Regioselectivity Switch in Palladium-Catalyzed Allenylic Cycloadditions of Allenic Esters: [4+1] or [4+3] Cycloaddition/Cross-Coupling

Article abstract of DOI:10.1002/anie.201901511

The first Pd-catalyzed asymmetric allenylic [4+1] cycloaddition was successfully developed. Alternatively, tuning the Pd catalyst switched the reactivity toward an unprecedented [4+3] cycloaddition/cross-coupling. Ligands play a vital role in controlling the reaction pathway, allowing highly selective access to different products from identical substrates. Biological evaluation of the obtained compounds led to the discovery of new antitumor targets. A possible mechanism is proposed, suggesting two interesting catalytic cycles for the cycloaddition with palladium-butadienyls. This study also demonstrated the potential and utility of allenic esters as 1,4-biselectrophiles and C₄ synthons for participating in cycloaddition reactions.

Full text of DOI:10.1002/anie.201901511

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Regioselectivity Switch in Palladium−Catalyzed Allenylic
Cycloadditions of Allenic Esters: [4+1] or [4+3] Cycloaddition/
Cross-Coupling by Ligands
Authors: Zhihui Shao, Long Li, Pengfei Luo, and Yuhua Deng
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901511
Angew. Chem. 10.1002/ange.201901511
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10.1002/anie.201901511
Angewandte Chemie International Edition
COMMUNICATION
Regioselectivity Switch in Palladium−Catalyzed Allenylic Cycloadditions
of Allenic Esters: [4+1] or [4+3] Cycloaddition/Cross-Coupling by
Ligands
Long Li,† Pengfei Luo,† Yuhua Deng, and Zhihui Shao*
Dedicated to Professor Shengming Ma
Abstract: The first Pd-catalyzed asymmetric allenylic [4+1] cycloaddition
was successfully developed. Alternatively, tuning Pd catalysts switched the
reactivity toward an unprecedented [4+3] cycloaddition/cross coupling.
Ligands play a vital role in controlling the reaction pathway, allowing highly
selective access to different products from identical substrates. Biological
evaluation of the obtained compounds led to the discovery of new good
antitumor targets. A possible mechanism was proposed, suggesting two
interesting catalytic cycles for the cycloaddition with palladium−butadienyls.
This study also demonstrated the potential and utility of allenic esters as 1,4-
biselectrophiles and C4 synthons for participating in cycloaddition reactions.
II that enable the generation of two chiral stereocenters with high level of
stereocontrol remain unrealized to date.
Another attractive feature of the current methodology is that changing the
ligand of the Pd catalyst switched the reactivity toward an unprecedented
[4+3] cycloaddition/cross-coupling. Reaction strategies allowing
regiodivergence represent one of the most cutting-edge developments in
synthetic organic chemistry and medicinal chemistry. However, such
examples are few.[6] To our knowledge, examples of transition-metal-
catalyzed [4+1] and [4+3] cycloaddition reactions by changing the ligand
have not been previously reported.
Synthetically, this study not only is valuable in the construction of
diverse and valuable carbocycles and heterocycles including 4-
spiropyrazolones,[7] but also provides a novel and straightforward synthesis
of [3]dendralenes. In recent years, [3]dendralenes or cross-conjugated trienes
have gained growing interests because of their unique role in polymer
chemistry, theoretical chemistry, and synthetic chemistry, as well as their
occurrence as a motif in many natural products.[8] To date only a few methods
are available for the synthesis of this important class of compounds.[9]
Transition-metal-catalyzed cycloadditions are of wide interest due to their
fundamental importance in organic, medicinal, and materials chemistry.[1]
Most reactions proceed through metal-associated dipolar-type intermediates,
which involve one electrophilic center and one nucleophilic center. A
tactically complementary method involves non-dipolar-type intermediates.
The development of such strategy will significantly expand the cycloaddition
chemistry, yet remains a formidable challenge.
