Bisphosphine catalyzed sequential [3 + 2] cycloaddition and Michael addition of ynones with benzylidenepyrazolones: Via dual α′,α′-C(sp3)-H bifunctionalization to construct cyclopentanone-fused spiro-pyrazolones

Article abstract of DOI:10.1039/c8ob02675k

A bisphosphine-catalyzed sequential [3 + 2] cycloaddition and Michael addition reaction of ynones with benzylidenepyrazolones has been developed. Under the catalysis of DPPB [1,4-bis(diphenylphosphino)butane], the reaction proceeded smoothly to give spiro-[cyclopentanone] pyrazolone derivatives in moderate to good yields with good diastereoselectivities via sequential dual α′,α′-C(sp³)-H bifunctionalization annulation. This strategy provides a novel route toward the synthesis of spiro-[cyclopentanone] pyrazolones containing three contiguous stereocenters which possess potential pharmaceutical activities.

Full text of DOI:10.1039/c8ob02675k

Organic &
Biomolecular Chemistry
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PAPER
Bisphosphine catalyzed sequential [3 + 2]
cycloaddition and Michael addition of ynones with
benzylidenepyrazolones via dual α’,α’-C(sp3)–H
bifunctionalization to construct cyclopentanone-
fused spiro-pyrazolones†‡
Cite this: Org. Biomol. Chem., 2018,
16, 9461
a,b
Jiayong Zhanga and Zhiwei Miao
*
A bisphosphine-catalyzed sequential [3 + 2] cycloaddition and Michael addition reaction of ynones with
benzylidenepyrazolones has been developed. Under the catalysis of DPPB [1,4-bis(diphenylphosphino)
butane], the reaction proceeded smoothly to give spiro-[cyclopentanone] pyrazolone derivatives in mod-
erate to good yields with good diastereoselectivities via sequential dual α’,α’-C(sp3)–H bifunctionalization
annulation. This strategy provides a novel route toward the synthesis of spiro-[cyclopentanone] pyrazo-
lones containing three contiguous stereocenters which possess potential pharmaceutical activities.
Received 29th October 2018,
Accepted 27th November 2018
DOI: 10.1039/c8ob02675k
rsc.li/obc
chemical and biomedical importance.7 This strategy provides a
practical and atom-economical way for substantially intriguing
Introduction
Pyrazolones are of considerable interest in both synthetic and syntheses. An extensive literature survey revealed that mono
medicinal chemistry and are used as versatile intermediates C–H bond functionalization on an sp3 carbon atom has been
for further transformation in the synthesis of drugs and widely studied.8 However, the dual α′,α′-C(sp3)–H bifunctionali-
natural products.1 Particularly intriguing is the spirocarbocyc- zation on the same carbon center has been much less explored
lic pyrazolone scaffold with a five-membered ring, which fea- so far and still remains a great challenge.
tures in a large number of natural and unnatural compounds
In the past few years, new progress has been made in dual
with important biological activities.2 For example, phenylbuta- α′,α′-C(sp3)–H bifunctionalizations of alkanes for C–C bond
zone has anti-inflammatory activity.3 BW357U shows anorexic formation.9 The dual α′,α′-C(sp3)–H bifunctionalization has
activity.4 4-Spiro-5-pyrazolones have been shown to possess attracted increasing and continuous interest because aliphatic
valuable biological properties, and have been identified as C–H bonds are ubiquitous in organic compounds and are
effective clinical pharmaceutical agents for use as PPAR α among the least reactive bonds. Undoubtedly, the α′,α′-C(sp3)–
antagonists and inhibitors of type-4 phosphodiesterases H bifunctionalization along with dual C–C bond formation
(Fig. 1).5 Therefore, the development of novel catalytic syn- provides attractive access to the diversity and complexity of the
thetic methods for accessing functionalized 4-spiro-5-pyrazo- final product.
lones with a five-membered ring has attracted attention from
synthetic chemists.6
Nucleophilic phosphine organocatalysis has been demon-
strated to be a versatile tool in the construction of carbo- and
Functionalization of sp3 C–H bonds for the construction of heterocycles.10
Organophosphine-catalyzed
[C(sp3)–H]-
carbon–carbon and carbon–heteroatom bonds has emerged as functionalization has been the subject of intense research. In
a powerful tool for assembling highly complex structures of
aState Key Laboratory and Institute of Elemento-Organic Chemistry, College of
Chemistry, Nankai University, Weijin Road 94, Tianjin 300071, People’s Republic of
China. E-mail: miaozhiwei@nankai.edu.cn
bCollaborative Innovation Center of Chemical Science and Engineering (Tianjin),
Tianjin 300071, People’s Republic of China
†Dedicated to 100th anniversary of Nankai University.
‡Electronic supplementary information (ESI) available. CCDC 1540162 and
1567473. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c8ob02675k
Fig. 1 Examples of spiro-[cyclopentanone]pyrazolone skeletons pos-
sessing biological activities.
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addition and Michael addition annulation product 3a was not
obtained; however a single [3 + 2] cycloadduct 4a was obtained
in 11% yield (Table 1, entry 1).
Triphenylphosphine (PPh3) was replaced by more strongly
nucleophilic phosphines, including ethyldiphenyl phosphine
(Ph2PEt), dimethyl(phenyl)phosphine (PhPMe2), methyl
(diphenyl)phosphane (Ph2PMe), and tributylphosphine (PBu3),
and these more nucleophilic phosphines all gave similar
results to each other (Table 1, entries 2–5). According to Ma’s
report, the sequential annulation reaction may involve two
molecules of ynone 1a. We hypothesized that the use of
bisphosphines could facilitate the formation of the biszwitter-
ionic intermediate and enable the second annulation to
proceed well in an intramolecular-like fashion.16
Next, we tested the sequential annulation reaction using a
number of bisphosphines as nucleophilic catalysts that have
previously been used in reactions involving ynones.17 To our
delight, when the bisphosphines 1,3-bis(diphenylphosphanyl)
propane (DPPP), 1,2-bis(diphenylphosphanyl)ethane (DPPE),
and 1,4-bis(diphenylphosphanyl)butane (DPPB) were used as
nucleophilic catalysts, we isolated the sequential cycloadduct
(i.e., 3a) and the single [3 + 2] cycloadduct (i.e., 4a) in low yield
with moderate to good diastereoselectivities (Table 1, entries
6–8). This implied that the nature of the phosphine catalyst
had a significant effect on the outcome of chemoselectivity.
Scheme 1 Previous and proposed work.
2016, Ramasastry and co-workers reported organophosphine-
catalyzed γ′[C(sp3)–H]-functionalization/intramolecular hydro-
alkylation of ynones for cyclopenta[b] annulated heteroarene
formation (Scheme 1a).11 In 2017, Zhou and co-workers devel-
oped a phosphine-catalyzed sp3 C–H bond dual-alkylation pro-
tocol for the synthesis of highly functionalized unsymmetrical
3,3-disubstituted benzofuranones from benzofuranones and
allenoates (Scheme 1b).12 In this aspect, our group has success-
fully developed a one-pot sequential [4 + 2]/[4 + 2] annulation for
the construction of highly substituted 2H-spiro[naphthalene-
pyrazole] skeletons. In this transformation, a series of tandem
C(sp3)–H/C(sp2)–H bond functionalizations is achieved by intra-
molecular annulation catalyzed by bisphosphine to construct
this polycyclic system (Scheme 1c).13 However, to the best of our
knowledge, bisphosphine catalyzed direct conversion of dual
C(sp3)–H bonds on the same carbon atom to double C–C func-
tionalities has not been documented yet.
Table 1 Optimization of the reaction conditionsa
T (°C)/
time (h) (%)
Yield 3ab Yield 4ab drc
Entry Catalyst Solvent
(%)
(3a)
Inspired by these studies, and in continuation of our inter-
est on bioactive fused polycyclic structure synthesis,13,14 we
here describe an unusually efficient bisphosphine-catalyzed
one-pot sequential [3 + 2] cycloaddition and Michael addition
reaction of ynones with benzylidenepyrazolones to deliver
spiro[cyclopentanone] pyrazolone skeletons in moderate to
good yields (Scheme 1d). The notable feature of this strategy is
the sequential formation of three new C–C bonds via dual
α′,α′-C(sp3)–H bifunctionalization of ynones on the same
carbon atom by using a single catalyst in one pot without the
need for isolation of the intermediates.
