Mannich bases as synthetic intermediates: Synthesis of 3- and 4-functionalized 2-pyrazolines

Article abstract of DOI:10.1515/znb-2007-0409

The reaction of styryl ketonic Mannich bases 2a - c with phenylhydrazine leads to 3-functionalized 2-pyrazolines 4 or 6 depending on the reaction conditions. 3-[β-(Arylamino)ethyl]-2-pyrazolines 8a,b were obtained via transamination between the methiodide

Full text of DOI:10.1515/znb-2007-0409

Mannich Bases as Synthetic Intermediates: Synthesis of 3- and
4-Functionalized 2-Pyrazolines
Elsayed M. Afsah, Ez-el-Din M. Kandeel, Mona M. Khalifa, and Waleed M. Hammouda
Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt
Reprint requests to Prof. Dr. E. M. Afsah. E-mail: emafsah@yahoo.com
Z. Naturforsch. 2007, 62b, 540 – 548; received September 15, 2006
The reaction of styryl ketonic Mannich bases 2a – c with phenylhydrazine leads to 3-functional-
ized 2-pyrazolines 4 or 6 depending on the reaction conditions. 3-[β-(Arylamino)ethyl]-2-pyrazol-
ines 8a,b were obtained via transamination between the methiodide salt 7 and primary arylamines.
Treatment of 1-(p-anisyl)-1,2,5-tri(N-piperidino)pentan-3-one (11) with phenylhydrazine affords the
3,4-difunctionalized 2-pyrazoline 12. The reactions of the keto bases 19 or 21 with hydrazines lead
to 4-functionalized 2-pyrazolines 20 and 22, the N-Mannich bases 23 and 24 are obtained from 22a.
The synthesis of 3-[β-(phenylthio)ethyl]-2-pyrazolines 28a,b has been achieved by treating 26 or 27
with phenylhydrazine.
Key words: Styryl Ketonic Mannich Bases, 3- and 4-Functionalized 2-Pyrazolines
Introduction
tained by transamination reaction between 2b and
N-phenylpiperazine. It was found that cyclization of
the phenylhydrazones 3a–c, derived from the styryl
keto bases 2a–c, can be directed selectively ac-
cording to the conditions. Thus, 3a–c were read-
ily isomerized to 5-aryl-3-[β-(morpholin-4-yl)ethyl]-
and 3-[ß-(4-phenyl-piperazin-1-yl)ethyl]-1-phenyl-2-
pyrazolines 4a – c, respectively, under mild conditions
(warming for a short time, Scheme 1).
Ketonic Mannich bases are of considerable impor-
tance as intermediates in the synthesis of condensed
heterocyclic systems [1 – 5] and of heterocycles car-
rying a potential basic side chain of alkaloidal na-
ture [6 – 10]. It has been reported earlier that Mannich
bases derived from methyl styryl ketones, react with
phenylhydrazine to give 3-[β-(substituted-amino)eth-
yl]-2-pyrazolines [11 – 13], which possess local anaes-
thetic activity comparable with cocaine [12]. However,
the literature of C-3 functionalized 2-pyrazolines pre-
pared from unsaturated ketonic Mannich bases is rela-
tively limited.
In view of this, and in connection with our studies
in this area [14 – 16], the reaction of phenylhydrazine
with styryl ketonic Mannich bases of the type 2, having
a morpholine or piperazine group as a structural unit,
and related compounds, was further investigated as a
route to C-3 and C-4 functionalized 2-pyrazolines of
pharmaceutical interest.
On the other hand, treatment of 3a,b with acetic
acid under more drastic conditions (refluxing for 1 h),
offers a facile method for the synthesis of 3-(p-
methoxystyryl)- and 3-(3,4-methylenedioxystyryl)-1-
phenyl-2-pyrazolines 6a,b. It is believed that hydra-
zones 3 undergo deamination on prolonged heating to
give 5, followed by cyclization. The formation of 6
is in line with an earlier report [19] on the reaction
of β-dimethylaminoethyl styryl ketone with phenyl-
hydrazine, and with the observation of Andrisano et
al. [20], who found that the styryl double bond is less
reactive than that formed by deamination of the Man-
nich base.
Results and Discussion
A practical advantage of the reactions leading to
In the present study, we prepared 1-(p-anisyl)- compounds 4 and 6 is that it is often unnecessary to iso-
5-(morpholin-4-yl)-1-penten-3-one hydrochloride (2a) late the intermediate phenylhydrazones 3. The struc-
and the 1-(3,4-methylenedioxyphenyl) analog (2b) by ture proposed for compounds 4a – c and 6a,b was sup-
the reaction of p-anisalacetone (1a) [17] or piper- ported by analytical and spectral data. The mass spec-
onalacetone (1b) [18] with formaldehyde and mor- tra of 4a – c showed very similar cleavage patterns.
pholine hydrochloride. The keto base 2c was ob- Cleavage of the side chain of 4a and b at the β bond
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E. M. Afsah et al. · Synthesis of 3- and 4-Functionalized 2-Pyrazolines
541
Scheme 2.
and 1325 cm−1 (C–N stretch of sec. aryl amine). Its
1H NMR spectrum revealed the presence of a sin-
glet for (NH) at δ = 9.0 and multiplets at 5.2 (5-H),
3.3 (4-H2) and 2.8 [(CH2)2NHAr]. Similar signals ap-
peared in the spectrum of 8b.
