Synthesis of 4-fluoroalkyl-substituted pyridazines from fluorinated diazodiketones

Article abstract of DOI:10.1016/j.jfluchem.2007.01.004

Two approaches are reported for the preparation of 3,4,6-trisubstituted pyridazines from fluoroalkyl-containing diazodiketones: the sequence of Wittig/Staudinger/diaza-Wittig and Staudinger/Wittig/diaza-Wittig reactions. The implementation of the Wittig reaction at the first stage gives rise to considerably higher yields of the targeted pyridazines than through initial phosphazines. In both approaches the final stages of the synthesis (the formation of vinylphosphazines and the subsequent diaza-Wittig reaction) occur as a tandem process. R^F-activated carbonyls are much more reactive in Wittig olefination of diazodicarbonyl and 1,3-dioxophosphazine molecules, than non-fluorinated acyl and aroyl carbonyl groups (R^FCO ? COAlk, COAr), and as a result non-fluorinated diazodiketones and their phosphazines do not produce pyridazines under the same conditions.

Full text of DOI:10.1016/j.jfluchem.2007.01.004

Journal of Fluorine Chemistry 128 (2007) 507–514
www.elsevier.com/locate/fluor
Synthesis of 4-fluoroalkyl-substituted pyridazines from
fluorinated diazodiketones
a,b
b
b
Valerij A. Nikolaev a, , Valerija M. Zakharova , Lothar Hennig , Joachim Sieler
*
a Saint-Petersburg State University, Department of Organic Chemistry, University pr. 26, 198504 Saint-Petersburg, Russia
b
¨ ¨
Universitat Leipzig, Institut fur Organische Chemie, Johannisallee 29, 04103 Leipzig, Germany
Received 12 November 2006; received in revised form 1 January 2007; accepted 5 January 2007
Available online 13 January 2007
Abstract
Two approaches are reported for the preparation of 3,4,6-trisubstituted pyridazines from fluoroalkyl-containing diazodiketones: the sequence of
Wittig/Staudinger/diaza-Wittig and Staudinger/Wittig/diaza-Wittig reactions. The implementation of the Wittig reaction at the first stage gives rise
to considerably higher yields of the targeted pyridazines than through initial phosphazines. In both approaches the final stages of the synthesis (the
formation of vinylphosphazines and the subsequent diaza-Wittig reaction) occur as a tandem process. RF-activated carbonyls are much more
reactive in Wittig olefination of diazodicarbonyl and 1,3-dioxophosphazine molecules, than non-fluorinated acyl and aroyl carbonyl groups
(RFCO ꢀ COAlk, COAr), and as a result non-fluorinated diazodiketones and their phosphazines do not produce pyridazines under the same
conditions.
# 2007 Elsevier B.V. All rights reserved.
Keywords: 2-Diazo-1,3-diketones; Fluoroalkyl-containing vinyldiazoketones; Phosphazines; Diaza-Wittig reaction; Pyridazines
1. Introduction
other groups [4,5] prompted us to study the synthesis of
substituted pyridazines from fluoroalkyl-containing diazodi-
ketones and other diazodicarbonyl compounds [6,7].
Based on the known reactions of diazo compounds [3–5,8]
one may envision several ways to pyridazine structure A from
diazocarbonyl substrate B, two of which (a,b,c) and (b,a,c) are
represented in Scheme 1.
Pyridazine structures are a rarity in nature, but most
synthetic objects of this series exhibit biological activity [1].
Furthermore, incorporation of fluorine atoms into pyridazine
molecule could considerably modify their biological properties
and enhance physiological activity [2]. For example, fluor-
oalkyl-containing triazolopyridazines are reported to be central
nervous system stimulants [2d], while trifluoromethyl-sub-
stituted pyridazinylquinolines may be used to modulate specific
in vivo or in vitro receptor activity in humans and domesticated
animals [2e]. This article describes two synthetic ways to
fluoroalkyl-substituted pyridazines.
Approach (a,b,c) implies the initial ‘‘olefination’’ of the
carbonyl group of diazo compound B using Wittig reaction (a)
followed by cyclization of vinyldiazocarbonyl compound C
into pyridazine structure A with the help of consecutive
Staudinger (b) and intramolecular diaza-Wittig (c) reactions.
The alternative route (b,a,c) implicates at first preparation
of phosphazine D by the Staudinger reaction (b) and then
transformation of this phosphazine to the targeted structure A
via two stage process (a),(c).
Recently the successful synthesis of substituted pyridazines
starting from aliphatic diazocarbonyl compounds has been
reported, during which the diazofunctionality of the initial
substrates was converted into nitrogen atoms of the pyridazine
heterocycle [3]. These data as well as publications from the
In both cases the key stage in the creation of pyridazine
structure A is the intramolecular diaza-Wittig reaction (c) of the
vinylphosphazine E, which occurs rather rarely in preparative
organic synthesis [3–5,9] and is not well understood, unlike the
related Wittig [10,11] and aza-Wittig [12] reactions.
As is evident from the above scheme, the successful
realization of the ways outlined could offer a powerful
* Corresponding author. Tel.: +812 428 4053; fax: +812 428 6939.
E-mail addresses: vnikola@VN6646.spb.edu (V.A. Nikolaev),
lhennig@chemie.uni-leipzig.de (L. Hennig).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.01.004

508
V.A. Nikolaev et al. / Journal of Fluorine Chemistry 128 (2007) 507–514
Scheme 1.
approach for the creation of pyridazine structures with different
substituents on heterocycle due to independent variation of
them in both reagents—initial diazo compound and Wittig
reagent. Our investigations in this area [7] are directed towards
elucidation of the structural elements in diazocarbonyl
compounds, which enable synthesis of three- and four-
substituted pyridazines.
