Annelation of perfluorinated heteroaromatic systems by 1,3-dicarbonyl derivatives

Article abstract of DOI:10.1016/j.tet.2010.02.083

Reactions of various perfluorinated heteroaromatic substrates such as tetrafluoro-4-cyanopyridine, tetrafluoropyrazine and tetrafluoropyridazine with 1,3-dicarbonyl systems gave corresponding [5,6]-ring fused furo derivatives. Subsequent reactions of the

Full text of DOI:10.1016/j.tet.2010.02.083

Tetrahedron 66 (2010) 3222–3227
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Annelation of perfluorinated heteroaromatic systems by 1,3-dicarbonyl
derivatives
,
Matthew W. Cartwright a, Emma L. Parks a, Graham Pattison a, Rachel Slater a, Graham Sandford a
,
*
Ian Wilson a, Dmitrii S. Yufit b, Judith A.K. Howard b, John A. Christopher c, David D. Miller c
a Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK
b Chemical Crystallography Group, Department of Chemistry, University of Durham, 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 various perfluorinated heteroaromatic substrates such as tetrafluoro-4-cyanopyridine,
tetrafluoropyrazine and tetrafluoropyridazine with 1,3-dicarbonyl systems gave corresponding [5,6]-
ring fused furo derivatives. Subsequent reactions of the [5,6] bicyclic scaffolds with nucleophiles gave
some highly functionalised heteroaromatic systems.
Received 9 November 2009
Received in revised form 1 February 2010
Accepted 22 February 2010
Available online 25 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
selectively at the 4-position as this site is most activated towards
nucleophilic attack13 and subsequent cyclisation onto the less ac-
Heterocyclic chemistry is, of course, of central importance to
the pharmaceutical industry and the majority of commercially
important life-science products contain at least one heterocyclic
sub-unit within their structures.1,2 Functional heterocycles gen-
erally possess drug-like properties, such as a useful solubility
profile, and their rigid structures may be accommodated by a wide
variety of receptors leading to valuable biological activity. In order
to further explore chemical space available for pharmaceutical
applications, there is a continued demand for the development of
new heterocyclic core scaffolds that have novel structures and bear
functionality that may be readily transformed into focused li-
braries of analogues for bioassay and subsequent hit-to-lead me-
dicinal chemistry development.
tivated but geometrically accessible 3-position occurs to furnish
the ring fused products 2, which may react further to give func-
tionalised systems 3. We have developed analogous procedures for
the synthesis of ring fused systems from tetrafluoropyridine de-
rivatives,12 tetrafluoropyridazine14 and trifluoropyridazinone15,16
providing an indication of the large range of synthetic opportu-
nities that this strategy offers.
F
Nuc1
Nuc1
F
F
F
F
F
F
Nuc2
F
F
Nuc2
Nuc4
Nuc3
Nuc4
Nuc1 Nuc2
N
N
2
Nuc3
N
1
3
In a developing research programme, we have been exploring
the chemistry of highly fluorinated heteroaromatic systems for the
synthesis of a range of polyfunctional heterocyclic derivatives such
as macrocycles,3,4 glycosyl donors5 and fluorinating agents.6 In the
context of polyfunctional heterocyclic synthesis for drug discov-
ery7 we have established that perfluoroheteroaromatic systems
such as pentafluoropyridine may be used as core scaffolds for the
synthesis of a range of highly functionalised heteroaromatic and
ring fused polycyclic systems.7–12 For example, reaction of penta-
fluoropyridine with various difunctional nucleophiles has pro-
vided rapid access to various [5,6]- and [6,6]-ring fused systems8,11
as shown in Scheme 1. Reactions of pentafluoropyridine 1 occur
Me
Me
Ph
N
N
N
N
F
N
F
N
N
Me
Me
NH
F
F
MeO
OEt
MeO
N
N
N
Ph
3c
3a
3b
Scheme 1. Polyfunctional scaffolds from pentafluoropyridine 1.
Our next goal was to expand the range of polycyclic scaffolds
that could be accessed by this approach using difunctional
nucleophiles derived from 1,3-dicarbonyl systems (Scheme 2),
which would, in principle, provide bicyclic systems incorporating
a furan ring.
* Corresponding author. Tel.: þ44 191 334 2039; fax: þ44 191 384 4737.
E-mail address: graham.sandford@durham.ac.uk (G. Sandford).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.083

M.W. Cartwright et al. / Tetrahedron 66 (2010) 3222–3227
3223
OH
O
R2
O
O
F
O
O
O
O
O
O
F
F
F
F
F
F
OEt
F
R1
NaH, THF
base
+
+
F
F
6a, 8%
+
OEt
OEt
R1
R2
reflux, 70 h
N
1
F
5a
N
F
Perfluoroheteroaromatic
substrate
CN
CN
CO2Et
F
F
F
F
F
F
NaH, THF
rt, 1 h
6b
, 31%
R2
O
R2
O
N
O
N
O
5a
4a
R1
CN
CN
R1
CO2Et
Ph
OH
F
F
F
F
F
O
O
F
F
NaH, THF
rt, 1 h
+
6c, 59%
Ph
OEt
O
N
N
4a
5b
O
OEt
Perfluoroheteroaromatic
substrate
F
F
N
F
O
O
F
N
N
NaH, THF
reflux, 1 d
6d
, 71%
+
+
OEt
F
CN
N
F
O
N
4b
F
F
F
5a
F
F
F
F
F
N
N
F
F
F
F
F
O
NEt2
N
F
F
N
F
F
O
O
O
O
F
F
N
N
F
N
F
NaH, THF
reflux, 1 d
F
N
F
6e
, 60%
NEt2
O
N
4b
F
= predicted sites of nucleophilic displacements
5c
Scheme 2. Synthetic strategy for [5,6]-ring fused heterocyclic synthesis.
