Regioselective synthesis of 1,3,5-Trisubstituted Pyrazoles from N-Alkylated Tosylhydrazones and terminal Alkynes

Article abstract of DOI:10.1021/ol403447g

An efficient synthesis of 1,3,5-trisubstituted pyrazoles from Nalkylated tosylhydrazones and terminal alkynes was developed. The protocol was applied to a wide range of substrates and demonstrated excellent tolerance to a variety of substituents, includin

Full text of DOI:10.1021/ol403447g

Letter
pubs.acs.org/OrgLett
Regioselective Synthesis of 1,3,5-Trisubstituted Pyrazoles from
N‑Alkylated Tosylhydrazones and Terminal Alkynes
Yuanfang Kong, Meng Tang,* and Yun Wang
School of Pharmacy, Lanzhou University, Lanzhou 730000, P. R. China
S
* Supporting Information
ABSTRACT: An efficient synthesis of 1,3,5-trisubstituted pyrazoles from N-
alkylated tosylhydrazones and terminal alkynes was developed. The protocol
was applied to a wide range of substrates and demonstrated excellent
tolerance to a variety of substituents, including both electron-donating and
-withdrawing groups. In comparison with the common approaches for
substituted pyrazole syntheses, this methodology proceeded with complete
regioselectivity, especially, in the cases that R2 and R3 are similar substituents.
a
Table 1. Screening the Reaction Conditions
s an important class of heteroaromatic ring systems,
Apyrazoles have found widespread application in the
Scheme 1. Two General Methods for the Pyrazole Synthesis
2a
18-crown-6
(equiv)
yield
b
entry (equiv)
base
solvent
time
12 h
(%)
1
4
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
NaH
0
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
THF
58
67
76
69
52
2
4
0.1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
3.5 h
15 min
15 min
15 min
25 min
15 min
36 h
3
4
4
3
5
1.5
1.5
4
c
6
51
d
7
64
8
4
20
9
4
NaOMe
KOH
24 h
trace
trace
−
Scheme 2. Our Previous Reported Work in Pyrazole
Synthesis
10
11
12
13
14
15
4
24 h
4
Cs2CO3
t-BuOK
t-BuOK
t-BuOK
t-BuOK
24 h
4
10 h
20
d
4
DMSO
DMF
24 h
14
4
10 h
trace
36
4
dioxane
10 h
a
Reactions were performed with 1a (0.18 mmol) in 1 mL of solvent.
b
c
Isolated yields. The reaction was performed with 1a (4.0 mmol) in 5
d
mL of pyridine. The reaction was carried out at room temperature.
attention from organic chemists because of their diverse
bioactivities.2
Of the many methods developed, the Knorr pyrazole
synthesis, the cyclocondensation of hydrazines with a 1,3-
dicarbonyl compound or surrogates thereof, has been adapted
as the standard method for its convenience and versatility.3
However, the lack of regiospecificity and somewhat limited
substrate scope greatly reduce the attractiveness of this method.
Especially, in the cases that R2 and R4 are similarly substituted
Scheme 3. Preparation of N-Alkylated Tosylhydrazones in a
One-Pot Version
agrochemical, material, and especially pharmaceutical indus-
tries.1 The syntheses of pyrazoles have received considerable
Received: November 28, 2013
© XXXX American Chemical Society
A
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Letter
a
Table 2. Regioselective Synthesis of 1,3,5-Trisubstituted Pyrazoles from N-Alkylated Tosylhydrazones and Terminal Alkynes
a
Reactions were performed with N-alkylated tosylhydrazones 1 (0.18 mmol), alkynes 2 (0.72 mmol), t-BuOK (0.38 mmol), and 18-crown-6 (0.09
b
mmol) in pyridine (1 mL) at 0 °C. Isolated yields.
with only minor differences both electronically and sterically,
complete control of the regioselectivity becomes a daunting
task (Scheme 1a). Recently, we reported an efficient one-pot
synthesis of substituted pyrazoles, in which we used TsNHNH2
and halides instead of monosubstituted hydrazines. And
compared with the Knorr pyrazole synthesis, the reaction we
developed could give a different type of product (Scheme 2a).4
Another prevalent strategy for constructing pyrazole rings is
the 1,3-dipolar cycloaddition of diazo compounds to alkenes or
alkynes (Scheme 1b).5 Usually, the significant electronegativity
difference of the two C atoms of the alkenes or alkynes allows
better control of the regioselectivity. But the difficulty in
preparing diazo compounds and handling reactive 1,3-dipolars
often limits their synthetic application. We developed a
B
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ring all gave the corresponding pyrazole derivatives in good to
high yields. However, a slightly lower yield was observed with
electron-withdrawing substituents (entries 26−32), possibly
due to their instability under the basic conditions. Additionally,
aliphatic terminal alkynes and N-alkylated aliphatic aldehyde
tosylhydrazones afforded the corresponding product in
extremely poor yield.
Scheme 4. Proposed Pathway for Pyrazole Formation
As shown in Table 2, the main favorable characteristics of
this reaction included the following: remarkably, our reaction
conditions show good compatibility with different substituents.
It was effective for a wide scope of substrates, and a series of
1,3,5-trisubstituted pyrazole derivatives were synthesized in
good yields; more importantly, complete control of the