Diazodiketones F-2a–h and H-3a–d were synthesized from
corresponding 1,3-diketones by means of diazotransfer reaction
[6,13].
2.2. Synthesis of pyridazines 1 using the approach (a,b,c)
The fluorine-containing vinyldiazoketones F-5 for the first
stage of the approach (a,b,c) were obtained from corresponding
fluorinated diazodiketones 2a–h via Wittig reaction (a) with
alkylidenephosphoranes 4a–c, according to the recently
developed protocol [14] (Scheme 3). The reaction proceeds
with a high regio- and stereoselectivity.
In this article the results of a comparison study of the
synthesis of pyridazines 1 from fluorine-containing and non-
fluorinated diazodiketones according to Scheme 1 are
considered.
Olefination of unsymmetrically substituted 2-diazo-1,3-
diketones F-2, bearing two different C O groups in the
molecule, occurs solely at the perfluoroacyl carbonyl group.
This regioselectivity is in good agreement with previous
observation on the RF-bearing carbonyl olefination of the ethyl
diazotrifluoroacetoacetate [3a]. Thus, one can conclude that
fluoroalkyl-activated carbonyls are much more reactive in
Wittig reaction of diazodicarbonyl molecules than non-
fluorinated acyl (aroyl) and alkoxycarbonyl groups
(RFCO ꢀ COAlk, COAr, CO2Alk).
2. Results and discussion
2.1. Objects of investigation
A series of fluorine-containing 2-diazo-1,3-diketones F-2a–
h was used in this research, which differ significantly in the
nature (Alk, Ar) and bulk of the substituents R1. To determine
the scope and limitations of the processes involved, appropriate
non-fluorinated diazodiketones H-3a–d were also tested in
these reactions (Scheme 2). Investigation was carried out with
the relatively persistent and easily available Wittig reagents—
stabilized (alkoxycarbonyl)methylenetriphenylphosphoranes
4a,b and in part with (benzoyl)methylenetriphenylphosphorane
4c.
As for stereochemistry of the obtained vinyldiazoketones F-
5, the reaction gives rise to only one, E-stereoisomer F-5, which
is a characteristic property of the stabilized triphenylpho-
sphonium ylides (Ph3PCHCOR0) olefinations [15].
The Staudinger reaction (b) of fluorinated vinyldiazoketones
5a–i with PPh3 was carried out in anhydrous diethyl ether at
room temperature (Scheme 4). On completion, the reaction
mixture was simply separated on a column packed with silica
gel. However, instead of the anticipated vinylphosphazines E
after chromatography directly 4-fluoroalkyl-substituted pyr-
idazines 1a–i were isolated in good yields (55–87%). By this
Scheme 2.
Scheme 3.

V.A. Nikolaev et al. / Journal of Fluorine Chemistry 128 (2007) 507–514
509
NMR spectra of compounds F-1 show the required sets of
proton, carbon and fluorine signals, which also fit well with the
1
proposed structure. H and 19F chemical shifts of pyridazines
F-1 are closely related to the appropriate parameters of the
initial vinyldiazoketones F-5 with a general weaker shielding
of the corresponding groups in the spectra of pyridazines. A
new strong signal of aromatic carbon C6 appears in their 13C
NMR spectra at 149–152 ppm instead of a weak signal of the
diazocarbon atom at 61–66 ppm. In the IR spectra strong
absorption bands of the carbonyl groups were registered at
1665–1722 cmꢁ1, while the absorption of the CN2 group from
the starting compounds at 2080–2095 cmꢁ1 disappeared.
Unlike fluorinated diazodiketones F-2 their analogs H-3 did
not react with Wittig reagents under the same conditions.1
Thus, H-vinyldiazoketones 5 were not available by olefination
of H-diazodiketones 3 via reaction (a) and for this reason a
similar approach (a,b,c) for the preparation of pyridazines H-1
from non-fluorinated diazodiketones 3 was not tested.
Scheme 4.
Table 1
Vinyldiazoketones F-5a–i and pyridazines F-1a–i
Compounds
RF
R1
R2
Yield (%)
F-1, 5
of F-1
a
b
c
d
e
f
g
h
i
CF3
CF3
CF3
CF3
CF3
CF3
CF3
C3F7
CF3
Me
OMe
OEt
71
82
55
74
58
67
67
87
80
Et
n-Bu
t-Bu
OMe
OMe
OMe
OMe
OEt
n-Pentyl
p-Tol
2-Naphthyl
Ph
OMe
Ph
Me
2.3. Synthesis of pyridazines 1 according to the approach
(b,a,c)
means two-stage process (b,c) occurred here as a one-pot
reaction (Table 1).
At the first stage of the approach (b,a,c) phosphazines 6,7
were obtained by Staudinger reaction (b) from diazodiketones
F-2, H-3 and triphenylphosphine. This reaction is rather
common to a variety of diazo compounds [3–6,8], and usually
preparation of crystalline phosphazine derivatives is useful for
the identification of liquid, and frequently unstable, aliphatic
diazo compounds.
