Chlorination of isatins with trichloroisocyanuric acid

Article abstract of DOI:10.1590/S0103-50532011000200010

Isatin and its derivatives have been extensively reported in the literature as having range of potential pharmacological compounds. The Sandmeyer method is the most widely used for isatin synthesis and furnishes different substituted isatins, usually with high yields. Although efficient, the Sandmeyer route has certain limitations, such as the formation of a mixture of regiosiomers and low yields depending on the type and position of the substituent. Thus, overcome these limitations, it is preferable that some derivative isatins be obtained by alternative methods. This article has investigated the chlorination of isatin derivatives using trichloroisocyanuric acid [1,3,5-trichloro- 1,3,5-triazine-2,4,6-(1H,3H,5H)-trione or TCCA] at different reaction conditions.

Full text of DOI:10.1590/S0103-50532011000200010

J. Braz. Chem. Soc., Vol. 22, No. 2, 257-263, 2011.
Printed in Brazil - ©2011 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Article
A
Chlorination of Isatins with Trichloroisocyanuric Acid
Bárbara V. Silva,* Pierre M. Esteves and Angelo C. Pinto
Instituto de Química-CT, Universidade Federal do Rio de Janeiro, Cidade Universitária,
21945-970 Rio de Janeiro-RJ, Brazil
A isatina e seus derivados são conhecidos na literatura por possuírem uma diversidade de
propriedades biológicas. O método de Sandmeyer é o mais utilizado para síntese de diferentes
isatinas substituídas, geralmente com altos rendimentos. Apesar de eficiente, este método
apresenta algumas limitações, tais como a formação de uma mistura de regioisômeros e baixos
rendimentos dependendo do tipo e posição do substituinte presente no material de partida, a
anilina. Para superar estas limitações, é preferível que alguns derivados de isatina sejam obtidos
por métodos alternativos. Este artigo descreve a cloração de derivados da isatina empregando
ácido tricloroisocianúrico [1,3,5-tricloro-1,3,5-triazina-2,4,6-(1H,3H,5H)-triona ou TCCA) em
diferentes condições reacionais.
Isatin and its derivatives have been extensively reported in the literature as having range of
potential pharmacological compounds. The Sandmeyer method is the most widely used for isatin
synthesis and furnishes different substituted isatins, usually with high yields. Although efficient,
the Sandmeyer route has certain limitations, such as the formation of a mixture of regiosiomers and
low yields depending on the type and position of the substituent. Thus, overcome these limitations,
it is preferable that some derivative isatins be obtained by alternative methods. This article has
investigated the chlorination of isatin derivatives using trichloroisocyanuric acid [1,3,5-trichloro-
1,3,5-triazine-2,4,6-(1H,3H,5H)-trione or TCCA] at different reaction conditions.
Keywords: isatin, trichloroisocyanuric acid, chlorination
Introduction
We have recently developed a new, efficient and fast
methodology for the preparation of methoxyisatins in the
presence of Lewis or Brønsted acids catalysts in different
imidazolium based ionic liquids.12
In continuation to our interest in the synthesis of
chloroisatins,wedescribehereinthestudyofthechlorination
of several substituted isatins with trichloroisocyanuric acid
(TCCA).13
Isatin is a natural compound found in plants of the
genus Isatis1 and in mammalian body fluids and tissues.
This compound is distributed throughout the central
nervous system and may be an endogenous modulator of
food intake.2-4
Isatin and its derivatives have been reported to possess
antiviral, antinflammatory, antitumoral, anticonvulsant
and sedative-hypnotic activities,5-8 and can be considered
as versatile buildings blocks for the synthesis of a variety
of pharmacologically active compounds.
The Sandmeyer method is the most common route
to prepare isatins.9 Despite its efficiency this method has
some limitations, such as the formation of a mixture of
regioisomers10 and low yields, depending on the type
and position of the substituent. But it fails whenever the
isonitrosoacetanilides bearing electrodonating groups is
used. In this case ring sulfonation occurs instead.11
Results and Discussion
The aromatic chlorination of the isatin with
trichloroisocyanuric acid (TCCA) using sulfuric acid
as a catalyst, was previously studied,14,15 which showed
the formation of 5-chloroisatin and 5,7-dichloroisatin in
excellent yields. Therefore, we started our investigation
reacting the 5-methylisatin (1), a monosubstituted
derivative, with TCCA in sulfuric acid (H2SO4). In this
condition, we found the formation of polychlorinated
products (Scheme 1), using molar ratio between (1) and
TCCA 1:0.4, 1:1 and 1:1.5.
*e-mail: barbara.iq@gmail.com

