A new mild synthetic route to N-arylated pyridazinones from aryldiazonium salts

Article abstract of DOI:10.1039/c4cc03190c

An efficient method for the synthesis of N-arylated pyridazinones from potassium 2-furantrifluoroborate and aryldiazonium salts is described. The reaction was run in water at 0-5 °C in short reaction times and without any catalyst or additive. A mechanistic proposal is made based on the experimental data and DFT calculations. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc03190c

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A new mild synthetic route to N-arylated
pyridazinones from aryldiazonium salts†
Cite this: Chem. Commun., 2014,
50, 8073
Ouissam El Bakouri,a Daniel Cassu,a Miquel Sola,a Teodor Parella,b
´
`
Anna Pla-Quintanaa and Anna Roglans*a
Received 29th April 2014,
Accepted 3rd June 2014
DOI: 10.1039/c4cc03190c
www.rsc.org/chemcomm
An efficient method for the synthesis of N-arylated pyridazinones compounds when reacted with several aryldiazonium salts but
from potassium 2-furantrifluoroborate and aryldiazonium salts is rather that N-arylated pyridazin-3(2H)-one derivatives were
described. The reaction was run in water at 0–5 8C in short reaction obtained. We then tested the same reaction without the palladium
times and without any catalyst or additive. A mechanistic proposal catalyst and found that the same heterocycles were obtained.
is made based on the experimental data and DFT calculations.
Therefore, we envisaged that a new simple and mild method for
the preparation of N-arylpyridazinones could be set up directly
Pyridazin-3(2H)-ones and their N-aryl substituted derivatives are from aryldiazonium salts and potassium 2-furantrifluoroborate
building blocks found in many biologically active compounds under mild conditions.
such as pharmaceuticals and pesticides.1 As an example, com-
We first focused on the optimization of the reaction conditions
pound 1 (Fig. 1), which is used in the treatment of central using potassium 2-furantrifluoroborate 2 and p-acetylphenyl-
nervous system disorders, a naphthalene-based compound was diazonium tetrafluoroborate 3a. The first parameter to be evalu-
synthesized by copper-catalyzed N-arylation of pyridazinone.2
ated was the ratio between reactants. A 53% yield of 4a was
Several methods for the de novo synthesis of this kind of obtained after three hours using a stoichiometric ratio (entry 1,
nitrogen heterocycles are described in the literature.3 The most Table 1). With an excess of aryldiazonium salt (1 : 2), the yield
common synthetic pathways are based on the introduction of dropped to just 35% after 20 hours (entry 2, Table 1). When an
the two nitrogen atoms from hydrazine4 and hydrazone5 deriva- excess of potassium 2-furantrifluoroborate 2 was used (2 : 1), the
tives, which are sometimes prepared from aryldiazonium salts. yield increased to 67% in just five minutes (entry 3, Table 1). The
In an ongoing study on palladium-catalyzed cross-coupling yield was similar (66%), although with an increased reaction time
reactions involving aryldiazonium salts and heteroaryltrifluorobo- (20 minutes), when the excess of 2 was reduced to 1.2 : 1 and the
rates using water as a solvent,6 our group found that potassium temperature was lowered to 0–5 1C (entry 4, Table 1).
2-furantrifluoroborate did not afford the expected cross-coupling
Given that we observed that the pH of the reaction medium
was highly acidic at the end of the reaction, we decided to test
Table 1 Optimization of the reaction between 2 and 3aa
Fig. 1 Structure of N-aryl pyridazin-3(2H)-one 1.
Entry Ratio 2 : 3a Reaction conditions
Yield of 4a (%)
1
2
3
4
5
6
7
1 : 1
1 : 2
2 : 1
1.2 : 1
1.2 : 1
1.2 : 1
1.2 : 1
25 1C, 3 h
25 1C, 20 h
25 1C, 5 min
53
35
67
66
0
a
´
`
Institut de Quımica Computacional i Catalisi (IQCC) and Departament de
´
Quımica, Universitat de Girona, E-17071 Girona, Catalonia, Spain.