regioselectivity was achieved, especially, in the cases that R2
and R3 are similar substituents with only minor differences,
such as the products 3j (entry 9), 3t (entry 19), 3v (entry 21),
3x (entry 23), 3bb (entry 27), 3dd (entry 29), 3ff (entry 31),
etc. which were prepared in good yields and are not easily
accessible with complete regioselectivity from other routes.
Additionally, by adjusting the structures of substrates 1 and 2,
the two regioisomers can be prepared respectively, for example,
as products 3b (entry 1) and 3o (entry 14), 3c (entry 2) and 3i
(entry 8), 3f (entry 5) and 3s (entry 18), 3g (entry 6) and 3l
(entry 11), 3j (entry 9) and 3q (entry 16), 3m (entry 12) and
3t (entry 19), which are usually prepared as a mixture of
regioisomers.
DABCO-promoted synthesis of pyrazoles from tosylhydrazones
and nitroalkenes. Compared to the 1,3-dipolar cycloaddition
reaction, the corresponding diazo intermediates were not
formed and the regioselectivity was reversed in this approach
(Scheme 2b).6
As an in situ source of diazo compounds,7 tosylhydrazones
have been reported to react with terminal alkynes to produce
pyrazoles under basic conditions8 and a TfOH mediated
cycloaddition reaction of tosylhydrazones and terminal alkynes
has also been reported.9 Using N-monosubstituted hydrazones
reacted with nitroalkenes, Deng et al. developed a novel
regioselective synthesis of pyrazoles under neutral, acidic, or
basic conditions.10 However, to our knowledge, N-alkylated
tosylhydrazones (1), which can be prepared according to our
recently reported procedure11 in an improved one-pot version
easily (Scheme 3),12 have not been used in pyrazoles syntheses.
In continuance of our interest in the regioselective synthesis of
pyrazoles, herein, we describe our endeavor toward the
synthesis of 1,3,5-trisubstituted pyrazoles from N-alkylated
tosylhydrazones and terminal alkynes with complete regiose-
lectivity.
A simple mechanism was proposed as shown in Scheme 4.
The reaction was initiated by the nucleophilic addition of
alkynyl potassium to N-alkylated tosylhydrazones resulting in
intermediate 4 by the loss of a p-toluenesulfinic acid anion and
then a 1,3-H shift, with deprotonation producing the anion 5,
which subsequently went through an intramolecular cyclization
and protonation to form pyrazoles 3.
In summary, we have reported a simple and efficient
procedure for the regioselective preparation of 1,3,5-trisub-
stituted pyrazole derivatives. The protocol was applied to a
wide range of substrates and demonstrated excellent tolerance
to a variety of substituents, including both electron-donating
and -withdrawing examples. In addition, compared with the 1,3-
dipolar cycloaddition reactions of diazo compounds with
terminal alkynes, the corresponding diazo intermediates were
not formed and the reaction is amenable to gram-scale
synthesis of pyrazoles and proceeded with complete
regioselectivity.
In an initial experiment, we conducted the reaction between
the N-methyl tosylhydrazone (1a) and phenylacetylene (2a) in
pyridine and in the presence of t-BuOK at 0 °C (Table 1). After
12 h, pyrazole 3a was given in 58% yield (entry 1). In order to
accelerate the reaction rate and improve the yield, we added 18-
crown-6 to the reaction mixture. Delightfully, the use of 0.1
equiv of 18-crown-6 could significantly shortened the reaction
time, and the reaction could be completed within 15 min in the
presence of 0.5 equiv of 18-crown-6 with a yield of 76% (entry
3). Decreasing the amount of 2a resulted in lower yields (enties
4, 5). To investigate the reaction’s practical utility, we also
performed the reaction with 4 mmol of 1a, and the yield was
not affected (entry 6). Furthermore, the reaction could be
carried out at room temperature, but the yield was lower (entry
7). Of the bases screened, NaH, NaOMe, KOH, and Cs2CO3
all gave unsatisfactory results (entries 8−11). Next, a variety of
different solvents were also evaluated; however, use of THF,
DMSO, DMF, and dioxane resulted in poor yields of 3a
(entries 12−15).
Under the above optimized conditions, we then attempted to
synthesize a variety of pyrazoles to test the generality and scope
of the method (Table 2). First, the scope of the reaction was
evaluated with regard to the structure of the alkynes. In general,
the electronic effect on the aromatic ring had little influence on
the reaction, and the alkynes bearing electron-donating (2b, 2c)
or -withdrawing substituents (2d) all resulted in good yields.
And the reaction is also general for all types of N-alkylated
aromatic aldehyde tosylhydrazones; N-alkylated tosylhydra-
zones derived from benzaldehyde featuring electron-donating
(1c−1j) or -withdrawing (1k−1n) substituents in an aromatic
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, and copies of
NMR spectra for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tangmeng@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSFC (No. 21002044) for financial support. We
also acknowledge Dr. Shao-Hua Wang of Lanzhou University
for his helpful discussions.
C
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