An efficient one-pot synthesis of novel 4-aryl-1-methyloxindoles

Article abstract of DOI:10.1016/j.tetlet.2006.04.103

An unprecedented synthetic approach to novel 4-aryl-1-methyloxindoles is described. The method involves the intramolecular palladium-catalyzed amidation of N-methyl-2,6-dibromophenylacetamide followed by an in situ Suzuki cross-coupling reaction with a (h

Full text of DOI:10.1016/j.tetlet.2006.04.103

Tetrahedron Letters 47 (2006) 4361–4364
An efficient one-pot synthesis of novel 4-aryl-1-methyloxindoles
Adri van den Hoogenband,* Jos H. M. Lange, Wouter I. Iwema-Bakker,
Jack A. J. den Hartog, Jord van Schaik, Rolf W. Feenstra and Jan Willem Terpstra
Solvay Pharmaceuticals, Research Laboratories, C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands
Received 31 March 2006; revised 13 April 2006; accepted 20 April 2006
Available online 15 May 2006
Dedicated to our colleague Willem Veerman (1959–2005)
Abstract—An unprecedented synthetic approach to novel 4-aryl-1-methyloxindoles is described. The method involves the intra-
molecular palladium-catalyzed amidation of N-methyl-2,6-dibromophenylacetamide followed by an in situ Suzuki cross-coupling
reaction with a (hetero)arylboronic acid in a one-pot reaction.
Ó 2006 Elsevier Ltd. All rights reserved.
1,3-Dihydroindol-2-ones (oxindoles) are of great phar-
maceutical importance. The oxindole motif is present
in the anti-Parkinson’s drug ropinirole,1 in growth hor-
mone secretagogues,2 P-glycoprotein-mediated multiple
drug resistance inhibitors,3 anti-inflammatory agents,4
non-opioid nociceptin receptor ligands5 and serotoner-
gics.6,7 In addition, the oxindole moiety constitutes a
key structural element in several natural products,8
including the antibiotic speradine9 and the cytostatic
welwistatin.10 As a consequence, the development of
novel synthetic strategies leading to substituted oxindole
derivatives is of paramount importance. Recently, we
published11 a new method for the preparation of 1-func-
tionalized oxindoles based on an intramolecular palla-
dium-catalyzed amidation reaction. In that study it
was discovered that the excellent Buchwald ligand
X-Phos (Scheme 1) plays a key role in the yield and rate
of this particular reaction. In addition, we were able to
prepare in one of our current projects, a set of differently
1-substituted oxindoles by applying the same method-
ology.12 More recently, Turner et al.,13 utilized micro-
wave irradiation in a closely related reaction and
concluded that X-Phos again was the ligand of choice.
Kitamura14 reported the use of alternative phenylnaph-
thyl phosphines as effective ligands in an analogues
intramolecular palladium-catalyzed amidation reaction
leading to 1-benzyloxindole.
Due to our interest in the synthesis of novel 4-(hetero)-
aryl-1-methyl oxindoles, it was decided to expand the
scope of the synthetic methodology outlined above.
The 2-bromophenylacetamide derivative 1 was used as
the key intermediate in the synthesis that led11 to the
pharmaceutically relevant5 1-(piperidin-4-yl)oxindole 2
(Scheme 1). We envisaged that application of the struc-
turally related N-methyl-2,6-dibromophenylacetamide 3
would lead to N-methyl-4-bromo-1,3-dihydroindol-2-
one 4. The remaining 4-bromo substituent would pro-
vide a handle for further transition metal catalyzed
cross-coupling reactions. This study focuses on Suzuki-
type arylations to produce novel oxindoles of general
formula 5.
The synthesis of the required key intermediate 315 is
depicted in Scheme 2. Benzylic bromination of 2,6-di-
bromotoluene 6 using N-bromosuccinimide in CCl4
gave 7. The bromide 7 was converted into the corre-
sponding cyanide 8, which was hydrolyzed to the
carboxylic acid 9. The carboxamide 3 was obtained via
conversion of the carboxylic acid to the corresponding
acid chloride and an in situ subsequent reaction with
methylamine. The yield of this reaction sequence was
reasonable (34% overall yield).