In an interesting extension of this study, it has
been found that a convenient route to the 3,4-
difunctionalized 2-pyrazoline 12 starts with the p-
methoxystyryl keto base 9 [23], which undergoes
bromination to give the corresponding dibromo deriva-
tive 10 in a good yield (Scheme 3).
Treatment of dibromide 10 with piperidine afforded
1-(p-anisyl)-1,2,3-tri(piperidin-1-yl)pentan-3-one(11),
the phenylhydrazone of which was readily converted
into the target molecule 5-(p-anisyl)-1-phenyl-3-[β-
(piperidin-1-yl)ethyl]-4-(piperidin-1-yl)-2-pyrazoline
(12). Supporting evidence for structure 12 was
provided by analytical and spectral data, and its
mass fragmentation pattern agreed with the pro-
posed structure (Scheme 3). The conversion of the
phenylhydrazone of 11 into 12 is an intramolecu-
lar amine exchange reaction, which occurs by the
elimination-addition sequence, that is operative with
β-aminoketones [1, 2, 24], and their phenylhydrazones
[1, 25, 26]. The formation of 12 as a sole product
suggests the intermediacy of the styryl intermediate 15
(Scheme 4). Therefore, of the two possible intermedi-
ates 15 and 16 only 15 is expected, because the aryl
group at C-1 increases the extent of the E1 elimina-
tion, since it stabilizes the carbonium character of the
transition state 14ꢀ, and also stabilizes the incipient
double bond of 15, which undergoes cyclization to
afford 12.
Scheme 1.
leads to the base peak at m/z = 100 (100%), due to
the N-morpholinomethyl ion [CH2–N(CH2CH2)2O],
which undergoes further fragmentation to give a char-
acteristic peak at m/z = 56 in the spectrum of 4a
(14.4%) and 4b (30 %). The basic side chain of 4c
can be identified by two peaks at m/z = 175 (100%)
[CH2–N(CH2CH2)2NPh] and 189 (23 %) [CH2CH2–
N(CH2CH2)2NPh]. The fragmentation pattern of 4a is
depicted in Scheme 2.
In connection with the present study, the synthesis
of 2-pyrazolines of the type 8, having a secondary ary-
lamino group on the side chain, has been achieved by
converting 4a into the methiodide salt 7, which was
treated with aniline or p-toluidine to give 5-(p-anisyl)-
3-[β-(phenylamino)ethyl]-1-phenyl-2-pyrazoline (8a)
and the 3-[β-(p-tolylamino)ethyl] analog 8b. The ad-
vantage of using 7 in this reaction lies in the fact
that transamination occurs readily between quaternary
However, this reaction is often complicated by a
salts and primary or secondary amines [21, 22]. The competing nucleophilic attack of the phenylhydrazone
IR spectrum of 8a showed strong bands at 3399 (NH) moiety on the incipient carbonium ion 14 to give 17,
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542
E. M. Afsah et al. · Synthesis of 3- and 4-Functionalized 2-Pyrazolines
Scheme 3.
followed by deprotonation to 12 (i. e. SN1 type mech- 2-hydroxy-3-(morpholin-4-yl)-1,3-diphenylpropan-1-
anism). one (21) with hydrazines. Mannich reaction of 22a
In addition, we have found that compounds 19a – c, with formaldehyde and piperidine or piperazine
which are structurally related to 11, could be used as afforded 23 and 24, respectively. The structures of
compounds 22 – 24 were supported by analytical and
intermediates for the synthesis of C-4 functionalized 2-
pyrazolines of the type 20. Thus, 2,3-di(morpholin-4- spectral data (Scheme 6).
yl)-1,3-diphenylpropan-1-one(19a) was obtained from
In the course of this study, the styryl keto bases 9
the dibromoketone 18a and morpholine as reported and 25 [23] were converted into the corresponding
earlier [27]. Analogously, treating 18a or b with β-phenylthioethyl styryl ketones 26a,b through their
the appropriate amine gave 19b,c. Reaction of 19a reaction with thiophenol according to a previous re-
and b with phenylhydrazine afforded 4-(1,3,5-triaryl- port [20]. The potential of compounds 26a,b as precur-
4,5-dihydro-1H-pyrazol-4-yl)morpholines 20a,b. The sors to 2-pyrazolines having a β-phenylthioethyl side
same reaction with 19c, obtainable in situ from 18a chain at C-3, was illustrated by treating their phenyl-
and N-methylpiperazine, proceeded equally well, pro- hydrazones with ethanolic HCl to afford 1,5-diaryl-3-
viding 20c. Compounds 20a–c are formed by a reac- (β-phenylthioethyl)-2-pyrazolines 28a,b (Scheme 7).
tion sequence identical to that depicted in Scheme 5.
Compound 28a was also obtained as a sole product
The mass and 1H NMR spectra are consistent with the from the phenylhydrazone of 27, indicating that the re-
proposed structures.
action involves the preferential elimination of the thio-
In line with this, the synthesis of 4-hydroxy-2- phenyl group at C-1 of 27. The 1H NMR spectrum of
pyrazolines 22a,b has been achieved by treating 28a showed multiplets at δ = 2.64– 2.76 [(CH2)2SPh],
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E. M. Afsah et al. · Synthesis of 3- and 4-Functionalized 2-Pyrazolines
543
Scheme 4.
