Preparation of 3-alkyl-oxindoles by copper(II)-mediated C-H, Ar-H coupling followed by decarboxyalkylation

Article abstract of DOI:10.1055/s-0029-1219392

A novel route for the conversion of anilides into 3-alkyl-oxindoles is described in which a copper(II)-mediated cyclization process is followed by an acid-mediated decarboxyalkylation. Scope and limitation studies are reported together with a telescoped variant which incorporates in situ N-deprotection. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219392

934
LETTER
Preparation of 3-Alkyl-Oxindoles by Copper(II)-Mediated C–H,
Ar–H Coupling Followed by Decarboxyalkylation
P
reparation of 3-A
a
lkyl-Oxind
v
oles id. S. Pugh, Johannes E. M. N. Klein, Alexis Perry, Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Fax +44(1904)434523; E-mail: rjkt1@york.ac.uk
Received 14 December 2009
Dedicated to Professor Saverio Florio in celebration of his 70th birthday
doles,3f we attempted to generalize this procedure. Un-
fortunately, the base-mediated saponification–
Abstract: A novel route for the conversion of anilides into 3-alkyl-
oxindoles is described in which a copper(II)-mediated cyclization
process is followed by an acid-mediated decarboxyalkylation.
Scope and limitation studies are reported together with a telescoped
variant which incorporates in situ N-deprotection.
decarboxylation sequence proved to be unsuccessful with
other 3-alkyl-3-carboethoxy-oxindoles 2 (e.g., 3-allyl and
3-benzyl analogues); such problems during basic proce-
dures are precedented.3g,h As shown in Scheme 3, we
therefore proposed the use of the corresponding tert-butyl
esters 4 to evaluate their utility5 in the copper(II)-mediat-
ed cyclization process with a view to exploring an acid-
mediated route to 3-alkyl-oxindoles 3.
Key words: oxindoles, 3-alkyl-oxindoles, anilides, cyclisation,
copper(II) catalysis, C–H activation, decarboxyalkylation
We recently developed a novel copper(II)-mediated route
for the conversion of anilides 1 into 3-alkyl-3-carbo-
ethoxy-oxindoles 2 by a formal C–H, Ar–H coupling pro-
cess as shown in Scheme 1.1,2 In the case of the 3-
methylated example 1a it proved possible to carry out a
‘one-pot’ cyclisation–decarboxyalkylation process to pro-
duce 3-methyl-oxindole (3a) in reasonable yield
(Scheme 2).1
To test this approach, anilide 4a (R = Me) was prepared as
shown in Scheme 4.6 Thus, Mukaiyama coupling7 of N-
methylaniline (6) and tert-butyl malonate (7) gave amide
8 in essentially quantitative yield. Alkylation using meth-
yl iodide also proceeded efficiently to give cyclization
precursor 4a. The key copper(II)-mediated cyclization
was investigated next using the Cu(OAc)2·H2O–DMF
procedure developed earlier.1 We were delighted to ob-
serve the formation of oxindole 5a in good yield using
these conditions. The second crucial step in this sequence,
the acid-mediated decarboxyalkylation to produce 3-
methyl-oxindole (3a), proved to be relatively straightfor-
ward (Scheme 4). This transformation could be achieved
using several acids but neat TFA (with anisole as a cation
trap)8 at room temperature proved to be the most effective.
R
CO2Et
O
CO2Et
O
R
KOt-Bu, DMF
Cu(OAc)2⋅H2O
N
Me
N
Me
1
2
Scheme 1
Me
Having established the viability of the copper(II)-mediat-
ed cyclization route on tert-butyl ester 4a and the decar-
boxyalkylation of tert-butyl ester 5a, we went on to
explore the scope of this cyclisation–decarboxyalkylation
sequence with a range of anilides 49 (Table 1).
