Synthesis of 2-hydroxy-3-indolinones and 3-hydroxy-2-indolinones by anionic cyclization, in situ oxidation and rearrangement

Article abstract of DOI:10.1016/j.tetlet.2010.02.159

Lithiation with butyllithium of 2-(benzylamino)benzamides (N-benzyl anthranilamides) occurs at the benzylic position to give an α-amino-organolithium that cyclizes to the 3-indolinone (indoxyl) ring (similar to a Parham cyclization). Autoxidation in air g

Full text of DOI:10.1016/j.tetlet.2010.02.159

Tetrahedron Letters 51 (2010) 2457–2460
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 2-hydroxy-3-indolinones and 3-hydroxy-2-indolinones
by anionic cyclization, in situ oxidation and rearrangement
*
Iain Coldham , Harry Adams, Neil J. Ashweek, Thomas A. Barker, Andrew T. Reeder, Melanie C. Skilbeck
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Lithiation with butyllithium of 2-(benzylamino)benzamides (N-benzyl anthranilamides) occurs at the
Received 14 January 2010
Revised 11 February 2010
Accepted 26 February 2010
Available online 4 March 2010
benzylic position to give an a-amino-organolithium that cyclizes to the 3-indolinone (indoxyl) ring (sim-
ilar to a Parham cyclization). Autoxidation in air gives 2-hydroxy-3-indolinones. In the absence of a pro-
ton source, rearrangement of the aryl group from C-2 to C-3 occurs to give the 3-hydroxy-2-indolinone
(oxindole) ring.
Ó 2010 Elsevier Ltd. All rights reserved.
The Parham-type cyclization of an organometallic species onto a
carboxylicamidegrouphasbeenusedforthepreparationof avariety
of substituted cyclic ketones.1 The chemistry is amenable to the
presence of a heteroatom in the ring to provide a method to prepare
heterocyclic ketones.2–5 Our research group has a long-standing
interest in the preparation of cyclic amines using an anionic cycliza-
tion (intramolecular carbometalation) strategy.6 This chemistry
O
CONEt2
SnBu3
BuLi
N
N
THF, –60 °C
64%
Ph
Ph
1
2
Scheme 1. Cyclization to the pyrrolidin-3-one 2.7
involves the cyclization of an
a-amino-organolithium onto an
alkene, although we have previously reported one example of a
cyclization onto a carboxylic amide (Scheme 1).7 In this case, the
organolithium derived from the stannane 1 undergoes cyclization
to give the pyrrolidin-3-one 2 after aqueous work-up.
CO2Me
NH2
CONEt2
NH2
CONEt2
Ph
i
ii
N
One of the problems with this chemistry is that it involves the
use of potentially toxic organotin compounds. We therefore
considered how to conduct such cyclizations by simple proton
abstraction. This would require a relatively acidic molecule that
could be deprotonated in preference to reaction of the base with
the carboxylic amide (or other carbonyl group). We reasoned that
benzylic organolithiums could be formed in this way and could be
sufficiently reactive to cyclize onto the pendant carbonyl group.4,5
We report here the successful demonstration of this approach and
its application to the preparation of 2- or 3-indolinones (oxindoles
or indoxyls).
To avoid complications with enolate formation, we selected the
carboxylic amide 5a for initial studies. Amide 5a was prepared in
two steps from methyl anthranilate (3) (Scheme 2). This was
accomplished by reaction of methyl anthranilate with lithium
diethylamide followed by double N-benzylation with excess
benzyl bromide in acetonitrile and potassium carbonate.
The key step in our sequence is the treatment of the benzyl-
amine 5a with a base. There are several protons that could be
Ph
3
4
5a
Scheme 2. Preparation of the carboxylic amide 5a. Reagents and conditions: (i)
Et2NH, BuLi, Et2O, 0 °C then heat, 90 min, 55%; (ii) PhCH2Br, MeCN, K2CO3, rt, then
heat, 24 h, 80%.
removed from compound 5a, although we were hoping that one
of the benzylic protons alpha to the nitrogen atom would be most
acidic, possibly helped by a complex-induced proximity effect.8
After screening several bases and conditions we found that n-BuLi
in Et2O provided a reasonable yield of a cyclization product arising
from benzylic deprotonation (Scheme 3). Lower yields were
O
CONEt2
i
OH
Ph
N
N
Ph
Ph
Ph
5a
6a
* Corresponding author. Tel.: +44 (0)114 222 9428; fax: +44 (0)114 222 9346.
