Synthesis of tetrahydropyrido- and pyrido-[1′,2′:1,2]imidazo[4, 5-b]pyrazine derivatives

Article abstract of DOI:10.1016/j.jfluchem.2010.03.010

Reactions of tetrafluoropyridazine with iminopiperidine and 2-aminopiccoline gave novel tetrahydropyrido- and pyrido-[1′,2′:1,2] imidazo[4,5-b]pyrazine heterocyclic frameworks respectively in high yields.

Full text of DOI:10.1016/j.jfluchem.2010.03.010

Journal of Fluorine Chemistry 131 (2010) 1086–1090
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of tetrahydropyrido- and pyrido-[10,20:1,2]imidazo[4,5-b]pyrazine
derivatives
Emma L. Parks a, Graham Sandford a, , Dmitrii S. Yufit a,b, Judith A.K. Howard a,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, Durham DH1 3LE, UK
c GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
A R T I C L E I N F O
A B S T R A C T
Article history:
Reactions of tetrafluoropyridazine with iminopiperidine and 2-aminopiccoline gave novel tetrahy-
dropyrido- and pyrido-[10,20:1,2]imidazo[4,5-b]pyrazine heterocyclic frameworks respectively in high
Received 25 January 2010
Received in revised form 12 March 2010
Accepted 18 March 2010
Available online 25 March 2010
yields.
ß 2010 Elsevier B.V. All rights reserved.
Keywords:
Heterocycle
Pyridazine
Perfluoroheteroaromatic
Scaffold
Nucleophilic aromatic substitution
1. Introduction
great extent and, consequently, the chemistry of such systems
remains relatively unexplored. Indeed, only a few reports of the
Heterocyclic compounds have, of course, found many applica-
tions in all parts of the chemical industry and significantly impact
on our daily lives as components of medicines, agrochemicals,
natural products and commodity chemicals [1]. Consequently,
there continues to be a demand for the development of effective
methodology for the synthesis of structurally new heterocyclic
architectures to unlock novel, valuable biological and physical
properties, in particular, in the pharmaceutical industry [2–4]. The
use of perfluoroheteroaromatic systems as precursors for the
synthesis of novel polyfunctional heterocycles is emerging and an
increasing variety of bi- and tricyclic heterocyclic structures that
bear a range of functionality have been synthesised in our
laboratories recently [5–10].
synthesis of a limited range of pyridoimidazopyrazine systems have
appeared in the literature. Heating 2-amino-pyrazine-4-oxide with
pyridineprovides access tothe non-functionalisedtricyclicsystem2
[11] whilst reaction of dichlorodicyanopyrazine with 2-aminopyr-
idine derivatives gives access to a range of dicyano-pyridoimida-
zopyrazine products [12] whose electrochemical and fluorescent
properties have been assessed [13]. However, these methods suffer
from low yields, difficulties in the synthesis of the starting materials
and do not permit the synthesis of pyridoimidazopyrazine
analogues bearing a wider range of functionality.
In this paper, we report synthetic methodology for the
preparation of pyridoimidazopyrazine systems from tetrafluor-
opyrazine. Reactions of tetrafluoropyrazine,
a perfluorinated
We were interested in expanding the use of perfluoroheteroaro-
matic derivatives as starting materials for the preparation of novel
heterocyclic molecular architectures and focused on the possibility
of synthesising derivatives of tetrahydropyrido- and pyrido-
[10,20:1,2]imidazo[4,5-b]pyrazine 1 and 2 respectively (Scheme 1).
Synthetic methodology for the preparation of tricyclic pyridoimi-
dazopyrazine derivatives 1 and 2 has not been developed to any
heteroaromatic system prepared by halogen exchange from the
corresponding tetrachloropyrazine and potassium fluoride [14],
with difunctional nucleophiles are rare and only a few examples of
annelation processes have been reported from our laboratories
previously [15].
2. Results and discussion
Tetrahydropyrido- and pyridoimidazolopyrazine scaffolds 3
and 4 were readily synthesised by heating tetrafluoropyrazine 5
with iminopiperidine 6 and 2-aminopicoline 7 respectively in
* Corresponding author. Tel.: +44 1913342039; fax: +44 1913844737.
