A concise and regioselective synthesis of 6-iodo-4-trifluoromethylisatin, an intermediate in the synthesis of the novel, non-peptidyl growth hormone secretagogue SM-130686

Article abstract of DOI:10.1016/S0040-4020(02)00300-9

The synthesis of 6-iodo-4-trifluoromethylisatin, an intermediate in the synthesis of the growth hormone secretagogue SM-130686, is disclosed. The synthesis is achieved in seven steps, with an overall yield of 32%, and requires a single recrystallisation as the only purification step. 2-Methyl-3-nitrobenzotrifluoride was converted to (4-iodo-6-nitro-2-trifluoromethylphenyl)acetic acid via iodination, condensation with dimethyloxalate and oxidative decarboxylation. Subsequent esterification followed by reductive cyclisation gave 6-iodo-4-trifluoromethyloxindole. Oxindole 3,3-dibromination followed by hydrolysis gave 6-iodo-4-trifluoromethylisatin.

Full text of DOI:10.1016/S0040-4020(02)00300-9

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 3605±3611
A concise and regioselective synthesis of
6-iodo-4-tri¯uoromethylisatin, an intermediate in the synthesis of
the novel, non-peptidyl growth hormone secretagogue SM-130686
W. Ewan Hume, Teruhisa Tokunaga and Ryu Nagatap
Sumitomo Pharmaceuticals Research Center, 1-98 Kasugade Naka-3-chome, Konohana-ku, Osaka 554-0022, Japan
Received 25 December 2001; accepted 8 March 2002
AbstractÐThe synthesis of 6-iodo-4-tri¯uoromethylisatin, an intermediate in the synthesis of the growth hormone secretagogue
SM-130686, is disclosed. The synthesis is achieved in seven steps, with an overall yield of 32%, and requires a single recrystallisation as
the only puri®cation step. 2-Methyl-3-nitrobenzotri¯uoride was converted to (4-iodo-6-nitro-2-tri¯uoromethylphenyl)acetic acid via iodi-
nation, condensation with dimethyloxalate and oxidative decarboxylation. Subsequent esteri®cation followed by reductive cyclisation gave
6-iodo-4-tri¯uoromethyloxindole. Oxindole 3,3-dibromination followed by hydrolysis gave 6-iodo-4-tri¯uoromethylisatin. q 2002 Elsevier
Science Ltd. All rights reserved.
1. Introduction
SM-130686. We therefore set about to improve our initial
synthesis of 6-iodo-4-tri¯uoromethylisatin (2), the key
intermediate in the synthesis of SM-130686. Our previous
synthesis of 2 was not amenable to scale up as it was
unregioselective and required several chromatographic
puri®cation steps. An improved synthesis of 2 would also
allow us to conduct a more detailed investigation into the
structure±activity relationships (SARs) at C3 and C6 as
substituents at these positions exert profound in¯uence
over the pharmacological activity (3, Scheme 1). In this
paper we wish to disclose our improved synthesis of 2.8
Growth hormone (GH) is a hormone released from the
somatotroph cells of the anterior pituitary gland under the
action of the hypothalamic hormone growth hormone
releasing hormone (GHRH) (also known as growth hor-
mone releasing factor (GRF)).1 De®ciency in GH, which
can result in conditions such as pituitary dwar®sm, can be
treated by subcutaneous administration of recombinant
human GH.2 Recently it has been found that GH can also
be released under a different mechanism, involving the acti-
vation of growth hormone secretagogue (GHS) receptors.3
Researchers at Merck synthesised MK-677, which is an
orally active, small peptidyl GHS receptor agonist and
induces GH release in rats and humans.4 We therefore
initiated a program to ®nd a novel, orally active GHS
receptor agonist to be possibly used in the treatment of
conditions resulting in GH de®ciency, and this culminated
in the discovery of the non-peptidyl oxindole derivative
SM-130686.5 Pharmacological evaluation of SM-130686
showed that it released GH from rat pituitary cells, with
an EC50ˆ6.3 nM, and displaced [35S] MK-677 binding to
the GHS receptor, transiently expressed in Chinese Hamster
Ovary cells, with an IC50ˆ1.2 nM.6 Compared to other
synthetic GHS agonists so far reported,7 SM-130686 is
structurally unique. For further toxicological and pharmaco-
kinetic studies we required multi-ten gram quantities of
During preliminary investigations into the structure±
activity relationships of the oxindole class of GHS,
SM-130686 was synthesised from 1 by an optical resolution
using preparative HPLC, with a chiral stationary phase,
followed by palladium(0) catalysed nitrile formation and
hydrolysis.5 We synthesised 1 from 2 in two steps, by ®rst
N-alkylation and subsequent reaction of the N-alkylated
isatin with (2-chlorophenyl)magnesium bromide. Our syn-
thesis of 2 involved the reaction of 3-iodo-5-nitrobenzo-
tri¯uoride with ethyl (methylthio)acetate and sulphuryl
chloride, followed by oxidation of the resulting regio-
isomeric 3-methylthiooxindoles.9 This resulted in the
formation of a 1:1 inseparable mixture of regioisomeric
isatins that could only be separated by column chroma-
tography after subsequent N-alkylation. Once we identi®ed
that the 6-carbamoyl and 4-tri¯uoromethyl substituents of
the oxindole were optimal, we synthesized the isatin in a
regioselective manner.10 We wanted a route that would
allow a degree of ¯exibility so as to allow further SAR
studies, thus it was decided that a 6-iodo substituent
would in fact be best. Standard chemistry could then be
Keywords: isatin; regioselective synthesis; growth hormone secretagogue;
SM-130686.
