An organocatalytic asymmetric double Michael cascade reaction of unsaturated ketones and unsaturated pyrazolones: Highly efficient synthesis of spiropyrazolone derivatives

Article abstract of DOI:10.1039/c2ob27095a

The first organocatalytic double Michael cascade reaction between unsaturated ketones and unsaturated pyrazolones has been developed which provides spiropyrazolone core structures containing two interval or three consecutive stereogenic centers with excellent diastereo- (>20:1) and enantioselectivities (up to 99% ee). Moreover, a pair of enantiomers 5 and 5′ can be achieved via different catalysts.

Full text of DOI:10.1039/c2ob27095a

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An Organocatalytic Asymmetric Double Michael Cascade Reaction of
Unsaturated Ketones and Unsaturated Pyrazolones: Highly Efficient
Synthesis of Spiropyrazolones Derivatives†
Jinyan Liang, a Qiao Chen, a Luping Liu, a Xianxing Jiang, a and Rui Wang*a,b
5
Received (in XXX, XXX) XthXXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Recently, Rios and coꢀworkers disclosed an organocatalytic
The first organocatalytic double Michael cascade reaction
between unsaturated ketones and unsaturated pyrazolones
has been developed which provides spiropyrazolones core
enantioselective pyrazolꢀ3ꢀone addition to maleimides catalyzed
9
by bifunctional thiourea catalysts.
All of the above
methodologies employ pyrazolones as nucleophiles. Considering
50 the similar electronic and structural properties between
pyrazolone and oxindole and the successful application of
unsaturated oxindole, the use of an unsaturated pyrazolone as an
electrophile is also promising. However, so far only a single
asymmetric catalytic entry currently available to spiropyrazolones
55 was described by Rios and coꢀworkers, consisting of a domino
cyclization reaction among aldehyde, unsaturated aldehyde and
unsaturated pyrazolone.10 No results have been reported in the
literature for constructing chiral spiropyrazolones using
unsaturated ketones and unsaturated pyrazolones. As part of our
60 ongoing research program toward the exploitation of
organocatalytic cascade reaction and our interests in seeking
enantioselective approach toward the construction of spirocyclic
motif, 11 we will in this context present the first asymmetric
organocatalytic double Michael cascade cycloaddition reaction of
65 unsaturated ketones and unsaturated pyrazolones, providing
spiropyrazolones derivatives in moderate yields and excellent
diastereoꢀ and enantioselectivities.
10 structures containing two interval or three consecutive
stereogenic centers with excellent diastereo- (>20:1) and
enantioselectivities (up to 99% ee). Moreover, a pair of
enantiomers 5a and 5a’ can be achieved via different catalyst.
The heteroatomꢀcontaining spirocyclic subunits are featured in a
15 number of naturally occurring products as well as biologically,
pharmaceutically, and medically active molecules. As
a
consequence, finding simple and effective synthetic methods to
realize functional diversity, architectural complexity, and
stereochemical unicity of the core draws increasing attention of
20 organic chemists and a number of excellent achievements have
been reported during the past decades especially based on the
flourishing development of asymmetric organocatalysis.1 To date,
many efforts are concentrated on the synthesis of chiral
spirooxindoles2 while other spiroheterocyclic motifs are rarely
25 involved.3
Pyrazolꢀ3ꢀone derivatives, because of their approved
antiinflammatory, antiviral, antitumor, and antibacterial
properties, exist widely in clinical and listed drugs.4 For example,
the very common structure of compound 4, which is known as
30 edavarone, is used in the treatment of blood brain barrier injury.