E-mail address: i.coldham@sheffield.ac.uk (I. Coldham).
Scheme 3. Cyclization to the 3-indolinone 6a. Reagents and conditions: (i) 2 equiv
n-BuLi, Et2O, À78 °C to rt, 4 h, then air, 30 min, then MeOH, 51%.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.159

2458
I. Coldham et al. / Tetrahedron Letters 51 (2010) 2457–2460
Figure 2. Single crystal X-ray structure of product 7c.
O
CONEt2
Li
Figure 1. Single crystal X-ray structure of product 6a.
5c
Ar
Ar
N
N
Ar
obtained using different bases or solvents (e.g., n-BuLi in THF,
PhMe or Et2O/TMEDA). Spectroscopic analysis revealed that the
product 6a was not that from simple cyclization and loss of dieth-
ylamide, but contained a hydroxy group. This was confirmed by
single crystal X-ray analysis (Fig. 1). From this we deduce that
the product from initial cyclization undergoes oxidation in air,
and indeed the yield of the product 6a was slightly enhanced by
allowing the mixture to stir in air after warming to room temper-
ature. This methodology therefore allows a novel and unusual en-
try to a 2-phenyl-2-hydroxy-3-indolinone (a 2-hydroxyindoxyl).9
To explore the scope of this transformation, we prepared the
carboxylic amides 5b and 5c by analogous chemistry, starting from
the amine 4 (Scheme 4). Treatment of the amide 5b with n-BuLi
under the same conditions as used for compound 5a gave none
of the desired cyclic product. Quenching this reaction with D2O
gave recovered starting material 5b, suggesting that no proton
abstraction was occurring. By contrast, the para-methyl analogue
5c did undergo the deprotonation–cyclization reaction, however
the product was not the expected ketone, but the oxindole 7c.
Evidence for the oxindole product 7c came from 13C NMR
spectroscopic studies (in CDCl3), in which the carbonyl carbon
resonates at 179 ppm, whereas the ketone carbon in compound
6a resonates at 198 ppm (in C6D6).
Ar
OLi
Ar
O
7c
N
6c
Ar
Scheme 5. Possible pathway for the formation of oxindole 7c.
We therefore re-explored the lithiation of the amide 5a with
n-BuLi and found that, under what seemed to be identical conditions
to those described in Scheme 3, the oxindole 7a was now the major
product, as judged by NMR spectroscopy (46% yield).12 The forma-
tion of the oxindoles (7a and 7c) seemed to depend on the amount
ofbasethatwasadded. Amorereliablemethodtopreparetheketone
6a was found, in which acetic acid was added at room temperature
before exposing to air (Scheme 6). It was reasoned that this should
promote protonation of any alkoxide and thereby disfavour rear-
rangement, and we were pleased to find that the ketone 6a was
formed under these conditions [38% yield, together with a small
amount (<10% yield) of starting material 5a, but no oxindole 7a].13
In addition, the ketone 6a could be transformed in high yield into
the oxindole 7a by heating with KOH in ethanol.
The ability to prepare either the 3-indolinones 6 or the 2-indoli-
nones 7 was confirmed by treating the amide 5c with butyllithium
followed by warming to room temperature, the addition of acetic
acid then exposure to air. This gave the desired 3-indolinone 6c
(and none of the oxindole 7c), (Scheme 7). This illustrates the abil-
ity to prepare either cyclization product (6 or 7) from the same
amide substrate (5).
