Metal-free and highly regioselective synthesis of N-heteroaryl substituted pyrazoles from α,β-unsaturated N-tosylhydrazones and heteroaryl chlorides

Article abstract of DOI:10.1016/j.tetlet.2019.07.034

A cascade cyclization/nucleophilic aromatic substitution (S_NAr) reaction of α,β-unsaturated N-tosylhydrazones with N-heteroaryl chlorides was developed for the synthesis of N-heteroaryl pyrazole derivatives. This one-pot reaction provided bi(he

Full text of DOI:10.1016/j.tetlet.2019.07.034

Accepted Manuscript
Metal-Free and Highly Regioselective Synthesis of N-Heteroaryl Substituted
Pyrazoles from α,β-Unsaturated N-Tosylhydrazones and Heteroaryl Chlorides
Lin Zeng, Xiao-Qiang Guo, Zai-Jun Yang, Ya Gan, Lian-Mei Chen, Tai-Ran
Kang
PII:
S0040-4039(19)30687-2
https://doi.org/10.1016/j.tetlet.2019.07.034
TETL 50943
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 May 2019
5 July 2019
15 July 2019
Please cite this article as: Zeng, L., Guo, X-Q., Yang, Z-J., Gan, Y., Chen, L-M., Kang, T-R., Metal-Free and Highly
Regioselective Synthesis of N-Heteroaryl Substituted Pyrazoles from α,β-Unsaturated N-Tosylhydrazones and
Heteroaryl Chlorides, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.07.034
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Graphical Abstract
Metal-Free and Highly Regioselective Synthesis of
N-Heteroaryl Substituted Pyrazoles from α,β-
Unsaturated N-Tosylhydrazones and Heteroaryl
Chlorides
Leave this area blank for abstract info.
Lin Zeng,a Xiao-Qiang Guo,b Zai-Jun Yang, a Ya Gan,b Lian-Mei Chenb,* and Tai-Ran Kanga, b, *
R1
Cl
Het
NNHTs
R2
R1 = aryl, alkyl
R2 = H, Me,
CF3, Ph
CH3CN
Cs2CO3
+
N
R2
R1
N
60 o
C
X
thieno[2,3-d]pyrimidine,
quinazoline, pyridine,
pyrimidine, pyrazine
Het
X
27 examples
65-98% yield
>20:1 regioselectivity
metal-free
operational simplicity
broad substrate scope
excellent yields and regioselectivity

