Experimental and Computational Studies of Palladium-Catalyzed Spirocyclization via a Narasaka-Heck/C(sp3or sp2)-H Activation Cascade Reaction

Wan-Xu Wei, Yuke Li, Ya-Ting Wen, Ming Li, Xue-Song Li, Cui-Tian Wang, Hong-Chao Liu, Yu Xia,

Article

Experimental and Computational Studies of Palladium-Catalyzed

Spirocyclization via a Narasaka−Heck/C(sp or sp )−H Activation

Cascade Reaction

‡

Bo-Sheng Zhang, Rui-Qiang Jiao, and Yong-Min Liang*

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sı Supporting Information

ABSTRACT: The ﬁrst synthesis of highly strained spirocyclobu-

tane-pyrrolines via a palladium-catalyzed tandem Narasaka−Heck/

C(sp or sp )−H activation reaction is reported here. The key step in

this transformation is the activation of a δ-C−H bond via an in situ

generated σ-alkyl-Pd(II) species to form a ﬁve-membered spiro-

palladacycle intermediate. The concerted metalation-deprotonation

(

CMD) process, rate-determining step, and energy barrier of the

entire reaction were explored by density functional theory (DFT)

calculations. Moreover, a series of control experiments was

conducted to probe the rate-determining step and reversibility of

the C(sp )−H activation step.

INTRODUCTION

Scheme 1. Previous Studies and This Study

■

Tremendous developments over the past few decades have

exploited the high atom and step economies of palladium-

catalyzed C−H bond activation, which has become a powerful

tool for fabricating useful compounds, including medicines,

industrial materials, and natural products. Numerous pioneer-

ing palladium-catalyzed directing-group-(DG)-assisted C−H

bond activations have been widely reported. Palladium-

catalyzed intramolecular Heck-type cyclization/C−H bond

activation reactions have also been extensively studied as a

complementary strategy for remote C−H activation. This

eﬃcient strategy consists of using a transient σ-alkyl-Pd(II)

species generated in situ during Heck cyclization to remotely

activate a C−H bond for the eﬀective one-step preparation of

complex heterocyclic and carbocyclic molecular skeletons from

well-designed starting materials. Grigg and co-workers

reported the ﬁrst example of utilizing the σ-alkyl-Pd(II)

intermediate of Heck cyclization for intramolecular C−H bond

activation. A wide range of spirocyclic compounds have since

been produced via Heck cyclization, C−H activation, and

direct reductive elimination or migratory insertion through

metal center. In most cases, oxidative addition of aryl

halogens has been used to trigger domino reactions that form

σ-alkyl-Pd(II) intermediates, and other generation mechanisms

ﬁve-membered palladacycle intermediate I (Scheme 1a). In

017, Lautens and co-workers successfully implemented this

protocol to activate C(sp )−H groups in alkene-tethered aryl

iodides to obtain spiro-fused benzocyclobutenes via ﬁve-

membered palladacycle intermediate I (Scheme 1a). In sharp

contrast to these achievements, C(sp )−H bond activation by

a σ-alkyl-Pd(II) intermediate has been signiﬁcantly less

exploited because of its low acidity, high bond dissociation

energy, and lack of stabilizing orbital interactions with the

Received: April 19, 2021

Published: May 11, 2021

2021 American Chemical Society

J. Am. Chem. Soc. 2021, 143, 7868−7875

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remain underexplored. To the best of our knowledge, the

Table 1. Optimization of the Tandem Narasaka−Heck/

ﬁve-membered palladacycle intermediate II (Scheme 1a)

C(sp )−H Activation Reaction Conditions

formed by δ-C(sp )−H activation by a σ-alkyl-Pd(II)

intermediate has not been reported to date, and its direct

reductive elimination would be an eﬀective route to build

highly strained cyclobutane.

