Phenyliodine bis(trifluoroacetate)-mediated oxidative C-C bond formation: Synthesis of 3-hydroxy-2-oxindoles and spirooxindoles from anilides

Article abstract of DOI:10.1021/ol300418h

The reaction of phenyliodine bis(trifluoroacetate) (PIFA) with a series of anilides 1 (E = CO₂Et) in CF₃CH₂OH was found to give 3-hydroxy-2-oxindole derivatives 2, while that with various anilides 1′ (E = CON(R⁴

Full text of DOI:10.1021/ol300418h

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2210–2213
Phenyliodine Bis(trifluoroacetate)-
Mediated Oxidative CꢀC Bond Formation:
Synthesis of 3-Hydroxy-2-oxindoles and
Spirooxindoles from Anilides
Junwei Wang, Yucheng Yuan, Rui Xiong, Daisy Zhang-Negrerie, Yunfei Du,* and
Kang Zhao*
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of
Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
duyunfeier@tju.edu.cn; kangzhao@tju.edu.cn
Received February 20, 2012
ABSTRACT
The reaction of phenyliodine bis(trifluoroacetate) (PIFA) with a series of anilides 1 (E = CO2Et) in CF3CH2OH was found to give 3-hydroxy-2-
oxindole derivatives 2, while that with various anilides 10 (E = CON(R4)Ar) afforded the C2-symmetric or unsymmetric spirooxindoles 3. These
processes feature a metal-free oxidative C(sp2)ꢀC(sp3) bond formation, followed by oxidative hydroxylation or spirocyclization.
Over the past two decades, the chemistry of hypervalent
iodine organic compounds has experienced prosperous
development.1 Especially, iodine(III) derivatives, such as
phenyliodine(III) diacetate (PIDA) and phenyliodine(III)
bis(trifluoroacetate) (PIFA), have been successfully ap-
plied to the construction of heterocycles via intramolecular
CꢀN,2 NꢀN,3 or NꢀS4 bond formation. In recent years, it
was found that they could also be used in the formation of
CꢀC bonds, without the need for a transition metal. While
most of these reactions involve the intra- or intermolecular
C(sp2)ꢀC(sp2) bond formation that can lead to spirodienones5
or biaryl compounds,6 there are only a few examples that
(1) (a) Varvoglis, A. Synthesis 1984, 709. (b) Stang, P. J.; Zhdankin,
V. V. Chem. Rev. 1996, 96, 1123. (c) Pohnert, G. J. Prakt. Chem. 2000,
342, 731. (d) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 2002, 102, 2523.
(e) Stang, P. J. J. Org. Chem. 2003, 68, 2997. (f) Moriarty, R. M. J. Org.
Chem. 2005, 70, 2893. (g) Wirth, T. Angew. Chem., Int. Ed. 2005, 44,
3656. (h) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
(i) Dohi, T.; Kita, Y. Chem. Commun. 2009, 2073.
(2) (a) Wardrop, D. J.; Basak, A. Org. Lett. 2001, 3, 1053. (b) Kikug-
awaY.; Nagashima, A.; Sakamoto, T.; Miyazawa, E.; Shiiya, M. J. Org.
Chem. 2003, 68, 6739. (c) Correa, A.; Herrero, M. T.; Tellitu, I.;
Domınguez, E.; Moreno, I.; SanMartın, R. Tetrahedron 2003, 59,
7103. (d) Correa, A.; Tellitu, I.; Domınguez, E.; Moreno, I.; SanMartın,
R. J. Org. Chem. 2005, 70, 2256. (e) Du, Y.; Liu, R.; Linn, G.; Zhao, K.
Org. Lett. 2006, 8, 5919. (f) Correa, A.; Tellitu, I.; Domınguez, E.;
SanMartin, R. J. Org. Chem. 2006, 71, 8316. (g) Malamidou-Xenikaki,
E.; Spyroudis, S.; Tsanakopoulou, M.; Hadjipavlou-Litina, D. J. Org.
