Regioselective [3 + 2]-annulation of hydrazonyl chlorides with 1,3-dicarbonyl compounds for assembling of polysubstituted pyrazoles

Article abstract of DOI:10.1039/c8ob02352b

A facile approach to polysubstituted pyrazoles from hydrazonyl chlorides and 1,3-dicarbonyl compounds has been developed. In the presence of DMAP combined with Et₃N, hydrazonyl chlorides reacted with N-phenyl-3-oxobutanamides smoothly to afford

Full text of DOI:10.1039/c8ob02352b

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Regioselective [3 + 2]-annulation of hydrazonyl
chlorides with 1,3-dicarbonyl compounds for
assembling of polysubstituted pyrazoles†
Cite this: Org. Biomol. Chem., 2018,
16, 7811
Received 21st September 2018,
Accepted 11th October 2018
Kun Liu,a Xinye Shang,a Yuyu Cheng,b Xiaoyong Chang,b Pengfei Li*b and
a
DOI: 10.1039/c8ob02352b
Wenjun Li
*
rsc.li/obc
A facile approach to polysubstituted pyrazoles from hydrazonyl tuted pyrazoles, developing additional methodologies are cur-
chlorides and 1,3-dicarbonyl compounds has been developed. In rently in demand.
the presence of DMAP combined with Et3N, hydrazonyl chlorides
We Voϕ have successfully developed an organocatalyzed 1,3-
reacted with N-phenyl-3-oxobutanamides smoothly to afford a dipolar cycloaddition of 3-oxobutanamides with nitrile oxides8
series of polysubstituted pyrazoles in 67–98% yields via the [3 + and azides9 for the construction of 3,4,5-trisubstituted isoxa-
2]-cycloaddition.
zoles and 1,4,5-trisubstituted 1,2,3-triazoles in high yields with
high regioselectivities. It’s no doubt that 1,3-dipolar cyclo-
addition provides an efficient and facile access to five-mem-
bered heterocycles.10 Based on the applications of 3-oxobuta-
namides as two-carbon units in the 1,3-dipolar cycloaddition
and as a continuation of our efforts in the development of
cycloaddition reaction,11 we here report the 1,3-dipolar cyclo-
addition reactions of hydrazonyl chlorides and 1,3-dicarbonyl
compounds for the regioselective construction of polysubsti-
tuted pyrazoles (Scheme 1D).
Pyrazoles are fascinating and versatile examples of five-mem-
bered heterocycles prevalently found in a wide variety of com-
pounds known to exhibit a broad spectrum of pharmaceutical
and agrochemical activities.1 Moreover, they have also been
successfully utilized as units in supramolecular architectures2
and as ligands in coordination compounds.3 Owing to the
functional diversity of pyrazoles, advanced methodologies for
such aza-heterocycles is highly desirable.
Among the methods developed over the past decades for
the construction of the pyrazole skeleton,4 the construction of
two C–N bonds by condensation of hydrazines with 1,3-dicar-
bonyl compounds or their 1,3-dielectrophilic equivalents is
one of the conventional approaches, wherein 1,3-dicarbonyl
compounds were employed as three-carbon units
(Scheme 1A).5 Another conventional approach involved the
generation of one C–N bond and one C–C bond by inter-
molecular [3 + 2]-cycloadditions of nitrogen-based 1,3-dipoles
with alkynes (Scheme 1B)6 or alkenes (Scheme 1C).7 Whereas
the aforementioned methodologies have realized high
efficiency, such procedures often suffer from regioselectivity
issues, which greatly reduces their attractiveness. With the aim
of increasing the regioselectivity in the preparation of substi-
As we all known, hydrazonyl chlorides could easily generate
reactive intermediate 1,3-dipolar in the presence of base to
aDepartment of Medicinal Chemistry, School of Pharmacy, Qingdao University,
Qingdao, Shandong, 266021, China. E-mail: liwj@qdu.edu.cn
bDepartment of Chemistry and Shenzhen Grubbs Institute, Southern University of
Science and Technology, Shenzhen, Guangdong, 518055, China.
E-mail: lipf@sustc.edu.cn, flyli1980@gmail.com
†Electronic supplementary information (ESI) available. CCDC 1867201. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c8ob02352b
Scheme 1 Conventional approaches for the construction of pyrazole
skeletons.
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Table 2 Substrate scope of hydrazonyl chloridesa
react with partners to furnish the desired product.
