Phosphine-Catalyzed Cascade Michael Addition/[4+2] Cycloaddition Reaction of Allenoates and 2-Arylidene-1,3-indanediones

Article abstract of DOI:10.1021/acs.orglett.0c00637

The phosphine-catalyzed cascade Michael addition/[4+2] cycloaddition reaction of tetrahydrobenzofuranone-derived allenoates and 2-arylidene-1,3-indanediones has been reported, affording spirocyclic 1,3-indanedione derivatives in moderate to high yields wi

Full text of DOI:10.1021/acs.orglett.0c00637

pubs.acs.org/OrgLett
Letter
Phosphine-Catalyzed Cascade Michael Addition/[4+2] Cycloaddition
Reaction of Allenoates and 2‑Arylidene-1,3-indanediones
Wangyu Shi, Biming Mao, Jiaqing Xu, Qijun Wang, Wei Wang, Yongjun Wu, Xuefeng Li,
and Hongchao Guo*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c00637
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The phosphine-catalyzed cascade Michael addition/
[4+2] cycloaddition reaction of tetrahydrobenzofuranone-derived
allenoates and 2-arylidene-1,3-indanediones has been reported,
affording spirocyclic 1,3-indanedione derivatives in moderate to
high yields with moderate to good diastereoselectivities. A scaled-
up reaction worked well under mild conditions, and a plausible
mechanism is proposed.
ucleophilic phosphine catalysis remains an active area of
Scheme 1. Previous Works and Our Strategy
N
organocatalysis.1 Particularly interesting phosphine-cata-
lyzed cycloaddition reactions have attracted more attention
and have been developed as an efficient access to a variety of
synthetically useful carbo- and heterocycles. In general,
nucleophilic attack of phosphine on an electron-deficient
phosphine acceptor generates zwitterionic intermediates,
which were then in situ trapped with electron-poor unsaturated
substrates leading to synthetic approaches to carbo- and
heterocycles. Obviously, the phosphine acceptor plays a key
role in these annulation reactions. Therefore, development of
nucleophilic phosphine catalysis is highly dependent on the
evolution of the phosphine acceptor. A handful of phosphine
acceptors, including electron-deficient alkenes, alkynes, and
allenes, have been exploited for phosphine catalysis.1 Among
these phosphine acceptors, allenes are very versatile precursors
with multiple reactivities, which have been successfully used in
many types of catalytic cycloaddition reactions. However, the
synthetic potential of classical allenes in phosphine-catalyzed
cycloaddition reactions has nearly been exhausted; therefore,
introduction of an additional functional group into allenoates,
giving them a new function, will offer certain opportunities for
development of novel reactions.
reaction (Scheme 1b).3 In most phosphine-catalyzed cyclo-
addition reactions reported so far involving allenes, allenes
were used as one-membered,4 two-membered,5 three-mem-
bered,6 and four-membered7 reactants, leading to the
construction of cyclic systems in which the allene unit is
Recently, the Lu group and our group reported a type of
allenoate having an electron-withdrawing group at the γ′-
carbon of the allenoates (Scheme 1).2,3 With this kind of
tetrahydrobenzofuranone-derived allenoate as the phosphine
acceptor, the Lu group achieved phosphine-catalyzed [4+2]
annulation involving α,β-unsaturated imine to give a chiral
tetrahydropyridine derivative in high yield with excellent
enantioselectivity, in which the allenoate worked as a C2
synthon (Scheme 1a).2 Our group developed phosphine-
catalyzed [4+2] cycloaddition of this tetrahydrobenzofura-
none-derived allenoate and sulfamate-derived cyclic imines.3
As opposed to the previous cycloaddition reaction of
allenoates, the γ′-carbon of the allenoate was involved in this
Received: February 18, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00637
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
partly or completely fused in the resulting ring. In comparison,
the use of the allenes involving more than four carbon atoms
(for instance, five) in cycloaddition reactions has not been
described. With our previous work as a basis,2,8 herein we
report a phosphine-catalyzed cascade Michael addition/[4+2]
cycloaddition of the tetrahydrobenzofuranone-derived alle-
noates and 2-arylidene-1,3-indanediones, giving valuable
spirocyclic 1,3-indanedione derivatives9 (Scheme 1c).