E-mail address: Graham.Sandford@durham.ac.uk (G. Sandford).
0022-1139/$ – see front matter ß 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2010.03.010

E.L. Parks et al. / Journal of Fluorine Chemistry 131 (2010) 1086–1090
1087
Scheme 1. Tetrahydropyrido- and pyrido-[10,20:1,2]imidazo[4,5-b]pyrazine
frameworks 1 and 2.
Fig. 2. Molecular structure of N,N-diethyl-3-fluoro-6,7,8,9-tetrahydropyrido[10,20:1
˚
,2]imidazo-[4,5-b]pyrazin-2-amine 8. Selected bond distances (A): F1–C1 1.357(1);
N1–C1 1.300(1); N1–C4 1.348(1); N2–C3 1.331(1); N2–C2 1.342(1); N4–C4
1.377(1); N4–C5 1.326(1); N5–C2 1.376(1).
Reactions of 3 with diethylamine and sodium phenoxide gave 8,
whose structure was confirmed by X-ray crystallography (Fig. 2),
and 9 respectively, where fluorine located at the 3-position is
displaced selectively in both cases (Scheme 3).
In contrast, reaction of 4 with diethylamine gave a mixture of
products 10a and 10b in a 1:1 ratio by 19F NMR analysis of the
crude reaction mixture (Scheme 4). The structure of product 10a
was determined by X-ray crystallography (Fig. 3), confirming the
regiochemistry of the nucleophilic substitution processes.
The regioselectivity of the nucleophilic aromatic substitution
processes described above may be explained by a consideration of
the relative stabilities of the intermediate Meisenheimer com-
plexes (Scheme 5). Attack at the 3-position in 3 gives a more stable
Meisenheimer intermediate in which the negative charge may be
delocalised over both the conjugated 5- and 6-membered ring
systems whereas this is not possible for corresponding attack at
the 2-position.
Fig. 1. Molecular structure of 2,3-difluoro-6-methylpyrido[10,20:1,2]imidazo[4,5-
˚
b]pyrazine 4. Selected bond distances (A): F1–C1 1.347(2); F2–C2 1.348(2); N1–C1
1.293(2); N1–C8 1.346(2); N2–C2 1.295(2); N2–C9 1.328(2); N4–C8 1.355(2); N4–
C7 1.340(2).
acetonitrile in the presence of a base (Scheme 2). Both 3 and 4 were
readily purified by crystallisation of the crude product mixture and
the structures followed from NMR, mass spectrometry and
elemental analysis. Additionally, the structure of 4 was confirmed
by X-ray crystallography (Fig. 1).
Reactions of the tetrahydropyrido- and pyridoimidazolopyr-
azine scaffolds 3 and 4 with representative nitrogen and oxygen
centred nucleophiles were studied in order to provide an
indication of the reactivity of these systems towards nucleophilic
attack and to establish the regioselectivity of such processes.
The most likely explanation for the lack of regioselectivity of the
nucleophilic aromatic substitution reactions involving 4 as the
substrate involves the significant aromaticity of the pyrido ring
system in each Meisenheimer intermediate (Scheme 6).
Scheme 2. Synthesis of tetrahydropyrido- and pyridoimidazolopyrazine scaffolds 3 and 4.
Scheme 3. Reactions of scaffold 3 with nucleophiles.

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E.L. Parks et al. / Journal of Fluorine Chemistry 131 (2010) 1086–1090
Scheme 4. Reaction of scaffold 4 with diethylamine.
Scheme 5. Meisenheimer intermediates in the nucleophilic aromatic substitution of 3.
Scheme 6. Significant Meisenheimer intermediates in the nucleophilic aromatic substitution of 4.
Charge delocalisation over the whole of the tricyclic ring system
the charge may not be efficiently delocalised over the whole of the
tricyclic ring system in both cases and so a mixture of products is
obtained.
