Diazo Strategy for the Synthesis of Pyridazines: Pivotal Impact of the Configuration of the Diazo Precursor on the Process

Article abstract of DOI:10.1002/chem.201503448

Phosphazenes of vinyldiazocarbonyl compounds having cis stereochemistry of the functional groups on the vinyl bond readily produce pyridazines by a diaza-Wittig process, whereas their counterparts with trans configuration remain intact under similar react

Full text of DOI:10.1002/chem.201503448

DOI: 10.1002/chem.201503448
Full Paper
&
Wittig Reactions |Hot Paper|
Diazo Strategy for the Synthesis of Pyridazines: Pivotal Impact of
the Configuration of the Diazo Precursor on the Process
Valerij A. Nikolaev,*[a] David Cantillo,*[b] C. Oliver Kappe,[b] Jury J. Medvedev,[a]
G. K. Surya. Prakash,*[c] and Murat B. Supurgibekov[a]
Abstract: Phosphazenes of vinyldiazocarbonyl compounds
having cis stereochemistry of the functional groups on the
vinyl bond readily produce pyridazines by a diaza-Wittig pro-
cess, whereas their counterparts with trans configuration
remain intact under similar reaction conditions. Upon UV ir-
radiation trans-phosphazenes furnish pyridazines through
a tandem trans-to-cis isomerization followed by intramolecu-
lar cyclization. At elevated temperatures trans-(triphenyl)-
phosphazenes dissociate to give the initial vinyldiazo com-
pounds, which produce pyrazoles in high yields. The first
theoretical study on the mechanism of the diaza-Wittig pro-
cess by DFT calculations at the M06-2X/6-31G(d) level of
theory suggest that for the cis-phosphazenes
a rapid
tandem [2+2] cycloaddition/cycloelimination process with
low energy barriers is preferred over trans isomers.
ture[7b,9a,b,e] and gives rise to pyridazine C by intramolecular
Introduction
diaza-Wittig cyclization (Scheme 1).
Pyridazine derivatives are very attractive from the pharmaceuti-
cal point of view.[1] They have been reported to exhibit a variety
of biological features ranging from anticancer and antitubercu-
losis[2] to antibacterial, antimicrobial,[3] and various other kind
of biological activities.[4] Some pyridazines are used in the
treatment of Parkinson’s, Alzheimer’s, and other neurodegener-
ative diseases.[5] Moreover, pyridazine derivatives are currently
considered as one of the most developable heterocyclic struc-
tures for small-molecule-based drug design.[6] Thus, elaboration
of new methods for the preparation of pyridazines is a topical
problem in synthetic organic chemistry.
Scheme 1. Diazo strategy for the synthesis of pyridazines.
In practice, only two types of diazo precursors have been
tested thus far in these reactions, namely, vinyldiazocarbonyl
compounds D[7,9,10a] and diazotricarbonyl compounds E[6b,8,10b]
(Figure 1). However, it is evident that, in principle, the diazo
strategy allows the employment of a range of different diazo-
carbonyl compounds for the synthesis of pyridazines and thus
enables the preparation of a wide variety of pyridazine deriva-
tives. Furthermore, the presence of functional groups in the
structure of the resulting pyridazines provides a means for fur-
ther modification of pyridazine scaffold in a site-selective
way.[6b,10] In an effort to scope out the synthetic potential of
the diazo approach for the synthesis of new pyridazine archi-
tectures, we explored the use of phosphazenes of fluoroalkyl-
containing vinyldiazocarbonyl compounds and their nonfluori-
One of the recent strategies adopted for the synthesis of
pyridazine derivatives is based on reactions of diazo com-
pounds with phosphines.[7–10] Thus, on reaction of a vinyldiazo-
carbonyl precursor A with a phosphine (PX3) the correspond-
ing phosphazene B is formed by a Staudinger reaction,[11]
which proceeds easily and in many cases at room tempera-
[a] Prof. Dr. V. A. Nikolaev, Dr. J. J. Medvedev, Dr. M. B. Supurgibekov
Department of Organic Chemistry
St-Petersburg State University
University pr. 26, 198504, Saint-Petersburg (Russia)
E-mail: vnikola@VN6646.spb.edu
[b] Dr. D. Cantillo, Prof. Dr. C. O. Kappe
Institute of Chemistry
University of Graz
Heinrichstrasse 28, 8010 Graz (Austria)
E-mail: david.cantillo@uni-graz.at
[c] Prof. Dr. G. K. S. Prakash
University of Southern California
837 Bloom Walk, Los Angeles, CA 90089-1661 (USA)
E-mail: gprakash@usc.edu
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503448.
Figure 1. Two types of diazo precursors D and E used for the synthesis of
pyridazines.
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nated counterparts D in this process (Figure 1; R1 =RF, H, alkyl
(Alk), etc.).
Table 1. Synthesis of phosphazenes 1 and 2.
According to the early studies by Guillaume et al.[7b] and oth-
ers,[9a,b,e] synthesis of 4-fluoroalkyl-substituted pyridazines can
be readily accomplished from the appropriate vinyldiazocar-
bonyl compounds D (Figure 1; R1 =RF) through a tandem Stau-
dinger/diaza-Wittig process. One would expect that, for the
preparation of their nonfluorinated analogues in a similar way,
the associated vinyldiazocarbonyl compounds D with R2 =H,
Alk, and so forth (Figure 1) can be simply used as a starting
materials. However, synthesis of pyridazines from nonfluorinat-
ed vinyldiazocarbonyl compounds by the same scheme fail-
ed.[9e]
Entry
Starting
compound
R1, R2, Alk
X
Yield of
1 or 2 [%]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
H, OMe, Me
Me, OMe, Me
Me, OEt, Et
Me, Me, Me
CF3, Me, Me
CF3, Me, Me
CF3, Me, Me
H, OMe, Me
Me, OEt, Et
Me, Me, Me
CF3, Me, Me
CF3, Me, Me
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
Ph
Ph
Ph
Ph
Ph
1a; 92
1b; 84
1c; 72
1d; 91
3e
1e; 87
3e,4e[a]
4e
1e; 47 (94)[b]
2e; 71
It was suggested that the main reason for the observed dis-
similar reactivity of the fluoroalkyl-containing (F) and nonfluori-
nated (H) vinyldiazocarbonyl compounds and their phospha-
zenes was dictated by the different stereochemistry (cis or
trans) of the functional groups (AlkO2C, CN2PX3) around their
vinylic double bonds.[9e] (Note that we use the cis and trans no-
tation for the spatial arrangement of functional groups
(CO2Alk, CN2) around the vinyl double bond, since application
of Z,E nomenclature implies the same Z or E symbols for fluo-
roalkyl-containing and nonfluorinated vinyldiazo substrates
with opposite configuration.) To the best of our knowledge,
the effect of the stereochemistry of the vinyl double bond of
phosphazenes on the outcome of their cyclization into pyrida-
zines has not been considered thus far. In this connection the
main goal of our current project was to carry out a detailed
study on the reactions of phosphazenes derived from cis- and
trans-vinyldiazocarbonyl compounds and to experimentally
and theoretically ascertain the effect of the vinyl double-bond
stereochemistry on the diaza-Wittig process.
3a
3c
3d
3e
3e,4e[a]
1a’; 87
1c’; 86
9
10
11
12
1d’; 74
1e’; 86
1e’; 40 (80)[b]
[a] Mixture of isomers 3e:4e (1:1) used for Staudinger reaction. [b] Yields
of 1e and 1e’ based on the initial 3e are shown in parentheses.
stage of the process and subjected in situ to the intramolecu-
lar Diaza–Wittig reaction without isolation in their pure state.
