A simple, enaminone-based approach to some bicyclic pyridazinium tetrafluoroborates

Article abstract of DOI:10.3762/bjoc.9.166

Easily obtainable cyclic enaminones (piperidin-2-ylidenealkanones) can be transformed into substituted bicyclic pyridazinium tetrafluoroborates upon treatment with corresponding diazonium salts. The transformation can be performed either in a one-pot way or in a two-step process with the isolation of single azo-coupled enaminone as the intermediate. The former method is superior. Under the optimized conditions, a number of pyridazinium salts substituted with both electron-donating and electron-withdrawing substituents was easily synthesized. A mechanism of the formation of the pyridazinium salts is suggested. A partial drawback is the possibility of the formation of a mixture of products when using a different diazonium salt in each step due to a reversibility of the azo coupling. This can be suppressed by using a more reactive diazonium salt before a less reactive one.

Full text of DOI:10.3762/bjoc.9.166

A simple, enaminone-based approach to some
bicyclic pyridazinium tetrafluoroborates
František Josefík1, Markéta Svobodová1, Valerio Bertolasi2
and Petr Šimůnek*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1463–1471.
1Institute of Organic Chemistry and Technology, Faculty of Chemical
Technology, University of Pardubice, Studentská 573, CZ 532 10,
Pardubice, Czech Republic and 2Dipartimento di Scienze Chimiche e
Farmaceutiche, Centro di Strutturistica Diffratometrica, Università di
Ferrara, Via L. Borsari 46, 441 00, Ferrara, Italy
doi:10.3762/bjoc.9.166
Received: 21 March 2013
Accepted: 28 June 2013
Published: 23 July 2013
Email:
Associate Editor: V. M. Dong
Petr Šimůnek* - petr.simunek@upce.cz
© 2013 Josefík et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
azo coupling; diazonium salt; enaminone; pyridazinium
Abstract
Easily obtainable cyclic enaminones (piperidin-2-ylidenealkanones) can be transformed into substituted bicyclic pyridazinium tetra-
fluoroborates upon treatment with corresponding diazonium salts. The transformation can be performed either in a one-pot way or
in a two-step process with the isolation of single azo-coupled enaminone as the intermediate. The former method is superior. Under
the optimized conditions, a number of pyridazinium salts substituted with both electron-donating and electron-withdrawing
substituents was easily synthesized. A mechanism of the formation of the pyridazinium salts is suggested. A partial drawback is the
possibility of the formation of a mixture of products when using a different diazonium salt in each step due to a reversibility of the
azo coupling. This can be suppressed by using a more reactive diazonium salt before a less reactive one.
Introduction
As heterocyclic compounds play a very important role in reviews see, e.g., [2-6]). During the past several years we have
everyday life, e.g., as pharmaceuticals, agrochemicals, dyes, dealt with the reaction of various enaminones with diazonium
etc. (for many monographies or textbooks on this topic see, e.g. salts and established a number of methods for the construction
[1]), searching for new heterocyclic systems or novel methods of some important or unusual heterocyclic systems [7-15],
for the synthesis of the existing ones represents a very impor- including a simple protocol leading from enaminones 1 to
tant part of organic chemistry. Enaminones, due to their ability 6-substituted 4-amino-5-aryldiazenyl-1-arylpyridazinium salts 2
to react with both electrophiles and nucleophiles, are versatile [14,15]. The procedure consists of the reaction of the corres-
synthons, and not only in heterocyclic chemistry (for many ponding enaminones and two equivalents of diazonium tetra-
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Scheme 2: Suggested transformation of the cyclic enaminones into
the corresponding bicyclic pyridazinium salts.
order to extend the applicability of the method. As the
substrates, we have chosen the exocyclic enaminones 3, which
would gain access to bicyclic pyridazinium salts 5 (Scheme 2).