The structures 4, 8 and 10a provide examples of how relatively
minor changes in molecular shape affect molecular packing. As we
observed previously [10], highly fluorinated heterocycles have a
tendency to form anti-parallel stacks in the crystal and the
nitrogen atoms of these heterocycles usually act as acceptors in
intermolecular C–H. . .N interactions. Indeed, essentially planar
molecules such as 4 in the crystal are linked into corrugated
would break this aromaticity and so, in both cases, only
delocalisation of the negative charge around the pyrazine ring
occurs to any significant extent. Consequently, there is not a
pronounced difference in the stabilities of the intermediates
arising from nucleophilic attack at the 2- or 3-positions because
ribbons by double C–H. . .N contacts while
p. . .p interactions
between heterocycles bind the ribbons into the layers (Fig. 4a).
Substitution of one fluorine atom in 4 by an NEt2-group 10a leaves
the C–H. . .N intermolecular interactions intact and 10a forms
similar ribbons linked in pairs by
p. . .p interactions in the crystal.
However, the terminal methyl groups disturb the planarity of the
molecules producing layers of double ribbons arranged in a
herring-bone motif (Fig. 4b). Molecule 8 is not only even more non-
planar than molecule 10a, due to the presence of the tetrahy-
dropyridine ring, but also lacks aromatic hydrogen atoms. As a
result the packing of molecules of 8 in the crystal changes
dramatically and isolated anti-parallel dimers which are linked
together by a number of C(Me)–H. . .N contacts are observed in this
case (Fig. 4c).
Fig. 3. Molecular structure of N,N-diethyl-2-fluoro-6-methylpyrido[10,20:1,
˚
2]imidazo[4,5-b]pyrazin-3-amine 10a. Selected bond distances(A): F1–C2
1.349(2); N1–C1 1.339(2); N1–C9 1.330(2); N2–C2 1.294(2); N2–C3 1.348(2);
N3–C3 1.371(2); N3–C4 1.335(2); N5–C1 1.363(2).

E.L. Parks et al. / Journal of Fluorine Chemistry 131 (2010) 1086–1090
1089
singlet; d, doublet; m, multiplet), J coupling constant (Hz).
Elemental analyses were conducted on an Exeter Analytical Inc.
CE-440 elemental analyser. All infra-red spectra were recorded
using a FT-IR Perkin Elmer Spectrum RX1 machine. Mass spectra
were recorded on a Thermo-Finnigan Trace instrument coupled
with a Hewlett Packard 5890 series II Gas Chromatograph. Melting
points were measured using a Gallenkamp melting point appara-
tus recorded at atmospheric pressure and are uncorrected. The
progress of reactions was monitored by 19F NMR. Column
chromatography 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.
3.2. Annelation reactions
3.2.1. 2,3-Difluoro-5,6,7,8-tetrahydropyrido[10,20:1,2]imidazo[4,5-
b]pyrazine 3
A mixture of tetrafluoropyrazine (1.02 g, 6.7 mmol), 2-imino-
piperidine hydrochloride (1.33 g, 9.9 mmol) and sodium hydrogen
carbonate (3.31 g, 40 mmol) in acetonitrile (30 mL) was heated to
reflux for 5 d. After cooling to rt, the reaction solvent was
evaporated and water (40 mL) added. Extraction into DCM
(3 ꢀ 40 mL), drying (MgSO4), solvent evaporation and crystal-
lisation from DCM gave 2,3-difluoro-5,6,7,8-tetrahydropyri-
do[10,20:1,2]imidazo[4,5-b]pyrazine 3 (1.12 g, 79%) as a yellow
solid; mp 144–146 8C (found: [MH]+, 211.0792. C9H8F2N4 requires:
[MH]+, 211.0790);
dH 1.97 (2H, m, CH2), 2.05 (2H, m, CH2), 3.06 (2H,
m, CH2), 4.13 (2H, m, CH2); dC 19.9 (s, CH2), 21.9 (s, CH2), 26.1 (s,
CH2), 42.5 (s, C-5), 134.2 (d, 3JCF 10, C-9a), 140.3 (dd, 1JCF 210, 2JCF
33, C-2), 141.9 (dd, 1JCF 210, 2JCF 33, C-3), 142.1 (dd, 3JCF 12, 4JCF 4, C-
3
4a), 154.7 (s, C-8a); dF ꢁ98.41 (1F, d, JFF 25, F-2), ꢁ100.38 (1F, d,
3JFF 27, F-3); m/z (EI+) 210 ([M]+, 100%), 182 (68), 154 (30).