In most of the cases, formation of phosphazenes 1a–e (X=
NMe2 or Ph) from the trans-vinyldiazo compounds 3a–e and
reactions of cis-vinyldiazo compounds 4 with P(NAlk2)3 pro-
ceeded rapidly (about 10 min) and irreversibly. At the same
time, reactions of cis-vinyldiazo compounds 4 with PPh3 usual-
ly occurred at a far slower rate (from 3 to 21 h) than with trans
isomers 3. Moreover, the equilibrium in the reactions with
triphenylphosphine was in many cases considerably displaced
1
to the starting compounds (as established by H NMR spectra),
and this prevented isolation of the pure target phosphazenes
2.
Results and Discussion
The structures of all phosphazenes 1 and 2 were confirmed
by conventional physicochemical methods. The stereochemis-
try of the vinylic C=C bond in the structure of the nonfluorinat-
ed phosphazene H-1c’ and fluoroalkyl-containing phospha-
zene F-1e’ was ascertained by X-ray crystallographic analysis
(Figures 3 and 4), and it was found to be the same as for the
initial vinyldiazocarbonyl compounds H-3c[9e] and F-3e.[9a] By
analogy with this stereochemical correlation, the configura-
tions of the other phosphazenes 1 and 2 were also surmised
to be the same as those of the parent trans- and cis-vinyldiazo-
carbonyl compounds 3 and 4, respectively.[7b,9a,b,d,e,12,13]
The structures of the starting trans- and cis-phosphazenes
1 and 2 of vinyldiazo compounds involved in our current re-
search are shown in Figure 2. They differ in the nature of sub-
stituents at the C-3 position of the phosphazene (R1 =H, Me,
CF3, Ph) and the nucleophilicity of the phosphine component
[PPh3, P(NMe2)3] used. The majority of phosphazenes 1 and 2
were prepared by known protocols[9] from the corresponding
vinyldiazocarbonyl compounds trans-3 and cis-4[9a,b,e,12,13] by
employing P(NMe2)3 and PPh3 as phosphine components in
yields of up to 92–94% (Table 1). Several of them (e.g., cis-
2 f,g,g’) were generated in the reaction mixture in the first
Figure 2. Structures of the initial trans- and cis-phosphazenes 1 and 2 used in the present work.
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studied, pyrazoles 6 were formed by way of dissociation of
phosphazenes 1a’,c’,d’ in solution to give PPh3 and starting
trans-vinyldiazo compounds 3a,c,d, followed by their intramo-
lecular cyclization to pyrazoles 6a,c,d at elevated tempera-
tures.[14a] Thermolysis of trans-phosphazene F-1e’, unlike ana-
logues H-1a’,c’,d’, under the same reaction conditions resulted
in the formation of a complex reaction mixture (similar to ther-
molysis of vinyldiazo ketone F-3e[14b]).
To avoid lability and dissociation of (triphenyl)phosphazenes
in the reaction mixture, more stable tris(dimethylamino)phos-
pazines 1a–d were prepared by reaction of trans-vinyldiazo
compounds 3a–d with more nucleophilic phosphine P(NMe2)3
instead of PPh3. However, it turned out that the resulting phos-
phazenes 1a-d were extremely inert, and did not undergo the
expected intramolecular diaza-Wittig reaction or any other
changes even on heating to reflux in benzene solution for 2 d.
The reactions of nonfluorinated cis-vinyldiazo compounds H-
4a,f,g with tris(dimethylamino)phosphine or PPh3 at room
temperature or on heating in benzene solution produced di-
rectly the corresponding pyridazines 5a,f,g in good to excel-
lent yields (Table 2, entries 1–5) instead of the anticipated
phosphazenes 2. In the case of diethyl cis-diazoglutaconate H-
4a (Table 2, entry 1) intermediate phosphazene 2a was also
isolated from the reaction mixture (20%), and it was shown
that under the reaction conditions it transforms into pyridazine
5a (Table 2, entries 1 and 2).
Figure 3. Molecular structure of trans-triphenylphosphazene H-1c’. The ellip-
soids denote 50% probability.[9e]
Interaction of 3-Ph-substituted cis-vinyldiazo ester H-4 f with
P(NMe2)3 for 2 h furnished 88% of pyridazine 5 f (Table 2,
entry 3). Similar reactions of carbocyclic cis-vinyldiazo ester 4g
with PPh3 and P(NMe2)3 produced pyridazine 5g in moderate
to high yields depending on the nature of phosphine compo-
nent used (53–89%; Table 2, entries 4 and 5). In the reaction of
H-4g with PPh3, in addition to pyridazine 5g, a small amount
of the corresponding hydrazone 7g, the product of hydrolytic
cleavage of the initial phosphazene 2g’, was also isolated
(Table 2).[15]
Fluorinated cis-vinyldiazo compound F-4e on short-term in-
teraction (for 10 min) with P(NMe2)3 in Et2O followed by silica-
gel separation of the reaction mixture gave rise to initially
formed fluoroalkyl-containing cis-phosphazene 2e (71%). On
storage or heating in benzene solution it produced 4-CF3-sub-
stituted pyridazine 5e in good yield (Table 2, entry 6). It is re-
markable that (triphenyl)phosphazene 2e’ was very reactive in
the subsequent diaza-Wittig process and underwent spontane-
ous cyclization to pyridazine 5e even at room temperature
(Table 2, entry 7; see also Refs. [9a,b]).
Figure 4. Molecular structure of trans-triphenylphosphazene F-1e’. The ellip-
soids denote 50% probability.
Thermal reactions of phosphazenes 1 and 2
On heating in benzene solution, trans-(triphenyl)phosphazenes
1a’,c’,d’ did not give rise to the expected pyridazines 5 but in-
stead produced the associated pyrazoles 6a,c,d in high yields
(89–96%, Scheme 2). Evidently, under the reaction conditions
To directly compare the reactivity of trans- and cis-phospha-
zenes under similar reaction conditions, a mixture of fluorinat-
ed trans- and cis-vinyldiazoketones F-3e:F-4e (1:1) was treated
Scheme 2. Thermolysis of trans-phosphazenes 1a’,c’,d’ followed by cyclization to pyrazoles 6a,c,d.
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test the assumed stereocontrol of the reaction and to verify
that trans-phosphazenes are fundamentally suitable for the
synthesis of pyridazines by the diaza-Wittig approach.
Table 2. Reactions of cis-vinyldiazo compounds 4 and phosphazenes 2 to
produce pyridazines 5
On short-wavelength UV irradiation of trans-phosphazene H-
1a (l>210 nm, room temperature, 20 h), followed by silica-gel
chromatography of the reaction mixture, pyridazine 5a’ (23%)
and a mixture of unconverted phosphazenes trans-1a and cis-
1
2a’ (R2 =OMe, 76%, ꢀ1:1.6 by H NMR spectroscopy) were iso-
lated. Since at room temperature the second stage of the pro-
cess (diaza-Wittig reaction) was apparently very slow, which
left mostly unconsumed cis-phosphazene 2a’ (R2 =OMe), the
photochemical experiment was repeated at 50–558C for 16 h,
which resulted in the formation of pyridazine 5a’ in 56% yield
(Table 3, entry 1).
In the case of UV irradiation of trans-phosphazene H-1b at
254 nm in hexane followed by heating of the reaction mixture
under reflux in CHCl3 solution, pyridazine 5b was isolated in
69% yield along with 29% of the recovered trans-phosphazene
1b (Table 3, entry 2).
Fluoroalkyl-containing trans-phosphazene F-1e on long-
wavelength irradiation (l=310–405 nm) also experienced slow
isomerization to produce the corresponding cis-phosphazene
F-2e. The initially formed 2e at elevated temperature fur-
nished 4-CF3-subsituted pyridazine 5e, which was isolated in
a yield of 47% (Table 3, entries 3 and 4).