258
Chlorination of Isatins with Trichloroisocyanuric Acid
J. Braz. Chem. Soc.
O
O
4
3
H2SO4
TCCA
2
5
6
O
O
N
N
1
7
1
Cl
H
H
Mixture of chlorinated products
Scheme 1. Chlorination of (1) with TCCA in H2SO4.
Thus, we have replaced the H2SO4 by acetic acid
(HOAc) in order to get a milder reaction conditions. The
chlorination of (1), in HOAc, varying time and proportion
isatin:TCCA furnished product N-chlorinated (1a) at
different rates (Table 1).
Table 1. Chlorination of (1) with TCCA in HOAc
O
O
AcOH
TCCA
O
O
N
N
1a
Cl
H
1
entry
Isatin:TCCA Temperature (°C) time (h) GC Conversiona
1
2
3
4
5
6
7
8
9
1:0.5
1:1
25
25
0.5
2
46%
79%
82%
69%
74%
59%
76%
78%
78%
1:2
25
1
1:2
25
2
Figure 1. a) Mass spectra of N-chloro-5-methylisatin (1a); b) Proposal
of fragmentation for the molecular ion of (1a).
1:2
25
6
1:2
80-90
25
1
1:2.5
1:2.5
1:2.5
0.5
1
compound N-chlorinated (0.48) is much higher than the
substrate (0.24) using hexane/ethyl acetate 50% as eluent.
As the literature reported the N-chlorination of
amides, carbamates and lactams with TCCA in acetone or
chloroform,16 we have examined the application of theses
solvents in the chlorination of (1) with molar ratio 1:2
(isatin:TCCA). The conversion in acetone was 84% and
74% in chloroform. These conversions were equivalent to
those obtained with HOAc. Although the conversions are
similar, the procedure using HOAc is simpler and faster,
since the addition of ice to the reaction medium at the end
of the reaction affords a precipitate, which is filtered off.
We have next tested the same reaction in HOAc
with isatin derivatives (Scheme 2 and Table 2) and the
fragmentation standard of the products obtained again
25
25
6
aGas chromatograph equipped with a flame ionization detector.
Approximately 1 μL of sample was injected with a split ratio of 1/20,
column DB-5. Initial temperature was 100 °C at 12°C min-1 until 210 °C
for 10 min. The injector and detector temperature was 280 °C.
As seen in the Table 1, using the proportion TCCA 1:0.5
(entry 1), the conversion was 46%. The decrease of the
molar ratio (entry 2) leads to an increase in the conversion.
To obtain higher conversions, the molar ratio 1:2 was
used, varying the temperature and the reaction time (entries
3-6). These experiments showed that increases in the molar
ratio and time do not influence the conversion rate. However,
higher temperature (entry 6) resulted in lower conversion
compared with the experiment in entry 3. The conversion
does not change significantly with the increase of the molar
ratio isatin:TCCA from 1:1 to 1:2.5 (entries 7-9).
Initially, the aromatic chlorination of (1) in position 7,
using HOAc as catalyst was expected. The analysis of
the mass spectrum of the product (Figure 1) revealed
the occurrence of N-chlorination, rather than aromatic
chlorination.
O
O
R1
R1
TCCA
Solvent
O
O
N
N
R2
R
R2
R
2 R = H, R1 = Br, R2 = H
3 R = H, R1 = NO2, R2 = H
4 R = H, R1 = H, R2 = CF3
5 R = Me, R1 = H, R2 =H
6 R = H, R1 =H, R2 = Me
2a R = Cl, R1 = Br, R2 = H
4b R = H, R1 = Cl, R2 = CF3
5b R = Me, R1 = Cl, R2 = H
6b R = H, R1 = Cl, R2 = Me
The reaction was also monitored by thin layer
chromatography. The retention coefficient (Rf) of the
Scheme 2. Chlorination reaction of isatin derivatives with TCCA in
HOAc or acetone..