The structure of the previously unknown 3,4,6-trisubstituted
pyridazines F-1 was established by means of 1H, 13C, 19F NMR
spectroscopy; their composition was confirmed by elemental
analysis. The molecular structure of 3-(tert-butyl)carbonyl-4-
trifluoromethyl-6-methoxypyridazine F-1d, has also been
confirmed by X-ray crystallography (Fig. 1).
In the course of our experiments with diazodiketones F-2
and H-3 it turned out that reactivity of fluorine-containing
diazodiketones 2a–h and their non-fluorinated counterparts 3a–
d in Staudinger reaction (b) was noticeably different. Thus,
interaction of diazodiketones F-2 with PPh3 is exothermic and
gives rise to the formation of corresponding phosphazines F-
6a–h in 10–15 min and in good yields (71–86%). Interaction of
H-diazodiketones 3a–d with triphenylphosphine proceeds
much slower (from 1 to 15 days), and in some cases (for
example with diazodiketone 3c) no crystalline adducts with
PPh3 were formed (Scheme 5; Table 2).
The compound F-1d crystallizes in hexagonal space group
P65 with six molecules in the cell. The pyridazine ring is nearly
planar, the mean deviation from the least squares plane with the
atoms N1, N2, C1, C2, C3 and C4 is 0.018(2)8. The plane with
the carbonyl atoms C5, O1 and the atom C6 gives a dihedral
angle of 57.7(1)8 with the pyridazine ring. The bond distance
N1–N2 in the pyridazine ring is 1.362(2) and as well as N–C
distances are in a good agreement with other structural data for
pyridazines [16].
The structure of phosphazines F-6a–h and H-7a,b,d was
confirmed by the data of NMR spectroscopy. Analysis of their
parameters shows that in the 1H and 13C NMR spectra of some
phosphazines 6 and 7, which were recorded just after
dissolution of the analytically pure samples in CDCl3, not
only the signals of phosphazines F-6, H-7 were observed, but
the patterns related to the initial diazodiketones F-6, H-7 and
PPh3 were present as well. It is evident that in these cases the
dissociation of adducts F-6, H-7 on the initial components
partially takes place in solution. The presence of bulky alkyl
and aryl substituents in the structure of phosphazines (as in the
case of the compounds 6d,f–h) considerably diminishes the
1
The Wittig reaction at elevated temperatures, which are usually applied for
Fig. 1. Molecular structure of pyridazine 1d. The ellipsoids denote 50%
probability.
relatively inert carbonyl compounds [15a], has not been tested in our study,
since diazodiketones H-3 decompose at temperatures above 50–60 8C.

510
V.A. Nikolaev et al. / Journal of Fluorine Chemistry 128 (2007) 507–514
Scheme 5.
Table 2
Phosphazines F-6a–h, H-7a,b,d
Compounds F-6, H-7
R
R1
Yield (%)
Scheme 7.
F-6a
b
c
d
e
f
g
h
CF3
Me
84
85
87
83
79
86
83
76
86
46
87
All attempts to carry out Wittig reaction (a) with non-
fluorinated phosphazines 7a,b,d, and thus to obtain pyridazines
H-1 using (b,a,c) approach, did not give positive results. Only
initial compounds 7 or their dissociation products – diazodi-
ketones H-3 and triphenylphosphine – were recovered after
ordinary work-up procedure of the reaction mixtures. It seems
that non-fluorinated phosphazines H-7, as well as H-
diazodiketones 3 [14], do not react with Wittig reagents 4 at
usual conditions.
CF3
CF3
CF3
CF3
CF3
CF3
C3F7
Me
Et
n-Bu
t-Bu
Pentyl
p-Tol
2-Naphthyl
Ph
H-7a
b
d
Me
Et
Et
Me
p-Tol
tendency of the adducts for dissociation, while the presence of
the linear alkyl groups (such as Me, Et, n-Bu, n-pentyl in
phospazines 6a–c,e, 7a,b) conversely favours this process.
The considerable difference in reactivity of diazodiketones
F-2a–h and H-3a–d with triphenylphosphine in Staudinger
reaction (b) is presumably caused by the increasing electro-
philic character of the diazofunction ( N2) on changing the a-
acyl to perfluoroacyl group. According to spectroscopic data [6]
this replacement cases a noticeable shift of the signals for the
key atoms C3 (ꢂ17 ppm) and C2 (3–4 ppm) in the 13C NMR
spectra. The latter upfield shift may be considered as an indirect
evidence of the stronger shielding (and the larger electronic
density on) the carbon atoms C2 of diazogroup in diazodike-
tones F-2, and accordingly as an argument in favour of the
enhancement of the positive charge on the diazofunction in the
molecule of these diazodiketones.
2.4. Concluding remarks
It is evident from the results obtained, that the formation of
fluoroalkyl-containing pyridazines 1 takes place via a two-stage
tandem process in both approaches considered; initially
vinylphosphazine E is formed and then in the course of the
spontaneous diaza-Wittig reaction intramolecular cyclization
of this intermediate occurs with the elimination of triphenyl-
phosphine oxide and production of pyridazine 1 (Scheme 7).
The extremely easy occurrence of the diaza-Wittig reaction-
cyclization at stage (c) is clearly assisted by the E-configuration
of the initial vinyldiazoketones F-5 [14], because their
stereochemistry strongly favours the formation of the typical
for Wittig reaction transition state G [10–12,15].
Lower yields of pyridazines F-1 in approach (b,a,c) perhaps
may be explained by partial dissociation of starting phospha-
zines F-6 into diazodiketones F-2 and PPh3 in solution of the
reaction mixture and/or owing to the lower reactivity of them in
Wittig reaction as compared with diazodiketones F-2.
