Dipyrido[1,2-a;3′,4′-d]imidazole systems

Article abstract of DOI:10.1016/j.tet.2009.11.036

Novel tricyclic dipyridoimidazole derivatives can be readily synthesised in one pot processes from various highly fluorinated pyridine systems such as pentafluoropyridine and relatively nucleophilic 2-aminopyridine derivatives. Further nucleophilic aromatic substitution reactions of the novel tricyclic scaffolds allow the regioselective synthesis of various nitrogen, oxygen, carbon and sulfur-functionalised dipyridoimidazole products.

Full text of DOI:10.1016/j.tet.2009.11.036

Tetrahedron 66 (2010) 519–529
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Dipyrido[1,2-a;30,40-d]imidazole systems
,
b
Matthew W. Cartwright a, Laura Convery a, Thomas Kraynck a, Graham Sandford a , Dmitrii S. Yufit ,
*
Judith A.K. Howard b, John A. Christopher c, David D. Miller c
a Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK
b Chemical Crystallography Group, Department of Chemistry, Durham University, South Road, DH1 3LE, UK
c GSK Pharmaceuticals, Gunnels Wood Road, Stevenage, Herts., SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2009
Received in revised form 22 October 2009
Accepted 5 November 2009
Available online 10 November 2009
Novel tricyclic dipyridoimidazole derivatives can be readily synthesised in one pot processes from var-
ious highly fluorinated pyridine systems such as pentafluoropyridine and relatively nucleophilic 2-
aminopyridine derivatives. Further nucleophilic aromatic substitution reactions of the novel tricyclic
scaffolds allow the regioselective synthesis of various nitrogen, oxygen, carbon and sulfur-functionalised
dipyridoimidazole products.
Ó 2009 Elsevier Ltd. All rights reserved.
Nuc1
Nuc1
1. Introduction
F
F
F
F
F
F
F
Nuc2
F
F
Nuc2
Nuc4
Nuc1 Nuc2
Nuc3
Nuc4
Many pharmaceuticals and plant protection agents are based
upon a heteroaromatic core scaffold1 and, consequently, there is
a continued demand for the development of methodology that
provides ready access to novel polyfunctional heterocyclic archi-
tectures as part of a wide ranging drug discovery programme.
Heteroaromatic systems that possess several functional groups that
can be rapidly and selectively transformed into a wide range of
related structural analogues are particularly useful and this ap-
proach has been reviewed extensively.2,3
Nuc3
N
3
N
1
N
2
Ph
Me
Me
N
N
N
N
N
F
N
F
N
N
N
H
F
F
Me
Me
MeO
N
OEt
MeO
N
3a
3b
3c
In this context, we have been developing a general approach to
the synthesis of a wide range of polyfunctional heterocyclic systems
involving annelation reactions between pentafluoropyridine 1 and
various difunctional nucleophiles (Scheme 1).4–7 Initial substitution
of the fluorine atom located at the most activated 4-position of
pentafluoropyridine8,9 is followed by displacement of the adjacent
fluorine atom at the 3-position leading to ring fused products 2. The
heterocyclic scaffolds, such as the pyrido-pyrazine systems
(2, Nuc1-Nuc2¼MeNHCH2CH2NHMe), prepared by this developing
general methodology may be further functionalised by sequential
reaction with other nucleophilic species. A range of analogues 3,
e.g., pyrido-pyrazine4 3a and imidazopyridine7 3c derivatives, were
synthesised from the novel core scaffold systems 2 (Scheme 1).4–6
In further developments, sequential reactions of pentafluoropyridine
with nucleophiles followed by subsequent annelation of tetra-
fluoropyridine derivatives 4 allowed the synthesis of a range of pol-
yfunctional ring-fused systems 5 (Scheme 1).
F
Nuc1
Nuc1
N
F
F
F
F
Nuc3
Nuc2
F
F
F
F
Nuc2 Nuc3
Nuc1
N
1
F
F
N
4
5
PhSO2
H
N
Br
PhSO2
F
F
N
N
F
N
Ph
F
N
N
O
N
F
N
F
N
H
5a
5b
5c
Scheme 1. Strategy for the synthesis of functional ring-fused systems 3 and 5 from
pentafluoropyridine 1.
Previously, we targeted the synthesis of pyridopyrazine and
imidazopyridine systems because of the wide ranging bioactivity
possessed by some of these heterocyclic systems.5,7 Adaptation of
our general heterocyclic synthesis strategy to the synthesis of rel-
atively unknown heterocyclic systems with unexplored biological
activity was our next goal.
* Corresponding author. Tel.: þ44(0)1913342039; fax: þ44(0)1913844737.
E-mail address: Graham.Sandford@durham.ac.uk (G. Sandford).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.036

520
M.W. Cartwright et al. / Tetrahedron 66 (2010) 519–529
Synthetic procedures for the construction of dipyridoimidazole
motifs are very rare10 and recent publications describe syntheses
involving reaction of 2-aminopyridine derivatives with an appro-
priate dihalogenated pyridine system catalysed by palladium ace-
tate or palladium acetate/copper (I) iodide in Buchwald–Hartwig
type processes.11,12 Alternatively, annelation of imidazo[1,2-a]pyr-
idine systems has allowed the synthesis of some functionalised
systems, albeit in low yield.10,13,14 In all cases, further functionali-
sation of the heterocyclic core scaffolds to provide analogue sys-
tems has not been reported because, in part, the multi-step
synthesis of functionalised dibrominated pyridine starting mate-
rials can be very difficult indeed.
In this paper, we describe very efficient methodology for the
synthesis of pyridoimidazole systems by reaction of penta-
fluoropyridine and various tetrafluoropyridine derivatives with
appropriate 2-amino-pyridine derivatives, further establishing the
use of perfluoroheteroaromatic systems for scaffold and function-
alised heteroaromatic analogue synthesis.
2. Results and discussion
Reaction of pentafluoropyridine 1 with 2-amino-3-picoline 6a
under basic conditions in acetonitrile at reflux or under microwave
heating gave a single product, dipyridoimidazole 7a. Three reso-
nances by 19F NMR (ꢀ82, ꢀ105 and ꢀ164 ppm), indicate displace-
ment of fluorine atoms attached to the 3- and 4-positions of the
pyridine ring (Scheme 2). X-ray crystallography confirmed the
structure of dipyridoimidazole 7a (Fig. 1). In contrast, analogous
reactions between the less nucleophilic 2-aminopyridine 6b or
2-amino-5-bromo-3-picoline 6c and 1 proceeded very slowly and
gave low yields of the corresponding dipyridoimidazole systems 7b
and 7c, respectively (Scheme 2).
Figure 1. X-ray structure of 7a.
very efficiently. Non-cyclised intermediate products 8 were not
observed by 19F NMR spectroscopic analysis of the reaction mixture,
indicating that intramolecular cyclisation is a very rapid process.
N
NH2
F
N
N
NH2
F
N
N
NH2
F
F
F
F
F
F
F
F
F
F
8
F
N
F
F
N
F
F
F
F
NaHCO3
N
F
F
F
7a, 82%
+
+
MeCN
N
H2N
N
6a
reflux, 70 h
N
1
Base
F
N
N
N
N
N
F
F
F
F
N
N
NH2
F
NaHCO3
F
F
F
F
H
F
N
F
F
F
- HF
7b, 25%
MeCN
N
1
H2N
N
6b
N
F
N
F
F
F
reflux, 70 h
N
Scheme 3. Mechanism of annelation.
Br
F
By a similar process, 3-chlorotetrafluoropyridine 9 reacted with
6a to give the corresponding tricyclic system 10 (Scheme 2).
In order to further develop routes to dipyridoimidazole systems
following the ideas outlined in Scheme 1, we studied reactions of
two tetrafluoropyridine derivatives 11 and 12 bearing phenyl-
sulfonyl and cyano functionality at the 4-positions, respectively.
However, reaction of 6a with 4-phenylsulfonyl-tetrafluoropyridine
11 was less selective than the reactions described above and three
major products, 13a, 13b and 7a, were present in the reaction
mixture as determined by 19F NMR spectroscopy. Purification
allowed the isolation of small quantities of the two major products
13a and 13b whose identities were confirmed by X-ray crystallog-
raphy (Fig. 2). 7a was also identified by 19F NMR spectroscopy and
GC–MS, but was not isolated from this product mixture.
3 NEt3,
Br
F
F
F
F
N
THF/DMSO
7c
+
, 10%
N
F
F
F
Microwave
150 oC, 2 h
N
6c
NH2
N
1
N
F
N
Cl
F
NaHCO3
N
Cl
F
10
, 41%
+
MeCN
F
N
F
H2N
N
reflux, 70 h
N
F
6a
9
Scheme 2. Syntheses of pyridoimidazole derivatives 7a–c, 10.
Initial attack of aminopyridine 6a occurs through the more nu-
cleophilic pyridine ring nitrogen to give the pyridinium in-
termediate 8, and subsequent ring closure involving nucleophilic
substitution at the adjacent 3-position gives rise to the product
obtained 7a (Scheme 3). The pyridinium group in 8 acts as an
electron withdrawing substituent, activating the fluorinated ring
towards nucleophilic attack and allowing ring annelation to occur
The mechanism for this reaction is given in Scheme 4 and pro-
vides an indication of how the products arise from initial nucleo-
philic attack by 6a at the 2-, 3- and 4-positions of the pyridine ring.
