Exploring a new, connective Pummerer reaction: Formation of oxindoles by the reaction of thiols with glyoxamides

Article abstract of DOI:10.1039/b613591a

The reaction of a range of thiols with mono- and bis-glyoxamides derived from secondary anilines, triggers a new, connective Pummerer cyclisation process and leads to the formation of oxindoles. The Royal Society of Chemistry.

Full text of DOI:10.1039/b613591a

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Exploring a new, connective Pummerer reaction: formation of oxindoles
by the reaction of thiols with glyoxamides{
Marc Miller,a William Tsang,a Andrew Merrittb and David J. Procter*a
Received (in Cambridge, UK) 19th September 2006, Accepted 16th October 2006
First published as an Advance Article on the web 31st October 2006
DOI: 10.1039/b613591a
In this communication, we explore the scope of this new
Pummerer process. Concentrating on the reactions of glyoxamides
derived from aniline derivatives has allowed us to look at the role
of the thiol component, the Lewis acid, and to pursue the idea of
two-directional Pummerer reactions. In addition, the products of
this Pummerer process possess a substituted oxindole structure and
are amenable for the synthesis of natural product and pharma-
ceutically interesting target molecules.
The reaction of a range of thiols with mono- and bis-
glyoxamides derived from secondary anilines, triggers a new,
connective Pummerer cyclisation process and leads to the
formation of oxindoles.
The Pummerer reaction1 has evolved into a useful tool for
synthesis.2 We have recently developed a fluorous synthesis of
N-heterocycles that utilises a Pummerer process to introduce the
fluorous tag and construct the heterocyclic scaffold in a single
step.3 The pivotal cyclisation step involves the reaction of a
fluorous thiol with glyoxamide substrates in the first example of a
‘connective’ Pummerer reaction.3 The classical Pummerer reaction
of sulfoxides and the connective Pummerer reaction are compared
in Scheme 1.
We began by examining the reaction of functionalised alkyl and
aryl thiols with glyoxamides5 1–4 derived from secondary anilines
containing neutral, electron-withdrawing and electron-releasing
Table 1 Reaction of thiols with glyoxamides derived from anilinesa,b
In the classical Pummerer reaction, sulfoxides are activated by
acylation of the sulfoxide oxygen. Elimination then generates a
thionium ion that is trapped by an external or internal nucleophile.
In the connective variant, thiol addition to an aldehyde generates a
hemithioacetal that upon activation generates a thionium ion. The
connective variant has several advantages over its traditional
counterpart: the process utilises widely-available thiol and
aldehyde starting materials, negating the need to prepare sulfoxide
or sulfide starting materials (sulfides are essentially prepared
in situ). In addition, the properties or structural features of the thiol
and aldehyde substituents are united in a single synthetic
operation, with concomitant addition of a nucleophile. Reactive
aldehydes such as glyoxylates4 and glyoxamides3 are ideal
substrates and the use of an internal nucleophile allows hetero-
cycles to be constructed.3 Attractively, the organosulfanyl group
can impart specific properties to the Pummerer adducts or can be
used as a synthetic handle for further manipulation.
Scheme 1 (a) Pummerer reaction of sulfoxides; (b) the connective
Pummerer reaction.
aSchool of Chemistry, University of Manchester, Oxford Rd.,
Manchester, UK M13 9PL. E-mail: david.j.procter@manchester.ac.uk
bGlaxoSmithKline, Gunnelswood Rd., Stevenage, UK SG1 2NY
{ Electronic supplementary information (ESI) available: Experimental
a
b
RSH (1 eq.), TFAA (9 eq.), BF3?OEt2 (4 eq.). Yields are for 2
c
steps as glyoxamides are not purified.
diastereoisomers.
1 : 1 mixture of
1
details, selected H and 13C NMR spectra. See DOI: 10.1039/b613591a
498 | Chem. Commun., 2007, 498–500
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Table 3 Connective Pummerer cyclisation of bis-1,4-glyoxamidesa,b
substituents (Table 1). The cyclisations were carried out by stirring
thiol with glyoxamide, followed by addition of trifluoroacetic
anhydride (TFAA), then BF3?OEt2. Omitting TFAA or the Lewis
acid led to the isolation of the hemithioacetal or trifluoroacetylated
hemithioacetal intermediates. We have found that at least two
equivalents of BF3?OEt2 and four equivalents of TFAA are
required before a significant degree of cyclisation is seen. A
preliminary survey of other Lewis acids showed that Sc(OTf)3 gave
comparable results to BF3?OEt2 when used in the cyclisation, while
Yb(OTf)3 also promoted the Pummerer reaction but gave lower
yields.
RSH
Isolated yieldb
Product
Linear : bentc,d
PhSH
55%
54%
26
27
.5 : 1
5 : 1
In all cases, the connective Pummerer cyclisation occurred to
give the corresponding oxindole products in moderate to good
