Introduction of N-containing heterocycles into pyrazole by nucleophilic aromatic substitution

Article abstract of DOI:10.1081/SCC-120030741

The nucleophilic aromatic substitution on 5-chloropyrazoles activated by the electron-withdrawing formyl group offers a useful method to introduce a wide range of N-containing heterocycles into them. The rate of reaction was greatly affected by the electronic nature of the N-1 substitution.

Full text of DOI:10.1081/SCC-120030741

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Introduction of N‐Containing Heterocycles into
Pyrazole by Nucleophilic Aromatic Substitution
Min‐Sup Park a b , Hyun‐Ja Park a , Koon Ha Park b & Kee‐In Lee a
a Bio‐Organic Science Division, Korea Research Institute of Chemical Technology, P.O. Box
107, Yusong, Taejon, 305‐600, Korea
b Department of Chemistry, Chungnam National University, Taejon, Korea
Version of record first published: 16 Aug 2006.
To cite this article: Min‐Sup Park , Hyun‐Ja Park , Koon Ha Park & Kee‐In Lee (2004): Introduction of N‐Containing
Heterocycles into Pyrazole by Nucleophilic Aromatic Substitution, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 34:9, 1541-1550
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 9, pp. 1541–1550, 2004
Introduction of N-Containing Heterocycles
into Pyrazole by Nucleophilic
Aromatic Substitution
Min-Sup Park,1,2 Hyun-Ja Park,1 Koon Ha Park,2
and Kee-In Lee1,
*
1Bio-Organic Science Division, Korea Research Institute of Chemical
Technology, Yusong, Taejon, Korea
2Department of Chemistry, Chungnam National University,
Taejon, Korea
ABSTRACT
The nucleophilic aromatic substitution on 5-chloropyrazoles activated
by the electron-withdrawing formyl group offers a useful method to
introduce a wide range of N-containing heterocycles into them. The
rate of reaction was greatly affected by the electronic nature of the N-1
substitution.
Key Words: Pyrazole; Nucleophilic aromatic substitution; Electron-
withdrawing group; Heterocyclic system.
*
Correspondence: Kee-In Lee, Bio-Organic Science Division, Korea Research
Institute of Chemical Technology, P.O. Box 107, Yusong, Taejon 305-600, Korea;
Fax: 042-861-7022; E-mail: kilee@krict.re.kr.
1541
DOI: 10.1081/SCC-120030741
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Park et al.
INTRODUCTION
For a long time, nucleophilic aromatic substitution (SNAr) has been a
valuable instrument to prepare a wide variety of functionalized heterocycles
and to obtain building blocks for the synthesis of target compounds. The
SNAr reaction of heterocycles[1] containing a nearby halogen atom has offered
an efficient method for introducing a wide variety of heteroatom-containing
nucleophiles into the heterocyclic ring. This reaction readily allows one to
make heteroatom–carbon bond formation, demonstrating relatively high
yields, a convenient reaction procedure, and an easy access to various nucleo-
philes containing nitrogen, oxygen, and sulfur atoms. Due to their confor-
mational rigidity and their wide range of properties, such heterocyclic
systems play an essential role as scaffolds in biologically active compounds.[2]
Many of them are currently being tested and/or clinically evaluated for new
drug discovery.
As part of our study, we are interested in SNAr reactions of pyrazoles, which
produce drug-like structures that are constrained to a limited number of confor-
mations by heterocyclic cores and hindered rotation by substituents. Indeed, the
derivatives of pyrazole have shown several biological activities as seen in COX-
2 inhibitors,[3] p38 MAP kinase inhibitors,[4] and therefore represent an interest-
ing template for combinatorial as well as medicinal chemistry.[5]
The pyrazole, as an electron-rich heteroaromatic nucleus, does not gener-
ally react with nucleophiles. To our knowledge, only a few examples of SNAr
on 5-chloropyrazole have been reported.[6] Such a displacement of halide from
a five-membered heterocyclic ring is extremely rare in the absence of electron-
withdrawing groups such as formyl or nitro group in a conjugated position of
the ring. Thus, it is ambitious that 4-formyl-5-chloropyrazole has a consider-
able potential for nucleophilic displacement of the halogen, activated by the
ortho-aldehyde.[1b,6b] Here, we would like to report the introduction of various
N-containing heterocycles into pyrazole as shown in Sch. 1.
The starting pyrazoles were prepared according to the well-known
procedure, in which the required pyrazolones were easily prepared by the
condensation of ethyl acetoacetate with methylhydrazine, phenylhydrazine,
2-hydrazinopyridine, and hydrazine monohydrate, respectively. The pyrazo-
lones were then subjected to the Vilsmeier–Haack chloroformylation[6b,7]
using DMF and an excess POCl3 to yield the corresponding 5-chloro-4-
formylpyrazoles 1–4.
First, we examined the nucleophilic substitution of 1[7] (R ¼ Me) with
pyrrole in polar solvents such as DMF and DMSO with different alkaline
bases. Each run showed a similar reaction profile, but with an increasing
time order of KOH, NaOH, Cs2CO3 , K2CO3 , LiOH ꢀ NaHCO3. Thus,
the reaction was conveniently carried out by heating (ca. 1208C) a mixture

