A new route to Septorin via controlled metalations of pyrazines. Diazines XXX

Article abstract of DOI:10.1016/S0040-4020(01)00950-4

The metalation of 2-chloro-3-(1-hydroxy-4-alkoxyphenylmethyl)pyrazines with LTMP in tetrahydrofuran has been studied and afforded regioselectively functionalized compounds at C₆. This regioselectivity was established by application of gradient

Full text of DOI:10.1016/S0040-4020(01)00950-4

TETRAHEDRON
Pergamon
Tetrahedron 57 /2001) 9429±9435
A new route to Septorin via controlled metalations of pyrazines.
Diazines XXX
p
 Â
Corinne Fruit, Alain Turck, Nelly Ple, Ljubica Mojovic and Guy Queguiner
 Â
Laboratoire de Chimie Organique Fine et Heterocyclique, IRCOF-INSA de ROUEN, UPRES-A 6014, B.P. 08,
F-76131 Mont-Saint-Aignan cedex, France
Received 1 June 2001; revised 17 September 2001; accepted 26 September 2001
AbstractÐThe metalation of 2-chloro-3-/1-hydroxy-4-alkoxyphenylmethyl)pyrazines with LTMP in tetrahydrofuran has been studied and
afforded regioselectively functionalized compounds at C6. This regioselectivity was established by application of gradient enhanced HMBC
sequence for the observation of long range 1H±15N heteronuclear couplings at natural abundance and by X-ray diffraction. Associated with
the regioselective metalation at C6, the transition metal catalyzed cross coupling reaction provides a new pathway to Septorin. q 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
of 1 was achieved by Ohta4 starting from l-isoleucine. An
overall yield of 1% was obtained over twelve steps.
A previous study of the metalation of 2-¯uoropyrazine1 has
highlighted the fact that it is possible to control the regio-
selectivity of the metalation of 2-¯uoro-3-substituted
pyrazines at C5 or C6.
The enantioselective synthesis of /1)-Septorin has been
described.4 The main drawback of this synthesis was in
the initial chlorination step which gave a mixture of three
products and led to dif®cult isolation of the required
compound via N-oxidation. Under these conditions, inter-
mediate 2 was obtained with a low overall yield of 4%
/Scheme 1).
These results could be used to perform regioselective
syntheses of polysubstituted pyrazines; a good example
could be the synthesis of Septorin /1) which is the main
agent of a wheat disease impeding growth.
The remainder of the Ohta's synthesis4 from intermediate 2
to Septorin 1 was very ef®cient and gave an 82% yield in
®ve steps.
Our expertise in metalation and cross coupling reactions of
pyrazines allowed us to synthesize intermediate 2 from the
commercially available 2-chloropyrazine 3.
The ®rst synthesis of a close precursor of 1 /6-acetoxy and
methylated on phenol) was performed by Barbier,2,3
however with very low yield. The ®rst complete synthesis
2. Results and discussion
The functionalization of 2-chloropyrazine 3 via the
Scheme 1.
Keywords: Septorin; pyrazine; metalation; regioselectivity; cross coupling reaction.
Corresponding author. Tel.: 133-2-3552-29-00; fax: 133-2-3552-29-62; e-mail: guy.queguiner@insa-rouen.fr
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020/01)00950-4

9430
C. Fruit et al. / Tetrahedron 57 32001) 9429±9435
Scheme 2.
metalation reaction has been previously described5 with
good yields. The lithio derivative was reacted with
4-methoxy and 4-methoxymethoxybenzaldehyde as the
electrophiles affording the 2,3-disubstituted pyrazines 4, 5
/Scheme 2).
functionalization at C6. In spite of an excess of metalating
agent /3.1 or 4.1 equiv., entries 4,5) and a longer reaction
time /entries 3,4), some starting material was always
recovered. In order to verify that the metalation took place
at C6, another regioselective synthetic route was used. Thus
2,6-dichloro-3-/4-methoxyphenyl-1-hydroxymethyl)pyrazine
8 was prepared regioselectively by metalation of 2,6-
dichloropyrazine 11 and reaction with 4-methoxybenz-
aldehyde /Scheme 4).
The lower yield in the case of 5 might result from a partial
cleavage of the methoxymethoxy group during puri®cation
by ¯ash chromatography on silica gel.
The next step was the introduction of the sec-butyl group in
the 6 position. As we planned to introduce a substituent at
this position by metalation, it was necessary to test the
regioselectivity of this reaction. So, a preliminary study
has been performed with compound 4 which was obtained
in better yield than 5. The usual aldehydes /acetaldehyde
and benzaldehyde) were used as electrophiles, then hexa-
chloroethane and iodine were chosen to introduce an
halogen atom allowing further substitutions or cross
coupling reactions /Scheme 3, Table 1).
