Relative Ortho-Directing Power of Fluorine, Chlorine and Methoxy Group for the Metalation Reaction in the Diazine Series. Diazines XXXV

Article abstract of DOI:10.1002/jhet.5570400517

The regioselectivity of the metalation of 2-chloro-6-methoxypyrazine, 2-fluoro-6-methoxypyrazine and 3-fluoro-6-chloropyridazine was studied; the relative ortho-directing power was F > OMe > Cl.

Full text of DOI:10.1002/jhet.5570400517

Sep-Oct 2003
855
Relative Ortho-Directing Power of Fluorine, Chlorine and Methoxy
Group for the Metalation Reaction in the Diazine Series. Diazines XXXV
a
a
a
a
Frédéric Toudic , Alain Turck *, Nelly Plé and Guy Quéguiner
b
b
b
Mircea Darabantu , Thierry Lequeux , Jean Claude Pommelet
a
: IRCOF, Laboratoire de Chimie Organique Fine et Hétérocyclique, UPRES-A 6014, INSA, B.P. 08, 76131
Mont St Aignan Cedex, France.
b
: Laboratoire de Chimie Moléculaire et Thioorganique, Université de Caen, ISMRA, 6 Boulevard du
Maréchal Juin, 14050 Caen, France
Fax: (33)2 35 52 29 62, E-mail: Alain.Turck@insa-rouen.fr
Received February 20, 2003
The regioselectivity of the metalation of 2-chloro-6-methoxypyrazine, 2-fluoro-6-methoxypyrazine and
3-fluoro-6-chloropyridazine was studied; the relative ortho-directing power was F > OMe > Cl.
J. Heterocyclic Chem., 40, 855 (2003).
Introduction.
The metalation of 2,6-dichloro-3-fluoropyridine [12]
with n-butyl lithium was regioselective in ortho to the
fluorine atom.
Some years ago (1996) [1], we studied the relative
ortho-directing power of the methoxy group and the
chlorine atom for the metalation reaction in the diazine
series. The substrate was 3-chloro-6-methoxypyridazine
and various hindered alkylamides were used as metalat-
ing agents. In this paper we have extended the compari-
son to 2-chloro and -fluoro-6-methoxypyrazine and to
3-fluoro-6-chloropyridazine.
At first we shall recall the main results in the benzene
and the pyridine series. The metalation of 4-fluoroanisole
was studied by Gilman [2] as early as the forties’, then
Slocum [3], Kirk [4], Schlosser [5] and Bridges [6] studied
again this metalation. In summary, when the metalating
agent was an alkyllithium, its complexation with the ortho-
directing group was the main parameter and the metalation
took place mainly in ortho-position to the methoxy group.
On the other hand, when a complexing agent was added or
a weakly complexing metalating agent was used (LIC-
KOR) [7], the acidity of the hydrogens became the main
parameter and the metalation took place mainly in ortho-
position to the fluorine atom.
-Competition Cl-OMe.
As mentioned above, in the diazine series the competi-
tion between a chlorine atom and a methoxy group has
been studied in our laboratory with 3-chloro-6-
methoxypyridazine [1]. The main isomer had the
substituent ortho to the methoxy group but the percentage
of the two isomers was strongly dependent on the bulki-
ness of the alkylamide used as metalating agent, it varied
between 60/40 and 97/3. The biggest base (LB ) led to an
1
highly regioselective metalation ortho to the methoxy
group (Scheme 1, table 1)[1].
Scheme 1 [1]
The metalation of 4-chloroanisole with n-butyllithium
[2,8] took place regioselectively in ortho-position to the
methoxy group. However, Iwao [8] studied the metalation of
2-chloroanisole with s-butyllithium and observed a complete
regiosepecificity in ortho to the chlorine atom and supposed
that the steric hindrance of the chlorine atom on the methoxy
group suppressed the complexing effect of this group.
The metalation of fluorochlorobenzenes [6,9] took place
mainly in ortho position to the fluorine atom and in some
cases highly regioselectively in this position.
In the pyridine series there are few results dealing with
the competition between a methoxy group and an halogen
atom. M. Mallet [10] metalated 2-chloro-6-methoxypyri-
dine with phenyllithium and diisopropylamine, the reac-
tion was regioselective in ortho-position to the chlorine
atom but Comins [11] observed a regioselective metalation
in ortho-position to the methoxy group when using t-butyl-
lithium as metalating agent.