Although various synthetic protocols have been achieved on the
construction of 4ꢀsubstitute pyrazolones, there are few reports
concerning on the synthesis of chiral pyrazolones with quaternary
stereogenic center at the Cꢀ4 position and intriguing
35 spiropyrazolones combining of multistereogenic cyclohexanone
and pyrozolone motifs. In 2010, Yuan and coꢀworkers reported
an enantioselective pyrazolone Michael addition to nitrostyrenes
by organocatalysis.5 In 2011, Feng’s group disclosed a highly
enantioselective reaction of pyrazolones and azodicarboxylates
40 by metal catalysis.6 Shortly after, Rios reported the first example
of MichaelꢀMichaelꢀaldol condensation of pyrazolone 4 and
unsaturated aldehydes for the preparation of chiral spiropyrazoloꢀ
nes.7 In 2012, Wang’s group reported a double Michael reaction
between pyrazolones and divinyl ketones that gave
45 spiropyrazolones with excellent yields and enantioselectivities.8
Scheme 1. General strategy for the construction of chiral
70
spiropyrazolones
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As early as in 2002, Barbas’s group firstly introduced
dienamine activation mode of unsaturated ketones with reactive
hydrogen at Cꢀterminal.12 They used secondary amines derived
from proline to catalyze the DA reaction of unsaturated ketones
and nitro olefins with excellent yields and no asymmetric
catalysis was referred to. Chen and Melchiorre’s group
independently13developed this concept and proved that quinine or
quinidine alkaloidꢀderived primary amine can act as powerful
catalyst to activate these ketones to complete chiral induction.
Using catalyst 1b, we were delighted to obtain spirocyclic
40 product 5a’ with comparable ee value, yield and reversed
configuration (entry 3). Although an acceptable ee value (93%)
was obtained with catalyst 1c, the reaction needed longer time
and afforded the product in lower yield (entry 4). Considering the
enantioselectivity as well as yield, catalyst 1a and 1b both
45 delivered ideal results and a pair of enantiomers 5a and 5a’ can
be achieved via different catalysis. However, in these two cases
the reaction was found to be somewhat sluggish, which
demanded 72h to completion. Therefore, taking primary amine 1a
as catalyst, the reaction conditions were further optimized.
50 Toluene was selected as the optimal solvent in terms of both yield
and enantioselectivity (entries 2 and 6ꢀ9). The temperature had a
pronounced effect on the reaction rate and would shorten the
reaction time from 72h to 3.5h without sacrificing of either yield
or enantioselectivity (entries 2 and 10) through the elevation of
55 temperature from rt to 40 °C.
5
10 Inspired by these experimental results, we envisaged the
following reaction mechanism Unsaturated ketone 3 should first
:
intercept the primary amine catalyst via HOMOꢀactivation
concept to generate the activated dienamine ion intermediate i.
The resulting prochiral carbon nucleophile i should be reactive
15 enough to initiate an intermolecular Michael addition to unsaturaꢀ
ted pyrazolones 2, and the LUMOꢀactive intermediate ii adduct
would further undergo an intramolecular conjugate addition, thus
affording the desired spiropyrazolone 5 in a oneꢀpot fashion
(Scheme 1).
Table 2. Substrate Scope of Cat 1a/ BzOHꢀCatalyzed Double Michael
Addition of Unsaturated Pyrazolones 2a-j and Unsaturated Ketones 3a-j
with Same Substituents[a]
20 Table 1. Screening of the Catalysts, Solvents, and Reaction Conditions
for the Reactions[a]
Ph
N
Ph
N
O
N
N
1a (20 mol%)
O
R
O
R
BzOH (40 mol%)
+
Tol, 40 0C
R
R
3
O
2
5
entry
5
R
yield[%]b
dr [%]c
ee d
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ph
87
75
81
88
84
68
83
71
64
55
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>99
>99
>99
>99
>99
>99
>99
>99
>99
nde
4ꢀCH3C6H4
4ꢀFC6H4
4ꢀClC6H4
4ꢀBrC6H4
4ꢀMeOC6H4
3ꢀClC6H4
3ꢀMeOC6H4
2ꢀnaphthyl
2ꢀfuryl
entry
Cat
solvent
Time[h]
yield[%]b
ee c
1
2d
1a
1a
1b
1c
1a
1a
1a
1a
1a
1b
Toluene
Toluene
Toluene
Toluene
MTBE
THF
CH2Cl2
MeCN
Toluene
Toluene
120
72
72
120
72
72
72
72
3.5
3.5
ꢀ
ꢀ
87
81
76
59
55
79
46
85
80
>99
>99
93
96
86
93
84
>99
>99
3d,f
4d
10
5j
60 [a] Unless noted, the reaction was performed on 0.1 mmol scale with 2a
(1.0 equiv), 3a (2.0 equiv), BzOH (40 mol%) and catalyst 1a (20 mol%)
at 40 °C for 3ꢀ12 h. The control comparative experiments details, see the
Supporting Information. [b] Yield of isolated product. [c] Measured by 1H
NMR spectroscopic analysis. [d] Determined by HPLC analysis on a
65 chiral stationary phase. [e] The ee value can not be determined by HPLC
analysis.
