Polyfunctional tetrahydropyrido[2,3-b]pyrazine scaffolds from 4-phenylsulfonyl tetrafluoropyridine

Article abstract of DOI:10.1021/jo051453v

Polyfunctional tetrahydropyrido[2,3-b]pyrazine scaffolds can be synthesized by sequential reaction of pentafluoropyridine with sodium phenylsulfinate and an appropriate diamine. The polyfunctionality possessed by the difluorinated tetrahydropyrido[2,3-b]pyrazine scaffolds was demonstrated in selected model reactions with nucleophiles to give access to various polysubstituted [6,6]-ring fused systems.

Full text of DOI:10.1021/jo051453v

Polyfunctional Tetrahydropyrido[2,3-b]pyrazine Scaffolds from
4-Phenylsulfonyl Tetrafluoropyridine
Aurelie Baron,† Graham Sandford,*,† Rachel Slater,† Dmitry S. Yufit,‡
Judith A. K. Howard,‡ and Antonio Vong§
Department of Chemistry and Chemical Crystallography Group, University of Durham, South Road,
Durham, DH1 3LE, United Kingdom, and GlaxoSmithKline Pharmaceuticals,
New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, United Kingdom
graham.sandford@durham.ac.uk
Received July 14, 2005
Polyfunctional tetrahydropyrido[2,3-b]pyrazine scaffolds can be synthesized by sequential reaction
of pentafluoropyridine with sodium phenylsulfinate and an appropriate diamine. The polyfunc-
tionality possessed by the difluorinated tetrahydropyrido[2,3-b]pyrazine scaffolds was demonstrated
in selected model reactions with nucleophiles to give access to various polysubstituted [6,6]-ring
fused systems.
Introduction
to synthesize small, polyfunctional heteroaromatic sys-
tems from simple systems such as pyridine because of
the inherent low reactivity and low regioselectivity of
such species in functionalization processes.
Procedures for the efficient synthesis of low molecular
weight heterocyclic systems that possess several sites for
further functionalization are attracting great interest
from the life science industries that is due, in part, to
the large and growing number of valuable pharmaceuti-
cal agents that possess heterocyclic structural subunits.1-3
Consequently, demand for appropriate polyfunctional
heterocyclic scaffolds that may be utilized for the genera-
tion of libraries of analogues for biological screening and
subsequent hit-to-lead development is increasing. Het-
erocyclic scaffolds that possess new and unusual geom-
etry are of particular interest due to the possibilities for
increasing the molecular diversity of library and com-
pound collections4,5 used for the discovery of new biologi-
cally active chemical entities. However, it is very difficult
In a previous paper,6 we outlined our general approach
to the synthesis of polyfunctional, heterocyclic fused ring
systems and demonstrated the successful synthesis of
various model tetrahydropyrido[3,4-b]pyrazines from
pentafluoropyridine. Our approach relies upon the fact
that pentafluoropyridine 1 is a highly electron deficient
aromatic ring system due to the presence of the five
fluorine atoms attached to the ring carbon atoms. Con-
sequently, the fluorine atoms impart high reactivity of
the system toward nucleophiles7-9 such that a sequence
of nucleophilic aromatic substitution processes10 can be
carried out to provide access to polysubstituted bicyclic
nitrogen heterocycles 2 and 3 (Scheme 1).
* Corresponding author. Phone: 44-191-334-2039. Fax: 44-191-384-
4737.
† Department of Chemistry, University of Durham.
‡ Chemical Crystallography Group, University of Durham.
§ GlaxoSmithKline.
(5) Obrecht, D.; Villalgordo, J. M. Solid supported combinatorial and
parallel synthesis of small molecular weight compound libraries;
Pergamon: Oxford, 1998.
(6) Sandford, G.; Slater, R.; Yufit, D. S.; Howard, J. A. K.; Vong, A.
J. Org. Chem. 2005, 70, 7208.
(7) Chambers, R. D.; Sargent, C. R. Adv. Heterocycl. Chem. 1981,
28, 1.
(8) Brooke, G. M. J. Fluorine Chem. 1997, 86, 1.