Corresponding author. Tel.: 181-6-6466-5193; fax: 181-6-6466-5483;
e-mail: rnagata@sumitomopharm.co.jp
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00300-9

3606
W. E. Hume et al. / Tetrahedron 58 (2002) 3605±3611
Scheme 1.
used to convert the 6-iodo into a carbamoyl substituent, or
a variety of other substituents. The initial route that we
chose comprised a regioselective synthesis of 6-iodo-4-
tri¯uoromethylindole (4) followed by its oxidation to 2
(Scheme 1). Use of a substituted ortho nitrotoluene would
allow the synthesis of a single indole regioisomer, hence
single isatin regioisomer, by correct choice of synthetic
method.
Scheme 2.

W. E. Hume et al. / Tetrahedron 58 (2002) 3605±3611
3607
Scheme 3.
2. Results and discussion
oxalate and sodium methoxide,18 in methanol, gave methyl
pyruvate 10 (Scheme 3). Oxidative decarboxylation of 10 to
give acetic acid 12 required an initial ester hydrolysis18
which unfortunately, under basic conditions, brought about
a retro-condensation reaction and recovered 6 was obtained
in 57% yield along with the desired pyruvic acid 11 (38%).
The possibility of carrying out a one-pot reaction, without
isolating 11 was investigated using various combinations of
30% hydrogen peroxide and bases, but retro-condensation
still occurred. Examination of the hydrolysis under acidic
conditions was then studied. Using 70% perchloric acid, 10
quantitively gave pyruvic acid 11, no other product was
Iodination of commercially available 2-methyl-3-nitro-
benzotri¯uoride11 (7) with N-iodosuccinimde, in 96% sul-
phuric acid,12 gave 5-iodo-2-methyl-3-nitrobenzotri¯uoride
(6) which was reacted with tris(dimethylamino)methane,13
in DMF at 608C, to give enamine 8 (Scheme 2). Nitro group
reduction using buffered aqueous titanium(III) chloride,
with concomitant hydrolysis of the enamine,14 gave 4.
Finally, indole bromination15 gave 3,3-dibromooxindole 9,
which was hydrolysed16 to give 2. Unfortunately, this route
suffered from two drawbacks that precluded its use in a
larger scale synthesis. Firstly it required the use of
the expensive tris(dimethylamino)methane17 and secondly
by-products arose from the indole bromination reaction15
and these made the puri®cation of the isatin dif®cult.
1
observed in the H NMR spectrum of the crude reaction
mixture (Scheme 3).
Owing to the lack of retro-condensation, a one-pot oxi-
dative-decarboxylation was investigated.19 At 508C, using
9.5 equiv. of 70% perchloric acid and 11 equivalents of
aqueous 30% hydrogen peroxide, in acetic acid, 12 was
obtained, along with a small amount of 11, but increasing
the amount of hydrogen peroxide to 16 equiv. suppressed
the formation of 11. Increasing the amount of hydrogen
peroxide still further, to 22 equiv., enhanced the conversion
We then investigated a second route to 2, via 6-iodo-4-
tri¯uoromethyloxindole (5, Scheme 1). Use of a suitably
substituted arene as in the previous route would permit the
formation of a single oxindole regioisomer. Fortunately we
were able to use the same intermediate 6 as that used in the
previous synthesis. Thus, reaction of 6 with excess dimethyl-
Scheme 4.

