Palladium-catalysed in situ zipper generation-cyclisation-anion capture. Synthesis of 3,3-disubstituted indolines and 2,3-dihydrobenzofurans

Article abstract of DOI:10.1016/S0040-4039(01)01811-1

A palladium-catalysed one-pot reaction for the in situ assembly of monocyclisation 'zippers' and subsequent cyclisation-anion capture with aryl/heteroaryl boronic acids produces 3,3-disubstituted indolines and 2,3-dihydrobenzofurans.

Full text of DOI:10.1016/S0040-4039(01)01811-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8677–8680
Palladium-catalysed in situ zipper generation–cyclisation–anion
capture. Synthesis of 3,3-disubstituted indolines and
2,3-dihydrobenzofurans
Ronald Grigg,* Edoardo Mariani and Visuvanathar Sridharan
Molecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, Leeds University,
Leeds LS2 9JT, UK
Received 23 July 2001; accepted 21 September 2001
Abstract—A palladium-catalysed one-pot reaction for the in situ assembly of monocyclisation ‘zippers’ and subsequent
cyclisation–anion capture with aryl/heteroaryl boronic acids produces 3,3-disubstituted indolines and 2,3-dihydrobenzofurans.
© 2001 Elsevier Science Ltd. All rights reserved.
Palladium-catalyzed cascade reactions provide versatile
and efficient methods for the assembly of a wide range
of organic compounds via carbonꢀcarbon and car-
bonꢀheteroatom bond formation. These cascades usu-
ally proceed under mild conditions and are tolerant of
a wide variety functional groups.1–4 They permit the
attainment of a high degree of molecular complexity in
a one-pot protocol where conventional methodology
would require technically demanding multistep synthe-
sis. Such reactions minimise reactor time and waste,
whilst offering interesting synthetic solutions.
We have developed two powerful catalytic cascade pro-
tocols: cyclisation–anion capture5 and relay switched
molecular queuing processes.6 Both of these involve
formation of one or more rings and utilise a suitable
starter species to achieve this. A typical example of a
starter species (‘zipper’) is shown in Scheme 1.
Cascade zipper generation of the type illustrated in
Scheme 1 is a challenging problem that potentially
offers access to a wide variety of ‘zippers’ that could
form the basis for expanded cascades in conjunction
with a cyclisation–anion capture sequence.
In this communication we report successful cyclisation–
anion capture cascade processes involving in situ syn-
thesis of two families of monocyclisation zippers and
their subsequent cyclisation–anion capture, using
boronic acids as terminating species, leading to 3,3-di-
substituted indolines and 2,3-dihydrobenzofurans.
Zipper 1 was synthesised in 80% yield from 2-iodothio-
phene (1 mol equiv.), allene (1 bar) and 2-iodo-N-tosyl-
aniline (1 mol equiv.), using Pd(PPh3)4 (10 mol%) as
catalyst and potassium carbonate (10 mmol) in toluene
at 65°C (Scheme 2).
Scheme 1.
Scheme 2.
The Pd(0) reacts selectively with iodothiophene, proba-
bly because the oxidative insertion step is facilitated by
coordination with the adjacent sulfur atom. The aryl-
palladium(II) species then reacts with allene giving a
p-allylpalladium(II) species that is captured by the
deprotonated 2-iodo-N-tosylaniline.
* Corresponding author. Tel.: +44-(0)113-233-6501; fax: +44-(0)113-
233-6501; e-mail: r.grigg@chem.leeds.ac.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01811-1

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R. Grigg et al. / Tetrahedron Letters 42 (2001) 8677–8680
Table 1. One-pot zipper formation–cyclisation–anion capture from aryl iodides, 2-iodo-N-tosylaniline, allene (1 bar) and boronic
acidsa

