Regioselective synthesis and metallation of fluoroiodopyrazines. Application to the synthesis of aryl and alkylbenzylpyrazines. Diazines. Part 31

Article abstract of DOI:10.1016/S0040-4020(01)01140-1

The regioselective metallation of 2-fluoropyrazine allowed the synthesis of various 5- and 6-iodoflouropyrazines. Use of cross-coupling reactions with iodoflouropyrazines under Suzuki or Negishi conditions led to aryl and alkylflouropyrazines. The benzylf

Full text of DOI:10.1016/S0040-4020(01)01140-1

TETRAHEDRON
Pergamon
Tetrahedron 58(2002) 283±293
Regioselective synthesis and metallation of ¯uoroiodopyrazines.
Application to the synthesis of aryl and alkylbenzylpyrazines.
Diazines. Part 31
p
   Â
Frederic Toudic, Nelly Ple, Alain Turck and Guy Queguiner
 Â
Laboratoire de Chimie Organique Fine et Heterocyclique, UMR 6014, IRCOF-INSA, Place E Blondel BP 08,
76131 Mont St Aignan cedex, France
Received 30 July 2001; revised 8October 2001; accepted 14 November 2001
AbstractÐThe regioselective metallation of 2-¯uoropyrazine allowed the synthesis of various 5- and 6-iodo¯uoropyrazines. Use of cross-
coupling reactions with iodo¯uoropyrazines under Suzuki or Negishi conditions led to aryl and alkyl¯uoropyrazines. The benzyl¯uoropyr-
azines have been used as building block to synthesize a wide range of arylbenzyl¯uoropyrazines which could exhibit mesomorphic proper-
ties. q 2002 Elsevier Science Ltd. All rights reserved.
The presence of a ¯uorine atom into a molecule is of par-
ticular interest because it makes considerable changes in its
physical and chemical behavior. Thus, this access to ¯uori-
nated compounds is of special interest for applications as
pharmaceuticals1 or highly polarizable materials.2 The
¯uorodiazines could be used as building blocks to synthe-
size such molecules. It has been recently reported that the
two-ring architecture of phenylpyrimidines have interesting
properties as liquid crystal devices.3 Furthermore the intro-
duction of¯uorine atoms as lateral substituents improves the
polarizability of the materials and ensures a low viscosity.4
of a great synthetic interest because it allows, using the
palladium-catalyzed cross-coupling reactions, the synthesis
of aryl or alkylpyrazines.
Previously the lithiation of ¯uoropyrazine 1 with stoichio-
metric amounts of LTMP and iodine used as the electrophile
has been described8 affording the 2-¯uoro-3-iodopyrazine 2
as sole product. The lithiation of ¯uoropyrazine 1 has been
reinvestigated using various equivalents of metallating
agent and iodine (Scheme 1, Table 1).
With 1.1 equiv. of LTMP and 2 equiv. of iodine (entry 1),
the 2-¯uoro-3-iodopyrazine 2 was the major product. With
2.1 equiv. of LTMP and iodine a mixture of the three mono,
di and triiodo derivatives 2, 3, 4 was obtained (entry 2).
When LTMP and iodine were in large excess the triiodo
compound 4 was obtained as the sole product (entry 3).
The ¯uorine atom has been previously used as an ortho-
directing group in the metallation reaction of various p-de®-
cient heterocycles such as pyridine,5 quinoline,6 pyrimidine7
and more recently with pyrazine.8 We report here the regio-
selective synthesis of various iodo¯uoropyrazines.
The introduction of a second halogen atom such as iodine is
The structure of the diodo compound 3 could be assigned
Scheme 1.
Table 1. Lithiation and iodation of 1
Entry
n
n0
2 (%)
3 (%)
4 (%)
1
2
3
1.1
2.1
4
2
2
4
50
11
±
6
35
±
6
15
65
Keywords: metallation; ¯uoropyrazines; cross-coupling reactions.
Corresponding author. Tel.: 133-2-35-52-29-00; fax: 133-2-35-52-29-
62; e-mail: guy.queguiner@insa-rouen.fr
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)01140-1

284
F. Toudic et al. / Tetrahedron 58 (2002) 283±293
Scheme 2.
Scheme 3.
unambiguously thanks to the observed long-range
hydrogen-¯uorine constant (3.5 Hz).This value is in
agreement with this previously given for ¯uoropyrazine
between the lithium of the metallating agent (LTMP) and
the two nitrogen atoms of the diazine moiety which behaves
as a chelating agent through its nitrogen atoms. The site of
deprotonation could be determined by the net charge of the
two hydrogen atoms (Scheme 4). The net charges deter-
mined with PM3 for H5 (0.168) and H6 (0.186) indicated
that this latter one was the more acidic, so the deprotonation
could, under kinetic conditions, occur at this position. When
the metallation is performed with alkylamides, the deproto-
nation is considered as thermodynamically controlled, then
it could be assumed that the heats of formation of the lithio
compounds could be examined in a simple approach for the
regioselectivity. The heats of formation of the two lithio
derivatives were determined with PM3; the 6-lithio deriva-
tive was found as the most stable (Scheme 4). This result
could explain the total regioselectivity of the function-
nalization at C6.
5
by Jovanic,9 who indicated a higher value for JF±H5
(4.7 Hz) than 4JF±H6 (1.4 Hz). This result allowed us to high-
light that under these conditions the iodine atoms were at C3
and C6 position.
The palladium-catalyzed coupling reaction has been tested
with 2 and phenylboronic acids under the Suzuki conditions
(Scheme 2).
A further lithiation of compound 5 was achieved with
3 equiv. of LTMP followed by reaction with various electro-
philes leading to trisubstituted pyrazines 7±10 (Scheme 3).
The structures of the compounds 7±10 have been assigned
thanks to long-range hydrogen±¯uorine coupling constant
5JF±H5 (4.0±5.6 Hz) highlighting that the functionalization
occurred exclusively at C6 position.
However, when compound 5 is reacted with 3 equiv. of
LTMP at 2788C for 5 min followed by reaction with
1 equiv. of iodine, a monoiodo derivative 11 was obtained
in 64% yield beside traces of diiododerivative (Scheme 5).
It would be interesting to explain the regioselectivity of the
metallation which occurred ortho to a nitrogen atom without
assistance of an ortho-directed group. So some theoretical
calculations using the Li/PM3 semi-empirical method have
been performed.
1
The H NMR spectrum of 11 showed a signal at 8.15 ppm
with a coupling constant of 1.7 Hz which could be assigned
to a JF±H6 and so indicated a iodation at C5. However, in
4
order to determine unambiguously the site of iodation, a
structure elucidation of compound 11 has been carried out
It could be assumed that ®rst a complexation occurred
Scheme 4.

F. Toudic et al. / Tetrahedron 58 (2002) 283±293
285
The unexpected iodination occurring at C5, whereas the
other electrophiles take place at C6 urged us to reinvestigate
the lithiation of 5 followed by reaction with iodine as the
electrophile under various experimental conditions
(Scheme 7, Table 2).
Scheme 5.
These results require some comments: with 1.1 equiv. of
metallating agent and an excess of iodine, the 6-iodo
derivative 12 was obtained in good yield (entry 1). An
excess of LTMP and of iodine gave the diiodo derivative
13 as sole product in good yield (entries 3, 5). When the
metallating agent was in excess in relation to iodine the
5-iodo derivative 11 was obtained as sole product (entries
2, 4 and 6).
applying gradient enhancement HMBC sequence, using
long-range 1H±15N heteronuclear coupling at natural
abundance. This method has been previously used to deter-
mine the structure of quinazoline10 derivatives and thio-
carboxamidepyrazines.11 The unequivocal 15N assignment
of compounds 1 and 5 was based on 2J(1H±15N) interaction
in proton-coupled nitrogen which was given in a range from
12
9.8to 14.4 Hz in diazine series. The 15N spectrum of 1
(Scheme 6) exhibited two signals: a doublet at 290 ppm
(2Jˆ10 Hz) assigned to N1 and a triplet at 350 ppm with
It could be assumed that the reaction of 5 with 1±4 equiv. of
LTMP at 2788C led ®rst to the 6-lithio derivative which
reacted with iodine to give the 6-iodo derivative 12. This
compound underwent a further isomerization involving an
iodine atom migration leading to the 5-iodo derivative 11.
Such isomerizations resulting from an halogen migration
has been previously described with bromopyridines,5f iodo-
pyridines13 and iodopyrimidines,14 it is known as a
`halogen-dance' mechanism which implies a halogen±
lithium exchange.
1
the same coupling constant for N4. The H NMR spectrum
of 1 showed three signals at 8.09, 8.32 and 8.37 ppm, which
have been allocated by applying a gradient HMBC pulse
sequence with a long-range delay optimized for a coupling
constant of 10 Hz. Correlations were observed between N1
at 290 ppm and H6 (8.09 ppm) and N4 at 350 Hz and H3 and
H5 (8.32 and 8.37 ppm). The 15N spectrum of 2-¯uoro-3-
phenylpyrazine 5 presented two signals at 290 and 345 ppm
assigned, respectively, to N1 and N4. The 1H spectrum
1
presented two signals at 8.16 and 8.60 ppm. The H±15N
To determine if such an exchange occurred, we have reacted
the 6-iodo derivative 12 with 3.1 equiv. of LTMP at 2788C
for 30 min followed by a reaction of hydrolysis with HCl in
ethanol. Under theses conditions, the 5-iodo derivative 11
was obtained in 89% (Scheme 8).
gradient HMBC spectrum showed correlation between N1
at 290 and H6 (8.16) and N4 at 345 and H5 (8.60). For the
compound 11 the 15N spectrum showed two signals at 300
and 322 ppm. The 1H±15N gradient HMBC spectrum
exhibited a correlation between N1 at 300 ppm and H6 at
8.15. These results allowed us to determine unambiguously
the structure of 11 as the 2-¯uoro-3-phenyl-5-iodopyrazine
(Scheme 6).