F
EtO2C
F
F
F
DIPEA, THF
rt, 4 d
O
6f
, 40%
F
+
N
OEt
Facile routes to, for example, functionalised furo[2,3-b]pyridines
are highly sought after because such compounds are useful in the
search for pharmacologically active substances and are also parent
systems for naturally occurring products such as furoquinolines
and pterocarpans.17
In this paper, we describe reactions between a variety of appro-
priate highly fluorinated heteroaromatic derivatives and represen-
tative 1,3-dicarbonyl substrates.
N
4c
N
N
F
5a
F
O
F
F
F
CO2Et
O
O
NaH, THF
reflux, 4 h
N
6g, 87%
O
N
+
N
N
OEt
O
O
5a
O
4d
2. Results and discussion
Scheme 3. Reactions of perfluoroheteroaromatic derivatives with 1,3-dicarbonyl
systems.
Reactions between a variety of perfluoroheteroaromatic de-
rivatives 1, 4a–d and representative 1,3-dicarbonyl substrates 5a–c
are collated in Scheme 3.
Reaction of ethyl acetoacetate 5a with pentafluoropyridine 1
gave 6a arising from substitution of fluorine at the 4-position but
no cyclised product was observed even when strong bases such as
LDA were added to the reaction mixture. Compound 6a exists ex-
clusively as the enol form in solution as determined by 1H NMR
spectroscopy in which the hydroxyl resonance occurs at 13.5 ppm
whereas no R3C–H resonance is observed. 19F NMR analysis of the
reaction mixture showed that the reaction gave 6a in high yield but
difficulties in purification led to a very low isolated yield.
Tetrafluorocyanopyridine 4a reacts with ethyl acetoacetate 5a
and 3-oxo-3-phenyl-propionic acid ethyl ester 5b to give the [5,6]-
ring fused systems 6b and 6c, respectively, in moderate yield and
the structure of 6b was confirmed by X-ray crystallography (Fig. 1).
The structure of 6b indicates that the carbon nucleophile attacks the
3-position of the pyridine ring, which is strongly activated by the
cyano group at the adjacent 4-position, as the first step of this pro-
cess. The annelation step could, in principle, provide two products
depending upon the site of ring closure whereby the oxygen
nucleophile could attack the carbon atom of the cyano group in
a process that is reminiscent of our earlier syntheses of pyrimidino-
pyridine systems11 but, in this case, reaction occurs selectively at the
2-position to give 6b. This regioselectivity reflects the attack of
a ‘hard’ oxygennucleophile at a‘hard’electrophilic siterather than at
the relatively softer carbon centre of the cyano group and the for-
mation of an aromatic furan ring being more favourable.
Figure 1. Molecular structure of 6b.
The structures of 6d and 6e, derived from reaction of tetra-
fluoropyrazine 4b, were confirmed by X-ray crystallography (Fig. 2).
Reaction of tetrafluoropyridazine 4c with 5a gave 6f arising
from attack of the dinucleophilic species at the 4- and 5-positions,
consistent with the regioselectivity of nucleophilic aromatic

3224
M.W. Cartwright et al. / Tetrahedron 66 (2010) 3222–3227
Figure 3. Molecular structure of 6g.
CN
CN
CO2Et
CO2Et
(i) Et2NH, n-BuLi,
THF, -78 oC,
(ii) rt, 2 d
F
F
7, 48%
8, 89%
O
O
F
N
Et2N
N
6b
O
O
OEt
OEt
OEt
NEt2
F
N
F
F
N
N
MeONa, MeOH
rt, 1 d
O
O
MeO
N
Figure 2. Molecular structures of 6d (above) and 6e (below).
6d
O
O
OEt
F
F
N
N
F
N
N
substitution reactions established previously.13 Protected pyr-
idazinone 4d gave 6g following a similar reactivity profile to that
established previously in which the 4-position is the site of initial
nucleophilic substitution. The structure of 6g was confirmed by X-
ray crystallography (Fig. 3).
Et2NH, MeCN
reflux, 1 d
9, 95%
O
O
Et2N
6d
O
O
NEt2
Each furo-fused ring system 6 possesses at least one fluorine
atom attached to carbon that is activated towards nucleophilic at-
tack and so we carried out reactions of representative annelated
systems 6b,d,e to provide an indication as to whether these sys-
tems could be utilised as scaffolds for array synthesis. Reactions of
fused ring systems 6b,d,e with representative nitrogen and oxygen
nucleophiles are shown in Scheme 4.
Reaction of 6b with lithium diethylamide gave 7, the position of
attack determined by a consideration of 19F NMR data, in which one
resonance was observed at ꢀ131.4 ppm consistent with fluorine
located meta to ring nitrogen.
F
N
N
F
F
N
N
Et2NH, MeCN
reflux, 1 d
10, 95%
O
O
Et2N
6e
Scheme 4. Reactions of ring fused scaffolds with nucleophiles.
Reaction of nucleophiles at C-3 gives the more stable Mei-
senheimer intermediate in which the negative charge may be
delocalised over both ring systems whereas this is not the case for
attack of the nucleophile at C-2, leading to substitution at C-3.
Furo[2,3-b]pyrazine 6d gave products 8 and 9 arising from the
substitution of the fluorine atoms located para to the furan ring
carbon–carbon double bond upon reaction with sodium methoxide
and diethylamine, respectively. Similarly, reaction of 6e with
diethylamine gave 10. The regioselectivity of these processes may
be explained by a consideration of the stability of the Mei-
senheimer intermediates (Scheme 5).
