Methyl carbonium ion migration during the reaction of 4-chloro-5-methoxyl- 3(2H)-pyridazinone with trifluoroethylation agents

Article abstract of DOI:10.3390/molecules14020777

To synthesize 4-chloro-5-methoxy-2-(β-trifluoroethyl)-3(2H)- pyridazinone (4), the reactions of 4-chloro-5-methoxy-3(2H)-pyridazinone (5) with RCH₂CF₃ (R = I, TsO, MsO, TfO) in different solvents were studied. It was found that methyl group migration took place during this reaction. An oxonium salt 9 was suggested as the active intermediate for the formation of the byproduct 4-chloro-5-methoxy-2-methyl-3(2H)-pyridazinone (7) and4-chloro-2-methyl-5-(β-trifluoroethoxy)-3(2)-pyridazinone(8).

Full text of DOI:10.3390/molecules14020777

Molecules 2009, 14, 777-784; doi:10.3390/molecules14020777
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Methyl Carbonium Ion Migration during the Reaction of 4-
Chloro-5-methoxyl-3(2H)-pyridazinone with Trifluoroethylation
Agents
Qin Li, Guichun Lin, Li Liu, Zhenjun Yang* and Li-He Zhang
The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences,
#
Peking University, Xue Yuan Road 38, Beijing 100191, P.R. China; E-mail: liqin@bjmu.edu.cn
(Q.L.)
* Author to whom correspondence should be addressed; E-mail: yangzj@bjmu.edu.cn
Received: 20 November 2008; in revised form: 18 December 2008 / Accepted: 4 January 2009 /
Published: 13 February 2009
Abstract: To synthesize 4-chloro-5-methoxy-2-(β-trifluoroethyl)-3(2H)-pyridazinone (4),
the reactions of 4-chloro-5-methoxy-3(2H)-pyridazinone (5) with RCH2CF3 (R = I, TsO,
MsO, TfO) in different solvents were studied. It was found that methyl group migration
took place during this reaction. An oxonium salt 9 was suggested as the active intermediate
for the formation of the byproduct 4-chloro-5-methoxy-2-methyl-3(2H)-pyridazinone (7)
and 4-chloro-2-methyl-5-(β-trifluoroethoxy)-3(2)-pyridazinone (8).
Keywords: 4,5-Dichloro-3(2H)-pyridazinone; 4-Chloro-5-methoxy-3(2H)-pyridazinone;
β-Trifluoroethylation; Oxonium; Methyl group migration; Alkylation.
Introduction
It is well-known that the incorporation of fluorine atoms into organic molecules often has profound
effects on their chemical and physical properties [1-2], thus there has been considerable interest in
organofluorine compounds as pharmaceutical and agrochemical agents [3-4]. Among fluorine-
containing groups, the β-trifluoroethyl moiety has been found in many drug molecules, where it can
retard or prevent oxidative dealkylation of an N-, S-, or O-alkyl function [5-10]. 2-Substituted 4-
chloro-5-methoxyl-3(2H)-pyridazinones are key intermediates in the synthesis of agrochemically and

