Copper-catalysed approach to spirocyclic oxindoles via a direct C-H, Ar-H functionalisation

Article abstract of DOI:10.1016/j.tetlet.2012.01.120

A practical and efficient entry to spirocyclic oxindoles from readily accessible anilide precursors, using only catalytic amounts of an inexpensive copper salt together with air as the sole re-oxidant, is described. In addition to providing access to a br

Full text of DOI:10.1016/j.tetlet.2012.01.120

Tetrahedron Letters 53 (2012) 1897–1899
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper-catalysed approach to spirocyclic oxindoles via a direct C–H, Ar-H
functionalisation
⇑
ˇ
Catherine L. Moody, Vilius Franckevicius, Pauline Drouhin, Johannes E.M.N. Klein, Richard J.K. Taylor
Department of Chemistry, University of York, Heslington, York YO10 5DD, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical and efficient entry to spirocyclic oxindoles from readily accessible anilide precursors, using
only catalytic amounts of an inexpensive copper salt together with air as the sole re-oxidant, is described.
In addition to providing access to a broad range of spiro-oxindole products, the utility of this method is
demonstrated in a formal synthesis of the natural product, horsfiline.
Received 12 December 2011
Accepted 27 January 2012
Available online 3 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Copper catalysis
Spirocyclic oxindoles
Radical cyclisation
C–H activation
Natural product synthesis
Me
N
H
The oxindole structure has long fascinated synthetic chemists,
partly due to the synthetic challenges that many oxindole-
containing targets present, and partly owing to the exciting biolog-
ical profiles they exhibit and their potential as pharmaceuticals.1
In terms of their structure, naturally-occurring oxindoles tend
to be appended with two substituents at the benzylic position
(i.e., 3,3-disubstituted), with a large proportion of these having
the side-chains tied together, thus giving rise to a spirocyclic junc-
tion.2 They can range from small members, such as horsfiline (1),3
to the more imposing representatives, such as the polycyclic alka-
loid gelsemine (2),4 which has stimulated a number of total syn-
thesis programmes across the globe simply as a result of the
attraction of its formidable and striking structure (Fig. 1).5 More
importantly, many spiro-oxindole natural products display
remarkable biological properties: for example, strychnofoline (3)
displays useful antimitotic activity against cultures of mouse mel-
anoma,6 and has already succumbed to a creative total synthesis by
the Carreira laboratories.7 Most notably, the prominence of the
oxindole motif in naturally-occurring compounds of medicinal
value has spurred the development of a valuable collection of
fully synthetic clinical drugs and candidates thereof. This is well
exemplified by satavaptan (4, SR-121463),8 an orally-active and
selective vasopressin V2 receptor antagonist, which belongs to a
new class of drugs developed for the treatment of hyponatraemia
and is currently in Phase III trials.
O
N
MeO
O
N
Me
O
O
N
H
H
N
O
gelsemine (2)
horsfiline (1)
MeO
N
O
H
N
S
MeO
O
O
H
O
H
N
N
H
N
MeN
HO
H
MeO
satavaptan (4)
Figure 1. Examples of spirocyclic oxindoles.
O
strychnofoline (3)
PREVIOUS WORK:
Me
stoichiometric [Cu]
Kündig,15 Taylor16
catalytic [Cu]
Ar/CO2R
O
O
Ar/CO2R
Me
N
N
Me
Me
Taylor17
R3
N
THIS WORK:
O
From the synthetic viewpoint, the transition metal catalysed
cyclisation of linear anilide precursors is a particularly efficient
O
O
catalytic [Cu]
R1
R1
O
R3
access to
spirocyclic oxindoles
N
N
N
R2
R2
⇑
Corresponding author. Tel.: +44 (0) 1904 322 606; fax: +44 (0) 1904 324 523.
E-mail address: richard.taylor@york.ac.uk (R.J.K. Taylor).
Scheme 1. Copper-mediated oxindole cyclisation.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.120

