Regioselective synthesis and metallation of tributylstannylfluoropyrazines. Application to the synthesis of some new fluorinated liquid crystals diazines. Part 34

Article abstract of DOI:10.1016/S0040-4020(03)00849-4

Starting from fluoropyrazine, a general synthetic route including metallation and palladium-catalyzed cross-coupling reactions is described to access to rod-like alkylaryl or diarylpyrazines. Among them, some have liquid crystalline properties.

Full text of DOI:10.1016/S0040-4020(03)00849-4

Tetrahedron 59 (2003) 6375–6384
Regioselective synthesis and metallation of
tributylstannylfluoropyrazines. Application to the synthesis of
some new fluorinated liquid crystals diazines. Part 34
*
Frederic Toudic, Arnault Heynderickx, Nelly Ple, Alain Turck and Guy Queguiner
´ ´
´
´
´ ´
Laboratoire de Chimie Organique Fine et Heterocyclique, UMR 6014, IRCOF-INSA, B.P. 08, 76131 Mont St Aignan Cedex, France
Received 11 February 2003; revised 27 March 2003; accepted 16 May 2003
Abstract—Starting from fluoropyrazine, a general synthetic route including metallation and palladium-catalyzed cross-coupling reactions is
described to access to rod-like alkylaryl or diarylpyrazines. Among them, some have liquid crystalline properties.
q 2003 Elsevier Ltd. All rights reserved.
According to its high electron-withdrawing effect and its
small size the fluorine atom makes considerable changes
in physical and chemical behaviors of fluorinated com-
pounds which have special interest for applications as
pharmaceuticals1 or highly polarizable materials.2
also been mentioned that the two-ring architecture of
phenylpyrimidines ensures a low viscosity and makes
them well suited for ferroelectric mixtures for displays.9b
The aim of this work was to use the fluoropyrazine as
building block to synthesize various alkylaryl and diaryl-
pyrazines which are aza-analogues of terphenyls which
could provide rod-like molecules with potential liquid
crystals applications.
Previously the fluorine atom has been used to induce the
ortho-metallation reaction in p-deficient heterocycles such
as pyridine,3 quinoline,4 pyrimidine5 series and more
recently with pyrazine.6 Using the fluoropyrazine 1 as
starting material, we report here the controlled regio-
selective synthesis of 3- or 6-tributylstannyl-2-fluoro-
pyrazines via the metallation reaction. Introduction of a
tributylstannyl group or an iodine atom allows further cross-
coupling reactions which provide an highly efficient and
flexible method to synthesize various alkyl or aryl
pyrazines.
1. Results
Recently, we have reported that the reaction of fluoro-
pyrazine 1 with an excess of lithium 2,2,6,6-tetramethyl-
piperidide (LTMP) and tributyltin chloride using the in situ
trapping method at low temperature (21008C) led to
2-fluoro-3,6-bistributylstannylpyrazine in good yield.6a
We have reinvestigated this reaction under various experi-
mental conditions to control the synthesis of monostannyl-
ated compounds (Scheme 1, Table 1).
Recently some papers dealing with the synthesis and the
mesomorphic properties of terphenyls with lateral fluoro
substituents and alkyl or alkoxy substituents in the 4 and 40
positions have been published.7–9 The presence of a fluoro-
substituent in terphenyls offers advantages for devising
ferroelectric host materials with the reduction of the melting
point and a tendency to form tilted smectic phases.9 It has
With 1.1 equiv. of LTMP at 2788C a mixture of mono-
stannylpyrazines 2 and 3 was observed (entry 1) whereas at
21008C the 3-stannyl compound 2 was obtained as the sole
Scheme 1.
Keywords: metallation; fluoropyrazines; cross-coupling reactions; liquid crystals.
*
Corresponding author. Tel.: þ33-235-522-902; fax: þ33-235-522-962; e-mail: nelly.ple@insa-rouen.fr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00849-4

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F. Toudic et al. / Tetrahedron 59 (2003) 6375–6384
Table 1. Result of lithiation of 1 with in situ trapping method with Bu3SnCl
as the electrophile
This unexpected result requires some comments: (a) The
distannylated compound 4 was obtained without addition of
tributyltin chloride, that implies a further metallation at C6
and that the tributylstannyl group was supplied either from 2
or from another stannylated intermediate. (b) The presence
of a secondary alcohol at C3 could result from an
intermediate 3-lithio derivative resulting from a tin–lithium
exchange, whereas the stannyl group at C6 could result as
for 4 from a further metallation.
Entry
n (equiv.)
t (8C)
2 (%)
2 (%)
4 (%)
1
2
3
4
1.1
1.1
2.1
4.0
278
11
54
15
–
26
–
10
20
–
–
2100
2100
2100
52
63
product (entry 2). When an excess of metallating agent was
used the distannyl compound 4 was obtained as the major
compound (entries 3 and 4).
In another way, the secondary alcohol 5 could be obtained
by direct metallation of 3 with 2.1 equiv. of LTMP at
2788C, followed by reaction with acetaldehyde as an
electrophile. Under these conditions 5 has been obtained in
high yield (97%) (Scheme 4).
In a previous paper6a it has been established that metallation
of fluoropyrazine 1 at 2788C with 1.1 equiv. of LTMP and a
short reaction time (5 min) led to the intermediate 2-fluoro-
3-lithiopyrazine 1a. So, in order to improve the yield of 2,
the lithio derivative 1a was obtained at 2788C, then the
temperature was lowered at 21008C and Bu3SnCl was
added at this temperature, under these experimental
conditions 2 has been obtained as the sole product in a
better yield (74%) (Scheme 2). When 1 reacted with
2.1 equiv. of LTMP and with 2.2 equiv. of Bu3SnCl under
the in situ trapping method at 21008C the 2-fluoro-3,6-
bistributylstannylpyrazine 4 was obtained in high yield
(Scheme 2).
This last result could allow us to propose an original
synthesis of the 2-fluoro-6-tributylstannylpyrazine 3. When
metallation of 2 was performed with 2.1 equiv. of LTMP at
2788C with a short reaction time and was followed by
protonation of the lithio derivative at this temperature,
compound 3 was obtained in 63% yield. So starting from
fluoropyrazine 1, compound 3 was obtained in a global yield
of 46% in two steps. The compound 3 has also been
obtained in better yields (72%) by metallation of 1 under the
in situ trapping method (Scheme 5).
When compound 2 was submitted to a further metallation
with 2.1 equiv. of LTMP at 2788C following by reaction
with acetaldehyde as electrophile, the compound 5 with a
tributylstannyl group at C6 and a secondary alcohol at C3
was obtained in 40–44% yield beside the distannylated
compound 4 in 20–25% yield (Scheme 3).
The aim of this work is the synthesis of rod-like molecules
like phenylalkyl or diarylpyrazines with one or three lateral
fluoro substituents, which implies that two consecutive
cross-coupling reactions must be achieved. The first one at
the C6 position could be performed under the Stille
conditions between the 2-fluoro-6-tributylstannylpyrazine
Scheme 2.
Scheme 3.
Scheme 4.

F. Toudic et al. / Tetrahedron 59 (2003) 6375–6384
6377
temperature for 60 min afforded the expected 3-iodo
derivatives 10–13 (Scheme 6).
Starting from the iodo compounds 10–13 various kinds of
cross-coupling reactions have been achieved to access to
various diaryl and alkylarylpyrazines 14–20 (Scheme 7).
Compounds 14–17 are arylpyrazines with a terminal long
alkyl chain and lateral fluoro substituents, whereas com-
pounds 18–20 are linear terphenyl aza-analogues with for
19 and 20 three lateral fluoro substituents in close proximity
to each other. These compounds such as fluoro substituted
terphenyl previously described9 have low melting points but
unfortunately do not exhibit mesomorphic properties.
Scheme 5.
3 and various aryl- iodides or bromides. The second one at
C3 could involve the reaction of a 2-fluoro-3-iodo-6-
arylpyrazines with arylboronic acids leading to diarylpyr-
azines. Reaction of 2-fluoro-3-iodo-6 arylpyrazines with
alkylzinc chlorides under the Negishi conditions or with
alkylacetylenes according to the Sonogashira coupling
reaction could afford the expected alkylphenylpyrazines.
In the aim to generate liquid crystalline compounds,
synthesis of a series of rod-like diarylpyrazines with two
terminal alkyl chains and lateral fluorosubstituents has been
achieved using the 2-fluoro-3-iodopyrazine as starting
material and cross-coupling reactions under Suzuki con-
ditions (Scheme 8).
First, we have tested the cross-coupling reaction between
the 2-fluoro-6-tributylstannylpyrazine 3 and various aryl-
iodides or bromides under the Stille conditions. Under these
conditions, the 2-fluoro-6-arylpyrazines 6–9 have been
obtained with moderate yields.