6d
7d
8d
9d
10d,e
11d,e,f
[a] Unless noted, the reaction was performed on 0.1 mmol scale with 2a
(1.0 equiv), 3a (2.0 equiv) and catalyst 1a (20 mol%) at rt ( 17 °C) for
25 displayed time. [b] Yield of isolated product. [c] Determined by HPLC
analysis on a chiral stationary phase. [d] BzOH (40 mol%) was used as
cocatalyst. [e] The reaction was performed at 40 °C. [f] The enantiomers
5’ of compound 5 was obtained using the same steps while catalyst 1b
was employed during the reaction process.
Having established the optimal reaction conditions (Table 1,
entry 10), we next examined the scope and limitations of the
above system with variants of reactants 2 and 3. Considering the
70 product 5 with two interval (same substituent on reactants 2 and 3)
or three consecutive stereocenters (different substituent on
reactants 2 and 3), we will describe them separately. We first
tested reactions of compound 2 and 3 with same substituent and
the results were summarized in Table 2. Unsaturated pyrazolones
30
To identify the validation of our strategy, we began the
investigation by testing the model reaction between 2a and 3a
catalyzed by primary amine 1a in toluene at rt. However, no 75 2 and unsaturated ketones 3 with same substituents in metaꢀ and
paraꢀ positions could be tolerated and underwent smooth
cyclization reactions, providing spiropyrazolones 5b-5h in good
yields and with excellent diastereoꢀ and enantioselectivities
(entries 2ꢀ8). The electronic properties of the substituents seemed
80 to have no influence on the enantioselectivity, although the
reaction yields were a little lower for reactants possessing
product was observed after 120h (Table 1, entry 1). Under the
same condition, the using of protic acid BzOH as cocatalyst to the
35 reactive system triggered the reaction and provided the desired
product 5a in 87% yield and >99% ee value after 72h (entry 2).
Encouraged by this outcome, we further explored 1b and 1c as
catalysts for this reaction, and the results were shown in Table 1.
2
|Journal Name, [year], [vol], 00–00
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electronꢀrich substituents (entries 6 and 8). Conjugated aromatic
(entry 9) and heteroaromatic (entry 10) substrates could also be
applied to the present process, despite the ee value of product 5j
could not be detected using HPLC.
enantioꢀ and diastereoselectivity and inversed configuration, so
we also tested the generality of the catalytic system and the
results were depicted in Table 4. The desired spirocyclic products
5g’ꢀ5h’, 5l’, 5r’ꢀ5x’ were obtained in 42ꢀ64% yields with 1:1ꢀ
5
Next, we were concentrated on constructing spiropyralones 5
with three consecutive stereocenters. Under optimized conditions,
we choosed reactants 2 and 3 with different substituent optionally
to manipulate the reaction, the results were somehow complicated
mainly displaying of poor dr value (1:1) and difficult separation
45 >20:1 dr’s and 98ꢀ >99% ee’s (Table 4, entries 1ꢀ10)
.
