Imidazopyridine and pyrimidinopyridine systems from perfluorinated pyridine derivatives

Article abstract of DOI:10.1016/j.tet.2007.05.016

Annelation of pentafluoropyridine via an intramolecular nucleophilic aromatic substitution process with benzamidine gave an imidazopyridine system in high yield in a two step process whilst alkyl amidines gave 4-aminotetrafluoropyridine by a competing eli

Full text of DOI:10.1016/j.tet.2007.05.016

Tetrahedron 63 (2007) 7027–7035
Imidazopyridine and pyrimidinopyridine systems from
perfluorinated pyridine derivatives
a
b
Matthew W. Cartwright,a Graham Sandford,a, Jamaal Bousbaa, Dmitrii S. Yufit,
*
Judith A. K. Howard,b John A. Christopherc and David D. Millerc
aDepartment of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK
bChemical Crystallography Group, Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK
cGlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
Received 13 February 2007; revised 19 April 2007; accepted 3 May 2007
Available online 8 May 2007
Abstract—Annelation of pentafluoropyridine via an intramolecular nucleophilic aromatic substitution process with benzamidine gave an
imidazopyridine system in high yield in a two step process whilst alkyl amidines gave 4-aminotetrafluoropyridine by a competing elimination
reaction. 4-Phenylsulfonyl tetrafluoropyridine reacts with amidines to give the corresponding imidazo[4,5-b]pyridine systems. In contrast, 4-
cyanotetrafluoropyridine gave a [6,6]-fused pyrimidinopyridine system arising from initial nucleophilic substitution at the C-3 position of the
pyridine ring followed by intramolecular cyclization onto the pendant cyano group. The systems prepared by this annelation methodology
further demonstrate the utility of perfluorinated heterocyclic substrates for the synthesis of heterocyclic scaffolds that possess multiple
functionality and have potential applications in the drug discovery arena.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
be efficiently processed into more sophisticated molecular
systems by a series of regio- and stereo-selective reactions.
An essential part of a drug discovery programme is the iden-
tification and ready synthesis of new chemical entities that
may provide leads to novel classes of valuable, pharmaco-
logically important systems.1 Consequently, for an increased
chance of discovering lead compounds, libraries of mole-
cules that maximise structural diversity are keenly sought.
In particular, syntheses of molecules possessing multiple
functionality and skeletal diversity, which can act as scaf-
folds for subsequent analogue synthesis, are an essential
component of library design and construction. For example,
the concept of privileged structures,2 in which common
structural sub-units of naturally occurring biologically
active systems are identified, has led to the synthesis of librar-
ies based upon an increasing variety of such core scaffolds.
By differing strategies, Diversity Orientated Synthesis3–5
(DOS) aims to develop wide ranging structural diversity
from simple polyfunctional starting materials while Rapid
Analogue Synthesis6,7 (RAS) is a complementary approach
that seeks to synthesise many analogues of structurally
related derivatives of a biologically active system. Although
these strategies are different in many respects, each relies
upon the ready availability of low molecular weight, core
scaffold molecules that bear multiple functionality and can
Awide variety of low molecular weight heterocyclic systems
have found application in the life science industries,8,9 in
part, due to the favourable combination of pharmacological
properties possessed by these systems, according to the well-
known Lipinski parameters.10 Consequently, the synthesis of
polyfunctional heterocyclic core scaffolds, such as benzo-
pyrans, pyranocoumarins, benzimidazoles and benzofuran
systems,2 that may be used as privileged structures in paral-
lel synthesis are increasingly valuable.2 However, although,
for example, polyfunctional pyridine systems and related
bicyclic ring fused derivatives possessing a pyridine sub-
structure have wide ranging bioactivity, it is surprising that
even some of the most structurally simple nitrogenated bicy-
clic heterocycles are very difficult to access. Consequently,
there exists a demand for the development of effective meth-
odology for the synthesis of new nitrogen containing
polyfunctional bicyclic scaffolds for library synthesis and
subsequent biological screening programmes. Of course,
many synthetic approaches to the synthesis of bicyclic sys-
tems have been developed to meet the demands of academia
and industry with varying degrees of success.8
Recently, we described a general approach towards the syn-
thesis of highly substituted [6,6]-ring fused nitrogen bicyclic
heterocyclic systems from highly fluorinated heterocyclic
* Corresponding author. Tel.: +44 191 334 2039; fax: +44 191 384 4737;
e-mail: graham.sandford@durham.ac.uk
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.016

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M. W. Cartwright et al. / Tetrahedron 63 (2007) 7027–7035
derivatives.11–13 Reaction of pentafluoropyridine 1 with var-
ious 1,2-diamine nucleophiles gave tetrahydropyrido[3,4-
b]pyridine systems 2, which could be used as core scaffolds
for the synthesis of substituted analogues 3 upon sequential
reaction with successive nucleophiles. By an adaptation of
this strategy, related tetrahydropyrido[2,3-b]pyridine sys-
tems 5, for example, could also be accessed by reaction of
1 with a nucleophile to give 4 followed by subsequent anne-
lation (Scheme 1).
R1
F
N
R1
F
N
H
X
X
X
HN
HN
NH2
NH2
+
+
N
N
6
R1
N
N
F
F
R1
X
N
N
H
7
Scheme 2. Strategy for the synthesis of imidazopyridine systems.
F
Nuc1
Nuc1
F
F
F
F
F
F
Nuc2
F
F
Nuc2
Nuc4
Nuc3
Nuc4
Nuc1Nuc2
N
1
N
2
Nuc3
N
3
diaminopyridine precursors and related analogues are not
trivial and subsequent derivatisation to give a range of
systems can be very difficult.
F
Nuc1
Nuc1
F
F
F
F
F
F
F
F
Nuc2
Nuc3
Nuc1
Nuc2 Nuc3
Here we report syntheses of imidazopyridine scaffolds 6 and
7 by reaction of perfluorinated pyridine substrates and vari-
ous amidines, following the retrosynthetic strategy shown in
Scheme 2. No reports of reactions between highly fluori-
nated pyridines and amidines have been described previ-
ously although related reactions involving urea and
guanidine, which did not give bicyclic products, have been
described by Coe.27 Various imidazopyridine systems have
been synthesised from highly fluorinated pyridine precur-
sors, using complex multi-step strategies, and have been pro-
cessed to deazaadenosine derivatives that possess useful
biological activity.28,29
N
F
N
4
F
N
5
1
Me
Me
Me
N
N
N
N
N
F
N
F
N
F
N
Me
OEt
Me
Me
MeO
MeO
N
MeO
N
3a
3c
3b
Me
N
PhSO2
PhSO2 Me
CN Me
N
F
F
N
Ph
Ph
F
F
N
F
N
N
N
F
N
N
Me
Me
5c
Me
2. Results and discussion
5a
5b
Reaction of pentafluoropyridine 1 with benzamidine hydro-
chloride 8, in the presence of sodium bicarbonate, led to the
amidine 9, arising from substitution of the most activated
fluorine atom at the 4-position of the pyridine ring (Scheme
3). Subsequent addition of LDA to a solution of 9 in THF
gave rise to the desired annelation product 10, which could
be readily purified by recrystallisation.
Scheme 1. Strategy for fused ring synthesis from perfluorinated pyridine
derivatives.