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Metal-Free and Highly Regioselective Synthesis of N-Heteroaryl Substituted
Pyrazoles from α,β-Unsaturated N-Tosylhydrazones and Heteroaryl Chlorides
Lin Zeng,a Xiao-Qiang Guo,b Zai-Jun Yang,a Ya Gan,b Lian-Mei Chen,b, * and Tai-Ran Kanga ,b, *
a
Collaborative Innovation Center of Tissue Repair Material of Sichuan Province, College of Chemistry & Chemical Engineering, China West Normal
University, Nanchong City, Sichuan, 637002, China.
b College of Pharmacy and Biological Engineering, Chengdu University, Chengdu City 610106, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A cascade cyclization/nucleophilic aromatic substitution (SNAr) reaction of α,β-unsaturated N-
tosylhydrazones with N-heteroaryl chlorides was developed for the synthesis of N-heteroaryl
pyrazole derivatives. This one-pot reaction provided bi(heteroaryl) derivatives in good to
excellent yields and with excellent regioselectivity. The procedure is operationally simple and
applicable to large-scale synthesis.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
N-Tosylhydrazones
Heteroaryl chlorides
N-Heteroaryl substituted pyrazoles
Transition-Metal-Free
1b),15 to give functionalized pyrazoles with excellent
regioselectivities. Recently, a palladium-catalyzed coupling of
Introduction
Carbon-nitrogen (C-N) linked bi(heteroaryl) compounds are
ubiquitous in biomolecules, natural products1a and nitrogen-
containing heterocyclic ligands.1b Pyrazoles, as a class of
heterocyclic compounds, possess a broad range of biological
activities, such as antibacterial,2 analgesic3 and antidepressant
properties.4 Thienopyrimidines exhibit remarkable activities,
such as analgesic, antibacterial, aurora kinase inhibitor,
antioxidant and antitumor properties.5, 6a In addition, C-N linked
bi(heteroaryl) compounds containing both pyrazole and
thienopyrimidine rings have also found numerous applications.6
Due to their unique structural characteristics,7, 8 the development
of efficient methods for the synthesis of these bi(heteroaryl)
compounds from easily accessible starting materials with a
simple operations is highly desired.
α,β-unsaturated tosylhydrazones with allenylphosphine oxides to
give pyrazolemethylene-substituted phosphinyl allenes was
reported by Wu and co-workers (Scheme 1c).16
Other classical approaches for preparing N-(hetero)aryl
pyrazoles include copper-17 and palladium-18catalyzed cross-
coupling reactions of aryl halides with N-H-containing heteroaryl
compounds (Ullman-type), that often require the use of metal
18
reagents and high reaction temperatures.17,
Therefore, the
development of metal-free approaches for the synthesis of N-aryl
pyrazoles is still highly desirable.
As an extension of our study regarding the use of
tosylhydrazones as diazo precursors,19 we envisioned that an
approach could be developed for constructing N-heteroaryl
pyrazoles from α,β-unsaturated N-tosylhydrazones and heteroaryl
chlorides. This method would rely on cyclization and Ullman-
type cross-coupling reactions. To the best of our knowledge, the
incorporation of two heteroaryl rings from heteroaryl halides and
Aside from the condensation of hydrazines with 1,3-
dicarbonyl compounds or α,β-unsaturated aldehydes with
ketones,7 the (3+2)-cycloaddition of diazo compounds with
alkenes or alkynes represents a classical method to obtain N-
substituted pyrazoles.8 N-Tosylhydrazones, as precursors of diazo
compounds, have been employed as building blocks for the
formation of C-C, C-N, C-B, C-O and C-Si bonds, which were
reported by the pioneering work of Barluenga,9 Valdés,10 Wang11
and Jiang.12 The (3+2)-cycloaddition of saturated N-
tosylhydrazones with alkenes or alkynes for synthesis of
pyrazoles are also well reported.13 However, the above mentioned
methods often suffer from poor regioselectivity.7-13 To resolve
this problem, there have been a few examples of the oxidative
cyclization of α,β-alkenic N-tosylhydrazones (Scheme 1a)14 and
electrophilic cyclization of α,β-alkynic hydrazones (Scheme
α,β-unsaturated
N-tosylhydrazones
in
one-pot
are
underdeveloped. Only one example can be found for the
synthesis of N-alkyl pyrazoles from α,β-unsaturated N-
tosylhydrazones and active alkyl halides, which was reported by
the group of Tang and Zhang (Scheme 1d).20a Herein, we report a
metal-free
approach
for
the
synthesis
of
pyrazolylthienopyrimidines and other N-heteroaryl pyrazoles
from α,β-unsaturated N-tosylhydrazones and N-heteroaryl
chlorides as starting materials under mild reaction conditions
(Scheme 1e).