The so-obtained compound presented physicochemical
properties, as well as IR and NMR spectra identical to
those of compound 8 previously obtained, thus proving
that the metalation of pyrazines 4 and 5 occurred at C6. It
may thus be assumed that compounds 6 and 7 /entries 1,2)
are also 2,3,6-trisubstituted pyrazines.
When iodine was used as the electrophile /entries 6±8), the
structure of iodo compounds 9 and 10 was not so clear since
some halogen dance reactions during the metalation and
reaction with electrophile, as previously described, could
occur.6 Structure elucidation of compounds 9 and 10 was
In all cases only one isomer was obtained with
Scheme 3.
Table 1. Metalation of compounds 4 and 5
Entry
R
n equiv. LTMP
Time /min)
E
Compound number
Yield /%)
Starting material /%)
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
MOM
MOM
3.1
3.1
3.1
3.1
4.1
3.1
3.1
4.1
15
15
15
60
15
15
15
15
CH3CH/OH)
Ph-CH/OH)
±Cl
±Cl
±Cl
±I
6
7
8
8
8
9
10
10
56
52
61
60
69
64
52
50
33
30
16
12
10
22
21
11
±I
±I
Scheme 4.

C. Fruit et al. / Tetrahedron 57 32001) 9429±9435
9431
Scheme 5.
Scheme 6.
performed by applying gradient-enhancement HMBC
/Scheme 7), the 6-lithio derivative 4a being more stable
than the 5-lithio derivative /4b) with a difference of heat
1
sequence optimized on long range H±15N heteronuclear
couplings at natural abundance7 with low-pass J-®lter to
suppress one-bond correlations. The unequivocal identi®ca-
of formation DDHfˆ6.8 kcal mol21
.
2
tion of 15N chemical shifts was based on J1H±15N inter-
actions in the proton-coupled nitrogen spectrum which
were only present in the spectrum of 10 /Scheme 5).
To return to the synthesis of 2, the most straightforward way
of introducing the sec-butyl moiety was to react 2-iodo-
butane with the C6 lithio derivative of 4. Both 2-iodobutane
and iodoethane were tested without success.
Finally an X-ray diffraction spectrum was performed on 10,
allowing con®rmation of the presence of the iodine atom at
C6 /Scheme 6).
Another route envisioned was by way of an addition
reaction of sec-BuLi on the 1±6 carbon±nitrogen bond, no
addition±elimination product could be isolated and as usual
an increase of temperature led to degradation.
Having established that metalation took place at C6 and that
all electrophiles including iodine atom were introduced at
this position, the pending question is: why is metalation
regioselective at C6? The compound which was actually
metalated was not 4 or 5 but a lithium complex resulting
from the abstraction of the labile hydrogen of the alcohol
moiety. The lithium atom forms a chelate between the
oxygen of the alcoholate and the neighboring nitrogen as
indicated by semi empiric Li/PM3 calculations.8 Moreover,
the lithio derivative of 4 at C6 /4a) may coordinate with the
free N1, whereas the lithio derivative at C5 /4b) cannot be
coordinated with N4 which is already chelated /Scheme 7).
The coupling reaction with organozinc derivatives was then
studied: the ®rst experiment was the metalation of 4 with
LTMP followed by a transmetallation reaction with ZnCl2
9
and cross coupling with iodoethane. Unfortunately this
reaction failed to give the desired product. Thereafter, we
tested the cross coupling reaction of iodo derivative 9 with
sec-butylzinc chloride /Scheme 8).
Compound 12 was obtained with a modest yield /28%),
isomerization leading to n-butyl derivative 11 accounting
for also 28% yield. This isomerization could be avoided
by the choice of a suitable catalyst10±12 under the right
experimetal conditions. It has been highlighted that PdCl2
This assumption is in agreement with the calculation of the
heat of formation of the two lithio derivatives by Li/PM3
Scheme 7.

9432
C. Fruit et al. / Tetrahedron 57 32001) 9429±9435
Scheme 8.
Scheme 9.
Scheme 10.
/dppf) was a very selective catalyst. So we tested this
reaction directly on the OMOM substituted compound 10
/Scheme 9).
3. Experimental
3.1. General
After optimization of the experimental conditions, a 61%
yield of 13 as the sole compound was obtained
unaccompanied by any isomerization product.