Molecules 2009, 14
778
pharmaceutically important 2,4,5-trisubstituted-3(2H)-pyridazinones [11-15]. Although several
approaches to nonfluorinated 2-substituted 4-chloro-5-methoxy-3(2H)-pyridazinones have been well
documented in the prior literatures [16-17], β-trifluoroethylated 2,4,5-trisubstituted-3(2H)-
pyridazinones are much less known. This is ascribed to the absence of practical and convenient
methods for the introduction of the β-trifluoroethyl group into organic compounds. We failed to
synthesize 4-chloro-5-methoxy-2-(β-trifluoroethyl)-3(2H)-pyridazinone (4) by treatment of 4,5-
dichloro-2-(β-trifluoroethyl)-3(2H)-pyridazinone (3), which was prepared from reaction of
mucochloric acid (1) and β-trifluoroethyl hydrazine (2) [18], with sodium methoxide (MeONa) in
methanol under reflux, because the β-trifluoroethyl group was sensitive to the strong base. Elimination
happened after treating 3 with strong base, and instead of compound 4, a low yield of a mixture (most
1
probably a mixture of 4-1 and 4-2, according H-NMR) was obtained, which could contain trace
amounts of 4 [19]. On the other hand, a weaker base like potassium carbonate (K2CO3) failed to
catalyze the substitution (Scheme 1). In this paper, we report the β-trifluoroethylation of 4-chloro-5-
methoxy-3(2H)-pyridazinone (5) to synthesize compound 4, while proposing formation of an oxonium
salt 9 during the reaction of compound 5 with LCH2CF3 (L = I, TsO, MsO, TfO ) under different
conditions, to further form 4-chloro-5-methoxy-2-methyl-3(2H)-pyridazinone (7) and 4-chloro-2-
methyl-5-trifluoroethyl-3(2H)-pyridazinone (8), in different ratios and yields, respectively.
Scheme 1. Direct introduction of trifluoroethyl group to the diazine 3.
OCH3
Cl
5
OCH3
OCH3
Cl
Cl
Cl
4
Cl
Cl
Cl
6
ii
OH
i
N
+
+
3
+ H2NNHCH2CF3
O
N
N
N
N
N
N
O
2N
1
O
O
1
O
C
2
O
CH2CF3
CH2CF3
CH=CF2
4-1
CF
4-2
3
4
.
Reagents and conditions: i). C2H5OH, reflux; ii). K2CO3/CH3OH, reflux or CH3ONa/CH3OH, reflux.
Results and Discussion
4,5-Dichloro-2-(β-trifluoroethyl)-3(2H)-pyridazinone (3) can be prepared from the reaction of
mucochloric acid (1) and β-trifluoroethyl hydrazine (2) [18]. However, the methoxyl substitution on
the 5-chloro of compound 3 was very difficult due to the elimination of β-trifluoroethyl group by the
base, resulting in a mixture of compound 4, 4-1 and 4-2 [17-19] (Scheme 1). Therefore, we tried to
prepare 4 by β-trifluoroethylation of the corresponding 4-chloro-5-methoxy-3(2H)-pyridazinone (5)
with several different agents.
Reaction of 5 with β-trifluoroethyl methanesulfonate (MsOCH2CF3) in the presence of K2CO3 in
o
HMPA at 140 C (Table 1, entry 5) afforded exclusively 4-chloro-2-methyl-5-(β-trifluoroethyl)-3(2H)-
pyridazinone (8) in 65% yield. When the reaction was carried out in DMF, we obtained only 4-chloro-
5-methoxy-2-methyl-3(2H)-pyridazinone (7) in 40% yield. When sodium hydride (NaH) was used
instead of K2CO3 (Table 1, entry 6), a mixture of compound 4 and 8 was obtained.

Molecules 2009, 14
Scheme 2. Synthesis of compound 4 with 7 and 8 as by-products.
779
OCH3
OCH3
OCH2CF3
Cl
Cl
Cl
i
+ CF3CH2L
4 +
+
N
N
N
N
N
N
O
O
O
H
CH3
CH3
L = I, TsO, MsO, or TfO
5
8
7
Reagents and conditions: i). see Table 1.
Table 1. Reactions of compound 5 with different alkylation reagents.
Entry
Condition
K2CO3/DMF, 80 °C
Product (yield)
4 (5%), 7 (20%)
No product
Time
12 h
20 h
20 h
20 h
20 h
20 h
24 h
1
2
3
4
5
6
7
ICH2CF3
TsOCH2CF3 K2CO3/DMF, 120 °C
MsOCH2CF3 K2CO3/18-crown-6/DMF, 120 °C
7 (40%)
MsOCH2CF3 K2CO3/18-crown-6/1,4-Dioxane, reflux 4 (trace), 7 (35%)
MsOCH2CF3 K2CO3/18-crown-6/HMPA, 140 °C
MsOCH2CF3 NaH/18-crown-6/HMPA, 140 °C
TfOCH2CF3 K2CO3/18-crown-6/HMPA, 60 °C
8 (45%)
4 (15%), 8 (25%)
4 (40%), 7 (25%)
Compounds 4 and 8 are a pair of isomers. The substitution position on 4 and 8 was confirmed by 1D
NOE NMR spectroscopy. Both 4 and 8 were subjected to a 1D NOE difference experiment. Irradiation
of the methyl peak of 4 gave signal enhancement for protons at position 6, whereas, irradiation of the
H-6 proton of 8 resulted in enhancement of the methylene proton NMR signal, in good agreement with
the structural assignment (Figure 1).
Figure 1. NOE between H-6 and methyl or trifluoroethyl group in compound 4 or 8.
CH3
CH2CF3
O
O
NOE
NOE
Cl
H
N
Cl
H
N
O
N
O
N
CH2CF3
CH3
4
8
Both compounds 7 and 8 have methyl groups on the N-2 position. To determine whether these
methyl groups come from the solvents or from the substrate 5, compound 5 was treated with β-
trifluoroethyl methanesulfonate (MsOCH2CF3) in 1,4-dioxane, yielding 7 (35%) as the major product,
with only trace amounts of 4 (Table 1, entry 4). It is obvious that compound 7 and 8 might be formed
by the methyl migration from O-5 of compound 5. When 5 was allowed to react with β-trifluoroethyl
trifluoromethanesulfonate (TfOCH2CF3) in the presence of K2CO3 and 18-crown-6 in HMPA at 60 °C
(Table 1, entry 7), compound 4 was obtained in 40% yield, while 7 was obtained in 25% yield.

