Novel synthesis of oxindoles from carbamoyl chlorides via palladium catalysed cyclisation-anion capture

Article abstract of DOI:10.1039/b006765m

The synthesis of 3,3-disubstituted and 3-methyleneox-indoles by palladium(0) catalysed cyclisation of carbamoyl chlorides onto proximate alkene or alkyne groups has been achieved in good yields.

Full text of DOI:10.1039/b006765m

Novel synthesis of oxindoles from carbamoyl chlorides via palladium catalysed
cyclisation–anion capture
Mark R. Fielding,a Ronald Grigg*a and Christopher J. Urchb
a Department of Chemistry, University of Leeds, Woodhouse Lane, Leeds, UK LS2 9JT.
E-mail: R.Grigg@chem.leeds.ac.uk
b Zeneca Agrochemicals, Jealott’s Hill Research Station, Bracknell, UK RG42 6ET
Received (in Cambridge, UK) 17th August 2000, Accepted 5th October 2000
First published as an Advance Article on the web 31st October 2000
The synthesis of 3,3-disubstituted and 3-methyleneox-
indoles by palladium(0) catalysed cyclisation of carbamoyl
chlorides onto proximate alkene or alkyne groups has been
achieved in good yields.
3,3-Disubstituted oxindoles are common structural motifs in a
Scheme 1 Reagents and conditions: i, PhCHO, MeOH, reflux then NaBH4,
reflux (45%, 86% based on 52% conv.); ii, TMSA, Pd(PPh3)4, Cul, NEt3,
DMF, rt (90%); iii, TBAF, THF–H2O, rt (91%); iv, COCl2, NaHCO3,
DCM–H2O, 0 °C (93%).
wide range of natural products. Gelsemine,1 paraherquamides2
and spirotryprostatins3 represent classes that possess oxindole
cores and have interesting biological profiles. 3-Methyleneox-
indoles, on the other hand, are versatile intermediates in
synthesis. Recently, Williams et al.4 used a diasterospecific
cycloaddition onto a methyleneoxindole in their total synthesis
of spirotryprostatin B. Classically, spirooxindoles can be
synthesised via an oxidative rearrangement of indoles5 and
methyleneoxindoles can be accessed by Wittig–Horner6 type
reactions of isatin. Oxindoles can conceptually be constructed
by palladium catalysed processes in a number of ways. There
are examples of intramolecular Heck and intramolecular
cyclisation–anion capture reactions on acrylamide derivatives
of 2-iodoanilines.7 We have applied our palladium catalysed
cyclisation–anion capture methodology to 3,3-disubstituted
oxindoles (including spirooxindoles)8 via formation of bond a
(Fig. 1). We have also developed a 3-component process9 which
constructs bonds a, b, and c. We now describe palladium
catalysed cyclisation–anion capture processes involving forma-
tion of bond b (Fig. 1).
2 with a two step Sonagashira13-deprotection procedure then
affords the 2-ethynyl derivative 3. Finally, addition of phos-
gene14 to aniline 3 at 0 °C for 10 min affords carbamoyl chloride
4.
A range of carbamoyl chlorides 4–7 were synthesised in a
similar way to provide a selection of 5- and 6-membered
heterocycle precursors. These carbamoyl chlorides are air and
moisture insensitive and can be purified on flash silica.
Substrates 4 and 5 are 3-methyleneoxindole precursors, whilst 6
The use of carbamoyl chlorides in palladium catalysed cross-
coupling reactions with stannanes was reported by Jousseaume
and Dubac.10 Its use in Heck-type cyclisations11 is rare, perhaps
because the initial reports employed forcing conditions and
toxic cosolvents for the synthesis of lactams. Our plan was to
use 2-ethynyl- or 2-isopropenyl-phenylcarbamoyl chlorides as
oxindole precursors (Fig. 1) in cyclisations which do not
terminate via b-hydride elimination (as in Heck processes) but
involve a group or atom transfer. This process (known as
cyclisation–anion capture)12 allows a large variety of groups to
be introduced onto the oxindole. By this route, (Z)-3-methylene-
oxindoles are stereospecifically formed and 3,3-disubstituted
oxindoles can be potentially synthesised by a catalytic,
enantioselective process.
is an example of a 6-ring isoquinolinone precursor. Carbamoyl
chloride 7 was synthesised from commercially available
2-isopropenylaniline.
Initially, we focused on the use of tributylstannanes as anion
capture agents for these substrates.15 It was found that treatment
