First study of syntheses and reactivity of Grignard compounds in the diazine series. Diazines. Part 27

Article abstract of DOI:10.1016/S0040-4020(99)00948-5

A preparation of Grignard derivatives of diazines is described using a halogen magnesium exchange reaction. This convenient method allows the functionalization of these rings at 0°C or even room temperature.

Full text of DOI:10.1016/S0040-4020(99)00948-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 265–273
First Study of Syntheses and Reactivity of Grignard Compounds
in the Diazine Series. Diazines. Part 27
a
a
a
b
a,
*
ˆ
´
´
A. Lepretre, A. Turck, N. Ple, P. Knochel and G. Queguiner
a
´ ´
IRCOF, Laboratoire de Chimie Organique Fine et Heterocyclique, UPRES-A 6014, B.P. 08, 76131 Mont St Aignan Cedex, France
b
¨
¨
Department of Chemistry, Ludwigs-Maximilians-Universtat Munchen, Butenandstraße 5-13, D-81377 Munich, Germany
Received 30 July 1999; accepted 20 October 1999
Abstract—A preparation of Grignard derivatives of diazines is described using a halogen magnesium exchange reaction. This convenient
method allows the functionalization of these rings at 0ЊC or even room temperature. ᭧ 1999 Elsevier Science Ltd. All rights reserved.
Introduction
Discussion
After some years of extensive research into lithio deriva-
tives of diazines, it was established that they are very power-
ful tools for the syntheses of such heterocycles. Their main
drawback are that they are generally only stable at very low
temperature (ϽϪ50ЊC). A possible solution to this problem
is to use other organometallic derivatives. We have recently
tested organozinc derivatives,1 which were useful for cross
coupling reactions, but they were poorly reactive with other
important electrophiles. We describe here the first con-
venient syntheses and reactivity of Grignard compounds
of diazines.
In the pyridazine series, the 3,6-dimethoxy-4-iodopyrida-
zine 1 was easily prepared7 and was used to establish the
optimal experimental conditions (Scheme 1, Table 1).
A first attempt with 1.1 equiv. of PhMgBr afforded only the
starting material, regardless of temperature and reaction
time (entries 1, 2). The most efficient metallation conditions
were obtained using 2 equiv. of PhMgBr at room tempera-
ture with a reaction time of 30 min (entry 3). On the
contrary, for i-PrMgCl or n-BuMgCl, a quasi-stoichiometric
amount was sufficient to obtain the magnesium derivative 2
with yields of 70–71% (entries 4, 7). Note that an excess of
i-PrMgCl or n-BuMgCl led to an important degradation of
the magnesium derivative 2 (entries 5, 8). Only half of a
molar equivalent of di-n-butylmagnesium was necessary to
obtain, after deuteriolysis, the deuteriated product 4 with a
yield of 72% (entry 9). One equivalent of n-Bu2Mg led to an
important degradation (entry 10). The use of ether as a
solvent (entry 6) produced lower yields. This could be
explained by the low solubility of the iodo derivative in
this solvent. Using the experimental conditions described
above, some electrophiles have been tested on the magne-
sium derivative 2, allowing synthesis of various trisubsti-
tuted pyridazines (Scheme 2, Table 2).
In the literature only two publications report the use of a
diazinic Grignard reagent. The first by Langley2 in 1956
who prepared a carboxylic acid of pyrimidine via direct
insertion of magnesium on a bromopyrimidine at low
temperature (Ϫ70ЊC). More recently Yokoama3 synthesized
Grignard derivatives from bromopyrimidines using an
exchange reaction with ethylmagnesium chloride. All
these reports investigated only pyrimidine derivatives, so
we developed a general method to prepare Grignard deriva-
tives of all diazines: pyridazine, pyrimidine and pyrazine.
It has been highlighted4–6 that good synthetic results were
obtained using an exchange reaction between halo-pyridines
and iso-propylmagnesium chloride. We wish to describe a
similar approach in the diazine series. The syntheses and
reaction of Grignard reagents of diazines with electrophiles
are described.
As previously observed, the same yields were obtained with
1 equiv. of i-PrMgCl or with 2 equiv. of PhMgBr (entries 1,
2). With a highly enolizable electrophile such as acetalde-
hyde, an important amount of compound 3 was observed
(entry 3). This results from protonation of the magnesium
derivative 2. With less reactive electrophiles such as ethyl
cyanoformate, N,N-dimethylformamide (DMF) or phenyl
sulfide, moderate yields were observed (entries 6–8).
Ethyl formate was unsuccessful for the preparation of the
formyl derivative 10, only compound 3 was obtained.
Keywords: Grignard reactions/reagents; pyrazines; pyridazines; pyrimi-
dines.
* Corresponding author. Tel.: ϩ33-2-3552-2900; fax: ϩ33-2-3552-2962;
e-mail: guy.queguiner@insa-rouen.fr
0040–4020/00/$ - see front matter ᭧ 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)00948-5

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A. Lepretre et al. / Tetrahedron 56 (2000) 265–273
266
Scheme 1.
Table 1. Determination of optimal experimental conditions
Entry
RMgX
n equiv.
t (h)
T (ЊC)
Hydrolysis
Prod.
Yield (%)
1
2
3
4
5
6
7
8
9
PhMgBr
PhMgBr
PhMgBr
i-PrMgCl
i-PrMgCl
i-PrMgCl
n-BuMgCl
n-BuMgCl
n-Bu2Mg
n-Bu2Mg
1.1
1.1
2.0
1.1
2.0
1.1
1.1
2.0
0.5
1.1
1
Ϫ40
20
20
20
20
20
20
20
20
20
H2O
H2O
3
3
4
4
3
4
4
4
4
4
0a
0a
0.5
0.5
0.5
0.5
1
0.5
0.5
0.5
0.5
DCl, EtOD
DCl, EtOD
DCl, EtOD
CH3OD
DCl, EtOD
DCl, EtOD
DCl, EtOD
DCl, EtOD
71
71
14
62b
70
0
72
0
10
a Starting material 1 was recovered quantitatively.
b This experiment was performed in ether, 15% of starting material 1 was recovered.
Scheme 2.
Table 2. Synthesis of trisubstituted pyridazines
Entry
RMgX
Electrophile
t (h)
E
Prod.
Yield (%)
1
2
3
4
5
6
7
8
PhMgBr
i-PrMgCl
i-PrMgCl
i-PrMgCl
i-PrMgCl
i-PrMgCl
i-PrMgCl
i-PrMgCl
PhCHO
PhCHO
1
1
1
2
1
1
2
12
PhCH(OH)
PhCH(OH)
CH3CH(OH)
C5H11CH(OH)
TMS–
EtOOC–
–CHO
PhS–
5
5
6
7
8
9
10
11
70a
73
CH3CHO
C5H11CHO
TMSCl
NC–COOEt
DMF
35b
69
41c
47d
42
PhSSPh
42
a Two equivalents of PhMgBr were used.
b The product 3 resulting from hydrolysis was obtained with yield of 49%.
c The product 3 resulting from hydrolysis was obtained with yield of 28%.
d The product 3 resulting from hydrolysis was obtained with yield of 5%.
Scheme 3.

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A. Lepretre et al. / Tetrahedron 56 (2000) 265–273
267
Table 3. Synthesis of tetrasubstituted pyridazines from dihalogeno deriva-
tives
of the remaining halogen atom by the dimethylamino
moiety of the DMF was observed, leading to compound 19.
Entry
X
Electrophile t (h)
E
Prod. Yield (%)
In the pyrimidine series, two derivatives 27 and 31 were
tested using the same experimental conditions at 0ЊC
(Scheme 4, Table 4).
1
2
3
4
5
6
7
8
I
I
I
I
I
I
I
I
PhCHO
PhCHO
1
2
PhCH(OH)
PhCH(OH)
CH3CH(OH)
C5H11CH(OH)
TMS–
EtOOC–
PhS–
–CHO
14
14
–
48a
75
0b
CH3CHO
C5H11CHO
TMSCl
1
2
1
15
16
17
18
19d
26
20
21
22
23
25
19d
74
70
30c
40
38
80
80
65
60
50
80
47
The iodine–magnesium exchange reaction with compound
27 was slower (1 h) than with compound 31 (0.5 h). The
formation of the carbanionic species at the 2-position in
the pyrimidine ring may be more difficult than at the
4-position. This may be due to the repulsive effect of the
two unshared nitrogen electron pairs on the pyrimidine
nucleus. However, once the magnesium derivatives of
these pyrimidines were prepared, their reactivity toward
aldehydes was comparable (compare entries 2 and 6, 3
and 7). When DMF was used as the electrophile, no formyl
compound was obtained with compound 27; whereas with
compound 31 2-methylsulfanyl-4-formylpyrimidine 35 was
obtained with a moderate yield (34%).
