Nickel-catalysed aromatic Finkelstein reaction of aryl and heteroaryl bromides

Article abstract of DOI:10.1039/c2cc30956d

A fast and efficient nickel-catalysed iodination reaction of aryl and heteroaryl bromides has been developed. The transformation was found to be general for a wide range of substrates and was used for the synthesis of iodo-PK11195, an imaging agent of Alzheimer's disease and iniparib, a compound used in the treatment of breast cancer.

Full text of DOI:10.1039/c2cc30956d

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COMMUNICATION
Nickel-catalysed aromatic Finkelstein reaction of aryl and heteroaryl
bromidesw
Alastair A. Cant,a Rajiv Bhalla,b Sally L. Pimlottc and Andrew Sutherland*a
Received 9th February 2012, Accepted 21st February 2012
DOI: 10.1039/c2cc30956d
A fast and efficient nickel-catalysed iodination reaction of aryl and
heteroaryl bromides has been developed. The transformation was
found to be general for a wide range of substrates and was used for the
synthesis of iodo-PK11195, an imaging agent of Alzheimer’s disease
and iniparib, a compound used in the treatment of breast cancer.
transformation (22–40 h at 110–130 1C). We were interested
in developing a metal-catalysed halogen exchange reaction
that would not only allow the general synthesis of aryl and
heteroaryl iodides, but one that could be applied for the rapid
radioiodination of potential SPECT imaging agents. Herein, we
report the development of a nickel-catalysed iodination reaction of
aryl and heteroaryl bromides that overcomes previous limitations.
As well as demonstrating the scope of this new process with
compounds used in SPECT imaging and anti-cancer therapy,
we also show that the iodination can be completed in as little
as 10 min using microwave accelerated heating.
Aryl and heteroaryl iodides are ubiquitous synthetic intermediates
used for a wide range of transformations, particularly metal-
catalysed cross-coupling reactions.1 The versatility of the C–I
bond makes aryl and heteroaryl iodides essential building blocks
in medicinal chemistry, material science and total synthesis.
Furthermore, radioiodinated aryl and heteroaryl compounds
are important in the field of single photon emission computed
tomography (SPECT) imaging for the non-invasive investigation
in humans of disease such as cancer and neurological disorders.2
Due to their general importance in chemical and medicinal
science, a number of methods have been developed for the
synthesis of aryl iodides from less reactive aryl bromides and
chlorides.3 Most common procedures involve nickel- or copper-
mediated reactions. The first nickel-catalysed reaction was
reported by Takagi and co-workers who used nickel(II)-bromide
with potassium iodide in HMPA as the solvent.4 An excess of
zinc was required as a reducing agent, resulting in the formation
of Ullmann-type homo-coupled bi-aryl species as by-products.4
Cheng and co-workers reported the efficient synthesis of
aryl iodides from aryl bromides but this procedure required
stoichiometric amounts of Ni(0) powder.5 Similar limitations
were observed with copper mediated processes6 until the work
of Klapars and Buchwald who demonstrated that a high
yielding aromatic Finkelstein reaction could be catalysed by
copper(I) iodide using diamine ligands.7 The scope of this
process was found to be general allowing the synthesis of a
wide range of aryl and heteroaryl iodides. The only drawback
with this reaction was the time for completion of the
The programme of research began by investigating the
iodination of 2-bromoacetanilide. Iodination of this substrate
would have to overcome the steric hinderance of the ortho-
substituent and possible reduction of the carbon–bromine bond
by the adjacent amide hydrogen during oxidative addition of the
nickel catalyst. Thus, it was believed that an optimised procedure
for this challenging substrate would lead to a general iodination
method for a wide range of aryl and heteroaryl bromides. Initially,
2-bromoacetanilide was heated to 140 1C with nickel bromide
(10 mol%) and sodium iodide (6 equiv.), however, this gave
none of the desired iodide (Table 1, entry 1). A ligand screen
was then implemented, with electron rich aryl and alkyl
phosphines showing conversion to the iodide (entries 3–7).
The best result was obtained with tri-n-butylphosphine which
gave 2-iodoacetanilide in 49% yield after 16 h (entry 7). It
should be noted that several diamine ligands such as DMEDA
(entry 2) that were successfully utilised in the Buchwald procedure,7
gave no iodide product when used in the nickel-catalysed reaction.
Having identified a suitable ligand, a temperature screen was
performed in an effort to shorten the reaction time. An optimal
temperature of 180 1C allowed the isolation of 2-iodoacetanilide
in 63% yield after only 3 h (entry 9). During this optimisation
study, various amounts of the reduced by-product, acetanilide
(6–30%) were also isolated from these reactions. By changing
the solvent to NMP, restricted this side-reaction and allowed
much cleaner reactions (entry 10).
a WestCHEM, School of Chemistry, The Joseph Black Building,
University of Glasgow, Glasgow G12 8QQ, UK.
E-mail: Andrew.Sutherland@glasgow.ac.uk;
The scope of the reaction was then explored with a range of
aryl and heteroaryl bromides (Table 2).8 The transformation
was found to give the corresponding iodides in high yields for
p-, m- and o-substituted aryl compounds with electron rich
and electron deficient substituents.
Fax: +44 141 330 4888; Tel: +44 141 330 5936
b GE Healthcare, The Grove Centre, White Lion Road, Amersham,
Buckinghamshire HP9 7LL, UK
c West of Scotland Radionuclide Dispensary,
NHS Greater Glasgow and Clyde, Glasgow G11 6NT, UK
w Electronic supplementary information (ESI) available: Full experi-
mental procedures, spectroscopic data, NMR spectra for all compounds
synthesised. See DOI: 10.1039/c2cc30956d
Based on previous studies of nickel-catalysed halogen
exchange reactions,3a,4,5 the mechanism likely involves the
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3993–3995 3993

