Asymmetric synthesis of spiropyrazolones through phosphine-catalyzed [4+1] annulation

Article abstract of DOI:10.1002/anie.201311214

An enantioselective synthesis of spiropyrazolones from allenoate-derived MBH acetates and pyrazolones through a phosphine-mediated [4+1] annulation process has been developed. Spiropyrazolones were readily prepared in good chemical yields and good to high enantioselectivities. This is the first asymmetric example in which α-substituted allenoates were utilized as a C₄ synthon for phosphine-catalyzed [4+1] annulation. Optically enriched 4-spiro-5-pyrazolones were prepared through phosphine-catalyzed enantioselective [4+1] annulation. In this study, substituted pyrazolones were used as a C₁ synthon in cycloaddition for the first time. Moreover, this is the first report in which α-substituted allenoates were utilized in an asymmetric [4+1] annulation.

Full text of DOI:10.1002/anie.201311214

Angewandte
Chemie
DOI: 10.1002/anie.201311214
Phosphine Catalysis
Asymmetric Synthesis of Spiropyrazolones through Phosphine-
Catalyzed [4+1] Annulation**
Xiaoyu Han, Weijun Yao, Tianli Wang, Yong Ren Tan, Ziyu Yan, Jacek Kwiatkowski, and
Yixin Lu*
Abstract: An enantioselective synthesis of spiropyrazolones
from allenoate-derived MBH acetates and pyrazolones
through a phosphine-mediated [4+1] annulation process has
been developed. Spiropyrazolones were readily prepared in
good chemical yields and good to high enantioselectivities. This
is the first asymmetric example in which a-substituted alle-
noates were utilized as a C4 synthon for phosphine-catalyzed
[4+1] annulation.
Chen,[6] and He.[7] Mechanistically, all the above reactions are
initiated by the addition of a phosphine to an MBH carbonate
to in situ generate a 1,1-dipolar synthon, which reacts with
various conjugated electrophilic reaction partners. Another
type of [4+1] annulation was disclosed by Tong in 2010,[8] in
which 2,3-butadienoate, an a-substituted allenoate, was
utilized as a C4 synthon under phosphine catalysis, affording
cyclopentene products (Scheme 1). Asymmetric versions of
O
ver the past decade, nucleophilic phosphine catalysis has
emerged as a powerful approach to structurally diverse and
synthetically valuable carbocyclic and heterocyclic building
blocks in organic chemistry.[1] Pioneered by Lu and co-
workers,[2] different types of phosphine-catalyzed cycloaddi-
tion reactions have been developed over the years. In
particular, [3+2] annulations of allenoates/alkynes or
Morita–Baylis–Hillman (MBH) acetate/carbonates with
alkenes or imines have been widely explored and established
as an effective method for contructing a wide range of highly
functionalized five-membered ring systems.[3] However, other
types of [m+n] annulations were studied to a much lesser
extent,[4] and the discovery of different cyclization modes with
novel reaction partners is highly desirable.
Scheme 1. Reported [4+1] annulations.
[4+1] annulations are very scarce; to the best of our knowl-
edge, there is only one report in the literature. Shi utilized
dicyano-2-methylenebut-3-enoates as a C4 synthon in the
annulation reaction with MBH carbonates, for the asymmet-
ric synthesis of highly functionalized cyclopentenes.[9] How-
ever, the utilization of a-substituted allenoates in asymmetric
[4+1] annulations is unknown. It thus became our goal to
develop an asymmetric variant of this promising transforma-
tion.