3. Conclusions
Various [5,6]-ring fused furo-pyridine, pyrazine and pyridazine
systems were synthesised by reaction of appropriate perfluorinated
heteroaromatic substrates and 1,3-dicarbonyl derivatives providing
a further illustration of the synthetic possibilities for heterocyclic

M.W. Cartwright et al. / Tetrahedron 66 (2010) 3222–3227
3225
R1
R1
R1
F
N
N
F
N
N
F
F
N
N
Nuc
R2
R2
R2
Attack at C-3
Nuc
Nuc
O
O
O
F
F
R1 = CO2Et
R2 = CH3
R1
R1
F
N
N
F
N
N
R2
R2
Nuc
Nuc
O
O
F
F
R1
R1
R1
Nuc
Nuc
F
F
N
N
N
Nuc
R2
Attack at C-2
F
F
R2
F
F
R2
O
N
O
O
N
N
Scheme 5. Mechanism of nucleophilic substitution for furo-pyrazine derivatives.
1
synthesis using highly fluorinated heterocyclic starting materials.
Regioselective functionalisations of the bicyclic systems were car-
ried out and these give a further indication of the use of highly
fluorinated scaffolds for analogue synthesis.
3/C-5), 143.6 (dm, JCF 245.4, C-2/C-6), 170.0 (COHCH3), 177.8 (s,
C]O); dF ꢀ91.70 (2F, m, F-2), ꢀ140.12 (2F, m, F-3); m/z (EIþ) 279
([M]þ, 78%), 43 (100%).
4.2.2. Ethyl
4-cyano-5,6-difluoro-2-methylfuro[2,3-b]pyridine-3-
4. Experimental
4.1. General
carboxylate 6b. Ethyl acetoacetate 5a (0.74 g, 5.68 mmol) and so-
dium hydride (0.27 g, 6.82 mmol, 60% dispersion in mineral oil)
were added to dry THF (50 mL) under argon and stirred at rt for 1 h.
2,3,5,6-Tetrafluoro-4-pyridinecarbonitrile 4a (1.0 g, 5.68 mmol)
was added and the reaction mixture heated to reflux for 1 d. The
reaction mixture was cooled, solvent evaporated and the residue
redissolved in dichloromethane (50 mL). The mixture was poured
into water (50 mL), further extracted with dichloromethane
(3ꢁ50 mL), dried (MgSO4) and evaporated to give the crude prod-
uct as a brown solid (0.94 g). Purification by column chromatog-
raphy on silica gel using n-hexane/ethyl acetate (3:1) as eluent gave
ethyl 4-cyano-5,6-difluoro-2-methylfuro[2,3-b]pyridine-3-carboxyl-
ate 6b (0.47 g, 31%) as a white solid; mp 91.8–93.3ꢂC. Found: C, 54.1;
H, 3.0; N, 10.6. C12H8F2N2O3 requires: C, 54.1; H, 3.0; N, 10.5%; Rf 0.5
(n-hexane/ethyl acetate, 3:1); dH 1.46 (3H, t, 3JHH 7.3, CH2CH3), 2.86
(3H, s, 3-CH3), 4.52 (2H, q, 3JHH 7.3, CH2); dC 14.6 (s, 3-CH3), 15.0 (s,
CH2CH3), 61.6 (s, CH2CH3), 106.0 (dd, 2JCF 14.9, 3JCF 3.8, C-4), 109.9–
All starting materials were obtained commercially. All solvents
were dried using literature procedures.18 NMR spectra
were recorded in deuteriochloroform, unless otherwise stated, on
a Varian Mercury 400 operating at 400 MHz (1H NMR), 376 MHz
(
19F NMR) and 100 MHz (13C NMR), respectively. Chemical shifts are
given in parts per million and coupling constants are recorded in
hertz, using tetramethylsilane and trichlorofluoromethane as
internal standards. IR spectra were obtained using a Perkin Elmer
1600 Series FTIR using a Golden Gate attachment and analysed
using GRAMS Analyst software. Mass spectra were recorded on
a Thermoquest Trace GC–MS spectrometer (in EI mode), a Micro-
mass LCT LC–MS spectrometer (in ESþ mode) or a Waters ZQ mass
spectrometer coupled to a Waters Acquity HPLC system (in ESþ/ꢀ
modes). Elemental analyses were obtained on an Exeter Analytical
CE-440 elemental analyser. Melting points and boiling points were
recorded at atmospheric pressure unless otherwise stated and
are uncorrected. The progress of reactions was monitored by 19F
NMR spectroscopy. Column chromatography was carried out on
silica gel.
3
110.0 (m, C-3), 110.2 (d, JCF 4.8, CN), 116.1–116.2 (m, C-3a), 146.0
1
2
1
2
(dd, JCF 266.4, JCF 28.9, C-5), 148.0 (dd, JCF 247.5, JCF 17.3, C-6),
151.6 (dd, 3JCF 15.0, 4JCF 3.4, C-1a), 161.8 (s, C]O),167.2 (d, 5JCF 4.4, C-
2); dF ꢀ89.51 (1F, d, 3JFF 21.0, F-6), ꢀ138.36 (1F, d, 3JFF 21.0, F-5); m/z
(EIþ) 266 ([M]þ, 36%), 193 ([MꢀCO2CH2CH3]þ, 30%), 138
([MꢀC6H8O3]þ, 26%).
