Synthesis of Spiropentadiene Pyrazolones by Rh(III)-Catalyzed Formal sp3 C-H Activation/Annulation

Article abstract of DOI:10.1021/acs.orglett.7b00930

A Rh-catalyzed enol-directed formal sp³ C-H activation/annulation of α-arylidene pyrazolones with alkynes has been developed. This reaction provides a convenient route to synthesize spiropentadiene pyrazolones in good to excellent yields at room temperature, exhibiting good functional group tolerance, gram scalability, and high regioselectivity. Of note, the α-arylidene pyrazolone was introduced as a novel C3 synthon in C-H activation/annulation.

Full text of DOI:10.1021/acs.orglett.7b00930

Letter
pubs.acs.org/OrgLett
Synthesis of Spiropentadiene Pyrazolones by Rh(III)-Catalyzed
Formal sp3 C−H Activation/Annulation
Jiuan Zheng, Panpan Li, Meng Gu, Aijun Lin,* and Hequan Yao*
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy, China
Pharmaceutical University, Nanjing 210009, China
S
* Supporting Information
ABSTRACT: A Rh-catalyzed enol-directed formal sp3 C−H
activation/annulation of α-arylidene pyrazolones with alkynes
has been developed. This reaction provides a convenient route
to synthesize spiropentadiene pyrazolones in good to excellent
yields at room temperature, exhibiting good functional group
tolerance, gram scalability, and high regioselectivity. Of note,
the α-arylidene pyrazolone was introduced as a novel C3 synthon in C−H activation/annulation.
a
piropyrazolones are important structural motifs that are
widely found in pharmaceuticals and biologically active
Table 1. Optimization of Reaction Conditions
S
molecules,1 such as antitumor and antibacterial agents, and type
4 phosphodiesterase inhibitors.2 Therefore, the exploration of
efficient methods to build such core frameworks has attracted
much attention in the synthetic community. In the past few
decades, significant effort has focused on the synthesis of 4-spiro-
5-pyrazolones with a six-membered ring.3 However, the methods
to prepare five-membered-ring 4-spiro-5-pyrazolones were rarely
explored. Recently, Lu4 and Enders5 independently reported a [1
+ 4] annulation reaction to achieve spirocyclopentane
pyrazolones employing pyrazolones as the C1 synthon (Scheme
1a). Du and co-workers developed a phosphine-mediated [2 + 3]
annulation reaction to offer spirocyclopentanone pyrazolones
with unsaturated pyrazolones as the C2 synthon (Scheme 1b).6
Shortly after, Enders further disclosed an efficient three-
component, one-pot method to deliver spiro-pyrazolones relying
on the in situ formed unsaturated pyrazolones as the C2 synthon
(Scheme 1b).7 Despite these elegant advances in realizing five-
membered-ring 4-spiro-5-pyrazolones, the substrate scope was
still limited to pyrazolones or unsaturated pyrazolones as the C1
or C2 synthon.8
b
entry
1
catalyst
additive
solvent
DMF
yield (%)
[Ru(p-cymene)Cl2]2
Pd(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
AgOAc
42
0
d
2
DMF
3
4
[IrCp*Cl2]2
[RhCp*Cl2]2
Rh(OAc)2
DMF
14
69
trace
trace
40
39
92
81
30
0
DMF
d
5
DMF
6
[Rh(COD)Cl]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
DMF
7
1,4-dioxane
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
8
9
10
11
12
Ag2CO3
K2S2O8
e
13
Cu(OAc)2
Cu(OAc)2
89
f
c
14
nr
g
c
15
[RhCp*Cl2]2
nr
Recently, transition-metal-catalyzed C−H functionalization as
an efficient tool was applied to construct spirocyclic com-
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (0.3 mmol, 1.5
equiv), catalyst (2.5 mol %), additive (1.0 equiv), solvent (1.0 mL) at
85 °C for 1 h under air atmosphere. Isolated yields. No reaction.
Catalyst (5.0 mol %). The reaction was conducted at room
b
c
d
e
Scheme 1. Methods To Construct Five-Membered-Ring 4-
Spiro-5-pyrazolones
f
g
temperature. Without [RhCp*Cl2]2. Without Cu(OAc)2.
12
pounds.9 Luan,10 You,11 and Gulıas reported Ru- or Rh-
́
catalyzed phenol-directed sp2 C−H activation/annulation of
naphthols or 2-alkenylphenols to offer spirocyclic enones. Lam
and co-workers13 demonstrated enol-directed sp2 C−H
activation/annulation of 2-aryl cyclic-1,3-dicarbonyl compounds
to synthesize spiroindenes. To the best of our knowledge, the
Received: April 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00930
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Organic Letters
Letter
a b
,
a b
,
Scheme 2. Substrate Scope of α-Arylidene Pyrazolones
Scheme 3. Substrate Scope of the Alkynes
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2b (0.3 mmol, 1.5
equiv), [RhCp*Cl2]2 (2.5 mol %), Cu(OAc)2 (1.0 equiv), MeCN (1.0
b
mL) at room temperature for 1 h under air atmosphere. Isolated
yields.
