Chemo- and Diastereoselective Construction of Indenopyrazolines via a Cascade aza-Michael/Aldol Annulation of Huisgen Zwitterions with 2-Arylideneindane-1,3-diones

Article abstract of DOI:10.1002/adsc.201701013

A cascade aza-Michael/Aldol annulation of 2-arylideneindane-1,3-diones with in situ generated Huisgen zwitterions has been developed. This reaction afforded the desired products in moderate to good yields (up to 87%) with excellent chemo- and diastereoselectivity (up to 20:1). This strategy allows facile diastereoselective preparation of biologically important indenopyrazoline derivatives containing two contiguous chiral centers including a quaternary stereogenic center. (Figure presented.).

Full text of DOI:10.1002/adsc.201701013

Title: Chemo- and Diastereoselective Construction of
Indenopyrazolines via a Cascade aza-Michael/Aldol Annulation of
Huisgen Zwitterions with 2-Arylideneindane-1,3-diones
Authors: Yuming Li, Haikun Zhang, Rong Wei, and Zhiwei Miao
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701013
Link to VoR: http://dx.doi.org/10.1002/adsc.201701013

10.1002/adsc.201701013
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Chemo- and Diastereoselective Construction of
Indenopyrazolines via a Cascade aza-Michael/Aldol Annulation
of Huisgen Zwitterions with 2-Arylideneindane-1,3-diones
Yuming Li,a Haikun Zhang,a Rong Wei,a and Zhiwei Miaoa,b*
a
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Weijin
Road 94, Tianjin 300071, People’s Republic of China
Fax: (+86)-22-2350-2351; e-mail: miaozhiwei@nankai.edu.cn
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, People’s Republic of
b
China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
and the correct structure was subsequently assigned
by Huisgen in 1969.[9] Huisgen zwitterions is the
critical component in the Mitsunobu reaction[10] and
early reported annulation reactions.[11] However, the
chemistry of Huisgen zwitterions received little
attention until very recently years. The renewed
interest has revealed that Huisgen zwitterions could
undergo a series of annulation reaction with electron-
deficient alkenes to give highly functionalized
pyrazolines (Scheme 1, a).[12] In addition, Nair and
co-workers have reported that the reaction of the
zwitterion with electron-dificient alkenes and
dienones affords pyrazoline and pyrazolopyridazine
derivatives, respectively (Scheme 1, b).[13]
Nevertheless, direct approaches for the synthesis of
the fused polycyclic indenopyrozoline frameworks
has not been explored. Inspired by these works, and
in our continuing interest in bioactive fused
polycyclic structure synthesis,[14] we disclose here a
direct access to fused polycyclic pyrazolines via a
cascade aza-Michael/Aldol annulation of the Huisgen
zwitterions and 2-arylideneindane-1,3-diones under
mild conditions in moderate to good yields with
excellent chemo- and diastereoselectivities (Scheme 1,
c).
Abstract. A cascade aza-Michael/Aldol annulation of 2-
arylideneindane-1,3-diones with in situ generated
Huisgen zwitterions has been developed. This reaction
afforded the desired products in moderate to good yields
(up
to
87%)
with
excellent
chemo-
and
diastereoselectivity (up to 20:1). This strategy allows
facile diastereoselective preparation of biologically
important indenopyrazoline derivatives containing two
contiguous chiral centers including
stereogenic center.
a
quaternary
Keywords: Huisgen zwitterions; Indenopyrazolines; aza-
Michael/Aldol annulation; Chemoselectivity;
Diastereoselectivity
Indenopyrazoline is an important heterocyclic
scaffold which occurs in a number of bioactive
compounds and useful synthetic building blocks.[1]
They have been reported for their application in
herbicides,[2] anti-bacterial,[3] anti-inflammatory
agents,[4] and anti-cancer agents.[5] For these reasons,
the development of new methodologies for
constructing these compounds has been an active
research area in organic synthesis and drug chemistry.
During the past decades, the construction of
multisubstituted and fused polycyclic pyrazoles has
been developed.[6] However, general methods for
functionalized pyrazoline rings are relatively few.[7]
Especially the construction of strained polycyclic
structures containing pyrazoline with multiple and
all-carbon-substituted stereogenic centers is still a
challenge. Within this context, the development of
novel efficient synthetic transformations for the
catalytic asymmetric assembly of such structures is
highly desirable.
