Synthesis and solid state study of pyridine- and pyrimidine-based fragment libraries

Article abstract of DOI:10.1016/j.tetlet.2011.07.147

A library of pyridines and pyrimidines has been synthesised in excellent yields employing microwave and flow chemistry methodologies. Work-up bottlenecks have been facilitated substantially by the use of supported reagents and many of the final compounds have been studied in the solid state by single crystal X-ray diffraction.

Full text of DOI:10.1016/j.tetlet.2011.07.147

Tetrahedron Letters 52 (2011) 5905–5909
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and solid state study of pyridine- and pyrimidine-based
fragment libraries
John Spencer a, , Hiren Patel a, Samantha K. Callear b, Simon J. Coles b, John J. Deadman c,
⇑
a School of Science, University of Greenwich at Medway, Chatham ME4 4TB, UK
b UK National Crystallography Service, School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
c Avexa Ltd, 576 Swan Street, Richmond, Victoria 3121, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A library of pyridines and pyrimidines has been synthesised in excellent yields employing microwave and
flow chemistry methodologies. Work-up bottlenecks have been facilitated substantially by the use of
supported reagents and many of the final compounds have been studied in the solid state by single crys-
tal X-ray diffraction.
Received 25 May 2011
Revised 29 June 2011
Accepted 29 July 2011
Available online 5 September 2011
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Keywords:
Heterocycles
Microwaves
Parallel synthesis
Piperazines
Flow chemistry
Pyridines and pyrimidines are privileged structures found in di-
verse bioactive molecules, including anticancer agents, CNS acting
drugs and antivirals.1 A number of these bioactive molecules are
associated with a piperazine unit, which can add water solubility
as well as act as a linker to attach other binding motifs (Fig. 1).2
We report here a parallel synthetic route to a library of pyri-
dines and pyrimidines, many of which contain a piperazine group.
Our methods include the use of microwave-assisted organic syn-
thesis (MAOS),3 flow chemistry4 and supported resins,5 and are
applicable to fragment-based drug discovery, since the molecules,
in general, obey the ‘rule of three’.6 The synthetic efforts have been
supported by solid state studies; in principle this could be used to
generate coordinates for docking studies of the products into en-
zymes/receptors for drug discovery.
2-Bromo-5-nitropyridine (1) was found to be a useful starting
point for the chemistry herein. Reaction of 1 with cyclic amines 2
and base, in a microwave apparatus, afforded coupled products 3.
The Boc-protected analogue 3a was deprotected with TFA affording
3b. Catalytic reduction of compounds 3 gave the amines 4. The
addition of 1.2 equiv of different aryl, alkyl or heterocyclic acid
chlorides to compound 3b in the presence of PS-NMM (polymer-
supported N-methylmorpholine) (Scheme 1) as a base furnished
the corresponding amide derivatives 5a–g in good to excellent
yields as yellow solids, after treatment with
a nucleophilic
F
H
N
O
N
H
N
N
N
N
S
N
O
N
N
O
O
N
N
N
N
N
H
N
N
N
H
N
O
Cl
OH
N
O
Azaperone
Dasatinib
Ateviridine
Piribedil
Figure 1. Bioactive piperazine-linked pyridines (blue) and pyrimidines (red).
⇑
Corresponding author. Tel.: +44 2083318215; fax: +44 2083319805.
E-mail addresses: j.spencer@gre.ac.uk, j.spencer@greenwich.ac.uk (J. Spencer).
Present address: JDJ Bioservices, 576 Swan Street, Richmond, Victoria 3121,
Australia.
0040-4039/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.147

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J. Spencer et al. / Tetrahedron Letters 52 (2011) 5905–5909
H2N
N
X
N
v)
4a: X=NBoc (90%)
4b: X=NH (96%)
i)
O2N
N
O2N
X
HN
Br
X
+
4c
: X=NMe (97%)
4d
: X=O (97%)
N
N
R
O
3b, iii), iv)
3a: X=NBoc (71%)
3b: X=NH (84%)
3c: X=NMe (35%)
3d: X=O (63%)
1
2
O2N
N
N
ii)
N
5
Product
R
Isolated
yield (%)a
5a
5b
5c
5d
5e
5f
CH3
C6H5
Cy
90
56
98
99
99
94
4-FC6H4
4-CH3OC6H4
S
5g
95
N
Scheme 1. Synthesis of amines 4 and amides 5. Reagents and conditions: (i) Na2CO3, H2O, MW, 150 °C, 15 min; (ii) TFA; (iii) RCOCl, CH2Cl2, PS-NMM; (iv) PS-trisamine; (v) H-
Cube; 70 °C, Pd/C. aIsolated yield after chromatography.
O2N
H2N
H-Cube
70 °C
N
N
N
N
1 ml min-1
10%
N
O
N
O
Pd/C
R
R
6
5
Product
R
Isolated
yield (%)a
6a
6b
6c
6d
6e
6f
CH3
C6H5
Cy
4-FC6H4
4-CH3OC6H4
97
93
93
95
96
97
S
6g
91
N
6c
6d
Scheme 2. Synthesis of amines 6. aIsolated yield after chromatography.