IR spectra were obtained from potassium bromide
pellets with a Perkin±Elmer FMR 1650 spectrophot-
ometer. The NMR spectra were recorded on a Bruker
AC 200F /200 MHz), Bruker Avance /300 MHz) or
Bruker ARX /400 MHz) spectrometer. All NMR spectra
were carried out with deuteriochloroform solutions and
d are given in ppm. Chemical shifts in CDCl3 were
reported down®eld from TMS /ˆ0) for 1H NMR. For
13C NMR, chemical shifts were reported in the scale
relative to CHCl3 /77.0 ppm for 13C NMR) as an exter-
nal reference. Microanalyses were performed with a
Carlo Erba 1106 apparatus. Melting points were deter-
mined with a Ko¯er hot-stage apparatus and were
uncorrected.
In a last step, the chlorine atom of 13 was substituted by a
methoxy group by reaction of sodium methoxide at the
re¯ux temperature of methanol for 48 h. Under these
conditions 2 was obtained in 70% yield together with a
small amount of starting material 13 /17%).
The complete synthetic pathway is summarized in Scheme
10).
Starting from 2-chloropyrazine, we have prepared the
intermediate 2 in four steps with an overall yield of 14%.
Metalations were carried out in dry solvents under an argon
atmosphere. Reagents were handled with syringes through
septa. Tetrahydrofuran /THF) was distilled from benzo-
phenone sodium and used immediately /water content
,60 ppm). Column chromatography was performed with
silica gel Merck /70±230 mesh ASTM).
This intermediate 2 can be used, following Ohta's method,4
to access racemic Septorin in ®ve steps and 82% yield. In
this way, it should be possible to prepare racemic Septorin
from commercial 2-chloropyrazine in nine steps with an
overall yield of 11.5%.

C. Fruit et al. / Tetrahedron 57 32001) 9429±9435
9433
3.2. General procedures for metalation
/CDCl3) d 12.4 /CH3), 20.2 /CH3), 29.7 /CH2), 40.6 /CH),
53.6 /OCH3), 56.4 /CH2OCH3), 70.6 /CH), 94.8 /OCH2O),
116.3 /CPh3,5), 128.6 /CPh2,6), 132.8 /C5), 136.0 /CPh1), 146.8
/C3), 152.0 /C6), 155.6 /C2), 157.8 /CPh4); Anal. Calcd for
C18H24N2O4: C, 65.04; H, 7.28; N, 8.43. Found: C, 65.23; H,
7.14; N, 8.37.
3.2.1. Method A. A solution of n-butyllithium /1.6 or 2.5 M
in hexane) was added to cold /2758C), stirred, anhydrous
THF /15 mL) under an atmosphere of dry argon, then
2,2,6,6-tetramethylpiperidine was added and the mixture
was warmed to 08C and kept at this temperature for
15 min in order to achieve a complete formation of the
amide. The solution was cooled to 2758C and a solution
of reagent /x mmol) in 5 mL of THF was added and the
mixture was stirred for t min at 2758C. Then the electro-
phile /1.2 equiv. mmol) was added dropwise and stirring
was continued for t min at 2758C. Hydrolysis was then
carried out at 2758C using a mixture of ethanol /1 mL)
and THF /1 mL). The solution was gently warmed to 08C
and the solvent was evaporated under reduced pressure. The
residue was extracted with dichloromethane /4£25 mL).
The organic extract was dried with MgSO4 and evaporated.
The crude product was puri®ed by column chromatography
on silica gel.
3.4. Synthesis of substituted pyrazines via metalation
reaction
3.4.1. 2-Chloro-3--1-hydroxy-4-methoxyphenylmethyl)-
pyrazine -4). Metalation of chloropyrazine 3 /0.78 mL,
8.7 mmol) according to the general procedure /method A)
with n-butyllithium 1.6 M /6.0 mL, 9.6 mmol) and 2,2,6,6-
tetramethylpiperidine /1.8 mL, 10.5 mmol), tˆ30 min, then
reaction with para-anisaldehyde /1.3 mL, 10.5 mmol),
tˆ60 min gave, after puri®cation by column chromato-
graphy on silica gel /ether petroleum/ethyl acetateˆ7:3), 4
/1.950 g, 89%) as a cream oil: IR /KBr) n 3412, 3005, 2958,
1
2935, 2837, 1610, 1511, 1370, 1029, 757 cm21; H NMR
/CDCl3) d 3.70 /s, 3H, OCH3), 4.85 /d, Jˆ6.0 Hz, 1H, OH),
5.97 /d, Jˆ6.0 Hz, 1H, CH), 6.80 /d, Jˆ9.0 Hz, 2H, HPh),
7.23 /d, Jˆ9.0 Hz, 2H, HPh), 8.20 /d, JH5,H6ˆ2.0 Hz, 1H,
H5), 8.42 /d, JH5,H6ˆ2.0 Hz, 1H, H6); 13C NMR /CDCl3) d
55.6 /OCH3), 72.0 /CH/OH)), 114.4 /CPh3,5), 129.2 /CPh2,6),
132.9 /CPh1), 141.5 /C5), 143.3 /C6), 147.9 /C3), 155.4 /C2),
158.4 /CPh4); Anal. Calcd for C12H11ClN2O2: C, 57.50; H,
4.42; N, 11.17. Found: C, 57.78; H, 4.78; N, 10.93.