The metal butadienyl species II, which features electronically distinct
sp2- and sp-hybridized electrophilic carbons, is a promising synthetic
intermediate in organic synthesis (Figure 1a). However, the cycloaddition
with the metal butadienyl intermediates has remained elusive. Pyrazolones
and pyrazoles are important heterocycles possessing a wide range of valuable
biological properties.[2] In particular, pyrazolones have been known for more
than one century and have emerged as a versatile and powerful synthon for
the synthesis of new, potentially bioactive pyrazole and pyrazolone
derivatives.[2c,d]
a) Previous work: Allenylic substitution
M/L
•
•
M/L
Nu
Nu
LG
Nu or
R1
R1
differentiating the relatively similar CH2=C=CH and R1
R1
R1
I
II
Challenges in stereocontrol:
b) This work: Allenylic cycloaddition
O
[Pd]
R2
Xylyl-PhanePhos
N
R1
N
[4+1] cycloaddition
R3
III
O
good yield
high dr and ee
Herein, we disclose the first example of cycloaddition of pyrazolones
with palladium−butadienyl intermediates (Figure 1b). This is also the first
time that terminal allenylic compounds of type I as 1,4-biselectrophiles and
four-atom units were used in cycloaddition. By identifying a new planar
chiral Pd catalyst, the catalytic asymmetric version of [4+1] cycloaddition
was also achieved, providing a novel and useful method for the construction
of cyclopentenes.[3] Achieving the asymmetric allenylic cycloadditions is far
from obvious. As documented by Ma,[4a,b] the differentiation of the relatively
similar propadienyl and R1 groups is challenging (Figure 1a).[5] Furthermore,
catalytic asymmetric allenylic transformations with metal butadienyl species
•
R2
N
LG
+
I
R1
N
[3]dendralene
R3
[Pd]
PPh3
O
R1
[4+3] cycloaddition R2
/cross-coupling
7
N
R1
IV
N
R3
up to 98% yield
>20:1 E/Z
Challenges: controlling chemo-, regio- and stereoselectivity
Figure 1. Design and development of allenylic cycloadditions. LG = leaving
group; M = metal.
At the outset of this study, we examined the reaction of allenyl acetate 1a
with pyrazolone 2a in the presence of different palladium complexes as the
catalysts. Interestingly, the use of the ligand t-BuDavePhos afforded
exclusively the [4+1] cycloaddition product 3a, while the use of the ligand
PPh3 led to the product 4a exclusively by a formal [4+3] cycloaddition/cross-
coupling process (Scheme 1).
[*]
L. Li, P. Luo, Dr. Y. Deng, Prof. Dr. Z. Shao
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of
Education, School of Chemical Science and Technology, State Key
Laboratory for Conservation and Utilization of Bio-Resources in Yunnan,
Yunnan University, Kunming 650091, China
E-mail: zhihui_shao@hotmail.com
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201901511
Angewandte Chemie International Edition
COMMUNICATION
O
O
O
Pd2(dba)3 (2.5 mol %)
[Pd(allyl)Cl]2 (2.5 mol %)
OAc
R2
R2
Ph
t-BuDavePhos (5.5 mol %)
N
P(t-Bu)2
L37 (5.5 mol %)
N
N
+
N
Ph
R1
N(Me)2
R1
K2CO3 (3.0 equiv)
O
N
N
PhMe, 30 o
C
DIPEA, CH3CN/C6HF5
4 Å MS, 30 oC, 10 h
3a
R3
3a,
R3
OAc
66% yield,
>20:1
10:1 dr
1
2
3
Ph
N
3a 4a
/
t-BuDavePhos
+
Ph
2 = C6H5, 65%, 8/1 dr, 89% ee
N
R
R
R
3b,
O
2 = 4-Me-C6H4, 60%, 9/1 dr, 90% ee
2 = 3-OMe-C6H4, 62%, 10/1 dr, 89% ee
1a
2a
Pd2(dba)3 (2.5 mol %)
PPh3 (12 mol %)
O
Ph
3c,
R2
Ph
N
N
3d, R2 = 4-Cl-C6H4, 67%, 6/1 dr, 91% ee
3e, R2 = 3-Cl-C6H4, 74%, 8/1 dr, 91% ee
3f, R2 = 3-Br-C6H4, 68%, 7/1 dr, 92% ee
3g, R2= 3-CF3-C6H4, 64%, 8/1 dr, 91% ee
3h,
K2CO3 (3.0 equiv)
PhMe, rt
N
Ph
4a
61% yield, >20:1 4a/3a, >20:1 E/Z
N
Me
Scheme 1. Initial results of Pd-catalyzed allenylic cycloaddition of allenyl
R
2 = 3,5-(CH3)2-C6H3, 76%, 8/1 dr, 91% ee
acetates and pyrazolones.
2 = 3,5-(Cl)2-C6H3, 82%, 6/1 dr, 93% ee
3i,
3j,
R
R
Me
1 = 4-Me- C6H4, 60%, 8/1 dr, 90 % ee
O
Encouraged by these results, we investigated the asymmetric version of
this novel Pd-catalyzed [4+1] cycloaddition using chiral ligands. In a
comprehensive screening of ligands L1–L38 (see the Supporting
Information for the details), most chiral ligands were unreactive or gave low
yield and poor enantioselectivity for the asymmetric [4+1] allenylic
cycloaddition. Pleasingly, phanePhos ligands with planar chirality afforded
the promising results, with moderate yield as well as enantio- and
diastereoselectivity (entries 4-6, Table 1).