NC–COOEt
PhSSPh
DMF
1
12
2
9
Br H2O
Br EtOD
Br PhCHO
Br C5H11CHO
Br NC–COOEt 12
0.5 –H
0.5 –D
2
2
10
11
12
13
14
15
PhCH(OH)
C5H11CH(OH)
EtOOC–
–I
Br I2
Br DMF
2
2
–CHO
a The product 1 resulting from hydrolysis was obtained with yield of
27%.
b The product 1 resulting from hydrolysis was obtained with yield of
45%.
c The product 1 resulting from hydrolysis was obtained with yield of 5%.
d 3,6-Dimethoxy-5-(N,N-dimethylamino)-4-formylpyridazine.
In the pyrazine series four compounds were tested: 2-iodo-
pyrazine 36, 2-iodo-3-methoxypyrazine 37, 2-chloro-3-
iodopyrazine 38 and 2,3-diiodopyrazine 39 (Scheme 5,
Table 5).
In the case of compound 36, it was not possible to use
i-PrMgCl or PhMgBr, even at low temperatures (Ϫ70 or
Ϫ40ЊC), this should be due to a greater sensitivity of the
diazine rings to nucleophilic attacks.3 Consequently,
n-BuMgCl, which is known to be less nucleophilic than
i-PrMgCl, was used successfully. Compound 37 bearing a
methoxy group is less readily attacked by nucleophiles. So it
could be reacted with i-PrMgCl to give the Grignard
derivative which, reacted with electrophiles, afforded yields
higher than 50%. The 3-chloro-2-iodopyrazine 38 is sensi-
tive to nucleophilic attack, so n-BuMgCl was used. The
reaction with benzaldehyde as the electrophile produced
yields only of 24% at 0ЊC (entry 6). It was supposed that
this low yield was due to a low stability of the Grignard
derivative and the same reaction was performed at Ϫ70ЊC
but the yield was only slightly increased (entry 7). However,
our aim was to achieve functionalization of the diazine
derivatives at a more convenient temperature (0 or 20ЊC).
From the previously performed studies in the pyridine
series,8 it has been shown that the addition of 1 equiv. of
triethylamine to the Grignard reagent could improve the
yields. From this work we assume that triethylamine stabi-
lized the organometallic derivative and consequently
enhanced its reactivity. The reaction performed with
n-BuMgCl and 1 equiv. of triethylamine produced the
Scheme 4.
The same reaction was performed with 4,5-diiodo-3,6-
dimethoxypyridazine 12 and 4,5-dibromo-3,6-dimethoxy-
pyridazine 13 (Scheme 3, Table 3).
Starting from the bromo- or the iodo-derivative, using the
same experimental conditions, the yields were approxi-
mately the same (compare entries 2 and 11, 4 and 12, 7
and 14). These results indicated that the nature of the halo-
gen was not important. Formation of compound 1 results
from protonation that can be explained in two ways: the
reaction of the magnesium derivative with the electrophile
was incomplete leading to the compound 1 after hydrolysis
(entries 1, 6) or the abstraction of the hydrogen atom of an
enolizable aldehyde could occur producing the compound 1
before hydrolysis (entry 3). When DMF was used as a
formylating agent, a subsequent nucleophilic substitution
Table 4. Synthesis of disubstituted pyrimidines
Entry
Starting material
Electrophile
t (h)
E
Prod.
Yield (%)
1
2
3
4
5
6
7
8
9
27
27
27
27
31
31
31
31
31
PhCHO
PhCHO
C5H11CHO
NC–COOEt
PhCHO
1
2
2
12
1
2
2
12
2
PhCH(OH)
PhCH(OH)
C5H11CH(OH)
EtOOC–
PhCH(OH)
PhCH(OH)
C5H11CH(OH)
EtOOC–
28
28
29
30
32
32
33
34
35
57
69
64
60
27
57
55
35
34
PhCHO
C5H11CHO
NC–COOEt
DMF
–CHO

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A. Lepretre et al. / Tetrahedron 56 (2000) 265–273
268
PhMgBr (1 M in THF), i-PrMgCl (2 M in THF), n-BuMgCl
(2 M in THF), n-Bu2Mg (1 M in heptane) were purchased
from Aldrich Chemical Co. or Acros.
The following diazines were synthesized according to
the literature: 2-iodopyrazine 36,9 2,3-diiodopyrazine 39,9
2-iodo-3-methoxypyrazine 37,10 2-chloro-3-iodopyrazine
38,11
4-iodo-2-methylsulfanylpyrimidine
31,9
3,6-
Scheme 5.
dimethoxypyridazine 37 and 4-iodo-3,6-dimethoxypyrida-
zine 1.7
same yield as the reaction performed without the amine at
Ϫ70ЊC (compare entries 6 and 8). The use of the couple
n-Bu2Mg/triethylamine gave the best result: a 44% yield
was obtained. The diiodo compound 39 produced a very
low yield and no optimization experiments were performed.
General procedure for metalation reaction
A solution of n-butyllithium (1.6 or 2.5 M in hexane) was
added to cold (Ϫ50ЊC), anhydrous THF under an atmos-
phere of dry argon, 2,2,6,6-tetramethylpiperidine was then
added. The mixture was stirred at 0ЊC for 20 min. The
mixture temperature was then lowered to Ϫ70ЊC. A solution
of diazine in THF (5 mL) was added and the mixture was
stirred for a time t1 at a temperature T1. The electrophile was
introduced and stirring was continued for a time t2 at T2.
Hydrolysis was then carried out using a solution of ethanol
(3 mL) and THF (5 mL) at Ϫ70ЊC. The solution was
warmed to room temperature. When the electrophile was
iodine, the solution was decolorized with sodium thio-
sulphate and evaporated nearly to dryness. Caution:
When the electrophile was cyanogen bromide, the reaction
medium was made basic with a solution of sodium hydrox-
ide (2 M) and cyanide ions were decomposed with a concen-
trated solution of sodium hypochlorite. The residue was
extracted with dichloromethane (3×15 mL). The organic
layer was dried over magnesium sulfate and evaporated.
The crude product was purified by column chromatography
on silica gel.
Conclusion
In summary, we have demonstrated that it was possible to
prepare Grignard reagents of diazines using an efficient and
reproducible method. These compounds were stable at a
convenient temperature (Ͼ0ЊC) and reacted with electro-
philes with acceptable yields. In some cases, when the
diazine rings did not bear a methoxy or a methylsulfanyl
group, we proposed some different exchange reactants and
even an additive that allowed yield enhancement.
Experimental
Melting points were determined on a Kofler hot stage. The
1H- and 13C NMR spectra were recorded in deuteriochloro-
form on a Bruker AC 200 instrument. 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. Mass spectra
were recorded at 70 eV (EI) on a JEOL JMS-AX 500
spectrometer.
General procedure for exchange reaction
The diazine derivative (1 mmol) dissolved in 3 mL of THF
was stirred and cooled to 0ЊC under an atmosphere of dry
argon. The magnesium reagent was added slowly. Then the
reaction mixture was allowed to stand at T1 for a time t1. The
electrophile was introduced and stirring was continued for a
time t2 at T2. Hydrolysis was then carried out using an
aqueous saturated solution of sodium chloride or ammonium
chloride when the expected product was an alcohol. The
aqueous layer was extracted with dichloromethane
(3×15 mL). The organic layer was dried over magnesium
Tetrahydrofuran was distilled from benzophenone/sodium
solution and used immediately. Water content of the solvent
was estimated by the modified Karl Fischer method (THF
less than 50 ppm water). Reactions were performed under
an argon atmosphere. Reagents were handled with syringes
through septa.
Table 5. Synthesis of pyrazine derivatives
Entry
Starting material
RMgX
Electrophile
E
Prod.
Yield (%)
1
2
3
4
5
6
7
8
36
36
37
37
37
38
38
38
38
38
38
39
n-BuMgCl
n-BuMgCl
i-PrMgCl
i-PrMgCl
i-PrMgCl
n-BuMgCl
n-BuMgCl
n-BuMgCl, NEt3
n-Bu2Mg
n-Bu2Mg, NEt3
n-BuMgCl
n-BuMgCl
PhCHO
PhCH(OH)
C5H11CH(OH)
PhCH(OH)
C5H11CH(OH)
–CHO
PhCH(OH)
PhCH(OH)
PhCH(OH)
PhCH(OH)
PhCH(OH)
C5H11CH(OH)
PhCH(OH)
40
41
42
43
44
45
45
45
45
45
46
47
59
33
56
50
51
24
32a
33
37
44
20
11
C5H11CHO
C5H11CHO
C5H11CHO
DMF
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
C5H11CHO
PhCHO
9
10
11
12
a Reaction performed at Ϫ70 ЊC.