Table 1 [1]
entry
metalating agent
yield
% 2a
% 2b
1
2
3
LDA [a]
LTMP [b]
85
90
89
40
20
3
60
80
97
LB [c]
1
[a] lithium diisopropylamide; [b] lithium 2,2,6,6-tetramethylpiperidide;
[c] lithium tert-butyl-(1-isopropylpentyl)amide.
In the pyrazine series, 2-chloro-6-methoxy pyrazine 1
was metalated [13] and the main product had the sub-
stituent ortho to the methoxy group.
We have reinvestigated this reaction and varied some
parameters using tetrahydrofuran as solvent (Scheme 2,
Table 2).

856
F. Toudic, A. Turck, N. Plé and G. Quéguiner, M. Darabantu, T. Lequeux and J. C. Pommelet
Vol. 40
Scheme 2
increased. This result is contrary to the one observed in the
pyridazine series[1].
-Competition F-OMe.
In order to compare the methoxy group and the fluorine
atom we studied the metalation of 2-fluoro-6-methoxy
pyrazine 7.
The metalation was first optimized with lithium 2,2,6,6-
tetramethylpiperidide as metalating agent, acetaldehyde as
electrophile, and tetrahydrofuran as solvent, then the meta-
lating agent was varied, a short metalation time (5 minutes)
gave the best results (Scheme 3, Table 4).
Table 2
Entry Metalating n eq. Metalation Electrophile Product Yield % a % b
Agent
time min
R =
Scheme 3
1*
2*
3
4
5
LDA
LTMP
LTMP
LTMP
LTMP
LTMP
LTMP
2.2
2.2
2.2
2.2
2.2
2.2
3.2
120
120
90
60
30
5
i-Pr
i-Pr
Me
Me
Me
Me
Me
5
5
4
4
4
4
4
90 % 13 87
57 % 15 85
73 % 20 80
80 % 32 68
66 % 29 71
60 % 30 70
73 % 33 67
6
7
60
* results previously described in ref [13].
Table 4
The identification of the a and b isomers was performed
by 2D NMR HMBC H- C using J CH correlation
Entry Metalating Electrophile Product Yield % Isomer a % Isomer b
1
13
2
Agent
between the hydrogens of the methoxy group and C then
6
between C and H for isomers a.
1
2
3
4
5
6
LDA
LDA
LTMP
LTMP
MeCHO
8
9
8
9
8
9
72
74
78
65
71
80
96
96
88
86
88
86
4
4
12
14
12
14
6
5
C H CHO
The best yield was obtained with lithium diisopropy-
lamide (entry 1). With lithium 2,2,6,6-tetramethylpiperi-
dide, the yield decreased as the metalation time increased
after 1 hour, (entries 2,3,4) but at the expense of isomer 4a.
It could be assumed that the lithio derivative in ortho to
the chlorine atom may produce hetaryne which, in these
series, are especially unstable.
5
11
MeCHO
C H CHO
5
11
LB
LB
MeCHO
C H CHO
1
1
5
11
The main isomer had the substituent in the ortho posi-
In the pyridazine series (table 1) the percentage of iso-
mers a and b was strongly dependent on the bulkiness of
the base. A short study with the three bases previously
used was performed, acetaldehyde and hexanal were used
as electrophiles at –78 °C with 1 h metalation time and 2.2
equivalents of metalating agent (Table 3).
tion relative to the fluorine atom, contrary to what was
observed with the chlorine atom. With lithium diisopropy-
lamide the metalation was highly regioselective in the
ortho position relative to the fluorine atom. The use of the
two other more bulky bases decreased slightly the regiose-
lectivity (Scheme 5).
The order of ortho directing power is F > OMe > Cl.