3608
W. E. Hume et al. / Tetrahedron 58 (2002) 3605±3611
Scheme 5.
of 10 to 12, from 89 to 94%. It should be noted that these
reactions were carried out on crude 10 and as such the
sample contained unreacted dimethyloxalate from the
previous step, thus probably accounting for the large
amount of hydrogen peroxide required for this transfor-
mation (Scheme 4). Esteri®cation of 12, using 10% hydro-
gen chloride in methanol, gave methyl ester 13. Aqueous
20% titanium(III) chloride reduction of the nitro group of
13 gave 5 as a crystalline solid, in 69% yield from 12.
Bromination of 5 gave 3,3-dibromide 9 which was subse-
quently hydrolysed to give isatin 2 in 95% yield from 5.
used without puri®cation. Thin-layer chromatography and
¯ash column chromatography were performed on silica
gel glass backed plates (5719, Merck) and silica gel 60
(230±400 or 70±230 mesh, Merck), respectively. Melting
points were recorded on a Thomas Hoover capillary melting
point apparatus and are uncorrected. IR spectra were
recorded on a Perkin±Elmer model 1640 FT-IR spectro-
1
meter using KBr discs. H NMR spectra were recorded at
270 MHz on a Jeol GX-270 spectrometer and 13C NMR
spectra were recorded at 100 MHz on a Bruker AVANCE
400 spectrometer in choroform-d or dimethylsulfoxide-d6 as
solvents. All chemical shifts are quoted in parts per million
relative to tetramethylsilane (d 0.00 ppm) and coupling
constants are measured in Hertz. The low-resolution
mass spectroscopy, high resolution mass spectroscopy
and elemental analyses were carried out by Sumitomo
Analytical Centre, Inc.
This improved synthetic route to isatin 2 was then followed
using 50.0 g of 2-methyl-3-nitrobenzotri¯uoride (7). This
gave 20.8 g of 2 in 32% overall yield and .99% purity, in
seven steps. Puri®cation of 5 was carried out by recrystalli-
sation, which accounts for the only puri®cation step that is
required in the entire synthetic route.
4.1.1. 5-Iodo-2-methyl-3-nitrobenzotri¯uoride (6). To
H2SO4 (220 ml, 96%) stirring under a nitrogen atmosphere
at 0±58C was added N-iodosuccinimide (82.27 g, 365.6
mmol) portionwise. The resulting dark red coloured mixture
was stirred at 0±58C for 40 min, after which time 2-methyl-
3-nitrobenzotri¯uoride (5, 50.0 g, 243.8 mmol), in H2SO4
(150 ml, 96%), was added dropwise over ca. 1 h. The
solution was stirred at 5±108C for 5 h and warmed slowly
to room temperature over 16 h. The resulting solution was
poured carefully into ice (ca. 2 kg) and extracted with
EtOAc (800 ml, 2£500 ml). The extracts were combined,
washed with saturated aqueous sodium hydrogensulphite
(2£500 ml) and H2O (500 ml). The organic phase was
then dried over anhydrous MgSO4. After ®ltration, the
solvent was removed in vacuo to give crude 6 (83.68 g) as
a light yellow oil which solidi®ed on standing. The crude
product was used for the preparation of 10 without puri®-
cation, however for characterisation purposes a small amount
was puri®ed by ¯ash column chromatography, hexane as
eluent, to give an analytically pure sample as a white solid;
mp 37±37.58C; IR (KBr) 3112, 3073, 1534, 1367, 1306,
As our synthesis of 2 was improved, this allowed us to
further investigate the SARs, in particular the SAR at
C3 (structure 3, Scheme 1). Thus, alkylation of 2 with
2-(diethylamino)ethyl chloride hydrochloride gave 14
which was then reacted with various lithiated hetero-
aromatic compounds (e.g. 2-lithiopyridine, 2-lithiothio-
phene). Transformation of the iodo substituent into a
carbamoyl was carried out by ®rst palladium(0) catalysed
nitrile formation followed by hydrolysis, which gave 15
(Scheme 5). Unfortunately compounds 15 exhibited much
weaker biological activities than racemic SM-130686.
Detailed results of the SAR at C3 will be published elsewhere.