When the diiodo derivative 13 was submitted to reaction
with LTMP under similar conditions, followed by reaction
either with HCl or with acetaldehyde, the compound 11 or
Scheme 6.
Scheme 7.
Table 2. Lithiation and iodation of 5
the secondary alcohol 14 were obtained in 67% yield. These
results highlighted that the iodine±lithium exchange
occurred exclusively at the C6 position.
Entry
n
n0
12 (%)
11 (%)
13 (%)
1
2
3
4
5
6
1.1
2.1
2.1
3.1
3.1
4.1
2.0
1.0
2.0
1.0
3
73
±
±
±
±
±
59
±
64
±
±
±
80
±
68
±
The compound 11 has been submitted to palladium-
catalysed cross-coupling reaction with phenyl boronic acid
under the Suzuki conditions and the butylzinc chloride
under the Negishi conditions (Scheme 9).
1.0
±
57

286
F. Toudic et al. / Tetrahedron 58 (2002) 283±293
Scheme 8.
Scheme 9.
In a previous paper8 we have reported that treatment of
2-¯uoro-3-(phenylhydroxymethyl)pyrazine with LTMP at
2788C for a short reaction time (5 min), followed by
reaction with iodine as the electrophile allowed the regio-
selective iodation at C6 leading to 2-¯uoro-6-iodo-3-
(phenylhydroxymethyl)pyrazine.
that the necessary polarity for molecular tilting is provided
by an ether oxygen and by the heterocyclic nitrogens, so
phenylpyrimidines have been described as ef®cient
moieties. It has been hightlighted that use of lateral ¯uoro
substituents provides the polarity for molecular tilting,4,15
moreover two lateral ¯uoro substituents ortho to each
other give better mesomorphic and physical properties.16
Using the ¯uoropyrazine as building block, we report here
the synthesis of a range of 6-iodo-3-benzylpyrazines by the
strategic use of metallation (Scheme 10).
So we have developed a ¯exible route (Scheme 11) that
allowed the synthesis of a wide structural range of
compounds utilizing the 2-¯uoro-6-iodo-3-benzylpyrazines
23±25 as starting materials. Introduction of alkyl group at
the C6 position was performed by a cross coupling reaction
with alkylzinc chlorides under Negishi conditions leading to
compounds 26±29 in good yields. Various arylboronics
acids were reacted with the compounds 23±25 under Suzuki
Compounds, having conjugate aromatic units leading long
terminal alkoxy chains are known to present optical aniso-
tropy and so are used as liquid crystal devices. The main
structural factors, which improve the mesomorphic proper-
ties have been recently reported. So it has been highlighted
Scheme 10.

F. Toudic et al. / Tetrahedron 58 (2002) 283±293
287
Scheme 11.
conditions allowing synthesis of a wide range of 2-¯uoro-3-
benzyl-6-arylpyrazines 30±36. Structural variations could
be obtained by the choice of suitable arylboronic acids
bearing alkoxy ether with terminal chains from different
length or with tri¯uoromethyl group. Lithiation ortho to
1,2-di¯uoroaromatic unit has provided the route to 2,3-
di¯uoroarylboronic acids which are implied in palladium-
catalyzed cross-coupling reaction to give compounds 35 and
36 with two ¯uorine atoms as lateral substituents. The
compounds 32, 34 and 36 have been tested for mesomorphic
properties.
All reagents were of commercial quality and were
purchased from Aldrich Chemical or Acros. Pd-catalysis
Pd(PPh3)4 was prepared according to the literature.17
4-Tri¯uoromethyl- and 4-alcoxyphenylboronic acids were
synthesized by halogen-metal exchange followed by
reaction with trimethoxyborane from the commercially
available 1-bromo-4-tri¯uoromethylbenzene or 1-bromo-
4-methoxybenzene. The 2,3-di¯uoro-4-alcoxyphenylboro-
nic acids were synthesized by ortho-lithiation of
corresponding 1-alcoxy-2,3-di¯uorobenzenes with n-butyl-
lithium followed by reaction with trimethoxyborane.
Only the compound 36 with low melting point (608C) has
highlighted a mesophase at 658C and an isotropic liquid at
708C.
Fluoropyrazine 1 and 2-¯uoro-3-iodopyrazine 2 were
synthesized according the procedure described in the
litterature.4
The skilled regioselective metallation of 2-¯uoropyrazines
allowed us to synthesize 5-and 6-iodo-2-¯uoropyrazines
which opened the route to a wide range of materials with
lateral ¯uoro substituents, one of them have exhibited meso-
morphic properties. The synthesis of various compounds
with aryl¯uorodiazines as central building block and
multiple lateral ¯uoro substituents to generate new liquid
crystal materials with low melting points is in progress.
1.1. Procedure A for direct lithiation by lithium 2,2,6,6-
tetramethylpiperidide
A solution of n-butyllithium (1.6 or 2.5 M in hexane) was
added to cold (2508C), stirred and anhydrous THF (15 mL)
under an atmosphere of dry argon. Then 2,2,6,6-tetra-
methylpiperidine (TMPH) was added. The mixture was
warmed to 08C. After 20 min, the mixture temperature
was then carried to the temperature u1 and the pyrazine
dissolved in 5 mL of THF added. After a time t1 at u1, the
electrophile was introduced and stirring was continued for a
time t2 at u2. Hydrolysis was then carried out at u2 using a
solution of 35% aqueous hydrochloric acid, ethanol and
THF (1/4/5) for u2ˆ2788C. At room temperature, the
mixture was made slightly basic with saturated sodium
hydrogen carbonate solution. When the electrophile was
iodine, the solution was decolorized with sodium thio-
sulphate and evaporated nearly to dryness. The residue
was extracted with dichloromethane (3£20 mL), the
1. Experimental
Melting points were determined on a Ko¯er hot-stage. The
1H, 13C and 19F NMR spectra were recorded in deuterio-
chloroform on Bruker instruments (AC 200 and Avance
300). Microanalyses were performed on a Carlo Erba
CHNOS 1160 apparatus. The IR spectra were obtained as
potassium bromide pellets with a Perkin±Elmer FTIR 1650
spectrophotometer.

288
F. Toudic et al. / Tetrahedron 58 (2002) 283±293
combined organic extracts were then dried over magnesium
sulphate and evaporated. The crude product was puri®ed by
column chromatography on silica gel.
(2 equiv., 1.036 g), t2ˆ60 min, u2ˆ2788C gave after puri-
®cation by column chromatography (silica, eluent: dichloro-
methane/petroleum ether (1/2)) 250 mg (35%) of 3 as a
1
yellow solid, mpˆ1488C, H NMR (CDCl3): d 8.58 (d,
1H, JH5±Fˆ3.7 Hz, H5); 19F NMR (CDCl3): d 272.38.
Anal. calcd for C4HFI2N2 (349.86): C, 13.73; H, 0.29; N,
8.01. Found: C, 13.5; H, 0.4; N, 8.2.
1.2. Procedure B for cross-coupling of arylboronic acids
with halodiazines under Suzuki conditions
A mixture of the halodiazine, the arylboronic acid
(n equiv.), Pd(PPh3)4 (0.05 equiv.), aqueous 2 M potassium
carbonate (2 equiv.) and ethanol (1 mL) in degassed toluene
(15 mL) was heated under re¯ux under nitrogen for a time t.
The reaction mixture was cooled, diluted with 20 mL of
water and dichloromethane (1/1) and the organic layer
separated. The aqueous layer was extracted with dichloro-
methane (3£20 mL), the combined organic extracts were
dried over magnesium sulphate and evaporated. The crude
product was puri®ed by column chromatography on silica
gel.
1.4.2. 2-Fluoro-3,5,6-triiodopyrazine (4). Metallation of 1
(200 mg, 2.04 mmol) according procedure A with n-BuLi
1.6 M (4.0 equiv., 5.10 mL), TMPH (4.1 equiv., 1.41 mL),
t1ˆ5 min, u1ˆ2788C, followed by reaction with iodine
(4 equiv., 2.072 g), t2ˆ60 min, u2ˆ2788C gave after puri-
®cation by column chromatography (silica, eluent: dichloro-
methane/petroleum ether (1/2)) 631 mg (65%) of 4 as a
yellow solid, mpˆ138±1398C, 19F NMR (CDCl3): d
267.62. Anal. calcd for C4FI3N2 (475.76): C, 10.10; N,
5.89. Found: C, 10.4; N, 5.8.
1.4.3. 2-Fluoro-3-phenylpyrazine (5). Coupling of phenyl-
boronic acid (1.2 equiv.) with 2 (494 mg, 2.2 mmol) accord-
ing to the general procedure B, tˆ24 h gave after
puri®cation by column chromatography (silica, eluent:
petroleum ether/dichloromethane (1/1)) 276 mg (72%) of
1.3. Procedure C for cross-coupling of organozincic with
idoopyrazines under Negishi conditions
A solution of alkyllithium in hexane was added to cold
(2788C), stirred and anhydrous THF (20 mL) under an
atmosphere of dry argon. Then a solution of dry zinc
chloride (9 equiv.) in dry THF (5 mL) was added. The
mixture was warmed to room temperature, then Pd(PPh3)4
(5 mol%) and a solution of substituted iodopyrazine
(1 equiv.) in THF (5 mL) were introduced. The mixture
was heated under re¯ux under nitrogen for a time t. After
cooling, an aqueous solution of EDTA (9 equiv.) was added,
the solution mixture was made slightly basic with saturated
sodium hydrogen carbonate solution. The reaction mixture
was diluted with 20 mL of water and dichloromethane (1/1).