1
2
3
4
5
6
7
8
PPh3
Ph2PEt
PhPMe2 Toluene 25/24
Ph2PMe Toluene 25/24
PBu3
Toluene 25/24
Toluene 25/24
—
—
—
—
—
34
21
42
61
72
88
32
25
42
32
38
55
11
15
26
21
28
16
12
13
22
5
7
10
9
17
15
8
—
—
—
—
—
Toluene 25/24
Toluene 25/24
Toluene 25/24
Toluene 25/24
Toluene 25/36
Toluene 40/36
Toluene 60/36
DPPPd
DPPEe
DPPBf
DPPB
DPPB
DPPB
DPPB
DPPB
DPPB
DPPB
DPPB
DPPB
10 : 1
15 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
9
10
11
12
13
14
15
16i
17j
DCMg
THF
25/36
60/36
60/36
60/36
DCEh
MeCN
Toluene 60/36
Toluene 25/48
23
Results and discussion
a Unless otherwise specified, all reactions were carried out using ethyl
4-phenylbut-3-yn-2-one 1a (0.22 mmol) and 4-benzylidene-5-methyl-2-
phenylpyrazolone 2a (0.10 mmol) in 1 mL solvent with 20 mol% of
catalyst. b Yield of isolated product after column chromatography.
c Determined by 1H NMR analysis. d DPPP = 1,3-bis(diphenylphos-
phino)propane. e DPPE = 1,2-bis(diphenylphosphino)ethane. f DPPB =
1,4-bis(diphenylphosphino)butane. g DCM = dichloromethane. h DCE =
1,2-dichloroethane. i 10 mol% DPPB was used. j 3.0 equiv. of 1a was used.
The studies were initiated by evaluating the reaction between
4-phenylbut-3-yn-2-one 1a15 and 4-benzylidene-5-methyl-2-
phenylpyrazolone 2a13 using triphenylphosphine (PPh3)
(20 mol%) as the catalyst in toluene at room temperature. We
were surprised to find that the desired sequential [3 + 2] cyclo-
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The yield of 3a could be improved from 42 to 61% by extending [3 + 2] cycloaddition and Michael addition annulation between
the reaction time to 36 h (Table 1, entry 9). The subsequent different ynones 1 and benzylidenepyrazolone 2, and the
change in the reaction temperature had a significant effect on results are shown in Table 2. In the cases of benzylidenepyra-
the overall yield and ratio of 3a to 4a (Table 1, entries 10 and zolone 2, either bearing a neutral, electron-withdrawing, or
11). Since DPPB gave a higher yield and good chemoselectivity electron-donating group at the ortho, meta or para position of
and diastereoselectivity of 3a (61%) than the other catalysts, it the benzene ring, the reactions proceeded smoothly to give
was used in further investigation at 60 °C.
cyclopentanone 4-spiro-pyrazolones 3a–e in moderate to good
We then examined the effect of the solvent on the yield. yields and diastereoselectivities, along with small amounts of
Compared with CH2Cl2, THF, DCE, and MeCN, the use of cycloadducts 4a–e (Table 2, entries 1–5). All of the major pro-
toluene as a solvent gave a better yield (Table 1, entries 12–15). ducts (i.e., 3) could be cleanly isolated from the reaction mix-
The loading of catalysts has some influence on the yield. tures. The substrate bearing two methyl groups on the aro-
Lower yield was observed when the catalyst loading was matic ring participated in the slower transformation, deliver-
decreased to 10 mol% (Table 1, entry 16). It is noteworthy that ing the sequential product 3e in 79% yield after 48 h, together
under the catalysis of DPPB, the use of excess 4-phenylbut-3- with a small amount of the cycloadduct 4e (Table 2, entry 5).
yn-2-one 1a did not significantly increase the sequential annu- We were delighted to find that pyrazolone derivatives 2f, 2g
lation yield (Table 1, entry 17). Thus, the optimal reaction con- and 2h, bearing furanyl, thienyl, and naphthyl groups, respect-
ditions for this transformation were determined to be 4-phenyl- ively, underwent smooth sequential annulations with 1a, to
but-3-yn-2-one (1a, 0.22 mmol), 4-benzylidene-5-methyl-2-phe- give the corresponding products (i.e., 3f, 3g and 3h) in high
nylpyrazolone (2a, 0.10 mmol), and DPPB (20 mol%) as a cata- yields with excellent diastereoselectivities (dr > 20 : 1) (Table 2,
lyst in toluene (1 mL) as a solvent at 60 °C.
entries 6–8). The structures of products 3a and 4h were
Using these optimized reaction conditions, we then exam- assigned on the basis of spectroscopic analyses and un-
ined the scope and limitation of the DPPB-catalyzed sequential ambiguously confirmed by X-ray diffraction of single crystals
Table 2 Substrate scope of the reactiona
Entry
R1
R2
R3
Yield 3b (%)
Yield 4b (%)
drc (3)
1
2
3
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
3-MeC6H4 (1b)
3-MeC6H4 (1b)
4-EtC6H4 (1c)
4-EtC6H4 (1c)
4-EtC6H4 (1c)
4-MeC6H4 (1d)
4-OMeC6H4 (1e)
4-OMeC6H4 (1e)
4-OMeC6H4 (1e)
4-FC6H4 (1f)
3-ClC6H4 (1g)
3-ClC6H4 (1g)
4-FC6H4 (1f)
2-thienyl (1h)
2-MeC6H4 (1i)
2-BrC6H4 (1j)
C6H5 (1a)
C6H5
C6H5 (2a)
C6H5 (2b)
C6H5 (2c)
C6H5 (2d)
C6H5 (2e)
C6H5 (2f)
C6H5 (2g)
C6H5 (2h)
C6H5 (2i)
C6H5 (2b)
C6H5 (2a)
C6H5 (2j)
C6H5 (2i)
C6H5 (2a)
C6H5 (2a)
C6H5 (2b)
C6H5 (2k)
C6H5 (2a)
C6H5 (2i)
C6H5 (2k)
C6H5 (2f)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
4-CH3C6H4 (2l)
CH3 (2m)
88 (3a)
85 (3b)
76 (3c)
84 (3d)
79 (3e)
89 (3f)
82 (3g)
75 (3h)
89 (3i)
83 (3j)
76 (3k)
64 (3l)
79 (3m)
86 (3n)
91 (3o)
88 (3p)
85 (3q)
63 (3r)
57 (3s)
49 (3t)
93 (3u)
87 (3v)
0 (3w)
0 (3x)
7 (4a)
5 (4b)
11 (4c)
9 (4d)
8 (4e)
>20 : 1
>20 : 1
10 : 1
10 : 1
10 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
10 : 1
10 : 1
10 : 1
9 : 1
10 : 1
4 : 1
5 : 1
10 : 1
4 : 1
>20 : 1
>20 : 1
—
3-MeC6H4
4-iPrC6H4
4-ClC6H4
2,4-(Me)2C6H3
2-Furanyl
2-Thienyl
1-Naphthyl
4-OEtC6H4
3-MeC6H4
C6H5
4
5d
6
6 (4f)
7
8
9
10 (4g)
11 (4h)
9 (4i)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
8 (4j)
14 (4k)
18 (4l)
10 (4m)
8 (4n)
5 (4o)
7 (4p)
10 (4q)
20 (4r)
19 (4s)
22 (4t)
4 (4u)
8 (4v)
2-OMeC6H4
4-OEtC6H4
C6H5
C6H5
3-MeC6H4
3-FC6H4
C6H5
4-OEtC6H4
3-FC6H4
2-Furanyl
C6H5
C6H5
C6H5
C6H5
C6H5
76 (4w)
72 (4x)
10 (4y)
67 (4z)
—
>20 : 1
—
78 (3y)
0 (3z)
C6H5 (1a)
a Reaction conditions: Ynone 1 (0.22 mmol), benzylidenepyrazolones 2 (0.10 mmol) in 1 mL of toluene at 60 °C in the presence of 20 mol% of
DPPB. b Yield of the isolated product after column chromatography. c Determined by 1H NMR analysis. d The reaction time was 48 h.
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entries 23–24). It appears that the N-protecting group in the
pyrazolone is critical for achieving the desired product 3.
Masking of the “N” (e.g., 4-CH3C6H4, entry 25) led to 3y in 78%
yield with good diastereoselectivity. However, the reaction of
N-methyl protected pyrazolone 2m with 4-phenylbut-3-yn-2-
one 1a under the catalysis of DPPB in toluene at 60 °C furn-
ished the [3 + 2] cycloaddition product of 4z in 67% yield
without the detection of the dual functionalization product 3z
(Table 2, entry 26).
To demonstrate the synthetic utility of the sequential [3 + 2]
cycloaddition and Michael addition adduct 3p, we subjected it
to the intramolecular aldol reaction. Treatment of 3p with
KOH delivered the corresponding spiro-pyrazolone fused hexa-
hydro-pentalene 5 in 36% yield (Scheme 2). The structure of
product 5 was assigned on the basis of 1H NMR, 13C NMR and
HRMS analyses (see the ESI‡).