Displacement of fluorine at the 2-position leads directly to product
13a, whilst displacement of fluorine at the 3-position gives in-
termediate 13c, which gives rise to 13d or 13e by intramolecular

M.W. Cartwright et al. / Tetrahedron 66 (2010) 519–529
521
Figure 2. X-ray structures of 13a (left) and 13b (right).
SO2Ph
F
SO2Ph
4 NaHCO3,
MeCN
Reflux
N
N
F
F
F
N
N
N
N
F
F
F
+
2.2
H2N
+
+
N
11
F
N
6a
N
F
F
N
13b
SO2Ph
F
N
7a
13a
, 4%
, 8%
13a 13b 7a
, 9 : 7 : 3
:
:
SO2Ph
SO2Ph
F
F
F
Attack
at C-2
NH2
N
N
N
N
F
6a
N
F
13a
N
N
N
+PhSO2
F
N
F
F
-PhSO2
F
N
13b
SO2Ph
F
N
13d
SO2Ph
F
SO2Ph
F
Attack
at C-3
F
F
N
- F
SO2Ph
F
NH
6a
N
11
F
2 F
N
13c
F
N
N
N
F
13e
Attack
at C-4
N
H2N
F
N
N
F
F
F
6a
F
F
N
7a
F
N
Scheme 4. Reaction of 4-phenylsulfonyl-tetrafluoropyridine 11 with 6a.
CN
CN
CN
4 eq NaHCO3,
F
F
F
F
F
F
F
N
N
N
MeCN
+
+
2
H2N
Reflux,
N
N
F
N
N
N
2 weeks
6a
14b
12
14a, 52 %
, not isolated
14a : 14b, 4 : 1
Scheme 5. Reaction of 4-cyano-tetrafluoropyridine 12 with 6a.

522
M.W. Cartwright et al. / Tetrahedron 66 (2010) 519–529
cyclisation at the 4 or 2 positions, displacing phenyl-sulfonyl or
fluorine, respectively. Reaction of 13d with the phenylsulfonyl
anion, which is now present in the reaction mixture, gives 13b.
This process is, therefore, complicated by the fact that the
phenylsulfonyl group, which is attached to the site para to ring
nitrogen that remains most activated towards nucleophilic attack,
is labile and may be readily displaced by nucleophiles.
Subsequently, therefore, we examined the reaction of 4-cyano-
tetrafluoropyridine 12 with 6a because the cyano group is a much
poorer leaving group than a phenylsulfonyl group but is a strong
electron withdrawing group that helps to activate the pyridine ring
towards nucleophilic attack. In this case, the reaction gave a mix-
ture of 14a and 14b arising from initial substitution at the 2- and
3-positions of 12 in a 4:1 ratio, respectively (Scheme 5) and this
reflects the activating influence of the cyano group on adjacent
sites, which competes with the activating influence of the ring
nitrogen to some extent.
Table 1
Reactions of 7a with amines 15a–d
N
N
5 eq R1R2NH 15
N
F
N
F
F
F
F
THF/DMSO,
MW, 170 °C, 30min
N
16
NR1R2
N
7a
With the synthesis of various dipyridoimidazole scaffolds
established, we turned our attention to assessing the suitability of
the dipyridoimidazole derivative 7a as a scaffold for analogue
synthesis and further functionalisation by nucleophilic aromatic
substitution reactions was studied. 7a reacted very efficiently with
N,N-diethylamine 15a, benzylamine 15b, N-benzylmethylamine
15c and p-anisidine 15d under either microwave or conventional
heating giving, in each case, single products, 16a–d, respectively, by
19F NMR spectroscopic analysis of the crude product mixture.
Recrystallisation of the crude solids obtained after work-up gave
pure products 16a–d in good to excellent yields and these results
are collated in Table 1.
X-ray crystallography confirmed the structure of 16b (Fig. 3) and
the structures of other products 16a,c,d were determined by
comparison of NMR spectroscopic data with those obtained for 16b.
Reaction of 7a with sodium methoxide or phenylmagnesium
bromide gave 17 and 18, respectively by selective displacement of
the fluorine atom located at the C-1 position (Scheme 6).
All reactions of 7a with nucleophiles (Table 1, Scheme 6) gave
products arising from selective displacement of fluorine located at
the C-1 position. We would expect sites C-1 and C-3 to be activated
towards nucleophilic attack because both these positions are ortho
to the pyridine ring nitrogen, but position C-3 may be predicted to
be further activated by the fluorine atom at the adjacent C-4 site
since fluorine ortho to the site of nucleophilic attack is established
to be highly activating.8 However, the observed regioselectivity
may be due to, for example, hydrogen bonding interactions be-
tween the incoming nucleophile with the ring nitrogen, directing
the nucleophile towards the adjacent C-1 site, consistent with the
regiochemistry of nucleophilic substitution processes in related
systems.
R1R2NH 15
Product 16 (Yield %)
N
H
N
N
F
16a (83)
F
N
N
15a
N
H
N
N
F
F
H
16b (63)
N
N
H
15b
N
H
N
Me
N
N
F
F
16c (77)
N
15c
Me
NH2
N
N
16d (12)
F
F
OMe
OMe
N
N
H
15d
Figure 3. X-ray structure of 16b.

M.W. Cartwright et al. / Tetrahedron 66 (2010) 519–529
523
cases, selective displacement of fluorine at the C-1 position, para to
the ring chlorine, occurred to furnish products 21a–e. In this case,
reaction of 10 with thiophenoxide gave only the monosubstituted
system 21e, reflecting the lower reactivity of the carbon–chlorine
bond towards nucleophilic substitution compared to the carbon–
fluorine bond.
N
N
1.1 NaOMe,
dry MeOH
N
F
N
F
F
F
F
17
, 90%
3 NEt3, Microwave
140 °C,30 min
N
7a
N
OMe
Table 2
N
Reactions of 10 with nucleophiles
N
N
F
N
F
2 PhMgBr
18, 48%
F
F
THF,
N
N
reflux, 93 h
Nucleophile
F
N
N
7a
N
F
N
Cl
Cl
THF/DMSO,
MW, 170 °C, 30 min
Scheme 6. Reactions of 7a.
F
N
21
X
F
N
10
Reaction of 7a with only one equivalent of lithium thiophen-
oxide gave the disubstituted derivative 19 as the major product
(44%) arising from displacement of fluorine atoms located at the
C-1 and C-4 positions, with only a small amount of the mono-
substituted product 20 (2%) present in the reaction mixture along
with some starting material (54%, by 19F NMR spectroscopy). Sub-
sequently, reaction of 7a with two equivalents of lithium thio-
phenoxide gave high yields of 19 (Scheme 7). The most effective
indicator as to the regiochemistry of this substitution reaction is by
19F NMR spectroscopy for which, in this case, the singlet resonance
occurs at ꢀ75 ppm, indicative of a fluorine atom situated ortho to
a ring nitrogen.
Nucleophile
Product 21 (Yield %)
N
N
Cl
21a (97)
NH2
F
N
N
H
N
N
N
Cl
21b (71)
21c (32)
N
H
F
N
N
N
N
F
N
F
F
S
F
2 eq LiSPh, THF
reflux, 17 h
N
N
S
N
19
, 61%
NaOMe
N
Cl
F
N
OMe
N
N
N
N
F
F
F
F
LiSPh
N
N
S
F
N
PhONa
21d (76)
N
Cl
20
LiSPh
F
N
O
N
N
N
F
S
PhSNa
21e (58)
N
N
N
Cl
S
F
- F-
F
N
S
F
N
S
N
S
Scheme 7. Reaction of 7a with lithium thiophenoxide.
The structure of 21e was confirmed by X-ray crystallography
(Fig. 4), and all other related products 21a–d were identified by
comparison of NMR data. In particular, 19F NMR spectroscopy
shows the chemical shift of fluorine atoms attached to the 3-posi-
tion are observed at ca. ꢀ85 ppm. The resonance attributed to the
carbon atom attached to chlorine (C-4) in the 13C NMR spectrum
has a distinctive chemical shift (ca. 90 ppm) and two-bond carbon–
fluorine coupling (2JCF 40 Hz), which would not be observed if
substitution had occurred at the C-3 site.
The chlorine atom attached to the pyridine ring in 10 provides
further opportunities for functionalisation of this scaffold in addi-
tion to the nucleophilic substitution processes shown in Table 2.
Reaction of 10 with ammonium formate in the presence of a pal-
ladium catalyst gives a good yield of 22 arising from substitution of
It is reasonable to assume that initial attack on 7a by the nu-
cleophile occurs, as before, at the C-1 site ortho to the activating
imine group and, therefore, the second equivalent of lithium
thiophenoxide must attack the fluoropyridine scaffold para to the
thiophenyl substituent to give the observed product 19 (Scheme 7).
This reflects the advantage of delocalising negative charge de-
veloped in the Meisenheimer intermediate onto the carbon bearing
the sulfur substituent, which would not be possible if attack
occurred at C-3, and the activating effect of sulfur substituents para
to sites of nucleophilic attack has been noted previously.8
Analogous reactions of chlorinated tricyclic system 10 with
a small range of nucleophiles were performed (Table 2) and, in all

524
M.W. Cartwright et al. / Tetrahedron 66 (2010) 519–529
Figure 5. X-ray structure of 23a.