Surprisingly, when compound 3 was subjected to the
amidation conditions outlined in Scheme 1, no forma-
tion of 1-methyl-4-bromooxindole 4 was observed at
all. Since all the starting material had disappeared the
products formed were isolated and purified. Structure
analysis revealed the formation of the dimeric oxindole
*
Corresponding author. Tel.: +31 (0)294 479605; fax: +31 (0)294
477138; e-mail: adri.vandenhoogenband@solvay.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.103

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A. van den Hoogenband et al. / Tetrahedron Letters 47 (2006) 4361–4364
O
O
N
N
N
O
Br
a)
N
H
N
N
H
a
1
2
PCy2
Pr-i
i-Pr
X-Phos
i-Pr
Br
Ar
Br
O
a)
Suzuki cross coupling
Ar-B(OH)2
O
O
N
N
Br
CH3
CH3
N
H
CH3
5
4
3
Scheme 1. Reagents and conditions: (a) 1 mol equiv 1, 2.5 mol equiv K2CO3, 3 mol % Pd(OAc)2, 7.5 mol % PhB(OH)2, 7.5 mol % X-Phos,a t-BuOH,
85 °C, 3 h.
Br
Br
Br
a)
b)
c)
Br
CN
Br
Br
Br
7
6
8
CH3
Br
N
Br
O
f)
O
O
d), e)
O
+
N
O
HN
OH
Br
N
Br
CH3
CH3
CH3
11
9
10
3
Scheme 2. Reagents and conditions: (a) 1 mol equiv 6, 1.1 mol equiv NBS, catalytic Bz2O2, CCl4, reflux, 89%; (b) 1 mol equiv 7, 2.7 mol equiv KCN,
EtOH/water 4:1, reflux, 67%; (c) 1 g 8, 15 ml 70% H2SO4, 170 °C, 90%; (d) 1 mol equiv 9, 20 mol equiv SOCl2, benzene, room temperature; (e)
10 mol equiv HNCH3ÆHCl, Et3N 64%; (f) reaction conditions according to Scheme 1.
analogue 1016 as the major product together with a trace
of the 4-phenyloxindole derivative 11 (Scheme 2). The
formation of 10 can be rationalized by invoking the ini-
tial formation of compound 4 which undergoes an inter-
molecular a-arylation,17 followed by a debromination
reaction to give compound 10. Transition metal-medi-
ated debrominations have been previously reported.18
Due to the presence of a catalytic amount of phenyl-
boronic acid, needed for a smooth reduction of the
cationic palladium complex according to Buchwald’s
original protocol,19 a minor fraction of compound 4
would in situ lead to a rapid Suzuki cross-coupling
reaction, eventually resulting in the formation of com-
pound 11.
In order to support this hypothesis, the amidation reac-
tion of 3 was repeated in the presence of a catalytic
amount of Pd2dba3/X-Phos in the absence of any phen-
ylboronic acid. According to expectation, the dimeric
oxindole analogue 10 was produced as the sole product.
Moreover, the reaction of 3 under the influence of cata-
lytic Pd(OAc)2/X-Phos in the presence of a stoichio-

A. van den Hoogenband et al. / Tetrahedron Letters 47 (2006) 4361–4364
4363
metric amount of phenylboronic acid proceeded
smoothly, leading to a nearly quantitative yield of com-
pound 11. A literature survey led to the conclusion that,
to the best of our knowledge, 1-methyl-4-aryloxindoles
constitute a hitherto unknown compound class. These
results prompted an exploration in more depth of this
unexpected reaction. The ease with which the 4-bromo
substituent in compound 4 is substituted in this reaction
sequence led to the concept of combining the intra-
molecular palladium-catalyzed amidation of N-methyl-
2,6-dibromophenylacetamide 3 with an in situ Suzuki
cross-coupling reaction in a one-pot reaction fashion.
We have briefly tried to extend the scope of this reaction
by substituting the boronic acid for morpholine with the
aim of preparing 1-methyl-4-(morpholin-4-yl)oxindole
under the same reaction conditions. However, this initial
attempt resulted only in the isolation of compound 10 as
the sole reaction product. Optimization of the reaction
parameters for this particular reaction is in progress.