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A. Lepretre et al. / Tetrahedron 56 (2000) 265–273
269
sulfate and evaporated. The crude product was purified by
column chromatography on silica gel.
procedure with i-PrMgCl 2.0 M (1 equiv., 0.5 mL),
t1ˆ30 min, T1ˆ20ЊC, followed by reaction with trimethyl-
silyl chloride (0.14 mL, 1.1 mmol), t2ˆ1 h, T2ˆ20ЊC, gave
after purification by column chromatography (silica, eluent:
dichloromethane) 87 mg (41%) of 8 as a red solid, mp
4-Deuterio-3,6-dimethoxypyridazine (4). Exchange reac-
tion of 1 (266 mg, 1.0 mmol) according to the general
procedure with i-PrMgCl 2.0 M (1 equiv., 0.5 mL),
t1ˆ30 min, T1ˆ20ЊC, followed by deuteriolysis with DCl,
EtOD (1 mL), t2ˆ15 min, T2ˆ20ЊC, gave after purification
by column chromatography (silica, eluent: dichloro-
methane) 100 mg (71%) of 4 as a white solid, mp 107ЊC;
1H NMR (CDCl3): d 6.95 (s, 1H, H5); 4.05 (s, 6H,
2×OCH3); 13C NMR (CDCl3): d 162.3; 121.7; 54.9. Anal.
Calcd for C6H7N2O2D (141.15): C, 51.06; H, 5.00; N, 19.85.
Found: C, 51.25; H, 4.78; N, 19.95.
1
Ͻ50ЊC; H NMR (CDCl3): d 6.90 (s, 1H, H5); 4.00 (s,
6H, 2×OCH3); 0.10 (s, 9H, SiMe3); 13C NMR (CDCl3): d
166.9; 164.0; 137.0; 129.1; 56.9; 0.0; IR: n 3352, 2952,
1727, 1462, 1368, 1242, 1013, 843, 701 cmϪ1. Anal.
Calcd for C9H16N2O2Si (212.33): C, 50.91; H, 7.60; N,
13.19. Found: C, 50.82; H, 7.72; N, 13.09.
Ethyl-3,6-dimethoxypyridazine-4-carboxylate
(9).
Exchange reaction of 1 (266 mg, 1.0 mmol) according to
the general procedure with i-PrMgCl 2.0 M (1 equiv.,
0.5 mL), t1ˆ30 min, T1ˆ20ЊC, followed by reaction with
ethyl cyanoformate (0.11 mL, 1.1 mmol), t2ˆ1 h,
T2ˆ20ЊC, gave after purification by column chromato-
graphy (silica, eluent: dichloromethane) 100 mg (47%) of
9 as a white solid, mp 148–149ЊC; 1H NMR (CDCl3): d 7.41
(s, 1H, H5); 4.38 (q, Jˆ4.8 Hz, 2H, CH2); 4.02 (s, 3H,
OCH3); 3.99 (s, 3H, OCH3); 1.34 (t, Jˆ4.8 Hz, 3H, CH3);
13C NMR (CDCl3): d 161.6; 160.4; 131.2; 121.8; 94.4; 63.3;
56.3; 55.7; 14.4; IR: n 2950, 2864, 1743, 1578, 1467, 1363,
1265, 1228, 1007, 896, 855, 772 cmϪ1. Anal. Calcd for
C9H12N2O4 (212.21): C, 50.94; H, 5.70; N, 13.20. Found:
C, 51.22; H, 5.88; N, 13.08.
3,6-Dimethoxy-4-hydroxybenzylpyridazine (5). Exchange
reaction of 1 (266 mg, 1.0 mmol) according to the general
procedure with i-PrMgCl 2.0 M (1 equiv., 0.5 mL),
t1ˆ30 min, T1ˆ20ЊC, followed by reaction with benz-
aldehyde (0.11 mL, 1.1 mmol), t2ˆ1 h, T2ˆ20ЊC, gave
after purification by column chromatography (silica, eluent:
dichloromethane) 180 mg (73%) of 5 as a white solid, mp
1
102ЊC, lit.ˆ99–101ЊC; H NMR (CDCl3): d 7.25 (m, 5H,
HPh); 7.15 (s, 1H, H5); 5.75 (s, 1H, CH); 4.05 (s, 3H, OCH3);
4.00 (s, 3H, OCH3); 3.70 (br, 1H, OH); IR: n 3300, 3030,
3000, 2960, 2900, 1630, 1500, 1475, 1460, 1390, 1265,
1220, 1140 cmϪ1. Anal. Calcd for C13H14N2O3 (246.27):
C, 63.40; H, 5.73; N, 11.38. Found: C, 63.53; H, 5.80; N,
11.22.
3,6-Dimethoxy-4-formylpyridazine (10). Exchange reac-
tion of 1 (266 mg, 1.0 mmol) according to the general
procedure with i-PrMgCl 2.0 M (1 equiv., 0.5 mL),
t1ˆ30 min, T1ˆ20ЊC, followed by reaction with DMF
(0.09 mL, 1.1 mmol), t2ˆ2 h, T2ˆ20ЊC, gave after purifica-
tion by column chromatography (silica, eluent: dichloro-
methane) 71 mg (42%) of 10 as a yellow solid, mp 84ЊC;
1H NMR (CDCl3): d 10.3 (s, 1H, CHO); 7.3 (s, 1H, H5);
4.20 (s, 3H, OCH3); 4.05 (s, 3H, OCH3); 13C NMR (CDCl3):
d 188.7; 163.4; 160.3; 125.4; 118.4; 55.5; IR: n 3380, 3068,
2998, 2958, 2885, 1702, 1618, 1473, 1451, 1383, 1321,
1238, 1145, 1024, 1008, 991, 940, 920, 764 cmϪ1. Anal.
Calcd for C7H8N2O3 (168.15): C, 50.00; H, 4.80; N,
16.66. Found: C, 49.78; H, 4.83; N, 16.89.
3,6-Dimethoxy-4-(1-hydroxy)ethylpyridazine (6). Exchange
reaction of 1 (266 mg, 1.0 mmol) according to the general
procedure with i-PrMgCl 2.0 M (1 equiv., 0.5 mL),
t1ˆ30 min, T1ˆ20ЊC, followed by reaction with acetalde-
hyde (2 mL), t2ˆ1 h, T2ˆ20ЊC, gave after purification by
column chromatography (silica, eluent: dichloromethane)
1
64 mg (35%) of 6 as a white solid, mp 84ЊC; H NMR
(CDCl3): d 7.10 (s, 1H, H5); 5.00 (q, Jˆ6.0 Hz, 1H, CH);
4.05 (s, 3H, OCH3); 4.00 (s, 3H, OCH3); 3.50 (br, 1H, OH);
1.50 (d, Jˆ6.0 Hz, 3H, CH3); IR: n 3300, 3020, 2980,
2960, 1630, 1475, 1380, 1280, 1235, 1155, 1095, 1020,
1010 cmϪ1. Anal. Calcd for C8H12N2O3 (184.20): C,
52.17; H, 6.57; N, 15.21. Found: C, 51.95; H, 6.40;
N, 15.34.
3,6-Dimethoxy-4-phenylsulfanylpyridazine (11). Exchange
reaction of 1 (266 mg, 1.0 mmol) according to the general
procedure with i-PrMgCl 2.0 M (1 equiv., 0.5 mL),
t1ˆ30 min, T1ˆ20ЊC, followed by reaction with phenyl sul-
fide (242 mg, 1.1 mmol), t2ˆ12 h, T2ˆ20ЊC, gave after puri-
fication by column chromatography (silica, eluent:
dichloromethane) 104 mg (42%) of 11 as an orange oil;
1H NMR (CDCl3): d 7.5 (m, 5H, HPh); 7.2 (s, 1H, H5);
4.10 (s, 3H, OCH3); 3.95 (s, 3H, OCH3); 13C NMR
(CDCl3): d 162.5; 157.9; 138.3; 136.3; 130.8; 127.5;
124.0, 114.1; 55.5; 54.8; IR: n 2948, 2864, 1581, 1466,
3,6-Dimethoxy-4-(1-hydroxy)hexylpyridazine (7). Exchange
reaction of 1 (266 mg, 1.0 mmol) according to the general
procedure with i-PrMgCl 2.0 M (1 equiv., 0.5 mL),
t1ˆ30 min, T1ˆ20ЊC, followed by reaction with hexanal
(0.13 mL, 1.1 mmol), t2ˆ2 h, T2ˆ20ЊC, gave after purifica-
tion by column chromatography (silica, eluent: dichloro-
1
methane) 166 mg (69%) of 7 as a yellow oil; H NMR
(CDCl3): d 7.00 (s, 1H, H5); 4.75 (m, 1H, CH); 4.02 (s,
3H, OCH3); 3.99 (s, 3H, OCH3); 3.25 (br, 1H, OH); 2.27
(m, 1H, CH); 1.60 (m, 1H, CH); 1.27 (m, 6H, 3×CH2); 0.86
(m, 3H, CH3); 13C NMR (CDCl3): d 163.1; 160.9; 139.6;
121.8; 68.2; 54.8; 54.7; 36.5; 31.6; 25.7; 23.0; 14.3; IR: n
3368, 2930, 2860, 1469, 1385, 1014 cmϪ1. Anal. Calcd for
C12H20N2O3 (240.30): C, 59.98; H, 8.39; N, 11.66. Found:
C, 59.75; H, 8.43; N, 11.33.
