Observations on the intramolecular Heck reactions of aromatic chlorides using palladium/imidazolium salts

Article abstract of DOI:10.1016/S0040-4039(02)02340-7

The intramolecular Heck reaction of aromatic amines and ethers using palladium/imidazolium salts is described. The use of tetra-n-butylammonium halide salts facilitates the reactivity of aromatic chlorides. An unexpected and novel palladium-mediated cyclisation is also described leading to the formation of a tricyclic adduct.

Full text of DOI:10.1016/S0040-4039(02)02340-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9347–9350
Observations on the intramolecular Heck reactions of aromatic
chlorides using palladium/imidazolium salts
Stephen Caddick* and William Kofie
Centre for Biomolecular Design and Drug Development, The Chemistry Laboratory, CPES, University of Sussex, Falmer,
Brighton BN1 9QJ, UK
Received 22 August 2002; revised 8 October 2002; accepted 18 October 2002
Abstract—The intramolecular Heck reaction of aromatic amines and ethers using palladium/imidazolium salts is described. The
use of tetra-n-butylammonium halide salts facilitates the reactivity of aromatic chlorides. An unexpected and novel palladium-
mediated cyclisation is also described leading to the formation of a tricyclic adduct. © 2002 Published by Elsevier Science Ltd.
The intramolecular Heck reaction has become widely
used for the synthesis of carbocyclic and heterocyclic
ring systems.1 Most conventionally these reactions
utilise palladium phosphine complexes and employ aro-
matic bromides and iodides as substrates. Such is the
reliability and practicability of these transformations
that they are considered one of the most powerful
methods for the construction of polycyclic ring systems.
A generally accepted mechanism involves (i) oxidative
addition of aryl halide to Pd(0); (ii) intramolecular
carbometallation; (iii) b-hydride elimination; (iv) reduc-
tive elimination to regenerate the Pd(0) catalyst.2
There is some value in attempting to find practical
alternatives to phosphines as ligands.6 The N-hetero-
cyclic carbene (NHC) system is often now regarded as
a potential replacement ligand for phosphine.7 It is
known that NHC ligands are excellent donors and tend
to form strong bonds with metals.8 In the case of
ruthenium the replacement of PCy3 with NHC has led
to new complexes with good catalytic activity.9
The NHC motif has also found use in palladium chem-
istry. There are many reports of palladium(II) com-
plexes in which the metal is ligated with the NHC
ligand and the catalytic activity of these complexes has
also been examined.10 Zero-valent palladium systems
are less common but have also been studied and their
catalytic activity described. It has been found that such
palladium–carbene complexes exhibit excellent catalytic
behaviour in amination, Heck, and Suzuki reactions.7,11
One of the current limitations of many palladium-
catalysed transformations is that they require the more
usual use of bromide or iodide substrates. There are
many important commercial and environmental reasons
for trying to develop protocols employing aromatic
chlorides. In recent times there has been extraordinary
research activity in the generation of new ligands for
palladium and the study of their mechanisms of action.3
The development of novel sterically hindered phosphine
ligands for palladium-catalysed transformations has
improved the applicability of many palladium-mediated
transformations.4 A key development has been the abil-
ity to apply these new protocols to chloride substrates.5
Further important advances are likely to be made as
the mechanistic details of these phosphine systems
become clearer.3
NHC–palladium complexes have also been invoked as
intermediates in systems utilising imidazolium salts12
and Hartwig,13 Nolan14 and others have described sys-
tems in which imidazolium salts can be useful additives
in palladium-catalysed transformations.15 Although the
detailed mechanistic understanding has yet to be
elucidated16 it seems likely that these systems generate
either neutral or cationic17 palladium–NHC complexes
and what is clear is these protocols have enormous
potential value in synthetic organic chemistry.
There are fewer reports of the use of NHC–Pd or other
reagent systems for intramolecular transformations of
aromatic chlorides.18 As part of our programme
directed towards the study of metal–NHC-catalysed
* Corresponding author. Tel./fax: +44(1273) 678734; e-mail:
s.caddick@sussex.ac.uk
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02340-7