2
Tetrahedron
Scheme 1.
Table 1.
Representative strategies for the synthesis of N-substituted
pyrazoles using α,β-unsaturated hydrazones.
Optimization of the reaction conditions.a
N
N
S
N
S
N
NNHTs
+
N
N
S
base
solvent
60 oC
Previous works
N
N
+
a. Oxidative cyclization of α,β-alkenic hydrazones
N
Ph
N
Ph
R4
N
Cl
R1
NNHR4
Oxidative
Ph
cyclization
N
3a'
1a
2a
3a
R1
R3
R2
Ref 14
Entry
1
Base
Solvent
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
toluene
Temp (oC)
Yield 3a (%) b
3a/3a’ c
-
R2
R3
b. Electrophilic cyclization of α,β-alkynic hydrazones
Et3N
60
60
60
60
60
60
60
60
60
60
60
60
90
50
< 5
< 5
75
84
88
90
50
68
80
84
78
95
90
45
R3
N
NNHR3
R2
R1
2
DBU
-
Electrophilic
cyclization
N
3
NaOtBu
Na2CO3
K2CO3
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
Ref 15
R1
R2
4
Coupling of α,β-alkenicN-tosylhydrazones with allenes
c.
5
O
NNHTs
R3
R4
PPh2
6
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
R1
R2
Pd(PPh3)2Cl2
Ref 16
R2
7
O
R3
R4
PPh2
N
N
+
8
1,4-dioxane
THF
OAr
9
R1
Coupling of α,β-alkenic N-tosylhydrazones with alkyl halides
d.
10
11
12
13
14
DMF
R
R2
DCE
N
Base
NNHTs
R2
+
R
X
N
MeCN
MeCN
MeCN
Ref 20
R1
X = Br, I
R1
R1
e. This work
NNHTs
Cl
aReagents and conditions: N-tosylhydrazone 1a (0.11 mmol,
1.1 equiv.), 4-chlorothieno[2,3-d]pyrimidine 2a (0.1 mmol, 1.0
equiv.), base (0.25 mmol, 2.5 equiv.), MeCN (1 mL), 6 h.
Metal-Free
One-pot
N
R2
N
+
het
R1
R2
X
het
bIsolated yield.
X = S, CH=CH
X
cThe ratio of 3a/3a’ was determined by 1H NMR analysis.
Results and Discussion
With the optimised conditions in hand (Table 1, entry 12), the
reactions of a variety of α,β-unsaturated N-tosylhydrazones 1a-p
derived from α,β-unsaturated enals or enones and 4-
chlorothieno[2,3-d]pyrimidine 2a were examined (Scheme 2).
The electronic nature of the aryl ring substituents at the β-
position of α,β-unsaturated tosylhydrazones had no apparent
effects on the reaction. The reaction occurred smoothly with
para-, ortho-, and meta- substituted aromatic N-tosylhydrazones
to afford the desired pyrazolylthienopyrimidines 3b-i in excellent
yields (92-98%) and with excellent regioselectivity (>20:1). Both
electron-donating (CH3) and electron-withdrawing (F, Cl, CN, Br,
NO2) groups were tolerated on the aromatic ring (Scheme 2, 3b-i).
The naphthyl substituted α,β-unsaturated N-tosylhydrazone 1j
was also a suitable substrate and afforded the desired product 3j
in 93% yield with excellent regioselectivity (>20:1). Notably,
heteroaromatic substituents, such as furan-2-yl, thiophen-2-yl,
and 1H-indol-3-yl substituted α,β-unsaturated N-tosylhydrazones,
also proceeded efficiently gave products 3k, 3l, and 3m in 92%,
96%, and 95% yield, and with >20:1, 5:1, and >20:1
regioselectivity, respectively. We were also pleased to find that
alkyl groups, such as 3-cyclopropylallylidene substituted N-
tosylhydrazone, reacted smoothly with N-heteroaryl halide 2a to
afford the corresponding pyrazolylthienopyrimidine 3n in 89%
yield, albeit with 3:1 regioselectivity which is lower than that of
aryl substituted α,β-unsaturated N-tosylhydrazones; presumably
Initially, α,β-unsaturated N-tosylhydrazone 1a and 4-
chlorothieno[2,3-d]pyrimidine 2a were selected as model
substrates to optimize the reaction conditions (Table 1). A variety
t
o
of bases were examined in BuOH at 60 C for 6 h (Entries 1-6).
The base played an important role in achieving a high yield of
3a. Using organic bases (Et3N and DBU) resulted the formation
of 3a in trace amounts (Entries 1, 2) since they were not strong
enough to convert 2a into the corresponding α,β-unsaturated
diazo compound. Stronger bases such as NaOtBu, Na2CO3,
K2CO3 and Cs2CO3 gave better results; Cs2CO3 proved to be the
best affording 3a in 90% yield (Entries 3-6) presumably due to
its stronger basicity and better solubility. Compound 3a was the
major isomer (3a/3a’>20:1, as determined by 1H NMR
spectroscopy on the crude reaction mixture, see ESI for details).
Solvents such as toluene, 1,4-dioxane, THF, DMF, DCE and
MeCN were examined (Entries 7-12), and MeCN afforded 3a in
95% yield and with the regioselectivity of 3a/3a’ >20:1 (Entry
12). Raising the reaction temperature to 90 oC led to a lower yield
of 3a (Entry 13); the side product (4-tosylthieno[2,3-
d]pyrimidine) was also observed. Lowering the reaction
temperature to 50 °C led to a lower yield of 3a, which may be
due to the insufficient conversion of N-tosylhydrazone 1a into
the corresponding diazo compound (Entry 14).