In 1999, Narasaka and co-workers ﬁrst reported that pyrrole

could be eﬃciently synthesized by the palladium-catalyzed

entry

Pd source

Pd(OAc)

ligand

PCy ·HBF

solvent

yield (%)

cyclization of a γ,δ-unsaturated oxime ester, a process known

as the Narasaka−Heck reaction. Since then, this type of

reaction has been widely used to synthesize structurally diverse

dioxane

toluene

MeCN

DMSO

toluene

trace

^P^d⁽^O^A^c⁾2

^P^d⁽^P^P^h3⁾

^P^C^y^·^H^B^F4

N-heterocyclic compounds, such as imidazoles, indoles,

^P^C^y^·^H^B^F4

pyridines, and isoquinolines. Bower, Tong, Zhu, and

^P^C^y^·^H^B^F4

PPh

P Bu ·HBF

other groups have used the σ-alkyl-Pd(II) intermediate of

Narasaka−Heck cyclization in many nucleophile-trapping

reactions to complete the acylation, carboxylation, arylation,

vinylation, alkynylation, and halogenation of pyrrolines

^P⁽^o^-^T^o^l⁾3

^P^C^y^p^·^H^B^F4

(Scheme 1b). In addition, in 2019, our group reported the

^P^C^y^·^H^B^F4

ﬁrst polyﬂuorophenylation of the σ-alkyl-Pd(II) intermediate

−

^P^d⁽^T^F^A⁾2

^P^d⁽^P^C^y3⁾

^P^C^y^·^H^B^F4

of Narasaka−Heck cyclization, in which a C F source was

−

produced via the decarboxylation of a C F CO leaving

^P^d⁽^O^A^c⁾2

^P^C^y^·^H^B^F4

group. Altogether, a series of functionalized pyrrolines and

N-heterocyclic compounds have been built by this type of

reaction, but the synthesis of spiropyrrolines, which are

regarded as signiﬁcant scaﬀolds in drug development and

discovery, remains a challenge. In addition, previous

Narasaka−Heck reactions mainly focused on the nucleophile-

trapping and β-hydrogen elimination of its σ-alkyl-Pd(II)

intermediate; tandem intramolecular C−H activation had not

been developed until now.

Domino Heck/C(sp )−H activation reactions of alkene-

tethered aryl halogens have been well-documented over the

years; in contrast, C(sp )−H activation of the transient

C(sp )-Pd species is challenging and has rarely been reported.

^P^C^y^·^H^B^F4

^P^d⁽^O^A^c⁾2

^P^C^y^·^H^B^F4

−

^P^C^y^·^H^B^F4

Reaction conditions unless otherwise noted: 1a (0.2 mmol), Pd

source (10 mol %), ligand (20 mol %), Cs CO (2.0 equiv), solvent

2 mL), 140 °C, 12 h, Ar; isolated yields. 150 °C. 24 h. K CO

used instead of Cs CO ; L1 = 1,2-bis(dicyclohexylphosphino)ethane;

(

2 3

PCyp ·HBF = tricyclopentylphosphine tetraﬂuoroborate.

eﬀective than PCy ·HBF (Table 1, entry 9). Using other

palladium sources, such as Pd(PPh ) , Pd(TFA) , and

Pd(PCy ) , did not improve the yield (Table 1, entries 10−

2). However, elevating the temperature to 150 °C improved

the isolated yield of 2a to 75% (Table 1, entry 13). Prolonging

the reaction time did not further increase the yield (Table 1,

entry 14). Replacing Cs CO with K CO (Table 1 , entry 15)

resulted in an isolated yield of 2a of 64% (see Supporting

Information for the further screening of bases). A control

experiment showed that palladium is necessary for the

transformation (Table 1, entry 16).