4.2. Syntheses of [5,6]-ring fused systems
4.2.3. Ethyl
4-cyano-5,6-difluoro-2-phenylfuro[2,3-b]pyridine-3-
carboxylate 6c. 3-Oxo-3-phenyl-propionic acid ethyl ester 5b
(1.09 g, 5.68 mmol) and sodium hydride (0.27 g, 6.82 mmol, 60%
dispersion in mineral oil) were added to dry THF (50 mL) under
argon and stirred at rt for 1 h. 2,3,5,6-Tetrafluoro-4-pyr-
idinecarbonitrile 4a (1.0 g, 5.68 mmol) was added and the reaction
mixture heated to reflux for 6 d. The reaction mixture was cooled to
rt, solvent evaporated and the residue redissolved in dichloro-
methane (50 mL). The mixture was poured onto water (50 mL),
extracted with dichloromethane (3ꢁ50 mL), dried (MgSO4) and the
solvent evaporated to yield the crude product as a brown oil
(1.37 g). Purification by column chromatography on silica gel using
n-hexane/ethyl acetate (7:1) as eluent gave ethyl 4-cyano-5,6-
difluoro-2-phenylfuro[2,3-b]pyridine-3-carboxylate 6c (1.1 g, 59%) as
a white solid; mp 118.4–120.3 ꢂC. Found: C, 62.2; H, 3.1; N, 8.5.
C17H10F2N2O3 requires: C, 62.2; H, 3.0; N, 8.5%; Rf 0.35 (n-hexane/
4.2.1. 3-Hydroxy-2-(2,3,5,6-tetrafluoro-pyridin-4-yl)-but-2-enoic
acid ethyl ester 6a. Sodium hydride (1.20 g, 30.0 mmol, 60% dis-
persion in mineral oil) was added to a stirred solution of penta-
fluoropyridine 1 (2.56 g, 15.0 mmol) and ethyl acetoacetate 5a
(3.90 g, 30 mmol) in dry THF (50 mL) and the reaction mixture was
heated to reflux for 70 h, cooled, poured into water (50 mL) and
extracted with dichloromethane (4ꢁ30 mL). Drying (MgSO4) and
evaporation gave a dark oil, which was distilled to give 3-hydroxy-
2-(2,3,5,6-tetrafluoro-pyridin-4-yl)-but-2-enoic acid ethyl ester 6a
(0.33 g, 8%) as a colourless oil; bp 32 ꢂC, 0.50 mbar. Found: C, 47.6;
H, 3.4; N, 5.0. C11H9F4NO3 requires: C, 47.3; H, 3.3; N, 5.0%; dH 1.21
(3H, t, 3JHH 7.1, CH2CH3), 1.94 (3H, s, CH3), 4.22 (2H, q, 3JHH 7.1, CH2),
13.52 (1H, br s, OH); dC 14.1 (s, CH2CH3), 20.1 (s, CH3), 61.9 (s, CH2),
89.6 (t, 3JCF 2.3, –C]), 128.4–128.8 (m, C-4), 140.4 (dm, 1JCF 257.3, C-

3226
M.W. Cartwright et al. / Tetrahedron 66 (2010) 3222–3227
ethyl acetate, 7:1); dH 1.43 (3H, t, 3JHH 7.2, CH3), 4.54 (2H, q, 3JHH 7.2,
CH2), 7.59–7.52 (3H, m, Ar H), 8.0–8.1 (2H, m, Ar H); dC 14.4 (s, CH3),
62.1 (s, CH2), 106.2 (dd, 2JCF 14.8, 3JCF 3.8, C-4),109.3 (s, C-3),110.1 (d,
3JCF 4.6, CN), 117.4 (d, 3JCF 5.3, C-3a), 127.4 (s, Ar C), 128.9 (s, Ar CH),
129.8 (s, Ar CH), 132.2 (s, Ar CH), 146.2 (dd, 1JCF 264.9, 2JCF 28.6, C-5),
148.6 (dd, 1JCF 247.0, 2JCF 16.8, C-6),151.7 (dd, 3JCF 15.2, 4JCF 3.5, C-7a),
162.7 (d, 5JCF 4.6, C-2), 161.6 (s, C]O); dF ꢀ88.11 (1F, d, 3JFF 21.1, F-6),
2JCF 28.6, 3JCF 10.1, C-1a),152.2 (dd, 1JCF 241.0, 4JCF 3.9, C-4),158.7 (dd,
4
4
1JCF 247.7, JCF5 2.3, C-7), 161.0 (s, C]O), 168.2 (d, JCF 2.2, C-2); dF
5
ꢀ76.5 (1F, d, JFF 33.5, F-4), ꢀ98.5 (1 F, d, JFF 33.5, F-7); m/z (EIþ)
242 ([M]þ, 49%), 214 (62), 197 (100), 170 (32).
4.2.7. Ethyl 7-fluoro-2-methyl-4-oxo-5-(tetrahydro-2H-pyran-2-yl)-
4,5-dihydrofuro[3,2-d]pyridazine-3-carboxylate 6g. 4,5,6-Trifluoro-
3
ꢀ137.90 (1F, d, JFF 21.1, F-5); m/z (EIþ) 328 ([M]þ, 84%), 283
2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one
4d
(0.10 g,
([MꢀOCH2CH3]þ, 100%).