Results and Discussion
Enaminones 3 were prepared as previously reported [12]
(Scheme 3). The last step of the synthesis is the deacetylation of
7 by sodium in ethanol. In the case of substrate 3a the deacetyl-
ation spontaneously takes place during the 2nd step.
Scheme 1: Syntheses of 1-arylpyridazinium salts.
The reaction of the enaminone 3a with two equivalents of
fluoroborates or hexafluorophosphates with the later giving 4-methylbenzenediazonium tetrafluoroborate under the same
better yields and applicability (Scheme 1, top).
conditions as described in [8] (i.e., DCM, rt, 2 equiv of diazo-
nium salt, 6 equiv of sodium acetate) afforded the corres-
It extends the existing procedure [16-24] for the construction of ponding pyridazinium salt 5a in 36% yield. The same proce-
the 1-arylpyridazinium scaffold based on acid- or base- dure applied to the benzoylacetone derivative 3b gave even
catalyzed cyclization of the corresponding hydrazones lower yield (19%) of the salt 5g.
(Scheme 1, bottom). Apart from this, reactions of enaminones
with diazonium salts giving substituted pyridazines are also The cause of the low yields probably lies in the method of
described [25-28]. Our method does not require any additive, performing the reaction. The solid diazonium salt, added in one
and the transformation from 1 to 2 is performed as a one-pot portion, could partially decompose before being able to react
procedure. Different substrates are used and different and novel causing both lowering of the yield and contamination of the
pyridazinium patterns are built under mild conditions [14,15].
reaction mixture with the decomposition products. Therefore,
the first attempt to improve the yields (method A) consisted in
The above-mentioned method [14,15] (Scheme 1, top) is, portionwise addition of the diazonium salt. The second portion
however, limited to electron-donating or slightly electron- was added after the first one had been fully consumed (tested by
withdrawing (-Cl) substituents on diazonium salts. Only the chromotropic acid). Using this method, we were able to prepare
enaminones having a C=C(NHR)–CH3 fragment were success- also mixed pyridazinium salts from two different diazonium
fully applied. In this study we decided to further examine the salts (Scheme 4, Ar1 ≠ Ar2). However, the yields were still, at
reaction of enaminones with diazonium tetrafluoroborates in best, moderate (Table 1).
Scheme 3: The synthesis of the starting β-enaminones.
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Scheme 4: Synthesis of the bicyclic pyridazinium salts using different methods.
Table 1: Comparison of the individual methods for the synthesis of the salts 5.
Entry
Salt
R
Ar1
Ar2
Method Aa
Yield [%]
Method B
Yield [%]
Method Cb
Yield [%]
1
5a
5b
5c
5d
5e
5f
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MePh
4-MeOPh
4-BrPh
4-MePh
40 (12)
39 (20)
47 (20)
24 (10)
24 (5)
16
70
92
60
45
57
85
80
72
53
26
61
93
76
41 (4a 89)
81 (4b 84)
61 (4c 78)
50 (4d 76)
79 (4e 88)
85 (4e 88)
71 (4f 95)
74 (4g 90)
55 (4h 58)
c, (d)
2
4-MeOPh
4-BrPh
3
4
4-Et2NPh
4-NO2Ph
4-NO2Ph
4-MePh
4-MeOPh
4-BrPh
4-Et2NPh
4-NO2Ph
4-Et2NPh
4-MePh
5
6
7
5g
5h
5i
50 (10)
10 (20)
40 (15)
32 (12)
1 (0)
8
4-MeOPh
4-BrPh
9
10
11
12
13
5j
4-Et2NPh
4-NO2Ph
4-MePh
4-NO2Ph
4-Et2NPh
4-NO2Ph
4-Et2NPh
4-MeOPh
5k
5l
68 (4j 93)
73 (4f 95)
85 (4j 93)
15
5m
–e
aYields for 6 equiv of AcONa are in parentheses. bYield for the 2nd step. Yields for the 1st step (product 4) are in parentheses. cFailed. dProduct 4i is
too unstable to be isolated and was used directly in the next reaction step. eNot performed.