Molecules 2009, 14
780
Reaction of 5 with β-trifluoroethyl iodide (CF3CH2I) in the presence of K2CO3 in DMF (entry 2)
provided compound 4 in very low yield (5%), while 7 in 20% yield. We presumed that intramolecular
elimination happened for CF3CH2I at basic condition and high temperature.
Scheme 3. Possible mechanism for the formation of compounds 7, 8 and oxonium ion 9.
OCH3
Cl
5
7
N
O
N
5-1
L
F3CH2C
Cl
CH3
O CH2CF3
O
a
Cl
8
5 + CF3CH2L
Direct trifluoroethylation
N
N
N
O
O
N
at 2-position of dazine
H
9
10
L = I, MsO, TfO
4
L
CH3
F3CH2C
Cl
O
a. Formation of oxonium 9
N
O
N
H
9
Based on these observations, a possible mechanism for the formation of compounds 4, 7 and 8 was
proposed (Scheme 3). ICH2CF3 and MsOCH2CF3 as alkylating reagents could attack N-2 of compound
+
5 to yield compound 4, while the carbonium ion CF3CH2 could form the oxonium salt 9 with
compound 5. The formation of compound 8 was proposed by methyl carbonium ion migration from
oxonium salt 9 to the intermediate 10. And oxonium salt 9 reacted with compound 5 via an
intermolecular methyl carbonium ion migration to yield compound 7 [20].
We had investigated the reaction of compound 5 with trifluoroethyl p-toluenesulfonate
(TsOCH2CF3) in the presence of sodium hydroxide (NaOH) in aqueous ethanol, which afforded 4-
chloro-5-ethoxy-2-ethyl-3(2H)-pyridazinone (6) in 70% yield. The mechanism of formation of
compound 6 as shown in Scheme 4 is suggested. The more basic ethoxyl group could competitively
substitute the trifluoroethoxyl group to form TsOCH2CH3, which then reacted with 5, leading to the N-
2 ethylation of 5. The replacement of 5-methoxyl group on the formed N-2 ethylation intermediate
gave 6. We also investigated the reaction of compound 5 with other three alkylating reagents (Scheme
5). Methylation of compound 5 with iodomethane(CH3I) and potassium carbonate in DMF gave
compound 7 in excellent yield.

Molecules 2009, 14
781
Scheme 4. Ethylation of diazinone 5 at the 2 and 4-positions.
OCH3
OCH3
OCH2CH3
CH3CH2O-
Cl
Cl
Cl
OH-
5
N
N
N
N
N
O
N
-
O
O
5-1
CH2CH3
CH2CH3
TsOCH2CH3
5-2
6
O
CH3CH2O-
4-CH -Ph S OCH2CF3
+
3
O
CH CH OH OH-
+
3
2
Hydroxyethylation of 5 with sodium hydroxide and 2-bromoethanol also afforded the corresponding
4-chloro-2-(β-hydroxyethyl)-5-methoxy-3(2H)-pyridazinone (11) in good yield. Reaction of 5 with 1-
chloro-2-(N-morpholino)ethane in the presence of potassium carbonate yielded the expected 4-chloro-
5-methoxy-2-{β-(N-morpholino)}ethyl-3(2H)-pyridazinone (12). No carbonium ion shift product was
detected in reaction of 5 with 2-bromoethanol or 2-(N-morpholino)-1-chloroethane.
Scheme 5. Alkylation at the 2-postion of diazinone 5.
OCH3
7. R = CH3;
Cl
i, or ii, or iii
11. R = CH2CH2OH;
CH CH
5
N
O
N
R
N
O
12. R =
2
2
Reagents and conditions: i). K2CO3/ CH3I/DMF, 50-60 °C, 2h; ii). 2N NaOH/BrCH2CH2OH/
CH3CH2OH, reflux, 3h; iii). K2CO3/ 2-(N-morpholino)-1-chloroethane.
Conclusions
In summary, the reaction of 4-chloro-5-methoxy-3(2H)-pyridazinone (5) with MsOCH2CF3 or
TfOCH2CF3 in polar aprotic solvents lead to the formation of an oxonium salt 9 which generated β-
trifluoroethyl and methyl carbonium ions. Compound 8 was formed by methyl carbonium ion
migration from O-5 of the intermediate 9 to N-2 of intermediate 10. Oxonium salt 9 reacted with
compound 5 via an intermolecular methyl carbonium ion migration, yielding compound 7. The β-
trifluoroethyl carbonium ion could also be an alkylating reagent, reacting directly with compound 5 to
furnish 4-chloro-5-methoxy-2-(β-trifluoroethyl)-3(2H)-pyridazinone (4).
Acknowledgements
This work was supported by the National Natural Science Foundation of China (20472006).