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N-Containing Heterocycles into Pyrazole by SNAr
1543
Scheme 1.
of 1 with pyrrole (3 equiv.) and powdered KOH (1.5 equiv.) in DMF and gave
5-pyrrolopyrazole 5 in 66% yield (entry 1).
With this promising result, we extended the SNAr reaction to the readily
available N-containing heterocycles such as imidazole, pyrazole, indole, pyrroli-
dine, and morpholine (entries 2–6) as summarized in Table 1. The reaction gen-
erously allowed the introduction of a wide range of heterocycles into the pyrazole
ring. A brief comparison of the data shows that the aromatic nucleophiles (entries
1–4) react much faster than the saturated heterocycles (entries 5 and 6). Even
though the reactions with the aromatics resulted in good yields, the yields from
pyrrolidine and morpholine were poor. While the rate of reaction was
even slower with morpholine, this led to the formation of the corresponding
5-morpholinopyrazole 10 and by-product 11 (Nu ¼ NMe2) in only 25% overall
yield. The structure of 11 was confirmed by comparison with the product from the
reaction with dimethylamine (entry 7). To verify the participation of DMF as a
substrate in nucleophilic substitution, 1 was just heated with DMF in KOH with-
out a proper nucleophile. Even though the reaction was not completed for a pro-
longed time, it gave 11 in 15% and 12 (Nu ¼ H) in 16% yields (entry 8). This
result clearly demonstrated that DMF is the source of the nucleophile. Contrary
to N-containing nucleophiles, the reactions with oxygen- and sulfur-nucleophiles,
such as phenol and thiophenol, resulted in excellent yields (entries 9 and 10).
Analogously, 2 (R ¼ Ph) and 3 (R ¼ 2-Py) were subjected to the SNAr
reactions.a The interesting feature was observed that the yields from 3 (entries
aGeneral procedure for the SNAr of 3 with pyrrolidine (entry 20): A mixture of 3
(40 mg, 0.18 mmol), pyrrolidine (45 mL, 0.54 mmol), and powdered KOH (15 mg,
0.27 mmol) in DMF (5 mL) was stirred at 1208C for 2 hr. The reaction mixture was
diluted with H2O (40 mL) and extracted with Et2O (3 ꢁ 20 mL). The combined organic
layers were washed successively with brine and water, dried over Na2SO4, and then