In our initial attempt, the model reaction of allenoate 1a and
2-benzylidene-1H-indene-1,3(2H)-dione 2a was investigated
in CH2Cl2 at 0 °C. A 1.2:1 molar ratio of allenoate (1a, 0.12
mmol) to alkene (2a, 0.1 mmol), which was often used in
phosphine, was utilized. Under catalysis with 20 mol % Ph3P,
an unexpected tandem reaction product 3aa was isolated in
25% yield with a trace amount of [4+2] cycloadduct 4aa.
Therefore, as shown in Table 1, a 1:2 molar ratio of allenoate
in 60% yield with a 7:1 dr and the byproduct 4aa was isolated
in 22% yield (entry 5). By contrast, (4-FC6H4)3P showed
similar catalytic reactivity, giving a 63% yield of 3aa with a 6:1
dr and a 24% yield of 4aa (entry 6). To our delight, Ph2PBn
displayed both good catalytic activity and chemical selectivity,
delivering an 84% yield of 3aa with a 13:1 dr and only a trace
of 4aa (entry 7). Further catalyst screening indicated that
tertiary amines such as 4-dimethylaminopyridine (DMAP),
1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,8-diazabicyclo-
[5,4,0]undec-7-ene (DBU) did not catalyze the reaction
(entries 8−10, respectively). Investigation of solvents indicated
that 1,2-dichloroethane (DCE) is most suitable for this cascade
reaction, affording the product 3aa in an 88% yield with a 15:1
dr (entry 11). Toluene (entry 12) gave a result similar to those
of DCE and DCM did (entries 7 and 11, respectively). Polar
solvent CH3CN led to an acceptable yield of only 45% of 3aa
with a 10:1 dr (entry 13). Increasing or decreasing the reaction
temperature did not improve the results (entries 14 and 15),
and 0 °C was a better choice in terms of yield and reaction
time. Decreasing the catalyst loading to 10% still resulted in
the product 3aa in an 85% yield with a 13:1 dr, albeit requiring
a longer reaction time (entry 16). Very interestingly, even
using a 1:1 molar ratio of 1a to 2a, only a trace amount of the
[4+2] cycloadduct 4aa was observed, although the yield of
tandem reaction product 3aa was reduced to 35% (entry 17).
On the basis of the results presented above, the optimal
reaction condition was determined to be one with Ph2PBn (20
mol %) as the catalyst in 1 mL of DCE at 0 °C. The relative
configuration of the annulation product has been unambigu-
ously confirmed by X-ray crystallography of products 3aa and
4aa.11
With the optimal condition in hand, we next explored the
scope of 2-arylidene-1,3-indanediones (Table 2). The results
showed that both electron-deficient and -rich substituents on
the benzene ring are suitable for this cascade reaction (entries
1−16). Most halogen-substituted substrates worked well to
give the desired products in good yields with moderate to good
diastereoselectivities (8:1 to 15:1 dr, ≤95% yield, entries 1−6).
A special dichloro-substituted 2-arylidene-1,3-indanedione 2j
showed moderate reactivity, giving the desired product 3aj in a
59% yield with a 15:1 dr (entry 9). Electron-deficient olefins
bearing strong electron-withdrawing groups on the benzene
such as 4-nitro-substituted olefin 2h and 4-trifluoromethyl-
substituted olefin 2i displayed high reactivities, affording the
desired products 3ah and 3ai in 83% and 72% yields,
respectively, with good diastereoselectivities (both >19:1 dr,
entries 7 and 8, respectively). A majority of 2-arylidene-1,3-
indanediones with electron-donating groups also showed good
reactivities. 2-Methyl-, 3-methyl-, 4-methyl-, and 3-methoxy-
substituted 2-arylidene-1,3-indanediones underwent the cas-
cade reaction efficiently with 78%, 83%, 78%, and 81% yields,
respectively, with moderate diastereoselectivity (entries 10−12
and 14, respectively). In particular, 4-ethyl-substituted 2-
arylidene-1,3-indanedione 2n afforded the product 3an in a
90% yield and a relatively better diastereoselectivity (entry 13).