3. Conclusion
We have presented our syntheses of 6-iodo-4-tri¯uoro-
methylisatin (2). Our preliminary synthesis was unregio-
selective,5 however the synthetic route was improved to a
regioselective one, through initially intermediate 4 and
subsequently intermediate 5. This new synthesis required
no chromatographic puri®cation and was accomplished in
seven steps from commercially available 2-methyl-3-nitro-
benzotri¯uoride (7).
1171, 1126, 1093, 884, 699 cm21 1H NMR (270 MHz,
;
CDCl3) d 8.19 (d, 1H, Jˆ1.3 Hz), 8.14 (d, 1H, Jˆ1.3 Hz),
2.49 (3H, s); 13C NMR (100 MHz, CDCl3) d 152.3, 138.3 (q,
2
3JCFˆ5.9 Hz), 135.6, 132.9 (q, JCFˆ30.8 Hz), 130.9, 122.2
4
(q, 1JCFˆ275.1Hz), 89.3, 14.6 (q, JCFˆ2.8 Hz); MS (EI) m/z
331(M 1, 34%), 314 (68), 286 (15), 158 (22), 18 (100);
Analysis calculated for C8H5F3INO2: C, 29.03; H, 1.52; N,
4.23. Found: C, 29.03; H, 1.72; N, 4.05.
4. Experimental
4.1. General
4.1.2. trans-2-(b-(Dimethylamino)vinyl)-5-iodo-3-nitro-
benzotri¯uoride (8). 5-Iodo-2-methyl-3-nitrobenzotri¯uoride
All reagents and solvents were obtained commercially and

W. E. Hume et al. / Tetrahedron 58 (2002) 3605±3611
3609
(6, 29.06 g, 87.8 mmol) was dissolved in anhydrous DMF
(170 ml) and tris(dimethylamino)methane (19.13 g, 131.7
mmol) was added. The resulting dark solution was heated
at 608C (bath temperature) for 5 h, under a nitrogen atmos-
phere. The solution was cooled and the solvent removed
in vacuo to give crude 8 as a red oil, which solidi®ed on
standing. The crude product was used directly for the
preparation of 4, however for characterisation purposes a
small amount was puri®ed by crystallisation from hexane
to give analytically pure 8 as an amorphous orange solid;
mp 112±1138C (with decomposition); IR (KBr) 3468, 2906,
1634, 1588, 1525, 1461, 1385, 1301, 1268, 1178, 1131,
chromatography, hexane/EtOAc 5:1as eluent, to give
an analytically pure sample as a grey solid; mp 160±
1628C (with decomposition); IR (KBr) 3129, 1722,
1603, 1436, 1388, 1316, 1290, 1209, 1179, 1144,
1133, 956, 889, 861, 814, 702, 673, 653 cm21
;
1H
NMR (270 MHz, DMSO-d6) d 11.73 (brs, 1H), 7.78
13
(s, 1 H), 7.56 (s, 1 H); C NMR (100 MHz, DMSO-d6)
3
2
d 170.3, 141.6, 129.5 (q, JCFˆ5.0 Hz), 127.4 (q, JCFˆ
1
33.8 Hz), 126.7, 124.2, 122.6 (q, JCFˆ275.2 Hz), 99.6,
43.1; HRMS calcd for C9H4Br2F3INO (MH1) 483.7656.
Found 483.7661.
1
1101, 960, 880, 783 cm21; H NMR (270 MHz, CDCl3) d
b. 6-Iodo-4-tri¯uoromethylisatin (2)
7.95 (d, 1H, Jˆ2.0 Hz), 7.85 (d, 1H, Jˆ2.0 Hz), 6.39 (d, 1H,
Jˆ13.0 Hz), 5.04 (d, 1H, Jˆ13.0 Hz), 2.83 (s, 6H); 13C
The above prepared crude 3,3-dibromo-6-iodo-4-tri¯uoro-
methyloxindole (9, 20.94 g, 43.2 mmol) was dissolved in
MeOH/H2O (4:1, 1000 ml) and the mixture was then heated
at re¯ux for 24 h. The solution was cooled and the MeOH
removed in vacuo to give a brown solid. The solid was
collected by ®ltration, washed with copious amounts of
H2O and dried in vacuo to give crude 2 as a brown solid.