The aqueous layer was extracted with dichloromethane
(3£20 mL), the combined organic extracts were dried over
magnesium sulphate and evaporated. The crude product was
puri®ed by column chromatography on silica gel.
1
5 as a colorless oil; H NMR (CDCl3): d 8.60 (q, 1H,
JH5±Fˆ4.6 Hz; JH5±H6ˆ2.4 Hz H5); 8.16 (m, 1H, H6); 8.08
(m, 2H, 2HPh); 7.53 (m, 3H, 3HPh); 13C NMR (CDCl3) d
156.8(d, JC2±Fˆ257.2 Hz, C2); 141.4 (d, JC3±Fˆ24.0 Hz,
C3); 140.7 (C5 or C6); 138.5 (C5 or C6); 132.3 (CPh); 129.3
(CHPh); 127.7 (CHPh); 19F NMR (CDCl3): d 274.66. Anal.
calcd for C10H7FN2 (174.11): C, 68.98; H, 4.05; N, 16.09.
Found: C, 68.82; H, 4.08; N, 16.29.
1.4.4. 2-Fluoro-3-(4-n-octyloxy)phenylpyrazine (6).
Coupling of 4 octyloxyphenylboronic acid (970 mg,
1.5 equiv.) with 2 (400 mg, 1.79 mmol) according to the
general procedure B, tˆ24 h gave after puri®cation by
column chromatography (silica, eluent: petroleum ether/
dichloromethane (1/1)) 395 mg (73%) of 6 as a white
1
solid, mpˆ32±348C; H NMR (CDCl3): d 8.45 (dd, 1H,
1.4. Procedure D for reduction of the phenylcarbinol
group into benzyl group
JH5±Fˆ4.9 Hz, JH5±H6ˆ2.6 Hz, H5); 7.96 (m, 3H,
H612HPh); 6.95 (d, 1H, Jˆ9.0 Hz, 2HPh); 3.95 (t, 2H,
CH2); 1.73 (m, 2H, CH2); 1.52±1.22 (massif, 10H, 5CH2);
0.82 (t, 3H, CH3); 13C NMR (CDCl3) d 161.3 (CPh); 157.9
(d, JC2±Fˆ256.5 Hz, C2); 142.6 (d, JC3±Fˆ24.0 Hz, C3);
141.9 (C5 or C6); 138.8 (C5 or C6); 130.7 (CHPh); 126.0
(CPh); 115.0 (CHPh); 68.5 (CH2); 32.2±23.1 (CH2); 14.5
(CH3); 19F NMR (CDCl3): d 274.46. Anal. calcd for
C18H23F3N2 (302.39): C, 71.50; H, 7.67; N, 9.26 Found:
C, 71.67; H,7.72; N, 9.46.
A mixture of trimethylsilyl chloride (6 equiv.) and sodium
iodide (6 equiv.) in dry acetonitrile (10 mL) were stirred at
room temperature for 5 min. Then a solution of phenyl-
pyrazine carbinol (1 equiv.) in acetonitrile (5 mL) was
introduced, the mixture was heated under re¯ux for a time
t. The reaction mixture was cooled, diluted with 60 mL of
water and dichloromethane (1/2), then the solution mixture
was made slightly basic with saturated sodium hydrogen
carbonate solution. The mixture was decolorized by treat-
ment with sodium thiosulphate to eliminate excess of
iodine. The aqueous layer was extracted with dichloro-
methane (3£20 mL), and the organic layer washed with
water (20 mL).The combined organic extracts were dried
over magnesium sulphate and evaporated. The crude
product was puri®ed by column chromatography on silica
gel.
1.4.5. 2-Fluoro-6-(1-hydroxyethyl)-3-phenylpyrazine (7).
Metallation of 5 (80 mg, 0.46 mmol) according procedure A
with n-BuLi 1.6 M (3.1 equiv., 0.89 mL), TMPH
(3.2 equiv., 0.25 mL), t1ˆ5 min, u1ˆ2788C, followed by
reaction with acetaldehyde in excess, t2ˆ60 min,
u2ˆ2788C gave after puri®cation by column chromato-
graphy (silica, eluent: ethylacetate/petroleum ether (1/4))
1
77 mg (77%) of 7 as a yellow oil, H NMR (CDCl3): d
8.67 (d, 1H, JH5±Fˆ4.7 Hz, H5); 8.03 (m, 2H, 2HPh); 7.51
(m, 3H, 3HPh); 5.00 (q, 1H, JCH±CH3ˆ6.6 Hz, CH); 3.00 (s
broad, 1H, OH); 1.61 (d, 3H, JCH3±CHˆ6.6 Hz, CH3); 13C
NMR (CDCl3): d 157.2 (d, JC2±Fˆ259.4 Hz, C2); 155.4
1.4.1. 2-Fluoro-3,6-diiodopyrazine (3). Metallation of 1
(200 mg, 2.04 mmol) according procedure A with n-BuLi
1.6 M (2.1 equiv., 2.66 mL), TMPH (2.2 equiv., 0.76 mL),
t1ˆ5 min, u1ˆ2788C, followed by reaction with iodine

F. Toudic et al. / Tetrahedron 58 (2002) 283±293
289
(C6); 140.9 (d, JC3±Fˆ24.0 Hz, C3); 38.8 (C5); 133.6 (CPh);
130.5 (CHPh); 129.1 (CHPh); 68.2 (CH); 24.0 (CH3); 19F
NMR (CDCl3): d 279.54. Anal. calcd for C12H11FN2O
(218.34): C, 66.01; H, 5.08; N, 12.83. Found: C, 65.92; H,
5.12; N, 12.76.
(CDCl3): d 8.36 (d, 1H, JH6±Fˆ1.7 Hz, H6); 8.06 (m, 2H
2HPh); 7.52 (m, 3H, 3HPh); 13C NMR (CDCl3): d 158.5 (d,
JC2±Fˆ257.2 Hz, C2); 147.7 (C6); 144.3 (d, JC3±Fˆ24.7 Hz,
C3); 132.6 (CPh); 131.3 (CHPh); 129.2 (CHPh); 110.6 (C5);
19F NMR (CDCl3): d 279.76. Anal. calcd for C10H6FIN2
(300.00): C, 40.03; H, 2.02; N, 9.30. Found: C, 40.16; H,
1.98; N, 9.48
1.4.6.
2-Fluoro-6-(1-phenylhydroxymethyl)-3-phenyl-
pyrazine (8). Metallation of 5 (104 mg, 0.60 mmol) accord-
ing procedure A with n-BuLi 1.6 M (3.1 equiv., 1.16 mL),
TMPH (3.2 equiv., 0.32 mL), uˆ2788C, followed by reac-
tion with benzaldehyde (3.1 equiv., 0.18mL), t2ˆ60 min,
gave after puri®cation by column chromatography (silica,
eluent: ethylacetate/petroleum ether (1/4)) 110 mg (72%) of
7 as a beige solid, mpˆ97±988C; 1H NMR (CDCl3): d 8.63
(d, 1H, JH5±Fˆ4.0 Hz, H5); 8.02 (m, 2H, 2HPh); 7.43 (m, 8H,
8HPh); 5.90 (d, 1H, JCH±OHˆ5.0 Hz, CH); 5.30 (s broad, 1H,
OH); 13C NMR (CDCl3): d 157.0 (d, JC2±Fˆ259.4 Hz, C2);
153.7 (C6); 141.7 (CPh); 140.9 (d, JC3±Fˆ23.3 Hz, C3); 139.5
(C5); 133.5 (CPh); 130.6±127.2 (CHPh); 74.4 (CH); 19F NMR
(CDCl3): d 276.15. Anal. calcd for C17H13FN2O (280.30):
C, 72.84; H, 4.67; N, 9.99. Found: C, 72.79; H, 5.03; N,
9.68.
1.4.10. 2-Fluoro-6-iodo-3-phenylpyrazine (12). Metalla-
tion of 5 (150 mg, 0.86 mmol) according procedure A
with n-BuLi 1.6 M (1.1 equiv., 0.59 mL), TMPH
(1.2 equiv., 0.17 mL), t1ˆ5 min, u1ˆ2788C, followed by
reaction with iodine (2 equiv., 438mg), t2ˆ60 min,
u2ˆ2788C gave after puri®cation by column chromato-
graphy (silica, eluent: dichloromethane/petroleum ether
1
(1/4)) 188 mg (73%) of 12 as a white solid, mpˆ978C; H
NMR (CDCl3): d 8.52 (d, 1H, JH5±Fˆ4.3 Hz, H5); 8.04 (m,
2H, 2HPh); 7.51 (m, 3H, 3HPh); 13C NMR (CDCl3): d 156.2
(d, JC2±Fˆ265.9 Hz, C2); 150.1 (C5); 140.9 (d,
JC3±Fˆ21.8Hz, C 3); 132.8(C Ph); 131.0 (CHPh); 129.0
(CHPh); 109.1 (C6); 19F NMR (CDCl3): d 271.17. Anal.
calcd for C10H6FIN2 (300.00): C, 40.03; H, 2.02; N, 9.30.