Disappointingly, 4-methoxy-substituted and 2,5-dimethyl-sub-
stituted olefins 2p and 2q showed low reactivity; the target
products 3ap and 3aq were produced in acceptable yields of
48% and 56%, respectively (entries 15 and 16, respectively). 2-
(1-Naphthylvinyl)-1,3-indanedione 2r also underwent this
reaction, and the desired product 3ar was obtained in a 69%
yield with a 10:1 dr (entry 17). Unfortunately, styryl-
substituted 2-arylidene-1,3-indanedione did not undergo this
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
catalyst
Ph3P
Ph2PMe
PhPMe2
n-Bu3P
(4-MeC6H4)3P
(4-FC6H4)3P
Ph2PBn
DMAP
DABCO
DBU
Ph2PBn
Ph2PBn
Ph2PBn
Ph2PBn
Ph2PBn
Ph2PBn
Ph2PBn
solvent
3aa/4aa yield (%)
t (h)
dr
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
toluene
CH3CN
DCE
DCE
DCE
62/22
72/trace
NR
1
24
24
24
1
1
1
24
24
24
1
8:1
7:1
−
−
NR
60/22
63/24
84/trace
NR
NR
NR
88/trace
82/trace
45/trace
82/trace
88/trace
85/trace
35/trace
7:1
6:1
13:1
−
9
−
−
10
11
12
13
15:1
11:1
10:1
10:1
14:1
13:1
13:1
1
72
0.5
24
24
1
d
14
e
15
16
f
g
17
DCE
a
Unless otherwise stated, reactions of 1a (0.10 mmol) and 2a (0.2
mmol) were carried out at 0 °C in the presence of a catalyst (0.02
b
c
1
mmol) in 1 mL of the solvent. Isolated yield. Determined by H
d
e
NMR analysis. The reaction was performed at 25 °C. The reaction
was performed at −10 °C. With 10 mol % catalyst. With 0.1 mmol
f
g
of 2a.
(1a, 0.1 mmol) to alkene (2a, 0.2 mmol) was used in the next
screening. With this molar ratio, Ph3P promoted the cascade
reaction to give the product 3aa in 62% yield with good
diastereoselectivity as well as a [4+2] cycloadduct 4aa in 22%
yield (entry 1). The stronger nucleophilic phosphine Ph2PMe
led to the product 3aa in 72% yield, and only a trace amount of
4aa was observed (entry 2). Surprisingly, the strong
nucleophilic phosphines PhPMe2 and n-Bu3P did not show
catalytic reactivity, and no product was observed (entries 3 and
4, respectively). On the basis of these results, several
diarylphosphines and triarylphosphines such as (4-
MeC6H4)3P, (4-FC6H4)3P, and Ph2PBn were examined.
When (4-MeC6H4)3P was used, the product 3aa was obtained
B
https://dx.doi.org/10.1021/acs.orglett.0c00637
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Table 2. Substrate Scope of 2-Arylidene-1,3-Indanedione
Scheme 2. Attempt with an Asymmetric Variant
b
c
entry
R in 2
3
t (h)
yield (%)
dr
1
2
3
4
5
6
7
8
2-FC6H4 (2b)
3-FC6H4 (2c)
4-FC6H4 (2d)
4-ClC6H4 (2e)
4-BrC6H4 (2f)
4-IC6H4 (2g)
4-CF3C6H4 (2h)
4-NO2C6H4 (2i)
2,4-Cl2C6H3 (2j)
2-MeC6H4 (2k)
3-MeC6H4 (2l)
4-MeC6H4 (2m)
4-EtC6H4 (2n)
3-OMeC6H4 (2o)
4-OMeC6H4 (2p)
2,5-Me2C6H3 (2q)
1-naphthyl (2r)
styryl (2s)
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
3ap
3aq
3ar
3as
1.5
1
1
1
1
2
1
3
2
1
1
1
2
2
1.5
2
11
24
95
88
80
84
87
84
83
72
59
78
83
78
90
81
48
56
69
8:1
15:1
15:1
14:1
13:1
12:1
>19:1
>19:1
15:1
8:1
11:1
12:1
15:1
9:1
10:1
12:1
10:1
−
Scheme 3. Scale-Up Reaction and Further Transformation
of the Product
9
10
11
12
13
14
15
16
17
18
trace
a
All reactions were carried out with 1a (0.1 mmol), 2 (0.2 mmol),
b
and Ph2PBn (20 mol %) in 1 mL of DCE at 0 °C. Isolated yield.
c
Only a trace of product 4 was detected for all cases. Determined by
1H NMR analysis.
reaction (entry 18). As shown in Table 3, several different
alkyl-substituted allenoates 1b−1d were examined, affording
a
Table 3. Substrate Scope of Allenoates
indanedione 2a (2 mmol, 0.47 g) under the optimal condition,
giving the product 3aa in an 83% yield with a 15:1 dr.
