A novel conversion of acetylenic 1,2,4-triazoles into 3-alkyl-5-arylpyridazines

Article abstract of DOI:10.1016/j.tet.2006.07.015

Bromination of 2-aryl-1-[1,2,4]triazol-1-ylalk-3-yn-2-ols gives 6-bromo-7-hydroxy-5-alkyl-7-aryl-7,8-dihydro-[1,2,4]triazolo[1,2-a]pyridazin-4-ylium salts, which are converted by treatment with strong alkali into novel 3-alkyl-5-arylpyridazines.

Full text of DOI:10.1016/j.tet.2006.07.015

Tetrahedron 62 (2006) 8966–8973
A novel conversion of acetylenic 1,2,4-triazoles into
3-alkyl-5-arylpyridazines
*
Patrick J. Crowley, Sally E. Russell and Laurence G. Reynolds
Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK
Received 14 March 2006; revised 14 June 2006; accepted 6 July 2006
Available online 26 July 2006
Abstract—Bromination of 2-aryl-1-[1,2,4]triazol-1-ylalk-3-yn-2-ols gives 6-bromo-7-hydroxy-5-alkyl-7-aryl-7,8-dihydro-[1,2,4]tri-
azolo[1,2-a]pyridazin-4-ylium salts, which are converted by treatment with strong alkali into novel 3-alkyl-5-arylpyridazines.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
pathogens. In the agrochemical field extensive work by
many groups10 has shown that R and R1 in 1 can be aryl rings
or alkyl chains, which in turn can be substituted by many dif-
ferent groups such as ethers, ketones, esters or even another
triazole ring. Important examples of antifungal triazoles are
the agricultural fungicide epoxiconazole11 2 and the phar-
maceutical fungicide fluconazole 39 (Fig. 1).
Pyridazines are an important class of heterocycle, which
have been the subject of extensive research, particularly in
the pharmaceutical and agrochemical areas, and their
synthesis and applications have been comprehensively re-
viewed.1–4 While there are numerous general methods for
the synthesis of pyridazines, there are only few methods
for making 3-substituted-5-arylpyridazines. These have
usually been based on cycloaddition chemistry, for example,
alkyl or alkylstannyl acetylenes undergo [4+2] cycloaddition
with 3-aryl-1,2,4,5-tetrazines to give mixtures of regio-
isomers, which can be manipulated to give a variety of
3,5-diarylpyridazines,5 and monohaloazodienes react with
enamines to give 3-alkyl-5-arylpyridazines in variable
yields.6 In another approach, addition of diazomethane to
diarylcyclopropene carboxylates gives diazabicyclohexenes,
which lose nitrogen in situ to give diarylpyridazine esters,
which are in turn hydrolysed and decarboxylated to give
3,5-diarylpyridazines.7 In this paper, we wish to report a
novel route to 3-alkyl-5-arylpyridazines from 1,2,4-triazolyl
alkynols. Our route involves the intramolecular attack of the
triazole ring nitrogen on a bromonium ion or bromovinyl
cation generated by bromination of an acetylene to give
a fused triazolium salt, which then breaks down on treatment
with aqueous alkali to give the 3-alkyl-5-arylpyridazines.
Cl
N
F
F
OH
OH
O
N
N
R
R1
F
F
N
N
N
N
N
N
N
N
N
1
2
3
Figure 1. Structures of fungicidal 1,2,4-triazoles 1–3.
2. Results
During our research into fungicides for agricultural use we
found that triazoles 1 where R was a substituted phenyl
group and R1 was an alkenyl or alkynyl group, showed
high fungicidal activity. We developed a simple synthesis
of acetylenic triazoles 6a–f12 (Scheme 1). Lithium acetyl-
ides, generated from the acetylenes by treatment with
n-butyl lithium, were added smoothly to chloroacetophe-
nones 4a–f to give moderate to excellent yields of the chloro-
hydrins 5a–f. The crude chlorohydrins were reacted directly
with the anion of 1,2,4-triazole, generated with sodium hy-
dride in DMF, to give the 1,2,4-triazolyl alkynols 6a–f in
moderate to good yields. For the synthesis of the ethynyl
compound 6a, the trimethylsilyl acetylene chlorohydrin 5a
was used and the trimethylsilyl group was removed by acidic
work-up after reaction with 1,2,4-triazole.
Substituted 1,2,4-triazoles have received a great deal of at-
tention owing to their biological activity against both agri-
cultural8 and human fungi.9 In particular, tertiary triazolyl
alcohols of general type 1 have been of great interest because
of their outstanding potency on a wide range of fungal
Keywords: Pyridazines; Triazoles; Acetylenes; Triazolium; Cyclisation.
* Corresponding author. Tel.: +44 1344 414840; fax: +44 1344 413739;
e-mail: patrick.crowley@syngenta.com
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.015

P. J. Crowley et al. / Tetrahedron 62 (2006) 8966–8973
8967
1,2,4-Triazole,
OH
O
OH
R
R
R1
NaH, DMF
R
R1
R1
n-BuLi, THF
-78 to -40°C
80-90°C,
3 h
Cl
N
Cl
N
N
crude yield
yield from 4a-e
4a R = 2,4-di-Cl
4b R = 4-Cl
4c R = 2,4-di-F
5a R = 2,4-di-Cl, R1 = Si(CH3)3, 88%
6a R = 2,4-di-Cl, R1 = H,
41%
6b R = 2,4-di-Cl, R1 = CH3,
6c R = 2,4-di-Cl, R1 = C2H5,
6d R = 2,4-di-Cl, R1 = n-C5H11
20%
58%
59%
41%
55%
5b R = 2,4-di-Cl, R1 = CH3,
5c R = 2,4-di-Cl, R1 = C2H5,
5d R = 2,4-di-Cl, R1 = n-C5H11
92%
37%
,
,
100%
100%
85%
R
1 = C2H5,
6e R = 4-Cl,
6f R = 2,4-di-F, R1 = C2H5,
R1 = C2H5,
5e R = 4-Cl,
5f R = 2,4-di-F, R1 = C2H5
Scheme 1. Synthesis of triazolyl alkynols 6a–f.