Found: C, 39.95; H, 2.09; N, 8.96.
1.4.7. 2-Fluoro-3-phenyl-6-(trimethylsilyl)pyrazine (9).
Metallation of 5 (103 mg, 0.59 mmol) according procedure
A with n-BuLi 1.6 M (3.1 equiv., 1.14 mL), TMPH
(3.2 equiv., 0.32 mL), uˆ2788C, followed by reaction
with trimethylsilyl chloride (3.1 equiv., 0.22 mL),
t2ˆ60 min gave after puri®cation by column chromato-
graphy (silica, eluent: ethylacetate/petroleum ether (1/4))
1.4.11. 3.5-Diodo-2-¯uoro-3-phenylpyrazine (13). Metal-
lation of 5 (73 mg, 0.42 mmol) according procedure A with
n-BuLi 1.6 M (2.1 equiv., 0.55 mL), TMPH (2.2 equiv.,
0.16 mL), t1ˆ5 min, u1ˆ2788C, followed by reaction
with iodine (2 equiv., 213 mg), t2ˆ60 min, u2ˆ2788C
gave after puri®cation by column chromatography (silica,
eluent: dichloromethane/petroleum ether (1/1)) 148mg
1
105 mg (73%) of 9 as a yellow oil; H NMR (CDCl3): d
1
8.65 (d, 1H, JH5±Fˆ5.5 Hz, H5); 8.08 (m, 2H, 2HPh); 7.50
(m, 3H, 3HPh); 0.31 (m, 9H, 3CH3); 13C NMR (CDCl3): d
160.8(C 6); 160.2 (d, JC2±Fˆ255.8Hz, C 2); 147.9 (C5); 143.3
(d, JC3±Fˆ24.7 Hz, C3); 135.8(C Ph); 132.2 (CHPh); 130.8
(CHPh); 0.0 (CH3); 19F NMR (CDCl3): d 277.74. Anal.
calcd for C13H15FN2Si (246.36): C, 63.38; H, 6.14; N,
11.37. Found: C, 63.81; H, 6.32; N, 11.34.
(83%) of 13 as a white solid, mpˆ115±1168C; H NMR
(CDCl3): d 8.03 (m, 2H, 2HPh); 7.51 (m, 3H, 3HPh); 13C
NMR (CDCl3): d 155.0 (d, JC2±Fˆ264.5 Hz, C2); 141.2 (d,
JC3±Fˆ23.3 Hz, C3); 131.8(C Ph); 131.5 (CHPh); 129.1
(CHPh); 124.1 (C5 or C6); 122.5 (C5 or C6); 19F NMR
(CDCl3): d 276.55. Anal. calcd for C10H5FI2N2 (425.90):
C, 28.20; H, 1.42; N, 6.58. Found: C, 28.33; H, 1.30; N,
6.28.
1.4.8. 2-Fluoro-3-phenyl-6-(tributylstannyl)pyrazine (10).
Metallation of 5 (75 mg, 0.43 mmol) according procedure A
with n-BuLi 1.6 M (3.1 equiv., 0.83 mL), TMPH (3.2 equiv.,
0.23 mL), t1ˆ5 min, u1ˆ2788C, followed by reaction with
tributyltin chloride (3 equiv., 0.35 mL), t2ˆ60 min,
u2ˆ2788C gave after puri®cation by column chromato-
graphy (silica, eluent: ethylacetate/petroleum ether (1/4))
1.4.12. 2-Fluoro-6-(1-hydoxyethyl)-5-iodo-3-phenylpyra-
zine (14). Metallation of 13 (200 mg, 0.47 mmol) according
to procedure A with n-BuLi 1.6 M (3.1 equiv., 0.91 mL),
TMPH (3.2 equiv., 0.25 mL), t1ˆ5 min, u1ˆ2788C,
followed by reaction with acetaldehyde in excess,
t2ˆ60 min, u2ˆ2788C gave after puri®cation by column
chromatography (silica, eluent: ethylacetate/petroleum
ether (1/4)) 108mg (67%) of 14 as a white solid,
mpˆ104±1058C; 1H NMR (CDCl3): d 7.94 (m, 2H,
2HPh); 7.39 (m, 3H, 3HPh); 5.03 (q, 1H, JCH±CH3ˆ6.4 Hz,
CH); 3.15 (s large, 1H, OH); 1.45 (d, 3H, JCH3±CHˆ6.4 Hz,
CH3); 13C NMR (CDCl3): d 157.8(d, JC2±Fˆ260.1 Hz, C2);
157.0 (C6); 142.4 (d, JC3±Fˆ24.7 Hz, C3); 132.3 (CPh); 131.1
1
117 mg (59%) of 10 as a yellow oil; H NMR (CDCl3): d
8.46 (d, 1H, JH5±Fˆ5.6 Hz, H5); 7.98(m, 2H, 2H Ph); 7.39 (m,
3H, 3HPh); 1.60±0.79 (massif, 27H, n-Bu); 13C NMR
(CDCl3): d 165.3 (C6); 158.9 (d, JC2±Fˆ255.7 Hz, C2);
148.9 (C5); 140.4 (d, JC3±Fˆ24.7 Hz, C3); 134.3 (CPh);
130.3 (CHPh); 129.1 (CHPh); 29.4 (CH2); 27.7 (CH2); 14.1
(CH3); 10.5 (CH2); 19F NMR (CDCl3): d 273.93; LRMS(IC)
[M1H]: 464 for C22H33FN2Sn (463.22).
(CHPh); 139.2 (CHPh); 110.0 (C5); 69.8(CH); 23.6 (CH ).
3
Anal. calcd for C12H10FIN2O (344.12): C, 41.88; H, 2.93; N,
8.14. Found: C, 41.93; H, 2.98; N, 8.16.
1.4.9. 2-Fluoro-5-iodo-3-phenylpyrazine (11). Metallation
of 5 (168mg, 0.97 mmol) according with procedure A with
n-BuLi 1.6 M (3.1 equiv., 1.87 mL), TMPH (3.2 equiv.,
0.52 mL), t1ˆ5 min, u1ˆ2788C, followed by reaction
with iodine (2 equiv., 245 mg), t2ˆ60 min, u2ˆ2788C
gave after puri®cation by column chromatography (silica,
eluent: dichloromethane/petroleum ether (1/4)) 165 mg
(64%) of 11 as a white solid, mp,508C; 1H NMR
1.4.13. 3.5-Diphenyl-2-¯uoropyrazine (15). Coupling of
phenylboronic acid (98mg, 1.2 equiv.) with 11 (200 mg,
0.67 mmol) according to the procedure B (toluene,
tˆ24 h) gave after puri®cation by column chromatography
(silica gel, eluent: petroleum ether/dichloromethane (2/1))
1
113 mg (68%) of 15 as a white solid, mpˆ69±708C; H

290
F. Toudic et al. / Tetrahedron 58 (2002) 283±293
NMR (CDCl3): d 8.38 (d, 1H, JH6±Fˆ1.9 Hz, H6); 8.07 (m,
2H, 2HPh); 7.93 (m, 2H, 2HPh); 7.39 (m, 6H, 6HPh); 13C
NMR (CDCl3): d 157.4 (d, JC2±Fˆ256.5 Hz, C2); 150.3
(C5); 140.39 (d, JC3±Fˆ24.0 Hz, C3); 136.6 (C6); 135.9
(CPh); 134.0 (CPh); 130.8±127.2 (CHPh); 19F NMR
(CDCl3): 279.57. Anal. calcd for C16H11N2F (250.26): C,
76.78; H, 4.43; N, 11.19. Found: C, 76.66; H, 4.45; N, 11.32.
2.04 mmol) according procedure A with n-BuLi 1.6 M
(1.1 equiv., 1.40 mL), TMPH (1.2 equiv., 0.41 mL),
t1ˆ5 min, u1ˆ2788C, followed by reaction with 4-n-dode-
cyloxybenzaldehyde (1.5 equiv., 0.84 mL), t2ˆ60 min,
u2ˆ2788C gave after puri®cation by column chromato-
graphy (silica, eluent: ethylacetate/cyclohexane (3/8))
1
523 mg (66%) of 19 as a white solid, mpˆ64±658C; H
NMR (CDCl3): d 8.34 (m, 1H, H5) 8.02 (s, 1H, H6); 7.17
(d, 2H, Jˆ8.4 Hz, 2HPh); 6.75 (d, 2H, Jˆ8.4 Hz, 2HPh); 5.83
(d, 1H, CH); 4.58(s, 1H, OH); 3.82 (t, 2H, CH 2); 1.65 (m,
1.4.14. 5-Butyl-2-¯uoro-3-phenylpyrazine (16). Cross-
coupling reaction of butylzinc chloride (obtained by reac-
tion of zinc chloride (676 mg, 9 equiv.) and n-BuLi 1.6 M
(3 equiv., 1.03 mL)) and 11 (165 mg, 0.55 mmol) with
32 mg of Pd(PPh3)4 according procedure C for a time of
24 h gave after puri®cation by column chromatography
(silica, eluent: dichloromethane/petroleum ether (1/2))
2H, CH2); 1.33±1.17 (m, 18H, 9CH2); 0.78(t, 3H, CH 3); 13
C
NMR (CDCl3): d 159.6 (CPh); 157.6 (d, JC2±Fˆ254.8Hz,
C2); 146.8(d, JC3±Fˆ28.9 Hz, C3); 140.7 (C5, C6) 138.0
(CPh); 128.1 (2CHPh); 115.0 (2CHPh), 70.7 (CH); 68.4
(CH2); 32.3±23.1 (CH2); 14.53 (CH3); 19F NMR (CDCl3):
d 276.81. Anal. calcd for C25H33FN2O2 (388.53): C, 71.10;
H, 9.86; N, 7.21. Found: C, 71.22; H, 9.77; N, 7.26.