In summary, application of two different approaches – the
sequence of Wittig/Staudinger/diaza-Wittig and Staudinger/
Wittig/diaza-Wittig reactions – for the synthesis of 4-
fluoroalkyl-substituted pyridazines via essentially two-stage
processes from fluorine-containing diazodiketones has been
demonstrated with higher yields in the first one. In both cases
the two final reactions occur as a tandem process and at usual
The reaction (a) of phosphazines F-6, H-7 with Wittig
reagent 4a was studied for the compounds F-6a,c,f and H-
7a,b,d in diethyl ether solution at 18–20 8C using 20% excess
of phosphorane 4a (Scheme 6). And as already observed in the
approach (a,b,c), after flash-chromatography of the reaction
mixture on silica gel directly 4-fluoroalkyl-containing pyr-
idazines 1a,c,f were isolated from F-phospazines 6a,c,f with
yields 17–60%. The compounds 1a,c,f obtained were in every
respect identical to the corresponding pyridazines prepared
with the approach (a,b,c).
Scheme 6.

V.A. Nikolaev et al. / Journal of Fluorine Chemistry 128 (2007) 507–514
511
reaction conditions vinylphosphazines cannot be isolated from
the reaction mixture. Non-fluorinated diazodiketones and the
relevant triphenylphosphazines do not interact with (alkox-
ycarbonyl)methylenetriphenylphosphoranes and thus do not
produce corresponding pyridazines.
CDCl3): d ꢁ70.7 (s, 3F). Anal. calcd for C24H20O2N2F3P: C,
63.2; H, 4.4; N, 6.1. Found: C, 63.2; H, 4.5; N, 6.2.
3.2.3. 1,1,1-Trifluoro-3-
(triphenylphosphoranylidene)azino-2,4-octanedione (6c)
Bright-yellow crystals; yield: 1.26 g (87%); mp 77–79 8C
[6a]. 1H NMR (600 MHz, CDCl3): d 0.89 (3H, t, J = 7 Hz), 1.38
(2H, m, J = 7 Hz), 1.67 (2H, m, J = 7 Hz), 2.80 (2H, t,
J = 7 Hz), 7.53–7.57 (6H, m), 6.64–7.70 (9H, m). 19F NMR
(282 MHz, CDCl3): d ꢁ70.7 (s, 3F). 13C NMR (150 MHz,
3. Experimental
3.1. General
1H, 13C and 19F NMR spectra were recorded at 200, 300,
600 MHz (1H), 50, 75, 150 MHz (13C), 188, 282 MHz (19F)
and at 81 MHz (31P) with Varian Gemini-2000, Varian
Mercury-300 or Bruker DRX-600 NMR spectrometers in
CDCl3 solution using TMS, CFCl3 and H3PO4 as internal
standards. IR spectra were recorded on a spectrophotometer
Genesis FTIR Unicam Analytical System (ATI Mattson) with
KBr pellets. Microanalysis was performed on a Heraeus
CHNO Rapid Analyser. UV–vis spectra were recorded on a
Beckman DU 650; lmax in nm (log e). Melting points were
measured on Boetius micro-melting-point apparatus and are
corrected. All reactions were carried out in carefully purified
and dried solvents and were monitored by thin-layer
chromatography (TLC) on plates of Silufol UV/VIS 254 nm
(KAVALIER) using UV light and iodine as visualizing agents.
Preparative column chromatography was carried out on neutral
silica gel (CHEMAPOL L 40/100 or MERCK 70–230 mesh)
with petroleum (40–70 8C) and diethyl ether as eluents in
gradient regime.
CDCl3): d 14.0, 22.5, 27.4, 43.4, 117.5 (q, JC–F = 292 Hz),
1
1
125.2 (d, JC–P = 95 Hz), 129.1 (d, JC–P = 12 Hz), 133.4 (d,
3
2
3
4JC–P = 2 Hz), 133.6 (d, JC–P = 9 Hz), 149.8 (d, JC–
2
P = 46 Hz), 175.7 (q, JC–F = 33 Hz), 204.0. Anal. calcd for
C26H24O2N2F3P: C, 64.5; H, 5.0; N, 5.8. Found: C, 64.3; H, 5.0;
N, 5.7.
3.2.4. 5,5-Dimethyl-1,1,1-trifluoro-3-
(triphenylphosphoranylidene)azino-2,4-hexanedione (6d)
Bright-yellow crystals; yield: 1.20 g (83%); mp 131–133 8C
[6a]. H NMR (600 MHz, CDCl3): d 1.23 (9H, s), 7.50–7.53
1
(6H, m), 7.63–7.66 (9H, m). 19F NMR (282 MHz, CDCl3): d
ꢁ70.8 (s, 3F). 13C NMR (150 MHz, CDCl3): d 26.4, 44.0, 117.3
1
(q, JC–F = 292 Hz), 125.5 (d, JC–P = 95 Hz), 129.1 (d, JC–
1
3
4
2
P = 12 Hz), 133.3 (d, JC–P = 2 Hz), 133.5 (d, JC–P = 9 Hz),
151.1 (d, 3JC–P = 47 Hz), 175.9 (q, 2JC–F = 33 Hz), 214.6. Anal.
calcd for C26H24O2N2F3P: C, 64.5; H, 5.0; N, 5.8. Found: C,
64.5; H, 4.9; N, 5.7.