Pyrazolone and their derivatives are important structural
motifs that widely occur in biologically active molecules and
pharmaceutical agents,[10] and they are also synthetically
valuable for the construction of heterocyclic and spirocyclic
structures.[11] Recently, 4-spiro-5-pyrazolones were found to
be inhibitors of type-4 phosphodiesterase,[12] resulting in the
need for efficient synthetic approaches to this challenging
structural motif. We envisioned that 4-spiro-5-pyrazolone
structural motifs may be conveniently assembled through
a phosphine-mediated [4+1] annulation reaction. The high
acidity of two protons at position 4 of 5-pyrazolone suggests
that it may be a suitable C1 synthon in the proposed
annulation. By employing 2,3-butadienoate as a reaction
partner, 4-spiro-5-pyrazolones could be readily constructed
(Scheme 2). In recent years, our group has investigated
enantioselective processes promoted by amino acid based
chiral phosphines, and the reactions we have disclosed
include: (aza)-MBH reactions, allylic alkylation, Michael
addition, g addition, and a number of [3+2] and [4+2]
cycloaddition reactions.[13] Herein, we describe the first
Phosphine-catalyzed [4+1] annulations represent an
alternative approach for the formation of five-membered
ring systems, and the successful development of this type of
annulation is dependent on careful selection and utilization of
C4 and C1 synthons for the projected cyclization. Recently,
MBH carbonates were used as a new C1 synthon in
phosphine-catalyzed [4+1] annulations for the construction
of five-membered heterocyclic ring structures by Zhang,[5]
[*] Dr. X. Han
Zhejiang Provincial Key Laboratory for Chemical & Biochemical
Processing Technology of Farm Products, School of Biological and
Chemical Engineering, Zhejiang University of Science and Tech-
nology
No. 318 Liuhe Road, Hangzhou, 310023 (China)
Dr. X. Han, Dr. W. Yao, Dr. T. Wang, Y. R. Tan,[+] Z. Yan,
J. Kwiatkowski, Prof. Dr. Y. Lu
Department of Chemistry & Medicinal Chemistry Program
Life Sciences Institute, National University of Singapore (NUS)
3 Science Drive 3, Singapore 117543 (Singapore)
E-mail: chmlyx@nus.edu.sg
[+] Exchange student from Imperial College.
[**] We thank the NUS (R-143-000-469-112) and the Ministry of
Education of Singapore (R-143-000-494-112) for generous financial
support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201311214.
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Table 1: Enantioselective [4+1] annulation of pyrazolones 1 to 2-
(acetoxymethyl)buta-2,3-dienoate (2a) catalyzed by amino acid derived
phosphines.[a]
Entry
R/1
Cat.
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph/1a
Ph/1a
Ph/1a
Ph/1a
Ph/1a
Ph/1a
Ph/1a
Ph/1a
Ph/1a
Ph/1a
Ph/1a
tBu/1b
tBu/1b
4a
4b
4c
4d
4e
5
6a
6b
6c
7
2
1
8
3
3
3
3
3
3
2
2
6
6
78
82
36
78
69
72
83
79
71
74
85
80
82
36
30
24
71
55
77
78
68
68
49
54
90
91
Scheme 2. Selected bioactive spiropyrazolones and proposed synthesis
through phosphine-catalyzed [4+1] annulation reaction.
application of a-substituted allenoates in phosphine-cata-
lyzed enantioselective [4+1] annulation for the formation of
optically enriched 4-spiro-5-pyrazolones.
9
10
11
12
13[d]
We first tested the feasibility of our proposed [4+1]
annulation process. Toward this end, 1,3-diphenyl-1H-pyra-
zol-5(4H)-one (1a) and 2-(acetoxymethyl)buta-2,3-dienoate
(2a) were treated with amino acid derived phosphines in the
presence of Cs2CO3 (Table 1). To our delight, the annulation
took place smoothly, and the reaction was completed within
a few hours. In the presence of valine-derived bifunctional
phosphines containing a carbamate or a sulfonamide, the
annulation product was obtained in high yield, but with low
enantioselectivity (Table 1, entries 1 and 2). When phosphine-
thiourea 4c was used, both yield and ee were poor (Table 1,
entry 3). Phosphine amide 4d turned out to be a promising
catalyst, furnishing the desired [4+1] annulation product in
78% yield and with 71% ee (Table 1, entry 4). A more
sterically hindered adamantyl amide did not offer further
improvement (Table 1, entry 5). We next examined phos-
phine amide catalysts derived from different amino acids.