3.2.2. 2,3-Difluoro-8-methylpyrido[10,20:1,2]imidazo[4,5-b]pyrazine 4
A mixture of tetrafluoropyrazine (1.50 g, 10 mmol), 2-amino-3-
picoline (1.57 g, 15 mmol) and sodium hydrogen carbonate (3.32 g,
39 mmol) in THF (300 mL) was stirred at rt for 19 h. The reaction
solvent was evaporated and water (40 mL) added. Extraction into
ethyl acetate (3 ꢀ 40 mL), drying (MgSO4), solvent evaporation and
crystallisation from ethyl acetate gave 2,3-difluoro-8-methylpyr-
ido[10,20:1,2]imidazo[4,5-b]pyrazine 4 (1.04 g, 30%) as a brown solid;
mp 213–215 8C (found: C, 54.4; H, 2.7; N, 25.5. C10H6F2N4 requires:
C, 54.6;H, 2.8; N, 25.5%);
dH 2.57 (3H, s, CH3), 7.15 (1H, m, Ar-H), 7.61
(1H, m, Ar-H), 8.74 (1H, m, Ar-H);
dC (d6-DMSO) 18.5 (s, CH3), 117.9
(s, C-6), 122.0 (s, C-5), 129.0 (s, C-7), 129.1 (m, C-4a), 132.1 (s, C-8),
140.2 (dd, 1JCF 377, 2JCF 35, C-3), 143.9 (m, C-9a), 144.1 (dd, 1JCF 374,
2JCF 31,C-2), 151. 3(s, C-8a);dF ꢁ89.52(1F,d, 3JFF 27,F-2),ꢁ98.62(1F,
d, 3JFF 27, F-3); m/z (EI+) 220 ([M]+, 100%), 192 (6), 167 (2).
Fig. 4. (a) Corrugated layers in the structure 4. (b) Double ribbons in the structure
10a. (c) Dimers of molecules in the structure 8.
In summary, novel polyfluorinated imidazolopyrazine scaffolds
3 and 4 may be synthesised in a one-step procedure from
tetrafluoropyrazine providing further examples of annelation
processes utilising mono-cyclic perfluorinated heteroaromatic
systems as starting materials.
3.3. Reactions of scaffolds with nucleophiles
3.3.1. N,N-Diethyl-2-fluoro-5,6,7,8-
tetrahydropyrido[10,20:1,2]imidazo[4,5-b]pyrazin-3-amine 8
A mixture of 3 (0.30 g, 1.4 mmol) and diethylamine (0.63 g,
8.6 mmol) in acetonitrile (50 mL) was heated at reflux for 3 d. The
reaction solvent was evaporated and water (40 mL) added.
Extraction into ethyl acetate (3 ꢀ 40 mL), drying (MgSO4), solvent
evaporation and crystallisation from DCM gaveN,N-diethyl-2-fluoro-
3. Experimental
3.1. General
5,6,7,8-tetrahydropyrido[10,20:1,2]imidazo[4,5-b]pyrazin-3-amine
(0.26 g, 69%) as a yellow solid; mp 89–91 8C (found: C, 59.2; H,
6.9; N, 26.5. C13H18FN5 requires: C, 59.3; H, 6.9; N, 26.6%); H 1.15
(6H, t, 3JHH 7, CH3), 2.06 (4H, m, CH2), 3.00 (2H, m, CH2), 3.48 (4H, m,
CH2), 4.03 (2H, m, CH2); C 13.7 (s, CH3), 20.7 (s, CH2), 22.5 (s, CH2),
26.0 (s, CH2), 41.7 (s, C-5), 44.8 (d, 4JCF 5.7, NCH2), 135.5 (d, 3JCF 13.4,
8
All starting materials were obtained commercially. All solvents
were dried using literature procedures. NMR spectra were
recorded in deuteriochloroform, unless otherwise stated. 1H, 13C,
19F, HSQC, COSY and HMBC NMR spectra were recorded on Bruker
Avance-200, Varian-500 and Varian-700 spectrometers in the
solvent stated. The 1H NMR data were reported as follows:
d
d
2
1
C-9a), 136.0 (s, C-4a), 140.8 (d, JCF 13.4, C-3), 145.79 (d, JCF 247,
C-2), 151.03 (m, C-8a); dF ꢁ84.37 (s); m/z (ES+) 264 ([MH]+, 100%).