A novel two-step reaction procedure has been devised
for the preparation of five representative novel
1-methyl-4-(hetero)aryloxindoles 11 and 17–20 in mod-
erate to high yields. The key steps comprise an intra-
molecular palladium-catalyzed amidation reaction
followed by an in situ intermolecular Suzuki cross-cou-
pling reaction in a one-pot reaction. We envisage that
the scope of this approach can be expanded to the
synthesis of a variety of (hetero)aryl-1,3-dihydroindol-
2-ones.
Three arylboronic acid derivatives 12–14 and two het-
eroarylboronic acids 15–16 were reacted with 3 under
the conditions described in Scheme 320,21 (Table 1). It
should be noted that all yields refer to isolated pure
products and were not optimized. High yields were
observed in the reactions with the arylboronic acids
12–14 which led to the products 11, 17 and 18, respec-
tively. A moderate yield was obtained for the reaction
of 3 with furan-2-boronic acid 15 leading to compound
19. A possible explanation, based on LC/MS results,
may be a concurrent side-reaction in which each bro-
mine atom in compound 3 was replaced by a furan ring
in a double Suzuki cross-coupling reaction. Disappoint-
ingly, the use of thiophene-2-boronic acid 16 as starting
boronic acid gave a poor yield of compound 20
even after 16 h heating and reflux. By adding more
Pd(OAc)2, X-Phos, K2CO3 and 16 to the reaction
mixture, we were able to isolate compound 20 in a mod-
est 18% yield after another 48 h reflux period. In this
case some of the dimeric compound 10 was formed as
well. Apparently, the Suzuki cross-coupling reaction of
the in situ formed 4 with the thiophene-2-boronic acid
16 under these reaction conditions is very slow, presum-
ably due to some palladium poisoning or deboronation
of 16, resulting in the concurrent formation of 10.
Acknowledgements
We wish to thank Sjoerd van Schaik for the isolation of
compound 10, Alice Borst, Pieter Spaans and Willem
Gorter for analytical support, Arnold den Hartog for
fruitful discussions and Peter Koelman and Paul Brun-
del for screening of the literature.
References and notes
1. Gallagher, G.; Lavanchi, P. G.; Wilson, J. W.; Hieble, J.
P.; DeMarinis, R. M. J. Med. Chem. 1985, 28, 1533–
1536.
2. Nagata, R.; Tokunaga, T.; Hume, W.; Umezone, T.;
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M. L.; Moore, R. E. Mol. Pharmacol. 1995, 47, 241–
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4. (a) Asmawi, M. Z.; Moilanen, E.; Alanko, J.; Vapaatalo,
H. Eicosanoids 1988, 1, 35–39; (b) Alcaraz, M.; Atkinson,
S.; Cornwall, P.; Foster, A. C.; Gill, D. M.; Humphries, L.
A.; Keegan, P. S.; Kemp, R.; Merifield, E.; Nixon, R. A.;
Noble, A. J.; O’Beirne, D.; Patel, Z. M.; Perkins, J.; Rowa,
P.; Sadler, P.; Singleton, J. T.; Tornos, J.; Watts, A. J.;
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Parrish, D.; Polgar, W.; Toll, L. J. Med. Chem. 2004, 47,
2973–2976.
Br
Ar
O
a)
ArB(OH)2
+
NHCH3
Br
N
O
CH3
11 and 17-20
12 -16
3
6. Kikuchi, C.; Hiranuma, T.; Koyama, M. Bioorg. Med.
Chem. Lett. 2002, 12, 2549–2552.
7. Mokrosz, M. J.; Duszynska, B.; Misztal, S.; Klodinska,
A.; Tatarzynska, E. Arch. Pharm. Pharm. Med. Chem.
1998, 331, 325–330.
Scheme 3. Reagents and conditions: (a) 1.5 mol equiv ArB(OH)2,
3 mol equiv K2CO3, 5 mol % Pd(OAc)2, 12.5 mol % X-Phos, t-BuOH,
85 °C.