Entry Reagent; R1, R2, Alk
X
Conditions
Yield of 5 [%]
5a; 78[a]
1
2
3
4
5
6
7
8
9
4a; H, OEt, Et
4a; H, OEt, Et
4 f; Ph, OEt, Et
4g; (CH2)3, OEt, Et
4g; (CH2)3, OEt, Et
2e; CF3, Me, Me
4e; CF3, Me, Me
4e+3e[c] -“-
NMe2 RT, 12 h, CH2Cl2
NMe2 80–818C, 2 h, CH3CN 5a; 92
NMe2 80–818C, 2 h, CH3CN 5 f; 88
Ph
RT, 5 days, Et2O
5g; 53
5g; 89
NMe2 RT, 36 h, CH3CN
NMe2 80–818C, 0.5 h, PhH 5e; 66[b]
Ph
Ph
RT, 19 h, Et2O
RT, 19 h, Et2O
5e; 88
5e; 41 (82)[d]
5e; 49[b](98)[d]
4e+3e[c] -“-
NMe2 50–608C, 2 h, PhH
[a] Under these conditions (entry 1) phosphazene 2a was also isolated in
20% yield. [b] Yield of two-stage process via 2e. [c] Mixture of cis-F-4e
and trans-F-3e (1:1) was used for this reaction. [d] Yield of 5e based on
the initial cis-F-4e is shown in parentheses.
Hence, fluorinated and nonfluorinated trans-phosphazenes
1 under UV irradiation undergo photochemical isomerization
to cis isomers 2 followed by thermal intramolecular diaza-
Wittig cyclization to produce pyridazines 5. This provides
a means for employing trans isomers for the synthesis of pyri-
dazines by the diaza-Wittig route.
with PPh3 and P(NMe2)3 (Table 2, entries 8 and 9). In the case of
PPh3, pyridazine 5e (41%) and trans-phosphazene 1e’ (40%)
were isolated after separation of the reaction mixture on silica
gel (Table 2, entry 8)
The experimental results allow us to conclude that formation
of pyridazines 5 from cis-vinyldiazocarbonyl compounds 4
The use of the more nucleophilic tris(dimethylami-
no)phosphine in this reaction at room temperature
furnished a mixture of trans and cis stereoisomers of
phosphazenes F-1e, F-2e in high overall yield and in
the same ratio as the initial trans- and cis-vinyldiazo-
ketones F-3e:F-4e (1:1). After subsequent heating of
the reaction mixture in benzene solution, pyridazine
5e and trans-phosphazene 1e were isolated in 49
and 47% yield, respectively (Table 2, entry 9). Thus,
under the conditions studied, trans-phosphazenes
were unreactive in the diaza-Wittig process to pro-
duce pyridazines.
Table 3. Photochemical isomerization of trans-1 to cis-2 phosphazenes followed by
diaza-Wittig reaction.
The structures of phosphazenes 1e, 1e’ and pyrid-
azine 5e were confirmed by their 1H and 13C NMR
spectra, and the geometry of the trans stereoisomer
of (triphenyl)phosphazene 1e’ was also unambigu-
ously established by X-ray crystallographic analysis
(Figure 4).
Entry Phosphazene; R1, R2 Reaction conditions
Yield of 5 [%]
5a’; 56
1
2
3
4
1a; H, OMe
1b; Me, OMe
1e; CF3, Me
1e; CF3, Me
l>210 nm, tBuOMe, 50–558C, 16 h
l=254 nm, hexane, 72 h; CHCl3, reflux 5b; 69 (97)[a]
l>310 nm, Et2O, reflux, 2 h
l=395–405 nm, benzene,408C, 70 h
5e; 7 (15)[a]
5e; 47
Photochemical isomerization of trans-phospha-
zenes 1a,b,e to cis stereoisomers 2a,b,e
[a] Yields of pyridazine 5 calculated with respect to the initial phosphazene are shown
in brackets.
Photochemical isomerization of trans-phosphazenes
1a,b,e to cis stereoisomers 2a,b,e was performed to
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occurs as a tandem process, which involves the initial forma-
tion of cis-vinylphosphazenes 2 followed by intramolecular
diaza-Wittig cyclization of these intermediates to produce pyri-
dazines 5 and elimination of the corresponding phosphine
oxide (Scheme 3). The facile nature of this process with vinyl-
diazocarbonyl compounds 4 is clearly related to and assisted
by the cis configuration of the vinyldiazo compounds and the
related phosphazenes 2, since cis stereochemistry strongly
favors the formation transition state F (Scheme 3), which is
typical of the Wittig reaction.[16]
phine oxide and the desired pyridazine 5a’ is formed. The pro-
cess is highly exothermic (À42.4 kcalmolÀ1). Furthermore, the
relative energies of the transition states for the [2+2] cycload-
dition and reversion are +10.4 and +10.5 kcalmolÀ1, respec-
tively (Figure 5). Notably, these relatively low energy barriers
are in agreement with the experimental results, as they explain
the rapid diaza-Wittig cyclization observed in most of the
cases with cis-phosphazenes 2.
Next we turned our attention to the cis-vinylphosphazene
2e’ (Alk=Me, R2 =OMe), which contains a CF3 group on the C-
3 atom. We expected that the presence of such a strongly elec-
tron withdrawing group could have some influence on the cal-
culated energy barriers or even on the properties of the calcu-
Scheme 3. General Scheme of diaza-Wittig reaction with cis-phosphazenes 2
to produce pyridazines 5.
The high reactivity of the cis-vinylphosphazenes 2 towards
intramolecular diaza-Wittig cyclization was rationalized by DFT
calculations at the M06-2X/6-31G(d) level of theory,[17] and cyc-
lization of 2a’ (Alk=Me) to give pyridazine 5a’ was initially se-
lected as a model reaction (Figure 5).[18] Thus, stationary points
corresponding to a tandem [2+2] cycloaddition/cycloelimina-
tion could be located and characterized. This mechanism is in
close analogy with that of the aza-Wittig reaction between
phosphazenes and aldehydes, which has been previously ana-
lyzed by DFT methods.[19]
According to our calculations, an initial [2+2] cycloaddition
of the phosphazene moiety to the carbonyl group takes place,
giving the cyclic oxazaphosphetane intermediate INT2a’!5a’
(Figures 5 and 7). Then, a cycloelimination releases the phos-
Figure 5. Energy profile [kcalmolÀ1] for the diaza-Wittig cyclization of cis-2a’
calculated at the M06-2X/6-31G(d) level of theory.
Figure 6. Energy profile [kcalmolÀ1] for the diaza-Wittig cyclization of cis-2e’, calculated at the M06-2X/6-31G(d) level of theory.
