NHC-Catalyzed Asymmetric Formal [4 + 2] Annulation to Construct Spirocyclohexane Pyrazolone Skeletons

Article abstract of DOI:10.1021/acs.orglett.9b02927

A chiral N-heterocyclic carbene (NHC)-catalyzed [4 + 2] annulation of γ-chloroenals and α-arylidene pyrazolinones was developed in the absence of expensive oxidants. The reaction proceeds smoothly via a vinyl enolate intermediate to afford spirocyclohexan

Full text of DOI:10.1021/acs.orglett.9b02927

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
NHC-Catalyzed Asymmetric Formal [4 + 2] Annulation To Construct
Spirocyclohexane Pyrazolone Skeletons
Chengtao Zhao, Kuangxi Shi, Gao He, Qingxiu Gu, Zhenyuan Ru, Limin Yang,* and Guofu Zhong*
College of Materials, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 311121, China
S
* Supporting Information
ABSTRACT: A chiral N-heterocyclic carbene (NHC)-catalyzed [4 + 2] annulation of γ-chloroenals and α-arylidene
pyrazolinones was developed in the absence of expensive oxidants. The reaction proceeds smoothly via a vinyl enolate
intermediate to afford spirocyclohexane pyrazolones in moderate to good yield (up to 86%) with high diastereoselectivities (up
to 15:1 dr) and excellent enantioselectivities (up to >99% ee).
ith special electronic properties,1 N-heterocyclic car-
Scheme 1. Selected Bioactive Molecules Containing
Spiropyrazolone Core Structures
Wbenes (NHCs) were commonly described as unique
ligands in organometallic catalysis.2 Since the discovery of the
isolation and crystallography of stable NHCs by Arduengo
during the early 1990s,3 multiple applications have been found
in catalytic transformations, including not only organometallic
catalysis but also organocatalysis.4 Early documents concerning
NHC organocatalytic transformations were focused on the
entrance to acyl anion intermediates by umpolung of
aldehydes.5 In addition to this, more recent research develop-
ments have been made on the reactivity of enolate equivalents
(activation of α-carbon),6 homoenolate equivalents (activation
of β-carbon),7 and vinyl enolate equivalents (activation of γ-
carbon).8 It is worth mentioning that γ-carbon activation by
using attractively synthetic strategies, it is valuable to explore
NHC organocatalysis has inaugurated new access to target
novel methods to construct this core structure efficiently.
molecules via in-situ-generated vinyl enolate species. The
Our group has revealed the constructions of spirocyclic
construction of heterospirocyclic compounds was realized via
oxindoles via in-situ-generated vinyl enolate species in an NHC-
an NHC organocatalytic strategy.9
The structure of pyrazol-3-one represents a simple and
organocatalyzed hetero-Diels−Alder reaction with isatins.17 We
continue investigating the application of the NHC-organo-
essential building block in a large family of clinical and listed
catalyzed transformation in the synthesis of spirocyclohexane
medicines.10 In particular, chiral spirocyclohexane pyrazolones
(SCHPs) derived from pyrazol-3-ones are fundamental
pyrazolone skeletons (SCHPs) from the diversity of in-situ-
generated vinyl enolate species (Scheme 2).18 Biju’s group has
skeletons encountered throughout natural products and
pharmaceuticals due to their broad biopharmaceutical activ-
ities.11 As presented in Scheme 1, medicinal bioactivities have
been found in SCHP skeletal compounds, such as p38 inhibitor
(I), antitumor agent (II), antiinflammatory (III), type-4
phosphodiesterase inhibitor (IV), and acetyl-CoA carboxylase
inhibitor (V).12 Thus the construction of the chiral spiropyr-
azolone skeleton has been of great importance and has triggered
vast investigation of their synthesis. Although the organo-
catalyzed reactions, such as the [1 + 2 + 2] or [1 + 4]
cycloaddition reaction,13 [1 + 5] annulation,14 [2 + 4]
annulation,15 and [3 + 3] annulation,16 have been described
reported an asymmetric synthesis of spiropyrazolones via the
formal [3 + 3] annulation of enals and α-arylidene pyrazolinones
catalyzed by NHC.19 Herein we report a different [4 + 2]
annulation of γ-chloroenals and α-arylidene pyrazolinones via
vinyl enolate intermediates for the enantioselective construction
of carbocyclic spiropyrazolone derivatives catalyzed by NHC.
In the initial investigation, the reaction was carried out
between γ-chloroenal 1a and 4-benzylidene-pyrazol-3-one 2a by
employing N-substituted triazolium salt as a precatalyst (Table
Received: August 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02927
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reaction with excellent enantiopurity (>99% ee) and good
diastereoselectivity (10:1 dr) and in high yield (79% yield).