We wished to make some triazoles of type 1 where R was
a substituted phenyl group and R1 was a halogenated alkyl
group, and it seemed likely that with the alkynyl analogues
6a–f in hand, simple addition of halogens would quickly
give examples for biological testing. Accordingly bromine
was added to the ethynyl compound 6a in chloroform at
room temperature, but gave no reaction. However, in the
presence of light (100 W tungsten lamp) smooth bromina-
tion took place and after 3 h a nearly quantitative yield of
E- and Z-isomers 7a and 7b in an approximately 2:5 ratio
was obtained (Scheme 2). The stereochemistry of 7a and
7b was assigned by 1H NMR. In the Z-isomer 7b the protons
H-1, H-5 and H-60 showed an NOE when olefinic proton H-4
was irradiated, whereas in the E-isomer 7a, when proton H-4
was irradiated no NOEs were detected.
of white crystalline solids. After treatment with aqueous
alkali to neutralise the reaction these solids yielded new com-
pounds, identified as the novel pyridazines 8b–f (Scheme 3).
The mass spectra for each of 8b–f showed a major ion for the
loss of two carbon atoms, one nitrogen atom and water from
the starting materials 6b–f, with no incorporation of bromine.
1
There was no alcohol present in their IR spectra. In the H
NMR spectrum, the triazole protons, typically as singlets at
around 7.80 and 8.20 ppm, were replaced by new singlets
1
at around 7.30 and 9.30 ppm. An H–13C HMBC study of
compound 8e confirmed all the key connectivities. Pyri-
dazine proton H-4 correlated with carbons C-6 and C-10, pyri-
dazine proton H-6 correlated with C-4 and C-5 and the ethyl
CH2 protons correlated with C-3 and C-4. Additionally, when
pyridazine proton H-6 was irradiated an NOE was shown by
the benzene proton H-20 and when the ethyl CH2 protons
were irradiated an NOE was shown by H-4. The microanaly-
ses were in agreement with the proposed structures.
In the expectation that the alkyl acetylenes 6b–f would
undergo similar radical bromination, we were surprised to
find that when bromine was added to the compounds in chlo-
roform at room temperature preparatory to carrying out the
light reaction, an exothermic reaction occurred, leading to
a rapid decolourisation followed by gradual precipitation
Having identified the final products we then turned our
attention to the precipitates formed in the bromination
Cl
Cl
HO
Cl
Br
4
HO
4
OH
Br
Br2,,CHCl3
Cl
H
Cl
Cl
+
RT, 100W lamp,
3 h
Br
N
Br
N
N
6'
1
1
6'
N
N
N
N
5
5
N
N
6a
7b
7a
7a:7b, 2:5
Scheme 2. Reaction of triazolyl alkynol 6a with bromine.
5'
Cl
6'
4'
HO
R
6,1'
R
3'
3,4
4
1
1'
R
(1) Br2/CHCl3/RT
(2) aq. NaOH
R1
5
3
1',3',
4'
2'
N
N
N
6
4,5
N
N
N
N
yield
89%
26%
6b R = 2,4-di-Cl, R1 = CH3
6c R = 2,4-di-Cl, R1 = C2H5
6d R = 2,4-di-Cl, R1 = n-C5H11
8b R = 2,4-di-Cl, R1 = CH3
8c R = 2,4-di-Cl, R1 = C2H5
8e
1H-13C correlations
8d R = 2,4-di-Cl, R1 = n-C5H11 40%
6e R = 4-Cl,
R1 = C2H5
8e R = 4-Cl,
R1 = C2H5
57%
80%
6f R = 2,4-di-F, R1 = C2H5
8f R = 2,4-di-F, R1 = C2H5
Scheme 3. Bromination of triazolyl alkynols 6b–f to give pyridazines 8b–f.

8968
P. J. Crowley et al. / Tetrahedron 62 (2006) 8966–8973
6,7,
8,1'
Br
10
Br
N
Br
6'
5'
OH
5,6
OH
OH
R
6
R1
Br -
1'
5
4'
Cl
Cl
7
+
18
1
N+
N
7,1',
4
Br -
N
N+ Br -
8
4
3'
2'
6,7,
N
3
N
1
4'
9
1,1'
N
N
2
3,8
1,3
9b R = 2,4-di-Cl, R1 = CH3
9c R = 2,4-di-Cl, R1 = C2H5
9d R = 2,4-di-Cl, R1 = n-C5H11
9e R = 4-Cl,
9f R = 2,4-di-F, R1 = C2H5
9e
9e
1H-13C and 1H-15
correlations
N
numbering
R1 = C2H5
Figure 2. Structures and NMR correlations for triazolium salts 9b–f.
reaction before work-up, which were found to be extremely
soluble in water and to have very high melting points. The
electrospray mass spectra showed strong ions corresponding
to the addition of one bromine atom and the microanalyses
were consistent with the addition of two bromine atoms to
the starting materials 6b–f. Bearing in mind the structures
of the pyridazine final products and the putative mechanisms
for their formation, it seemed possible that the precipitates
could be the novel triazolium salts of structures 9b–f.
In the 1H NMR the signals for the triazole protons, typically
singlets at around 7.80 and 8.20 ppm in the starting mate-
rials 6b–f, were replaced by two very low field singlets at
around 9.5 and 10.00 ppm, which was consistent with the
structures being highly electron deficient triazolium salts
(Fig. 2).
3. Discussion
The mechanism of formation of triazolium salts 9b–f was
rationalised as addition of bromine to the triple bond to
give an ionic intermediate, which is then intercepted by a
triazole nitrogen (Scheme 4). The addition of bromine to
triple bonds in a range of solvents is known to proceed to
give either a cyclic bromonium ion or vinyl cation,13
which then reacts with an available nucleophile such as a
bromide ion or a solvent molecule to give mainly E-prod-
ucts. In the case of electron deficient acetylenes, nucleo-
philic attack by bromine or bromide ion has also been
proposed14 as the first step, but it would seem unlikely in
this instance, as the acetylene is not activated. In the present
case we therefore, propose that a cyclic bromonium ion 10
or vinyl cation 11 is formed, which reacts in a 6-endo-trig
attack by the 2-nitrogen of the triazole to form the tri-
azolium salt 9b–f. 6-endo-trig cyclisation is favoured by
Baldwin’s rules,15 but seems to have been rather rarely re-
ported for attack of nitrogen nucleophiles onto acetylenes,
having been more commonly observed when a nitrogen
anionundergoesnucleophilicadditionto anelectrondeficient
acetylene16 or in metal catalysed reactions.17 However, a
useful synthesis of iodo isoquinolines18 has been developed
based on a 6-endo-trig cyclisation of t-butylimines onto
arylacetylenes in the presence of iodine or iodine mono-
chloride and Larock has proposed a similar mechanism to
ours, with attack of the imine nitrogen onto an iodonium
ion. In the latter case the cyclisation onto alkyl acetylenes
proceeded poorly with iodine, but the yields were much
higher when silver nitrate or cuprous iodide was used to
The structures were confirmed as 9b–f by an 1H–13C HMBC
experiment on compound 9e, which showed that triazole H-1
correlated to triazole C-3 and methylene C-8, triazole proton
H-3 correlated to triazole C-1, quaternary benzylic carbon
C-7 correlated to benzene ring protons H-20/H-60 and meth-
ylene protons H-8 and the hydroxyl proton correlated to
methylene carbon C-8 and vinyl carbon C-6. In addition
an 1H–15N HMBC study was carried out. This showed that
ethyl CH2 and ring methylenes H-8 correlated to triazolium
N-4, ring methylenes H-8 correlated with triazolium N-9 and
triazoliums H-1 and H-3 correlated to triazolium N-2. The
chemical shifts of N-4 and N-9 were very similar, as ex-
pected for a triazolium salt, while N-2 was at slightly lower
field. The yields of the triazolium salts 9b–f from triazoles
6b–f were 84–92%.