3.2.2. Method B -in situ trapping method). A solution of
n-butyllithium /1.6 or 2.5 M in hexane) was added to cold
/2758C), stirred, anhydrous THF /15 mL) under an
atmosphere of dry argon, then 2,2,6,6-tetramethylpiperidine
was added and the mixture was warmed to 08C and kept at
this temperature for 15 min in order to achieve a complete
formation of the amide. The solution was cooled to 2758C
and a mixture of the reagent /x mmol) and the electrophile
/1.2 equiv. mmol) in 5 mL of THF was added slowly and
the mixture was stirred for 2 h at 2758C. Hydrolysis was
then carried out at 2758C using a mixture of ethanol /1 mL)
and THF /1 mL). The solution was gently warmed to 08C
and the solvent was evaporated under reduced pressure. The
residue was extracted with dichloromethane /4£25 mL).
The organic extract was dried with MgSO4 and evaporated.
The crude product was puri®ed by column chromatography
on silica gel.
3.4.2. 4-Methoxymethoxybenzaldehyde. To a solution of
4-hydroxybenzaldehyde /2.442 g, 20 mmol) in acetone
/30 mL) was added dry K2CO3 /5.530 g, 40 mmol). This
solution was allowed to stir for 15 min at room temperature
/orange color). To this solution, MOMCl /1.60 mL,
21 mmol) was added slowly by syringe through a septum.
After complete addition, the reaction mixture was warmed
up to re¯ux during 2 h. Again, the reaction mixture was
cooled down to room temperature. After ®ltration of excess
K2CO3 on a Buchner funnel, solvent was evaporated under
reduced pressure to give 4-methoxymethoxy-benzaldehyde
/3.318 g, 100%) as an orange visquous liquid. IR /KBr) n
3368, 2958, 2903, 2829, 2741, 1695, 1600, 1579, 1508,
3.3. Synthesis of the Septorin precursor
3.3.1.
6-sec-Butyl-3--1-hydroxy-4-methoxymethoxy-
1241, 1215, 1152, 1082, 986, 835 cm21
;
1H NMR
phenylmethyl)-2-methoxypyrazine -2). To a solution of
13 /0.075 g, 0.22 mmol) in methanol /10 mL) was added
sodium methoxide /anhydrous powder) /0.060 g,
1.1 mmol) by fractions. The resulting mixture was warmed
at re¯ux during 48 h. The reaction mixture was again cooled
down to room temperature and was hydrolysed with 1 mL of
water. Methanol was evaporated under vacuum and the
aqueous layer was extracted with methylene chloride
/6£15 mL). The resulting organic phase was dried over
magnesium sulphate and evaporated. A ¯ash chromato-
graphy on silica gel /ether petroleum/ethyl acetateˆ4:1)
gave 2 /0.051 g, 70%) as a colorless oil: IR /KBr) n 3438,
2961, 2932, 2874, 1610, 1545, 1509, 1460, 1320, 1234,
/CDCl3) d 3.42 /s, 3H, OCH3), 5.19 /s, 2H, OCH2), 7.06
/d, Jˆ8.8 Hz, 2H, HPh3,5), 7.79 /d, Jˆ8.8 Hz, 2H, HPh2,6),
9.82 /s, 1H, CHO); 13C NMR /CDCl3) d 56.4 /OCH3), 94.3
/OCH2), 116.5 /CPh3,5), 130.9 /CPh1), 132.0 /CPh2,6), 162.4
/C1), 191.0 /CHO); Anal. Calcd for C9H10O3: C, 65.05; H,
6.07. Found: C, 64.94; H, 5.89.
Caution: methoxymethyl chloride is very toxic and should
be handled with care.