Fig. 2 The X-ray crystallographic structure of 3a.
In order to gain insight into the mechanism, we carried out
three control experiments (Scheme 3). Under the identified
conditions, the treatment of 1-phenylpent-1-yn-3-one 6 with
4-benzylidene-5-methyl-2-phenylpyrazolone 2a in the presence
of 20 mol% of DPPB at 60 °C furnished the normal [3 + 2]
Fig. 3 The X-ray crystallographic structure of 4h.
of 3a and 4h, thus allowing the determination of the relative
configurations of three adjacent stereogenic centers of 3a and
two adjacent stereogenic centers of 4h (Fig. 2 and 3).18
Scheme 2 Transformation of product 3p.
Finally, selected 4-aryl-but-3-yn-2-ones (1) were further
examined in the sequential dual α′,α′-C(sp3)–H bifunctionaliza-
tion reaction with representative benzylidenepyrazolones 2.
The substituents in the ynone 1 were well tolerated, leading to
the formation of the desired products 3 in moderate to high
yields with moderate to good diastereoselectivities and a small
amount of the [3 + 2] cycloaddition products 4 (Table 2,
entries 9–22). When substrate 1 bearing an electron-donating
group at the meta or para position of the benzene ring was
used, the reaction proceeded much better compared to those
bearing electron-withdrawing groups (Table 2, entries 18–20).
However, when 5-methyl-2-phenyl-4-(tetrahydro-furan-2-yl-
methylene)-2,4-dihydro-pyrazolone 2f and 4-(4-fluoro-phenyl)-
but-3-yn-2-one 1f were employed in this reaction, the sequen-
tial annulation product 3u was obtained in 93% yield with dr >
20 : 1 (Table 2, entry 21). In a similar manner, when 4-thio-
phen-2-yl-but-3-yn-2-one 1h was employed as the substrate, the
desired product 3v was obtained in 87% yield with good
diastereoselectivity (Table 2, entry 22). It is noteworthy that
steric hindrance significantly affected the efficiency of the dual
α′,α′-C(sp3)–H bifunctionalization reaction. When ynone 1
bearing an electron-withdrawing or -donating group at the
ortho position of the benzene ring was employed, the desired
Scheme 3 Control experiments and deuterium labelling experiment for
sequential annulation products 3 were not obtained (Table 2, mechanism study.
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annulation product 7 in 79% yield (Scheme 3a). Further annu- as the N-protecting group at 4-alkenyl pyrazolin-3-one 2 were
lation of [3 + 2] cycloadduct product 4h with 4-phenylbut-3-yn- critical for the dual α′,α′-C(sp3)–H bifunctionalization annula-
2-one 1a under the catalysis of DPPB did not obtain the tions to occur. To gain more mechanistic insights we per-
sequential annulation product 3h (Scheme 3b).
formed an isotopic labeling experiment by adding 20 equiv. of
In addition, when 4-benzylidene-5-methyl-2-methyl- D2O to the reaction system; the reaction was carried out under
pyrazolone 2m reacted with 1a, the [3 + 2] cycloadduct product the standard conditions (Scheme 3d). The deuterated product
1
4z was produced in 67% yield, and no corresponding sequen- D-3f was obtained in a yield of 46%. H NMR analysis showed
tial annulation product was obtained (Scheme 3c). These 50% deuterium incorporation at the A position, and 100%
results indicated that the methyl group in ynone 1 and phenyl deuterium incorporation at the B position, indicating the
possibility of the involvement of a carbanion intermediate.
To further investigate the mechanism, the formation of 3a
was monitored by 31P NMR spectroscopy as shown in Fig. 4
(the reaction was monitored by the application of room temp-
erature 31P NMR spectroscopy). The DPPB in toluene-d8 showed
a signal in the 31P NMR spectrum at δ = −16.16 ppm. After
4-phenylbut-3-yn-2-one 1a was added to the solution of DPPB,
the peak shifted from δ = −16.16 to 32.08 and 31.87 ppm as
intermediates A and A′ are formed. When 4-benzylidene-5-
methyl-2-phenylpyrazolone 2a was added to the mixture, the
expected Michael addition product intermediate C was pro-
duced (multi peaks at δ = 27.25, 27.29 and 27.53 ppm) in
3 hours. In the meantime, there are three intermediates that
appeared during the synthesis of 3a. The signals at δp = 32.01,
Fig. 4 Time-elapsed 31P NMR spectra for the synthesis of 3a.
Scheme 4 Proposed reaction mechanism.
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32.22 and 32.51 ppm may belong to intermediates D, E and F, and distilled prior to use according to the standard methods.
respectively. The reaction was almost completed after 36 hours Unless otherwise indicated, all materials were obtained from
according to the 31P NMR spectra (Fig. 4). The 31P chemical commercial sources, and used as purchased without dehydra-
shift of intermediates A and A′ was assigned by comparing the tion. Flash column chromatography was performed on silica
similar chemical structure of biszwitterion and monozwitterion gel (particle size 10–40 µm, Ocean Chemical Factory of
in the literature,16,19,20 and the resulting intermediates C, D, E Qingdao, China). Nitrogen gas (99.999%) was purchased from
1
and F were tentatively assigned by analogy.
Boc Gas Inc. H NMR and 13C NMR spectra were recorded in
On the basis of the above experimental results and the pre- CDCl3 on Bruker 400 MHz spectrometers, and TMS served as
1
vious literature,16,19 the possible mechanism for this sequential the internal standard (δ = 0 ppm) for H NMR and 13C NMR.
[3 + 2] cycloaddition and Michael addition annulation reaction is The crystal structure was determined on a Bruker SMART 1000
outlined in Scheme 4. The first step involves the nucleophilic CCD diffractometer. Mass spectra were obtained using an elec-
attack of the bisphosphine DPPB on ynone 1 to give biszwitterion trospray ionization (ESI-TOF) mass spectrometer. Melting
A or monozwitterion A′. Biszwitterion A can isomerize to inter- points were determined on a T-4 melting point apparatus
mediate B. Intermediate B is assumed to undergo nucleophilic (uncorrected).
addition to the carbon–carbon double bond of benzylidenepyra-
zolone 2 to furnish intermediate C. A sequential intramolecular
General procedure for the synthesis of products 3 and 4
Michael addition reaction of C gives cycloadduct D. This is the Under a nitrogen atmosphere, to a mixture of benzylidenepyra-
initial methyl ketone group α′-C(sp3)–H functionalization of zolone 2 (0.1 mmol, 1.0 equiv.) and DPPB (8.5 mg, 0.02 mmol,
ynone 1. Subsequently, intermediate D undergoes a transform- 20 mmol%) was added toluene (1 mL) via a syringe and
ation of the carbanion to afford the biszwitterionic intermediate allowed to stir for 5 min at 60 °C. Ynones 1 (0.22 mmol, 2.2
E. Finally, intermediate E effects intramolecular nucleophilic equiv.) were added and the reaction was allowed to stir for
addition to give the cyclic adduct F. Then, 1,2-H shift of F leads 36 h at 60 °C. The reaction was monitored by TLC. After the
to intermediate G. Expulsion of the bisphosphine catalyst DPPB reaction was completed, the reaction mixture was directly puri-
from G then produces the dual α′,α′-C(sp3)–H bifunctionalization fied by flash column chromatograph (eluted with 5 : 1 pet-
annulation product 3. In the second cycle, intermediate A′ can roleum ether/EtOAc) to afford the corresponding cycloaddition
isomerize to intermediate B′. An intermolecular Michael addition products 3 and 4.
of intermediate B′ to benzylidenepyrazolone 2 leads to the
6-((E)-Benzylidene)-4-methyl-8-((E)-3-oxo-1-phenylbut-1-en-2-yl)-
addition intermediate C′, which undergoes an intramolecular 2,9-diphenyl-2,3-diazaspiro[4.4]non-3-ene-1,7-dione (3a). Yellow
Michael addition to form D′. Intermediate D′ can be converted to solid, mp: 153–155 °C. 1H NMR (400 MHz, CDCl3) δ 7.91 (s,
intermediate E′ via an H-shift. Upon releasing the bisphosphine 1H), 7.84 (s, 1H), 7.40 (d, J = 35.3 Hz, 6H), 7.27 (s, 1H), 7.18 (t,
DPPB the products 4 are finally furnished.