1
68mg (53%) of 16 as a colorless oil; H NMR (CDCl3): d
7.98(m, 2H, 2H Ph); 7.85 (d, 1H, JH6±Fˆ1.5 Hz, H6); 7.39
(m, 3H, 3HPh); 2.78(t, 2H, CH ); 1.69 (m, 2H, CH2); 1.33
2
(m, 2H, CH2); 0.88 (t, 3H, CH3); 13C NMR (CDCl3): d 156.9
(d, JC2±Fˆ260.1 Hz, C2); 155.1 (C5); 140.9 (d,
JC3±Fˆ24.0 Hz, C3); 138.7 (C6); 134.1 (CPh); 130.4
(CHPh); 129.1 (CHPh); 34.6 (CH2); 31.0 (CH2); 22.7
(CH2); 14.3 (CH3); 19F NMR (CDCl3): d 281.52. Anal.
calcd for C14H15N2F (230.28): C, 73.02; H, 6.57; N, 12.16.
Found: C, 72.80; H, 6.64; N, 12.28.
1.4.18. 2-Fluoro-3-(phenylhydroxymethyl)-6-iodopyra-
zine (20). Metallation of 17 (500 mg, 2.45 mmol) according
procedure A with n-BuLi 1.6 M (3.1 equiv., 4.75 mL),
TMPH (3.1 equiv., 3.1 mL), t1ˆ5 min, u1ˆ2788C,
followed by reaction with iodine (2.0 equiv., 1.25 g),
t2ˆ60 min, u2ˆ2788C gave after puri®cation by column
chromatography (silica, eluent: ethylacetate/cyclohexane
1
(1/4)) 679 mg (84%) of 20 as a colorless liquid; H NMR
1.4.15. 2-Fluoro-3-(1-phenylhydroxymethyl)pyrazine (17).
Metallation of 1 (200 mg, 2.04 mmol) according procedure A
with n-BuLi 1.6 M (1.1 equiv., 1.40 mL), TMPH (1.2 equiv.,
0.41 mL), t1ˆ5 min, u1ˆ2788C, followed by reaction with
benzaldehyde (1.5 equiv., 0.31 mL), t2ˆ60 min, u2ˆ2788C
gave after puri®cation by column chromatography (silica,
eluent: ethylacetate/cyclohexane (3/8)) 296 mg (71%) of 17
(CDCl3): d 8.70 (d, 1H, JH5±Fˆ3.7 Hz, H5), 7.31 (m, 5H,
phenyl), 5.90 (d, 1H, JCH±OHˆ7.0 Hz, CH), 4.32 (d, 1H,
JOH±CHˆ7.0 Hz, OH); 19F NMR (CDCl3): d 274.41. Anal.
calcd for C11H8FIN2O (330.10): C, 40.02; H, 2.44; N, 8.48.
Found: C, 39.90; H, 2.41; N, 8.62.
1.4.19.
2-Fluoro-3-[1-(4-n-decyloxyphenyl)hydroxy-
1
as a white solid, mpˆ81±828C; H NMR (CDCl3): d 8.46
methyl)]-6-iodopyrazine (21). Metallation of 8 (200 mg,
0.56 mmol) according procedure A with n-BuLi 1.6 M
(3.1 equiv., 1.07 mL), TMPH (3.2 equiv., 0.30 mL),
t1ˆ5 min, u1ˆ2788C, followed by reaction with iodine
(2 equiv., 282 mg), t2ˆ60 min, u2ˆ2788C gave after
puri®cation by column chromatography (silica, eluent:
ethylacetate/cyclohexane (1/4)) 162 mg (60%) of 21 as a
(dd, 1H, JH5±H6ˆ2.7 Hz, J5-Fˆ3.9 Hz, H5), 8.14 (m, 1H, H6),
7.30 (m, 5H, phenyl), 5.97 (d, 1H, JCH±OHˆ5.6 Hz, CH), 4.64
(d, 1H, OH); 19F NMR (CDCl3): d 277.58. Anal. calcd for
C11H9FN2O (204.20): C, 64.70; H, 4.44; N, 13.70. Found: C,
64.6; H, 4.3; N, 13.9.
1
1.4.16.
methyl]pyrazine (18). Metallation of
2-Fluoro-3-[1-(4-n-decyloxyphenyl)hydroxy-
(200 mg,
white solid, mpˆ46±478C; H NMR (CDCl3): d 8.63 (d,
1
1H, JH5±Fˆ3.8Hz, H 5); 7.16 (d, 2H, Jˆ8.7 Hz, 2HPh); 6.76
(d, 2H, Jˆ8.7 Hz, 2HPh); 5.78(s, 1H, CH); 4.14 (s. large,
1H, OH); 3.83 (t, 2H, CH2); 1.67 (m, 2H, CH2); 1.36±1.18
(massif, 14H, 7CH2); 0.77 (t, 3H, CH3); 13C NMR (CDCl3):
d 159.7 (CPh); 155.6 (d, JC2±Fˆ262.9 Hz, C2); 149.0 (C5);
145.0 (d, JC3±Fˆ27.1 Hz, C3); 132.2 (CPh); 128.4 (2CHPh);
115.2 (2CHPh); 109.9 (C6); 70.5 (CH); 68.4 (CH2); 32.3±
23.1 (CH2); 13.53 (CH3); 19F NMR (CDCl3): d 273.52.
Anal. calcd for C21H28FIN2O2 (486.62): C, 51.83; H, 5.80;
N, 5.76. Found: C, 51.88; H, 5.86; N, 5.74.
2.04 mmol) according procedure A with n-BuLi 1.6 M
(1.1 equiv., 1.40 mL), TMPH (1.2 equiv., 0.41 mL),
t1ˆ5 min, u1ˆ2788C, followed by reaction with 4-n-
decyloxybenzaldehyde (1.5 equiv., 0.84 mL), t2ˆ60 min,
u2ˆ2788C gave after puri®cation by column chromato-
graphy (silica, eluent: ethylacetate/cyclohexane (3/8))
1
518mg (71%) of 18 as a white solid, mpˆ62±638C; H
NMR (CDCl3): d 8.36 (d, 1H, JH5±Fˆ3 Hz, H5); 8.05 (s,
1H, H6); 7.18(d, 2H, Jˆ8.6 Hz, 2HPh); 6.77 (d, 2H,
Jˆ8.6 Hz, 2HPh); 5.85 (d, 1H, JCH±OHˆ6.4 Hz, CH); 4.53
(d, 1H, JOH±CHˆ6.4 Hz, OH); 3.83 (t, 2H, CH2); 1.66 (m,
1.4.20. 2-Fluoro-3-[1-(4-n-dodecyloxyphenyl)hydroxy-
methyl)]-6-iodopyrazine (22). Metallation of 19 (300 mg,
0.77 mmol) according procedure A with n-BuLi 1.6 M
(3.1 equiv., 1.50 mL), TMPH (3.2 equiv., 0.42 mL),
t1ˆ5 min, u1ˆ2788C, followed by reaction with iodine
(2 equiv., 392 mg), t2ˆ60 min, u2ˆ2788C gave after puri-
®cation by column chromatography (silica, eluent: ethyl-
acetate/cyclohexane (1/4)) 233 mg (59%) of 22 as a
yellow solid, mpˆ51±528C; 1H NMR (CDCl3): d 8.72
(d,1H, JH5±Fˆ3.5 Hz, H5); 7.25 (d, 2H, Jˆ8.3 Hz, 2HPh)
6.65 (d, 2H, Jˆ8.3 Hz, 2HPh); 5.87 (d, 1H, JCH±OHˆ6.0 Hz,
2H, CH2); 1.36±1.18(m, 14H, 7CH 2); 0.79 (t, 3H, CH3); 13
C
NMR (CDCl3): d 159.6 (CPh); 157.6 (d, JC2±Fˆ254.5 Hz,
C2); 146.4 (d, JC3±Fˆ29.0 Hz, C3); 140.7 (C5, C6) 132.8
(CPh); 128.5 (2CHPh); 115.1 (2CHPh); 70.7 (CH); 68.4
(CH2); 32.3±23.1 (CH2); 12.4 (CH3); 19F NMR (CDCl3):
d 276.77. Anal. calcd for C21H29FN2O2 (360.42): C,
69.97; H, 8.11; N, 7.77. Found: C, 69.80; H, 8.52; N, 7.97.