chemical shift (
d ppm), multiplicity (the peak integration; s,

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E.L. Parks et al. / Journal of Fluorine Chemistry 131 (2010) 1086–1090
3.3.2. 2-Fluoro-3-phenoxy-5,6,7,8-
solved by direct method and refined by full-matrix least squares on
F2 for all data using SHELXTL and Olex2 software. All non-hydrogen
non-disordered atoms were refined with anisotropic displacement
parameters, H-atoms were located on the difference map and
refined isotropically. The hydrogen atoms of disordered ethylene
group in molecule 8 were put in calculated positions and refined in
riding mode. Crystallographic data for the structures have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication CCDC-762827–762829.
tetrahydropyrido[10,20:1,2]imidazo[4,5-b]pyrazine 9
A mixture of 3 (0.30 g, 1.4 mmol) and sodium phenoxide
(0.63 g, 8.6 mmol) in acetonitrile (50 mL) was heated at reflux for
3 d. The reaction solvent was evaporated and water (40 mL) added.
Extraction into DCM (3 ꢀ 40 mL), drying (MgSO4), solvent eva-
poration and crystallisation from hexane gave 2-fluoro-3-phenoxy-
5,6,7,8-tetrahydropyrido[10,20:1,2]imidazo[4,5-b]pyrazine 9 (0.22 g,
54%) as a white solid; mp 108–110 8C (found: C, 63.2; H, 4.6; N,
19.6. C15H13FN4O requires: C, 63.4; H, 4.6; N, 19.7%);
m, CH2), 3.13 (2H, m, CH2), 4.04 (2H, m, CH2), 7.14–7.39 (5H, m, Ar-
H); C 20.8 (s, CH2), 22.6 (s, CH2), 26.5 (s, CH2), 42.7 (s, C-5), 120.6 (s,
C-20), 125.4 (s, C-40), 130.3 (s, C-30), 134.9 (d, 4JCF 2, C-4a), 140.9 (d,
3JCF 12, C-9a), 143.5 (d, 2JCF 30, C-3), 149.0 (d, 1JCF 247, C-2), 154.9 (s,
C-8a), 155.8 (d, 4JCF 2, C–O); dF ꢁ93.08 (s); m/z (EI+) 284 ([M]+, 90%),
255 (77), 206 (33).
d
H 2.07 (4H,
Crystal data for 4: C10H6F2N4, M = 220.19, monoclinic, space
˚
group
P
21/n, a = 11.0365(6), b = 7.0160(4), c = 13.1936(7) A,
3
˚
d
b
= 112.05(1)8,
U = 946.88(9) A ,
F(0 0 0) = 448,
Z = 4,
Dc = 1.545 mg mꢁ3
,
m
= 0.127 mmꢁ1. 9311 reflections were col-
lected yielding 2516 unique data (Rmerg = 0.059). Final wR2ðF2Þ ¼
0:0843 for all data (169 refined parameters), conventional
R(F) = 0.0380 for 1224 reflections with I ꢂ 2
s, GOF = 1.063.
Crystal data for 8: C13H18FN5, M = 263.32, monoclinic, space
3.3.3. N,N-Diethyl-2-fluoro-8-methylpyrido[10,20:1,2]imidazo[4,5-
b]pyrazin-3-amine 10a and N,N-diethyl-3-fluoro-8-
group
P
21/n, a = 11.2712(3), b = 7.6210(2), c = 14.9705(5) A,
˚
3
˚
b
= 96.87(1)8,
U = 1276.69(6) A ,
F(0 0 0) = 560,
Z = 4,
methylpyrido[1’,2’:1,2]imidazo[4,5-b]pyrazin-2-amine 10b
Dc = 1.370 mg mꢁ3
,
m
= 0.097 mmꢁ1. 16002 reflections were col-
A mixture of 4 (200 mg, 0.9 mmol), diethylamine (140 mg,
1.8 mmol) and DIPEA (376 mg, 2.7 mmol) in THF (50 mL) was
stirred at rt for 20 h and 19F NMR analysis showed 10a and 10b in a
1:1 ratio. The THF was evaporated and the residue partitioned
between DCM and brine. The organic layer was collected, dried
(MgSO4) and solvent evaporated to give a crude product (269 mg).