Table 3
Entry Metalating Electrophile Product Yield % Isomer a % Isomer b
Scheme 4
Agent
1
2
3
4
5
6
LDA
LDA
LTMP
LTMP
MeCHO
C H CHO
4
6
4
6
4
6
91
74
80
82
71
79
12
12
32
33
38
39
88
88
68
67
62
61
5
11
MeCHO
C H CHO
5
11
LB
LB
MeCHO
C H CHO
1
1
5
11
The percentage of the two isomers was not dependent
on the aldehydes but as noted before, was dependent on
the bulkiness of the base. The regioselectivity in ortho to
the methoxy group lowered when the bulkiness of the base

Sep-Oct 2003
Relative Ortho-Directing Power of Fluorine, Chlorine and Methoxy Group
857
-Competition F-Cl.
metalation of a mixture richer in product 12 (15 %) led to
difluorinated functionnalized products with the same per-
centage (15 %). This regioselective metalation ortho to the
fluoro atom by comparison with the chlorine atom con-
firms the ordering preferentially obtained with halogeno
methoxy diazines.
In order to compare directly the two halogens we
planned to perform the metalation of fluoro-chloro-
diazines.
We have recently published the use of a mixture of pro-
ton sponge and the triethylamine fluorhydric acid complex
to replace a chlorine atom by fluorine with 3,6-dichloropy-
ridazine [14]. However the reaction gave an untractable
mixture of products. The monofluoro compound 11 was
the main product beside 28 % of starting material and a
small amount (5 %) of difluoro derivative 12. The metala-
tion was performed on this mixture (Scheme 6).
Conclusion.
In the diazine series, the methoxy group is a better ortho
directing group than the chlorine atom for the metalation
reaction. However, their relative ortho directing power can
be dependent on the metalating agent.
Scheme
5
The fluorine atom is a better ortho directing atom than
the methoxy group and consequently than the chlorine
atom. This last effect has been verified with 3-fluoro-6-
chloro pyridazine. The order of ortho directing efficiency
in the diazine series is: F > OMe > Cl.
Although the metalations were performed with alkyl-
amides, there must be a complexation of the metalating
agent or/and of the lithio derivative with the ortho
directing group to explain the better ortho directing
power of the methoxy group than of the chlorine atom.
In the case of the fluorine atom, its very strong electron-
withdrawing effect makes the ortho hydrogens much
more acidic, so there is no need for complexation to
achieve the metalation.
This metalation was performed with three electrophiles
and the relative proportions of functionnalized compounds
was determined by analysis of H NMR spectra (Table 6).
1
The proportions of the functionalized products 13-21
were constant with the electrophiles, the metalating agent
and the time and reflected the proportion of the starting
material; this showed a similar behavior of the three com-
pounds (10-12) with regard to the metalation reaction. The
most important result was that the metalation of 11 was
regioselective in ortho position relative to the fluorine
atom, leading to the conclusion that the fluorine atom was
a much better ortho-directing group than the chlorine atom
in these series. We could not isolate products coming from
the metalation of the difluoropyridazine 12, however the
Table 5
Entry
Metalating
Agent
Metalating
Time
Electrophile
Yield
Product [a]
% [b]
Product
% [b]
(%)
1
2
3
4
5
6
LDA
LTMP
LTMP
LTMP
LTMP
LTMP
5
5
20
90
90
90
MeCHO
MeCHO
MeCHO
MeCHO
PhCHO
46
44
48
63
55
37
13 + 15
13 + 15
13 + 15
13 + 15
16 + 18
19 +21
77
72
74
77
72
77
14
14
14
14
17
20
23
28
26
23
28
23
I
2
[a] The amount of difluorocompounds 15, 18, 21 was too low to be quantified (< 5 %); [b] % determined by NMR.

858
F. Toudic, A. Turck, N. Plé and G. Quéguiner, M. Darabantu, T. Lequeux and J. C. Pommelet
Vol. 40
EXPERIMENTAL
2-Chloro-3-(1-hydroxyisopropyl)-6-methoxypyrazine (5a) and
2-Chloro-6-(1-hydroxyisopropyl)-6-methoxypyrazine (5b). See
reference 13.
General Data.
2-Chloro-3-(1-hydroxyhexyl)-6-methoxypyrazine (6a).