(9) Chambers, R. D. Fluorine in Organic Chemistry; Blackwell:
Oxford, 2004.
(10) Chambers, R. D.; Hoskin, P. R.; Sandford, G.; Yufit, D. S.;
Howard, J. A. K. J. Chem. Soc., Perkin Trans 1 2001, 2788.
(1) Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic Chem-
istry; Pergamon Press: Oxford, 1984; Vol. Vols. 1-8.
(2) Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Hetero-
cycles in Life and Society; John Wiley and Sons: New York, 1997.
(3) Joule, J. A.; Mills, K. Heterocyclic Chemistry; Blackwell: Oxford,
2000.
(4) Gordon, E. M.; Kerwin, J. F. Combinatorial Chemistry and
Molecular Diversity in Drug Discovery; John Wiley and Sons: New
York, 1998.
10.1021/jo051453v CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/14/2005
J. Org. Chem. 2005, 70, 9377-9381
9377

Baron et al.
of 2,3-diamino pyridines with dicarbonyl systems11-13
(Hinsberg reaction), cyclizations involving appropriate
chloro-aminopyridine derivatives,14,15 or reduction16,17 of
polycyclic heteroaromatic precursors. In general, all these
reported synthetic procedures require multistep se-
quences where the synthesis of the appropriate function-
alized pyridine precursors can be very difficult indeed.
Further diversification of scaffolds is hindered by the low
reactivity of the largely unfunctional scaffolds that can
be accessed by such processes. In this paper, we describe
successful syntheses of model polysubstituted tetra-
hydropyrido[2,3-b]pyrazine scaffolds (5, Scheme 2) by
sequential reaction of 1 with appropriate bifunctional
nucleophiles.
SCHEME 1. Strategy for Polysubstituted
Tetrahydropyrido[3,4-b]pyrazine Synthesis
Initially, reaction of pentafluoropyridine 1 with a
bifunctional nucleophile (Nuc1-Nuc2) occurs at the most
activated 4-position followed by cyclization at the geo-
metrically accessible 3-position to give 2. Subsequent
reactions with nucleophiles (Nuc3, Nuc4) gave systems
such as 3a-c.
Results and Discussion
The first step of the strategy outlined in Scheme 2
requires the synthesis of 4-substituted tetrafluoro-
pyridines, and we initially chose to prepare the 4-phen-
ylsulfonyl derivative 9 (Nuc1 ) PhSO2) by reaction of
pentafluoropyridine 1 with sodium phenylsulfinate 8 in
DMF, following a literature procedure18 (Scheme 3). The
phenylsulfonyl group is a strong electron withdrawing
group that should help to maintain the reactivity of the
pyridine ring toward further nucleophilic substitution
processes, allowing annelation and further functional-
ization to proceed.
Before investigating annelation processes of 4-phenyl-
sulfonyl tetrafluoropyridine 9 (Nuc1 ) SO2Ph) with
difunctional nitrogen nucleophiles, we needed to establish
the effect of the 4-phenylsulfonyl substituent on the
reactivity and product profile of this pyridine system
toward further attack by aliphatic nitrogen nucleophiles.
Reaction of diethylamine, after reflux in acetonitrile, gave
a mixture of 10a, with no other momo-aminated products
observed, and two disubstituted systems 10b,c. Purifica-
To increase the molecular diversity4 of the scaffolds
that can be accessed by this approach, we sought to adapt
the strategy outlined in Scheme 1 to obtain polyfunctional
tetrahydropyrido[2,3-b]pyrazine scaffolds following a pro-
cess that is shown in Scheme 2. Here, pentafluoropyri-
dine 1 is first functionalized at the 4-position by reaction
with a mono-functional nucleophile (Nuc1) to give 4 before
annelation to 5 and further elaboration to 6. Initially,
we focused upon the synthesis of tetrahydropyrido-
[2,3-b]pyrazine scaffolds that we envisaged could be
prepared by reaction of 4 with appropriate diamines to
demonstrate the feasibility of this approach and compli-
ment our earlier studies.