Scheme 6.
tal microanalyses were carried out at the Microanalytical
Unit, Faculty of Science, Cairo University. Infrared spec-
tra were measured on a Mattson 5000 FTIR spectrome-
ter. 1H NMR data were obtained in CDCl3solution on a
Varian XL 200 MHz instrument using TMS as internal
standard. Chemical shifts δ are reported in ppm down-
field from internal TMS. Mass spectra were recorded on
a GC-MS QP-1000 EX Shimadzu instrument. The course
of the reaction and the purity of the synthesized com-
pounds was monitored by TLC using EM science silica gel
Scheme 5.
3.21– 3.46 (4-H2) and 4.91 – 5.02 (5-H). Similar sig-
nals appeared in the spectrum of 28b. The formation
of 28a from 27 is in harmony with the formation of 12
from 11.
Experimental Section
All melting points (uncorrected) were determined on coated plates with visualization by irradiation with an ul-
traviolet lamp. Compounds 1a [17], 1b [18], 9 [23], 18a,b,
a Gallenkamp electric melting point apparatus. Elemen-
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544
E. M. Afsah et al. · Synthesis of 3- and 4-Functionalized 2-Pyrazolines
1-(3,4-Methylenedioxyphenyl)-5-(4-phenylpiperazin-1-yl)-
1-penten-3-one (2c)
A mixture of 2b (0.3 g, 1 mmol) and N-phenylpiper-
azine (0.16 g, 1 mmol) in 50 % aqueous ethanol (20 mL)
was refluxed for 90 min. The product that was obtained
on cooling was filtered and crystallized from ethanol to
give 2c. – M. p. 110 ◦C. Yield 82 % (yellow crystals). –
IR (KBr): ν = 1680 (α,β-unsaturated CO), 1610, 1480,
1350, 1115, 1040 cm−1. – 1H NMR (200 MHz, CDCl3,
25 ◦C, TMS): δ = 2.31 (t, 2H, COCH2CH2N), 2.44 (m,
4H, N(CH2CH2)2NPh), 2.62 (t, 2H, COCH2CH2N), 3.11 (m,
4H, N(CH2CH2)2NPh), 5.88 (s, 2H, O–CH2–O), 6.63 (d,
1H, CH=CH–CO), 7.22 – 7.53 (m, 8H, aromatic), 7.64 (d,
1H, CH=CH–CO). – C22H24N2O3 (364.44): calcd. C 72.50,
H 6.64, N 7.69; found C 72.38, H 6.51, N 7.54.
1-Aryl-5-(morpholin-4-yl)-1-penten-3-one phenylhydrazone
hydrochlorides 3a, b
To a solution of 2a (0.62 g), or 2b (0.65 g, 2 mmol)
in ethanol (20 mL), phenylhydrazine (0.22 g, 2 mmol) and
acetic acid (0.2 mL) were added. After standing at r. t. for
30 min, yellow crystals of the phenylhydrazines were sepa-
rated. The products were recrystallized from ethanol to give
3a,b.
Scheme 7.
19a [27], 25 [23], and 26b [20] were prepared as previously
1-(p-Anisyl)-5-(morpholin-4-yl)-1-penten-3-one phenylhydr-
azone hydrochloride (3a)
described.
1-Aryl-5-(morpholin-4-yl)-1-penten-3-one hydrochlorides
2a, b
◦
M. p. 181 C (ethanol). Yield 84 % (yellow crystals). –
IR (KBr): ν = 3289 (NH), 1605 (C=N), 1495, 1390, 1108,
1025 cm−1. – C22H28ClN3O2 (401.93): calcd. C 65.74,
H 7.02, N 10.45; found C 65.66, H 6.92, N 10.30.
To a solution of p-anisalacetone (1a) (1.76 g, 10 mmol) or
piperonalacetone (1b) (1.9 g, 10 mmol) and morpholine hy-
drochloride (1.23 g, 10 mmol) in absolute ethanol (20 mL),
paraformaldehyde (0.45 g, 15 mmol) was added, and the
mixture was refluxed for 1 h. Paraformaldehyde (0.15 g,
5 mmol) was added and the reaction mixture was refluxed
for another 1 h. On cooling, yellow crystals of 2a,b were
separated, and were recrystallized from ethanol.
1-(3,4-Methylenedioxyphenyl)-5-(morpholin-4-yl)-1-penten-
3-one phenylhydrazone hydrochloride (3b)
◦
M. p. 179 C (ethanol). Yield 77 % (yellow crystals). –
IR (KBr): ν = 3275 (NH), 1615 (C=N), 1449, 1380, 1120,
1010 cm−1. – C22H26ClN3O3 (415.91): calcd. C 63.53,
H 6.30, N 10.10; found C 63.33, H 6.10, N 9.85.