Table 4. Substrate Scope of Cat 1b/ BzOHꢀCatalyzed Double Michael
Addition of Unsaturated Pyrazolones 2 and Unsaturated Ketones 3[a]
10 on HPLC (Table 3, entry 14). When an orthoꢀsubstituented
unsaturated pyrazolone or unsaturated ketone was used, the
diastereoselectivity was improved greatly and the results were
described in Table 3. When 2ꢀClꢀbenzalacetone was utilized,
electronꢀneutral (entry 2), electronꢀwithdrawing (entries 3ꢀ4),
15 electronꢀdonating (entries 5ꢀ6), and doubleꢀsubstituted (entry 7)
unsaturated pyrazolones 2 on the aryl ring were well tolerated and
provided reaction products in moderate yields and excellent
enantioꢀ and diastereoselectivities; moreover, fused aromatic
unsaturated pyrazolone was also suitable substrate for this
20 reaction (entry 8). When 2ꢀClꢀsubstituted unsaturated pyrazolone
was employed, a wide range of unsaturated ketones were also
tested. In most cases, the reactions were completed with excellent
ee’s (>99%) and dr’s (>20:1) (entries 9ꢀ12) except in the occasion
of alkylꢀsubstituted unsaturated ketone with a 2:1 dr value (entry
25 13). The absolute configuration of the products was determined
by Xꢀray crystallography analysis of compound 5s (see
Supporting Information).14
en
try
1
2
3
4
5
6
7
R1
R2
5’
yield
[%]b
57
63
61
50
55
64
48
ee
dr d
[%]c
>99
>99
>99
>99
>99
>99
>99
>99
98
3ꢀClPh
3ꢀMeOPh
4ꢀCH3Ph
2ꢀnaphthyl
2ꢀClPh
2ꢀClPh
2ꢀClPh
2ꢀClPh
2ꢀClPh
Ph
3ꢀClPh
3ꢀMeOPh
2ꢀClPh4
2ꢀClPh
4ꢀBrPh
4ꢀMeOPh
Ph
2ꢀfuryl
iꢀBu
4ꢀCH3Ph
5g’
5h’
5l’
5r’
5s’
5t’
5u’
5v’
5w’
5x’
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
2:1
8
9
10
52
54
42
>99
1:1
[a] Unless noted, the reaction was performed on 0.1 mmol scale with 2a
50 (1.0 equiv), 3a (2.0 equiv), BzOH (40 mol%) and catalyst 1a (20 mol%)
at 40 °C for 3ꢀ12 h. The control comparative experiments details, see the
Supporting Information. [b] Yield of isolated product. [c] Determined by
HPLC analysis on a chiral stationary phase. [d] Measured by H NMR
spectroscopic analysis.
1
Table 3. Substrate Scope of Cat 1a/ BzOHꢀCatalyzed Double Michael
Addition of Unsaturated Pyrazolones 2 and Unsaturated Ketones 3 with
30 Different Substituents[a]
55 Conclusions
In summary, we have developed the first organocatalytic double
Michael cascade reaction of unsaturated ketones and unsaturated
pyrazolones that provides spiropyrazolones core structures with
two interval or three consecutive stereogenic centers, including a
60 spiro quaternary center with excellent diastereoꢀ (>20:1) and
en
try
1
2
3
4
5
6
7
R1
R2
5
yield
[%]b
67
63
65
64
48
52
54
52
69
52
68
50
67
82
ee
dr d
[%]c
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
98
enantioselectivities (up to 99% ee). Moreover,
a pair of
enantiomers 5a and 5a’ can be achieved via different catalysit.
This simple and effective reaction provides rapid entry to
stereochemically complex spiropyrazolones derivatives.
Ph
4ꢀCH3Ph
4ꢀClPh
2ꢀClPh
2ꢀClPh
2ꢀClPh
2ꢀClPh
2ꢀClPh
2ꢀClPh
2ꢀClPh
2ꢀClPh
4ꢀBrPh
4ꢀMeOPh
Ph
5k
5l
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
2:1
5m
5n
5o
5p
5q
5r
5s
3ꢀClPh
4ꢀMeOPh
3ꢀMeOPh
3,4ꢀ(CH3)2Ph
2ꢀnaphthyl
2ꢀClPh
2ꢀClPh
2ꢀClPh
2ꢀClPh
2ꢀClPh
65 Acknowledgment
We are grateful for the grants from the National Natural Science
Foundation of China (nos. 91213302, 20932003 and 21272102),
the Key National S&T Program “Major New Drug Development”
of the Ministry of Science and Technology of China
70 (2012ZX09504ꢀ001ꢀ003).