Polyfunctional tetrahydropyrido[2,3-b]pyrazine deriva-
tives 7 are difficult to synthesize by conventional meth-
odology and have previously been prepared by reactions
SCHEME 2. Strategy for Polysubstituted Tetrahydropyrido[2,3-b]pyrazine Synthesis
SCHEME 3. Synthesis of 4-Phenylsulfonyl Tetrafluoropyridine and Reaction with Diethylamine
9378 J. Org. Chem., Vol. 70, No. 23, 2005

Tetrahydropyrido[2,3-b]pyrazine Scaffolds
TABLE 1. Synthesis of
tion of 10a was achieved by column chromatography,
while 10b,c could be identified by a combination of 19F
NMR and mass spectral data. The location of the dialky-
lamino substituent at the 2-position in 10a, rather than
the 3-position as in the other possible isomer 10d, is
confirmed by a consideration of 19F NMR chemical shifts.
For 10a, we would expect to observe one resonance at a
higher frequency (between -70 and -90 ppm), which can
be attributed to the fluorine atom located ortho to ring
nitrogen. In contrast, for isomer 10d, two such higher
frequency resonances would be expected, but this is not
the case for the product obtained. Disubstituted product
10c is readily identified by the observation of only one
fluorine resonance due to the symmetry of this system,
while 10b gives two fluorine resonances.
Tetrahydropyrido-[2,3b]-pyrazine Scaffolds
With this encouraging result in hand, we turned our
attention toward annelation reactions, and we found that
aliphatic diamines 11 react efficiently with 9 to give
tetrahydropyrido[2,3-b]pyrazine systems (Table 1). Bi-
functional nucleophiles 11a,b, where both nucleophilic
sites are primary amino groups, reacted efficiently with
9 to give high yields of ring fused systems 12a and 12b,
respectively. Purification of 12a was achieved by recrys-
tallization of the crude product mixture from dichloro-
methane, while 12b was purified by column chromatog-
raphy on silica gel, resulting in a lower isolated yield.
The reaction of 9 with an unsymmetrical diamine 11c
bearing both primary and secondary amino sites gave a
mixture of products 12c,d in the ratio of 4.3:1 by 19F NMR
analysis of the reaction mixture, arising from initial
attack of the secondary or primary amine sites at the
2-position of the pyridine ring and subsequent cyclization,
respectively. Identification of 12c followed from 19F NMR
analysis in which the resonance attributed to fluorine
located ortho to ring nitrogen had a chemical shift of
-95.4 ppm, similar to shifts observed for the dimethyl
derivatives 12g. The corresponding resonance for F-6 in
12d occurs at -108.2 ppm, similar to the analogous
system 12a in which F-6 is adjacent to the NH group
(-108.9 ppm). These structural assignments were con-
firmed by X-ray crystallography (see Supporting Infor-
mation for ORTEP diagrams and analysis). Given the
results shown in Scheme 3 (9-10a), the major product
12c is most likely formed from initial attack of the
secondary amine site, reflecting the higher nucleophilicity
of secondary amines over primary systems. Products 12e
and 12f were formed in essentially equal amounts
(1.3:1) upon reaction of 9 with diamine 11d, indicating
no significant difference in the reactivity of the nucleo-
philic sites. After repeated recrystallization from toluene,
a pure sample of 12f was isolated and identified by X-ray
crystallography (see Supporting Information).
SCHEME 4. Synthesis of [6,7]-Fused Ring System
The secondary amine, N,N′-dimethylethylenediamine
11e, gave 12g upon reaction with 9 in high yield (Table
1), and by an analogous procedure, the [6,7]-fused ring
system 14 was synthesized from 9 and the appropriate
1,3 diaminopropane 13 (Scheme 4).
With preparatively useful quantities of several tetra-
hydropyrido[2,3-b]pyrazine scaffolds in hand, we carried
out preliminary reactions of scaffolds 12a and 12g with
representative O, N, and S centered nucleophiles.