9348
S. Caddick, W. Kofie / Tetrahedron Letters 43 (2002) 9347–9350
protocols for organic synthesis, we have investigated
the potential for carrying out intramolecular Heck reac-
tions using aromatic chlorides.19 We describe our stud-
(entries 2, 6, 10, 14 and 19). Aromatic chloride sub-
strates were particularly sluggish in their reactivity and
the yields of these transformations were poor (entries 3,
7, 11, 15 and 20). However, we found that the yields of
these reactions could be dramatically improved to 50–
70% (entries 4, 8, 12, 16, and 21) by the addition of one
ies
on
the
palladium/imidazolium
catalysed
intramolecular Heck reactions of aromatic iodides, bro-
mides and chlorides. Our findings indicate that
intramolecular Heck reactions of aromatic chlorides is
possible using Pd/imidazolium salt protocols.
equivalent
of
tetra-n-butylammonium
bromide
(TBAB)20 showing that aromatic chlorides can partici-
pate effectively in intramolecular Heck reactions. We
were interested to note that a similar effect could be
observed using an equivalent of tetra-n-butylammo-
nium nitrate (TBAN, entry 17).
In order to carry out these preliminary studies we have
focused on nitrogen and oxygen containing systems.
The substrates described in this study were prepared in
good to excellent yields by alkylation of 2-halo-anilines
((a) LDA, THF, −78°C, 72–95%) or 2-halo-phenols ((b)
K2CO3, NaI, acetone, reflux, 71–99%) (Scheme 1).
Further studies on substrate 1a–c were frustrated by
problems of isomer separation; however, we have tenta-
tively assigned the product as a mixture of regioisomers
2a–c (yields, between 20 and 70%) (Scheme 2).
However, more satisfactorily we were able to isolate a
single product 4 from reaction of substrates 3a–c. We
found that the iodide 3a and bromide 3b proceeded to
give the product 4 in good to excellent yields (I, 82%, 1
h; Br, 60%, 5 h) but the chloride 3c gave only 4% of
Scheme 1.
Table
1 presents the results of our studies on
intramolecular Heck reactions using Pd2dba3 and imi-
dazolium salt A.
As anticipated iodide precursors were found to undergo
high yielding and rapid intramolecular Heck reactions
(entries 1, 5, 9, 13 and 18). Aryl bromides also reacted
satisfactorily proceeding in slightly slower reaction
times and with slightly lower yields than the iodides
Scheme 2.
Table 1.
Entry
R1
R2
X
Y
Time (h)
Adda
Isolated yield (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
H
H
H
H
H
I
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
O
0.5
1
24
24
1
81
77
18
65
82
71
21
64
78
70
27
70
76
56
21
58
52
84
61
17
63
Br
Cl
Cl
I
Br
Cl
Cl
I
Br
Cl
Cl
I
Br
Cl
Cl
Cl
I
TBAB
TBAB
TBAB
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
2
24
24
2
9
10
11
12
13
14
15
16
17
18
19
20
21
5
24
24
2
24
48
48
48
24
48
48
48
TBAB
TBAN
H
H
H
Br
Cl
Cl
O
O
O
TBAB
Typically these reactions were carried out using 1 mol% catalyst, 1 mol% ligand, Cs2CO3 (1.5. equiv.) in DMA at 140°C.
a 1 equiv.

S. Caddick, W. Kofie / Tetrahedron Letters 43 (2002) 9347–9350
9349
Acknowledgements
product 4. However, repetition of the reaction but
using tetra-n-butylammonium bromide20 or iodide, had
a dramatic effect, improving the yield of 4 from 4% to
28–32% (Scheme 3).
We gratefully acknowledge Dr. John Hayler at GSK
for his encouragement, support and helpful comments
throughout this project. We also gratefully acknowl-
edge support of this project from GSK and EPSRC.
We also acknowledge financial support from
AstraZeneca, Novartis, Pfizer, BBSRC, and AICR. We
are grateful to EPSRC Mass Spectrometry Service at
Swansea and Drs. Abdul-Sada, Avent and Hitchcock
for their contributions to this work.
Perhaps the most surprising result was obtained from a
study of substrates 5a–c. Although we only isolated
traces of products from chloride 5c we were very sur-
prised to discover that, from either the iodide 5a or
bromide 5b, we were able to isolate the tricyclic adduct
6,21 in yields of 41 and 32%, respectively (Scheme 4).
Although we are unable to provide any further experi-
mental evidence for a mechanism for the formation of
6 at this time, we speculate that the reaction might
proceed via an initial dimerisation to provide 5*. This
dimer 5* undergoes deallylation and deamidation to
give an aryl palladium species 5** which then under-
goes intramolecular amination to give 6. Irrespective of
the detailed mechanism of this transformation this lat-
ter result is unusual and will be the subject of further
work (Scheme 5).
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