Vol. 22, No. 2, 2011
Silva et al.
259
Table 2. Results of chlorination reaction of isatin derivatives with TCCA in HOAc or acetone
entry
Isatin
Isatin:TCCA
1:0.5
1:1
Temperature (°C)
time (h)
Solvent
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
Acetone
Acetone
HOAc
GC Conversiona
1
2
3
4
5
6
7
8
9
10
2
2
2
3
4
4
5
5
5
6
25
25
0.5
5
44%
45%
61%
NR
1:2
25
1
1:2
25
2
1:2
25
2
NR
1:2
80-90
25
1
12%
96%
51%
91%
100%
1: 2
2
1:0.5
1: 2
25
2
25
2
1:1
25
1
aSame conditions shown in the footnote of Table 1; NR: no reaction.
showed the N-chlorination for isatin (2). Nitroisatin with the
nitro group at position 5 (3) did not react. The deactivated
isatin 4 reacted at higher temperature (80-90 °C), but
with low conversion. The fragmentation standard of (4b)
revealed chlorination occurs at the aromatic ring. On the
other hand N-methylisatin (5) and 7-methylisatin (6) gave
excellent conversions (entries 7-10) at room temperature.
The fragmentation proposal of the product (4b) and
(5b) is showed in Scheme 3.
chlorination agent was 7% sodium hypochlorite (NaClO).
This reagent was described as a new convenient oxidant.
Whenever the isatin derivative presents a NH bond
without substituent in position 7, the N-chlorination is
favored (entries 1-3). The experiments carried out with the
N-methylisatin (5) and 7-methylisatin (6) (entries 7-10)
suggested that the use of acids promotes ring chlorination
of isatin. Previous works showed that superelectrophiles
could be involved in such processes.15
The first report of N-chlorination of isatins was done
by Berti and Greci.17 They also used HOAc, but the
In order to better understand the chlorination process of
isatins with TCCA, we have carried out DFT calculations,
at M06-2x/6-311++G(d,p) level, for the chlorination of
parent isatin by TCCA (see supporting information for
computational details). Figure 2 shows the computed van
der Waals complex between TCCA and isatin.
a)
.+
.
.+
.
O
O
.+
.
Cl
C
O
Cl
Cl
- CO
O
NH
Despite the original configuration the outcome of the
optimization of the geometry leads to a complex involving
N
NH
H
CF3
CF3
m/z 249
CF3
m/z 221
m/z 221
-HCN
Cl
Cl
+
+
-CO
C=O
F3C
F3C
m/z 194
m/z 166
b)
.+
.
O
.+
.
O
-CO
Cl
O
Cl
NMe
N
Me
m/z 195
m/z 167
.+
.
O
.+
.
C
-CO
Cl
m/z 139
NMe
Cl
NMe
m/z 167
Figure 2. Optimized geometries for isatin TCCA and a complex between
Scheme 3. Fragmentation proposal of (4b) (a) and (5b) (b).
them, calculated at M06-2X/6-311++G(d,p).