1382, 1234, 1029, 1011 cmϪ1
.
Anal. Calcd for
C12H12N2O2S (248.31): C, 58.05; H, 4.87; N, 11.28.
Found: C, 58.25; H, 4.65; N, 11.02.
4,5-Diiodo-3,6-dimethoxypyridazine (12). Metallation of
3 (700 mg, 5.0 mmol) according to the general procedure
with n-BuLi 1.6 M (7.2 mL, 11.5 mmol), TMPH (1.9 mL,
11.5 mmol), Vˆ75 mL, t1ˆ1 h, T1ˆϪ70ЊC, followed by
reaction with iodine (3.0 g, 11.8 mmol), t2ˆ1 h 30 min,
3,6-Dimethoxy-4-trimethylsilylpyridazine (8). Exchange
reaction of 1 (266 mg, 1.0 mmol) according to the general

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A. Lepretre et al. / Tetrahedron 56 (2000) 265–273
270
T2ˆϪ70ЊC, gave after purification by column chromato-
3H, OCH3); 3.95 (s, 3H, OCH3); 0.40 (s, 9H, SiMe3); 13C
NMR (CDCl3): d 161.9; 158.7; 129.3; 103.0; 55.1; 54.6;
0.0; IR: n 2985, 2947, 2898, 1458, 1346, 1246, 1020, 877,
847, 772 cmϪ1. Anal. Calcd for C9H15IN2O2Si (338.22): C,
31.96; H, 4.47; N, 8.28. Found: C, 32.08; H, 4.61; N, 8.16.
graphy (silica, eluent: petroleum ether/ethylacetate (9/1))
1
1.49 g (76%) of 12 as a white solid, mp 192ЊC; H NMR
(CDCl3): d 4.01 (s, OCH3); 13C NMR (CDCl3): d 160.5;
152.7; 56.9; IR: n 2984, 2941, 2854, 1527, 1460, 1343,
1190, 1008, 865, 780, 653 cmϪ1. MS: (M)ϩ⅐, 392. Anal.
Calcd for C6H6I2N2O2 (391.94): C, 18.39; H, 1.54; N,
7.15. Found: C, 18.26; H, 1.60; N, 7.22.
Ethyl-3,6-dimethoxy-5-iodopyridazine-4-carboxylate (17).
Exchange reaction of 12 (392 mg, 1.0 mmol) according to
the general procedure with i-PrMgCl 2.0 M (1 equiv.,
0.5 mL), t1ˆ30 min, T1ˆ20ЊC, followed by reaction with
ethyl cyanoformate (0.11 mL, 1.1 mmol), t2ˆ1 h,
T2ˆ20ЊC, gave after purification by column chromato-
graphy (silica, eluent: dichloromethane) 101 mg (30%) of
17 as a white solid, mp 98–100ЊC; 1H NMR (CDCl3): d 4.41
(q, Jˆ7.1 Hz, 2H, CH2); 4.03 (s, 3H, OCH3); 4.01 (s, 3H,
OCH3); 1.34 (t, Jˆ7.1 Hz, 3H, CH3); 13C NMR (CDCl3): d
164.0; 160.3; 157.3; 134.5; 93.1; 63.3; 56.6; 55.9; 14.4; IR:
n 2994, 2951, 2860, 1719, 1581, 1519, 1466, 1360, 1276,
1136, 1039, 1011, 768 cmϪ1. MS: (M)ϩ⅐, 338. Anal. Calcd
for C9H11IN2O4 (338.10): C, 31.97; H, 3.28; N, 8.29. Found:
C, 32.05; H, 3.08; N, 8.65.
4,5-Dibromo-3,6-dimethoxypyridazine (13). Metallation
of 3 (700 mg, 5.0 mmol) according to the general procedure
with n-BuLi 1.6 M (7.2 mL, 11.5 mmol), TMPH (1.9 mL,
11.5 mmol), Vˆ75 mL, t1ˆ1 h, T1ˆϪ70ЊC, followed by
reaction with cyanogen bromide (1.5 g, 12.0 mmol),
t2ˆ1 h 30 min, T2ˆϪ70ЊC, gave after purification by
column chromatography (silica, eluent: dichloromethane)
1
2.2 g (74%) of 13 as a white solid, mp 146–148ЊC; H
NMR (CDCl3): d 4.05 (s, OCH3); 13C NMR (CDCl3): d
161.3; 124.9; 58.6; IR: n 3006, 2955, 2864, 1560, 1469,
1365, 1194, 1016, 882, 793, 659 cmϪ1. Anal. Calcd for
C6H6Br2N2O2 (297.93): C, 24.19; H, 2.03; N, 9.40. Found:
C, 24.10; H, 1.96; N, 9.68.
3,6-Dimethoxy-4-iodo-5-phenylsulfanylpyridazine (18).
Exchange reaction of 12 (392 mg, 1.0 mmol) according to
the general procedure with i-PrMgCl 2.0 M (1 equiv.,
0.5 mL), t1ˆ30 min; T1ˆ20 ЊC, followed by reaction with
phenyl sulfide (242 mg, 1.1 mmol), t2ˆ12 h, T2ˆ20 ЊC,
gave after purification by column chromatography (silica,
eluent: dichloromethane) 150 mg (40%) of 19 as a yellow
solid, mp 70–72ЊC; 1H NMR (CDCl3): d 7.19 (s, 5H, HPh);
4.03 (s, 3H, OCH3); 3.76 (s, 3H, OCH3); 13C NMR (CDCl3):
d 161.0; 159.6; 136.3; 133.3; 130.7; 129.5; 128.0; 104.9;
56.6; 55.8; IR: n 3052, 2947, 1460, 1358, 1020, 791,
740, 662 cmϪ1. Anal. Calcd for C12H11IN2O2S (374.20):
C, 38.52; H, 2.96; N, 7.49. Found: C, 38.69; H, 2.77;
N, 7.55.
3,6-Dimethoxy-5-hydroxybenzyl-4-iodopyridazine (14).
Exchange reaction of 12 (392 mg, 1.0 mmol) according to
the general procedure with i-PrMgCl 2.0 M (1 equiv.,
0.5 mL), t1ˆ30 min, T1ˆ20ЊC, followed by reaction with
benzaldehyde (0.11 mL, 1.1 mmol), t2ˆ2 h, T2ˆ20ЊC,
gave after purification by column chromatography (silica,
eluent: dichloromethane) 279 mg (75%) of 14 as a yellow
1
solid, mp 124–126ЊC; H NMR (CDCl3): d 7.40 (m, 5H,
HPh); 6.15 (d, Jˆ11.0 Hz, 1H, CH); 5.00 (br, 1H, OH); 4.15
(s, 3H, OCH3); 4.00 (s, 3H, OCH3); 13C NMR (CDCl3): d
159.6; 157.3; 139.1; 137.9; 127.5; 126.8; 124.3; 98.1; 78.2;
55.2; 54.3; IR: n 3512, 3234, 2949, 1461, 1366, 1274, 1004,
737, 714, 678 cmϪ1. MS: (M)ϩ⅐, 372. Anal. Calcd for
C13H13IN2O3 (372.16): C, 41.96; H, 3.52; N, 7.53. Found:
C, 42.14; H, 3.35; N, 7.68.
3,6-Dimethoxy-5-(N,N-dimethylamino)-4-formylpyrida-
zine (19). Exchange reaction of 12 (392 mg, 1.0 mmol)
according to the general procedure with i-PrMgCl 2.0 M
(1 equiv., 0.5 mL), t1ˆ30 min; T1ˆ20 ЊC, followed by reac-
tion with DMF (0.09 mL, 1.1 mmol), t2ˆ2 h; T2ˆ20 ЊC,
gave after purification by column chromatography (silica,
eluent: dichloromethane) 88 mg (38%) of 19 as a yellow
3,6-Dimethoxy-5-(1-hydroxy)hexyl-4-iodopyridazine (15).