Compared with the reaction on a 0.1 mmol scale, no obvious
loss of yield or diastereoselectivity was observed. In the
presence of ethyl 2-(acetoxymethyl)acrylate and Ph2PBn,
allylation of the product 3aa occurred in DCE at room
temperature to give adduct 5a in a 66% yield with a 15:1 dr.
On the basis of the general law of phosphine-catalyzed
reactions,1,3 a plausible mechanism was proposed (Scheme 4).
At first, nucleophilic attack of a phosphine catalyst on
tetrahydrobenzofuranone-derived allenoate 1a leads to for-
mation of zwitterionic intermediate A, which attacks 2-
arylidene-1,3-indanedione 2a to give intermediate B. Then,
intermediate B undergoes a proton migration to afford
intermediate C, which attacks another 2-arylidene-1,3-
indanedione 2a to produce intermediate D. Then an
intramolecular cycloaddition occurs to generate intermediate
E. Subsequent formation of a double bond leads to
regeneration of the phosphine catalyst with simultaneous
generation of intermediate F, which isomerizes to tandem
reaction product 3aa. In another catalytic cycle, intermediate A
performs a consecutive proton transfer or isomerization to give
intermediate I, which attacks electron-deficient alkene 2a to
produce intermediate J. Consequent intramolecular nucleo-
philic substitution results in [4+2] cycloaddition product 4aa.
b
c
entry
R in 1
3
yield (%)
dr
1
2
3
Et (1b)
n-Pr (1c)
i-Pr (1d)
3ba
3ca
3da
84
59
89
12:1
6:1
10:1
a
All reactions were carried out with 1 (0.1 mmol), 2a (0.2 mmol),
b
and Ph2PBn (20 mol %) in 1 mL of DCE at 0 °C. Isolated yield. A
c
1
trace of product 4 was detected for all reactions. Determined by H
NMR analysis.
the corresponding product 3ba−3da, respectively, in moderate
to good yields with good diastereoselectivities.
As shown in Scheme 2, this reaction with an asymmetric
variant was not successful. Using the optimal chiral bifunctinal
phosphine P1,10a an only 3% ee was obtained. Other chiral
phosphines such as P26e and P310b led to a trace amount of
the product. To demonstrate the synthetic potential of the
current cascade reaction, a scale-up reaction was performed
(Scheme 3a). The tetrahydrobenzofuranone-derived allenoate
1a (1 mmol, 0.19 g) was reacted with 2-arylidene-1,3-
C
https://dx.doi.org/10.1021/acs.orglett.0c00637
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Authors
Scheme 4. A Plausible Reaction Mechanism
Wangyu Shi − Department of Chemistry, China Agricultural
University, Beijing 100193, P. R. China
Biming Mao − Department of Chemistry, China Agricultural
University, Beijing 100193, P. R. China
Jiaqing Xu − Department of Chemistry, China Agricultural
University, Beijing 100193, P. R. China
Qijun Wang − Department of Chemistry, China Agricultural
University, Beijing 100193, P. R. China
Wei Wang − College of Public Health, Zhengzhou University,
Zhengzhou 450001, P. R. China
Yongjun Wu − College of Public Health, Zhengzhou University,
Zhengzhou 450001, P. R. China
Xuefeng Li − College of Public Health, Zhengzhou University,
Zhengzhou 450001, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00637
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the National Natural Science
Foundation of China (21572264 and 21871293) and the
Chinese Universities Scientific Fund (2018TC052,
2018TC055, and 2019TC085).
REFERENCES
■
(1) For recent reviews, see: (a) Wang, Z.; Xu, X.; Kwon, O.
Phosphine Catalysis of Allenes with Electrophiles. Chem. Soc. Rev.
2014, 43, 2927. (b) Xiao, Y.; Sun, Z.; Guo, H.; Kwon, O.
ChiralPhosphines in Nucleophilic Organocatalysis. Beilstein J. Org.
Chem. 2014, 10, 2089. (c) Xiao, Y.; Guo, H.; Kwon, O.
NucleophilicChiral Phosphines: Powerful and Versatile Catalysts for
AsymmetricAnnulations. Aldrichimica Acta 2016, 49, 3. (d) Wang, T.;
Han, X.; Zhong, F.; Yao, W.; Lu, Y. Amino Acid-Derived
BifunctionalPhosphines for Enantioselective Transformations. Acc.
Chem. Res. 2016, 49, 1369. (e) Li, W.; Zhang, J. Recent Developments
inthe Synthesis and Utilization of Chiral β-Aminophosphine
Derivativesas Catalysts or Ligands. Chem. Soc. Rev. 2016, 45, 1657.