0-5 1C, 20 min
E-mail: anna.roglans@udg.edu; Fax: +34 972418150; Tel: +34 972418275
tBuOK (5 eq.), 0–5 1C, 2 h
NaOAc (5 eq.), 0–5 1C, 20 min
b
´
`
Servei de RMN and Departament de Quımica, Universitat Autonoma de Barcelona,
47
E-08193 Bellaterra (Barcelona), Catalonia, Spain
NaOAc (1.2 eq.), 0–5 1C, 20 min 67
† Electronic supplementary information (ESI) available: Experimental details,
spectroscopic data and spectra of all synthesized compounds, computational
details and Cartesian coordinates of all optimized stationary points. See DOI:
10.1039/c4cc03190c
a
Experimental procedure: 3a dissolved in H2O (0.107 M) was added to a
stirred aqueous solution of 2 (in 6 mL of water) and the flask was
protected from light.7
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the effect of adding a base.8 The addition of an excess of tBuOK the process. A low yield was obtained, which could not be
resulted in decomposition (entry 5, Table 1) so, a weaker base improved by increasing the reaction time. More challenging
such as NaOAc was then tested and a 47% yield of 4a was aryldiazonium salts were then tested. As potassium naphthyldia-
obtained (entry 6, Table 1). Using only 1.2 eq. of NaOAc, the zoniumtetrafluoroborate was unstable, the corresponding hexa-
yield was the same as that obtained without the base (compare fluorophosphate salt was prepared and reacted resulting in
entries 4 and 7, Table 1). We therefore concluded that the base moderate yields of the corresponding pyridazinone 4k. The
was not required. When the reaction was run in solvents other heteroaromatic thiophendiazonium salt also reacted affording
than water such as ethanol or acetonitrile, a wide range of a 32% yield of N-heteroarylpyridazinone 4l. The scale up of the
undesired and undefined products were detected. But when process was also successful since starting with 0.5 g (2.14 mmols)
water was added to the organic media (EtOH : H2O (3 : 7) and of 3a the yield of 4a was 56%.
CH3CN : H2O (3 : 7)) the product was obtained although with a
The next step was to study the mechanism of this process. It
slightly decreased yield, showing that water is necessary for is well known that aryldiazonium salts have an electrophilic
such a process. As a last set of experiments, in situ generation character in the aromatic substitution of activated rings giving
of the aryldiazonium salt was tested. Neither by using mixtures the corresponding azo derivatives. Mayr et al.9 have recently
of HBF4–NaNO2, HCl–NaNO2, tBuONO nor with tBuONO– published that the BF3K group in heteroayl trifluoroborates such
CH3SO3H did the results improve. Only low yields of pyridazi- as 2-furantrifluoroborate 2 increases the nucleophilicity of the
none and decomposition products were obtained.
remote position of the p-system in the electrophilic aromatic
Therefore, the reaction conditions of entry 4 were used to substitutions. Given this, an initial nucleophilic attack of the
study the scope of the reaction. Both electronic and steric effects 5-remote position (see chart of Table 1) of the furan derivative to
were evaluated in the aryldiazonium salt partner (Chart 1). When the nitrogen atom of the diazonium partner could be proposed.
the diazonium salt had an electron-withdrawing substituent, However, aryldiazonium salts have also been described as
pyridazinone 4 was obtained more efficiently in a shorter reac- acting as dienophiles in Diels–Alder (DA) reactions with several
tion time. With an NO2 substituent, either in the para or ortho 1,3-dienes.10 Since the furan derivative can act as a diene, this is
position, the reaction gave good yields in just five minutes another possibility in our system that we wanted to consider.
(4b and 4c). As the electron-donating nature of the substituent
To unravel the reaction mechanism for the synthesis of 4a
increased, the reaction time lengthened lowering the yield of the and 4j we conducted DFT calculations. Geometry optimizations
pyridazinone derivative (4d–4j). In an attempt to improve the and frequency calculations were carried out using the Gaussian 09
yields of 4g and 4j, the reaction was warmed to room tempera- program with the M06-2X/6-31G++(d,p) method under water
ture and left for 24 hours affording a 42% yield for 4g and 29% solution simulated with the SMD method (ESI†). The Gibbs
for 4j. The effect of an added base (5 eq. of NaOAc) was tested in energy profiles obtained are shown in Scheme 1. We initially
the case of 4j without any improvement in yield being obtained. studied the DA cycloaddition between the aryldiazonium salt
In the case of o-Me, 4h, both the electronic nature of the acting as a dienophile and the furan derivative as a diene but
substituent and steric hindrance had an important effect on we were unable to locate the transition state (TS) and the
expected product of the addition. Consequently, the DA reac-
tion was ruled out as a possible initial step for this reaction.