Investigation of the Substrate Scope. Having opti-

mized the reaction conditions (Table 1, entry 13), we

examined the generality of the reaction. As shown in Table

2, the smooth reactions of many γ,δ-unsaturated oxime ester

substrates 1 produced moderate to good yields of the

corresponding spirocyclobutane-pyrroline products 2. First,

the inﬂuence of the aromatic ring subunit on the reaction

outcome was evaluated. Notably, γ,δ-unsaturated oxime esters

with electron-donating groups, including methyl (2b),

methoxy (2c), dimethylamino (2d), and phenyl (2e) groups,

at the para-position of the aryl rings showed high reactivity in

this reaction. Furthermore, substrates with electron-with-

drawing substituents, such as ﬂuoro (1f), triﬂuoromethoxy

(1g) and triﬂuoromethyl (1h) groups, at the para-position

were transformed into 2f, 2g, and 2h in 64%, 79%, and 67%

yields, respectively. Both electron-donating (methyl, 2i) and

electron-withdrawing (ﬂuoro, triﬂuoromethyl, 2j−2l) groups

in the meta-position were well tolerated, and good yields of the

corresponding spirocyclobutane-pyrrolines were obtained.

Only a 20% yield was achieved for the transformation of

substrate 1l bearing Me in the ortho-position of the aryl ring,

Nevertheless, our group has been studying domino C(sp )−H

activation by a σ-alkyl-Pd(II) intermediate. We designed a

novel palladium-catalyzed domino intramolecular Narasaka−

Heck/C(sp )−H activation reaction (Scheme 1c) to synthe-

size spirocyclobutane-pyrrolines from γ,δ-unsaturated oxime

esters via the new ﬁve-membered palladacycle intermediate II

which is formed by δ-C(sp )−H activation. The reaction is

triggered by oxidative addition to the N−O bond, which is

diﬀerent from the domino Heck/C−H activation reaction of

an alkene-tethered aryl halogen.

RESULTS AND DISCUSSION

■

Reaction Optimization. To meet the above-mentioned

challenges, we ﬁrst employed γ,δ-unsaturated oxime ester 1a as

a substrate to verify the feasibility of the well-designed domino

process (Table 1). The introduction of a tertiary butyl group

ensures the formation of a σ-alkyl-Pd(II) species without a β-

hydrogen atom and provides a suitable site for C(sp )−H

activation. The anticipated domino reaction was conducted in

the presence of Pd(OAc) , PCy ·HBF , and Cs CO in 1,4-

dioxane at 140 °C for 12 h under an argon atmosphere,

generating the desired product 2a in 41% yield (Table 1, entry

). Next, various solvents (Table 1, entries 1−4) were carefully

screened, and toluene was identiﬁed as the optimal choice

because it resulted in an improved isolated product yield of

0%. Further studies were used to determine that the electron-

rich monophosphine PCy ·HBF₄was the most suitable

phosphine ligand for this system (Table 1, entries 5−8). The

bisphosphine ligand was also suitable for this process but less

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Table 2. Substrate Scope of the Tandem Narasaka−Heck/

Unfortunately, substrate 1z failed to give the corresponding

product, possibly because the freely rotating methyl group was

less accessible to the palladium center and there were fewer

reactive C−H bonds.

C(sp )−H Activation Reaction

The above-mentioned results showed that the σ-alkyl-Pd(II)

intermediate of Narasaka−Heck cyclization can be used for

intramolecular δ-C(sp )−H activation. Inspired by these

results, we explored the tandem Narasaka−Heck/C(sp )−H

activation reaction using substrate 3a . Considerable inves-

tigation (see the Supporting Information) led to the following

optimized conditions, under which 4a was produced in 63%

yield: a catalytic system consisting of Pd(P Bu ) , XPhos, and

Cs CO in 1,4-dioxane at 100 °C for 12 h under an argon

atmosphere. We then explored the substrate scope of this

reaction. The alkyl moiety and the two aromatic rings of the

substrate could be changed, thus providing a new class of

spirocyclobutane-pyrrolines (4a−4q) (Table 3). The aryl ring

Table 3. Substrate Scope of the Tandem Narasaka−Heck/

C(sp −H) Activation Reaction

Reaction conditions unless otherwise noted: 1 (0.2 mmol),

Pd(OAc)₂(10 mol %), PCy ·HBF (20 mol %), Cs CO (2.0

equiv), toluene (2 mL), 150 °C, 12 h, Ar; isolated yields. The

diastereomeric ratio was determined by H NMR.