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Figure 7. Key stationary points located for the diaza-Wittig cyclizations of cis-H-2a’ (top) and cis-F-2e’ (bottom).
lated stationary points. Surprisingly, the theoretical calculations
revealed a different energy profile for this transformation
(Figure 6). The initial transition state (TS12e’!5e’) was found to
be highly asynchronous, with a very long PÀO distance of
3.44 Š (Figure 7). After the oxazaphosphetane INT12e’!5e’ a new
open intermediate was located (INT22e’!5e’), in which the NÀP
bond is broken (see Figure 6 and Figure 7). In this step, 9.4 kcal
molÀ1 of energy is released, probably due to the ring strain in
the oxazaphosphetane structure and stabilization of the nega-
tive charge on the ring by the electron-withdrawing CF3
group. Unfortunately, the saddle point (TS22e’!5e’) for this ring
opening could not be located, and all attempts at geometry
groups CO2Alk with respect to CN2PX3 prevents the required
approach of C=O and P=N groups involved in the ring-forma-
tion process. Therefore, formation of the transition state of
type F becomes essentially impossible, and intramolecular
diaza-Wittig cyclization with trans-phosphazenes 1 is not realiz-
ed. Moreover, DFT calculations revealed that the thermal trans–
cis isomerization of compounds 1 to 2 is not possible under
the present experimental conditions. Compounds trans-1a and
trans-1e were selected as models for this study. As expected,
calculation of the transition states for the hypothetical thermal
trans–cis isomerizations resulted in very high energy barriers
(+52.3 and 48.9 kcalmolÀ1 for 1a and 1e, respectively), and
this type of process can therefore be ruled out. Gratifyingly, UV
irradiation of trans-phosphazenes resulted in photochemical
isomerization of trans-to cis-hosphazenes, which are reactive
and ultimately led to the conversion of trans-1 compounds to
the desired pyridazines 5.
optimization led to the structure of INT22e’!5e’
.
We believe that this ring-opening process must have a very
low or negligible energy barrier. Release of the phosphine
oxide from INT22e’!5e’ is very fast. In this case the correspond-
ing transition structure could be located (TS32e’!5e’), and the
calculated barrier with respect to the intermediate was only
+2.2 kcalmolÀ1 (Figure 6). The overall energy barrier for this
process is +10.1 kcalmolÀ1, and therefore analogous to that
calculated for the Diaza–Wittig reaction of cis-2a. Apparently
the presence of the electron-withdrawing group does not
affect significantly the reactivity of the starting cis-vinylphos-
phazene. However, according to the calculations, it does influ-
ence the actual mechanism of the reaction by stabilizing
a new open intermediate INT22e’!5e’. Although the mechanism
of the aza-Wittig reaction of phosphazenes with aldehydes has
been previously assessed by DFT calculations,[19] to the best of
our knowledge this is the first theoretical study on the mecha-
nism of the diaza-Wittig process.
Conclusion
The observed difference in the reactivity of cis- and trans-phos-
phazenes towards diaza-Wittig reactions is caused by the dif-
ferent location of the functional groups (AlkO2C, CN2PX3)
around their vinylic C=C bonds: phosphazenes with cis config-
uration readily undergo the diaza-Wittig reaction producing
the corresponding pyridazines, whereas their counterparts
with trans stereochemistry remain intact under similar reaction
conditions. Nevertheless, on UV irradiation of trans-phospha-
zenes, photochemical trans-to-cis isomerization occurs fol-
lowed by intramolecular diaza-Wittig cyclization to form pyri-
dazines. Hence, in principle, both vinyldiazocarbonyl stereoiso-
mers can be used for the synthesis of 3,4,6-trisubstituted pyri-
In the case of trans-phosphazenes 1 derived from vinyldiazo-
carbonyl compounds 3, trans alignment of the functional
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were carried out at the same level of theory as the geometry opti-
mizations to ascertain the nature of the stationary points. Ground
and transition states were characterized by none and one imagina-
ry frequency, respectively. All of the presented relative energies are
free energies at 298.15 K.
dazines. DFT calculations at the M06-2X/6-31G(d) level of
theory suggest a rapid tandem [2+2] cycloaddition/cycloelimi-
nation process for the cis-phosphazenes with low energy barri-
ers. The presence of a strongly electron withdrawing group
such as CF3 on the C-3 atom of the starting phosphazene re-
sults in a more complex reaction pathway in which a stabilized
ring-opened intermediate is possible. At the same time, when
heated to 808C or above, trans-(triphenyl)substituted phospha-
zenes dissociate to give the initial trans-vinyldiazo compounds
followed by their 1,5-electrocylization to pyrazoles.
Synthesis of trans-phosphazenes 1a–d from vinyldiazo com-
pounds 3a–d and P(NMe2)3
Tris(dimethylamino)phosphine (2.7 mmol) was added dropwise to
a solution of diazo compound 3a–d (2.7 mmol) in 10 mL of Et2O,
whereupon the reaction mixture took on a bright yellow color. The
mixture was stirred for 10 min until the reaction was complete (by
TLC), applied to 2.5 g of silica gel, transferred to a short column
with 6 g of silica gel, and eluted with ethyl acetate (ca. 30 mL). The
obtained eluate was dried with MgSO4 and, after removing the sol-
vents, the residue was recrystallized from Et2O to provide phospha-
zenes 1a–d.
Experimental Section
General methods
NMR spectra were recorded at 200, 300, and 600 MHz (1H), 50, 75,
and 150 MHz (13C), 188 282 MHz (19F), and 81 MHz (31P) in CDCl3 so-
lution with TMS, CHCl3, or H3PO4 as internal standard. A single crys-
tal of F-1e’ suitable for X-ray diffraction was selected from an ana-
lytically purified sample. Crystallographic measurements were
made with an IPDS1 diffractometer [graphite-monochromated
MoKa radiation (l=0.71073 Š)]. The structure was solved by direct
methods by using the program SIR2002[20] and was refined by ani-
sotropic approximation for the non-hydrogen atoms with SHELX-
90 software.[21] All hydrogen atoms were calculated and refined in
riding modus. CCDC 788805 (F-1e’) contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre.
Dimethyl ester of trans-4-[tris(dimethylamino)phosphoranyl-
idene]azinopent-2-endioic acid (1a): Yield: 862 mg (92%), orange
solid (Et2O), m.p. 84–858C; Rf =0.34 (EtOAc); 1H NMR (300 MHz,
3
CDCl3): d=2.73 (d, J(H,P)=9.5 Hz, 18H; CH3), 3.74 (s, 3H; OCH3),
3
3.78 (s, 3H; OCH3), 7.34 (d, J(H,H)=16.0 Hz, 1H; C2H), 7.93 ppm (d,
3J(H,H)=16.0 Hz, 1H; C3H); 13C NMR (75 MHz, CDCl3): d=37.7 (6”
CH3), 51.6, 51.7 (2”COOCH3), 118.0 (C2), 130.2 (C3), 137.1 (d,
3J(C,P)=43.8 Hz; C=N), 167.3, 170.8 ppm (2”COOCH3); UV (EtOH):
l
max(lge)=234 nm (3.17), 358 nm (3.39); UV (CH3CN): lmax (lge)=
229 nm (3.41), 357 nm (3.37); elemental analysis calcd (%) for
C13H26N5O4P: C 45.0, H 7.5, N 20.1; found: C 45.17, 45.12, H 7.61,
7.66, N 19.61, 19.62.
