Oxidative Cleavage of C2-C3 Bond in Isatin Using (Diacetoxyiodo)benzene: A Facile Synthesis of Carbamates of Alkyl Anthranilates

Article abstract of DOI:10.1055/s-0035-1560990

On reaction with (diacetoxyiodo)benzene, isatin and N-acetyl isatin undergo the oxidative C2-C3 bond cleavage to form carbamates of alkyl anthranilates and alkyl 2-acetamidobenzoate, respectively.

Full text of DOI:10.1055/s-0035-1560990

SYNLETT
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1
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1
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-
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0
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© Georg Thieme Verlag Stuttgart · New York
2016, 27, 763–768
letter
763
A. H. Kalbandhe et al.
Letter
Synlett
Oxidative Cleavage of C2–C3 Bond in Isatin Using (Diacetoxyiodo)
benzene: A Facile Synthesis of Carbamates of Alkyl Anthranilates
Amit H. Kalbandhe
Ashish C. Kavale
O
O
R1
R1
OR2
PhI(OAc)2
R2OH, r.t.
17 examples
31–79% yield
Prerana B. Thorat
Nandkishor N. Karade*
O
N
NH
O
H
Department of Chemistry, Rashtrasant Tukadoji Maharaj
Nagpur University, Nagpur, Maharashtra 440 033, India
nnkarade@gmail.com
O
OR2
OR2
O
R1
R1
PhI(OAc)2
R2OH, r.t.
7 examples
48–72% yield
O
N
NH
O
O
Received: 08.05.2015
Accepted after revision: 21.10.2015
Published online: 22.12.2015
DOI: 10.1055/s-0035-1560990; Art ID: st-2015-b0351-l
Nu
OH
or
O
O
Abstract On reaction with (diacetoxyiodo)benzene, isatin and N-ace-
tyl isatin undergo the oxidative C2–C3 bond cleavage to form carba-
mates of alkyl anthranilates and alkyl 2-acetamidobenzoate, respec-
tively.
N
N
H
H
3
2
C-3 attack
nucleophilic
addition
Key words Hofmann rearrangement, phthalimide, isatin, hypervalent
iodine, 1,2-dicarbonyl cleavage
O
O
O
nucleophilic
substitution
O
[O]
O
O
Nu
C-2 attack
Isatin is an archetypical indole derivative with two
types of carbonyl groups, that is, keto and lactam group.
Nucleophilic attack at C2 and/or C3 positions of isatin is
possible, and the chemoselectivity of these reactions de-
pends on several factors including the nature of nucleo-
phile. In general, the C3 carbonyl group in isatins is suscep-
tible to nucleophilic addition to form a wide range of deriv-
atives 2 together with biologically active spiro-fused cyclic
frameworks 3 (Scheme 1).1 Alternatively, the nucleophilic
substitution at C2 carbonyl group of isatin is also observed
in some cases, leading to the cleavage of lactam-type het-
erocyclic ring.2 The oxidation of isatin with CrO3 or potassi-
um persulfate forms isatoic anhydrides 5.3 A literature sur-
vey further revealed that the reactions of isatin involving
the definite cleavage of C2–C3 bond under oxidative condi-
tions is relatively less documented, and therefore, needs to
be investigated.
The Hofmann rearrangement of aliphatic and aromatic
amides, cyclic imides, and sulfonamides mediated by hy-
pervalent iodine reagents is the most intensively investigat-
ed reaction in organic synthesis.4 The Hofmann rearrange-
ment of cyclic imides such as phthalimide is particularly
useful for the synthesis of anthranilic acids or alkyl anthra-
nilates which are important building blocks for the synthe-
N
N
H
O
NH2
cleavage of lactam
H
1
4
5
oxidative cleavage
of C-2 and C-3 bond
[O]
O
Nu
O
NH
Nu
6
Scheme 1 Possible transformations of isatin due to keto and lactam
groups
sis of many dyes, pigments, perfumes, and pharmacological
agents.5 However, the substituted phthalimides form two
Hofmann rearrangement products due to the symmetrical
nature of the five-membered cyclic imide substructural
skeletons.6 Recently, Togo and co-workers have demonstrat-
ed the Hofmann rearrangement of phthalimide using in
situ generated hypervalent iodine(III) reagent (from iodo-
benzene, MCPBA, and PTSA·H2O) in the presence of a base
(DBU) in alcohol to provide anthranilic acid derivatives.6a
Isatin has a close structural resemblance to phthalimide
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 763–768

764
A. H. Kalbandhe et al.
Letter
Synlett
and therefore we were intrigued with the possibility of
Hofmann-type rearrangement of isatin derivatives using
hypervalent iodine reagents. It is observed that the reaction
of isatin derivatives with (diacetoxyiodo)benzene leads to
oxidative cleavage of the C2–C3 bond to form anthranilic
acid derivatives. Similarly, on reaction with DIB and alcohol,
N-acetyl isatin undergoes C2–C3 oxidative cleavage to form
alkyl 2-acetamidobenzoate derivatives (Scheme 2).
of isatin even after refluxing for 24 hours in methanol.