Scheme 2. Construction of Spiropyrazolones
a
Table 2. Substrates Scope of Pyrazolinones
b
c
d
entry
1
2
3
4
5
6
7
8
R1, R2, R3
Ph, H, Me (3a)
yield (%)
dr
ee (%)
79
76
66
69
76
81
80
77
67
60
65
40
75
76
86
75
64
62
65
70
68
69
60
61
45
69
10:1
10:1
12:1
13:1
10:1
9:1
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
90
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
e
Ph, H, Me (3a)
4-F-Ph, H, Me (3b)
4-Cl-Ph, H, Me (3c)
4-Br-Ph, H, Me (3d)
4-Me-Ph, H, Me (3e)
4-MeO-Ph, H, Me (3f)
4-i-Pr-Ph, H, Me (3g)
4-CF3−Ph, H, Me (3h)
4-NO2−Ph, H, Me (3i)
3-Cl-Ph, H, Me (3j)
2-Cl-Ph, H, Me (3k)
thiophen-2-yl, H, Me (3l)
naphthalen-2-yl, H, Me (3m)
cyclohexyl, H, Me (3n)
4-Ph-Ph, H, Me (3o)
Ph, F, Me (3p)
Ph, Cl, Me (3q)
Ph, Br, Me (3r)
Ph, Me, Me (3s)
Ph, MeO, Me (3t)
Ph, i-Pr, Me (3u)
Ph, CF3, Me (3v)
Ph, H, Et (3w)
Ph, H, i-Pr (3x)
Ph, H, Bn (3y)
1). Different chiral triazolium salt precatalysts were screened.
The reaction could proceed smoothly (61% yield, >99% ee)
10:1
9:1
9
12:1
15:1
14:1
10:1
7:1
10:1
13:1
10:1
9:1
10:1
12:1
8:1
9:1
9:1
a
Table 1. Optimization of Reaction Conditions
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
b
c
d
entry
solvent
cat.
base
TEA
TEA
TEA
TEA
TEA
TEA
NaOAc
NaOAc
NaOAc
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
THF
THF
THF
toluene
DCM
DCE
DCE
DCE
DCE
A
B
C
A
A
A
A
A
A
61
26
42
40
67
67
67
79
79
2:1
2:1
10:1
4:1
6:1
99
99
70
90
94
96
95
95
99
13:1
8:1
7:1
8:1
a
Unless otherwise specified, reactions were performed on 1a (0.10
7:1
b
c
mmol), 2 (0.10 mmol). Yields of isolated products. dr values
d
10:1
10:1
10:1
1
determined by H NMR. ee values determined via HPLC analysis.
e
e
8
Reaction was performed on a 1 mmol scale.
ef
,
9
a
Unless otherwise specified, the reaction was performed on a 0.10
After establishing the optimal reaction conditions, we
investigated the substrate scope of the formal [4 + 2] annulation
catalyzed by NHC (Tables 2 and 3). As shown in Table 2, a
broad spectrum of pyrazolinones were explored and produced
spirocyclohexane pyrazolone products in good yield and with
excellent enantioselectivities. First, a wide range of 5-methyl-2-
phenyl-pyrazolinones was tested under optimal conditions (R1,
3a−o). In most cases, the reactants bearing aromatic R1 were
well-tolerated to offer spiropyrazolones with excellent enantio-
selectivities (>99% ee), except for aliphatic-substituted pyr-
azolinone (3n, cyclohexyl, 90% ee). 4-Chloro-3-phenylbut-2-
enal 1a reacted flatly with 4-benzylidene-pyrazolinones carrying
either electron-withdrawing (3b−d, 3h−k) or electron-
donating (3e−g) substituents on the phenyl ring. As for the
substituent position on the phenyl ring, it showed that it has a
very slight impact on the reaction results (3c,j,k). Second, we
modified substituents (R2) on 2-phenyl ring of 4-benzylidene-5-
methyl-2-phenyl-pyrazolinones. Spirocyclohexane pyrazolones
were produced in good yield and with high enantiopurities in all
of the cases. As for the substituents R3 on the five-position of
pyrazolinones, both the aromatic group and the aliphatic group
b
mmol scale in the solvent (1.5 mL) at room temperature. Yields of
c
d
isolated products. dr values determined by 1H NMR. ee values
determined by HPLC analysis on Chiralcel AD-H and OD-H
columns (see the SI). 50 mg 4 Å molecular sieve was added. 3.0
equiv NaOAc was used.
