Organocatalytic enantioselective 1,3-dipolar cycloadditions between seyferth-gilbert reagent and isatylidene malononitriles: Synthesis of chiral spiro-phosphonylpyrazoline-oxindoles

Article abstract of DOI:10.1021/acs.orglett.5b00311

A new method has been developed for the catalytic enantioselective 1,3-dipolar cycloaddition of the Seyferth-Gilbert reagent (SGR) to isatylidene malononitriles using a cinchona alkaloid derivative as a catalyst. This method allowed for the synthesis of a series of chiral spiro-phosphonylpyrazoline-oxindoles in good yields with excellent enantioselectivities. The synthetic utility of this method was further demonstrated by its use in a three-component domino reaction involving isatin, malononitrile, and SGR based on sequential Knoevenagel condensation and 1,3-dipolar cycloaddition reactions.

Full text of DOI:10.1021/acs.orglett.5b00311

Letter
pubs.acs.org/OrgLett
Organocatalytic Enantioselective 1,3-Dipolar Cycloadditions
between Seyferth−Gilbert Reagent and Isatylidene Malononitriles:
Synthesis of Chiral Spiro-phosphonylpyrazoline-oxindoles
Taiping Du, Fei Du, Yanqiang Ning, and Yungui Peng*
Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest
University, Chongqing 400715, China
S
* Supporting Information
ABSTRACT: A new method has been developed for the catalytic enantioselective 1,3-dipolar cycloaddition of the Seyferth−
Gilbert reagent (SGR) to isatylidene malononitriles using a cinchona alkaloid derivative as a catalyst. This method allowed for the
synthesis of a series of chiral spiro-phosphonylpyrazoline-oxindoles in good yields with excellent enantioselectivities. The
synthetic utility of this method was further demonstrated by its use in a three-component domino reaction involving isatin,
malononitrile, and SGR based on sequential Knoevenagel condensation and 1,3-dipolar cycloaddition reactions.
In fact, racemic phosphonylpyrazolines have been docu-
mented as intermediates during the 1,3-dipolar cycloaddition
reactions of olefinic dipolarophiles with the Bestmann−Ohira
reagent (BOR), which was smoothly converted to an anion of
the SGR in situ under basic reaction conditions. The
aromatization of the resulting phosphonylpyrazolines via
deprotonation resulted in the corresponding phosphonyl
pyrazoles (Scheme 1).7 Two studies were recently reported
in the literature concerning the synthesis of racemic
phosphonylpyrazolines via 1,3-dipolar cycloaddition reactions
involving BOR or an SGR analogue by choosing an appropriate
dipolarophile or exercising effective control over the reaction
conditions.5e,7e
The catalytic asymmetric [3 + 2] reactions of isatylidene
malononitriles allow for the facile construction of spirocyclic
oxindoles with two contiguous quaternary centers.8 Spirocyclic
oxindoles are privileged synthetic motifs that constitute a large
family of natural products and exhibit a broad range of
biological activities.9 For this reason, the combination of chiral
spirocyclic oxindoles with pyrazolines bearing a phosphonate
moiety represents an exciting prospect.
hiral organophosphonates have attracted significant
Cinterest from researchers working in various fields because
of their diverse range of biological activities and applications,1
which led to a major impetus toward their synthesis.2
Pyrazolines are heterocyclic compounds that have been
reported to exhibit a variety of intriguing biological properties.3
Furthermore, the bioactivities of pyrazolines can be enhanced
by incorporation with phosphonates.4 For this reason, the
development of new methods for the synthesis of chiral
phosphonylpyrazolines are highly desired. However, there have
been very few reports pertaining to the synthesis of racemic
phosphonylpyrazolines,5 let alone investigations directed
toward the development of catalytic enantioselective reactions
for the synthesis of chiral variants of these products.
The chiral Lewis acid mediated asymmetric 1,3-dipolar
cycloaddition reactions of olefinic dipolarophiles and diazo
compounds (e.g., diazoacetates) have been well documented in
the literature and represent a straightforward and efficient
approach to the synthesis of chiral pyrazolines.6 In contrast,
catalytic asymmetric 1,3-dipolar cycloaddition reactions involv-
ing the Seyferth−Gilbert reagent (SGR), which could be used
as an isosteric analogue of diazoacetate for the synthesis of
chiral phosphonylpyrazolines, have not yet been reported. The
lack of reports in this area could be attributed to the unique
steric and electronic properties of the SGR. The development
of a catalytic system capable of efficiently catalyzing the
enantioselective 1,3-dipolar cycloaddition reactions of the SGR
to provide access to various chiral phosphonylpyrazolines
therefore remains a challenging and interesting area of synthetic
chemistry.