of 4 with tributyl(2-thienyl)tin and Pd(OAc)2–tris(2-furyl)phos-
phine in toluene at 50 °C for 5 min affords the desired
3-methyleneoxindole 8 in 88% yield (Scheme 2). Repetition of
this latter reaction using 1 mol% Pd(OAc)2–2 mol% tris(2-
furyl)phosphine and a reaction time of 30 min afforded 8 in 91%
yield emphasising the scope for considerable reduction in
catalyst loading. The use of tributyl(phenylethynyl)tin also
resulted in a high yield of product (81%), whilst vinyl transfer
affords a 4+3 mixture of geometrical isomers 10 and 11 in 76%
overall yield. Cyclisation–anion capture employing tributyl(2-
furyl)tin was also complete within 5 min at 50 °C, and afforded
(Z) 12 in 78% yield.
The synthesis of the required carbamoyl chlorides was
achieved from the appropriate 2-haloaniline in high overall
yield (Scheme 1). 2-Iodoaniline 1 is converted to its N-benzyl
derivative 2 using a reductive amination protocol. Treatment of
This methodology can also be extended to 6-ring cyclisation–
anion capture and to the synthesis of 3,3-disubstituted oxindoles
(Scheme 3).
Cyclisation of 6 affords 13 (87%), a 4-methyleneisoquinolin-
3-one in 5 min at 50 °C. However, cyclisation onto the
isopropenyl group of 7 to form 14 is much slower (4 h), but
proceeds in excellent yield (84%). The use of boronic acids as
anion capture reagents8 is currently being studied. A prelimi-
nary study involving 7 and phenylboronic acid afforded 15
(50%) (Scheme 3). This reaction was considerably slower (50 h,
90 °C) than those involving organostannane anion capture
reagents and since a small amount of water was present
Fig. 1
DOI: 10.1039/b006765m
Chem. Commun., 2000, 2239–2240
This journal is © The Royal Society of Chemistry 2000
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tris(tert-butyl)phosphine gave, over 48 h at rt, a 60% yield of
lactam 17.
The two strategic bond formation modes (Fig. 1, a and b)
allow both (E)- and (Z)-3-methyleneoxindoles to be accessed
stereoselectively. Thus formation of bond a by palladium
catalysed cyclisation onto a proximate alkyne with anion
capture affords E-isomers16 whilst formation of bond b by
palladium catalysed cyclisation affords Z-isomers.
In summary, these preliminary results on the palladium
catalysed cyclisation–anion capture of carbamoyl chlorides
demonstrate that (Z)-3-methylene- and 3,3-disubstituted ox-
indoles can be accessed under mild conditions in high yields.
Further studies of these and related processes are in hand.
We thank the EPSRC, University of Leeds and Zeneca
Agrochemicals for support.
Scheme 2 Reagents and conditions: A = Pd(OAc)2 (10 mol%), tris(2-
furyl)phosphine (20 mol%), 1.1 equiv. Bu3SnY, toluene, 50 °C. All
reactions were complete within 5 min at 50 °C.
Notes and references
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Scheme 3 Reagents and conditions: A = Pd(OAc)2 (10 mol%), tris(2-
furyl)phosphine (20 mol%), 1.1 equiv. Bu3SnY, toluene, 50 °C, 5 min; B =
Pd(OAc)2 (10 mol%), tris(2-furyl)phosphine (20 mol%), 1.1 equiv.
Bu3SnY, toluene, 85 °C, 4 h; C = Pd(OAc)2 (10 mol%), triphenylphos-
phine (20 mol%), 2 equiv. PhB(OH)2, toluene, water (2 drops), 90 °C,
50 h.
(Scheme 3, C) there was some destruction of the carbamoyl
chloride 7.
The presence of the benzene ring in the above examples is
one factor promoting the rapid cyclisation of these carbamoyl
chlorides. To extend the scope of this cyclisation–anion capture
methodology, we synthesised an example of a non-aryl based
carbamoyl chloride. Substrate 16 was derived from but-3-yn-
1-ol via its tosylate and reacted with benzylamine and then
phosgene14 in the normal fashion. At the typical reaction
temperature of 50 °C, only 35% of product 17 was isolated.
However, replacing tris(2-furyl)phosphine by the electron rich
15 P. Fretwell, R. Grigg, J. M. Sansano, V. Sridharan, S. Sukirthalingam,
D. Wilson and J. Redpath, Tetrahedron, 2000, 56, 7525.
16 R. Grigg, V. Loganathan, V. Sridharan, P. Stevenson, S. Sukirthalingam
and T. Worakun, Tetrahedron, 1996, 52, 11479; R. Grigg and V. Savic,
Tetrahedron Lett., 1996, 37, 6565.
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Chem. Commun., 2000, 2239–2240