The use of enaminones and enamines as effective synthons for MSA-catalyzed regioselective synthesis of 1,3,4-tri- And 1,3,4,5-tetrasubstituted pyrazoles

Article abstract of DOI:10.1039/c9nj03701b

In the present work, an efficient regioselective synthesis of 1,3,4-tri- and 1,3,4,5-tetrasubstituted pyrazoles via a methanesulfonic acid (MSA)-catalyzed reaction of hydrazones with enaminones or enamines is reported. Mechanistically, the formation of the title compounds involves the [2+3] cycloaddition of hydrazones with enaminones or enamines followed by aromatization with acid and oxygen. This convenient method under mild conditions with various hydrazones, enaminones, and enamines was well-tolerated to afford products in good to excellent yields. Compared with the literature methods, this strategy has advantages such as materials that are available economically, metal-free catalysis, excellent regioselectivity, and high efficiency.

Full text of DOI:10.1039/c9nj03701b

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The use of Enaminones and Enamines as effective synthons for MSA-catalyzed
regioselective synthesis of 1,3,4-Tri- and 1,3,4,5-Tetrasubstituted Pyrazoles
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Liancheng Duan, Hui Zhou, Yucheng Gu, Ping Gong*, Mingze Qin*
Key Laboratory of Structure-based Drug Design and Discovery (Shenyang Pharmaceutical
University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016,
People’s Republic of China
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Syngenta Jealott’s Hill International Research Center, Bracknell, Berkshire RG42 6EY, U.K.
Abstract:
In the present work, an efficient regioselective synthesis of 1,3,4-tri- and 1,3,4,5-tetrasubstituted
pyrazoles via Methanesulfonic acid（MSA）-catalyzed reaction of hydrazones with enaminones
or enamines is reported. Mechanistically, the formation of the title compounds involves the [2+3]
cycloaddition of hydrazones with enaminones or enamines followed by aromatization with acid
and oxygen. This convenient method under mild conditions with various hydrazones, enaminones,
and enamines was well-tolerated to afford products in good to excellent yields. Compared with
literature methods, this strategy has advantages such as materials are available economically,
Metal-free catalysis, excellent regioselectivity, and high efficiency.
Figure 1. Selected examples of pharmacologically active substances containing pyrazole moiety
Pyrazole is an important building block in drug design (Figure 1)[1,2], and can be found in many
therapeutic drugs, such as Celebrex, Viagra, and Acomplia, and drugs containing pyrazole moiety
have shown a wide spectrum of therapeutic such as anti-inflammatory[3], analgesic[4],
antibacterial[5] and anticancer[6]. Due to its importance, there are already so many methods for
preparation pyrazole scaffold has been developed. In the 19th century, Knorr prepared
1,3,5-trisubstituted pyrazoles by the condensation reaction of hydrazines and 1,3-diketones for the
first time[7]. However, the Knorr reaction lacks regiospecificity. In the past few decades,
considerable progress has been achieved in the synthesis of pyrazole. Deng has developed a
regioselective synthesis of 1,3,5-tri- and 1,3,4,5-tetrasubstituted pyrazoles by the reaction of
electron-deficient N-arylhydrazones with nitroolefins[8]. And Li’s group designed a synthetic
strategy to synthesize substituted 4-acyl pyrazole derivatives from N-propynylsulfonyl hydrazide
and diaryl iodide salts[9]. Recently, Florian, Fan and Tian obtained pyrazole derivatives by the free
radical reaction independently, providing an alternative synthetic method for pyrazoles(Scheme
1)[10,11,12]. However, there are still some limitations, for example, difficulties in obtaining the

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substrates[13,14], poor regioselectivity[15], harsh reaction conditions[16], and need noDnO-oI:x1y0.g10e3n9/C9NJ03701B
oxidants or metals. Therefore, developing a more selective and versatile method for the
preparation of substituted pyrazoles from economical and readily available substrates remains a
very challenging subject.
1,3-Dipolar cycloaddition reactions are the basic reaction in organic chemistry[17], and it has
always been favored and applied by chemists, and constantly broaden the scope of application.
1,3-Dipolar cycloaddition provides a powerful and reliable synthetic method for obtaining a
five-membered heterocyclic ring by means of regional and stereo control[18]. Indeed, the
1,3-dipolar cycloaddition reaction has been described as “the single most important method for the
construction of heterocyclic five-membered rings in organicchemistry”[19]. Due to the
characteristics of 1,3-dipolar cycloaddition reactions, it is still one of the most interesting topics
for chemists to design the reactions which are involved in 1,3-dipolar cycloaddition directly or
indirectly.
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Unsaturated ketone is a kind of important intermediate is widely used in organic synthesis. It can
easily occur in the Michael addition reaction and Diels Alder reaction. Utilizing these
characteristics, unsaturated ketone structure was introduced to design enaminones as synthon, it
was designed to undergo 1,3-dipolar cycloaddition reaction with hydrazones to construct
1,3,4-trisubstituted pyrazoles. Further, enamines were designed as synthon by removing the
carbonyl group of enaminones. Herein, we report a new method for synthesis of 1,3,4-tri- and
1,3,4,5-tetrasubstituted pyrazoles via Methanesulfonic acid（MSA）-catalyzed reaction, excellent
regioselectivity can be achieved on the reaction of hydrazones with enaminones or enamines.
Scheme 1. Previous works and this work
Table 1. Exploration of reaction conditions[a].