3.2.5. 1,1,1-Trifluoro-3-
3.2. General procedure for the synthesis of phosphazines
F-6a–h, H-7a,b,d
(triphenylphosphoranylidene)azino-2,4-nonanedione (6e)
Bright-yellow crystal; yield: 1.20 g (79%). 1H NMR
(600 MHz, CDCl3): d 0.90–1.70 (9H, m), 2.83 (2H, t), 7.51–
7.58 (6H, m), 6.66–7.71 (9H, m). 19F NMR (282 MHz, CDCl3):
d ꢁ70.7 (s, 3F). Anal. calcd for C27H26O2N2F3P: C, 65.1; H,
5.3; N, 5.6. Found: C, 65.2; H, 5.4; N, 5.6.
The stirred and cooled to 0–5 8C solution of 0.83 g
(3.15 mmol) PPh3 in Et2O (5 mL) was treated dropwise with
2-diazo-1,3-diketones 2,3 (3 mmol). After stirring for 1–2 h the
mixture was cooled in refrigerator to ꢁ10 to 15 8C, precipitated
bright-yellow crystals of phosphazines 6,7 were isolated by
filtration, washed with cold Et2O (2ꢃ 5 mL) and dried on air.
3.2.6. 4-(4-Methylphenyl)-1,1,1-trifluoro-3-
(triphenylphosphoranylidene)azino-2,4-butanedione (6f)
Bright-yellow crystals; yield: 1.34 g (86%); mp 143–145 8C
[6b]. 1H NMR (600 MHz, CDCl3): d 2.40 (3H, s), 7.22 (2H, d,
J = 8 Hz), 7.75 (2H, d, J = 8 Hz), 7.48–7.49 (6H, m), 7.53–7.57
(6H, m), 7.63 (3H, t, J = 7 Hz). 19F NMR (282 MHz, CDCl3): d
ꢁ70.6 (s, 3F). 13C NMR (150 MHz, CDCl3): d 21.8, 117.5 (q,
3.2.1. 1,1,1-Trifluoro-3-
(triphenylphosphoranylidene)azino-2,4-pentanedione (6a)
Bright-yellow crystals; yield: 1.12 g (84%); mp 102–103 8C
[6a]. H NMR (600 MHz, CDCl3): d 2.58 (3H, s), 7.51–7.58
1
(6H, m), 7.63–7.71 (9H, m). 19F NMR (282 MHz, CDCl3): d
ꢁ70.7 (s, 3F). 13C NMR (150 MHz, CDCl3): d 31.4, 117.5 (q,
1JC–F = 292 Hz), 125.2 (d, JC–P = 85 Hz), 128.0 (d, JC–
1
3
4
P = 12 Hz), 128.7, 129.2, 133.3 (d, JC–P = 2 Hz), 133.6 (d,
1
3
1JC–F = 293 Hz), 125.0 (d, JC–P = 95 Hz), 129.0 (d, JC–
2JC–P = 9 Hz), 134.0, 144.1, 148.8 (d, 3JC–P = 47 Hz), 175.9 (q,
2JC–F = 33 Hz), 195.9. Anal. calcd for C29H22O2N2F3P: C, 67.2;
H, 4.3; N, 5.4. Found: C, 67.1; H, 4.3; N, 5.4.
4
2
P = 12 Hz), 133.5 (d, JC–P = 2 Hz), 133.6 (d, JC–P = 9 Hz),
149.2 (d, 3JC–P = 44 Hz), 175.7 (q, 2JC–F = 33 Hz), 199.8. Anal.
calcd for C23H18O2N2F3P: C, 62.5; H, 4.1; N, 6.3. Found: C,
62.3; H, 4.2; N, 6.1.
3.2.7. 4-(2-Naphthyl))-1,1,1-trifluoro-3-
(triphenylphosphoranylidene)azino-2,4-butanedione (6g)
Bright-yellow crystals; yield: 1.38 g (83%); mp 153–155 8C
3.2.2. 1,1,1-Trifluoro-3-
(triphenylphosphoranylidene)azino-2,4-hexanedione (6b)
Bright-yellow crystals; yield: 1.16 g (85%); mp 83–85 8C
[6a]. 1H NMR (200 MHz, CDCl3): d 1.20 (3H, t), 2.90 (2H, q),
7.50–7.59 (6H, m), 7.65–7.75 (9H, m). 19F NMR (282 MHz,
[6b]. 1H NMR (300 MHz, CDCl3): d 7.33–8.29 (22 H, m). 19
F
NMR (282 MHz, CDCl3): d ꢁ70.5 (s, 3F). 13C NMR (75 MHz,
1
CDCl3): d 117.6 (q, JC–F = 293 Hz), 124.0, 124.4, 125.3 (d,
3
1JC–P = 95 Hz), 127.9, 128.5, 128.5, 129.1 (d, JC–P = 12 Hz),

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V.A. Nikolaev et al. / Journal of Fluorine Chemistry 128 (2007) 507–514
4
129.7, 131.5, 132.9, 133.4 (d, JC–P = 2 Hz), 133.6 (d, JC–
2
stirred for approximately 24 h until disappearance of diazo-
compound 5. Solid matter was removed by filtration, resultant
filtrate was concentrated in vacuo and charged on to a small
column with silica gel; the gradient elution was performed with
petroleum ether and diethyl ether mixture. On removing the
solvents pyridazines F-1 were obtained as white solids in the
case of F-1a,b,d,f–i or as a liquids in the case of F-1c,e.