e
f
when catalyzed by N-mesityl-substituted triazolium (catalyst A)
employing triethylamine as the base in tetrahydrofuran (THF),
albeit with low diastereoselectivity (2:1 dr) (entry 1). Catalyst B
with a penta-fluorophenyl group gave an even worse result (26%
yield). When the catalyst was derived from an electron-
withdrawing group on the indanol ring (catalyst C), it exhibited
more efficient diastereoselectivity (10:1 dr) but was invalid on
the control of stereoselectivity (70% ee). With mesityl-
substituted triazolium salt A as the most suitable catalyst, the
screening of solvents indicated that the best solvent was DCE
(1,2-dichloroethane), leading to spirocyclohexane pyrazolone
3a in high yield and with good diastereoselectivity compared
with other solvents, such as toluene and DCM (dichloro-
methane). An inorganic base was screened to be suitable for the
B
DOI: 10.1021/acs.orglett.9b02927
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Substrates Scope of γ-Chloroenals
Scheme 3. Proposed Catalytic Pathway
b
c
d
entry
Ar
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
9
10
4-F-Ph (4a)
4-Cl-Ph (4b)
4-Br-Ph (4c)
4-Me-Ph (4d)
4-MeO-Ph (4e)
4-Ph-Ph (4f)
3-Cl-Ph (4g)
2-Cl-Ph (4h)
68
66
61
81
62
69
63
40
80
77
10:1
12:1
12:1
10:1
9:1
10:1
12:1
10:1
9:1
>99
>99
>99
>99
>99
>99
>99
>99
92
naphthalen-2-yl (4i)
thiophen-3-yl (4j)
8:1
96
a
Unless otherwise specified, reactions were performed on 1 (0.10
b
c
mmol), 2a (0.10 mmol). Yields of isolated products. dr values
determined by H NMR. ee values determined via HPLC analysis.
d
1
addition of NHC catalyst to γ-chloroenal 1a and a 1,2-H
migration to oxygen from carbon. Subsequently, enolene II was
afforded via a tautomerization along with a C−Cl bond cleavage.
Then, enone intermediate III was produced via an enolene−
enone rearrangement along with a 1,5-H shift. After that, vinyl
enolate IV was generated by the base capture of the acidic γ-
proton. Finally, the reaction was finished by the cycloaddition of
vinyl enolate IV with pyrazolone derivate 2a, generating the
enantioenriched spiropyrazolones 3a and releasing NHC
catalyst.
Given that the spirocyclohexane pyrazolone skeletons are
important building blocks and moieties in pharmaceuticals, we
tried to demonstrate the synthetic utility of this formal [4 + 2]
annulation by transforming the products to other useful
molecules by simple protocols. The phosphoric ester 5a was
obtained with no loss of enantiopurity (87% yield, >99% ee) by
the treatment of optically enriched spiropyrazolone 3a with
hypochlorous (diphenyl phosphoric) anhydride at −78 °C in
THF (Scheme 4).
were tolerated in the [4 + 2] cycloaddition reaction, in which the
spiropyrazolone products were afforded in moderate to good
yield and with excellent enantioselectivities (>99% ee) (3a, 3w−
y).
Next, we varied the γ-chloroenal substrate of the reaction
(Table 3). The desired products of spirocyclohexane
pyrazolones were obtained in satisfactory yield and with
excellent enantioselectivities in all of the cases. The electron-
donating substituents as well as the electron-withdrawing ones
were well tolerated on the β-phenyl ring. The ortho-, para-, and
meta-chlorophenyl γ-chloroenals were investigated in the
reaction and gave comparable results. It seemed that the
substituent position on the β-phenyl ring had a limited impact
on the reaction outcome. The scope of naphthalen-2-yl- and
thiophen-3-yl substituted γ-chloroenals (4i−j) afforded spi-
rocyclohexane pyrazolones in high yield, however, with
relatively lower enantioselectivities.
The absolute configuration of spirocyclohexane pyrazolone
3a was confirmed based on the X-ray crystallographic analysis
(Figure 1, CCDC 1948486). The prepared (5aR,10bS)-(+)-cis-
Scheme 4. Transformation of Spiropyrazolone 3a
In summary, we have developed a chiral NHC-catalyzed [4 +
2] cycloaddition between γ-chloroenals with pyrazolinones in
the absence of expensive oxidants. The desired spirocyclohexane
pyrazolone products were obtained in moderate to good yield,
with high diastereoselectivities and excellent enantioselectivities.
This methodology accommodates the great prospects of
constructing biologically relevant spirocyclohexane pyrazolone
skeletons. Further investigations are undergoing.
Figure 1. X-ray crystal structure of 3a. Thermal ellipsoids are shown at
50% probability.
