Directing-Group-Based Strategy Enabling Intermolecular Heck-Type Reaction of Cycloketone Oxime Esters and Unactivated Alkenes

Article abstract of DOI:10.1021/acs.orglett.0c00963

A new type of coupling between unactivated olefins and nonstabilized alkyl radicals was achieved, which enabled the first intermolecular Heck-type reaction of cycloketone oxime esters and unactivated alkenes. This directing-group-based strategy was compatible with various unactivated alkenes and cyclobutanone-, cyclopentanone-, and cyclohexanone-derived oxime esters. Density functional theory calculations showed that both excellent regioselectivities and good diastereoselectivities could be ascribed to the 2-butanol-assisted concerted H-OBz elimination of the conformationally strained metallacyclic transition state.

Full text of DOI:10.1021/acs.orglett.0c00963

pubs.acs.org/OrgLett
Letter
Directing-Group-Based Strategy Enabling Intermolecular Heck-Type
Reaction of Cycloketone Oxime Esters and Unactivated Alkenes
Yi Deng,# Chunyang Zhao,# Yu Zhou,# Hongwei Wang, Xuexiang Li, Gui-Juan Cheng, and Junkai Fu*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c00963
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A new type of coupling between unactivated olefins and nonstabilized alkyl radicals was achieved, which enabled the
first intermolecular Heck-type reaction of cycloketone oxime esters and unactivated alkenes. This directing-group-based strategy was
compatible with various unactivated alkenes and cyclobutanone-, cyclopentanone-, and cyclohexanone-derived oxime esters. Density
functional theory calculations showed that both excellent regioselectivities and good diastereoselectivities could be ascribed to the 2-
butanol-assisted concerted H−OBz elimination of the conformationally strained metallacyclic transition state.
functional group, the fleeting carbon radical intermediate is
he Nobel Prize-winning Mizoroki−Heck reaction of aryl/
Tvinyl (pseudo) halides and alkenes is considered as one of difficult to efficient capture with the already weakly reactive
the most powerful methods in constructing Csp2−Csp2 bonds.1
olefin partners. In addition, the control of both regio- and
diastereoselectivities would be challenging due to the potential
competing pathways for the final β-hydride elimination.7
Recently, the β-C−C bond cleavage of cycloketone oxime
esters11 has been demonstrated to be an efficient way to access
nonstabilized alkyl radicals containing a distal cyano group via
a SET process with transition metal catalysts12 or photoredox
catalysis.13 This chemistry has been successfully applied to a
variety of transformations of alkenes, including difunctionaliza-
tions,14 couplings,15 and type I Heck-like reactions16 (Figure
1b). However, all of these reactions are restricted to activated
alkene partners, presumably due to the difficulty in handling
these highly reactive alkyl radicals without the stabilization
modes.