Mass-directed auto-preparative HPLC purification gave N,N-
diethyl-2-fluoro-8-methylpyrido[10,20:1,2]imidazo[4,5-b]pyrazin-3-
amine 10a (56 mg, 45%) as a brown solid; mp 146–147 8C (found:
C, 61.5; H, 5.9; N, 25.9. C14H16FN5 requires: C, 61.5; H, 5.9; N,
lected yielding 3559 unique data (Rmerg = 0.058). Final wR2ðF2Þ ¼
0:0984 for all data (253 refined parameters), conventional
R(F) = 0.0350 for 2921 reflections with I ꢂ 2
Crystal data for 10a: C14H16FN5, M = 273.32, orthorhombic,
space group P212121, a = 7.5730(2), b = 12.5894(3),
U = 1298.83(5) A , F(0 0 0) = 576, Z = 4,
= 0.099 mmꢁ1. 17010 reflections were col-
lected yielding 2081 unique data (Rmerg = 0.075). Final wR2ðF2Þ ¼
0:0934 for all data (245 refined parameters), conventional
s, GOF = 1.127.
3
˚
˚
c = 13.6232(3) A,
Dc = 1.398 mg mꢁ3
, m
R(F) = 0.0350 for 1860 reflections with I ꢂ 2
s, GOF = 1.102.
25.6%);
3JHH 6, CH2), 6.82 (1H, m, Ar-H), 7.18 (1H, m, Ar-H), 8.37 (1H, m, Ar-
H);
C 13.9 (s, CH3), 17.3 (s, CH3), 44.9 (d, 4JCF 6, CH2), 111.8 (s, C-6),
d
H 1.28 (6H, t, 3JHH 7, CH3), 2.67 (3H, s, CH3), 3.64 (4H, q,
Acknowledgements
d
121.1 (d, 3JCF 11, C-9a), 121.6 (s, C-5), 127.7 (s, C-7), 127.8 (s, C-8),
138.7 (d, 4JCF 6, C-4a), 143.6 (d, 1JCF 256, C-2), 144.7 (d, 2JCF 28, C-3),
145.9 (s, C-8a); dF ꢁ75.23 (s); m/z (ES+) 274 ([MH]+, 85%); and, N,N-
diethyl-3-fluoro-8-methylpyrido[10,20:1,2]imidazo[4,5-b]pyrazin-2-
amine 10b (34 mg, 27%) as a yellow solid; mp 158–159 8C (found:
C, 61.3; H, 5.9; N, 25.7. C14H16FN5 requires: C, 61.5; H, 5.9; N,
We thank EPSRC for funding and GlaxoSmithKline.
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3.4. X-ray crystallography
Single crystal X-ray data for compounds 4, 8 and 10a were
collected on a Bruker SMART-CCD 6000 diffractometer equipped
with Cryostream (Oxford Cryosystem) cooling device at 120.0 K (8
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a
radiation
[12] T. Suzuki, Y. Nagae, K. Mitsuhashi, J. Heterocycl. Chem. 23 (1986) 1419–1421.
[13] S. Iwata, K. Tanaka, J. Heterocycl. Chem. 35 (1998) 939–941.
[14] G.M. Brooke, J. Fluorine Chem. 86 (1997) 1–76.
[15] M.W. Cartwright, E.L. Parks, G. Pattison, R. Slater, G. Sandford, I. Wilson, D.S. Yufit,
J.A.K. Howard, J.A. Christopher, D.D. Miller, Tetrahedron 66 (2010) 3222–3227.
˚
(
l
= 0.71073 A). The data for the compound 4 were collected at
250 K due to a phase transition, which takes place at about 200 K
and proceeds with destruction of the crystal. All structures were