Herein, we report for the first time the catalytic asymmetric
1,3-dipolar cycloaddition reaction of the SGR with a series of
isatylidene malononitriles using cinchona alkaloid derivative as
a catalyst. This reaction provided rapid access to the
corresponding series of chiral spiro-phosphonylpyrazoline-
oxindoles bearing two adjacent quaternary carbons in high
yields and excellent enantioselectivities.
Received: January 30, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b00311
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Organic Letters
Letter
Scheme 1. 1,3-Dipolar Cycloaddition Reactions of SGR and
Olefinic Dipolarophiles
Table 1. Selected Screening Results for the 1,3-Dipolar
Cycloaddition Reaction between the SGR and Isatylidene
Malononitrile
b
c
temp
(°C)
time
(h)
yield
(%)
ee
a
entry
cat.
solvent
(%)
1
C1 DCM
C1 DCM
C1 DCM
C1 Et2O
C1 THF
25
−40
−40
−40
−40
−40
−40
−40
−40
−40
−40
−40
−40
−40
−40
−40
−40
22
36
96
36
36
36
36
36
96
96
96
96
96
96
96
96
72
11
49
6
75
96
96
48
20
32
48
55
55
56
66
52
79
80
58
58
93
2
3
4
55
98
72
38
55
95
72
72
84
90
92
89
61
92
5
6
C1 2-Me-THF
C1 tBuOMe
C1 CPME
C1 CPME
C2 CPME
C3 CPME
C4 CPME
C5 CPME
C6 CPME
C7 CPME
C8 CPME
7
8
9
A preliminary survey revealed that quinine could promote
the asymmetric cycloaddition reaction of the SGR with
isatylidene malononitrile 1a to give the desired spiro-
phosphonylpyrazoline-oxindole 3a in poor yield (11%) with
good enantioselectivity (75% ee) (Table 1, entry 1).10
Lowering the reaction temperature from +25 to −40 °C led
to a significant increase in both the yield and enantioselectivity
of the reaction up to 49% and 96% ee, respectively, following an
extended reaction time of 36 h (Table 1, entries 1 and 2).
However, further increasing the reaction time to 96 h led to a
decrease in the yield to 6%, albeit with the same
enantioselectivity (Table 1, entry 3). This reduction in the
yield was attributed to the decomposition of the product in the
DCM solvent during the reaction to other unidentified
materials, which were subsequently detected by TLC. Several
other solvents, including Et2O, THF, 2-Me-THF, tBuOMe, and
CPME, were screened in an attempt to increase the stability
and the yield of the product (Table 1, entries 4−8). An
excellent yield was achieved when the reaction was conducted
in THF, although the enantioselectivity was very low at only
20% ee (Table 1, entry 5). The reaction proceeded with both
moderate yield (55%) and enantioselectivity (55% ee) when it
was conducted in CPME (Table 1, entry 8), and this yield
could be further improved to 95% when the reaction time was
extended to 96 h (Table 1, entry 9). This result indicated that
the product was stable in CPME.
Significant variations have been seen in the stereochemical
performances of cinchona alkaloid catalysts toward 1,3-dipolar
cycloaddition reactions in different solvents. These differences
in the performance of the catalysts could be attributed to the
impact of the different solvents on the preferred conformation
of the cinchona alkaloids through the rotation of their C4′−C9
and C8−C9 bonds.11 Thus, the preferred conformation in
solution could play a critical role in determining the nature of
the chiral control exerted by the catalyst during the reaction.
When DCM was used as the solvent, quinine would have
adopted its preferred conformation, which would have led to
the observed excellent enantioselectivity for the 1,3-dipolar
cycloaddition reaction. It was envisaged that a similar
conformation could be achieved in CPME by modifying the
10
11
12
13
14
15
16
17
C6 CPME/DCM
= 1/3
18
C6 CPME/DCM
−60
9 d
84
98
= 1/3
a
All reactions were performed on a 0.1 mmol scale using 1a (0.1
mmol), 2 (0.12 mmol) and catalyst (0.01 mmol) in anhydrous solvent
(0.05 M). Isolated yield. Determined by HPLC analysis. CPME =
b
c
cyclopentyl methyl ether.
structure of the cinchona alkaloid.11b,12 In view of the
accessibility of cinchona alkaloid derivatives, we decided to
modify quinine by changing the substituent at C6. Indeed, a
survey of several modified catalysts revealed that the
enantioselectivity of the reaction could be improved by
increasing the steric bulk of the substituents. When catalysts
C5 and C6 bearing bulky neopentoxy and 2,2,3-trimethylbu-
toxy substituents were used in the reaction, the enantiose-
lectivity improved to 79% ee and 80% ee, respectively. To
achieve both good yield and enantioselectivity, we investigated
the effect of using a mixed solvent system. Pleasingly, the use of
a 3:1 (v/v) mixture of DCM and CPME led to a significant
increase in the enantioselectivity of the reaction to 93% ee,
which was further improved to 98% ee when the temperature of
the reaction was reduced to −60 °C (Table 1, entry 18).