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Park et al.
18–20) with the saturated heterocycles were substantially superior to those
from 1 (entries 5 and 6) and 2 (entries 13 and 14). Indeed, 3, upon reaction
with the cyclic secondary amines such as pyrrolidine, piperidine, and morpho-
line, afforded the corresponding 5-substituted pyrazoles in good yields
(71–89%). Also, it was found that the reaction rates are highly dependent
on the blocking groups of pyrazole at N-1 position. Remarkably, the reaction
of 3 was completed much faster than that of 1 with morpholine (entries
6 and 20). The difference can be explained in terms of the electronic nature
of the substantial groups attached at the adjacent N-1 nitrogen. On the assump-
tion that their stability depends on the relative energies of the transition states,
the relative rates reflect their degree of delocalization of negative charge
developed on the transition states. Another feature that was observed was
the reaction of 3 in DMF without a nucleophile, in less than 2 hr, ended up
with 27 (Nu ¼ NMe2) in 57% yield (entry 22). It is also interesting to note
that in the reaction of 4 (R ¼ H) even with imidazole, there was no reaction
(entry 23). All new compounds were satisfactorily characterized by 1H
NMR, mass spectrometry, and elemental analysis and are shown in Table 2.
When the reaction of 1 with morpholine was carried out in DMSO, the
corresponding 5-morpholinopyrazole 10 (18%) and the a,b-unsaturated sulf-
oxide 28 (20%) were isolated as shown in Sch. 2. It has been known that the
dimsyl anion[8] formed in solutions of DMSO containing bases such as sodium
hydride or alkali metal alkoxides, undergoes aldol reaction with carbonyl
compounds. The structure of the aldol product 28b was determined by NMR
and MS, and the E-geometry was judged by the coupling constants; d 7.06
(d, 1H, J ¼ 15.7 Hz) and 6.81 (d, 1H, J ¼ 15.7 Hz). The yields in DMSO
were very similar compared to those obtained in DMF in many other cases.
evaporated under reduced pressure to give a solid residue. The residue was purified by
flash chromatography on silica gel with ethyl acetate as the eluent to give 41 mg (89%)
of 23 as a solid: mp 135–1378C; EIMS m/z (rel. intensity) 256 (Mþ, 3), 227 (3), 213
(4), 199 (3), 118 (18), 78 (100); 1H NMR (CDCl3) d 1.88–1.94 (m, 4H), 2.46 (s, 3H),
3.36 (t, 4H, J ¼ 6.5 Hz), 7.27–7.30 (m, 1H), 7.62 (d, 1H, J ¼ 8.0 Hz), 7.82–7.88
(m, 1H), 8.51 (dd, 1H, J ¼ 4.8, 1.6 Hz), 9.98 (s, 1H); 13C NMR (CDCl3) d 15.4,
26.2, 53.6, 109.6, 120.8, 123.1, 139.0, 148.6, 152.2, 153.4, 153.6, 183.4. Anal. Calcd
for C14H16N4O: C, 65.61%; H, 6.29%; N, 21.86%. Found: C, 65.92%; H, 6.46%; N,
21.63%.
b28: Mp 111–1138C; EIMS m/z (rel. intensity) 220 (Mþ þ 2, 14), 218 (Mþ, 47), 203
(70), 185 (38), 167 (74), 154 (100); HRMS (EI) calcd for C8H11ClN2OS: 218.0281
found 218.0280; 1H NMR (CDCl3) d 7.06 (d, 1H, J ¼ 15.7 Hz), 6.81 (d, 1H,
J ¼ 15.7 Hz), 3.80 (s, 3H), 2.70 (s, 3H), 2.34 (s, 3H).

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N-Containing Heterocycles into Pyrazole by SNAr
1545
Table 1. Introduction of nucleophiles into 4-formyl-5-chloropyrazoles 1–4 in DMF.
Reaction
time (hr)
Product
(yield, %)
Entry
R
Nu-H
Mp (8C)
1
2
3
4
5
6
Me
Me
Me
Me
Me
Me
Pyrrole
2
2
5 (66)
6 (75)
7 (77)
100
92–94
92
Imidazole
Pyrazole
Indole
2
2
8 (76)
9 (34)
Oil
Oil
Pyrrolidine
Morpholine
5
22
10 (14)
11a (11)
11a (68)
11a (15)
12e (16)
13 (91)
14 (87)
15 (80)
16 (83)
17 (33)
18 (10)
19a (15)
20 (82)
21 (79)
22 (81)
23 (89)
24 (75)
25 (71)
26 (50)
27a (57)
68–70
Oil
Oil
7
8
Me
Me
Dimethylamineb
DMFc
21
80d
Oil
43–46
Oil
Oil
9
10
11
12
13
14
Me
Me
Ph
Ph
Ph
Ph
Phenol
2
2
4
4
3
5
Thiophenol
Imidazole
Pyrazole
125–127
135
152
Pyrrolidine
Morpholine
132–134
Oil
15
16
17
18
19
20
21
22
23
Ph
Phenol
2
2
94–95
130
2-Pyf Imidazole
2-Py
2-Py
2-Py
2-Py
2-Py
2-Py
H
Pyrazole
2
121–125
135–137
95
Pyrrolidine
Piperidine
Morpholine
1-Methylpiperazine
DMFc
2
2
2
101–103
108
Oil
2
2
24
g
g
—
Imidazole
—
aNu ¼ NMe2.
b40 wt.% solution in water (8 equiv.) was used.
cDMF was used as a source of dimethylamine.
dThe reaction was not completed.
eNu ¼ H.
f2-Py ¼ 2-pyridinyl.
gNo reaction observed.
In conclusion, the SNAr reactions on 4-formyl-5-chloropyrazole offer a
useful method to introduce a wide range of N-containing heterocycles into
them. Such reactivity can be explained in terms of a combination of the
electron-withdrawing effects of formyl group in a conjugated position and

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Park et al.
d

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N-Containing Heterocycles into Pyrazole by SNAr
1547

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Park et al.
d

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N-Containing Heterocycles into Pyrazole by SNAr
1549
Scheme 2.
of the adjacent N-1 ring nitrogen. The rate of SNAr reaction was greatly
affected by the electronic nature of the N-1 substituted pattern.
ACKNOWLEDGMENTS
We would like to thank Korea Research Council for Industrial Science
and Technology (KK-0201-G0) for financial support.
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Received in the UK July 29, 2003

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