3
due to the reduced steric hindrance. Interestingly, when the N-
tosylhydrazones 1o-r derived from α,β-unsaturated enones (R=
CH3 and CF3) were reacted with 2a, the desired products 3o-r
were obtained in 88%, 90%, and 91% yield, respectively, and
with excellent regioselectivity (Scheme 2). Using N-
tosylhydrazone 1s derived from (E)-chalcone (R= Ph) as
substrate, product 3s was afforded only in 65% yield; presumably
due to the steric hindrance of the aryl group.
corresponding pyrazoles (4a-i) in good to excellent yields and
with excellent regioselectivity (>20:1).
Scheme 3.
Substrate scope of the heteroaryl chlorides.a,b
Ph
Cl
N
CH3CN
Cs2CO3
N
Ph
NNHTs
N
N
+
+
het
Ph
60 oC
Scheme 2.
het
het
Substrate scope of the N-tosylhydrazones 1a-p.a,b
1a
4'
2
4
N
N
N
S
S
CH3CN
Cs2CO3
N
S
N
Ph
N
NNHTs
R2
Ph
Ph
+
+
N
N
R2
R1
R1
60 oC
N
N
N
N
N
N
Cl
N
N
R1
R2
3a'-p'
1a-p
2a
3a-p
N
N
N
N
S
3a
3a/3a
' > 20:1
R = H
, 95%,
O2N
CO2Me
3b
3c
3d
3b3b'
3c/3c
CN
4a,
4a/4a'
4-F
4-Cl
, 98%,
, 94%,
, 92%,
> 20:1
' > 20:1
N
N
93% yield
4c,
4c/4c'
90% yield
4b,
81% yield
3d/3d'
4-CN
4-Me
3-Br
3-Me
2-NO2
2-OMe
> 20:1
' > 20:1
3f/3f'
> 20:1
> 20:1
> 20:1
4b/4b'
> 20:1
N
3e
3e/3e
, 94%,
, 96%,
Ph
Ph
3f
Ph
3g
3h
3i
3g/3g'
3h/3h'
, 93%,
, 94%,
, 93%,
> 20:1
> 20:1
N
N
N
N
N
4-6 hours
N
3i/3i'
> 20:1
N
N
R
N
N
N
N
N
S
S
X = O
3k
3k/3k'
F3C
O
N
O
N
N
N
, 92%,
4d,
4d/4d'
95% yield
4f,
85% yield
4f/4f'
4e,
4e/4e'
96% yield
> 20:1
N
3j
3j/3j'
, 93%,
N
> 20:1
> 20:1
Ph
> 20:1
X = S
N
> 20:1
3l
, 96%,
3l/3
Ph
Ph
l' = 5:1
6 hours
6 hours
N
N
X
N
N
N
N
N
N
N
N
S
S
O
N
S
NC
N
N
N
N
N
O
3n
3n/3n
, 89%,
N
N
3m
, 95%,
N
' = 3:1
4g,
4g/4g'
88% yield
N
4h,
4i,
87% yield
4i/4i'
> 20:1
92% yield
3m/3m'
> 20:1
> 20:1
4h/4h'
> 20:1
6 hours
6 hours
aReagents and conditions: N-tosylhydrazone 1a (0.11 mmol,
1.1 equiv.), N-heteroaryl halides 2 (0.1 mmol, 1.0 equiv.),
Cs2CO3 (0.25 mmol, 2.5 equiv.), MeCN (1 mL), 4-8 h.
N
Boc
N
R1 = CH3,
R2 = H
3-Br
S
bIsolated yield.
3o
3p
3o/3o'
3p/3p'
, 88%,
> 20:1
> 20:1
N
N
Gram-scale experiments
, 90%,
N
standard
conditions
N
R1 = CF3, R2 = H
R1
S
NNHTs
H
3a
3r
3r/3r'
, 91%,
3s
> 20:1
N
1
2
+
89%
R = Ph, R = H , 65%
Ph
8 hours
Cl
R2
1.24 g
S
5.5 mmol
5.0 mmol
aReagents and conditions: N-tosylhydrazones 1 (0.11 mmol,
1.1 equiv.), 4-chlorothieno[2,3-d]pyrimidine 2a (0.1 mmol, 1.0
equiv.), Cs2CO3 (0.25 mmol, 2.5 equiv.), MeCN (1 mL), 4-8 h.
N
N
bIsolated yield
N
N
To further expand the scope of N-heteroaryl halides, N-
tosylhydrazone 1a was examined in the reactions with a series of
N-heteroaryl chlorides (Scheme 3). The reaction tolerated a
variety of N-heteroaryl chlorides, such as 2-chloropyridine, 2-
chloropyrimidine, 4-chloropyrimidine, 2-chloropyrazine and 4-
chloroquinazoline. Heteroaryl halides containing CN, CO2Me,
NO2, CF3, MeO, and MeS groups were all converted into the
Ph
3a
CCDC 1881187
Figure 1. Gram-scale experiment and the X-ray structure of
compound 3a.