8
9
10
11
12
13
14
5t
5u
5v
5w
5x
2ꢀfuryl
iꢀBu
4ꢀCH3Ph
Ph
>99
1:1
Notes and references
[a] Unless noted, the reaction was performed on 0.1 mmol scale with 2a
(1.0 equiv), 3a (2.0 equiv), BzOH (40 mol%) and catalyst 1a (20 mol%)
at 40 °C for 3ꢀ12 h. The control comparative experiments details, see the
35 Supporting Information. [b] Yield of isolated product. [c] Determined by
HPLC analysis on a chiral stationary phase. [d] Measured by H NMR
spectroscopic analysis. [d] Determined by HPLC analysis on a chiral
a
Key Laboratory of Preclinical Study for New Drugs of Gansu Province,
School of Life Sciences, School of Basic Medical Sciences, School of
Pharmacy, State Key Laboratory of Applied Organic Chemistry and
75 Institute of Biochemistry and Molecular Biology, Lanzhou University,
Lanzhou, 730000, China
1
stationary phase.
Fax: (+86)-931-891-1255; e-mail: wangrui@lzu.edu.cn
b
In the initial screening of catalysts, we found that catalyst 1b
40 also resulted in spiropyrazolones 5’ with comparable yield,
State Key Laboratory of Chiroscience and Department of Applied
Biology & Chemical Technology, The Hong Kong Polytechnic University,
80 Kowloon, Hong Kong
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E-mail: bcrwang@polyu.edu.hk
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4
|Journal Name, [year], [vol], 00–00
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Page 5 of 6
Organic & Biomolecular Chemistry
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Table 1．
entry
Cat
1a
1a
1b
1c
solvent
Toluene
Toluene
Toluene
Toluene
MTBE
THF
Time[h]
120
72
yield[%]b
ee c
-
1
-
2d
87
81
76
59
55
79
46
85
80
>99
>99
93
3d,f
4d
72
120
72
6d
96
1a
1a
1a
1a
1a
1b
7d
72
86
8d
CH2Cl2
MeCN
72
93
9d
72
84
10d,e
11d,e,f
Toluene
Toluene
3.5
3.5
>99
>99
Table 2.
entry
5
R
yield[%]b
87
dr [%]c
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
ee d
>99
>99
>99
>99
>99
>99
>99
>99
>99
nde
1
2
Ph
5a
4-CH3C6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
3-ClC6H4
3-MeOC6H4
2-naphthyl
2-furyl
75
5b
5c
5d
5e
5f
3
81
4
88
5
84
6
68
7
83
5g
5h
5i
8
71
9
64
10
55
5j
Table 3.
entry
R1
R2
yield
[%]b
67
ee [%]c
dr d
5
1
2
Ph
4-CH3Ph
4-ClPh
2-ClPh
2-ClPh
2-ClPh
2-ClPh
2-ClPh
2-ClPh
2-ClPh
2-ClPh
4-BrPh
4-MeOPh
Ph
5k
5l
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
98
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
2:1
63
3
65
5m
5n
5o
5p
5q
5r
5s
4
3-ClPh
64
5
4-MeOPh
3-MeOPh
3,4-(CH3)2Ph
2-naphthyl
2-ClPh
48
6
52
7
54
8
52
9
69
10
11
12
13
14
2-ClPh
52
5t
2-ClPh
5u
5v
5w
5x
68
2-ClPh
2-furyl
i-Bu
50
2-ClPh
67
Ph
4-CH3Ph
82
>99
1:1

Organic & Biomolecular Chemistry
Page 6 of 6
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Table 4.
entry
R1
R2
yield
[%]b
57
ee [%]c
dr d
5’
1
2
3-ClPh
3-MeOPh
4-CH3Ph
2-naphthyl
2-ClPh
2-ClPh
2-ClPh
2-ClPh
2-ClPh
Ph
3-ClPh
3-MeOPh
2-ClPh4
2-ClPh
4-BrPh
4-MeOPh
Ph
>99
>99
>99
>99
>99
>99
>99
>99
98
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
2:1
5g’
5h’
5l’
63
3
61
4
50
5r’
5s’
5t’
5
55
6
64
7
48
5u’
5v’
5w’
5x’
8
2-furyl
i-Bu
52
9
54
10
4-CH3Ph
42
>99
1:1