With the optimized reaction conditions in hand, we
proceeded to investigate the substrate scope of the reaction,
and the corresponding chiral spiro-phosphonylpyrazoline-
oxindoles were obtained in high yields and excellent
enantioselectivities. As shown in Scheme 2, the electronic
properties of the substituents on the aryl ring of isatylidene
malononitriles had no discernible impact on the enantiose-
lectivity of the reaction, although substrates bearing an
electron-donating group generally afforded lower yields of the
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DOI: 10.1021/acs.orglett.5b00311
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Scheme 2. Substrate Scope for the 1,3-Dipolar Cycloaddition
Reactions between SGR and Isatylidene Malononitriles
Scheme 3. One-Pot Construction of Chiral Spiro-pyrazoline-
oxindoles
a
a
Scheme 4. Single-Crystal X-ray Structure of 6
a
See the Supporting Information for experimental details.
Based on previous results, we have proposed a plausible
mechanism for the current reaction (Scheme 5). The cinchona
Scheme 5. Proposed Mechanism
a
All reactions were performed on a 0.1 mmol scale using 1 (0.1
mmol), 2 (0.12 mmol), and C6 (0.01 mmol) in anhydrous solvent
(0.05 M) for 96 h or 9 d at −60 °C. Isolated yield by flash
chromatography. Enantioselectivities were determined by HPLC
analysis.
corresponding products (Scheme 2, 3c and 3g). The position
of the substituent was found to have a slight impact on the
enantioselectivity of the reaction. For example, isatylidene
malononitriles with C7 substituents gave slightly lower
enantioselectivities (Scheme 2, 3h, 3k, 3l, and 3m).
alkaloid derivative could act as a bifunctional catalyst in that the
hydroxyl group could act as a Brønsted acid to activate the
isatylidene malononitrile via hydrogen bonding and the amine
moiety could act as a base to activate the SGR to attack the C3
position of the isatylidene malononitrile from its Si face.
Different from the Lewis acid mediated direct 1,3-dipolar
cycloaddition reactions, this [3 + 2] cycloaddition reaction was
assumed to proceed via a Michael-type 1,4-addition and
cyclization sequence. The resulting intermediate would then
undergo an intramolecular hydrogen transfer to form the final
chiral spiro-pyrazoline-oxindole.
In conclusion, we have reported for the first time the catalytic
asymmetric 1,3-dipolar cycloaddition of the SGR with a series
of isatylidene malononitriles using a cinchona alkaloid
derivative as a catalyst. These reactions proceeded smoothly
to give the corresponding chiral spiro-phosphonylpyrazoline-
oxindoles in good yields with excellent enantioselectivies. The
first catalytic asymmetric three-component reaction between
isatin, malononitrile and the SGR has also been developed.
Investigations toward evaluating the bioactivity of the chiral
spiro-phosphonylpyrazoline-oxindoles generated in this study,
as well as research toward identifying further applications for
the SGR in asymmetric reactions, are currently underway in our
laboratory.
Encouraged by the straightforward nature of these 1,3-
dipolar cycloaddition reactions for the efficient synthesis of
chiral spiro-phosphonylpyrazoline-oxindoles, we further eval-
uated the synthetic potential of this reaction by investigating
the construction of several valuable compounds according to a
convergent three-component reaction strategy. Based on a
domino Knoevenagel condensation/1,3-dipolar cycloaddition
sequence, we conducted a three-component reaction between
readily available isatin, malononitrile, and the SGR which was
efficiently catalyzed by the cinchona alkaloid derivative C6 (see
the Supporting Information for the experimental details).
Compared with the straightforward two-component reactions
(3a, 92% yield, 93% ee; 3e, 95% yield, 98% ee), the
enantioselectivities of this reaction are maintained, albeit with
a slight decrease in the yields of the reaction (Scheme 3).
The absolute configurations of the cycloaddition products of
this reaction were determined on the basis of the analysis of the
X-ray crystal structure of 6, which was prepared by diacetylating
of 3e (Scheme 4).13
C
DOI: 10.1021/acs.orglett.5b00311
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
Tamborini, L.; Madsen, U.; Nielsen, B.; Braeuner-Osborne, H.;
̈
Experimental procedures and detailed characterization data of
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: pengyungui@hotmail.com, pyg@swu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Science
Foundation of China (21472151).
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