1.4.17. 2-Fluoro-3-[1-(4-n-dodecyloxyphenyl)hydroxy-
1
methyl]pyrazine (19). Metallation of
(200 mg,

F. Toudic et al. / Tetrahedron 58 (2002) 283±293
291
1
CH); 4.27 (d, 1H, JOH±CHˆ6.0 Hz, OH); 3.92 (t, 2H, CH2)
1.76 (m, 2H, CH2); 1.27 (massif, 18H, 9CH2) 0.89 (t, 3H,
CH3); 13C NMR (CDCl3): d 159.7 (CPh); 155.6 (d,
JC2±Fˆ262.6 Hz, C2); 148.9 (C5); 132.2 (CPh); 128.4
(2CHPh); 115.1 (2CHPh); 109.9 (C6); 70.5 (CH); 68.4
(CH2); 32.3±23.1 (CH2); 14.5 (CH3); 19F NMR (CDCl3):
d 273.53. Anal. calcd for C23H32FIN2O2 (514.43): C,
53.69; H, 6.29; N, 5.45. Found: C, 53.76; H, 6.68; N, 5.27.
(72%) of 26 as a yellow oil; H NMR (CDCl3): d 8.27 (d,
1H, JH5±Fˆ4.1 Hz, H5), 7.29 (m, 5H, 5HPh), 4.14 (s, 2H,
CH2), 2.73 (t, 2H, CH2) 1.69 (qt, 2H, CH2), 1.37 (qt, 2H,
CH2), 0.95 (t, 3H, CH3); 13C NMR (CDCl3): d 158.4 (d,
JC2±Fˆ253.5 Hz, C2); 154.8(C ); 142.0 (d, JC3±Fˆ29.1 Hz,
6
C3); 140.5 (C5); 137.7 (CPh); 129.2 (CHPh); 126.1 (CHPh);
38.2±22.7 (CH2); 14.2 (CH3); 19F NMR (CDCl3): d 279.94.
Anal. calcd for C15H17FN2 (244.32): C, 73.74; H, 7.01; N,
11.47. Found: C, 73.31; H, 7.03; N, 11.78.
1.4.21. 2-Fluoro-3-benzyl 6-iodopyrazine (23). Reduction
of 20 (686 mg, 2.08 mmol) according procedure D with
heating for 6 h gave after puri®cation by column chromato-
graphy (silica, eluent: dichloromethane/petroleum ether
(1/1)) 450 mg (69%) of 23 as a white solid, mpˆ51±
H5), 7.30 (m,5H, 5HPh), 4.16 (s, 2H, CH2); 13C NMR
(CDCl3): d 157.1 (d, JC2±Fˆ263.3 Hz, C2); 149.9 (C5);
144.0 (d, JC3±Fˆ27.1 Hz, C3); 136.7 (CPh); 129.2 (CHPh);
127.5 (CHPh); 109.1 (C6); 38.0 (CH2); 19F NMR (CDCl3):
d 274.59. Anal. calcd for C11H8FIN2 (314.10): C, 42.06; H,
2.56; N, 8.92. Found: C, 42.02; H, 2.42; N, 9.06.
1.4.25. 2-Fluoro-3-benzyl-6-hexylpyrazine (27). Cross-
coupling reaction of hexylzinc chloride (obtained by
reaction of zinc chloride (82 mg, 9 equiv.) and n-HexLi
33 wt% (3 equiv., 0.81 mL)) and 23 (210 mg, 0.67 mmol)
with 39 mg of Pd(PPh3)4 according procedure C for a time
of 24 h gave after puri®cation by column chromatography
(silica, eluent: dichloromethane/petroleum ether (1/1))
1
528C; H NMR (CDCl3): d 8.68 (d, 1H, JH5±Fˆ3.8Hz,
1
164 mg (90%) of 27 as an orange oil; H NMR (CDCl3):
d 8.26 (d, 1H, JH5±Fˆ4.4 Hz, H5); 7.25 (m, 5H, 5HPh); 4.19
(s, 2H, CH2); 2.72 (t, 2H, CH2); 1.69 (m, 2H, CH2); 1.32
(m, 6H, 3CH2); 0.89 (t, 3H, CH3); 13C NMR (CDCl3): d
158.4 (d, JC2±Fˆ253.4 Hz, C2); 154.3 (C6); 142.0 (d,
JC3±Fˆ29.1 Hz, C3); 140.8(C 5); 137.7 (CPh); 129.0
(CHPh); 127.2 (CHPh); 38.2±20.0 (CH2); 14.4 (CH3); 19F
NMR (CDCl3): d 279.84. Anal. calcd for C17H21FN2
(272.36): C, 77.96; H, 7.77; N, 10.29. Found: C, 74.92; H,
7.66; N, 10.28.
1.4.22. 2-Fluoro-3-(4-n-decyloxybenzyl)-6-iodopyrazine
(24). Reduction of 21 (400 mg, 0.82 mmol) according
procedure D with heating for 6 h gave after puri®cation by
column chromatography (silica, eluent: dichloromethane/
petroleum ether (1/1)) 300 mg (78%) of 24 as a white
1
solid, mpˆ42±438C; H NMR (CDCl3): d 8.66 (d, 1H,
JH5±Fˆ3.8Hz, H 5); 7.20 (d, 2H, Jˆ8.6 Hz, 2HPh); 6.84 (d,
2H, Jˆ8.6 Hz, 2HPh); 4.08(s, 2H, CH 2); 3.92 (t, 2H, CH2);
1.77 (m, 2H, CH2); 1.44±1.28(massif, 12H, 6CH 2); 0.90 (t,
3H, CH3); 13C NMR (CDCl3): d 158.7(CPh); 157.1 (d,
JC2±Fˆ263.0 Hz, C2); 149.9 (C5); 144.4 (d, JC3±Fˆ26.9 Hz,
C3); 130.4 (2CHPh); 128.4 (CPh); 115.2 (2CHPh); 108.7 (C6);
68.4 (CH2); 37.2±23.1 (CH2); 14.5 (CH3); 19F NMR
1.4.26. 2-Fluoro-3-(4-n-decyloxybenzyl)-6-hexylpyrazine
(28). Cross-coupling reaction of hexylzinc chloride
(obtained by reaction of zinc chloride (419 mg, 9 equiv.)
and n-HexLi 33 wt% (3 equiv., 0.42 mL)) and 24
(160 mg, 0.84 mmol) with 20 mg of Pd(PPh3)4 according
procedure C for a time of 24 h gave after puri®cation by
column chromatography (silica, eluent: dichloromethane/
petroleum ether (1/1)) 69 mg (47%) of 28 as a white solid,
(CDCl3):
d
274.92. Anal. calcd for C21H28FION2
(470.36): C, 53.62; H, 6.00; N, 5.96. Found: C, 53.70; H,
6.39; N, 5.96.
mpˆ22±238C; 1H NMR (CDCl3):
d 8.16 (d, 1H,
JH5±Fˆ4.1 Hz, H5); 7.14 (d, 2H, Jˆ8.3 Hz, HPh); 6.74 (d,
2H, Jˆ8.3 Hz, 2HPh); 4.02 (s, 2H CH2); 3.83 (t, 2H, CH2);
2.63 (t, 2H, CH2); 1.66 (m, 4H, 2CH2); 1.35±1.19 (massif,
20H, 10CH2); 0.80 (t, 3H, CH3); 13C NMR (CDCl3): d 158.4
(CPh); 158.3 (d, JC2±Fˆ253.5 Hz, C2); 154.1 (C6); 142.4 (d,
JC3±Fˆ28.9 Hz, C3); 140.7 (C5); 130.3 (2CHPh); 129.5 (CPh);
115.0 (2CHPh); 68.3 (CH2); 37.4±26.4 (CH2); 14.5 (CH3);
19F NMR (CDCl3): d 279.93. Anal. calcd for C28H41FN2
(428.57): C, 75.67; H, 9.64; N, 6.54. Found: C, 75.45; H,
9.73; N, 6.65.
1.4.23. 2-Fluoro-3-(4-n-dodecyloxybenzyl)-6-iodopyra-
zine (25). Reduction of 22 (218mg, 0.42 mmol) according
procedure D with heating for 2 h gave after puri®cation by
column chromatography (silica, eluent: dichloromethane/
petroleum ether (1/1)) 176 mg (84%) of 25 as a white
1
solid, mpˆ49±508C; H NMR (CDCl3): d 8.57 (d, 1H,
JH5±Fˆ3.8Hz, H 5); 7.10 (d, 2H, Jˆ8.3 Hz, 2HPh); 6.75 (d,
2H, Jˆ8.3 Hz, 2HPh); 3.99 (s, 2H, CH2); 3.83 (t, 2H, CH2);
1.67 (m, 2H, CH2); 1.38±1.19 (massif, 18H, 9CH2); 0.80 (t,
3H, CH3); 13C NMR (CDCl3): d 157.2 (CPh); 155.6 (d,
JC2±Fˆ262.8Hz, C 2); 148.4 (C5); 143.0 (d, JC3±Fˆ26.9 Hz,
C3); 128.9 (2CHPh); 126.9 (CPh); 113.7 (2CHPh); 107.3 (C6);
66.9 (CH2); 35.7±21.7 (CH2); 13.1 (CH3); 19F NMR
1.4.27. 2-Fluoro-3-(4-n-dodecyloxybenzyl)-6-hexylpyra-
zine (29). Cross-coupling reaction of hexylzinc chloride
(obtained by reaction of zinc chloride (433 mg, 9 equiv.)
and n-HexLi 33 wt% (3 equiv., 0.43 mL)) and 25
(176 mg, 3.5 mmol) with 20 mg of Pd(PPh3)4 according
procedure C for a time of 24 h gave after puri®cation by
column chromatography (silica, eluent: dichloromethane/
petroleum ether (1/1)) 126 mg (79%) of 29 as a white
(CDCl3):
d
274.92. Anal. calcd for C23H32FION2
(498.43): C, 55.42; H, 6.47; N, 5.62. Found: C, 55.64; H,
6.73; N, 5.78.
