), 7.09 (dd, 1H, J ) 7 Hz), 2.99
(sept, 1H, J ) 8 Hz), 1.29 (d, 6H, J ) 8 Hz); 13C NMR (CDCl3)
δ 180.4, 143.6, 141.9 (two carbons), 137.7, 133.2, 130.5, 128.5,
128.3, 127.2, 124.8, 123.7, 122.8, 63.2, 28.9, 22.5; EI MS (low
res) 327 (M+), 300, 285, 165; HRMS calcd for C23H21NO 327.1623,
found 327.1624.
pound 4 ionizes cleanly to dication 42 in FSO3H-SbF5-
SO2ClF solution.
In conclusion, we have found that aryl-substituted oxyindoles
may be prepared in good to excellent yields by the reactions of
R-hydroxy and R-ketoamides with an arene in superacidic
CF3SO3H. In some cases, R-hydroxyamides may undergo a
cyclization to the fluorene-type ring system. Mechanisms are
proposed for these conversions involving dicationic superelec-
trophiles.
5-Fluoro-3,3-diphenyl-1,3-dihydroindol-2-one (19): white solid;
mp 220-223 °C; 1H NMR (CDCl3) δ 8.99 (s, 1H), 7.36-7.32 (m,
6H), 7.30-7.28 (m, 4H), 6.98 (d, 1H, J ) 8 Hz), 6.94 (s, 1H),
6.92 (d, 1H, J ) 8 Hz); 13C NMR (CDCl3) δ 180.4, 159.2 (d, JC-F
) 159 Hz), 141.1, 136.3, 135.2, 128.7, 128.3, 127.7, 114.8 (d, JC-F
) 24 Hz), 114.0 (d, JC-F ) 25 Hz), 111.2 (d, JC-F ) 8 Hz), 63.7;
EI MS (low res) 303 (M+), 274, 198, 165; HRMS calcd for
C20H14FNO 303.1059, found 303.1058.
5-Phenoxy-3,3-diphenyl-1,3-dihydroindol-2-one (20): white solid;
mp 196-200 °C; 1H NMR (CDCl3) δ 7.68 (s, 1H), 7.34-7.30 (m,
12H), 7.07-7.10 (m, 1H), 7.03 (s, 1H), 6.95 (d, 2H, J ) 8 Hz),
6.93-6.94 (m, 2H); 13C NMR (CDCl3) δ 179.1, 162.9, 141.3, 135.6,
129.7, 128.5, 128.3, 127.5, 122.8, 119.2, 118.8, 117.7, 110.5, 65.8;
EI MS (low res) 377(M+), 348, 254, 165; HRMS calcd for
C26H19NO2 377.1416, found 377.1418.
4-Methoxy-1,1-diphenyl-1,3-dihydro-10-oxa-3-azacyclopenta[a]flu-
oren-2-one (21): yellow solid; mp 279-282 °C; 1H NMR (CDCl3)
δ 7.88 (s, 2H), 7.50-7.46 (m, 5H), 7.41-7.28 (m, 10H), 4.04 (s,
3H); 13C NMR (CDCl3) δ 177.6, 156.4, 146.4, 141.1, 140.0 (two
carbons), 128.7, 128.4, 128.2, 127.5, 126.1, 124.6, 122.7, 119.9,
119.5, 116.3, 111.9, 102.3, 56.3; EI MS (low res) 405(M+), 376,
361, 285; HRMS (ESI, M + 1 ion) calcd for C27H20NO3 406.1443,
found 406.1441.
N-(2-Isopropylphenyl)-2-phenylacrylamide (27): white solid; mp
101-104 °C; 1H NMR (CDCl3) δ 7.99 (d, 1H, J ) 2.0 Hz),
7.45-7.51(m, 4H),7.34 (s, 1H), 7.18-7.19 (m, 2H), 7.16-7.17 (m,
1H), 6.44 (s, 1H), 5.74 (s, 1H) 2.66 (sept, 1H, J ) 6.8 Hz), 1.16
(d, 6H, J ) 6.8 Hz); 13C NMR (CDCl3) δ 164.8, 145.0, 139.1,
137.0, 134.2, 128.9, 128.8, 128.5, 126.5, 125.6, 125.4, 123.9, 123.3,
28.0, 22.6; MS 265 (M+), 222, 162, 103; HRMS (ESI, M+1 ion)
calcd for C18H20NO 266.1545, found 266.1532.