presumably because of steric congestion, whereas substrate 1m

with a tethered ortho-substituent gave 2m in a satisfactory yield

of 65%. Polysubstituted reactants 1n-1q were successfully

transformed, aﬀording 2n−2q in 74%−55% yields. Similarly,

electron-rich naphthalene oxime ester 1r could participate in

the process. The 2-thiophene-substituted product 2s was

generated in a 62% yield, indicating the compatibility of the

heterocycle. Substrate 1t bearing spirocyclobutane at the alkyl

chain moieties was also transformed by this reaction to give 2t

in 41% yield. However, substrate 1y was poorly tolerated and

failed to give the corresponding product, probably because of

the absence of the gem-dimethyl eﬀect. The structures of 2e

and 2n were deﬁ nitively elucidated by X-ray crystal structure

analysis (see the Supporting Information).

Reaction conditions unless otherwise noted: 3 (0.2 mmol),

Pd(P Bu ) (10 mol %), XPhos (20 mol %), Cs CO (2.0 equiv),

,4-dioxane (2 mL), 100 °C, 12 h, Ar; isolated yields. 24 h.

on the oxime ester could be substituted at the meta- or para-

position with a wide scope of functional groups, including

electron-donating methyl (4b) and methoxy (4c) groups and

electron-withdrawing triﬂuoromethyl (4d and 4e) groups.

Unfortunately, the reaction of the sterically hindered substrate

3f did not proceed smoothly, and the expected cascade

product 4f was detected only in trace amounts. However,

several polysubstituted reactants (3g−3i) were perfectly

tolerated, aﬀording 4g−4i in 61%, 60%, and 51% yields,

respectively. A substrate containing electron-rich naphthalene

(3j) could also be transformed into the corresponding product.

Next, we explored the scope of γ,δ-unsaturated oxime ester

substrates without tert-butyl groups. As expected, substrates

(

2v and 2w) with esters on the quaternary carbon were

tolerated under the optimized conditions. Substrate 1u bearing

an ethyl group cyclized smoothly and satisfactorily at the

methyl group to generate the desired product 2u in 68% yield

with a 1:1 diastereomeric ratio. Note that substrate 1x bearing

an isopropyl group instead of a tert-butyl group also aﬀorded

the target product 2x, indicating that a quaternary carbon is

Remarkably, substrate 3k with spirocyclobutane as the R and

R substituents could also cyclize. Substituting the aryl ring on

not essential for this cascade C(sp )−H bond activation.

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J. Am. Chem. Soc. 2021, 143, 7868−7875

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Figure 1. Computed Gibbs free energy proﬁle of the tandem Narasaka−Heck/C(sp )−H activation reaction. The relative free energies are

−

presented in kcal mol .

the alkene with electron-rich or electron-deﬁcient groups, such

as ﬂuoro (3l and 3p), methyl (3m and 3n), methoxy (3o) and

triﬂuoromethyl (3q) groups, aﬀorded the desired products 4l−

Scheme 2. Control Experiments

q of the cascade reaction. Subsequently, the structures of 4a

and 4i were deﬁnitively elucidated by X-ray crystal structure

analysis (see the Supporting Information ).

Computational Studies and Control Experiments.

Figure 1 shows the results of DFT calculations that were

performed to gain insight into the mechanism of the tandem

Narasaka −Heck/C(sp )−H activation reaction (see the

Supporting Information for details). As shown in Figure 1,

coordination of the palladium catalyst to γ,δ-unsaturated oxime

ester 1 provides intermediate B, which undergoes an oxidative

addition process to generate intermediate D. Steric hindrance

−

prevents C F CO in intermediate D from chelating with the

palladium center. Subsequently, intermediate E undergoes

Narasaka−Heck cyclization through transition state F-ts with

an energy barrier of 14.3 kcal mol⁻to form the σ-alkyl-Pd(II)

intermediate G. Intermediate G undergoes concerted metal-

ation-deprotonation (CMD) via transition state H-ts with an

energy barrier of 31.9 kcal mol⁻to produce ﬁve-membered

spiro-palladacycle intermediate J. Then, the reductive elimi-

nation of intermediate J, which has an energy barrier of 17.7

−

kcal mol , generates intermediate M, and the desired product

is obtained via the dissociation of complex M. In summary,

the DFT calculation results indicated that the energy barrier of

−

the entire reaction is 31.9 kcal mol , and C(sp )−H bond

intermolecular competition experiment using equimolar

cleavage during CMD is the rate-determining step.