0.43 mmol), ethyl acetoacetate 5a (0.18 g, 1.28 mmol) and sodium
hydride (0.033 g, 1.28 mmol, 60% dispersion in mineral oil) was
heated at reflux in THF (10 mL) for 4 h. The mixture was concen-
trated and partitioned between dichloromethane (3ꢁ10 mL) and
water. The combined organic phases were dried and concentrated,
and purification by column chromatography using n-hexane/ethyl
acetate (2:1) as eluent gave ethyl 7-fluoro-2-methyl-4-oxo-5-(tet-
4.2.4. Ethyl 2,3-difluoro-6-methylfuro[2,3-b]pyrazine-7-carboxylate
6d. Ethyl acetoacetate 5a (2.56 g, 13 mmol) and sodium hydride
(0.75 g, 19 mmol, 60% dispersion in mineral oil) were added to THF
(250 mL) and stirred at rt for 2 h before the addition of tetra-
fluoropyrazine 4b (1.5 g,10 mmol). The reaction mixture was heated
at reflux for 1 d. The reaction solvent was evaporated, added to water
(40 mL), extracted with ethyl acetate (3ꢁ40 mL), dried (MgSO4) and
evaporated. Column chromatography on silica gel using n-hexane/
ethyl acetate (4:1) as eluent gave ethyl 2,3-difluoro-6-methylfuro[2,3-
b]pyrazine-7-carboxylate 6d (1.70 g, 71%) as a white solid; mp 98.9–
102.4 ꢂC. Found: C, 49.7; H, 3.4; N, 11.4. C10H8F2N2O3 requires: C,
49.6; H, 3.3; N,11.6%; Rf 0.4 (n-hexane/ethyl acetate, 4:1); dH 1.42 (3H,
t, 3JHH 7.2, CH2CH3), 2.86 (3H, s, 6-CH3), 4.43 (2H, q, 3JHH 7.2, CH2); dC
14.5 (s, CH2CH3), 15.4 (s, CH3), 61.5 (s, CH2), 109.7 (s, C-7), 131.6 (dd,
3JCF 11.8, 4JCF 5.3, C-7a), 143.5 (dd, 1JCF 257.0, 2JCF 34.0, C-3), 146.5 (dd,
rahydro-2H-
pyran-2-yl)-4,5-dihydrofuro[3,2-d]pyridazine-3-car-
boxylate 6g (0.12 g, 87%) as white crystals; mp 113–115 ꢂC. Found C,
55.5; H, 5.3; N, 8.3. C15H17FN2O5 requires C, 55.6; H, 5.3; N, 8.6%; Rf
0.25 (n-hexane/ethyl acetate, 2:1); nmax/cmꢀ1 2952, 1737, 1681,
3
1602, 1432, 1311, 1277, 1210, 1167, 1080; dH 1.41 (3H, t, JHH 7.7,
CH2CH3),1.50–1.70 (4H, m, CH2), 2.00–2.20 (2H, m, CH2), 2.72 (3H, s,
3
2-CH3), 3.70–4.10 (2H, m, CH2), 4.41 (2H, q, JHH 7.7, CH2CH3), 6.07
3
(1H, d, JHH 10.5, CH-O); dC 14.4 (s, CH3), 14.5 (s, 2-CH3), 23.2 (s,
CH2), 25.1 (s, CH2), 29.2 (s, CH2), 61.8 (s, CH2CH3), 69.0 (s, C-60), 82.8
(s, C-20), 113.9 (d, 4JCF 2.9, C-3), 124.2 (d, 3JCF 6.9, C-3a), 141.1 (d, 2JCF
34.2, C-7a), 142.4 (d, 1JCF 235.9, C-7), 156.4 (s, C-2), 161.9 (s, C]O),
164.7 (s, N–C]O); dF ꢀ105.4 (s); m/z (ESþ) 241 (100), 325 ([MH]þ,
5%), 347 ([MþNa]þ, 13%).
2
3
4
1JCF 245.9, JCF 28.2, C-2), 147.3 (dd, JCF 8.0, JCF 1.9, C-4a), 161.9 (s,
C]O), 168.5 (d, 5JCF 5.4, C-6); dF ꢀ93.26 (1F, d, 3JFF 22.0, F-2), ꢀ95.61
(1F, d, 3JFF 22.0, F-3); m/z (EIþ) 242 ([M]þ, 44%).
4.2.5. N,N-Diethyl-2,3-difluoro-6-methylfuro[2,3-b]pyrazine-7-
carboxamide 6e. N,N-Diethylacetoacetamide 5c (4.40 g, 30 mmol)
and sodium hydride (1.31 g, 30 mmol, 60% dispersion in mineral
oil) were added to dry THF (400 mL) and stirred at rt for 2 h before
the addition of tetrafluoropyrazine 4b (2.07 g, 14 mmol). The re-
action mixture was heated to reflux for 1 d. The reaction solvent
was evaporated and water (40 mL) added to the residue. The
aqueous phase was extracted with ethyl acetate (3ꢁ40 mL), dried
(MgSO4) and evaporated. Column chromatography on silica gel
using n-hexane/ethyl acetate (4:1) as eluent gave N,N-diethyl-2,3-
difluoro-7-methylfuro[2,3-b]pyrazine-6-carboxamide 6e (2.04 g,
60%) as yellow crystals; mp 73–75 ꢂC. Found: C, 53.7; H, 4.9; N, 15.4.
