Facile and general synthesis of quaternary 3-aminooxindoles

Article abstract of DOI:10.1021/ol801028e

(Chemical Equation Presented) A novel approach to the valuable quaternary 3-aminooxindole skeleton is reported on the basis of intramolecular arylation of enolates of substituted amino acids. The reaction tolerates dialkyl- and arylalkylamines as well as a range of carbon substituents (primary and secondary alkyl, aryl). The cyclization of N-indolyl-substituted substrates is accompanied by direct C-H arylation of the indole, leading to indolo-fused benzodiazepines.

Full text of DOI:10.1021/ol801028e

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2905-2908
Facile and General Synthesis of
Quaternary 3-Aminooxindoles
Stephen P. Marsden,*,† Emma L. Watson,† and Steven A. Raw‡
School of Chemistry, UniVersity of Leeds, Leeds LS2 9JT, U.K., and AstraZeneca
Process R&D, Charter Way, Silk Road Business Park, Macclesfield SK10 2NA, U.K.
s.p.marsden@leeds.ac.uk
Received May 5, 2008
ABSTRACT
A novel approach to the valuable quaternary 3-aminooxindole skeleton is reported on the basis of intramolecular arylation of enolates of
substituted amino acids. The reaction tolerates dialkyl- and arylalkylamines as well as a range of carbon substituents (primary and secondary
alkyl, aryl). The cyclization of N-indolyl-substituted substrates is accompanied by direct C-H arylation of the indole, leading to indolo-fused
benzodiazepines.
3,3-Disubstituted oxindoles constitute a valuable class of
biologically active molecules. Among these structures,
several quaternary 3-aminooxindoles have been promoted
as pharmaceutical candidates, including the potent gastrin/
CCK-B receptor antagonist AG-041R (1)1 and the vaso-
pressin VIb receptor antagonist SSR-149415 (2)2 (Figure 1).
Moreover, several members of the indole alkaloid family of
natural products contain skeleta that could potentially be
accessed synthetically via 3-aminooxindoles. Pertinent ex-
amples include the 3H-indole skeleton of the chartellines
(e.g., chartelline C, 3)3 and the hexahydropyrroloindole
skeleton of the immunosuppressant psychotrimine (4).4
Figure 1. Bioactive quaternary aminooxindoles and indolines.
Quaternary 3-aminooxindoles have previously been syn-
thesized by a variety of methods, including alkylation of
3-aminooxindoles,5 substitution of 3-chlorooxindoles by
amines,6 Mannich reactions7 and Staudinger [2 + 2] cy-
cloadditions8 of isatin imines, [3 + 2] cycloadditions of
isatin-derived azomethine ylides,9 radical addition10 and
† University of Leeds.
‡ AstraZeneca Process R&D.
(1) Ochi, M.; Kawasaki, K.; Kataoka, H.; Uchio, Y. Biochem. Biophys.
Res. Commun. 2001, 283, 1118.
(2) (a) Bernard, K.; Bogliolo, S.; Ehrenfeld, J. Br. J. Pharmacol. 2005,
144, 1037. (b) Gilles, G.; Claudine, S. L. Stress 2003, 6, 199.
(3) (a) Chevolot, L.; Chevolot, A.-M.; Gajhede, M.; Larsen, C.; Anthoni,
U.; Christophersen, C. J. Am. Chem. Soc. 1985, 107, 4542. (b) Anthoni,
U.; Chevolot, L.; Larsen, C.; Nielsen, P. H.; Christophersen, C. J. Org.
Chem. 1987, 52, 4709. (c) Nielsen, P. H.; Anthoni, U.; Christophersen, C.
Acta Chem. Scand. 1988, B42, 489.
(6) (a) Magnus, P.; Turnbull, R. Org. Lett. 2006, 8, 3497. (b) Ghosh,
A. K.; Schiltz, G.; Perali, R. S.; Leschenko, S.; Kay, S.; Walters, D. E.;
Koh, Y.; Maeda, K.; Mitsuya, H. Bioorg. Med. Chem. Lett. 2006, 16, 1869.
(7) Nishikawa, T.; Kajii, S; Isobe, M. Chem. Lett. 2004, 33, 440.
(8) For recent examples, see:(a) Lin, X.; Weinreb, S. M. Tetrahedron
Lett. 2001, 42, 2631. (b) Sun, C.; Lin, X.; Weinreb, S. M. J. Org. Chem.
2006, 71, 3159. (c) Singh, G. S.; Mmolotsi, B. J. J. Heterocycl. Chem.
2006, 43, 1665. (d) Jarrahpour, A.; Khalili, D. Tetrahedron Lett. 2007, 48,
7140.
(4) Takayama, H.; Mori, I.; Kitajima, M. Org. Lett. 2004, 6, 2945.
(5) (a) Emura, T.; Eseki, T.; Tachibana, K.; Shimizu, M. J. Org. Chem.
2006, 71, 8559. (b) Zhao, H.; Thurkauf, A.; Braun, J.; Brodbeck, R.;
Kieltyka, A. Bioorg. Med. Chem. Lett. 2000, 10, 2119.
10.1021/ol801028e CCC: $40.75
Published on Web 06/06/2008
2008 American Chemical Society