J = 4.0 Hz, 2H), 7.12–7.00 (m, 7H), 6.88 (d, J = 7.3 Hz, 2H), 6.45
(s, 2H), 4.53 (d, J = 11.8 Hz, 1H), 4.31 (d, J = 12.1 Hz, 1H), 2.32
(s, 3H), 1.81 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 201.8,
197.08, 171.8, 158.58, 146.4, 139.8, 139.1, 137.4, 135.4, 133.8,
133.7, 132.7, 131.2, 129.9, 129.6, 129.5, 129.3, 129.0, 128.9,
Conclusions
In conclusion, we have developed a new and efficient bispho- 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.0, 127.1, 126.7,
sphine-triggered sequential [3 + 2] cycloaddition and Michael 125.4, 119.6, 66.7, 54.8, 48.7, 25.7, 16.5. HRMS (ESI): calcd for
addition reaction of 4-benzylidene-5-methyl-2-phenyl-2,4-di- C37H31N2O3 [M + H]+ m/z 551.2329, found 551.2331.
hydropyrazolones with β-aryl-substituted ynones through an
6-((E)-Benzylidene)-4-methyl-8-((E)-3-oxo-1-phenylbut-1-en-2-yl)-
unpresented dual α′,α′-C(sp3)–H bifunctionalization annula- 2-phenyl-9-(m-tolyl)-2,3-diazaspiro[4.4]non-3-ene-1,7-dione (3b).
tion. This protocol provides a simple and practical strategy for Yellow solid, mp: 162–165 °C. 1H NMR (400 MHz, CDCl3)
the synthesis of cyclopentanone-fused spiro-pyrazolone deriva- δ 7.98 (s, 1H), 7.91 (s, 1H), 7.52 (s, 3H), 7.46 (s, 2H), 7.36 (d, J =
tives with three contiguous stereocenters, which possess 7.8 Hz, 2H), 7.29 (d, J = 7.5 Hz, 2H), 7.14 (ddd, J = 14.6, 14.0,
potential pharmaceutical activities. The bond-forming 7.1 Hz, 6H), 6.91 (d, J = 7.4 Hz, 1H), 6.83 (t, J = 7.7 Hz, 1H),
efficiency, accessibility of starting materials and functional 6.32 (s, 2H), 4.62 (d, J = 12.6 Hz, 1H), 4.36 (d, J = 12.1 Hz, 1H),
group tolerance makes this reaction a promising approach 2.40 (s, 3H), 1.92 (s, 3H), 1.87 (s, 3H). 13C NMR (101 MHz,
with a great substrate scope. Further studies on the scope CDCl3) δ 200.9, 170.8, 157.5, 145.1, 138.7, 138.2, 136.9, 136.3,
extension and asymmetric version of this reaction are currently 134.5, 132.8, 132.7, 131.6, 128.9, 128.5, 128.4, 127.9, 127.8,
underway in our laboratory and will be reported in due course. 127.6, 127.5, 127.3, 127.1, 126.6, 124.2, 123.1, 118.5, 65.1, 53.8,
47.6, 24.6, 20.1, 15.3. HRMS (ESI): calcd for C38H33N2O3
[M + H]+ m/z 565.2486, found 565.2495.
6-((E)-Benzylidene)-9-(4-isopropylphenyl)-4-methyl-8-((E)-3-oxo-
Experimental section
General information
1-phenylbut-1-en-2-yl)-2-phenyl-2,3-diaza-spiro[4.4]non-3-ene-1,7-
1
dione (3c). Yellow solid, mp: 158–162 °C. H NMR (400 MHz,
All reactions were performed under an N2 atmosphere in oven- CDCl3) δ 7.98 (s, 1H), 7.91 (s, 1H), 7.47 (d, J = 7.0 Hz, 3H), 7.34
dried glassware with magnetic stirring. Solvents were dried (t, J = 7.4 Hz, 4H), 7.29 (d, J = 7.7 Hz, 2H), 7.19–7.14 (m, 3H),
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7.08 (dd, J = 10.5, 4.6 Hz, 3H), 6.80 (d, J = 8.1 Hz, 2H), 6.55 (d, 138.7, 137.5, 135.2, 133.7, 132.6, 129.9, 129.5, 129.4, 128.9,
J = 8.1 Hz, 2H), 5.00 (d, J = 12.4 Hz, 1H), 4.09 (d, J = 12.4 Hz, 128.6, 128.5, 128.4, 126.7, 125.3, 124.7, 119.4, 66.1, 51.3, 50.2,
1H), 2.67 (dt, J = 13.8, 6.9 Hz, 1H), 2.42 (s, 3H), 1.79 (s, 3H), 25.6, 16.5. HRMS (ESI): calcd for C35H29N2O3S [M + H]+ m/z
1.03 (d, J = 2.1 Hz, 3H), 1.01 (d, J = 2.1 Hz, 3H). 13C NMR 557.1893, found 557.1895.
(101 MHz, CDCl3) δ 201.0, 197.5, 170.9, 157.5, 147.8, 146.7,
6-((E)-Benzylidene)-4-methyl-9-(naphthalen-1-yl)-8-((E)-3-oxo-
137.4, 137.3, 135.8, 133.9, 132.5, 131.4, 129.1, 129.0, 128.4, 1-phenylbut-1-en-2-yl)-2-phenyl-2,3-diaza-spiro[4.4]non-3-ene-1,7-
1
128.3, 127.9, 127.5, 127.4, 127.3, 126.9, 124.9, 124.7, 119.4, dione (3h). Yellow solid, mp: 183–185 °C. H NMR (400 MHz,
65.3, 50.1, 47.2, 32.6, 28.7, 24.9, 22.8, 22.6, 12.6. HRMS (ESI): CDCl3) δ 7.95 (s, 1H), 7.85 (s, 1H), 7.54 (s, 3H), 7.43–7.24 (m,
calcd for C40H37N2O3 [M + H]+ m/z 593.2799, found 593.2799.
7H), 7.18 (dd, J = 8.8, 6.9 Hz, 3H), 7.12–6.99 (m, 7H), 6.71 (d,
6-((E)-Benzylidene)-9-(4-chlorophenyl)-4-methyl-8-((E)-3-oxo-1- J = 8.1 Hz, 2H), 4.73 (d, J = 12.5 Hz, 1H), 4.49 (d, J = 12.6 Hz,
phenylbut-1-en-2-yl)-2-phenyl-2,3-diazaspiro-[4.4]non-3-ene-1,7- 1H), 2.31 (s, 3H), 1.80 (s, 3H). 13C NMR (101 MHz, CDCl3)
1
dione (3d). Yellow solid, mp: 172–174 °C. H NMR (400 MHz, δ 201.7, 197.0, 171.9, 158.6, 146.3, 140.0, 139.2, 137.4, 135.6,
CDCl3) δ 7.98 (s, 1H), 7.93 (s, 1H), 7.53 (s, 3H), 7.45–7.33 (m, 133.8, 132.9, 132.8, 131.6, 129.9, 129.7, 129.5, 129.2, 128.7,
5H), 7.30 (d, J = 7.4 Hz, 2H), 7.16 (ddd, J = 11.6, 9.1, 4.8 Hz, 128.6, 128.2, 127.8, 127.5, 126.2, 126.1, 125.8, 125.4, 125.0,
5H), 6.92 (d, J = 8.3 Hz, 2H), 6.43 (s, 2H), 4.54 (d, J = 11.6 Hz, 119.5, 66.1, 54.7, 48.7, 25.6, 16.3. HRMS (ESI): calcd for
1H), 4.35 (d, J = 12.1 Hz, 1H), 2.41 (s, 3H), 1.88 (s, 3H). C41H33N2O3 [M + H]+ m/z 601.2486, found 601.2488.
13C NMR (101 MHz, CDCl3) δ 201.2, 196.9, 171.6, 158.2, 146.4,
9-(4-Ethoxyphenyl)-4-methyl-6-((E)-3-methylbenzylidene)-8-
140.0, 138.9, 137.2, 135.3, 133.8, 133.7, 132.4, 131.2, 130.0, ((E)-3-oxo-1-(m-tolyl)but-1-en-2-yl)-2-phenyl-2,3-diazaspiro[4.4]
129.7, 129.4, 129.0, 128.9, 128.7, 128.6, 128.5, 128.4, 128.3, non-3-ene-1,7-dione (3i). Yellow solid, mp: 173–176 °C.
128.0, 125.4, 119.8, 119.4, 118.9, 66.0, 54.2, 48.8, 25.7, 16.5. 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.86 (s, 1H), 7.37 (d,
HRMS (ESI): calcd for C37H30ClN2O3 [M + H]+ m/z 585.1939, J = 7.6 Hz, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.25–7.19 (m, 3H),
found 585.1936.