N-mesityl-substituted triazolium salt A provided exclusively
(5S,10R)-4-methyl-2,8,10-triphenyl-2,3-diazaspiro[4.5]deca-
3,7-diene-1,6-dione 3a.
We proposed the mechanism for this formal [4 + 2]
annulation of enals and α-arylidene pyrazolinones (Scheme
3). First, Breslow intermediate I was offered via the nucleophilic
C
DOI: 10.1021/acs.orglett.9b02927
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of Saturated Carboxylic Acids through in Situ Activation Strategy:
Access to δ-Lactam. Org. Lett. 2015, 17, 6234.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02927.
■
S
(5) (a) Breslow, R. On the Mechanism of Thiamine Action. IV.1
Evidence from Studies on Model Systems. J. Am. Chem. Soc. 1958, 80,
3719. (b) Sheehan, J.; Hunneman, D. H. Homogeneous Asymmetric
Catalysis. J. Am. Chem. Soc. 1966, 88, 3666. (c) Stetter, H. Catalyzed
Addition of Aldehydes to Activated Double BondsA New Synthetic
Approach. Angew. Chem., Int. Ed. Engl. 1976, 15, 639. (d) Enders, D.;
Breuer, K.; Runsink, J.; Teles, J. H. The First Asymmetric Intra-
molecular Stetter Reaction. Preliminary Communication. Helv. Chim.
Acta 1996, 79, 1899.
Experimental procedures, characterization data, and
NMR spectra for 3a−z, 4a−j, and 5a (PDF)
Accession Codes
CCDC 1948486 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
(6) (a) He, M.; Struble, J. R.; Bode, J. W. Highly Enantioselective
Azadiene Diels−Alder Reactions Catalyzed by Chiral N-Heterocyclic
Carbenes. J. Am. Chem. Soc. 2006, 128, 8418. (b) He, M.; Uc, G. J.;
Bode, J. W. Chiral N-Heterocyclic Carbene Catalyzed, Enantioselective
Oxodiene Diels−Alder Reactions with Low Catalyst Loadings. J. Am.
Chem. Soc. 2006, 128, 15088. (c) Struble, J. R.; Kaeobamrung, J.; Bode,
J. W. Synthesis of an N-Mesityl Substituted Chiral Imidazolium Salt for
NHC-Catalyzed Reactions. Org. Lett. 2008, 10, 957. (d) He, M.;
Beahm, B. J.; Bode, J. W. Chiral NHC-Catalyzed Oxodiene Diels−
Alder Reactions with α-Chloroaldehyde Bisulfite Salts. Org. Lett. 2008,
10, 3817.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: myang@hznu.edu.cn (L.Y.).
*E-mail: zgf@hznu.edu.cn (G.Z.).
(7) (a) Sohn, S. S.; Rosen, E. L.; Bode, J. W. N-Heterocyclic Carbene-
Catalyzed Generation of Homoenolates: γ-Butyrolactones by Direct
Annulations of Enals and Aldehydes. J. Am. Chem. Soc. 2004, 126,
14370. (b) Burstein, C.; Glorius, F. Organocatalyzed Conjugate
Umpolung of α, β-Unsaturated Aldehydes for the Synthesis of γ-
Butyrolactones. Angew. Chem., Int. Ed. 2004, 43, 6205. (c) He, M.;
Bode, J. W. Org. Lett. 2005, 7, 3131. (d) Chan, A.; Scheidt, K. A. Highly
Stereoselective Formal [3 + 3] Cycloaddition of Enals and Azomethine
Imines Catalyzed by N-Heterocyclic Carbenes. J. Am. Chem. Soc. 2007,
129, 5334. (e) Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A. Highly
Diastereo- and Enantioselective Additions of Homoenolates to
Nitrones Catalyzed by N-Heterocyclic Carbenes. J. Am. Chem. Soc.
2008, 130, 2416.
ORCID
Limin Yang: 0000-0003-1021-3942
Guofu Zhong: 0000-0001-9497-9069
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(8) (a) Mo, J.; Chen, X.; Chi, Y. Oxidative γ-Addition of Enals to
Trifluoromethyl Ketones: Enantioselectivity Control via Lewis Acid/
N-Heterocyclic Carbene Cooperative Catalysis. J. Am. Chem. Soc. 2012,
134, 8810. (b) Xu, J.; Jin, Z.; Chi, Y. Organocatalytic Enantioselective γ-
Aminoalkylation of Unsaturated Ester: Access to Pipecolic Acid
Derivatives. Org. Lett. 2013, 15, 5028. (c) Chen, X.; Yang, S.; Song,
B.; Chi, Y. Functionalization of Benzylic C(sp3)-H Bonds of Heteroaryl
Aldehydes through N-Heterocyclic Carbene Organocatalysis. Angew.