Melting points were determined on Kofler apparatus and are
uncorrected. The H NMR spectra were recorded at 300 MHz on
a Bruker Avance-300 NMR spectrometer. Chemical shifts (δ) are
quoted in parts per million (ppm) downfield from an internal
standard, tetramethylsilane in deuteriochloroform, or hexam-
1
Metalation of 3 (141 mg, 0.98 mmol) was performed accord-
ing to the general procedure with n-butyllithium 1.6 M (2.2
equiv., 1.34 mL), 2,2,6,6-tetramethylpiperidine (2.3 equiv., 0.38
mL), t = 60 min, θ = -78 °C, followed by reaction with
1
1
ethyldisiloxane in d -dimethylsulfoxide. Coupling constants (J)
6
acetaldehyde in excess, t = 60 min, θ = -78 °C gave after purifi-
2
2
are given in hertz (Hz). Elemental analyses were performed on a
Carlo-Erba CHN apparatus. Mass spectra were recorded on a
JEOL JMS-AX500 mass spectrometer; samples were vaporized
in a direct inlet system. Column chromatography was carried out
cation by column chromatography (silica, eluent: petroleum
ether/ethylacetate (14/1)) 64 mg (27 %) of 6a as colorless liquid
and 131 mg (55 %) of 6b as a colorless liquid.
1
Compound 6a has H NMR (deuteriochloroform, 300 MHz): δ
on SiO , Merck – Geduran SI60 (70-230 mesh).
2
= 8.04 (s, 1H, H ); 4.90 (m, 1H, CH); 3.91 (s, 3H, OCH ); 3.34
5
3
(br, 1H, OH); 1.71 (m, 2H, CH ); 1.58-1.17 (m, 6H, 3CH ); 0.79
2
2
General Procedure for Metalation.
13
(m, 3H, CH ); C NMR (deuteriochloroform, 300 MHz): δ
3
A solution of n-butyllithium (1.6 M or 2.5 M in hexane) was
added to cold (-50 °C), stirred and anhydrous tetrahydrofuran (15
mL) under an atmosphere of dry argon, then 2,2,6,6-tetram-
ethylpiperidine or diisopropylamine was added and the mixture
was warmed to 0 °C. After 20 min, the mixture temperature was
=159.1 (C ); 146.6 (C ); 142.6 (C ); 132.3 (C ); 69.8 (CH); 54.9
6
5
2
5
(OCH ); 37.6 (CH ); 31.9 (CH ); 25.3 (CH ); 22.9 (CH ); 14.4
3
2
2
2
2
-1
(CH ); IR (KBr) (cm ): 3429; 2930; 2859; 1708; 1567; 1528;
3
1473; 1419; 1399; 1340; 1254; 1170; 1123; 1058; 1019; 916.
Anal. Calcd. for C H ClN O (244.72): C, 53.99; H, 7.00;
11 17
2 2
then carried to the temperature θ and the diazine dissolved in 5
1
N, 11.45. Found: C, 53.87; H, 7.02; N, 11.15.
mL of tetrahydrofuran. After a time t at θ , the electrophile was
introduced and stirring was continued for a time t at θ .
Hydrolysis was then carried out at θ using a solution of 35 %
1
1
1
Compound 6b has: H NMR (deuteriochloroform, 300 MHz):
2
2
δ = 8.00 (s, 1H, H ); 4.80 (m, 1H, CH); 3.94 (s, 3H, OCH ); 3.61
3
3
2
(d, 1H, J
= 7.9 Hz, OH); 1.72 (m, 2H, CH ); 1.53-1.19 (m,
OH-CH
2
aqueous hydrochloric acid, ethanol, tetrahydrofuran (1/4/5). At
room temperature the mixture was made slightly basic with a sat-
urated hydrogen carbonate solution. When the electrophile was
iodine, the solution was decolorized with a sodium thiosulfate
solution. The solvent was removed under reduced pressure. The
residue was extracted with dichloromethane (4 x 20 mL), the
combined organic extracts were dried over magnesium sulphate
and evaporated. The crude product was purified by column chro-
matography on silica gel.
13
6H, 3CH ); 0.79 (m, 3H, CH ); C NMR (deuteriochloroform,
2
3
300 MHz): δ = 155.1 (C ); 144.7 (C ); 142.9 (C ); 132.3 (C );
6
5
2
3
67.8 (CH); 53.5 (OCH ); 35.2 (CH ); 30.6 (CH ); 23.9 (CH );
3
2
2
2
-1
22.5 (CH ); 13.0 (CH ). IR (KBr) (cm ): 3448; 2954; 2930;
2
3
2860; 1707; 1542; 1460; 1421; 1370; 1220; 1171; 1138, 1071;
1011; 927.