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Table 1 Development of the nickel-catalysed iodination reaction of
2-bromoacetanilide
Table 2 Scope of the nickel-catalysed iodination reaction
Entry
1
Bromide
Temp. (1C) Time (h) Yield (%)a
Entry
Ligand
Temp. (1C)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
None
DMEDAb
Xantphos
Ph3P
140
140
140
140
140
140
140
160
180
180
16
16
16
16
16
16
16
16
3
0
0
180
3
87
14
15
19
19
49
58
63
65
dppp
dppb
2
3
4
180
180
180
3
16
3
84
83
57
nBu3P
nBu3P
9
nBu3P
10c
nBu3P
3
a
b
c
Isolated yields. N,N0-dimethylethylenediamine. Reaction conducted
using NMP as the solvent.
tri-n-butylphosphine mediated reduction of Ni(II) to Ni(0)
which then oxidatively adds into the carbon–bromine bond.9
This intermediate can then undergo halogen exchange with the
excess iodide.10 As expected, 4-bromoacetanilide (entry 3) with
a distal amide hydrogen atom and N-(2-bromophenyl)-
N-methylacetamide (with no acidic hydrogen, entry 7) gave
the corresponding iodides very cleanly with none of the reduced
by-product. Heteroaryl bromides such as 5-bromo-2-thiophene-
carboxaldehyde (entry 10) and 5-bromoindole (entry 11) were
also iodinated cleanly and in good yield. Several of the
substrates (entries 3, 7–9 and 11) required longer reaction
times for optimal yields. Despite the longer reaction times at
high temperatures, the products were isolated very cleanly with
minimal decomposition. This was typified by the iodination of
more complex substrates such as the translocator protein (TSPO)
ligand, I-PK11195 2 and the PARP inhibitor, iniparib 5.
5
6
7
160
180
190
3
3
7
67
77
70
8
140
180
16
16
86
74
[
123I]-PK11195 2, a high affinity ligand for TSPO has been
9
developed for in vivo SPECT imaging of human neurodegenera-
tive diseases such as Alzheimer’s disease.11,12 Using the nickel-
catalysed iodination reaction at 160 1C, Br-PK11195 113 was
cleanly converted to I-PK11195 2 in 75% yield (Scheme 1).
The preparation of [123I]-PK11195 has been reported using a
two-stage synthesis from 1 via an organotin derivative.14
Organotin compounds can be unstable making radioiodination
reactions unreliable. In addition, the potential of tin residues in
clinical preparations raises toxicity concerns. Using [123I]-sodium
iodide with this more direct nickel-catalysed reaction has the
potential to provide an alternative route that will reliably
allow the radiosynthesis of imaging agents more safely for
in vivo studies.
10
160
160
3
65
64
11
16
a
Isolated yields.
As the nickel-catalysed iodination reaction was able to
produce the desired iodides more quickly at higher temperatures
while still maintaining good yields, it was proposed that faster
reaction times could be achieved using microwave irradiation to
promote the process.18 Furthermore, the optimal solvent for the
iodination reaction, NMP, has a relatively good tand (0.275) and
so is effective at transforming electromagnetic energy into heat.
Therefore, a preliminary study was conducted with a number
of aryl bromides to investigate the efficiency of a microwave
promoted reaction (Table 3).19 Even at temperatures of up to
200 1C, many of the substrates were converted to the corresponding
iodides in comparable yields to that of the conventional heated
The nickel-catalysed iodination reaction was also used as
the key step in a new synthesis of iniparib 5. Iniparib was the
first poly-ADP-ribose-polymerase (PARP) inhibitor to commence
phase III clinical trials for the treatment of triple negative breast
cancer.15,16 Reaction of commercially available 4-bromobenzonitrile
(3) with potassium nitrate and sulfuric acid gave 4-bromo-3-
nitrobenzamide (4) in 74% yield (Scheme 2).17 Nickel-catalysed
iodination of 4 was found to proceed at 140 1C and after 16 h,
gave iniparib 5 in 54% yield.
c
3994 Chem. Commun., 2012, 48, 3993–3995
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corresponding iodide in only 30% yield (cf. Table 2, entry 8).20
Nevertheless, this rapid iodination procedure has the potential
for application in the development of a wide range of radio-
iodinated SPECT imaging agents.
