A mild and highly efficient one-pot synthesis of 1,3,5-triaryl-2- pyrazolines

Full text of DOI:10.1007/s10593-013-1199-z

Chemistry of Heterocyclic Compounds, Vol. 48, No. 11, February, 2013 (Russian Original Vol. 48, No. 11, November, 2012)
A MILD AND HIGHLY EFFICIENT ONE-POT
SYNTHESIS OF 1,3,5-TRIARYL-2-PYRAZOLINES
B. Movassagh1*, H. Rooh1, and H. R. Bijanzadeh2
Keywords: tert-butyl alcohol, chalcones, potassium tert-butoxide, 1,3,5-triaryl-2-pyrazolines, Claisen–
Schmidt condensation, one-pot synthesis.
Pyrazolines are prominent 5-membered nitrogen-containing heterocyclic compounds, which play a
crucial role in the development of heterocyclic chemistry theory and are also extensively used as valuable
synthons in organic synthesis [1]. Among its various derivatives, 2-pyrazolines (4,5-dihydro-1H-pyrazines)
seem to be the most frequently studied pyrazoline-type compounds. One of the most popular methods for the
preparation of 2-pyrazolines involves the reaction of α,β-unsaturated aldehydes and ketones with hydrazines [2].
Because of various disadvantages, such as long reaction times, high temperatures, and two-step procedures
encountered in the reported methodologies, we decided to develop a more efficient and convenient method. As
far as we know, there is only one report on constructing 1,3,5-triaryl-2-pyrazolines by one-pot reaction of an
aryl aldehyde, acetophenone derivatives, and phenylhydrazine in 10% NaOH [3], but the reaction mixture was
refluxed in ethanol for relatively long times.
We have now developed an improved and highly convenient methodology for the synthesis of
3,5-diaryl-1-phenyl-2-pyrazoline derivatives via the reaction of phenylhydrazine with various chalcones,
generated in situ by Claisen–Schmidt condensation of aryl methyl ketones and aldehydes, with catalytic
amounts of t-BuOK (5 mol%) in anhydrous t-BuOH at room temperature.
HA
Ar
O
PhNHNH2
O
HB
Ar1
t-BuOK
4
+ Ar1CHO
N
Ar
Me
Ar
Ar1
t-BuOH, room temp.
room temp.
N
1
2
3
Ph
5a–s
To establish the generality of this process, various acetophenones and aromatic aldehydes possessing either
electron-withdrawing or electron-donating groups were treated with phenylhydrazine (Table 1). These reactions
were in general very fast (3–13 min) and clean, and 2-pyrazolines were obtained as the sole products in high yields
(69-89%). Surprisingly, the reactions of acetophenone with 4-nitrobenzaldehyde and 9-anthraldehyde
_______
*To whom correspondence should be addressed, e-mail: bmovass1178@yahoo.com.
1Department of Chemistry, K. N. Toosi University of Technology, P.O. Box 16315-1618, Tehran, Iran.
2Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran; e-mail:
bijan_hr@yahoo.com.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1835-1837, November, 2012.
Original article submitted May 29, 2011.
0009-3122/13/4811-1719© 2013 Springer Science+Business Media New York
1719