Both sodium methoxide and potassium phenoxide gave
mixtures of products arising from substitution of the
fluorine atom located adjacent to the pyridine ring
nitrogen and the phenylsulfonyl group, which could not
be separated satisfactorily. However, lithium diethyl-
amide and sodium thiophenoxide led to products 15 and
16, respectively, arising from substitution of the phenyl-
(11) Elliot, R. D.; Temple, C.; Montgomery, J. A. J. Org. Chem. 1966,
31, 1890.
(12) Abasolo, M. I.; Bianchi, D.; Atlasovich, F.; Gaozza, C.; Fernan-
dez, B. M. J. Heterocycl. Chem. 1990, 27, 157-162.
(13) Mederski, W. W. K. R.; Kux, D.; Knoth, M.; Schwarzkopf-
Hofmann, M. J. Heterocycles 2003, 60, 925.
(14) Couture, A.; Grandclaudon, P. Synthesis 1991, 11, 982-984.
(15) Savelli, F.; Boido, A. J. Heterocycl. Chem. 1992, 29, 529-533.
(16) Armand, J.; Boulares, L.; Bellec, C.; Pinson, J. Can. J. Chem.
1988, 66, 1500-1505.
(17) Cosmao, J. M.; Collignon, N.; Queguiner, G. Can. J. Chem.
1982, 60, 2785.
(18) Banks, R. E.; Haszeldine, R. N.; Legge, K. H.; Rickett, F. E. J.
Chem. Soc., Perkin Trans 1 1974, 2367.
J. Org. Chem, Vol. 70, No. 23, 2005 9379

Baron et al.
temperature, stirred with benzenesulfonic acid scavenger resin
(200 mg) for 6 h, dried (MgSO4), filtered, and evaporated to
give a yellow oil that consisted of three major components in
a ratio of 34:4:1 (0.58 g). Purification by column chromatog-
raphy on silica gel (5:1 hexane/ethyl acetate) gave N,N′-diethyl-
3,5,6-trifluoro-4-(phenylsulfonyl)pyridine-2-amine 10a (0.51 g,
38%) as a yellow oil; ([M + H]+ 345.0885, C15H15F3N2O2S
requires [M + H]+ 345.0879); 19F NMR δ: -88.55 (1F, dd, 3JFF
31.6, 5JFF 27.1), -134.06 (1F, dd, 3JFF 33.8, 4JFF 11.3), -156.72
(1F, dd, 4JFF 27.1, 5JFF 11.3); 1H NMR δ: 8.06 (2H, d, 3JHH 7.2),
SCHEME 5. Reactions of Scaffolds 12a,g with
Nucleophiles.
3
3
3
7.69 (1H, tm, JHH 7), 7.57 (2H, tm, JHH 7), 3.41 (4H, q, JHH
3
1
7), 1.14 (6H, t, JHH 7); 13C NMR δ: 145.36 (ddd, JCF 234.1,
4
1
2JCF 16.3, JCF 2.4), 142.79 (m), 140.78 (s), 139.34 (dm, JCF
265.3), 134.94 (s), 130.00 (m), 129.5 (dd, 1JCF 259.38, 2JCF 33.9),
129.70 (s), 128.39 (s), 44.7 (d, 4JCF 4.6), 13.7 (s); m/z (EI+) 344
([M]+, 53), 329 ([M - CH3]+, 100), 301 ([M - CH3CH2N]+, 76)
and traces of 3,6-difluoro-N,N,N′,N′-tetraethyl-4-(phenylsul-
fonyl)-pyridine-2,5-diamine 10b; 19F NMR δ: -73.33 (1F, d,
5JFF 33.8), -134.99 (1F, d, 5JFF 31.3); m/z (EI+) 397 ([M]+, 70),
382 ([M - CH3]+, 100), 368 ([M - CH3CH2]+, 33), 77 ([M-
C9H20N3F2SO2]+, 30) and 3,5-difluoro-N,N,N′,N′-tetraethyl-4-
(phenylsulfonyl)-pyridine-2,6-diamine 10c; 19F NMR δ: -152.61
(s); m/z (EI+) 397 ([M]+, 28), 382 ([M - CH3]+, 40), 368 ([M -
CH3CH2]+, 64), 77 ([M - C9H20N3F2SO2]+, 54).