isolated yields (over two steps) indicating that the process is
compatible with thiols bearing a range of functional groups (aryl
rings, ester, bromide, amino and hydroxyl groups). The reaction of
3 with a thiol derived from cysteine proceeded to give the expected
product 14 (Table 1). This preliminary result suggests that the
connective Pummerer reaction could form the basis of a method
for chemical ligation:6 hemithioacetal formation through the
reaction of a carbonyl compound, or a masked derivative, with
a cysteine residue could be followed by cyclisation to make the
attachment permanent.
61%
56%
28
29
y3 : 1
5 : 1
50%
30
2 : 1
a
b
See Table 1 for reaction conditions. Yields are for 2 steps as
c
glyoxamides are not purified. Regioisomer ratios are estimated
d
from 1H NMR.
diastereoisomers.
Each regioisomer is a 1 : 1 mixture of
ducts could be separated by chromatography (e.g. 30) or
recrystallisation (e.g. 27).
We have also examined the reaction of readily accessible bis-1,3-
glyoxamides and bis-1,4-glyoxamides with thiols. To the best of
our knowledge these represent the first examples of two-directional
Pummerer cyclisations (Tables 2 and 3). Although, the overall
yields are somewhat lower than those obtained with simple
glyoxamides, the expected bis-oxindoles are obtained in acceptable
yields and good purity. In the case of bis-1,3-glyoxamides, the
oxindole products were obtained as single, linear regioisomers and
inseparable y1 : 1 mixtures of cis and trans diastereoisomers.
The corresponding reaction of bis-1,4-glyoxamides proceeded to
give oxindoles with the linear regioisomers predominating
(approximately 2 : 1 to .5 : 1) (vide infra). The use of bulkier
thiols such as thiophenol and para-bromobenzylthiol gave more
linear isomer presumably due to unfavourable steric interactions
involved in the formation of the bent isomers. Both the linear and
bent regioisomers were obtained as y1 : 1 mixtures of cis and trans
diastereoisomers. In most cases regioisomeric bis-oxindole pro-
Due to the symmetry present in the linear and bent isomers of
26–30, NMR did not allow the isomers to be distinguished. The
nature of the isomers obtained from the cyclisation of bis-1,4-
glyoxamides was determined by the following experiments: after
the isolation of the major pair of isomers from the reactions to
form 29 and 30, independent treatment of each mixture with
7
SmI2 gave a single product 31 in good yield after reductive
removal of the sulfanyl groups8 (Scheme 2). Thus, the major
isomer pair from each reaction are diastereoisomers and the major
isomer pairs for 29 and 30 belong to the same regioisomeric family.
The structure of the major regioisomers was confirmed by partial
SmI2 reduction to break the symmetry and provide 32. The
presence of two singlets in the 1H NMR for the aromatic protons
in 32 confirmed the major products of cyclisation to be linear
isomers.
In summary, we have assessed the scope of a new, connective
Pummerer process and have carried out the first, two-directional
Pummerer cyclisations. We are currently exploring the utility of the
connective Pummerer process in several areas including the
synthesis of linear, fused-ring organic materials.
Table 2 Connective Pummerer cyclisation of bis-1,3-glyoxamidesa,b
R2SH
R1
Isolated yieldb
Product
BnSH
PhSH
n-Pr
n-Pr
n-Pr
51%
47%
45%
19c
20c
21c
n-Pr
56%
22c
BnSH
PhSH
a
Bn
Bn
62%
45%
b
23c
24c
See Table 1 for reaction conditions. Yields are for 2 steps as
Scheme 2 Investigating the selectivity of the Pummerer cyclisations of
c
glyoxamides are not purified. 1 : 1 mixture of diastereoisomers.
bis-1,4-glyoxamides.
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5 M. A. Marx, A.-L. Grillot, C. T. Louer, K. A. Beaver and P. A. Bartlett,
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Notes and references
6 P. F. van Swieten, M. A. Leeuwenburgh, B. M. Kessler and
H. S. Overkleeft, Org. Biomol. Chem., 2005, 3, 20.
1 R. Pummerer, Ber. Dtsch. Chem. Ges., 1909, 42,
2282.
7 (a) D. J. Edmonds, D. Johnston and D. J. Procter, Chem. Rev., 2004, 104,
3371; (b) H. B. Kagan, Tetrahedron, 2003, 59, 10351; (c) P. G. Steel,
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2 For recent reviews on the Pummerer reaction; see: (a) K. S. Feldman,
Tetrahedron, 2006, 62, 5003; (b) S. K. Bur and A. Padwa, Chem. Rev.,
2004, 104, 2401.
3 L. A. McAllister, R. A. McCormick, S. Brand and D. J. Procter, Angew.
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4 For thiol addition to glyoxalates, see: J. Milton, S. Brand,
M. F. Jones and C. M. Rayner, Tetrahedron Lett., 1995, 36,
6961.
8 (a) L. A. McAllister, S. Brand, R. de Gentile and D. J. Procter, Chem.
Commun., 2003, 2380; (b) K. L. Turner, T. M. Baker, S. Islam,
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500 | Chem. Commun., 2007, 498–500
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