Recent advances show that alkyl electrophiles could serve as
alternative partners to couple with alkenes and ultimately forge
the Csp2−Csp3 bonds.2 This Heck-type alkenylation typically
relies on a single-electron transfer (SET) process of alkyl
electrophiles to generate alkyl radical intermediates, which can
avoid neither slow oxidative addition nor β-hydride elimination
(Figure 1a).3 Current research mainly focuses on the
exploration of new catalytic systems or appropriate alkyl
radical precursors to cooperate with activated alkenes, e.g.,
styrenes, acrylates, or vinyl ethers (type I).4 In comparison, the
intermolecular Heck-type reaction of alkyl electrophiles with
unactivated olefins has received far less attention, with only a
few cases using functionalized alkyl electrophiles bearing
adjacent functionalities (type II). Dong,5 Gevorgyan,6 and
Fu7 have independently reported the Heck-type reaction of
unactivated alkenes and α-cyano/ester alkyl radical intermedi-
ates, leading to the formation of γ,δ-unsaturated nitriles and
esters. Various electrophilic trifluoromethylating reagents8 and
benzyl electrophiles9 were successfully employed to couple
with unactivated alkenes via either radical or ionic (due to no
detachable β-hydrogens) pathways. However, to the best of
our knowledge, the intermolecular Heck-type reaction of
unactivated alkenes and nonstabilized alkyl radical intermedi-
ates without adjacent functionalities10 has remained underex-
plored (type III). Without the stabilization by an adjacent
In conjunction with our continuing efforts in directed
copper-catalyzed functionalizations of unactivated alkenes,7,17
we envisioned that a combination of cycloketone oxime esters
and a directing-group-based strategy might be a potential
solution to realizing type III Heck-type reaction. The weak N−
Received: March 16, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00963
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Table 1. Optimization of the Reaction Conditions
% yield
c
(recovery of
rr
(3a:3a′) E:Z
b
c
entry
catalyst
CuCl
CuI
Cu(MeCN)4PF6 DMSO
solvent
DMSO
DMSO
1a)
1
2
3
4
5
6
7
8
32 (46)
44 (32)
34 (47)
35 (36)
48 (35)
46 (40)
0 (90)
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
−
−
−
5:1
5:1
1:1.2
1:1.8
1:1.4
1:1.5
1:1.7
1:1.5
−
CuCl2
Cu(OAc)2·H2O
Cu(OBz)2
FeCl2
NiCl2
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
THF
0 (84)
−
−
d
9
trace (82)
42 (35)
34 (40)
10
11
2.5:1
Figure 1. Intermolecular Heck-type reaction of alkyl electrophiles and
alkenes.
1,4-
dioxane
2:1
12
13
14
15
16
17
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
−
toluene
MeOH
25 (57)
45 (23)
60 (12)
31 (40)
68 (6)
<1:20
>20:1
>20:1
13:1
−
4:1
3:1
1.5:1
7.5:1
−
O bond and ring strain make the cycloketone oxime esters
easily undergo SET processes with the metal salts, especially
these having a low oxidation−reduction potential, such as
Cu(I), and therefore generate the nonstabilized alkyl radicals
very fast. In the meantime, installation of a directing group
might facilitate the intermolecular addition of a newly formed
alkyl radical to an unactivated olefin moiety and control the
regioselectivity via a kinetically favorable conformation of the
metallacyclic intermediate.18 This hypothesis ultimately
enabled the development of the first case of type III Heck-
type reaction of cycloketone oxime esters and unactivated
alkenes, providing an efficient cyanide-free synthesis of diverse
cyanoalkenes with excellent regioselectivities and good E
selectivities.
For optimization of the reaction conditions, we used 3-
butenoic acid masked as its 8-aminoquinoline (AQ)19 amide
1a and cyclobutanone O-benzoyl oxime 2a as standard
substrates (Table 1). Primary results demonstrated that
running the reactions in the presence of copper salts in
DMSO at 80 °C led to the formation of the desired coupled
products (entries 1−6). Despite excellent regioselectivities, as
expected, probably due to the assistance of DMSO,7 these
reactions suffered from inefficiency as well as low diaster-
eoselectivities.20 Other reductive metal salts, including Fe(II)
and Ni(II), were shown to be ineffective (entries 7 and 8,
respectively). Here we chose more readily available Cu(OAc)2
for further screening of conditions, although Cu(OBz)2
afforded a similar result. Contrary to expectation, addition of
base, which was thought to be beneficial for the coordination
of the directing group and metal salt, gave only a trace amount
of the desired product (entry 9).21 Switching the solvent to
THF or 1,4-dioxane resulted in a dramatically decreased
regioselective ratio, and only 3a′ was isolated in 25% yield
when nonpolar toluene was used (entries 10−12). Further
screening of solvents showed that the alcohols were crucial for
controlling both regio- and diastereoselectivities (entries 13−
16), with 2-butanol serving as the most effective solvent to
iPrOH
tBuOH
2-butanol
2-butanol
2-butanol
>20:1
−
>20:1
0 (81)
56 (16)
e
18
Cu(OAc)2·H2O
6:1
a
Conditions: 1a (0.20 mmol) and 2a (0.50 mmol) in solvent (2.0
mL) with metal salt (0.04 mmol) at 80 °C. Isolated yields of 3a and
b
c
1
3a′. The rr values and E:Z ratios were determined by H NMR.
d
e
With Cs2CO3 (0.20 mmol). Replacement of 2a with 2a′ (0.50
mmol).
afford 3a in a yield of 68% with an excellent rr value (>20:1)
and a good E:Z ratio (7.5:1) (as standard reaction conditions).