7.17–7.07 (m, 5H), 6.98 (d, J = 7.5 Hz, 1H), 6.85 (s, 1H), 6.57 (d,
6-((E)-Benzylidene)-9-(2,4-dimethylphenyl)-4-methyl-8-((E)-3-oxo- J = 8.7 Hz, 2H), 6.47 (d, J = 8.6 Hz, 2H), 4.95 (d, J = 12.5 Hz,
1-phenylbut-1-en-2-yl)-2-phenyl-2,3-diaza-spiro[4.4]non-3-ene- 1H), 4.05 (d, J = 12.4 Hz, 1H), 3.84–3.77 (m, 2H), 2.41 (s, 3H),
1,7-dione (3e). Yellow solid, mp: 155–158 °C. 1H NMR 2.40 (s, 3H), 2.12 (s, 3H), 1.76 (s, 3H), 1.27 (t, 3H). 13C NMR
(400 MHz, CDCl3) δ 7.98 (s, 1H), 7.91 (s, 1H), 7.53 (d, J = (101 MHz, CDCl3) δ 200.9, 197.5, 171.1, 157.5, 146.9, 137.5,
6.0 Hz, 3H), 7.47 (s, 2H), 7.39 (d, J = 7.9 Hz, 2H), 7.32–7.26 (m, 137.3, 137.0, 136.2, 133.9, 132.4, 131.4, 129.9, 129.1, 128.6,
2H), 7.25–7.04 (m, 6H), 6.70 (d, J = 7.6 Hz, 1H), 6.27 (d, J = 128.4, 127.9, 127.8, 127.5, 127.3, 125.6, 124.4, 124.3, 123.8,
8.6 Hz, 2H), 4.61 (d, J = 12.2 Hz, 1H), 4.35 (d, J = 12.6 Hz, 1H), 118.6, 112.9, 65.4, 62.3, 49.9, 47.7, 24.9, 20.5, 20.3, 13.6, 12.6.
2.39 (s, 3H), 2.08 (s, 3H), 1.86 (s, 3H), 1.81 (s, 3H). 13C NMR HRMS (ESI): calcd for C41H39N2O4 [M + H]+ m/z 623.2904,
(101 MHz, CDCl3) δ 200.9, 195.8, 170.9, 157.6, 145.1, 138.7, found 623.2908.
138.2, 136.4, 135.5, 135.4, 134.5, 132.8, 131.7, 130.1, 129.9,
4-Methyl-6-((E)-3-methylbenzylidene)-8-((E)-3-oxo-1-(m-tolyl)
128.9, 128.6, 128.5, 127.9, 127.8, 127.6, 127.4, 127.0, 124.2, but-1-en-2-yl)-2-phenyl-9-(m-tolyl)-2,3-diaza-spiro[4.4]non-3-ene-
123.3, 118.5, 65.2, 53.5, 47.6, 24.6, 18.4, 18.3, 15.4. HRMS 1,7-dione (3j). Yellow solid, mp: 161–163 °C. 1H NMR
(ESI): calcd for C39H35N2O3 [M + H]+ m/z 579.2642, found (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.84 (s, 1H), 7.36 (t, J = 7.5 Hz,
579.2644.
1H), 7.24–7.01 (m, 10H), 6.96 (d, J = 7.5 Hz, 1H), 6.83 (d, J = 7.0
6-((E)-Benzylidene)-9-(furan-2-yl)-4-methyl-8-((E)-3-oxo-1-phenyl- Hz, 3H), 6.46 (d, J = 6.9 Hz, 1H), 6.40 (s, 1H), 5.03 (d, J = 12.5
but-1-en-2-yl)-2-phenyl-2,3-diaza-spiro[4.4]non-3-ene-1,7-dione Hz, 1H), 4.04 (d, J = 12.5 Hz, 1H), 2.39 (s, 3H), 2.38 (s, 3H),
1
(3f). Yellow solid, mp: 167–170 °C. H NMR (400 MHz, CDCl3) 2.11 (s, 3H), 1.94 (s, 3H), 1.74 (s, 3H). 13C NMR (101 MHz,
δ 7.93 (s, 2H), 7.53–7.43 (m, 5H), 7.34–7.28 (m, 4H), 7.14 (ddt, CDCl3) δ 202.0, 198.5, 171.9, 158.6, 148.0, 138.6, 138.3, 138.2,
J = 18.9, 11.9, 7.0 Hz, 6H), 6.99 (s, 1H), 6.07 (dd, J = 3.1, 1.9 Hz, 138.1, 137.5, 137.1, 135.0, 133.4, 132.8, 132.4, 130.9, 130.2,
1H), 5.64 (s, 1H), 4.51 (d, J = 12.0 Hz, 1H), 4.32 (d, J = 12.5 Hz, 129.6, 128.9, 128.8, 128.3, 127.7, 126.7, 125.7, 125.4, 125.3,
1H), 2.44 (s, 3H), 2.00 (s, 3H). 13C NMR (101 MHz, CDCl3) 119.5, 66.3, 51.5, 48.4, 25.9, 21.4, 21.3, 21.1, 13.7. HRMS (ESI):
δ 200.9, 197.0, 171.4, 159.0, 148.9, 146.7, 142.4, 139.8, 139.0, calcd for C40H37N2O3 [M + H]+ m/z 593.2799, found 593.2802.
137.6, 135.1, 133.7, 132.5, 129.9, 129.4, 129.3, 128.8, 128.6,
6-((E)-4-Ethylbenzylidene)-8-((E)-1-(4-ethylphenyl)-3-oxobut-1-
128.5, 128.2, 125.2, 119.3, 110.2, 108.2, 64.6, 49.2, 48.9, 25.6, en-2-yl)-4-methyl-2,9-diphenyl-2,3-diazaspiro-[4.4]non-3-ene-1,7-
1
16.1. HRMS (ESI): calcd for C35H29N2O4 [M + H]+ m/z 541.2122, dione (3k). Yellow solid, mp: 176–178 °C. H NMR (400 MHz,
found 541.2125.
CDCl3) δ 7.97 (s, 1H), 7.87 (s, 1H), 7.35 (d, J = 8.0 Hz, 6H), 7.28
6-((E)-Benzylidene)-4-methyl-8-((E)-3-oxo-1-phenylbut-1-en-2- (d, J = 7.5 Hz, 2H), 7.15–7.08 (m, 2H), 7.02 (d, J = 8.2 Hz, 2H),
yl)-2-phenyl-9-(thiophen-2-yl)-2,3-diazaspiro-[4.4]non-3-ene-1,7- 6.95 (dd, J = 11.7, 7.8 Hz, 4H), 6.54 (s, 2H), 4.64 (d, J = 11.5 Hz,
1
dione (3g). Yellow solid, mp: 178–182 °C. H NMR (400 MHz, 1H), 4.39 (d, J = 12.7 Hz, 1H), 2.77 (q, J = 7.6 Hz, 2H), 2.51 (q,
CDCl3) δ 7.96 (d, J = 8.3 Hz, 2H), 7.53–7.42 (m, 7H), 7.30 (t, J = J = 7.6 Hz, 2H), 2.38 (s, 3H), 1.90 (s, 3H), 1.32 (t, J = 7.6 Hz,
7.9 Hz, 2H), 7.20–7.09 (m, 6H), 6.98 (d, J = 4.9 Hz, 1H), 3H), 1.07 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) 201.9,
6.72–6.62 (m, 1H), 6.24 (s, 1H), 4.62 (d, J = 12.4 Hz, 1H), 4.50 198.6, 171.9, 158.9, 147.9, 146.8, 145.9, 144.9, 138.5, 137.9,
(d, J = 12.5 Hz, 1H), 2.42 (s, 3H), 1.96 (s, 3H). 13C NMR 136.9, 133.1, 132.2, 131.5, 130.7, 129.7, 128.6, 128.5, 128.4,
(101 MHz, CDCl3) δ 200.9, 197.0, 171.4, 158.4, 146.7, 140.0, 128.3, 128.0, 127.9, 125.6, 120.2, 66.2, 51.4, 48.4, 28.8, 26.9,
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15.3, 15.1, 13.7. HRMS (ESI): calcd for C41H39N2O3 [M + H]+ 129.9, 129.2, 129.1, 129.0, 127.8, 127.6, 127.2, 127.0, 126.9,
m/z 607.2955, found 607.2955. 126.3, 125.9, 124.8, 124.6, 119.0, 113.4, 112.9, 64.6, 54.3, 29.5,
6-((E)-4-Ethylbenzylidene)-8-((E)-1-(4-ethylphenyl)-3-oxobut-1- 28.7, 24.9, 18.2, 12.7. HRMS (ESI): calcd for C39H35N2O5
en-2-yl)-9-(2-methoxyphenyl)-4-methyl-2-phenyl-2,3-diazaspiro [M + H]+ m/z 611.2540, found 611.2544.
[4.4]non-3-ene-1,7-dione (3l). Yellow solid, mp: 159–162 °C.