Alanine-based catalyst 5 afforded the spiropyrazolone 3a
with 77% ee (Table 1, entry 6). Examination of l-threonine-
derived O-silylated phosphines showed that 6a was a good
catalyst, furnishing the desired product with a slightly
improved ee value (Table 1, entry 7). However, dipeptide
phosphines turned out to be ineffective (Table 1, entries 10–
11). Having identified 6a as the best catalyst, we next
examined the influence of N substitution of the pyrazolone
on the reaction. Variation of the N substituent on pyrazolone
showed that tert-butyl was the best group (Table 1, entry 12).
Decreasing the concentration of the reaction slightly
enhanced the results, and the desired annulation product
was obtained in 82% yield and with 91% ee (Table 1,
entry 13). The use of different a-substituted allenonate
esters for the annulation, the employment of different base
additives, or the lowering of the reaction temperature did not
result in further improvement (see the Supporting Informa-
tion for details).
8
6a
6a
[a] Reactions were performed with 1a (0.12 mmol), 2a (0.1 mmol),
Cs2CO3 (0.12 mmol), and the catalyst (0.02 mmol) in toluene (1 mL) at
room temperature. [b] Yields of isolated products. [c] Determined by
HPLC analysis on a chiral stationary phase. [d] The reaction was run in
1.5 mL of toluene. Boc=tert-butyloxycarbonyl, TBS=tert-butyldimethyl-
silyl, TMS=trimethylsilyl, TPS=triphenylsilyl, Ts=4-toluenesulfonyl.
were obtained (Table 2, entries 13–16). The absolute config-
urations of the annulation products were assigned based on
a single-crystal X-ray analysis of a derivative of 3k.[14]
Furthermore, we examined the feasibility of utilizing b’-
substituted allenoate in this [4+1] annulation. The annulation
between allenoate 2h and pyrazolone 1b proceeded
smoothly, and the desired product was obtained virtually as
a single diastereomer, and with 81% ee [Eq. (1)]. When tert-
butyl-substituted pyrazolone was used, high enantioselectivity
was attainable [Eq. (2)]. However, only moderate enantiose-
lectivity was obtained when iso-propyl-substituted pyrazo-
With the optimized reaction conditions in hand, we next
established the scope of this annulation process (Table 2).
Both electron-rich and electron-deficient aryl substituents on
the pyrozolones were well-tolerated, and the reaction was
also applicable to aryl rings with different substitution
patterns (Table 2, entries 1–11). Moreover, when pyrozolones
with heteroaromatic rings were utilized, equally good results
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We have done some preliminary investigations on the
proposed mechanistic pathway of the reaction. In light of
excellent reports on the influence of water on cycloaddition
reactions,[15] our reaction was performed in the presence of
various amounts of D2O. As shown in Table 3, deuterium
incorporation at the b position of the adduct was observed.
Table 2: Asymmetric synthesis of spiropyrazolones 3.[a]
Table 3: The effect of H2O on the [4+1] annulation.[a]
Entry
R
3
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
C6H5
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
6
12
8
8
6
82
77
76
80
80
79
81
75
77
88
83
71
84
81
76
57
91
86
91
91
91
90
87
90
90
92
90
86
87
90
88
85
2-Me-C6H4
3-Br-C6H4
3-Cl-C6H4
3-NO2-C6H4
4-F-C6H4
4-Me-C6H4
4-OMe-C6H4
4-CF3-C6H4
4-NO2-C6H4
4-Br-C6H4
2-naphthyl
2-furyl
Entry
D2O (x equiv)
t [h]
D [%]
Yield [%][b]
ee [%][c]
1
2
3
4
–
1
2
3
5
10
6
5
5
5
5
5
5
0
82
75
81
80
76
73
61
91
82
83
82
83
78
65
25
29
32
34
45
89
8
12
12
8
6
8
10
12
12
12
18
5
9
6
10
11
12
13
14
15
16
7[d]
D2O/toluene
[a] Reactions were performed with 1b (0.12 mmol), 2a (0.1 mmol),
Cs2CO3 (0.12 mmol), D2O (x equiv), and 6a (0.02 mmol) in toluene
(1.5 mL) at room temperature. [b] Yields of isolated products.