Chem., Int. Ed. 2013, 52, 11134. (d) Xu, J.; Yuan, S.; Miao, M. N-
Heterocyclic Carbene Catalyzed [4 + 2] Annulation Reactions with in
Situ Generated Heterocyclic ortho-Quinodimethanes. Org. Lett. 2016,
18, 3822. (e) Frogley, B. J.; Wright, L. J. A Metallaanthracene and
Derived Metallaanthraquinone. Angew. Chem., Int. Ed. 2017, 56, 1.
(9) (a) Biswas, A.; DeSarkar, S.; Tebben, L.; Studer, A.
Enantioselective Cyclopropanation of Enals by Oxidative N-hetero-
cyclic Carbene Catalysis. Chem. Commun. 2012, 48, 5190. (b) Lv, H.;
Jia, W.-Q.; Sun, L.-H.; Ye, S. N-Heterocyclic Carbene Catalyzed [4 + 3]
Annulation of Enals and o-Quinone Methides: Highly Enantioselective
Synthesis of Benzo-ε-Lactones. Angew. Chem., Int. Ed. 2013, 52, 8607.
(c) Lu, S.; Poh, S. B.; Siau, W.-Y.; Zhao, Y. Kinetic Resolution of
Tertiary Alcohols: Highly Enantioselective Access to 3-Hydroxy-3-
Substituted Oxindoles. Angew. Chem., Int. Ed. 2013, 52, 1731.
(d) Izquierdo, J.; Orue, A.; Scheidt, K. A. A Dual Lewis Base Activation
Strategy for Enantioselective Carbene-Catalyzed Annulations. J. Am.
Chem. Soc. 2013, 135, 10634. (e) Guo, C.; Schedler, M. C.; Daniliuc,
G.; Glorius, F. N-Heterocyclic Carbene Catalyzed Formal [3 + 2]
Annulation Reaction of Enals: An Efficient Enantioselective Access to
Spiro-heterocycles. Angew. Chem., Int. Ed. 2014, 53, 10232.
(f) Mahatthananchai, J.; Zheng, P.-G.; Bode, J. W. α. β-unsaturated
Acyl Azoliums from N-Heterocyclic Carbene Catalyzed Reactions:
Observation and Mechanistic Investigation. Angew. Chem., Int. Ed.
2011, 50, 1673. (g) Zhu, Z.-Q.; Zheng, X.-L.; Jiang, N.-F.; Wan, X.;
Xiao, J.-C. Chiral N-heterocyclic Carbene Catalyzed Annulation of α, β-
unsaturated Aldehydes with 1, 3-dicarbonyls. Chem. Commun. 2011, 47,
We thank the NSFC (21302032, 21373073, and 21672048) and
the PCSIRT (IRT 1231) for financial support. G.Z. appreciates a
QianJiang Scholar award from Zhejiang Province in China.
REFERENCES
■
(1) (a) Bourissou, D.; Guerret, O.; Gabbai, F. P.; Bertrand, G. Stable
Carbenes. Chem. Rev. 2000, 100, 39. (b) Herrmann, W. A. N-
Heterocyclic Carbenes: A New Concept in Organometallic Catalysis.
Angew. Chem., Int. Ed. 2002, 41, 1290. (c) Movassaghi, M.; Schmidt, M.
A. N-Heterocyclic Carbene-Catalyzed Amidation of Unactivated Esters
with Amino Alcohols. Org. Lett. 2005, 7, 2453.
(2) (a) Herrmann, W. A.; Weskamp, T.; Bohm, V. P. W. Metel
Complexes of Stable Carbene. Adv. Organomet. Chem. 2001, 48, 1.
(b) Scott, N. M.; Nolan, S. P. Stabilization of Organometallic Species
Achieved by the Use of N-Heterocyclic Carbene (NHC) Ligands. Eur.
J. Inorg. Chem. 2005, 2005, 1815.
(3) Arduengo, A. J.; Harlow, R. L.; Kline, M. A. A Stable Crystalline
Carbine. J. Am. Chem. Soc. 1991, 113, 361.
(4) (a) Seebach, D. Methods of Reactivity Umpolung. Angew. Chem.,
Int. Ed. Engl. 1979, 18, 239. (b) Enders, D.; Niemeier, O.; Henseler, A.
Organocatalysis by N-Heterocyclic Carbenes. Chem. Rev. 2007, 107,
5606. (c) Moore, J. L.; Rovis, T. Insights into the Carbene Initiated
Aggregation of Fe(cot)2. Top. Curr. Chem. 2009, 291, 77.
(d) Mahatthananchai, J.; Bode, J. W. On the Mechanism of N-
Heterocyclic Carbene-Catalyzed Reactions Involving Acyl Azoliums.