Thus, the optimization conditions revealed that the DIB is
the most efficient trivalent iodine reagent of those studied
for inducing the oxidative C2–C3 cleavage of isatin.
The scope and generality of the C2–C3 oxidative cleav-
age of isatin in various alcohols was subsequently investi-
gated under the optimized conditions employing DIB as the
oxidizing agent. The results listed in Scheme 3 indicate that
a wide range of primary alcohols such as methanol, etha-
nol, propanol, CF3CH2OH, and ethoxyethanol were success-
fully used for the oxidative C2–C3 cleavage of isatin.9 The
yield of carbamates 2 was found to be maximum using
methanol as a solvent. Yields of the oxidative C2–C3 cleav-
age of isatin depend on the nature of substituents. Isatins
with electron-withdrawing groups (F, Cl, Br, and NO2) give
better yields of 2f–n while isatins with electron-releasing
groups (Me and OMe) furnishes 2o–r in poor yields. It is
important to note that that the substituted isatins fur-
nished only one carbamate derivative accompanied by oxi-
dative cleavage of the C2–C3 bond. This is a remarkable fea-
ture of the methodology in comparison to the formation of
two Hofmann rearrangement products formed from the
substituted phthalimide using hypervalent iodine. The re-
action of N-acetyl isatin with DIB in methanol and ethanol
O
O
R1
R1
OR2
OR2
PhI(OAc)2
R2OH, r.t.
O
N
NH
H
O
17 examples
31–79% yield
O
O
R1
R1
OR2
PhI(OAc)2
R2OH, r.t.
O
N
NH
O
O
7 examples
48–72% yield
Scheme 2 Oxidative cleavage of C2–C3 bond of substituted isatin and
N-acetyl isatin derivatives using (diacetoxyiodo)benzene
Table 1 Oxidative Cleavage of the C2–C3 Bond in Isatin Using (Diace-
toxyiodo)benzenea,b
Initially, the reaction of isatin (1a) in methanol with dif-
ferent oxidizing agents was chosen as a model reaction, and
the optimization results are summarized in Table 1.
O
COOR
"oxidant"
When isatin was treated with three different trivalent
iodine reagents (Table 1, entries 1–5) in methanol, the reac-
tion proceeded smoothly at room temperature to form the
product 2a in good yields.7 However, the maximum yield of
2a was obtained by using 1.7 equivalents of (diacetoxyio-
do)benzene with reduced reaction time. The screening of
other alcohols such as ethanol, isopropyl alcohol, and tert-
butyl alcohol for the oxidation of isatin using DIB was also
examined (Table 1, entries 6–8). However, the C2–C3 oxida-
tive cleavage of isatin using DIB was successful only with
primary alcohol, while secondary and tertiary alcohols did
not furnish any isolable yields of respective carbamates and
it may be due to steric reasons. Encouraged by these results,
we attempted the C2–C3 oxidative cleavage of isatin using
the in situ generated hypervalent iodine(III) reagents from
the reactions of catalytic iodoarene with terminal oxidants
such as MCPBA or oxone (Table 1, entries 9–11). However in
all the cases, we could not obtain the corresponding carba-
mate 2 which is in agreement with the literature report
that the oxidation of isatin with MCPBA forms the Baeyer–
Villiger oxidation product.8 The reaction of isatin with mo-
lecular iodine (Table 1, entries 12 and 13) was also investi-
gated to validate the necessity of hypervalent iodine re-
agents under similar reaction conditions. Molecular iodine
was found to be inferior to induce oxidative C2–C3 cleavage
O
ROH
N
NHCOOR
H
2
1
Entry Oxidative conditions
Solvent
Time Yield
(h)
(%)a
1
2
3
4
5
6
7
8
9
PhI(OAc)2 (1.1 equiv)
PhI(OAc)2 (1.7 equiv)
PhI(OCOCF3)2 (1.1 equiv)
PhI(OCOCF3)2 (1.7 equiv)
PhI(OH)OTs (1.1 equiv)
PhI(OAc)2 (1.7 equiv)
PhI(OAc)2 (1.1 equiv)
PhI(OAc)2 (1.1 equiv)
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
12
61
79
43
52
26
64
0
9
12
24
24
9
2-PrOH
t-BuOH
MeOH
24
24
24
0
PhI (0.1 equiv), MCPBA (1.5 equiv),
AcOH, reflux
0
10
11
PhI (0.1 equiv), MCPBA (1.5 equiv),
PTSA (1.5 equiv), DBU (2 equiv)
MeOH
MeOH
24
24
0
0
PhI (0.1 equiv), Oxone (1.5 equiv),
PTSA (1.5 equiv), DBU (2 equiv)
12
13
I
2 (1.1 equiv)
MeOH
MeOH
24
24
0
I2 (1.1 equiv), K2CO3, reflux
18
a Isolated yields.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 763–768

765
A. H. Kalbandhe et al.
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was also examined (Scheme 4). In this case, the C2–C3 oxi-
dative cleavage of isatin was also observed with longer reac-
tion time, leading to form methyl or ethyl 2-acetamidoben-
zoate in satisfactory yields.