3.4.3. 2-Chloro-3--1-hydroxy-4-methoxymethoxyphenyl-
methyl)pyrazine -5). Metalation of chloropyrazine 3
/4.5 mL, 50 mmol) according to the general procedure
/method A) with n-butyllithium 2.5 M /22 mL, 55 mmol)
and 2,2,6,6-tetramethylpiperidine /9.3 mL, 55 mmol),
tˆ30 min, then reaction with 4-methoxymethoxybenzalde-
hyde /9.97 g, 60 mmol), tˆ60 min gave, after puri®cation
by column chromatography on silica gel /ether petroleum/
ethyl acetateˆ3:2), 5 /8.002 g, 57%) as an orange oil: IR
/KBr) n 3401, 2958, 2827, 1609, 1509, 1236, 1152, 1081,
1
1173, 1153, 1080, 1005 cm21; H NMR /CDCl3) d 0.76
/t, JCH2,CH3ˆ7.3 Hz, 3H, CH2CH3), 1.17 /dd, JCH,CH3
ˆ
6.8 Hz, 3H, CHCH3), 1.50±1.65 /m, JCH2,CH3ˆ7.3 Hz, 2H,
CH2), 2.63 /m, JCH,CH3ˆ6.8 Hz, 1H, CH), 3.38 /s, 3H,
CH2OCH3), 3.83 /s, 3H, OCH3), 4.76 /d, JCH,OHˆ7.2 Hz,
1H, OH), 5.07 /s, 2H, OCH2O), 5.75 /d, JCH,OHˆ7.2 Hz,
1H, CH), 6.88 /d, Jˆ8.6 Hz, 2H, HPh3,5), 7.22 /d,
Jˆ8.6 Hz, 2H, HPh2,6), 7.85 /s, 1H, H5); 13C NMR

9434
C. Fruit et al. / Tetrahedron 57 32001) 9429±9435
1
1000 cm21; H NMR /CDCl3) d 3.39 /s, 3H, OCH3), 4.81
/d, JCH,OHˆ6.0 Hz, 1H, OH), 5.11 /s, 2H, OCH2), 6.06 /d,
JCH,OHˆ6.0 Hz, 1H, CH), 6.98 /d, Jˆ9.0 Hz, 2H, HPh3,5),
7.30 /d, Jˆ9.0 Hz, 2H, HPh2,6), 8.24 /d, JH5,H6ˆ2.0 Hz,
1H, H5), 8.46 /d, JH5,H6ˆ2.0 Hz, 1H, H6); 13C NMR
/CDCl3) d 56.3 /OCH3), 71.9 /CH/OH)), 94.5 /OCH2),
116.6 /CPh3,5), 129.1 /CPh2,6), 134.2 /CPh1), 141.8 /C5),
143.2 /C6), 147.7 /C3), 155.4 /C2), 157.4 /CPh4); 15N NMR
/CDCl3) d 326 /d, Jˆ10.5 Hz, N1), 331 /d, Jˆ10.5 Hz, N4);
Anal. Calcd for C13H13ClN2O3: C, 55.62; H, 4.67; N, 9.98.
Found: C, 55.51; H, 4.82; N, 10.09.
1.1 mmol), para-anisaldehyde /0.13 mL, 1.1 mmol), tˆ4 h
gave, after puri®cation by column chromatography on silica
gel /cyclohexane/ethyl acetateˆ3:2), 8 /0.040 g, 25%) as a
yellow oil which crystallized: mpˆ1078C /CH2Cl2); IR
/KBr) n 3423, 3002, 2934, 2836, 1609, 1511, 1305, 1251,
1
1174, 1156, 1032, 836 cm21; H NMR /CDCl3) d 3.76 /s,
3H, OCH3), 4.29 /d, JCH,OHˆ6.9 Hz, 1H, OH), 5.98 /d,
JCH,OHˆ6.9 Hz, 1H, CH), 6.85 /d, Jˆ8.7 Hz, 2H, HPh3,5),
7.24 /d, Jˆ8.7 Hz, 2H, HPh2,6), 8.54 /s, 1H, H5); 13C NMR
/CDCl3) d 55.1 /OCH3), 71.3 /CH), 114.0 /CPh3,5), 128.5
/CPh2,6), 131.9 /CPh1), 140.9 /C5), 145.2 /C6), 146.1 /C3),
153.0 /C2), 159.4 /CPh4); MS 284 /M1), HRMS 284.0119;
Anal. Calcd for C12H10Cl2N2O2: C, 50.55; H, 3.54; N, 9.82.
Found: C, 50.48; H, 3.66; N, 9.75.