6-((E)-4-Methoxybenzylidene)-8-((E)-1-(4-methoxyphenyl)-3-
1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.83 (s, 1H), 7.29 (d, oxobut-1-en-2-yl)-4-methyl-2-phenyl-9-(m-tolyl)-2,3-diazaspiro
J = 8.3 Hz, 3H), 7.22 (d, J = 7.3 Hz, 2H), 7.17 (d, J = 7.4 Hz, 2H), [4.4]non-3-ene-1,7-dione (3p). Yellow solid, mp: 162–165 °C.
7.13–7.03 (m, 6H), 7.00 (t, J = 7.8 Hz, 1H), 6.64 (d, J = 8.1 Hz, 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.85 (d, J = 4.6 Hz,
1H), 6.56 (d, J = 7.7 Hz, 1H), 6.41 (t, J = 7.5 Hz, 1H), 4.99 (d, J = 1H), 7.48–7.39 (m, 4H), 7.31 (t, J = 8.0 Hz, 2H), 7.15 (t, J = 7.4
12.6 Hz, 1H), 4.79 (d, J = 12.6 Hz, 1H), 3.61 (s, 3H), 2.74 (q, J = Hz, 1H), 7.06 (dd, J = 11.0, 8.6 Hz, 4H), 6.94–6.85 (m, 2H), 6.67
7.6 Hz, 2H), 2.62 (dd, J = 15.2, 7.6 Hz, 2H), 2.40 (s, 3H), 1.79 (s, (d, J = 8.8 Hz, 2H), 6.39 (s, 2H), 4.65 (d, J = 12.8 Hz, 1H), 4.39
3H), 1.31 (t, J = 7.6 Hz, 3H), 1.20 (t, J = 7.6 Hz, 3H). 13C NMR (d, J = 12.9 Hz, 1H), 3.91 (s, 3H), 3.66 (s, 3H), 2.37 (s, 3H), 1.93
(101 MHz, CDCl3) δ 201.5, 197.3, 171.3, 159.6, 157.1, 146.7, (s, 3H), 1.89 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 201.3, 196.2,
145.7, 144.7, 137.5, 137.2, 136.1, 130.8, 128.6, 127.6, 127.5, 171.2, 160.1, 159.6, 157.9, 145.1, 138.7, 136.8, 136.5, 132.9,
127.4, 127.3, 126.9, 124.4, 120.8, 119.2, 118.9, 108.8, 65.1, 64.8, 130.9, 129.0, 127.8, 127.7, 127.6, 127.1, 126.8, 125.3, 124.3,
53.8, 47.5, 42.6, 27.7, 24.9, 14.2, 14.1, 13.0. HRMS (ESI): calcd 124.2, 123.0, 118.6, 113.4, 113.1, 112.4, 65.3, 54.5, 54.2,
for C42H41N2O4 [M + H]+ m/z 637.3061, found 637.3072.
9-(4-Ethoxyphenyl)-6-((E)-4-ethylbenzylidene)-8-((E)-1-(4-ethyl- [M + H]+ m/z 625.2697, found 625.2699.
47.6, 25.9, 24.6, 20.1, 15.4. HRMS (ESI): calcd for C40H37N2O5
phenyl)-3-oxobut-1-en-2-yl)-4-methyl-2-phenyl-2,3-diazaspiro
9-(3-Fluorophenyl)-6-((E)-4-methoxybenzylidene)-8-((E)-1-(4-
[4.4]non-3-ene-1,7-dione (3m). Yellow solid, mp: 174–176 °C. methoxyphenyl)-3-oxobut-1-en-2-yl)-4-methyl-2-phenyl-2,3-di-
1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.87 (s, 1H), azaspiro[4.4]non-3-ene-1,7-dione (3q). Yellow solid, mp:
1
7.40–7.32 (m, 6H), 7.29 (d, J = 7.5 Hz, 2H), 7.13 (t, J = 7.3 Hz, 171–174 °C. H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.86 (d,
1H), 7.02 (d, J = 8.2 Hz, 2H), 6.96 (d, J = 8.2 Hz, 2H), 6.44 (s, J = 9.0 Hz, 1H), 7.49–7.42 (m, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.32
4H), 4.58 (d, J = 12.5 Hz, 1H), 4.32 (d, J = 12.5 Hz, 1H), 3.87 (q, (t, J = 7.9 Hz, 2H), 7.16 (t, J = 7.4 Hz, 1H), 7.05 (d, J = 8.7 Hz,
J = 7.0 Hz, 2H), 2.77 (q, J = 7.5 Hz, 2H), 2.49 (q, J = 7.6 Hz, 2H), 3H), 6.95 (d, J = 6.4 Hz, 1H), 6.87–6.73 (m, 2H), 6.65 (d, J =
2.38 (s, 3H), 1.89 (s, 3H), 1.33 (t, J = 6.9 Hz, 6H), 1.07 (t, J = 7.6 8.7 Hz, 2H), 6.45 (d, J = 6.2 Hz, 1H), 6.20 (s, 1H), 4.57 (d, J =
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 202.0, 197.2, 171.9, 13.0 Hz, 1H), 4.41 (d, J = 12.5 Hz, 1H), 3.91 (s, 3H), 3.65 (s,
158.9, 158.4, 146.6, 146.4, 146.1, 139.8, 138.7, 137.5, 132.8, 3H), 2.38 (s, 3H), 1.89 (d, J = 27.5 Hz, 3H). 13C NMR (101 MHz,
132.0, 131.3, 129.7, 128.6, 128.5, 128.3, 128.2, 128.1, 125.7, CDCl3) δ 200.6, 196.4, 170.9, 160.2, 159.7, 157.6, 145.5, 138.9,
125.2, 119.6, 114.0, 66.3, 63.2, 54.4, 49.1, 28.8, 28.7, 25.7, 16.4, 136.8 (d, JC–F = 7.0 Hz), 135.8, 135.7, 130.8, 130.6, 129.9 (d,
15.6, 15.1, 14.7. HRMS (ESI): calcd for C43H43N2O4 [M + H]+ JC–F = 8.0 Hz), 128.8, 127.8, 127.7, 125.2, 124.4, 123.3 (d, JC–F
m/z 651.3217, found 651.3219. 3.0 Hz), 122.3, 118.7, 118.5, 115.0 (d, JC–F = 21.0 Hz), 114.3 (d,
=
4-Methyl-6-((E)-4-methylbenzylidene)-8-((E)-3-oxo-1-(p-tolyl)but- JC–F = 34.0 Hz), 113.5, 113.1, 65.1, 54.4, 54.2, 24.6, 18.2, 15.5,
1-en-2-yl)-2,9-diphenyl-2,3-diazaspiro[4.4]non-3-ene-1,7-dione (3n). 12.71. HRMS (ESI): calcd for C39H34FN2O5 [M + H]+ m/z
Yellow solid, mp: 166–168 °C. 1H NMR (400 MHz, CDCl3) 629.2446, found 629.2450.
δ 7.96 (s, 1H), 7.86 (s, 1H), 7.76–7.43 (m, 2H), 7.30 (d, J = 20.7
6-((E)-4-Fluorobenzylidene)-8-((E)-1-(4-fluorophenyl)-3-oxobut-
Hz, 2H), 7.22 (d, J = 7.7 Hz, 3H), 7.16 (d, J = 7.7 Hz, 2H), 7.09 1-en-2-yl)-4-methyl-2,9-diphenyl-2,3-diazaspiro-[4.4]non-3-ene-
(dd, J = 11.6, 7.7 Hz, 3H), 7.03 (t, J = 7.2 Hz, 2H), 6.97 (t, J = 7.3 1,7-dione (3r). Yellow solid, mp: 167–169 °C. 1H NMR
Hz, 2H), 6.69 (d, J = 7.4 Hz, 2H), 5.05 (d, J = 12.5 Hz, 1H), 4.14 (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.85 (s, 1H), 7.38 (d, J =
(d, J = 12.5 Hz, 1H), 2.44 (s, 3H), 2.39 (s, 3H), 2.33 (s, 3H), 1.82 7.9 Hz, 3H), 7.31 (t, J = 7.9 Hz, 2H), 7.22 (t, J = 8.4 Hz, 2H),
(s, 3H). 13C NMR (101 MHz, CDCl3) δ 201.1, 197.7, 170.9, 7.18–7.13 (m, 2H), 7.12–7.06 (m, 3H), 6.99 (t, J = 7.5 Hz, 2H),
157.9, 147.1, 139.7, 138.6, 137.5, 136.7, 135.9, 132.0, 130.9, 6.83 (t, J = 8.6 Hz, 2H), 6.56 (s, 2H), 4.50 (d, J = 9.2 Hz, 1H),
130.4, 129.9, 129.5, 128.7, 128.5, 128.2, 127.6, 127.4, 127.2, 4.37 (d, J = 12.5 Hz, 1H), 2.40 (d, J = 4.2 Hz, 3H), 1.91 (s, 3H).