cyclization reactions,11 reductive cyclization of SNAr-derived
nitroarylglycines,12 and aziridination of 3-methylideneoxin-
doles.13 However, these strategies lack generality in that a
given protocol cannot be commonly applied to diverse C3-
substituents (alkyl or aryl carbon substituents; alkyl or aryl
amine substituents) or can only provide access to spirocyclic
derivatives.8,9,13 The development of a novel method for the
synthesis of 3-aminooxindoles that enables complete control
of the C3-substituents would therefore be of significant value.
We report herein the first use of palladium-catalyzed enolate
arylation to achieve this goal.
reaction conditions for the efficient cyclization of substrate
5a, containing a basic pyrrolidinyl group as the nitrogen
substituent (Table 1).
Table 1. Optimization of Arylation Reaction Conditions
The synthesis of oxindoles (including 3,3-disubstituted
variants) by palladium-catalyzed intramolecular arylation of
anilide enolates developed by Hartwig14 has received some
attention,15 and asymmetric variants14b,16 of the reaction with
usable (>90% ee) levels of enantioselectivity were recently
reported by Ku¨ndig.16d
The application of this reaction to the synthesis of
3-aminooxindoles is very appealing since the requisite anilide
substrates 5 can be readily accessed from commercially
available R-haloalkanoyl halides or amino acid methyl esters,
leading to diverse substitution in the product oxindoles 6
(Figure 2). The tolerance of the intramolecular enolate
entry
base
ligand
% cat. T (°C) yielda (%)
1
2
3
4
5
6
7
8
9
10
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
HPCy3·BF4
HPCy3·BF4
HPCy3·BF4
10
10
10
10
10
10
10
10
5
100b
110b
110
110
110
110
110
110
110
130
10c
12
76
61
0
0
28
8
NaO-t-Bud HPCy3·BF4
LHMDS
Cs2CO3
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
HPCy3·BF4
HPCy3·BF4
DavePhos
e
PPh3
HPCy3·BF4
HPCy3·BF4
33
70
10
a Isolated yield. b Conventional heating (oil bath). c Reaction carried
out in dioxane. d 2 equiv of base used. e Pd(PPh3)4 used as palladium/ligand
source.
Initial reactions were carried out (using conditions close
to Hartwig’s original report14) under conventional heating
(oil bath) in dioxane and toluene, with both systems giving
poor conversions (entries 1 and 2). In the reaction in dioxane,
some hydrodebromination of the starting material was also
observed, so toluene became the solvent of choice. On
moving to microwave-mediated heating (fixed temperature)
in a sealed vessel, complete consumption of the starting
material was observed and a 76% isolated yield of aminoox-
indole obtained (entry 3). Altering the stoichiometry or nature
of the base did not improve the process (entries 4-6), and
other phosphine ligands were less effective than tricyclo-
hexylphosphine (entries 7 and 8).
Figure 2. Enolate arylation strategy for the synthesis of quaternary
3-aminooxindoles.
arylation to heteroatom substituents has not been widely
probed, however; there has been only a single application
to a C3-oxygenated oxindole,14b and at the outset of this
work there were no examples of the synthesis of nitrogen-
substitutedoxindoles.Giventhepotentiallystrongmetal-ligand
interaction between an amine and the palladium catalyst, the
innocent behavior of the nitrogen substituent in the reaction
could not be guaranteed. We therefore set out to establish
With optimized conditions identified, we next examined
the substrate scope of the reaction with respect to both the
nitrogen and carbon enolate substituents (Table 2).
The reaction shows remarkable tolerance to a range of
substituents with markedly different steric and electronic
properties. We first examined the influence of the nitrogen
substituent, keeping the (ethyl) carbon substituent constant
(entries 1-8). The reaction works equally well with cyclic
and acyclic dialkylamine substituents, and pleasingly, aro-
matic amines are also tolerated (entries 5 and 6). Cyclization
of the protected prolinol-containing substrate 5h was suc-
cessful but with no evidence for any stereocontrol in the
cyclization reaction from the existing asymmetric center
(entry 7). More readily deprotected N-Bn oxindoles can also
be prepared (entry 8). With respect to carbon substituents,
ꢀ-branched primary and secondary alkyl substituents have
little if any deleterious effect on yield (entries 9-11), while
substrates with aromatic substituents also cyclize effectively
(entries 12-14).
(9) (a) Ardill, H.; Dorrity, M. J. R.; Grigg, R.; Leon-Ling, M. S.; Malone,
J. F.; Sridharan, V.; Thianpatanagul, S. Tetrahedron 1990, 46, 6433, and
references thereinFor auxiliary-controlled asymmetric examples, see: (b)
Coulter, T.; Grigg, R.; Malone, J. F.; Sridharan, V. Tetrahedron Lett. 1991,
32, 5417.
(10) Miyabe, H.; Yamaoka, Y.; Takemoto, Y. J. Org. Chem. 2005, 70,
3324.
(11) (a) Beckwith, A. L. J.; Storey, J. M. D. J. Chem. Soc., Chem.
Commun. 1995, 977. (b) Jones, K.; Ho, T. C. T.; Wilkinson, J. Tetrahedron
Lett. 1995, 36, 6743. (c) Bella, A. F.; Slawin, A. M. Z.; Walton, J. C. J.
Org. Chem. 2004, 69, 5926.
(12) O’Connor, S. J.; Liu, Z. Synlett 2003, 2135.
(13) Loreto, M. A.; Migliorini, A.; Tardella, P. A.; Gambacorta, A. Eur.
J. Org. Chem. 2007, 2365.
(14) (a) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org.
Chem. 1998, 63, 6546. (b) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66,
3402.
2906
Org. Lett., Vol. 10, No. 13, 2008