Acc. Chem. Res. 2014, 47, 696. (e) Xu, J.-H.; Zheng, S.-C.; Zhang, J.-W.;
Liu, X.-Y.; Tan, B. Construction of Tropane Derivatives by the
Organocatalytic Asymmetric Dearomatization of Isoquinolines. Angew.
Chem., Int. Ed. 2016, 55, 11834. (f) Xiao, Z.; Yu, C.; Li, T.; Wang, X.;
Yao, C. N-Heterocyclic Carbene/Lewis Acid Strategy for the
Stereoselective Synthesis of Spirocyclic Oxindole−Dihydropyranones.
Org. Lett. 2014, 16, 3632. (g) Que, Y.; Xie, Y.; Li, T.; Yu, C.; Tu, S.; Yao,
C. An N-Heterocyclic Carbene-Catalyzed Oxidative γ-Aminoalkylation
D
DOI: 10.1021/acs.orglett.9b02927
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
8670. (h) Yang, L.; Wang, F.; Chua, P. J.; Lv, Y.; Zhong, L.; Zhong, G.
N-Heterocyclic Carbene (NHC)-Catalyzed Highly Diastereo- and
Enantioselective Oxo-Diels−Alder Reactions for Synthesis of Fused
Pyrano[2,3-b]indoles. Org. Lett. 2012, 14, 2894. (i) Zhang, B.; Feng, P.;
Cui, Y.; Jiao, N. NHC-catalyzed C−O or C−N Bond Formation:
Efficient Approaches to α, β-unsaturated Esters and Amides. Chem.
Commun. 2012, 48, 7280. (j) He, L.; Guo, H.; Li, Y.-Z.; Du, G.-F.; Dai,
B. N-Heterocyclic Carbene-Catalyzed Formal Cross-Coupling Reac-
tion of α-Haloenals with Thiols: Organocatalytic Construction of sp2
Carbon−Sulfur Bonds. Chem. Commun. 2014, 50, 3719. (k) Ryan, J. S.;
Candish, L.; Lupton, D. W. N-Heterocyclic Carbene-Catalyzed [4 + 2]
Cycloaddition/Decarboxylation of Silyl Dienol Ethers with α, β-
Unsaturated Acid Fluorides. J. Am. Chem. Soc. 2011, 133, 4694.
(l) Candish, L.; Lupton, D. W. N-Heterocyclic Carbene-Catalyzed
Ireland−Coates Claisen Rearrangement: Synthesis of Functionalized β-
Lactones. J. Am. Chem. Soc. 2013, 135, 58.
(10) (a) Varvounis, G. Pyrazol-3-ones. Part IV: Synthesis and
Applications. Adv. Heterocycl. Chem. 2009, 98, 143−224. (b) Horton,
D. A.; Bourne, G. T.; Smythe, L. M. The Combinatorial Synthesis of
Bicyclic Privileged Structures or Privileged Substructures. Chem. Rev.
2003, 103, 893 and references therein. . (c) Chauhan, P.; Mahajan, S.;
Enders, D. Asymmetric Aynthesis of Pyrazoles and Pyrazolones
Employing the Reactivity of Pyrazolin-5-one Derivatives. Chem.
Commun. 2015, 51, 12890. (d) Ke, B.; Tian, M.; Li, J.; Liu, B.; He,
G. Targeting Programmed Cell Death Using Small-Molecule
Compounds to Improve Potential Cancer Therapy. Med. Res. Rev.
2016, 36, 983.
azolones Containing Four Consecutive Stereocenters through
Asymmetric Sequential Reactions. Org. Chem. Front. 2016, 3, 1087.
For recent reviews on asymmetric synthesis of spiro compounds, see:
(c) Rios, R. Enantioselective Methodologies for the Synthesis of Spiro
Compounds. Chem. Soc. Rev. 2012, 41, 1060. Xie, X.; Huang, W.; Peng,
C.; Han, B. Organocatalytic Asymmetric Synthesis of Six-Membered
Carbocycle-Based Spiro Compounds. Adv. Synth. Catal. 2018, 360, 194.
(d) Han, X.; Yao, W.; Wang, T.; Tan, Y. R.; Yan, Z.; Kwiatkowski, J.; Lu,
Y. Asymmetric Synthesis of Spiropyrazolones through PhosphineCa-
talyzed [4 + 1] Annulation. Angew. Chem., Int. Ed. 2014, 53, 5643.
(15) (a) Zea, A.; Alba, A.-N. R.; Mazzanti, A.; Moyano, A.; Rios, R.
Highly Enantioselective Cascade Synthesis of Spiropyrazolones. Org.