a
Reaction conditions: 1q (0.2 mmol, 1.0 equiv), 2 (0.3 mmol, 1.5
equiv), [RhCp*Cl2]2 (2.5 mol %), Cu(OAc)2 (1.0 equiv), MeCN (1.0
b
employment of α-arylidene pyrazolones3f as the C3 synthon to
construct five-membered-ring 4-spiro-5-pyrazolones has not
been reported. In view of our continuous interest in preparing
spirocyclic scaffolds,14 herein, we describe a Rh-catalyzed enol-
directed formal sp3 C−H activation/annulation of α-arylidene
pyrazolones with internal alkynes to synthesize spiropentadiene
pyrazolones at room temperature (Scheme 1c).
mL) at room temperature for 1 h under air atmosphere. Isolated
yields.
3ab−cb in 81−89% yields, whereas electron-withdrawing groups
(EWGs) underwent moderate conversion into the products.
Substrates with methyl and methoxy groups on the arylidene
moiety (R2) offered 3hb and 3ib in 80 and 94% yields. Functional
groups, such as bromide, ester, and boronate groups gave 3jb−lb
in 58−77% yields, which presented an opportunity for further
transformation. Steric hindrance of the aromatic ring did not
obviously affect the reaction performance, offering 3mb and 3nb
in 83 and 72% yield, respectively. As expected, the presence of
EDGs and EWGs at R3 yielded 3pb−sb in 70−93% yields.
Polyfluorinated phenyl and naphthyl groups took place smoothly
to deliver 3tb and 3vb in 68 and 88% yield, respectively. When
the aryl group was replaced by methyl group, 3wb was obtained
in 18% yield.
Next, the substrate scope of alkynes was investigated using 1q
as a representative α-arylidene pyrazolone. As shown in Scheme
3, symmetrical alkynes with various aryl substituents were all
found to be suitable for the reaction and gave 3qa and 3qc−qf in
moderate to good yields. 2-Thienyl-substituted alkyne could
deliver 3qg in 96% yield. With nonsymmetrical alkynes, the C−C
bond formation in alkyne insertion step preferentially occurred at
the alkyne carbon with the alkyl group, exhibiting excellent
regioselectivity. 1-Phenyl-1-butyne 2h delivered 3qh in 90%
yield. Similarly, 94% yield of 3qi was obtained from
(cyclopropylethynyl)benzene 2i. 3-Phenylprop-2-yn-1-ol 2j
with a hydroxyl group produced 3qj in 91% yield. Other
unsymmetrical alkynes with ester group (2k) or trifluoromethyl
group (2l) on the benzene ring were both adaptable. More
We commenced our research by examining (E)-1,3-diphenyl-
4-(1-phenylethylidene)-1H-pyrazol-5(4H)-one 1a and dipheny-
lethyne 2a as the model substrates (Table 1). Screening of
catalysts found that [RhCp*Cl2]2 with stoichiometric Cu(OAc)2
as the additive in DMF at 85 °C offered the desired
spiropentadiene pyrazolone 3aa in 69% yield (Table 1, entry
4), whereas other catalysts such as [Ru(p-cymene)Cl2]2,
Pd(OAc)2, [IrCp*Cl2]2, Rh(OAc)2, and [Rh(COD)Cl]2
revealed inferior capacities (Table 1, entries 1−6). The structure
of 3aa was assigned by an X-ray crystallographic analysis (see the
Supporting Information (SI) for details).15 The yield of 3aa
could be further increased to 92% when MeCN was chosen as a
solvent (Table 1, entries 4 and 7−9). Employment of other
additives instead of Cu(OAc)2 failed to promote the efficiency of
the reaction (Table 1, entries 10−12). Gratifyingly, the reaction
could also proceed at room temperature without significant loss
of the yield, and 3aa could be isolated in 89% yield (Table 1,
entry 13). Control experiments showed that [RhCp*Cl2]2 and
Cu(OAc)2 played a pivotal role in the transformation of the
reaction (Table 1, entries 14 and 15).
Having optimized the reaction conditions, we then examined
the substrate scope of α-arylidene pyrazolones, and the results
are shown in Scheme 2. The reaction worked well with electron-
donating groups (EDGs) on the N-aryl moiety (R1), providing
B
DOI: 10.1021/acs.orglett.7b00930
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Organic Letters
Letter
To evaluate the efficiency and practicality of this reaction, a
gram-scale experiment was examined. As shown in Scheme 4a,
the preliminary test of 1a with 2a led to 1.01 g of 3aa in 90% yield.
This efficient and facile protocol could also find applications in
some pharmacologically active molecules (Scheme 4b). The
alkyne 2q derived from pargyline, which was mainly used for
clinical severe hypertension, afforded 3qq in 87% yield.