Method A was then modified. To achieve better homogeneity of The pyridazinium salts prepared were characterized by means
the reaction mixture, a solution of the diazonium salt in of 1H and 13C NMR spectroscopy and elemental analysis or
methanol was used instead of the solid salt (method B). This HRMS (see Experimental and Supporting Information File 1).
modification led to a substantial increase of the yields (Table 1). Some of them were characterized also by means of X-ray
analysis (see below).
Further modification (method C) comprises step-by-step imple-
mentation of the methodology B. After the consumption of the The mechanism of the azo coupling of primary and secondary
first equivalent of the diazonium salt the reaction mixture was enaminones was studied in [29]. The formation of compounds 4
worked-up and the product was isolated and characterized by can be assumed to proceed in an analogous way. A possible ex-
means of 1H and 13C NMR in solution and elemental analysis planation of the formation of the pyridazinium salts 5 from the
or HRMS. The isolated intermediates 4 were subjected to the intermediates 4 is shown in Scheme 5.
reaction with another equivalent of the diazonium salt. The
same products as in the case of the one-pot procedures (methods Compound 4, formed either in situ (methods A,B) or in a sepa-
A,B) were isolated (Scheme 4). For comparison of the stepwise rate experiment (method C) can exist in equilibrium with its
procedure (method C) with the other ones see Table 1. The enol form. It reacts with another equivalent of the diazonium
methodology failed only in the case of compound 4i (Table 1, salt to form the product of double azo coupling Im (Scheme 5).
entry 10), which was too unstable and decomposed upon an We have observed the formation of similar compounds upon
attempt of its isolation.
azo coupling of some enaminones [11,30,31]. Fluoroboric acid,
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Scheme 5: Possible mechanism of the formation of the pyridazinium salts 5.
liberated during the formation of Im, is not captured by the base ion 5 is slower but irreversible. The less electrophilic benzene-
(as no equivalent of sodium acetate is used in the 2nd step) and diazonium ion (4-methoxy) is preferentially eliminated from Ip
could catalyze an intramolecular attack of hydrazone NH to give 4j (the product of the exchange of the diazenyl groups).
nitrogen to the carbonyl group. After a subsequent loss of water, 4j can further react either with another equivalent of 4-nitroben-
the molecule of pyridazinium salt 5 is formed. This hypothesis zenediazonium (to give 5k) or with 4-methoxybenzenediazo-
is supported by the fact that the use of an excess of sodium nium (formed by cleavage from the Ip intermediate) to give 5m
acetate led to significantly lower yields (for comparison see (both in the sense of Scheme 5). Compound 5n is not formed as
Table 1, method A). However, the above-mentioned scheme is it requires the cleavage of the more electrophilic benzenediazo-
only a speculation (as the intermediate Im has never been nium ion (4-nitro) from Ip (disfavored).
isolated) based on the observations made on similar reactions
and on the knowledge of structures of the starting compounds The above-mentioned appears to be a drawback of the method-
and the products.
ology: the more reactive diazonium salt should be used before
the less reactive one otherwise a mixture of products can arise.
An attempt at preparation of 4-(4-methoxyphenyldiazenyl)-2-
(4-nitrophenyl)-3-phenyl 5,6,7,8-tetrahydropyrido[3,2-c]pyrid- Similar results were obtained on reaction of 4b with an equiva-
azin-2-ium tetrafluoroborate (5n) failed. A mixture of com- lent of 4-bromobenzenediazonium tetrafluoroborate: a mixture
pounds 5k + 5m (approx. 1:2) was obtained instead. Crystal- of products was obtained. Attempts to separate the components
lization of the mixture gave a mixed crystal (5k + 5m, for of such mixtures failed, probably due to the very similar prop-
discussion of its structure see below). A possible explanation erties of the pyridazinium salts formed.
for this lies in an exchange of the diazonium ions (Scheme 6).