amounts of 1v and 1v-D gave an intermolecular KIE value

To gain further insight into the reaction mechanism, a series

of control experiments was performed (Scheme 2). Consider-

of 2.6 (Scheme 2b), suggesting that the cleavage of the

C(sp )−H bond during the CMD step of the tandem

2−

ing that CO₃from Cs CO is also likely to function during

Narasaka−Heck/C(sp )−H activation reaction might be the

the CMD process, we used C F COOCs instead of Cs CO

rate-determining step, which is consistent with the results of

under the standard conditions, and substrate 1a could be

transformed into 2a in 73% yield (Scheme 2a), which

the computational studies. To probe whether the C(sp )−H

activation step (intermediate G to I via H-ts) is reversible,

which seems possible based on the DFT-calculated energies, a

well-designed H/D scrambling experiment was performed with

−

2−

indicated that it might be C F COO rather than CO₃

that functions as a ligand during the CMD process. Next, an

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J. Am. Chem. Soc. 2021, 143, 7868−7875

Journal of the American Chemical Society

v-D (Scheme 2c). However, no H/D-exchanged products

were detected in the NMR spectrum (see the Supporting

Information), probably because the subsequent steps are easier

https://pubs.acs.org/doi/10.1021/jacs.1c04114.

Article

H bonds by the in situ-generated σ-alkyl-Pd(II) species to

form a ﬁve-membered spiro-palladacycle intermediate. The

reaction has a wide substrate scope, and the product yield is as

high as 80%. A series of computational studies and control

experiments provided some insights into the reaction

mechanism, which should facilitate the development of novel

catalytic domino reactions for challenging diverse C−H

functionalization procedures.

for intermediate I. Similarly, intermolecular kinetic experi-

ments with substrates 3a and 3a-D revealed that C(sp )−H

bond cleavage is most likely the rate-determining step in the

tandem Narasaka−Heck/C(sp )−H activation reaction

(Scheme 2d).

We proposed a mechanism for the palladium-catalyzed

tandem Narasaka−Heck/C(sp )−H activation reaction (see

ASSOCIATED CONTENT

sı Supporting Information

■

Scheme 3) based on the above experimental results and

The Supporting Information is available free of charge at

Scheme 3. Proposed Mechanism of the Palladium-Catalyzed

Tandem Narasaka−Heck/C(sp )−H Activation Reaction

Experimental procedures, compound characterization,

and NMR spectra (PDF)

Accession Codes

CCDC 2050684, 2050686 , and 2050688−2050689 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.

AUTHOR INFORMATION

■

Corresponding Author

Yong-Min Liang − State Key Laboratory of Applied Organic

Chemistry, Lanzhou University, Lanzhou 730000, China;

orcid.org/0000-0001-8280-8211; Email: liangym@

lzu.edu.cn

Authors

Wan-Xu Wei − State Key Laboratory of Applied Organic

Chemistry, Lanzhou University, Lanzhou 730000, China

Yuke Li − Department of Chemistry and Centre for Scientiﬁc

Modeling and Computation, Chinese University of Hong

Kong, Shatin, Hong Kong, China

Ya-Ting Wen − State Key Laboratory of Applied Organic

Chemistry, Lanzhou University, Lanzhou 730000, China

Ming Li − State Key Laboratory of Applied Organic

Chemistry, Lanzhou University, Lanzhou 730000, China

Xue-Song Li − State Key Laboratory of Applied Organic

Chemistry, Lanzhou University, Lanzhou 730000, China

Cui-Tian Wang − State Key Laboratory of Applied Organic

Chemistry, Lanzhou University, Lanzhou 730000, China

Hong-Chao Liu − State Key Laboratory of Applied Organic

Chemistry, Lanzhou University, Lanzhou 730000, China

Yu Xia − Urumqi Key Laboratory of Green Catalysis and

Synthesis Technology, College of Chemistry, Xinjiang

University, Urumqi 830046, P.R. China

mechanistic studies, as well as results reported in the

literature. Initially, imino-Pd(II) intermediate D is formed

through the oxidative addition of the in situ generated Pd(0)