oxidative cleavage using DIB in alcohol. However, there is a
report that the formation of intermediate analogues to 8 in-
volving the N–I bond is possible only when the sodium salt
of isatin10 or phthalimidate6 reacts with hypervalent io-
dine(III) reagent. Thus, the failure of N-methyl or N-benzyl
isatin for the C2–C3 oxidative cleavage does not guarantee
the intermediacy of 8 in the reaction mechanism. In con-
trast to N-methyl or N-benzyl isatin, N-acetyl isatin under-
goes smooth C2–C3 oxidative cleavage to form methyl 2-acet-
amidobenzoate (Scheme 4). The presence of the N-acetyl
group enhances the electrophilicity of the C3 position com-
pared to the N-alkyl group through the electron-withdraw-
ing resonance effect of the amide moiety. This facilitates the
generation of hemiketal 5 more efficiently. Therefore, oxi-
dative C2–C3 cleavage of isatin and N-acetyl isatin must be
taking place through the hemiketal 5 oxidation induced by
DIB. This is also supported by the fact that isatin with an
The tentative mechanism for the C2–C3 oxidative cleav-
age of isatin using DIB and alcohol is shown in Scheme 5.
The isatin can form hemiketal 5 followed by its ligand-ex-
change reaction with DIB to form 6. The propensity of 6 for
reductive elimination of iodobenzene promotes the con-
comitant oxidative cleavage of the C2–C3 bond with subse-
quent formation of isocyanate derivative 7, which will be
trapped by alcohol to form carbamate derivative 2. Alterna-
tively, the weakly nucleophilic isatin 1 can react with elec-
trophilic DIB through ligand-exchange reaction to form hy-
pervalent amidoiodane 8. This possibility of formation of
intermediate 6 can be partially accepted due to the fact that
the N-methyl or N-benzyl isatin failed to undergo C2–C3
O
R2
R2
CO2R3
PhI(OAc)2
R3OH, r.t.
O
NHCO2R3
N
H
R1
R1
1a–r
2a–r
CO2Et
CO2Me
CO2n-Pr
CO2CH2CF3
NHCO2Et
NHCO2Me
NHCO2n-Pr
2c 55% (24 h)
NHCO2CH2CF3
2d 61% (16 h)
2a 79% (9 h)
2b 64% (9 h)
CO2CH2CH2OEt
F
CO2Me
Cl
CO2Me
Cl
CO2Et
NHCO2CH2CH2OEt
NHCO2Me
2f 77% (10 h)
NHCO2Me
NHCO2Et
2e 65% (22 h)
2g 78% (10 h)
2h 61% (14 h)
Br
CO2Me
Br
CO2Me
Br
CO2Et
Br
CO2Et
NHCO2Me
NHCO2Me
NHCO2Et
NHCO2Et
Br
2k 77% (12
h)
Br
2l 56% (16 h)
2i 74% (11 h)
2j 57% (16 h)
O2N
CO2Et
O2N
CO2Me
Me
CO2Me
Me
CO2Et
NHCO2Et
NHCO2Me
NHCO2Me
NHCO2Et
2n 55% (20 h)
2o 43% (20 h)
2m 77% (14 h)
2p 37% (24 h)
Me
CO2CH2CF3
MeO
CO2Me
NHCO2CH2CF3
2q 31% (24 h)
NHCO2Me
2r 0% (38 h)
Scheme 3 Oxidative cleavage of C2–C3bond in isatin using (diacetoxyiodo)benzene. Reagents and conditions: isatin (1 mmol), DIB (1.7 mmol), alcohol
(5 mL), r.t. stirring. Isolated yields are given.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 763–768

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A. H. Kalbandhe et al.
Letter
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O
R1
COOR
R1
PhI(OAc)2 (2 equiv)
ROH, r.t., 48 h
O
N
NHCOMe
O
4a–g
3a–g
Cl
COOEt
COOMe
COOEt
Cl
COOMe
NHCOMe
NHCOMe
NHCOMe
NHCOMe
4c (69%)
4a (68%)
Br
4b (62%)
4d (60%)
COOMe
COOMe
Br
COOEt
H3C
NHCOMe
NHCOMe
NHCOMe
4g (48%)
4e (72%)
4f (61%)
Scheme 4 Formation of alkyl 2-acetamidobenzoate from N-acetyl isatin using DIB and alcohol. Isolated yields are given.