Anal. Calcd. for C H ClN O (244.72): C, 53.99; H, 7.00;
11 17
2 2
N, 11.45. Found: C, 54.03; H, 7.07; N, 11.52.
2-Fluoro-6-methoxypyrazine (7) [15].
2-Chloro-3-(1-hydroxyethyl)-6-methoxypyrazine (4a) and 2-
Chloro-5-(1-hydroxyethyl)-6-methoxypyrazine (4b).
A mixture of 2,6-difluoropyrazine (868 mg, 7.48 mmol) in
methanol containing dissolved sodium metal (0.9 equiv., 0.158 g)
was refluxed for 2 h. After cooling, the solvent was distilled at
atmospheric pressure. The residue was washed with 10 mL of
water and extracted with (3 x 20 mL). The combined organic
extracts were dried over magnesium sulphate and evapored to
Metalation of 3 (150 mg, 1.04 mmol) was performed accord-
ing to the general procedure with n-butyllithium 1.6 M (2.2
equiv., 1.43 mL), diisopropylamine (2.3 equiv., 0.33 mL), t = 60
1
min, θ = -78 °C, followed by reaction with acetaldehyde in
1
1
excess, t = 60 min, θ = -78 °C gave after purification by column
afford 491 mg (51 %) of 7 as a colorless liquid; H NMR (deu-
2
2
chromatography (silica, eluent: dichloromethane) 178 mg (91 %)
teriochloroform, 300 MHz): δ = 8.00 (d, 1H, J
= 4.1 Hz, H );
H5-F
5
13
of an unseparable mixture containing 12 % of 4a and 88 % of 4b
7.83 (d, 1H, J
= 7.9 Hz, H ); 3.83 (s, 3H, OCH ); C NMR
H3-F
3
3
1
as a pale yellow oil. H NMR (deuteriochloroform, 300 MHz):
(deuteriochloroform, 300 MHz): δ = 159.2 (d, J
= 7.2 Hz,
= 4.3 Hz,
C6-F
4a, δ = 8.04 (s, 1H, H ); 5.05 (qt, 1H, J = 6.4 Hz, CH); 3.87 (s,
C ); 158.7 (d, J
= 255.8 Hz, C ); 131.7 (d, J
5
6
C2-F
2
C5-F
19
1
3H, OCH ); 3.69 (m, 1H, OH); 1.38 (d, 3H, J = 6.4 Hz, CH ); H
C ); 122.3 (d, J
= 34.9 Hz, C ); 54.2 (OCH ); F NMR (deu-
3
3
5
C3-F
3 3
-1
NMR (deuteriochloroform, 300 MHz): 4b, 8.00 (s, 1H, H ); 4.92
teriochloroform, 200 MHz): δ = -85.11. IR (KBr) (cm ): 3079;
3
(qt, 1H, J = 6.4 Hz, CH); 3.90 (s, 3H, OCH ); 3.85 (m, 1H, OH);
2995; 2948; 1592; 1537; 1480; 1435; 1405; 1329; 1252; 1201;
3
13
+
1.36 (d, 3H, J = 6.4 Hz, CH ); C NMR (deuteriochloroform,
1180; 1140; 1046; 1009; 976; 854; 628; 488. LRMS (IE) [M ]:
3
300 MHz): 4a, δ = 159.3 (C ); 147.0 (C ); 144.4 (C ); 132.3
128 for C H FN O (128.11).
6
3
2
5
5
2
13
(C ); 66.3 (CH); 54.9 (OCH ); 23.5 (CH ); C NMR (deuteri-
5
3
3
2-Fluoro-3-(1-hydroxyethyl)-6-methoxypyrazine (8a).
ochloroform, 300 MHz): 4b, δ = 156.4 (C ); 146.6 (C ); 144.4
6
5
(C ); 133.6 (C ); 65.6 (CH); 54.9 (OCH ); 22.6 (CH ). IR (KBr)
Metalation of 7 (149 mg, 1.16 mmol) was performed accord-
ing to the general procedure with n-butyllithium 1.6 M (2.2
2
3
3
3
-1
for the mixture of 4a and 4b (cm ): 3412; 2978; 2953; 2932;
2869; 1734; 1542; 1463; 1419; 1369; 1291; 1222; 1175; 1140;
1082; 1053; 1010; 923.