J. Spencer et al. / Tetrahedron Letters 52 (2011) 5905–5909
5907
X
N
N
N
7c: X=NMe
7d: X=O
4c 4d
,
v)
O
H2
N
4a
, i), ii), vi)
HN
N
N
N
N
X
NH
4
8a
4a
, iii), iv)
H
N
H2
N
+
NH2
N
N
H+
+
NH2
10a
3 Cl-
Scheme 3. Acetylation and guanylation reactions. Reagents and conditions: i) Acetyl chloride, PS-NMM, CH2Cl2. ii) PS-trisamine. iii) l,3-bis-(tert-butoxycarbonyl)-2-methyl-
O
OMe. vi) TFA.
MeO
2-thiopseudourea, PS-NMM, CH2Cl2, HgCl2. iv) 5 M HCl, ether. v) acetic acid,
i), ii)
N
N
N
N
NH
N
R
12
11
Product
R
Isolated
yield (%)
12a
12b
12c
12d
12e
COCH3
COC6H5
SO2C6H5
SO2CH3
87
76
72
83
69
12a
O
O
O
S
12f
68
64
O
N
12g
12h
12i
12j
COCy
80
77
92
4-FC6H4CO
4-MeOC6H4CO
12c
12d
Scheme 4. Synthesis of a pyridyl piperazine library. Reagents and conditions: (i) RCl, CH2Cl25 PS-NMM, rt; (ii) PS-trisamine.

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J. Spencer et al. / Tetrahedron Letters 52 (2011) 5905–5909
N
N
i), ii)
N
N
N
N
N
NH
R
13
14
Product
R
Isolated
yield (%)
94
14a
14b
14c
14d
COCH3
SO2C6H5
SO2CH3
82
81
73
O
O
14a
O
S
14e
14f
73
88
O
N
14g
14h
14i
COCy
4-FC6H4CO
4-MeOCOC6H4CO
76
87
92
14e
Scheme 5. Synthesis of a pyrimidyl piperazine library. Reagents and conditions: (i)RCOCl, CH2Cl2, PS-NMM, rt; (ii) PS-trisamine.
scavenger resin, which was employed to sequester any unreacted
acid chloride, necessitating a simple filtration as work-up (Scheme
1).
Reduction of nitro compounds 5 was performed in an H-cube™
with 10% Pd/C as the catalyst (Scheme 2) to afford amines 6 in
excellent yields. A number of analogues were crystallised and their
solid state structures determined by single crystal X-ray diffraction
studies (ORTEP diagrams are shown). Analogue 6c displayed disor-
der of the cyclohexyl ring in its solid state structure.
technique enabled efficient nitro reductions and supported resins
were used in amide and sulfonamide library syntheses. This library
should be appealing for use in fragment-based drug discovery,
especially given the ease of incorporation of solubilising groups. In-
deed, during the preparation of this manuscript we became aware
of a publication outlining the synthesis of a range of bioactive ana-
logues related to compounds 6 and 14.7
Acknowledgements
The pyrroles 7 were prepared employing a microwave-medi-
ated cyclisation of 4c and 4d with 2,5-dimethoxytetrahydrofuran.
Amide 8a was obtained by standard methods using acetyl chloride
as the acetylating agent followed by Boc deprotection (Scheme 3).
Compound 10a was formed by guanylation of 4a in the presence of
a mercury(II) salt followed by Boc deprotection (Scheme 3). Com-
pound 10a was recrystallised from methanol/toluene and a single
X-ray diffraction study confirmed a protonated guanidine group
(as well as pyridine and piperazine units) along with three chloride
counterions and water.
This work is taken in part from the PhD thesis of Hiren Patel
(Greenwich, 2010) which was kindly sponsored by Avexa Ltd, Mel-
bourne. Mass spectra were recorded by the EPSRC Mass Spectrom-
etry Service at the University of Swansea. The School of Science and
University of Greenwich are thanked for their financial assistance,
notably for providing a Thales Nano H-cube. BP and the School of
Science are thanked for funding for CEM Discover and Explorer
microwave units.
We next prepared simple pyridines devoid of a nitro or amine
substituent at the 5-position. In a medicinal chemistry context, this
would lead to the synthesis of smaller fragments compared to
compounds 5–10 and would enable an assessment of the effect
of a lack of a substituent at the 5-pyridyl position on potential bio-
logical activity and solubility. Hence, commercially available 11
was functionalised as above to yield a range of amides and sulfon-
amides 12 (Scheme 4). The solid state structures of a number of
derivatives were determined and the sulfonamide 12c was found
to have two independent molecules in its unit cell (see ORTEP
structures below).
Supplementary data
Supplementary data (synthesis and spectral data (1H and 13C
NMR, IR and HRMS spectra) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.07.147.
The X-ray structures described herein and in the supplementary
data have been submitted to the CCDC and have been assigned
the following numbers: 6a, 827283; 6d, 827284; 10a,
827285;12a, 827278; 12c, 827279; 12d, 827282; 12e, 827280;
12f, 827281; 14a, 835142; 14e, 827281; 14f, 835637; 14h, 835638.
A similar pyrimidine library was also synthesised and the prod-
ucts 14 were formed in excellent yields (Scheme 5).
References and notes
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