2-aminopyridine derivatives. In particular, model dipyr-
idoimidazole systems 7a and 10 can be utilised as scaffolds for
further nucleophilic aromatic substitution, reacting regioselectively
and under relatively mild conditions, to yield a series of nitrogen,
oxygen, carbon and sulfur-functionalised dipyridoimidazole ana-
logues. In addition, the carbon–chlorine bond of 10 allows func-
tionalisation by dechlorolithiation and trapping by carbon centred
electrophiles. Application of our general strategy for the synthesis
of polyfunctional heterocyclic scaffolds from highly fluorinated
heteroaromatic starting materials has, therefore, been extended to
the synthesis of very rare polyfunctional heteroaromatic systems.
Figure 4. X-ray structure of 21e.
N
N
N
F
N
Cl
HCOONH4
Pd
F
N
10
F
N
F
4. Experimental
4.1. General
22, 50%
N
N
N
BuLi
R-X
N
All starting materials were obtained commercially (Sigma-
Aldrich) and all solvents were dried using standard laboratory
procedures. NMR spectra were recorded in deuteriochloroform,
unless otherwise stated, on a Varian VXR 400S NMR spectrometer
with tetramethylsilane and trichlorofluoromethane as internal
standards. Assignments were made with the aid of data collected
by 1H–1H COSY and 1H–13C HETCOR experiments and coupling
constants are given in Hz. 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.
Elemental analyses were obtained on either a Perkin-Elmer 240 or
a Carlo Erba Elemental Analyser. Melting points were recorded at
atmospheric pressure and are uncorrected. Column chromatogra-
phy was carried out on silica gel (Merck No. 1-09385, 230–400
mesh) and T.L.C. analysis was performed on silica gel T.L.C. plates.
The following numbering scheme is used for indicating NMR
assignments for dipyridoimidazole systems.
Cl
R
F
F
N
10
F
N
F
R-X
MeI
23a
23b
23c
, R = CH3, 59%
Br
, R = CH2=CH-CH2 , 37%
, R = Ac, 63%
O
Cl
Scheme 8. Substitution of chlorine in 10.
chlorine by hydrogen (Scheme 8). Dechlorometallation of 10 by
reaction with butyl lithium followed by trapping of the resulting
lithiated heterocycle with electrophiles, such as methyl iodide, allyl
bromide and acetyl chloride, give ready access to systems 23a–c,
respectively, functionalised at the C-4 position (Scheme 8) and
X-ray crystallography confirmed the structure of 23a (Fig. 5).
8
7
9
6
1a
2a
N
4'd
N
3. Conclusions
F
F
4
3'd
3
1
Tricyclic dipyridoimidazole scaffolds can be readily synthesised
in one pot processes from pentafluoropyridine and various
tetrafluoropyridine derivatives and relatively nucleophilic
N
2
F

M.W. Cartwright et al. / Tetrahedron 66 (2010) 519–529
525
4.2. Synthesis of dipyridoimidazole derivatives
an atmosphere of argon for 72 h. MeCN was removed under re-
duced pressure and the reaction mixture was poured into water
(50 mL) and extracted with DCM (3ꢁ30 mL). The reaction mixture
was dried (MgSO4), solvent evaporated and the residue recrystal-
lised to give 4-chloro-1,3-difluoro-9-methyl-dipyrido[1,2-a; 30,40-
d]imidazole 10 (1.06 g, 41%) as a yellow solid; mp 193–194 ꢂC
(MeCN) (Found: C, 52.0; H, 2.3; N, 16.6. C11H6N3F2Cl requires: C,
52.0; H, 2.3; N 16.5%); dH 2.63 (3H, s, CH3), 6.86 (1H, t, 3JHH 7.0, H-7),
7.31 (1H, d, 3JHH 7.0, H-8), 9.00 (1H, d, 3JHH 7.0, H-6); dF ꢀ77.85 (1F, d,
4JFF 13, F-3), ꢀ86.15 (1F, d, 4JFF 13, F-1); dC 17.58 (s, CH3), 97.33 (dd,
4.2.1. 1,3,4-Trifluoro-9-methyl-dipyrido[1,2-a;30,40-d]imidazole
7a. Pentafluoropyridine 1 (1.69 g, 10.0 mmol), 3-methyl-pyridin-
2-ylamine 6a (2.38 g, 22.0 mmol) and sodium hydrogencarbonate
(3.36 g, 40.0 mmol) were heated in dry MeCN (200 mL) at reflux
temperature, under an atmosphere of argon, for 70 h. The solvent
was evaporated, water (50 mL) was added and extracted with
dichloromethane (3ꢁ40 mL). Drying (MgSO4), solvent evaporation
and recrystallisation from acetonitrile gave 1,3,4-trifluoro-9-
methyl-dipyrido[1,2-a;30,40-d]imidazole 7a (1.94 g, 82%) as a white
solid; mp 174–176 ꢂC (Found: C, 55.6; H, 2.5; N, 17.8. C11H6F3N3
requires: C, 55.5; H, 2.6; N, 17.7%.); dH 2.67 (3H, s, CH3), 6.93 (1H, t,
3JHH 6.9, H-7), 7.36 (1H, dm, 3JHH 6.9, H-8), 8.49 (1H, d, 3JHH 7.1, H-6);
dF ꢀ79.01 (1F, dd, 3JFF 34.8, 4JFF 13.7, F-3), ꢀ102.43 (1F, dd, 5JFF 20.1,
4
2JCF 41.29, JCF 8.13, C-4), 112.69 (s, C-7), 124.37 (s, C-6), 127.20
(dd, 2JCF 33.9, 4JCF 3.9, C-30d), 129.43 (s, C-9), 129.66 (s, C-8), 135.60
(dd, 3JCF 11.12, 3JCF 5.9, C-40d),149.44 (dd, 1JCF 253.91, 3JCF 14.79, C-3),
149.71 (dd, 1JCF 231.79, 3JCF 13.97, C-1),151.37 (s, C-2a); m/z (EIþ) 253
([M]þ, 28%), 255 ([M]þ, 28%), 116 (39), 39 (100).
3
5
4JFF 12.8, F-1), ꢀ164.73 (1F, dd, JFF 33.7, JFF 20.1, F-4); dC 17.57
(s, CH3), 113.20 (s, C-7), 124.93 (d, 4JCF 5.1, C-6), 127.63 (dd, 2JCF 35.3,
3JCF 3.8, C-40d), 128.24 (m, C-30d), 129.44 (s, C-9), 129.87 (s, C-8),
131.17 (ddd, 1JCF 257.1, 2JCF 32.8, 4JCF 8.7, C-4), 140.94 (ddd, 1JCF 233.9,
2JCF 13.7, 2JCF 13.7, C-3), 145.22 (dd, 1JCF 251.3, 2JCF 14.5, C-1), 151.07
(s, C-2a); m/z (EIþ) 237 ([M]þ, 60%). Crystals suitable for X-ray
crystallography were grown from acetonitrile.
4.2.5. 4-Benzenesulfonyl-2,3-difluoro-6-methyl-dipyrido[1,2-a;3020-
d]imidazole 13a and 3-benzenesulfonyl-1,4-difluoro-6-methyl-dipyr-
ido[1,2-a;40,30-d]imidazole 13b. 4-Benzenesulfonyl-2,3,5,6-tetrafluo
ropyridine 11 (1.46 g, 5.0 mmol), 2-amino-3-picoline 6a (1.19 g,
11.0 mmol) and sodium hydrogen carbonate (1.68 g, 20.0 mmol)
were stirred together in dry MeCN (100 mL) at reflux temperature,
under argon. After one week the reaction was evaporated to dry-
ness, poured onto a 1 M HCl solution (50 mL) and extracted into
DCM (3ꢁ40 mL). Drying (MgSO4), solvent evaporation and recrys-
tallisation from MeCN gave 3-benzenesulfonyl-1,4-difluoro-6-
methyl-dipyrido[1,2-a;40,30-d]imidazole 13b (0.14 g, 8%) as planar
yellow crystals; mp 288–290 ꢂC; (Found: C, 56.6; H, 3.0; N, 11.8.
C17H11F2N3O2S requires: C, 56.8; H, 3.1; N, 11.7%); dH 2.74 (3H, s,
CH3), 7.11 (1H, d, 3JHH 7.5, H-8), 7.52–7.56 (3H, m, H-30,40), 7.62 (1H,
t, 3JHH 7.5, H-7), 8.15 (2H, d, 3JHH 7.2, H-20), 8.60 (1H, d, 3JHH 6.8, H-9);
4.2.2. 1,3,4-Trifluoro-dipyrido[1,2-a;30,40-d]imidazole 7b. 1 (1.69 g,
10.0 mmol), 2-amino-pyridine 6b (1.88 g, 20.0 mmol) and sodium
hydrogen carbonate (3.36 g, 40.0 mmol) were stirred together in
dry MeCN (200 mL) at reflux temperature, under an atmosphere of
argon, for 96 h. The solvent was evaporated, water (50 mL) was
added and extracted with dichloromethane (3ꢁ40 mL). Drying
(MgSO4) and evaporation of the solvent yielded a dark red solid,
which was recrystallised from acetonitrile to give 1,3,4-trifluoro-
dipyrido[1,2-a;30,40-d]imidazole 7b (0.55 g, 25 %) as a pale orange
solid; mp 197–198 ꢂC (Found: C, 53.8; H, 1.7; N, 18.9. C10H4F3N3
requires: C, 53.8; H, 1.8; N, 18.8%); dH 7.01–7.08 (1H, m, H-7), 7.56–
5
5
dF ꢀ76.61 (1F, d, JFF 30.9, F-1), ꢀ132.08 (1F, d, JFF 31.6, F-4); m/z
(ESþ) 360.1 ([MH]þ, 100%). Crystals suitable for X-ray crystallogra-
phy were grown from MeCN.