Annelation ProcessessGeneral Procedure. Diamine 11
and sodium hydrogen carbonate were mixed in acetonitrile
under argon. Compound 9 was added, and the solution was
heated to reflux. The reaction mixture was cooled to room
temperature and evaporated, and the residue was taken into
dichloromethane. The solution was poured into 1 M hydro-
chloric acid (50 mL), extracted with dichloromethane (3 × 50
mL), and dried (MgSO4). Evaporation gave the crude material
that was dissolved in dichloromethane and filtered through
silica gel to remove the brown coloration. Evaporation left the
crude product, which was purified by recrystallization or
column chromatography on silica gel.
sulfonyl group that is, of course, a good leaving group
that is attached to a site para to the ring nitrogen that
is still activated toward nucleophilic attack. These results
are due to the soft nitrogen and sulfur nucleophiles
preferentially attacking softer C-S sites. Acetylation of
the pyrazine ring in 12a proceeds selectively at N-1 to
give 17, reflecting the greater nucleophilicity of this site
as compared to N-4.
Conclusions
6,7-Difluoro-8-phenylsulfonyl-1,2,3,4-tetrahydropyrido-
[2,3-b]pyrazine 12a. Ethylenediamine 11a (1.2 g, 20 mmol),
9 (2.91 g, 10 mmol), sodium hydrogen carbonate (3.36 g, 40
mmol), and acetonitrile (400 mL) gave an orange-yellow solid
that was recrystallized from dichloromethane to give 6,7-
difluoro-8-phenylsulfonyl-1,2,3,4-tetrahydropyrido[2,3-b]pyra-
zine 12a (2.87 g, 92%) as yellow crystals; mp 177.5-178.5°C;
found: C, 50.5; H, 3.5; N, 13.4. C13H11F2N3O2S requires: C,
50.2; H, 3. 6; N, 13.6%; 19F NMR δ: -108.93 (1F, d,3JFF 24.8),
-157.01 (1F, d, 3JFF 24.8); 1H NMR δ: 8.00 (2H, m), 7.66 (1H,
m), 7.55 (2H, m), 3.49 (4H, s); 13C NMR δ: 141.48 (s), 140.98
Tetrahydropyrido[2,3-b]pyrazine systems may be ac-
cessed very readily by reaction of 4-phenylsulfonyl tetra-
fluoropyridine with diamines, following the strategy
outlined in Scheme 2 (Nuc1 ) PhSO2 and Nuc2-Nuc3 )
diamine). Further reactions of these scaffolds with rep-
resentative nucleophiles proceed to give predominantly
substitution of the phenylsulfonyl group, providing access
to related functional [6,6]-fused ring systems.
1
2
3
4
(dd, JCF 225.8, JCF 16.8), 140.63 (dd, JCF 14.9, JCF 3.8),
134.36 (s), 132.27 (dd, 1JCF 249.3, 2JCF 29.7), 129.36 (s), 127.75
(dm, 3JCF 2.5), 127.40 (s), 116.65 (d, 2JCF 13.4), 39.17 (s), 39.01
(s); m/z (EI+) 311 ([M]+, 100), 168 ([M - H2SO2Ph]+, 84), 77
([M - C7H6N3SO2F2]+), 62).
Experimental Procedures
Synthesis of 4-Benzenesulfonyl-2,3,5,6-tetrafluoro-
pyridine 9. Pentafluoropyridine 1 (5.34 g, 31.6 mmol) was
added to a solution of phenylsulfinic acid sodium salt 8 (4.99
g, 30.4 mmol) in DMF (25 mL) under argon. The reaction
mixture was heated to reflux for 22 h, after which time 19F
NMR indicated 100% conversion of starting material. The
reaction mixture was cooled to room temperature and poured
into water (250 mL), and the precipitate was isolated by
filtration. Recrystallization from ethanol gave 4-benzenesulfo-
nyl-2,3,5,6-tetrafluoropyridine18 9 (2.84 g, 89%) as beige
crystals; mp 148.0-149.0 °C; found: C, 45.6; H, 1.8; N, 4.9;
C11H5F4NO2S requires: C, 45.4; H, 1.7; N, 4.8%; 19F NMR δ:
-86.19 (2F, m), -137.48 (2F, m); 1H NMR δ: 8.12 (2H, m),
7.78 (1H, m), 7.65 (2H, m); 13C NMR δ: 144.3 (dm, 1JCF 198.4),
139.4 (s), 138.9 (dm, 1JCF 188.5), 136.0 (s), 133.3 (t, 2JCF 10.7),
130.2 (s), 128.7 (s); m/z (EI+) 291 ([M]+, 80), 141 ([M - C5F4N]+,
88), 77 ([M - C5F4NSO2]+, 100).