A control experiment performed without Cu(OAc)2·H2O
demonstrated that a copper catalyst is essential for the reaction
(entry 17). In addition, O-acetyl oximes 2a′ showed an inferior
yield of 56% with a moderate E:Z ratio (entry 18), while other
amide directing groups22 all failed to give either 3a or 3a′.
With the optimal reaction conditions established, we then
investigated the substrate scope of unactivated alkenes
(Scheme 1). A wide range of α-substituted terminal alkenes,
including n-butyl, electronically diverse (−OMe, −Cl, and
−Br) benzyl, and naphthyl forms, proved to be good partners
to afford 3b−g as single regioisomers with good to excellent
E:Z ratios. It is noteworthy that the addition of 2,6-di-tert-
butylpyridine in a mixed solvent improved the E:Z ratios for 3e
and 3g.23 The β−γ double bond could be selectively
functionalized in the presence of γ−δ olefin or acetylene
moieties to produce 3h and 3i. The formation of 3j−n
demonstrated that this reaction was compatible with diverse
functionalities, including halogen atom, ether, acetal, cyclo-
propyl, and even free hydroxyl groups. With regard to the
sterically hindered α,α-dimethyl- or -dibutyl-substituted
alkenes, the Heck-type reactions gave the corresponding
products 3o and 3p as single regioisomers and E isomers.
For the 1,1-disubstituted alkene, 3q was obtained with a minor
B
https://dx.doi.org/10.1021/acs.orglett.0c00963
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a,b
a,b
Scheme 1. Substrate Scope of Unactivated Alkenes
Scheme 2. Substrate Scope of Cycloketone Oxime Esters
a
b
c
Standard reaction conditions. Isolated yields. 2-Butanol/1,4-
dioxane (2:1, 2.0 mL) as the solvent with 2,6-di-tert-butylpyridine
d
(0.20 mmol) as the additive. 2-Butanol/THF (2:1, 2.0 mL) as the
solvent with 2,6-di-tert-butylpyridine (0.20 mmol) as the additive.
e
f
CuI (0.04 mmol). CuI (0.08 mmol).
amount of regioisomer (rr = 10:1) that was most likely
generated through the β-hydride elimination of a hydrogen on
the methyl group. To our delight, internal alkenes were shown
to be suitable substrates. The linear coupled product 3r was
isolated in a moderate yield of 48% (30% of alkene recovered;
2:1 E:Z), while cyclic 3s was formed in 73% yield in a highly
regioselective manner (rr = 13:1). However, as a limitation of
this protocol, the substrate with a γ−δ double bond failed.24
Next, we continued to test the generality of the developed
sequence by varying the structure of cycloketone oxime esters
(Scheme 2). The nonsymmetrical cyclobutanone oxime esters
with alkyl, olefin, substituted benzyl, haloalkyl, or ether groups
at the C2 position all underwent ring-opening processes
selectively at the more substituted carbon center, giving the
corresponding products 4a−i in good yields with both
excellent rr values and E:Z ratios. For symmetrical mono-
and disubstituted cyclobutanone oxime esters, including those
with diverse functionalities (substituted phenyl, ester, ether,
and amide groups), the internal alkenes 4j−t were obtained in
62−90% yields with slightly inferior E:Z ratios compared to
those of the C2-substituted oxime esters. Notably, the bicyclic
oxime esters proved to be suitable partners. The bicy-
clo[4.2.0]-type oxime ester afforded trans product 4u as a
major product, while the oxime ester derived from camphor
furnished 4v in 91% yield. To our delight, the less strained
a
b
c
Standard reaction conditions. Isolated yields. 2-Butanol/THF (2:1,
2.0 mL) as the solvent with 2,6-di-tert-butylpyridine (0.20 mmol) as
the additive. Cu(acac)2 (0.04 mmol).