3
7.60 (1H, m, H-8), 7.75–7.80 (1H, m, H-9), 8.64 (1H, dm, JHH 7.0,
Column chromatography of the remaining material on silica gel
using ethyl acetate: hexane (2:1) as elutant followed by recrystal-
lisation from MeCN gave 4-benzenesulfonyl-2,3-difluoro-6-
methyl-dipyrido[1,2-a;3020-d]imidazole 13a (0.08 g, 4%) as a yellow
solid; mp 242–244 ꢂC; (Found: C, 56.8; H, 3.1; N, 11.9.
C17H11F2N3O2S requires: C, 56.8; H, 3.1; N, 11.7%); dH 2.71 (3H, s,
CH3), 6.94–6.98 (1H, m, H-8), 7.34–7.40 (1H, m, H-7), 7.50–7.58 (2H,
m, H-30), 7.62–7.68 (1H, m, H-9), 8.36–8.46 (3H, m, H-20,40); dF
ꢀ91.53 (1F, d, 3JFF 24.8, F-2), ꢀ140.24 (1F, d, 3JFF 24.6, F-3); dC 17.02
(s, CH3), 112.87 (s, C-8), 121.95 (s, C-40), 128.51 (m, C-30d), 128.99 (s,
H-6); dF ꢀ79.05 (1F, dd, 3JFF 34.3, 4JFF 13.4, F-3), ꢀ102.07 (1F, dd, 5JFF
4
3
5
19.9, JFF 13.3, F-1), ꢀ164.36 (1F, dd, JFF 34.4, JFF 20.3, F-4); dC
4
113.08 (s, C-7), 119.30 (s, C-9), 127.44 (d, JCF 5.0, C-6), 127.73 (m,
C-30d), 128.00 (dd, 2JCF 35.4, 3JCF 3.8, C-40d), 131.22 (ddd, 1JCF 256.6,
3JCF 32.1, JCF 8.5, C-4), 131.95 (s, C-8), 141.07 (ddd, JCF 233.7, JCF
4
1
2
2
1
2
13.6, JCF 13.6, C-3), 145.07 (dd, JCF 250.7, JCF 14.8, C-1), 150.24
(s, C-2a); m/z (EIþ) 223 ([M]þ, 100 %), 203 (21), 176 (24).
4.2.3. 7-Bromo-1,3,4-trifluoro-9-methyl-dipyrido[1,2-a;30,40-d]imid-
azole 7c. 1 (0.30 g, 1.77 mmol), 2-amino-5-bromo-3-methylpyr-
idine 6c (0.50 g, 2.66 mmol) and triethylamine (0.54 g, 5.32 mmol)
were stirred together in a mixture of THF (10.00 mL) and DMSO
(4.00 mL) in a sealed 20 mL vial under microwave heating for 2 h at
150 ꢂC. The resulting mixture was evaporated to dryness and pu-
rification by column chromatography using DCM/MeOH as elutant
(0.5–4% MeOH gradient over 15 min) gave 7-bromo-1,3,4-trifluoro-
9-methyl-dipyrido[1,2-a;30,40-d]iþmidazole 7c (0.06 g, 10%) as a yel-
low solid; mp 249–251 ꢂC ([MH] , 315.9687. C11H5N3F3Br requires:
[MH]þ, 315.9697); dH 2.72 (3H, s, CH3), 7.45 (1H, br s, H-8), 8.65
4
C-6), 129.14 (s, C-30), 129.26 (s, C-20), 130.24 (s, C-7), 131.29 (d, JCF
2
3.1, C-10), 133.90 (dm, JCF 15.2, C-4), 134.62 (s, C-9), 140.66
(s, C-20d), 141.44 (dd, 1JCF 267.9, 2JCF 30.2, C-3), 147.21 (dd, 1JCF 243.9,
2JCF 19.8, C-2),151.21 (s, C-2a);m/z (ESþ) 360.0 ([MH]þ,100%). Crystals
suitable for X-ray crystallography were grown from chloroform.
4.2.6. 2,3-Difluoro-6-methyl-dipyrido[1,2-a,30,20d]imidazole-4-car-
bonitrile 14a. 2,3,5,6-Tetrafluoro-4-pyridinecarbonitrile 12 (0.88 g,
5.0 mmol), 2-amino-3-picoline 6a (1.08 g, 10.0 mmol) and sodium
hydrogen carbonate (1.68 g, 20.0 mmol) were stirred together in
dry MeCN at reflux temperature, under dry argon. After two weeks
the reaction was cooled to room temperature and the solvent
evaporated. The residue was redissolved in DCM and poured onto
water (50 mL). Extraction of the organic products into DCM, drying
(MgSO4), solvent evaporation and column chromatography on sil-
ica gel (n-hexane: ethyl acetate, 1:1) gave 2,3-difluoro-6-methyl-
dipyrido[1,2-a,30,20d]imidazole-4-carbonitrile 14a (0.63 g, 52%) as
a yellow solid; mp 197–198 ꢂC (Found: C, 58.9; H, 2.4; N, 23.1.
C12H6N4F2 requires: C, 59.2; H, 2.5; N, 22.9%); dH 2.73 (3H, br s, CH3),
3
4
(1H, br s, H-6); dF ꢀ77.80 (1F, dd, JFF 34.4, JFF 13.8, F-3), ꢀ100.90
(dd, 5JFF 20.1, 4JFF 13.2, F-1), ꢀ164.49 (dd, 3JFF 34.4, 5JFF 19.5, F-4); dC
4
17.33 (s, CH3), 107.42 (s, C-7), 124.51 (d, JCF 5.2, C-6), 127.76
(m, C-40d), 130.52 (s, C-9), 130.83 (ddd, 1JCF 257.0, 2JCF 32.0, 4JCF 8.6,
C-4), 133.20 (s, C-8), 141.29 (ddd, 1JCF 236.0, 2JCF 14.0, 2JCF 14.0, C-3),
145.16 (dd, 1JCF 252.1, 3JCF 11.8, C-1), 149.27 (s, C-2a); m/z (ESþ) 318.0
([MH]þ, 100%), 316.0 ([MH]þ, 100%).
4.2.4. 4-Chloro-1,3-difluoro-9-methyl-dipyrido[1,2-a; 30,40-d]imid-
azole 10. 3-Chlorotetrafluoropyridine 9 (2.0 g, 1.1 mmol), 2-amino-
3-picoline 6a (1.28 g, 1.2 mmol) and sodium hydrogen carbonate
(1.81 g, 2.2 mmol) were heated to reflux in MeCN (200 mL) under
3
3
7.02 (1H, t, JHH 6.9, H-8), 7.45 (1H, dm, JHH 6.9, H-7), 8.53 (1H, d,
3JHH 6.9, H-9); dF ꢀ91.96 (1F, d, JFF 22.5, F-2), ꢀ135.23 (1F, d, JFF
3
3
23.1, F-3); dC 17.03 (s, CH3), 101.49 (dd, 2JCF 13.0, 3JCF 4.5, C-4), 109.91

526
M.W. Cartwright et al. / Tetrahedron 66 (2010) 519–529
(d, 3JCF 5.0, CN), 113.28 (s, C-8), 122.31 (s, C-9), 128.94 (s, C-6), 131.03
(s, C-7), 133.50 (m, C-30d), 134.72 (d, 3JCF 2.9, C-20d), 145.72 (dd, 1JCF
268.5, 2JCF 31.6, C-3), 146.35 (dd, 1JCF 245.5, 2JCF 17.3, C-2), 151.79 (s,
C-2a); m/z (ESþ) 243.8 ([M]þ, 100%).
26.0, F-4); dC 17.21 (s, CH3), 37.00 (s, NCH3), 54.57 (s, CH2), 111.79
(s, C-7), 124.28 (d, 4JCF 6.1, C-6), 124.98 (dd, 1JCF 245.4, 2JCF 36.3, C-4),
2
3
125.90 (dd, JCF 8.2, JCF 7.0, C-40d), 126.50 (s, Ar), 127.06 (s, Ar),
127.99 (s, Ar),128.12 (m, C-30d),128.46 (s, Ar),128.71 (s, C-9),139.09
1
2
3
(s, C-10), 143.38 (dd, JCF 219.5, JCF 12.1, C-3), 144.88 (d, JCF 16.6,
4.3. Reactions of 1,3,4-trifluoro-9-methyl-dipyrido[1,2-a;30,
40-d]imidazole 7a with nucleophiles
C-1),146.71 (br s, C-2a); m/z (ESþ) 339.1 ([MH]þ, 100%).