Chem. 2009, 74, 7315.
(4) (a) Correa, A.; Tellitu, I.; Domınguez, E.; SanMartin, R. Org.
Lett. 2006, 8, 4811. (b) Huang, J.; Lu, Y.; Qiu, B.; Liang, Y.; Dong, D.
Synthesis 2007, 2791. (c) Brahemi, G.; Kona, F. R.; Fiasella, A.; Buac,
D.; Soukupova, J.; Brancale, A.; Burger, A. M.; Westwell, A. D. J. Med.
Chem. 2010, 53, 2757.
(5) Selected examples: (a) Kita, Y.; Tohma, H.; Inagaki, M.;
Hatanaka, K.; Yakura, T. J. Am. Chem. Soc. 1992, 114, 2175. (b) Kita,
Y.; Takada, T.; Gyoten, M.; Tohma, H.; Zenk, M. H.; Eichhorn, J.
J. Org. Chem. 1996, 61, 5857. (c) Node, M.; Kodama, S.; Hamashima,
Y.; Baba, T.; Hamamichi, N.; Nishide, K. Angew. Chem., Int. Ed. 2001,
40, 3060. (d) Baxendale, I. R.; Deeley, J.; Griffiths-Jones, C. M.; Ley,
S. V.; Saaby, S.; Tranmer, G. K. Chem. Commun. 2006, 2566. (e) Zhang,
Y.; Panek, J. S. Org. Lett. 2009, 11, 3366. (f) Li, Y.; Chen, H.; Shi, C.; Shi,
D.; Ji, S. J. Comb. Chem. 2010, 12, 231.
ꢀ
(6) Selected examples: (a) Hamamoto, H.; Anilkumar, G.; Tohma,
H.; Kita, Y. Chem. Commun. 2002, 450. (b) Mirk, D.; Willner, A.;
€
Frohlich, R.; Waldvogel, S. R. Adv. Synth. Catal. 2004, 346, 675.
(3) (a) Correa, A.; Tellitu, I.; Domınguez, E.; Moreno, I.; SanMartın,
R. J. Org. Chem. 2006, 71, 3501. (b) Correa, A.; Tellitu, I.; Domınguez,
E.; SanMartin, R. Tetrahedron 2006, 62, 11100. (c) Yasunari, M.;
Kazuyuki, H.; Tomohiro, M.; Kosaku, H.; Hironao, S. Heterocycles
2009, 79, 669. (d) Wang, K.; Fu, X.; Liu, J.; Liang, Y.; Dong, D. Org.
Lett. 2009, 11, 1015.
(c) Dohi, T.; Morimoto, K.; Kiyono, Y.; Maruyama, A.; Tohma, H.; Kita,
Y. Chem. Commun. 2005, 2930. (d) Dohi, T.; Morimoto, K.; Maruyama,
A.; Kita, Y. Org. Lett. 2006, 8, 2007. (e) Dohi, T.; Ito, M.; Morimoto, K.;
Iwata, M.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 1301. (f) Kita, Y.;
Morimoto, K.; Ito, M.; Ogawa, C.; Goto, A.; Dohi, T. J. Am. Chem. Soc.
2009, 131, 1668.
r
10.1021/ol300418h
Published on Web 04/12/2012
2012 American Chemical Society

describe the metal-free, iodine(III) oxidant-mediated
C(sp2)ꢀC(sp2) formation in the construction of
heterocycles.7
there are few examples describing the construction of
oxindole rings from anilide derivatives via C(sp2)ꢀC(sp3)
bond formation by using iodine(III) reagents as the sole
oxidant.7d We report herein a novel approach for construct-
ing the naturally occurring and biologically important
3-hydroxy-2-oxindole11 and spirooxindole12 skeletons via
PIFA-mediated tandem oxidation of anilide derivatives.