260
Chlorination of Isatins with Trichloroisocyanuric Acid
J. Braz. Chem. Soc.
Figure 3. Optimized geometries for the intermediates formed from the attack of Cl+ of isatin, calculated at M06-2X/6-311++G(d,p).
the N-H and the carbonyl group of the isatin. This complex
is 2.4 kcal mol-1 more stable in relation to the separated
isatin and TCCA. The amide carbonyl group pointing
into the TCCA ring indicates that this complex can be a
donor-acceptor complex. Thus, this preliminary complex
can lead to the preferred formation of the N-chloroisatin.
For this purpose we have computed the relative stability of
the several intermediates formed through the electrophilic
addition of Cl+ to isatin. Figure 3 presents these structures,
with their relative energies.
It can be seen from the calculations that the most stable
intermediate is C. The N-chlorination of the isatin leads to
intermediate A, which is 23.4 kcal mol-1 higher in energy
than C. This indicates that the N-chlorination should be a
kinetically driven process. Considering that the relative
stability of the arenium ions reflect the relative stability
in the transition state prior to them, it can be seen that the
pattern for the ring substitution is followed, i.e., ortho-para
substituion in relation to the nitrogenated substituent.
Because of the possibility of involvement of
superelectrophiles in the process when the reaction takes
place at more acid solvents, we decided to go back to our
investigations for the chlorination of some isatin derivatives
in concentrated H2SO4. The results are showed in Table 3.
When the isatins reacts in the presence of H2SO4 the
aromatic ring chlorination always occurs. Conversely, in
HOAc, the N-chlorination takes place. In order to explain
this result, we proceeded to the following experiment: (1a),
the 5-methyl-N-chloroisatin obtained from the reaction
of 5-methylisatin (1) in HOAc, was treated with H2SO4
concentrated and stirred at room temperature for 4 h. After
this period, ice was added to the reaction medium and the
solid precipitate was filtered under vacuum and analyzed
by gas chromatography mass spectrometry (GC-MS). The
chromatogram and mass spectrum showed that under this
condition, the reaction furnished a mixture of mono and
dichlorinated products in the aromatic ring.
Therefore, we conclude that the N-chlorinated product
should be formed as an intermediate for the reaction of
chlorination in the aromatic ring. Once the acetic acid
is not acid enough for lead to further protonate this
chlorinated intermediate, the transfer of “Cl+” probably
becomes difficult. Further evidence that the N-chlorinated
isatin is actually a reaction intermediate is the tendency
of the N-chloroisatins have of turning, in a few days, into
their respective parent isatins. In order to confirm the
formation of N-chlorinated compound and its reactivity
toward other nucleophiles, an experiment of chlorination
of anisole was performed, using isatin (1a) in HOAc.
The products were analyzed by GC-MS and showed the
formation of mono and dichlorinated methoxybenzene
and isatin (1).
The halogens Br and F are weak electron withdrawing
groups. Thus, the isatin (2) and (7) had their aromatic rings
(entries 2 and 4) chlorinated only at position 7 with molar
ratio isatin:TCCA 1:1.
The trifluoromethyl group strongly deactivates the
aromatic ring for electrophilic substitution aromatic and
no product was formed in an attempt to chlorination isatin
(4) at room temperature (entry 3).

Vol. 22, No. 2, 2011
Silva et al.
261
Table 3. Chlorination of isatin derivatives with TCCA in concentrated H2SO4 at room temperature
entry
1
Isatin
Isatin: TCCA
1:0.4
time (h)
Product/yields or conversion (%)a
O
Cl
O
6
1
N
6b
H
74%
O
Br
O
2
3
4
2
4
1:1
1:1
1:1
4
48
2
N
2b
Cl
H
77%
NR
O
O
F
F
O
O
N
N
7b
Cl
H
7
H
60%
Cl
Br
Cl
O
O
MeO
+
MeO
Br
O
O
N
N
Br
Br
Cl
or
H
O
H
8bb
MeO
Br
73%
O
5
1:1
2
Br
N
O
MeO
8
H
O
N
Cl
Cl
H
8cb
24%
O
O
Cl
I
O
O
N
6
1:1
2
N
H
Cl
H
9
9
9b
61%
O
O
I
Cl
O
+
O
N
7
8
9
1:0.4
1:0.4
1:0.4
20
24
4
N
9cb
H
Cl
9bb
H
59%
Cl
40%
O
Br
O
NR
N
Br
H
10
Br
Br
O
O
Br
Cl
O
Cl
Br
O
+
O
O
N
N
H
Br
N
Br
H
Cl
2%
11cb
H
11bb
11
98%
aGC-MS conversion; bchromatographic yields; NR: no reaction.