4.3.4. (3,4-Difluoro-9-methyl-dipyrido[1,2-a;30,40-d]imidazol-1-yl)-
(4-methoxy-phenyl)-amine 16d. 7a (0.10 g, 0.42 mmol), p-anisidine
15d (0.08 g, 0.63 mmol) and triethylamine (0.13 g, 1.26 mmol)
were stirred together in THF (1.0 mL) and DMSO (0.2 mL) at 170 ꢂC
for 2 h (MW). Solvent was evaporated and purification of the
residue by mass directed HPLC gave (3,4-difluoro-9-methyl-
dipyrido[1,2-a;30,40-d]imidazol-1-yl)-(4-methoxy-phenyl)-aminþe
16d (0.02 g, 12%) as a yellow solid; mp 161–162 ꢂC ([MH] ,
341.1208. C18H14N4OF2 requires: [MH]þ, 341.1214); dH 2.65 (3H, s,
4.3.1. 3,4-Difluoro-(9-methyl-dipyrido[1,2-a,30,40-d]imidazol-1-yl)-
diethyl-amine 16a. 7a (0.25 g, 1.06 mmol) and diethylamine 15a
(0.39 g, 5.27 mmol) were stirred together in a mixture of DMSO
(4.0 mL) and THF (10 mL) and irradiated by microwave heating for
30 min at 170 ꢂC. The reaction mixture was evaporated to dryness,
water (50 mL) was added and the organic products extracted into
dichloromethane (3ꢁ40 mL). Drying (MgSO4), evaporation and
recrystallisation from acetonitrile gave 3,4-difluoro-(9-methyl-
dipyrido[1,2-a,30,40-d]imidazol-1-yl)-diethyl-amine 16a (0.51 g, 83
%) as a pale yellow solid; mp 91–93 ꢂC (Found: C, 62.3; H, 5.5; N,
19.2. C15H16N4F2 requires: C, 62.1; H, 5.6; N, 19.3%); dH 1.28 (6H, t,
3JHH 6.8,–CH2CH3), 2.63 (3H, s, CH3), 4.03 (4H, q, 3JHH 7.0, CH2), 6.74–
6.80 (1H, m, H-7), 7.15 (1H, d, JHH 6.7, H-8), 8.42 (1H, d, JHH 6.9,
H-6); dF ꢀ102.42 (1F, d, 3JFF 27.0, F-3), ꢀ181.52 (1F, d, 3JFF 26.8, F-4);
dC 13.79 (s, NCH2CH3), 17.20 (s, CH3), 43.73 (s, CH2), 111.66 (s, C-7),
124.42 (d, 4JCF 6.0, C-6), 124.45 (dd, 1JCF 243.6, 2JCF 36.7, C-4), 126.00
(m, C-40d), 126.16 (s, C-8), 127.94 (m, C-30d), 128.76 (s, C-9), 143.68
(dd, 1JCF 218.0, 2JCF 12.1, C-3), 144.28 (d, 3JCF 17.0, C-1), 146.81 (s, C-
2a); m/z (EIþ) 290 ([M]þ, 90%), 275 ([M-CH3]þ, 100), 261 (76), 247
(85), 219 (52).
3
CH3), 3.82 (3H, s, OCH3), 6.81 (1H, t, JHH 6.9, H-7), 6.93 (2H, AX,
3JAX 9.0, Ar-H), 7.21 (1H, dm, 3JHH 6.8, H-8), 7.63 (1H, br s, NH), 7.74
(2H, AX, 3JAX 8.8, Ar-H), 8.42 (1H, d, 3JHH 6.9, H-6); dF ꢀ102.9 (1F, d,
3JFF 24.3, F-3), ꢀ176.5 (1F, d, 3JFF 24.1, F-4); m/s (ESþ) 341.1 ([MH]þ,
100%).
3
3
4.3.5. 3,4-Difluoro-1-methoxy-9-methyl-dipyrido[1,2-a,30,40-d]imid-
azole 17. 7a (0.40 g, 1.69 mmol), sodium methoxide (0.10 g,
1.86 mmol) and triethylamine (0.51 g, 5.08 mmol) were stirred to-
gether in anhydrous MeOH (10 mL) under microwave irradiation for
30 min at 140 ꢂC. The reaction mixture was poured into water
(10 mL) and evaporation under reduced pressure gave a white crude
product, which was triturated with water to give 3,4-difluoro-1-
methoxy-9-methyl-dipyrido[1,2-a;3040-d]imidazole 17 (0.38 g, 90%)
as a white solid; mp 187–188 ꢂC (Found: C, 57.6; H, 3.5; N, 16.6.
C12H9F2N3O requires: C, 57.8; H, 3.6; N, 16.9%); dH 2.68 (3H, s, CH3),
4.16 (3H, s, OCH3), 6.80–6.87 (1H, m, H-7), 7.21–7.28 (1H, m, H-8),
8.41–8.52 (1H, m, H-6); dF ꢀ104.3 (1F, d, 3JFF 22.0, F-3), ꢀ172.8 (1F, d,
3JFF 21.9, F-4); dC 17.73 (s, CH3), 54.87 (s, OCH3),112.64 (s, C-7),124.82
4.3.2. Benzyl-(3,4-difluoro-9-methyl-dipyrido[1,2-a;30,40-d]imidazol-
1-yl)-amine 16b. 7a (0.50 g, 2.11 mmol) and benzylamine 15b
(1.13 g, 10.54 mmol) were stirred together in a mixture of THF
(10 mL) and DMSO (2 mL) under microwave heating at 170 ꢂC for
30 min. The reaction mixture was evaporated to dryness, water
(50 mL) was added and the organic products extracted into
dichloromethane (3ꢁ40 mL). Drying (MgSO4), evaporation and
recrystallisation from acetonitrile gave benzyl-(3,4-difluoro-9-
methyl-dipyrido[1,2-a;30,40-d]imidazol-1-yl)-amine 16b (0.43 g,
63%) as a yellow solid; mp 148–149 ꢂC (Found: C, 66.7; H, 4.3; N,
17.3. C18H14F2N4 requires: C, 66.7; H, 4.4; N, 17.3%); dH 2.57 (3H, s,
CH3), 4.75 (2H, d, 3JHH 5.6, CH2), 6.12 (1H, br s, NH), 6.72–6.78 (1H,
m, H-7), 7.14 (1H, dm, 3JHH 6.8, H-8), 7.26–7.31 (3H, m, H-30,40), 7.39
(2H, dm, 3JHH 7.6, H-20), 8.34 (1H, dm, 3JHH 6.8, H-6); dF ꢀ103.97 (1F,
4
(d, JCF 5.2, C-6), 126.04 (m, C-40d), 128.38 (s, C-8), 128.49 (dd, 1JCF
251.5, 2JCF 33.7, C-4),128.71 (m, C-30d),129.35 (s, C-9),142.70 (dd,1JCF
2
3
4
227.0, JCF 14.0, C-3), 148.55 (dd, JCF 13.8, JCF 1.2, C-1), 149.51 (s,
C-2a); m/z (ESþ) 250.1 ([MH]þ, 100%).
4.3.6. 3,4-Difluoro-9-methyl-1-phenyl-dipyrido[1,2-a;30,40-d]imid-
azole 18. 7a (0.41 g, 1.70 mmol) and phenylmagnesium bromide
(3.49 mL 1 M soln in THF, 3.50 mmol) were heated at reflux in THF
(40 mL) for 93 h. The resulting mixture was poured into 0.5 M HCl
solution (50 mL) and extracted with DCM (3ꢁ10 mL). Drying
(MgSO4), evaporation of solvent and recrystallisation from aceto-
nitrile gave 3,4-difluoro-9-methyl-1-phenyl-dipyrido[1,2-a;30,40-
d]imidazole 18 (0.25 g, 48%) as a pale yellow solid; mp 188–189 ꢂC
(Found: C, 69.2; H, 3.7; N, 14.2. C17H11F2N3 requires: C, 69.2; H, 3.8;
3
m, F-3), ꢀ179.55 (1F, d, JFF 23.7, F-4); dC 17.56 (s, CH3), 45.60
(s, CH2), 112.31 (s, C-7), 124.40 (dd, 2JCF 16.1, 3JCF 8.9, C-40d), 124.89
(d, 4JCF 4.6, C-6), 125.65 (dd, 1JCF 246.2, 2JCF 35.3, C-4), 127.48 (s, Ar),
127.54 (s, Ar), 128.27 (s, Ar), 128.40 (m, C-30d), 128.66 (s, Ar), 128.74
3
1
(s, Ar), 139.03 (s, C-10), 144.40 (d, JCF 18.4, C-1), 144.77 (dd, JCF
222.0, JCF 12.7, C-3), 148.30 (s, C-2a); m/z (ESþ) 325.1 ([MH]þ, 100
2
3
%). Crystals suitable for X-ray crystallography were grown from
acetonitrile.
N, 14.2%); dH 2.66 (3H, s, CH3), 6.78 (1H, t, JHH 6.7, H-7), 7.24 (1H,
dm, 3JHH 6.7, H-8), 7.41–7.48 (1H, m, H-40), 7.50–7.54 (2H, m, H-30),
8.42 (1H, d, 3JHH 6.9, H-6), 8.79 (2H, dm, 3JHH 8.3, H-20); dF ꢀ99.8 (1F,
d, 3JFF 28.2, F-3), ꢀ162.9 (1F, d, 3JFF 27.5, F-4); dC 17.49 (s, CH3), 112.29
4.3.3. Benzyl-(3,4-difluoro-9-methyl-dipyrido[1,2-a;30,40-d]imidazol-
1-yl)-methyl-amine 16c. 7a (0.50 g, 2.11 mmol) and N-benzylme-
thylamine 15c (1.28 g, 10.54 mmol) were stirred together in a mix-
ture of THF (10 mL) and DMSO (2 mL) at 170 ꢂC for 30 min (MW).
