Open vessel and cooling while heating microwave-assisted synthesis of pyridinyl N-Aryl hydrazones

Article abstract of DOI:10.1021/co100015b

We reported the first example of open vessel and cooling while heating microwave-assisted synthesis of pyridinyl N-aryl hydrazones. Compounds were prepared in excellent isolated yields (88-98%) in only 5 min, by reacting 4- and 2,4-(di)substituted phenylhydrazines, bearing both electron-donating (4-CH ₃, 4-OCH₃) and -withdrawing (4-Cl, 4-Br, 4-CF₃, 4-NO₂, 2,4-Cl₂) groups with 2-, 3-, and 4-acetylpyridine. The method was successfully extended to other carbonyl compounds.

Full text of DOI:10.1021/co100015b

LETTER
pubs.acs.org/acscombsci
Open Vessel and Cooling while Heating Microwave-Assisted
Synthesis of Pyridinyl N-Aryl Hydrazones
Giuseppe La Regina,* Valerio Gatti, Francesco Piscitelli, and Romano Silvestri
Istituto Pasteur, Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universitꢀa di Roma,
Piazzale Aldo Moro 5, I-00185, Rome, Italy
S Supporting Information
b
ABSTRACT: We reported the first example of open vessel and cooling
while heating microwave-assisted synthesis of pyridinyl N-aryl hydrazones.
Compounds were prepared in excellent isolated yields (88-98%) in only
5 min, by reacting 4- and 2,4-(di)substituted phenylhydrazines, bearing
both electron-donating (4-CH3, 4-OCH3) and -withdrawing (4-Cl, 4-Br,
4-CF3, 4-NO2, 2,4-Cl2) groups with 2-, 3-, and 4-acetylpyridine. The
method was successfully extended to other carbonyl compounds.
KEYWORDS: hydrazones, microwave synthesis, cooling while heating,
open vessel
ryl hydrazones (e.g., 1, 3, and 5) are key building blocks for
the synthesis of some heterocyclic compounds, such as
4-OCH3) and -withdrawing (4-Cl, 4-Br, 4-CF3, 4-NO2, 2,4-Cl2)
groups, with 2- (15), 3- (16), and 4-acetylpyridine (17) (Scheme 1).
To the best of our knowledge, methods involving the use of cooling
while heating approach in open vessel mode for the synthesis of aryl
hydrazones have not been reported.
As a model study, we investigated the reaction of phenylhy-
drazine hydrochloride (7) with 2-acetylpyridine (15) in the pres-
ence of sodium acetate in 96° ethanol to furnish 2-(1-(2-phenyl-
hydrazono)ethyl)pyridine (18) (Table 1). The best molar ratio
phenylhydrazine hydrochloride/2-acetylpyridine/sodium acetate was
found to be 1.5/1/1.5 (data not shown). Ethanol was the solvent of
choice mainly due to its high loss tangent value (tan δ = 0.041),11
allowing a rapid microwave heating of the reaction mixture. By
comparison, oil bath heating required a time of 5 h at reflux tem-
perature to furnish compound 18 in high yields (entry 1, Table 1), as
reported by Lemster and co-workers.12
Attempts to synthesize 18 in closed vessel mode showed very
low yields. In fact, when we heated the reaction mixture at 80 °C for
2 min by applying a microwave irradiation of 50 W with or without
in situ cooling, derivative 18 was isolated in 15% and 23% yields,
respectively (entries 2 and 3, Table 1). Raising the temperature up to
130 °C caused a decrease of the yield (entries 4 and 5, Table 1),
probably because ofthe dielectric overheating of the starting materials
or the reaction products. On the contrary, compound 18 was isolated
in 50% yield, by heating the reaction mixture at 80 °C for 5 min in
open vessel mode with a power of 250 W (entry 6, Table 1). Thus,
the best yield (98%) was reached when the mixture was in situ cooled
during microwave irradiation under the same reaction conditions
(entry 7, Table 1). This result could be explained by taking into
A
indole and pyrazole. Our experience in this field led to the identifi-
cation of new anti-HIV-1 agents (e.g., 2),1 inhibitors of tubulin
polymerization (e.g., 4),2 and partial agonist/antagonist cannabi-
noid ligands (e.g., 6)3 (Chart 1). The biological importance of aryl
hydrazones was reviewed by Rollas and K€uc-€ukg€uzel, showing their
antidepressant, analgesic, antiinflammatory, antiplatelet, antimalar-
ial, antimicrobial, antimycobacterial, antitumoral, vasodilator, and
antiviral activities.4
The synthesis of aryl hydrazones is well-known and generally
involves the reaction of aryl hydrazines or aryl diazonium salts with
carbonyl compounds.5-7 Recent innovations in microwave-assisted
organic synthesis prompted to apply this new energy source also to
hydrazone preparation.8 For example, Polshettiwar and Varma
developed an efficient and general microwave protocol for the
synthesis of cyclic, bicyclic and heterocyclic hydrazones using
polystyrene sulfonic acid as catalyst in aqueous medium.9 Further-
more, N-acylhydrazones were prepared in high yields under micro-
wave irradiation, starting from benzo, salicyloyl, and isonicotinic
hydrazides in the absence of solvents and catalysts.10
Our medicinal chemistry projects required a fast and efficient
route to pyridinyl N-aryl hydrazones. Preliminary experiments
suggested that this class of compounds does not tolerate prolonged
heating and high temperatures, which lead to product decomposi-
tion. These results were supported by our observation that some
pyridinyl N-aryl hydrazones decompose spontaneously at room
temperature and must be stored at -20 °C.