Puri®cation was carried out by ¯ash column chroma-
tography, hexane/EtOAc 5:1as eluent, to give 2 (16.26 g,
65% from 4) as a brown solid; mp 223±224.58C (with
decomposition); IR (KBr) 3315, 3265, 1775, 1744, 1598,
1417, 1352, 1303, 1270, 1181, 1139, 1077, 926, 882, 871,
3
NMR (100 MHz, CDCl3) d 150.3, 145.8, 137.7 (q, JCFˆ
2
6.1 Hz), 135.3, 132.6, 130.0 (q, JCFˆ29.8 Hz), 122.9 (q,
1JCFˆ274.5 Hz), 85.2, 40.6; MS (EI) m/z 386 (M1, 100%),
369 (55), 326 (18), 313 (51), 286 (61), 212 (21), 158
(26), 86 (97), 58 (22), 42 (45); Analysis calculated for
C11H10F3IN2O3: C, 34.22; H, 2.61; N, 7.26. Found: C,
34.26; H, 2.37; N, 7.01.
4.1.3. 6-Iodo-4-tri¯uoromethylindole (4). The above
prepared crude 8 was dissolved in acetone (250 ml) and
added slowly to a stirred solution of aqueous 20% titanium-
(III) chloride (420 g, 544 mmol) and aqueous 4 M ammo-
nium acetate (840 g), while cooling in an ice-water bath.
When the addition was completed, the cooling bath was
removed and stirring continued at room temperature for
5 h. The resulting mixture was then extracted with EtOAc
(12£250 ml). The organic extracts were combined and dried
over anhydrous MgSO4. After ®ltration, the solvent was
removed in vacuo to give crude 4. Puri®cation was carried
out by ¯ash column chromatography, hexane/EtOAc 20:1as
eluent, to give 4 (22.71g, 83% from 6) as a light yellow oil;
IR (KBr) 3790, 3441, 1608, 1442, 1399, 1356, 1331, 1302,
1248, 1189, 1121, 1078, 949, 897, 856, 777, 732, 643 cm21;
1H NMR (270 MHz, CDCl3) d 8.38 (brs, 1H), 7.92 (s, 1H),
7.68 (s, 1H), 7.27 (m, 1H), 6.71 (m, 1H); 13C NMR (100
1
684 cm21; H NMR (270 MHz, DMSO-d6) d 11.31 (brs,
1H), 7.68 (s, 1H), 7.55 (s, 1H); 13C NMR (100 MHz,
3
DMSO-d6) d 180.0, 158.4, 152.9, 127.7 (q, JCFˆ5.6 Hz),
2
1
126.1 (q, JCFˆ35.2 Hz), 125.3, 121.7 (q, JCFˆ274.6 Hz),
113.9, 107.0; MS (EI) m/z 341(M 1, 74%), 313 (100),
286 (37), 158 (11), 131 (9); Analysis calculated for
C9H3F3INO2´H2O: C, 30.11; H, 1.40; N, 3.90. Found: C,
30.32; H, 1.30; N, 3.86.
4.1.5. Methyl (4-iodo-6-nitro-2-tri¯uoromethylphenyl)-
pyruvate (10). Dimethyl oxalate (127.79 g, 1.08 mol) was
added to sodium methylate (216.4 ml, 1.08 mol, 28%) and
the mixture stirred at room temperature for 1.5 h. A solution
of crude 6 (71.64 g) in MeOH (216 ml) was added and the
dark red coloured mixture stirred at room temperature for
20 h. The solvent was removed in vacuo to give a red solid
which was subsequently added to aqueous 2.5N HCl
(800 ml) and extracted with EtOAc (500 ml, 2£300 ml).
The extracts were combined and dried over anhydrous
MgSO4. After ®ltration, the solvent was removed in vacuo
to give crude 10 (161.41 g) as a yellow solid. The crude
product was used in the following reaction without puri®ca-
tion, however for characterisation purposes a small amount
was puri®ed by ¯ash column chromatography, hexane/
EtOAc 15:1±10:1 as eluent, to give an analytically pure
sample as a light yellow solid; mp 115±1168C; IR (KBr)
3086, 2963, 1734, 1543, 1356, 1307, 1278, 1170, 1151,
3
MHz, CDCl3) d 137.8, 126.5, 126.3 (q, JCFˆ4.8 Hz),
1
2
124.0 (q, JCFˆ272.5 Hz), 123.9, 123.7, 123.6 (q, JCFˆ
32.9 Hz), 102.2; HRMS calcd for C9H5NIF3 (M1)
310.9418. Found 310.9384.
4.1.4. 6-Iodo-4-tri¯uoromethylisatin (2) from 4.