Experimental Section
General Methods. Triflic acid was purchased from a commercial
supplier and distilled prior to its use. The R-ketoamides were
prepared by dicyclohexylcarbodiimide (DCC) promoted coupling
reactions between R-ketoacids and anilines according to a published
method,10 while compound 34 was prepared similarly from
mandelic acid. Compounds 4, 44, and 45 were prepared by reactions
of the appropriate R-ketoamides with PhMgBr solution using
standard procedures. Benzene was dried over 4 Å sieves prior to
its use. Low-temperature NMR experiments were done using stable
ion conditions;19 FSO3H and SbF5 were obtained from commercial
suppliers while SO2ClF was prepared according to a published
procedure.20 Other reagents and solvents were used as received
from commercial suppliers.
Preparation of Aryl-Substituted Oxyindoles (6, 15-21,
and 33) and Compounds 27-32 and 37. The R-ketoamide (1
mmol) with the arene nucleophile (i.e., 1 mL of C6H6) was dissolved
in CHCl3 (5 mL), and CF3SO3H (2 mL, 23 mmol) was slowly
added. The resulting solution was stirred overnight (ca. 18 h) at 50
°C. The mixture was then poured over ca. 15 g of ice and extracted
twice with CHCl3. The organic phase was then washed once with
water andtwice with brine and dried over anhydrous Na2SO4. If
necessary, the product was further purified by column chromatog-
raphy (hexane/ether).
Cyclization to Products 35 and 45-47. The substrate (1 mmol)
and CHCl3 (5 mL) were combined, and CF3SO3H (2 mL, 23 mmol)
was slowly added. The resulting solution was stirred overnight (ca.
18 h) at 50 °C. The mixture was then poured over ca. 15 g of ice
and extracted twice with CHCl3. The organic phase was then washed
once with water and twice with brine and dried over anhydrous
Na2SO4. If necessary, the product was further purified by column
chromatography (hexane:ether).
N,2-Diphenylbut-2-enamide (29): white solid; mp 205-209 °C;
1H NMR (CDCl3) δ 7.50-7.53 (m, 2H), 7.42-7.47 (m, 4H),
7.31-7.27 (m, 4H), 7.07-7.10 (m, 1H), 7.05 (s, 1H), 1.74 (d, 3H,
J ) 4.5 Hz); 13C NMR (CDCl3) δ 164.6, 137.8, 137.5, 137.0, 135.1,
129.9, 129.2, 128.8, 128.4, 124.2, 119.8, 15.3; EI MS (low res)
237 (M+), 145, 117, 91; HRMS (ESI, M+1 ion) calcd for C16H16NO
238.1232, found 238.1220.
3,3,5-Triphenyl-1,3-dihydroindol-2-one (15): white solid; mp
1
288-291 °C; H NMR (DMSO-d6) δ 10.88 (s, 1H), 7.26 (d, 1H,
J ) 7 Hz), 7.52 (s, 1H), 7.58 (t, 3H, J ) 15 Hz), 7.41 (t, 2H, J )
15 Hz), 7.24-7.36 (m, 10H), 7.09 (d, 1H, J ) 7 Hz); 13C NMR
(DMSO-d6) δ 178.6, 142.3, 141.4, 140.4, 134.8, 134.3, 129.3, 128.9,
128.5, 127.5, 127.4, 127.3, 126.8, 124.6, 111.0, 62.9; EI MS (low
res) 361 (M+), 332, 254, 165; HRMS calcd for C26H19NO 361.1467,
found 361.1465.
N-(2-isopropylphenyl)-2-phenylbut-2-enamide (30): white solid;
1
mp 110-115 °C; H NMR (CDCl3) δ 7.99 (d, 1H, J ) 2.0 Hz),
7.45-7.51 (m, 4H),7.34 (s, 1H), 7.18-7.19 (m, 2H), 7.16-7.17
(m, 1H), 6.44 (s, 1H), 5.74 (s, 1H) 2.66 (sept, 1H, J ) 6.8 Hz),
1.16 (d, 6H, J ) 6.8 Hz); 13C NMR (CDCl3) δ 166.9, 139.7, 138.7,
137.9, 134.0, 131.9, 128.8, 128.0, 127.2, 126.4, 125.8, 125.5, 123.9,
27.9, 22.8, 15.7; MS 279 (M+), 264, 117, 91; HRMS (ESI, M + 1
ion) calcd for C19H22NO 280.1701, found 280.1688.