(f) Wei, Y.; Shi, M. Lu’s [3 + 2] Cycloaddition of Allenes with
Electrophiles:Discovery, Development and Synthetic Application.
Org. Chem. Front. 2017, 4, 1876. (g) Ni, H.; Chan, W.-L.; Lu, Y.
Phosphine-Catalyzed Asymmetric Organic Reactions. Chem. Rev.
2018, 118, 9344. (h) Guo, H.; Fan, Y. C.; Sun, Z.; Wu, Y.; Kwon, O.
Phosphine Organocatalysis. Chem. Rev. 2018, 118, 10049. (i) Li, E.-
Q.; Huang, Y. Recent Advances in Phosphine Catalysis Involving γ-
Substituted Allenoates. Chem. Commun. 2020, 56, 680.
(2) Yao, W.; Dou, X.; Wen, S.; Wu, J.; Vittal, J. J.; Lu, Y.
Enantioselective Desymmetrization of Cyclohexadienones via an
Intramolecular Rauhut−Currier Reaction of Allenoates. Nat.
Commun. 2016, 7, 13024.
(3) Mao, B.; Shi, W.; Liao, J.; Liu, H.; Zhang, C.; Guo, H.
Phosphine-Catalyzed [4 + 2] Annulation of Allenoate with Sulfamate-
Derived Cyclic Imines: A Reaction Mode Involving γ’-Carbon of α-
Substituted Allenoate. Org. Lett. 2017, 19, 6340.
In conclusion, a phosphine-catalyzed cascade Michael
addition/[4+2] cycloaddition reaction of allenoates and 2-
arylidene-1,3-indanedione has been achieved under mild
conditions, affording diverse multisubstituted spirocyclic 1,3-
indanedione derivatives in good yields with moderate to good
diastereoselectivities. It is worth mentioning that five carbon
atoms were involved in this tandem reaction, offering
allenoates as phosphine acceptors with more features.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00637.
Experimental procedures, characterization data, HPLC
analysis data, and NMR spectra (PDF)
Accession Codes
CCDC 1898871 and 1921150 contain 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.
(4) For selected examples, see: (a) Meng, X.; Huang, Y.; Chen, R.
Bifunctional Phosphine-Catalyzed Domino Reaction: Highly Stereo-
selective Synthesis of cis-2,3-Dihydrobenzofurans from Salicyl N-
Thiophosphinyl Imines and Allenes. Org. Lett. 2009, 11, 137.
(b) Zhang, Q.; Yang, L.; Tong, X. 2-(Acetoxymethyl)buta-2,3-
dienoate, a Versatile 1,4-Biselectrophile for Phosphine-Catalyzed
(4+n) Annulations with 1, n-Bisnucleophiles (n = 1, 2). J. Am. Chem.
Soc. 2010, 132, 2550. (c) Szeto, J.; Sriramurthy, V.; Kwon, O.
Phosphine-Initiated General Base Catalysis: Facile Access to
AUTHOR INFORMATION
Corresponding Author
■
Hongchao Guo − College of Public Health, Zhengzhou
University, Zhengzhou 450001, P. R. China; orcid.org/
0000-0002-7356-4283; Email: hchguo@cau.edu.cn
D
https://dx.doi.org/10.1021/acs.orglett.0c00637
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Benzannulated 1,3-Diheteroatom Five-Membered Rings via Double-
Michael Reactions of Allenes. Org. Lett. 2011, 13, 5420. (d) Gao, Z.;
Wang, C.; Yuan, C.; Zhou, L.; Xiao, Y.; Guo, H. Phosphine-Catalyzed
[4 + 1] Annulation of 2-Tosylaminochalcones with Allenoates:
Synthesis of trans-2,3-Disubstitued Indolines. Chem. Commun. 2015,
51, 12653. (e) Zielke, K.; Waser, M. Formal (4 + 1)-Addition of
Allenoates to o-Quinone Methides. Org. Lett. 2018, 20, 768.
(7) For selected examples, see: (a) Zhu, X.-F.; Lan, J.; Kwon, O. An
Expedient Phosphine-Catalyzed [4 + 2] Annulation: Synthesis of
Highly Functionalized Tetrahydropyridines. J. Am. Chem. Soc. 2003,
125, 4716. (b) Castellano, S.; Fiji, H. D. G.; Kinderman, S. S.;
Watanabe, M.; de Leon, P.; Tamanoi, F.; Kwon, O. Small-Molecule
Inhibitors of Protein Geranylgeranyltransferase Type I. J. Am. Chem.