This strategy relies upon the fact that highly fluorinated
pyridine systems are very susceptible towards nucleophilic
attack due to the presence of highly electronegative fluorine
atoms attached to the heterocyclic ring14,15 and the high re-
gioselectivity of subsequent nucleophilic aromatic substitu-
tion processes on the ‘core scaffolds’. In particular, we found
that pentafluoropyridine, 4-phenylsulfonyl and 4-cyano-
tetrafluoropyridine derivatives were excellent starting mate-
rials for the synthesis of core tetrahydropyridopyrazine
scaffolds that bear multiple functionality.
Both 9 and 10 exist as pairs of tautomers 9a/9b and 10a/10b,
respectively, but, for simplicity, 9a and 10a are used to denote
these scaffolds throughout this paper. The structure of 10 fol-
lowed from NMR data and, in particular, the 19F NMR spec-
trum showed three resonances at ꢀ82, ꢀ102 and ꢀ162 ppm
in a 1:1:1 ratio. In attempts to synthesise 10 in a one-pot
procedure from 1 using LDA in THF, we found that 10
was, indeed, formed but isolation from tarry material made
purification tedious. Since microwave heating did not yield
any cyclised product 10 by a one-step process either, we pre-
fer to synthesise 10 by the two stage process described above.
In this paper, we further develop our general annelation strat-
egy to the synthesis of [5,6]-ring fused bicyclic systems by
carrying out reactions of highly fluorinated pyridines and
appropriate difunctional nitrogen nucleophiles. We targeted
the synthesis of core scaffolds based upon the imidazopyri-
dine structural units 6 and 7 (Scheme 2), in part, because
molecules containing this heterocyclic skeleton possess
a range of bioactivities.16–20 Retrosynthetic analysis of imid-
azopyridine systems 6 and 7 shows that ring fused scaffolds
should be accessible by reaction of a polyfluorinated pyri-
dine system and an appropriate amidine.
2-Iminopiperidine 11 gave the tricyclic system 12 upon heat-
ing with 1 under microwave irradiation. (Scheme 3) Acet-
amidine 13 and 1 gave the analogous amidine 14 but all
attempts to promote cyclisation to the desired imidazopyri-
dine, using a variety of organic bases, gave 4-aminotetra-
fluoropyridine 15 as the only product in this particular
case. Formamidine 16 and 1 gave a mixture of 4-amidine
derivatives 17 and 15 in a 1:2 ratio upon reflux in acetoni-
trile. Attempted cyclization also led to conversion of 17 to
4-aminotetrafluoropyridine.
Reported syntheses of imidazopyridines of type 6 and 7
almost always involve reaction of aldehyde or acid deriv-
atives with 3,4- and 2,3-diaminopyridine systems, res-
pectively.21–26 However, multi-step syntheses of the

M. W. Cartwright et al. / Tetrahedron 63 (2007) 7027–7035
7029
F
Given the successful synthesis of imidazopyridines 10 and
12, we studied analogous reactions involving 4-phenylsul-
fonyl tetrafluoropyridine 18. Both 13 and 8 gave annelated
products 19 and 20 in one-pot processes in good yield, albeit
after prolonged heating, following recrystallisation of the
crude products (Scheme 5).
F
F
F
F
N
NaHCO3
MeCN
reflux, 16 h
LDA
N
1
N
NH2
F
N
F
F
F
H
NH
NH2
.HCl
THF
-78 °C-r.t.
24 h
F
F
N
+
N
F
8
9, 96%
10, 91%
SO2Ph
SO2Ph
F
F
F
F
F
NH
NH2
N
NaHCO3
+
R
R
MeCN
r.t., 5 d
N
H
N
N
F
H
.HCl
N
NH
F
N
NH2
F
18
F
F
F
13, R = Me
8, R = Ph
19, R = Me, 26%
20, R = Ph, 36%
N
9b
F
F
N
9a
F
CN
F
F
F
R
N
N
NH2
CN
H
F
F
F
F
22a, R = Me, 19%
22b, R = Ph, 20%
N
N
NH
NaHCO3
N
F
N
F
+
F
F
F
F
H
R
NH2
.HCl
MeCN
reflux, 4 d
N
H2N
F
N
R
N
10a
N
10b
13, R = Me
8, R = Ph
21
N
F
+
F
F
N
F
F
F
N
N
23a, R = Me, 8%
23b, R = Ph, 5%
NaHCO3
MeCN
+
F
N
NH2
.HCl
N
F
microwave
F
N
F
N
180 °C, 30 min
1
11
CN
N
12, 52%
F
F
F
F
F
F
N
NH2
NH
NH2
CH3
R
H3C
N
F
F
NH2
N
N
NH2
F
13
F
F
F
21
24
F
F
F
F
NaHCO3
F
NaHCO3
MeCN
MeCN
F
N
reflux, 17 h
F
N
F
14, 88%
15, 73%
1
H
N
H
NH
H2N
N
R
N
N
R
H
H
NH2 .HCl
16
F
F
N
F
F
N
N
N
NH2
F
NH2
F
F
F
F
F
F
F
F
F
NaHCO3
MeCN
r.t., 24 h
+
N
23
F
F
F
N
1
F
N
15
F
17, 24%
Scheme 5. Annelation reactions of 18 and 21.
17:15, 1:2
The reactions were monitored by 19F NMR and we observed
that initial nucleophilic attack of the amidine system on 18
occurs at both the 2 and the 3 positions of the pyridine
ring in approximately 2:1 ratio, consistent with our earlier
findings involving other nitrogen nucleophiles. Heating the
reaction permitted cyclisation to occur, which for this sys-
tem, of course, gives the ring fused product regardless of
the site of initial attack.
Scheme 3. Reactions of pentafluoropyridine with amidines.
A postulated mechanism for the elimination process that
leads to 15 is shown in Scheme 4 and involves elimination
of acetonitrile from the amidine substituent, adapting
a mechanism postulated by Coe27 concerning reactions
between pentafluoropyridine and urea.
R
R
H
Base
The identity of 19 was confirmed by an X-ray crystallo-
graphic study of its methanol hemi-solvate. The molecular
geometry of 19 does not show any unexpected features
(Fig. 1a), and the molecules in the crystal are linked together
in infinite chains along the c-axis by N–H/N and N–H/O
(methanol) hydrogen bonds. The heterocyclic systems of
adjacent molecules from the different chains are in an anti-
parallel arrangement with the shortest interatomic distance
N
Py
NH2
HN
Py
N
Py = C5F4N
H2O
NH
Py
Py-NH2
+
R
N
˚
Scheme 4. Elimination reaction mechanism.
equal to 3.185 A (C1/C1).

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M. W. Cartwright et al. / Tetrahedron 63 (2007) 7027–7035
by X-ray crystallography. Both molecules are planar
(Fig. 1b–d) and the anti-parallel stacking in the crystals
are typical for bicyclic fluoropyridine derivatives.11–13
Molecule 22b form the stacks along the a-axis while the
molecule 23b form layers, where each molecule is sand-
wiched between four adjacent molecules. Both stacks in
the structure of 22b and layers in the structure of 23b
are linked together by networks of N–H/N hydrogen
bonds.