3k, R1 = 3-Me-C6H4, 55%, 8/1 dr, 90% ee
3l, R1 = 3-F-C6H4, 60%, 7/1 dr, 90% ee
3m, R1 = 2-Np, 50%, 9/1 dr, 89% ee
N
Me
N
R1
Me
O
1
3o,
R = 3-Me-C6H4, 74%, 8/1 dr, 91% ee
3p[b], R1= 4-CF3-C6H4, 51%, 11/1 dr, 85% ee
3q, R1= 2-Np, 50%, 9/1 dr, 89% ee
N
N
R1
Me
MeO
O
O
N
Table 1. Pd-catalyzed asymmetric allenylic [4+1] cycloaddition with chiral
ligands.[a]
N
N
N
O
O
[Pd(allyl)Cl]2 (2.5 mol %)
ligand (5.5 mol %)
O
Ph
Me
Et
Ph
OAc
N
N
Ph
N
N
N
N
Ph
+
+
Ph
K2CO3
PhMe, 30 oC
3n,
3r,
68%, 7/1 dr, 88% ee OPh
67%, 6/1 dr, 87% ee
Ph
Ph
4a
Scheme 2. The scope of Pd-catalyzed asymmetric allenylic [4+1] cycloaddition.
[a] See the Supporting Information for detailed reaction conditions. [b] C6HF5
was used as the solvent.
2a
3a
1a
Entry
Ligand
3a/4a[b]
Yield [%][c]
dr[b]
ee[d]
1
2
3
4
5
6
L1
L2
L10
L36
L37
L38
10:1
-
-
30
trace
18
-
-
-
10
-
Next, we turned our attention to the allenylic [4+3] cycloaddition. We
identified Pd(cod)Cl2/Ph3 as the optimal catalyst for this reaction (see the
Supporting Information for the details). This unprecedented [4+3]
cycloaddition/cross-coupling reaction displayed a broad scope of allenyl
acetates 1 and pyrazolones 2, providing a novel family of [3]dendralene
(Scheme 3). This reaction is also the first catalytic [4+3] cycloaddition of
pyrazolones. Taken together, this study represents the first catalyst-
controlled [4+1] and [4+3] cycloadditions of pyrazolones. The structure of
the product 4w was determined by X-ray crystal analysis.[12]
-
6:1
7:1
5:1
46
51
33
4/1
4/1
4/1
53
57
45
[a] Reactions were performed with 1a (0.1 mmol), 2a (0.15 mmol), [Pd(allyl)Cl]2 (2.5 mol %),
ligand (5.5 mol %) and K2CO3 (5.0 equiv) in 0.5 mL of PhMe at 30 oC for 10 h. [b] Determined
by 1NMR. [c] Yield of isolated product 3a. [d] Determined by chiral HPLC.
O
O
PAr2
O
O
PPh2
PPh2
O
O
PPh2
PPh2
PAr 2
PAr 2
PAr2
O
O
L36, Ar = Ph
L2
L1
L10
Ar = 3,5-(t-Bu)2-4-OMe-C6H2
L37
Ar = 3,5-(Me) 2-C6H2
, Ar = 4-OMe-C6H3
L38
To improve the stereoselectivity and yield, bases and solvents were next
examined. When DIPEA was used as the base, enantio- and
diastereoselectivity were significantly improved (see the Supporting
Information for the details). Among solvents screened, the mixture solvent
CH3CN/C6HF5 was found to be the best one. With the addition of 4 Å MS,
the formation of [4+3] cycloaddition product 4a was completely suppressed.
Finally, the chiral allenylic [4+1] cycloaddition product 3a was obtained in
65% yield with 8:1 dr and 89% ee (Scheme 2).
With the optimized catalyst and conditions in hand, the scope of Pd-
catalyzed asymmetric allenylic [4+1] cycloaddition was investigated.