i. KOt-Bu, DMF
CO2Et
O
Me
N
Cu(OAc)2⋅H2O
O
ii. NaOH
then NH4Cl
N
Me
Me
69%
1a
3a
As can be seen, this cyclisation–decarboxyalkylation se-
quence was used to prepare a range of 3-substituted oxin-
doles including those with saturated alkyl substituents
(entries 1–3), allyl, benzyl, phenethyl, and naphthylmeth-
yl substituents (entries 4–7), as well as the benzyloxypro-
Scheme 2
In view of the utility of 3-alkylated oxindoles as synthetic
building blocks3 and as drug candidates,4 and given the
low yields often observed in the 3-alkylation of oxin-
R
R
CO2t-Bu
O
CO2t-Bu
O
R
acid
KOt-Bu, DMF
O
Cu(OAc)2⋅H2O
N
Me
N
Me
N
Me
4
3
5
Scheme 3
SYNLETT 2010, No. 6, pp 0934–0938
x
x.
x
x.
2
0
1
0
Advanced online publication: 18.02.2010
DOI: 10.1055/s-0029-1219392; Art ID: D36209ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Preparation of 3-Alkyl-Oxindoles
935
1.1 equiv KOt-Bu
1.05 equiv MeI
THF, r.t., 1 h
CO2t-Bu
O
N
Cl
CO2t-Bu
O
–
Me
I
88%
CH2Cl2, Et3N
0 °C, 30 min
HO
N
Me
NHMe
97%
8
7
6
Me
Me
1.1 equiv KOt-Bu
1.0 equiv Cu(OAc)2⋅H2O
CO2t-Bu
O
CO2t-Bu
O
Me
acid
O
see
below
N
Me
N
Me
DMF, 110 °C, 14 h
82%
N
Me
5a
3a
4a
PTSA, PhMe, Δ, 3 h
59%
TFA, PhOMe, CH2Cl2, Δ, 2 h
TFA, PhOMe, CH2Cl2, r.t., 3 d
TFA, PhOMe, r.t. , 2 h
68%
42%
78%
Scheme 4
pyl (entry 8) and 4-pyridylmethyl (entry 9) examples. All is the profound steric effect observed for the cyclization of
reactions proceeded in the expected manner in fair to ex- the isopropyl system with oxindole 5c being obtained in
cellent yield. The conditions devised for 4a and 5a only 42% yield after a reaction time of 72 hours.
(Scheme 4) were employed in all examples; it is likely
that the lower yields could be improved with further opti-
mization studies. One notable observation from this study
Table 1 Scope of the Cyclisation–Decarboxyalkylation Sequence
R
R
TFA
PhOMe
r.t., 2 h
CO2t-Bu
O
1.1 equiv KOt-Bu
1.0 equiv Cu(OAc)2⋅H2O
CO2t-Bu
O
R
O
DMF, 110 °C
14–24 h
N
Me
N
Me
N
Me
4
5
3
Entry
Cyclisation product 5
Yield 5 (%)
3-Alkyl-oxindole 3
Yield 3 (%)
Me
Me
CO2t-Bu
O
O
1
2
82
76
78
N
N
Me
Me
5a
3a
(CH2)9Me
Me(CH2)9
CO2t-Bu
O
O
90
68
N
Me
N
Me
5b
3b
Me
Me
Me
Me
CO2t-Bu
3
4
46a
O
O
N
Me
N
Me
5c
3c
CO2t-Bu
O
59
92
O
N
Me
N
Me
5d
3d
Synlett 2010, No. 6, 934–938 © Thieme Stuttgart · New York

936
D. S. Pugh et al.
LETTER
Table 1 Scope of the Cyclisation–Decarboxyalkylation Sequence (continued)
R
R
TFA
PhOMe
r.t., 2 h
CO2t-Bu
O
1.1 equiv KOt-Bu
1.0 equiv Cu(OAc)2⋅H2O
CO2t-Bu
O
R
O
DMF, 110 °C
14–24 h
N
Me
N
Me
N
Me
4
5
3
Entry
Cyclisation product 5
Yield 5 (%)
3-Alkyl-oxindole 3
Yield 3 (%)
Ph
Ph
CO2t-Bu
O
O
5
6
93
71
98
62
N
Me
N
Me
5e
3e
Ph
Ph
CO2t-Bu
O
O
N
Me
N
Me
5f
3f
CO2t-Bu
7
8
9
7310
9311
O
O
N
N
Me
Me
5g
3g
Ph
Ph
O
O
CO2t-Bu
O
65
86
O
N
Me
N
Me
5h
3h
N
N
CO2t-Bu
O
68
92
O
N
Me
N
Me
5i
3i
aA reaction time of 72 h was required.