In both reactions, 22 is formed by nucleophilic substitution
of the 2-fluorine whereas 23 arises from competing substitu-
tion of the 3-fluorine to give 24, which is activated towards
nucleophilic attack by the adjacent cyano group, as dis-
cussed in our previous paper,13 followed by intramolecular
cyclization onto the cyano group as outlined in the mecha-
nism in Scheme 5.
Reaction of 21 with 2 equiv of either 13 or 8 gave only 25,
which could be formed by either of two possible pathways
(Scheme 6).
H2N
F
N
R
CN
F
F
F
F
NH
NH2
.HCl
N
F
NaHCO3
MeCN
R
+
2
R
N
H2N
N
N
21
13, R = Me
8, R = Ph
25a, R = Me, 16%
25b, R = Ph, 58%
H2N
F
N
R
NH
NH2
N
F
R
25
F
N
23
CN
F
F
N
F
NH2
NH
NH2
CN
R
N
+
F
F
R
24
F
N
21
F
CN
F
F
F
R
N
N
NH2
22
CN
N
H2N
N
F
F
cyclisation
R
25
R
N
NH2
26
Figure 1. (a) Molecular structure of 19. The hydrogen atom of the imidazole
ring is disordered over two positions; (b) molecular structure of 22b; (c) mo-
lecular structure of 23b; (d) H-bonded stacks of the molecules in 22b.
Scheme 6. Formation of 25.
Initially, 21 reacts with the amidine derivatives 13 and 8 to
give 22 and 24, in a 1:1 ratio. Then 22 reacts with a further
equivalent of 8 to give 26, arising from selective displace-
ment of fluorine located at the 5-position. The 5-site is acti-
vated towards nucleophilic attack by the presence of ortho
In contrast, reaction of 4-cyanopyridine 21 with 1 equiv of
either 13 or 8 gave a mixture of two products 22 and 23 in
a 1:1 ratio (Scheme 5), whose structures were confirmed

M. W. Cartwright et al. / Tetrahedron 63 (2007) 7027–7035
7031
Figure 2. Molecular structure of 25b.
cyano and fluorine substituents, meta fluorine and the ab-
sence of deactivating para fluorine atoms. Of course, the
other sites on the pyridine ring in 26 are slightly deactivated
by para fluorine atoms. Intramolecular cyclization of 26
gives 25 by the process indicated in Scheme 5. Cyclization
of 24 gives 23, which undergoes further regioselective
nucleophilic substitution at the 6-position to give 25. In
23, the 6-position is activated by the ortho fluorine and
ring nitrogen atoms and bears similarities to the regioselec-
tivity of nucleophilic substitution processes of perfluoroiso-
quinoline.14,15 Similar to molecules 22b and 23b, the
molecule 25b is planar (Fig. 2) and in the crystal lattice
the molecules are arranged in anti-parallel dimers, linked
in layers by N–H/N hydrogen bonds.
Figure 3. (a) Molecular structure of 29; (b) H-bonded chains in the structure
of 29.
Reactions of scaffold 10 with N-methylbenzylamine 27 and
methyl iodide 28 gave 29 and 30 (as a mixture of isomers),
respectively, providing an indication of the types of mole-
cules that could be readily accessed from this system
(Scheme 7). Nucleophilic substitution occurs at the 2-posi-
tion, in agreement with earlier work.28
3. Conclusion
The strategy outlined in Schemes 1 and 2 has allowed short
and efficient syntheses of target [5,6]-ring fused systems
of types 6 and 7 by reaction of pentafluoropyridine and
4-phenylsulfonyl-tetrafluoropyridine, respectively, with ap-
propriate difunctional amidine nucleophiles. In contrast,
4-cyanopyridine gave [6,6]-ring fused pyrimidino–pyridine
system by intramolecular cyclization involving the cyano
group. These initial studies and our earlier work11,12
provide an indication of the large number of new fused
[5,6] and [6,6]-bicyclic polyfunctional heterocyclic scaf-
folds that can, potentially, be accessed using our general
annelation strategy involving reactions between highly
fluorinated heterocycles and appropriate difunctional
nucleophiles.
N
Ph
N
H
N
27
N
N
F
F
H
N
F
F
F
H
N
N
10
29, 54%
28, MeI
4. Experimental
4.1. General
N
N
F
F
F
Me
All starting materials were obtained commercially. All sol-
vents were dried using literature procedures. NMR spectra
were recorded in deuterochloroform, unless otherwise
stated, on a Varian VXR 400S NMR spectrometer operating
at 500 MHz (1H NMR), 376 MHz (19F NMR) and 100 MHz
(13C NMR) with tetramethylsilane and trichlorofluorome-
thane as internal standards. Mass spectra were recorded on
either a VG 7070E spectrometer or a Fisons VG Trio 1000
spectrometer coupled with a Hewlett Packard 5890 series
II gas chromatograph. Accurate mass measurements were
performed by the EPSRC National Mass Spectrometry ser-
vice, Swansea, UK. Elemental analyses were obtained on
an Exeter Analytical CE-440 elemental analyser. Melting
N
30, 87%
Scheme 7. Reactions of scaffold 10.
The structure of 29 has been determined by X-ray crystallo-
graphic study of its methanol solvate (1:2). The most note-
worthy feature of the crystal packing of molecule 29 is the
pattern of hydrogen bonds, which link molecules into chains
along the b-axis and the molecules are connected by double
methanol bridges (Fig. 3). The usual anti-parallel stacking
arrangement exists between the molecules of adjacent
chains.

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M. W. Cartwright et al. / Tetrahedron 63 (2007) 7027–7035
points and boiling points were recorded at atmospheric pres-
sure unless otherwise stated and are uncorrected. The prog-
ress of reactions were monitored by 19F NMR. Column
chromatography was carried out on silica gel.
