Synthesis of γ-Lactams via Pd(II)-Catalyzed C(sp3)-H Olefination Using a Self-Cleaving Polyfluoroethylsulfinyl Directing Group

Article abstract of DOI:10.1021/acs.orglett.0c00326

A monodentate directing group, 2-chlorotetrafluoroethylsulfinylmide (-NHSOCF2CF2Cl), for inert C(sp3)-H bond activation is reported. This directing group shows efficient ability in Pd(II)-catalyzed C(sp3)-H olefination. The desired olefination products un

Full text of DOI:10.1021/acs.orglett.0c00326

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Letter
Synthesis of γ‑Lactams via Pd(II)-Catalyzed C(sp3)−H Olefination
Using a Self-Cleaving Polyfluoroethylsulfinyl Directing Group
Nan-Qi Shao, Yu-Hao Chen, Chen Li,* and Dong-Hui Wang*
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ABSTRACT: A monodentate directing group, 2-chlorotetrafluor-
oethylsulfinylmide (-NHSOCF2CF2Cl), for inert C(sp3)−H bond
activation is reported. This directing group shows efficient ability in
Pd(II)-catalyzed C(sp3)−H olefination. The desired olefination
products undergo subsequent Michael addition and in situ
expulsion of the auxiliary to provide the free NH γ-lactam
products. Preliminary mechanistic studies reveal that the auxiliary
group is crucial for C(sp3)−H activation.
ransition-metal-catalyzed C−H olefination has attracted a
T
tremendous amount of interest, as this family of synthetic
methods can enable rapid construction of bioactive molecules.1
Nevertheless, the activation of aliphatic C(sp3)−H bonds
remains challenging, due to the combination of high pKa (pKa
> 40) and high bond dissociation energy (BDE > 400 kJ/
mol).2 Moreover, selectively targeting only one C−H bond
among many alternative C−H bonds in a similar chemical
environment is difficult.3 In recent years, using a directing
group strategy, several C(sp3)−H olefination precedents have
been reported with Pd catalysts. Using heterocyclic directing
groups (e.g., pyridine4a or pyrazole4b) or cyclic aliphatic
amines4c,d as directing groups, Sanford, Yu, and Gaunt
developed straightforward C(sp3)−H olefinations that afforded
open-chain or cyclized products (Figure 1a).4 A removable
directing group strategy has also proven to be successful,5 as
initially reported by Yu in the β-C(sp3)−H olefination of
N-perfluorinated aryl amides.5a Similar types of auxiliaries have
also facilitated γ-C(sp3)−H olefination of amine/amide
substrates with the aid of pyridine- or quinoline-based ligands,
providing lactams or pyrrolidines after subsequent intra-
molecular cyclization.5b−d Maiti achieved γ-C(sp3)−H olefina-
tion to give open-chain products with widely used bidentate 8-
aminoquinoline6 as the directing group (Figure 1b).5e
Though these seminal breakthroughs demonstrated the
ability to achieve reactivity and selectivity in C(sp3)−H
olefination, the removal of these exogenous auxiliaries is
required, which generally involves tedious concession steps
and/or harsh conditions.7 To overcome this problem, Yu
reported a free carboxylic acid-directed ligand-enabled β-
C(sp3)−H olefination in 2018. This transformation provided
γ-lactones by the subsequent 1,4-addition (Figure 1c),8 but the
synthesis of γ-lactams via facile C(sp3)−H activation is not
compatible. Very recently, Yu reported that native amides are
Figure 1. Direct olefination of inert C(sp3)−H.
Received: July 28, 2020
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A