equiv., 1.60 mL), diisopropylamine (2.3 equiv., 0.37 mL), t = 5
1
min, θ = -78 °C, followed by reaction with acetaldehyde in
1
Anal. Calcd. for the mixture of 4a and 4b C H ClN O
excess, t = 60 min, θ = -78 °C gave after purification by column
7
9
2
2
2 2
chromatography (silica, eluent: petroleum ether/dichloromethane
(1/1)) 144 mg (72 %) of 8a as a pale yellow oil; H NMR
(188.61): C, 44.58; H, 4.81; N, 14.85. Found: C, 44.72; H, 5.02;
N, 14.47.
1

Sep-Oct 2003
Relative Ortho-Directing Power of Fluorine, Chlorine and Methoxy Group
859
(deuteriochloroform, 300 MHz): δ = 8.01 d, 1H, J
= 3.8 Hz,
CH); 3.93 (s, 3H, OCH ); 3.51 (br, 1H, OH) 1.66 (m, 2H, CH );
3 2
H5-F
19
H ); 4.99 (m, 1H, CH); 3.89 (s, 3H, OCH ); 3.63 (br, 1H, OH) ;
1.33-1.17 (m, 6H, 3CH ); 0.77 (m, 3H, CH ); F NMR (deuteri-
5
3
2
3
13
1.42 (d, 3H, J = 6.4 Hz, CH ). C NMR (deuteriochloroform,
ochloroform, 300 MHz): δ = -88.21.
3
300 MHz): δ = 158.9 (C ); 155.0 (d, J
= 255.8 Hz, C );
Anal. Calcd. for C H FN O (228.27): C, 57.88; H, 7.51; N,
6
C2-F
2
11 17 2 2
135.9 (d, J
= 28.3 Hz, C ); 130.3 (C ); 64.7 (CH); 54.9
12.27. Found: C, 58.20; H, 7.52; N, 12.16.
C3-F
3
5
19
(OCH ); 23.4 (CH ); F NMR (deuteriochloroform, 300 MHz): δ
3
3
3-Chloro-6-fluoro-5-(1-hydroxyethyl)pyridazine (13) and 3,6-
Dichloro-4-(1-hydroxyethyl)pyridazine (14).
-1
= -83.82. IR (KBr) (cm ): 3401; 2981; 2949; 1595; 1538; 1490;
1447; 1424; 1389; 1331; 1179; 1155; 1091; 1039; 1017; 978; 899.
Metalation of the mixture (160 mg, 1.18 mmol) of 3-chloro-6-
fluoropyridazine (67 %, 0.81 mmol), 3,6-dichloropyridazine (28
%, 0.30 mmol) and 3,6-difluoropyridazine (5 %, 0.07 mmol) was
performed according to the general procedure with n-butyllithium
1.6 M (1.2 equiv., 0.89 mL), 2,2,6,6-tetramethylpiperidine (1.3
Anal. Calcd. for C H FN O (172.16): C, 48.84; H, 5.27; N,
16.27. Found: C, 48.67; H, 5.56; N, 16.06.
7
9
2 2
2-Fluoro-5-(1-hydroxyethyl)-6-methoxypyrazine (8b).