In addition, X-ray crystallographic analysis of 7c showed the
oxindole ring system (Fig. 2). The conversion of the amide 5c into
the oxindole 7c presumably occurs through the ketone 6c (formed
by autoxidation of the intermediate indolin-3-one) followed by
rearrangement (Scheme 5). This rearrangement has been proposed
in related chemistry.10,11
To investigate the possibility of carrying out the chemistry with
substituents on the benzamide ring, we prepared compounds 10,
13a and 13b (Scheme 8). Starting with the substituted anthranilic
CONEt2
Ar
OH
i
ii
4
Ph
O
OH
from 5c
O
CONEt2
Ph
N
i
ii
OH
Ph
N
O
Ar
5b
5c
Ar = C6H4-p-OMe
Ar = C6H4-p-Me
N
N
N
7c
Ph
Ph
Ph
5a
6a
7a
Scheme 4. Formation of the substrates 5b and 5c and treatment with base.
Reagents and conditions: (i) p-MeOC6H4CH2Cl or p-MeC6H4CH2Br, MeCN, K2CO3, rt,
then heat, 24 h, 5b 47%, 5c 79%; (ii) 2 equiv n-BuLi, Et2O, À78 °C to rt, 6 h, then air,
30 min, then MeOH, 7c 47%.
Scheme 6. Cyclization to the ketone 6a and conversion into the oxindole 7a.
Reagents and conditions: (i) 2 equiv n-BuLi, Et2O, À78 °C to rt, 6 h, then AcOH
(4 equiv), air, 1 h, then MeOH 6a, 38%; (ii) KOH, EtOH, heat, 7a, 88%.

I. Coldham et al. / Tetrahedron Letters 51 (2010) 2457–2460
2459
O
CONEt2
Ar
i
OH
Ar
N
N
Ar
Ar
Ar = C6H4-p-Me
5c
6c
Scheme 7. Cyclization to the ketone 6c. Reagents and conditions: (i) 2 equiv n-BuLi,
Et2O, À78 °C to rt, 16 h, then AcOH, air, 1 h, then MeOH, 33%.
CO2H
NH2
CONEt2
NH2
CONEt2
Ph
i
ii
Cl
Cl
Cl
N
Ph
CONEt2
Ar
8
9
10
Figure 3. Single crystal X-ray structure of product 17.
CO2H
NH2
CONEt2
NH2
i
ii
In line with the other oxindole products, the carbonyl carbon in
compound 17 resonates at 180 ppm in the 13C NMR spectrum (in
CDCl3). An authentic sample of the oxindole 17 was prepared from
N-methylisatin and phenylmagnesium chloride and its spectro-
scopic data were identical to that from the product of deprotona-
tion–cyclization of 16. In addition, a single crystal X-ray structure
of the oxindole 17 was obtained (Fig. 3). An attempt to carry out
the cyclization with acetic acid quench gave only a very low yield
of the 3-indolinone product.
N
Ar
11
12
13a
13b
Ar = Ph
Ar = C6H4-p-Me
Scheme 8. Preparation of the carboxylic amides 10, 13a and 13b. Reagents and
conditions: (i) N-hydroxysuccinimide, DCC, dioxane, rt, 3 d, then isolation of the
(crude) activated ester (from 8 67%, from 11 55%), then Et2NH, 60 °C, 4 h, 9 43%, 12
56%; (ii) ArCH2Br, MeCN, K2CO3, rt, then heat, 2 d, 10 67%, 13a 57%, 13b 50%.
In summary, we have demonstrated a simple method for the
preparation of 2-aryl-2-hydroxy-3-indolinones and 3-aryl-3-hy-
droxy-oxindoles. This occurs by regioselective lithiation at the ben-
zylic position of N-benzyl anthranilic acid amides followed by
cyclization onto the carboxylic amide group. The 3-indolinone
products were found to be the result of autoxidation in air and
these rearrange under basic conditions to oxindole ring products.
acids 8 and 11, the carboxylic amides 9 and 12 were obtained via the
activated esters of 8 and 11 (using N-hydroxysuccinimide plus dicy-
clohexylcarbodiimide followed by treatment with diethylamine).
