Sequential Pd/Ru-catalysed allenylation/olefin metathesis/1,3-dipolar cycloaddition route to novel heterocycles

Article abstract of DOI:10.1016/S0040-4039(02)02736-3

A novel sequential palladium/ruthenium-catalysed four component process is described involving carbonylation of an aryl/heteroaryl iodide followed by allenylation to generate (π-allyl) palladium species which are intercepted by nitrogen nucleophiles to af

Full text of DOI:10.1016/S0040-4039(02)02736-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1023–1026
Sequential Pd/Ru-catalysed allenylation/olefin
metathesis/1,3-dipolar cycloaddition route to novel heterocycles
Ronald Grigg,a,* Anne Hodgson,b James Morrisa and Visuvanathar Sridharana
aMolecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, Leeds University,
LS2 9JT, UK
bProcess R and D, GlaxoSmithKline, Dartford DA1 5HA, UK
Received 1 October 2001; revised 22 November 2002; accepted 29 November 2002
Abstract—A novel sequential palladium/ruthenium-catalysed four component process is described involving carbonylation of an
aryl/heteroaryl iodide followed by allenylation to generate (p-allyl) palladium species which are intercepted by nitrogen
nucleophiles to afford 1,6-dienes. Subsequent Ring-Closing Metathesis (RCM) affords C-acyl-N-heterocycles in good yield. These
heterocycles proved to be active dipolarophiles in sequential and cascade 1,3-dipolar cycloaddition reactions (1,3-DC) as
exemplified by reactions with nitrones and azomethine ylides. © 2003 Elsevier Science Ltd. All rights reserved.
Carbon monoxide and allene are versatile building
blocks in palladium-catalysed processes1,2 and they
function as powerful relay switches in palladium-
catalysed cyclisation–anion capture cascades.3 Recently
we have developed a series of novel palladium-catalysed
3-component processes utilising either carbon monox-
ide or allene as relay switches.4–6 We have also inter-
The development of second generation air stable, Ru
faced our palladium-catalysed cascade chemistry with
catalysts such as 116–18 which exhibit higher thermal
stability, wider functional group tolerance and accom-
other transition metal-catalysed processes. Such
bimetallic cascades include electrochemically driven Pd/
Cr Nozaki–Hiyama–Kishi reaction,7 Pd/In Barbier type
allylation,8,9 Pd/Ag Heck/1,3-DC,10 Pd/Ru Heck/
metathesis,11,12 Pd/Ru termolecular queuing processes/
metathesis,13 Rh/Pd cycloaddition–cyclisation-anion
capture processes14 and Rh/Pd cycloaddition–Friedel
Crafts reactions.15 In this paper we describe the combi-
nation of a Pd catalysed 4-component cascade with
RCM and 1,3-DC.
modate a higher density of substitution on the double
bond formed in RCM opens up new avenues for com-
bination with Pd-catalysed multicomponent processes
together with core organic reactions. Thus the four
component process (Scheme 1) involving Pd/Ru cataly-
sis combined with 1,3-DC has been developed. The
initial reaction of aryl iodides 2 with carbon monoxide,
allene and a nucleophile 3 in the presence Pd(0)
Scheme 1.
* Corresponding author. Tel.: +44-113-233-6501; fax: +44-113-233-6501; e-mail: r.grigg@chem.leeds.ac.uk
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02736-3

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R. Grigg et al. / Tetrahedron Letters 44 (2003) 1023–1026
Table 1. Four-component allenylation-amination cascadesa/RCMb

R. Grigg et al. / Tetrahedron Letters 44 (2003) 1023–1026
1025
furnishes 1,6-dienes 4, which undergo ruthenium
catalysed RCM to give D3-pyrrolines 5. The enones 5
undergo 1,3-DC with nitrones and azomethine ylides to
produce bicyclic cycloadducts 6. The overall process
results in the formation of two rings, six bonds, three or
four stereocentres and one or two tetrasubstituted car-
bon centres.
at room temperature afforded a single diastereoisomeric
cycloadduct 23. Product 23 arises via an endo transition
state of the syn-dipole (Scheme 2) in 80% yield. The
regio- and stereochemistry of the cycloadduct were
established by NOE studies and conforms to that
expected for our metal-catalysed proline synthesis.19
Reaction (toluene, 110°C, 44 h) of nitrone 24 (1.5
mmol) with enones 14, 15 and 18 (1 mmol) was then
Thus, aryl/heteroaryl iodide 2 (1.2 mmol) react with
CO (1 atm), allene (1 atm), Pd(OAc)2 (10 mol%), PPh3
(20 mol%), K2CO3 (2 mol equiv.), and N-allyl benzene-
sulfonamide 3 (1 mmol), in toluene (70°C, 36 h) to
afford 7–12 (Table 1, entries 1–7) in 55–75% yield.
Subsequent RCM of these products produced the D3-
pyrrolines 14–19 (Table 1) in excellent yields. This
process is compatible with our cyclisation–anion cap-
ture methodology.3 Thus, 21 reacts with CO (1 atm),
allene (1 atm) and nucleophile 3 (1 mol equiv.), in the
presence of Pd(OAc)2 (10 mol%), PPh3 (20 mol%) and
K2CO3 (2 mol equiv.) in toluene at 70°C over 24 h to
afford 13 in 65% yield (Table 1 entry 7). RCM on 13
furnishes 20 in 94% yield.
explored. In each case
a
single cycloadduct
diastereomer 25–27, arising from an endo-transition
state, was obtained in good yield (Scheme 3). Perform-
ing these cycloadditions at 90°C afforded a 3.5:1 mix-
ture of 28 and 29, respectively, in 70% yield under
kinetic control (Scheme 4),20 whereas heating 28 in
refluxing toluene affords thermodynamic isomer 26 via
a retro-cycloaddition-1,3-DC sequence along with trace
amounts of 18, and nitrone 24. Thus, we have a syn-
thetically useful temperature control of cycloaddition
regiochemistry.
Finally a RCM/nitrone cycloaddition cascade was
achieved. Dienone 11 and nitrone 24 were heated to
75°C with 1 (5 mol%) in toluene, for 2 h after which the
temperature was raised to 90°C for 20 h affording a 3:1
mixture of cycloadducts 28 and 29 in a 59% overall
yield (Scheme 4).
Next we briefly studied azomethine ylide cycloaddition
of 18 with imine 22 (Scheme 2). Treating enone 18 (1
mmol), with imine 22 (1.2 mmol), silver acetate (1.5
mmol) and triethylamine (1.5 mmol) in toluene for 20 h
Scheme 2.
Scheme 3.

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R. Grigg et al. / Tetrahedron Letters 44 (2003) 1023–1026
Scheme 4.
In conclusion we have demonstrated a novel sequential,
Pd catalysed carbonylation/allene insertion/nucleophile
incorporation followed by ruthenium-catalysed RCM
for the synthesis of D3-pyrroline dipolarophiles as
exemplified by both azomethine ylide and nitrone
cycloadditions.
7. Grigg, R.; Putnikovic, B.; Urch, C. Tetrahedron Lett.
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V. J. Chem. Soc., Chem. Commun. 2000, 645–646.
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Chem. Commun. 2000, 933–934.
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Acknowledgements
We thank Leeds University, GlaxoSmithKline and the
EPSRC for support.
13. Dondas, H. A.; Balme, G.; Clique, B.; Grigg, R.;
Hodgeson, A.; Morris, J.; Sridharan, V. Tetrahedron
Lett. 2001, 42, 8673–8675.
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