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also capable of directing β-C(sp3)−H olefination to provide
open-chain products, but the removal of the directing group is
still problematic.9 The application of a traceless directing
group strategy, which is well established in aryl C(sp2)−H
activation,10 would be highly enabling in C(sp3)−H function-
alization but remains underdeveloped.11 Herein, we report a
self-cleaving amide auxiliary, 2-chlorotetrafluoroethylsulfinyl
(SORf), and its application in C(sp3)−H olefination. In this
transformation, the auxiliary group (SORf) is automatically
removed from the desired products during the course of the
reaction, thus providing a straightforward protocol for
synthesizing free NH γ-lactams, an important bioactive core
structure.12 The N-2-chlorotetrafluoroethylsulfinyl (NHSORf)
auxiliary originates from an abundant industrial waste product,
ICF2CF2Cl, and can thus be easily prepared on a large scale.
Liu and Ellman have independently reported elegant uses of
this auxiliary in asymmetric nucleophilic addition.13
We began the study by examining the reaction of N-2-
chlorotetrafluoroethanesulfinyl pivalamide (1a) and ethyl
acrylate (2a) (Scheme 1). When using 10 mol % Pd(OAc)2
as the catalyst, 2 equiv of AgOAc as the oxidant, and
hexafluoro-2-propanol (HFIP) as the solvent, the desired
product 3a, resulting from C(sp3)−H olefination and the
subsequent Michael addition, was afforded in 14% yield (entry
1). The addition of a base to the reaction mixture significantly
increased the yield of 3a. For example, the use of 2 equiv of
NaTFA gave 3a in 52% yield (entry 2), and the use of CsF
afforded 3a in 72% yield (entry 3). To our delight, we isolated
lactam 4a as a second product in 12% yield, which indicated
that the polyfluoroalkylsulfinyl auxiliary (SORf) was removed
in situ under the reaction conditions. Next, we extensively
screened various bases, hoping to achieve the convenient
synthesis of γ-lactam by using this auxiliary as a self-cleaving
directing group in C(sp3)−H olefination (for details, see the
Supporting Information). It turned out that the yield of 4a
could be increased to 81% (78% isolated yield) when using 2
equiv of Na2CO3 as the base (entry 4). Other bases, such as
K2CO3, Cs2CO3, and NaHCO3, were found not only to
strongly inhibit the formation of 4a but also to depress
alkenylation of 1a (entries 5−7). We examined various
oxidants, only to find that AgOAc was optimal and that
other Ag+ or Cu2+ salts were less effective or ineffective for the
formation of 3a or 4a (entries 8−11). Under these conditions,
the reaction was equally effective under either N2 or O2
atmospheres (entry 12), indicating that AgOAc is likely
playing a key role in reoxidizing the Pd catalyst. Other solvents,
such as MeCN, PhCH3, and DCE, gave only 3a in low yields
or did not lead to product formation (entries 13−15,
respectively). The decreased reaction temperature resulted in
lower yield of 4a or incomplete conversion of the starting
material (entries 16 and 17). On the basis of these findings, we
chose entry 4 as the optimal conditions.
Different polyfluoroalkylsulfinyl (SORf) auxiliaries were next
tested under the optimal conditions (Scheme 2). Pivalamide
with a -CF3 auxiliary afforded a 35% yield of 4a, and the -C4F9
and -C6F13 auxiliaries provided 4a in 62% and 56% yields,
respectively. All of these auxiliaries were less efficient than
-CF2CF2Cl, demonstrating the unique proprieties of this
group.
a
Scheme 1. Optimization of the Reaction Conditions
Scheme 2. Efficiencies of Different Auxiliaries
Having optimized the conditions, we evaluated the substrate
scope for this transformation. Various α,α-dialkyl-substituted
propionic amides bearing the N-2-chlorotetrafluoroethylsulfin-
yl (NHSORf) auxiliary were examined, and the desired γ-
lactams were afforded in moderate to good yields via C(sp3)−
H activation (Scheme 3). The linear substituents on the
propionic amides, such as methyl, ethyl, 1-propyl, 2-propyl,
and 1-butyl, were compatible with this protocol and afforded
the desired γ-lactams in 56−78% yield (4a−4e). The
connectivity of 4a was confirmed by X-ray diffraction. α,α-
Diethyl-substituted propionic amide provided a 50% yield of
4f. Spirocyclic propionic amide was tolerated under the
reaction conditions, and the desired product 4g was achieved
in 51% yield. A substrate bearing a methoxy group was also
suitable, offering a 52% yield of the desired product 4h with a
1.5:1 diastereoselectivity. Phenyl substituents at the β, γ, or δ
position of the propionic amides were well tolerated (4i−4n),
and halogen substituents (i.e., -F, -Cl, and -Br) could be readily
accommodated on these aryl species (4i−4k and 4m). Though
a
Reaction conditions: 1a (0.2 mmol), 2b (0.6 mmol), Pd(OAc)2 (10
b
mol %), oxidant (2 equiv), base (2 equiv), HFIP (2 mL). Yields were
determined by 1H NMR analysis relative to the CH2Br2 internal
c
d
e
standard. Under a N2 or an O2 atmosphere. 100 °C. 80 °C.
B
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a
a
Scheme 3. Substrate Scope for β-C(sp3)−H Olefination
Scheme 4. Substrate Scope for Acrylates
a
Reaction conditions: 1a (0.2 mmol), 2b (3 equiv), Pd(OAc)2 (10
mol %), AgOAc (2 equiv), Na2CO3 (2.0 equiv), HFIP (2 mL), 120
°C, 12 h. 2,2,2-Trifluoroethyl acrylate was used, resulting in a
mixture of 5k (35%) and 5j (35%).
a
Reaction conditions: 1a (0.2 mmol), 2b (3 equiv), Pd(OAc)2 (10
mol %), AgOAc (2 equiv), Na2CO3 (2.0 equiv), HFIP (2 mL), 120