In our previous work, we successfully realized the for-
mation of the indole framework (C) by PIDA-mediated
oxidative ring closure of N-aryl enamine compounds (A),
in which the NH was proposed to be oxidized by PIDA
involving a NꢀI intermediate B (Scheme 1, eq 1).7c Inspired
by this, we envisaged that the enol form tautomer of anilide
derivatives D may very well undergo a similar process in the
presence of an iodine(III) oxidant but via an OꢀI inter-
mediate E to realize a C(sp2)ꢀC(sp2) bond formation and
give the oxindole compounds (Scheme 1, eq 2).
Scheme 1. Proposed Route to Access Oxindoles Based on the
Previously Reported PIDA-Mediated Synthesis of Indoles
The oxindole skeleton is widely found in natural prod-
ucts and pharmaceutically active compounds.8 Anilide
derivatives have been vastly applied as substrates in the
syntheses of oxindoles via transition-metal-catalyzed and -
mediated processes through CꢀC bond formation be-
tween C(3)ꢀC(3a).9 The employment of PhI(OAc)2 along
with stoichiometric I2 on N-alkyl-N-arylacrylamide deri-
vatives has provided an alternative metal-free access to this
important type of heterocycle, with concurrent introduc-
tion of two iodine atoms.10 To the best of our knowledge,
Table 1. Optimization of Reaction Conditionsa
concn
t
time
(h)
yield
(%)b
entry
oxidant
solvent
(mol/L)
(°C)
1c
2
PIDA
PIDA
PIFA
PhIO
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
DCE
DCE
DCE
DCE
MeCN
toluene
EtOH
EtOAc
TFE
0.20
0.20
0.20
0.05
0.20
0.20
0.20
0.20
0.20
0.20
0.10
0.05
0.05
60
60
60
rt
6
4
3
24
5
5
5
5
1
1
1
1
1
23
44
55
22
60
50
20
45
60
67
75
83
50
(7) Selected examples: (a) Kita, Y.; Tohma, H.; Hatanaka, K.;
Takada, T.; Fujita, S.; Mitoh, S.; Sakurai, H.; Okas, S. J. Am. Chem.
Soc. 1994, 116, 3684. (b) Arisawa, M.; Ramesh, N. G.; Nakajima, M.;
Tohma, H.; Kita, Y. J. Org. Chem. 2001, 66, 59. (c) Yu, W.; Du, Y.;
Zhao, K. Org. Lett. 2009, 11, 2417. (d) Liang, J.; Chen, J.; Du, F.; Zeng,
X.; Li, L.; Zhang, H. Org. Lett. 2009, 11, 2820. (e) Ye, Y.; Zheng, C.;
Fan, R. Org. Lett. 2009, 11, 3156.
(8) (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209.
(b) Trost, B.; Brennan, M. K. Synthesis 2009, 3003. (c) Zhou, F.; Liu,
Y. L.; Zhou, J. Adv. Synth. Catal. 2010, 352, 1381. (d) Millemaggi, A.;
Taylor, R. J. K. Eur. J. Org. Chem. 2010, 4527.
3
4
5
60
60
60
60
60
rt
6
7
8
9
10
11
12
13d
TFE
(9) For recent reviews, see: (a) Klein, J. E. M. N.; Taylor, R. J. K.
Eur. J. Org. Chem. 2011, 6821. For selected examples, see: (b) Ashimori,
A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998,
120, 6477. (c) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402.
TFE
rt
TFE
rt
TFE
0ꢀrt
€
(d) Kundig, E. P.; Seidel, T. M.; Jia, Y.; Bernardinelli, G. Angew. Chem.,
a Reaction conditions: 1a (1.0 mmol), oxidant (2.2 mmol) in solvent
Int. Ed. 2007, 46, 8484. (e) Marsden, S. P.; Watson, E. L.; Raw, S. A. Org.
Lett. 2008, 10, 2905. (f) Ruck, R. T.; Huffman, M. A.; Kim, M. M.;
Shevlin, M.; Kandur, W. V.; Davies, I. W. Angew. Chem., Int. Ed. 2008,
unless otherwise stated. b Isolated yields. c 1.3 equiv of PIDA was used.
d BF3 Et2O (10 mol %) was added.