3.4.4. 2-Chloro-3--1-hydroxy-4-methoxyphenylmethyl)-
6--1-hydroxyethyl)pyrazine -6). Metalation of 4 /0.300 g,
1.2 mmol) according to the general procedure /method A)
with n-butyllithium 1.6 M /2.3 mL, 3.7 mmol) and 2,2,6,6-
tetramethylpiperidine /0.65 mL, 3.8 mmol), tˆ15 min, then
reaction with acetaldehyde /0.4 mL, 7.1 mmol), tˆ45 min
gave, after puri®cation by column chromatography on silica
gel /cyclohexane/ethyl acetateˆ1:1), 6 /0.200 g, 56%) as a
yellow oil: IR /KBr) n 3401, 2977, 2934, 2837, 1702, 1610,
1512, 1251, 1175, 1083, 1033, 756 cm21; 1H NMR /CDCl3)
d 1.49 /d, JCH,CH3ˆ6.8 Hz, 3H, 1dia, CH3), 1.50 /d,
JCH,CH3ˆ6.8 Hz, 3H, 1dia, CH3), 2.70 /p, 1H, OH), 3.70
/s, 3H, OCH3), 4.60 /p, 1H, OH), 4.89 /q, JCH,CH3ˆ6.8 Hz,
1H, CH), 5.90 /s, 1H, CH), 6.77 /d, Jˆ8.7 Hz, 2H, HPh3,5),
7.18 /d, Jˆ8.7 Hz, 2H, HPh2,6), 8.56 /s, 1H, 1dia, H5), 8.57
/s, 1H, 1dia, H5); 13C NMR /CDCl3) d 24.11 /CH3, 1dia),
24.15 /CH3, 1dia), 55.7 /OCH3), 68.42 /CH/CH3), 1dia),
68.46 /CH/CH3), 1dia), 72.0 /CH/OH)), 114.4 /CPh3,5),
129.1 /CPh2,6), 132.94 /C6, 1dia), 132.98 /C6, 1dia), 138.6
/C5), 153.4 /C2), 158.53 /C3, 1dia), 158.57 /C3, 1dia), 159.9
/CPh4); Anal. Calcd for C14H15ClN2O3: C, 57.06; H, 5.19; N,
9.50. Found: C, 56.87; H, 5.55; N, 9.39.
3.4.7. 2-Chloro-3--1-hydroxy-4-methoxyphenylmethyl)-
6-iodopyrazine -9). Metalation of 4 /0.210 g, 0.8 mmol)
according to the general procedure /method A) with n-butyl-
lithium 2.5 M /1.0 mL, 2.5 mmol) and 2,2,6,6-tetramethyl-
piperidine /0.44 mL, 2.6 mmol), tˆ15 min, then reaction
with iodine /0.240 g, 0.9 mmol), tˆ120 min gave, after
puri®cation by column chromatography on silica gel /cyclo-
hexane/ethyl acetateˆ3:2), 9 /0.200 g, 64%) as a red oil: IR
/KBr) n 3412, 3004, 2956, 2932, 2836, 1610, 1509, 1305,
1251, 1175, 1117, 1035, 832, 756 cm21; 1H NMR /CDCl3)
d 3.76 /s, 3H, OCH3), 4.28 /d, JCH,OHˆ7.5 Hz, 1H, OH),
5.92 /d, JCH,OHˆ7.5 Hz, 1H, CH), 6.87 /d, Jˆ8.7 Hz, 2H,
HPh3,5), 7.27 /d, Jˆ8.7 Hz, 2H, HPh2,6), 8.78 /s, 1H, H5); 13
C
NMR /CDCl3) d 55.3 /OCH3), 71.3 /CH), 111.5 /C6), 114.0
/CPh3,5), 128.6 /CPh2,6), 131.9 /CPh1), 146.4 /C3), 149.5 /C5),
153.6 /C2), 159.6 /CPh4); Anal. Calcd for C12H10ClIN2O2: C,
38.27; H, 2.68; N, 7.44. Found: C, 38.45; H, 2.76; N, 7.21.