Molecules 2009, 14
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Experimental
General
Column chromatography was performed on silica gel (200-300 mesh). Melting points were
determined on a Mel-temp II and are uncorrected. NMR spectra were recorded on a Varian INOVA-
500 NMR spectrometer operating at 499.821 MHz for 1H and 125.71 MHz for 13C. Chemical shifts (δ)
are referenced to internal TMS and reported in ppm. Splitting patterns were as follows: s, singlet; br,
broad; d, doublet; t, triplet; q, quartet; m, multiplet. Mass spectra were recorded under fast
bombardment (FAB), on a Micromass Autospect high-resolution mass spectrometer unless noted.
Elemental analyses were recorded on PE-240C. Infrared spectra (IR) were obtained with a Nicolet
NEXUS-470 FTIR spectrometer as KBr pellets.
4,5-Dichloro-2-(β-trifluoroethyl)-3(2H)-pyridazinone (3). Mp 83-85 °C. MS (ESI): m/z 247 [M+1]+.
Anal. calcd. for C6H3Cl2 F3N2O: C 29.18, H 1.22, N 11.34; Found: C 29.19, H 1.26, N 11.34.
o
4-Chloro-5-methoxy-3(2H)-pyridazinone (5). Mp 123-124 C. 1H-NMR (DMSO-d6) δ 11.59 (br, 1 H,
H-2), 7.78 (s, 1 H, H-6), 4.063 (s, 3 H, -OCH3).
4-Chloro-5-ethoxy-2-ethyl-3(2H)-pyridazinone (6): To a solution of 5 (1.0 g, 6.2 mmol) in C2H5OH
(60 mL) were added TsOCH2CF3 (6.2 g, 25.2 mmol) and 2 N NaOH (10 mL). The mixture was stirred
under reflux for 14 h. After cooling to room temperature, the reaction mixture was evaporated to
dryness under reduced pressure. The residue was dissolved in CH2Cl2 and solution was washed with
brine. The organic layer was separated, dried over anhydrous sodium sulfate (Na2SO4) and
concentrated. The resulting residue was purified by column chromatography (hexane/ethyl acetate) to
give compound 6 (877 mg, 70%) as a colorless solid. Mp 64-66 °C; 1H-NMR (CDCl3) δ 7.79 (s, 1 H,
H-6), 4.32 (q, J = 7.0 Hz, 2 H, OCH2CH3), 4.24 (q, 2H, J = 7.0 Hz, N-CH2CH3), 1.50 (t, J = 7.0 Hz, 3
13
H, -OCH2CH3), 1.37 (t, J = 7.0Hz, 3 H, N-CH2CH3); C NMR (CDCl3) δ 158.3 (C=O), 154.3 (C-6),
126.7 (C-5), 116.5 (C-4), 66.4 (OCH2CH3), 47.6 (N-CH2CH3), 14.8 (-OCH2CH3), 13.4 (-NCH2CH3);
MS (FAB): m/z 203 [M+1]+; Anal. calcd. for C8H11Cl1N2O2: C 47.42, H 5.47, N 13.82; Found: C
47.13, H 5.44, N, 13.48.
General procedure for the synthesis of compound 4
To the solution of 5 in solvent were added LCH2CF3 and base. The mixture was stirred under reflux
for 14 h. After cooling to room temperature, the reaction mixture was evaporated to dryness under
reduced pressure. CH2Cl2 and water were added. The organic layer was separated and dried over
anhydrous sodium sulfate (Na2SO4). After evaporation, the residue was purified by column
chromatography (hexane/ethylacetate) to give compound 4 and 7 or 8.
4-Chloro-5-methoxy-2-(β-Trifluoro)ethyl-3(2H)-pyridazinone (4). White powder; mp 90-92 °C; IRνmax
1
(cm--1): 3318-2853 (m), 1671, 1609, 1466, 1385, 1320, 1286, 1267, 1219, 1150, 1106, 892, 772; H-
NMR (CDCl3) δ 7.88 (s, 1 H, H-6), 4.82 (q, J = 8.5 Hz, 2 H, -NCH2-), 4.11 (s, 3 H, OCH3); 13C-NMR
(CDCl3) δ 158.5 (C=O), 155.0 (C-6), 127.9 (C-5), 123.0 (q, 1JC,F = 153.6 Hz, -CF3), 116.5 (C-4), 58.5