3
2
P = 9 Hz), 148.5 (d, JC–P = 46 Hz), 176.0 (q, JC–F = 33 Hz),
196.3. Anal. calcd for C32H22O2N2F3P: C, 69.3; H, 4.0; N, 5.1.
Found: C, 69.4; H, 4.1; N, 5.0.
3.2.8. 1,1,1,2,2,3,3-Heptafluoro-4-phenyl-3-
(triphenylphosphoranylidene)azino-2,4-butanedione (6h)
Bright-yellow crystals; yield: 1.38 g (76%); mp 108–110 8C.
1H NMR (600 MHz, CDCl3): d 7.42 (2H, t, J = 8 Hz), 7.43–
7.49 (6H, m), 7.50–7.56 (7H, m), 7.62 (3H, t, J = 7 Hz), 7.85
(2H, d, J = 8 Hz). 19F NMR (282 MHz, CDCl3): d ꢁ80.0 (t, 3F,
J = 9 Hz), ꢁ113.6 (t, 2F, J = 9 Hz), ꢁ124.8 (s, 2F). 13C NMR
3.4. General procedure for the synthesis of pyridazines F-
1a,c,f from phosphazines F-6a,c,f
To a stirred suspension of 0.77 g (2.3 mmol) (methoxycar-
bonyl)methylenetriphenylphosphorane 4a in Et2O (5 mL) the
solution of phosphazine F-6a,c,f (1.9 mmol) in Et2O (2 mL)
was added dropwise. The reaction mixture was stirred for a 3–4
days at rt. After disappearance of phosphazine F-6 in the
reaction mixture solid matter was removed by filtration, the
resultant filtrate was concentrated in vacuo and the obtained
residue was purified by column chromatography to furnish
pyridazines F-1a,c,f.
1
2
(150 MHz, CDCl3):
d 108.9 (tq, JC–F = 267 Hz, JC–
1
F = 37 Hz), 111.2 (tq, JC–F = 268 Hz, JC–F = 33 Hz), 117.9
2
1
(qt, JC–F = 288 Hz, JC–F = 34 Hz), 128.6, 128.9 (d, JC–
2
1
3
P = 95 Hz), 129.0, 129.5 (d, JC–P = 12 Hz), 133.2, 133.4 (d,
4JC–P = 2 Hz), 133.5 (d, JC–P = 9 Hz), 136.4, 150.7 (d, JC–
2
3
2
P = 47 Hz), 177.0 (t, JC–F = 23 Hz), 196.7. Anal. calcd for
C30H20O2N2F7P: C, 59.6; H, 3.3; N, 4.6. Found: C, 59.4; H, 3.4;
N, 4.6.
3.2.9. 3-(Triphenylphosphoranylidene)azino-2,4-
pentanedione (7a)
3.4.1. 6-Methoxy-3-methylcarbonyl-4-
trifluoromethylpyridazine (1a)
Bright-yellow crystals; yield: 1.00 g (86%); mp 112–113 8C.
1H NMR (200 MHz, CDCl3): d 2.19 (6H, s), 7.51–7.57 (6H, m),
7.62–7.73 (9H, m). 31P NMR (81 MHz, CDCl3): d 22.4. 13C
NMR (50 MHz, CDCl3): d 28.5, 126.7 (d, 1JC–P = 94 Hz), 128.6
(d, JC–P = 13 Hz), 132.9 (d, JC–P = 3 Hz), 133.7 (d, JC–
P = 18 Hz), 154.3 (d, 3JC–P = 43 Hz), 195.8, 205.9. Anal. calcd
for C23H21O2N2P: C, 71.1; H, 5.5; N, 7.2. Found: C, 71.4; H,
5.4; N, 7.3.
White solid; yield: 0.22 g (71%) (Section 3.3), 0.25 g (60%)
(Section 3.4); mp 56–58 8C. IR (KBr): n 1717 cmꢁ1 (C O).
UV (CHCl3): 243 (3.92), 275 (3.42). 1H NMR (200 MHz,
CDCl3): d 2.76 (3H, s), 4.24 (3H, s), 7.29 (1H, s). 19F NMR
(282 MHz, CDCl3): d ꢁ63.0 (s, 3H). 13C NMR (50 MHz,
3
4
2
3
1
CDCl3): d 28.0, 56.2, 116.3 (q, JC–F = 6 Hz), 121.3 (q, JC–
2
F = 274 Hz), 131.2 (q, JC–F = 37 Hz), 150.1, 166.0, 196.4.
Anal. calcd for C8H7O2N2F3: C, 43.6; H, 3.2; N, 12.7. Found:
C, 43.6; H, 3.2; N, 12.4.
3.2.10. 4-(Triphenylphosphoranylidene)azino-3,5-
heptanedione (7b)
3.4.2. 6-Ethoxy-3-ethylcarbonyl-4-
trifluoromethylpyridazine (1b)
White solid; yield: 0.28 g (82%) (Section 3.3); mp 31–33 8C.
IR (KBr): n 1717 cmꢁ1 (C O). UV (CHCl3): 244 (3.92), 277
1
(3.37). H NMR (200 MHz, CDCl3): d 1.15 (3H, t, J = 7 Hz),
Bright-yellow crystals; yield: 0.58 g (46%); mp 73–75 8C.
1H NMR (200 MHz, CDCl3): d 1.15 (4H, t), 2.74 (6H, q), 7.47–
7.52 (6H, m), 7.61–7.68 (9H, m). 31P NMR (81 MHz, CDCl3): d
23.0. Anal. calcd for C25H25O2N2P: C, 72.1; H, 6.1; N, 6.7.
Found: C, 71.9; H, 6.1; N, 6.0.