Phenyl 6,7-Difluoro-1,4-dimethyl-1,2,3,4-tetrahydro-
pyrido[2,3-b]pyrazine-8-sulfinate 12g. N,N′-Dimethyleth-
ylenediamine 11e (0.58 g, 6.70 mmol), 9 (1.0 g, 3.44 mmol),
sodium hydrogen carbonate (1.15 g, 13.75 mmol), and aceto-
nitrile (200 mL) gave an orange solid (1.7 g). Purification by
recrystallization from n-hexane gave phenyl 6,7-difluoro-1,4-
dimethyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-8-sulfinate 12g
(0.75 g, 65%) as yellow-orange light sensitive crystals; mp
∼160°C (dec.); ([M + H]+ 340.0928, C15H16F2N3SO2 requires
3
[M + H]+ 340.0926); 19F NMR δ: -95.57 (1F, d, JFF 27),
3
1
-157.04 (1F, d, JFF 27); H NMR δ: 7.95 (2H, m), 7.60 (1H,
m), 7.49 (2H, m), 3.35 (2H, m), 3.06 (3H, s), 2.92 (3H, s), 2.77
(2H, m); 13C NMR δ: 146.3 (dd, JCF 231.0, JCF 16.7), 146.2
1
2
3
1
2
(d, JCF 13.7), 142.2 (s), 133.8 (s), 132.1 (dd, JCF 253.1, JCF
3
31.7), 131.1 (d, JCF 10.5), 128.7 (s), 127.9 (s), 126.9 (m), 47.1
Reactions of 4-Benzenesulfonyl-2,3,5,6-tetrafluoro-
pyridine 9 with Diethylamine. Diethylamine (0.29 g, 4.0
mmol) and sodium carbonate (0.34 g, 4.0 mmol) were added
to acetonitrile (150 mL) under argon. Compound 9 (1.16 g, 4.0
mmol) was added, and the resulting solution was heated to
reflux for 3 days. The reaction mixture was cooled to room
(s), 47.0 (s), 43.4 (s), 37.0 (s); m/z (EI+) 339 ([M]+, 100), 198
([M - SO2Ph]+, 16).
9-Benzenesulfonyl-7,8-difluoro-1,5-dimethyl-2,3,4,5-
tetrahydro-1H-pyrido[3,4-b][1,4]diazepine 14. N,N′-Di-
methylpropane-1,3-diamine 13 (2.04 g, 20 mmol), 9 (2.91 g,
9380 J. Org. Chem., Vol. 70, No. 23, 2005

Tetrahydropyrido[2,3-b]pyrazine Scaffolds
10 mmol), sodium hydrogen carbonate (3.36 g, 40 mmol), and
acetonitrile (400 mL) gave a brown-yellow oil. Purification
by column chromatography on silica gel (5:1 n-hexane/ethyl
acetate) gave 9-benzenesulfonyl-7,8-difluoro-1,5-dimethyl-
2,3,4,5-tetrahydro-1H-pyrido[3,4-b][1,4]diazepine 14 (2.19 g,
62%) as yellow crystals; mp 133.0-135.0°C; found: C, 54.1;
H, 4.9; N, 11.6. C13H11F2N3O2S requires: C, 54.4; H, 4.8; N,
11.9%; 19F NMR δ: -89.87 (1F, d,3JFF 24.3), -152.62 (1F, d,
evaporated to give crude material as a yellow-green oil.