Br+
HO
R
R1
Br
OH
N
R
R1
Br -
N
OH
R
R1
N
Br2/CHCl3/RT
N+
N
10
or
N
N
R = Cl, F
N
R1 = n-alkyl
Br
N
N
HO
R
C+
N
6b-f
9b-f
R1
N
11
Scheme 4. Proposed mechanism of conversion of triazolyl alkynols 6b–f to triazolium salts 9b–f.

P. J. Crowley et al. / Tetrahedron 62 (2006) 8966–8973
8969
Br
Br
N
OH
R
Br
N
R1
OH
R
R1
R
R1
HO-
H
O
+ Br -
N
N
N
N
N
CHO
N
N
9b-f
12
13
OH
Br
Br
H
R
R
R1
R1
R1
N
N
N
H
N
H
N
H
N
8b-f
14
Scheme 5. Possible mechanism of conversion of triazolium salts 9b–f to pyridazines 8b–f.
activate the triple bond. The reaction with the ethynyl com-
pounds was not reported.
considerably improved by dissolving the salts in a small
amount of water and adding the subsequent solution to hot
5 N sodium hydroxide, followed by extraction into ethyl
acetate after a few minutes (Table 1).
The difference between ethynyl compound 6a and alkyl
acetylenes 6b–f in their mode of reaction with bromine is
striking. There is some evidence that terminal acetylenes
are less reactive to bromine than disubstituted acetylenes,19
which is consistent with the lack of reaction of bromine with
ethynyl compound 6a. Additionally, in a recently reported
case of competition between disubstituted and monosubsti-
tuted acetylenes in reaction with an iminium ion, the only
product obtained was from the disubstituted acetylene,
with none from the terminal acetylene being found.20 In
our case we presume that the alkyl groups in 6b–f both
impart greater nucleophilicity to the triple bond and provide
extra stabilisation of the vinyl cation or bromonium ion by
hyperconjugation.
For comparison we attempted chlorination of the acetylenes.
With the ethynyl compound 6a chlorination proceeded to
give a mixture of E- and Z-isomers, but only in the presence
of light. No reaction took place at room temperature. With
the ethyl acetylene 6c the reaction with chlorine with or
without light gave very messy reactions from which no addi-
tion products or triazolium salts could be isolated.
4. Conclusion
In conclusion we have discovered a novel synthesis of 3-
alkyl-5-arylpyridazines, which to our knowledge is the first
example of formation of a pyridazine from a 1,2,4-triazole,
and which constitutes a useful additional approach to specif-
ically substituted examples of these ring systems.
A possible mechanism for conversion of the triazolium salts
9b–f to the pyridazines 8b–f is shown in Scheme 5, although
the exact order of steps and identity of the intermediates can
only be a matter of conjecture, as no intermediates could be
isolated. It is likely to start with the known addition of
hydroxide ion to triazolium rings21 to give a pseudo-bases
of type 12, or their regioisomers, followed by ring-opening
and elimination of water to give 13. Cleavage of the form-
amido methylene group to 14, followed by a prototropic shift
and elimination of HBr could then lead to the pyridazines
8b–f.
5. Experimental
5.1. General
€
Melting points were taken using a Buchi B-545 apparatus,
and were uncorrected. Infrared Spectra were run on a
Perkin–Elmer Spectrum One spectrometer as solid or liquid
thin films on a KBr window. 1H and 13C NMR spectra were
measured on a Varian Inova-400 (1H, 400 MHz; 13C,
100 MHz), HMBC and HSQC spectra were measured on
a Varian Inova-500 NMR spectrometer (1H, 500 MHz).
Chemical shifts are in parts per million relative to TMS
The reaction to form the triazolium salts 9b–f followed by
the transformation to the pyridazines was general for a small
selection of acetylenic triazoles tried. The bromination
reaction to form the triazolium salts went in high yield, but
it was found that conversion to the pyridazines could be
Table 1. Reaction of triazoles 6b–f to form triazolium salts 9b–f and pyridazines 8b–f
Starting triazole
R
R1
Triazolium salt
Isolated yield
from 6b–f (%)
Pyridazine
Isolated yield
from 9b–f (%)
6b
6c
6d
6e
6f
2,4-Di-Cl
2,4-Di-Cl
2,4-Di-Cl
4-Cl
CH3
9b
9c
9d
9e
9f
89
92
88
84
88
8b
8c
8d
8e
8f
100
28
45
68
C2H5
n-C5H11
C2H5
C2H5
2,4-Di-F
91

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P. J. Crowley et al. / Tetrahedron 62 (2006) 8966–8973
(1H, 13C 0.0 ppm) and coupling constants (J) are measured
in hertz (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet,
m ¼ multiplet, dd ¼ double doublet, qd ¼ quartet of dou-
blets, qq ¼ quartet of quartets). Mass spectra were recorded
on Micromass PlatformLC. Microanalyses were performed
by MEDAC Ltd, Englefield Green, Surrey, UK. All commer-
cially available compounds were used without further puri-
fication. Flash chromatography was performed on Merck
Kieselgel 60 silica gel, and thin-layer chromatography was
performed using Analtech Silica Gel GF 2000 micron plates.
J¼11.0 Hz), 3.68 (d, 1H, J¼11.0 Hz), 2.98 (s, OH), 2.32
(q, 2H, J¼7.5 Hz), 1.20 (t, 3H, J¼7.5 Hz).
5.2.6. 1-Chloro-2-(2,4-difluorophenyl)-hex-3-yn-2-ol (5f).