Benzylations then provided the substrates 10, 13a and 13b. In addi-
tion to these substrates, we prepared the N-benzyl-N-methyl deriv-
ative 16 (see Scheme 9) from commercial methyl N-methyl
anthranilate byamideformation (Et2NLi)followedbyN-benzylation.
Treatment of the substrates 10, 13a and 13b with n-BuLi in Et2O
(no acetic acid quench) gave the oxindoles 14, 15a and 15b, respec-
tively, in moderate yields (Scheme 9). In each case IR and NMR
spectroscopic data, together with high resolution mass spectrome-
try, confirmed the identity of the products. The substrate 16 gave
mixed results, with the ketone 18 as the major product using n-
BuLi. However, using sec-BuLi a reasonable yield of the cyclized
product 17 was obtained (Scheme 9).
Acknowledgements
We thank the University of Sheffield, the Nuffield Foundation
(URB/34219) and Pfizer for support for undergraduate student bur-
saries. Mr. C. Lloyd is acknowledged for preliminary work. Profes-
sor C. J. Moody is thanked for helpful discussions. We are grateful
to the EPSRC X-ray crystallography service for the structure of 6a
(CCDC 217920). We wish to acknowledge the use of the Chemical
Database Service at Daresbury,14 and the software ConQuest15 and
Mercury16 for crystal structure searching and visualization. Com-
pounds 7c and 17 have been submitted to the Cambridge Crystal-
lographic Data Centre: 7c CCDC 754780, 17 CCDC 754779.
Ar
OH
CONEt2
COBu
i
O
References and notes
N
N
Ar
N
Ph
R
R
Me
R'
1. (a) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300; (b) Clayden, J.
Organolithiums: Selectivity for Synthesis; Pergamon, 2002. p 282, Chapter 7.2; (c)
Mealy, M. J.; Bailey, W. F. J. Organomet. Chem. 2002, 646, 59; (d) Sotomayor, N.;
Lete, E. Curr. Org. Chem. 2003, 7, 275.
2. (a) Lage, S.; Villaluenga, I.; Sotomayor, N.; Lete, E. Synlett 2008, 3188; (b) Ruiz,
J.; Sotomayor, N.; Lete, E. Tetrahedron 2006, 62, 6182; (c) Ruiz, J.; Ardeo, A.;
Ignacio, R.; Sotomayor, N.; Lete, E. Tetrahedron 2005, 61, 3311; (d) Ruiz, J.;
Sotomayor, N.; Lete, E. Org. Lett. 2003, 5, 1115.
3. (a) Lohse, O.; Beutler, U.; Fünfschilling, P.; Furet, P.; France, J.; Kaufmann, D.;
Penn, G.; Zaugg, W. Tetrahedron Lett. 2001, 42, 385; (b) MacNeil, S. L.; Gray, M.;
Briggs, L. E.; Snieckus, V. Synlett 1998, 419; (c) MacNeil, S. L.; Gray, M.; Gusev,
D. G.; Briggs, L. E.; Snieckus, V. J. Org. Chem. 2008, 73, 9710.
4. (a) Sanz, R.; Miguel, D.; Martínez, A.; Pérez, A. J. Org. Chem. 2006, 71, 4024; (b)
Pradhan, T. K.; De, A. Tetrahedron Lett. 2005, 46, 1493; (c) Linderman, R. J.;
Viviani, F. G.; Kwochka, W. R. Tetrahedron Lett. 1992, 33, 3571.
R'
18
R
Ar
Ph
Ph
R′
Ph
10
4-Cl
14 35%
15a 53%
13a 3-Me Ph
13b 3-Me C6H4- C6H4- 15b 39%
p-Me p-Me
16
H
H
Ph
17 43%
5. For cyclizations onto nitriles or other carbonyl derivatives, see: (a) Seong, C. M.;
Park, C. M.; Park, N. S. Tetrahedron Lett. 2009, 50, 1029; (b) Boger, D. L.; McKie, J.
A.; Nishi, T.; Ogiku, T. J. Am. Chem. Soc. 1997, 119, 311; (c) Lötter, A. N. C.;
Pathak, R.; Sello, T. S.; Fernandes, M. A.; van Otterlo, W. A. L.; de Koning, C. B.