1-(p-Anisyl)-5-(morpholin-4-yl)-1-penten-3-one hydrochlor-
ide (2a)
5-Aryl-3-[β-(morpholin-4-yl)ethyl]-1-phenyl-2-pyrazoline
hydrochlorides 4a, b
M. p. 178 ◦C (ethanol). Yield 60 % (yellow crystals). – IR
(KBr): ν = 1683 (α,β-unsaturated CO), 1601, 1497, 1445,
1250, 1150 cm−1. – C16H22ClNO3 (311.80): calcd. C 61.63,
H 7.11, N 4.49; found C 61.55, H 7.08, N 4.33.
A solution of 3a or 3b (1 g, 2.5 mmol) in 1N HCl (20 mL)
was heated on a water bath for 10 min. The products obtained
on cooling were filtered and crystallized from water to give
4a,b.
1-(3,4-Methylenedioxyphenyl)-5-(morpholin-4-yl)-1-penten-
3-one hydrochloride (2b)
5-(p-Anisyl)-3-[β-(morpholin-4-yl)ethyl]-1-phenyl-2-pyr-
azoline hydrochloride (4a)
M. p. 192 ◦C (water). Yield 87 % (white crystals). –
IR (KBr): ν = 1610 (C=N), 1520, 1450, 1345, 1250,
M. p. 164 ◦C (ethanol). Yield 67 % (yellow crystals). – IR
(KBr): ν = 1678 (α,β-unsaturated CO), 1600, 1485, 1330,
1235, 1039 cm−1. – C16H20ClNO4 (325.79): calcd. C 58.99,
H 6.19, N 4.30; found C 58.90, H 6.07, N 3.91.
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E. M. Afsah et al. · Synthesis of 3- and 4-Functionalized 2-Pyrazolines
545
1130 cm−1. – MS (EI, 70 eV): m/z (%) = 365 (4) [M – HCl]+, 3-(3,4-Methylenedioxystyryl)-1-phenyl-2-pyrazoline (6b)
115 (2) [CH2–CH2–N(CH2CH2)2O + H]+, 100 (100) [CH2–
M. p. 138 ◦C. Yield 72 % (pale brown crystals). – IR
N(CH2CH2)2O]+, 77 (7) [Ph]+, 56 (14) [C3H6N]+. –
(KBr): ν = 1605 (C=N), 1505, 1442, 1352, 1250, 1127,
C22H28ClN3O2 (401.93): calcd. C 65.74, H 7.02, N 10.45;
found C 65.72, H 6.87, N 10.13.
◦
1034 cm−1. – 1H NMR (200 MHz, CDCl3, 25 C, TMS):
δ = 2.66 (m, 2H, 4-H2), 3.29 (m, 2H, 5-H2), 5.91 (s, 2H,
O–CH2–O), 6.15 (d, 1H, Ar–CH=CH–), 6.92 (d, 1H, Ar–
CH=CH–), 7.21 – 7.48 (m, 8H, aromatic). – C18H16N2O2
(292.33): calcd. C 73.95, H 5.52, N 9.58; found C 73.88,
H 5.42, N 9.35.
5-(3,4-Methylenedioxyphenyl)-3-[β-(morpholin-4-yl)ethyl]-
1-phenyl-2-pyrazoline hydrochloride (4b)
M. p. 188 ◦C (water). Yield 70 % (white crystals). –
IR (KBr): ν = 1605 (C=N), 1512, 1435, 1325, 1210,
1066 cm−1. – MS (EI, 70 eV): m/z (%) = 379 (12)
[M – HCl]+, 100 (100) [CH2–N(CH2CH2)2O]+, 77 (13)
[Ph]+, 56 (30) [C3H6N]+. – C22H26ClN3O3 (415.91): calcd.
C 63.53, H 6.30, N 10.10; found C 63.44, H 5.90, N 9.96.
5-(p-Anisyl)-3-[β-(arylamino)ethyl]-1-phenyl-2-pyrazolines
8a, b
The free base of 4a, obtained by basification of 1.2 g
(3 mmol) of 4a with dilute NH4OH, was treated in ethanol
(20 mL) with methyl iodide (0.43 g, 3 mmol), and the mix-
ture was heated on a water bath at 50 ◦C for 1 h. Then aniline
(0.28 g, 3 mmol) or p-toluidine (0.32 g, 3 mmol) was added
and the mixture was refluxed for 1 h. The products obtained
on cooling were filtered and crystallized from ethanol – ethyl
acetate (1 : 1) to give 8a,b.
5-(3,4-Methylenedioxyphenyl)-3-[β-(4-phenylpiperazin-1-
yl)ethyl]-1-phenyl-2-pyrazoline (4c)
A solution of 2c (0.73 g, 2 mmol) and phenylhydrazine
(0.22 g, 2 mmol) in ethanol (20 mL) containing (0.1 mL)
of acetic acid, was heated on a water bath for 15 min. The
product obtained on cooling was filtered and crystallized
◦
5-(p-Anisyl)-3-[β-(phenylamino)ethyl]-1-phenyl-2-pyrazol-
ine (8a)
from ethanol to give 4c. M. p. 148 C. Yield 65 % (yellow
crystals). – IR (KBr): ν = 1605 (C=N), 1496, 1339, 1260,
1120 cm−1. – 1H NMR (200 MHz, CDCl3, 25 ◦C, TMS): δ =
2.41 (m, 4H, N(CH2CH2)2NPh), 2.56 (t, 2H, CH2CH2N),
2.71 (t, 2H, CH2CH2N), 2.95 [m, 4H, N(CH2CH2)2NPh],
3.27 (d, 2H, 4-H2), 5.23 (m, 1H, 5-H), 5.88 (s, 2H, O–
CH2–O), 7.24 – 7.63 (m, 8H, aromatic). – MS (EI, 70 eV):
m/z (%) = 332 (17) [M – C6H3:O2CH2-3,4]+, 300 (35) [M –
2Ph]+, 189 (23) [CH2CH2–N(CH2CH2)2NPh], 175 (100)
[CH2–N(CH2CH2)2NPh]+, 77 (28) [Ph]+. – C28H30N4O2
(454.56): calcd. C 73.98, H 6.65, N 12.33; found C 73.78,
H 6.52, N 12.10.