It should be emphasized that the above-mentioned suggestions
The mechanism of the exchange is described in [32]. Its appli- on the mechanism are only suppositions based on the structures
cation to the reaction of 4g with 4-nitrobenzenediazonium ion of the isolated compounds and reactants as well as the results
(Scheme 6) can explain the formation of the mixture of pyridaz- obtained in similar reactions.
inium salts 5k + 5m: 4g can react with another molecule of the
diazonium salt either to give the bishydrazone intermediate Im The structures of the compounds 5a,b,d,f,g,j,l,m were also
and subsequently the pyridazinium salt 5n (in the sense of solved by using X-ray diffractometry. ORTEP [33] views of the
Scheme 5) or it can undergo an ipso attack to form the inter- compounds 5f and 5l are shown in Figure 1 and Figure 2, the
mediate Ip, consisting of 4-methoxy and 4-nitrophenyldiazenyl others are given in Supporting Information File 1. Almost all
groups. The ipso attack is faster but reversible, whereas the for- the structures display some disorder. Structures 5d, 5f, 5j and 5l
mation of Im followed by the cyclization to the pyridazinium show disorder in the C3–C7,N3 six-membered rings and the
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Scheme 6: An attempt at synthesis of 5n and possible explanation of the failure.
C5H2 moieties were refined over two sites. All the BF4− anions probably due to a partial decomposition of the diazonium salt
exhibit high temperature factors; in 5d and 5l the fluorine atoms during the reaction. An implementation of homogeneous reac-
were refined over two split sites. In 5m the asymmetric unit is tion conditions using a methanolic solution of the corres-
built up by two cations, which differ only in the conformation ponding diazonium tetrafluoroborates led to a substantial
of the O–CH3 moiety, and two BF4− anions. Also in 5k + 5m increase of both yields and the scope of the existing procedure.
the asymmetric unit is built up by two cations, but while the Two variations of the homogeneous procedure were tested:
structure of the cation A did not present any problems during
the refinement, the cation B revealed a structure with two super-
imposed substituents, –OCH3 and –NO2, in para position at
C20b–C25b phenyl ring. The two different substituents were
refined independently with occupancies of 0.5 each.
1. A two-step procedure (method C) with the isolation and
characterization of the intermediates 4 followed by their
reaction with another equivalent of the diazonium salt.
2. A one-pot procedure (method B) with the addition of
another equivalent of the diazonium salt into the reac-
tion mixture directly after the consumption of the first
equivalent without the isolation of the intermediate 4.
The crystal data are given in Supporting Information File 1
(Table S1). A selection of bond distances and angles and the
intramolecular hydrogen bond parameters are also reported in
Supporting Information File 1 (Table S2 and Table S3).
The single-stage protocol (method B) is superior to the other
ones as it gives comparable or better yields without the need to
isolate the intermediate 4.
Conclusion
We have developed an improved simple methodology for the
construction of bicyclic pyridazinium tetrafluoroborates. The Pyridazinium salts 5 arise from azo-coupled enaminones 4
heterogeneous variant (method A) suffers from low yields, probably via the products of double azo coupling (Im) through
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Beilstein J. Org. Chem. 2013, 9, 1463–1471.
Figure 2: ORTEP view of the cation of compound 5l showing the
thermal ellipsoids at 30% probability level. Both the disordered C5H2
and C5’H2 moieties are displayed.
Figure 1: ORTEP view of the cation of compound 5f showing the
thermal ellipsoids at 30% probability level. Both the disordered C5H2
and C5’H2 moieties are displayed.
Compound 6 was prepared from δ-valerolactam and dimethyl
sulfate according to the procedure described in [34]. Com-
an intramolecular nucleophilic addition followed by the loss of pounds 3a,b and 7 were prepared according to the procedures
water. The statement is, however, based only on the structures published in [12].
of the reactants and products and on the comparison with
similar reactions.