the latter being the only subject to date of a published
synthetic approach.19 However, a survey of the literature
revealed limited examples of the enolate chemistry of
R-(N-indolyl)carboxyl substrates20 and only a sole example
leading to a quaternary center,20c raising concerns about
the viability of these species in the arylation process. In
the event, under our standard conditions, compound 5p
underwent efficient arylation to deliver the desired ary-
lation product 6p in 65% yield (Scheme 1). This com-
Table 2. Substrate Scope of Enolate Arylation Approach to
Quaternary Aminooxindoles
Scheme 1. Arylation Reactions of Indole-Containing Substrates
pound was accompanied by a small amount (3%) of what
appeared to be the indolo-fused benzodiazepinone 7a, the
product of a competing direct intramolecular C2-arylation
of the indole.21 The identity of the compound and its likely
mechanism of formation were established by repeating the
reaction under identical conditions, but utilizing only
sufficient base to liberate the free phosphine ligand. In
the absence of any base to promote enolate formation,
compound 7 was the sole product of the reaction, isolated
in a modest 26% yield. Interestingly, compounds with this
heterocyclic skeleton have been shown to have interesting
activity against hepatitis C virus,22 and further optimiza-
tion of this reaction may provide a useful approach to
this system. In this regard, when the N-benzyl-protected
substrate 5q was treated under the standard enolate
arylation conditions, the reaction afforded only the ben-
zodiazepinone 7b in an unoptimized 60% yield. This
suggests that the balance between enolate and direct indole
arylation can be engineered by modification of the
substrate structure as well as the reaction conditions.
a Isolated yield. b 1:1 mixture of diastereoisomers.
A further interesting class of substrates we wished to
examine was the N-indolyl-substituted substrates 5p,q.
These are of interest since the transformation could serve
as an approach to the 3-(N-indolyl)-substituted indole
alkaloids such as the kapakahines,17 the chetomin/cheto-
seminudin/chaetococcin family,18 and psychotrimine (4),4
(18) (a) McInnes, A. G.; Taylor, A.; Walter, J. A. J. Am. Chem. Soc.
1976, 98, 6741. (b) Fujimoto, H.; Sumino, M.; Okuyama, E.; Ishibashi, M.
J. Nat. Prod. 2004, 67, 98. (c) Li, G.-Y.; Li, B.-G.; Yang, T.; Yan, J.-F.;
Liu, G.-Y.; Zhang, G.-L. J. Nat. Prod. 2006, 69, 1374.
(19) Matsuda, Y.; Kitajima, M.; Takyama, H. Org. Lett. 2008, 10, 125.
(20) (a) Batt, D. G.; Qiao, J. X.; Modi, D. P.; Houghton, G. C.; Pierson,
D. A.; Rossi, K. A.; Luettgen, J. M.; Knabb, R. M.; Jadhav, P. K.; Wexler,
R. R. Bioorg. Med. Chem. Lett. 2004, 14, 5269. (b) Bennasar, M.-L.; Zulaica,
E.; Alonso, Y.; Vidal, B.; Vazquez, J. T.; Bosch, J. Tetrahedron: Asymmetry
2002, 13, 95, and references therein. (c) Della Salla, G.; Capozzo, D.; Izzo,
I.; Giordano, A.; Iommazzo, A.; Spinella, A. Tetrahedron Lett. 2002, 43,