3.4.8. 2-Chloro-3--1-hydroxy-4-methoxymethoxyphenyl-
methyl)-6-iodopyrazine -10). Metalation of 5 /2.873 g,
10 mmol) according to the general procedure /method A)
with n-butyllithium 2.5 M /12.4 mL, 31 mmol) and 2,2,6,6-
tetramethylpiperidine /5.2 mL, 31 mmol), tˆ15 min, then
reaction with iodine /2.793 g, 11 mmol), tˆ120 min gave,
after puri®cation by column chromatography on silica gel
/ether petroleum/ethyl acetateˆ7:3), 10 /2.114 g, 52%) as
an orange oil which crystallized: mpˆ668C /CH2Cl2); IR
/KBr) n 3478, 2954, 2897, 1607, 1509, 1415, 1388, 1306,
3.4.5. 2-Chloro-3--1-hydroxy-4-methoxyphenylmethyl)-
6--1-hydroxyphenylmethyl) pyrazine -7). Metalation of
4 /0.200 g, 0.8 mmol) according to the general procedure
/method A) with n-butyllithium 1.6 M /1.6 mL, 2.5 mmol)
and 2,2,6,6-tetramethylpiperidine /0.44 mL, 2.6 mmol),
tˆ15 min, then reaction with benzaldehyde /0.1 mL,
1.0 mmol), tˆ60 min gave, after puri®cation by column
chromatography on silica gel /cyclohexane/ethyl acetateˆ
7:3), 7 /0.148 g, 52%) as a yellow oil: 1H NMR /CDCl3) d
3.36 /p, 1H, OH), 3.50 /p, 1H, OH), 3.75 /s, 3H, OCH3),
5.61 /s, 1H, CH), 5.92 /s, 1H, CH), 6.82 /d, Jˆ8.7 Hz, 2H,
HPh3,5), 7.30 /d, Jˆ8.7 Hz, 2H, HPh2,6), 8.60 /s, 1H, H5);
Anal. Calcd for C19H17ClN2O3: C, 63.96; H, 4.80; N, 7.85.
Found: C, 64.20; H, 4.67; N, 7.71.
1
1229, 1004, 834 cm21; H NMR /CDCl3) d 3.33 /s, 3H,
OCH3), 4.64 /p, 1H, OH), 5.04 /s, 2H, OCH2O), 5.87 /s,
1H, CH), 6.88 /d, Jˆ9.1 Hz, 2H, HPh3,5), 7.18 /d, Jˆ9.1 Hz,
2H, HPh2,6), 8.65 /s, 1H, H5);13C NMR /CDCl3) d 56.3
/OCH3), 71.7 /CH), 94.5 /OCH2O), 113.1 /C6), 116.6
/CPh3,5), 128.9 /CPh2,6), 133.7 /CPh1), 146.7 /C2), 150.1
/C5), 154.2 /C3), 157.5 /CPh4); 15N NMR /CDCl3) d 328.8
/s, N1), 330.1 /d, Jˆ10.5 Hz, N4); Anal. Calcd for
C13H12ClIN2O2: C, 38.40; H, 2.97; N, 6.89. Found: C,
38.67; H, 3.14; N, 7.28.
3.4.6.
methyl)pyrazine -8). 1st method: Metalation of
2,6-Dichloro-3--1-hydroxy-4-methoxyphenyl-
4
/0.330 g, 1.3 mmol) according to the general procedure
/method A) with n-butyllithium 1.6 M /2.5 mL, 4.0 mmol)
and 2,2,6,6-tetramethylpiperidine /0.71 mL, 4.2 mmol),
tˆ15 min, then reaction with hexachloroethane /0.380 g,
1.6 mmol), tˆ60 min gave, after puri®cation by column
chromatography on silica gel /cyclohexane/ethyl acetateˆ
3:2), 8 /0.250 g, 61%) as a yellow oil which crystallized.
2nd method: Metalation of 2,6-dichloropyrazine 11
/0.150 g, 1.0 mmol) according to the general procedure
/method B) with n-butyllithium 2.5 M /0.44 mL,
1.1 mmol) and 2,2,6,6-tetramethylpiperidine /0.13 mL,
3.5. Synthesis of alkylpyrazines via cross-coupling
reaction with organozinc reagent
3.5.1. 6-n-Butyl-2-chloro-3--1-hydroxy-4-methoxyphenyl-
methyl)pyrazine -11) and 6-sec-butyl-2-chloro-3--1-
hydroxy-4-methoxyphenylmethyl)pyrazine -12). A solu-
tion containing 12.5 equiv. of zinc chloride /0.885 g,
6.5 mmol) /previously dried under vaccum with a ¯ameless
heat gun) dissolved in 5 mL of THF under an atmosphere of

C. Fruit et al. / Tetrahedron 57 32001) 9429±9435
9435
