Palladium catalysed tetramolecular queuing cascades of aryl iodides, carbon monoxide, amines and a polymer supported allene

Article abstract of DOI:10.1039/b007170f

Chemo- and regio-specific palladium catalysed four component processes, involving formation of 3 new bonds, initiated by oxidative addition of Pd(0) with aryl iodides followed by sequential incorporation of CO (1 atm), a polymer supported allene and an am

Full text of DOI:10.1039/b007170f

Palladium catalysed tetramolecular queuing cascades of aryl iodides, carbon
monoxide, amines and a polymer supported allene
Ronald Grigg,*a William MacLachlanb and Marcello Rasparinia
a MIDAS Centre, School of Chemistry, University of Leeds, Leeds, UK LS2 9JT. E-mail: R.Grigg@chem.leeds.ac.uk
b SmithKline Beecham Pharmaceuticals, Third Avenue, Harlow, UK CM19 5AW
Received (in Cambridge, UK) 6th September 2000, Accepted 5th October 2000
First published as an Advance Article on the web 31st October 2000
Chemo- and regio-specific palladium catalysed four compo-
nent processes, involving formation of 3 new bonds, initiated
by oxidative addition of Pd(0) with aryl iodides followed by
sequential incorporation of CO (1 atm), a polymer supported
allene and an amine provides complex heterocycles with 3
points of diversity in good yield and excellent purity after
cleavage.
A well designed cascade can deliver highly complex molecules
whilst avoiding lengthy multistep procedures and the need for
protection–deprotection of many functional groups.1 This
approach can be further enhanced by locating one of the
reagents on a polymer support thus allowing the pure final
product to be isolated by washing the resin and cleavage.
The objective of the present study was to explore the
Scheme 3
reactivity of a polymer bound allenic alcohol in a palladium
catalysed four-component queuing cascade2 (Scheme 1).
(CHNCNCH2), 5.1 (CHNCNCH2) and FT-IR (KBr disc) 1953
cm21 (CHNCNCH2 stretch).
The experimental conditions for the palladium-catalysed
cascade (Scheme 4) were as follows: resin 5 (1.0 mol eq.),
iodobenzene or 2-iodothiophene (4.0 mol eq.), iPr2NEt (5.0 mol
eq.), piperidine (4.0 mol eq.), Pd(OAc)2 (0.1 mol eq.), tris(2-
furyl)phosphine (0.2 mol eq.), toluene (10 ml mmol21) and a
Scheme 1
balloon containing carbon monoxide attached to the reaction
vessel. After all the components were added to the flask
containing the resin swollen in toluene, a sequence of
evacuation (water pump–CO addition) was performed three
times. Subsequently the flask was immersed in an oil bath at
50 °C and magnetically stirred for 24 h.
This cascade is initiated by addition of Pd(0) into the Ar–I
bond, followed by CO insertion, allene insertion and capture of
the resultant p-allylpalladium(II) complex by a secondary amine
(Scheme 2).
In this preliminary study we attached hexa-4,5-dien-1-ol 2
(prepared from the alkyne 1 by a Crabbe`3 reaction) to a gel-type
polystyrene resin by means of a traceless silicon linker. The
reason for this choice is three-fold: alkyl substituted allenes are
particularly stable, the alcohol group is convenient for the
introduction of further diversity and the cleavage conditions
were anticipated to be particularly mild (Scheme 3).
The silane resin 3 (Argonaut Technologies, loading 1.59
mmol g21 SiH) was chlorinated and immediately loaded4 with
the allenic alcohol 2 to give the resin 5 (loading 1.45 mmol
g21).5 The colourless resin 5 was characterised by gel-phase 1H
NMR (250 MHz, CDCl3) d = 3.7 (CH2CHNCNCH2), 4.7
The reaction was monitored by FT-IR following the dis-
appearance of the allene stretching band at 1953 cm21. After
24 h a small allenic peak was still present. The resin was washed
with DMF, 1+1 DMF–H2O, DCM, MeOH, dried and recycled
in a second run to complete the conversion. The reaction was
not optimised at this stage. The rate determining step appears to
be the oxidative addition of Pd(0) into the Ar–I bond. Thus the
iodoacrylamide 8 undergoes complete conversion to product in
18 h. In the case of 8 initial coordination of Pd(0) to the olefinic
bond would facilitate the oxidative addition step, which is
followed by a facile 5-exo-trig cyclisation, carbonylation, allene
insertion and amine capture (Scheme 5).
Cleavage of indolinone 9 was achieved using HF/Py (0.4 M
HF/Py, THF). Reaction times longer than 25 min led to the
formation of a diastereomeric mixture of tetrahydrofurans (1+1
Scheme 2
Scheme 4
DOI: 10.1039/b007170f
Chem. Commun., 2000, 2241–2242
This journal is © The Royal Society of Chemistry 2000
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Scheme 5
Scheme 7
Scheme 6
ratio by HPLC, 70% yield); 10 deriving from acid-catalysed
intramolecular Michael addition (Scheme 6).
After exposing the resin for 20 min to the cleavage mixture
the filtrate was quenched with a saturated solution of NaHCO3,
extracted with AcOEt, the solvent removed in vacuo to afford
the alcohol (60%) whose purity was 98% by HPLC-MS. The
residue was acetylated (Ac2O, pyridine, DMAP, DCM, 2 h, rt)
and the acetate 11 was purified by silica gel chromatography
(AcOEt–PE–triethylamine 50+50+2) and obtained in 90% yield
from the alcohol (Scheme 7).
Notes and references
1 R. Grigg and V. Sridharan, J. Organomet. Chem., 1999, 576, 65.
2 R. Grigg, S. Brown, V. Sridharan and M. Uttley, Tetrahedron Lett., 1997,
38, 5031.
3 S. Searles, Y. Li, B. Nassim, M. T. Robert Lopes, P. T. Tran and P.
Crabbe`, J. Chem. Soc., Perkin Trans. 1, 1984, 747.
4 Y. Hu, J. A. Porco, J. W. Labadie, O. W. Gooding and B. M. Trost, J. Org.
Chem., 1998, 63, 4518.
The loading of resin 9 was found to be 1.1 mmol g21
(calculated on the yield of the crude product after cleavage).
Similarly the resins 12–14 were prepared. After cleavage and
work-up the alcohols 15–17 were found to be 98% pure by
HPLC-MS and no further purification was carried out.6
It is worth noting that all the products 11–17 were obtained as
single stereoisomers.7
In conclusion, the resin supported allene 5 is an excellent
scaffold for the construction of complex heterocycles. Further
investigations using a broader range of anion capture agents and
starter molecules are in progress.
5 The loading was the average of two determinations: 1) weight increase
after washing and overnight drying in vacuo, 2) yield of 2 after cleavage
(TBAF, 1.0 M in THF) and chromatographic purification (Et2O–PE
1+1).
6 Overall from 5 to 15–17.
7 In similar experiments we found that the CNC geometry is Z (NOE data):
this stereochemical outcome is rationalised by attack of the amine on the
more stable anti p-allylpalladium(II) complex (R. Grigg and M.
Rasparini, unpublished data).
We thank Leeds University, the EU and SmithKline
Beecham for support.
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Chem. Commun., 2000, 2241–2242