Metalation of 2 (156 mg, 1.22 mmol) was performed accord-
ing to the general procedure with n-butyllithium 1.6 M (2.2
equiv., 1.67 mL), 2,2,6,6-tetramethylpiperidine (2.3 equiv., 0.47
mL), t = 5 min, θ = -78 °C, followed by reaction with acetalde-
equiv., 0.26 mL), t = 90 min, θ = -78 °C, followed by reaction
1
1
with acetaldehyde in excess, t = 60 min, θ = -78 °C gave after
2
2
purification by column chromatography (silica, eluent: petroleum
ether/ethylacetate (2/1)) 138 mg (63 %) of an untractable mixture
1
1
hyde in excess, t = 60 min, θ = -78 °C gave after purification by
2
2
1
column chromatography (silica, eluent: petroleum
ether/dichloromethane (1/1)) 167 mg (78 %) of a pale yellow oil
containing 77 % of 13 + 15 and 23 % of 14; H NMR (deuteri-
ochloroform, 300 MHz): 13, δ = 7.85 (d, 1H, J
= 7.9 Hz, H );
H4-F
4
1
containing 88 % of 8a and 12 % of 8b; H NMR (deuteriochloro-
5.07 (q, 1H, J
= 6.4 Hz, CH); 1.48 (d, 3H, J
= 6.4
CH3-CH
CH-CH3
1
form, 300 MHz): 8b, δ = 7.81 (d, 1H, J
= 8.3 Hz, H ); 4.99
Hz, CH ); H NMR (deuteriochloroform, 300 MHz): 14, δ = 7.83
H3-F
3
3
(m, 1H, CH); 3.93 (s, 3H, OCH ); 3.63 (br, 1H, OH); 1.37 (d, 3H,
(s, 1H, H ); 5.07 (q, 1H, J
= 6.4 Hz, CH); 1.48 (d, 3H,
3
5
CH-CH3
13
19
J = 6.4 Hz, CH ); F NMR (deuteriochloroform, 300 MHz): 8b,
J
= 6.4 Hz, CH ); C NMR (deuteriochloroform, 300
3
CH3-CH
3
-1
δ = -88.09. IR (KBr) for the mixture of 8a and 8b (cm ): 3400;
MHz) 13: 163.8 (d, J
= 245.6 Hz, C ); 155.9 (C ); 139.3 (d,
6 3
C6-F
13
2981; 2949; 1682; 1594; 1538; 1489; 1446; 1424; 1391; 1331;
1179; 1155; 1091; 1039; 978.
J
= 27.6 Hz, C ); 130.3 (C ); 63.4 (CH); 23.7 (CH );
C
C5-F
5
4
3
NMR (deuteriochloroform, 300 MHz): 14, 157.2 (C or C );
3
6
Anal. Calcd. for the mixture of 8a and 8b C H FN O
(172.16): C, 48.84; H, 5.27; N, 16.27. Found: C, 48.89; H, 5.33;
N, 16.55.
154.2 (C or C ); 149.2 (C ); 127.8 (C ); 65.9 (CH); 23.3 (CH );
F NMR (deuteriochloroform, 200 MHz): 13, -87.05.
7
9
2
2
3
6
4
5
3
19
3-Chloro-6-fluoro-5-(1-hydroxyphenylmethyl)pyridazine (16)
and 3,6-Dichloro-4-(1-hydroxyphenylmethyl)pyridazine (17).
2-Fluoro-3-(1-hydroxyhexyl)-6-methoxypyrazine (9a).
Metalation of 7 (159 mg, 1.24 mmol) was performed accord-
ing to the general procedure with n-butyllithium 1.6 M (2.2
Metalation of the mixture (152 mg, 1.12 mmol) of 3-chloro-6-
fluoropyridazine (67 %, 0.77 mmol), 3,6-dichloropyridazine (28
%, 0.29 mmol) and 3,6-difluoropyridazine (5 %, 0.06 mmol) was
performed according to the general procedure with n-butyllithium
1.6 M (1.2 equiv., 0.84 mL), 2,2,6,6-tetramethylpiperidine (1.3
equiv., 1.71 mL), diisopropylamine (2.3 equiv., 0.40 mL), t = 5
1
min, θ = -78 °C, followed by reaction with hexanal (2.2 equiv.,
1
0.33 mL), t = 60 min, θ = -78 °C gave after purification by col-
2
2
umn chromatography (silica, eluent: petroleum ether/ethylacetate
(14/1)) 210 mg (74 %) of 9a as a colorless liquid; H NMR (deu-
equiv., 0.25 mL), t = 90 min, θ = -78 °C, followed by reaction