Finally, we briefly explored the utility of this methodolo- these deprotection procedures should be of value when the
gy for the preparation of unprotected oxindoles product oxindoles are required for further synthetic elab-
(Scheme 5). Thus, we established that p-methoxybenzyl oration.
(PMB) protection is compatible with the copper(II)-medi-
ated cyclization (9 → 10) and then investigated deprotec-
tion protocols.
In summary, an inexpensive and operationally straightfor-
ward sequence for the conversion of readily available
anilides 4 into 3-substituted-N-methyl-oxindoles 3 has
Treatment of oxindole 10 using the TFA and room tem- been developed, based on a copper(II)-mediated C–H,
perature conditions developed earlier, for 2 hours, gave Ar–H coupling process followed by decarboxyalkylation.
efficient decarboxyalkylation producing the N-PMB-pro- This procedure is compatible with alkyl, arylalkyl, and
tected 3-benzyl-oxindole 11 in excellent yield. The use of functionalized substituents and can also be utilized to pre-
a higher temperature and a longer reaction time gave both pare 3-substituted oxindoles in the N–H form. We are cur-
decarboxyalkylation and N-deprotection producing 3- rently applying this new methodology in natural product
benzyl-oxindole 12 in 87% yield. The complementarity of areas.
Synlett 2010, No. 6, 934–938 © Thieme Stuttgart · New York

LETTER
Preparation of 3-Alkyl-Oxindoles
937
Ph
TFA
PhOMe
r.t., 2 h
84%
O
N
PMB
Ph
Ph
11
1.1 equiv KOt-Bu
1.0 equiv Cu(OAc)2⋅H2O
CO2t-Bu
O
CO2t-Bu
O
TFA
PhOMe
Δ, 3 d
DMF, 110 °C, 14 h
69%
N
N
PMB
PMB
Ph
87%
10
9
O
N
H
12
Scheme 5
exceptions of i-Pr (5c, 55%), PhCH2CH2 (5f, 63%),
PhCH2O(CH2)3 (5h, 69%), and 4-PyCH2 (5i, 46%).
(10) Representative Procedure for the Copper-Mediated
Cyclisation: tert-Butyl 1-Methyl-3-(naphthalen-2-yl-
methyl)-2-oxoindoline-3-carboxylate (5g)
Acknowledgment
We thank the ESPRC for postgraduate (D.S.P., EP/E041302/1) and
postdoctoral (A.P., EP/029841/1) support. We are also grateful to
the University of York Wild fund for additional postgraduate fun-
ding (J.E.M.N.K.).