[c] Determined by HPLC analysis on a chiral stationary phase. [d] V/
V=4:1.
2-thienyl
3-thienyl
3-pyridyl
[a] Reactions were performed with 1 (0.24 mmol), 2a (0.20 mmol),
Cs2CO3 (0.24 mmol), and 6a (0.04 mmol) in toluene (3 mL) at room
temperature. [b] Yields of isolated products. [c] Determined by HPLC
analysis on a chiral stationary phase.
lone was employed, and high enantioselectivity was also not
attainable for other pyrazolones containing less-hindered/
linear alkyl groups.[16]
A possible mechanism depicting the formation of [4+1]
annulation products is shown in Scheme 3.[8,3n] The reaction is
initiated by the nucleophilic attack of the phosphorus atom on
The reactions were slightly faster, and enantioselectivities
were reduced. When annulation product 3b (with H) was
treated with D2O, no deuterium incorporation occurred. We
believed that the hydrogen-bonding interaction contributed
significantly to the asymmetric induction in our catalytic
systems, thus also carried out studies to demonstrate its
importance. Employment of N-methylated catalyst 9 led to
the formation of the cyclization product 3a in 36% yield and
with only 19% ee. Under otherwise identical conditions, the
use of catalyst 6 with its free NH group resulted in 82% yield
and 91% ee. Based on the above experimental results, we
propose that a water molecule participates in the 1,3-proton
transfer.[17] The key hydrogen-bonding interactions between
the NH group of the amide and the pyrazolone enolate is
crucial for the stereochemical outcome of the reaction (see
the transition state depicted in Table 3). When water was
added to the reaction system, the hydrogen-bond network
was disrupted, and erosion of enantioselectivity was observed.
We also applied the [4+1] annulation described here to
synthesize a structural analogue of spiropyrazolone, which
provided an entry to chiral inhibitors of type-4 phosphodies-
terase (Scheme 4).
Scheme 3. Proposed reaction mechanism.
the 2,3-butadienoate 2a to form intermediate A. Subsequent
elimination of an acetate group gives B, which is most likely
attacked at the g-carbon position by the enolate derived from
pyrazolone 1 to give rise to phosphonium ylide C. Proton
transfer takes place to give intermediate D. This is followed
by an intramolecular Michael addition and elimination of the
phosphine catalyst to furnish the final [4+1] annulation
adduct 3.
In conclusion, we have disclosed an efficient phosphine-
catalyzed [4+1] annulation for the synthesis of highly
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Scheme 4. Synthesis of potential inhibitors of type-4 phosphodiester-
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optically enriched 4-spiro-5-pyrazolones, which are a class of
compounds with potentially great biological significance. It is
noteworthy that this is the first time that substituted
pyrazolones were used in cycloaddition, and that this report
also represents the first asymmetric application of a-substi-
tuted allenoates in [4+1] annulation. Various chiral spirocy-
clic structures may be accessible by using the documented
approach, which we are currently investigating.
Received: December 26, 2013
Revised: March 3, 2014
Published online: April 15, 2014
Keywords: [4+1] annulation · allenoates · chiral phosphines ·
.
spiro compounds · spiropyrazolones
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[16] See the Supporting Information.
[17] When the starting pyrazolone was treated with base in the
presence of D2O under the reaction conditions, deuterium was
incorporated at position C4. We cannot exclude the potential
proton transfer from C4 (intermediate C to D). However, the
participation of a water molecule in the 1,3-proton transfer
seems more likely based on theoretical studies in the literature,
as the non-water assisted four-membered proton transfer was
shown to have a high energy barrier, see: V. K. Aggarwal, S. Y.
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[14] CCDC 976440 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
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Angew. Chem. Int. Ed. 2014, 53, 5643 –5647
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