NMR spectra were measured using a Bruker AVANCE III
spectrometer operating at 400.13 (1H) and 100.62 MHz (13C).
A drawback of the method is the fact that azo coupling is a re- Some spectra were also measured using a Bruker Avance 500
versible reaction. The more reactive diazonium salt can replace spectrometer operating at 500.13 (1H) and 125.77 MHz (13C).
the less reactive one to give a mixture of products. The ideal All the pulse sequences were taken from the Bruker software
combination is to use the more reactive diazonium salt fol- library. Proton spectra measured in CDCl3 were calibrated
lowed by the less reactive one, as the diazonium exchange is based on internal TMS (δ = 0.00) and (in DMSO-d6) based on
suppressed here.
the middle signal of the solvent multiplet (δ = 2.55). Carbon
NMR spectra were calibrated on the middle signal of the
solvent multiplet (δ = 77.23 (CDCl3) and 39.60 (DMSO-d6)).
Experimental
All the solvents and reagents were purchased from commercial
suppliers and were used without further purification. Diazo- Elemental analyses were performed on a Flash 2000 CHNS
nium tetrafluoroborates were prepared according to an ordinary Elemental Analyzer. Melting points were measured on a Kofler
procedure (diazotization using cold NaNO2/HCl with subse- hot-stage microscope Boetius PHMK 80/2644 and were not
quent precipitation, from the filtered solution of the diazonium corrected. MALDI HRMS were measured using a MALDI LTQ
chloride, by aqueous sodium tetrafluoroborate). Precipitated Orbitrap XL (Thermo Fisher Scientific) with DCTB as the
diazonium tetrafluoroborates were dried in vacuo in a desic- matrix dissolved in acetonitrile. The crystal data of all the com-
cator and stored in a refrigerator.
pounds were collected at room temperature using a Nonius
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Kappa CCD diffractometer with graphite monochromated dichloromethane (50 mL). After the diazonium salt had been
Mo Kα radiation. The data sets were integrated with the Denzo- consumed (negative test on chromotropic acid), an equivalent of
SMN package [35] and corrected for Lorentz, polarization and 4-diethylaminobenzenediazonium tetrafluoroborate (5 mmol)
absorption effects (SORTAV) [36]. The structures were solved was immediately added. The reaction mixture was then stirred
by direct methods using the SIR97 [37] system of programs and at ambient temperature for 4 days. Sodium acetate was removed
refined anisotropically by using full-matrix least-squares for all by suction, and the filtrate was evaporated to dryness in vacuo.
non-hydrogen atoms and hydrogen atoms included on their The residue was dissolved in methanol/chloroform (1:10) and
calculated positions, riding on their carrier atoms; except the subjected to flash chromatography on silica gel. Subsequent
N–H hydrogens forming intramolecular hydrogen bonds, which crystallization from methanol afforded the desired product.
were refined isotropically. In the structure 5m an ill-defined
region of residual electron density was found. For this reason Method B: The procedure is analogous to method A, only
the program SQUEEZE was used to cancel out the effects of the methanol was used as the solvent and the diazonium salts were
undetermined disordered solvent. SQUEEZE is a part of the added dropwise (as saturated methanolic solutions) into the
PLATON system of programs. All calculations were performed reaction mixture. The second equivalent of the diazonium salt
by using SHELXL-97 [38], PARST [39] and PLATON [40] was added after the consumption of the first one (negative test
implemented in WINGX [41] system of programs. Crystallo- on chromotropic acid). The solvent was then evaporated in
graphic data (excluding structure factors) have been deposited vacuo and the crude was purified by flash chromatography and
at the Cambridge Crystallographic Data Centre and allocated crystallization.