4.3. Attempted cyclisation of N-(2,3,5,6-tetrafluoro-
pyridin-4-yl)acetamidine 14
LDA (1.11 ml, 1.8 M solution in heptane/THF/ethyl-
benzene, 2.0 mmol) was added to a stirred solution of N-
(2,3,5,6-tetrafluoro-pyridin-4-yl)acetamidine 14 (0.21 g,
1.0 mmol) in dry THF (25 ml) at ꢀ78 ꢂC, under an atmo-
sphere of dry argon. After warming to room temperature,
the solution was stirred for 65 h. After the addition of water
(50 ml), the aqueous phase was extracted into DCM
(3ꢁ40 ml). The organicphasewas dried (MgSO4) and evapo-
rated to leave a brown oil, which was identified as 2,3,5,6-
tetrafluoro-pyridin-4-ylamine 15 (0.12 g, 73%), which was
not purified further. dF ꢀ96.2 (2F, m, F-2), ꢀ165.6 (2F, br
m, F-3); m/z (EI+) 166 ([M]+, 100%); as compared to the
literature data.30
4.2. Formation of tetrafluoro-pyridin-4-yl amidine
derivatives
4.2.1. N-(2,3,5,6-Tetrafluoro-pyridin-4-yl)benzamidine 9.
Pentafluoropyridine 1 (6.76 g, 40 mmol), benzamidine hy-
drochloride 8 (13.78 g, 88 mmol) and sodium hydrogen car-
bonate (6.72 g, 80 mmol) were stirred under an atmosphere
of argon in acetonitrile (400 ml) for 16 h at reflux tempera-
ture. The reaction mixture was poured into water (50 ml)
and extracted with dichloromethane (3ꢁ40 ml). Drying
(MgSO4) and evaporation of the solvent gave N-(2,3,5,6-
tetrafluoro-pyridin-4-yl)benzamidine 9 (10.35 g, 96%) as
a white solid. Mp 157–159 ꢂC (Found: C, 53.4; H, 2.6; N,
15.7. C12H7F4N3 requires: C, 53.54; H, 2.6; N, 15.6%); dH
(Acetone-d6) 8.01 (2H, m, H-20), 7.56 (1H, m, H-40), 7.49
(2H, m, H-30), 7.02 (2H, s, NH2); dF ꢀ94.90 (2F, m, F-2),
ꢀ153.88 (2F, m, F-3); dC 159.44 (s, C]N), 144.73 (dm,
1JCF 236.6, C-2), 143.72 (m, C-4), 136.53 (dm, 1JCF 236.8,
C-3), 134.94 (s, C-10), 132.31 (s, C-40), 129.32 (s, C-30),
128.37 (s, C-20); m/z (EI+) 269 (100%, [M]+), 253 (72),
249 (90), 77 (94).
4.4. Formation of imidazopyridine systems
4.4.1. 4,6,7-Trifluoro-2-phenyl-3H-imidazo[4,5-c]pyri-
dine 10. LDA (17.19 ml, 1.8 M solution in heptane/THF/
ethylbenzene, 30.9 mmol) was added to a stirred solution
of
N-(2,3,5,6-tetrafluoro-pyridin-4-yl)benzamidine
9
(3.79 g, 14.1 mmol) in dry THF (250 ml) at ꢀ78 ꢂC, under
an atmosphere of dry argon. After warming to room temper-
ature, the solution was stirred for 24 h. The reaction mixture
was evaporated and 0.5 M HCl solution (50 ml) added.
Extraction of the aqueous layer by dichloromethane
(3ꢁ40 ml) and drying (MgSO4) followed by evaporation
gave a brown crude solid. Recrystallisation from acetonitrile
gave 4,6,7-trifluoro-2-phenyl-3H-imidazo[4,5-c]pyridine 10
(3.20 g, 91%) as an off-white solid. Mp 208–209 ꢂC (Found:
C, 57.8; H, 2.4; N, 17.0. C12H6F3N3 requires: C, 57.8; H, 2.4;
N, 16.9%); dH (DMSO-d6) 8.18 (2H, br m, H-20), 7.56–7.52
(3H, br m, H-30,40); dF major tautomer (67% by 19F NMR)
ꢀ83.08 (1F, br s, F-6), ꢀ102.02 (1F, br s, F-4), ꢀ161.60
(1F, br s, F-7); minor tautomer (33%) ꢀ82.60 (1F, br s,
F-6), ꢀ104.33 (1F, br s, F-4), ꢀ163.00 (1F, br s, F-7); dC
4.2.2. N-(2,3,5,6-Tetrafluoro-pyridin-4-yl)acetamidine
14. Pentafluoropyridine 1 (3.38 g, 20.0 mmol), acetamidine
hydrochloride 13 (4.16 g, 44.0 mmol) and sodium hydrogen
carbonate (3.36 g, 40.0 mmol) were stirred under argon in
dry acetonitrile for 17 h at reflux temperature. The reaction
solvent was evaporated and the remaining residue treated
with water (50 ml). Extraction by dichloromethane
(3ꢁ40 ml), drying (MgSO4) and evaporation of the solvent
gave N-(2,3,5,6-tetrafluoro-pyridin-4-yl)acetamidine 14
(3.64 g, 88%) as an off-white solid. Mp 142–145 ꢂC (Found:
C, 40.6; H, 2.4; N, 20.2. C7H5F4N3 requires: C, 40.6; H, 2.4;
N, 20.3%); dH (DMSO-d6) 7.42 and 6.94 (2H, br s, NH2),
1.97 (3H, s, CH3); dF ꢀ94.96 (m, F-2), ꢀ154.09 (m, F-3);
1
155.42 (br m, C-2), 143.80 (m, C-4), 142.50 (dm, JCF
228.5, C-6), 135.20 (br m, C-5c), 131.25 (s, C-40), 129.53
(m, C-7), 128.95 (s, C-30), 128.07 (s, C-10), 127.26 (s,
C-20); m/z (EI+) 249 ([M]+, 100).
1
dC 161.15 (s, C-7), 143.34 (dm, JCF 237.3, C-2), 142.96
1
(m, C-4), 135.49 (dm, JCF 249.5, C-3), 20.65 (s, CH3);
m/z (EI+) 207 (100%, [M]+), 192 (82).
4.4.2. 1,3,4-Trifluoro-6,7,8,9-tetrahydro-dipyrido[1,2-a;
30,40-d]imidazole 12. Pentafluoropyridine
4.2.3. N-(2,3,5,6-Tetrafluoro-pyridin-4-yl)formamidine
17. Pentafluoropyridine 1 (1.69 g, 10 mmol), formamidine
hydrochloride 16 (1.61 g, 20 mmol) and sodium hydrogen
carbonate (3.36 g, 40 mmol) were stirred under argon in ace-
tonitrile for 23 h at room temperature. The reaction mixture
was treated with water (50 ml) and the organic products ex-
tracted into dichloromethane (3ꢁ40 ml). The organic phase
was dried (MgSO4) and evaporated to leave a brown waxy
solid that consisted of 17 and 2,3,5,6-tetrafluoro-pyridin-
4-ylamine 15 in a 1:2 ratio by 19F NMR analysis.30
Recrystallisation of this residue from acetonitrile gave
N-(2,3,5,6-tetrafluoro-pyridin-4-yl)formamidine 17 (0.47 g,
24%) as a white crystalline solid. Mp 168–170 ꢂC (Found:
C, 37.2; H, 1.5; N, 21.8. C6H3N3F4 requires: C, 37.3; H,
1.6; N, 21.8%); dH (DMSO-d6) 7.95 (3H, br m, NH2,
NCHNH2); dF ꢀ95.17 (2F, m, F-2), ꢀ156.89 (2F, br m,
F-3); dC 157.66 (s, NCHNH2), 143.73 (m, C-4), 143.38
1
(0.30 g,
1.77 mmol), 2-iminopiperidine hydrochloride 11 (0.36 g,
2.67 mmol) and triethylamine (0.54 g, 5.34 mmol) were
stirred together in a mixture of THF (11.25 ml) and
DMSO (4.50 ml), in a sealed 20 ml vial, under microwave
heating, for 30 min at 180 ꢂC. The reaction mixture was
evaporated to dryness, heated in THF (50 ml) and filtered
to remove excess starting material. The product mixture
was absorbed onto silica gel and purified by column chroma-
tography (120 g silica column, 40–80% ethyl acetate in
hexane) to give 1,3,4-trifluoro-6,7,8,9-tetrahydro-dipyr-
ido[1,2-a; 30,40-d]imidazole 12 (0.21 g, 52%) as a white
solid. Mp 175–178 ꢂC (Found: C, 52.8; H, 3.4; N, 18.1.