Soc. 2007, 129, 5843. (c) Tran, Y. S.; Kwon, O. Phosphine-Catalyzed
[4 + 2] Annulation: Synthesis of Cyclohexenes. J. Am. Chem. Soc.
2007, 129, 12632. (d) Baskar, B.; Dakas, P.-Y.; Kumar, K. Natural
Product Biosynthesis Inspired Concise and Stereoselective Synthesis
of Benzopyrones and Related Scaffolds. Org. Lett. 2011, 13, 1988.
(e) Xiao, H.; Chai, Z.; Wang, H.-F.; Wang, X.-W.; Cao, D.-D.; Liu,
W.; Lu, Y.-P.; Yang, Y.-Q.; Zhao, G. Bifunctional N-Acyl-Amino-
phosphine-Catalyzed Asymmetric [4 + 2] Cycloadditions of
Allenoates and Imines. Chem. - Eur. J. 2011, 17, 10562. (f) Jing, C.;
Na, R.; Wang, B.; Liu, H.; Zhang, L.; Liu, J.; Wang, M.; Zhong, J.;
Kwon, O.; Guo, H. Phosphine-Catalyzed [3 + 2] and [4 + 3]
Annulation Reactions of C, N-Cyclic Azomethine Imines with
Allenoates. Adv. Synth. Catal. 2012, 354, 1023. (g) Villa, R. A.; Xu,
Q.; Kwon, O. Total Synthesis of ( )-Hirsutine: Application of
Phosphine-Catalyzed Imine-Allene [4 + 2] Annulation. Org. Lett.
2012, 14, 4634. (h) Yu, H.; Zhang, L.; Li, Z.; Liu, H.; Wang, B.; Xiao,
Y.; Guo, H. Phosphine-Catalyzed [4 + 2] Cycloaddition of Sulfamate-
Derived Cyclic Imines with Allenoates: Synthesis of Sulfamate-Fused
Tetrahydropyridines. Tetrahedron 2014, 70, 340. (i) Liu, H.; Liu, Y.;
Yuan, C.; Wang, G.-P.; Zhu, S.-F.; Wu, Y.; Wang, B.; Sun, Z.; Xiao, Y.;
Zhou, Q.-L.; Guo, H. Enantioselective Synthesis of Spirobarbiturate-
Cyclohexenes through Phosphine-Catalyzed Asymmetric [4 + 2]
Annulation of Barbiturate-Derived Alkenes with Allenoates. Org. Lett.
2016, 18, 1302. (j) Yuan, C.; Zhou, L.; Xia, M.; Sun, Z.; Wang, D.;
Guo, H. Phosphine-Catalyzed Enantioselective [4 + 3] Annulation of
Allenoates with C, N-Cyclic Azomethine Imines: Synthesis of
Quinazoline-Based Tricyclic Heterocycles. Org. Lett. 2016, 18, 5644.
(8) Zhang, L.; Liu, H.; Qiao, G.; Hou, Z.; Liu, Y.; Xiao, Y.; Guo, H.
Phosphine-Catalyzed Highly Enantioselective [3 + 3] Cycloaddition
of Morita-Baylis-Hillman Carbonates with C, N-Cyclic Azomethine
Imines. J. Am. Chem. Soc. 2015, 137, 4316. (b) 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 Spirocy-
clohexenes. ACS Catal. 2017, 7, 3142. (c) Zhou, L.; Yuan, C.; Zeng,
Y.; Liu, H.; Wang, C.; Gao, X.; Wang, Q.; Zhang, C.; Guo, H.
Phosphine-Catalyzed [5 + 1] Annulation of δ-Sulfonamido-Sub-
stituted Enones with N-Sulfonylimines: A Facile Synthesis of
Tetrahydropyridines. Chem. Sci. 2018, 9, 1831. (d) Wang, C.;
Chen, Y.; Li, J.; Zhou, L.; Wang, B.; Xiao, Y.; Guo, H. Phosphine-
Catalyzed Asymmetric Cycloaddition Reaction of Diazenes: Enantio-
selective Synthesis of Chiral Dihydropyrazoles. Org. Lett. 2019, 21,
7519. (e) Zhou, L.; Zeng, Y.; Gao, X.; Wang, Q.; Wang, C.; Wang, B.;
Wang, W.; Wu, Y.; Zheng, B.; Guo, H. A Chiral Squaramide-
Catalyzed Asymmetric Dearomative Tandem Annulation Reaction
through a Kinetic Resolution of MBH Alcohols: Highly Enantiose-
lective Synthesis of Three-Dimensional Heterocyclic Compounds.