Pale yellow oil, crude yield 85%: IR (cmꢀ1) 3454, 2238,
1614, 1499, 1272, 1139, 1097, 971, 849. 1H NMR
(CDCl3): d 7.75 (td, J¼8.8, 6.5 Hz), 6.92 (qq, 1H, J¼8.8,
2.5, 1.0 Hz), 6.84 (qd, 1H, J¼8.6, 2.6 Hz), 4.00 (d, 1H,
J¼11.0 Hz), 3.91 (d, 1H, J¼11.0 Hz), 3.02 (s, OH), 2.28
(q, 2H, J¼7.5 Hz), 1.17 (t, 3H, J¼7.5 Hz).
5.2. General procedure for the synthesis of 1-chloro-2-
arylalkyn-2-ols (5a–f)
5.3. General procedure for the synthesis of 2-aryl-1-
[1,2,4]triazol-1-ylalkyn-2-ols (6a–f)
n-Butyl lithium (30 mmol of a 1.6 M solution in hexane) was
added dropwise to the alkyne (30 mmol) in 25 mL dry THF
at ꢀ78 ꢁC, and after completion of the addition the reac-
tion mixture was stirred for 1 h. The haloacetophenone
(20 mmol) in 50 mL dry THF was added dropwise keeping
the temperature below ꢀ70 ꢁC. After completion of the
addition the reaction mixture was stirred for 1 h and then
warmed to ꢀ40 ꢁC, and then poured carefully into water
and extracted four times with 50 mL diethyl ether. The ethe-
real extracts were combined, washed with dilute hydrochlo-
ric acid followed by water, and then dried over magnesium
sulfate. After evaporation the products 5a–f were obtained
1,2,4-Triazole (28 mmol) was added portionwise to a suspen-
sion of sodium hydride (29 mmol of a 50% dispersion in oil)
in dry DMF. After stirring at room temperature for 30 min,
the crude 1-chloro-2-arylalkyn-2-ol (14 mmol) in 10 mL
dry DMF was added dropwise. After completion of the addi-
tion the reaction mixture was heated to 80–90 ꢁC for 3 h. The
reaction mixture was cooled and poured into 300 mL water
and extracted with 100 mL diethyl ether three times. The
combined extracts were washed with water, dried over mag-
nesium sulfate and evaporated to give residues, which were
either recrystallised or purified by flash column chromato-
graphy on silica gel to give the products 6a–f.
1
as oils, which were characterised by H NMR, IR and MS,
and were used for the next step without further purification.
5.3.1. 2-(2,4-Dichlorophenyl)-1-[1,2,4]triazol-1-yl-but-3-
yn-2-ol (6a). White solid, yield 41%: mp 129–131 ꢁC
(hexanes/ethyl acetate). IR (cmꢀ1) 3263, 3034, 1513,
5.2.1. 1-Chloro-2-(2,4-dichlorophenyl)-4-trimethyl-
silanylbut-3-yn-2-ol (5a). Pale yellow oil, crude yield
1
1137, 1079, 1049, 803. H NMR (CDCl3): d 8.13 (s, 1H),
1
88%: IR (cmꢀ1) 3480, 2170, 1580, 1490, 1373, 840. H
7.77 (d, 1H, J¼8.6 Hz), 7.94 (s, 1H), 7.44 (d, 1H,
J¼2.15 Hz), 7.26 (dd, 1H, J¼8.6, 2.15 Hz), 4.93 (d, 1H,
J¼14.1 Hz), 4.84 (s, 1H), 4.63 (d, 1H, J¼14.1 Hz), 2.56
(s, 1H). 13C NMR (CDCl3): d 151.84, 144.54, 135.39,
134.89, 131.94, 130.97, 129.13, 127.49, 80.88, 75.94,
70.47, 56.51. MS m/z¼282 (235Cl) [M]+, 284 (35Cl, 37Cl)
[M+2]+, 286 (237Cl) [M+4]+. Anal. Calcd for C12H9Cl2N3O:
C 51.09; H 3.22; N 14.89. Found: C 51.25; H 3.33; N 14.66.
NMR (CDCl3): d 7.88 (d, 1H, J¼8.7 Hz), 7.47 (d, 1H,
J¼2.15 Hz), 7.36 (dd, 1H, J¼8.7, 2.15 Hz), 4.25 (d, 2H,
J¼11.0 Hz), 4.02 (d, 2H, J¼11.0 Hz), 3.36 (s, OH), 0.20
(s, 9H).
5.2.2. 1-Chloro-2-(2,4-dichlorophenyl)-pent-3-yn-2-ol
(5b). Pale yellow oil, crude yield 92%: IR (cmꢀ1) 3460,
2244, 1585, 1467, 1376, 1048, 823, 795. 1H NMR (CDCl3):
d 7.85 (d, 1H, J¼8.6 Hz), 7.43 (d, 1H, J¼2.15 Hz), 7.31
(dd, 1H, J¼8.6, 2.15 Hz), 4.19 (d, 1H, J¼11.15 Hz), 3.96
(d, 1H, J¼11.15 Hz), 1.91 (s, 3H).
5.3.2. 2-(2,4-Dichlorophenyl)-1-[1,2,4]triazol-1-ylpent-
3-yn-2-ol (6b). White crystalline solid, yield 20% from
2,4-dichloroacetophenone: mp 145–147 ꢁC (hexanes/ethyl
acetate). IR (cmꢀ1) 3064, 1510, 1203, 1131, 1074, 1048,
1
5.2.3. 1-Chloro-2-(2,4-dichlorophenyl)-hex-3-yn-2-ol
(5c). Pale yellow oil, crude yield 37%: IR (cmꢀ1) 3460,
2239, 1586, 1467, 1377, 1048, 823, 793. 1H NMR (CDCl3):
d 7.85 (d, 1H, J¼8.7 Hz), 7.31 (dd, 1H, J¼8.7, 2.15 Hz),
4.17 (d, 1H, J¼11.1 Hz), 3.97 (d, 1H, J¼11.1 Hz), 3.11 (s,
OH), 2.28 (q, 2H, J¼7.5 Hz), 1.16 (t, 3H, J¼7.5 Hz).
800. H NMR (CDCl3): d 8.02 (s, 1H), 7.84 (s, 1H), 7.65
(d, 1H, J¼8.6 Hz), 7.34 (d, 1H, J¼2.15 Hz), 7.15 (dd, 1H,
J¼8.6, 2.15 Hz), 4.75 (d, 1H, J¼14.0 Hz), 4.61 (d, 1H,
J¼14.0 Hz), 4.35 (s, 1H), 1.70 (s, 3H). 13C NMR (CDCl3):
d 151.72, 144.43, 135.93, 134.97, 131.99, 130.89, 129.05,
127.31, 84.47, 76.70, 70.74, 56.82, 3.52. MS m/z¼296
(235Cl) [M]+, 298 (35Cl, 37Cl) [M+2]+, 300 (237Cl)
[M+4]+. Anal. Calcd for C13H11Cl2N3O: C 52.72; H 3.74;
N 14.19. Found: C 52.95; H 3.65; N 13.90.