Column chromatography on silica gel (4:1 n-hexane/ethyl
acetate) gave 6,7-difluoro-8-phenylsulfanyl-1,2,3,4-tetrahydro-
pyrido[2,3-b]pyrazine 16 (0.19 g, 13%) as yellow-orange
crystals. mp 148-149°C; found: C, 55.8; H, 4.1; N, 14.7.
C13H11F2N3S requires: C, 55.9; H, 4.0; N, 15.0%; 19F NMR δ:
-106.13 (1F, d,3JFF 24.8), -153.57 (1F, d, 3JFF 24.8); 1H NMR
δ: 7.34-7.15 (5H, m), 4.99 (1H, br s), 4.68 (1H, br s), 3.51
1
3
3JFF 24.3); H NMR δ: 7.89 (2H, m), 7.58 (1H, m), 7.51 (2H,
(1H, m), 3.50 (1H, d, JHH 3.4), 3.38 (1H, m); 13C NMR δ:
m), 3.05 (2H, m), 2.90 (3H, s), 2.55 (3H, s), 2.22 (2H, m), 1.72
142.22 (dd, 1JCF 227, 2JCF 17.2), 139.18 (dd, 3JCF 13.8, 4JCF 3.0),
3
1
1
2
(2H, m); 13C NMR δ: 154.80 (dm, JCF 10.8), 146.92 (dd, JCF
137.08 (dd, JCF 242, JCF 27.4), 133.43 (s), 129.44 (s), 128.95
(dd, 3JCF 4.48, 4JCF 1.86), 127.82 (s), 126.78 (s), 112.77 (d, 2JCF
17.7), 40.25 (s), 39.68 (s); m/z (EI+) 279 ([M]+, 100), 200 ([M -
C6H5H2]+, 28) and a mixture of two other products that could
not be identified.
236.5, JCF 16.8), 142.81 (s), 138.45 (dd, JCF 4.2,3JCF 3.0),
2
2
1
2
3
133.92 (dd, JCF 264.5, JCF 33.0), 133.28 (s), 131.05 (dd, JCF
5.8,4JCF 3.5), 128.711 (s), 127.43 (s), 57.37 (s), 50.00 (s), 41.70
(s), 41.12 (s), 24.80 (s); m/z (EI+) 353 ([M]+, 100), 324 ([M -
NCH3]+, 89), 182 ([M - HSO2Ph]+, 91).
4-Acetyl-6,7-difluoro-8-(phenylsulfonyl)-1,2,3,4-tetra-
hydropyrido[2,3-b]pyrazine 17. Acetic anhydride (0.06 g,
0.60 mmol) was added to a solution of 12a (0.09 g, 0.30 mmol)
in acetic acid (50 mL), and the reaction mixture was stirred
at room temperature for 5 h before heating to reflux for 24 h.