Chem. Commun. 2019, 55, 10464. (f) Zhou, L.; Yuan, C.; Zeng, Y.;
Wang, Q.; Wang, C.; Liu, M.; Wang, W.; Wu, Y.; Zheng, B.; Guo, H.
Direct Activation of Unmodified Morita-Baylis-Hillman Alcohols
through Phosphine Catalysis for Rapid Construction of Three-
Dimensional Heterocyclic Compounds. Org. Lett. 2019, 21, 4882.
(9) Turroni, S.; Tolomeo, M.; Mamone, G.; Picariello, G.;
Giacomini, E.; Brigidi, P.; Roberti, M.; Grimaudo, S.; Pipitone, R.
M.; Di Cristina, A.; Recanatini, M. A Natural-Like Synthetic Small
Molecule Impairs Bcr-Abl Signaling Cascades and Induces Mega-
karyocyte Differentiation in Erythroleukemia Cells. PLoS One 2013, 8,
No. e57650. (b) Sudhapriya, N.; Perumal, P. T.; Balachandran, C.;
Ignacimuthu, S.; Sangeetha, M.; Doble, M. Synthesis of New Class of
Spirocarbocycle Derivatives by Multicomponent Domino Reaction
and Their Evaluation for Antimicrobial, Anticancer Activity and
Molecular Docking Studies. Eur. J. Med. Chem. 2014, 83, 190.
(5) For selected examples, see: (a) Na, R.; Jing, C.; Xu, Q.; Jiang, H.;
Wu, X.; Shi, J.; Zhong, J.; Wang, M.; Benitez, D.; Tkatchouk, E.;
Goddard, W. A., III; Guo, H.; Kwon, O. Phosphine-Catalyzed
Annulations of Azomethine Imines: Allene-Dependent [3 + 2], [3 +
3], [4 + 3], and [3 + 2+3] Pathways. J. Am. Chem. Soc. 2011, 133,
13337. (b) Ashtekar, K. D.; Staples, R. J.; Borhan, B. Development of
a Formal Catalytic Asymmetric [4 + 2] Addition of Ethyl-2,3-
butadienoate with Acyclic Enones. Org. Lett. 2011, 13, 5732. (c) Pei,
C.-K.; Jiang, Y.; Wei, Y.; Shi, M. Enantioselective Synthesis of Highly
Functionalized Phosphonate-Substituted Pyrans or Dihydropyrans
Through Asymmetric [4 + 2] Cycloaddition of β,γ-Unsaturated α-
Ketophosphonates with Allenic Esters. Angew. Chem., Int. Ed. 2012,
51, 11328. (d) Zheng, J.; Huang, Y.; Li, Z. Phosphine-Catalyzed
Domino Benzannulation: An Efficient Method to Construct Biaryl
Skeletons. Org. Lett. 2013, 15, 5064. (e) Yao, W.; Dou, X.; Lu, Y.
Highly Enantioselective Synthesis of 3,4-Dihydropyrans through a
Phosphine-Catalyzed [4 + 2] Annulation of Allenones and β,γ-
Unsaturated α-Keto Esters. J. Am. Chem. Soc. 2015, 137, 54. (f) Ni,
H.; Yao, W.; Waheed, A.; Ullah, N.; Lu, Y. Enantioselective [4 + 2]-
Annulation of Oxadienes and Allenones Catalyzed by an Amino Acid
Derived Phosphine: Synthesis of Functionalized Dihydropyrans. Org.
Lett. 2016, 18, 2138. (g) Wang, C.; Gao, Z.; Zhou, L.; Yuan, C.; Sun,
Z.; Xiao, Y.; Guo, H. Phosphine-Catalyzed [2 + 4] Annulation of
Allenoates with Thiazolone-Derived Alkenes: Synthesis of Function-
alized 6,7-Dihydro-5H-pyrano[2,3-d]thiazoles. Org. Lett. 2016, 18,
3418. (h) Wang, Z.; Wang, T.; Yao, W.; Lu, Y. Phosphine-Catalyzed
Enantioselective [4 + 2] Annulation of o-Quinone Methides with
Allene Ketones. Org. Lett. 2017, 19, 4126.