All reactions were carried out in carefully purified and dried sol-
vents and were monitored by TLC with UV light and iodine as visu-
alizing agents. Preparative column chromatography was carried
out with neutral silica gel (70–230 mesh) and petroleum (40–708C)
and diethyl ether as eluents in gradient regime. The yields deter-
Dimethyl ester of trans-3-Me-[tris(dimethylamino)phosphoranyl-
idene]azinopent-2-endioic acid (1b): Yield: 819 mg (84%), orange
oil, Rf =0.35 (EtOAc); 1H NMR (400 MHz, CDCl3): d=2.39 (d,
3
4J(H,H)=1.0 Hz, 3H; CH3), 2.67 (d, J(H,P)=9.0 Hz, 18H; CH3), 3.67
4
1
(s, 3H; OCH3), 3.81 (s, 3H; OCH3), 5.52 ppm (q, J(H,H)=1.0 Hz, 1H;
mined by H NMR spectroscopy are given in brackets; (CHCl2)2 was
CH); 13C NMR (100 MHz, CDCl3): d=13.5 (Me), 37.2 (d, 2J(C,P)=
2.2 Hz, NMe), 51.2, 50.6 (2”OMe), 112.5 (C3), 147.6 (d, 3J(C,P)=
47.1 Hz, C=N), 150.9 (C2), 167.8, 169.1 ppm (2”COOMe); 31P NMR
(160 MHz, CDCl3): d=38.76; IR (KBr): n˜ =1726, 1709 (CO),
1597 cmÀ1 (P=N); HRMS (ESI-LCQ) calcd for C14H29N5O4P [M+H]+:
362.1952; found: 362.1955.
used as the internal standard. Starting vinyldiazocarbonyl com-
pounds 3 and 4 were prepared by two known approaches:[12]
1) formation of the 2-vinylcarbonyl motif followed by diazo transfer
to the methylene group of this compound (3a–e, 4 f,g; yields: 16–
85%); 2) synthesis of a diazodicarbonyl compound accompanied
by olefination of one of the carbonyl groups by the Wittig reaction
or with the help of the other reaction manifolds (3 f, 4a,e,f; yields:
3–69%). Photochemical reactions were carried out by irradiation of
phosphazenes 1a,b,e at 40–688C with a medium-pressure mercury
lamp (100–130 W) in a 25 mL reactor equipped with a quartz or
Pyrex jacket (l>210 or 310 nm without any monochromatization;
phosphazenes H-1a, F-1e), with monochromatic light (l=254 nm;
phosphazene H-1b), or with a UV LED spotlight (395–405 nm;
phosphazene F-1e).
Diethyl ester of trans-3-methyl-4-[tris(dimethylamino)phosphor-
anylidene]azinopent-2-endioic acid (1c): Yield: 757 mg (72%),
1
orange oil, Rf =0.24 (EtOAc); H NMR (300 MHz, CDCl3): d=1.25 (t,
J=7.3 Hz, 3H; CH3), 1.33 (t, J=7.3 Hz, 3H; CH3), 2.39 (s, 3H; CH3),
2.68 (d, 3J(H,P)=8.7 Hz, 18H; CH3), 4.13 (q, J=7.3 Hz, 2H; CH2),
4.32 (q, J=7.3 Hz, 2H; CH2), 5.56 ppm (s, 1H; CH=); 13C NMR
(75 MHz, CDCl3): d=14.0, 14.8 (CH2CH3), 37.7 (CH3), 59.7, 60.6 (2”
CH2CH3), 113.8 (CH=), 148.5 (3J(C,P)=46.9 Hz; C=N), 151.1 (C3),
168.0, 169.1 ppm (CO2Et); 31P NMR (81 MHz, CDCl3): d=39.70; IR
(KBr): n=1597 (CN), 1701 (CO), 1726 cmÀ1 (CO); UV (EtOH):
Computational details
l
max(lge)=336 nm (4.30); MS (EI, 70 eV): m/z: 389.4 [M+]; HRMS
(ESI-LCQ) calcd for C16H32N5O4P [M+H]+: 389.2192; found:
All calculations were carried out with the Gaussian 09 package.[22]
The M06-2X density functional method[17] in conjunction with the
6-31G(d) basis set was selected for all the geometry optimizations
and frequency analysis. The geometries were optimized with inclu-
sion of solvation effects. For this purpose, the SMD solvation
method[23] was employed. Photochemical isomerization of trans-
phosphazene 1a into the cis isomer 2a’ followed by cyclization
was carried out in tBuOMe. Because this solvent is not internally
stored in the Gaussian solvent list, diisopropyl ether was selected
as solvent for all calculations because of their analogous proper-
ties. Frequency calculations at 298.15 K on all stationary points
389.2194.
Methyl ester of trans-3-methyl-5-oxo-4-[tris(dimethylamino)-
phosphoranylidene]azinohex-2-enoic acid (1d): Yield: 850 mg
(91%), yellow solid, m.p. 57–588C (Et2O); Rf =0.11 (EtOAc); UV
1
(EtOH): lmax(lge)=212 nm (4.01), 318 nm (4.24); H NMR (300 MHz,
4
CDCl3): d=2.29 (d, J(H,H)=1.5 Hz, 3H; CH3), 2.33 (s, 3H; CH3), 2.72
(d, 3J(H,P)=8.7 Hz, 18H; CH3), 3.67 (s, 3H; OCH3), 5.68 ppm (d,
3J(H,H)=1.5 Hz, 1H; C2H=); 13C NMR (75 MHz, CDCl3): d=18.5, 25.6
(2”CH3), 37.7 (6”NCH3), 51.1 (COOCH3), 119.8 (C2H=), 153.8 (C3),
153.91 (d, 3J(C,P)=44.8 Hz, C=N), 167.7 (COOCH3), 192.6 ppm
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180
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(COCH3); 31P NMR (81 MHz, CDCl3): d=39.88; IR (KBr): n˜ =1626
(CN), 1649 (CO), 1713 cmÀ1 (CO); elemental analysis calcd (%) for
C14H28N5O3P: C 48.7, H 8.1, N 20.3; found: C 48.61, 48.54, H 8.03,
8.00, N 20.22, 20.19.
Attempts to carry out diaza-Wittig cyclization with trans-
phosphazenes 1a’,c’,d’,e’, and 1a–d
A solution of (triphenyl)phosphazene 1a’,c’,d’,e’ (0.4 mmol) in ab-
solute benzene (ꢀ3 mL ) was heated at 75–808C for 1–2 h until
the initial phosphazene disappeared (by TLC). The precipitate
formed after cooling was separated by filtration, washed with
hexane, and dried in air to give pyrazole 7a (230 mg, 89%),[14a] 7c
(266 mg, 96%),[14a] 7d (245 mg, 96%).[14a] trans-Phosphazene F-1e’,
on being heated under similar reaction conditions, gave a complex
reaction mixture.[14b] Attempts to carry out the same reaction with
tris(dimethylamino)phosphazenes 1a–d failed. After heating ben-
zene solutions of these phosphazenes to reflux for 30 h, no
changes in the reaction mixtures were observed (by TLC and
1H NMR spectroscopy).
Synthesis of trans-phosphazenes 1a’,c’,d’ by reactions of
vinyldiazo compounds 3 a’,c’,d’ with PPh3.
trans-Diazo compound 3a,c,d (1 mmol) was added to a solution of
triphenylphosphine (1 mmol) in of Et2O (ꢀ3 mL) without immedi-
ate visible changes in the reaction mixture. After 3–21 h away from
light and air at room temperature, a precipitate was separated by
filtration, washed with benzene (2”1 mL), and dried under
vacuum in a desiccator at 10–15 mmHg to furnish phosphazenes
1a’,c’,d’. Phosphazenes 1c’,d’ in CDCl3 solution are slowly hydro-
1
lyzed (evidently by protic-acid catalysis), and in the H NMR spectra
of these compounds the signals of the hydrazone impurities
appear with time (at room temperature in 2–3 d).
Tandem process for the synthesis of pyridazines 5 by
reactions with P(NMe2)3
Dimethyl ester of trans-4-(triphenylphosphoranylidene)azino-
pent-2-endioic acid (1a’): Yield: 388 mg (87%), yellow solid, m.p.