Exchange reaction of 12 (392 mg, 1.0 mmol) according to
the general procedure with i-PrMgCl 2.0 M (1 equiv.,
0.5 mL), t1ˆ30 min, T1ˆ20ЊC, followed by reaction with
hexanal (0.13 mL, 1.1 mmol), t2ˆ2 h, T2ˆ20ЊC, gave after
purification by column chromatography (silica, eluent:
1
solid, mp 115–116ЊC; H NMR (CDCl3): d 10.08 (s, 1H,
1
dichloromethane) 271 mg (74%) of 15 as a yellow oil; H
CHO); 3.99 (s, 3H, OCH3); 3.96 (s, 3H, OCH3); 3.02 (s, 6H,
NMe2); 13C NMR (CDCl3): d 185.3; 160.9; 153.9; 139.4;
105.6; 52.9; 43.6; IR: n 2975, 2947, 2887, 1664, 1553,
1462, 1407, 1390, 1346, 1315, 1178, 1091, 1064, 952,
769, 691 cmϪ1. Anal. Calcd for C9H13N3O3 (211.22):
C, 51.18; H, 6.20; N, 19.89. Found: C, 51.31; H, 6.11; N,
19.58.
NMR (CDCl3): d 4.81 (m, 1H, CH); 4.00 (s, 3H, OCH3);
3.95 (s, 3H, OCH3); 3.52 (br, 1H, OH); 2.23 (m, 1H, CH);
1.55 (m, 1H, CH); 1.24 (m, 6H, 3×2CH2); 0.82 (m, 3H,
CH3); 13C NMR (CDCl3): d 160.9; 158.7; 140.2; 98.0;
78.4; 56.5; 55.6; 35.8; 31.9; 25.7; 23.3; 14.3; IR: n 3418,
2952, 2860, 1462, 1369, 1049, 1016 cmϪ1. MS: (M)ϩ⅐, 366.
Anal. Calcd for C12H19IN2O3 (366.20): C, 39.36; H, 5.23; N,
7.65. Found: C, 39.52; H, 5.38; N, 7.57.
4-Bromo-5-deuterio-3,6-dimethoxypyridazine
(20).
Exchange reaction of 13 (298 mg, 1.0 mmol) according to
the general procedure with i-PrMgCl 2.0 M (1 equiv.,
0.5 mL), t1ˆ30 min; T1ˆ20 ЊC, followed by hydrolysis
with EtOD (1 mL), t2ˆ15 min; T2ˆ20 ЊC, gave after
purification by column chromatography (silica, eluent:
dichloromethane) 176 mg (80%) of 20 as a white solid,
3,6-Dimethoxy-4-iodo-5-trimethylsilylpyridazine (16).
Exchange reaction of 12 (392 mg, 1.0 mmol) according to
the general procedure with i-PrMgCl 2.0 M (1 equiv.,
0.5 mL), t1ˆ30 min, T1ˆ20ЊC, followed by reaction with
trimethylsilyl chloride (0.14 mL, 1.1 mmol), t2ˆ1 h,
T2ˆ20ЊC, gave after purification by column chromato-
graphy (silica, eluent: dichloromethane) 237 mg (70%) of
16 as a white solid, mp 55ЊC; 1H NMR (CDCl3): d 4.00 (s,
1
mp 74–76ЊC; H NMR (CDCl3): d 4.04 (s, 3H, OCH3);
3.96 (s, 3H, OCH3); IR: n 2988, 2952, 1589, 1462, 1370,
1230, 1061, 1026, 1006, 894, 774 cmϪ1. Anal. Calcd for

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A. Lepretre et al. / Tetrahedron 56 (2000) 265–273
271
C6H6N2O2BrD (220.04): C, 32.75; H, 2.75; N, 12.73. Found:
C, 32.64; H, 2.71; N, 12.58.
4-Bromo-3,6-dimethoxypyridazine (26). Exchange reac-
tion of 13 (298 mg, 1.0 mmol) according to the general
procedure with i-PrMgCl 2.0 M (1 equiv., 0.5 mL),
t1ˆ30 min, T1ˆ20ЊC, followed by hydrolysis with water
(1 mL), t2ˆ15 min, T2ˆ20ЊC, gave after purification by
column chromatography (silica, eluent: dichloromethane)
4-Bromo-3,6-dimethoxy-5-hydroxybenzylpyridazine
(21). Exchange reaction of 13 (298 mg, 1.0 mmol) accord-
ing to the general procedure with i-PrMgCl 2.0 M (1 equiv.,
0.5 mL), t1ˆ30 min; T1ˆ20 ЊC, followed by reaction with
benzaldehyde (0.11 mL, 1.1 mmol), t2ˆ2 h; T2ˆ20 ЊC,
gave after purification by column chromatography (silica,
eluent: dichloromethane) 211 mg (65%) of 21 as an orange
solid, mp 92ЊC; 1H NMR (CDCl3): d 7.25 (s, 5H, HPh); 6.25
(d, Jˆ7.0 Hz, 1H, CH); 5.21 (d, Jˆ7.0 Hz, 1H, OH); 4.06 (s,
3H, OCH3); 3.95 (s, 3H, OCH3); 13C NMR (CDCl3): d
159.7; 159.4; 140.5; 135.0; 128.9; 128.3; 125.7; 119.7;
73.6; 56.3; 55.8; IR: n 3391, 2952, 1468, 1376, 1039,
1017, 776, 739, 715 cmϪ1. Anal. Calcd for C13H13BrN2O3
(325.16): C, 48.02; H, 4.03; N, 8.62. Found: C, 48.18; H,
3.87; N, 8.51.
1
175 mg (80%) of 26 as a white solid, mp 75ЊC; H NMR
(CDCl3): d 7.21 (s, 1H, H5); 4.08 (s, 3H, OCH3); 4.00 (s, 3H,
OCH3); 13C NMR (CDCl3): d 162.1; 158.9; 124.2; 119.8;
56.0; 55.4; IR: n 2955, 1560, 1470, 1367, 1017, 793,
659 cmϪ1. Anal. Calcd for C6H7N2O2Br (219.04): C,
32.90; H, 3.22; N, 12.79. Found: C, 32.71; H, 3.46; N, 13.00.
2-Iodo-4-methoxypyrimidine (27). A solution of 2,4-
dichloropyrimidine (5.0 g, 33.6 mmol) in aqueous hydro-
iodic acid (57%, w/w, 30 mL) was vigorously stirred for
8 h at room temperature. The solution was made basic
with solid K2CO3 (pHˆ8) and extracted with dichloro-
methane (5×25 mL). The organic layer was decolorized
with sodium thiosulfate, dried over magnesium sulfate and
evaporated to give crude 2,4-diiodopyrimidine. Crystalliza-
tion from petroleum ether afforded 10.0 g (90%) of a
4-Bromo-3,6-dimethoxy-5-(1-hydroxy)hexylpyridazine
(22). Exchange reaction of 13 (298 mg, 1.0 mmol) accord-
ing to the general procedure with i-PrMgCl 2.0 M (1 equiv.,
0.5 mL), t1ˆ30 min; T1ˆ20 ЊC, followed by reaction with
hexanal (0.13 mL, 1.1 mmol), t2ˆ2 h; T2ˆ20 ЊC, gave after
purification by column chromatography (silica, eluent:
dichloromethane) 191 mg (60%) of 22 as a red solid, mp
1
white solid, mp 125–126ЊC; H NMR (CDCl3): d 7.97 (d,
J6–5ˆ6.0 Hz, 1H, H6); 7.80 (d, J5–6ˆ6.0 Hz, 1H, H5); 13C
NMR (CDCl3): d 157.5; 132.6; 129.7; 127.6; MS: (M)ϩ⅐,
332. A mixture of 2,4-diiodopyrimidine (3.3 g, 10.0 mmol)
in methanol (35 mL) containing sodium methylate, which
was prepared in situ from sodium metal (230 mg,
10.0 mmol) was refluxed for 5 h. The reaction was moni-
tored by GC. After cooling and hydrolysis with water
(10 mL), the methanol was removed under reduced pres-
sure. The aqueous layer was then exctracted three times
with dichloromethane (3×15 mL). The organic extract was
dried over magnesium sulfate and evaporated to give crude
2-iodo-4-methoxypyrimidine. Purification by column
chromatography (silica gel, eluent:dichloromethane)
afforded 2.24 g (95%) of 27 as a white solid, mp 133ЊC;
1H NMR (CDCl3): d 8.03 (d, Jˆ6.0 Hz, 1H, H6); 6.63 (d,
Jˆ6.0 Hz, 1H, H5); 3.91 (s, 3H, OCH3); 13C NMR (CDCl3):
d 168.8; 158.2; 127.9; 108.3; 55.0; IR: n 2950, 1585, 1563,
1536, 1461, 1394, 1308, 1218, 1152, 1008, 974, 862, 832,
760, 695 cmϪ1. MS: (M)ϩ⅐, 236. Anal. Calcd for C5H5IN2O2
(236.01): C, 25.45; H, 2.14; N, 11.87. Found: C, 25.53; H,
2.09; N, 11.98.