To check the influence of number of aromatic rings, we
have also synthesized using cross-coupling reaction under
Stille conditions a tetraaromatic compound 32 with a
bipyrazine as central moiety, six lateral fluoro substituents
and two terminal alkoxy chains on the phenyl rings
(Scheme 9).
Then, the fluorine atom at C2 has been used as ortho-
directing group to induce a lithiation at C3. So, treatment of
compounds 6–9 with 1.1 equiv. of LTMP at 2788C for
5 min, followed by reaction with 2 equiv. of iodine at this
Scheme 6.
Scheme 7.

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F. Toudic et al. / Tetrahedron 59 (2003) 6375–6384
Scheme 8.
Scheme 9.
Compounds with one, three or six lateral fluoro substituents
and alkoxy substituents on the end positions exhibit
mesophases. The transition temperatures given in Table 2
have been measured with a polarizing microscope and were
confirmed using differential scanning calorimetry (DSC) at
the IPCMS (Institut de Physique et de Chimie des
triaryl compound 30 while the tetraaromatic compound 32
have mesophases with higher transition temperatures.
2. Conclusion
´
Marteriaux de Strasbourg) in the laboratory of the Professor
J. F. Nicoud.
Starting from fluoropyrazine as building block, we have
described a general synthetic route to access to various
alkylaryl or diaryl pyrazines with multiple fluoro-
substituents in strategic lateral position to generate a wide
range of molecules. Some diarylpyrazines with lateral fluoro
substituents and alkoxy groups in end positions are low-
melting liquid crystals. The general synthetic routes
involved the selective metallation at low temperature of
fluoropyrazine and various palladium-catalyzed cross
coupling reactions to introduce selectively linear alkyl or
substituted phenyl groups.
The presence of one or three lateral fluoro substituents on
the diarylpyrazines 27–29 generates low-melting liquid
crystals with wide-range smectic C phases (29 to 67.88C).
The trifluoro compounds have lower melting points with a
decreasing of the smectic phase stability. For the penta-
fluoro compounds we observe the lost of mesophases in the
Table 2. Transition temperatures and mesophases
Compound
Mesophases
3. Experimental
3.1. General
27
28
29
30
32
C 89.7 SC 157.5 N 179.1 I
C 66.5 SC 114.0 N 134.5 I
C 82.5 SC 111.0 N 149.0 I
C 128.9 I
Melting points were determined on a Kofler hot-stage.
The 1H, 13C and 19F NMR spectra were recorded in
C 145.0 SC 164.0 N 196.0 I

F. Toudic et al. / Tetrahedron 59 (2003) 6375–6384
6379
deuteriochloroform 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.
Procedure D 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 (1 equiv.)
and ethanol (1 mL) in degassed toluene (15 mL) was heated
under reflux 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 dichloromethane
(3£20 mL), the combined organic extracts were dried over
magnesium sulphate and evaporated. The crude product was
purified by column chromatography on silica gel.
All reagents were of commercial quality and were
purchased from Aldrich Chemical Co. or Acros.
Pd-catalysis Pd(PPh3)4 was prepared according to the
literature.10 The 2- or 4-trifluoromethyl- and 4-alcoxyphe-
nylboronic acids were synthesized by halogen-metal
exchange followed by reaction with trimethoxyborane
from the commercially available 1-bromo-2- or -4-trifluoro-
methylbenzenes and 1-bromo-4-methoxybenzene according
to the literature.8d The 2,3-difluoro-4-alcoxyphenylboronic
acids were synthesized by ortho-lithiation of corresponding
1-alcoxy-2,3-difluorobenzenes with n-butyllithium
followed by reaction with trimethoxyborane.8a
Procedure E for cross-coupling of alkylacetylenes with
iodopyrazines under Sonogashira conditions. A mixture of
1-octyne, CuI (0.035 equiv. per coupling), PdCl2(PPh3)2
(0.02 equiv. per coupling) was added to dry triethylamine
(15 mL) previously flushed with nitrogen. The mixture was
stirred for 30 min at room temperature before introduction
of 6-aryl-2-fluoro-3-iodopyrazine then kept at this tempera-
ture for 3 h. After elimination of triethylamine iodide by
filtration, the solution was dried over magnesium sulfate.
The solvent was removed and the reaction mixture was
purified by column chromatography on silica gel.
Fluoropyrazine 1 was synthesized according the procedure
described in the literature.6a
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-tetramethylpiperidine (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 u2¼2788C). 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 thiosulphate and evaporated nearly to dryness. The
residue was extracted with dichloromethane (3£20 mL), the
combined organic extracts were then dried over magnesium
sulphate and evaporated. The crude product was purified by
column chromatography on silica gel.
3.1.1. 2-Fluoro-3-tributylstannylpyrazine (2). Metallation
of 1 (200 mg, 2.04 mmol) according to the procedure A with
n-BuLi 2.5 M (1.1 equiv., 0.9 mL), TMPH (1.2 equiv.,
0.41 mL), t1¼5 min, u1¼21008C, followed by reaction of
tributyltin chloride (1.2 equiv., 0.66 mL) in THF (5 mL),
t2¼60 min, u2¼21008C gave after purification by column
chromatography (silica, eluent: dichloromethane/cyclo-
1
hexane (1:1)) 584 mg (74%) of 2 as a colorless liquid. H
NMR (CDCl3): d 8.59 (dd, 1H, J6–5¼2.5 Hz, JH5–F¼5.7 Hz,
H5); 7.97 (m, 1H, H6); 1.8–0.53 (m, 27H, Bu); 19F NMR
(CDCl3): d 269.4. Anal. calcd for C16H29FN2Sn (387.13): C,
49.64; H, 7.55; N, 7.23. Found: C, 49.5; H, 7.6; N, 7.2.
3.1.2. 2-Fluoro-6-tributylstannylpyrazine (3). Metallation
of 1 (200 mg, 2.04 mmol) according to the procedure B with
n-BuLi 1.6 M (3.1 equiv., 2.95 mL), TMPH (3.15 equiv.,
1.08 mL), and tri-n-butyltin chloride (1 equiv., 0.58 mL),
t¼2.5 h, u1¼21008C, u2¼2408C gave after purification by
column chromatography (silica gel, eluent: dichloro-
methane/cyclohexane (1:1)) 501 mg (54%) of 3 as a
colorless liquid. 1H NMR (CDCl3): d 8.41 (d, 1H,
JH5–F¼5.5 Hz, H5); 8.17 (d, 1H, JH3–F¼8.3 Hz, H3); 1.8–
0.53 (m, 27H, Bu); 19F NMR (CDCl3): d 279.11. Anal.
calcd for C16H29FN2Sn (387.13): C, 49.64; H, 7.55; N, 7.23.
Found: C, 49.5; H, 7.4; N, 7.1.
Procedure B for ‘in situ’ trapping metallation by lithium
2,2,6,6-tetramethylpiperidide. The fluoropyrazine dissolved
in 10 mL THF and tri-n-butyltin chloride were simul-
taneously introduced at 21008C into the solution containing
metallating agent (LTMP) prepared according to procedure
A. The mixture was then stirred for a time t, during this time,
temperature was slowly increase from u1 to u2. The
following steps are similar to procedure A.
3.1.3. 2-Fluoro-3,6-bis(tributylstannyl)pyrazine (4).
Metallation of 1 (300 mg, 3.06 mmol) according to the
Procedure C for cross-coupling of aryl halides with
tributylstannylpyrazine under Stille conditions. A solution
general procedure
B with n-BuLi 1.6 M (4.1 mL,
of
2-fluoro-6-tributylstannylpyrazine,
arylhalide
2.1 equiv.), TMPH (1.1 mL, 2.15 equiv.), t¼60 min,
u¼21008C and tri-n-butyltin chloride (2.0 g, 6.27 mmol)
afforded after purification by column chromatography
(silica gel, eluent: dichloromethane/cyclohexane (3:2))
(0.8 equiv.) and Pd(PPh3)4 (0.05 equiv.) in degassed toluene
(15 mL) was heated under reflux under nitrogen atmosphere
for a time t. After cooling, a mixture of water (10 mL) and
dichloromethane (10 mL) was added. The organic phase
was extracted with dichloromethane (3£20 mL).The com-
bined organic extracts were then dried over magnesium
sulphate and evaporated. The crude product was purified by
column chromatography on silica gel.
1
1.86 g (90%) of 4 as a colorless liquid. H NMR (CDCl3):
d 8.56 (d, 1H, J5,F¼6.8 Hz, J5,Sn¼3.8 Hz, H5); 1.8–0.53 (m,
54H, Bu); 19F NMR (CDCl3): d 267.89. Anal. calcd for
C28H55FN2Sn2 (676.17): C, 49.73; H, 8.20; N, 4.14. Found:
C, 49.9; H, 8.5; N, 4.3.