Tetrahedron 2007, 63, 2263; (d) Wang, Y.; Ma, D. Tetrahedron: Asymmetry 2001,
12, 725; (e) Cartoon, M. E. K.; Cheeseman, G. W. H. J. Organomet. Chem. 1981,
Scheme 9. Cyclization to the oxindoles 14, 15a, 15b and 17. Reagents and
conditions: (i) for 10, 13a and 13b: 2 equiv n-BuLi, Et2O, À78 °C to rt, then air,
1 h, then MeOH; or, for 16: 2 equiv n-BuLi, Et2O, À78 °C to rt, 6 h, then air, 1 h, then
MeOH, 17 <10%, 18 78%; or 2 equiv sec-BuLi, Et2O, À78 °C to rt, 17 h, then air, 1 h,
then MeOH, 17 43%, 18 <10%.

2460
I. Coldham et al. / Tetrahedron Letters 51 (2010) 2457–2460
212, 1; For a recent cyclization onto an alkyne, see: (f) Kanazawa, C.; Goto, K.;
Terada, M. Chem. Commun. 2009, 5248.
Chem. Soc. 2006, 128, 16488; (h) Shintani, R.; Inoue, M.; Hayashi, T. Angew.
Chem., Int. Ed. 2006, 45, 3353; (i) Suárez-Castillo, O. R.; Sánchez-Zavala, M.;
Meléndez-Rodríguez, M.; Castelán-Duarte, L. E.; Morales-Ríos, M. S.; Joseph-
Nathan, P. Tetrahedron 2006, 62, 3040.
6. (a) Coldham, I.; Price, K. N.; Rathmell, R. E. Org. Biomol. Chem. 2003, 1, 2111; (b)
Ashweek, N. J.; Coldham, I.; Snowden, D. J.; Vennall, G. P. Chem. Eur. J. 2002, 8,
195; (c) Coldham, I.; Hufton, R.; Price, K. N.; Rathmell, R. E.; Snowden, D. J.;
Vennall, G. P. Synthesis 2001, 1523; (d) Coldham, I.; Vennall, G. P. Chem.
Commun. 2000, 1569; (e) Coldham, I.; Fernàndez, J.-C.; Price, K. N.; Snowden, D.
J. J. Org. Chem. 2000, 65, 3788; (f) Coldham, I.; Fernàndez, J.-C.; Snowden, D. J.
Tetrahedron Lett. 1999, 40, 1819; (g) Coldham, I.; Hufton, R.; Rathmell, R. E.
Tetrahedron Lett. 1997, 38, 7617; (h) Coldham, I.; Hufton, R. Tetrahedron 1996,
52, 12541; (i) Coldham, I.; Hufton, R.; Snowden, D. J. J. Am. Chem. Soc. 1996, 118,
5322; (j) Coldham, I.; Hufton, R. Tetrahedron Lett. 1995, 36, 2157; Coldham, I. J.
Chem. Soc., Perkin Trans. 1 1993, 1275.
12. Typical procedure for the formation of the oxindole 7a: n-BuLi (0.22 mL,
0.54 mmol, 2.5 M in hexanes) was added to the amide 5a (0.1 g, 0.27 mmol)
in dry Et2O (5 mL) at À78 °C. The mixture was allowed to warm to room
temperature over 4 h then air was blown over the surface for 30 min. MeOH
(1 mL) was added, the solvent was evaporated and the residue was purified by
column chromatography on silica gel, eluting with petrol–EtOAc (3:1), to give
7a (0.04 g, 46%) as a solid; mp 139–141 °C (lit.10b 144–145 °C); Rf [petrol–
EtOAc (4:1)] 0.17; vmax (cmÀ1) 3360, 3060, 3025, 1700, 1615; dH (400 MHz,
CDCl3) 3.41 (1H, s), 4.86 (1H, d, J 15.5 Hz), 5.08 (1H, d, J 15.5 Hz), 6.80–6.82 (1H,
m), 7.05–7.09 (1H, m), 7.23–7.45 (12H, m),10b found MH+ (ES) 316.1338,
C21H18NO2 requires 316.1338.