Here, we wish to report the microwave-assisted synthesis of a
focused library of N-aryl hydrazones prepared under cooling while
heating open vessel mode. Compounds 18-41 were synthesized in
excellent yields in only 5 min, by reacting 4- and 2,4-(di)substituted
phenylhydrazines (7-14), bearing both electron-donating (4-CH3,
Received: September 24, 2010
Revised:
September 27, 2010
Published: November 9, 2010
r
2010 American Chemical Society
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LETTER
Chart 1. Examples of Aryl Hydrazones (1, 3, and 5) Involved
in the Synthesis of Biologically Active Compounds 2, 4, and 6
account that the external cooling prevents microwave overheating by
continuously removing latent heat of the reaction, allowing a higher
level of microwave output power to be directly transferred to the
reaction mixture.13
Encouraged by these very promising results, we examined the
scope and limits of the present method, by reacting 2- (15), 3- (16),
and 4-acetylpyridine (17) with a wide range of 4- and 2,4-(di)sub-
stituted phenylhydrazines (7-14), bearing both electron-donating
(4-CH3, 4-OCH3) and -withdrawing (4-Cl, 4-Br, 4-CF3, 4-NO2, 2,4-
Cl2) groups (Table 2).
Thus, 4-H- (7), 4-CH3- (8), 4-OCH3- (9), 4-Cl- (10),
4-Br- (11), and 2,4-Cl2-phenylhydrazine (14) hydrochlorides
rapidly reacted with 2- (15),3-(16), and 4-acetylpyridine (17) inthe
presence of sodium acetate to furnish the corresponding hydra-
zones 19-32 (entries 2-15, Table 2), 39 (entry 22, Table 2), and
41 (entry 24, Table 2), under the optimized reaction conditions
for derivative 18 (method A). Similarly, reaction of (4-(trifluoro-
methyl)phenyl)hydrazine (12) with 2- (15), 3- (16), and 4-acetyl-
pyridine (17), as well as that of (4-nitrophenyl)hydrazine (13) with
2-acetylpyridine (15) gave the corresponding derivatives 33-35
(entries 16-18, Table 2) and 36 (entry 19, Table 2), respectively
(method B). All experiments proceeded expeditiously and delivered
excellent isolated yields, ranging from 88% to 98%. The isolation
procedure simply involved the filtration of the high purity precipi-
tated pyridinyl N-aryl hydrazones, followed by washing with petro-
leum ether and drying. The method very well tolerated both
electron-donating and -withdrawing substituents on the phenylhy-
drazines, as well as the different position of the acetyl group on the
pyridine nucleus. Reaction time was considerably shorter com-
pared to conventional thermal process (e.g., 60-fold time reduc-
tion for compound 18).
Scheme 1. Synthesis of Pyridinyl N-Aryl Hydrazones 18-41
However, when we applied these reaction conditions to the
synthesis of derivatives 37 (entry 20, Table 2), 38 (entry 21,
Table 2), and 40 (entry 23, Table 2), the desired compounds
were not isolated in good yields, even prolonging the reaction
time up to 20 min (data not shown). Our experiments showed
that phenyl hydrazones 37, 38, and 40 can be successfully
prepared with a microwave-assisted protocol by dissolving the
appropriate starting materials in methanol in the presence of a
catalytic amount of concentrated HCl (method C).