5.2.4. 1-Chloro-2-(2,4-dichlorophenyl)-non-3-yn-2-ol
(5d). Pale yellow oil, crude yield 100%: IR (cmꢀ1) 3460,
2230, 1586, 1467, 1377, 1049, 780. H NMR (CDCl3):
1
d 7.85 (d, 1H, J¼8.6 Hz), 7.31 (dd, 1H, J¼8.6, 2.15 Hz),
4.19 (d, 1H, J¼11.1 Hz), 3.96 (d, 1H, J¼11.1 Hz), 2.26 (t,
2H, J¼7.1 Hz), 3.10 (s, OH), 1.49–1.59 (m, 4H), 1.25–
1.41 (m, 2H), 0.89 (t, 3H, J¼7.0 Hz).
5.3.3. 2-(2,4-Dichlorophenyl)-1-[1,2,4]triazol-1-ylhex-3-
yn-2-ol (6c). White solid, yield 58% from 2,4-dichloro-
acetophenone: mp 133–134 ꢁC (hexanes/ethyl acetate). IR
(cmꢀ1) 3150, 1506, 1463, 1378, 1130, 1048, 798. 1H
NMR (CDCl3): d 8.11 (s, 1H), 7.91 (s, 1H), 7.73 (d, 1H,
J¼8.6 Hz), 7.41 (d, 1H, J¼2.15 Hz), 7.23 (dd, 1H, J¼8.6,
2.15 Hz), 4.83 (d, 1H, J¼14.0 Hz), 4.65 (d, 1H,
J¼14.0 Hz), 4.38 (s, 1H), 2.13 (q, 2H, J¼7.6 Hz), 1.03 (t,
3H, J¼7.6 Hz). 13C NMR (CDCl3): d 151.78, 144.47,
5.2.5. 1-Chloro-2-(4-chlorophenyl)-hex-3-yn-2-ol (5e).
Pale yellow oil, crude yield 100%: IR (cmꢀ1) 3420, 2232,
1489, 1091, 1014, 828. 1H NMR (CDCl3): d 7.60 (d,
2H, J¼8.7 Hz), 7.37 (d, 2H, J¼8.7 Hz), 3.74 (d, 1H,

P. J. Crowley et al. / Tetrahedron 62 (2006) 8966–8973
8971
135.91, 134.72, 132.02, 130.91, 129.07, 127.32, 90.09,
76.80, 70.78, 56.90, 13.21, 12.29. MS m/z¼310 (235Cl)
[M]+, 312 (35Cl, 37Cl) [M+2]+, 314 (237Cl) [M+4]+. Anal.
Calcd for C14H13Cl2N3O: C 54.21; H 4.22; N 13.55. Found:
C 54.01; H 4.48; N 13.38.
was extracted twice with 25 mL ethyl acetate. The organic
extract was washed with 10 mL water, dried over magne-
sium sulfate and evaporated to give 1.66 g (100%) of a white
foam, shown by 1H NMR to consist of a 2:5 mixture of E:Z
isomers 7a and 7b. The isomers were separated by HPLC on
elution with 99:1 t-butyl ether/methanol, to give 0.41 g of
the E-isomer 7a as a white crystalline solid, and 0.90 g of
the Z-isomer 7b as a white powdery solid.
5.3.4. 2-(2,4-Dichlorophenyl)-1-[1,2,4]triazol-1-ylnon-3-
yn-2-ol (6d). White crystalline solid, yield 59% from 2,4-di-
chloroacetophenone: mp 83–84 ꢁC (hexanes/ethyl acetate).
IR (cmꢀ1) 3078, 1509, 1463, 1135, 800. 1H NMR (CDCl3):
d 8.01 (s, 1H), 7.83 (s, 1H), 7.65 (d, 1H, J¼8.7 Hz), 7.33
(d, 1H, J¼2.15 Hz), 7.14 (dd, 1H, J¼8.7, 2.15 Hz), 4.75 (d,
1H, J¼14.0 Hz), 4.55 (d, 1H, J¼14.0 Hz), 4.28 (2, 1H),
2.02 (t, 2H, J¼7.0 Hz), 1.32 (t, 2H, J¼7.0 Hz), 1.13–1.18
(m, 2H), 0.76 (t, 3H, J¼7.0 Hz). 13C NMR (CDCl3):
d 151.84, 144.45, 135.91, 134.96, 131.99, 130.90, 129.07,
127.33, 89.02, 77.39, 70.85, 56.88, 30.94, 27.77, 22.05,
18.54, 13.90. MS m/z¼352 (235Cl) [M]+, 354 (35Cl, 37Cl)
[M+2]+. Anal. Calcd for C17H19Cl2N3O: C 57.96; H 5.44;
N 11.93. Found: C 57.70; H 5.71; N 12.19.
5.4.1. (E)-3,4-Dibromo-2-(2,4-dichlorophenyl)-1-
[1,2,4]triazol-1-ylbut-3-en-2-ol (7a). White crystalline
solid, yield 26%: mp 138–141 ꢁC (hexanes/ethyl acetate).
1
IR (cmꢀ1) 3075, 1511, 1466, 1200, 1132, 1080, 1015. H
NMR (CDCl3): d 7.84 (s, 1H), 7.81 (s, 1H), 7.38 (d, 1H,
J¼2.15 Hz), 7.82 (d, 1H, J¼8.7 Hz), 7.09 (dd, J¼8.7,
2.15 Hz), 6.78 (s, 1H), 5.19 (d, 1H, J¼13.8 Hz), 4.91 (d,
1H, J¼13.8 Hz), 4.85 (s, 1H). 13C NMR (CDCl3):
d 151.69, 144.48, 136.59, 135.27, 131.43, 130.49, 129.88,
127.02, 124.81, 105.45, 78.17, 56.45. MS m/z¼442
[279Br]+, 444 [79Br, 81Br]+, 446 [281Br]+. Anal. Calcd for
C12H9Br2Cl2N3O: C 32.61; H 2.05; N 9.51. Found: C
32.78; H 2.46; N 9.22.
5.3.5. 2-(4-Chlorophenyl)-1-[1,2,4]triazol-1-ylhex-3-yn-
2-ol (6e). Pale yellow gum, yield 41% from 4-chloroaceto-
phenone: IR (cmꢀ1) 3079, 1508, 1488, 1130, 1084, 831.