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F. Toudic et al. / Tetrahedron 59 (2003) 6375–6384
3.1.4. 2-Fluoro-3-(1-hydroxyethyl)-6-(tributylstannyl)-
pyrazine (5). Metallation of 4 (790 mg, 2.04 mmol)
0.8 equiv.) with 3 (1.78 g, 4.59 mmol) according to the
procedure C (t¼48 h) gave after purification by column
chromatography (silica gel, eluent: dichloromethane/ether
petroleum (1:2)) 655 mg (74%) of 9 as a yellow solid mp
83–848C. 1H NMR (CDCl3): d 8.99 (d, 1H, JH5–F¼4.6 Hz,
H5); 8.44 (d, 1H, JH3–F¼8.3 Hz, H3); 8.15 (d, 2H,
J¼8.2 Hz, 2HPh); 7.77 (d, J¼8.2 Hz, 2HPh); 13C NMR
(CDCl3): d 160.1 (d, JC2–F¼254.2 Hz, C2); 149.2 (C6);
139.0 (C5); 138.9 (CPh); 132.7 (d, JC3–F¼37.3 Hz, C3);
132.3 (q, JC–F¼32.5 Hz, CPh); 127.8 (2CHPh); 126.5
(2CHPh); 124.2 (q, JC–F¼272.4 Hz, CF3). 19F NMR
(CDCl3): d 263.22 (CF3); 278.83 (Fpyr). Anal. calcd for
C11H6F4N2 (242.18): C, 54.56; H, 2.50; N, 11.57. Found: C,
54.49; H, 2.61; N, 11.46.
according to the procedure
A with n-BuLi 2.5 M
(2.1 equiv., 1.8 mL), TMPH (2.2 equiv., 0.80 mL),
t1¼5 min, u1¼2788C, followed by reaction with acet-
aldehyde in excess, t2¼60 min, u2¼2788C gave after
purification by column chromatography (silica gel, eluent:
dichloromethane/ethylacetate (10:1)) 853 mg (97%) of 5 as
a colorless liquid. 1H NMR (CDCl3): d 8.39 (d, 1H,
JH5–F¼5.2 Hz, H5); 5.04 (m, 1H, CH); 4 (m, 1H, OH); 1.8–
0.85 (m, 30H, Bu, Me); 19F NMR (CDCl3): d 269.4. Anal.
calcd for C18H23FON2Sn (431.18): C, 50.14; H, 7.71; N,
6.49. Found: C, 50.5; H, 8.0; N, 6.8.
3.1.5. 2-Fluoro-6-phenylpyrazine (6). Coupling of iodo-
benzene (0.05 mL, 0.8 equiv.) with 3 (200 g, 0.52 mmol)
according to the procedure C (t¼24 h) gave after purifi-
cation by column chromatography (silica gel, eluent:
dichloromethane/ether petroleum (1:1)) 49 mg (68%) of 6
as a white solid, mp 59–608C. 1H NMR (CDCl3): d 8.97 (d,
1H, JH5–F¼4.7 Hz, H5); 8.51 (d, 1H, JH3–F¼8.5 Hz, H3);
8.05 (m, 2H, Ph); 7.53 (m, 3H, Ph); 13C NMR (CDCl3): d
160.2 (d, JC2–F¼253.6 Hz, C2); 150.8 (C6); 138.7 (C5);
134.9 (CPh); 131.4 (d, JC3–F¼37.8 Hz, C3); 130.9 (CHPh);
129.5 (CHPh); 127.5 (CHPh); 19F NMR (CDCl3): d 280.07.
Anal. calcd for C10H7FN2 (174.11): C, 68.98; H, 4.05; N,
16.09. Found: C, 69.11; H, 4.18; N, 16.12.
3.1.9. 2-Fluoro-3-iodo-6-phenylpyrazine (10). Metallation
of 6 (295 mg, 1.69 mmol) according to the procedure A with
n-BuLi 1.6 M (1.1 equiv., 1.16 mL), TMPH (1.2 equiv.,
0.34 mL), t1¼5 min, u1¼2788C, followed by reaction with
iodine (2 equiv., 858 mg), t2¼60 min, u2¼2788C gave after
purification by column chromatography (silica gel, eluent:
dichloromethane/petroleum ether (1:2)) 289 mg (57%) of
10 as a colorless solid, mp 105–1068C; H NMR (CDCl3): d
8.75 (d, 1H, JH5–F¼4.0 Hz, H3); 8.01 (m, 2H, HPh); 7.32 (m,
3H, HPh); 13C NMR (CDCl3): d 159.3 (d, JC2–F¼251.4 Hz,
C2); 150.1 (C6); 139.6 (C5); 133.9 (CPh); 131.4 (CHPh);
129.7 (CHPh); 127.4 (CHPh); 100.0 (d, JC3–F¼45.8 Hz, C3);
19F NMR (CDCl3): d 265.00. Anal. calcd for C10H6FIN2
(300.00): C, 40.03; H, 2.02; N, 9.30. Found: C, 40.29; H,
2.06; N, 9.24.
3.1.6. 2-Fluoro-6-(2-fluorophenyl)pyrazine (7). Coupling
of 1-fluoro-2-iodobenzene (0.1 mL, 0.8 equiv.) with 3
(400 mg, 1.03 mmol) according to the procedure C
(t¼48 h) gave after purification by column chromatography
(silica gel, eluent: dichloromethane/ether petroleum (1:2))
107 mg (67%) of 7 as a colorless solid, mp ,508C. 1H NMR
3.1.10. 2-Fluoro-6-(2-fluorophenyl)-3-iodopyrazine (11).
Metallation of 7 (226 mg, 1.17 mmol) according to the
procedure A with n-BuLi 1.6 M (1.1 equiv., 0.81 mL),
TMPH (1.2 equiv., 0.24 mL), t1¼5 min, u1¼2788C, fol-
lowed by reaction with iodine (2 equiv., 597 mg),
t2¼60 min, u2¼2788C gave after purification by column
chromatography (silica gel, eluent: dichloromethane/
petroleum ether (1:2)) 218 mg (58%) of 11 as a brown
solid, mp ,508C. 1H NMR (CDCl3): d 8.80 (dd, 1H,
JH5–Fpyr¼4.4 Hz, JH5–FPh¼1.8 Hz, H5); 8.00 (t, 1H, HPh);
7.47–7.13 (m, 3H, 3HPh); 13C NMR (CDCl3): d 161.2 (d,
JC–F¼252.1 Hz, C2 or CPh–F); 159.1 (JC–F¼252.1 Hz, C2
or CPh–F); 146.0 (C6); 143.1 (C5); 132.9 (CHPh); 131.1
(CDCl3): d 8.87 (dd, 1H, JH5–Fpyr¼4.9 Hz, JH5–FPh
¼
1.9 Hz, H5); 8.36 (d, 1H, JH3–F¼8.6 Hz, H3); 8.01 (t, 1H,
Ph); 7.5–7.14 (m, 3H, Ph); 13C NMR (CDCl3): d 160.1 (d,
JC–F¼252.1 Hz, C2 or CPh–F); 160.0 (d, JC–F¼253.6 Hz,
C2 or CPh–F); 146.3 (C6); 142.3 (C5); 132.5 (CHPh); 131.8
(d, JC3–F¼37.1 Hz, C3); 131.2 (CHPh); 125.2 (CHPh); 122.8
(CPh); 116.8 (d, JC–F¼22.5 Hz, CHPh); 19F NMR (CDCl3):
d 279.66 (Fpyr); 2114.18.(FPh). Anal. calcd for C10H6F2N2
(192.17): C, 62.50; H, 3.15; N, 14.58. Found: C, 62.62; H,
3.04; N, 14.49.
(CHPh); 125.4 (CHPh); 121.9 (CPh); 117.0 (d, JC–F
¼
3.1.7. 2-Fluoro-6-(2-trifluoromethylphenyl)pyrazine (8).
Coupling of 1-bromo-2-trifluoromethylbenzene (0.56 mL,
0.8 equiv.) with 3 (2 g, 5.16 mmol) according to the
procedure C (t¼48 h) gave after purification by column
chromatography (silica gel, eluent: dichloromethane/ether
petroleum (1:2)) 724 mg (72%) of 8 as a colorless liquid. 1H
NMR (CDCl3): d 8.65 (d, 1H, JH5–F¼4.3 Hz, H5); 8.49 (d,
1H, JH3–F¼8.3 Hz, H3); 7.85–7.51 (m, 4H, Ph); 13C NMR
(CDCl3): d 159.5 (d, JC2–F¼255.8 Hz, C2); 151.0 (C6);
141.8 (C5); 134.8 (CPh); 132.6 (d, JC3–F¼36.3 Hz, C3);
132.3 (CHPh); 132.1 (CHPh); 130.1 (CHPh); 128.7 (q,
22.5 Hz, CHPh); 100.8 (d, JC3–F¼45.0 Hz, C3); 19F NMR
(CDCl3): d 264.50 (FPyr); 2113.2 (FPh). Anal. calcd for
C10H5F2IN2 (318.06): C, 37.76; H, 1.58; N, 8.81. Found: C,
37.97; H, 1.79; N, 8.46.