1.43 (3H, t, J = 7 Hz), 3.20 (2H, q, J = 7 Hz), 4.64 (2H, q,
J = 7 Hz), 7.23 (1H, s). 19F NMR (188 MHz, CDCl3): d ꢁ63.0 (s,
3H). 13C NMR (50 MHz, CDCl3): d 7.7, 14.3, 33.5, 65.1, 116.3
3.2.11. 1-(4-Methylphenyl)-2-
3
1
2
(triphenylphosphoranylidene)azino-1,3-butanedione (7d)
Bright-yellow crystals; yield: 1.21 g (87%); mp 88–90 8C.
1H NMR (200 MHz, CDCl3): d 2.26 (3H, s), 2.35 (3H, s), 7.43–
7.75 (15H, m). 31P NMR (81 MHz, CDCl3): d 22.7. 13C NMR
(50 MHz, CDCl3): d 21.7, 25.0, 126.6 (d, 1JC–P = 92 Hz), 127.5,
128.7 (d, 3JC–P = 12 Hz), 129.2, 131.9, 132.7 (d, 4JC–P = 3 Hz),
133.3 (d, 2JC–P = 9 Hz), 143.5, 154.5 (d, 3JC–P = 43 Hz), 196.2,
199.8. Anal. calcd for C29H25O2N2P: C, 75.0; H, 5.4; N, 6.0.
Found: C, 74.8; H, 5.4; N, 5.9.
(q, JC–F = 6 Hz), 121.4 (q, JC–F = 274 Hz), 131.2 (q, JC–
F = 36 Hz), 150.0, 165.8, 199.6. Anal. calcd for C10H11O2N2F3:
C, 48.4; H, 4.4; N, 11.3. Found: C, 48.5; H, 4.4; N, 11.2.
3.4.3. 3-(n-Butyl)carbonyl-6-methoxy-4-
trifluoromethylpyridazine (1c)
White oil; yield: 0.20 g (55%) (Section 3.3), 0.16 g (32%)
(Section 3.4). IR (KBr): n 1707 cmꢁ1 (C O). UV (CHCl3): 242
(3.48), 281 (3.32). 1H NMR (300 MHz, CDCl3): d 0.89 (3H, t,
J = 8 Hz), 1.37 (2H, m, J = 8 Hz), 1.67 (2H, m, J = 8 Hz), 3.21
(2H, t, J = 8 Hz), 4.23 (3H, s), 7.28 (1H, s). 19F NMR
(282 MHz, CDCl3): d ꢁ62.8 (s, 3H). 13C NMR (75 MHz,
CDCl3): d 13.9, 22.3, 25.8, 39.9, 56.2, 116.3 (q, 3JC–F = 6 Hz),
3.3. General procedure for the synthesis of pyridazines F-
1a–i from vinyldiazoketones F-5a–i
1
2
To a magnetically stirred solution of 0.45 g (1.7 mmol)
triphenylphosphine in Et2O (5 mL) vinyldiazoketone 5a–i
(1.4 mmol) was added dropwise. The reaction mixture was
121.4 (q, JC–F = 274 Hz), 131.3 (q, JC–F = 37 Hz), 150.5,
165.9, 199.2. Anal. calcd (%) for C11H13O2N2F3: C, 50.4; H,
5.0; N, 10.7. Found: C, 50.4; H, 4.7; N, 10.6.

V.A. Nikolaev et al. / Journal of Fluorine Chemistry 128 (2007) 507–514
513
3.4.4. 3-(t-Butyl)carbonyl-6-methoxy-4-
trifluoromethylpyridazine (1d)
(2H, d, J = 8 Hz). 19F NMR (188 MHz, CDCl3): d ꢁ124.3 (s,
2F), ꢁ108.2 (m, 2F, J = 8 Hz), ꢁ80.6 (t, 3F, J = 11 Hz). 13C
NMR (50 MHz, CDCl3): d 56.1, 108.4 (tq, 1JC–F = 267 Hz, 2JC–
F = 39 Hz), 114.0 (tt, 1JC–F = 260 Hz, 2JC–F = 39 Hz), 117.7 (qt,
1JC–F = 288 Hz, JC–F = 34 Hz), 117.8 (tt, JC–F = 8 Hz, JC–
F = 2 Hz), 128.8, 130.6, 130.6 (t, 2JC–F = 26 Hz), 134.3, 135.6,
152.0, 165.1, 190.2. Anal. calcd for C15H9O2N2F7: C, 47.2; H,
2.3; N, 7.3. Found: C, 47.2; H, 2.2; N, 7.2.
White solid; yield: 0.27 g (74%) (Section 3.3); mp 55–
57 8C. IR (KBr): n 1716 cmꢁ1 (C O). UV (CHCl3): 245 (3.91).
1H NMR (300 MHz, CDCl3): d 1.33 (9H, s), 4.20 (3H, s), 7.25
(1H, s). 19F NMR (282 MHz, CDCl3): d ꢁ62.2 (s, 3H). 13C
2
3
4
3
NMR (75 MHz, CDCl3): d 27.3, 44.8, 56.0, 116.0 (q, JC–
F = 5 Hz), 121.4 (q, 1JC–F = 274 Hz), 131.0 (q, 2JC–F = 36 Hz),
3
152.3 (q, JC–F = 2 Hz), 165.0, 206.5. Anal. calcd for
C11H13O2N2F3: C, 50.4; H, 5.0; N, 10.7. Found: C, 50.3; H,
5.0; N, 10.4.