Biomol. Chem. 2011, 9, 6519. (b) Zhang, J.-X.; Li, N.-K.; Liu, Z.-M.;
Huang, X.-F.; Geng, Z.-C.; Wang, X.-W. Enantioselective Synthesis of
Unsymmetrical Diaryl-Substituted Spirocyclohexanonepyrazolones
through a Cascade [4 + 2] Double Michael Addition. Adv. Synth.
Catal. 2013, 355, 797. (c) Chauhan, P.; Mahajan, S.; Loh, C. C. J.;
Raabe, G.; Enders, D. Streocontrolled Construction of Six Vicinal
Stereogenic Centers on Spiropyrazolones via Organocascade Michael/
Michael/1, 2-Addition Reactions. Org. Lett. 2014, 16, 2954. (d) Li, J.-
H.; Du, D.-M. Organocatalyzed Cascade Aza-Michael/Michael
Addition for the Asymmetric Construction of Highly Functionalized
Spiropyrazolone Tetrahydroquinolines. Chem. - Asian J. 2014, 9, 3278.
(e) Yang, W.; Zhang, Y.; Qiu, S.; Zhao, C.; Zhang, L.; Liu, H.; Zhou, L.;
Xiao, Y.; Guo, H. Phosphine-Catalyzed [4 + 2] Cycloaddition of
Unsaturated Pyrazolones with Allenoates: A Concise Approach toward
Spiropyrazolones. RSC Adv. 2015, 5, 62343. (f) Liang, J.; Chen, Q.; Liu,
L.; Jiang, X.; Wang, R. An organocatalytic Asymmetric Double Michael
Cascade Reaction of Unsaturated Ketones and Unsaturated Pyrazo-
lones: Highly Efficient Synthesis of Spiropyrazolone Derivatives. Org.
Biomol. Chem. 2013, 11, 1441. (g) Han, B.; Huang, W.; Ren, W.; He, G.;
Wang, J.-H.; Peng, C. Asymmetric Synthesis of Cyclohexane-Fused
Drug-Like Spirocyclic Scaffolds Containing Six Contiguous Stereo-
genic Centers via Organocatalytic Cascade Reactions. Adv. Synth. Catal.
2015, 357, 561.
(16) (a) Rassu, G.; Zambrano, V.; Pinna, L.; Curti, C.; Battistini, L.;
Sartori, A.; Pelosi, G.; Casiraghi, G.; Zanardi, F. Direct and
Enantioselective Vinylogous Michael Addition of α-Alkylidenepyr-
azolinones to Nitroolefins Catalyzed by Dual Cinchona Alkaloid
Thioureas. Adv. Synth. Catal. 2014, 356, 2330. (b) Liu, J.-Y.; Zhao, J.;
Zhang, J.-L.; Xu, P.-F. Quaternary Carbon Center Forming Formal [3 +
3] Cycloaddition Reaction via Bifunctional Catalysis: Asymmetric
Synthesis of Spirocyclohexene Pyrazolones. Org. Lett. 2017, 19, 1846.
(c) Yang, W.; Sun, W.; Zhang, C.; Wang, Q.; Guo, Z.; Mao, B.; Liao, J.;
Guo, H. Lewis-Base-Catalyzed Asymmetric [3 + 3] Annulation
Reaction of Morita−Baylis−Hillman Carbonates: Enantioselective
Synthesis of Spirocyclohexenes. ACS Catal. 2017, 7, 3142.
(17) (a) Yan, J.; Shi, K.; Zhao, C.; Ding, L.; Jiang, S.; Yang, L.; Zhong,
G. NHC-catalyzed [4 + 2] Cycloaddition Reactions for the Synthesis of
3′-Spirocyclic Oxindoles via a C−F Bond Cleavage Protocol. Chem.
Commun. 2018, 54, 1567. (b) Lin, Y.; Yang, L.; Deng, Y.; Zhong, G.
Cooperative Catalysis of N-heterocyclic Carbine and Brønsted Acid for
A Highly Enantioselective Route to Unprotected Spiro-indoline-
pyrans. Chem. Commun. 2015, 51, 8330.
(11) (a) Sondhi, M.; Dinodia, M.; Singh, J.; Rani, R. Heterocyclic
Compounds as Anti-Inflammatory Agents. Curr. Bioact. Compd. 2007,
3, 91. (b) Varvounis, G. Chapter 2 Pyrazol-3-ones. Part IV: Synthesis
and Applications. Adv. Heterocycl. Chem. 2009, 98, 143. (c) Schmidt, A.;
Dreger, A. Recent Advances in the Chemistry of Pyrazoles. Properties,
Biological Activities, and Syntheses. Curr. Org. Chem. 2011, 15, 1423.