126.9, 124.6, 119.2, 65.2, 64.5, 50.3, 47.3, 24.9, 20.5, 12.7. 13C NMR (101 MHz, CDCl3) δ 200.5, 170.6, 163.6 (d, JC–F = 15.0
HRMS (ESI): calcd for C39H35N2O3 [M + H]+ m/z 579.2642, Hz), 161.2 (d, JC–F = 13.0 Hz), 157.3, 144.0, 137.6, 136.2, 132.6,
found 579.2645.
131.5, 130.7 (d, JC–F = 9.0 Hz), 129.3 (d, JC–F = 8.0 Hz), 128.9
6-((E)-4-Methoxybenzylidene)-8-((E)-1-(4-methoxyphenyl)-3- (d, JC–F = 4.0 Hz), 127.8, 127.4, 127.2, 125.9, 124.5, 118.3, 115.2
oxobut-1-en-2-yl)-4-methyl-2,9-diphenyl-2,3-diazaspiro[4.4]non- (d, JC–F = 22.0 Hz), 114.8 (d, JC–F = 22.0 Hz), 65.1, 47.6, 28.7,
3-ene-1,7-dione (3o). Yellow solid, mp: 151–153 °C. 1H NMR 24.6, 15.5. HRMS (ESI): calcd for C37H29F2N2O3 [M + H]+ m/z
(400 MHz, CDCl3) δ 7.94 (s, 1H), 7.83 (s, 1H), 7.72 (dd, J = 5.7, 587.2141, 587.2143.
3.3 Hz, 1H), 7.53 (dd, J = 5.7, 3.3 Hz, 1H), 7.33 (d, J = 8.7 Hz,
6-((E)-3-Chlorobenzylidene)-8-((E)-1-(3-chlorophenyl)-3-oxobut-
2H), 7.21 (dt, J = 8.7, 7.7 Hz, 4H), 7.08 (t, J = 10.4 Hz, 3H), 7.00 1-en-2-yl)-9-(4-ethoxyphenyl)-4-methyl-2-phenyl-2,3-diazaspiro
(d, J = 8.4 Hz, 3H), 6.79 (d, J = 8.8 Hz, 2H), 6.71 (d, J = 7.4 Hz, [4.4]non-3-ene-1,7-dione (3s). Yellow solid, mp: 148–150 °C.
2H), 5.08 (d, J = 12.4 Hz, 1H), 4.17 (d, J = 12.5 Hz, 1H), 3.90 (s, 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.81 (s, 1H),
3H), 3.79 (s, 3H), 2.38 (s, 3H), 1.87 (s, 3H). 13C NMR (101 MHz, 7.48–7.40 (m, 4H), 7.34–7.27 (m, 4H), 7.17–7.09 (m, 4H), 7.03
CDCl3) δ 201.4, 171.14, 160.3, 146.7, 137.3, 135.9, 132.1, 130.6, (d, J = 7.9 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.50 (d, J = 8.1 Hz,
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2H), 6.45 (s, 1H), 4.41 (d, J = 7.2 Hz, 1H), 4.28 (d, J = 9.6 Hz, 2H), 6.52 (s, 2H), 4.60 (d, J = 11.5 Hz, 1H), 4.37 (d, J = 11.5 Hz,
1H), 3.88 (q, J = 7.0 Hz, 2H), 2.39 (s, 3H), 1.93 (s, 3H), 1.33 (t, 1H), 2.40 (s, 3H), 2.30 (s, 3H), 1.88 (s, 3H). 13C NMR (101 MHz,
J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 201.2, 196.8, CDCl3) δ 201.8, 196.9, 171.5, 158.2, 146.3, 139.7, 139.2, 135.5,
171.5, 158.7, 158.3, 144.4, 140.2, 137.9, 137.2, 137.1, 135.5, 135.0, 134.9, 133.8, 132.7, 129.9, 129.6, 129.5, 129.2, 128.9,
135.0, 134.7, 134.1, 130.2, 129.9, 129.8, 129.4, 129.3, 128.9, 128.6, 128.3, 128.0, 127.1, 119.7, 66.1, 54.8, 48.7, 25.7, 21.0,
128.6, 128.3, 128.1, 127.3, 126.3, 125.3, 124.9, 120.0, 119.4, 16.4. HRMS (ESI): calcd for C38H33N2O3 [M + H]+ m/z 565.2486,
114.2, 66.2, 63.3, 54.4, 49.0, 25.6, 16.5, 14.7. HRMS (ESI): calcd found 565.2495.
for C39H33Cl2N2O4 [M + H]+ m/z 663.1812, found 663.1816.
6-((E)-Benzylidene)-4-methyl-2,9-diphenyl-2,3-diazaspiro[4.4]
6-((E)-3-Chlorobenzylidene)-8-((E)-1-(3-chlorophenyl)-3-oxobut- non-3-ene-1,7-dione (4a). Yellow solid, mp: 105–108 °C.
1-en-2-yl)-9-(3-fluorophenyl)-4-methyl-2-phenyl-2,3-diazaspiro 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.3 Hz, 1H), 7.43 (d,
[4.4]non-3-ene-1,7-dione (3t). Yellow solid, mp: 167–169 °C. J = 7.4 Hz, 1H), 7.31 (d, J = 7.0 Hz, 3H), 7.25 (dd, J = 12.6,
1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.85 (s, 1H), 7.50 5.4 Hz, 6H), 7.20–7.09 (m, 3H), 7.05 (t, J = 7.2 Hz, 2H),
(ddd, J = 19.0, 7.0, 3.8 Hz, 3H), 7.41–7.28 (m, 5H), 7.16 (dd, J = 4.15–3.95 (m, 0.5H), 3.78–3.53 (m, 1H), 3.09 (ddd, J = 26.1,
8.2, 2.8 Hz, 2H), 7.11–7.04 (m, 2H), 6.96 (dd, J = 15.7, 7.2 Hz, 18.0, 10.5 Hz, 1H), 2.77 (dd, J = 15.9, 5.4 Hz, 0.5H), 1.87 (s,
2H), 6.84 (dd, J = 10.3, 8.1 Hz, 1H), 6.39 (s, 1H), 6.15 (s, 1H), 1H), 1.70 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 201.98, 172.59,
4.42 (s, 1H), 4.34 (s, 1H), 2.42 (s, 3H), 1.95 (s, 3H). 13C NMR 171.82, 159.21, 157.98, 140.22, 138.23, 137.34, 137.00, 135.18,
(101 MHz, CDCl3): δ 199.6, 170.2, 162.7, 156.9, 137.3, 136.0, 133.48, 133.16, 130.33, 129.37, 128.97, 127.82, 126.9, 125.68,
135.8, 135.0, 134.3 (d, JC–F = 7.0 Hz), 133.7, 132.7, 129.9, 129.4, 119.78, 66.92, 50.33, 48.17, 39.77, 39.28, 16.44, 13.85. HRMS
129.1, 128.9, 128.7 (d, JC–F = 12.0 Hz), 128.2, 127.6, 127.2, (ESI): calcd for C27H23N2O2 [M + H]+ m/z 407.1754, found
126.2, 125.2, 124.5, 122.1 (d, JC–F = 2.0 Hz), 118.3, 114.3 (d, 407.1752.
JC–F = 21.0 Hz), 112.7 (d, JC–F = 22.0 Hz), 64.9, 53.5, 28.7, 24.6,
15.5. HRMS (ESI): calcd for C37H28Cl2FN2O3 [M + H]+ m/z diazaspiro[4.4]non-3-ene-1,7-dione (4h). Eluent: PE/EtOAc
637.1456, found 637.1458.
(5 : 1). Yield: 21% (9.6 mg). Mp: 135–138 °C. 1H NMR
(E)-6-Benzylidene-4-methyl-9-(naphthalen-1-yl)-2-phenyl-2,3-
6-((E)-4-Fluorobenzylidene)-8-((E)-1-(4-fluorophenyl)-3-oxobut-1- (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.91 (dd, J = 7.5, 3.4 Hz, 2H),
en-2-yl)-9-(furan-2-yl)-4-methyl-2-phenyl-2,3-diazaspiro[4.4]non- 7.84–7.78 (m, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.60–7.50 (m, 1H),
3-ene-1,7-dione (3u). Yellow solid, mp: 198–200 °C. 1H NMR 7.47–7.29 (m, 6H), 7.25 (s, 2H), 7.15–7.06 (m, 3H), 6.94 (dd, J =
(400 MHz, CDCl3) δ 7.87 (d, J = 1.8 Hz, 2H), 7.55–7.51 (m, 2H), 46.9, 4.2 Hz, 1H), 4.68 (dd, J = 13.6, 7.2 Hz, 1H), 3.78 (dd, J =
7.36–7.32 (m, 2H), 7.31–7.27 (m, 2H), 7.19–7.13 (m, 3H), 17.4, 13.6 Hz, 1H), 2.93 (dd, J = 17.4, 7.2 Hz, 1H), 1.75 (s, 3H).