3.1.11. 2-Fluoro-3-iodo-6-(2-trifluoromethylplenyl)pyra-
zine (12). Metallation of 8 (300 mg, 1.24 mmol) according
to the procedure A with n-BuLi 1.6 M (1.1 equiv., 0.85 mL),
TMPH (1.2 equiv., 0.25 mL), t1¼5 min, u1¼2788C, fol-
lowed by reaction with iodine (2 equiv., 629 mg),
t2¼60 min, u2¼2788C gave after purification by column
chromatography (silica gel, eluent: dichloromethane/
petroleum ether (1:2)) 255 mg (56%) of 12 as a beige
solid, mp 96–978C. 1H NMR (CDCl3): d 8.44 (d, 1H,
JH5–F¼4.0 Hz, H5); 7.84–7.50 (m, 4H, 4HPh); 13C NMR
(CDCl3): d 158.7 (d, JC2–F¼253.6 Hz, C2); 150.1 (C6);
142.7 (C5); 133.7 (CPh); 132.4 (CHPh); 132.1 (CHPh); 130.4
(CHPh); 129.1 (q, JC–F¼31.2 Hz, CPh); 127.3 (CHPh); 124.0
JC–F¼31.2 Hz, CPh); 127.1 (CHPh); 124.1 (q, JC–F
¼
273.9 Hz, CF3); 19F NMR (CDCl3): d 257.13 (CF3);
279.66 (Fpyr). Anal. calcd for C11H6F4N2 (242.18): C,
55.56; H, 2.50; N, 11.57. Found: C, 54.33; H, 2.42; N, 11.85.
3.1.8. 2-Fluoro-6-(4-trifluoromethylphenyl)pyrazine (9).
Coupling of 1-bromo-4-trifluoromethylbenzene (0.52 mL,

F. Toudic et al. / Tetrahedron 59 (2003) 6375–6384
6381
(q, JC–F¼273.9 Hz, CF3); 101.13 (d, JC3–F¼44.3 Hz, C3);
19F NMR (CDCl3): d 256.31 (CF3); 264.50 (FPyr). Anal.
calcd for C11H5F4IN2 (368.07): C, 35.90; H, 1.37; N, 7.61.
Found: C, 35.97; H, 1.45; N, 7.63.
for C19H18F4N2 (350.36): C, 65.14; H, 5.18; N, 8.00. Found:
C, 65.11; H, 5.53; N, 7.76.
3.1.15. 2-Fluoro-3-(oct-1-ynyl)-6-(4-trifluoromethyl-
phenyl)pyrazine (16). Coupling reaction of 13 (250 mg,
0.68 mmol) according to the procedure F with CuI (5 mg,
0.036 equiv.), PdCl2(PPh3)2 (10 mg, 0.020 equiv.) and
1-octyne (0.12 mL, 1.2 equiv.) gave after purification by
column chromatography (silica gel, eluent: dichloro-
methane/petroleum ether (1:1)) 186 mg (78%) of 16 as a
colorless solid, mp 84–858C. 1H NMR (CDCl3): d 8.82 (d,
1H, JH5–F¼4.1 Hz, H5); 8.05 (d, 2H, J¼8.3 Hz, 2HPh); 7.67
(d, 2H, J¼8.3 Hz, 2HPh); 2.46 (t, 2H, CH2); 1.60 (m, 2H,
CH2); 1.40 (m, 2H, CH2); 1.24 (m, 4H, 2CH2); 0.83 (m, 3H,
CH3); 13C NMR (CDCl3): d 159.8 (d, JC2–F¼257.2 Hz, C2);
3.1.12. 2-Fluoro-3-iodo-6-(4-trifluoromethylplenyl)pyra-
zine (13). Metallation of 9 (400 mg, 1.65 mmol) according
to the procedure A with n-BuLi 1.6 M (1.1 equiv., 1.14 mL),
TMPH (1.2 equiv., 0.33 mL), t1¼5 min, u1¼2788C, fol-
lowed by reaction with iodine (2 equiv., 838 mg),
t2¼60 min, u2¼2788C gave after purification by column
chromatography (silica gel, eluent: dichloromethane/
petroleum ether (1:2)) 345 mg (57%) of 13 as a colorless
1
solid, mp 126–1258C. H NMR (CDCl3): d 8.76 (d, 1H,
JH5–F¼4.2 Hz, H5); 8.13 (d, 2H, J¼8.2 Hz, 2HPh); 7.76 (d,
2H, J¼8.2 Hz, 2HPh); 13C NMR (CDCl3): d 159.3 (d,
JC2–F¼253.9 Hz, C2); 148.3 (C6); 139.7 (C5); 137.2 (CPh);
132.5 (q, JC–F¼33.0 Hz, CPh); 127.7 (2CHPh); 126.6
(2CHPh); 124.1 (q, JC–F¼272.5 Hz, CF3); 101.9 (d,
JC3–F¼45.0 Hz, C3); 19F NMR (CDCl3): d 263.36 (CF3);
264.28 (FPyr). Anal. calcd for C11H5F4IN2 (368.07): C,
35.90; H, 1.37; N, 7.61. Found: C, 35.97; H, 1.36; N, 7.52.
146.7 (C6); 138.4 (C5); 137.9 (CPh); 132.6 (q, JC–F
¼
32.7 Hz, CPh); 128.5 (d, JC3–F¼30.5 Hz, C3); 127.7
(2CHPh); 126.5 (2CHPh); 124.2 (q, JC–F¼272.5 Hz, CF3);
101.7 (Csp1); 74.1 (Csp1); 31.6 (CH2); 29.0 (CH2); 28.8
(CH2); 22.9 (CH2) 20.1 (CH2); 14.4 (CH3); 19F NMR
(CDCl3): d 263.37 (CF3); 273.14 (FPyr). Anal. calcd for
C19H18F4N2 (350.36): C, 65.14; H, 5.18; N, 8.00. Found: C,
65.24; H, 5.32; N, 7.96.
3.1.13. 2-Fluoro-6-(2-fluorophenyl)-3-(oct-1-ynyl)pyra-
zine (14). Coupling reaction of 11 (121 mg, 0.38 mmol)
according to the procedure E with CuI (3 mg, 0.035 equiv.),
PdCl2(PPh3)2 (5 mg, 0.018 equiv.) and 1-octyne (0.07 mL,
1.2 equiv.) gave after purification by column chromato-
graphy (silica gel, eluent: dichloromethane/petroleum ether
(1:1)) 69 mg (60%) of 14 as a colorless solid, mp ,508C. 1H
3.1.16. 2-Fluoro-3-hexyl-6-phenylpyrazine (17). A sol-
ution of n-hexyllithium in hexane (0.81 mL, 3 equiv.) was
added to cold (2788C), stirred and anhydrous THF (30 mL)
under an atmosphere of dry argon. Then a solution of dry
zinc chloride (82 mg, 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 10 (200 mg,
0.67 mmol) in THF (5 mL) were introduced. The mixture
was heated under reflux under nitrogen for 24 h. 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
purified by column chromatography on silica gel (eluent
dichloromethane/petroleum ether (1:2) to give 114 mg
NMR (CDCl3):
d
8.90 (dd, 1H, JH5–FPyr¼4.5 Hz,
JH5–FPh¼1.9 Hz, H5); 7.97 (m, 1H, HPh); 7.38–7.08 (m,
3H, 3HPh); 2.46 (t, 2H, J¼7.1 Hz, CH2); 1.61 (qt, J¼7.1 Hz,
CH2); 1.41 (m, 2H, CH2); 1.24 (m, 4H, 2CH2); 0.83 (m, 3H,
CH3); 13C NMR (CDCl3): d 161.0 (d, JC–F¼252.1 Hz, C2 or
CPh–F); 159.7 (d, JC–F¼255.7 Hz, C2 or CPh–F); 144.6
(C6); 142.0 (C5); 132.5 (CHPh); 131.2 (CHPh); 127.6 (d,
JC3–F¼31.9 Hz, C3); 125.3 (CHPh); 122.7 (CPh); 116.9 (d,
JC–F¼22.5 Hz, CHPh); 101.0 (Csp1); 74.3 (Csp1); 31.7
(CH2); 29.0 (CH2); 28.4 (CH2); 22.9 (CH2); 20.1 (CH2);
14.4 (CH3); 19F NMR (CDCl3): d 273.31 (FPyr); 2113.59
(FPh). Anal. calcd for C18H18F2N2 (300.35): C, 71.98; H,
6.04; N, 9.33. Found: C, 71.92; H, 6.12; N, 9.42.