1
1.4.24. 2-Fluoro-3-benzyl-6-butylpyrazine (26). Cross-
coupling reaction of butylzinc chloride (obtained by reac-
tion of zinc chloride (1.13 g, 9 equiv.) and n-BuLi 1.6 M
(3 equiv., 1.72 mL)) and 23 (290 mg, 0.92 mmol) with
53 mg of Pd(PPh3)4 according procedure C for a time of
24 h gave after puri®cation by column chromatography
(silica, eluent: ethylacetate/petroleum ether (1/4)) 161 mg
solid, mpˆ37±388C; H NMR (CDCl3): d 8.15 (d, 1H,
JH5±Fˆ4.1 Hz, H5); 7.12 (d, 2H, Jˆ8.6 Hz, 2HPh); 6.73 (d,
2H, Jˆ8.6 Hz, 2HPh); 4.00 (s, 2H, CH2); 3.81 (t, 2H, CH2);
2.61 (t, 2H, CH2); 1.63 (m, 4H, 2CH2); 1.33±1.17 (massif,
24H, 12CH2); 0.79 (m, 6H, 2CH3); 13C NMR (CDCl3): d
158.4 (CPh); 158.3 (d, JC2±Fˆ253.6 Hz, C3); 154.1 (C6);
142.4 (d, JC3±Fˆ29.0 Hz, C3); 140.7 (C5); 130.3 (2CHPh);

292
F. Toudic et al. / Tetrahedron 58 (2002) 283±293
129.5 (CPh); 115.0 (2CHPh); 68.3 (CH2); 37.4±22.9
(CH2); 14.4 (CH3). Anal. calcd for C29H45FN2 (456.68):
C, 76.27; H, 9.93; N, 6.13. Found: C, 76.35; H, 9.91; N,
6.04.
1.4.31. 2-Fluoro-3-(4-n-decyloxybenzyl)-6-(4-n-octyloxy-
phenyl)pyrazine (33). Coupling of 4-n-octyloxyphenyl-
boronic acid (71 mg, 1.2 equiv.) with 25 (89 mg,
0.19 mmol) according to the general procedure B (toluene,
tˆ24 h) gave after puri®cation by column chromatography
(silica gel, eluent: petroleum ether/dichloromethane (1/1))
85 mg (82%) of 33 as a white solid, mpˆ70±718C; 1H NMR
(CDCl3): d 8.77 (d, 1H, JH5±Fˆ4.5 Hz, H5); 7.92 (d, 2H,
Jˆ8.5 Hz, 2HPh); 7.25 (d, 2H, Jˆ8.1 Hz, 2HPh); 6.99 (d,
2H, Jˆ8.5 Hz, 2HPh); 6.84 (d, 2H, Jˆ8.1 Hz, 2HPh); 4.16
(s, 2H, CH2); 4.01 (t, 2H, CH2); 3.92 (t, 2H, CH2); 1.72 (m,
4H, 2CH2); 1.44±1.28(m, 24H, 12CH 2); 0.90 (m, 6H,
2CH3); 13C NMR (CDCl3): d 161.3 (CPh); 158.4 (CPh);
158.0 (d, JC2±Fˆ252.9 Hz, C2); 148.9 (C6); 142.2 (d,
JC3±Fˆ29.8Hz, C 3); 137.5 (C5); 130.3 (2CHPh): 129.6
(CPh); 128.6 (2CHPh); 127.4 (CPh); 115.4 (2CHPh); 115.1
(2CHPh); 68.4 (CH2); 37.4±23.1 (CH2); 14.5 (CH3); 19F
NMR (CDCl3): d 279.63. Anal. calcd for C35H49FN2
(548.78): C, 76.60; H, 9.00; N, 5.10. Found: C, 76.85; H,
9.18; N, 5.36.
1.4.28.
2-Fluoro-3-benzyl-6-phenylpyrazine
(30).
Coupling of phenylboronic acid (96 mg, 1.2 equiv.) with
23 (206 mg, 0.66 mmol) according to the general procedure
B (toluene, tˆ24 h) gave after puri®cation by column
chromatography (silica gel, eluent: petroleum ether/
dichloromethane (2/1)) 148mg (85%) of 30 as a white
1
solid, mpˆ95±968C; H NMR (CDCl3): d 8.86 (d, 1H,
JH5±Fˆ4.8Hz, H 5); 7.99 (m, 2H, 2HPh); 7.50 (m, 3H, 3
HPh); 7.36 (m, 5H, 5 HPh); 4.27 (s, 2H, CH2); 13C NMR
(CDCl3): d 156.9 (d, JC2±Fˆ254.3 Hz, C2); 147.6 (C6);
141.7 (d, JC3±Fˆ29.8Hz, C 3); 136.7 (C5); 136.1 (CPh);
133.6 (CPh); 129.1 (CHPh); 127.9 (CHPh); 127.7 (CHPh);
125.4 (CHPh); 36.8(CH ); 19F NMR (CDCl3): d ±79.16.
2
Anal. calcd for C17H13FN2 (264.31): C, 77.24; H, 4.95; N,
10.60. Found: C, 77.38; H, 4.98; N, 10.68.
1.4.29. 2-Fluoro-3-(4-n-decyloxybenzyl)-6-(4-tri¯uoro-
methylphenyl)pyrazine (31). Coupling of 4-tri¯uoro-
methylphenylboronic acid (90 mg, 1.5 equiv.) with 24
(150 mg, 0.32 mmol) according to the general procedure
B (toluene, tˆ24 h) gave after puri®cation by column
chromatography (silica gel, eluent: petroleum ether/
dichloromethane (2/1)) 125 mg (80%) of 31 as a white
1.4.32. 2-Fluoro-3-(4-n-dodecyloxybenzyl)-6-(4-n-octyl-
oxyphenyl)pyrazine (34). Coupling of 4-n-octyloxy-
phenylboronic acid (104 mg, 1.2 equiv.) with 25 (173 mg,
0.35 mmol) according to the general procedure B (toluene,
tˆ24 h) gave after puri®cation by column chromatography
(silica gel, eluent: petroleum ether/dichloromethane (1/1))
1
143 mg (71%) of 34 as a white solid mpˆ80±818C; H
1
solid, mpˆ76±778C; H NMR (CDCl3): d 8.88 (d, 1H,
NMR (CDCl3): d 8.67 (d, 1H, JH5±Fˆ4.5 Hz, H5); 7.82
(d, 2H, Jˆ8.7 Hz, 2HPh); 7.15 (d, 2H, Jˆ8.1 Hz, 2HPh);
6.88 (d, 2H, Jˆ8.7 Hz, 2HPh); 6.74 (d, 2H, Jˆ8.1 Hz);
4.05 (s, 2H, CH2); 3.90 (t, 2H, CH2); 3.81 (t, 2H, CH2);
JH5±Fˆ4.4 Hz, H5); 8.10 (d, 2H, Jˆ8.7 Hz, 2HPh); 7.75 (d,
2H, Jˆ8.7 Hz, 2HPh); 6.86 (d, 2H, Jˆ8.7 Hz, 2HPh); 4.21 (s,
2H, CH2); 3.92 (t, 2H, CH2); 1.75 (m, 2H, CH2); 1.44±1.27
(m, 12H, 6CH2); 0.86 (t, 3H, CH3); 13C NMR (CDCl3): d
158.6 (CPh); 158.2 (d, JC2±Fˆ255.8Hz, C 2); 147.2 (C6);
145.1 (d, JC3±Fˆ29.1 Hz, C3); 138.4 (CPh); 138.4 (C5);
132.2 (q, JC±Fˆ32.7 Hz, CPh); 125.9 (2CHPh); 126.5 (CPh);
126.4 (2CHPh); 126.3 (2CHPh); 124.3 (q, JC±Fˆ272.5 Hz,
CF3); 115.1 (2CHPh); 68.4 (CH2); 37.6±23.1 (CH2); 14.5
(CH3); 19F NMR (CDCl3): d 279.39. Anal. calcd for
C28H32F4N2 (488.56): C, 68.84; H, 6.60; N, 5.73. Found:
C, 68.69; H, 6.89; N, 5.58.
1.68(m, 4H, 2CH ); 1.33±1.00 (m, 28H, 14CH2); 0.80
2
(m, 6H, 2CH3); 13C NMR (CDCl3): d 161.3 (CPh); 158.4
(CPh); 158.3 (d, JC2±Fˆ253.8Hz, C 2); 148.9 (C6); 142.2 (d,
JC3±Fˆ29.1 Hz, C3); 137.5 (C5); 130.4 (2CHPh); 129.6 (CPh);
128.6 (2CHPh); 127.4 (CPh); 115.4 (2CHPh); 115.1 (2CHPh);
68.4 (2CH2); 37.4±23.0 (CH2); 14.5 (CH3); 19F NMR
(CDCl3): d 279.62. Anal. calcd for C37H53FN2 (576.34):
C, 77.04; H, 9.26; N, 4.86. Found: C, 77.12; H, 9.38; N,
5.02.