3.4.9. 3-Methylcarbonyl-6-phenyl-4-
trifluoromethylpyridazine (1i)
White solid; yield: 0.30 g (80%) (Section 3.3); mp 68–
70 8C. IR (KBr): n 1722 cmꢁ1 (C O). UV (CHCl3): 276 (4.09).
1H NMR (300 MHz, CDCl3): d 2.91 (3H, s), 7.58 (3H, m), 8.17
(3H, m). 19F NMR (282 MHz, CDCl3): d ꢁ62.5 (s, 3H). 13C
NMR (75 MHz, CDCl3): d 28.5, 121.7 (q, 3JC–F = 5 Hz), 121.9
(q, JC–F = 275 Hz), 127.7, 129.0 (q, JC–F = 33 Hz), 129.6,
131.9, 134.2, 152.3, 161.2, 197.3. Anal. calcd for C13H9ON2F3:
C, 58.7; H, 3.4; N, 10.5. Found: C, 58.7; H, 3.4; N, 10.4.
3.4.5. 6-Methoxy-3-(n-pentyl)carbonyl-4-
trifluoromethylpyridazine (1e)
White oil; yield: 0.22 g (58%) (Section 3.3). IR (KBr): n
1
1716 cmꢁ1 (C O). UV (CHCl3): 245 (3.96), 281 (3.62). H
1
2
NMR (300 MHz, CDCl3): d 0.85 (3H, t, J = 7 Hz), 1.31 (2H, m,
J = 7 Hz), 1.69 (2H, m, J = 7 Hz), 3.20 (2H, t, J = 7 Hz), 4.23
(3H, s), 7.28 (1H, s). 19F NMR (282 MHz, CDCl3): d ꢁ62.8 (s,
3H). 13C NMR (75 MHz, CDCl3): d 13.9, 22.5, 23.3, 23.4, 40.2,
56.1, 116.3 (q, 3JC–F = 6 Hz), 121.4 (q, 1JC–F = 275 Hz), 131.3
4. X-ray crystal structure analysis
2
(q, JC–F = 36 Hz), 150.5, 165.9, 199.3. Anal. calcd for
C12H15O2N2F3: C, 52.2; H, 5.4; N, 10.1. Found: C, 51.8; H,
5.3; N, 10.0.
Single crystals of the compound 1d suitable for X-ray
diffraction were obtained from solution of petroleum ether. The
intensities were measured on an IPDS1 diffractometer (Fa.
STOE). The structures were solved by direct methods, and
refinement was performed with SHELX-97 [17]. The details of
the structure analyses have been deposited at the Cambridge
Crystallographic Data Centre, CCDC-625100. The copies of
the data can be obtained, free of charge, from CCDC,
Cambridge, UK (fax: +44 1233 336033; e-mail: deposi-
te@ccdc.cam.ac.uk, internet: www.ccdc.cam.ac.uk).
3.4.6. 6-Methoxy-3-( p-tolyl)carbonyl-4-
trifluoromethylpyridazine (1f)
White solid; yield: 0.28 g (67%) (Section 3.3), 0.10 g (17%)
(Section 3.4); mp 91–93 8C. IR (KBr): n 1671 cmꢁ1 (C O).
UV (CHCl3): 270 (4.15). 1H NMR (200 MHz, CDCl3): d 2.31
(3H, s), 4.15 (3H, s), 7.17 (2H, d, J = 8 Hz), 7.26 (1H, s), 7.71
(2H, d, J = 8 Hz). 19F NMR (188 MHz, CDCl3): d ꢁ62.3 (s,
3
3H). 13C NMR (50 MHz, CDCl3): d 21.8, 56.0, 115.8 (q, JC–
1
F = 5 Hz), 121.5 (q, JC–F = 275 Hz), 129.4, 130.9, 131.8 (q,
References
2JC–F = 36 Hz), 132.9, 145.6, 151.4, 165.2, 190.1. Anal. calcd
for C14H11O2N2F3: C, 56.8; H, 3.7; N, 9.5. Found: C, 56.9; H,
3.9; N, 9.7.
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trifluoromethylpyridazine (1g)
White solid; yield: 0.32 g (67%) (Section 3.3); mp 104–
106 8C. IR (KBr): n 1665 cmꢁ1 (C O). UV (CHCl3): 258
(4.76), 268 (4.71). 1H NMR (200 MHz, CDCl3): d 1.51 (3H, t,
J = 7 Hz), 4.74 (2H, q, J = 7 Hz), 7.38 (1H, s), 7.47–8.34 (7H,
m). 19F NMR (188 MHz, CDCl3): d ꢁ63.2 (s, 3H). 13C NMR
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1
(q, JC–F = 275 Hz), 125.1, 127.1, 128.1, 128.9, 129.5, 130.2,
2
132.2 (q, JC–F = 35 Hz), 132.9, 134.3, 136.3, 151.3, 165.3,
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White solid; yield: 0.47 g (87%) (Section 3.3); mp 59–
61 8C. IR (KBr): n 1688 cmꢁ1 (C O). UV (CHCl3): 199 (3.96),
256 (4.13). H NMR (200 MHz, CDCl3): d 4.19 (3H, s), 7.22
1
(1H, s), 7.38 (2H, dd, J = 8 Hz), 7.54 (1H, dd, J = 8 Hz), 7.74

514
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¨
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