d
cyclopentanone- and cyclohexanone-derived oxime esters
could also undergo the desired reaction pathway in a highly
regio- and diastereoselective manner. Products 4w−z were
obtained in superior yields (>90%), and a relatively low yield
of 45% for 4aa was found in the presence of Cu(acac)2.
Subjecting the estrone-based oxime derivative to the optimized
reaction conditions produced 4ab in 87% yield as a mixture of
diastereoisomers, showing the potential application of this
protocol in complex systems.
To demonstrate the synthetic applications, further trans-
formations of the coupled product 4b have been performed
(Scheme 3). Treatment of 4b with BF3·OEt2 in ethanol could
C
https://dx.doi.org/10.1021/acs.orglett.0c00963
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 3. Representative Derivatizations
convert the amide into corresponding ester 5 in 94% yield. A
two-step approach via protection followed by substitution
achieved the secondary amide transamidation to afford tertiary
amide 6. The cyano and amide groups could be reduced by
diisobutyl aluminum hydride into aldehyde and secondary
amine moieties, respectively, to give 7 in 85% yield. In
comparison, diamine compound 8 was obtained when
reduction of 4b with lithium aluminum hydride in refluxing
diethyl ether. Moreover, 4b could be hydrogenated into
cyanoamide 9 or undergo dihydroxylation to produce diol 10.
Several control experiments were conducted to gain insight
into the mechanism (Scheme 4). Addition of 3.0 equiv of
Figure 2. Proposed reaction mechanism.
nearby Cu(II) species. This formal migratory insertion process
afforded a putative directing-group-coordinated Cu(III)
intermediate M5.7,27,29 Eventually, Ha and Hb were distin-
guished during the concerted Ha−OBz (path a) or Hb−OBz
(path b) elimination of the conformationally strained metal-
lacyclic intermediate M5.8b,18 Major product 3a and minor one
3a′ were produced through the subsequent protodemetalation,
along with the regeneration of Cu(I) salt. The screening
conditions in Table 1 indicated that the solvent played a key
role in controlling the reaction selectivities, with 2-butanol
serving as the most effective one. Further DFT calculations
performed at the SMD(2-butanol)/(U)M06/[6-31G(d,p)/
LanL2DZ(Cu)] level (see Figure S1) showed that 2-butanol
was involved in the transition state of the concerted H−OBz
elimination process. The concerted Ha−OBz elimination is
much more difficult than concerted Hb−OBz elimination
(ΔΔG⧧ = 2.2 kcal/mol), and the barriers leading to the
formation of E- and Z-M7 were 19.0 and 20.5 kcal/mol,
respectively. It was found that the slight preference for E-M7
was attributed to the steric effect. In the transition state leading
to the formation of Z-M7, the distance between the hydrogen
of 2-butanol and the hydrogen of the substrate was only 2.2 Å.
These calculated results were consistent with the experimental
data of an excellent rr value and a good E:Z ratio.
In summary, a directed intermolecular Heck-type reaction of
cycloketone oxime esters and unactivated alkenes was achieved
for the first time, which represented a conceptually new type of
coupling between the unactivated alkene and alkyl electrophile
via nonstabilized alkyl radical species. All cyclobutanone-,
cyclopentanone-, and cyclohexanone-derived oxime esters and
a wide range of unactivated alkenes, including α-substituted,
1,1-disubstituted, and internal alkenes, were compatible.
Further derivatization of the resultant cyanoalkenes showed
the potential application prospect of this methodology in
organic synthesis. Detailed mechanistic studies and DFT
calculations disclosed that 2-butanol-assisted concerted H−
OBz elimination of the conformationally strained Cu(III)
cyclic transition state is the key to delivering the coupled
products in excellent regioselectivities and good E:Z ratios.