C10H8F3N3 requires: C, 52.9; H, 3.6; N, 18.5%); dH
3
3
(DMSO-d6) 4.36 (2H, t, JHH 6.0, H-6), 3.01 (2H, t, JHH
6.0, H-9), 2.05 (2H, m, H-7), 1.93 (2H, m, H-8); dC 156.11
(q, JCF 1.3, C-2a), 143.06 (dd, JCF 244.5, JCF 14.2,
4
1
3
1
1
1
2
3
(dm, JCF 236.5, C-2), 135.97 (dm, JCF 248.9, C-3); m/z
(EI+) 193 (95%, [M]+).
C-1), 141.02 (ddd, JCF 227.7, JCF 15.2, JCF 15.0, C-3),
2
3
3
134.44 (ddd, JCF 11.7, JCF 7.7, JCF 5.8, C-40d), 129.57

M. W. Cartwright et al. / Tetrahedron 63 (2007) 7027–7035
7033
(ddd, 1JCF 253.71, 2JCF 32.0, 4JCF 7.8, C-4), 125.57 (dd, 2JCF
34.8, 3JCF 3.2, C-30d), 44.91 (d, 4JCF 2.8, C-6), 24.97 (s, C-
9), 21.65 (s, C-7), 19.17 (s, C-8); dF ꢀ85.36 (dd, 3JFF 31.8,
ꢀ167.93 (m, F-4); m/z (ES+) 228 (100%, [MH]+).
a brown/black solid. Filtration of the crude material through
alumina (dichloromethane as eluent) gave N-(4-cyano-3,5,6-
trifluoro-pyridin-2-yl)acetamidine 22a (0.09 g, 17%) as
a yellow solid. ([MH]+ 215.0540. C8H6F3N4 requires
[MH]+ 215.0539); dH (DMSO-d6) 8.02–7.76 (2H, br m,
5
4
4JFF 13.3, F-3), ꢀ104.36 (dd, JFF 22.0, JFF 13.4, F-1),
3
5
NH2), 2.04 (3H, s, CH3); dF ꢀ88.94 (dd, JFF 29.5, JFF
5
4
4.4.3. 7-Benzenesulfonyl-5,6-difluoro-2-methyl-1H-
imidazo[4,5-b]pyridine 19. 4-Benzenesulfonyl-2,3,5,6-
tetrafluoropyridine 18 (1.46 g, 5 mmol), acetamidine 13
(0.95 g, 10 mmol) and sodium hydrogen carbonate (1.68 g,
20 mmol) were stirred together at room temperature under
argon in acetonitrile (200 ml) for 120 h. The reaction mix-
ture was poured into water (50 ml) and extracted into
dichloromethane (4ꢁ30 ml). Drying (MgSO4) and evapora-
tion of the solvent gave a yellow solid. Recrystallisation
from acetonitrile gave 7-benzenesulfonyl-5,6-difluoro-2-
methyl-1H-imidazo[4,5-b]pyridine 19 (0.40 g, 26%) as yel-
low crystals. Mp 225–227 ꢂC (Found: C, 50.5; H, 3.0; N,
13.8. C13H9F2N3O2S requires: C, 50.5; H, 2.9; N, 13.6%);
dH (DMSO-d6) 13.14 (1H, br s, NH), 8.11 (2H, m, H-20),
7.77 (1H, m, H-40), 7.68 (2H, m, H-30), 2.42 (3H, s, CH3);
26.2, F-6), ꢀ124.26 (m, F-5), ꢀ145.02 (dd, JFF 23.2, JFF
6.9, F-3); dC 163.35 (s, C-7), 147.91 (ddd, 1JCF 266.6, 2JCF
6.2, JCF 3.1, C-6), 144.61 (m, C-2), 143.38 (ddd, JCF
4
1
2
3
1
232.1, JCF 13.1, JCF 3.3, C-5), 136.55 (dd, JCF 263.2,
3JCF 34.6, C-3), 108.43 (m, C-8), 102.19 (m, C-4), 21.26
(s, CH3); m/z (EI) 214 (90%, [M]+), 197 (100). Washing
the alumina with methanol followed by recrystallisation of
the residue from acetonitrile gave 5,6,8-trifluoro-2-methyl-
pyrido[3,4-d]pyrimidin-4-ylamine 23a (0.04 g, 8%) as an
orange solid. ([MH]+ 215.0541. C8H6N4F3 requires [MH]+
215.0545); dH (DMSO-d6) 8.56 (2H, br s, NH2), 2.46 (3H,
3
4
s, CH3); dF ꢀ77.42 (dd, JFF 35.1, JFF 14.0, F-6),
5
4
3
ꢀ100.78 (dd, JFF 22.1, JFF 14.0, F-8), ꢀ145.35 (dd, JFF
5
3
35.0, JFF 22.2, F-5); dC 166.42 (s, C-2), 158.18 (d, JCF
3.4, C-4), 149.36 (ddd, JCF 252.4, JCF 11.0, JCF 2.2,
1
2
3
3
3
1
3
4
dF ꢀ93.18 (1F, d, JFF 28.2, C-5), ꢀ148.80 (1F, d, JFF
C-6), 140.99 (ddd, JCF 234.4, JCF 18.3, JCF 13.3, C-8),
136.74 (ddd, JCF 258.6, JCF 27.0, JCF 7.1, C-5), 134.30
1
2
4
27.5, C-6); dC 159.44 (s, C-2), 147.80 (br m, C-4b),
1
2
147.05 (dd, JCF 232.0, JCF 17.3, C-5), 139.53 (s, C-10),
(dm, 2JCF 28.3, C-3d), 112.78 (m, C-4d), 25.80 (s, CH3).
1
2
136.94 (dd, JCF 257.7, JCF 32.5, C-6), 135.34 (s, C-40),
130.05 (s, C-30), 127.71 (s, C-20), 122.91 (m, C-7), 121.55
(br m, C-5b), 15.31 (s, CH3); m/z (EI+) 309 (80%, [M]+),
77 (100). Crystals suitable for X-ray crystallography were
grown from MeOH.
4.4.6. N-(4-Cyano-3,5,6-trifluoro-pyridin-2-yl)benzami-
dine 22b and 5,6,8-trifluoro-2-phenyl-pyrido[3,4-d]-
pyrimidin-4-ylamine
23b.
2,3,5,6-Tetrafluoro-4-
pyridinecarbonitrile 21 (0.44 g, 2.5 mmol), benzamidine
hydrochloride 8 (0.39 g, 2.5 mmol) and sodium hydrogen
carbonate (0.42 g, 5.0 mmol) were stirred together under
argon in acetonitrile (100 ml) for 7 d at 80 ꢂC. The reaction
mixture was treated with water (50 ml) and extracted into di-
chloromethane (3ꢁ40 ml). The organic phase was dried
(MgSO4) and the solvent removed under reduced pressure
to give an orange/red crude solid. Column chromatography
on alumina (dichloromethane/hexane 3:2) gave N-(4-cya-
no-3,5,6-trifluoro-pyridin-2-yl)benzamidine 22b (0.14 g,
20%) as a pale yellow solid. Mp 123–124 ꢂC (Found; C
56.2; H, 2.6; N, 20.2. C13H7F3N4 requires; C, 56.5; H, 2.6;
N, 20.3%); dH (DMSO-d6) 8.37 (2H, br s, NH2), 8.02 (2H,
m, H-20), 7.58 (1H, m, H-40), 7.51 (2H, m, H-30); dF
4.4.4. 7-Benzenesulfonyl-5,6-difluoro-2-phenyl-1H-
imidazo[4,5-b]pyridine 20. 4-Benzenesulfonyl-2,3,5,6-
tetrafluoropyridine 18 (2.33 g, 8 mmol), benzamidine
hydrochloride 8 (2.51 g, 16 mmol) and sodium hydrogen
carbonate (2.69 g, 32 mmol) were stirred together at room
temperature under argon in acetonitrile (300 ml) for 120 h.