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Entry
1
Catalyst
Sc(CF3SO3)3
Sc(CF3SO3)3
Ni(CF3SO3)
Ag(CF3SO3)
Ag(CF3SO3)
Cu(OAc)2.H2O
Mn(OAc)2
CuCl2.2H2O
BiCl3
Solvent
DCM
Condition
RT, 5h
Yield[b](％)
trace
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2
Toluene
DCM
100℃, 5h
RT, 5h
3
NR
NR
NR
trace
trace
12
4
DCM
RT, 5h
5
Toluene
DCM
100℃, 5h
RT, 5h
6
7
DCM
RT, 5h
8
DCM
RT, 5h
9
DCM
RT, 5h
trace
NR
NR
NR
18
10
11
12
13
14[c]
15[c]
16[d]
17
18
19
NiCl2
DCM
RT, 5h
MgCl2
DCM
RT, 5h
(CF3COO)2Cu.H2O
DCM
DCM
RT, 5h
FeCl3.6H2O
AlCl3
AlCl3
AlCl3
TsOH
–
RT, 5h
DCM
RT, 5h
28
Toluene
DCM
100℃, 5h
RT, 5h
22
trace
trace
NR
NR
DCM
RT, 5h
DCM
RT, 5h
–
Toluene
100℃, 5h
[a]Reaction conditions: 1a (0.10 mmol, 1.0 equiv.), 2a (0.10 mmol, 1.0 equiv.), catalyst (0.10
mmol, 1.0 equiv.), solvent (3.0 mL); [b] Isolated yield; [c] A few drops of water was added; [d]
Anhydrous dichloromethane, under N2 atmosphere; NR: no reaction.
Initial reactions were progressed with enaminones and hydrazones as model substrates. At the
beginning, we investigate the effects of Lewis acid on the reaction. However, the catalytic amount
(5.0 mol ％ ) of Lewis acid did not make the reaction proceed smoothly at room temperature
(Table 1, Entry 1, 3, 4). And raising the temperature of the reaction, the results are still not good
enough (Table 1, Entry 2, 5). To our surprise, we found that the reaction occurred by using the
equivalent of CuCl2.2H2O and FeCl3.6H2O as catalysts, although the reaction yield is low (Table
1, Entry 8, 13). Then we control the reaction using AlCl3 as a catalyst with the N2 atmosphere and
anhydrous dichloromethane to afford the product in trace yield (Table 1, Entry 16). When a few
drops of water were added, the yield was improved significantly (Table 1, Entry 14). Based on
the above results, we assumed that hydrogen ion may promote the reaction. Subsequently, diverse
Protonic Acid was used as the catalysis, and their effects on the reaction were evaluated.

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Table 2. Optimization of reaction conditions[a].
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Entry
Catalyst
AcOH
Solvent
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Condition
RT, 5h
RT, 5h
RT, 5h
RT, 5h
RT, 5h
RT, 5h
RT, 5h
RT, 5h
Yield[b](％)
1
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42
28
73
18
30
2[c]
3[d]
4
HCl
H2SO4
CF3COOH
CF3SO3H
CH3SO3H
(CF3SO3)2NH
Naphthalene-1-sulphonic
acid
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8
9
(CF3SO3)2O
Et3N
DCM
DCM
RT, 5h
RT, 5h
19
NR
NR
70
71
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60
29
52
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27
36
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20
21
Et3N
Toluene
DCM
100℃, 5h
RT, 24h
reflux, 5h
RT, 5h
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
DCM
Et2O
THF
RT, 5h
DMF
RT, 5h
Toluene
Dioxane
Dioxane
MeCN
MeOH
RT, 5h
RT, 5h
100℃, 5h
RT, 5h
RT, 5h
[a]Reaction conditions: 1a (0.10 mmol, 1.0 equiv.), 2a (0.10 mmol, 1.0 equiv.), catalyst (0.10
mmol, 1.0 equiv.), solvent (3.0 mL); [b] Isolated yield; [c] conc. HCl; [d] conc. H2SO4; NR: no
reaction.
To further verify our hypothesis and improve reaction efficiency. We selected some organic and
inorganic acids and examined the effect of acid on this reaction (Table 2, Entries 1-9). From the
results we can see, CF3COOH and CH3SO3H gave higher yields of 3aa than AlCl3 (Table 2,
Entry 4, 6), while the strong acidic H2SO4, (CF3SO3)2NH and (CF3SO3)2O as catalysts, the target
compound was obtained at lower yields (Table 2, Entry 3, 7, 9). Furthermore, under the condition
of triethylamine as a base, no reaction was observed (Table 2, Entry 10, 11). The results show
that the most effective catalyst was methanesulfonic acid (MSA), which afforded the target
product in 73% yield in DCM at room temperature (Table 2, Entry 6). Rising the temperature has