Scheme 4. Mechanistic Investigations
either BHT or TEMPO to the reaction mixture completely
suppressed the formation of desired product 3a, and the
cyanoalkyl−BHT and −TEMPO adducts 11 and 12 were
isolated in 57% and 68% yields, respectively, based on the
amount of oxime ester 2a.12f Moreover, a radical clock
experiment using oxime ester 13 as the substrate produced
ring-closed product 14 in 45% yield as a mixture of
diastereoisomers.12b,d These results indicate that the reaction
may involve a cyanoalkyl radical species.
According to the aforementioned experimental results and
previous reports,25−27 we propose a plausible reaction
mechanism. As shown in Figure 2, the disproportionation
reaction of the Cu(II) catalyst generated a Cu(I) species.28
Then species M1 was generated through the coordination of
Cu(I) salt with alkene 1a. A SET process between M1 and
oxime ester 2a would give the oxidized Cu(II)−OBz species
M2 and an iminyl radical M3, which underwent a fast selective
β-C−C bond scission to generate cyanoalkyl radical M4.
Subsequently, the nonstabilized radical species M4 might be
trapped in time by the environmental olefin moiety of M2, and
the resultant carbon radical would recombine rapidly with the
D
https://dx.doi.org/10.1021/acs.orglett.0c00963
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Soc. Rev. 2015, 44, 1070. (b) Nishikata, T.; Ishikawa, S. Challenges in
the substitution of terminal C−C double bonds with tertiary alkyl
groups. Synlett 2015, 26, 716.
(3) (a) Luh, T.-Y.; Leung, M.-k.; Wong, K.-T. Transition metal-
catalyzed activation of aliphatic C−X bonds in carbon−carbon bond
formation. Chem. Rev. 2000, 100, 3187. (b) Kwiatkowski, M. R.;
Alexanian, E. J. Transition-metal (Pd, Ni, Mn)-catalyzed C−C bond
constructions involving unactivated alkyl halides and fundamental
synthetic building blocks. Acc. Chem. Res. 2019, 52, 1134.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00963.
■
sı
Computational details, Figure S1, supplementary data,
experimental procedures, and analytical data for all new
compounds (PDF)
(4) For selected examples of intermolecular radical alkenylation of
alkyl electrophiles, see: (a) Lebedev, S. A.; Lopatina, V. S.; Petrov, E.
S.; Beletskaya, I. P. Condensation of organic bromides with vinyl
compounds catalysed by nickel complexes in the presence of zinc. J.
Organomet. Chem. 1988, 344, 253. (b) Ikeda, Y.; Nakamura, T.;
Yorimitsu, H.; Oshima, K. Cobalt-catalyzed Heck-type reaction of
alkyl halides with styrenes. J. Am. Chem. Soc. 2002, 124, 6514. (c) Liu,
C.; Tang, S.; Liu, D.; Yuan, J.; Zheng, L.; Meng, L.; Lei, A. Nickel-
catalyzed Heck-type alkenylation of secondary and tertiary α-carbonyl
alkyl bromides. Angew. Chem., Int. Ed. 2012, 51, 3638. (d) Nishikata,
T.; Noda, Y.; Fujimoto, R.; Sakashita, T. An efficient generation of a
functionalized tertiary-alkyl radical for copper-catalyzed tertiary-
alkylative Mizoroki−Heck type reaction. J. Am. Chem. Soc. 2013,
135, 16372. (e) McMahon, C. M.; Alexanian, E. J. Palladium-
catalyzed Heck-type cross-couplings of unactivated alkyl iodides.
Angew. Chem., Int. Ed. 2014, 53, 5974. (f) Zou, Y.; Zhou, J. Palladium-
catalyzed intermolecular Heck reaction of alkyl halides. Chem.