262
Chlorination of Isatins with Trichloroisocyanuric Acid
J. Braz. Chem. Soc.
Cl
O
Cl
Br
O
MeO
Br
MeO
Br
+
O
O
O
Br
"Cl+"
or
N
N
O
MeO
Br
H
H
Br
O
Br
+
O
O
N
MeO
Cl
MeO
Br
"Cl+"
8
O
H
N
N
Cl
H
H
O
O
N
O
Cl
Cl
"Cl+"
I
I
+
O
O
O
N
N
H
H
9
H
Scheme 4. Mechanism of ipso substitution for isatin (8) and (9).
Ipso substitution on the aromatic ring was observed in
isatins (8) and (9) (entries 5-7) (Scheme 4). Reaction with
isatin (8) resulted in mixture of products. The product (8b)
was expected (substitution at position 7) and product (8c)
resulted from the ipso substitution at position 4 or 6.
Isatin (9) suffered cleavage of C–I bond furnishing
product (9b), substituted in positions 5 and 7, when the
molar ratio isatin:TCCA was 1:1. Mixture of products was
obtained when the molar ratio was decreased to 1:0.4. In this
case an ipso substitution also occurs providing the product
(9b) and a common electrophilic aromatic substituition
conducted to new product (9c) in 59% conversion.
Since we found that the substitution at the ipso position
competes with the unsubstituted positions when the isatin
has a bromine atom, we have investigated the same reaction
with isatins (10) and (11) (entries 8 e 9). We could not detect
products coming from ipso substitution in such cases. Isatin
(10) did not react and isatin (11) resulted in substitution at
positions 5 and 7, as expected.
was competition for ipso substitution. The proposed
methodology furnished the new pure compound (2b) and
mixture of products also not previously reported in the
literature, (8b), (8c), (9c), (11b) and (11c). The substances
already reported (6b) and (7b) were obtained pure. Thus,
we have shown that TCCA, a non toxic and inexpensive
reagent, is an interesting alternative for the preparation of
chlorinated isatins.
Supplementary Information
Supplementary information associated with this paper
contains the spectroscopic data, NMR spectra (1H and 13C),
mass spectrum and infrared of the synthesized compounds.
These data are available free of charge at http://jbcs.sbq.
org.br, as a PDF file.
Acknowledgments
The electron donating methoxy group in isatin (8) is
probably, essential for the ipso substitution. For the isatin
(9), the substitution at ipso position can be explained in
terms of the high lability of the C-I bond.
The authors thank the Brazilian agencies Conselho
Nacional de Desenvolvimento Científico e Tecnológico
(CNPq) and Fundação de Amparo à Pesquisa do Estado
do Rio de Janeiro (FAPERJ).
Conclusions
References
In conclusion, we performed a study on the behavior
of substituted isatins in H2SO4 and HOAc with TCCA.
In HOAc we found that the formation of N-chlorinated
products occurs at different reaction conditions since
the isatin nitrogen has not replaced by a methyl group
or a substituent in position 7. In H2SO4 always occurs
the chlorination of the aromatic ring. The methyl group
in position 5 strongly activates the aromatic ring,
resulting in a mixture of chlorinated products when the
substrate is 5-methylisatin (1). Isatins with substituents
electron withdrawing yield 1 product, except when there
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Submitted: June 5, 2010
Published online: September 21, 2010

J. Braz. Chem. Soc., Vol. 22, No. 2, S1-S20, 2011.
Printed in Brazil - ©2011 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Supplementary Information
SI
Chlorination of Isatins with Trichloroisocyanuric Acid
Bárbara V. Silva,* Pierre M. Esteves and Angelo C. Pinto
Instituto de Química-CT, Universidade Federal do Rio de Janeiro, Cidade Universitária,
21945-970 Rio de Janeiro-RJ, Brazil
Synthesis and characterization of the chloroisatins
Computational details
Typical procedure for the reaction in HOAc
All calculations were carried out with the Gaussian
09 package1 using the M06-2X functional with the
6-311++G** basis set. The optimized geometries were
characterized as minima on the potential energy surface
by the absence of imaginary vibrational frequencies. All
energy differences correspond to enthalpies differences at
298K and 1 atm.
To a suspension of TCCA and HOAc the isatin
derivative was added. The reaction medium was kept
stirring at different temperatures and times (Tables 1
and 2). The mixture was then poured over cracked ice.
The precipitate was filtered under vacuum and washed
thoroughly with water. Subsequently, the product was
solubilized in ethyl acetate, filtered and the solution
evaporated at reduced pressure to separate the isocyanuric
acid formed as byproduct.
Spectroscopic data
1a: IR (film) νmax/cm-1: 3085, 2923, 1764, 1729, 1614,
1596, 1483, 1315, 1294, 1176, 1126, 950, 427. 1H NMR
d (200 MHz, CDCl3): 3.23 (3H, s), 6.85 (1H, d, J 8.0 Hz),
7.51-7.57 (2H, m); 13C NMR d (50 MHz, CDCl3): 26.5
(CH3), 111.4 (CH), 118.3 (q), 125.2 (CH), 129.7 (q), 137.9
(CH), 149.8 (q), 157.8 (q), 182.4 (q); MS (70 eV) m/z 195
[M]+, 197 [M+2]+, 160, 104.
Typical procedure for the reaction in H2SO4
To a suspension of TCCA and H2SO4 was added the
isatin derivative in an ice bath. After the complete addition
of the isatin, the ice bath was removed, and the mixture
was kept stirring during the time described in Table 3. The
mixture was then poured over cracked ice. The precipitate
was filtered under vacuum and washed thoroughly with
water. Subsequently, the product was solubilized in ethyl
acetate, filtered and the solution evaporated at reduced
pressure to separate the isocyanuric acid formed as
byproduct. The products (9b) and (9c) were separated by
high performance liquid chromatography (HPLC) and
analyzed separately by 1H and 13C NMR.
2a: IR (film) νmax/cm-1: 3060, 1770, 1743, 1606, 1456,
1423, 1307, 1270, 1178, 1160, 827, 717, 466. 1HNMRd(200
MHz, CDCl3): 7.07 (1H, d, J 8.0 Hz), 7.71 (1H, d, J 2.0 Hz),
7.81 (1H, dd, J 2.0 and 8.0 Hz); 13C NMR d (50 MHz,
CDCl3): 113.0 (CH), 118.0 (q), 120.5 (q), 127.9 (CH), 141.2
1. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Scalmani, G.; Barone,V.; Mennucci, B.; Petersson,
G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A.
F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota,
K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda,Y.; Kitao,
O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.; Peralta, J. E.; Ogliaro,
F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V.
N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant,
J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.;
Klene, M.; Knox, J. E.; 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.; Martin, R. L.; Morokuma, K.; Zakrzewski,
V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels,
A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D.
J.; Gaussian 03, Revision C.02, Gaussian, Inc.: Wallingford CT, 2004.
Separation by HPLC
Separation by HPLC of (9b) and (9c) was performed on
Agilent 1100 series chromatograph detection by ultraviolet
(UV, λmax/nm 280). Semi-preparative method in a reversed
phase column C-18 (Agilent Zorbax Eclipse, 9.4 mm
(diameter) × 250 mm (length), 5 micron) under isocratic
conditions using 45% water and 55% methanol as mobile
phase, flow 3 mL/min, with 30 min elution was employed.
*e-mail: barbara.iq@gmail.com