Generally, the reaction displayed a broad scope of allenyl acetates 1 and
pyrazolones 2 (Scheme 2). Various valuable chiral five membered 4-
spiropyrazolones[10] were obtained in good yields with high chemo-, enantio-,
and diastereoselectivities. This reaction is also the first metal-catalyzed
asymmetric [4+1] cycloaddition of pyrazolones. The relative and absolute
configuration of the product 3p was determined by X-ray crystal analysis.[11]
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10.1002/anie.201901511
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COMMUNICATION
with allenyl acetates. So far only few enantioselective methods for the
asymmetric synthesis of isoxazolinones with C-centered electrophiles has
been reported due to the difficulty in regiocontrol of different competitive
nucleophilic centers (C, N, O).[14] Pleasingly, the desired product 6 could be
accessed smoothly in 64% with 7:1 dr and 88% ee in the presence of a planar
chiral Pd catalyst (Scheme 5).
O
Pd(cod)Cl2 (5 mol %)
R1
OAc
R2
PPh3 (12 mol %)
O
N
+
R2
R1
N
N
K2CO3, CHCl3
rt, 10 h
R1
R3
N
R3
1
4
(> 20:1 E/Z)
2
4a, R1 = Ph, 92%
4b, R1 = 4-Me-C6H4, 77%
4c, R1 = 3-Me-C6H4, 90%
4g, R1 = 3-CF3-C6H4, 85%
4h, R1 = 4-Cl-C6H4, 94%
4i, R1 =3,5-(Me) 2-C6H3, 75%
O
O
O
R1
Pd(dba)2 (5.0 mol %)
OAc
Ph
Ph
4d, R1 = 4-OPh-C6H4, 85% 4j, R1 =3,5-(F) 2-C6H3, 79%
N
N
L37
(5.5 mol %)
O
*
*
O
R1
+
1
4e,
4f,
4k,
4l,
R
1 = 4-Ph-C6H4, 76%
1 = 4-CF3-C6H4, 70%
R = 2-Furan, 70%
Ph
N
N
Ph
Et3N , THF
50 oC, 10 h
1
Me
R
R = 2-Np, 90%
Ph
Ph
1a
5
6
2
2
4m,
4q,
R = 4-Me-C6H4, 93%
R = 4-Br-C6H4, 98%
64%, 7/1 dr, 88% ee
4n, R2= 3-OMe-C6H4, 83% 4r, R2= 3-Br-C6H4, 98%
4o, R2= 3-OCF3-C6H4, 91% 4s, R2= 3,5-(F)2-C6H3, 88%
4p, R2= 4-CF3-C6H4, 86%
O
Scheme 5. Regio-, chemo-, diastereo-, and enantioselective [4+1] cycloaddition
of isoxazolinone 5a with allenyl acetate 1a.
Ph
R2
N
4t, R2= 2-Np, 98%
N
Ph
Ph
In summary, we have successfully developed the allenylic cycloaddition
with the metal butadienyl intermediates. By identifying a planar chiral ligand,
the first Pd-catalyzed asymmetric allenylic [4+1] cycloaddition was also
achieved, providing a novel and useful method for the construction of
cyclopentenes. Furthermore, a switch in catalyst also allowed an allenylic
[4+3] reaction pathway, leading to an unprecedented [4+3]
cycloaddition/cross-coupling. These reactions allow to selective access to
different products from identical substrates by tuning the ligands of the
catalysts. This study not only is valuable in the construction of diverse and
valuable carbocycles and heterocycles, but also provides a novel and
straightforward synthesis of [3]dendralenes. Biological evaluation of the
obtained compounds led to the discovery of new good antitumor molecules.
The present study demonstrated the potential and utility of allenic esters as
versatile 1,4-biselectrophiles and C4 synthons for participating in
cycloaddition.
Me
Br
O
O
3
Ph
4u,
R = Et, 95%
R3= Ph, 91%
Ph
N
CF3
N
4v,
N
N
R3
Me
4w,
88%
CF3
Scheme 3. The scope of Pd-catalyzed [4+3] allenylic cycloaddition/cross-
coupling. See the Supporting Information for detailed reaction conditions.
A possible reaction mechanism was tentatively proposed in Scheme 4.
1a
1a
Ph
Pd(II)
Ph
AcO
Pd(II)
O
Ph
O
N
Ph
N
N
F
OAc
Pd(II)
N
L
E
Pd(0)L
Ph
Ph
4a
3a
A
OH
Acknowledgments
2a+Base
Pd(II)
Ph
L
Pd(0)
N
Ph
N
This work was supported by NSFC (21672184, 21861042), the Program for
Changjiang Scholars and Innovative Research Team in University
(IRT13095), the Program for Innovative Research Team (in Science and
Technology) in University of Yunnan Province, Yunnan Province
Government (2018FY001(016)), and Yunling Scholar of Yunnan Province.