108–1098C (Et2O); Rf =0.16 (petroleum ether/EtOAc 3:1); 1H NMR
(300 MHz, CDCl3): d=3.76 (s, 3H; OCH3), 3.78 (s, 3H; OCH3), 7.42–
7.74 (m, 16H; 3”C6H5, C2H=), 8.12 ppm (d, 3J(H,H)=16.0 Hz, 1H,
C3H=); 13C NMR (75 MHz, CDCl3): d=51.8, 51.9 (COOCH3), 119.9
Tris(dimethylamino)phosphine (0.32 g, 2 mmol) was added drop-
wise to a solution of cis-vinyldiazoacetate 4a,f,g (2 mmol) in 5 mL
of absolute CH2Cl2 (4a), CH3CN (4a,f), or Et2O (4g). The addition
was accompanied by exothermic process, and the reaction mixture
was stirred at room temperature for 12 h (4a), at 80–818C for 2 h
(4a,f), or 36 h (4g) until the reaction was complete (monitoring by
1
3
(C2), 127.1 (d, J(C,P)=93.8 Hz; i-C-arom.), 129.3 (d, J(C,P)=10.9 Hz;
m-C-arom.), 130.1 (C3), 133.2 (p-C-arom.), 134.1 (d, J(C,P)=8.9 Hz;
2
o-C-arom.), 141.0 (d, 3J(C,P)=41.9 Hz; C=N), 166.7, 170.4 ppm
(COOCH3); UV (EtOH): lmax(lge)=219 nm (3.53), 359 nm (3.33); UV
(CH3CN): lmax(lge)=223 nm (3.90), 355 nm (3.73); elemental analy-
sis calcd (%) for C25H23N2O4P: C 67.3, H 5.2, N 6.3; found: C 67.21,
67.37, H 5.11, 5.17, N 6.33, 6.61.
1
TLC and H NMR or 31P NMR spectra). After removal of the solvent
the residue was subjected to flash chromatography (10 g of SiO2,
eluents: hexane and Et2O in gradient regime) to furnish pyridazines
5a,f,g.
6-Ethoxy-3-ethoxycarbonylpyridazine (5a): Yield (in CH3CN):
361 mg (92%), colorless solid, m.p. 80–818C (hexane), Rf =0.49
Diethyl ester of trans-3-methyl-4-(triphenylphosphoranyl-
idene)azinopent-2-endioic acid (1c’): Yield: 420 mg (86%), yellow
1
(EtOAc); H NMR (300 MHz, CDCl3): d=1.45 (t, J=7.4 Hz, 3H; CH3),
1
solid, m.p. 145–1468C (Et2O); Rf =0.21 (EtOAc); H NMR (300 MHz,
1.47 (t, J=7.0 Hz, 3H; CH3), 4.48 (q, J=7.4 Hz, 2H; CH2), 4.67 (q, J=
7.0 Hz, 2H; CH2), 7.00 (d, 3J(H,H)=9.4 Hz, 1H; C5H), 8.05 ppm (d,
3J(H,H)=9.4 Hz, 1H; C4H); 13C NMR (100 MHz, CDCl3 d=14.2, 14.4
(2”CH2CH3), 62.1, 64.2 (2”CH2CH3), 117.0 (C5), 130.1 (C4), 147.7 (C3),
164.1 (C6), 165.8 ppm (CO2Et); IR (KBr): n˜ =3065 (CH d), 1716 (CO),
1581, 1445 cmÀ1 (ring, g); HRMS (ESI-GCT) calcd for C9H12N2O3
[M+H]+: 197.0926; found: 197.0930.
CDCl3): d=1.26 (t, J=7.3 Hz, 3H; CH3), 1.34 (t, J=7.3 Hz, 3H, CH3),
2.31 (s, 3H; CH3), 4.14 (q, J=7.3 Hz, 2H; CH2), 4.32 (q, J=7.3 Hz,
2H; CH3), 5.66 (s, 1H; CH=), 7.45–7.72 ppm (m, 15H; 3”C6H5);
13C NMR (75 MHz, CDCl3): d=14.1 (2”CH3), 14.8, 14.9 (2”CH2CH3),
59.8, 60.9 (2”CH2CH3), 115.21 (C2H=), 128.6 (d, 1J(C,P)=93.8 Hz; i-C-
arom.), 129.0 (d, 3J(C,P)=12.0 Hz; m-C-arom.), 150.7 (C3), 132.7 (p-C-
arom.), 133.8 (d, 2J(C,P)=8.0 Hz; o-C-arom.), 151.7 (d, 3J(C,P)=
45.9 Hz; C=N), 167.8, 168.8 ppm (2”CO2Et); 31P NMR (81 MHz,
CDCl3): d=20.17 ppm; IR (KBr): n˜ =1606 (CN), 1701 (CO), 1724 cmÀ1
(CO); UV (EtOH): lmax(lge)=209 (4.08), 221 (4.05), 345 nm (3.97); el-
emental analysis calcd (%) for C28H29N2O4P: C 68.9, H 5.98, N 5.73;
found: C 68.88, H 5.99, N 5.73.
6-Ethoxy-3-ethoxycarbonyl-4-phenylpyridazine
(5 f):
Yield:
480 mg (88%). Colorless solid, m.p. 67–698C (Et2O), Rf =0.12
(hexane/Et2O 2:1); 1H NMR (400 MHz, CDCl3): d=1.15 (t, 3J(H,H)=
3
7.3 Hz, 3H; OCH2CH3), 1.45 (t, J(H,H)=7.0 Hz, 3H; OCH2CH3), 4.25
(q, 3J(H,H)=7.3 Hz, 2H; OCH2CH3), 4.66 (q, 3J(H,H)=7.0 Hz, 2H;
OCH2CH3), 6.91 (s, 1H; CH=), 7.34–7.31 (m, 2H; o-H-arom.), 7.43–
7.42 ppm (m, 3H, m,p-H-arom.); 13C NMR (100 MHz, CDCl3): d=
13.3, 14.0 (CH2CH3), 61.4, 63.5 (CH2CH3), 116.3 (CH=), 127.4 (o-C-
arom.), 128.2 (m-C-arom.), 128.8 (p-C-arom.), 134.9 (i-C-arom.),
142.3 (C3), 148.7 (C6), 164.9 ppm (CO2Et); IR (neat): n˜ =1734 (CO2Et),
1590, 1497 cmÀ1 (Ph); HRMS (ESI-GCT) calcd for C15H16N2O3 [M+H]+
: 273.1239, found: 273.1239.
Methyl ester of trans-3-methyl-5-oxo-4-(triphenylphosphoranyl-
idene)azinohex-2-enoic acid (1d’): Yield: 329 mg (74%), pale-
yellow solid, m.p. 1228C (Et2O); Rf =0.17 (EtOAc); 1H NMR
(300 MHz, CDCl3): d=2.19 (s, 3H; CH3), 2.34 (d, J=1.45 Hz, 3H;
CH3), 3.71 (s, 3H; OMe), 5.81 (d, J=1.45 Hz, 1H; CH=), 7.49–
7.71 ppm (m, 15H; 3”C6H5); 13C NMR (75 MHz, CDCl3): d=18.7,
25.8 (2”CH3), 51.2 (COOCH3), 120.3 (CH=), 127.74 (d, 1J(C,P)=
6-Ethoxy-3-ethoxycarbonyl-4,5-propanopyridazine (5g): Yield:
420 mg (89%), colorless solid, m.p. 139–1408C (Et2O); Rf =0.33
(hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3): d=1.45 (t, J=
7.3 Hz, 3H; CH3), 1.47 (t, J=6.5 Hz, 3H; CH3), 2.22–2.12 (m, 2H;
CH2), 2.93–2.88 (m, 2H; CH2), 3.34–3.28 (m, 2H; CH2), 4.46 (q, J=
7.3 Hz, 2H; CH2), 4.69 ppm (q, J=6.5 Hz, 2H; CH2); 13C NMR
(100 MHz, CDCl3): d=14.0, 14.3 (2”CH2CH3), 23.2, 28.6, 33.1
(CH2CH2CH2), 61.3, 63.4 (2”CH2CH3), 133.5 (C=CCOEt), 145.2
(CCO2Et), 149.0 (C=CCO2Et), 163.6 (COEt), 164.4 ppm (CO2Et); ele-
mental analysis calcd (%) for C12H16N2O3: C 61.02, H 6.78, N 11.86;
found: C 61.12, 61.03, H 6.83, 6.93, N 11.93, 11.93.