C12H13F2N3O2 requires: C, 53.5; H, 4.8; N, 15.6%; Rf 0.3 (n-hexane/
ethyl acetate, 4:1); dH 1.04 (3H, t, 3JHH 7.0, CH3), 1.17 (3H, t, 3JHH 7.0,
CH3), 2.56 (1H, s, 6-CH3), 3.30 (2H, q, 3JHH 7.0, CH2), 3.50 (2H, q, 3JHH
7.0, CH2); dC 13.6 (s, CH3), 14.3 (s, CH3), 15.1 (s, 6-CH3), 39.6 (s, CH2),
43.3 (s, CH2), 114.2 (s, C-7), 131.9 (dd, 3JCF 12.1, 4JCF 5.2, C-7a), 143.4
4.3. Reactions of ring fused scaffolds
4.3.1. 4-Cyano-6-diethylamino-5-fluoro-2-methylfuro[2,3-b]pyri-
dine-3-carboxylic acid ethyl ester 7. n-Butyl lithium (0.83 mL,
1.32 mmol, 1.6 M in pentane) and diethylamine (0.10 g, 1.32 mmol)
were added to THF (5 mL) at ꢀ78ꢂC and the solution was stirred for
1 h before warming to rt. The solution was added to ethyl 4-cyano-
5,6-difluoro-2-methylfuro[2,3-b]pyridine-3-carboxylate 6b (0.35 g,
1.32 mmol) in THF (45 mL) and stirred at rt for 2 d. Solvent was
evaporated and the residue redissolved in dichloromethane
(50 mL). The mixture was poured onto water (50 mL), extracted
with dichloromethane (3ꢁ50 mL), dried (MgSO4) and solvent
evaporated. Purification by column chromatography on silica gel
using n-hexane/ethyl acetate (4:1) as eluent gave 4-cyano-6-
diethylamino-5-fluoro-2-methylfuro[2,3-b]pyridine-3-carboxylic acid
ethyl ester 7 (0.20 g, 48%) as a yellow oil; ([MH]þ, 320.1406.
C16H18FN3O3 requires: [MH]þ, 320.1405); Rf 0.3 (n-hexane/ethyl
acetate, 4:1); dH 1.18 (6H, t, 3JHH 7.0, NCH2CH3), 1.37 (3H, t, 3JHH 7.3,
OCH2CH3), 2.67 (3H, s, 2-CH3), 3.50 (4H, qd, 3JHH 7.0, 5JHF 2.0, NCH2),
4.40 (2H, q, 3JHH 7.3, OCH2); dC 13.9 (s, N(CH2CH3)2), 14.5 (s, 2-CH3),
14.7 (s, OCH2CH3), 44.9 (d, 4JCF 6.3, N(CH2CH3)2), 61.0 (s, OCH2CH3),
1
2
2
(dd, JCF 250.8, JCF 34.3, C-2), 147.2 (dd, 1JCF 240.4, JCF 29.3, C-3),
3
147.4 (s, C-4a), 147.6 (s, C-6), 161.4 (s, C]O); dF ꢀ95.80 (1F, d, JFF
3
25.3, F-2), ꢀ97.37 (1F, d, JFF 25.3, F-3); m/z (EIþ) 269 ([M]þ, 48%),
197 (100), 141 (18).
2
3
103.5 (d, JCF 19.2, C-4), 105.3 (s, CN), 109.3 (d, JCF 1.4, C-3a), 112.1
4
2
1
4.2.6. 4,7-Difluoro-2-methylfuro[2,3-d]pyridazine-3-carboxylic acid
ethyl ester 6f. DIPEA (0.67 g, 5.17 mmol) and ethyl acetoacetate 5a
(0.25 g, 1.96 mmol) were added to a stirred solution of tetra-
fluoropyridazine 4c (0.31 g, 2.05 mmol) in THF (10 mL). After 4 d at
rt, the mixture was concentrated and partitioned between
dichloromethane (3ꢁ10 mL) and water. The combined organic
phases were dried and concentrated, and the residue purified by
column chromatography on silica gel using n-hexane/ethyl acetate
(1:1) as eluent to give 4,7-difluoro-2-methylfuro[2,3-d]pyridazine-3-
carboxylic acid ethyl ester 6f (0.19 g, 40%) as a colourless oil. Found:
C, 49.6; H, 3.4; N, 11.9. C10H8F2N2O3 requires: C, 49.6; H, 3.3; N,
11.6%; Rf 0.3 (n-hexane/ethyl acetate, 1:1); nmax/cmꢀ1 2988, 1719,
1615, 1587; dH 1.44 (3H, t, 3JHH 7.1, CH2CH3), 2.92 (3H, s, 2-CH3), 4.44
(d, JCF 1.9, C-3), 144.9 (d, JCF 9.6, C-6), 148.9 (d, JCF 262.0, C-5),
4
5
155.0 (d, JCF 2.4, C-7a), 161.8 (d, JCF 1.9, C-2), 163.0 (s, C]O); dF
ꢀ131.43 (s); m/z (EIþ) 319 ([M]þ, 78%), 304 ([MꢀCH3]þ, 100%), 290
([MꢀCH2CH3]þ, 30%).
4.3.2. Ethyl
2-fluoro-3-methoxy-6-methylfuro[2,3-b]pyrazine-7-
carboxylate 8. A solution of ethyl 2,3-difluoro-6-methylfuro[2,3-
b]pyrazine-7-carboxylate 6d (0.30 g, 1.2 mmol), and sodium
methoxide (0.06 g, 1.2 mmol) in methanol (50 mL) was stirred at rt
for 1 d. The reaction solvent was evaporated and the sample par-
titioned between ethyl acetate (3ꢁ40 mL) and water (40 mL). The
organic layer was separated, dried (MgSO4), evaporated and
recrystallised from ethyl acetate to give ethyl 2-fluoro-3-methoxy-6-
methylfuro[2,3-b]pyrazine-7-carboxylate 8 (0.27 g, 89%) as white
needles; mp 159–160 ꢂC. Found: C, 51.7; H, 4.3; N,10.8. C11H11FN2O4
3
(2H, q, JHH 7.1, CH2); dC 14.2 (s, CH3), 14.7 (s, 2-CH3), 62.0 (s, CH2),
2
109.1 (d, 3JCF 3.6, C-3), 119.1 (dd, JCF 35.4, 3JCF 5.9, C-3a), 141.8 (dd,

M.W. Cartwright et al. / Tetrahedron 66 (2010) 3222–3227
3227
requires: C, 52.0; H, 4.4; N, 11.0%; dH 1.37 (3H, t, 3JHH 7.0, CH3), 2.75
rameters), conventional R1(F)¼0.0506 for 1820 reflections with I>2
s,
(3H, s, 6-CH3), 4.03 (3H, s, OCH3), 4.39 (2H, q, 3JHH 7.0, CH3); dC 14.6
(s, CH3), 15.1 (s, CH3), 55.2 (s, OCH3), 61.3 (s, CH2), 109.6 (s, C-7),
125.0 (d, 3JCF 12.4, C-7a), 145.0 (d, 2JCF 30.5, C-3), 147.1 (d, 1JCF 248, C-
2), 149.1 (s, C-4a), 162.7 (s, C-6), 164.3 (s, C]O); dF ꢀ91.90 (s); m/z
(EIþ) 254.0 ([M]þ, 14%), 208 (100), 180 (82).
