Synthesis of 1,3,5-trisubstituted pyrazolines via Zn(ii)-catalyzed double hydroamination of enynes with aryl hydrazines

Article abstract of DOI:10.1039/c1cc14850h

An efficient Zn(ii)-catalyzed intermolecular double hydroamination of 1,3-enynes with aryl hydrazines, for the synthesis of pyrazolines, has been discussed.

Full text of DOI:10.1039/c1cc14850h

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COMMUNICATION
Synthesis of 1,3,5-trisubstituted pyrazolines via Zn(II)-catalyzed double
hydroamination of enynes with aryl hydrazinesw
Nitin T. Patil* and Vipender Singh
Received 5th August 2011, Accepted 22nd August 2011
DOI: 10.1039/c1cc14850h
An efficient Zn(II)-catalyzed intermolecular double hydroamination
of 1,3-enynes with aryl hydrazines, for the synthesis of pyrazolines,
has been discussed.
Pyrazolines represent an important class of compounds that
find extensive use in pharmaceutical applications. Pyrazolines
are used as antitumor,1 immunosuppressive,2 antibacterial3
and antitubercular agents.4 Some of the pyrazoline derivatives
are reported to possess anti-inflammatory,5 antidiabetic,6
antidepressant,7 antimalarial,8 antiamoebic9 and anti-WN
virus activity.10 Most importantly, the pyrazolines can readily
be oxidized11 to pyrazoles—a class of compounds also known
to exhibit promising biological activities.12 As a consequence,
Fig. 1 Concept of metal-catalyzed synthesis of pyrazolines.
To explore our hypothesis, initial efforts were directed towards
finding an appropriate metal catalyst for the proposed reaction
using phenyl hydrazine (1a) with (E)-1-(but-1-en-3-ynyl)benzene
(2a) as model substrates (Table 1). However, the reaction did
not occur when AuCl, Ph3PAuOTf and Ph3PAuNTf2 were
used as catalysts, even though these catalysts are commonly used
in intermolecular hydroamination of alkynes (entries 1–3).18 No
reaction occurred in the presence of PtCl2, PtI2 and PtCl4
catalyst as well (entries 4–6). We assumed that this failure could
be probably due to the inhibition of catalyst and/or reduction
of metal salts to metal(0) particles.19 With hope that the
judicious choice of catalyst can influence the outcome of the
proposed cyclization reaction, we opted to study the conversion
of 1a to 3a in greater detail using a variety of metal catalysts.
Very interestingly, when a sample of 1a was allowed to react
with 2a in the presence of 5 mol% ZnCl2 and Zn(OTf)2 under
stirring at 100 1C, pyrazoline 3a was formed in 30% and 45%
yields, respectively (entries 7 and 8).15c,20 A slight increase in
the yield was observed when 1 equiv. of Zn(OTf)2 was used
(entry 9). Gratifyingly, the use of 3 equivalents of Zn(OTf)2
provided 65% yield of 3a (entry 10). In order to optimize the
reaction further, we examined other Zn(II) salts such as ZnI2;
however, 3a was obtained only in 10% yield (entry 11). We
were pleased to find that when a mixture of 1a and 2a together
with 3 equiv. of Zn(OTf)2 catalyst was irradiated at a ceiling
temperature of 150 1C and a maximum power of 40 W for 1 h,
the desired product 3a was isolated in 76% yield (entry 12).
The use of Zn(II) salts such as ZnCl2 and ZnI2 gave inferior results
under MW assisted conditions (entries 13 and 14). It should be
noted that various solvents such as MeOH, DCE and THF were
tested; however, all of them were found to be inferior.21
pyrazolines have received considerable attention over the
years, and many methods for their preparation have been
developed and described in the literature. Pyrazolines have usually
been prepared by reacting hydrazines with a,b-unsaturated
carbonyl compounds13 or by 1,3-dipolar cycloadditions between
diazoalkanes dipoles with activated olefins.14 Recently some
other methods have also appeared in the literature for the
synthesis of pyrazolines.15
During the course of our ongoing development of p-acid
catalyzed reaction and more particularly on hydroamination
initiated cyclization,16 we became interested in whether enynes
2 could be used as a partner to react with aryl hydrazines 1 in
metal-catalyzed intermolecular hydroamination to afford the
(E)-hydrazones A which, in part, would be in equilibrium with
(Z)-isomer B (Fig. 1). The (Z)-hydrazones B would then
readily undergo an intramolecular cyclization providing a
strategically novel, atom economical route to pyrazolines 3.
Since the process involves the overall addition of two N–H
bonds across enynes, we termed this process as double hydro-
amination. Herein, we report Zn(II)-catalyzed double hydro-
amination of enynes with aryl hydrazines for the synthesis of
1,3,5-trisubstituted pyrazolines.17 To the best of our knowledge,
this is the first report on the synthesis of 2-pyrazolines via a
transition metal-catalyzed double hydroamination reaction.
Organic Chemistry Division-II, Indian Institute of Chemical
Technology (CSIR), Hyderabad – 500 607, India.
E-mail: nitin@iict.res.in, patlnitint@yahoo.com;
Fax: +91 40-2719-3382; Tel: +91 04027191471
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc14850h
c
11116 Chem. Commun., 2011, 47, 11116–11118
This journal is The Royal Society of Chemistry 2011