1
(66%) of 17 as a orange liquid. H NMR (CDCl3): d 8.74
(d, 1H, JH5–F¼4.5 Hz, H5); 7.89 (m, 2H, 2HPh); 7.38 (m,
3H, 3HPh); 2.84 (t, 2H, CH2); 1.69 (m, 2H, CH2); 1.36–1.21
(m, 6H, 3CH2); 0.81 (t, 3H, CH3); 13C NMR (CDCl3): d
158.4 (d, JC2–F¼253.6 Hz, C2); 148.3 (C6); 145.0 (d,
JC3–F¼29.8 Hz, C3); 137.9 (C5); 135.2 (CPh); 130.3 (CHPh);
129.4 (CHPh); 127.2 (CHPh); 32.0–22.9 (5CH2); 14.4
(CH3); 19F NMR (CDCl3): d 280.08. Anal. calcd for
C16H19FN2 (258.34): C, 74.39; H, 7.41; N, 10.84. Found: C,
74.32; H, 7.64; N, 10.86.
3.1.14. 2-Fluoro-3-(oct-1-ynyl)-6-(2-trifluoromethyl-
phenyl)pyrazine (15). Coupling reaction of 12 (150 mg,
0.41 mmol) according to the procedure E with CuI (3 mg,
0.036 equiv.), PdCl2(PPh3)2 (6 mg, 0.019 equiv.) and
1-octyne (0.07 mL, 1.2 equiv.) gave after purification by
column chromatography (silica gel, eluent: dichloro-
methane/petroleum ether (1:1)) 97 mg (68%) of 15 as a
yellow oil. 1H NMR (CDCl3): d 8.47 (d, 1H, JH5–F¼4.1 Hz,
H5); 7.72 (d, 1H, J¼7.2 Hz, HPh); 7.58 (t, 1H, J¼7.2 Hz,
HPh); 7.53 (t, 1H, J¼7.2 Hz, HPh); 7.43 (d, 1H, J¼7.2 Hz,
HPh); 2.46 (t, 2H, J¼7.1 Hz, CH2); 1.62 (q, 2H, J¼7.1 Hz,
CH2); 1.41 (m, 2H, CH2); 1.25 (m, 4H, 2CH2); 0.81 (m, 3H,
CH3); 13C NMR (CDCl3): d 157.8 (d, JC2–F¼257.9 Hz, C2);
147.2 (C6); 139.9 (C5); 133.3 (CPh); 130.9 (CHPh); 130.7
(CHPh); 128.7 (CHPh); 127.7 (q, JC–F¼31.2 Hz, CPh); 127.1
3.1.17. 3,6-Diphenyl-2-fluoropyrazine (18). Coupling of
phenylboronic acid (45 mg, 1.2 equiv.) with 10 (92 mg,
031 mmol) according to the general procedure D (t¼24 h)
gave after purification by column chromatography (silica
gel, eluent: dichloromethane/petroleum ether (1:2)) 66 mg
1
(86%) of 18 as a colorless solid, mp 113–1148C. H NMR
(CDCl3): d 8.89 (d, 1H, JH5–F¼5.3 Hz, H5); 8.02–7.94 (m,
(d, JC3–F¼29.8 Hz, C3); 125.8 (CHPh); 122.7 (q, JC–F
273.9 Hz, CF3); 99.9 (Csp1); 72.7 (Csp1); 30.3 (CH2); 27.5
(CH2); 27.0 (CH2); 21.5 (CH2); 18.7 (CH2); 13.0 (CH3); 19
NMR (CDCl3): d 257.11 (CF3); 273.91 (FPyr); Anal. calcd
¼
4H, 4HPh); 7.40 (m, 6H, 6HPh); 13C NMR (CDCl3): d 156.0
F
(d, JC2–F¼256.5 Hz, C2); 147.5 (C6); 138.5 (d, JC3–F¼
24.0 Hz, C3); 137.0 (C5); 133.4 (CPh); 132.4 (CPh);

6382
F. Toudic et al. / Tetrahedron 59 (2003) 6375–6384
129.3–125.9 (10CHPh); 19F NMR (CDCl3): d 275.15).
Anal. calcd for C16H11FN2 (250.27): C, 76.79; H, 4.43; N,
11.19. Found: C, 76.71; H, 4.89; N, 10.73.
126.0 (CPh); 115.0 (2CHPh); 68.5 (OCH2); 32.2–23.1
(6CH2); 14.5 (CH3); 19F NMR (CDCl3): d 274.46. Anal.
calcd for C18H23FN2O (302.39): C, 71.50; H, 7.67; N, 9.26.
Found: C, 71.67; H, 7.72; N, 9.46.
3.1.18. 3-(2,3-Difluoro-4-n-octyloxyphenyl)-2-fluoro-6-
(2-fluorophenyl)pyrazine (19). Coupling of 2,3-difluoro-
4-n-octyloxyphenylboronic acid (108 mg, 1.2 equiv.) with
11 (100 mg, 0.31 mmol) according to the general procedure
D (t¼24 h) gave after purification by column chromato-
graphy (silica gel, eluent: ethylacetate/petroleum ether
(1:4)) 100 mg (74%) of 19 as a colorless solid, mp
3.1.21. 3-(2,3-Difluoro-4-n-hexyloxyphenyl)-2-fluoro-
pyrazine (22). Coupling of 2,3-difluoro-4-n-hexyloxy-
phenylboronic acid (432 mg, 1.5 equiv.) with 2-fluoro-3-
iodopyrazine (250 mg, 1.12 mmol) according to the general
procedure D (t¼24 h) gave after purification by column
chromatography (silica gel, eluent: dichloromethane/
petroleum ether (1:1)) 264 mg (76%) of 22 as a white
1
,508C. H NMR (CDCl3): d 9.06 (dd, 1H, JH5–Fpyr¼4.5
1
Hz, J
¼2.1 Hz, H5); 8.04 (m, 1H, HPh); 7.43–7.11 (m,
solid, mp 29–308C. H NMR (CDCl3): d 8.49 (dd, 1H,
H5 – FPh
4H, 4HPh); 6.82 (m, 1H, HPh); 4.04 (t, 2H, J¼6.6 Hz,
OCH2); 1.77 (q, 2H, J¼6.6 Hz, CH2); 1.41–1.17 (m, 10H,
5CH2); 0.80 (m, 3H, CH3); 13C NMR (CDCl3): d 161.1 (d,
JC–F¼252.1 Hz, C2 or CPh–F); 157.3 (d, JC–F¼256.5 Hz,
C2 or CPh–F); 150.7 (CPh); 149.9 (dd, JC–F¼253.6, 11.6 Hz,
CPh–F); 146.0 (C6); 142.1 (C5); 141.8 (dd, JC–F¼247.7,
14.2 Hz, CPh–F); 136.5 (d, JC3–F¼31.2 Hz, C3); 132.5
(CHPh); 131.3 (CHPh); 125.4 (2CHPh); 122.8 (CPh); 116.9 (d,
JC–F¼23.2, CHPh); 115.9 (CPh); 109.9 (CHPh); 70.3
(OCH2); 32.2–23.04 (6CH2); 14.5 (CH3); 19F NMR
(CDCl3): d 274.60 (FPyr); 2113.71 (FPh); 2136.99 (FPh);
2158.64 (FPh). Anal. calcd for C24H24F4N2O (432.47): C,
66.66; H, 5.59; N, 6.48. Found: C, 66.61; H, 5.63; N, 6.47.
JH5–F¼4.5 Hz, JH5–H6¼1.9 Hz, H5); 8.13 (m, 1H, H6); 7.25
(m, 1H, HPh); 6.80 (m, 1H, HPh); 4.02 (t, 2H, OCH2); 1.76
(m, 2H, CH2); 1.43–1.23 (m, 6H, 3CH2); 0.81 (t, 3H, CH3);
13C NMR (CDCl3): d 156.8 (d, JC2–F¼253.5 Hz, C2); 149.3
(CPh); 148.4 (dd, JC–F¼253.6, 11.6 Hz, CPh–F); 140.7 (C5
or C6); 140.3 (dd, JC–F¼248.5, 14.2 Hz, CPh–F); 139.5 (C5
or C6); 137.4 (d, JC3–F¼29.1 Hz, C3); 123.9 (CHPh); 114.4
(CPh); 107.4 (CHPh); 68.8 (OCH2); 30.4–21.5 (4CH2); 12.9
(CH3); 19F NMR (CDCl3): d 274.60 (Fpyr); 2137.45
(FPh); 2158.76 (FPh). Anal. calcd for C16H17F3N2O
(310.32): C, 61.93; H, 5.52; N, 9.03. Found: C, 61.92; H,
5.59; N, 9.02.