1
94ЊC; H NMR (CDCl3): d 5.00 (m, 1H, CH); 4.05 (s, 3H,
OCH3); 4.00 (s, 3H, OCH3); 3.30 (br, 1H, OH); 1.80 (m, 1H,
CH); 1.60 (m, 1H, CH); 1.15 (m, 6H, 3×CH2); 0.90 (m, 3H,
CH3); 13C NMR (CDCl3): d 161.1; 159.8; 135.9; 118.6;
73.1; 56.2; 55.7; 36.0; 31.8; 25.6; 22.9; 14.4; IR: n 3428,
2953, 2930, 2860, 1466, 1376, 1051, 1018 cmϪ1. Anal.
Calcd for C12H19BrN2O3 (319.20): C, 45.15; H, 6.00; N,
8.78. Found: C, 44.94; H, 5.87; N, 8.90.
Ethyl-5-bromo-3,6-dimethoxypyridazine-4-carboxylate
(23). Exchange reaction of 13 (298 mg, 1.0 mmol) accord-
ing to the general procedure with i-PrMgCl 2.0 M (1 equiv.,
0.5 mL), t1ˆ30 min, T1ˆ20ЊC, followed by reaction with
ethyl cyanoformate (0.11 mL, 1.1 mmol), t2ˆ12 h,
T2ˆ20ЊC, gave after purification by column chromato-
graphy (silica, eluent: dichloromethane) 145 mg (50%) of
23 as a white solid, mp 64–65ЊC; 1H NMR (CDCl3): d 4.37
(q, Jˆ7.0 Hz, 2H, CH2); 4.05 (s, 3H, OCH3); 4.00 (s, 3H,
OCH3); 1.31 (t, Jˆ7.0 Hz, 3H, CH3); 13C NMR (CDCl3): d
162.6; 158.6; 157.8; 128.8; 116.7; 63.1; 56.2; 55.8; 14.3; IR:
2-Hydroxybenzyl-4-methoxypyrimidine (28). Exchange
reaction of 27 (236 mg, 1.0 mmol) according to the general
procedure with i-PrMgCl 2.0 M (1 equiv., 0.5 mL), t1ˆ1 h,
T1ˆ0ЊC, followed by reaction with benzaldehyde (0.11 mL,
1.1 mmol), t2ˆ2 h, T2ˆ0ЊC, gave after purification by
column chromatography (silica, eluent: dichloromethane)
149 mg (69%) of 28 as a colorless oil, that rapidly decom-
posed into a brown oil; 1H NMR (CDCl3): d 8.40 (d,
Jˆ5.8 Hz, 1H, H6); 7.60 (m, 2H, HPh); 7.30 (m, 3H, HPh);
6.60 (d, Jˆ5.8 Hz, 1H, H5); 5.75 (s, 1H, CH); 5.00 (br, 1H,
OH); 3.95 (s, 3H, OCH3).
n 2884, 2958, 1742, 1474, 1367, 1278, 1017, 766 cmϪ1
.
Anal. Calcd for C9H11BrN2O4 (291.10): C, 37.13; H, 3.81;
N, 9.62. Found: C, 37.38; H, 3.62; N, 9.78.
4-Bromo-3,6-dimethoxy-5-iodopyridazine (25). Exchange
reaction of 13 (298 mg, 1.0 mmol) according to the general
procedure with i-PrMgCl 2.0 M (1 equiv., 0.5 mL),
t1ˆ30 min, T1ˆ20ЊC, followed by reaction with iodine
(280 mg, 1.1 mmol), t2ˆ2 h, T2ˆ20ЊC, gave after puri-
fication by column chromatography (silica, eluent: dichloro-
methane) 276 mg (80%) of 25 as a white solid, mp 154ЊC;
1H NMR (CDCl3): d 4.09 (s, 3H, OCH3); 4.08 (s, 3H,
OCH3); 13C NMR (CDCl3): d 161.1; 158.4; 128.4; 102.9;
56.5; 56.4; IR: n 2989, 2947, 2858, 1540, 1464, 1443, 1349,
1008, 786, 658 cmϪ1. MS: (M)ϩ⅐, 344. Anal. Calcd for
C6H6BrIN2O2 (344.94): C, 20.89; H, 1.75; N, 8.12. Found:
C, 21.08; H, 2.00; N, 8.05.
2-(1-Hydroxy)hexyl-4-methoxypyrimidine (29). Exchange
reaction of 27 (236 mg, 1.0 mmol) according to the general
procedure with i-PrMgCl 2.0 M (1 equiv., 0.5 mL), t1ˆ1 h,
T1ˆ0ЊC, followed by reaction with hexanal (0.13 mL,
1.1 mmol), t2ˆ2 h, T2ˆ0ЊC, gave after purification by
column chromatography (silica, eluent: dichloromethane)

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272
134 mg (64%) of 29 as a colorless oil; 1H NMR (CDCl3): d
8.30 (d, Jˆ6.0 Hz, 1H, H6), 6.53 (d, Jˆ6.0 Hz, 1H, H5); 4.60
(m, 1H, CH); 4.00 (br, 1H, OH); 3.91 (s, 3H, OCH3); 1.86
(m, 1H, CH); 1.61 (m, 1H, CH); 1.30 (m, 6H, 3×CH2); 0.80
(m, 3H, CH3); 13C NMR (CDCl3): d 171.7; 169.9; 156.9;
106.8; 73.5; 54.1; 37.6; 32.1; 25.2; 22.9; 14.0; IR: n 3456,
2930, 2860, 1582, 1477, 1416, 1333, 1026, 832 cmϪ1. Anal.
Calcd for C11H18N2O2 (210.28): C, 62.83; H, 8.63; N, 13.32.
Found: C, 63.01; H, 8.75; N, 13.20.
T2ˆ0ЊC, gave after purification by column chromatography
(silica, eluent: dichloromethane) 69 mg (35%) of 34 as a
yellow solid, mp 136ЊC; H NMR (CDCl3): d 8.72 (d,
1
Jˆ5.0 Hz, 1H, H6); 7.59 (d, Jˆ5.0 Hz, 1H, H5); 4.40 (q,
Jˆ6.8 Hz, 2H, CH2); 2.63 (s, 3H, SCH3); 1.38 (t,
Jˆ6.8 Hz, 3H, CH3); IR: n 3352, 2987, 2944, 1760, 1588,
1557, 1486, 1417, 1371, 1338, 1267, 1150,1097, 1010,
907, 853, 782 cmϪ1
. Anal. Calcd for C8H10N2O2S
(198.25): C, 48.47; H, 5.08; N, 14.13. Found: C, 48.35; H,
5.16; N, 13.96.
Ethyl-4-methoxypyrimidine-2-carboxylate (30). Exchange
reaction of 27 (236 mg, 1.0 mmol) according to the general
procedure with i-PrMgCl 2.0 M (1 equiv., 0.5 mL), t1ˆ1 h,
T1ˆ0ЊC, followed by reaction with ethyl cyanoformate
(0.11 mL, 1.1 mmol), t2ˆ12 h, T2ˆ0ЊC, gave after purifica-
tion by column chromatography (silica, eluent: dichloro-
2-Methylsulfanyl-4-formylpyrimidine (35). Exchange
reaction of 31 (252 mg, 1.0 mmol) according to the general
procedure with i-PrMgCl 2.0 M (1 equiv., 0.5 mL),
t1ˆ30 min, T1ˆ0ЊC, followed by reaction with DMF
(0.09 mL, 1.1 mmol), t2ˆ2 h, T2ˆ0ЊC, gave after puri-
fication by column chromatography (silica, eluent: dichloro-
methane) 53 mg (34%) of 35 as a white solid, mp 68ЊC;
1H-NMR (CDCl3): d 9.87 (s, 1H, CHO); 8.70 (d,
Jˆ4.8 Hz, 1H, H6); 7.36 (d, Jˆ4.8 Hz, 1H, H5); 2.56 (s,
3H, SCH3); 13C NMR (CDCl3): d 193.0; 174.8; 159.6;
158.1; 111.9; 14.6; IR: n 3402, 3124, 3064, 2929, 2849,
1736, 1711, 1554, 1467, 1426, 1366, 1323, 1256, 1214,
1
methane) 109 mg (60%) of 30 as a colorless oil; H NMR
(CDCl3): d 8.42 (d, Jˆ5.8 Hz, 1H, H6); 6.70 (d, Jˆ5.8 Hz,
1H, H5); 4.15 (q, Jˆ6.8 Hz, 2H, CH2); 3.97 (s, 3H, OCH3);
1.27 (t, Jˆ6.8 Hz, 3H, CH3); 13C NMR (CDCl3): d 170.5;
158.0; 152.1; 114.1; 109.7; 65.5; 54.8; 14.6; IR: n 3364,
3105, 2987, 2926, 2855, 1760, 1668, 1588, 1557, 1484,
1418, 1372, 1266, 1151, 1096, 1001, 907, 852, 780 cmϪ1
.