A 100 mL round-bottomed flask fitted with a condenser
and stirrer-bar was charged with tert-butyl ester 4g
(R = naphthalen-2-yl-methyl, 195 mg, 0.50 mmol) and DMF
(10 mL). KOt-Bu (62 mg, 0.55 mmol) was added in a single
portion, followed by copper(II) acetate monohydrate (100
mg, 0.50 mmol). The green-black suspension was heated to
110 °C (oil bath temperature) over 15 min. After stirring at
110 °C for 18 h, the reaction was cooled to r.t. and quenched
with a sat. solution of NH4Cl (10 mL), diluted with H2O (20
mL), and extracted with EtOAc (20 mL). The organic layer
was washed with a sat. brine solution (2 × 20 mL), dried
(Na2SO4), filtered, and concentrated in vacuo to give an
orange oil. Purification by flash column chromatography
(SiO2, 7:2:1 PE–CH2Cl2–EtOAc) gave product 5g (141 mg,
73%) as a colorless gum; Rf = 0.44 (3:1 PE–EtOAc). IR
(film): nmax = 3056, 2978, 2932, 1734, 1715, 1610, 1493,
1471, 1370, 1351, 1306, 1251, 1155, 1086, 997, 909, 750
cm–1. 1H NMR (400 MHz, CHCl3-d1): d = 1.41 (9 H, s,
CMe3), 2.89 (3 H, s, NMe), 3.64 (1 H, d, J = 13.5 Hz, CH2),
3.69 (1 H, d, J = 13.5 Hz, CH2), 6.50 (1 H, d, J = 7.5 Hz,
ArH), 6.98 (1 H, dd, J = 8.5, 2.0 Hz, ArH), 7.06 (1 H, ddd,
J = 7.5, 7.5, 1.0 Hz, ArH), 7.17 (1 H, ddd, J = 7.5, 7.5, 1.5
Hz, ArH), 7.33–7.37 (3 H, m, ArH), 7.38 (1 H, ddd, J = 7.5,
1.5, 0.5 Hz, ArH), 7.48 (1 H, d, J = 8.5 Hz, ArH), 7.60 (1 H,
dd, J = 6.0, 3.5 Hz, ArH), 7.67 (1 H, dd, J = 6.0, 3.5 Hz,
ArH). 13C NMR (100 MHz, CHCl3-d1): d = 26.1 (NMe), 27.8
(CMe3), 39.7 (CH2), 61.8 (C), 82.6 [OC(CH3)3], 108.1
(ArH), 122.3 (ArH), 123.6 (ArH), 125.4 (ArH), 125.5 (ArH),
126.9 (ArH), 127.3 (ArH), 127.7 (ArH), 127.8 (Ar), 128.3
(ArH), 128.8 (2 × ArH), 132.1 (Ar), 132.5 (Ar), 132.9 (Ar),
144.1 (Ar), 168.1 (C=O), 173.8 (C=O). ESI-MS: m/z =
410 [MNa]+. ESI-HRMS: m/z calcd for C25H25NNaO3:
410.1727; found: 410.1731 [MNa]+; 0.6 ppm error.
References and Notes
(1) Perry, A.; Taylor, R. J. K. Chem. Commun. 2009, 3249.
(2) For related processes, see: (a) Jia, Y.-X.; Kündig, E. P.
Angew. Chem. Int. Ed. 2009, 48, 1636. (b) Miura, T.; Ito,
Y.; Murakami, M. Chem. Lett. 2009, 38, 328. (c) Liang, J.;
Chen, J.; Du, F.; Zeng, X.; Li, L.; Zhang, H. Org. Lett. 2009,
11, 2820. (d) Teichert, A.; Jantos, K.; Harms, K.; Studer, A.
Org. Lett. 2004, 6, 3477.
(3) (a) Bui, T.; Borregan, M.; Barbas, C. F. III. Org. Lett. 2009,
11, 8935. (b) Qian, Z.-Q.; Zhou, F.; Du, T.-P.; Wang, B.-L.;
Ding, M.; Zhao, X.-L.; Zhou, J. Chem. Commun. 2009,
6753. (c) Jiang, K.; Peng, J.; Cui, H.-L.; Chen, Y.-C. Chem.
Commun. 2009, 3955. (d) Kato, Y.; Furutachi, M.; Chen, Z.;
Mitsunuma, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2009, 131, 9168. (e) Sano, D.; Nagata, K.; Itoh, T. Org.
Lett. 2008, 10, 1593. (f) Nakazawa, N.; Tagami, K.; Iimori,
H.; Sano, S.; Ishikawa, T.; Nagao, Y. Heterocycles 2001, 55,
2157. (g) Miah, S.; Moody, C. J.; Richards, I. C.; Slawin,
A. M. Z. J. Chem. Soc., Perkin Trans. 1 1997, 2405.
(h) Damavandy, J. A.; Jones, R. A. Y. J. Chem. Soc., Perkin
Trans. 1 1981, 712.