OAc
O
RO
RO
O
I
OH
••
ROH
••
PhI(OAc)2
– AcOH
ligand
exchange
Ph
O
O
O
••
••
••
N
N
N
H
H
H
5
6
1
reductive
elimination
– PhI
••
ROH
••
O
O
O
O
ligand
exchange
reductive
elimination
OR
O
OR
C
O
O
••
– AcOH
– PhI
– AcOH
N
N
NH
N
O
1
H
I
OAc
OAc
7
Ph
OAc
RO
••
ROH
••
Ph
I
8
2
Scheme 5 Plausible mechanism for oxidative cleavage of C2–C3 bond of isatins using (diacetoxyiodo)benzene
electron-withdrawing group at the 5-position gives better
yields of products than those with an electron-donating
group at the 5-position (Scheme 3).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560990.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
In summary, we have developed a new reaction of isatin
and N-acetyl isatin involving oxidative cleavage of C2–C3
bond to form highly functionalized carbamates of alkyl an-
thranilates and alkyl 2-acetamidobenzoate, respectively.
This methodology opens up a new synthesis of anthranilic
acid derivatives from isatins under mild conditions using
transition-metal-free oxidizing agent.
References and Notes
(1) Reviews: (a) da Silva, J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz.
Chem. Soc. 2001, 12, 273. (b) Girija, S.; Singh, G. S.; Desta, Z. Y.
Chem. Rev. 2012, 112, 6104. (c) Lashgari, N.; Ziarani, G. M.
ARKIVOC 2012, (i), 277.
(2) (a) Bergman, J.; Engelhardt, P.; Kiss, A. I.; Lindström, J. O.;
Wärnmark, K. Stud. Org. Chem. 1988, 35, 1. (b) Ogata, M.;
Matsumoto, H. Chem. Ind. 1976, 1067. (c) Ranganathan, S.;
Ranganathan, D.; Ramachandran, P. V.; Mahanty, M. K.;
Bamezai, S. Tetrahedron 1981, 37, 4171. (d) Bergman, J.;
Carlsson, R.; Lindström, J. O. Tetrahedron Lett. 1976, 40, 3611.
(3) (a) Czuba, W.; Sedzik-Hibner, D. Pol. J. Chem. 1989, 63, 113.
(b) Reissenweber, G.; Mangold, D. Angew. Chem., Int. Ed. Engl.
1980, 92, 196. (c) Reissenweber, G.; Mangold, D. US 4297491,
Acknowledgment
The authors are thankful to the Department of Science and Technolo-
gy, New Delhi, India (No. SR/S1/OC-72/2009) for the financial support.
The authors are also grateful to SAIF, Punjab University, Chandigarh,
India, for recording the NMR spectra.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 763–768

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A. H. Kalbandhe et al.
Letter
Synlett
1981; Ger. Offen. 2,944,696 1981; Chem. Abstr. 1981, 95,
P132913w. (d) Reissenweber, G.; Niess, R. DE 3,323,975, 1984;
Chem. Abstr. 1981, 100, P174428u.
MHz, CDCl3): δ = 3.78 (3 H, s, CH3), 3.92 (3 H, s, CH3), 7.25 (1 H,
ddd, J = 11.1, 6.9, 3.0 Hz, ArH), 7.66 (1 H, dd, J = 3.1, 9.2 Hz, ArH),
8.42 (1 H, dd, J = 5.0, 9.3 Hz ArH), 10.41 (1 H, br s, NH). 13C NMR
(100 MHz, CDCl3): δ = 52.3, 52.5, 115.5 (d, 3JC–F = 6 Hz), 116.6 (d,
2JC–F = 24 Hz), 120.5 (d, 3JC–F = 7 Hz), 121.6 (d, 2JC–F = 23 Hz), 138.1
(d, 4JC–F = 2 Hz), 154.1, 158.3, (d, 1JC–F = 241 Hz), 167.4 (d, 4JC–F = 2
Hz). IR: 3260, 1733, 1689, 1601, 1526, 1427, 1255, 1214, 1056
cm–1. ESI-MS: m/z [M+] calcd for C10H10FNO4: 227.0594; found
[M + 23]: 250.
(4) (a) Loudon, G. M.; Radhakrishna, A. S.; Almond, M. R.; Blodgett,
J. K.; Boutin, R. H. J. Org. Chem. 1984, 49, 4272. (b) Boutin, R. H.;
Loudon, G. M. J. Org. Chem. 1984, 49, 4277. (c) Lazbin, I. M.;
Koser, G. F. J. Org. Chem. 1986, 51, 2669. (d) Moriarty, R. M.;
Chany, C. J. II.; Vaid, R. K.; Prakash, O.; Tuladhar, S. M. J. Org.