TABLE 1. t-BuOK-Catalysed One-pot Synthesis of 3,5-Diaryl-1-phenyl-
2-pyrazolines
Com-
pound
Ar
Ar1
Time, min
Yield*, %
Mp, °C
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
6
87
81
82
79
82
69
—
—
83
82
77
87
73
88
86
78
84
85
89
135-137 (134-135 [4])
121-123 (110-113 [4])
135-137 (134-135 [5])
133-135 (128-130 [4])
135-137 (135-136 [4])
174-176 (173-174 [6])
—
5a
5b
5c
5d
5e
5f
4-MeOC6H4
2-ClC6H4
4-MeC6H4
4-ClC6H4
1-Naphthyl
4-O2NC6H4
9-Anthranyl
4-NCC6H4
4-MeC6H4
4-ClC6H4
Ph
5
11
5
13
11
24 h
24 h
8
5g
5h
5i
—
178-180 (151-152 [7])
144-146 (143-145 [8])
142-144 (155 [9])
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-BrC6H4
4-BrC6H4
4-FC6H4
6
5j
11
6
5k
5l
148-149 (149-151 [10])
154-156 (167-169 [10])
151-153 (162-164 [10])
173-175 (174-176 [10])
145-147 (147-148 [6])
152-154 (120 [9])
4-ClC6H4
4-MeC6H4
4-BrC6H4
4-MeOC6H4
4-ClC6H4
Ph
6
5m
5n
5o
5p
5q
5r
5s
3
5
11
9
6
135-137 (144-147 [5])
146-148 (110 [9])
4-ClC6H4
3
_______
* Yields of pure isolated products.
did not produce the expected 2-pyrazolines (5g,h, Table 1) after prolonged reaction times (24 h) and even at
reflux. It was observed that in the synthesis of compound 5g the low solubility of the corresponding chalcone in
t-BuOH prevented its reaction with phenylhydrazine, while in the case of compound 5h the expected chalcone
was not formed at all.
In conclusion, we have developed a new convenient and efficient method for the one-pot synthesis of
3,5-di-aryl-1-phenyl-2-pyrazolines. This method offers significant advantages over earlier reported procedures,
in that it avoids the need to prepare and isolate chalcones and features a simple reaction procedure, mild
conditions, very short reaction times, and high product yields.
IR spectra (KBr) were obtained using an ABB FTLA 2000 instrument. The 1H and 13C NMR spectra were
recorded on a Bruker AQS-300 spectrometer (300 and 75 MHz, respectively) in CDCl3 solution using TMS as
internal standard. Melting points were determined on a Büchi B-540 apparatus and were uncorrected. Chemicals
were purchased from Merck.
Synthesis of Compounds 5a–s (General Method). A solution of t-BuOK (0.011 g, 0.1 mmol) in dry
t-BuOH (2 ml) was placed in a round-bottom flask. With stirring at room temperature (25°C), a mixture of
aldehyde (2.0 mmol) and ketone (2.0 mmol) was added to the above solution, and stirring was continued for
several minutes. The progress of the reaction was monitored by TLC (n-hexane–EtOAc, 4:1) until the starting
materials had completely disappeared; then phenylhydrazine (3.0 mmol) is added, and the mixture was stirred
until completion of the reaction. The solid product was collected after filtration, washed with water, and
recrystallized from 95% EtOH. Spectral data of compounds 5a–e,g,h,j-o,q-s corresponded to that given in the
literature.
5-(1-Naphthyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazine (5f). IR spectrum, ν, cm-1: 1602 (C=N).
1H NMR spectrum, δ, ppm (J, Hz): 3.18 (1H, dd, J = 16.9, J = 6.7, 4-CHAHB); 4.07 (1H, dd, J = 16.9, J = 12.6,
4-CHAHB); 5.96 (1H, dd, J = 12.6, J = 6.7, 5-CH); 6.82 (1H, t, J = 7.2, H Ar); 7.08-7.80 (14H, m, H Ar); 7.97
13
(1H, d, J = 7.8, H Ar); 8.12 (1H, d, J = 8.2, H Ar). C NMR spectrum, δ, ppm: 42.7 (C-4); 63.2 (C-5); 113.3,
1720

119.1, 122.9, 123.3, 125.7, 125.8, 126.0, 126.5, 128.1, 128.6, 128.7, 129.0, 129.3, 129.9, 132.7, 134.4, 136.6,
147.3 (C Ar); 144.9 (C-3).
5-(4-Cyanophenyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazine (5i). IR spectrum, ν, cm-1: 1597 (C=N); 2228
1
(C≡N). H NMR spectrum, δ, ppm (J, Hz): 3.10 (1H, dd, J = 17.0, J = 7.0, 4-CHAHB); 3.88 (1H, dd, J = 17.0,
J = 12.7, 4-CHAHB); 5.32 (1H, dd, J = 12.7, J = 7.0, 5-CH); 6.79-7.74 (14H, m, H Ar). 13C NMR spectrum, δ,
ppm: 43.3 (C-4); 64.0 (C-5); 111.6 (C≡N); 113.3, 118.6, 119.7, 125.8, 126.8, 128.7, 129.0, 129.1, 132.2, 133.1,
144.4, 147.8 (C Ar); 146.8 (C-3).
5,3-Bis(4-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazine (5p). IR spectrum, ν, cm-1: 1597
1
(C=N). H NMR spectrum, δ, ppm (J, Hz): 3.09 (1H, dd, J = 17.0, J = 7.3, 4-CHAHB); 3.73-3.85 (1H, m,
4-CHAHB); 3.79 (3H, s, OCH3); 3.85 (3H, s, OCH3); 5.18 (1H, dd, J = 12.1, J = 7.3, 5-CH); 6.79 (1H, t, J = 7.2,
H Ar); 6.88 (2H, d, J = 8.6, H Ar); 6.93 (2H, d, J = 8.8, H Ar); 7.08-7.28 (6H, m, H Ar); 7.68 (2H, d, J = 8.8,
H Ar). 13C NMR spectrum, δ, ppm: 43.9 (C-4); 55.4 (2OCH3); 64.0 (C-5); 113.3, 114.0, 114.5, 118.8, 125.6,
127.1, 127.2, 128.9, 134.8, 145.3, 158.9, 160.1 (C Ar); 146.8 (C-3).
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