4
Tetrahedron
3.
(a) Lan, R.; Liu, Q.; Fan, P.; Lin, S.; Fernando, S. R.; McCallion,
D.; Pertwee, R.; Makriyannis, A. J. Med. Chem. 1999, 42, 769.
Moore, K. W.; Bonner, K.; Jones, E. A.; Emms, F.; Leeson, P. D.;
Marwood, R.; Patel, S.; Rowley, M.; Thomas, S.; Carling, R. W.
Bioorg. Med. Chem. Lett. 1999, 9, 1285.
A large scale reaction using 5.5 mmol of 1a gave product 3a
(1.24 g) in 89% yield without a significant decrease in its
efficiency (Fig. 1). The structure of 3a was confirmed by X-ray
crystallography (Fig. 1).21
4.
5.
6.
Selected Reviews: (a) Ibrahim, Y. A.; Elwahy, A. H. M.; Kadry,
A. M. Adv. Heterocycl.Chem., 1996, 65, 235. (b) Varvounis, G.;
Giannopoulos, T. Adv. Heterocycl. Chem. 1996, 65, 193. (c)
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A.; Mongin, F. Org. Biomol. Chem. 2009, 7, 4782. (c) Park, J. W.;
Song, Y.-H.; Heterocycl. Commun. 2017, 23, 281.
Based on previous work,16 a plausible mechanism was
proposed as illustrated in Figure 2. α,β-Unsaturated diazo
intermediate A is generated in situ from α,β-unsaturated N-
tosylhydrazone 1a upon treatment with Cs2CO3. 3-Phenyl-3H-
pyrazole B is formed from diazo intermediate A via an
intermolecular cyclization process. Then, 3-phenyl-3H-pyrazole
B is easily transformed into the more stable 3-phenyl-1H-
pyrazole C and 5-phenyl-1H-pyrazole C’ through proton transfer
tautomerization. 3-Phenyl-1H-pyrazole
C
is the major
intermediate due to its larger conjugation compared to C’.16 An
intermolecular nucleophilic aromatic substitution (SNAr) reaction
of 4-chlorothieno[2,3-d]pyrimidine 2a with the anion of pyrazole
provides the major product 3a and minor product 3a’ under basic
conditions. Product 3a was the major isomer partly because the
rate of 5-phenyl-1H-pyrazole C’ reacting with 2a is slower than
that of C due to its larger steric hindrance.
7.
8.
Fustero, S.; Sanchez-Rosello, M.; Barrio, P.; Simon-Fuentes, A.;
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N
N
N
Ph
proton
transfer
cyclization
N
NNHTs
base
H
B
Ph
Ph
-H+, -Ts
A
N
Cl
Ph
NH
N
N
Ph
N
N
N
C
major
S
Base
+
N
3a 3a'
+
H
N
SNAr
9.
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N
C'
minor
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Figure 2. Proposed reaction mechanism.
Conclusion
In summary, a cascade reaction of α,β-unsaturated N-
tosylhydrazones with N-heteroaryl chlorides to directly access
carbon-nitrogen (C-N) linked bi(heteroaryl) derivatives bearing
both pyrazole and thienopyrimidine rings, as well as other N-
heteroaryl rings (pyridine, pyrimidine, pyrazine, and quinazoline)
was developed.
A
broad range of α,β-unsaturated N-
tosylhydrazone reagents and N-heteroaryl chloride compounds
were tolerated. The reaction proceeds under metal-free conditions,
giving highly functionalized bi(heteroaryl) products with good to
excellent yields and regioselectivities. The procedure is
operationally simple and applicable to large-scale synthesis.
Acknowledgments
We are grateful for financial support from the National
Natural Science Foundation of China (NO. 21672172), and the
project of Youth Science and Technology Innovation Team of
Sichuan Province (NO. 2017TD0008), and the Education
Department of Sichuan Province (NO. 15CZ0016).
References and notes
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5
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21. CCDC 1881187 (3a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data request/cif.

6
Tetrahedron
Highlights:

A new reaction of N-tosylhydrazones
with N-heteroaryl chlorides has been
developed


The reaction provided bi(heteroaryl)s in
excellent yield and regioselectivity
The procedure is operationally simple
and applicable for the large-scale
synthesis