Accordingly, we started our investigations by screening a series
of catalyst combined with triethylamine (Et3N) as base for the
model [3 + 2]-annulation reaction of hydrazonyl chloride (2a)
with 3-oxo-N-phenylbutanamide (1a) in CHCl3 at room temp-
erature for 12 h and the representative results were listed in
Table 1. To our delight, all the tested organocatalysts com-
bined with Et3N could accelerate the annulation to generate
the desired 5-methyl-N,1,3-triphenyl-1H-pyrazole-4-carboxa-
mide 3aa in the moderate yield, respectively (entries 1–6). In
particular, 3aa with 60% yield was obtained in the presence of
DMAP combined with Et3N (entry 6). Further screening of reac-
tion media indicated that solvent affected the yield signifi-
cantly (entries 7–10) and the yield was improved to 64% when
the reaction was carried out in CH2Cl2 (entry 7). An enhance-
ment of yield was achieved when the reaction time was pro-
longed (entries 11–13) and 3aa with 92% yield was obtained
after 48 h (entry 13). In consideration of cost, replacing DMAP
with Et3N was surveyed and product 3aa was obtained in 80%
yield when the reaction was carried out in CH2Cl2 after 48 h
(entry 14). Importantly, a yield of 87% was still obtained with a
catalyst loading of 10 mol% after 72 h (entry 15).
Entry
R1
R2
Isolated yield (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3-FC6H4
2-ClC6H4
i-Pr
Ph
3aa, 87
3ab, 95
3ac, 98
3ad, 92
3ae, 90
3af, 83
3ag, 90
3ah, 67
3ai, 72
3aj, 77
3ak, 56
—
4-MeC6H4
4-MeOC6H4
4-FC6H4
3-MeC6H4
2-BrC6H4
2-Naphthyl
2-Furanyl
Ph
9
10
11b
12
Ph
Ph
Me
a Unless noted, reactions were performed with 1a (0.05 mmol), 2a–l
(0.10 mmol), Et3N (0.10 mmol), DMAP (10 mol%) in CH2Cl2 (0.30 mL)
at room temperature for 72 h. b The reaction was performed in CHCl3
at 80 °C for 48 h.
Under the optimal reaction conditions, the 1,3-dipolar properties, steric hindrances, and substitution positions on
cycloadditions of hydrazonyl chlorides and 1,3-dicarbonyl the aromatic ring, were broadly tolerated, furnishing pyrazoles
compounds were explored. The results of these reactions were 3ab–af in 83–98% yields (entries 2–6). Notably, the reaction of
shown in Table 2. The scope of hydrazonyl chlorides 2 was 1-(chloro(naphthalen-2-yl)methylene)-2-phenylhydrazine also
examined. The 1,3-dipolar cycloaddition of 1a and 2a furn- afforded the desired pyrazole 3ag in 90% yield (entry 7). The
ished pyrazole 3aa in 87% yield (entry 1). Pleasingly, various hetero hydrazonyl chloride was also compatible to furnish
substituted hydrazonyl chlorides, regardless of the electronic product 3ah in 67% yield (entry 8). The using of 1-(chloro
(phenyl)methylene)-2-(3-fluorophenyl)hydrazine and 1-(chloro
(phenyl)methylene)-2-(2-chlorophenyl)hydrazine also resulted
in the formation of 3ai and 3aj in good yields (entries 9 and
Table 1 Optimization of reaction conditionsa
10). To our delight, if we changed R2 as i-Pr, the desired
product 3ak was obtained with 56% yield (entry 11). It was
found that no reaction occurred between 1-(1-chloroethyl-
idene)-2-phenylhydrazine and 1a (entry 12).
To further explore the 1,3-dipolar cycloaddition of hydrazo-
nyl chlorides and 1,3-dicarbonyl compounds, the scope of 1,3-
dicarbonyl compounds was then surveyed (Table 3). Pleasingly,
a variety of 3-oxo-N-arylbutanamide substrates with different
substitution patterns on their aromatic ring were tolerated,
affording the corresponding pyrazoles 3ba–ga in 74–86%
yields (entries 1–6). Importantly, we did not observe any dis-
cernible electronic effects or steric hindrance effects on the
aromatic moiety. It should be noted that 4-methyl-3-oxo-N-phe-
nylpentanamide was found to be compatible to afford the
desired product 3ha in 92% yield (entry 7). Furthermore,
3-oxo-N,3-diphenylpropanamide was also compatible to
furnish the corresponding pyrazole 3ia in 90% yield (entry 8).