the deposition numbers CCDC 928078-928086. These data can
be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/ Method C: Saturated methanolic solution of 4-diethylamino-
retrieving.html or on application to CCDC, Union Road, benzenediazonium tetrafluoroborate (5 mmol) was added drop-
Cambridge, CB2 1EZ, UK [fax: (+44)1223-336033, e-mail: wise into the cold (5 °C) methanolic solution (5 mmol, 20 mL)
deposit@ccdc.cam.ac.uk].
of azo compound 4e (prepared according to the above-
mentioned procedure) over 30 minutes. The reaction mixture
was stirred for 4 days at room temperature. The solvent was
then evaporated in vacuo. The residue was dissolved in
Typical procedure for the synthesis of com-
pounds 4
Enaminone 3a (5 mmol) and AcONa (5 mmol) were dissolved methanol/chloroform (1:10) and subjected to flash chromatog-
in cold (5 °C) methanol. A saturated methanolic solution of raphy on silica gel. Subsequent crystallization from methanol
4-methylbenzenediazonium tetrafluoroborate (5 mmol) was afforded the desired product.
added dropwise over 30 minutes. The mixture was then stirred
at ambient temperature for 24 h. The solvent was evaporated in 2-(4-(Diethylamino)phenyl)-4-(4-nitrophenyldiazenyl)-3-
vacuo, and the crude product was dissolved in dichloromethane methyl-5,6,7,8-tetrahydropyrido[3,2-c]pyridazin-2-ium
and subjected to flash chromatography on silica gel. Subse- tetrafluoroborate (5f) Yields: A: 16%, B: 85%, C : 85%, red
quent crystallization from n-hexane/ethanol afforded the pure crystals, mp 150–152 °C; 1H NMR (400 MHz, DMSO-d6)
products.
δ 11.39 (br s, 1H), 8.48–8.45 (m, 2H), 8.36–8.34 (m, 2H),
7.43–7.41 (m, 2H), 6.85–6.83 (m, 2H), 3.43 (q, J = 7.0 Hz, 4H),
1-[2-(4-Methylphenyl)diazen-1-yl]-1-(piperidin-2- 3.08–3.05 (m, 2H), 2.86 (s, 3H), 2.17–2.11 (m, 2H), 1.15 (t, J =
ylidene)propan-2-one (4a, R = Me, Ar1 = 4-MePh) yield 7.0 Hz, 6H); 13C NMR (101 MHz, DMSO-d6): 158.6, 155.0,
89%, yellow crystals, mp 92–93 °C; 1H NMR (400 MHz, 151.4, 148.8, 148.3, 137.1, 129.6, 126.8, 125.1, 124.0, 111.0,
CDCl3) δ 15.18 (br s, 1H), 7.42–7.41 (br m, 2H), 7.16–7.14 (br 43.9, 42.2, 27.6, 18.2, 17.0, 12.3; Anal. calcd for
m, 2H), 3.46 (br s, 2H), 3.08–3.06 (m, 2H), 2.50 (s, 3H), 2.33 C24H28BF4N7O2: C, 54.05; H, 5.29; N, 18.38; found: C, 54.01;
(s, 3H), 1.71–1.73 (m, 4H) ppm; 13C NMR (101 MHz, CDCl3) H, 5.45; N, 18.10.
197.7, 162.5, 148.5, 135.9, 129.5, 128.1, 119.2, 42.3, 28.2, 28.0,
21.0, 20.7, 18.6 ppm; Anal. calcd for C15H19N3O: C, 70.01; H,
Supporting Information
7.44; N, 16.33; found: C, 69.87; H,7.40; N, 16.53.
Supporting Information File 1
Experimental procedures, characterization data and X-ray
Typical procedures for the synthesis of pyrid-
azinium salts 5
parameters.
Method A: Solid 4-nitrobenzenediazonium tetrafluoroborate
(5 mmol) was added in one portion into a cold (5 °C) mixture of
enaminone 3a (5 mmol) and sodium acetate (5 mmol) in
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-166-S1.pdf]
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