7-Methoxy-4-methyl-3,3-diphenyl-1,3-dihydroindol-2-one (16):
white solid; mp 192-197 °C; H NMR (CDCl3) δ 7.76 (s, 1H),
1
7.36-7.28 (m, 10 H), 6.83 (d, 1H, J ) 8 Hz), 6.79 (d, 1H, J ) 8
Hz), 3.9 (s, 3H), 1.85 (s, 3H); 13C NMR (CDCl3) δ 179.2, 142.3,
138.4, 132.3, 129.1, 129.0, 128.3, 128.2, 127.4, 125.0, 110.0, 70.1,
55.7, 18.31; EI MS (low res) 329 (M+), 300, 285, 165; HRMS
calcd for C22H19NO 329.1416, found 329.1416.
N,2,3-Triphenylacrylamide (31): white solid; mp 138-141 °C;
1H NMR (CDCl3) δ 7.643-7.62 (m, 2H), 7.56-7.55 (m, 2H),
7.46-7.41 (m, 4H), 7.39-7.29 (m, 6H), 7.18-7115 (m, 1H), 7.12
(s, 1H); 13C NMR (CDCl3) δ 167.7, 138.3, 137.5, 137.1, 135.1,
130.8, 129.5, 129.0, 128.8, 128.7, 128.6, 128.5, 126.5, 124.8, 120.2;
EI MS (low res) 299(M+), 207, 179; HRMS (ESI, M + 1 ion)
calcd for C21H18NO 300.1388, found 300.1382.
Compound 17: white solid; mp 275-279 °C; 1H NMR (CDCl3)
δ 8.38 (s, 1H), 7.33-7.26 (m, 10 H), 7.03 (d, 1H, J ) 7.6 Hz),
6.97 (d, 1H, J ) 7.6 Hz), 2.96 (t, 2H, J ) 14 Hz), 2.88 (t, 2H, J
) 14 Hz), 2.17 (pent, 2H, J ) 14 Hz); 13C NMR (CDCl3) δ 180.3,
145.8, 142.1, 136.0, 131.0, 128.4, 128.3, 127.1, 125.4, 124.2, 118.5,
(Z)-2-(4-Chlorophenyl)-N-phenylbut-2-enamide (32): white solid;
1
mp 144-147 °C; H NMR (CDCl3) δ 7.58 (d, 2H, J ) 8 Hz),
7.38-7.31 (m, 6H), 7.18-7.14 (m, 1H), 6.23 (q, 1H, J ) 7 Hz),
2.08 (d, 3H, J ) 7 Hz); 13C NMR (CDCl3) δ 166.5, 138.0, 137.5,
135.6, 133.9, 130.6, 129.1, 129.0, 127.9, 124.7, 119.8, 15.8; EI
MS (low res) 273 (M+), 271, 151, 115.
(19) Laali, K. K.; Okazaki, T.; Sultana, F.; Bunge, S. D.; Banik, B. K.; Swartz,
C. Eur. J. Org. Chem. 2008, 1740–1752.
(20) Reddy, V. P.; Bellew, D. R.; Prakash, G. K. S. J. Fluorine Chem. 1992,
56, 195–197.
J. Org. Chem. Vol. 73, No. 17, 2008 6511

Sai et al.
3-(2,5-Dimethoxyphenyl)-7-isopropyl-3-phenyl-1,3-dihydroindol-
2-one (33): brown solid; mp 210-214 °C; 1H NMR (CDCl3) δ 8.88
(s, 1H), 7.53 (s, 1H), 7.34-7.28 (m, 2H), 7.17 (d, 2H, J ) 8 Hz),
7.02-6.99 (m, 1H), 6.92 (d, 2H, J ) 8 Hz), 6.77 (s, 2H), 6.53 (s,
1H), 3.67 (s, 3H), 3.35 (s, 3H), 2.98 (septet, 1H, J ) 7 Hz), 1.30
(d, 6H, J ) 7 Hz); 13C NMR (CDCl3) δ 180.8, 153.84, 152.0, 139.0,
138.9, 134.0, 132.6, 129.5, 129.2, 128.0, 127.4, 124.4, 123.4, 121.9,
117.3, 113.9, 112.7, 60.3, 56.3, 55.6, 29.0, 22.7, 22.1; EI MS (low
res) 387 (M+), 356, 133, 91; HRMS calcd for C25H25NO3 387.1834,
found 387.1833.