The reaction mixture was evaporated to dryness, water (50 mL) was
added and the organic products extracted into dichloromethane
(3ꢁ40 mL). Drying (MgSO4), evaporation and recrystallisation from
4
(s, C-7), 125.19 (d, JCF 5.5, C-6), 125.84 (m, C-40d), 128.52 (s, Ar),
129.10 (s, Ar), 129.20 (s, C-9), 129.39 (s, Ar), 129.52 (s, Ar), 131.68
1
2
(dd, JCF 264.5, JCF 36.6, C-4), 136.19 (s, C-10), 139.35 (m, C-30d),
140.26 (dd, JCF 13.5, JCF 5.6, C-1), 144.03 (dd, 1JCF 223.7, JCF 11.9,
3
4
2
C-3), 150.60 (s, C-2a); m/z (EIþ) 295 ([M]þ, 100%).
acetonitrile
gave
benzyl-(3,4-difluoro-9-methyl-dipyrido[1,
4.3.7. 3-Fluoro-9-methyl-1,4-bis-phenylsulfanyl-dipyrido[1,2-a;30,
40-d]imidazole 19. 7a (0.47 g, 2.0 mmol) and lithium thiophenoxide
(4.00 mL 1 M solution in THF, 4.0 mmol) in THF (10 mL) were
heated at reflux for 17 h. Evaporation of the solvent was followed by
addition of 0.5 M HCl solution (50 mL), extraction into DCM
(3ꢁ40 mL), drying (MgSO4), evaporation and recrystallisation
from acetonitrile gave 3-fluoro-9-methyl-1,4-bis-phenylsulfanyl-
2-a;30,40-d]imidazol-1-yl)-methyl-amine 16c (0.55 g, 77%) as a dark
green solid; mp 111–113 ꢂC (Found: C, 67.7; H, 4.7; N, 16.8.
C19H16N4F2 requires: C, 67.5; H, 4.8; N, 16.6%); dH 2.53 (3H, s, CH3),
3.37 (3H, s, NCH3), 5.46 (2H, s, CH2), 6.64–6.70 (1H, m, H-7), 7.06
3
(1H, dm, JHH 6.7, H-8), 7.37–7.22 (5H, m, H-20, 30, 40), 8.31 (1H, d,
3
3
3JHH 7.1, H-6); dF ꢀ102.56 (1F, d, JFF 26.3, F-3), ꢀ180.01 (1F, d, JFF

M.W. Cartwright et al. / Tetrahedron 66 (2010) 519–529
527
dipyrido[1,2-a;30,40-d]imidazole 19 (0.51 g, 61%) as a yellow solid;
mp 174–176 ꢂC (Found: C, 65.9; H, 3.8; N, 10.2. C23H16N3FS2 re-
quires: C, 66.2; H, 3.9; N, 10.1%); dH 2.70 (3H, s, CH3), 6.70–6.73 (1H,
m, H-7), 7.15–7.09 (3H, m, Ar-H), 7.24–7.17 (3H, m, H-9, Ar-H), 7.49–
7.45 (3H, m, Ar-H), 7.75–7.72 (2H, m, Ar-H), 9.31 (1H, d, 3JHH 7.1, H-
6); dC 17.71 (s, CH3), 93.13 (d, JCF 44.3, C-4), 112.06 (s, C-7), 125.26 (s,
C-6), 126.62 (s, Ar), 127.11 (s, Ar), 127.99 (s, C-9), 128.76 (s, Ar),
128.98 (s, Ar), 129.36 (s, Ar), 129.51 (s, C-8), 129.58 (s, Ar), 134.86
(d, 3JCF 5.9, C-40d), 135.25 (br s, C-30d), 135.58 (s, Ar), 136.74 (d, 4JCF
gave 4-chloro-3-fluoro-1-methoxy-9-methyl-dipyrido[1,2-a;30,40-
d]imidazole 21c (0.1 g, 32%) as a white solid; mp 229–230 ꢂC
(MeOH) (Found: C, 53.9; H, 3.3; N, 15.4. C12H9N3OFCl requires: C,
54.2; H, 3.4, N, 15.8%); dH 2.63 (3H, s, CH3), 4.13 (3H, s, OCH3), 6.75–
6.81 (1H, m, H-7), 7.18–7.23 (1H, m, H-8), 8.94–9.01 (1H, m, H-6); dF
ꢀ87.47 (s); dc 17.78 (s, CH3), 54.97 (s, OMe), 92.00 (d, 2JCF 41.69, C-4),
112.15 (s, C-7), 124.33 (s, C-6), 128.11 (s, C-8), 128.70 (d, 4JCF 3.37, C-
30d), 129.35 (s, C-9), 132.67 (d, 3JCF 6.08, C-40d), 149.82 (d, 5JCF 1.81,
C-2a),151.64 (d, 1JCF 227.37, C-3),152.52 (d, 3JCF 15.25, C-1); m/z (EIþ)
265.0 ([M]þ, 100%), 249.9 (55).
5
1.9, C-10), 150.60 (d, JCF 1.8, C-2a), 152.00 (d, JCF 17.7, C-1), 158.57
(d, 1JCF 230.6, C-3); dF -75.6 (1F, s, F-3); m/z (ESþ) 418 ([MH]þ, 100%).
4.4.4. 4-Chloro-3-fluoro-9-methyl-1-phenoxy-dipyrido[1,2-a;30,40-
d]imidazole 21d. 4-Chloro-1,3-difluoro-9-methyl-dipyrido[1,2-a;
30,40-d]imidazole 10 (0.5 g, 1.97 mmol) and sodium phenoxide
(0.34 g, 2.9 mmol) were heated at reflux in dry MeCN for 24 h un-
der an atmosphere of argon. The reaction mixture was evaporated
under reduced pressure, water (50 mL) was added and extracted
with DCM (3ꢁ50 ml). Drying (MgSO4), solvent evaporation and
recrystallisation from ethyl acetate gave 4-chloro-3-fluoro-9-
methyl-1-phenoxy-dipyrido[1,2-a;30,40-d]imidazole 21d (0.49 g,
76%) as a white solid; mp 170.5–171.2 ꢂC; (Found: C, 62.3; H, 3.6; N,
12.5. C17H11ClFN3O requires C, 62.3; H, 3.4; N, 12.8%); dH 2.64 (3H, s,
4.4. Reactions of 4-chloro-1,3-trifluoro-9-methyl-dipyrido-
[1,2-a;30,40-d]imidazole 10 with nucleophiles
4.4.1. Butyl-(4-chloro-3-fluoro-9-methyl-dipyrido[1,2-a;30-40d]-
imidazol-1-yl)amine 21a. 4-Chloro-1,3-difluoro-9-methyl-dipyr-
ido[1,2-a;30,40-d]imidazole 10 (0.3 g, 0.1 mmol), n-butylamine
(0.17 g, 0.2 mmol) and sodium hydrogen carbonate (1.81 g,
2.2 mmol) were heated at reflux in MeCN (40 mL) under an atmo-
sphere of argon for 21 h. MeCN was removed under reduced pres-
sure, the reaction mixture was poured into water (50 mL) and
extracted with DCM (3ꢁ30 mL). The reaction mixture was dried
(MgSO4), solvent evaporated and the residue recrystallised to give
butyl-(4-chloro-3-fluoro-9-methyl-dipyrido[1,2-a;30-40d]imidazol-
1-yl)amine 21a (0.35 g, 97%) as a white solid; mp 104.8–105.6 ꢂC
(MeCN) (Found: C, 58.4; H, 5.1; N,16.9. C15H16N4FCl requires: C, 58.7;
H, 5.2; N, 18.2); dH 0.99 (3H, t, 3JHH 7.0, CH3), 1.45–1.55 (2H, m, CH2),
1.70–1.76 (2H, m, CH2), 2.66 (3H, s, CH3), 3.58–3.66 (2H, m, CH2),
6.70–6.76 (1H, m, H-7), 7.09–7.15 (1H, m, H-8), 8.90–8.96 (1H, m, H-
6); dF ꢀ86.78 (s); dC 14.02 (s, C-14), 17.55 (s, C-10), 20.34 (s, C-13),
31.82 (s, C-12), 41.14 (s, C-11), 85.36 (d, 2JCF 43.60, C-4),111.75 (s, C-7),
124.41 (s, C-6), 127.10 (s, C-9), 127.12 (s, C-8), 130.15 (d, 4JCF 6.34, C-
40d), 148.03 (d, 3JCF 19.92, C-30d), 148.18 (m, C-1), 153.84 (d, 1JCF 221,
C-3); m/z (EIþ) 305.9 ([M]þ, 46%), 262.9 (100).
3
3
CH3), 6.82 (1H, t, JHH 7.00, H-7), 7.23 (1H, t, JHH 7.50, H-14), 7.24
3
3
(2H, d, JHH 7.50, H-12,16), 7.25 (1H, d, JHH 7.00, H-8), 7.39 (2H, t,
3JHH 7.50, H-13,15), 9.02 (1H, d, JHH 7.00, H-6); dF ꢀ85.75 (s); dC
3
17.95 (s, CH3), 93.71 (d, 2JCF 41.72, C-4), 112.6 (s, C-7), 118.87 (s, Ar),
3
122.12 (s, Ar), 124.54 (s, C-6), 124.89 (d, JCF 11.94, C-40d), 125.76
(s, C-8), 129.22 (m, C-40d), 129.52 (s, C-9), 129.78 (s, Ar), 133.83
1
(m, C-30d), 149.66 (s, C-2a), 153.17 (s, C-1), 154.41 (d, JCF 247.94,
C-3); m/z (EIþ) 327.0 ([M]þ, 100%), 292.0 (60).