a. 3,3-Dibromo-6-iodo-4-tri¯uoromethyloxindole (9)
6-Iodo-4-tri¯uoromethylindole (4, 22.71g, 73.0 mmol) was
dissolved in tert-butanol (810 ml) and water (5 ml) followed
by pyridinium bromide perbromide (77.87 g, 219.1 mmol,
90%) were added. The mixture was stirred at room tempera-
ture for 4 h, under a nitrogen atmosphere, and then the
solvent was removed in vacuo. The resulting brown solid
was dissolved in EtOAc/H2O (1:1, 2000 ml). The organic
phase was separated and the aqueous phase extracted with
EtOAc (4£250 ml). The organic phases were combined,
washed with half saturated brine and dried over anhydrous
MgSO4. After ®ltration, the solvent was removed in vacuo
to give crude 3,3-dibromo-6-iodo-4-tri¯uoromethyloxin-
dole (9). The crude product was used in the following
reaction without puri®cation, however for characterisation
purposes a small amount was puri®ed by ¯ash column
1
1125, 1109, 1093, 1065, 898, 696 cm21; H NMR (270
MHz, CDCl3) d 8.54 (d, 1H, Jˆ1.3 Hz), 8.29 (d, 1H,
Jˆ1.3 Hz), 4.63 (s, 2H), 3.96 (s, 3H); 13C NMR (100
3
MHz, CDCl3) d 186.9, 160.1, 150.6, 139.8 (q, JCFˆ
2
5.9 Hz), 137.3, 133.4 (q, JCFˆ30.7 Hz), 127.4, 121.9 (q,
1JCFˆ275.7 Hz), 92.3, 53.6, 39.4; MS (EI) m/z 358 (72%),
330 (M12C3H3O3, 100), 313 (65), 272 (20), 145 (53), 87
(16), 59 (49), 15 (22); Analysis calculated for C11H7F3INO5:
C, 31.68; H, 1.69; N, 3.36. Found: C, 31.78; H, 1.85; N,
3.33.

3610
W. E. Hume et al. / Tetrahedron 58 (2002) 3605±3611
4.1.6. (4-Iodo-6-nitro-2-tri¯uoromethylphenyl)acetic acid
(12). To a suspension of crude 10 (157.9 g) in glacial AcOH
(3 l) was added aqueous 30% H2O2 (1025 ml) and 70%
HClO4 (159 ml). The mixture was heated at 508C (bath
temperature) for 4 h and then cooled. To the solution was
added portionwise sodium sulphite (400 g) (CAUTION:
addition is very exothermic) and the solvent was removed
in vacuo. The resulting solid was dissolved in H2O (2 l) and
extracted with EtOAc (3£1l). The extracts were combined
and subsequently extracted with aqueous 2N NaOH
(9£500 ml). The aqueous extracts were combined, cooled
in an ice-H2O bath and acidi®ed with aqueous 36% HCl.
The precipitate was collected by ®ltration, washed with
cold H2O and dried in vacuo to give 12 (37.14 g, 49%
from 7) as a white solid; mp 194±195.58C; IR (KBr) 3386,
3100, 2970, 2730, 2650, 2552, 1728, 1713, 1604, 1537,
1404, 1355, 1310, 1291, 1239, 1202, 1182, 1133, 1092,
12) as a light yellow solid; mp 263.5±2658C (with decom-
position); IR (KBr) 3151, 3046, 1704, 1608, 1448, 1386,
1
1330, 1293, 1172, 1136, 974, 861, 696 cm21; H NMR
(270 MHz, CDCl3) d 7.93 (brs, 1H), 7.60 (s, 1H), 7.39 (s,
1H), 3.97 (s, 2H); 13C NMR (100 MHz, DMSO-d6) d 175.4,
2
3
146.8, 126.9 (q, JCFˆ32.3 Hz), 125.7 (q, JCFˆ4.2 Hz),
3
1
124.1 (q, JCFˆ2.5 Hz), 123.2 (q, JCFˆ273.6 Hz), 121.3,
93.4, 35.3; MS (EI) m/z 327 (M1, 100%), 299 (12), 298
(11), 200 (7), 172 (10); Analysis calculated for
C9H5F3INO: C, 33.05; H, 1.54; N, 4.28. Found: C, 33.37;
H, 1.70; N, 4.27.