Commun. 2014, 50, 3725. (g) Liu, W.; Li, L.; Chen, Z.; Li, C.-J. A
transition-metal-free Heck-type reaction between alkenes and alkyl
iodides enabled by light in water. Org. Biomol. Chem. 2015, 13, 6170.
(h) Xie, J.; Li, J.; Weingand, V.; Rudolph, M.; Hashmi, A. S. K.
Intermolecular photocatalyzed Heck-like coupling of unactivated alkyl
bromides by a dinuclear gold complex. Chem. - Eur. J. 2016, 22,
12646. (i) Kurandina, D.; Parasram, M.; Gevorgyan, V. Visible light-
induced room-temperature Heck reaction of functionalized alkyl
halides with vinyl arenes/heteroarenes. Angew. Chem., Int. Ed. 2017,
56, 14212. (j) Wang, G.-Z.; Shang, R.; Cheng, W.-M.; Fu, Y.
Irradiation-induced Heck reaction of unactivated alkyl halides at room
temperature. J. Am. Chem. Soc. 2017, 139, 18307. (k) Zhu, K.; Dunne,
J.; Shaver, M. P.; Thomas, S. P. Iron-catalyzed Heck-type alkenylation
of functionalized alkyl bromides. ACS Catal. 2017, 7, 2353. (l) Wang,
G.-Z.; Shang, R.; Fu, Y. Irradiation-induced palladium-catalyzed
decarboxylative Heck reaction of aliphatic N-(acyloxy)phthalimides at
room temperature. Org. Lett. 2018, 20, 888. (m) Zhou, H.; Ge, L.;
Song, J.; Jian, W.; Li, Y.; Li, C.; Bao, H. HOTf-catalyzed alkyl-Heck-
type reaction. iScience 2018, 3, 255. (n) Chuentragool, P.; Yadagiri,
D.; Morita, T.; Sarkar, S.; Parasram, M.; Wang, Y.; Gevorgyan, V.
Aliphatic radical relay Heck reaction at unactivated C(sp3)−H sites of
alcohols. Angew. Chem., Int. Ed. 2019, 58, 1794. (o) Jiang, X.; Zhang,
M.-M.; Xiong, W.; Lu, L.-Q.; Xiao, W.-J. Deaminative (carbonylative)
alkyl-Heck-type reactions enabled by photocatalytic C−N bond
activation. Angew. Chem., Int. Ed. 2019, 58, 2402.
(5) Wu, X.; Riedel, J.; Dong, V. M. Transforming olefins into γ,δ-
unsaturated nitriles through copper catalysis. Angew. Chem., Int. Ed.
2017, 56, 11589.
(6) Kurandina, D.; Rivas, M.; Radzhabov, M.; Gevorgyan, V. Heck
reaction of electronically diverse tertiary alkyl halides. Org. Lett. 2018,
20, 357.
(7) Tang, C.; Zhang, R.; Zhu, B.; Fu, J.; Deng, Y.; Tian, L.; Guan,
W.; Bi, X. Directed copper-catalyzed intermolecular Heck-type
reaction of unactivated olefins and alkyl halides. J. Am. Chem. Soc.
2018, 140, 16929.
(8) (a) Parsons, A. T.; Buchwald, S. L. Copper-catalyzed
trifluoromethylation of unactivated olefins. Angew. Chem. 2011, 123,
9286. (b) Xu, J.; Fu, Y.; Luo, D.-F.; Jiang, Y.-Y.; Xiao, B.; Liu, Z.-J.;
Gong, T.-J.; Liu, L. Copper-catalyzed trifluoromethylation of terminal
alkenes through allylic C−H bond activation J. J. Am. Chem. Soc.