GOF¼0.947.
4.4.2. Crystal data for 6d. C10H8F4N2O3, M¼242.18, triclinic, space
group P-1, a¼7.7365(4), b¼8.3890(4), c¼8.8129(5) Å,
a
¼67.79(2),
b¼73.89(2),
g
¼76.26(2)ꢂ, U¼503.05(5) Å3, F(000)¼248, Z¼2,
Dc¼1.599 mg mꢀ3
,
m
¼0.143 mmꢀ1. 4451 reflections yielded 2610
4.3.3. 3-(Diethylamino)-2-fluoro-6-methylfuro[2,3-b]pyrazine-7-
carboxylate 9. Ethyl 2,3-difluoro-6-methylfuro[2,3-b]pyrazine-7-
carboxylate 6d (0.42 g, 1.7 mmol) and diethylamine (0.25 g,
3.4 mmol) in acetonitrile (50 mL) were stirred at reflux for 1 d. The
reaction solvent was evaporated and partitioned between ethyl
acetate (3ꢁ40 mL) and water (40 mL). The organic layer was sep-
arated, dried (MgSO4), evaporated and recrystallised from ethyl
acetate to give 3-(diethylamino)-2-fluoro-6-methylfuro[2,3-b]pyr-
azine-7-carboxylate 9 (0.48 g, 95%) as yellow crystals; mp 43–45 ꢂC.
Found: C, 56.7; H, 6.2; N, 14.2. C14H18FN3O3 requires: C, 56.9; H, 6.1;
N,14.2%; dH 1.0–1.3 (9H, m, CH3), 2.68 (3H, s, 6-CH3), 3.4–3.6 (6H, m,
CH2); dC 13.8 (s, CH3),14.7 (s, CH3),15.0 (s, CH3), 44.9 (s, CH2), 61.0 (s,
CH2), 109.2 (s, C-7), 120.4 (d, 3JCF 11.1, C-7a), 141.0 (d, 2JCF 21.4, C-3),
unique data (Rmerg¼0.0352). Final wR2(F2)¼0.1119 for all data (186
refined parameters), conventional R1(F)¼0.0385 for 2249 re-
flections with I>2
s
, GOF¼1.041.
4.4.3. Crystal data for 6e. C12H13F2N3O2, M¼269.25, monoclinic,
space group P21/c, a¼8.0742(2), b¼20.5408(6), c¼7.8994(2) Å,
b
¼109.89(1)ꢂ, U¼1231.97(6) Å3, F(000)¼560, Z¼4, Dc¼1.452 mg mꢀ3
,
m
¼0.121 mmꢀ1
; 13,735 reflections yielded 3423 unique data
(Rmerg¼0.0649). Final wR2(F2)¼0.0973 for all data (224 refined pa-
rameters), conventional R1(F)¼0.0365 for 2522 reflections with I>2
s,
GOF¼1.045.
4.4.4. Crystal data for 6g. C15H17FN2O5, M¼324.31, monoclinic, space
1
148.3 (s, C-4a), 151.4 (d, JCF 196.6, C-2), 161.8 (s, C-6), 163.2 (s,
group
P2/c,
a¼11.1242(6),
b¼7.2292(4),
c¼18.7744(10) Å,
C]O); dF ꢀ82.54 (s); m/z (EIþ) 295 ([M]þ, 52%), 280 (100), 249 (62).
b
¼94.35(2)ꢂ, U¼1505.46(14) Å3, F(000)¼680,Z¼4,Dc¼1.431 mg mꢀ3
,
m
¼0.116 mmꢀ1
; 16,527 reflections yielded 3640 unique data
4.3.4. 3-(Diethylamino)-N,N-diethyl-2-fluoro-6-methylfuro[2,3-
b]pyrazine-7-carboxamide 10. N,N-Diethyl-2,3-difluoro-7-methyl-
furo[2,3-b]pyrazine-6-carboxamide 6e (0.50 g, 1.9 mmol) and
diethylamine (0.28 g, 3.8 mmol) in acetonitrile (40 mL) were stirred
at reflux for 1 d. The reaction solvent was evaporated and the
sample dissolved into ethyl acetate (3ꢁ40 mL) and water (40 mL).