The reaction mixture was poured into water (50 ml) and ex-
tracted into dichloromethane (4ꢁ30 ml). Drying (MgSO4)
and evaporation of the solvent gave a yellow solid. Recrys-
tallisation from acetonitrile gave 7-benzenesulfonyl-5,6-
difluoro-2-phenyl-1H-imidazo[4,5-b]pyridine 20 (1.1 g,
36%) as a yellow powder. Mp 241–245 ꢂC (Found: C,
58.3; H, 3.0; N, 11.6. C18H11F2N3O2S requires: C, 58.2;
H, 3.0; N, 11.3%); dH (DMSO-d6) 8.25 (2H, m, C-20), 8.22
(2H, m, C-200), 7.80 (1H, m, C-40), 7.70 (2H, m, C-30),
3
5
3
ꢀ88.90 (dd, JFF 30.0, JFF 25.2, F-6), ꢀ123.03 (dd, JFF
29.4, 4JFF 7.0, F-5), ꢀ144.10 (dd, 5JFF 25.0, 4JFF 6.5, F-3);
1
2
4
dC 159.44 (s, C-7), 148.53 (ddd, JCF 268.0, JCF 7.5, JCF
3.2, C-6), 145.01 (m, C-2), 143.39 (ddd, JCF 234.2, JCF
3
1
2
7.61–7.58 (3H, m, C-300,400); dF ꢀ91.33 (1F, d, JFF 27.9,
3
1
3
F-5), ꢀ147.73 (1F, m, F-6); dC 156.42 (br m, C-2, C-4b),
13.7, JCF 3.9, C-5), 136.88 (dd, JCF 264.6, JCF 34.1,
C-3), 134.60 (s, C-10), 131.51 (s, C-40), 128.40 (s, C-30),
127.75 (s, C-20), 108.39 (m, C-8), 102.50 (m, C-4); m/z
(EI+) 276 (78%, [M]+), 257.0 (100). Crystals suitable for
X-ray crystallography were grown from acetonitrile. Re-
crystallisation of the remaining crude material recovered
from the silica column from acetonitrile gave 5,6,8-tri-
1
2
147.92 (dd, JCF 236.1, JCF 18.0, C-5), 139.99 (s, C-10),
1
2
138.06 (dd, JCF 259.6, JCF 31.1, C-6), 135.13 (s, C-40),
131.43 (s, C-400), 129.70 (s, C-30), 129.08 (s, C-300), 128.63
(s, C-20), 128.34 (s, C-200), 127.52 (br s, C-100, C-7), 125.99
(br m, C-5b); m/z (EI+) 371 ([M]+, 100%).
4.4.5. N-(4-Cyano-3,5,6-trifluoro-pyridin-2-yl)acet-
amidine 22a and 5,6,8-trifluoro-2-methyl-pyrido[3,4-
d]pyrimidin-4-ylamine 23a. 2,3,5,6-Tetrafluoro-4-pyridi-
necarbonitrile 21 (0.44 g, 2.5 mmol), acetamidine 13
(0.24 g, 2.5 mmol) and sodium hydrogen carbonate
(0.42 g, 5.0 mmol) were stirred together under argon in ace-
tonitrile (100 ml) for 7 d. Evaporation under reduced pres-
sure was followed by treatment with water (50 ml).
Extraction of the organic products by dichloromethane
(3ꢁ40 ml), drying (MgSO4), filtering and evaporation gave
fluoro-2-phenyl-pyrido[3,4-d]pyrimidin-4-ylamine
23b
(0.036 g, 5%) as a yellow solid. Mp 220–223 ꢂC (Found;
C 56.1; H, 2.5; N, 20.4. C13H7F3N4 requires; C, 56.5; H,
2.6; N, 20.3%); dH (DMSO-d6) 8.67 and 7.9 (2H, br s,
NH2), 8.40 (2H, m, H-20), 7.54–7.48 (3H, m, H-30,40);
3
4
dF ꢀ76.92 (dd, JFF 34.9, JFF 14.0, F-6), ꢀ100.11 (dd,
4
3
5
5JFF 21.7, JFF 13.8, F-8), ꢀ145.26 (dd, JFF 35.3, JFF
3
22.0, F-5); dC 161.84 (s, C-2), 158.65 (d, JCF 3.4, C-4),
149.93 (ddd, JCF 253.8, JCF 10.7, JCF 2.0, C-8), 141.40
(ddd, JCF 236.5, JCF 18.6, JCF 13.5, C-6), 136.87 (ddd,
1
3
4
1
3
3

7034
M. W. Cartwright et al. / Tetrahedron 63 (2007) 7027–7035
1JCF 259.6, 2JCF 27.5, 4JCF 7.1, C-5), 136.81 (s, C-10), 134.76
imidazo[4,5-c]pyridine-4-yl)methyl-amine 29 (0.0424 g,
54%) as a white solid. Mp 79–83 ꢂC; ([MH]+ 351.1416.
C20H16F2N4 requires [MH]+ 351.1416); dH (DMSO-d6)
10.05 (1H, br s, NH), 7.99–7.89 (2H, m, H-20), 7.50–7.43
2
(dm, JCF 31.4, C-3d), 131.19 (s, C-40), 128.52 (s, C-30),
128.10 (s, C-20), 113.41 (m, C-4d); m/z (EI+) 276 (100%,
[M]+), 260 (49). Crystals suitable for X-ray crystallography
were grown from acetonitrile.
3
(3H, m, H-30,40), 7.37 (2H, d, JHH 7.6, H-200), 7.33 (2H, t,
3
3JHH 7.6, H-300), 7.27 (1H, t, JHH 7.6, H-400), 5.34 (2H, s,
4.4.7. N-(4-Amino-5,8-difluoro-2-methyl-pyrido[3,4-
d]pyrimidin-6-yl)acetamidine 25a. 2,3,5,6-Tetrafluoro-4-
pyridinecarbonitrile 21 (0.44 g, 2.5 mmol), acetamidine 13
(0.47 g, 5.0 mmol) and sodium hydrogen carbonate
(0.84 g, 10.0 mmol) were stirred together under argon in
acetonitrile (100 ml) for 72 h at 80 ꢂC. The reaction mixture
was treated with water (100 ml) and the organic products
were extracted into DCM (3ꢁ100 ml). The organic phase
was dried (MgSO4) and the solvent removed under reduced
pressure. The resulting crude was recrystallised from aceto-
nitrile to give N-(4-amino-5,8-difluoro-2-methyl-pyr-
ido[3,4-d]pyrimidin-6-yl)acetamidine 25a (0.10 g, 16%) as
a yellow solid. Mp 224–228 ꢂC; ([MH]+ 253.1009.