R. Grigg et al. / Tetrahedron Letters 42 (2001) 8677–8680
8679
there is the advantage of avoiding purification and
recharging the solvent and the catalyst.
Subsequently we tested the generality of the reaction
using commercially available boronic acids as capture
agents (Scheme 4) (Table 1).8
Good to excellent yields were obtained. Steric effects
underlie the trend in the yield of product from the
isomeric dimethoxyphenylboronic acids (Table 1,
entries 3–5) and the nearly quantitative yield obtained
with b-styrylboronic acid (entry 2).
Scheme 3.
We first tested the isolated zipper 1 in a cyclisation–
anion capture procedure using sodium tetraphenyl-
borate as anion capture agent (Scheme 3). The desired
product 2 was formed 82% yield.
We then synthesised several other zippers of the same
family using substituted iodobenzenes in place of
iodothiophene (Table 1). The reaction proved to be
quite general, working with activated (entry 8) and
non-activated (entry 9) iodoarenes in addition to 4-
iodoanisole (entry 10), which interestingly, afforded the
Next we performed the entire sequence without isola-
tion of the intermediate zipper, simply adding the cap-
ture agent at the end of the first step.7 The overall yield
of the one-pot protocol (66%) is about equal to that
obtained previously by the two-step procedure, but
Scheme 4.
Table 2. One-pot synthesis from 2-iodo-N-tosylaniline, substitutes allenes and 2-iodothiophene

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R. Grigg et al. / Tetrahedron Letters 42 (2001) 8677–8680
Scheme 5.
highest yield, whilst 4-nitroiodobenzene gave the poorest
yield.
References
1. Nemoto, H.; Miyata, J.; Raku, N.; Fukumoto, K. J.
Org. Chem. 1997, 22, 7850–7857 and references cited
therein.
2. Namoto, H.; Yoshida, M.; Fukumoto, K. J. Org. Chem.
1997, 19, 6450–6451.
We have briefly investigated the reaction with 2-iodophe-
nol in place of 2-iodo-N-tosylaniline. The corresponding
3,3-disubstituted 2,3-dihydrobenzofuran 4 was isolated
in 40% yield (Scheme 5).
3. Garrido, J. L.; Alonso, I.; Carretero, J. C. J. Org. Chem.
1998, 25, 9406–9413 and references cited therein.
4. La, C.-W.; Oh, K. S.; Kim, K. S.; Ahn, K. H. Org. Lett.
2000, 9, 1213–1216.
5. Grigg, R.; Sridharan, V. J. Organomet. Chem. 1999, 576,
65–87.
Finally, we also evaluated several substituted allenes in
this reaction (Table 2). All the reported allenes gave the
required intermediate with moderate to good yields, the
alkyl-allenes generally requiring higher temperature of
reaction. In all cases except one (entry 2) the nucleophilic
attack of 2-iodo-N-tosylaniline was found to occur at the
unsubstituted terminus of the allene; the exception,
methoxyallene, reflects the enolic nature of this species.
The subsequent cascade proved to be more problematic,
with steric hindrance (entry 1) and competing processes
like hydrolysis (entry 2), b-hydride elimination (entry 3)
or direct capture (entry 4) preventing or diverting the
desired outcome of the reaction.
6. Grigg, R.; Sridharan, V. Pure Appl. Chem. 1998, 70,
1047–1057.
7. Iodothiophene (2 mmol), 2-iodo-N-tosylaniline (2 mmol),
potassium carbonate (4 mmol), Pd(PPh3)4 (10 mol%) and
toluene (10 ml) were charged in a 100 ml glass pressure
vessel, the mixture was degassed by two freeze–pump–
thaw cycles and allene (1 bar) was finally added; the flask
was immersed in an oil bath at 65°C and stirred for 16 h.
After cooling to rt allene was vented and NaBPh4 (2
mmol) added, the flask was immersed in an oil bath at
110°C and stirred for 22 h. Filtration and evaporation of
the solvent in vacuo afforded the crude product, which
was purified by column chromatography to afford 1
(66%).
Further studies of in situ assembly of ‘zippers’ as well as
the use of substituted allenes are currently under inves-
tigation in our laboratories and the results will be
published in due course.
8. Grigg, R.; Sansano, J. M.; Santhakumar, V.; Sridharan,
V.; Thangavelanthum, R.; Thornton-Pett, M.; Wilson, D.
Tetrahedron 1997, 53, 11803–11826.
Acknowledgements
We thank Leeds University and the EPRSC for support.