◦
M. p. 110 C. Yield 68 % (yellow crystals). – IR (KBr):
ν = 3399 (NH), 1605 (C=N), 1325 (C–N stretch of sec. aryl
ami◦ne), 1259, 1100 cm−1. – 1H NMR (200 MHz, CDCl3,
25 C, TMS): δ = 2.81 (m, 4H, (CH2)2–N), 3.34 (d, 2H,
4-H2), 4.02 (s, 3H, ArOCH3), 5.21 (m, 1H, 5-H), 7.12 –
7.60 (m, 14H, aromatic), 9.03 (s, 1H, PhNH). – C24H25N3O
(371.47): calcd. C 77.60, H 6.78, N 11.31; found C 77.49,
H 6.58, N 11.08.
5-(p-Anisyl)-3-[β-(p-tolylamino)ethyl]-1-phenyl-2-pyrazol-
ine (8b)
3-(Substituted styryl)-1-phenyl-2-pyrazolines 6a, b
◦
M. p. 128 C. Yield 73 % (yellow crystals). – IR (KBr):
A solution of 3a or 3b (1 g, 2.5 mmol) in glacial acetic
acid (10 mL) was heated on a steam bath for 1 h, poured
onto water (50 mL) and basified with NH4OH. The products
obtained were filtered and crystallized from ethanol – ethyl
acetate (1 : 1) to give 6a,b.
ν = 3375 (NH), 1615 (C=N), 1320 (C–N stretch of sec.
aryl amine), 1294, 1252, 1132 cm−1. – 1H NMR (200 MHz,
◦
CDCl3, 25 C, TMS): δ = 2.04 (s, 3H, (Ar–CH3), 2.73 (m,
4H, (CH2)2–N), 3.31 (d, 2H, 4-H2), 3.75 (s, 3H, ArOCH3),
5.35 (m, 1H, 5-H), 7.21 – 7.67 (m, 13H, aromatic), 9.58 (s,
1H, ArNH). – C25H27N3O (385.50): calcd. C 77.89, H 7.06,
N 10.90; found C 77.78, H 6.88, N 10.79.
3-(p-Methoxystyryl)-1-phenyl-2-pyrazoline (6a)
M. p. 170 ◦C. Yield 65 % (yellow crystals). – IR
1-(p-Anisyl)-1,2-dibromo-5-(piperidin-1-yl)pentan-3-one
(10)
(KBr): ν = 1597 (C=N), 1503, 1460, 1377, 1254, 1174,
◦
1030 cm−1. – 1H NMR (200 MHz, CDCl3, 25 C, TMS):
δ = 2.68 (m, 2H, 4-H2), 3.31 (m, 2H, 5-H2), 3.77 (s,
A solution of 9 (0.82 g, 3 mmol) in carbon tetrachlo-
3H, ArOCH3), 5.88 (d, 1H, Ar–CH=CH–), 6.95 (d, 1H, ride (40 mL) was cooled and bromine (0.5 g, 6 mmol) was
Ar–CH=CH–), 7.23 – 7.54 (m, 9H, aromatic). – C18H18N2O added with stirring. After standing for 30 min, the prod-
(278.35): calcd. C 77.67, H 6.52, N 10.06; found C 77.49, uct was filtered and washed with hot ethanol (2 × 10 mL).
H 6.33, N 9.91.
Crystallization from benzene-ethanol (2 : 1) gave 10. M. p.
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546
E. M. Afsah et al. · Synthesis of 3- and 4-Functionalized 2-Pyrazolines
208 ◦C. – Yield 90 % (white crystals). – IR (KBr): ν = 1656 4-(1,3,5-Triphenyl-4,5-dihydro-1H-pyrazol-4-yl)morpholine
(CO), 1601, 1512, 1459, 1364, 1256, 1223, 1019 cm−1. – (20a)
C17H23Br2NO2 (433.18): calcd. C 47.14, H 5.35, N 3.23;
found C 47.02, H 5.22, N 3.02.