The ethyl acetate was separated, dried (MgSO4), evaporated and
recrystallised to give 3-(diethylamino)-N,N-diethyl-2-fluoro-6-
methylfuro[2,3-b]pyrazine-7-carboxamide 10 (0.56 g, 95%) as yellow
crystals; mp 66–68 ꢂC. Found: C, 59.4; H, 7.2; N, 17.2. C16H23FN4O2
requires: C, 59.6; H, 7.2; N, 17.4%; dH 1.0–1.3 (12H, m, CH3), 2.41 (3H,
s, 6-CH3), 3.2–3.6 (8H, m, CH2); dC 13.7 (s, CH3), 13.8 (s, CH3), 14.0 (s,
CH3), 14.3 (s, CH3), 15.1 (s, CH3), 39.6 (s, CH2), 43.2 (s, CH2), 44.7 (s,
CH2), 44.8 (s, CH2), 113.7 (s, C-7), 120.8 (d, 3JCF 13.4, C-7a), 140.7 (d,
2JCF 25.9, C-3), 148.1 (d, 1JCF 244, C-2), 151.1 (s, C-4a), 154.1 (s, C-6),
162.5 (s, C]O); dF ꢀ83.54 (s); m/z (EIþ) 322 ([M]þ, 96%), 249 (100),
221 (94).
(Rmerg¼0.0751). Final wR2(F2)¼0.1098 for all data (264 refined pa-
rameters), conventional R1(F)¼0.0461 for 2095 reflections with I>2
s,
GOF¼1.047.
Acknowledgements
We thank GlaxoSmithKline R&D and EPSRC for funding.
References and notes
1. Pozharskii, A. F.; Soldantenkov, A. T.; Katritzky, A. R. Heterocycles in Life and
Society; John Wiley and Sons: New York, NY, 1997.
2. Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic Chemistry; Pergamon:
Oxford, 1984; Vols. 1–8.
3. Chambers, R. D.; Hoskin, P. R.; Kenwright, A. R.; Khalil, A.; Richmond, P.;
Sandford, G.; Yufit, D. S.; Howard, J. A. K. Org. Biomol. Chem. 2003, 1, 2137–2147.
4. Sandford, G. Chem.dEur. J. 2003, 9, 1464–1469.
5. Hargreaves, C. A.; Sandford, G.; Davis, B. G. In Current Fluoroorganic Chemistry;
Soloshonok, V. A., Ed.; ACS Symposium Series 949; ACS: Washington, DC, 2007;
pp 323–336.
6. Murray, C. B.; Sandford, G.; Korn, S. R.; Yufit, D. S.; Howard, J. A. K. J. Fluorine
Chem. 2005, 126, 571–576.
4.4. X-ray structures
7. Armstrong, D.; Cartwright, M. W.; Parks, E. L.; Pattison, G.; Sandford, G.; Slater,
R.; Wilson, I.; Christopher, J. A.; Miller, D. D.; Smith, P. W.; Vong, A. In Fluorine in
Medicinal Chemistry and Chemical Biology; Ojima, I., Ed.; John Wiley and Sons:
New York, NY, 2009; pp 291–312.
8. Sandford, G.; Slater, R.; Yufit, D. S.; Howard, J. A. K.; Vong, A. J. Org. Chem. 2005,
70, 7208–7216.
Single crystal X-ray data were collected on Bruker Proteum-M (6b
and 6d) and SMART 6000 (6e and 6g) diffractometers equipped with
Cryostream (Oxford Cryosystems) nitrogen coolers at 120 K using
graphite monochromated MoK
a
radiation (
l
¼0.71073 Å,
u-scan). All
structures were solved by direct methods and refined by full-matrix
least squares on F2 for all data using SHELXL software. All non-
disordered non-hydrogen atoms were refined with anisotropic dis-
placement parameters, non-disordered H-atoms were located on the
difference map and refined isotropically.
9. Baron, A.; Sandford, G.; Slater, R.; Yufit, D. S.; Howard, J. A. K.; Vong, A. J. Org.
Chem. 2005, 70, 9377–9381.
10. Cartwright, M. W.; Convery, L.; Kraynck, T.; Sandford, G.; Yufit, D. S.; Howard, J.
A. K.; Christopher, J. A.; Miller, D. D. Tetrahedron 2010, 66, 519–529.
11. Cartwright, M. W.; Sandford, G.; Bousbaa, J.; Yufit, D. S.; Howard, J. A. K.;
Christopher, J. A.; Miller, D. D. Tetrahedron 2007, 63, 7027–7035.
12. Hargreaves, C. A.; Sandford, G.; Slater, R.; Yufit, D.; Howard, J. A. K.; Vong, A.
Tetrahedron 2007, 63, 5204–5211.
13. Brooke, G. M. J. Fluorine Chem. 1997, 86, 1–76.
14. Sandford, G.; Wilson, I.; Christopher, J. A.; Miller, D. D., unpublished results,
2010.
Crystallographic data for structures 6b, 6d, 6e and 6g have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publications CCDC 753504–753507.
15. Pattison, G.; Sandford, G.; Yufit, D. S.; Howard, J. A. K.; Christopher, J. A.; Miller,
D. D. J. Org. Chem. 2009, 74, 5533–5540.
16. Pattison, G.; Sandford, G.; Yufit, D. S.; Howard, J. A. K.; Christopher, J. A.; Miller,
D. D. Tetrahedron 2009, 65, 8844–8850.
17. Friedrichsen, W. Comprehensive Heterocyclic Chemistry; Pergamon: Oxford,
1984; Vol. 3, Chapter 3.17.
18. Vogel, A. I. Practical Organic Chemistry; Longmans: London, 1962.
4.4.1. Crystal data for 6b. C12H8F2N2O3, M¼266.20, monoclinic,
space group P21/c, a¼112.7367(6), b¼4.9712(2), c¼18.2403(8) Å,
b¼105.90(4)ꢂ, U¼1110.7(2) Å3, F(000)¼544, Z¼4, Dc¼1.592 mg mꢀ3
,
m
¼0.138 mmꢀ1
; 7702 reflections yielded 3049 unique data
(Rmerg¼0.0951). Final wR2(F2)¼0.1218 for all data (204 refined pa-