3
€
47, 4711. (g) Jia, Y. X.; Kundig, E. P. Angew. Chem., Int. Ed. 2009, 48,
1636. (h) Ueda, S.; Okada, T.; Nagasawa, H. Chem. Commun. 2010, 46,
2462. (i) Zhu, J.; Zhang, W.; Zhang, L.; Liu, J.; Zheng, J.; Hu, J. J. Org.
Chem. 2010, 75, 5505. (j) Klein, J. E. M. N.; Perry, A.; Pugh, D. S.;
Taylor, R. J. K. Org. Lett. 2010, 12, 3446.
(10) Wei, H. L.; Piou, T.; Dufour, J.; Neuville, L.; Zhu, J. Org. Lett.
2011, 13, 2244.
Ethyl 3-(methyl (phenyl)amino)-3-oxo-propanoate 1a,
readily prepared via condensation of N-methylaniline with
monoethyl malonate,13 was chosen as the model substrate
to probe the feasibility of the proposed conversion. We
were pleased to find that the reaction of 1a with PIDA,
under the conditions for the conversion of A to C, success-
fully afforded 3-hydroxy-2-oxindole 2a (Table 1, entry 1),
which implies that not only the expected CꢀC bond
formation occurred but also a second oxidative hydroxyla-
tion was also realized. Since at least 2 equiv of the oxidant
were required for the process, the dosage of PIDA was
increased from 1.3 to 2.2 equiv, and the yield was raised
accordingly (Table 1, entry 2). Switching PIDA to other
(11) For recent reviews, see: (a) Peddibhotla, S. Curr. Bioact. Compd.
2009, 5, 20. For selected examples, see: (b) Tomita, D.; Yamatsugu, K.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 6946. (c) Guo,
Q.; Bhanushali, M.; Zhao, C. G. Angew. Chem., Int. Ed. 2010, 49, 9460.
€
(d) Jia, Y. X.; Katayev, D.; Kundig, E. P. Chem. Commun. 2010, 46, 130.
(e) Liu, Y. L.; Wang, B. L.; Cao, J. J.; Chen, L.; Zhang, Y. X.; Wang, C.;
Zhou, J. J. Am. Chem. Soc. 2010, 132, 15176. (f) Gorokhovik, I.;
Neuville, L.; Zhu, J. Org. Lett. 2011, 13, 5536.
(12) For selected examples, see: (a) Trost, B. M.; Cramer, N.;
Silverman, S. M. J. Am. Chem. Soc. 2007, 129, 12396. (b) Bencivenni,
G.; Wu, L. Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M. P.;
Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200.
(c) Deppermann, N.; Thomanek, H.; Prenzel, A. H. G. P.; Maison, W.
J. Org. Chem. 2010, 75, 5994. (d) Wang, L. L.; Peng, L.; Bai, J. F.; Jia,
L. N.; Luo, X. Y.; Huang, Q. C.; Xu, X. Y.; Wang, L. X. Chem. Commun.
2011, 47, 5593. (e) Hande, S. M.; Nakajima, M.; Kamisaki, H.; Tsukano,
C.; Takemoto, Y. Org. Lett. 2011, 13, 1828.
(13) Wee, A. G. H.; McLeod, D. D. Heterocycles 2000, 53, 637.
Org. Lett., Vol. 14, No. 9, 2012
2211

Table 2. Synthesis of 3-Substituted-3-hydroxy-2-oxindoles by
PIFAa
Table 3. Synthesis of Spirooxindoles by PIFAa
entry
R1
R2
R3
R4
product 3
yield (%)b
1
2
3
4
5
6
7
8
H
Cl
H
H
H
H
H
H
Me
Me
Bn
Ph
H
Me
Me
Bn
Ph
Bn
Me
Me
Me
3a
3b
3c
3d
3e
3f
75
60
65
63
53
50
60
40
Cl
H
H
Me
Me
Me
Me
H
Me
Cl
3g
3h
NO2
a General conditions: See Table 2. b Isolated yields.