In summary, an efficient nickel-catalysed aromatic Finkelstein
reaction has been developed for the general iodination of aryl
and heteroaryl bromides. The procedure was applicable for the
synthesis of relatively complex targets such as the translocator
protein ligand, I-PK11195 2 and the anti-cancer compound,
iniparib 5. These reactions could be greatly accelerated using
microwave irradiation and application of this protocol for the
radioiodination of potential SPECT imaging agents is currently
underway.
Scheme 1 Nickel-catalysed iodination of Br-PK11195 1.
Financial support from the Scottish Funding Council,
SINAPSE and GE Healthcare Ltd is gratefully acknowledged.
Notes and references
1 (a) Metal-Catalysed Cross-Coupling Reactions, ed. F. Diederich
and P. J. Stang, Wiley-VCH, New York, 1998; (b) N. Kambe,
T. Iwasaki and J. Terao, Chem. Soc. Rev., 2011, 40, 4937.
2 S. L. Pimlott and A. Sutherland, Chem. Soc. Rev., 2011, 40, 149.
3 (a) T. D. Sheppard, Org. Biomol. Chem., 2009, 7, 1043 and
references therein; (b) A. C. Bissember and M. G. Banwell,
J. Org. Chem., 2009, 74, 4893 and references therein.
4 (a) K. Takagi, N. Hayama and T. Okamoto, Chem. Lett., 1978,
191; (b) K. Takagi, N. Hayama and S. Inokawa, Bull. Chem. Soc.
Jpn., 1980, 53, 3691.
Scheme 2 Two-step synthesis of iniparib 5.
Table 3 Microwave accelerated iodination reactions
5 S. H. Yang, C. S. Li and C. H. Cheng, J. Org. Chem., 1987, 52, 691.
6 For a general review, see: J. Lindley, Tetrahedron, 1984, 40, 1433.
7 A. Klapars and S. L. Buchwald, J. Am. Chem. Soc., 2002,
124, 14844.
8 After optimisation of the iodination of aryl and heteroaryl
bromides, several aryl chlorides and aryl fluorides were explored
as possible substrates. However, neither of these substrate classes
showed any reactivity.
9 To rule out a SNAr type reaction mechanism, several of the
reactions in Table 1 were repeated in the absence of nickel bromide
and tri-n-butylphosphine. However, no conversion to the iodides,
even at elevated temperatures and extended reaction times was
observed.
10 The proposed mechanism seems highly plausible by the observation
that Ni(0) powder in the absence of any phosphine ligands also
catalyses iodination of aryl bromides under our conditions, although
in lower yields.
Entry
1
Bromide
Temp. (1C) Time (min) Yield (%)a
200
200
160
30
10
10
74
67
49
2
3
11 A. M. Scarf, L. M. Ittner and M. Kassiou, J. Med. Chem., 2009,
52, 581 and references therein.
4
5
6
160
200
10
30
72
51
12 J. J. Versijpt, F. Dumont, K. J. V. Laere, D. Decoo, P. Santens,
K. Audenaert, E. Achten, G. Slegers, R. A. Dierckx and J. Korf,
Eur. Neurol., 2003, 50, 39.
13 L. Stevenson, S. L. Pimlott and A. Sutherland, Tetrahedron Lett.,
2007, 48, 7137.
14 S. L. Pimlott, L. Stevenson, D. J. Wyper and A. Sutherland, Nucl.
Med. Biol., 2008, 35, 537.
15 E. C. Y. Woon and M. D. Threadgill, Curr. Med. Chem., 2005,
12, 2373.
16 (a) J. Mendeleyev, E. Kirsten, A. Hakam, K. G. Buki and E. Kun,
Biochem. Pharmacol., 1995, 50, 705; (b) J. O’Shaughnessy,
C. Osbourne, J. E. Pippen, M. Yoffe, D. Patt, C. Rocha,
I. C. Koo, B. M. Sherman and C. Bradley, N. Engl. J. Med.,
2011, 364, 205.
180
160
10
60
68
30
7
17 M. Schopff, Ber. Dtsch. Chem. Ges., 1890, 23, 3435.
¨
a
18 C. O. Kappe, Angew. Chem., Int. Ed., 2004, 43, 6250.
19 A microwave mediated halogen exchange reaction for the synthesis
of aryl chlorides and aryl bromides using stoichiometric amounts
of nickel chloride and nickel bromide, respectively has been pre-
viously reported: R. K. Arvela and N. E. Leadbeater, Synlett,
2003, 1145.
20 The build up of pressure within the sealed vessel during microwave
heating of 2-bromocinnamic acid suggests that under these conditions,
the compound undergoes decarboxylation.
Isolated yields.
process. More importantly, the reactions were found to be
complete in times ranging from 10 to 30 min (entries 1–6). The
only drawback with microwave heating is that not all functional
groups are tolerated. This was exemplified by 2-bromocinnamic
acid (entry 7) which under microwave heating produced the
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3993–3995 3995