7-Isopropyl-3-phenyl-1,3-dihydroindol-2-one (34): white solid;
mp 138-141 °C; 1H NMR (CDCl3) δ 8.89 (s, 1H), 7.38 (d, 2H, J
) 7 Hz), 7.32 (d, 1H, J ) 7.5 Hz), 7.28-7.26 (mult, 3H), 7.19 (d,
1 H, J ) 7.5 Hz), 7.04-7.02 (m, 1H), 4.68 (s, 1H), 2.96 (sept, 1
H, J ) 6 Hz), 1.28 (d, 6H, J ) 6 Hz); 13C NMR (CDCl3) δ 178.7,
139.1, 136.6, 130.1, 129.3, 128.8, 128.5, 127.5, 124.9, 122.8, 122.7,
52.8, 28.9, 22.5, 22.3; EI MS (low res) 251 (M+), 208, 180, 152;
HRMS calcd for C17H17NO 251.1310, found 251.1312.
7.79 (d, 2H, J ) 7.5 Hz), 7.52 (t, 2 h, J ) 15 Hz), 7.43 (t, 2H, J
) 15 Hz), 7.33-7.28 (mult, 2H), 6.95 (t, 2H, J ) 15 Hz), 6.82 (s,
1H), 4.95 (s, 1H); 13C NMR (CDCl3) δ 168.8, 159.4 (d, JC-F
)
243 Hz), 141.2 (d, JC-F ) 69 Hz), 133.3, 128.7, 128.0, 125.4, 121.8
(d, JC-F ) 8 Hz), 120.5, 115.5 (d, JC-F ) 22 Hz), 56.9; EI MS
(low res) 303 (M+), 160, 139, 110; HRMS calcd for C20H14FNO
303.1059, found 303.1063.
N-(2-Methoxy-5-methylphenyl)-9H-fluorene-9-carboxamide (47):
1
yellow solid; mp 143-146 °C; H NMR (CDCl3) δ 8.19 (s, 1H),
7.85-7.81 (mult, 4H), 7,75 (s, 1H), 7.49 (t, 2H, J ) 15 Hz), 7.41
(t, 2H, J ) 15 Hz), 6.78 (d, 1H, J ) 8 Hz), 6.64 (d, 1H, J ) 8 Hz),
4.95 (s, 1H), 3.58 (s, 3H), 2.30 (s, 3H); 13C NMR (CDCl3) δ 168.3,
146.1, 141.4, 141.2, 130.5, 128.4, 127.7, 127.1, 125.5, 124.0, 120.3,
109.9, 57.1, 55.7, 20.9; EI MS (low res) 329 (M+), 166, 149, 122;
HRMS calcd for C22H19NO2 329.1416, found 329.1414.
Acknowledgment. Grateful acknowledgement is made to the
donors of the American Chemical Society Petroleum Research
Fund for support of this work (PRF no. 44697-AC1). We thank
Dr. Heike Hofstetter for assistance with the NMR experiments
and the manuscript reviewers for helpful mechanistic comments.
3,3-Diphenyl-1H-benzo[de]quinolin-2(3H)-one (36): white solid;
1
mp 240-244 °C; H NMR (CDCl3) δ 10.88 (s, 1H), 8.01 (d, 1H,
J ) 8 Hz), 7.90 (d, 1H, J ) 8 Hz), 7.64 (d, 2H, J ) 8 Hz),
7.55-7.52 (m, 2H), 7.45-7.25 (mult, 10H); 13C NMR (CDCl3) δ
182.1, 141.6, 136.5, 133.5, 128.6, 128.5, 128.5, 128.1, 127.4, 126.4,
126.3, 126.3.2, 122.7, 121.9, 120.0, 64.3; EI MS (low res) 335 (M+),
306, 258, 230, 152; HRMS calcd for C24H17NO 335.1310, found
335.1313.
1
Supporting Information Available: H and 13C spectra of
new compounds, representative experimental procedures, and
computational data. This material is available free of charge
via the Internet at http://pubs.acs.org.
N-(4-Fluorophenyl)-9H-fluorene-9-carboxamide (46): white solid;
1
mp 261-264 °C; H NMR (CDCl3) δ 7.86 (d, 2H, J ) 7.5 Hz),
JO801208M
6512 J. Org. Chem. Vol. 73, No. 17, 2008