4.4.5. 4-Chloro-3-fluoro-9-methyl-1-phenylsulfanyl-dipyrido[1,2-
a;30,40-d]imidazole 21e. 4-Chloro-1,3-difluoro-9-methyl-dipyrido
[1,2-a;30,40-d]imidazole 10 (0.5 g, 1.99 mmol) and sodium thio-
phenolate (0.34 g, 2.59 mmol) were heated at reflux in dry MeCN
for 120 h under an atmosphere of argon. The reaction mixture was
evaporated under reduced pressure, water (50 mL) was added and
extracted with DCM (3ꢁ50 mL). Drying (MgSO4), solvent evapora-
tion and recrystallisation from acetonitrile gave 4-chloro-3-fluoro-
4.4.2. (4-Chloro-3-fluoro-9-methyl-dipyrido[1,2-a;30,40-d]imidazol-
1-yl)-diethyl-amine
21b. 4-Chloro-1,3-difluoro-9-methyl-dipyr-
ido[1,2-a; 30,40-d]imidazole 10 (0.3 g, 0.1 mmol), diethylamine
(0.17 g, 0.2 mmol) and sodium hydrogen carbonate (1.81 g,
2.2 mmol) were heated at reflux in MeCN (40 mL) under an at-
mosphere of argon for 21 h. MeCN was removed under reduced
pressure, the reaction mixture was poured into water (50 mL) and
extracted with DCM (3ꢁ30 mL). The reaction mixture was dried
(MgSO4), solvent evaporated and the residue recrystallised from
ethyl acetate to give (4-chloro-3-fluoro-9-methyl-dipyrido
[1,2-a;3040-d]imidazol-1-yl)-diethyl-amine 21b (0.2 g, 71%) as a yel-
low solid; mp 101–102.5 ꢂC (MeCN) (Found: C 58.61; H 5.15; N 18.08.
C15H16N4ClF requires: C 58.82; H 5.22; N 18.30%); dH 1.29 (6H, m,
CH2CH3), 2.57 (3H, s, CH3), 4.00–4.09 (4H, m, CH2), 6.65–6.71 (1H, m,
H-7), 7.04–7.11 (1H, m, H-8), 8.94–9.00 (1H, m, H-6); dF ꢀ85.71 (s);
9-methyl-1-phenylsulfanyl-dipyrido[1,2-a;30,40-d]imidazole
21e
(0.40 g, 58%) as green crystals; mp 149–150 ꢂC; (Found: C, 59.2; H,
3.2; N, 12.3%. C17H11ClFN3S requires C, 59.4; H, 3.2; N, 12.2%); dH
2.66 (3H, s, CH3), 6.82 (1H, t, 3JHH 6.00, H-7), 7.24 (1H, d, 3JHH 6.00,
3
3
H-8), 7.39 (1H, t, JHH 6.50, H-14), 7.40 (2H, t, JHH 6.50, H-13,15),
7.63 (2H, d, 3JHH 6.50, H-12,16), 8.96 (1H, d, 3JHH 7.00, H-6); dF -84.0
(s); dC 17.85 (s, CH3), 96.43 (d, 2JCF 43.61, C-4), 112.27 (s, C-7), 116.19
(s, Ar),118.87 (s, Ar),124.85 (s, C-6),128.59 (s, C-40d),129.02 (s, C-8),
129.44 (s, Ar), 129.48 (s, C-9), 131.10 (m, C-30d), 135.53 (s, Ar), 137.61
(s, C-1), 147.44 (d, 5JCF 15.46, C-2a), 153.18 (d, 1JCF 228.71, C-3); m/z
(EIþ) 343.0 ([M]þ, 100%), 308.0 (95).
2
dC 13.79 (s, CH2CH3), 17.28 (s, CH3), 43.99 (s, CH2), 83.94 (d, JCF
4.5. Reactions of 10 involving displacement of ring chlorine
45.14, C-4), 111.31 (s, C-7), 124.09 (s, C-6), 126.08 (s, C-8), 127.82 (d,
3JCF 2.56, C-40d), 128.66 (s, C-9), 132.07 (d, 3JCF 6.54, C-1), 146.82 (d,
5JCF 1.75, C-2a),147.21 (d, 3JCF 18.95, C-1), 152.79 (d, 1JCF 219.39, C-3);
m/z (EIþ) 306.0 ([M]þ, 75%), 291.0 (88), 276.9 (75), 262.8 (100),
234.6 (55).
4.5.1. 1,3-Difluoro-9-methyl-dipyrido[1,2-a;30,40-d]imidazole
22.
4-Chloro-1,3-difluoro-9-methyl-dipyrido[1,2-a;30,40-d]imidazole
10 (4.01 g, 1.57 mol), ammonium formate (0.89 g, 1.57 mol) and 30%
palladium on charcoal were heated at reflux in THF (160 mL)
for 48 h. The reaction mixture was filtered, poured into water
(100 mL) and extracted with DCM (4ꢁ30 ml). Drying (MgSO4),
solvent evaporation and recrystallisation gave 1,3-difluoro-9-
methyl-dipyrido[1,2-a;30,40-d]imidazole 22 (1.38 g, 50%) as
a white solid; mp 234–235 ꢂC (MeOH) (Found: C 60.06; H 3.26; N
19.15. C11H7N3F2 requires: C 60.27; H 3.19; N 19.17%); dH (DMSO)
2.47 (3H, s, CH3), 6.97–7.03 (1H, m, H-7), 7.41–7.48 (1H, m, H-8),
8.00–8.06 (1H, m, H-4), 8.78–8.84 (1H, m, H-6); dF ꢀ74.92 (1F, d,
4.4.3. 4-Chloro-3-fluoro-1-methoxy-9-methyl-dipyrido[1,2-a;30,40-
d]imidazole
21c. 4-Chloro-1,3-difluoro-9-methyl-dipyrido[1,2-
a;30,40-d]imidazole 10 (0.3 g, 0.1 mmol) and sodium methoxide
(0.13 g, 0.2 mmol) were heated at reflux in MeOH (30 mL) under an
atmosphere of argon for 23 h. MeOH was removed under reduced
pressure, the reaction mixture was poured onto water (50 mL) and
extracted with DCM (3ꢁ30 mL). The reaction mixture was dried
(MgSO4), solvent evaporated and recystallisation of the residue
4
4JFF 13.03), ꢀ79.47 (1F, d, JFF 12.80); dC 16.68 (s, CH3), 90.59 (dd,

528
M.W. Cartwright et al. / Tetrahedron 66 (2010) 519–529
4
2
4
3
4
2JCF 43.73, JCF 7.37, C-4), 112.17 (s, C-7), 124.83 (dd, JCF 32.60, JCF
H-8), 9.04 (1H, d, JHH 7.50, H-6); dF ꢀ77.25 (1F, d, JFF 13.17, F-1),
4
3.87, C-30d), 125.10 (s, C-6), 127.62 (s, C-9), 130.22 (s, C-8), 140.83
ꢀ85.60 (1F, d, JFF 13.17, F-3); dC 14.43 (s, CH3), 31.18 (s, CH3CO),
3
3
1
3
2
4
(dd, JCF 12.4, JCF 12.4, C-30d), 149.97 (dd, JC3F 248.82, JCF 16.30,
C-3), 150.61 (s, C-2a), 153.03 (dd, 1JCF 229.95, JCF 13.72, C-1); m/z
(EIþ) 219.0 ([M]þ, 100%).
97.46 (dd, JCF 31.66, JCF 8.55, C-4), 112.34 (s, C-7), 124.51 (s, C-6),
127.34 (dd, 2JCF 33.55, 4JCF 9.43, C-30d), 129.62 (s, C-8), 129.74 (s, C-
9), 135.68 (m, C-40d), 149.63 (dd, 1JCF 253.16, 3JCF 14.45, C-3), 149.90
(dd, 1JCF 233.99, JCF 13.82, C-1), 151.51 (s, C-2a), 207.24 (s, C]O);
3
4.5.2. 1,3-Difluoro-4,9-dimethyl-dipyrido[1,2-a;30,40-d]imidazole
23a. BuLi (0.139 g, 1.35 mL 1.6 M soln in hexanes, 2.17 mmol) was
added slowly to a stirred solution of 4-chloro-1,3-difluoro-9-
methyl-dipyrido[1,2-a;30,40-d]imidazole 10 (0.5 g,1.97 mmol) in dry
THF (50 mL) at ꢀ78 ꢂC. After stirring for 1 h, methyl iodide (0.31 g,
2.17 mmol) was added and the reaction mixture was left to stir for
72 h. The reaction mixture was concentrated under reduced pres-
sure, 1.0 M HCl (50 ml) was added and extracted with DCM
(3ꢁ50 mL). Drying (MgSO4), solvent evaporation and purification by
column chromatography on silica gel (6:1 n-hexane/ethyl acetate)
gave 1,3-difluoro-4,9-dimethyl-dipyrido[1,2-a;30,40-d]imidazole 23a
(0.272 g, 59%) as off-white crystals; mp 241.1–241.5 ꢂC; (Found: C,
61.5; H, 3.6; N, 17.9. C12H9F2N3 requires: C, 61.8; H, 3.9; N, 18.0%); dH
2.70 (3H, s, CH3), 2.71 (3H, s, CH3), 6.92 (1H, t, 3JHH 7.00, H-7), 7.36
(1H, d, 3JHH 7.00, H-8), 9.07 (1H, d, 3JHH 7.00, H-6); dF ꢀ80.87 (1F, 4JFF
13.17, F-1), 89.52 (1F, 4JFF 13.74, F-3); dC 16.58 (s, CH3), 17.72 (s, CH3),
97.54 (d, 2JCF 41.21, C-4),112.74 (s, C-7),124.23 (s, C-6),128.49 (d, 2JCF
33.61, C-30d),129.66 (s, C-8),129.87 (s, C-9),135.45 (m, C-40d),149.03
m/z (EIþ) 261.0 ([M]þ, 100%).