2011, 133, 15300. (c) Wang, X.; Ye, Y.; Zhang, S.; Feng, J.; Xu, Y.;
Zhang, Y.; Wang, J. Copper-catalyzed C(sp3)−C(sp3) bond formation
using a hypervalent iodine reagent: an efficient allylic trifluorome-
AUTHOR INFORMATION
Corresponding Author
■
Junkai Fu − Jilin Province Key Laboratory of Organic Functional
Molecular Design & Synthesis, Department of Chemistry,
Northeast Normal University, Changchun 130024, China;
orcid.org/0000-0002-7714-8818; Email: fujk109@
nenu.edu.cn
Authors
Yi Deng − Jilin Province Key Laboratory of Organic Functional
Molecular Design & Synthesis, Department of Chemistry,
Northeast Normal University, Changchun 130024, China
Chunyang Zhao − Jilin Province Key Laboratory of Organic
Functional Molecular Design & Synthesis, Department of
Chemistry, Northeast Normal University, Changchun 130024,
China
Yu Zhou − Warshel Institute for Computational Biology, School
of Life and Health Sciences, The Chinese University of Hong
Kong (Shenzhen), Shenzhen 518172, China; School of Life
Sciences, University of Science and Technology of China,
230027 Hefei, Anhui, China
Hongwei Wang − Jilin Province Key Laboratory of Organic
Functional Molecular Design & Synthesis, Department of
Chemistry, Northeast Normal University, Changchun 130024,
China
Xuexiang Li − School of Chemistry and Chemical Engineering,
Northwestern Polytechnical University, Xi’an 710072, China
Gui-Juan Cheng − Warshel Institute for Computational Biology,
School of Life and Health Sciences, The Chinese University of
Hong Kong (Shenzhen), Shenzhen 518172, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00963
Author Contributions
#Y.D., C.Z., and Y.Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the NNSFC (21702027,
21971034, 21602175, and 21871221) and the Fundamental
Research Funds for the Central Universities (2412019FZ017).
REFERENCES
■
(1) (a) Heck, R. F.; Nolley, J. P. Palladium-catalyzed vinylic
hydrogen substitution reactions with aryl, benzyl, and styryl halides. J.
Org. Chem. 1972, 37, 2320. (b) Mizoroki, T.; Mori, K.; Ozaki, A.
Arylation of olefin with aryl iodide catalyzed by palladium. Bull. Chem.
Soc. Jpn. 1971, 44, 581. (c) Dieck, H. A.; Heck, R. F. Organo-
phosphinepalladium complexes as catalysts for vinylic hydrogen
substitution reactions. J. Am. Chem. Soc. 1974, 96, 1133.
(2) For selected reviews, see: (a) Tang, S.; Liu, K.; Liu, C.; Lei, A.
Olefinic C−H functionalization through radical alkenylation. Chem.
E
https://dx.doi.org/10.1021/acs.orglett.0c00963
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
thylation. J. Am. Chem. Soc. 2011, 133, 16410. (d) Iqbal, N.; Choi, S.;
Kim, E.; Cho, E. J. Trifluoromethylation of alkenes by visible light
photoredox catalysis. J. Org. Chem. 2012, 77, 11383. (e) Beniazza, R.;
Visible-light-driven copper-catalyzed C(sp3)−O cross-coupling of
benzylic radicals with phenols. Org. Lett. 2020, 22, 2333.
(14) (a) Yu, X.-Y.; Zhao, Q.-Q.; Chen, J.; Chen, J.-R.; Xiao, W.-J.
Copper-catalyzed radical cross-coupling of redox-active oxime esters,
styrenes, and boronic acids. Angew. Chem., Int. Ed. 2018, 57, 15505.
(b) Ma, Z.-Y.; Guo, L.-N.; Gu, Y.-R.; Chen, L.; Duan, X.-H. Iminyl
radical-mediated controlled hydroxyalkylation of remote C(sp3)−H
bond via tandem 1,5-HAT and difunctionalization of aryl alkenes.
Adv. Synth. Catal. 2018, 360, 4341. (c) Zhang, J.; Li, X.; Xie, W.; Ye,
S.; Wu, J. Photoredox-catalyzed sulfonylation of O-acyl oximes via
iminyl radicals with the insertion of sulfur dioxide. Org. Lett. 2019, 21,
4950.