(4) (a) Shimazawa, R.; Kuriyama, M.; Shirai, R. Bioorg. Med.
Chem. Lett. 2009, 18, 3350. (b) Rizzi, E.; Cassinelli, G.;
Dallavalle, S.; Lanzi, C.; Cincinelli, R.; Nannei, R.;
Cuccuru, G.; Zunino, F. Bioorg. Med. Chem. Lett. 2007, 17,
3962.
(5) (a) Henderson, D.; Richardson, K. A.; Taylor, R. J. K.;
Saunders, J. Synthesis 1983, 996; and references therein.
(b) Successful decarboxyalkylation of related systems under
acidic conditions is precedented: Tani, M.; Matsumoto, S.;
Aida, Y.; Arikawa, S.; Nakane, A.; Yokoyama, Y.;
Murakami, Y. Chem. Pharm. Bull. 1994, 42, 443.
(6) All novel compounds were fully characterised..
(7) Bald, E.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975, 4,
1163.
(11) Representative Procedure for Decarboxyalkylation:
1-Methyl-3-(naphthalen-2-ylmethyl) indolin-2-one (3g)
A 10 mL round-bottomed flask with stirrer bar was charged
with tert-butyl ester 5g (97 mg, 0.25 mmol) and anisole (82
mL, 0.75 mmol), a septum was fitted and the flask purged
with argon(balloon). TFA (1 mL) was added, and the
resulting brown solution was stirred for 2 h. The reaction
mixture was concentrated in vacuo to give a yellow gum.
Purification by flash column chromatography (SiO2, 4:1 PE–
EtOAc) gave oxindole 3g (67 mg, 93%) as a yellow solid.
(8) Millemaggi, A.; Perry, A.; Taylor, R. J. K. Eur. J. Org.
Chem. 2009, 2947.
(9) Prepared by the alkylation of amide 8 using the route shown
in Scheme 4; all yields were greater than 88% with the
Synlett 2010, No. 6, 934–938 © Thieme Stuttgart · New York

938
D. S. Pugh et al.
LETTER
Rf = 0.39 (3:1 PE–EtOAc); mp 91–93 °C. IR (film): nmax
=
ArH), 7.43–7.47 (2 H, m, ArH), 7.60 (1 H, br s, ArH), 7.73–
7.82 (3 H, m, ArH). 13C NMR (100 MHz, CHCl3-d1): d =
26.2 (NMe), 37.0 (CH2), 46.9 (CH), 107.9 (ArH), 122.1
(ArH), 124.5 (ArH), 125.5 (ArH), 126.0 (ArH), 127.6 (3 ×
ArH), 127.9 (2 × ArH), 128.0 (ArH), 128.3 (Ar), 132.3 (Ar),
133.3 (Ar), 135.5 (Ar), 144.1 (Ar), 177.0 (C=O). ESI-MS:
m/z = 310 [MNa]+. ESI-HRMS: m/z calcd for C20H17NNaO:
310.1202; found: 310.1196 [MNa]+; 1.6 ppm error.
3053, 2920, 2853, 1709, 1612, 1493, 1469, 1422, 1375,
1350, 1256, 1127, 1089, 750, 732 cm–1. 1H NMR (400 MHz,
CHCl3-d1): d = 3.04 (1 H, dd, J = 13.5, 9.5 Hz, CH2), 3.17 (3
H, s, NMe), 3.67 (1 H, dd, J = 13.5, 4.5 Hz, CH2), 3.84 (1 H,
dd, J = 9.5, 4.5 Hz, CH), 6.71–6.77 (2 H, m, J = 7.5 Hz,
ArH), 6.88 (1 H, ddd, J = 7.5, 7.5, 1.0 Hz, ArH), 7.21 (1 H,
dd, J = 8.0, 8.0 Hz, ArH), 7.34 (1 H, dd, J = 8.5, 1.5 Hz,
Synlett 2010, No. 6, 934–938 © Thieme Stuttgart · New York