Previous work:
EtOOC COOEt
OR1
EtO2C
COOR1
COOR1 R2OOC
Ph3P
R1OOC
Ph3P
N
N
(a)
N
N
EtO2C
R2O2C
N
R1OOC
N
CO2R1
Huisgen zwitterion
O
O
CO2R
R2
N
RO2C
N
RO2C
RO2C
N
CO2R
R2
Ph3P +
R1
R2
R1
N
N
N
R1
R2
H
toluene, reflux
Ar, 12 h
toluene, reflux
Ar, 3 h
N N
R1
(b)
(c)
CO2R
RO2
C
CO2R
This work:
O
O
N
CO2R2
R1
R1
COOR2
COOR2
Ph3P
Ph3P
N
N
N
N
O
The Huisgen zwitterions formed from the reaction
of triphenylphosphine with dialkyl azodicarboxylate
was first observed by Cookson and Locke in 1963,[8]
R2OOC
R2OOC
toluene, reflux, Ar
N
CO2R2
Huisgen zwitterion
Scheme 1. Previous and proposed work.
1
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10.1002/adsc.201701013
Advanced Synthesis & Catalysis
2-Aryldeneindane-1,3-diones 1 are highly reactive
1,1-diactivated alkenes that have been used
extensively as acceptors in organo-catalytic reactions
for the synthesis of spirocyclic compounds.[15] It is
interesting to employ 1,1-diactivated alkenes
developing cycloaddition reactions which led to
highly substituted indenopyrazoline derivatives. The
investigation was initiated by the model reaction of 2-
naphthalen-1H-indene-1,3(2H)-dione 1a (0.3 mmol)
and diethyl azodicarboxylate (DEAD) 2a (0.45
mmol) in the presence of a stoichiometric amount of
triphenylphosphine in anhydrous toluene at room
temperature. Under argon atmosphere, the reaction
To further improve the reaction efficiency, a brief
survey on the model reaction conditions was carried
out (Table 1). A solvent screening was subsequently
performed, and DCE was identified to be the best
solvent for the reaction, whereas other solvent such as
THF, 1,4-dioxane, DMF, CH3CN and DCM, could
readily afford the desired product 3a in inferior yields
(Table 1, entries 2-7). Similarly, several commonly
used phosphines were investigated to this reaction at
room temperature. The utility of other phosphines,
such as PBu3, P(OEt)3 and MePPh2, led to a
corresponding decrease in the yield for 3a (Table 1
entries 8-10). Additionally, the effect of temperature
on the reaction was also evaluated, and the results
suggested that the reaction worked efficiently at 110
C in toluene, leading to the desired product 3a in
81%yield in a shortened reaction time (Table 1, entry
11). Whereas compound 3a was afforded in 57%
yield at 89 C in DCE for 6 hours (Table 1, entry 12).
With toluene chosen as the solvent, increasing or
decreasing the loadings of both azodicarboxylate 2a
and Ph3P resulted in a substantial decrease in the
yield of 3a (Table 1, entries 13-15), and the substrate
molar ratio of 1:1.5:1.5 was preferred (Table 1, entry
11). Finally, the optimal reaction conditions for this
transformation were determined to be 2-
arylideneindane-1,3-dione 1 (0.3 mmol), dialkyl
azodicarboxylate 2 (0.45 mmol), and Ph3P (0.45
mmol) in toluene (2 mL) as a solvent at 110 C.
afforded
a
product that was subsequently
characterized as the 3-naphthalen-2-yl-4-oxo-
indenopyrazole-2,3-diethyl dicarboxylate 3a in 58%
yield with 20:1 dr (Scheme 1, entry 1). Surprisingly,
the expected 3-naphthalen-2-yl-4-oxo-3,4-dihydro-
indenopyrazole-1,2-diethyl dicarboxylate 4a was not
formed. The structure of the indenopyrazoline
derivative 3a was determined by 1H NMR, 13C NMR,
and 2D NMR spectroscopy and mass spectrometry.[16]
Unambiguous evidence for structure of 3f (Table 2,
entry 6) was obtained from single-crystal X-ray
analysis (Figure 1), which showed the carboethyloxy
group connected to the fused carbon atom of the
indenopyrazoline and formed a quaternary center.[17]
Triphenylphosphine oxide was also isolated from the
reaction
mixture,
which
indicated
that
triphenylphosphine participated in the reaction and
was oxidized into triphenylphosphine oxide.