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(CH), 148.0 (q), 154.7 (q), 176.8 (q), 182.4 (q); MS (70 eV)
7b: IR (film) νmax/cm-1: 3488, 3473, 3180, 3114, 1743,
1754, 1621, 1600, 1479, 1299, 1211, 1099, 925, 867,
796; 1H NMR d (200 MHz, CDCl3+DMSO): 6.92 (1H, d
J 7.0 Hz), 7.04 (1H, d J 7.0 Hz), 11.04 (1H, br s, NH); 13C
NMR d(50 MHz, CDCl3+DMSO): 110.1 (CH, d J 27 Hz),
117.7 (q, d J 7.0 Hz), 118.6 (q, d, J 7.0 Hz) 124.4 (CH, d,
J 27 Hz), 144.3 (q, d, J 2.5 Hz), 157.7 (q, d, J 246.5 Hz),
158.9 (q), 182.8 (q, d J 2.5 Hz). MS (70 eV) m/z 199 [M]+,
201 [M+2]+, 171, 143.
m/z 259 [M]+, 261, [M+2]+, 263 [M+3]+, 168, 226.
2b: IR (film) νmax/cm-1: 3471, 3174, 3110, 1754, 1610,
1457, 1425, 1290, 1224, 1168, 837; 1H NMR d(200 MHz,
CDCl3+DMSO): 7.47 (1H, s), 7.58 (1H, s), 11.43 (1H, br
s, NH); 13C NMR d (50 MHz, CDCl3+DMSO): 114.8 (q),
118.2 (q), 119.5 (q), 125.5 (CH), 139.1 (CH), 146.8 (q),
158.3 (q), 182.1 (q); MS (70 eV) m/z 259 [M]+, 261, [M+2]+,
263 [M+3]+, 233, 205.
9c: IR (film) νmax/cm-1: 3193, 3182, 3099, 1770, 1745,
5b: IR (film) νmax/cm-1: 3467, 3423, 1751, 1727, 1608,
1457, 1467, 1326, 1176, 1108, 827; 1H NMR d (200 MHz,
CDCl3+DMSO): 3.16 (3H, s), 6.89 (1H, d, J 8.0 Hz),
7.43 (1H, s), 7.52 (1H, d, J 8.0 Hz), 11.43 (1H, br s, NH);
13C NMR d (50 MHz, CDCl3+DMSO): 25.4 (CH3), 116.6
(CH), 123.1 (q), 129.5 (CH), 134.0 (q), 142.6 (CH), 154.6
(q), 162.6 (q), 187.3 (q); MS (70 eV) m/z 195 [M]+, 197
[M+2]+, 167, 139.
1610, 1450, 1164, 983, 688; H NMR d (200 MHz,
1
CDCl3+DMSO): 7.71 (1H, d J 1.5 Hz), 7.77 (1H, d
J 1.5 Hz), 10.78 (1H, br s, NH); 13C NMR d (50 MHz,
CDCl3+DMSO): 84.79 (q), 118.97 (q), 120.36 (q), 132.03
(CH), 145.34 (CH), 147.48 (q), 158.23 (q), 182.14 (q); MS
(70 eV) m/z 307 [M]+, 309 [M+2]+, 279, 251.
11b: IR (film) νmax/cm-1: 3479, 3465, 3268, 3087,
1
1766, 1791, 1594, 1558, 1388, 1247, 958; H NMR d
6b: IR (film) νmax/cm-1: 3452, 3415, 3178, 3102,
(200 MHz, CDCl3+DMSO): 6.29 (1H, s), 10.40 (1H, br s,
NH); 13C NMR d (50 MHz, CDCl3+DMSO): 114.3 (CH),
118.7 (q), 126.3 (q), 127.8 (q), 129.5 (q), 148.6 (q), 156.4
(q), 178.5 (q); MS (70 eV) m/z 337 [M]+, 339 [M+2]+, 341
[M+3]+, 343 [M+4]+, 311, 284, 204.
1
1743, 1616, 1469, 1297, 889, 700; H NMR d (200
MHz, CDCl3+DMSO): 2.15 (3H, s), 7.20 (1H, br s), 7.27
(1H, br s), 11.13 (1H, br s, NH); 13C NMR d (50 MHz,
CDCl3+DMSO): 14.2 (CH3), 117.0 (q), 120.3 (CH), 122.8
(q), 126.3 (CH), 137.2 (CH), 146.9 (q), 158.3 (q), 182.6
(q); MS (70 eV) m/z 195 [M]+, 197 [M+2]+, 167, 139, 104.
1H and 13C NMR spectra
Figure S1. 1H NMR of 1a.