1898
C. L. Moody et al. / Tetrahedron Letters 53 (2012) 1897–1899
strategy for the synthesis of 3,3-disubstituted oxindoles.9 Most of
these methods make use of palladium catalysis, namely in Heck
cyclisations,10 C–H activation processes,11 and enolate arylations,12
as well as others.13 Copper salts have also found utility as reagents
for cyclisations leading to oxindoles,14 however, it was in 2009 that
Kündig and Jia,15 as well as ourselves,16 reported a copper-medi-
ated cyclisation of unfunctionalised anilides to the 3,3-disubstituted
ables the installation of a quaternary all-carbon centre via a direct
C–H, Ar-H functionalisation by means of copper catalysis without
the need for additional base.
In the current study, the use of just 10 mol % of the environ-
mentally benign and inexpensive copper(II) acetate monohydrate
as the catalyst and air as the stoichiometric re-oxidant enabled
us to rapidly establish the broad scope of this spirocyclisation
reaction (Table 1). The cyclisation precursors 5 were easily
prepared in just three straightforward synthetic steps from
protected lactams (see Supporting Information). All cyclisations
were carried out with mesitylene as the solvent at 170 °C, thus
cutting down on reaction time (30–90 min). Comparable results
could also be achieved by running the reactions in refluxing tol-
uene (120 °C), although a longer reaction time was needed in or-
der to achieve full conversion (typically overnight). Oxygen in air
was all that was required to re-oxidise the copper catalyst. In
certain cases a small amount of substrate 5 was found to undergo
cleavage to the corresponding aniline and lactam/imide under the
reaction conditions, resulting in lower yields of the oxindole
products 6. This obstacle was eventually overcome by simply
bubbling air through the refluxing reaction mixture, thus acceler-
ating the rate of copper re-oxidation and, ultimately, oxindole
cyclisation. In this way, the undesired cleavage of the starting
anilides 5 was minimised and the efficiency of the cyclisation
step improved.
In terms of substrate scope, anilides containing butyrolactam
unit 5a–d, appended with a range of substituents on the nitrogen
atoms and the benzene ring, as well as that incorporating the suc-
cinimide motif (5e), all provided the cyclic products 6a–e in good
to excellent yields (Table 1). The desired oxindoles 6f–i were also
successfully obtained with six-membered valerolactam-containing
anilides 5f–i as substrates. We were able to obtain a suitable crys-
tal of spirocyclic product 6i for X-ray crystallographic analysis and
conclusively established its identity (Fig. 2).18
oxindole core via
a formal double C–H activation approach
(Scheme 1). We subsequently disclosed an improved variant of this
reaction process,17 which utilised sub-stoichiometric amounts
(5 mol %) of a copper catalyst with no loss in reaction efficiency.
Herein we communicate a practical extension of this methodology
for the straightforward synthesis of spirocyclic oxindoles, which en-
Table 1
Reaction scope investigation (yields are isolated)
R3
N
Cu(OAc)2·H2O (10 mol%)
mesitylene ,170 ºC, 30-90 min
O
O
O
R1
R3
N
R1
O
N
a) air atmosphere
or
b) air bubbled through
N
R2
R2
6
5
R
N
Me
N
Me
N
O
O
O
Cl
O
O
O
N
N
N
Me
Bn
Me
6a (R = Me): 61%,a 76%c
6b (R = Boc): 76%a
6c: 58%,a 80%b
6d: 66%,a 76%b
R
N
Me
O
N
BocN
O
O
O
Substitution on the benzene ring was next explored and prod-
ucts 6j–m were furnished in good yields. It is noteworthy that
access to aryl chlorides of type 6j allows for further palladium-
mediated manipulation to structurally more elaborate, and
potentially medicinally relevant, oxindoles. The result obtained
with the meta-methoxy-substituted example 5l was also intrigu-
ing: a mixture of regioisomers 6l and 6l0 was isolated,13f with the
major isomer 6l arising from radical addition to the position more
encumbered sterically, but potentially preferred electronically,
presumably due to the higher degree of stabilisation of the inter-
mediate cyclohexadienyl radical. Glutaramide- and caprolactam-
based anilides 5n and 5o also furnished spirocyclic oxindoles 6n
and 6o, respectively, in good yields. Of potential medicinal interest
are ß-lactam-containing oxindoles of type 6p,19 albeit the effi-
ciency of the cyclisation of 5p was found to be somewhat lower.
Postulating that, mechanistically, this reaction proceeds via an
intermediate enol, the lower yield of cyclic product 6p could be
attributed to the high strain associated with the enol (or the resul-
tant radical species following oxidation of the enol), which con-
tains three adjacent sp2 centres within a four-membered ring. It
should be noted that, to the best of our knowledge, all the oxindole
products described here and accessed via the copper-catalysed
cyclisation method are novel compounds.
O
O
O
N
N
N
Me
Me
Bn
a
6i: 69%b
6e
6f (R = Me): 76%b
6g (R = Bn): 83%b
6h (R = PMB): 73b
: 70%
BocN
MeO
BocN
O
NBoc
O
Cl
O
O
MeO
MeO
O
O
O
N
N
6l
N
Me
Me
+
6j: 70%b
NBoc
OMe
6k: 73%b
BocN
O
O
O
6l'
N
MeO
Me
6l:6l' = 3.2:1
76%a
O
N
Me
PMBN
O
OMe
6m: 60%b
6n: 91%b
O
N
Boc
N
Me
BocN
O
O
Having established the broad scope of this cyclisation method-
ology we sought to demonstrate its utility in the synthesis of the
natural product horsfiline (1, Scheme 2).3 In this context, benzyl-
carboxylation of commercially available N-methylpyrrolidone (7)
afforded intermediate 8 which, upon hydrogenolysis and amide
coupling, swiftly furnished the linear cyclisation precursor 9 on
gram scale in excellent overall yield. Ready access to anilide 9
paved the way for the application of our copper(II)-mediated cyc-
lisation, which successfully provided the desired oxindole 10 in a
O
O
N
N
Me
Me
6o: 64%a
6p: 26%a
a
Reaction was carried out with the reflux condenser open to air.
b
Reaction was carried out by vigorously bubbling compressed air through the
refluxing reaction mixture.
c
Reaction was carried out in toluene at 120 °C for 15 h with the reflux condenser
open to air.