́
́
́
(d) Fustero, S.; Sanchez-Rosello, M.; Barrio, P.; Simon-Fuentes, A.
From 2000 to Mid-2010: A Fruitful Decade for the Synthesis of
Pyrazoles. Chem. Rev. 2011, 111, 6984.
(12) (a) Zhang, Y.; Wu, S.; Wang, S.; Fang, K.; Dong, G.; Liu, N.;
Miao, Z.; Yao, J.; Li, J.; Zhang, W.; Sheng, C.; Wang, W. Divergent
Cascade Construction of Skeletally Diverse “Privileged” Pyrazole
Derived Molecular Architectures. Eur. J. Org. Chem. 2015, 2015, 2030−
2037. (b) Han, B.; Xu, S.; Wang, P. Chiral Pyrazolone Helical
Derivative as well as Preparation Method and Application Thereof in
Medicaments. CN Patent CN104610148, 2015. (c) Silay-chev, P. S.;
Filimonov, V. O.; Maslivets, A. N.; Makhmu-dov, R. R. Demonstrating
Analgesic Activity and Method for Obtaining Thereof. Russ. Patent,
RU2577528, 2014. (d) Barnes, D.; Bebernitz, G. R.; Cohen, S. L.;
Damon, R. E.; Day, R. F.; Jain, M.; Karki, R. G.; Kirman, L. C.; Patel, T.
J.; Raymer, B. K.; Schuster, H. F.; Zhang, W. Cyclohexane Derivatives as
Inhibitors of Acetyl-coa Carboxylase (Acc). PCT Int. Appl.
WO2011067306, 2011. (e) Adolphi, H.; Dietsche, W.; Merger, F.;
Beutel, P.; Huber, R. German Pat. Appl. DE 2163063, 1973. (f) Philipp,
B.; Sarah, W. Amido-Substituted Cyclohexane Derivatives. PCT Int.
Appl. WO2018078009, 2011. (g) Wu, S.; Li, Y.; Xu, G.; Chen, S.;
Zhang, Y.; Liu, N.; Dong, G.; Miao, C.; Su, H.; Zhang, W.; Sheng, C.
Novel Spiropyrazolone Antitumor Scaffold with Potent Activity:
Design, Synthesis and Structureeactivity Relationship. Eur. J. Med.
Chem. 2016, 115, 141.
(18) (a) Yan, J.; Sun, R.; Shi, K.; Li, K.; Yang, L.; Zhong, G. NHC-
Catalyzed Asymmetric Benzoin Reaction in Water. J. Org. Chem. 2018,
83, 7547. (b) Yang, L.; Lv, Y.; Wang, F.; Zhong, G. Chiral NHC-
catalyzed 1, 3-diploar [3 + 2] Cycloadditon of Azomethine Imines with
α-Chloroaldehydes for Synthesis of Bicyclic Pyrazolidinones. Org.
Biomol. Chem. 2018, 16, 4433.
(19) Yetra, S. R.; Mondal, S.; Mukherjee, S.; Gonnade, R. G.; Biju, A.
T. Enantioselective Synthesis of Spirocyclohexadienones by NHC-
Catalyzed Formal [3 + 3] Annulation Reaction of Enals. Angew. Chem.,
Int. Ed. 2016, 55, 268.
́
(13) (a) Companyo, X.; Zea, A.; Alba, A.-N.; Mazzanti, R. A.;
Moyano, A.; Rios, R. Organocatalytic Synthesis of Spiro Compounds
via A Cascade Michael−Michael-Aldol Reaction. Chem. Commun.
2010, 46, 6953. (b) Alba, A.-N.; Zea, R. A.; Valero, G.; Calbet, T.; Font-
Bardía, M.; Mazzanti, A.; Moyano, A.; Rios, R. Highly Stereoselective
Synthesis of Spiropyrazolones. Eur. J. Org. Chem. 2011, 2011, 1318.
(14) (a) Wu, B.; Chen, J.; Li, M.-Q.; Zhang, J.-X.; Xu, X.-P.; Ji, S.-J.;
Wang, X.-W. Highly Enantioselective Synthesis of Spiro-
[cyclohexanone-oxindoles] and Spiro[cyclohexanone-pyrazolones] by
Asymmetric Cascade [5 + 1] Double Michael Reactions. Eur. J. Org.
Chem. 2012, 2012, 1318. (b) Li, J.-H.; Cui, Z.-H.; Du, D.- M. Diastereo-
and Enantioselective Construction of Cyclohexanone-fused Spirospyr-
E
DOI: 10.1021/acs.orglett.9b02927
Org. Lett. XXXX, XXX, XXX−XXX