Table 1. Optimization of conditions of the aza-Michael/Aldol annulation of 1a and 2a.a)
EtO2C
O
O
CO2Et
N
N
CO2Et
N
CO2Et
3a
EtOOC
N
PR3
conditions
+
N
COOEt
O
N
O
1a
2a
4a
not observed
Entry
PR3
Molar ratio
1a:2a:PR3
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.2:1.2
1:2.0:2.0
1:3.0:3.0
Solvent
Time (h)
Drb)
Yield (%)c)
T (C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PBu3
P(OEt)3
MePPh2
PPh3
PPh3
PPh3
25
25
25
25
25
25
25
25
25
25
110
89
110
110
110
toluene
THF
24
24
24
24
24
24
24
24
24
24
3
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
58
66
51
47
46
54
71
34
27
19
81
57
60
74
48
1,4-dioxane
DMFd)
MeCN
DCMe)
DCEf)
DCE
DCE
DCE
toluene
DCE
6
3
3
3
toluene
toluene
toluene
PPh3
PPh3
a) Unless otherwise specified, all reactions were carried out using 2-naphthalen-1H-indene-1,3(2H)-dione 1a (0.3 mmol),
diethyl azodicarboxylate 2a (0.45-0.9 mmol), phosphine (0.45-0.9 mmol) in 2 mL solvent. b) Diastereomeric ratio (dr)
c)
d)
values were determined by 1H NMR of crude products. Yield of isolated product of 3a after column chromatography.
DMF = N,N-dimethylformamide. e) DCM = dichloromethane. f) DCE = dichloroethane.
2
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10.1002/adsc.201701013
Advanced Synthesis & Catalysis
arylideneindane-1,3-diones 1 that included electron-
withdrawing and -donating substituents were well
tolerated under these conditions. With an electron-
withdrawing group in the 4-substituted 2-
arylideneindane-1,3-diones, the reaction proceeded
smoothly with diethyl azodicarboxylate 2a to give the
desired product 3 in good yields with excellent
diastereoselectivities (Table 2, entries 2-5). Those
with electron-donating groups (Ar = 4-MeC6H4, 4-
OEtC6H4) worked very well, giving the desired
products 3f-3g in high yields with excellent
diastereoselectivities (Table 2, entries 6-7). meta-
Substituents (Ar = 3-MeC6H4, 3-ClC6H4) and even
ortho-substituents (Ar = 2-MeC6H4, 2-ClC6H4, 2-
FC6H4) were tolerated, affording cycloadduts 3h-3l in
moderate to good yields (Table 2, entries 8-12). The
arylidene indanedione with two electron-withdrawing
groups (Ar = 3,4-Cl2C6H3) resulted in good yield
(3m) with excellent diastereoselectivity (Table 2,
entry 13). Both arylidenes with 1-naphthyl and with
4-pyrityl reacted well to furnish cycloadducts 3n and
3o in moderate yields with good stereoselectivities
(>20:1 dr) (Table 2, entries 14-15). Phenyl-substitute
1p could also furnish the annulation product 3p in
87% yield with good diastereoselectivity (Table 2,
Figure 1. The X-ray crystal structure of 3f.
Having established the optimized reaction conditions,
the generality of this annulation was investigated
(Table 2). With diethyl azodicarboxylate 2a
employed as a representative reactant, a variety of 2-
arylideneindane-1,3-diones 1 were explored. For all
the substrates studied, various substituted 2-
entry
16).
Table 2. Substrate scope of the reactiona)
O
O
2
1
2
CO R
2
COOR
R
PPh
N N
3
+
2
1
R OOC
o
R
toluene, Ar, 110 C
N
N
O
2
CO R
2
1
2
3
Drb)
Entry
1
2
3
4
5
6
7
8
Product
3a
3b
3c
R1
R2
Time (h)
Yield (%)c)
81
2-naphthyl (1a)
4-NO2C6H4 (1b)
4-CNC6H4 (1c)
4-ClC6H4 (1d)
4-OCF3C6H4 (1e)
4-CH3C6H4 (1f)
4-OEtC6H4 (1g)
3-CH3C6H4 (1h)
3-ClC6H4 (1i)
2-CH3C6H4 (1j)
2-ClC6H4 (1k)
2-FC6H4 (1l)
3,4-Cl2C6H3 (1m)
1-naphthyl (1n)
4-pyridyl (1o)
C6H5 (1p)
2-naphthyl (1a)
C6H5 (1p)
4-NO2C6H4 (1b)
C6H5 (1p)
4-CH3C6H4 (1f)
E-styryl (1q)
cyclo-hexyl (1r)
C6H5 (1p)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
i-Pr (2b)
i-Pr (2b)
i-Pr (2b)
Bn (2c)
Bn (2c)
Et (2a)
Et (2a)
Et (2a)
3
1.5
1.5
3
3
3
3
3
6
3
3
3
2.5
3
3
3
3
3
3
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1

79
76
73
64
74
76
70
60
63
70
64
82
60
66
87
63
76
67
75
72


78
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3p
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24d)
3
3
24
24
3

>20:1
3
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10.1002/adsc.201701013
Advanced Synthesis & Catalysis
a)
Reaction conditions: under a Ar atmosphere, 2-arylideneindane-1,3-diones 1 (0.3 mmol), dialkyl azodicarboxylate 2
(0.45 mmol), Ph3P (0.45 mmol) in 2 mL of toluene at 110 C. b) Diastereomeric ratio (dr) values were determined by H
1
NMR of crude products. c) Isolated yield after silica gel chromatography of 3. d) Run on a 3.0 mmol scale.