Anal. Calcd for C8H10N2O3 (182.18): C, 52.74; H, 5.53; N,
15.38. Found: C, 52.70; H, 5.76; N, 15.21.
1180, 1078, 971, 877, 854, 768, 748, 720, 652, 477 cmϪ1
.
Anal. Calcd for C6H6N2OS (154.19): C, 46.74; H, 3.92; N,
18.17. Found: C, 46.68; H, 3.76; N, 18.30.
4-Hydroxybenzyl-2-methylsulfanylpyrimidine
(32).
Exchange reaction of 31 (252 mg, 1.0 mmol) according to
the general procedure with i-PrMgCl 2.0 M (1 equiv.,
0.5 mL), t1ˆ30 min, T1ˆ0ЊC, followed by reaction with
benzaldehyde (0.11 mL, 1.1 mmol), t2ˆ2 h, T2ˆ0ЊC, gave
after purification by column chromatography (silica, eluent:
dichloromethane) 133 mg (57%) of 32 as a brown solid, mp
88ЊC; 1H NMR (CDCl3): d 8.29 (d, Jˆ5.2 Hz, 1H, H6); 7.25
(m, 5H, HPh); 6.77 (d, Jˆ5.2 Hz, 1H, H5); 5.55 (s, 1H, CH);
4.69 (s, 1H, OH); 2.50 (s, 3H, SCH3); 13C NMR (CDCl3): d
172.4; 170.3; 157.7; 141.7; 129.1; 128.7; 127.4; 113.6; 75.1;
14.6; IR: n 3350, 2929, 2871, 1567, 1545, 1351, 1200, 1064,
2-Hydroxybenzylpyrazine (40). Exchange reaction of 36
(206 mg, 1.0 mmol) according to the general procedure with
n-BuMgCl 2.0 M (1 equiv., 0.5 mL), t1ˆ30 min, T1ˆ0ЊC,
followed by reaction with benzaldehyde (0.11 mL,
1.1 mmol), t2ˆ2 h, T2ˆ0ЊC, gave after purification by
column chromatography (silica, eluent: dichloromethane)
1
109 mg (59%) of 40 as an orange solid, mp 108ЊC; H
NMR (CDCl3): d 8.49 (s, 1H, H3); 8.28 (m, 2H, H5,6);
7.23 (m, 5H, HPh); 5.74 (s, 1H, CH); 5.02 (br, 1H, OH);
IR: n 3320, 3060, 1493, 1453, 1402, 1148, 1062, 1018,
701 cmϪ1. Anal. Calcd for C11H10N2O (186.22): C, 70.95;
H, 5.41; N, 15.04. Found: C, 70.72; H, 5.59; N, 14.98.
.
702, 603 cmϪ1 MS: (M)ϩ⅐, 232. Anal. Calcd for
C12H12N2OS (232.31): C, 62.04; H, 5.21; N, 12.06. Found:
C, 62.25; H, 5.43; N, 11.87.
(1-Hydroxy)hexylpyrazine (41). Exchange reaction of 36
(206 mg, 1.0 mmol) according to the general procedure with
n-BuMgCl 2.0 M (1 equiv., 0.5 mL), t1ˆ30 min, T1ˆ0ЊC,
followed by reaction with hexanal (0.13 mL, 1.1 mmol),
t2ˆ2 h, T2ˆ0ЊC, gave after purification by column
chromatography (silica, eluent: dichloromethane) 60 mg
4-(1-Hydroxy)hexyl-2-methylsulfanylpyrimidine (33).
Exchange reaction of 31 (252 mg, 1.0 mmol) according to
the general procedure with i-PrMgCl 2.0 M (1 equiv.,
0.5 mL), t1ˆ30 min, T1ˆ0ЊC, followed by reaction with
hexanal (0.13 mL, 1.1 mmol), t2ˆ2 h, T2ˆ0ЊC, gave after
purification by column chromatography (silica, eluent:
dichloromethane) 124 mg (55%) of 33 as a colorless oil;
1H NMR (CDCl3): d 8.38 (d, Jˆ5.3 Hz, 1H, H6); 6.90 (d,
Jˆ5.3 Hz, 1H, H5); 4.55 (m, 1H, CH); 3.60 (br, 1H, OH);
2.49 (s, 3H, SCH3); 1.70 (m, 2H, CH2); 1.30 (m, 6H,
3×CH2); 0.80 (m, 3H, CH3); 13C NMR (CDCl3): d 172.4;
171.9; 159.2; 113.0; 72.8; 38.1; 32.0; 25.6; 23.3; 22.9; 14.4;
1
(33%) of 41 as a colorless oil; H NMR (CDCl3): d 8.57
(s, 1H, H3); 8.42 (m, 2H, H5,6); 4.74 (m, 1H, CH); 3.73 (br,
1H, OH); 1.75 (m, 2H, CH2); 1.24 (m, 6H, 3×CH2); 0.79 (m,
3H, CH3); 13C NMR (CDCl3): d 158.6; 143.7; 143.6; 143.2;
72.3; 38.6; 32.0; 25.3; 22.9; 14.4; IR: n 3369, 2956, 2930,
2859, 1694, 1529, 1469, 1403, 1312, 1152, 1121, 1058,
1018, 928, 845, 768, 727, 680 cmϪ1. Anal. Calcd for
C10H16N2O (180.25): C, 66.64; H, 8.95; N, 15.54. Found:
C, 66.58; H, 9.17; N, 15.38.
IR: n 3391, 2929, 2860, 1567, 1351, 1204, 1074, 837 cmϪ1
.
Anal. Calcd for C11H18N2OS (226.34): C, 58.37; H, 8.02; N,
12.38. Found: C, 58.50; H, 7.88; N, 12.25.
2-Hydroxybenzyl-3-methoxypyrazine (42). Exchange
reaction of 37 (236 mg, 1.0 mmol) according to the general
procedure with i-PrMgCl 2.0 M (1 equiv., 0.5 mL),
t1ˆ30 min, T1ˆ0ЊC, followed by reaction with benzalde-
hyde (0.11 mL, 1.1 mmol), t2ˆ2 h, T2ˆ0ЊC, gave after puri-
fication by column chromatography (silica, eluent:
dichloromethane) 121 mg (56%) of 42 as a white solid,
Ethyl-2-methylsulfanylpyrimidine-4-carboxylate (34).
Exchange reaction of 31 (252 mg, 1.0 mmol) according to
the general procedure with i-PrMgCl 2.0 M (1 equiv.,
0.5 mL), t1ˆ30 min, T1ˆ0ЊC, followed by reaction with
ethyl cyanoformate (0.11 mL, 1.1 mmol), t2ˆ12 h,

ˆ
A. Lepretre et al. / Tetrahedron 56 (2000) 265–273
273
mp 98ЊC; 1H NMR (CDCl3): d 8.03 (d, Jˆ0.1 Hz, 1H, H5);
7.95 (d, Jˆ0.1 Hz, 1H, H6); 7.25 (m, 5H, HPh); 5.80 (d,
Jˆ6.0 Hz, 1H, CH); 4.85 (d, Jˆ6.0 Hz, 1H, OH); 3.84 (s,
3H, OCH3); 13C NMR (CDCl3): d 157.6; 146.7; 142.0;
140.3; 135.0; 128.7; 128.1; 127.4; 71.2; 54.1; IR: n 3459,
3059, 2953, 2859, 1546, 1462, 1385, 1312, 1185, 1116,
1071, 1011, 843 cmϪ1. Anal. Calcd for C12H12N2O2
(216.24): C, 66.65; H, 5.59; N, 12.95. Found: C, 66.40; H,
5.80; N, 12.62.