position of the phenyl ring reacted smoothly to afford the
expected oxindoles 2bꢀc in desirable yields, while the yields
for substrates bearing electron-donating methyl group(s)
were relatively lower (2dꢀe). In the case of a substrate
bearing 3,4-dimethyl substituents, two regioisomeric pro-
ducts were formed. The substrates can also be extended to
N-benzylated and N-arylated substrates, with no obvious
effect on the yields (Table 2, entries 6ꢀ10), except for
substrate 1j, where two inseparable regioisomers were
formed. The structure of 2c was further established by
X-ray crystallography (see Supporting Information), which
unambiguously confirmed the structure of the obtained
3-hydroxy-2-oxindole compounds.
In order to understand the reaction in more detail,
anilides 1kꢀ1m were examined for the oxidative cycliza-
tion. Unfortunately, however, no cyclized product was
detected when either anilide 1k or 1l was treated with
PIFA under the optimal conditions whereas precyclized
oxindole 1m gave the hydroxylated oxindole 2a in 65%
yield (Table 2, entries 11ꢀ13). The unsuccessful cyclization
of 1l and the successful hydroxylation of 1m clearly
indicate the reaction process adopts a sequence of oxdida-
tive C(sp2)ꢀC(sp3) bond formation with the subsequent
oxidative hydroxylation.
To our delight, when the ethoxycarbonyl group in the
substrate was switched to an arylaminocarbonyl group,
the corresponding N1,N3-diphenylmalonamides 10 were
conveniently converted to the spirooxindoles 3 under the
described conditions (Table 3). This result clearly indicates
that the oxidative spirocyclization was realized after the
expected CꢀC bond formation. The C2-symmetric spir-
ooxindoles 3bꢀd can be achieved by introducing a halogen
atom to the phenyl rings or using the N-benzylated and N-
arylated substrates. Furthermore, the C2-unsymmetric
spirooxindoles 3eꢀh can also be realized by installing
different substituents to the N-atom or phenyl ring. It is
worth noting that the presence of a strong electron-with-
drawing nitro group was also applicable to the method. In
a General conditions: 1 (1.0 equiv), PIFA (2.2 equiv) in TFE at rt
unless otherwise stated. b Isolated yields. c 2e was obtained in 42% yield,
with the other isomer being isolated in 27% yield. d The two regioisomers
were inseparable, 2j/2j0 = 3:1. e 1m (1.0 equiv), PIFA (1.2 equiv) in
TFE, rt.
iodine(III) oxidants, namely, PIFA and PhIdO, shows
that PIFA afforded the best yield (Table 1, entries 2ꢀ4).
Solvent screening experiments revealed that the reaction in
trifluoroethanol (TFE) gave the best yield in the shortest
time, even at rt (Table 1, entries 5ꢀ10). Further study
showed that when the concentration of 1a was lowered
from 0.20 to 0.10 and 0.05 mol/L, the yield gradually
improved due to less byproducts being formed during the
reactions (Table 1, entries 10ꢀ12). Attempts to further
increase the yield by the use of BF3 Et2O were unsuccessful.
3
Under the optimal reaction conditions (Table 1, entry 12),
we explored the scope and limitations of this newly devel-
oped method by using various substituted anilides, bearing
a terminal ethoxycarbonyl functionality. Anilides with weak
electron-withdrawing groups (Cl, F) at the para or meta
2212
Org. Lett., Vol. 14, No. 9, 2012

Table 4. Oxidative Hydroxylation of 4a
Scheme 2. Proposed Mechanism
entry
R1
R2
E
product 5
yield (%)b
1
2
3
4
4-NO2
2-Br
H
Me
Me
Bn
Me
CO2Et
5a
5b
5c
5d
90
75
80
53
CO2Et
COMe
H
CON(n-Pr)2
a General conditions: See Table 2. b Isolated yields.
all of the above cases, no corresponding 3-hydroxy-2-
oxindole compound was detected during the process.