Selected dialkyl azodicarboxylates 2 were further
examined in the annulation reaction with
representative 2-arylideneindane-1,3-diones 1. Under
the standard conditions, diisopropyl and dibenzyl
azodicarboxylates 2b and 2c both delivered their
annulation products 3 in moderate to good yields with
excellent diastereoselectivities (Table 2, entries 17-
21). It was observed that E-styryl substituted 1q and
aliphatic cyclo-hexyl-substituted 1r failed to yield the
desired annulation products even through it was
reacted for 24h, presumably due to the steric and
electronic effects (Table 2, entries 22-23). A gram-
scale synthesis of 3p was also illustrated in 87% yield
with 3.0 mmol of 1k used (Table 2, entry 24). It is
noteworthy that all indenopyrazoline derivatives 3
were obtained as virtually single diastereomers (dr
>20:1) with cis-configuration (Figure 1).
group of 2-benzylideneindane-1-one 5, following a
process resembling the aza-Wittig/Staudinger
reaction undergoing a ring closure to produce the
fused indenopyrazoline 6.[13]
The mechanism of this cascade aza-Michael/Aldol
reaction is proposed on the basis of previous
literatures[12],[13],[18] as shown in Scheme 3.
Presumably, the Huisgen zwitterions A formed from
triphenylphosphine and DEAD conjugates to 2-
arylideneindane-1,3-dione 1 to furnish a tetrahedral
intermediate B. The Huisgen zwitterions A had been
investigated thoroughly for its reactivity with various
aldehydes and ketones, including chalcones.[19] On
the basis of its reported chemoselectivity, we could
find out the intermediate B, which is formed by the
addition of A to 1 through a conjugate 1,4-addition
rather than a 1,2-addition. The zwitterion B
undergoes an intramolecular Aldol addition on the
ester group of the azoester to deliver the intermediate
C. Intermediate C can exist in a zwitterionic form D,
which undergoes intramolecular N-addition of the N-
phosphonium to one of the carbonyls of indandione
to give an intermediate E. Subsequently E eliminates
triphenylphosphine oxide via betaine F to produce 3.
The diastereoselectivity observed in generating the
indenopyrazoline 3 implies that conformational
factors may play a role in the cycloaddition process.
In fact, the stereoselectivity can be attributed to the
steric hindrance effects and electronic repulsions
between carboethyloxy group and triphenyl-
phosphonium in intermediate D. The 1,2-addition of
the N-phosphonium preferentially anti attack for
steric reasons, and thus lead to the observed
stereoselectivity in the formation of indenopyrazoline
3.
EtO C
2
O
CO Et
2
N
N
COOEt
PPh
3
+
N
N
o
toluene, Ar, 110 C
EtOOC
5
2a
6
Scheme 2. Control experiment for the synthesis of fused
indenopyrazoline 6.
In order to gain insight into the mechanism, we
carried out one control experiment (Scheme 2).
Under the identified conditions, treatment of the 2-
benzylideneindane-1-one 5 with DEAD 2a (1.5
equiv.) and triphenyl phosphine (1.5 equiv.) furnished
3-phenyl-3,4-dihydro-indenopyrazole-1,2-diethyl
dicarboxylate 6 in 54% yield. This result suggested
that the Huisgen Zwitterions attacked to the carbonyl
O
O O
O
EtO
O
OEt
PPh3
N
N
CO2Et
N N
N PPh3
+
CO2Et
N
R1
CO2Et
EtO2C
PPh3
R1
R1
O
O
Huisgen zwitterion
O
1
A
B
C
O
O
O
CO2Et
R1
CO2Et
O
R1
CO2Et
R1
CO2Et
R1
N CO2Et
PPh3
N
O
N
O
N
N
CO2Et
O
Ph3P=O
CO2Et
N
N
CO2Et
N
PPh3
Ph3P
anti-attack
3
F
E
D
Scheme 3. Proposed reaction mechanism.