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almost no effect on the yield of the reaction (Table 2, Entry 13, 19). Prolonging the reaction timVeiew Article Online
DOI: 10.1039/C9NJ03701B
to 12 h could not improve the yield (Table 2, Entry 12). Under this condition, the solvent
screening showed that DCM is optimal, dioxane, tetrahydrofuran, and toluene were also favorable
(Table 2, Entry 15, 17, 18).
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Table 3. The scope of various Hydrazons[a].
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Entry
Hydrazon
Product
Yield[b]
N
N
1
73％ (3aa)
N
N
O
H
CH3
N
CH3
N
2
3
4
70％ (3ab)
63％ (3ac)
54％ (3ad)
O
N
N
H
F
N
F
N
O
N
N
H
NO2
N
NO2
N
O
N
N
H

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O
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N
O
N
5
64％ (3ae)
O
N
N
H
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HN
N
N
N
6
68％ (3af)
70％ (3ag)
57％ (3ah)
59％ (3ai)
76％ (3aj)
O
H
N
N
N
N
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O
F
N
F
F
F
N
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O
N
N
H
O
N
F
O
F
N
9
O
N
N
H
O
N
O
N
O
10
N
N
H

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S
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N
S
N
O
11
74％ (3ak)
N
N
H
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H
N
N
N
12
62％ (3al)
O
N
HN
N
H
13
14
15
64％ (3am)
76％ (3an)
72％ (3ao)
N
N
N
N
N
H
O
N
N
N
H
O
N
O
N
N
H
N
[a]Reaction conditions: 1a (0.10 mmol, 1.0 equiv.), 2a (0.10 mmol, 1.0 equiv.), catalyst (0.10
mmol, 1.0 equiv.), solvent (3.0 mL); [b] Isolated yield.
With the optimized conditions in hand, the scope of this reaction with various enaminones and
hydrazones was investigated. As shown in Table 3, the reactions of enaminones and hydrazones
bearing an electron-donating or electron-withdrawing group proceeded smoothly to give the
corresponding product in 54–76% yields. The electron-donating groups, such as 4-OMe, 4-Me,
attached to phenyl rings exhibited good reactivity (Table 3, 3ab and 3ae), and the
electron-withdrawing groups, such as 4-NO2, could obviously decrease the yield slightly (Table 3,
3ad), which suggested that the electron density of two benzene rings of hydrazone has little effect
on the reaction efficiency. Then we replace R1 with 1 and 2-naphthyl, the reaction gave a good
yield, indicating the bulky structure did not affect the proceeding of the reaction significantly

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(Table 3, 3af and 3ag). And when a double bond was inserted between C and N in the hydrazone,
the reaction can also proceed smoothly (Table 3, 3am). Notably, hydrazone with aromatic
heterocyclic rings, such as furan, thiophene, and indole also formed the corresponding products in
good yield (Table 3, 3aj-3al). In addition to arylhydrazones, representative alkylhydrazones were
tested, which suggested that the reactivity of alkylhydrazones was also very good, rendering target
products readily (Table 3, 3an and 3ao).
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Table 4. The scope of various Enaminones and Enamines[a]
Entry
Enamine
Product
Yield[b]
O
O
1
73％ (3aa)
N
N
N
F
O
2
70％ (3ap)
N
O
N
N
F
O
3
66％ (3aq)
N
O
N
N

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NO2
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6
7
O
N
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9
4
5
6
82％ (3ar)
O
N
N
O2N
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O
O
66％ (3as)
N
O
N
N
O
F
O
F
64％ (3at)
N
O
N
N
F
F
O
O
O
O
O
7
62％ (3au)
N
O
N
N
O
8
71％ (3av)
O
N
N
N