3
93.8 Hz; i-C-arom.), 129.2 (d, J(C,P)=12.0 Hz; m-C-arom.), 132.4 (d,
2J(C,P)=9.5 Hz; o-C-arom.), 133.1 (p-C-arom.), 153.7 (C3), 156.6 (d,
3J(C,P)=42.0 Hz; C=N), 167.6 (COOCH3), 196.7 ppm (COCH3);
31P NMR (81 MHz, CDCl3): d=21.32 ppm; IR (KBr): n˜ =1648 (CO),
1714 cmÀ1 (CO); UV (EtOH): lmax(lge)=209 (4.37), 220 (4.41), 223
(4.39), 274 (3.95), 326 nm (4.27); elemental analysis calcd (%) for
C26H25N2O3P: C 70.27, H 5.6, N 6.3; found: C 70.23, 70.40, H 5.69,
5.78, N 6.34, 6.27.
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by flash chromatography (7 g of SiO2, eluent: petroleum ether/
EtOAc 10:1 then 3:1) to give 95 mg of pyridazine 5e and 15 mg of
trans-phosphazene 1e’ (total: 210 mg).
Tandem process for the synthesis of pyridazines 5 by
reactions with PPh3
PPh3 (61 mg, 0.23 mmol) was added portionwise to a solution of
cis-vinyldiazoketone F-4e (55 mg, 0.23 mmol) in Et2O (7 mL). The
solution was stirred for 19 h and then reaction mixture was sepa-
rated by flash chromatography (7 g of SiO2, eluent: petroleum
ether/EtOAc, 2:1, 50 mL) to give 107 mg (88%) of pyridazine 5e.
Pyridazine 5e: Yield: 95 mg (41%, 82% calculated on the basis of
cis-4e), colorless solid, m.p. 56–588C.[9a]
Methyl
ester
of
trans-5-oxo-4-(triphenylphosphoranyl-
idene)azino-3-trifluoromethyl-hex-2-enoic acid (1e’): Yield:
210 mg (40%), yellow solid, m.p. 140–140,58C (decomp), (Et2O);
Rf =0.13 (EtOAc); 1H NMR (300 MHz, CDCl3): d=2.22 (s, 3H; CH3),
3.79 (s, 3H; OCH3), 6.12 (s, 1H; CH), 7.45–7.72 ppm (m, 15H; 3”
C6H5); 13C NMR (75 MHz, CDCl3): d=24.4 (Me), 52.6 (OMe), 120.4 (q,
6-Methoxy-3-methylcarbonyl-4-(trifluoromethyl)pyridazine 5e:
Yield: 62mg (66%), colorless solid, m.p. 56–588C.[9a]
Methyl ester of cis-5-oxo-4-[tris(dimethylamino)phosphoranyl-
idene]azino-3-trifluoromethylhex-2-enoic acid (2e): Yield:
2
1J(C,F)=276.2 Hz; CF3), 128.4 (d, J(C,P)=13.0 Hz; o-C-arom.), 130.1
1
(q, 2J(C,F)=35.9 Hz; CCF3), 132.0 (m-C-arom.), 132.1 (p-C-arom.),
132.3 (d, 1J(C,P)=103.4 Hz; i-C-arom.), 132.4 (q, 3J(C,F)=2.7 Hz;
CH=), 137.1 (C=N), 162.9 (CO2Me), 195.4 ppm (COMe); IR (KBr): n˜ =
1656 (CO), 1739 cmÀ1 (CO); UV (EtOH): lmax(lge)=336 nm (4.30); el-
emental analysis calcd (%) for C26H22N2O3F3P: C 62.6, H 4.5, N 5.6;
found: C 62.33, H 4.50, N 5.55.
120 mg (71%), dark green oil, Rf =0.38 (EtOAc); H NMR (300 MHz,
CDCl3): d=2.38 (s, 3H; CH3), 2.71 (d, 3J(H,P)=9.3 Hz, 18H; CH3),
3.63 (s, 3H, OCH3), 6.52 ppm (s, 1H; CH=); 13C NMR (75 MHz,
CDCl3): d=25.3 (CH3), 37.5 (6”NCH3), 51.8 (COOCH3), 122.7 (q,
1J(C,F)=276.3 Hz; CF3), 126.1 (q, 3J(C,F)=5.0 Hz; CH=), 142.3 (q,
2J(C,F)=32.9 Hz; CCF3), 143.1 (d, 3J(C,P)=46.9 Hz; C=N), 164.7
(CO2CH3), 195.9 ppm (COCH3); HRMS (ESI-GCT) calcd for
C14H25F3N5O3P [M+H]+: 400.1725, found: 400.1728.
Reaction of the mixture of trans- and cis-vinyldiazoketones
F-3e/F-4e with P(NMe2)3
A solution of diazoester 4g (0.65 g, 2.6 mmol) in Et2O (ꢀ2 mL) was
added to a solution of triphenylphosphine (0.68 g, 2.6 mmol) in ab-
solute Et2O (5 mL). After 5 d at room temperature away from light
and air the reaction mixture was separated by flash chromatogra-
phy (15 g of SiO2, eluent: petroleum ether/tBuOMe in different
ratios) to give pyridazine 5g (317 mg) and hydrazone 7g (111 mg).
Tris(dimethylamino)phosphine (92 mg, 0.56 mmol) was added
dropwise to a mixture of vinyldiazoketones F-3e/F-4e (120 mg,
0.56 mmol, 1:1) in 10 mL of Et2O, whereby a slightly exothermic re-
action was observed and the solution turned bright green. After
10 min at room temperature the reaction mixture was subjected to
flash chromatography (6 g SiO2, eluent: ethyl acetate, 30 mL) to
give a mixture of stereoisomeric phosphazenes 1e/2e [152 mg,
ꢀ5:3; yield: 47% of 1e (94% based on F-3e)] as a dark green, oily
material. A solution of the obtained phosphazenes 1e/2e in 3 mL
of benzene was heated at 50–608C for 2 h, whereupon the reaction
mixture was separated by flash chromatography (10 g SiO2, eluent:
petroleum ether/ethyl acetate from 10:1 to 1:1) to give in order of
elution from the column: pyridazine 5e (55 mg) and trans-phos-
phazene 1e (74 mg).
Pyridazine 5g: Yield: 317 mg (53%).
Ethyl [2’-(ethoxycarbonyl)-cyclopent-1’-ene]-2-hydrozoneacetate
(7g): Yield: 111 mg (17%), colorless solid, m.p. 68–698C (Et2O), Rf =
0.4 (petroleum ether/tBuOMe 1:1); 1H NMR (300 MHz, CDCl3): d=
1.21 (t, J=6.5 Hz, 3H; CH3), 1.22 (t, J=6.5 Hz, 3H; CH3), 1.96–1.86,
2.78–2.72 m (6H; CH2CH2CH2), 4.10 (q, J=6.5 Hz, 2H; CH2), 4.15 (q,
J=6.5 Hz, 2H; CH2), 8.17 ppm (brs, 2H; NH2); 13C NMR (75 MHz,
CDCl3): d=14.4, 14.6 (2”CH2CH3), 21.9, 34.5, 38.0 (CH2CH2CH2),
60.5, 60.7 (2”CH2CH3), 129.9 (C=N), 131.4 (C=CCO2Et), 149.3 (C=
CCO2Et), 162.6, 166.1 ppm (2”CO2Et); elemental analysis calcd (%)
for C12H18N2O4: C 56.69, H 7.09, N 11.02; found: C 56.61, 56.63, H
7.38, 7.21, N 10.97, 10.97.