8. Thiericke, R.; Tang, Y. Q.; Sattler, I.; Grabley, S.; Feng,
X. Z. Eur. J. Org. Chem. 2001, 261–267.
Table 1.
9. Tsuda, M.; Mugishima, T.; Komatzu, K.; Sone, T.;
Tanaka, M.; Mikami, Y.; Shiro, M.; Hirai, M.; Ohizumi,
Y.; Kobayashi, J. Tetrahedron 2003, 59, 3227–3230.
10. Zhang, X.; Smith, C. D. Mol. Pharmacol. 1996, 49, 288–
294.
11. Van den Hoogenband, A.; Den Hartog, J. A. J.; Lange, J.
H. M.; Terpstra, J. W. Tetrahedron Lett. 2004, 45, 8535–
8537.
ArB(OH)2
Product
Time
(h)
Yield
(%)
Phenylboronic acid 12
11
17
18
19
20
16
5
16
16
60
90
75
80
55
18
4-Methoxyphenylboronic acid 13
2-Methylphenylboronic acid 14
Furan-2-boronic acid 15
Thiophene-2-boronic acid 16

4364
A. van den Hoogenband et al. / Tetrahedron Letters 47 (2006) 4361–4364
12. Van den Hoogenband, A., unpublished results.
13. Turner, N. J.; Poondra, R. R. Org. Lett. 2005, 7, 863–866.
14. Kitamura, Y.; Hashimoto, A.; Yoshikawa, S.; Odaira, J.;
Furuta, T.; Kan, T.; Tanaka, K. Synlett 2006, 115–
117.
dibromophenylacetamide 3 (155 mg, 0.5 mmol) at 35 °C.
The temperature of the magnetically stirred mixture was
then raised to 80 °C, until a clear solution was obtained.
After cooling down again to 35 °C, Pd(OAc)2 (5.6 mg,
0.025 mmol), the aryl- or heteroarylboronic acid
(0.75 mmol), X-Phos (30 mg, 0.0625 mmol) and K2CO3
(410 mg, 3 mmol) were successively added. The resulting
reaction mixture was heated at 85 °C under a nitrogen
atmosphere until the starting compound 3 had disap-
peared (LCMS, TLC monitoring: CH2Cl2/acetone = 95/5
(v/v)). The reaction mixture was allowed to attain room
temperature. Water and ethyl acetate were added. The
organic layer was separated and dried over MgSO4,
filtered and concentrated in vacuo. The obtained crude
product was further purified by flash chromatography
(silica gel 60 (0.040–0.063 mm, Merck), CH2Cl2/ace-
tone = 95/5 (v/v)).
15. Selected analytical data for compound 3: 1H NMR
(400 MHz, CDCl3): d 2.81 (d, J = 4 Hz, 3H), 4.04 (s,
2H), 5.25–5.30 (br s, 1H), 7.04 (t, J = 8 Hz, 1H), 7.58 (d,
J = 8 Hz, 2H); HRMS (ES+): calcd for C9H9Br2NO
(M+H) 305.9129; found: 305.9128.
16. Selected analytical data for compound 10: 1H NMR
(400 MHz, CDCl3): d 3.05 (d, J = 22 Hz, 1H), 3.11 (s, 3H),
3.16 (d, J = 22 Hz, 1H), 3.21 (s, 3H), 4.58 (s, 1H), 6.70 (d,
J = 8 Hz, 1H), 6.81 (d, J = 8 Hz, 1H), 6.84 (d, J = 8 Hz,
1H), 6.95–7.02 (m, 2H), 7.20 (t, J = 8 Hz, 1H), 7.27 (t,
J = 8 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 26.01,
26.20, 34.07, 50.52, 107.42, 108.07, 122.71, 123.09, 123.26,
124.47, 127.20, 128.24, 128.53, 132.76, 144.14, 145.55,
174.48, 174.76. HRMS (ES+): calcd for C18H16N2O2
(M+H) 293.1290; found: 293.1282.
17. Some selected literature references describing Pd-mediated
a-arylations: (a) Bignan, G. C.; Battista, K.; Connolly, P.
J.; Orsini, J. L.; Middleton, S. A.; Reitz, A. B. Bioorg.