7.10–7.06 (m, 2H), 7.03 (d, J = 1.2 Hz, 1H), 6.85–6.79 (m, 2H), 13C NMR (101 MHz, CDCl3) δ 201.1, 171.1, 157.4, 137.6, 135.9,
6.10 (dd, J = 3.2, 1.9 Hz, 1H), 5.71 (d, J = 2.7 Hz, 1H), 4.43 (d, 132.7, 132.4, 132.2, 131.0, 129.4, 129.3, 128.4, 128.3, 128.0,
J = 12.1 Hz, 1H), 4.30 (d, J = 12.3 Hz, 1H), 2.43 (s, 3H), 2.02 (s, 127.6, 127.5, 127.2, 125.1, 124.6, 124.5, 124.4, 124.0, 120.6,
3H). 13C NMR (101 MHz, CDCl3) δ 199.7, 195.9, 170.3, 163.5 (d, 118.6, 52.4, 40.7, 20.4, 13.7. HRMS (ESI): calcd for C31H25N2O2
JC–F = 27.0 Hz), 161.0 (d, JC–F = 24.0 Hz), 158.0, 147.7, 144.5, [M + H]+ m/z 457.1911, found 457.1915.
141.5, 138.2, 137.6, 136.5, 131.3, 130.7 (d, JC–F = 9.0 Hz), 130.0
(E)-6-Benzylidene-2,4-dimethyl-9-phenyl-2,3-diazaspiro-[4.4]
(d, JC–F = 4.0 Hz), 129.2 (d, JC–F = 9.0 Hz), 128.8 (d, JC–F = 3.0 non-3-ene-1,7-dione (4z). Eluent: PE/EtOAc (5 : 1). Yield: 72%
Hz), 127.8, 124.4, 118.1, 115.0 (d, JC–F = 19.0 Hz), 114.9 (d, (24.8 mg). Yellow solid, mp: 108–112 °C. 1H NMR (400 MHz,
JC–F = 19.0 Hz), 109.4, 107.5, 63.6, 48.0, 47.9, 24.6, 15.1. HRMS CDCl3) δ 7.75 (s, 1H), 7.29 (d, J = 7.2 Hz, 1H), 7.27–7.21 (m,
(ESI): calcd for C35H27F2N2O4 [M + H]+ m/z 577.1933, found 5H), 7.16–7.10 (m, 2H), 6.97 (d, J = 7.2 Hz, 2H), 3.59 (dd, J =
577.1936.
16.6, 14.4 Hz, 1H), 3.45 (dd, J = 14.4, 6.4 Hz, 1H), 2.79 (s, 3H),
6-Methyl-8-((E)-3-oxo-1-(thiophen-2-yl)but-1-en-2-yl)-2,9-diphenyl- 2.67 (dd, J = 16.7, 6.4 Hz, 1H), 1.55 (s, 3H). 13C NMR (101 MHz,
6-(thiophen-2-ylmethylene)-2,3-diazaspiro-[4.4]non-3-ene-1,7-dione CDCl3) δ 201.2, 171.7, 156.1, 136.7, 132.8, 132.2, 132.1, 129.3,
1
(3v). Yellow solid, mp: 124–126 °C. H NMR (400 MHz, CDCl3) 128.4, 127.4, 127.3, 127.2, 126.8, 65.0, 46.9, 38.2, 29.8, 12.7.
δ 8.09 (s, 1H), 7.85 (s, 1H), 7.64 (d, J = 7.9 Hz, 2H), 7.59 (d, J = HRMS (ESI): calcd for C22H21N2O2 [M + H]+ m/z 345.1598,
5.0 Hz, 1H), 7.43 (d, J = 4.4 Hz, 1H), 7.36 (t, J = 7.9 Hz, 3H), found 345.1598.
7.22–7.10 (m, 5H), 7.08–7.03 (m, 2H), 7.00 (s, 2H), 4.90 (d, J =
4-((E)-4-Methoxybenzylidene)-1-((Z)-4-methoxybenzylidene)-
12.8 Hz, 1H), 4.64 (d, J = 13.1 Hz, 1H), 2.36 (s, 3H), 2.07 3′-methyl-1′-phenyl-3-(m-tolyl)-3a,4-dihydro-1H-spiro[pentalene-
(s, 3H). 13C NMR (101 MHz, CDCl3) δ 199.9, 196.6, 172.0, 2,4′-pyrazole]-5,5′(1′H,3H)-dione (5). Eluent: PE/EtOAc (3 : 1).
1
157.2, 138.1, 137.6, 137.0, 136.7, 135.9, 135.3, 133.9, 133.0, Yield: 36% (21.8 mg). Yellow solid, mp: 136–139 °C. H NMR
132.8, 131.6, 129.5, 128.8, 128.4, 128.3, 128.0, 127.6, 127.4, (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.79 (d, J = 7.7 Hz, 2H), 7.43
125.4, 119.5, 66.5, 56.0, 50.5, 25.8, 16.6. HRMS (ESI): calcd for (t, J = 7.8 Hz, 3H), 7.29 (s, 4H), 7.18 (d, J = 7.5 Hz, 1H), 7.07 (d,
C33H27N2O3S2 [M + H]+ m/z 563.1458, found 563.1454.
J = 7.6 Hz, 1H), 6.95 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H),
6-((E)-Benzylidene)-4-methyl-8-((E)-3-oxo-1-phenylbut-1-en-2-yl)- 6.63 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 8.8 Hz, 2H), 4.43 (d, J =
9-phenyl-2-(p-tolyl)-2,3-diazaspiro[4.4]non-3-ene-1,7-dione (3y). 3.3 Hz, 1H), 3.75 (s, 6H), 3.69 (d, J = 3.2 Hz, 1H), 2.50 (s, 3H),
Yellow solid, mp: 163–165 °C. 1H NMR (400 MHz, CDCl3) 2.28 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 199.2, 160.6, 160.5,
δ 7.98 (s, 1H), 7.91 (s, 1H), 7.51 (s, 3H), 7.43 (s, 2H), 7.18 (ddd, 152.4, 146.9, 146.8, 141.0, 139.2, 139.1, 136.9, 130.4, 130.3,
J = 19.1, 9.3, 4.6 Hz, 5H), 7.12–7.06 (m, 5H), 6.95 (t, J = 7.3 Hz, 129.3, 129.1, 129.0, 128.2, 126.3, 125.6, 122.4, 114.2, 113.9,
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56.1, 55.4, 55.3, 31.9, 25.8, 21.5, 14.1. HRMS (MALDI): calcd
for C40H35N2O4 [M + H]+ m/z 607.2591, found 607.2594.
(E)-6-Benzylidene-4,8-dimethyl-2,9-diphenyl-2,3-diaza-spiro[4.4]
non-3-ene-1,7-dione (7). Eluent: PE/EtOAc (5 : 1). Yield: 79%
(33.2 mg). Yellow solid, mp: 110–114 °C. 1H NMR (400 MHz,
CDCl3) δ 7.92 (s, 1H), 7.39–7.30 (m, 5H), 7.30–7.26 (m, 5H),
7.22–7.11 (m, 3H), 7.09 (d, J = 7.4 Hz, 2H), 3.76 (dq, J = 13.5,
6.7 Hz, 1H), 3.15 (d, J = 13.7 Hz, 1H), 1.71 (s, 3H), 1.20 (d, J =
6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 202.9, 170.8, 157.1,
137.1, 135.9, 132.2, 131.9, 131.8, 128.2, 127.7, 127.6, 127.5,
127.4, 127.0, 124.7, 118.9, 64.8, 54.7, 42.2, 12.8, 11.1. HRMS
(ESI): calcd for C28H25N2O2 [M + H]+ m/z 421.1911, found
421.1914.
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Conflicts of interest
7 For selected reviews on C(sp3)–H bond activation, see:
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There are no conflicts to declare.
Acknowledgements
We thank the National Natural Science Foundation of China
(21072102), the Rural Affairs Commission of the CPC Tianjin
Municipal Committee (2016D01A016) and the State Key
Laboratory of Elemento-Organic Chemistry in Nankai
University for financial support. We also thank the anonymous
reviewer’s helpful suggestions improving our manuscript.
8 For selected reviews on mono C(sp3)–H bond activation,
see: (a) C.-J. Li, Acc. Chem. Res., 2009, 42, 335; (b) R. Jazzar,
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