M. p. 141 ◦C. Yield 53 % (yellow crystals). – IR
(KBr): ν = 1610 (C=N), 1594, 1490, 1294, 1258, 1134,
◦
1056 cm−1. – 1H NMR (200 MHz, CDCl3, 25 C, TMS):
5-(p-Anisyl)-3-[β-(piperidin-1-yl)ethyl]-4-(piperidin-1-yl)-
1-phenyl-2-pyrazoline (12)
δ = 2.83 – 2.96 (m, 4H, CH2–N–CH2 of morpholine), 3.12 –
3.25 (m, 4H, CH2–O–CH2 of morpholine), 3.25 (d, 1H, 4-
H), 5.12 (d, 1H, 5-H), 7.05 – 7.56 (m, 15H, aromatic). –
MS (EI, 70 eV): m/z (%) = 383 (3) [M]+, 196 (100)
[PhNH–N=CHPh]+, 195 (79) [PhN=N=CHPh]+, 92 (66)
[PhNH]+, 77 (28) [Ph]+, 66 (18) [C3H2N2]+, 65 (44)
[C3H2N2 – H]+. – C25H25N3O (383.49): calcd. C 78.30,
H 6.57, N 10.96; found C 78.11, H 6.38, N 10.77.
A solution of 10 (0.87 g, 2 mmol) and piperidine (0.5 g,
6 mmol) in absolute ethanol (30 mL) was stirred at r. t. for
24 h, to give 11 which was not isolated, and then phenyl-
hydrazine (0.22 g, 2 mmol) and acetic acid (1 mL) were
added. The reaction mixture was heated on a steam bath
for 45 min. The crystals obtained on cooling were filtered
and crystallized from ethanol to give 12. M. p. 165 ◦C.
Yield 63 % (yellow crystals). – IR (KBr): ν = 1615 (C=N),
1598, 1462, 1345, 1256, 1173, 1030 cm−1. – 1H NMR
4-[(3-Biphenyl-4-yl)-1,5-diphenyl-4,5-dihydro-1H-pyrazol-
4-yl)]morpholine (20b)
◦
M. p. 150 ◦C. Yield 58 % (yellow crystals). – IR
(KBr): ν = 1613 (C=N), 1595, 1442, 1385, 1347, 1281,
1154 cm−1. – 1H NMR (200 MHz, CDCl3, 25 ◦C, TMS): δ =
2.80 – 2.95 (m, 4H, CH2–N–CH2 of morpholine), 3.15 – 3.25
(m, 4H, CH2–O–CH2 of morpholine), 3.30 (d, 1H, 4-H), 5.15
(d, 1H, 5-H), 6.85 – 7.40 (m, 19H, aromatic). – C31H29N3O
(459.58): calcd. C 81.02, H 6.36, N 9.14; found C 80.92,
H 6.21, N 9.01.
(200 MHz, CDCl3, 25 C, TMS): δ = 1.45 – 1.58 (2 × m,
12H, 2 × (3-H2, 4-H2, 5-H2) of piperidine units), 2.38 (t,
2H, CH2CH2N), 2.45 (m, 4H, 2H2, 6H2 of piperidine at
side chain), 2.58 (t, 2H, CH2CH2N), 2.65 (m, 4H, 2H2,
6H2 of 4-(piperidin-1-yl)), 3.40 (d, 1H, 4-H), 3.75 (s, 3H,
ArOCH3), 4.88 (d,1H, 5-H), 7.15 – 7.52 (m, 9H, aromatic). –
MS (EI, 70 eV): m/z (%) = 446 (3) [M]+, 369 (31) [M –
Ph]+, 362 (40) [M – C5H10N]+, 348 (100) [M – C5H10N–
CH2]+, 264 (13) [M – (C5H10N + C5H10N–CH2)]+, 112
(37) [C5H10N–CH2–CH2]+, 108 (43) [C6H4OMe + H]+,
105 (32) [PhN=N]+, 98 (8) [C5H10N–CH2]+, 77 (28) [Ph]+,
65 (24) [C3H3N2 – 2H]+. – C28H38N4O (446.63): calcd.
C 75.30, H 8.58, N 12.54; found C 75.15, H 8.28, N 12.22.
1-Methyl-4-[(1,3,5-triphenyl)-4,5-dihydro-1H-pyrazol-4-yl]
piperazine (20c)
A solution of 18a (1.1 g, 3 mmol) and N-methylpiperazine
(1.2 g, 12 mmol) in ethanol (50 mL) was stirred at r. t. for
24 h, to give 19c which was not isolated. Then phenyl-
hydrazine (0.33 g, 3 mmol) and acetic acid (1 mL) were
added, and the reaction mixture was heated on a steam
bath for 45 min. The yellow crystals obtained on cool-
ing were filtered and crystallized from ethanol to give 20c.
M. p. 118 ◦C. Yield 65 % (yellow crystals). – IR (KBr):
ν = 1605 (C=N), 1592, 1459, 1373, 1244, 1174 cm−1. –
1-(Biphenyl-4-yl)-2,3-di(morpholin-4-yl)-3-phenylpropan-
1-one (19b)
To a suspension of 18b (1.3 g, 3 mmol) in absolute ethanol
(50 mL), morpholine (0.9 g, 10 mmol) was added with stir-
ring. After standing at r. t. for 24 h, the yellow crystals ob-
tained were filtered and washed with water (4 × 10 mL).
The product was crystallized from ethanol to give 19b. M. p.
120 ◦C. Yield 66 % (yellow crystals). – IR (KBr): ν =
1665 (CO), 1596, 1449, 1320, 1250, 1113, 1071 cm−1. –
C29H32N2O3 (456.58): calcd. C 76.29, H 7.06, N 6.14; found
C 76.12, H 6.93, N 5.94.