4.1.9. 6-Iodo-4-tri¯uoromethylisatin (2) from 5.
a. 3,3-Dibromo-6-iodo-4-tri¯uoromethyloxindole (9)
To a suspension of 5 (21.00 g, 64.2 mmol) in tBuOH
(610 ml) was added pyridinium bromide perbromide
(91.32 g, 256.8 mmol, 90%) and the mixture stirred rapidly
at room temperature for 4 h. Water (1.2 l) was added and the
mixture stirred until a solution formed. The solution was
extracted with EtOAc (4£250 ml), the extracts were com-
bined and then dried over anhydrous MgSO4. After ®l-
tration, the solvent was removed in vacuo to give crude 9
(35.2 g) as a light purple/grey solid.
;
929, 898, 853, 702, 688 cm21 1H NMR (270 MHz,
DMSO-d6) d 12.92 (brs, 1H), 8.65 (d, 1H, Jˆ1.6 Hz), 8.42
(d, 1H, Jˆ1.6 Hz), 3.92 (s, 2H); 13C NMR (100 MHz,
3
DMSO-d6) d 169.9, 151.6, 139.1 (q, JCFˆ5.6 Hz), 137.3,
2
1
131.3 (q, JCFˆ30.4 Hz), 128.0, 122.7 (q, JCFˆ275.3 Hz),
94.3, 34.2; MS (EI) m/z 375 (M1, 19%), 331 (20), 329 (37),
314 (100), 286 (29), 202 (17), 159 (29), 145 (33); Analysis
calculated for C9H5F3INO4: C, 28.82; H, 1.34; N, 3.73.
Found: C, 28.76; H, 1.48; N, 3.78.
b. 6-Iodo-4-tri¯uoromethylisatin (2)
4.1.7. Methyl (4-iodo-6-nitro-2-tri¯uoromethylphenyl)-
acetate (13). A solution of 12 (34.7 g, 96.2 mmol) in 10%
HCl±MeOH (300 ml) was heated at re¯ux for 4.5 h. The
solution was cooled and the solvent removed in vacuo.
The resulting oil was dissolved in EtOAc (400 ml), washed
with saturated aqueous NaHCO3 (2£100 ml) and dried over
anhydrous MgSO4. After ®ltration, the solvent was removed
in vacuo to give crude 13 (33.20 g) as a colourless oil. The
crude product was used in the following reaction without
puri®cation, however for characterisation purposes a small
amount was puri®ed by ¯ash column chromatography,
hexane/EtOAc 10:1 as eluent, to give an analytically pure
sample as a white solid; mp 81±828C; IR (KBr) 3087, 3010,
2956, 1741, 1605, 1540, 1460, 1430, 1402, 1354, 1307,
1286, 1264, 1240, 1202, 1177, 1134, 1111, 1089, 1012,
To a solution of crude 9 (35.11 g) in MeOH (1.2 l) was
added H2O (300 ml) and aqueous 48% HBr (10 ml). The
solution was heated at re¯ux for 27 h after which time the
MeOH was removed in vacuo to give brown/yellow solid.
The solid was collected by ®ltration, washed with copious
amounts of H2O and dried in vacuo to give 2 (20.82 g, 95%
from 5) as a light brown solid.
References
1 . MÈluler, E. E.; Locatelli, V.; Cocchi, D. Physiol. Rev. 1999, 79,
511.
2. Tritos, N. A.; Mantzolos, C. S. Am. J. Med. 1998, 105, 44.
3. Howard, A. D.; Feighner, S. D.; Cully, D. F.; Arena, J. P.;
Liberator, P. A.; Rosenblum, C. I.; Hamelin, M.; Hreniuk,
D. L.; Palyha, O. C.; Anderson, J.; Paress, P. S.; Diaz, C.;
Chou, M.; Liu, K. K.; McKee, K. K.; Pong, S.-S.; Chaung,
L.-Y. P.; Elbrecht, A.; Dashkevicz, M.; Heavens, R.; Rigby,
M.; Sirinathsinghji, D. J. S.; Dean, D. C.; Melillo, D. G.;
Patchett, A. A.; Nargund, R. P.; Grif®n, P. R.; DeMartino,
J. A.; Gupta, S. K.; Schaeffer, J. M.; Smith, R. G.; Van der
Ploeg, L. H. T. Science 1996, 273, 974.