4.6. X-ray structures of 7a, 13a, 13b, 16b, 21e and 23a
Single crystal X-ray data for the structures were collected on
a Bruker Proteum-M (7a, 13b, 16b) and Bruker SMART CCD 6000
(13a, 21e, 23a) diffractometers equipped with Cryostream (Oxford
Cryosystems) nitrogen cooler at 120 K using graphite mono-
chromated MoKa radiation (
l¼0.71073 Å,
u
-scan, 0.3ꢂ/frame). All
structures were solved by direct method and refined by full-matrix
least squares on F2 for all data using SHELXTL software. All non-
hydrogen atoms were refined with anisotropic displacement pa-
rameters, H-atoms were located on the difference map and refined
isotropically. Crystallographic data for the structure have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publications CCDC 741321–741326.
4.6.1. Crystal data for 7a. C11H6F3N3, M¼237.19,orthorhombic,space
1
3
1
(s, C-2a), 151.85 (dd, JCF 251.37, JCF 13.19, C-3), 153.71 (dd, JCF
group
P
nma, a¼13.5814(7), b¼6.4202(3), c¼10.6503(5) Å,
223.27, 3JCF 13.92, C-1); m/z (EIþ) 233.0 ([M]þ, 100%).
U¼928.66(8) Å3, F(000)¼968, Z¼4, Dc¼1.696 mg mꢀ3
,
m¼0.148
mmꢀ1. 8647 reflections yielded1342 uniquedata (Rmerg¼0.046). Final
4.5.3. 4-Allyl-1,3-difluoro-9-methyl-dipyrido[1,2-a;30,40-d]imidazole
23b. BuLi (0.15 g, 1.48 mL 1.6 M soln in hexanes, 2.37 mmol) was
added slowly to a stirred solution of 4-chloro-1,3-difluoro-9-
methyl-dipyrido[1,2-a;30,40-d]imidazole 10 (0.5 g, 1.97 mmol) in
dry THF (50 mL) at ꢀ78 ꢂC. After stirring for 1 h, allyl bromide
(0.29 g, 2.37 mmol) was added and the reaction mixture was left to
stir for 20 h. The reaction mixture was evaporated under reduced
pressure, 1.0 M HCl (50 mL) was added and extracted with DCM
(3ꢁ50 mL). Drying (MgSO4), solvent evaporation and purification
by column chromatography on silica gel (6:1 n-hexane/ethyl ace-
tate) gave 4-allyl-1,3-difluoro-9-methyl-dipyrido[1,2-a;30,40-d]im-
idazole 23b (0.19 g, 37%) as a white solid; (Found: C, 65.2; H, 4.2; N,
16.0%. C14H11F2N3 requires: C, 64.9; H, 4.3; N, 16.2%); dH 2.68 (3H,
s, CH3), 3.03–3.12 (2H, m, CH2), 4.13 (1H, d, 3JHH 14.68, C]CH2), 4.49
(1H, d, 3JHH 9.09, C]CH23), 5.21–5.35 (1H, m,]C–H), 6.89 (1H, t, 3JHH
wR2(F2)¼0.1144 for all data (119 refined parameters), conventional
R1(F)¼0.0414 for 1016 reflections with Iꢃ2 , GOF¼0.955.
s
4.6.2. Crystal data for 13a. C17H11F2N3O2S, M¼359.35, monoclinic,
space group P 21/c, a¼14.3633(6), b¼10.1474(4), c¼10.2507(4) Å,
b
¼93.70(1)ꢂ, U¼1490.9(1) Å3, F(000)¼736, Z¼4, Dc¼1.601 mg mꢀ3
,
m
¼0.258 mmꢀ1
. 17242 reflections yielded 4146 unique data
(Rmerg¼0.0589). Final wR2(F2)¼0.1006 for all data (270 refined pa-
rameters), conventional R1(F)¼0.0360 for 3161 reflections with
Iꢃ2 , GOF¼0.995.
s
4.6.3. Crystal data for 13b. C17H11F2N3O2S, M¼359.35, triclinic,
space group P -1, a¼8.3285(3), b¼8.7801(3), c¼11.6055(4) Å,
a¼72.64(2),
b
¼82.70(2),
g
¼66.35(1)ꢂ, U¼741.92(4)Å3, F(000)¼368,
Z¼4, Dc¼1.609 mg mꢀ3
,
m
¼0.259 mmꢀ1. 7607 reflections yielded
3
7.00, H-7), 7.46 (1H, d, JHH, H-8), 9.05 (1H, d, JHH 7.00, H-6); dF
3971 unique data (Rmerg¼0.0327). Final wR2(F2)¼0.1205 for all data
(270 refined parameters), conventional R1(F)¼0.0469 for 3653 re-
4
4
ꢀ80.42 (1F, JFF 14.83, F-1),ꢀ87.48 (1F, JFF 14.48, F-3); dC 14.31
3
5
2
(s, CH3), 30.85 (dd, JCF 37.03, JCF 6.86, CH2), 97.62 (dd, JCF 33.67,
4JCF 8.35, C-4), 116.54 (s,]CH2), 112.36 (s, C-7), 122.08 (s, C-6),
124.43 (s, C-8), 126.85 (d, 2JCF 34.55, 4JCF 8.23, C-30d), 128.90 (d, 5JCF
5.45, C-9), 130.26 (m, C-40d), 133.42 (s,]CH), 143.48 (s, C-2a), 146
flections with Iꢃ2 , GOF¼1.078.
s
4.6.4. Crystal data for 16b. C18H14F2N4, M¼324.33, monoclinic,
space group P 21/n, a¼8.5739(2), b¼17.9700(4), c¼10.3211(2) Å,
(dd, 1JCF 253.13, JCF 14.63, C-3), 152.57 (dd, 1JCF 239.32, JCF 13.04,
b
¼110.42(1)ꢂ, U¼1490.25(6) Å3, F(000)¼672, Z¼4, Dc¼1.446
3
3
C-1); m/z (EIþ) 259.0 ([M]þ, 100%).
mg mꢀ3
,
m
¼0.107 mmꢀ1.13265 reflections yielded 4130 unique data
(Rmerg¼0.0296). Final wR2(F2)¼0.1153 for all data (273 refined pa-
4.5.4. 1-(1,3-Difluoro-9-methyl-dipyrido[1,2-a;30,40-d]imidazol-4-
yl)-ethanone 23c. BuLi (1.34 mL 1.6 M soln in hexanes, 2.20 mmol)
was added slowly to a stirred solution of 4-chloro-1,3-difluoro-
dipyrido[1,2-a;30,40-d]imidazole 10 (0.5062 g, 2.00 mmol) in dry
THF (50 mL) at ꢀ78 ꢂC. After stirring for 1 h, acetyl chloride (0.18 g,
2.4 mmol) was added and the reaction mixture was stirred for
a further 72 h. The reaction mixture was evaporated under reduced
pressure, 1.0 M HCl (50 mL) was added and the organic products
extracted with DCM (3ꢁ50 mL). Drying (MgSO4), solvent evapora-
tion and purification by column chromatography on silica gel (6:1
n-hexane/ethyl acetate) gave 1-(1,3-difluoro-9-methyl-dipyr-
ido[1,2-a;30,40-d]imidazol-4-yl)-ethanone 23c (0.323 g, 63%) as
a white solid; mp 223–225 ꢂC (Found: C, 59.7; H, 3.3; N, 15.9%.
C13H9F2N3O requires: C, 59.8; H, 3.5; N, 16.1 %); dH 2.15 (3H, s, CH3),
2.68 (3H, s, COCH3), 6.90 (1H, t, 3JHH 7.50, H-7), 7.34 (1H, d, 3JHH 7.50,
rameters), conventional R1(F)¼0.0454for 3632 reflectionswith Iꢃ2
s,
GOF¼1.052.
4.6.5. Crystal data for 21e. C17H11ClFN3S, M¼343.80, monoclinic,
space group P 21/c, a¼12.0775(4), b¼17.1203(5), c¼7.0518(2) Å,
b
¼93.06(2)ꢂ, U¼1456.02(8) Å3, F(000)¼704, Z¼4, Dc¼1.568
mg mꢀ3
,
m
¼0.418 mmꢀ1. 17174 reflections yielded 4234 unique data
(Rmerg¼0.0602). Final wR2(F2)¼0.0896 for all data (252 refined pa-
rameters), conventional R1(F)¼0.0379 for 2875 reflections with
Iꢃ2 , GOF¼0.988.
s
4.6.6. Crystal data for 23a. C12H9F2N3, M¼233.22, monoclinic,
space group P 21/n, a¼6.8959(3), b¼13.8687(5), c¼10.8782(4) Å,
b
¼107.05(1)ꢂ, U¼994.66(7) Å3, F(000)¼480, Z¼4, Dc¼1.557 mg mꢀ3
,
m
¼0.123 mmꢀ1
. 12194 reflections yielded 2904 unique data

M.W. Cartwright et al. / Tetrahedron 66 (2010) 519–529
529
(Rmerg¼0.0685). Final wR2(F2)¼0.0982 for all data (190 refined
parameters), conventional R1(F)¼0.0409 for 1865 reflections with
4. Sandford, G.; Slater, R.; Yufit, D. S.; Howard, J. A. K.; Vong, A. J. Org. Chem. 2005,
70, 7208–7216.
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s
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We thank EPSRC and GlaxoSmithKline Pharmaceuticals for
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Undergraduate Degree Programme for funding.
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References and notes
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