Fukui function calculations corroborated the result by Mayr
et al.9 that position 5 of the 2-furantrifluoroborate 2 is the most
nucleophilic. Then, and not totally unexpectedly, the initial step
is a nucleophilic attack of the 5-position of the furan derivative 2
to the terminal N atom of the diazonium partner 3 via TS(R,I)
with a relatively low Gibbs energy barrier (7.6 kcal molꢀ1 for 3a
and 10.7 kcal molꢀ1 for 3j) to afford intermediate I, a trans
diazene species, in an almost thermoneutral process. The for-
mation of a cis diazene species is also possible but the barriers
are much higher (about 20 kcal molꢀ1), and, therefore, these
were not considered relevant species in the reaction mechanism.
Not surprisingly, the barrier giving I is lower for the diazonium
salt 3a, as it has an electron-withdrawing substituent in the para
position of the aryl group.11 In support of this first step, we
found that the reaction with furan instead of 2 only led to the
recovery of starting materials. Furan itself is not sufficiently
nucleophilic9 to attack the aryldiazonium salt. The next step
involves a nucleophilic attack of an explicit water molecule at
position 2 of the furan ring and simultaneous proton transfer of
a water proton to the N directly attached to the aryl ring. This
Chart 1 Synthesis of N-arylated pyridazinones 4. Reaction conditions: 3
(0.42 mmol, 1 eq.) dissolved in H2O (4 mL) was added to a stirred aqueous
solution (6 mL) of 2 (0.51 mmol, 1.2 eq.) at 0–5 1C in a covered flask. Mass
balance mainly corresponds to decomposition. a Product isolated with
traces of 4-hydrated derivative.
process, which yields intermediate II, has a small Gibbs energy
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Scheme 1 Gibbs energy profiles in a water solution at 298 K (electronic energies in parentheses) leading to the formation of 4a (blue) and 4j (red).
barrier of ca. 6 kcal molꢀ1. A subsequent proton transfer of the advanced intermediate, probably IV0, supporting again the
same proton to the O of the furan ring breaks the C(5)–O bond of involvement of a water molecule, which after fragmentation
the five-membered ring and yields intermediate III in a slightly again loses BF3 to afford intermediate V. Analogous behaviour
endergonic and barrierless step. The lone pair of the N bonded was observed for aryl diazonium salt 3e (see ESI†).
to the aryl ring then attacks C(2) of the initial furan ring
In conclusion, a new method for the synthesis of N-arylated
providing the six-membered ring intermediate IV. TS(III,IV) is pyridazinones is described starting with potassium 2-furan-
the stationary point with the highest energy along the reaction trifluoroborate and several aryldiazonium tetrafluoroborates.
coordinate and the energy span between TS(III,IV) and inter- The method is easy, fast, and simple. Furthermore, it is
mediate Iꢁ ꢁ ꢁH2O is the energy barrier that has to be surmounted environmentally benign since no catalysts or additives were
to reach the products. This energy barrier is 19.7 (Ar = p-C6H4- needed and water is used as the solvent. DFT calculations
COMe) and 21.9 (Ar = p-C6H4-OMe) kcal molꢀ1. The lower barrier performed to elucidate the mechanism showed that the initial
found for TS(IIIa,IVa) than TS(IIIj,IVj) can be explained by the attack does not involve a Diels–Alder cycloaddition but rather a
electron-withdrawing nature of the COMe substituent that nucleophilic attack of the furan derivative to the diazonium
increases the electrophilic character of the N atom. This result partner. The reaction mechanism was corroborated by isotope
agrees with the experimentally observed higher reactivity of the labelling and ESI-MS experiments.
diazonium salts containing electron-withdrawing substituents.
We thank MINECO (Projects CTQ2011-23121, 23156, and
In a subsequent step, IV rearranges to IV0, a more stable boat- CTQ2012-32436) and the Generalitat de Catalunya (Project
shape conformational isomer. Next, IV0 loses BF3, which is 2009SGR637, ICREA Academia for M.S.) for financial support.
responsible for the final acidity of the reaction medium, to form
V with a barrier of about 14 kcal molꢀ1 in a very exergonic
Notes and references
1 W. J. Coates, in Comprehensive Heterocyclic Chemistry II, ed.
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A. R. Katritzky, C. W. Reesand and E. F. V. Scriven, Elsevier Science
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reaction (4). Therefore, it can be concluded that the O atom of
the pyridazinone ring comes from a water solvent molecule.
Isotope experiments were then carried out (ESI†). The reac-
tion between 2 and 3e was run in D2O and no incorporation of
deuterium in the final product was detected. In the reaction run
in H218O, incorporation of 18O in 4e was detected in the final
product by GC-MS in accordance with the mechanistic
proposal.
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