8839. (d) Christie, B. D.; Rapoport, H. J. Org. Chem. 1985, 50, 1239.
(21) Other examples of palladium-catalyzed C2-arylation of N-alkylin-
doles:(a) Kozikowski, A. P.; Ma, D. Tetrahedron Lett. 1991, 32, 3317. (b)
Kozikowski, A. P.; Ma, D.; Brewer, J.; Sun, S.; Costa, E.; Romeo, E.;
Guidotti, A. J. Med. Chem. 1993, 36, 2908. (c) Desarbre, E.; Me´rour, J.-Y.
Heterocycles 1995, 41, 1987. (d) Toure´, B. B.; Lane, B. S.; Sames, D. Org.
Lett. 2006, 8, 1979. (e) Avila-Zarraga, J. G.; Lujan-Montelongo, A.;
Covarrubias-Zuniga, A.; Romero-Ortega, M. Tetrahedron Lett. 2006, 47,
7987. (f) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Paladino, G.; Rossi,
E. Synthesis 2006, 2404.
(15) (a) Freund, R.; Mederski, W. W. K. R. HelV. Chim. Acta 2000, 83,
1247. (b) Zhang, T. Y.; Zhang, H. Tetrahedron Lett. 2002, 43, 193. (c)
Zhang, T. Y.; Zhang, H. Tetrahedron Lett. 2002, 43, 1363. (d) Bignan,
G. C.; Battista, K.; Connolly, P. J.; Orsini, M. J.; Liu, J.; Middleton, S. A.;
Reitz, A. B. Bioorg. Med. Chem. Lett. 2005, 15, 5022.
(16) (a) Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C. Chem.
Commun. 2002, 2704. (b) Arao, T.; Kondo, K.; Aoyama, T. Chem. Pharm.
Bull. 2006, 54, 1743. (c) Arao, T.; Kondo, K.; Aoyama, T. Tetrahedron
Lett. 2006, 47, 1417. (d) Ku¨ndig, E. P.; Seidel, T. M.; Jia, Y.-X. Angew.
Chem., Int. Ed. 2007, 46, 8484.
(17) (a) Nakao, Y.; Yeung, B. K. S.; Yoshida, W. Y.; Scheuer, P. J.;
Kelly-Borges, M. J. Am. Chem. Soc. 1995, 117, 8271. (b) Yeung, B. K. S.;
Nakao, Y.; Kinnel, R. B.; Carney, J. R.; Yoshida, W. Y.; Scheuer, P. J.;
Kelly-Borges, M. J. Org. Chem. 1996, 61, 7168. (c) Nakao, Y.; Kuo, J.;
Yoshida, W. Y.; Kelly, M.; Scheuer, P. J. Org. Lett. 2003, 5, 1387.
Org. Lett., Vol. 10, No. 13, 2008
2907

In summary, we have demonstrated that palladium-
catalyzed enolate arylation chemistry is tolerant of a wide
range of amine substituents on the enolate, leading to an
efficient and novel approach to the biologically interesting
3-aminooxindole structure. The substrates are readily pre-
pared from widely available amino acid or R-halocarbonyl
starting materials, greatly enhancing the synthetic potential
of the method. The development of asymmetric variants and
synthetic applications of the method are under evaluation,
as are further studies of the formation of benzodiazepinones
7 by direct arylation, and the results will be reported in due
course.
Acknowledgment. We thank the EPSRC and AstraZeneca
for a CASE award (E.L.W.) and the EPSRC for further
support (EP/D002818/1).
Supporting Information Available: Compound charac-
terization data and spectra for compounds 5a-q, 6a-p, and
7a/b, together with standard experimental protocols. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) Ikegashira, K.; Oka, T.; Hirashima, S.; Noji, S.; Yamanaka, H.;
Hara, Y.; Adachi, T.; Tsuhara, J.-I.; Doi, S.; Hase, Y.; Noguchi, T.; Ando,
I.; Ogura, N.; Ikeda, S.; Hashimoto, H. J. Med. Chem. 2006, 49, 6950.
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