3.1.22. 3-(2,3-Difluoro-4-n-octyloxyphenyl)-2-fluoro-
pyrazine (23). Coupling of 2,3-difluoro-4-n-octyloxy-
phenylboronic acid (1.34 g, 1.5 equiv.) with 2-fluoro-3-
iodopyrazine (700 mg, 3.13 mmol) according to the general
procedure D (t¼24 h) gave after purification by column
chromatography (silica gel, eluent: dichloromethane/
petroleum ether (1:1)) 775 mg (73%) of 23 as a colorless
3.1.19. 3-(2,3-Difluoro-4-n-octyloxyphenyl)-2-fluoro-6-
(2-trifluoromethylphenyl)pyrazine (20). Coupling of 2,3-
difluoro-4-n-octyloxyphenylboronic
acid
(166 mg,
1.2 equiv.) with 12 (179 mg, 0.49 mmol) according to the
general procedure D (t¼24 h) gave after purification by
column chromatography (silica gel, eluent: dichloro-
methane/petroleum ether (1:41)) 166 mg (71%) of 20 as a
colorless solid, mp 72–738C. 1H NMR (CDCl3): d 8.60 (d,
1H, JH5–F¼4.5 Hz, H5); 7.72–7.46 (m, 4H, 4HPh); 7.31 (m,
1H, HPh); 6.80 (m, 1H, HPh); 4.00 (t, 2H, OCH2); 1.75 (m,
2H, CH2); 1.40–1.18 (m, 10H, 5CH2); 0.77 (t, 3H, CH3);
13C NMR (CDCl3): d 155.4 (d, JC2–F¼257.9 Hz, C2); 149.4
(CPh); 148.6 (C6); 148.5 (dd, JC–F¼253.9, 11.8 Hz, CPh–F);
140.3 (dd, JC–F¼248.2, 14.2 Hz, CPh–F); 140.2 (C5); 135.8
(d, JC3–F¼29.0 Hz, C3); 133.3 (CPh); 130.9 (2CHPh); 128.7
(CHPh); 127.7 (q, JC–F¼31.2 Hz, CPh); 125.7 (CHPh); 124.1
(CHPh); 122.8 (q, JC–F¼273.9 Hz, CF3); 114.1 (CPh); 108.4
(CHPh); 68.8 (OCH2); 30.8–21.6 (6CH2); 13.0 (CH3); 19F
NMR (CDCl3): d 256.74 (CF3); 275.15 (FPyr); 2136.83
(FPh); 2158.68 (FPh). Anal. calcd for C25H24F6N2O
(482.47): C, 62.24; H, 5.01; N, 5.81. Found: C, 62.28; H,
4.97; N, 5.78.
1
solid, mp 41–428C. H NMR (CDCl3): d 8.48 (dd, 1H,
JH5–F¼4.5 Hz, JH5–H6¼2.6 Hz, H5); 8.11 (m, 1H, H6); 7.23
(m, 1H, HPh); 6.78 (m, 1H, HPh); 4.00 (t, 2H, OCH2); 1.75
(m, 2H, CH2); 1.42–1.18 (m, 10H, 5CH2); 0.79 (t, 3H,
CH3); 13C NMR (CDCl3): d 158.2 (d, JC2–F¼255.7 Hz, C2);
150.7 (CPh); 149.8 (dd, JC–F¼253.6, 11.6 Hz, CPh-F); 142.1
(C5 or C6); 141.7 (dd, JC–F¼248.1 Hz, JC–F¼14.1 Hz,
CPh–F); 140.9 (C5 or C6); 138.8 (d, JC3–F¼29.1 Hz, C3);
125.3 (CHPh); 115.7 (CPh); 109.8 (CHPh) 70.2 (OCH2);
32.1–23.0 (6CH2); 14.4 (CH3); 19F NMR (CDCl3): d
274.51 (Fpyr); 2137.34 (FPh); 2158.63 (FPh). Anal. calcd
for C18H21F3N2O (338.37): C, 63.89; H, 6.26; N, 8.28.
Found: C, 63.93; H, 6.38; N, 8.34.
3.1.23. 2-Fluoro-6-iodo-3-(4-n-octyloxyphenyl)pyrazine
(24). Metallation of 21 (95 mg, 0.32 mmol) according to
the procedure A with n-BuLi 1.6 M (1.1 equiv., 0.22 mL),
TMPH (1.2 equiv., 0.06 mL), t1¼5 min, u1¼2788C, fol-
lowed by reaction with iodine (2 equiv., 160 mg),
t2¼60 min, u2¼2788C gave after purification by column
chromatography (silica gel, eluent: dichloromethane/
petroleum ether (1:2)) 99 mg (73%) of 24 as a pale yellow
solid, mp 58–598C. 1H NMR (CDCl3): d 8.67 (d, 1H,
JH5–F¼4.5 Hz, H5); 7.94 (d, 2H, J¼9.0 Hz, 2HPh); 6.91 (d,
2H, J¼9.0 Hz, 2HPh); 3.93 (t, 2H, OCH2); 1.73 (m, 2H,
CH2); 1.40–1.21 (m, 10H, 5CH2); 0.82 (t, 3H, CH3); 13C
NMR (CDCl3): d 161.6 (CPh); 155.8 (d, JC2–F¼265.2 Hz,
C2); 149.9 (C5); 140.8 (d, JC3–F¼21.8 Hz, C3); 130.6
(2CHPh); 124.9 (CPh); 115.2 (2CHPh); 107.2 (C6);
68.6 (OCH2); 32.2–23.1 (6CH2); 14.5 (CH3); 19F NMR
3.1.20. 2-Fluoro-3-(4-n-octyloxyphenyl)pyrazine (21).
Coupling of 4-n-octyloxyphenylboronic acid (670 mg,
1.5 equiv.)
with
2-fluoro-3-iodopyrazine
(400 mg,
1.79 mmol) according to the general procedure D (t¼24 h)
gave after purification by column chromatography (silica
gel, eluent: dichloromethane/petroleum ether (1:1)) 393 mg
1
(73%) of 21 as a colorless solid, mp 34–358C. H NMR
(CDCl3): d 8.45 (dd, 1H, JH5–F¼4.9 Hz, JH5–H6¼2.6 Hz,
H5); 7.96 (m, 3H, H6þ2HPh); 6.95 (d, 1H, J¼9.0 Hz, 2HPh);
3.95 (t, 2H, OCH2); 1.73 (m, 2H, CH2); 1.52–1.22 (m, 10H,
5CH2); 0.82 (t, 3H, CH3); 13C NMR (CDCl3): d 161.3 (CPh);
157.9 (d, JC2–F¼256.5 Hz, C2); 142.6 (d, JC3–F¼24.0 Hz,
C3); 141.9 (C5 or C6); 138.8 (C5 or C6); 130.7 (2CHPh);

F. Toudic et al. / Tetrahedron 59 (2003) 6375–6384
6383
(CDCl3): d 270.96. Anal. calcd for C18H22FIN2O (428.28):
C, 50.48; H, 5.17; N, 6.54. Found: C, 50.81; H, 5.36; N,
6.55.
Anal. calcd for C32H43FN2O2 (506.70): C, 75.85; H, 8.55;
N, 5.53. Found: C, 75.77; H, 8.72; N, 5.45.
3.1.27. 3-(2,3-Difluoro-4-n-hexyloxyphenyl)-2-fluoro-6-
(4-n-octloxyphenyl)pyrazine (28). Coupling of 4-n-octyl-
oxyphenylboronic acid (87 mg, 1.5 equiv.) with 3-(2,3-
difluoro-4-nhexyloxyphenyl)-2-fluoro-6-iodopyrazine (101
mg, 0.23 mmol) according to the general procedure D
(t¼24 h) gave after purification by column chromatography
(silica gel, eluent: dichloromethane/petroleum ether (1:2))
112 mg (94%) of 28 as a colorless solid, transitions (8C) C
3.1.24. 3-(2,3-Difluoro-4-n-hexyloxyphenyl)-2-fluoro-6-
iodopyrazine (25). Metallation of 22 (200 mg,
0.64 mmol) according to the procedure A with n-BuLi
1.6 M (1.1 equiv., 0.44 mL), TMPH (1.2 equiv., 0.13 mL),
t1¼5 min, u1¼2788C, followed by reaction with iodine
(2 equiv., 326 mg), t2¼60 min, u2¼2788C gave after
purification by column chromatography (silica gel, eluent:
dichloromethane/petroleum ether (1:2)) 191 mg (68%) of
1
66.5 SC 114.0 N 134.5 I. H NMR (CDCl3): d 8.88 (d,
1
25 as a colorless solid, mp 53–548C. H NMR (CDCl3): d
JH5–F¼4.9 Hz, H5); 7.95 (d, 2H, J¼9.0 Hz, 2HPh); 7.29 (m,
1H, HPh); 6.95 (d, 2H, J¼9.0 Hz, 2HPh); 6.80 (m, 1H, HPh);
4.04 (t, 2H, OCH2); 3.96 (t, 2H, OCH2); 1.75 (m, 4H,
8.75 (d, 1H, JH5–F¼3.8 Hz, H5); 7.23 (m, 1H, HPh); 6.80 (m,
1H, HPh); 4.03 (t, 2H, OCH2); 1.78 (m, 2H, CH2); 1.43–1.24
(m, 6H, 3CH2); 0.81 (t, 3H, CH3); 13C NMR (CDCl3): d
156.1 (d, JC2–F¼265.2 Hz, C2); 151.0 (CPh); 150.2 (C5);
149.7 (dd, JC–F¼254.3, 11.6 Hz, CPh–F); 141.7 (dd,
JC–F¼248.8, 14.2 Hz, CPh–F); 137.0 (d, JC3–F¼27.6 Hz,
C3); 125.2 (CHPh); 114.7 (CPh); 110.6 (C6); 109.9 (CHPh);
70.3 (OCH2); 31.9–22.9 (4CH2); 14.4 (CH3); 19F NMR
(CDCl3): d 276.76 (Fpyr); 2136.44 (FPh); 2158.52 (FPh).