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Figure S2. 13C NMR of 1a.
Figure S3. 1H NMR of 2a.

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Figure S4. 13C NMR of 2a.
Figure S5. 1H NMR of 2b.

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Figure S6. 13C NMR of 2b.
Figure S7. 1H NMR of 5b.

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Figure S8. 13C NMR of 5b.
Figure S9. 1H NMR of 6b.

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Figure S10. 13C NMR of 6b.
Figure S11. 1H NMR of 7b.

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Chlorination of Isatins with Trichloroisocyanuric Acid
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Figure S12. 13C NMR of 7b.
Figure S13. 1H NMR of 9c.

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Figure S14. 13C NMR of 9c.
Figure S15. 1H NMR of 11b (mixture with 11c).

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Chlorination of Isatins with Trichloroisocyanuric Acid
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Figure S16. 13C NMR of 11b.
FTIR spectra
Figure S17. FTIR spectra of 1a.

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Figure S18. FTIR spectra of 2a.
Figure S19. FTIR spectra of 2b.

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Figure S20. FTIR spectra of 5b.
Figure S21. FTIR spectra of 6b.

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Figure S22. FTIR spectra of 7b.
Figure S23. FTIR spectra of 9c.

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Figure S24. FTIR spectra of 11b.
Mass Spectra
Figure S25. Mass spectrum of 1a.

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Figure S26. Mass spectrum of 2a.
Figure S27. Mass spectrum of 2b.

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Figure S28. Mass spectrum of 4b.
Figure S29. Mass spectrum of 5b.

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Figure S30. Mass spectrum of 6b.
Figure S31. Mass spectrum of 7b.

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Chlorination of Isatins with Trichloroisocyanuric Acid
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Figure S32. Mass spectrum of 8b.
Figure S33. Mass spectrum of 8c.

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Figure S34. Mass spectrum of 9b.
Figure S35. Mass spectrum of 9c.

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Chlorination of Isatins with Trichloroisocyanuric Acid
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Figure S36. Mass spectrum of 11b.
Figure S37. Mass spectrum of 11c.