to γ,δ-unsaturated oxime ester 1. Then, σ-alkyl-Pd(II)

intermediate G is generated by an intramolecular Heck

cyclization, which cannot undergo β-hydrogen elimination

because of the presence of the angular tertiary butyl group.

Instead, intermediate G undergoes CMD via transition state

H-ts to produce ﬁve-membered spiro-palladacycle intermedi-

ate J, thus completing the activation of the C(sp )−H bond,

and the desired product 3 is produced through subsequent

reductive elimination.

Bo-Sheng Zhang − College of Chemistry and Chemical

Engineering, Northwest Normal University, Lanzhou, Gansu

CONCLUSIONS

In summary, we developed a palladium-catalyzed intra-

■

730070, P.R. China; orcid.org/0000-0003-1148-0065

Rui-Qiang Jiao − State Key Laboratory of Applied Organic

Chemistry, Lanzhou University, Lanzhou 730000, China

molecular Narasaka−Heck/C(sp or sp )−H activation

cascade reaction, which is an economically eﬃcient protocol

for assembling highly strained spirocyclobutane-pyrrolines.

This reaction represents the ﬁrst case of using the σ-alkyl-

Pd(II) intermediate of Narasaka−Heck cyclization for intra-

Complete contact information is available at:

https://pubs.acs.org/10.1021/jacs.1c04114

molecular C(sp or sp )−H activation. Remarkably, the key

Author Contributions

W.-X.W. and Y.L. contributed equally to this work.

‡

step of this reaction requires the activation of δ-C(sp or sp )−

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J. Am. Chem. Soc. 2021, 143, 7868−7875

Journal of the American Chemical Society

C Bond Formation. J. Am. Chem. Soc. 2016 , 138 , 6384 −6387.

Article

Funding

c) Baudoin, O. Ring Construction by Palladium(0)-Catalyzed

Scott, M. E.; Lautens, M. Aryl −Aryl Bond Formation by Transition-

National Natural Science Foundation of China (NSF

C(sp )−H Activation. Acc. Chem. Res. 2017 , 50 , 1114 −1123.

21532001 and 21772075).

(4) (a) Shilov, A. E.; Shul’pin, G. B. Activation of C −H Bonds by

Notes

Metal Complexes. Chem. Rev. 1997 , 97 , 2879 −2932. (b) Alberico, D.;

Metal-Catalyzed Direct Arylation. Chem. Rev. 2007, 107, 174−238.

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

d) Zhu, R.-Y.; Liu, L.-Y.; Yu, J.-Q. Highly Versatile β -C(sp )−H

The computations reported in this paper were performed on

the computer clusters at the Centre for Scientiﬁc Modeling and

Computation, CUHK. We thank ACS Authoring Services for

providing language editing assistance during the preparation of

this manuscript.

Iodination of Ketones Using a Practical Auxiliary. J. Am. Chem. Soc.

017 , 139 , 12394 −12397. (e) Daugulis, O.; Do, H.-Q.; Shabashov, D.

Palladium- and Copper-Catalyzed Arylation of Carbon −Hydrogen

Bonds. Acc. Chem. Res. 2009 , 42 , 1074 −1086. (f) Park, H.; Yu, J.-Q.

Palladium-Catalyzed [3 + 2] Cycloaddition via Twofold 1,3-C(sp )−

H Activation. J. Am. Chem. Soc. 2020 , 142 , 16552 −16556. (g) Zhang,

Y.-H.; Shi, B.-F.; Yu, J.-Q. Pd(II)-Catalyzed Olefination of Electron-

Deficient Arenes Using 2,6-Dialkylpyridine Ligands. J. Am. Chem. Soc.

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