Anal. calcd for C16H16F3IN2O (436.21): C, 44.06; H, 3.70;
N, 6.42. Found: C, 44.19; H, 3.82; N, 6.48.
2CH2); 1.52–1.18 (m, 16H, 8CH2); 0.80 (m, 6H, 2CH3); 13
C
NMR (CDCl3): d 161.7 (CPh); 157.5 (d, JC2–F¼255.0 Hz,
C2); 150.3 (CPh); 150.0 (C6); 149.8 (dd, JC–F¼253.6,
11.6 Hz, CPh–F); 141.8 (dd, JC–F¼247.8, 14.5 Hz, CPh–F);
137.8 (C5); 134.7 (d, JC3–F¼30.5 Hz, C3); 128.9 (2CHPh);
126.9 (CPh); 125.1 (CHPh); 116.1 (CPh); 115.5 (2CHPh);
109.8 (CHPh); 70.3 (OCH2); 68.6 (OCH2); 32.2–22.9
(10CH2); 14.5 (2CH3); 19F NMR (CDCl3): d 275.69
(Fpyr); 2137.21 (FPh); 2158.76 (FPh). Anal. calcd for
C30H37F3N2O2 (514.63): C, 70.02; H, 7.25; N, 5.44. Found:
C, 69.89; H, 7.14; N, 5.34.
3.1.25. 3-(2,3-Difluoro-4-n-octyloxyphenyl)-2-fluoro-6-
iodopyrazine (26). Metallation of 23 (151 mg,
0.44 mmol) according to the procedure A with n-BuLi
1.6 M (1.1 equiv., 0.31 mL), TMPH (1.2 equiv., 0.09 mL),
t1¼5 min, u1¼2788C, followed by reaction with iodine
(2 equiv., 226 mg), t2¼60 min, u2¼2788C gave after
purification by column chromatography (silica gel, eluent:
dichloromethane/petroleum ether (1:4)) 126 mg (61%) of
26 as a yellow oil. 1H NMR (CDCl3): d 8.74 (d, 1H,
JH5–F¼3.8 Hz, H5); 7.23 (m, 1H, HPh); 6.79 (m, 1H, HPh);
4.02 (t, 2H, OCH2); 1.77 (m, 2H, CH2); 1.44–1.17 (m, 10H,
5CH2); 0.80 (t, 3H, CH3); 13C NMR (CDCl3): d 156.1 (d,
JC2–F¼265.2 Hz, C2); 151.0 (CPh); 150.2 (C5); 149.7 (dd,
JC–F¼254.3, 11.6 Hz, CPh–F); 141.7 (dd, JC–F¼248.5,
14.5 Hz, CPh–F); 137.0 (d, JC3–F¼27.6 Hz, C3); 125.2
(CHPh); 114.7 (CPh); 110.6 (C6); 109.9 (CHPh); 70.3
(OCH2); 32.3–23.0 (6CH2); 14.5 (CH3); 19F NMR
(CDCl3): d 270.95 (Fpyr); 2136.77 (FPh); 2158.31
(FPh). Anal. calcd for C18H20F3IN2O (464.26): C, 46.57;
H, 4.34; N, 6.03. Found: C, 46.34; H, 4.25; N, 6.26.
3.1.28. 6-(2,3-Difluoro-4-n-hexyloxyphenyl)-2-fluoro-3-
(4–octyloxyphenyl)pyrazine (29). Coupling of 2,3-
difluoro-4-n-hexyloxyphenylboronic
acid
(82 mg,
1.5 equiv.) with 2-fluoro-6-iodo-3-(4-n-octyloxyphenyl)-
pyrazine (90 mg, 0.21 mmol) according to the general
procedure D (t¼24 h) gave after purification by column
chromatography (silica gel, eluent: dichloromethane/
petroleum ether (1:2)) 99 mg (91%) of 29 as a colorless
solid, transitions (8C); C 82.0 SC 111.0 N 149.0 I. 1H NMR
(CDCl3): d 8.93 (dd, 1H, JH5–Fpyr¼5.3 Hz, JH5–FPh
¼
2.3 Hz, H5); 8.02 (d, 2H, J¼9.0 Hz, 2HPh); 7.71 (m, 1H,
HPh); 6.94 (d, 2H, J¼9.0 Hz, 2HPh); 6.78 (m, 1H, HPh); 4.02
(t, 2H, OCH2); 3.95 (t, 2H, OCH2); 1.74 (m, 4H, 2CH2);
1.44–1.16 (m, 16H, 8CH2); 0.82 (m, 6H, 2CH3); 13C NMR
(CDCl3): d 159.8 (CPh); 155.4 (d, JC2–F¼257.2 Hz, C2);
149.0 (CPh); 149.0 (dd, JC–F¼252.5, 11.8 Hz, CPh–F);
141.6 (C6); 140.4 (dd, JC–F¼247.8, 14.5 Hz, CPh–F); 139.6
(C5); 138.4 (d, JC3–F¼23.3 Hz, C3); 129.1 (2CHPh); 124.5
(CPh); 122.9 (CHPh); 115.2 (CPh); 113.6 (2CHPh); 108.5
(CHPh); 68.8 (OCH2); 67.1 (OCH2); 30.8–21.5 (10CH2);
13.0 (2CH3); 19F NMR (CDCl3): d 274.39 (Fpyr); 2137.97
(FPh); 2158.86 (FPh). Anal. calcd for C30H37F3N2O2
(514.63): C, 70.02; H, 7.25; N, 5.44. Found: C, 70.03; H,
7.34; N, 5.43.
3.1.26. 3,6-Di(4-n-octyloxyphenyl)-2-fluoropyrazine (27).
Coupling of 4-n-octyloxyphenylboronic acid (118 mg,
1.5 equiv.) with 24 (134 mg, 0.31 mmol) according to the
general procedure D (t¼24 h) gave after purification by
column chromatography (silica gel, eluent: dichloro-
methane/petroleum ether (1:1)) 117 mg (73%) of 27 as a
colorless solid, transitions (8C) C 89.7 SC 157.5 N 179.1 I.
1H NMR (CDCl3): d 8.79 (d, 1H, JH5–F¼5.3 Hz, H5); 7.95
(d, 2H, J¼8.6 Hz, 2HPh); 7.89 (d, 2H, J¼8.6 Hz, 2HPh); 6.92
(d, 2H, J¼8.6 Hz, 2HPh); 6.90 (d, 2H, J¼8.6 Hz, 2HPh); 3.91
(m, 4H, 2OCH2); 1.71 (m, 4H, 2CH2); 1.39–1.21 (m, 20H,
10CH2); 0.81 (m, 6H, 2CH3); 13C NMR (CDCl3): d 161.3
(CPh); 161.0 (CPh); 157.1 (d, JC2–F¼255.8 Hz, C2); 147.8
(C6); 138.6 (d, JC3–F¼24.7 Hz, C3); 137.5 (C5); 130.3
(2CHPh); 128.6 (2CHPh); 127.3 (CPh); 126.3 (CPh); 115.4
(2CHPh); 115.0 (2CHPh); 68.5 (2OCH2); 32.2–23.1
(12CH2); 14.5 (2CH3); 19F NMR (CDCl3): d 275.41.
3.1.29. 3-(2,3-Difluoro-4-n-hexyloxyphenyl)-6-(2,3-
difluoro-4-n-octyloxyphenyl)-2-fluoropyrazine
(30).