Chem. 1993, 58, 2478. (e) Moriarty, R. M.; Enache, L. A.; Zhao, L.;
Gilardi, R.; Mattson, M. V.; Prakash, O. J. Med. Chem. 1998, 41,
468. (f) Tohma, H.; Maruyama, A.; Maeda, A.; Maegawa, T.; Dohi,
T.; Shiro, M.; Morita, T.; Kita, Y. Angew. Chem. Int. Ed. 2004, 43,
3595. (g) Yusubov, M. S.; Funk, T. V.; Chi, K.-W.; Cha, E.-H.; Kim,
G. H.; Kirschning, A.; Zhdankin, V. V. J. Org. Chem. 2008, 73, 295.
(h) Okamoto, N.; Miwa, Y.; Minami, H.; Takeda, K.; Yanada, R.
Angew. Chem. Int. Ed. 2009, 48, 9693. (i) Zagulyaeva, A. A.;
Banek, C. T.; Yusubov, M. S.; Zhdankin, V. V. Org. Lett. 2010, 12,
4644. (j) Yoshimura, A.; Luedtke, M. W.; Zhdankin, V. V. J. Org.
Chem. 2012, 77, 2087. (k) Miyamoto, K.; Sakai, Y.; Goda, S.;
Ochiai, M. Chem. Commun. 2012, 48, 982.
(5) (a) Thorarensen, A.; Li, J.; Wakefield, B. D.; Romero, D. L.;
Marotti, K. R.; Sweeney, M. T.; Zurenko, G. E.; Sarver, R. W.
Bioorg. Med. Chem. Lett. 2007, 17, 3113. (b) Roy, A. D.;
Subramanian, A.; Roy, R. J. Org. Chem. 2006, 71, 382. (c) Liu, J.-F.;
Ye, P.; Zhang, B.; Bi, G.; Sargent, K.; Yu, L.; Yohannes, D.; Baldino,
C. M. J. Org. Chem. 2005, 70, 6339. (d) Yoo, C. L.; Fettinger, J. C.;
Kurth, M. J. J. Org. Chem. 2005, 70, 6941. (e) Kamal, A.; Reddy, K.
S.; Prasad, B. R.; Babu, A. H.; Ramana, A. V. Tetrahedron Lett.
2004, 45, 6517. (f) Larksarp, C.; Alper, H. J. Org. Chem. 2000, 65,
2773.
Compound 2g: Yield 0.1905 g (78%), mp 122 °C. 1H NMR (400
MHz, CDCl3): δ = 3.78 (3 H, s, CH3), 3.92 (3 H, s, CH3), 7.46 (1 H,
dd, J = 9.0, 2.6 Hz, ArH), 7.95 (1 H, d, J = 2.6 Hz, ArH), 8.40 (1 H, d,
J = 9.0 Hz, ArH), 10.41 (1 H, s, NH). 13C NMR (100 MHz, CDCl3): δ
= 52.4, 52.5, 115.6, 120.2, 126.6, 130.3, 134.4, 140.3, 153.9,
167.4. IR: 3251, 1730, 1686, 1587, 1513, 1447, 1281, 1213 cm–1
.
ESI-MS: m/z [M]+ calcd for C10H10ClNO4: 243.0298; found [M +
23]: 266.
Compound 2h: Yield 0.1676 g (61%), mp 84 °C. 1H NMR (400
MHz, CDCl3): δ = 1.32 (3 H, t, J = 7.1 Hz, CH3), 1.41 (3 H, t, J = 7.1
Hz, CH3), 4.22 (2 H, q, J = 7.1 Hz, CH2), 4.38 (2 H, q, J = 7.1 Hz,
CH2), 7.46 (1 H, dd, J = 9.0, 2.6 Hz, ArH), 7.97 (1 H, d, J = 2.6 Hz,
ArH), 8.42 (1 H, d, J = 9.1 Hz, ArH), 10.43 (1 H, br s, NH). 13C NMR
(100 MHz, CDCl3): δ = 14.1, 14.4, 61.3, 61.7, 115.9, 120.2, 126.4,
130.3, 134.3, 140.5, 153.5, 167.0. IR: 3233, 1727, 1694, 1588,
1516, 1458, 1237, 1211, 1053 cm–1. ESI-MS: m/z [M]+ for
C
12H14ClNO4: 271.0611; found [M + 1] and [M + 23]: 272 and
294.