7. Coldham, I.; Lang-Anderson, M. M. S.; Rathmell, R. E.; Snowden, D. J.
Tetrahedron Lett. 1997, 38, 7621.
8. Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int. Ed. 2004, 43,
2206.
13. Typical procedure for the formation of the 3-indolinone 6a: n-BuLi (0.44 mL,
1.08 mmol, 2.45 M in hexanes) was added to the amide 5a (0.2 g, 0.54 mmol) in
dry Et2O (10 mL) at À78 °C. The mixture was allowed to warm to room
temperature over 6 h, then acetic acid (0.12 mL, 2.2 mmol) was added and the
mixture was exposed to the atmosphere for 1 h. MeOH (1 mL) was added, the
solvent was evaporated and the residue was purified by column
chromatography on silica gel, eluting with petrol–EtOAc (9:1), to give 6a
(0.065 g, 38%) as a solid; mp 78–80 °C; Rf [petrol–EtOAc (4:1)] 0.37; vmax
(cmÀ1) 3390, 3060, 3030, 1690, 1615; dH (400 MHz, CDCl3) 3.47 (1H, s), 4.43
(2H, s), 6.59–6.61 (1H, m), 6.78–6.82 (1H, m), 7.24–7.61 (12H, m); dC (100 MHz,
CDCl3) 47.2, 91.6, 109.0, 117.6, 118.6, 126.0, 126.1, 127.1, 127.3, 128.7, 128.9,
129.0, 136.5, 137.7, 138.8, 160.7, 199.7; found MH+ (ES) 316.1331, C21H18NO2
requires 316.1338.
14. Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem. Inf. Comput. Sci. 1996, 36,
746.
15. Bruno, I. J.; Cole, J. C.; Edgington, P. R.; Kessler, M.; Macrae, C. F.; McCabe, P.;
Pearson, J.; Taylor, R. Acta Crystallogr., Sect B 2002, 58, 389.
16. Macrae, C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor, R.;
Towler, M.; van de Streek, J. J. Appl. Crystallogr. 2006, 39, 453.
9. (a) Higuchi, K.; Sato, Y.; Tsuchimochi, M.; Sugiura, K.; Hatori, M.; Kawasaki, T.
Org. Lett. 2009, 11, 197; (b) Higuchi, K.; Sato, Y.; Kojima, S.; Tsuchimochi, M.;
Sugiura, K.; Hatori, M.; Kawasaki, T. Tetrahedron 2010, 66, 1236. The literature
(Ref. 2) suggests that the N-methyl-N-methoxy (Weinreb) amide analogue of 5
should be a slightly better substrate for cyclization, although attempts to
prepare this substrate from methyl N,N-dibenzylanthranilate or from the N-
methyl-N-methoxy amide of anthranilic acid were unsuccessful.
10. Sukari, M. A.; Vernon, J. M. J. Chem. Soc., Perkin Trans. 1 1983, 2219; (b) Kafka, S.;
Klasek, A.; Kosmrlj, J. J. Org. Chem. 2001, 66, 6394; (c) Hewitt, M. C.; Shao, L.
Arkivoc 2006, 11, 37.
11. For some recent references describing 3-hydroxy-2-indolinones, see: (a)
Tomita, D.; Yamatsugu, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009,
131, 6946; (b) Lai, H.; Huang, Z.; Wu, Q.; Qin, Y. J. Org. Chem. 2009, 74, 283; (c)
Hillgren, J. M.; Marsden, S. P. J. Org. Chem. 2008, 73, 6459; (d) Durbin, M. J.;
Willis, M. C. Org. Lett. 2008, 10, 1413; (e) Ramachary, D. B.; Reddy, G. B.;
Mondal, R. Tetrahedron Lett. 2007, 48, 7618; (f) Cariou, K.; Ronan, B.; Mignani,
S.; Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed. 2007, 46, 1881; (g)
Ishimaru, T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa, S. J. Am.