Pd(II)
Ph
C
O
O
Base
Ph
Ph
N
N
Base-H OAc
Ph
Base-H
N
N
B
D
Scheme 4. Proposed reaction mechanism of Pd-catalyzed [4+1] and [4+3]
cycloaddition.
Keywords: cycloaddition • Pd • regiodivergence • 1,4-biselectrophiles
Oxidative addition of allenyl acetate 1a by the resulting chiral Pd(0) complex
affords Pd(II) butadienyl species A, which then undergoes allenylic
substitution with pyrazolone 2a to give the intermediate C. Pd-catalyzed
• [3]dendralenes
[1]
[2]
[3]
a) Cycloaddition Reactions in Organic Synthesis, (Eds.: S. Kobayashi, K. A.
Jorgensen), Wiley-VCH, Weinheim, 2001; b) P. A. Inglesby, P. A. Evans, Chem.
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913.
intramolecular carbopalladation furnishes
D
which undergoes
protodepalladation to produce the spirocyclic product 3a and regenerate the
Pd(II) complex to the next catalytic cycle. With PPh3 as the ligand, Pd(II)-
catalyzed intramolecular oxypalladation of C generates the seven-membered
intermediate E, which then undergoes a cross-coupling reaction with another
molecule of allene 1a to give species F. Finally, trans-β-
deacyloxypalladation generates the product 4a with exclusive formation of
the E-isomer and concomitant regeneration of the palladium(II) species to
the next catalytic cycle.
For a book on pyrazolone chemistry, see: a) “Pyrazol-3-ones. Part IV: Synthesis
and Applications”: G. Varvounis in Advances in Heterocyclic Chemistry, Vol.
98 (Ed.: A. R. Katritzky), Academic Press, New York, 2009, p. 143; For selected
review, see: b) D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev. 2003,
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12890; d) S.-Y. Liu, X.-Z. Bao, B.-M. Wang, Chem. Commun. 2018, 54, 11515,
and references cited therein.
Newly synthesized allenylic cycloaddition products were preliminarily
evaluated for their in vitro anticancer activities against cervical cancer cell
lines (A549, SGC7901 and HeLa) (see the Supporting Information for the
details). To our delight, several compounds displayed good inhibition
activities. Among them, 4-spiropyrazolone 3q exhibited the best inhibitory
activity against HeLa and SGC7901 cell lines with IC50 of 1.9 μM and 2.7
μM, respectively.
The cyclopentene scaffold is widely present in numerous bioactive naturally
occurring molecules. For elegant reviews on the construction of cyclopentenes,
see: a) R. A. A. Widenhoefer, Angew. Chem. Int. Ed. 2009, 48, 6950; b) J.-R.
Chen, X.-Q. Hu, L.-Q. Lu, W.-J. Xiao, Chem. Rev. 2015, 115, 5301.
a) Q. Li, C. Fu, S. Ma, Angew. Chem. Int. Ed. 2012, 51, 11783; b) Q. Li, C. Fu,
S. Ma, Angew. Chem. Int. Ed. 2014, 53, 6511.
[4]
[5]
As an important expansion of scope for the Pd-catalyzed asymmetric
allenylic [4+1] cycloaddition, we examined isoxazolinones, another
biologically and synthetically interesting class of heterocycles,[13] to react
Indeed, few catalytic enantioselective allenylic substitutions with metal
butadienyl species II exist in the literature. a) ref. 4; b) D. A. Petrone, M.
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10.1002/anie.201901511
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COMMUNICATION
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[7]
4-Spiro-5-pyrazolones are inhibitors of type-4 phosphodiesterase. a) I.
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[11] CCDC 1892650 [(5S,6R)-3p] contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
[12] CCDC 1892652 [(E)-4w] contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
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10.1002/anie.201901511
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
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COMMUNICATION
Long Li, Pengfei Luo, Yuhua Deng, and
Zhihui Shao*
Page No. – Page No.
Regioselectivity Switch in
Palladium−Catalyzed Allenylic
Cycloadditions of Allenic Esters:
[4+1] or [4+3] Cycloaddition/Cross-
Coupling by Ligands
Switchable regioselectivity. The application of the metal−butadienyl species in the
cycloaddition is exemplified by the first Pd-catalyzed asymmetric allenylic [4+1]
cycloaddition. Notably, tuning Pd catalysts switched the reactivity toward an
unprecedented [4+3] cycloaddition/cross coupling. These reactions not only are
valuable in the construction of diverse and valuable carbocycles and heterocycles,
but also provide a novel and straightforward synthesis of [3]dendralenes. Biological
evaluation of the obtained compounds led to the discovery of new good antitumor
targets.
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