Compound 2j: Yield 0.5709 g (57%), mp 88 °C. 1H NMR (400
MHz, CDCl3): δ = 1.32 (3 H, t, J = 7.1 Hz, CH3), 1.41 (3 H, t, J = 7.1
Hz, CH3), 4.23 (2 H, q, J = 7.1 Hz, CH2), 4.39 (2 H, q, J = 7.1 Hz,
CH2), 7.60 (1 H, dd, J = 9.0, 2.4 Hz, ArH), 8.12 (1 H, d, J = 2.4 Hz,
ArH), 8.36 (1 H, d, J = 9.0 Hz, ArH), 10.44 (1 H, br s, NH). 13C NMR
(100 MHz, CDCl3): δ = 14.1, 14.4, 61.3, 61.7, 113.6, 116.2, 120.5,
133.2, 137.1, 141, 153.5, 166.9. IR: 3239, 1730, 1693, 1586,
1511, 1369, 1246, 1212, 1053, 840 cm–1. ESI-MS: m/z [M+] calcd
for C12H14BrNO4: 315.0106; found [M + 23]: 338.
(6) (a) Moriyama, K.; Ishida, K.; Togo, H. Chem. Commun. 2012, 48,
8574. (b) Moriyama, K.; Ishida, K.; Togo, H. Org. Lett. 2012, 14,
946.
(7) General Procedure
To the stirred solution of isatin (1 mmol) in an appropriate
alcohol (5 mL), (diacetoxyiodo)benzene (1.7 mmol) was added.
The reaction mixture was stirred for 9–24 h at r.t. The progress
of the reaction was monitored by TLC. After completion of reac-
tion, the solvent was evaporated on rotatory vacuum evapora-
tor, and the crude product was purified by column chromatog-
raphy using PE and EtOAc to afford 2a–q in moderate yields.
(8) Sahu, A.; Chatterjee, A. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 1990, 29, 603.
Compound 2k: Yield 0.2818 g (77%), mp 104 °C. 1H NMR (400
MHz, CDCl3): δ = 3.77 (3 H, s, CH3), 3.90 (3 H, s, CH3), 7.55 (1 H,
br s, NH), 7.89 (1 H, d, J = 2.2 Hz, ArH), 7. 94 (1 H, d, J = 2.2 Hz,
ArH). 13C NMR (100 MHz, CDCl3): δ = 52.8, 53.1, 118.5, 121.5,
128, 132.6, 135.1, 138.8, 153.9, 165.4. IR: 3255, 1729, 1706,
1553, 1512, 1434, 1260, 1228, 1062 cm–1. ESI-MS: m/z [M]+
calcd for C10H981Br2NO4: 366.8898; found [M + 23]: 390.
Compound 2l: Yield 0.2233 g (56%), mp 59 °C. 1H NMR (400
MHz, CDCl3): δ = 1.28 (3 H, t, J = 7.1 Hz, CH3), 1.36 (3 H, t, J = 7.1
Hz, CH3), 4.21 (2 H, q, J = 7.1 Hz, CH2), 4.35 (2 H, q, J = 7.1 Hz,
CH2), 7.49 (1 H, br s, NH), 7.88 (1 H, d, J = 2.3 Hz, ArH), 7.94 (1 H,
d, J = 2.3 Hz, ArH). 13C NMR (100 MHz, CDCl3): δ = 14.1, 14.4, 62,
62.1, 118.3, 121.4, 128.3, 129.4, 132.6, 135.1, 138.7, 153.5, 165.
IR: 3240, 1698, 1512, 1450, 1382, 1255, 1190, 1063 cm–1. ESI-
MS: m/z [M+] calcd for C12H1381Br2NO4: 394.9211; found [M +
23]: 418.
(9) Spectral Data for the New Products
Compound 2c: Yield 0.1462 g (55%), pale yellow oil. 1H NMR
(300 MHz, CDCl3): δ = 0.983 (3 H, t, J = 7.8 Hz, CH3), 1.03 (3 H, t,
J = 7.5 Hz, CH3), 1.67–1.84 (4 H, m, 2 CH2), 4.12 (2 H, t, J = 9.2 Hz,
OCH2), 4.27 (2 H, t, J = 8.8 Hz, OCH2), 7.02 (1 H, t, J = 10.4 Hz,
ArH), 7.54 (1 H, t, J = 9.6 Hz, ArH), 8.02 (1 H, dd, J = 10.8, 2 Hz,
ArH), 8.45 (1 H, d, J = 11.2 Hz, ArH), 10.56 (1 H, br s, NH).
13C NMR (75 MHz, CDCl3): δ = 10.4, 10.6, 22.1, 22.3, 66.9 (2 C),
114.8, 118.8, 121.4, 130.9, 134.5, 142, 153.9, 168.2.
Compound 2e: Yield 0.2123 g (65%), yellow oil. 1H NMR (300
MHz, CDCl3): δ = 1.25 (6 H, t, J = 9.2 Hz, 2 CH3), 3.54–3.59 (4 H,
m, 2 OCH2), 3.68 (2 H, t, J = 6.4 Hz, OCH2), 4.33 (2 H, t, J = 6.4 Hz,
OCH2), 4.45 (2 H, t, J = 6.4 Hz, OCH2), 7.05 (1 H, t, J = 9.6 Hz, ArH),
7.52 (1 H, td, J = 9.6, 2.0 Hz, ArH), 8.05 (1 H, dd, J = 2.0 Hz, 10.8
Hz, ArH), 8.44 (1 H, d, J = 11.2 Hz, ArH), 10.46 (1 H, br s, NH).