◦
1H NMR (200 MHz, CDCl3, 25 C, TMS): δ = 2.22 (s,
3H, NCH3), 2.54 (m, 4H, MeN(CH2CH2)2N)), 3.12 (m, 4H,
MeN(CH2CH2)2N)), 3.28 (d, 1H, 4-H), 5.13 (d, 1H, 5-H),
7.10 – 7.57 (m, 15H, aromatic). – MS (EI, 70 eV): m/z (%) =
396 (3) [M]+, 319 (28) [M – Ph]+, 242 (38) [M – 2Ph]+, 195
(79) [PhNH–N=CHPh – H]+, 194 (100) [PhNH–N=CHPh –
2H]+, 165 (30) [M – 3Ph]+, 104 (8) [PhCH=CH2]+, 99
(68) [MeN(CH2CH2)2N]+, 66 (19) [C3H2N2]+, 65 (45)
[C3H2N2 – H]+. – C26H28N4 (396.53): calcd. C 78.75,
H 7.12, N 14.13; found C 78.61, H 6.98, N 13.89.
4-(1,3,5-Triaryl-4,5-dihydro-1H-pyrazol-4-yl)morpholines
20a, b
A solution of 19a (1.2 g) or 19b (1.4 g, 3 mmol) and
phenylhydrazine (0.33 g, 3 mmol) in 15 mL of 50 % acetic
acid was heated on a steam bath. The reaction time was
30 min for 20a, and 90 min for 20b. The crystals obtained
on cooling were filtered and crystallized from ethanol to give
20a,b.
2-Hydroxy-3-(morpholin-4-yl)-1,3-diphenylpropan-1-one
(21)
A solution of chalcone epoxide [28] (2.24 g, 10 mmol)
and morpholine (1.75 g, 20 mmol) in ethanol (50 mL) was re-
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E. M. Afsah et al. · Synthesis of 3- and 4-Functionalized 2-Pyrazolines
547
◦
fluxed for 3 h. The solvent was evaporated and the oily prod- from ethanol to give 24. M. p. > 250 C. Yield 58 % (yel-
uct was purified by preparative chromatography on Al2O3 low crystals). – IR (KBr): ν = 3373 (OH), 1605 (C=N),
using pet. ether 40 – 60 ◦C / ethyl acetate (3 : 1) as elu- 1588, 1454, 1371, 127◦1, 1113, 1073 cm−1. – 1H NMR
ent. The product was crystallized from ethanol to give 21. (200 MHz, CDCl3, 25 C, TMS): δ = 2.35 – 2.60 (m, 8H,
M. p. 135 ◦C. Yield 45 % (yellow crystals). – IR (KBr): N(CH2 CH2)2N), 3.85 (d, 2H, 2 (4-H)), 4.75 (s, 2H, 2 OH),
ν = 3475 (OH), 1660 (CO), 1596, 1447, 1376, 1270, 1114, 5.15 (s, 4H, 2 (N–CH2–N) of side chain), 5.71 (m, 2H,
1065 cm−1. – C19H21NO3 (311.37): calcd. C 73.29, H 6.80, 2 (5-H)), 6.92 – 7.43 (m, 20H, aromatic). – C36H38N6O2
N 4.50; found C 73.11, H 6.62, N 4.22.
(586.73): calcd. C 73.69, H 6.53, N 14.32; found C 73.55,
H 6.35, N 14.12.
4-Hydroxy-3,5-diphenyl-2-pyrazolines 22a, b
1-(p-Anisyl)-5-(phenylthio)-1-penten-3-one (26a)
A solution of 21 (0.62 g, 2 mmol), hydrazine hydrate
(0.1 g, 2 mmol) or phenylhydrazine (0.22 g, 2 mmol) in
ethanol (25 mL) containing acetic acid (1 mL), was refluxed
for 3 h. After standing at r. t. for 24 h, the product obtained
was filtered and crystallized from ethanol to give 22a,b.
A mixture of 9 (0.62 g, 2 mmol) and thiophenol (0.22 g,
2 mmol) in toluene (20 mL) was refluxed for 90 min.
The solvent was removed under reduced pressure, and the
oily prod◦uct was crystallized from ethanol to give 26a.
M. p. 80 C. Yield 65 % (white powder). – IR (KBr): ν =
1644 (α,β-unsaturated CO), 1599, 1460, 1373, 1239, 1169,
1030 cm−1. – C18H18O2S (298.40): calcd. C 72.45, H 6.08;
found C 72.38, H 6.01.
4-Hydroxy-3,5-diphenyl-2-pyrazoline (22a)
◦
M. p. 201 C. Yield 65 % (yellow crystals). – IR (KBr):
ν = 3387 (OH), 3183 (NH), 1610 (C=N), 1577, 1466, 1343,
1255, 1038 cm−1. – C15H14N2O (238.28): calcd. C 75.61,
H 5.92, N 11.76; found C 75.50, H 5.81, N 11.58.
1-(p-Anisyl)-1,5-di(phenylthio)-1-pentan-3-one (27)
A solution of 9 (0.93 g, 3 mmol) and thiophenol (0.83 g,
7.5 mmol) in 50 % aq. ethanol (25 mL) was refluxed for 1 h.