The reaction mixture was cooled to room temperature, poured
into water (30 mL), extracted with dichloromethane (100 mL),
dried (MgSO4), and evaporated to give crude product as a
brown oil (0.12 g). Purification by mass directed automated
preparative HPLC (30-85% acetonitrile in formic acid) gave
4-acetyl-6,7-difluoro-8-(phenylsulfonyl)-1,2,3,4-tetrahydro-
pyrido[2,3-b]pyrazine 17 (0.07 g, 66%) as a yellow oil; ([M -
H]+ 352.0567, C13H20N4F2 requires [M - H]+ 352.0566); 19F
NMR δ: -104.66 (1F, d, 3JFF 26.3), -140.85 (1F, dd, 3JFF 26.3);
1H NMR δ: 8.04 (2H, dm, 3JHH 8.4), 7.72 (1H, tt, 3JHH 7.2, 4JHH
Reactions of Scaffolds with Nucleophiles. N,N-Dieth-
yl-6,7-difluoro-1,4-dimethyl-1,2,3,4-tetrahydropyrido[2,3-
b]pyrazin-8-amine 15. Butyllithium (0.47 mL, 1.18 mmol,
2.5 M in THF) was added to a solution of diethylamine (0.086
g, 1.18 mmol) in cold (-78 °C) THF (25 mL). The solution was
stirred at -78 °C for 1 h before warming to room temperature
and the addition of 12g (0.20 g, 0.59 mmol). The reaction
mixture was heated to reflux for 2 days after which time 19F
NMR indicated 100% conversion of the starting material. The
reaction mixture was cooled to room temperature, the solvent
was evaporated, and the residue was redissolved in dichlo-
romethane, poured onto water (50 mL), extracted with dichlo-
romethane (100 mL), and dried (MgSO4). The solvent was
evaporated to give crude product as a brown-yellow oil (0.87
g). Purification by column chromatography on silica gel (2:1
n-hexane/ethyl acetate) gave N,N-diethyl-6,7-difluoro-1,4-di-
methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-8-amine 15 (0.02
g, 13%) as a yellow oil; ([M + H]+ 271.1728, C13H20N4F2
3
3
1.2), 7.60 (2H, tm, JHH 8.4), 7.42 (1H, br s), 3.95 (2H, t, JHH
4.8), 3.52 (2H, m), 2.42 (3H, s); 13C NMR δ: 169.7 (s), 140.7
(s), 139.0 (dd, 1JCF 230.7, 2JCF 17.5), 138.9 (dd, 1JCF 263.0, 2JCF
3
4
3
30.4), 134.8 (s), 131.2 (dd, JCF 4.2, JCF 1.2), 130.7 (dd, JCF
3
requires [M + H]+ 271.1729); 19F NMR δ: -99.24 (1F, d, JFF
4
2
12.0, JCF 5.0), 129.5 (s), 127.5 (s), 119.3 (d, JCF 12.0), 41.0
(s), 36.7 (s), 24.5 (s,); m/z (EI+) 352 ([M - H]+, 100), 309 ([M
-HCOCH3]+, 92).
27.4), -168.29 (1F, d, 3JFF 27.3); 1H NMR δ: 3.26 (4H, qd, 3JHH
5
7.0, JHF 1.5), 3.17 (2H, m), 2.97 (3H, s), 2.96 (2H, m), 2.56
(3H, s), 0.98 (6H, t, 3JHH 7.5); 13C NMR δ: 145.7 (dd, 1JCF 224.6,
2JCF 15.3), 143.7 (d, 3JCF 16.8), 139.6 (m), 132.6 (dd, 1JCF 240.0,
Acknowledgment. We thank GlaxoSmithKline plc/
EPSRC (Industrial CASE Studentship to R.S.) and the
European Union ERASMUS Scheme for funding this
work, Dr. Paul W. Smith (GSK) for helpful discussions,
and Dr. Mark B. Vine (GSK) for the assignment of NMR
data.
3
4
2JCF 29.1), 120.4 (d, JCF 4.8), 47.5 (s), 43.6 (d, JCF 4.8), 42.0
(s), 40.5 (s), 35.9 (s), 12.3 (s); m/z (EI)+ 270 ([M]+, 100), 255
([M - CH3]+, 16), 241 ([M - CH2CH3]+, 26), 226 ([M - (CH3)2-
CH2]+, 52), 211 ([M - (CH3)3CH2]+, 70).
6,7-Difluoro-8-phenylsulfanyl-1,2,3,4-tetrahydro-pyrido-
[2,3-b]pyrazine 16. Sodium hydride (0.48 g, 20 mmol) was
added to a solution of benzenethiol (2.20 g, 20 mmol) in
tetrahydrofuran (40 mL) under argon. After hydrogen gas
evolution had subsided, 12a (1.56 g, 5 mmol) was added, and
the solution heated to reflux until 19F NMR indicated 100%
conversion. The reaction mixture was cooled to room temper-
ature, poured into water (20 mL), extracted with dichlo-
romethane (3 × 20 mL), and dried (MgSO4). The solvent was
Supporting Information Available: Representative NMR
spectra of all compounds and X-ray CIF files for those given
in the text. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO051453V
J. Org. Chem, Vol. 70, No. 23, 2005 9381