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S
5
6
7
O
O
S
9
81％ (3aw)
N
N
N
8
9
N
N
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O
O
O
10
43％ (3ax)
41％ (3ay)
68％ (3ba)
72％ (3bb)
64％ (3bc)
N
O
11
N
N
N
N
N
O
N
12[c]
13[c]
14[c]
O2N
O2N
N
N
N
N
O2N
N
N
O2N
N
N
N
N
O
HO
15
70％ (3az)
N
O
N
N
OH

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O
O
HO
O
16[c]
80％ (3az)
N
N
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[a]Reaction conditions: 1a (0.10 mmol, 1.0 equiv.), 2a (0.10 mmol, 1.0 equiv.), catalyst (0.10
mmol, 1.0 equiv.), solvent (3.0 mL); [b] Isolated yield; [c] the reaction temperature was 100℃ in
toluene.
To further expand the scope of the substrates, diversity of enaminone and enamine was
investigated. As shown in Table 4, first enaminones were used as reactants, compared with the
electron-donating groups, enaminones containing the electron-withdrawing groups, such as 4-NO2
attached to phenyl rings exhibited good reactivity (Table 4, 3ap-3au). And the substrates
containing other aromatic rings such as thiofuran and naphthalene afforded the corresponding
products in good yield (Table 4, 3av and 3aw). However, lower yields were observed when
enaminone was substituted by alkyl rather than aromatic ring (Table 4, 3ax and 3ay). The
carbonyl group in enaminones was removed considering that the carbonyl group did not change
after the reaction, then enamines we used as reactants. In order to verify the versatility of the
reaction and the diversity of substrates, we selected several enamines which containing
cyclohexene, substituted benzene and imidazole moiety respectively. However, it was found that
the reaction did not proceed under standard conditions. Based on previous results, toluene was
used as a solvent and heated to 100℃, target compounds were obtained to our satisfaction (Table
4, 3ba-3bc). Indeed, the reaction of enamines and hydrazones confirmed the diversity of
substrates and the broadness of the reaction. Furthermore, we have known from the literature[20]
that Chromone can be prepared by 2az under acidic conditions. Then Chromone is used instead of
2az as substrate under standard conditions. To our delight, the ring-opening reaction proceeds
smoothly, target product 3az was obtained in high yield conveniently (Table 4 Entry 16).
In summary, our results are hydrazones (1.0 equiv), enaminones (1.0 equiv), methanesulfonic acid
(1.0 equiv) as a catalyst in DCM at room temperature gave the best yield after 5 h, and hydrazones
(1.0 equiv), enamines (1.0 equiv), methanesulfonic acid (1.0 equiv) as a catalyst in toluene at 100℃
gave the best yield after 5 h.

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Scheme 2. Control experiments
To explore the reaction mechanism, several control experiments were employed. We performed an
experiment when a radical scavenger (butylated hydroxytoluene, BHT) was added under the
standard conditions (Scheme 2, Eq. 1). But the yield of reaction has almost no changed. This
result suggested that a radical process may not be involved in this transformation. Then we
performed an experiment in the absence of oxygen (Scheme 2, Eq. 2), the yield of the reaction
decreased significantly. Based on the above results and previous literature and studies, a plausible
mechanism for this cyclization reaction is proposed in Scheme 3. First, Hydrazone undergoes a
conjugate addition with enamine to afford adduct A. Next, an intramolecular nucleophilic addition
occurs to afford tetrahydropyrazole B. Finally, B is converted into final product 3 via successive
and rapid oxidative dehydrogenation and acid dehydrogenation reaction. It can be inferred from
the reaction mechanism that the carbonyl of enaminones participates in the reaction and the
reaction activity was higher than that of enamines. Therefore, enaminones reacted with hydrazone
under mild conditions, while enamines require higher temperatures (Table 4 Entries 12-16).

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Scheme 3. Plausible mechanism of the reaction
In conclusion, a practical and regioselective synthesis of 1,3,4tri- or 1,3,4,5-tetrasubstituted
pyrazoles from hydrazones and enamines has been demonstrated. A plausible mechanism
through the methanesulfonic acid-catalyzed was conjectured and explained the regioselective. A
range of various hydrazones and enamines were well-tolerated while affording products in good
yields. With advantages such as Metal-free catalysis, materials are available economically,
excellent regioselectivity and high efficiency. This new synthetic strategy is expected to be widely
used in the fields of organic chemistry and medicinal chemistry.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We are grateful to the Program for Innovative Research Team of the Ministry of Education, The
Program of Liaoning Revitalization Talents Program (XLYC1808037). We also gratefully
acknowledge a Syngenta Postgraduate Fellow-ship awarded to L.-C.D. and for financial support.
(see in Supporting Information, SI).

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