C. L. Moody et al. / Tetrahedron Letters 53 (2012) 1897–1899
1899
J.E.M.N.K.) for generous financial support, as well as Dr. Robert
Thatcher and Dr. Adrian Whitwood for help with X-ray crystallo-
graphic analysis.
Supplementary data
Supplementary data (full experimental procedures, character-
isation data, 1H NMR traces and crystallographic data) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2012.01.120.
References and notes
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MeO
O
O
O
O
O
b, c
a
BnO
NMe
N
NMe
NMe
Dmb
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9
8
7
Me
N
Me
N
2 steps
Trost et al.20
d
O
MeO
MeO
O
O
N
H
N
Dmb
( )-horsfiline (1)
10
Scheme 2. Formal total synthesis of horsfiline (1). Reagents and conditions: (a)
LDA, CbzCl, THF, ꢀ78 °C, 1 h (48%); (b) H2, Pd/C, EtOAc, rt, 1 h (97%); (c) N-Dmb-4-
methoxyaniline, 2-chloro-1-methylpyridinium iodide, Et3N, CH2Cl2, 0 °C to rt, 1 h
(97%); (d) Cu(OAc)2ꢁH2O (10 mol %), mesitylene, air bubbled through, 170 °C,
90 min (71%). LDA = lithium di-iso-propylamide; Cbz = carboxybenzyl; THF = tetra-
hydrofuran; Dmb = 2,4-dimethoxybenzyl.
71% yield and intercepted Trost’s intermediate for the formal syn-
thesis of horsfiline (1).20
In summary, the copper(II)-mediated cyclisation methodology
enables entry to a large class of spirocyclic oxindoles via a direct
C–H, Ar-H functionalisation with high efficiency from easily acces-
sible starting materials with cheap reagents. This method allows
the installation of a quaternary carbon centre at the spirocycle
junction and constitutes an attractive approach for the preparation
of oxindole-based natural products and their analogues. The devel-
opment of a stereoselective variant of this process is currently
underway in our laboratories: preliminary studies have been car-
ried out using enantiopure additives but, to date, no significant
enantioselectivity has been obtained.
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E. M. N.; Perry, A.; Taylor, R. J. K. Synlett 2010, 934; (c) Franckevicius, V.;
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17. Klein, J. E. M. N.; Perry, A.; Pugh, D. S.; Taylor, R. J. K. Org. Lett. 2010, 12,
3446.
18. X-ray data for 6i has been deposited with the Cambridge Crystallographic Data
Centre (CCDC 857976), which can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
19. For a recent example, see: Xu, Z. X.; Huang, K.; Liu, T.; Xie, M. J.; Zhang, H. B.
Chem. Commun. 2011, 47, 4923.
20. Trost, B. M.; Brennan, M. K. Org. Lett. 2006, 8, 2027.
We gratefully acknowledge the University of York (C.L.M., V.F.,
P.D., J.E.M.N.K.) and the University of York Wild Fund (P.D.,