C10H11F2N6 requires [MH]+ 253.1013); dH (DMSO-d6)
8.02 and 7.17 (4H, br s, NH2), 2.41 (3H, s, C-10), 1.92
CH2), 3.35 (3H, s, CH3); dF (DMSO-d6) ꢀ100.09 (1F, d,
351 (100%, [MH]+).
3
3JFF 27.1, F-6), ꢀ174.97 (1F, d, JFF 26.9, F-7); m/z (ES+)
4.4.10. 4,6,7-Trifluoro-N-methyl-2-phenyl-3H-imid-
azo[4,5-c]pyridine 30. Butyllithium (1.4 ml, 1.6 M solution
in hexanes) was added to a stirring solution of 4,6,7-
trifluoro-2-phenyl-3H-imidazo[4,5-c]pyridine 10 (0.49 g,
2.0 mmol) in THF (40 ml), at ꢀ78 ꢂC. After 1 h, methyl
iodide 28 (0.37 ml, 6.0 mmol) was added to the reaction
mixture and the vessel allowed to warm to room tempera-
ture. After 18 h, the resulting mixture was poured into water
(50 ml) and extracted into dichloromethane (3ꢁ40 ml). Dry-
ing (MgSO4) and evaporation gave a pale yellow solid.
Column chromatography on silica gel (ethyl acetate/hex-
ane, 1:1) gave 4,6,7-trifluoro-N-methyl-2-phenyl-3H-imid-
azo[4,5-c]pyridine 30 (0.46 g, 87%) as a mixture of
isomers. Mp 103–106 ꢂC (Found: C, 59.3; H, 3.0; N, 16.0.
C13H8F3N3 requires: C, 59.3; H, 3.1; N, 16.0%); dH 7.77–
7.52 (5H, m, Ar-H), 4.05 (3H, m, CH3); dF major isomer
5
(3H, s, C-11); dF ꢀ98.58 (d, JFF 28.12, C-8), ꢀ155.18 (d,
5JFF 27.88, C-5); dC 163.69 (s, C-2), 160.61 (s, C-9),
158.92 (m, C-4), 154.29 (dd, JCF 12.9, JCF 3.0, C-6),
2
3
1
4
143.52 (dd, JCF 226.2, JCF 15.6, C-8), 140.05 (m, C-3d),
132.30 (dd, JCF 254.9, JCF 30.7, C-5), 110.06 (dd, JCF
1
4
2
8.2, 3JCF 3.2, C-4d), 25.80 (s, C-11), 20.78 (s, C-10).
(52% by 19F NMR) ꢀ81.59 (dd, JFF 32.3, JFF 12.9, F-6),
3
4
5
4
3
ꢀ100.51 (dd, JFF 20.6, JFF 13.1, F-4), ꢀ169.39 (dd, JFF
5
4.4.8. N-(4-Amino-5,8-difluoro-2-phenyl-pyrido[3,4-
d]pyrimidin-6-yl)benzamidine 25b. 2,3,5,6-Tetrafluoro-4-
pyridinecarbonitrile 21 (0.44 g, 2.5 mmol), benzamidine
hydrochloride 8 (0.78 g, 5.0 mmol) and sodium hydrogen
carbonate (0.84 g, 10.0 mmol) were stirred together under
argon in acetonitrile (100 ml) for 170 h at 80 ꢂC. The reac-
tion mixture was treated with water (50 ml) and the organic
products extracted into dichloromethane (3ꢁ40 ml). The or-
ganic phase was dried (MgSO4) and the solvent removed
under reduced pressure. Recrystallisation from acetonitrile
gave N-(4-amino-5,8-difluoro-2-phenyl-pyrido[3,4-d]pyri-
midin-6-yl)benzamidine 25b (1.09 g, 58%) as a yellow
solid. Mp 215–216 ꢂC; ([MH]+ 377.1320. C20H15F2N6
requires [MH]+ 377.1321); dH (DMSO-d6) 8.41 (2H, m,
H-20), 8.21, 7.76 and 7.38 (4H, br s, NH2), 8.11 (2H, m,
H-200), 7.55–7.47 (6H, m, H-30,300,40,400); dF ꢀ97.79 (d,
32.6, JFF 20.8, F-7); minor isomer (48%) ꢀ86.67 (dd,
3JFF 32.8, JFF 13.9, F-6), ꢀ102.59 (dd, JFF 18.8, JFF
4
5
4
3
5
14.2, F-4), ꢀ162.18 (dd, JFF 33.0, JFF 19.1, F-7); dC
159.79–119.61, 34.09 (m, CH3); m/z (EI+) 263 (60%,
[M]+), 262 (100).
4.5. X-ray crystallography
The data were collected on a Bruker SMART CCD 6K (19,
22b, 23b and 25b) and Bruker APEX Proteum-M CCD (29)
at 120 K using graphite monochromated Mo Ka radiation
˚
(l¼0.71073 A). All structures were solved by direct method
and refined by full-matrix least squares on F2 for all data
using SHELXL software. All non-hydrogen atoms were
refined with anisotropic displacement parameters, H-atoms
were found in the difference Fourier maps and refined iso-
tropically except those of the disordered solvent methanol
molecules in the structure of 19, which were placed in calcu-
lated positions and refined using ‘riding model’. Crystallo-
graphic data for the structures have been deposited with
the Cambridge Crystallographic Data Centre as supplemen-
tary publications CCDC 636999–637003.
5
5JFF 28.0, F-8), ꢀ153.97 (d, JFF 29.3, F-5); dC 159.59 (s,
2
C-2), 159.35 (m, C-4), 157.80 (s, C-9), 154.90 (dd, JCF
12.8, JCF 3.7, C-6), 144.19 (dd, JCF 227.9, JCF 16.9,
3
1
4
C-8), 140.25 (m, C-3d), 137.82 (s, C-10), 135.64 (s, C-100),
1
4
132.99 (dd, JCF 254.8, JCF 30.8, C-5), 130.87 (s, C-400),
130.42 (s, C-40), 128.35 (s, C-30), 128.31 (s, C-300), 127.80
2
3
(s, C-20), 127.65 (s, C-200), 110.99 (dd, JCF 8.3, JCF 3.6,
C-4d); m/z (ES+) 377 (100%, [MH]+). Crystals suitable for
X-ray crystallography were grown from acetonitrile.
4.5.1. Crystal data for 19. C13H9F2N3O2S$0.5CH3OH,
M¼325.31, monoclinic, space group C2/c, a¼16.2592(3),
b¼10.1481(2), c¼17.6509(3) A, b¼112.20(1)ꢂ, U¼
˚
3
ꢀ3
˚
4.4.9. Benzyl(6,7-difluoro-2-phenyl-3H-imidazo[4,5-
c]pyridine-4-yl)methyl-amine 29. 4,6,7-Trifluoro-2-phen-
yl-3H-imidazo[4,5-c]pyridine 10 (0.0555 g, 0.2227 mmol)
and N-benzylmethylamine 27 (0.1349 g, 1.1136 mmol)
were stirred together in THF (2.25 ml) and DMSO
(0.90 ml) at 180 ꢂC (microwave) for 30 min. The reaction
solvents were evaporated and the crude material dissolved
in methanol/DMSO (1:1 mixture, 2 ml). Mass directed
auto purification gave benzyl-(6,7-difluoro-2-phenyl-3H-
2696.48(9) A , F(000)¼1336, Z¼8, Dc¼1.603 mg m
,
m¼0.278 mmꢀ1
,
12,057 reflections (2.42ꢃqꢃ29.00ꢂ),
3579 unique data (Rmerg¼0.0449). Final wR2(F2)¼0.0972
for all data (244 refined parameters), conventional
R1(F)¼0.0349 for 3107 reflections with Iꢄ2s, GOF¼1.021.