dry nitrogen was added to 5.0 equiv. of sec-butyllithium
1.3 M /2.0 mL, 2.6 mmol) at 2758. The mixture was then
gently warmed to room temperature. A solution containing
5 mol% tetrakis/triphenylphosphine)palladium13 /0.031 g,
0.026 mmol) and 2-chloro-3-/1-hydroxy-4-methoxyphenyl-
methyl)-6-iodopyrazine 9 /0.200 g, 0.53 mmol) dissolved in
5 mL of THF was added to the organozinc derivative and
the mixture was warmed at re¯ux during 48 h. The reaction
mixture was then hydrolysed with a solution containing
12.5 equiv. of ethylenediamine tetraacetic acid and 15 mL
of water. THF was evaporated under vacuum and the
aqueous layer was extracted with methylene chloride
/4£15 mL). The resulting organic layer was dried over
magnesium sulphate and evaporated. After a ¯ash chroma-
tography on silica gel /ether petroleum/ethyl acetateˆ7:3), a
mixture /50/50) /0.090 g, 55%) of products 11 and 12 was
isolated as an orange oil: IR /KBr) n 3426, 2959, 2931,
2872, 2837, 1610, 1511, 1462, 1250, 1175, 1034,
extracted with methylene chloride /4£15 mL). The resulting
organic layer was dried over magnesium sulphate and
evaporated. A ¯ash chromatography on silica gel /ether
petroleum/ethyl acetateˆ3:2) gave 13 /0.103 g, 61%) as a
0.78 /t,
pale yellow oil: 1H NMR /CDCl3)
d
JCH2,CH3ˆ7.3 Hz, 3H, CH2CH3), 1.22 /dd, JCH,CH3ˆ6.8 Hz,
3H, CHCH3), 1.57±1.67 /m, 2H, CH2), 2.72±2.80 /m, 1H,
CH), 3.37 /s, 3H, OCH3), 4.52 /d, JCH,OHˆ7.5 Hz, 1H, OH),
5.07 /s, 2H, OCH2O), 5.87 /d, JCH,OHˆ7.5 Hz, 1H, CH),
6.90 /d, Jˆ8.7 Hz, 2H, HPh3,5), 7.20 /d, Jˆ8.7 Hz, 2H,
HPh2,6), 8.28 /s, 1Hdia, H5), 8.29 /s, 1Hdia, H5); 13C NMR
/CDCl3) d 12.4 /CH3/CH2)), 20.07 /CH3, 1dia), 20.13 /CH3,
1dia), 29.8 /CH2), 40.93 /CH, 1dia), 40.97 /CH, 1dia), 56.4
/OCH3), 71.8 /CH/OH)), 94.7 /OCH2O), 116.3 /CPh3,5),
129.1 /CPh2,6), 134.6 /CPh1), 140.0 /C5, 1dia), 140.1 /C5,
1dia), 146.85 /C2, 1dia), 146.92 /C2, 1dia), 151.9 /C3),
157.4 /CPh4), 161.46 /C6, 1dia), 161.53 /C6, 1dia); MS 337
/MH1) m/z 319, HRMS 337.1288; Anal. Calcd for
C17H21ClN2O3: C, 60.57; H, 6.23; N, 8.31. Found: C,
60.65; H, 6.39; N, 8.45.
1
806 cm21; H NMR /11) /CDCl3) d 0.95 /t, 3H, CH3),
1.34 /m, 2H, CH2), 1.72 /m, 2H, CH2), 2.80 /t,
JCH2,CH2ˆ7.7, 2H, CH2), 3.78 /s, 3H, OCH3), 4.60 /d,
JCH,OHˆ7.4 Hz, 1H, OH), 5.95 /d, JCH,OHˆ7.4 Hz, 1H,
CH), 6.84 /d, Jˆ8.6 Hz, 2H, HPh3,5), 7.27 /d, Jˆ8.6 Hz,
Acknowledgements
1
2H, HPh2,6), 8.36 /s, 1H, H5); H NMR /12) /CDCl3) d
We thank E. Condamine /COBS, UMR 6014, Rouen) for
NMR experiments and L. Toupet /GMCM, CNRS 6626,
Rennes) for the X-ray diffraction study.
0.86 /t, JCH2,CH3ˆ7.5 Hz, 3H, CH2CH3), 1.28 /dd,
JCH,CH3ˆ7.5 Hz, 3H, CHCH3), 1.50±1.65 /m, 2H, CH2),
2.80 /m, JCH,CH3ˆ7.5 Hz, 1H, CH), 3.78 /s, 3H, OCH3),
4.60 /d, JCH,OHˆ7.4 Hz, 1H, OH), 5.95 /d, JCH,OHˆ7.4 Hz,
1H, CH), 6.84 /d, Jˆ8.6 Hz, 2H, HPh3,5), 7.27 /d, Jˆ8.6 Hz,
2H, HPh2,6), 8.37 /s, 1H, H5); 13C NMR /11) /CDCl3) d 14.2
/CH3), 22.7 /CH2), 31.8 /CH2), 34.8 /CH2), 56.6 /OCH3),
71.8 /CH), 114.3 /CPh3,5), 129.1 /CPh2,6), 133.4 /C6), 140.7
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