To further investigate the mechanism, the formation
of 3p was monitored by 31P NMR spectroscopy as
shown in Figure 2 (the reaction was proceeded at 110
C and monitored by application of room temperature
31P NMR spectroscopy). The triphenylphosphine in
toluene-d8 showed signal in the 31P NMR spectrum at
4
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10.1002/adsc.201701013
Advanced Synthesis & Catalysis
Acknowledgements
 = -5.53 ppm. After 2-phenylideneindane-1,3-dione
1p and diethyl azodicarboxylate 2a were added to the
solution of Ph3P, the peak shifted from  = -5.53 to
44.21 ppm as Huisgen zwitterions A is formed. In the
meantime, there are three intermediates that appeared
during the synthesis of 3p. The signals at p = 53.60,
56.08 and 56.67 ppm may belong to intermediate B,
C and E, respectively. As time progressed, the 31P
NMR signals of Ph3P disappeared gradually and the
signals of Ph3PO (signal peak at  = 29.10 ppm)
increased. The reaction was almost complete after 3
hours according to the 31P NMR spectra (Figure 2).
The 31P chemical shift of intermediate B was assigned
by comparing the similar chemical structure of
phosphonium salts in literatures,[20] and the resulting
N-phosphonium ion C and E were tentatively
assigned by analogy.
We thank the National Natural Science Foundation of China
(21072102), the Committee of Science and Technology of Tianjin
(15JCYBJC20700) and State Key Laboratory of Elemento-
Organic Chemistry in Nankai University for financial support.
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Figure 2. Time-elapsed 31P NMR spectra for the synthesis
of 3p.
In conclusion, we have developed a novel aza-
Michael/Aldol
annulation
reaction
of
2-
arylideneindane-1,3-diones with in situ generated
Huisgen zwitterions, leading to efficient synthesis of
indenopyrazoline derivatives in moderate to good
yields with excellent chemo- and diastereoselectivity.
This reaction represents a rare annulation reaction
and accordingly reveals the new protocol to construct
highly functionalized indenopyrazolines with two
contiguous stereocenters, including a quaternary
stereogenic center. Further studies on the reactions of
Huigen zwitterions to complex molecular synthesis
are currently underway in our laboratory and will be
reported in due course.
Experimental Section
General procedure for the synthesis of 3-aryl-4-
oxoindeno[1,2-c] pyrazole dicarboxylate 3.
Under a Ar atmosphere, to a solution of 2-arylideneindane-
1,3-dione 1 (0.3 mmol) and dialkyl azodicarboxylate 2
(0.45 mmol) in toluene (2.0 mL) was added PPh3 (118 mg,
0.45 mmol). The resulting mixture was stirred at 110 C
for a specified time (Tables 2). The reaction was monitored
by TLC spectroscopy. After the reaction was completed,
the solvent was then removed on a rotary evaporator at
reduced pressure and the residue was subjected to column
chromatographic isolation on silica gel (eluted with
petroleum ether/EtOAc 4:1-2:1) to give the annulation
product 3.
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5
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10.1002/adsc.201701013
Advanced Synthesis & Catalysis
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fax:
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6
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10.1002/adsc.201701013
Advanced Synthesis & Catalysis
COMMUNICATION
Chemo- and Diastereoselective Construction of
Indenopyrazolines via a Cascade aza-
O
Michael/Aldol Annulation of Huisgen Zwitterions
O
2
with 2-Arylideneindane-1,3-diones
CO R
2
1
2
2
Ph P
1
R
COOR
Ph P
3
COOR
R
3
N
N
N
N
O
2
2
R OOC
R OOC
toluene, reflux, Ar
N
N
2
CO R
2
Huisgen zwitterion
Adv. Synth. Catal. Year, Volume, Page – Page
1
R
R
= aryl, 2-naphthyl, 24 examples
up to 87% yield
up to 20:1 dr
4-pyridyl
2
= Et, iPr, Bn
Yuming Li, Haikun Zhang, Rong Wei, Zhiwei
Miao*
7
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