13C NMR (75 MHz, CDCl3): δ = 15.2, 19.5, 64, 64.5, 66.7, 66.8,
68.6, 69.9, 114.7, 118.9, 121.6, 131.1, 134.6, 141.7, 153.6, 168.
IR: 3304, 1736, 1689, 1525, 1450, 1385, 1238, 1211, 1260, 752
Compound 2n: Yield 0.1546 g (55%), mp 70 °C. 1H NMR (400
MHz, CDCl3): δ = 1.35 (3 H, t, J = 7.1 Hz, CH3), 1.46 (3 H, t, J = 7.1
Hz, CH3), 4.28 (2 H, q, J = 7.1 Hz, CH2), 4.45 (2 H, q, J = 7.1 Hz,
CH2), 8.35 (1 H, dd, J = 9.4, 2.8 Hz, ArH), 8.66 (1 H, d, J = 9.4 Hz,
ArH), 8.91 (1 H, d, J = 2.7 Hz, ArH), 10.89 (1 H, br s, NH). 13C NMR
(100 MHz, CDCl3): δ = 14.4 (2 C), 62.0, 62.4, 114.3, 118.8, 127.0,
129.2, 140, 147.2, 153.1, 166.6. IR: 3253, 1734, 1682, 1584,
1505, 1462, 1243, 1202, 1003 cm–1. ESI-MS: m/z [M+] calcd for
C
12H14N2O6: 282.0852; found [M + 1] and [M + 18]: 283 and 305.
cm–1
Compound 2f: Yield 0.1756 g (77%), mp 98 °C. 1H NMR (400
.
Compound 2p: Yield 0.0942 g (37%), pale yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 1.31 (3 H, t, J = 7.1 Hz, CH3), 1.41 (3 H, t,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 763–768

768
A. H. Kalbandhe et al.
Letter
Synlett
J = 7.1 Hz, CH3), 2.31 (3 H, s, CH3), 4.22 (2 H, q, J = 7.0 Hz, CH2),
4.36 (2 H, q, J = 7.1 Hz, CH2), 7.32 (1 H, dd, J = 8.6, 2.0 Hz, ArH),
7.80 (1 H, d, J = 1.8 Hz, ArH), 8.31 (1 H, d, J = 8.6 Hz, ArH), 10.36
(1 H, br s, NH). 13C NMR (100 MHz, CDCl3): δ = 14.2, 14.5, 20.5,
61.0, 61.2, 114.6, 118.8, 130.7, 130.8, 135.2, 139.5, 153.7, 168.1.
2853, 1688, 1600, 1511, 1469, 1359, 1250, 1106, 835, 788, 733
cm–1
.
Compound 4d: Yield 0.1466 g (60%). 1H NMR (400 MHz, CDCl3):
δ = 1.42 (3 H, t, J = 7.0 Hz, CH3), 2.23 (3 H, s, CH3), 4.39 (2 H, q, J =
7.0 Hz, CH2), 7.48 (1 H, dd, J = 2.6, 9.0 Hz, ArH), 8.00 (1 H, d, J =
2.6 Hz, ArH), 8.69 (1 H, d, J = 9.0 Hz, ArH), 11.02 (1 H, br s, NH).
13C NMR (100 MHz, CDCl3): δ = 14.1, 25.4, 61.8, 116.3, 121.7,
127.4, 130.3, 134.3, 140.1, 167.2, 169. IR: 3266, 2922, 2852,
IR: 3303, 1727, 1687, 1591, 1523, 1470, 1241, 1206, 747 cm–1
.
Compound 2q: Yield 0.112 g (31%), pale yellow oil. 1H NMR (400
MHz, CDCl3): δ = 2.36 (3 H, s, CH3), 4.56 (2 H, q, J = 8.4 Hz, CH2),
4.70 (2 H, q, J = 8.28 Hz, CH2), 7.43 (1 H, dd, J = 8.6, 1.92 Hz, ArH),
7.84 (1 H, d, J = 1.72 Hz, ArH), 8.29 (1 H, d, J = 8.6 Hz, ArH), 10.27
(1 H, br s, NH). IR: 3290, 1751, 1707, 1596, 1539, 1457, 1286,
1699, 1681, 1523, 1400, 1366, 1234, 838, 789, 734 cm–1
.