However, when the substrate in 1a is a para-methoxy
group on the phenyl ring, no desired 3-hydroxy-2-oxindole
product was obtained (not shown). Surprisingly, for ani-
lide with a para-NO2 or an ortho-Br substituent, uncyclized
hydroxylated products (5a, 5b) were formed as illustrated
inTable4.14 Furthermore, whenthe ethoxycarbonyl group
was changed to the acetyl group or alkylaminocarbonyl
group, hydroxylated products 5c and 5d were formed
respectively (Table 4). No cyclized products were detected
when these hydroxylated products (5aꢀd) were heated at
similar sequence as described above to give the intermedi-
ate J. The nucleophilic attack of the trifluoroacetate anion
on the sp2 carbon center that is connected with the
ethoxycarbonyl group regenerates the oxindole K, which
realizes the trifluoroacetoxylation of oxindole I. Finally,
the alcoholysis15 of the trifluoroacetic ester group affords
the hydroxylated oxindole 2a (Scheme 2, path a). As to the
spirolization observed in the conversion of 10 to 3, we
propose a second intramolecular ring-closure reaction
takes place between the phenyl ring in the side chain in
L, assisted by the adjacent amino group, and the electron-
deficient sp2 carbon, along with the cleavage of the
OꢀI bond. The formed intermediate G undergoes
further proton loss to furnish the spirooxindole 3a
(Scheme 2, path b).16
In summary, we have shown a novel metal-free synthesis
of 3-hydroxy-2-oxindoles and spirooxindoles via a PIFA-
mediated cascade oxidation of anilide derivatives that bear
an appropriate R-alkoxycarbonyl or R-arylaminocarbonyl
group. These processes feature the oxidative cross-coupling
of an sp2 carbon with a side-chained sp3 carbon, followed by
further oxidative hydroxylation or spirocyclization. On-
going studies are in progress to find proper oxidative
conditions for the other unsuccessful anilide derivatives
using such an iodine(III)-mediated CꢀC bond strategy.
reflux, even in the presence of a Lewis acid (BF3 Et2O) or
3
€
Bronsted acid (TFA). These results further imply that the
formation of cyclized 3-hydroxy-2-oxindole does not go
through the hydroxylated intermediate. Disappointingly,
when the ethoxycarbonyl group in 1a was replaced with a
cyano group, the corresponding substrate was inert under the
identical conditions, even at reflux temperature (not shown).
Based on the experimental results, a plausible mechan-
istic sequence is proposed for this PIFA-mediated tandem
oxidation process (Scheme 2). First, the nucleophilic at-
tack on the iodine center by the carbonyl oxygen in 1a
affords intermediate G, with the release of a trifluoroace-
tate anion. Then the capture of the acidic R-proton by the
generated trifluoroacetate transforms the imine salt G into
enamine H. Next, the electrocyclic ring closure,7c along
with the concomitant cleavage of the IꢀO bond, occurs in
H, with subsequent aromatization by the loss of a proton
to afford the oxindole I. Consistent with the experimental
result, the unsuccessful cyclization of 4a might result from
the delocalization of the electron pair on the amino group
into the nitro group through resonance, thus preventing
this step from taking place and resulting in the uncyclized
product (5a). Further oxidation of I by PIFA adopts a
Acknowledgment. We acknowledge the National Nat-
ural Science Foundation of China (#21072148) for finan-
cial support.
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds and
X-ray structural data of 2c (CIF). This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(14) For recent acetoxylation of anilide using PIDA, see: Liu, W. B.;
Chen, C.; Zhang, Q.; Zhu, Z. B. Beilstein J. Org. Chem. 2011, 7, 1436.
(15) Control experiments indicate that H2O is not necessary for the
process.
(16) This spirocyclization proccess may also adopt an intramolecular
FriedelꢀCrafts reaction; for such an example, see: England, D. B.;
Merey, G.; Padwa, A. Org. Lett. 2007, 9, 3805.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
2213