In particular, the reaction partner could extend to 1,3-dike-
tones. The 1,3-dipolar cycloaddition of 1,3-diphenylpropane-
1,3-dione furnished the corresponding product 3ja in 97%
yield (entry 9). The reaction of pentane-2,4-dione also furn-
ished the desired product 3ka in good yield (79%, entry 10).
However, no reaction occurred if R4 was replaced with ester
group (entry 11).
Entry
Catalyst
Time (h)
Solvent
Isolated yield (%)
1
2
3
4
5
6
7
8
Pyrrolidine
Et3N
DBU
DABCO
TMG
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
Et3N
12
12
12
12
12
12
12
12
12
12
24
36
48
48
72
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
CH3CN
EtOH
DMSO
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3aa, 57
3aa, 57
3aa, 57
3aa, 51
3aa, 45
3aa, 60
3aa, 64
3aa, 55
3aa, 34
3aa, 14
3aa, 72
3aa, 81
3aa, 92
3aa, 80
3aa, 87
9
10
11
12
13
14
15
DMAP (10 mol%)
a Unless noted, a mixture of 1a (0.05 mmol), 2a (0.10 mmol), Et3N
(0.10 mmol), catalyst (20 mol%) in the solvent (0.30 mL) was stirred at
room temperature for the time given.
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Table 3 Substrate scope of 1,3-dicarbonyl compoundsa
Entry
R3
R4
Isolated yield (%)
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
i-Pr
Ph
4-MeC6H4NH
4-MeOC6H4NH
2,4-Me2C6H3NH
2-MeC6H4NH
2-MeOC6H4NH
2-ClC6H4NH
PhNH
PhNH
Ph
Me
OMe
3ba, 80
3ca, 74
3da, 78
3ea, 86
3fa, 77
3ga, 74
3ha, 92
3ia, 90
3ja, 97
3ka, 79
—
Scheme 4 Synthetic potential.
chlorides 2 in the presence of Et3N to give the desired products
3 via cascade reactions.
9
10
11
Ph
Me
Me
To highlight the synthetic potential of this methodology, we
evaluated the gram-scale synthesis of 3aa. Under the standard con-
ditions, 3.5 mmol of 1a reacted smoothly with 7.0 mmol of 2a to
afford 3aa in 87% yield (1.10 g, Scheme 4A). Furthermore, we also
tried the 1,3-dipolar cycloadditions of hydrazonyl chloride 2a with
1,3-cyclohexanedione (Scheme 4B) and 2-pentanone (Scheme 4C)
under the standard conditions, respectively. However, the reac-
tions were sluggish and almost no desire product was obtained.
a Unless noted, reactions were performed with 1b–l (0.05 mmol), 2a
(0.10 mmol), Et3N (0.10 mmol), DMAP (10 mol%) in CH2Cl2 (0.30 mL)
at room temperature for 72 h.
Conclusions
In conclusion, we have developed a regioselective 1,3-dipolar
cycloaddition between hydrazonyl chlorides and 1,3-dicarbonyl
compounds for the construction of polysubstituted pyrazoles.
In the presence of DMAP combined with Et3N, the reactions
between hydrazonyl chlorides and 1,3-dicarbonyl compounds
proceeded smoothly to furnish a wide range of pyrazoles in
67–98% yields via a 1,3-dipolar cycloaddition. Practically, syn-
thesis of pyrazoles compounds was achieved through the 1,3-
dipolar cycloaddition with high regioselectivity.
Scheme 2 X-ray of 3ka.
The configuration of the polysubstituted pyrazole was
unambiguously determined based on the X-ray crystal struc-
ture of 3ka (Scheme 2).12 Accordingly, a possible reaction
pathway was suggested as shown in Scheme 3. Catalyzed by
DMAP, 1,3-dicarbonyl compounds 1 generated the nucleophile
to react with the nitrilimines 2′ formed in situ from hydrazonyl
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors acknowledge the financial support from National
Natural Science Foundation of China (21502043, 21871128),
the Natural Science Foundation of Shandong Province (No.
ZR2017JL011), Special Funds for the Development of Strategic
Emerging Industries in Shenzhen (JCYJ20170817110526264),
and the Shenzhen Nobel Prize Scientists Laboratory Project
(C17213101).
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Scheme 3 Reaction mechanism.
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7814 | Org. Biomol. Chem., 2018, 16, 7811–7814
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