1H NMR (CDCl3): d 8.11 (s, 1H), 7.59 (s, 1H), 7.55 (dt,
2H, J¼7.8, 2.0 Hz), 7.84 (dt, 2H, J¼7.8, 2.0 Hz), 4.84 (s,
2H), 4.14 (s, 1H), 2.16 (q, 2H, J¼7.5 Hz), 1.05 (t, 3H,
J¼7.5 Hz). 13C NMR (CDCl3): d 151.75, 144.36, 139.43,
134.49, 128.62, 127.21, 90.39, 78.22, 72.19, 60.96, 13.47,
12.24. MS m/z¼276 (35Cl) [M]+, 278 (35Cl, 37Cl) [M+2]+.
Anal. Calcd for C14H14ClN3O: C 60.98; H 5.12; N 15.24.
Found: C 61.26; H 4.83; N 15.01.
5.4.2. (Z)-3,4-Dibromo-2-(2,4-dichlorophenyl)-1-
[1,2,4]triazol-1-ylbut-3-en-2-ol (7b). White powdery solid,
yield 58%: mp 162–164 ꢁC (hexanes/ethyl acetate). IR
1
(cmꢀ1) 3031, 1516, 1135, 1020. H NMR (CDCl3): d 7.84
(s, 1H), 7.72 (s, 1H), 7.40 (d, 1H, J¼8.6 Hz), 7.26 (d, 1H,
J¼2.15 Hz), 7.08 (dd, 1H, J¼8.6, 2.15 Hz), 6.79 (s, 1H),
5.21 (d, 1H, J¼14.1 Hz), 4.87 (d, 1H, J¼14.1 Hz).
13C NMR (CDCl3): d 151.79, 144.41, 135.72, 135.25,
131.97, 131.19, 130.14, 127.56, 114.21, 80.15, 55.00. MS
m/z¼442 [279Br]+, 444 [79Br, 81Br]+, 446 [281Br]+. Anal.
Calcd for C12H9Br2Cl2N3O: C 32.61; H 2.05; N 9.51. Found:
C 32.40; H 2.31; N 9.28.
5.3.6. 2-(2,4-Difluorophenyl)-1-[1,2,4]triazol-1-ylhex-3-
yn-2-ol (6f). White crystalline solid, yield 55% from 2,4-di-
fluoroacetophenone: mp 76–78 ꢁC (hexanes/ethyl acetate).
IR (cmꢀ1) 3108, 1615, 1600, 1509, 1492, 1269, 964.
1H NMR (CDCl3): d 8.06 (s, 1H), 7.85 (s, 1H), 7.56 (td,
1H, J¼9.0, 6.4 Hz), 6.73–6.80 (m, 2H), 4.53 (q, 2H, J¼
11.3 Hz), 4.27 (s, 1H), 2.06 (q, 2H, J¼7.5 Hz), 0.96 (t, 3H,
J¼7.5 Hz). 13C NMR (CDCl3): d 163.01 (d, J¼250 Hz),
159.60 (d, J¼250 Hz), 151.80, 144.90, 129.06 (dd, J¼9.6,
4.6 Hz), 123.78 (dd, J¼11.10, 3.8 Hz), 111.19 (dd, J¼21.1,
3.4 Hz), 104.58 (t, J¼25.7 Hz), 89.34, 77.34, 69.51, 58.17,
13.36, 12.22. MS m/z¼287 [MH]+. Anal. Calcd for
C14H13F2N3O: C 60.65; H 4.73; N 15.15. Found: C 60.35;
H 4.89; N 15.42.
5.5. General procedure for the synthesis of 6-bromo-7-
aryl-7-hydroxy-5-alkyl-7,8-dihydro-[1,2,4]triazolo-
[1,2-a]pyridazine-4-ylium bromides (9b–f)
Bromine (18 mmol) in chloroform (10 mL) was added drop-
wise to a stirred solution of the triazolyl acetylene (18 mmol)
in chloroform (50 mL) at a rate sufficient to allow decolouri-
sation and to maintain the temperature at 30 ꢁC or less.
After all the bromine had been added the resultant yellow
mixtures were stirred for 1 h and the white precipitates
were filtered, washed well with chloroform and air dried to
give the products 9b–f as white solids, which were analysed
without further purification.
5.4. Preparation of (E)- and (Z)-3,4-dibromo-2-(2,4-
dichlorophenyl)-1-[1,2,4]triazol-1-ylbut-3-en-2-ols
(7a) and (7b)
5.5.1. 6-Bromo-7-(2,4-dichlorophenyl)-7-hydroxy-5-
methyl-7,8-dihydro-[1,2,4]triazolo[1,2-a]pyridazine-4-
ylium bromide (9b). White solid, yield 89%: mp
1
2-(2,4-Dichlorophenyl)-1-[1,2,4]triazol-1-yl-but-3-yn-2-ol
(0.99 g, 3.5 mmol) was stirred as a slurry in 5 mL chloro-
form and a few drops of a solution of bromine (0.56 g,
3.5 mmol) in 5 mL chloroform were added. The reaction
mixture was irradiated with a 100 W tungsten lamp and after
10 min some decolourisation occurred. The remainder of the
bromine in chloroform solution was added and irradiation
was continued with stirring until all the colour had disap-
peared. The reaction mixture was poured into 25 mL water
containing a few millilitres of 2 N sodium hydroxide and
324–325 ꢁC (dec). IR (cmꢀ1) 3148, 2179, 1351, 1089. H
NMR (DMSO-d6): d 9.85 (s, 1H), 9.51 (s, 1H), 7.93 (d,
1H, J¼8.6 Hz), 7.77 (d, 1H, J¼2.15 Hz), 7.64 (dd, 1H,
J¼8.6, 2.15 Hz), 5.19 (d, 1H, J¼14.2 Hz), 5.11 (d, 1H,
J¼14.2 Hz), 2.61 (s, 3H). 13C NMR (DMSO-d6): d 149.69,
145.39, 135.88, 131.84, 130.63, 130.25, 128.85, 127.81,
120.16, 71.72, 53.78, 17.15. MS m/z¼374 (79Br, 235Cl)
[M]+, 376 (81Br, 235Cl) [M+2]+, 378 (81Br, 35Cl, 37Cl)
[M+4]+. Anal. Calcd for C13H12Br2ClN3O: C 34.24; H
2.43; N 9.22. Found: C 33.98; H 2.57; N 8.89.