Spiropentadiene pyrazolones could be conveniently installed
on estrone to construct 3qr in 91% yield, albeit with a large steric
hindrance. The synthetic utility of the products was further
demonstrated by their ability to undergo several transformations
(Scheme 4c). The reduction of the amide group in 3qa with
DIBAL-H at −78 °C provided pyrazoline derivative 4 in 93%
yield. Treatment of 3qa with Lawesson’s reagent in toluene
afforded spiropyrazole-5-thione 5 in 81% yield. To compare the
activity of alkynes, the treatment of 1q with 1-phenyl-1-butyne
2h and diphenylacetylene 2a was tested, affording 3qh as the
preferential product in 78% yield and 3qa in 17% yield (Scheme
4d). This result suggested that the steric hindrance of alkyne may
influence the reactivity.
Scheme 4. Further Study of Rh-Catalyzed C−H Activation/
Annulation of α-Arylidene Pyrazolones with Alkynes
On the basis of previous reports,10−13 a putative mechanism
was proposed as shown in Scheme 5. Mixture of [RhCp*Cl2]2
with Cu(OAc)2 forms the activated Rh catalyst. Deprotonation
of substrate 1 generates a dienolate 1′. The in situ formed enol
group bonds to the Rh catalyst through ligand-to-ligand
exchange, which then cleaves the adjacent C−H bond to
generate a six-membered rhodacycle intermediate I. Coordina-
tion and regioselective migratory insertion of alkyne 2 generates
an eight-membered rhodacycle intermediate II.16 To relieve the
unfavorable steric interaction between R2 and R3,12,17 the key six-
membered intermediate III is formed after isomerization,
whereas the [5 + 2] annulation product 3′ could not be formed
under the standard reaction conditions. Finally, C−C bond
reductive elimilation takes place to offer the spirocyclic product
3, and the activated Rh catalyst is regenerated after oxidation by
Cu(OAc)2.
Scheme 5. Proposed Mechanism
In summary, we have developed an unprecedented Rh-
catalyzed enol-directed formal sp3 C−H activation/oxidative
annulation of α-arylidene pyrazolones with alkynes, providing
spiropentadiene pyrazolones in good to excellent yields at room
temperature. The α-arylidene pyrazolone was first introduced as
a novel C3 synthon in C−H activation/annulation. Further
applications of α-arylidene pyrazolones in transition-metal-
catalyzed C−H functionalization to synthesize spiropyrazolones
are currently underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00930.
1H and 13C NMR spectra for all new compounds (PDF)
X-ray data for 3aa (CIF)
X-ray data for 3qh (CIF)
X-ray data for 3qn (CIF)
importantly, this reaction could be further amplified by
replacement of the aromatic ring with indolyl group (3qm).
Alkynes bearing symmetrical alkyl groups underwent prosper-
ously. 4-Octyne 2n provided 3qn in 66% yield. 2-Butyne-1,4-diol
2o with two hydroxyl groups gave 3qo in 84% yield. The reaction
could also proceed with conjugated enynes like 2p, leading to
3qp in 79% yield. The structures of 3qh and 3qn were both
confirmed by X-ray crystallographic analysis (see the SI for
details).15
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ajlin@cpu.edu.cn.
*E-mail: hyao@cpu.edu.cn or cpuhyao@126.com.
ORCID
Aijun Lin: 0000-0001-5786-4537
C
DOI: 10.1021/acs.orglett.7b00930
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Angew. Chem., Int. Ed. 2016, 55, 373. (h) Per
́ ́ ́
ez-Gomez, M.; Hernandez-
Hequan Yao: 0000-0003-4865-820X
Notes
Ponte, S.; Bautista, D.; García-Lopez, J. Chem. Commun. 2017, 53, 2842.
́
(i) Burns, D. J.; Best, D.; Wieczysty, M. D.; Lam, H. W. Angew. Chem.,
Int. Ed. 2015, 54, 9958. (j) Zheng, H.; Zhu, Y.; Shi, Y. Angew. Chem., Int.
Ed. 2014, 53, 11280. (k) Piou, T.; Neuville, L.; Zhu, J. Angew. Chem., Int.
Ed. 2012, 51, 11561.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(10) Nan, J.; Zuo, Z.; Luo, L.; Bai, L.; Zheng, H.; Yuan, Y.; Liu, J.; Luan,
X.; Wang, Y. J. Am. Chem. Soc. 2013, 135, 17306.
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262.
Generous financial support from the National Natural Science
Foundation of China (NSFC21502232 and NSFC 21572272),
the Natural Science Foundation of Jiangsu Province
(BK20140655), the Foundation of State Key Laboratory of
Natural Medicines (ZZYQ201605), and the Innovative Research
Team in University (Grant No. IRT_15R63) is gratefully
acknowledged.
(12) Seoane, A.; Casanova, N.; Quinones, N.; Mascarenas, J. L.; Gulías,
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M. J. Am. Chem. Soc. 2014, 136, 7607.
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Crystallographic Data Centre as deposition numbers CCDC 1525039
(3aa), 1525058 (3qh), and 1525049 (3qn). Detailed information can be
found in the Supporting Information.
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