C11H9ClN2O (220.66): C, 59.88; H, 4.11; N, 12.70.
Found: C, 60.09; H, 4.38; N, 12.95.
2-(1-Hydroxy)hexyl-3-chloropyrazine (46). Exchange
reaction of 38 (240.5 mg, 1.0 mmol) according to the
general procedure with n-BuMgCl 2.0 M (1 equiv.,
0.5 mL), t1ˆ30 min, T1ˆ0ЊC, followed by reaction with
hexanal (0.13 mL, 1.1 mmol), t2ˆ2 h, T2ˆ0ЊC, gave after
purification by column chromatography (silica, eluent:
1
dichloromethane) 42 mg (20%) of 46 as a colorless oil; H
2-(1-Hydroxy)hexyl-3-methoxypyrazine (43). Exchange
reaction of 37 (236 mg, 1.0 mmol) according to the general
procedure with i-PrMgCl 2.0 M (1 equiv., 0.5 mL),
t1ˆ30 min, T1ˆ0ЊC, followed by reaction with hexanal
(0.13 mL, 1.1 mmol), t2ˆ2 h, T2ˆ0ЊC, gave after puri-
fication by column chromatography (silica, eluent: dichloro-
NMR (CDCl3): d 8.61 (d, Jˆ2.6 Hz, 1H, H5); 8.48 (d,
Jˆ2.6 Hz, 1H, H6); 4.15 (m, 1H, CH); 3.50 (br, 1H, OH);
2.25 (m, 2H, CH2); 1.18 (m, 6H, 3×CH2); 0.83 (m, 3H,
CH3); 13C NMR (CDCl3): d 154.9; 141.4; 140.5; 124.2;
70.0; 36.8; 31.7; 24.9; 22.4; 13.9; IR: n 3450, 2956, 2926,
2855, 1729, 1465, 1378, 1347, 1288, 1142, 1091, 1058,
1024, 859, 737 cmϪ1. Anal. Calcd for C10H15ClN2O
(214.70): C, 55.94; H, 7.04; N, 13.05. Found: C, 55.98; H,
6.86; N, 13.15.
1
methane) 105 mg (50%) of 43 as a colorless oil; H NMR
(CDCl3): d 7.97 (d, Jˆ5.9 Hz, 1H, H5); 7.95 (d, Jˆ5.9 Hz,
1H, H6); 4.82 (m, 1H, CH); 3.92 (s, 3H, OCH3); 3.60 (br,
1H, OH); 2.25 (m, 1H, CH); 1.75 (m, 1H, CH); 1.30 (m, 6H,
3×CH2); 0.79 (m, 3H, CH3); 13C NMR (CDCl3): d 157.6;
148.2; 139.7; 135.0; 69.3; 54.0; 36.6; 31.8; 25.6; 23.0; 14.3;
IR: n 3454, 2930, 2860, 1731, 1546, 1461, 1384, 1313,
1268, 1172, 1116, 1070, 1034, 1012, 843 cmϪ1. Anal.
Calcd for C11H18N2O2 (210.28): C, 62.83; H, 8.63; N,
13.32. Found: C, 62.76; H, 8.50; N, 13.50.
3-Hydroxybenzyl-2-iodopyrazine (47). Exchange reaction
of 39 (332 mg, 1.0 mmol) according to the general pro-
cedure with n-BuMgCl 2.0 M (1 equiv., 0.5 mL),
t1ˆ30 min, T1ˆ0ЊC, followed by reaction with benzalde-
hyde (0.11 mL, 1.1 mmol), t2ˆ2 h, T2ˆ0ЊC, gave after puri-
fication by column chromatography (silica, eluent:
1
dichloromethane) 33 mg (11%) of 47 as a yellow oil; H
2-Formyl-3-methoxypyrazine (44). Exchange reaction
of 37 (236 mg, 1.0 mmol) according to the general
procedure with i-PrMgCl 2.0 M (1 equiv., 0.5 mL),
t1ˆ30 min, T1ˆ0ЊC, followed by reaction with DMF
(0.09 mL, 1.1 mmol), t2ˆ2 h, T2ˆ0ЊC, gave after purifi-
cation by column chromatography (silica, eluent:
dichloromethane) 138 mg (51%) of 44 as a white
solid, mp 66–67ЊC; 1H NMR (CDCl3): d 10.25 (s,
1H, CHO); 8.35 (s, 2H, H5,6); 4.10 (s, 3H, OCH3);
13C NMR (CDCl3): d 190.3, 160.8, 146.0, 137.7,
136.4, 54.8; ir: n 3408, 3067, 3010, 2956, 2798,
2707, 1711, 1569, 1534, 1471, 1443, 1398, 1366,
1306, 1224, 1153, 1074, 996, 894, 876, 766, 665,
602 cmϪ1. Anal. Calcd for C6H6N2O2 (138.13): C,
52.17; H, 4.38; N, 20.28. Found: C, 52.39; H, 4.59;
N, 20.00.
NMR (CDCl3): d 8.46 (d, 1H, Jˆ2.5 Hz, H5); 8.24 (d, 1H,
Jˆ2.5 Hz, H6); 7.27 (m, 5H, HPh); 5.94 (d, 1H, Jˆ7.8 Hz,
CH); 4.72 (br, 1H, OH); IR: n 3401, 2926, 2856, 1727,
1513, 1494, 1455, 1362, 1188, 1136, 1081, 1024, 862,
757, 699 cmϪ1. Anal. Calcd for C11H9N2OI (312.11): C,
42.33; H, 2.91; N, 8.98. Found: C, 42.50; H, 3.22; N, 8.76.
References
´
ˆ
`
´
1. Turck, A.; Ple, N.; Lepretre-Gaquere, A.; Queguiner, G.
Heterocycles 1998, 49, 205.
2. Langley, B. W. J. Am. Chem. Soc. 1956, 78, 2136.
3. Shimura, A.; Momotake, A.; Togo, H.; Yokoama, M. Synthesis,
1999, 3, 495; Momotake, A.; Mito, J.; Yamaguchi, K.; Togo, H.;
Yokoyama, M. J. Org. Chem., 1998, 63, 7207; Momotake, A.;
Togo, H.; Yokoyama, M. J. Chem. Soc., Perkin Trans. 1, 1999,
1193.
2-Hydroxybenzyl-3-chloropyrazine (45). Exchange reac-
tion of 38 (240.5 mg, 1.0 mmol) according to the general
procedure with n-Bu2Mg 2.0 M (1 equiv., 0.5 mL),
t1ˆ30 min, T1ˆ0ЊC, followed by addition of triethylamine
(0.14 mL, 1.0 mmol). After 10 min under stirring, the reac-
tion with benzaldehyde (0.11 mL, 1.1 mmol), t2ˆ2 h,
´
ˆ
´
´
4. Berillon, L.; Lepretre, A.; Turck, A.; Ple, N.; Queguiner, G.;
Cahiez, G.; Knochel, P. Synlett 1998, 1359–1360.
´
ˆ
¨
5. Rottlander, M.; Boymond, L.; Berillon, L.; Lepretre, A.;
´
Varchi, G.; Avolio, S.; Laaziri, H.; Queguiner, G.; Ricci, A.;
Cahiez, G.; Knochel, P. Chem. Eur. J. 1999, in press.
´
T2ˆ0ЊC,
gave
after
purification
by
column
6. Trecourt, F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.;
´
chromatography (silica, eluent: dichloromethane) 97 mg
Queguiner, G. Tetrahedron Lett. 1999, 40, 4339–4342.
1
(44%) of 45 as an orange oil; H NMR (CDCl3): d 8.45
7. Ndzi, B. Thesis, University of Rouen, France, 1990.
8. Breton, G. Thesis, University of Rouen, France, 1999.
(d, Jˆ2.5 Hz, 1H, H5); 8.26 (d, Jˆ2.5 Hz, 1H, H6); 7.24
(m, 5H, HPh); 5.95 (d, Jˆ7.0 Hz, 1H, CH); 4.60 (d,
Jˆ7.0 Hz, 1H, OH); 13C NMR (CDCl3): d 155.2; 148.0;
143.5; 141.6; 140.7; 129.0; 128.7; 127.9; 72.5; IR: n
3370, 2900, 1600, 1375, 1050 cmϪ1. Anal. Calcd for
´
´
9. Ple, N.; Turck, A.; Heynderickx, A.; Queguiner, G. Tetrahedron
1998, 54, 9701–9710.
10. Trohay, D. Thesis, University of Rouen, France, 1990.
11. Mojovic, L. Thesis, University of Rouen, France, 1990.