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Table 1 Catalyst screening studiesa
Table 2 Scope with arylhydrazinesa
R1
Product
Yield (%)b
Entry
M
Condition
Yield (%)b
Entry
1
R
c
1
2
3
4
5
6
7
8
5 mol% AuCl
100 1C
100 1C
100 1C
100 1C
100 1C
100 1C
100 1C
100 1C
100 1C
100 1C
100 1C
MW
—
—
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
H
Cl
F
H
OMe
H
H
I
Br
Cl
F
H
Cl
Me
H
CN
COOMe
H
H
3b
3c
3d
3e
3f
3g
3h
3i
74
76
71
69
d
5 mol% Ph3PAuOTf
5 mol% Ph3PAuNTf2
5 mol% PtCl2
5 mol% Ptl2
5 mol% PtCl4
5 mol% ZnCl2
5 mol% Zn(OTf)2
1 equiv. Zn(OTf)2
3 equiv. Zn(OTf)2
5 mol% ZnI2
3 equiv. Zn(OTf)2
3 equiv. ZnCl2
3 equiv. ZnI2
c
—
—
c
c
—
—
68
c
65c
72
30
45
80
62
9
49
9
1j
1k
1l
3j
3k
3l
10
11
12
13
14
65e
10
10
11
12
71
CF3
NO2
78c
52c
76f
40f
10f
1m
3m
MW
MW
a
A solution of aryl hydrazines 1 (1.172 mmol), (E)-1-(but-1-en-3-
ynyl)benzene 2a (0.391 mmol) and Zn(OTf)2 (3 equiv.) in toluene (2 mL)
was subjected to microwave irradiation at 150 1C (P = 40–50 W) for 1 h
a
A solution of phenyl hydrazine 1a (1.172 mmol), (E)-1-(but-1-en-3-
ynyl)benzene 2a (0.391 mmol) and the metal catalyst in toluene (2 mL)
b
(Biotage, Initiator Eight, single-mode reactor). Isolated yields.
c
Irradiated for 2 h.
b
c
was heated at 100 1C for 24 h. Isolated yields. Quantitative recovery
of 2a. The catalyst Ph3PAuOTf was generated by mixing equimolar
e
amounts of Ph3PAuCl and AgOTf. 3 equiv. of Zn(OTf)2 was used.
d
f
Table 3 Scope with enynesa
The reaction was performed using 3 equiv. of Zn(II) salt under
microwave conditions in toluene at 150 1C for 1 h.
Entry 1a
2
3
Yield (%)b
Under the optimal reaction conditions, a series of aryl
hydrazines 1 were reacted with (E)-1-(but-1-en-3-ynyl)benzene
(2a) and the results are summarized in Table 2. From entries
1–6, it can be seen that various halo groups such as I, Br, Cl
and F on aryl hydrazines were well tolerated to give products
3b–g in moderate to high yields (65–76%). The reactions of
1h and 1i with 2a under the standard reaction conditions
afforded expected pyrazolines 3h and 3i in 72 and 80% yields,
respectively (entries 7 and 8). As exemplified in entries 9–11,
this method is equally applicable to the aryl hydrazines
bearing electron withdrawing groups such as CN, COOMe
and CF3 to give corresponding products 3j–l in good yields.
However, the reaction of 3-nitrophenylhydrazine 1m was
found to be sluggish; a product 3m was isolated only in 52%
yield even after heating for 2 h (entry 12).
1
2
3
4
5
6
7
8
9
1a 2b R2 = R3 = H, R4 = Br
1a 2c R2 = R3 = H, R4 = Cl
1a 2d R2 = Cl, R3 = R4 = H
1a 2e R2 = R3 = H, R4 = Me
1a 2f R2 = Me, R3 = R4 = H
3n
3o
3p
3q
3r
72
75
76c
73
71
72
1a 2g R2 = R3 = H, R4 = OMe 3s
1a 2h R2 = H, R3 = OPh, R4 = H 3t
69
1a 2i R2 = CF3, R3 = R4 = H
1a
3u
60c
53c
Next, the scope of the reaction with various enynes was
studied (Table 3). The enynes, bearing halo groups, such as 2b,
2c and 2d reacted well giving corresponding products 3n, 3o
and 3p in high yields (entries 1–3). As can be judged from
entries 4–7, the electron donating group on the aromatic rings
of enynes can also be used as substrates. On the other hand
electron withdrawing groups such as CF3 on aromatic ring
gave slightly lesser yield (entry 8). Even aliphatic enyne 2j and
2k were reacted with 1a giving the corresponding products 3v
and 3w in 53 and 62% yields, respectively (entries 9 and 10).
Further exploration of the substrate scope revealed that the
1-ethynylcyclohexene (4) was also suitable for the double
hydroamination reaction (eqn (1)). The reaction of 4 proceeded
smoothly with aryl hydrazines 1a, 1c, 1f and 1k under the
optimized reaction conditions to afford corresponding annulated
pyrazolines3b,22 in 63–74% yield.
10
1a
62c
a
A solution of phenyl hydrazine 1a (1.172 mmol), enynes 2 (0.391 mmol)
and Zn(OTf)2 (3 equiv.) in toluene (2 mL) was subjected to microwave
irradiation at 150 1C (P = 40–50 W) for 1 h (Biotage, Initiator Eight,
b
c
single-mode reactor). Isolated yields. Irradiated for 2 h.
We were pleased to find that pyrazolines 3p and 3s on
reaction with Pd/C in acetic acid gave corresponding pyrazoles
6a and 6b in 95 and 96% yield, respectively (eqn (2)).11e The
structural similarity that these heterocycles share with the
drugs such as celecobix (Celebrex), sildenafil (Viagra), and
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11116–11118 11117

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This journal is The Royal Society of Chemistry 2011