1.4.30.
¯uoromethylphenyl)pyrazine
2-Fluoro-3-(4-n-dodecyloxybenzyl)-6-(4-tri-
(32). Coupling of
1.4.33. 2-Fluoro-3-(4-n-decyloxybenzyl)-6-(2,3-di¯uoro-
4-n-octyloxyphenyl)pyrazine (35). Coupling of 2,3-
di¯uoro-4-n-octyloxyphenylboronic acid (73 mg, 1.2
equiv.) with 24 (100 mg, 0.21 mmol) according to the
general procedure B (toluene, tˆ24 h) gave after puri®ca-
tion by column chromatography (silica gel, eluent:
petroleum ether/dichloromethane (1/1)) 78mg (63%) of
4-tri¯uoromethylphenylboronic acid (90 mg, 1.5 equiv.)
with 25 (157 mg, 0.82 mmol) according to the general
procedure B (toluene, tˆ24 h) gave after puri®cation by
column chromatography (silica gel, eluent: petroleum
ether/dichloromethane (2/1)) 104 mg (86%) of 32 as a
1
1
white solid, mpˆ78±798C; H NMR (CDCl3): d 8.88 (d,
35 as a white solid mpˆ70±718C; H NMR (CDCl3): d
1H, JH5±Fˆ4.4 Hz, H5); 8.10 (d, 2H, Jˆ8.2 Hz, 2HPh); 7.75
(d, 2H, Jˆ8.2 Hz, 2HPh); 7.27 (d, 2H, Jˆ8.5 Hz, 2HPh); 6.86
(d, 2H, Jˆ8.5 Hz, 2HPh); 4.21 (s, 2H, CH2); 3.93 (t, 2H,
CH2); 1.72 (m, 2H, CH2); 1.43±1.27 (m, 18H, 9CH2);
0.89 (t, 3H, CH3); 13C NMR (CDCl3): d 158.6 (CPh):
158.2 (d, JC2±Fˆ255.7 Hz, C2); 147.2 (C6); 145.1 (d,
JC3±Fˆ29.1 Hz, C3); 135.4 (CPh): 138.3 (C5); 131.8(q,
JC±Fˆ32.7 Hz, CPh); 130.4 (2CHPh); 128.9 (CPh); 127.5
(2CHPh); 126.4 (2CHPh); 124.3 (q, JC±Fˆ271.6 Hz, CF3);
115.1 (2CHPh); 68.4 (CH2); 37.6±23.1 (CH2); 14.50
(CH3); 19F NMR (CDCl3): d 278.47. Anal. calcd for
C30H36F4N2 (516.62): C, 69.75; H, 7.02; N, 5.42. Found:
C, 69.62; H, 7.42; N, 5.59.
8.80 (dd, 1H, JH5±Fˆ4.5 Hz, JH5±Fˆ2.2 Hz, H5); 7.63 (m,
1H, HPh); 7.16 (d, 1H, Jˆ8.3 Hz, 2HPh); 6.75 (m, 3H,
3HPh); 4.09 (s, 2H, CH2); 4.01 (t, 2H, CH2); 3.83 (t, 2H,
CH2); 1.75 (m, 2H, CH2); 1.66 (m, 2H, CH2); 1.42±1.18
(massif, 24H, 12CH2); 0.79 (m, 6H, 2CH3); 13C NMR
(CDCl3): d 157.1 (CPh); 156.6 (d, JC2±Fˆ255.0 Hz, C2);
149.0 (CPh); 148.8 (dd, JC±Fˆ252.5 Hz, JC±Fˆ11.6 Hz,
CPh±F); 142.7 (C6); 142.4 (d, JC3±Fˆ29.8Hz, C 3); 140.4
(dd, JC±Fˆ247.0 Hz, JC±Fˆ14.5 Hz, CPh±F); 139.6 (C5);
129.0 (2CHPh); 127.7 (CPh); 123.0 (CHPh); 115.2 (CPh);
113.6 (2CHPh); 108.5 (CHPh); 68.8 (CH2); 66.9 (CH2);
36.1±21.6 (CH2); 13.1 (CH3); 19F NMR (CDCl3): d
278.68 (Fpyr); 2138.38 (FPh); 2158.82 (FPh). Anal.

F. Toudic et al. / Tetrahedron 58 (2002) 283±293
293
3. (a) Zaschke, H. J. Prakt. Chem. 1975, 315, 617. (b) Geelhaar,
T. Ferroelectrics 1988, 85, 329.
calcd for C35H47F3N2O2 (584.76): C, 71.89; H, 8.10; N, 4.79.
Found: C, 71.97; H, 8.28; N, 4.74.
4. Gray, G. W.; Hird, M.; Lacey, D.; Toyne, K. J. J. Chem. Soc.,
Perkin Trans. 2 1989, 2041.
Â
5. (a) Marsais, F.; Granger, P.; Queguiner, G. J Org Chem 1981,
1.4.34. 2-Fluoro-3-(4-n-dodecyloxybenzyl)-6-(2,3-di¯uoro-
4-n-octyloxyphenyl)pyrazine (36). Coupling of 2,3-
Â
46, 4494. (b) Gungor, T.; Marsais, F.; Queguiner, G. J.
Â
di¯uoro-4-n-octyloxyphenylboronic
acid
(106 mg,
È
Organomet. Chem. 1979, 171, 273. (c) Marsais, F.; Queguiner,
1.2 equiv.) with 25 (155 mg, 0.31 mmol) according to the
general procedure B (toluene, tˆ24 h) gave after puri®ca-
tion by column chromatography (silica gel, eluent:
petroleum ether/dichloromethane (1/1)) 132 mg (70%) of
Â
G. Tetrahedron 2009, 39, 1983. (d) Mallet, M.; Queguiner, G.
Â
Tetrahedron 1979, 35, 1625. (e) Mallet, M.; Queguiner, G.
Tetrahedron 1982, 38, 3035. (f) Mallet, M.; Marsais, M.;
Â
Branger, G.; Queguiner, G. J. Organomet. Chem. 1990, 382,
1
36 as a white solid mpˆ70±718C; H NMR (CDCl3): d
8.78 (dd, 1H, JH5±Fˆ4.5 Hz, JH5±Fˆ1.9 Hz, H5); 7.61 (m,
1H, HPh); 7.15 (d, 1H, Jˆ8.3 Hz, 2HPh); 6.73 (m, 3H,
3HPh); 4.07 (s, 2H, CH2); 3.99 (t, 2H, CH2); 3.81 (t, 2H,
CH2); 1.70 (m, 4H, 2CH2); 1.38±1.16 (m, 28H, 14CH2);
319.
6. Marsais, F.; Bouley, E.; Queguiner, G. J. Organomet. Chem.
1979, 171, 273.
Â
 Â
7. Ple, N.; Turck, A.; Heynderickx, A.; Queguiner, G. J. Hetero-
cycl. Chem. 1997, 34, 551.
0.78(m, 6H, 2CH ); 13C NMR (CDCl3): d 158.5 (CPh);
3
 Â
8. Ple, N.; Turck, A.; Heynderickx, A.; Queguiner, G.
158.1 (d, JC2±Fˆ254.3 Hz, C2); 150.4 (CPh); 150.3 (dd,
JC±Fˆ252.8Hz, JC±Fˆ12.3 Hz, CPh±F); 144.2 (C6); 143.8
Tetrahedron 1998, 54, 4899.
9. Jovanovic, M. V. Heterocycles 1984, 22, 1105.
Â
10. Gautheron-Chapoulaud, V.; Salliot, I.; Ple, N.; Turck, A.;
(d, JC3±Fˆ29.1 Hz, C3); 141.8(dd,
JC±Fˆ247.0 Hz,
JC±Fˆ14.5 Hz, CPh±F); 130.4 (2CHPh); 129.1 (CPh); 124.4
(CHPh); 116.6 (CPh); 115.1 (2CHPh); 110.0 (CHPh); 70.2
(CH2); 68.3 (CH2); 37.5±23.0 (CH2); 14.5 (CH3). Anal.
calcd for C37H51F3N2O2 (612.81): C, 72.52; H, 8.39; N,
4.57. Found: C, 72.49; H, 8.29; N, 4.48.
Â
Queguiner, G. Tetrahedron 1999, 55, 5389.
Â
11. Fruit, C.; Turck, A.; Ple, N.; Queguiner, G. Heterocycles 1999,
Â
51, 2349.
12. Stefaniak, L.; Roberts, J. D.; Witanowski, M.; Webb, G. A.
Org. Magn. Reson. 1984, 22, 201.
13. (a) Rocca, P.; Cochennec, C.; Marsais, F.; Thomas-dit-
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Dumont, L.; Mallet, M.; Godard, A.; Queguiner, G. J. Org.
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Â
F.; Godard, A.; Queguiner, G. Synthesis 1995, 321.
 Â
14. (a) Ple, N.; Turck, A.; Couture, K.; Queguiner, G. Tetrahedron
Â
1994, 50, 10299. (b) Ple, N.; Turck, A.; Heynderickx, A.;
Â
Queguiner, G. J. Heterocycl. Chem. 1994, 31, 1311.
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