The product obtained on cooling was filtered off and crys-
4-Hydroxy-1,3,5-triphenyl-2-pyrazoline (22b)
◦
tallized from ethanol to give 27. M. p. 60 C. Yield 75 %
◦
(white powder). – IR (KBr): ν = 1701 cm−1 (CO), 1610,
1582, 1462, 1364, 1260, 1179, 1028 cm−1. – C24H24O2S2
(408.58): calcd. C 70.55, H 5.92; found C 70.35, H 5.81.
M. p. 124 C. Yield 72 % (yellow crystals). – IR (KBr):
ν = 3262 (OH), 1608 (C=N), 1596, 1495, 1323, 1136,
1033 cm−1. – C21H18N2O (314.37): calcd. C 80.23, H 5.77,
N 8.91; found C 80.10, H 5.59, N 8.71.
5-(p-Anisyl)-1-phenyl-3-(β-phenylthioethyl)-2-pyrazoline
(28a)
4-Hydroxy-1-(piperidin-1-ylmethyl)-3,5-diphenyl-2-pyrazol-
ine (23)
Procedure A: A solution of 26a (0.6 g, 2 mmol), phenyl-
hydrazine (0.22 g, 2 mmol) and 0.1 mL of conc. HCl in
ethanol (25 mL) was heated on a water bath for 30 min. Af-
ter standing at r. t. for 24 h, the product obtained was filtered
and crystallized from ethanol to give 28a. M. p. 70 ◦C. Yield
80 % (white crystals). – IR (KBr): ν = 1610 (C=N), 1593,
1456, 1325, 1252, 1168, 1090 cm−1. – 1H NMR (200 MHz,
CDCl3, 25 ◦C, TMS): δ = 2.64 – 2.76 (m, 4H, (CH2)2–
SPh), 3.21 – 3.46 (d, 2H, 4-H2), 3.79 (s, 3H, ArOCH3),
4.91 – 5.02 (m, 1H, 5-H), 7.12 – 7.52 (m, 14H, aromatic). –
C24H24N2OS (388.53): calcd. C 74.19, H 6.23, N 7.21;
found C 74.01, H 6.11, N 7.03.
Procedure B: A mixture of 27 (0.82 g, 2 mmol), phen-
ylhydrazine (0.22 g, 2 mmol) and 0.1 mL of conc. HCl in
ethanol (25 mL) was refluxed for 1 h, and worked up as above
to give 28a. M. p. 69 – 70 ◦C. Yield 65 %. The structure was
confirmed by a comparison of 1H NMR data, m. p. and TLC
with that from procedure A.
A solution of 22a (1.2 g, 5 mmol), formalin (37 %,
0.5 mL, 6 mmol) and piperidine (0.43 g, 5 mmol) in ethanol
(40 mL) was refluxed for 6 h. The crystals obtained on
cooling were filtered off and recrystallized from ethanol to
◦
give 23. M. p. 170 C. Yield 55 % (yellow crystals). – IR
(KBr): ν = 3383 (OH), 1612 (C=N), 1433, 1352, 1◦267, 1141,
1043 cm−1. – 1H NMR (200 MHz, CDCl3, 25 C, TMS):
δ = 1.55 – 1.58 (m, 6H, 3-H2, 4-H2, 5-H2 of piperidine),
2.63 (m, 4H, CH2–N–CH2 of piperidine), 3.75 (d, 1H, 4-H),
4.73 (s, 1H, OH), 5.15 (s, 2H, N–CH2–N of side chain), 5.75
(m, 1H, 5-H), 7.19 – 7.75 (m, 10H, aromatic). – C21H25N3O
(335.44): calcd. C 75.19, H 7.51, N 12.53; found C 75.02,
H 7.32, N 12.33.
1,4-Bis(4-hydroxy-3,5-diphenyl-4,5-dihydro-1H-pyrazol-1-
ylmethyl)piperazine (24)
A solution of 22a (2.4 g, 10 mmol), formalin (37 %,
1.2 mL, 15 mmol) and piperazine (0.44 g, 5 mmol) in
ethanol (50 mL) was refluxed for 6 h. After standing at r. t.
1,5-Diphenyl-3-(β-phenylthioethyl)-2-pyrazoline (28b)
This compound was obtained in the same manner as
for 24 h, the product obtained was filtered and crystallized described for 28a (procedure A), but using 26b (0.54 g,
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548
E. M. Afsah et al. · Synthesis of 3- and 4-Functionalized 2-Pyrazolines
2 mmol) instead of 26a. The product crystallized from TMS): δ = 2.69 – 2.75 (m, 4H, (CH2)2–SPh), 3.24 – 3.38 (d,
◦
ethanol to give 28b. M. p. 73 C. Yield 66 % (white crys- 2H, 4-H2), 5.27 – 5.34 (m, 1H, 5-H), 7.15 – 7.55 (m, 15H,
tals). – IR (KBr): ν = 1615 (C=N), 1600, 1510, 1447, 1319, aromatic). − C23H22N2S (358.50): calcd. C 77.06, H 6.19,
◦
1260, 1120 cm−1. – 1H NMR (200 MHz, CDCl3, 25 C, N 7.81; found C 76.93, H 6.01, N 7.67.
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