1
1
1
with benzaldehyde (1.5 equiv., 0.17 mL), t = 60 min, θ = -78 °C
2
2
teriochloroform, 300 MHz): δ = 7.99 (d, 1H, J
4.81 (t, 1H, J = 6.4 Hz, CH); 3.87 (s, 3H, OCH ); 3.57 (br, 1H,
= 3.4 Hz, H )
gave after purification by column chromatography (silica, eluent:
petroleum ether/ethylacetate (2/1)) 150 mg (55 %) of an unsepara-
ble mixture containing 72 % of 16 + 18 and 28 % of 17; H NMR
H5-F
5
3
1
OH); 1.66 (m, 2H, CH ); 1.33-1.17 (m, 6H, 3CH ); 0.77 (m, 3H,
2
2
13
CH ); C NMR (deuteriochloroform, 300 MHz): δ = 158.7 (C );
(deuteriochloroform, 300 MHz): 16, 7.90 (d, 1H, J
= 7.7 Hz,
3
6
H4-F
1
155.1 (d, J
= 255.8 Hz, C ); 135.5 (d, J
= 28.3 Hz, C );
H ); 7.20 (m, 5H, 5H ); 5.85 (s, 1H, CH); 3.92 (br , 1H, OH); H
C2-F
2
C3-F
3
4
Ph
130.4 (C ); 68.2 (CH); 54.7 (OCH ); 37.4 (CH ); 31.9 (CH );
NMR (deuteriochloroform, 300 MHz): 17, 7.92 (s, 1H, H ); 7.20
5
3
2
2
5
19
25.2 (CH ); 22.8 (CH ); 14.2 (CH ); F NMR (deuteriochloro-
(m, 5H, 5H ); 5.85 (s, 1H, CH); 3.92 (br, 1H, OH).
2
2
3
Ph
-1
form, 300 MHz): δ = -84.33. IR (KBr) (cm ): 3411; 2932; 2860;
1595; 1540; 1488; 1459; 1425; 1389; 1331; 1177; 1150; 1113;
1039; 979.
3-Chloro-6-Fluoro-5-iodopyridazine (19) and 3,6-Dichloro-4-
iodopyridazine (20).
Metalation of the mixture (174 mg, 1.28 mmol) of 3-chloro-6-
fluoropyridazine (67 %, 0.88 mmol), 3,6-dichloropyridazine (28
%, 0.33 mmol) and 3,6-difluoropyridazine (5 %, 0.07 mmol) was
performed according to the general procedure with n-butyl-
lithium 1.6 M (1.2 equiv., 0.96 mL), 2,2,6,6-tetramethylpiperi-
Anal. Calcd. for C H FN O (228.27): C, 57.88; H, 7.51; N,
12.27. Found: C, 57.87; H, 7.61; N, 12.36.
11 17
2 2
2-Fluoro-5-(1-hydroxyhexyl)-6-methoxypyrazine (9b).
Metalation of 7 (156 mg, 1.22 mmol) was performed accord-
ing to the general procedure with n-butyllithium 1.6 M (2.2
equiv., 1.67 mL), 2,2,6,6-tetramethylpiperidine (2.3 equiv., 0.47
mL), t = 5 min, θ = -78 °C, followed by reaction with hexanal
dine (1.3 equiv., 0.28 mL), t = 90 min, θ = -78 °C, followed by
1
1
reaction with iodine (1.1 equiv., 357 mg), t = 60 min, θ = -78
2
2
°C gave after purification by column chromatography (silica,
eluent: petroleum ether/dichloromethane (2/1)) 123 mg (37 %) of
an unseparable mixture containing 77 % of 19 + 21 and 23 % of
1
1
(2.2 equiv., 0.32 mL), t = 60 min, θ = -78 °C gave after purifi-
2
2
cation by column chromatography (silica, eluent: petroleum
1
ether/ethylacetate (14/1)) 15 mg (5 %) of 9b as a colorless liquid
20; H NMR (deuteriochloroform, 300 MHz): 19, 8.03 (d, 1H,
1
1
(besides 169 mg (60 %) of 9a); H NMR (deuteriochloroform,
J
= 6.6 Hz, H ); H NMR (deuteriochloroform, 300 MHz):
H4-F
4
300 MHz): δ = 7.82 (d, 1H, J
= 8.3 Hz, H ); 4.82 (m, 1H,
20, 7.99 (s, 1H, H ).
H3-F
3
5

860
F. Toudic, A. Turck, N. Plé and G. Quéguiner, M. Darabantu, T. Lequeux and J. C. Pommelet
Vol. 40
REFERENCES AND NOTES
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