Spiro-oxindoles via bimetallic [Pd(0)/Ag(I)] catalytic intramolecular Heck-1,3-dipolar cycloaddition cascade reactions

Article abstract of DOI:10.1016/S0040-4039(02)00331-3

The combination of an intramolecular Heck reaction with a subsequent Ag(I) catalysed imine→azomethine ylide→cycloaddition cascade is described for the formation of novel spiro-oxindoles. The reaction proceeds regiospecifically with good to excellent stere

Full text of DOI:10.1016/S0040-4039(02)00331-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2605–2608
Spiro-oxindoles via bimetallic [Pd(0)/Ag(I)] catalytic
intramolecular Heck-1,3-dipolar cycloaddition cascade reactions
Ronald Grigg,* Emma L. Millington and Mark Thornton-Pett
Molecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, The University of Leeds,
Leeds LS2 9JT, UK
Received 26 November 2001; revised 8 February 2002; accepted 12 February 2002
Abstract—The combination of an intramolecular Heck reaction with a subsequent Ag(I) catalysed imine“azomethine ylide“
cycloaddition cascade is described for the formation of novel spiro-oxindoles. The reaction proceeds regiospecifically with good
to excellent stereoselectivity and creates two new rings, three bonds and three stereocentres. © 2002 Elsevier Science Ltd. All
rights reserved.
We have recently developed a significant number of
mixture by the cycloaddition cascade counteracts its
instability.
1,2
sequential and cascade tactical combinations in which
two disparate ring forming reactions are combined to
provide one-pot access to target molecules possessing a
high degree of molecular complexity. We now report a
combination of two powerful ring forming processes,
the intramolecular Heck reaction and our imine“
azomethine ylide“cycloaddition, in which the former
Pd-catalysed process generates the dipolarophile for the
latter Ag(I)-catalysed process. The Heck substrate 3
was produced as outlined in Scheme 1.
The silver(I) salt, in the presence of base, generates a
metallo-azomethine ylide, which generally cycloadds
5
both regio- and stereospecifically to dipolarophiles. At
room temperature, the kinetic syn-dipole has the imine
The cascade process (Scheme 2) utilised a Pd(OAc)2/
PPh3 precatalyst combination for the intramolecular
Heck reaction which affords 4 in situ. The known
Scheme 1. (a) 1.1 equiv. of Et
DCM, rt; (b) NaH, MeI, DMF, 0°C to rt.
N, 1.1 equiv. of CH CHCOCl,
2
3
3
instability of 4 dictated a search for mild reaction
conditions. Using dichloromethane as solvent allowed
the reaction to be carried out at room temperature. A
subsequent Ag(I) catalysed imine“azomethine ylide“
cycloaddition cascade leads to spiro-oxindoles regiospe-
cifically in good yield with a reaction time of 16–18 h
for the total cascade.
The cycloadducts comprise a ca. 4:1 to >9:1 mixture of
two stereoisomers (Table 1).
Although it is not unknown for Heck reactions to occur
4
at room temperature, it is unusual that the reaction
should be so efficient in dichloromethane. The constant
removal of the Heck product 4 from the reaction
Scheme 2. (a) 10 mol% of Pd(OAc) , 20 mol% of PPh , 1
2
3
equiv. of K CO ; (b) 1 equiv. of imine (5a–g, see Table 1), 10
*
Corresponding author. Tel.: +44-113-233-6501; fax: +44-113-233-
501; e-mail: r.grigg@chem.leeds.ac.uk
2
3
6
mol% of Ag O, 1 equiv. of DBU, DCM, rt.
2
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00331-3

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R. Grigg et al. / Tetrahedron Letters 43 (2002) 2605–2608
Table 1. Product ratios of spiro-oxindoles resulting after
the Heck-1,3-dipolar cycloaddition reaction
this isomer is such that the metallo-azomethine ylide
involved must have had anti conformation (Fig. 1).
Significant syn–anti dipole isomerisation is rare in
Ag(I)-catalysed cycloaddition reactions. It occurs when
structural features conspire to slow the cycloaddition
step; sterically hindered 1,1-disubstituted amide dipo-
6
larophiles are particularly prone to this process.
It was suspected that the minor isomer arose from the
syn-dipole. Unfortunately in each of the cases 6a–g it
did not prove possible to isolate a suitable crystal of a
minor isomer for X-ray structure determination. A
separate experiment was therefore carried out using an
imine derived from methyl glycinate (Scheme 3). In this
case the isomer ratio 7a/7b was 1.2:1 and crystals of
both the major and minor isomers were obtained and
their structures determined by X-ray crystallography
(
Fig. 3). As expected, the minor isomer resulted from
the syn-dipole.
Figure 1.
Figure 2. X-Ray crystal structure of the major stereoisomer
of product 6a.
nitrogen and the carbonyl oxygen of the ester moiety
coordinated to the silver, locking the dipole conforma-
tion (Fig. 1).
The stereochemistry of the major isomer of product 6a
was determined by X-ray crystallography (Fig. 2), indi-
cating that the 1,3-dipolar cycloaddition proceeded
with endo-selectivity. However, the stereochemistry of
Scheme 3. (a) 10 mol% of Pd(OAc) , 20 mol% of PPh , 1
2
3
equiv. of K CO , 10 mol% of Ag O, 1 equiv. of DBU, DCM,
2
3
2
rt.

R. Grigg et al. / Tetrahedron Letters 43 (2002) 2605–2608
2607
mM for 8 and 14 mM for 9, thus, having the potential
to act as antineoplastic agents. Recent synthetic work
9
by Danishefsky has identified more active unnatural
analogues. The synthesis of such analogues, together
10
with the natural products, is currently attracting
much attention.
Acknowledgements
We thank Leeds University for support.
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