Molecules 2009, 14
783
2
(-OCH3), 52.5 (q, JC,F = 35.1 Hz, -N-CH2-); MS (EI): m/z 242.0 [M]+; Anal. calcd. for
C7H6Cl1F3N2O2: C 34.66, H 2.49, N 11.55; Found: C 34.69, H 2.52, N 11.41.
o
4-Chloro-5-methoxy-2-methyl-3(2H)-pyridazinone (7). White powder; yield 75%; mp 131 - 133 C;
1H-NMR (CDCl3) δ 7.78 (s, 1 H, H-6), 4.07 (s, 3H, -OCH3), 3.83 (s, 3 H, N-CH3).
4-Chloro-2-methyl-5-(β-trifluoroethoxy)-3(2)-pyridazinone (8). White powder. Mp164-166 °C. IRνmax
(cm-1) 3409 - 2927 (m), 1653, 1602, 1468, 1397, 1334, 1301, 1271, 1208, 1170, 1111, 1000, 967, 876;
1H-NMR (CDCl3) δ 7.71 (s, 1 H, H-6), 4.60 (q, 2H, 3JH,F = 7.5 Hz, -OCH2-), 3.83 (s, 3 H, N-CH3); 13C-
NMR (CDCl3) δ 158.5 (C=O), 153.5 (C-6), 127.9 (C-5), 122.3 (q, 2JC,F = 153.6 Hz, -CF3), 120.1 (C-4),
2
67.6 (q, JC,F = 35.1 Hz, N-CH2-), 41.0 (-NCH3); MS (EI): m/z 242.0 [M]+; Anal. calcd. for
C7H6Cl1F3N2O2: C 34.66, H 2.49, N 11.55; Found: C 34.76, H 2.56, N 11.38.
4-Chloro-2-(β-hydroxyethyl)-5-methoxy-3(2H)-pyridazinone (11). Mp: 166-168 °C; 1H-NMR (DMSO-
d6): δ 8.26 (s, 1 H, H-6), 4.83 (brs, 1 H, OH), 4.15 (t, J = 6.6 Hz, 2H, -NCH2-), 4.07 (s, 3 H, -OCH3),
3.69 (t, J = 4.5 Hz, 2 H, -OCH2); MS (FAB): m/z 205.0 [M+1]+; Anal. calcd. for C7H9Cl1N2O3: C
41.09, H 4.43, N 13.69; Found: C 40.80, H 4.46, N 13.74.
1
4-Chloro-5-methoxy-2-(β-N-morphilinoethyl)-3(2H)-pyridazinone (12). Mp 170-172 °C. H NMR
(DMSO-d6): δ 8.24 (s, 1 H, H-3), 4.21 (t, J = 6.6 Hz, 2H, -NCH2-), 4.06 (s, 3 H, -OCH3), 4.08 (t, J =
4.5 Hz, 4 H, 2 x OCH2), 2.62 (t, J = 6.6 Hz, 2 H, -NCH2), 2.39 (t, J = 4.5 Hz, 4 H, 2 x -NCH2). MS
(EI): m/z 273 [M]+. Anal. Calcd. for C11H16Cl1N3O3: C 48.27, H 5.89, N 15.35; Found: C 48.50, H
6.02, N 15.52.
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Sample Availability: Samples of the compounds 4, 6, 8 are available from the authors.
© 2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).