1
949, 896, 889, 832, 704, 684 cm21; H NMR (270 MHz,
CDCl3) d 8.49 (d, 1H, Jˆ1.3 Hz), 8.26 (d, 1H, Jˆ1.3 Hz),
4.11 (s, 2H), 3.73 (s, 3H); 13C NMR (100 MHz, CDCl3) d
168.7, 151.2, 139.4 (q, 3JCFˆ5.9 Hz), 137.1, 133.0 (q, 2JCFˆ
30.9 Hz), 127.9, 122.1 (q, 1JCFˆ275.5 Hz), 91.9, 52.7, 33.8;
MS (EI) m/z 389 (M1, 3%), 358 (9), 343 (100), 330 (15),
159 (16), 145 (46), 87 (21), 59 (70), 15 (30); Analysis
calculated for C10H7F3INO4: C, 30.87; H, 1.81; N, 3.60.
Found: C, 30.83; H, 1.88; N, 3.58.
4. Patchett, A. A.; Nargund, R. P.; Tata, J. R.; Chen, M.-H.;
Barakat, K. J.; Johnston, D. B. R.; Cheng, K.; Chan,
W. W.-S.; Butler, B.; Hickey, G.; Jacks, T.; Schleim, K.;
Pong, S.-S.; Chaung, L.-Y. P.; Chen, H. Y.; Frazier, E.;
Leung, K. H.; Chiu, S.-H. L.; Smith, R. G. Proc. Natl Acad.
Sci. USA 1995, 92, 7001.
4.1.8. 6-Iodo-4-tri¯uoromethyloxindole (5). To a solution
of crude 13 (33.11 g) in MeOH (1 l) cooled to 0±58C was
added dropwise aqueous 20% TiCl3 (815 g, 1.06 mol). The
cooling bath was removed and the solution stirred at room
temperature for 20 h after which time aqueous 6N HCl
(900 ml) was added. The resulting mixture was extracted
with EtOAc/toluene (1:1, 3£1l; 2:1, 3 £900 and 3£500
ml). The extracts were combined and dried over anhydrous
MgSO4. After ®ltration, the solvent was removed in vacuo
to give a light brown solid which was puri®ed by recrystal-
lisation from EtOH (300 ml) to give 5 (21.59 g, 69% from
5. Tokunaga, T.; Hume, W. E.; Umezome, T.; Okazaki, K.; Ueki,
Y.; Kumagai, K.; Hourai, S.; Nagamine, J.; Seki, H.; Taiji, M.;
Noguchi, H.; Nagata, R. J. Med. Chem. 2001, 44, 4641.
6. Nagamine, J.; Nagata, R.; Seki, H.; Akimaru, N.; Ueki, Y.;
Kumagai, K.; Taiji, M.; Noguchi, H. J. Endocrinol. 2001, 171,
481.

W. E. Hume et al. / Tetrahedron 58 (2002) 3605±3611
3611
7. Nargund, R. P.; Patchett, A. A.; Bach, M. A.; Murphy, M. G.;
Smith, R. G. J. Med. Chem. 1998, 41, 3103.
11. 2-Methyl-3-nitrobenzotri¯uoride is available from Lancaster
Synthesis, Ltd.
12. Katayama, S.; Ae, N.; Nagata, R. J. Org. Chem. 2001, 66,
3474.
8. This work has been communicated in preliminary form at the
220th National ASC meeting: see Nagata, R.; Tokunaga, T.;
Hume, W. E.; Okazaki, K.; Ueki, Y.; Kumagai, K.; Nagamine,
J.; Seki, H.; Taiji, M.; Noguchi, H. Book of Abstracts, 220th
American Chemical Society National Meeting, Washington,
DC, August 20±24, 2000; American Chemical Society:
Washington, DC, 2000; MEDI-309.
13. Kruse, L. I. Heterocycles 1981, 16, 1119.
14. Clark, R. D.; Repke, D. B. Heterocycles 1984, 22, 195.
15. Marfat, A.; Carta, M. P. Tetrahedron Lett. 1987, 28, 4027.
16. Parrick, J.; Yahya, A.; Ijaz, A. S.; Yizun, J. J. Chem. Soc.,
Perkin Trans. 1 1989, 2009.
17. The cost of tris(dimethylamino)methane is ¥43,000 for 25 g
from Aldrich Chemical Company, Inc.
9. Gassman, P. G.; Roos, J. J.; Lee, S. J. J. Org. Chem. 1984, 49,
717.
18. Wright, Jr., W. B.; Collins, K. H. J. Am. Chem. Soc. 1956, 78,
221.
19. Lef¯er, J. E. J. Org. Chem. 1951, 16, 1785.
10. For a regioselective method for synthesis of isatins see:
Kraynack, E. A.; Dalgard, J. E.; Gaeta, F. C. A. Tetrahedron
Lett. 1998, 39, 7679.