4.5.2. Crystal data for 22b. C13H7F3N4, M¼276.23, tri-
clinic, space group P-1, a¼6.7260(8), b¼8.175(1ꢂ),
˚
c¼10.908(1) A, a¼94.36(1), b¼90.07(1), g¼104.96(1) ,

M. W. Cartwright et al. / Tetrahedron 63 (2007) 7027–7035
7035
3
ꢀ3
˚
4. Schrieber, S. L. Chem. Eng. News 2003, March 3, 51.
U¼577.7(1) A , F(000)¼280, Z¼2, Dc¼1.588 mg m
,
m¼0.134 mmꢀ1; 4956 reflections (1.87ꢃqꢃ28.00ꢂ), 2757
unique data (Rmerg¼0.079). Final wR2(F2)¼0.0946 for all
data (209 refined parameters), conventional R1(F)¼0.0508
for 1380 reflections with Iꢄ2s, GOF¼0.941.
5. Spring, D. R. Org. Biomol. Chem. 2003, 1, 3867.
6. Collins, I. J. Chem. Soc., Perkin Trans. 1 2000, 2845.
7. Collins, I. J. Chem. Soc., Perkin Trans. 1 2002, 1921.
8. Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic
Chemistry; Pergamon: Oxford, 1984; Vols. 1–8.
9. Pozharskii, A. F.; Soldantenkov, A. T.; Katritzky, A. R.
Heterocycles in Life and Society; John Wiley and Sons: New
York, NY, 1997.
10. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.
Adv. Drug Delivery Rev. 1997, 23, 3.
11. Sandford, G.; Slater, R.; Yufit, D. S.; Howard, J. A. K.; Vong, A.
J. Org. Chem. 2005, 70, 7208.
12. Baron, A.; Sandford, G.; Slater, R.; Yufit, D. S.; Howard,
J. A. K.; Vong, A. J. Org. Chem. 2005, 70, 9377.
13. Hargreaves, C. A.; Sandford, G.; Slater, R.; Yufit, D.; Howard,
J. A. K.; Vong, A. Tetrahedron 2007, 63, 5204.
14. Chambers, R. D.; Sargent, C. R. Adv. Heterocycl. Chem. 1981,
28, 1.
15. Brooke, G. M. J. Fluorine Chem. 1997, 86, 1.
16. Montgomery, J. A.; Hewson, K. J. Med. Chem. 1966, 9, 105.
17. Montgomery, J. A.; Salemink, C. A. J. Med. Chem. 1966,
9, 354.
18. De Roos, K. B.; Salemink, C. A. Recl. Trav. Chim. Pays-Bas
1971, 90, 1166.
19. Benedict, W. F.; Baker, M. S.; Haroun, L.; Choi, E.; Ames,
B. N. Cancer Res. 1977, 37, 2209.
20. Barraclough, P.; Gillam, J.; King, W. R.; Nobbs, M. S.; Vine,
S. J. J. Chem. Res., Synop. 1997, 196.
21. Middleton, R. W.; Wibberley, D. G. J. Heterocycl. Chem. 1980,
17, 1757.
22. Temple, C.; Rose, J. D.; Comber, R. N.; Rener, G. A. J. Med.
Chem. 1987, 30, 1746.
23. Viscardi, G.; Savarino, P.; Barni, E.; Carigano, R.
J. Heterocycl. Chem. 1990, 27, 1825.
4.5.3. Crystal data for 23b. C13H7F3N4, M¼276.23, ortho-
rhombic, space group Fdd2, a¼25.0648(3), b¼25.7841(3),
3
˚
˚
c¼6.9063(1) A, U¼4463.4(1) A , F(000)¼2240, Z¼16,
Dc¼1.644 mg mꢀ3
,
m¼0.139 mmꢀ1
, 13,639 reflections
(2.27ꢃqꢃ29.00ꢂ), 1602 unique data (Rmerg¼0.0584). Final
wR2(F2)¼0.0918 for all data (209 refined parameters), con-
ventional R1(F)¼0.0321 for 1543 reflections with Iꢄ2s,
GOF¼1.108.
4.5.4. Crystal data for 25b. C20H14F2N6, M¼376.37, ortho-
rhombic, space group Pbca, a¼11.3937(2), b¼8.9080(2),
3
˚
˚
c¼33.5493(7) A, U¼3405.1(1) A , F(000)¼1552, Z¼8,
Dc¼1.468 mg mꢀ3
,
m¼0.108 mmꢀ1
, 23,179 reflections
(2.16ꢃqꢃ28.00ꢂ), 4108 unique data (Rmerg¼0.0538). Final
wR2(F2)¼0.1106 for all data (309 refined parameters), con-
ventional R1(F)¼0.0388 for 2817 reflections with Iꢄ2s,
GOF¼1.030.
4.5.5. Crystal data for 29. C20H16F2N4$2CH3OH,
M¼414.45, triclinic, space group P1, a¼10.0524(9), b¼
˚
11.0747(9), c¼11.3796(10) A, a¼111.62(3), b¼94.38(3),
3
ꢂ
˚
g¼116.04(3) , U¼1014.3(2) A , F(000)¼436, Z¼2, Dc¼
1.357 mg mꢀ3, m¼0.101 mmꢀ1, 10,683 reflections (2.62ꢃ
qꢃ29.00ꢂ), 5260 unique data (Rmerg¼0.0337). Final
wR2(F2)¼0.1119 for all data (367 refined parameters), con-
ventional R1(F)¼0.0389 for 4070 reflections with Iꢄ2s,
GOF¼1.010.
24. Katner, A. S.; Brown, R. F. J. Heterocycl. Chem. 1990, 27, 563.
25. Bakke, J. M.; Riha, J. J. Heterocycl. Chem. 1999, 36, 1143.
26. Yang, D.; Fokas, D.; Li, J.; Yu, L.; Baldino, C. M. Synthesis
2005, 47.
Acknowledgements
We thank GlaxoSmithKline R&D for funding this work.
27. Coe, P. L.; Rees, A. J.; Whittaker, J. J. Fluorine Chem. 2001,
107, 13.
References and notes
28. Liu, M. C.; Luo, M. Z.; Mozdziesz, D. E.; Lin, T. S.;
Dutschmann, G. E.; Gullen, E. A.; Cheng, Y. C.; Sartorelli,
A. C. Nucleosides, Nucleotides, Nucleic Acids 2001, 20, 1975.
29. Sakthivel, K.; Cook, P. D. Tetrahedron Lett. 2005, 46,
3883.
1. Gordon, E. M.; Kerwin, J. F. Combinatorial Chemistry and
Molecular Diversity in Drug Discovery; John Wiley and
Sons: New York, NY, 1998.
2. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893.
3. Schrieber, S. L. Science 2000, 287, 1964.
30. Banks, R. E.; Burgess, J. E.; Haszeldine, R. N. J. Chem. Soc.
1965, 575.