Med. Chem. Lett. 2005, 15, 5022–5026; (b) Barberis, M.;
Garcia-Losada, P.; Pleite, S.; Rodriguez, J. R.; Soriano, J.
F.; Mendiola, J. Tetrahedron Lett. 2005, 46, 4847–4850; (c)
De Filippis, A.; Pardo, D. G.; Cossy, J. Synthesis 2004,
2930–2933; (d) Trost, B. M.; Frederiksen, M. U. Angew.
Chem., Int. Ed. 2005, 44, 308–310; (e) De Filippis, A.;
Pardo, D. G.; Cossy, J. Tetrahedron 2004, 60, 9757–9767;
(f) Cossy, J.; De Filippis, A.; Pardo, D. G. Synlett 2003,
2171–2174; For an excellent overview about Pd-catalysed
a-arylation reactions: Culkin, D. A.; Hartwig, J. F. Acc.
Chem. Res. 2003, 36, 234–245.
21. Selected analytical data for compounds 11 and 17–20:
Compound 11: 1H NMR (400 MHz, CDCl3): d 3.25 (s,
3H), 3.60 (s, 2H), 6.83 (d, J = 8 Hz, 1H), 7.12 (d, J = 8 Hz,
1H), 7.36–7.40 (m, 2H), 7.46 (d, J = 4 Hz, 4H). 13C NMR
(100 MHz, CDCl3): d 26.33, 35.81, 107.07, 122.17, 123.01,
127.71, 128.08, 128.40, 128.72, 138.35, 139.61, 145.63,
174.95. HRMS (ES+): calcd for C15H13NO (M+H)
224.1074; found 224.1068. Compound 17: 1H NMR
(400 MHz, CDCl3): d 3.24 (s, 3H), 3.59 (s, 2H), 3.86 (s,
3H), 6.79 (d, J = 8 Hz, 1H), 6.98 (d, J = 8 Hz, 2H), 7.09
(d, J = 8 Hz, 1H), 7.32–7.41 (m, 3H). HRMS (ES+): calcd
for C16H15NO2 (M+H) 254.1181; found: 254.1169. Com-
pound 18: 1H NMR (400 MHz, CDCl3): d 2.14 (s, 3H),
3.24 (s, 3H), 3.27 (s, 2H), 6.82 (d, J = 8 Hz, 1H), 6.92 (d,
J = 8 Hz, 1H), 7.14 (d, J = 8 Hz, 1H), 7.22–7.35 (m, 4H).
HRMS (ES+): calcd for C16H15NO (M+H) 238.1232;
found: 238.1222. Compound 19: 1H NMR (400 MHz,
CDCl3): d 3.24 (s, 3H), 3.74 (s, 2H), 6.53 (dd, J = 4 and
2 Hz, 1H), 6.64 (d, J = 4 Hz, 1H), 6.75 (d, J = 8 Hz, 1H),
7.33 (t, J = 8 Hz, 1H), 7.42 (d, J = 8 Hz, 1H), 7.53 (d,
J = 2 Hz, 1H). HRMS (ES+): calcd for C13H11NO2
(M+H) 214.068; found: 214.0862. Compound 20: 1H
NMR (400 MHz, CDCl3): d 3.25 (s, 3H), 3.73 (s, 2H), 6.78
(t, J = 4 Hz, 1H), 7.14 (t, J = 4 Hz, 1H), 7.31–7.34 (m,
3H), 7.38 (d, J = 4 Hz, 1H). HRMS ES+: calcd for
C13H11NOS (M+H) 230.0640; found: 230.0637.
18. Diederich, P.; Stang, P. J. Metal-catalyzed Cross-coupling
Reactions; Wiley-VCH: Weinheim, Germany, 1998.
19. Huang, X. H.; Anderson, K. W.; Zim, D.; Jiang, L.;
Klapars, A.; Buchwald, S. L. J. Am.Chem. Soc. 2003, 125,
6653–6655.
20. General procedure for the preparation of the compounds
11 and 17–20 (Table 1): A dried 50 mL, three-necked
reaction vessel was charged with anhydrous and degassed
t-BuOH (25 mL), followed by addition of N-methyl-2,6-