Table 1. Optimization of Reaction Conditions for Compound 18
entry
heating
mode
temp (°C)
ramp time
hold time
power (W)
maxpressa (PSI)
air-cooling
yieldb (%)
1
2
3
4
5
6
7
oil bath
MWd
MW
80
80
5 h
90c
15
23
10
3
CVe
CV
CV
CV
OVf
OV
1 min
1 min
1 min
1 min
1 min
1 min
2 min
2 min
2 min
4 min
5 min
5 min
50
100
125
150
250
250
250
250
250
250
off
on
off
off
off
on
80
MW
110
130
80
MW
MW
50
98
MW
80
a maxpress: maximum pressure. b isolated yield. c From ref 12. d MW: microwave. e CV: closed vessel. f OV: open vessel.
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LETTER
Table 2. Microwave Synthesis of Pyridinyl N-Aryl Hydrazones 18-41
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LETTER
Table 2. Continued
a Isolated yield. b A: Hydrazine (1.5 equiv), acetylpyridine (1 equiv), CH3COONa (1.5 equiv), 96° ethanol, open vessel, 250 W, air-cooling, 80 °C,
5 min. c B: Hydrazine (1.5 equiv), acetylpyridine (1 equiv), 96° ethanol, open vessel, 250 W, air-cooling, 80 °C, 5 min. d C: Hydrazine (1.5 equiv),
acetylpyridine (1 equiv), catalytic 37% HCl, methanol, open vessel, 250 W, air-cooling, 65 °C, 5 min.
Table 3. Microwave Synthesis of Hydrazones 52-61
a Isolated yield. b Hydrazine (1.5 equiv), carbonyl compound (1 equiv), CH3COONa (1.5 equiv), 96° ethanol, open vessel, 250 W, air-cooling, 80 °C, 5 min.
To further validate the present method, we decided to explore
the reaction of phenylhydrazine hydrochloride (7) with other
carbonyl compounds 42-51 (Table 3).
Thus, benzaldehyde (42), acetophenone (43), 2-naphthal-
dehyde (44), 1-(naphthalen-2-yl)ethanone (45), 1H-pyrrole-
2-carbaldehyde (46), 1-(1H-pyrrol-2-yl)ethanone (47), furan-
2-carbaldehyde (48), 1-(furan-2-yl)ethanone (49), thiophene-
2-carbaldehyde (50), and 1-(thiophen-2-yl)ethanone (51) were
converted, according to the method A, to the correspond-
ing phenylhydrazones 52-61 in excellent yields (entries 1-10,
Table 3). Experiments confirmed that the method is useful to
prepare not only N-pyridinyl- but also N-(hetero)aryl hydra-
zones.
In conclusion, we have developed a new microwave-assisted
protocol for a very fast synthesis of pyridinyl N-aryl hydrazones
in open vessel mode, under cooling while heating conditions.
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LETTER
Hydrazones were prepared in excellent isolated yields in only 5 min,
by reacting a wide range of phenylhydrazines with 2-, 3-, and
4-acetylpyridine. The method was successfully extended to other
carbonyl compounds. High power microwave heating allowed us to
slash the time of the reaction. At the same time, the external cooling
precluded the decomposition of both starting materials and reaction
products. Finally, the open vessel mode could lead to a rapid scale
up of the reaction to multigram level.
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lyzed Greener Synthesis of Hydrazones in Aqueous Medium Using
Microwaves. Tetrahedron Lett. 2007, 48, 5649–5652.
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CEM Publishing: Matthews, 2002; pp 29-76.
(12) Lemster, T.; Pindur, U.; Lenglet, G.; Depauw, S.; Dassi, C.;
David-Cordonnier, M.-H. Photochemical Electrocyclisation of 3-Viny-
lindoles to Pyrido[2,3-a]-, Pyrido[4,3-a]-, and Thieno[2,3-a]-carbazoles:
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, charac-
b
terization data of all synthesized compounds, example of microwave
output graphics, and copies of 1H NMR spectra of compounds
20-23, 25, 26, 31-35, 37-41, and 55-59. This information is
available free of charge via the Internet at http://pubs.acs.org/.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: giuseppe.laregina@uniroma1.it. Phone: þ39 0649913404.
Fax: þ39 0649913133.
’ ACKNOWLEDGMENT
Authors wish to thank Ministero dell'Universitꢀa e della Ricerca
(PRIN 2008, Prot. n 200879X9N9), Istituto Pasteur, Fondazione
Cenci Bolognetti (Grant 2009), and FILAS (Finanziaria Laziale
di Sviluppo, Grant 2010) for financial support and Andrea Rota
(CEM srl, Italy) for skillful technical assistance.
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