Compound 4e: Yield 0.1958 g (72%), mp 122 °C. 1H NMR (400
MHz, CDCl3): δ = 2.24 (3 H, s, CH3), 3.93 (3 H, s, OCH3), 7.62 (1 H,
dd, J = 2.3, 9.0 Hz, ArH), 8.14 (1 H, d, J = 2.4 Hz, ArH), 8.63 (1 H, d,
J = 9.0 Hz, ArH), 10.97 (1 H, br s, NH). 13C NMR (100 MHz,
CDCl3): δ = 25.4, 52.6, 114.7, 116.3, 122, 133.3, 137.3, 140.6,
167.6, 169. IR: 3282, 2922, 2852, 1696, 1680, 1597, 1465, 1361,
1167, 785 cm–1
.
Compound 4a: Yield 0.1325 g (68%), mp 94 °C. 1H NMR (400
MHz, CDCl3): δ = 2.23 (3 H, s, CH3), 3.92 (3 H, s, OCH3), 7.07 (1 H,
td, J = 1.2, 8.2 Hz, ArH), 7.53 (1 H, td, J = 1.6, 8.6 Hz, ArH), 8.01 (1
H, dd, J = 1.6, 8.0 Hz, ArH), 8.69 (1 H, dd, J = 0.76, 8.6 Hz, ArH),
11.04 (1 H, br s, NH). 13C NMR (100 MHz, CDCl3): δ = 25.4, 52.3,
114.7, 120.3, 122.4, 130.7, 134.6, 141.6, 168.7, 169. IR: 3270,
1257, 1086, 834, 787, 754 cm–1
.
Compound 4f: Yield 0.1746 g (61%), mp 120 °C. 1H NMR (400
MHz, CDCl3): δ = 1.42 (3 H, t, J = 7.1 Hz, CH3), 2.23 (3 H, s, CH3),
4.37 (2 H, q, J = 7.1 Hz, CH2), 7.60 (1 H, dd, J = 2.4, 9.0 Hz, ArH),
8.14 (1 H, d, J = 2.4 Hz, ArH), 8.64 (1 H, d, J = 9.0 Hz, ArH), 11.02
(1 H, br s, NH). 13C NMR (100 MHz, CDCl3): δ = 14.1, 25.4, 61.8,
114.7, 116.6, 122, 133.2, 137.2, 140.6, 167.1, 169. IR: 3260,
2922, 2852, 1698, 1677, 1599, 1469, 1365, 1255, 1089, 836,
2921, 2853, 1687, 1584, 1450, 1367, 1260, 1080, 756 cm–1
.
Compound 4b: Yield 0.1296 g (62%), mp 62 °C. 1H NMR (400
MHz, CDCl3): δ = 1.41 (3 H, t, J = 7.1 Hz, CH3), 2.23 (3 H, s, CH3),
4.37 (3 H, s, J = 7.1 Hz, CH3), 7.06 (1 H, td, J = 1.1, 8.2 Hz, ArH),
7.52 (1 H, td, J = 1.6, 8.7 Hz, ArH), 8.03 (1 H, dd, J =1.6, 8.0 Hz,
ArH), 8.69 (1 H, dd, J = 1.6, 8.0 Hz, ArH), 11.09 (1 H, br s, NH).
13C NMR (100 MHz, CDCl3): δ = 14.1, 25.4, 61.3, 115, 120.2,
122.3, 130.7, 134.5, 141.6, 168.3, 169. IR: 3252, 2923, 2852,
788, 719 cm–1
.
Compound 4g: Yield 0.0789 g (48%), mp 68 °C. 1H NMR (400
MHz, CDCl3): δ = 2.22 (3 H, s, CH3), 2.32 (3 H, s, CH3), 3.92 (3 H, s,
OCH3), 7.35 (1 H, dd, J = 2.0, 8.5 Hz, ArH), 7.82 (1 H, d, J = 2.0 Hz,
ArH), 8.57 (1 H, d, J = 8.5 Hz, ArH), 10.92 (1 H, br s, NH). 13C NMR
(100 MHz, CDCl3): δ = 0.6, 25.4, 52.2, 114.7, 120.3, 130.8, 131.9,
135.4, 139.2, 168.8, 168.9. IR: 3270, 2922, 2853, 1683, 1594,
1705, 1681, 1590, 1442, 1360, 1261, 1085, 752 cm–1
.
Compound 4c: Yield 0.1571 g (69%). 1H NMR (400 MHz, CDCl3):
δ = 2.23 (3 H, s, CH3), 3.94 (3 H, s, OCH3), 7.48 (1 H, dd, J = 2.6,
9.0 Hz, ArH), 7.99 (1 H, d, J = 2.6 Hz, ArH), 8.69 (1 H, d, J = 9.0 Hz,
ArH), 10.96 (1 H, br s, NH). 13C NMR (100 MHz, CDCl3): δ = 25.4,
52.6, 116, 121.7, 127.4, 130.3, 134.5, 140.1, 169. IR: 3273, 2923,
1455, 1367, 1266, 1087, 838, 790, 722 cm–1
(10) Papadopoulou, M.; Varvoglis, A. J. Chem. Res., Synop. 1983, 66.
.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 763–768