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P. J. Crowley et al. / Tetrahedron 62 (2006) 8966–8973
5.5.2. 6-Bromo-7-(2,4-dichlorophenyl)-5-ethyl-7-hy-
droxy-7,8-dihydro-[1,2,4]triazolo[1,2-a]pyridazin-4-
ylium bromide (9c). White solid, yield 92%: mp
5.6. General procedure for the synthesis of 5-aryl-
3-alkylpyridazines (8b–f)
1
323–324 ꢁC (dec). IR (cmꢀ1) 3158, 2256, 1349. H NMR
The triazolium salt (1.1 mmol) was stirred in water (20 mL)
and warm 5 N sodium hydroxide (20 mL) was added
quickly. The mixture was shaken for a few minutes and
then extracted with ethyl acetate, and the ethyl acetate ex-
tracts were washed with water, dried over magnesium sulfate
and evaporated. The residues were purified by flash column
chromatography (hexane/ethyl acetate, 3:7) to give the
pyridazines 8b–f as solids.
(DMSO-d6): d 9.95 (s, 1H), 9.52 (s, 1H), 7.95 (d, 1H,
J¼8.6 Hz), 7.77 (d, 1H, J¼2.15 Hz), 7.64 (dd, 1H, J¼8.6,
2.15 Hz), 7.54 (s, OH), 5.19 (d, 1H, J¼14.4 Hz), 5.09 (d,
1H, J¼14.4 Hz), 3.04 (q, 2H, J¼7.5 Hz), 1.50–1.70 (m,
2H), 1.44–1.21 (m, 4H), 1.23 (q, 1H, J¼11.0 Hz). 13C
NMR (DMSO-d6): d 149.86, 145.11, 135.95, 134.69,
133.14, 131.85, 130.59, 130.28, 127.83, 119.87, 71.67,
53.80, 23.83, 10.36. MS m/z¼388 (79Br, 235Cl) [M]+, 390
(81Br, 235Cl) [M+2]+, 392 (81Br, 35Cl, 37Cl) [M+4]+. Anal.
Calcd for C14H13Br2Cl2N3O: C 35.78; H 2.79; N 8.94.
Found: C 35.56; H 2.52; N 8.67.
5.6.1. 5-(2,4-Dichlorophenyl)-3-methylpyridazine (8b).
White solid, yield 100%: mp 153–155 ꢁC (hexanes/ethyl
acetate). IR (cmꢀ1) 1596, 1475, 1359, 1105, 861, 822. H
1
NMR (CDCl3): d 9.13 (s, 1H), 7.57 (d, 1H, J¼1.9 Hz),
7.42 (s, 1H), 7.41 (dd, 1H, J¼8.3, 1.9 Hz), 7.29 (d, 1H,
J¼8.3 Hz), 2.81 (s, 3H). 13C NMR (CDCl3): d 159.78,
149.17, 136.67, 136.18, 133.26, 132.79, 131.57, 130.38,
127.92, 126.60, 22.37. MS m/z¼238 (235Cl) [M]+, 240
(35Cl, 37Cl) [M+2]+. Anal. Calcd for C11H8Cl2N2: C 55.25;
H 3.37; N 11.72. Found C 54.88; H 3.50; N 11.45.
5.5.3. 6-Bromo-7-(2,4-dichlorophenyl)-7-hydroxy-5-pen-
tyl-7,8-dihydro-[1,2,4]triazolo[1,2-a]pyridazin-4-ylium
bromide (9d). White solid, yield 88%: mp 272–273 ꢁC
1
(dec). IR (cmꢀ1) 3118, 3048, 2163, 1352, 1084. H NMR
(DMSO-d6): d 9.96 (s, 1H), 9.53 (s, 1H), 7.95 (d, 1H,
J¼8.6 Hz), 7.77 (d, 1H, J¼2.15 Hz), 7.64 (dd, 1H, J¼8.6,
2.15 Hz), 7.52 (s, OH), 5.19 (d, 1H, J¼14.2 Hz), 5.11 (d,
1H, J¼14.2 Hz), 3.03 (t, 2H, J¼7.5 Hz), 1.65 (octet, 2H,
J¼7.5, 7.0 Hz), 1.50–1.30 (m, 4H), 0.89 (t, 3H,
J¼7.25 Hz). 13C NMR (DMSO-d6): d 149.84, 145.15,
135.99, 134.69, 132.25, 131.73, 130.57, 130.24, 127.83,
120.49, 71.74, 53.70, 30.31, 29.73, 25.47, 21.81. MS
m/z¼430 (79Br, 235Cl) [M]+, 432 (81Br, 235Cl) [M+2]+, 434
(81Br, 35Cl, 37Cl) [M+4]+. Anal. Calcd for C17H19Br2Cl2N3O:
C 39.87; H 3.74; N 8.21. Found: C 39.66; H 3.59; N 8.05.
5.6.2. 5-(2,4-Dichlorophenyl)-3-ethylpyridazine (8c).
Beige solid, yield 28%: mp 98–100 ꢁC (hexanes/ethyl ace-
tate). IR (cmꢀ1) 1597, 1477, 1106, 861, 818. 1H NMR
(CDCl3): d 9.14 (s, 1H), 7.57 (d, 1H, J¼1.9 Hz), 7.42 (s,
1H), 7.41 (dd, 1H, J¼8.3, 1.9 Hz), 7.30 (d, 1H, J¼8.3 Hz),
3.10 (q, 2H, J¼7.6 Hz), 1.43 (t, 3H, J¼7.6 Hz). 13C NMR
(CDCl3): d 164.45, 149.31, 136.70, 136.09, 133.28,
132.97, 131.58, 130.37, 127.90, 125.51, 29.51, 13.62. MS
m/z¼252 (235Cl) [M]+, 256 (35Cl, 37Cl) [M+2]+. Anal. Calcd
for C12H10Cl2N2: C 56.91; H 3.95; N 11.07. Found C 56.80;
H 3.79; N 11.05.
5.5.4. 6-Bromo-7-(4-chlorophenyl)-5-ethyl-7-hydroxy-
7,8-dihydro-[1,2,4]triazolo[1,2-a]pyridazin-4-ylium bro-
mide (9e). Pale yellow solid, yield 84%: mp 285–286 ꢁC
1
(dec). IR (cmꢀ1) 3195, 2162, 1491, 1347, 1090. H NMR
5.6.3. 5-(2,4-Dichlorophenyl)-3-pentylpyridazine (8d).