Pyridazine 5e: Yield: 55 mg (49%; 98% based on cis-4e), colorless
solid, m.p. 56–588C.[9a]
Methyl ester of trans-5-oxo-4-[tris(dimethylamino)phosphoranyl-
idene]azino-3-trifluoromethyl-hex-2-enoic acid (1e): Yield: 74 mg
(36%), dark green, oily material, Rf =0.38 (EtOAc); 1H NMR
(300 MHz, CDCl3): d=2.36 (s, 3H; CH3), 2.71 (d, 3J(H,P)=9.3 Hz,
18H; CH3), 3.76 (s, 3H; OCH3), 6.01 ppm (s, 1H; CH=); 13C NMR
(75 MHz, CDCl3): d=25.3 (CH3), 37.5 (6”NCH3), 52.0 (COOCH3),
121.5 (q, 1J(C,F)=276.2 Hz; CF3), 128.4 (q, 3J(C,F)=3.50 Hz; CH=),
142.3 (q, 2J(C,F)=32.9 Hz; CCF3), 143.1 (d, 3J(C,P)=46.9 Hz; C=N),
164.0 (CO2CH3), 195.6 ppm (COCH3); HRMS (ESI-GCT) calcd for
C14H25F3N5O3P [M+H]+: 400.1725, found: 400.1728.
Two-stage synthesis of pyridazine 5e by reaction with
P(NMe2)3
Tris(dimethylamino)phosphine (69 mg, 0.4 mmol) was added drop-
wise to a solution of cis-vinyldiazoketone F-4e (100 mg, 0.4 mmol)
in 2 mL of Et2O (slightly exothermic reaction, solution turned
bright yellow). After 10 min the reaction mixture was separated by
flash chromatography (7g of SiO2, eluent: petroleum ether/EtOAc,
2:1, 50 mL) to give 120 mg of cis-phosphazene 2e. A solution of
the obtained phosphazene 2e (120 mg, 0.3 mmol) in 2 mL of ben-
zene was heated at 80–818C for 30 min until the reaction was com-
plete (by TLC), and after flash chromatography (7g of SiO2, eluent:
petroleum ether/EtOAc, 2:1, 50 mL) followed by usual workup pro-
cedures, pyridazine 5e (62 mg) was isolated.
Photochemical isomerization of trans-phosphazenes 1a,b,e
to cis isomers 2a,b,e followed by cyclization to pyridazines
5a’,b,e
Pyridazine 5a’: Irradiation of phosphazene trans-1a (0.43 g,
1.24 mmol) in 20 mL of tBuOMe was carried out with UV light (l>
210 nm) at 50–558C for 16 h, and the oily residue after removing
the solvent was subjected to flash chromatography (7 g SiO2,
eluent: tBuOMe) to furnish 6-methoxy-3-(methoxycarbonyl)pyrida-
zine (5a’). Yield: 117 mg (56%), colorless solid, m.p. 119–1208C
(Et2O), Rf =0.6 (EtOAc); 1H NMR (300 MHz, CDCl3): d=4.05 (s, 3H;
OCH3), 4.24 (s, 3H; OCH3), 7.07 (d, 3J(H,H)=9.0 Hz, 1H; C5H),
Interaction of the mixture of trans- and cis-vinyldiazo-
ketones F-3e/F-4e with PPh3
A mixture of trans- and cis-vinyldiazoketones F-3e/F-4e (250 mg,
1 mmol, 1:1) was added to a solution of triphenylphosphine
(278 mg, 1 mmol) in Et2O (3 mL). After 19 h at room temperature
away from light and air a precipitate formed and was separated by
filtration, washed with cold Et2O (2”1 mL), and dried to give phos-
phazene 1e’ (195 mg). The residue from the filtrate was separated
3
8.08 ppm (d, J(H,H)=9 Hz, 1H; C4H); 13C NMR (75 MHz, CDCl3): d=
53.40, 55.87 (2”OCH3), 117.40 (HC5=), 130.61 (HC4=), 148.09
Chem. Eur. J. 2016, 22, 174 – 184
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(CCO2Me), 164.85 (CO2CH3), 166.45 ppm (COMe); HRMS (ESI-GCT)
calcd for C7H8N2O3 [M+H]+: 169.0613, found: 169.0615.
Pyridazine 5b: Irradiation of phosphazene trans-1b (0.85 g,
2.4 mmol) in 100 mL of hexane was performed with monochromat-
ic UV light (l=254 nm) for 72 h (monitoring by 31P NMR spectra)
followed by flash chromatography of the reaction mixture (25 g
SiO2, eluent: hexane/EtOAc in gradient regime) to give pyridazine
5b (170 mg, 39%) and a mixture of trans- and cis-phosphazenes
1b and 2b. The isolated mixture of phosphazenes 1b/2b was
heated in CHCl3 solution at 608C for 12 h followed by flash chroma-
tography (25 g SiO2, eluent: hexane/EtOAc in gradient regime) to
give, after standard workup procedures, pyridazine 5b (130 mg; to-
tally 300 mg) and unconsumed trans-phosphazene 1b (195 mg,
23%). 4-Methyl-6-methoxy-3-(methoxycarbonyl)pyridazine 5b:
Yield: 300 mg (69%), colorless solid, m.p. 119–1208C (hexane), Rf =
0.42 (EtOAc); H NMR (400 MHz, CDCl3): d=6.81 (q, J(H,H)=1.0 Hz,
1H; CH), 4.17 (s, 3H; OMe), 3.99 (s, 3H; OMe), 2.54 ppm (d,
4J(H,H)=1.0 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=165.4
(CO2Me), 165.0 (C6), 148.1 (C3), 142.1 (C4), 117.8 (C5), 54.9, 52.5 (2”
OMe), 19.5 ppm (CH3); IR (KBr): n˜ =1734 (CO), 1592, 1442 cmÀ1
(ring, g); HRMS (ESI-GCT) calcd for C8H10N2O3 [M+H]+: 183.0770,
found: 183.0774.
1
4
Pyridazine 5e: Irradiation of phosphazene trans-1e (140 mg,
0.35 mmol) in 10 mL of Et2O was carried out with UV light (l>
310 nm) at room temperature for 2 h, and the oily residue after re-
moving the solvent was subjected to flash chromatography (7 g
SiO2, eluent: tBuOMe) to give 5.5 mg (7%) of pyridazine 5e.
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for 70 h, and the oily residue after removing the solvent was sub-
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Partial support of the work with a short-term fellowship to
M.B.S. by the Loker Hydrocarbon Research Institute is gratefully
acknowledged. M.B.S. and V.A.N. thank Saint Petersburg State
University for the financial support of this research at USC
(order 1831/1; 02.06.2011). D.C. thanks the Research Technolog-
ical Innovation, and Supercomputing Center of Extremadura
(CenitS) for their support in the use of LUSITANIA computer re-
sources. The authors are also greatly appreciate Prof. Dr. J.
Sieler (Universität Leipzig, Institut für Anorganische Chemie,
Germany) for performing X-ray analysis of (triphenyl)phospha-
zenes H-1c’ and F-1e’. This project was carried out in part
using the resources of the “Center for Chemical Analysis and
Materials Research”, “Center for Magnetic Resonance”, “Center
for Optical and Laser Methods Research” and “X-ray Diffraction
Centre” of St-Petersburg State University.
Keywords: cyclization
· isomerization · phosphazenes ·
photochemistry · Wittig reactions
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Received: August 29, 2015
Published online on November 25, 2015
Chem. Eur. J. 2016, 22, 174 – 184
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