°C, 12 h.
b
low yields were obtained with β-aryl-substituted substrates,
moderate yields were provided when the aromatic rings were
instead located at the γ or δ positions, and the desired products
were obtained in 52−60% yields (4l−4n). This in situ
removable directing group could also be applied to aryl
C(sp2)−H olefination, when α,α-dimethyl-α-phenyl amide was
used as the starting material; under the optimal reaction
conditions, C−H olefination took place at the aryl C(sp2)−H
bond, providing the corresponding benzo-fused δ-lactam in
85% yield (4o).
The scope of the acrylate substrates was next examined with
N-2-chlorotetrafluoroethanesulfinyl pivalamide (1a). Various
acrylates were tolerated and provided the corresponding
products in moderate to good yields (Scheme 4). For simple
acrylates, such as methyl, tert-butyl, iso-butyl, cyclohexyl, and
benzyl acrylate, C(sp3)−H olefination took place smoothly and
provided the desired products in 66−75% yields (5a−5e,
respectively). The reaction also performed well for acrylates
that contain various functional groups; for example, methoxyl,
2-furanyl, and hydroxyl groups on the alkoxy fragment of the
acrylates were compatible and provided the corresponding γ-
lactams in 70−73% yields (5f−5h). A cyano group on the
acrylate was tolerated, albeit in a lower yield (5i). Hexafluoro-
2-propanyl acrylate afforded the desired coupling product in
60% yield (5j). When phenyl acrylate was used as the starting
material, the reaction delivered a 62% yield of 5j as the final
product, rather than the expected phenyl ester product, most
likely due to the alcoholysis with the HFIP solvent. Similarly,
2,2,2-trifluoroethyl acrylate afforded a mixture of free NH γ-
lactam 5j (35%) and 5k (35%) under these conditions.
Because self-cleaving directing groups have rarely been
reported in C−H functionalization research, several experi-
ments were conducted to shed light on the mechanistic details
of this reaction. First, when the reaction was performed in the
absence of acrylate, the starting material 1a was recovered in
81% isolated yield, and a trace amount of pivalamide 6 was
detected (eq 1). This result indicates that 1a is relatively stable
under the reaction conditions. Furthermore, when pivalamide
6 was used as the starting material in lieu of 1a under the
standard conditions, 6 was recovered, and no C(sp3)−H
activation products were detected (eq 2). This observation
suggests that amide 1a containing the polyfluoroalkylsulfinyl
(SORf) auxiliary is the active substrate in C(sp3)−H activation,
rather than pivalamide 6. On the basis of this insight, we
reasoned that the cleavage of the auxiliary group likely takes
place after the C(sp3)−H activation/olefination sequence,
though we have never isolated the C(sp3)−H activation/
olefination product(s). Finally, when we used the optically
enriched 1a (94% ee) as the starting material, we obtained the
desired γ-lactam product in 47% ee, in 71% isolated yield (eq
3). This result also supports the notion that the auxiliary group
is expelled after completion of the C(sp3)−H olefination/
cyclization cascade.
On the basis of these results, we propose a plausible reaction
mechanism for this Pd-catalyzed self-cleaving polyfluoroalkyl-
sulfinyl (SORf) auxiliary-directed C(sp3)−H olefination/
C
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Accession Codes
CCDC 1974038 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Dong-Hui Wang − Key Laboratory of Synthetic and Self-
Assembly Chemistry for Organic Functional Molecules, Center
for Excellence in Molecular Synthesis, University of Chinese
Academy of Sciences, Shanghai Institute of Organic Chemistry,
CAS, Shanghai 200032, China; orcid.org/0000-0002-
4318-5450; Email: dhwang@sioc.ac.cn
Chen Li − School of Biotechnology & Health Sciences, Wuyi
University, Jiangmen, Guangdong 529020, China;
Email: wyuchemlc@126.com
cyclization process (Scheme 5). The PdII catalyst coordinates
to the polyfluoroalkylsulfinylamide and activates the proximal
methyl C(sp3)−H bond to afford a five-membered palladacycle
intermediate A. The coordination of acrylate and 1,2-migratory
insertion of the Pd−C(sp3) bond into the olefin generate
intermediate C. Subsequent β-H elimination provides
olefinated intermediate D; the PdII catalyst is regenerated by
Ag+ to close the catalytic cycle. Olefinated intermediate D
undergoes intramolecular Michael addition and in situ cleavage
of the auxiliary to give the final γ-lactam product.
Authors
Nan-Qi Shao − Key Laboratory of Synthetic and Self-Assembly
Chemistry for Organic Functional Molecules, Center for
Excellence in Molecular Synthesis, University of Chinese
Academy of Sciences, Shanghai Institute of Organic Chemistry,
CAS, Shanghai 200032, China
Yu-Hao Chen − School of Biotechnology & Health Sciences,
Wuyi University, Jiangmen, Guangdong 529020, China
Scheme 5. Proposed Mechanism
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00326
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge support from the National
Key R&D Program of China (2016YFA0202900), the Strategic
Priority Research Program of the CAS (XDB20000000), and
CNSF 21871286. Y.-H.C. and C.L. thank the Foundation from
Guangdong Education Department (2016KCXTD005 and
2017KSYS010). The authors gratefully acknowledge Professor
Jin-Tao Liu of SIOC for his donation of ICF2CF2Cl.
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00326.
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