White solid, yield 45%: mp 60–64 ꢁC (hexanes/ethyl ace-
tate). IR (cmꢀ1) 1598, 1476, 1104, 864, 820. 1H NMR
(CDCl3): d 9.13 (s, 1H), 7.57 (d, 1H, J¼2.15 Hz), 7.41
(dd, 1H, J¼8.3, 2.15 Hz), 7.40 (s, 1H), 7.30 (d, 1H,
J¼8.3 Hz), 3.05 (d, 1H, J¼7.8 Hz), 1.83 (quintet, 2H,
J¼7.5 Hz), 1.40 (m, 4H), 0.91 (t, 3H, J¼7.25 Hz). 13C
NMR (CDCl3): d 163.58, 149.23, 136.56, 136.09, 133.30,
132.96, 131.57, 130.37, 127.89, 125.97, 36.28, 31.40,
29.66, 29.31, 22.40, 13.93. MS m/z¼294 (235Cl) [M]+, 296
(35Cl, 37Cl) [M+2]+. Anal. Calcd for C15H16Cl2N2: C
61.02; H 5.46; N 9.49. Found C 61.27; H 5.60; N 8.99.
(DMSO-d6): d 9.94 (s, 1H), 9.47 (s, 1H), 7.54 (d, 1H,
J¼8.6 Hz), 7.48 (d, 1H, J¼8.6 Hz), 7.27 (s, OH), 5.11 (d,
1H, J¼14.0 Hz), 5.01 (d, 1H, J¼14.0 Hz), 3.03 (q, 2H,
J¼7.5 Hz), 1.25 (q, 3H, J¼7.5 Hz). 13C NMR (DMSO-d6):
d 149.15, 145.05, 139.13, 133.75, 133.37, 128.45, 128.17,
121.52, 71.81, 56.49, 24.07, 10.80. MS m/z¼354 (79Br,
235Cl) [M]+, 356 (81Br, 235Cl) [M+2]+, 358 (81Br, 35Cl,
37Cl) [M+4]+. Anal. Calcd for C14H14Br2ClN3O: C 38.60;
H 3.24; N 9.65. Found C 38.30; H 3.06; N 9.30.
5.5.5. 6-Bromo-7-(2,4-difluorophenyl)-5-ethyl-7-hy-
droxy-7,8-dihydro-[1,2,4]triazolo[1,2-a]pyridazin-4-
ylium bromide (9f). White solid, yield 88%: mp
5.6.4. 5-(4-Chlorophenyl)-3-ethylpyridazine (8e). Pale
yellow solid, yield 68%: mp 108–109 ꢁC (hexanes/ethyl ace-
tate). IR (cmꢀ1) 1596, 1493, 1090, 822. 1H NMR (CDCl3):
d 9.28 (d, 1H, J¼2.15 Hz), 7.61 (d, 1H, J¼8.7 Hz), 7.52
(d, 1H, J¼8.7 Hz), 7.47 (d, 1H, J¼2.15 Hz), 3.09 (q, 2H,
J¼7.6 Hz), 1.43 (t, 3H, J¼7.6 Hz). 13C NMR (CDCl3):
d 164.84, 147.58, 137.65, 136.36, 133.26, 129.72, 128.35,
122.57, 29.48, 13.74. MS m/z¼218 (235Cl) [M]+, 220
(35Cl, 37Cl) [M+2]+. Anal. Calcd for C12H11ClN2: C 65.90;
H 5.07; N 12.81. Found C 65.72; H 5.33; N 12.52.
1
294–295 ꢁC (dec). IR (cmꢀ1) 3185, 2162, 1501, 1114. H
NMR (DMSO-d6): d 9.95 (s, 1H), 9.53 (s, 1H), 7.79 (td, 1H,
J¼8.8, 6.5 Hz), 7.45 (s, OH), 7.42 (qd, 1H, J¼9.0, 2.6 Hz),
7.26 (td, 1H, J¼8.6, 2.5 Hz), 5.21 (d, 1H, J¼14.2 Hz), 4.82
(d, 1H, J¼14.2 Hz), 3.03 (qd, 2H, J¼7.5, 1.2 Hz), 1.23
(t, 3H, J¼7.5 Hz); 13C NMR (DMSO-d6): d 163.0 (d,
J¼248 Hz), 158.5 (d, J¼248 Hz), 149.69, 144.94, 132.96,
129.72, 123.52 (d, J¼14.20 Hz), 120.42, 111.72 (d,
J¼28.4 Hz), 104.77 (t, J¼26.50 Hz), 70.40, 54.43, 23.97,
10.69; MS m/z¼354 (79Br, 235Cl) [M]+, 356 (81Br, 235Cl)
[M+2]+, 358 (81Br, 35Cl, 37Cl) [M+4]+. Anal. Calcd for
C14H13BrF2N3O; C 38.44; H 2.97; N 9.61. Found C 38.60;
H 2.94; N 9.69.
5.6.5. 5-(2,4-Difluorophenyl)-3-ethylpyridazine (8f). Pale
yellow solid, yield 91%: mp 53–54 ꢁC (hexanes/ethyl ace-
tate). IR (cmꢀ1) 1595, 1504, 1139, 843. 1H NMR (CDCl3): d

P. J. Crowley et al. / Tetrahedron 62 (2006) 8966–8973
8973
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9.22 (s, 1H), 7.51 (td, 1H, J¼7.5, 6.4 Hz), 7.49 (s, 1H),
7.06 (qq, 1H, J¼7.0, 2.4, 1.0 Hz), 7.01 (qd, 1H, J¼8.6,
2.4 Hz), 3.09 (q, 2H, J¼7.5 Hz), 1.43 (t, 3H, J¼7.5 Hz).
13C NMR (CDCl3): d 164.66, 163.79 (dd, J¼253,
11.9 Hz), 160.44 (dd, J¼253, 11.9 Hz), 148.72 (d, J¼
4.0 Hz), 133.43, 131.08 (dd, J¼9.6, 4.6 Hz), 124.57 (d,
J¼4 Hz), 119.30 (d, J¼13 Hz), 112.65 (q, J¼21, 4 Hz),
105.15 (t, J¼25 Hz), 29.52, 13.67. MS m/z¼220 [M]+.
Anal Calcd for C12H10F2N2: C 65.44; H 4.58; N 12.72;
Found C 65.09; H 4.68; N 12.51.
Acknowledgements
12. Crowley, P. J.; Noon, R. A.; Worthington, D. M. European
Patent 97426, 1984; Chem. Abstr. 1984, 100, 139124v.
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pp 606–608.
The authors are indebted to M. R. Kipps, P. D. Stanley and
V. Caer for their detailed work on the NMR spectroscopy
of these compounds.
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