(6) For selected examples, see: (a) Fujiwara, Y.; Fu, G. Application
of a New Chiral Phosphepine to the Catalytic Asymmetric Synthesis
of Highly Functionalized Cyclopentenes that Bear an Array of
Heteroatom-Substituted Quaternary Stereocenters. J. Am. Chem. Soc.
2011, 133, 12293. (b) Zhong, F.; Han, X.; Wang, Y.; Lu, Y. Highly
Enantioselective [3 + 2] Annulation of Morita−Baylis−Hillman
Adducts Mediated by l-Threonine−Derived Phosphines: Synthesis of
3-Spirocyclopentene-2-Oxindoles Having Two Contiguous Quater-
nary Centers. Angew. Chem., Int. Ed. 2011, 50, 7837. (c) Han, X.;
Wang, Y.; Zhong, F.; Lu, Y. Enantioselective [3 + 2] Cycloaddition of
Allenes to Acrylates Catalyzed by Dipeptide-Derived Phosphines:
Facile Creation of Functionalized Cyclopentenes Containing
Quaternary Stereogenic Centers. J. Am. Chem. Soc. 2011, 133, 1726.
̈
̈
(d) Dakas, P.-Y.; Parga, J. A.; Hoing, S.; Scholer, H. R.; Sterneckert, J.;
Kumar, K.; Waldmann, H. Discovery of Neuritogenic Compound
Classes Inspired by Natural Products. Angew. Chem., Int. Ed. 2013, 52,
9576. (e) Henry, C. E.; Xu, Q.; Fan, Y. C.; Martin, T. J.; Belding, L.;
Dudding, T.; Kwon, O. Hydroxyproline-Derived Pseudoenantiomeric
[2.2.1] Bicyclic Phosphines: Asymmetric Synthesis of (+)- and
(−)-Pyrrolines. J. Am. Chem. Soc. 2014, 136, 11890. (f) Sankar, M. G.;
Garcia-Castro, M.; Golz, C.; Strohmann, C.; Kumar, K. Engaging
Allene-Derived Zwitterions in an Unprecedented Mode of Asym-
metric [3 + 2]-Annulation Reaction. Angew. Chem., Int. Ed. 2016, 55,
9709. (g) Chan, W.; Tang, X.; Zhang, F.; Quek, G.; Mei, G.; Lu, Y.
Phosphine-Catalyzed (3 + 2) Annulation of Isoindigos with Allenes:
Enantioselective Formation of Two Vicinal Quaternary Stereogenic
Centers. Angew. Chem., Int. Ed. 2019, 58, 6260. (h) Li, K.; Goncalves,
T. P.; Huang, K. W.; Lu, Y. Dearomatization of 3-Nitroindoles by a
Phosphine-Catalyzed Enantioselective [3 + 2] Annulation Reaction.
Angew. Chem., Int. Ed. 2019, 58, 5427. (i) Wang, H.; Zhang, J.; Tu, Y.;
Zhang, J. Phosphine-Catalyzed Enantioselective Dearomative [3 + 2]-
Cycloaddition of 3-Nitroindoles and 2-Nitrobenzofurans. Angew.
Chem., Int. Ed. 2019, 58, 5422.
E
https://dx.doi.org/10.1021/acs.orglett.0c00637
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(10) (a) Xiao, H.; Chai, Z.; Zheng, C.-W.; Yang, Y.-Q.; Liu, W.;
Zhang, J.-K.; Zhao, G. Asymmetric [3 + 2] Cycloadditions of
Allenoates and Dual ActivatedOlefins Catalyzed by Simple Bifunc-
tional N-Acyl Aminophosphines. Angew. Chem., Int. Ed. 2010, 49,
4467. (b) Zhu, S.-F.; Yang, Y.; Wang, L.-X.; Liu, B.; Zhou, Q.-L.
Synthesis and Application of Chiral Spiro Phosphocin Ligand in Pd-
Catalyzed Asymmetric Allylation of Aldehydes with Allylic Alcohols.
Org. Lett. 2005, 7, 2333.
(11) Crystallographic data for 3aa and 4aa has been deposited with
the Cambridge Crystallographic Data Centre as deposition number
CCDC 1898871 and 1921150, respectively.
F
https://dx.doi.org/10.1021/acs.orglett.0c00637
Org. Lett. XXXX, XXX, XXX−XXX