Coupling of 2,3-difluoro-4-n-octyloxyphenylboronic acid
(88 mg, 1.5 equiv.) with 26 (90 mg, 0.21 mmol) according
to the general procedure D (t¼24 h) gave after purification
by column chromatography (silica gel, eluent: dichloro-
methane/petroleum ether (1:2)) 96 mg (85%) of 30 as a
1
colorless solid, mp 127–1288C. H NMR (CDCl3): d 8.99
(m, 1H, JH5–F¼4.5 Hz, H5); 7.76 (m, 1H, HPh); 7.32 (m, 1H,
HPh); 6.81 (m, 2H, 2HPh); 4.04 (t, 4H, 2OCH2); 1.78 (m, 4H,
2CH2); 1.44–1.18 (m, 16H, 8CH2); 0.79 (m, 6H, 2CH3); 13
C

6384
F. Toudic et al. / Tetrahedron 59 (2003) 6375–6384
NMR (CDCl3): d 155.8 (d, JC2–F¼256.5 Hz, C2); 149.3 (m,
2CPh); 149.0 (dd, JC–F¼252.4, 12.3 Hz, CPh–F); 148.5 (dd,
JC–F¼253.3, 11.6 Hz, CPh–F); 143.9 (C6); 140.4 (dd,
JC–F¼247.8, 15.2 Hz, CPh–F); 140.3 (dd, JC–F¼247.8,
14.5 Hz, CPh–F); 139.8 (C5); 134.6 (d, JC3–F¼30.5 Hz, C3);
123.9 (CHPh); 123.3 (CHPh); 114.8 (m, CPh); 114.4 (m, CPh);
108.6 (CHPh); 108.4 (CHPh); 68.8 (2OCH2); 30.8–21.5
(10CH2); 13.0 (2CH3); 19F NMR (CDCl3): d 274.66 (Fpyr);
2137.02 (FPh); 2137.74 (Fph); 2158.65 (2FPh). Anal.
calcd for C30H35F5N2O2 (550.61): C, 65.44; H, 6.41; N,
5.09. Found: C, 65.38; H, 6.64; N, 4.99.
Acknowledgements
We thank Professor Jean-Franc¸ois Nicoud and Dr Bertrand
Donnio (GMO–IPCMS Strasbourg) for their collaboration
and the determination of the transition temperatures
measured with a polarising microscope and using DSC.
References
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Chemistry; Wiley: New York, 1991.
3.1.30. 3-(2,3-Difluoro-4-n-hexyloxyphenyl)-2-fluoro-6-
tributylstannylpyrazine (31). Metallation of 22 (192 mg,
0.62 mmol) according to the procedure A with n-BuLi
1.6 M (3.1 equiv., 1.20 mL), TMPH (3.2 equiv., 0.33 mL),
t1¼5 min, u1¼2788C, followed by reaction with tributyltin
chloride (3 equiv., 0.52 mL), t2¼60 min, u2¼2788C gave
after purification by column chromatography (silica gel,
eluent: dichloromethane/petroleum ether (1:4)) 199 mg
2. (a) Reiffenrath, V.; Krause, J.; Plach, H. J.; Weber, G. Liq.
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Goodby, J. W.; Hird, M.; Toyne, K. J. J. Chem. Soc., Perkin
Trans. 2 1999, 481.
1
(54%) of 31 as a yellow oil. H NMR (CDCl3): d 8.46 (d,
1H, JH5–F¼5.6 Hz, H5); 7.24 (m, 1H, HPh); 6.78 (m, 1H,
HPh); 4.01 (t, 2H, OCH2); 1.76 (m, 2H, CH2); 1.62–1.00 (m,
24H, 12CH2); 0.81 (t, 12H, 4CH3); 13C NMR (CDCl3): d
166.7 (C6); 158.7 (d, JC2–F¼255.0 Hz, C2); 150.4 (CPh);
149.8 (dd, JC–F¼253.6, 11.6 Hz, CPh–F); 148.8 (C5); 141.8
´
3. (a) Marsais, F.; Granger, P.; Queguiner, G. J. Org. Chem.
´
1981, 46, 4494. (b) Gu¨ngor, T.; Marsais, F.; Queguiner, G.
J. Organomet. Chem. 1981, 215, 139. (c) Marsais, F.;
´
Queguiner, G. Tetrahedron 1983, 39, 2009. (d) Mallet, M.;
´
Queguiner, G. Tetrahedron 1979, 35, 1625. (e) Mallet, M.;
´
Queguiner, G. Tetrahedron 1982, 38, 3035. (f) Mallet, M.;
´
Marsais, M.; Branger, G.; Queguiner, G. J. Organomet. Chem.
(dd, JC–F¼248.1, 14.2 Hz, CPh–F); 136.4 (d, JC3–F
¼
30.5 Hz, C3); 125.2 (CHPh); 116.3 (CPh); 109.8 (CHPh);
70.2 (OCH2); 31.9–22.9 (11CH2); 14.4 (CH3); 13.9 (3CH3);
10.5 (3CH2); 19F NMR (CDCl3): d 274.08 (Fpyr); 2137.3
(FPh); 2158.8 (FPh). C28H43F3N2OSn (M¼599.36) MS
(mþ1/z) 601.
1990, 382, 319.
4. Marsais, F.; Bouley, E.; Queguiner, G. J. Organomet. Chem.
´
1979, 171, 273.
´ ´
5. Ple, N.; Turck, A.; Heynderickx, A.; Queguiner, G.
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´ ´
6. (a) Ple, N.; Turck, A.; Heynderickx, A.; Queguiner, G.
3.1.31. 6,60-Difluoro-5-(2,3-difluoro-4-n-hexyloxy-
phenyl)-50-(2,3-difluoro-4-n-octylphenyl)-2,20-bipyrazine
(32). Coupling of 31 (140 mg, 1.2 equiv.) with 26 (90 mg,
0.19 mmol) according to the general procedure C (t¼48 h)
gave after purification by column chromatography (silica,
eluent: dichloromethane/petroleum ether (1:2)) 114 mg
(90%) of 32 as a colorless solid, transitions (8C) C 145.0
´
Tetrahedron 1998, 54, 4899. (b) Toudic, F.; Ple, N.; Turck, A.;
´
Queguiner, G. Tetrahedron 2002, 58, 283.
7. (a) Gray, G. W.; Hird, M.; Toyne, K. J. Mol. Cryst. Liq. Cryst.
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150B, 335. (c) Chan, L. K. M.; Gray, G. W.; Lacey, D.; Toyne,
K. J. Mol. Cryst. Liq. Cryst. 1988, 158B, 209.
1
SC 164.0 N 196.0 I. H NMR (CDCl3): d 9.43 (d, 2H,
JH5–F¼4.1 Hz, 2H5); 7.88 (m, 2H, 2HPh); 6.84 (m, 2H,
2HPh); 4.05 (t, 4H, J¼6.6 Hz, 2OCH2); 1.79 (m, 2H, 2CH2);
1.42–1.17 (m, 16H, 8CH2); 0.93 (m, 6H, 2CH3); 13C NMR
(CDCl3): d 157.0 (d, JC2–F¼259.4 Hz, 2C2); 151.1 (2CPh);
150.0 (dd, JC–F¼254.3, 11.6 Hz, 2CPh-F); 146.5 (2C6);
141.8 (dd, JC–F¼235.4, 14.2 Hz, 2CPh-F); 140.4 (2C5);
139.6 (d, JC3–F¼32.0 Hz, 2C3); 125.5 (2CHPh); 115.5
(2CPh); 110.0 (2CHPh); 70.3 (2OCH2); 32.1–23.0
(10CH2); 14.4 (2CH3); 19F NMR (CDCl3): d 274.73
(Fpyr); 2136.44 (2FPh); 2158.54 (2FPh). Anal. calcd for
C34H36F6N4O2 (646.68): C, 63.15; H, 5.61; N, 8.66. Found:
C, 63.19; H, 5.67; N, 8.53.
8. (a) Gray, G. W.; Hird, M.; Lacey, D.; Toyne, K. J. J. Chem.
Soc., Perkin Trans. 2 1989, 2041. (b) Gray, G. W.; Hird, M.;
Toyne, K. J. Mol. Cryst. Liq. Cryst. 1991, 204, 43. (c) Hird,
M.; Toyne, K. J.; Gray, G. W.; McDonnel, D. G.; Sage, I. C.
Liq. Cryst. 1995, 18, 1. (d) Gray, G. W.; Hird, M.; Toyne, K.
J. Mol. Cryst. Liq. Cryst. 1991, 195, 221.
9. (a) Glendenning, M. E.; Goodby, J. W.; Hird, M.; Toyne, K. J.
J. Chem. Soc., Perkin Trans. 2 1999, 481. (b) Glendenning,
M. E.; Goodby, J. W.; Hird, M.; Toyne, K. J. J. Chem. Soc.,
Perkin Trans. 2 2000, 27.
10. Coulson, D. R. Inorg. Synth. 1972, 13, 121.