(15) (a) Zhao, J.-F.; Duan, X.-H.; Gu, Y.-R.; Gao, P.; Guo, L.-N.
Iron-catalyzed decarboxylative olefination of cycloketone oxime esters
with α,β-unsaturated carboxylic acids via C−C Bond cleavage. Org.
Lett. 2018, 20, 4614. (b) Shen, X.; Zhao, J.-J.; Yu, S. Photoredox-
catalyzed intermolecular remote C−H and C−C vinylation via iminyl
radicals. Org. Lett. 2018, 20, 5523.
(16) (a) Zhao, B.; Shi, Z. Copper-catalyzed intermolecular Hec-like
coupling of cyclobutanone oximes initiated by selective C−C bond
cleavage. Angew. Chem., Int. Ed. 2017, 56, 12727. (b) Yu, X.-Y.; Chen,
J.-R.; Wang, P.-Z.; Yang, M.-N.; Liang, D.; Xiao, W.-J. A visible-light-
driven iminyl radical-mediated C−C single bond cleavage/radical
addition cascade of oxime esters. Angew. Chem., Int. Ed. 2018, 57, 738.
(17) Li, Y.; Liang, Y.; Dong, J.; Deng, Y.; Zhao, C.; Su, Z.; Guan, W.;
Bi, X.; Liu, Q.; Fu, J. Directed copper-catalyzed intermolecular
aminative difunctionalization of unactivated alkenes. J. Am. Chem. Soc.
2019, 141, 18475.
(18) For the directing-group-coordinated metallacyclic intermediate
in regioselective β-hydride elimination, see: (a) Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. Ligand-accelerated C−H activation reactions:
evidence for a switch of mechanism. J. Am. Chem. Soc. 2010, 132,
14137. (b) Liu, B.; Fan, Y.; Gao, Y.; Sun, C.; Xu, C.; Zhu, J.
Rhodium(III)-catalyzed N-nitroso-directed C−H olefination of
arenes. High-yield, versatile coupling under mild conditions. J. Am.
Chem. Soc. 2013, 135, 468. (c) Maity, S.; Kancherla, R.; Dhawa, U.;
Hoque, E.; Pimparkar, S.; Maiti, D. Switch to allylic selectivity in
cobalt-catalyzed dehydrogenative Heck reactions with unbiased
aliphatic olefins. ACS Catal. 2016, 6, 5493.
(19) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. Highly
regioselective arylation of sp3 C−H bonds catalyzed by palladium
acetate. J. Am. Chem. Soc. 2005, 127, 13154. (b) Tran, L. D.; Popov,
I.; Daugulis, O. Copper-promoted sulfenylation of sp2 C−H bonds. J.
Am. Chem. Soc. 2012, 134, 18237.
(20) The control of E:Z selectivity is sometimes difficult during the
formation of 1,2-dialkyl-substituted alkenes, especially for those with a
weaker steric effect: Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.;
Grubbs, R. H. A general model for selectivity in olefin cross
metathesis. J. Am. Chem. Soc. 2003, 125, 11360.
(21) Oxime ester 2a decomposed smoothly with copper salt at
elevated temperatures, and the addition of base dramatically
accelerated the decomposition. Control experiments with
Cu(OAc)2·H2O (20 mol %) and 2a in DMSO (0.25 M) at 80 °C
showed that 50% of 2a was recovered after 1.5 h, while 2a was totally
decomposed in the presence of Cs2CO3 (1.0 equiv).
(22) (a) Gurak, J. A., Jr.; Engle, K. M. Regioselective hydro-
amination using a directed nucleopalladation/protodepalladation
strategy. Synlett 2017, 28, 2057. (b) Lin, C.; Shen, L. Recent progress
in transition metal-catalyzed regioselective functionalization of
unactivated alkenes/alkynes assisted by bidentate directing groups.
ChemCatChem 2019, 11, 961.
́
̀
Molton, F.; Duboc, C.; Tron, A.; McClenaghan, N. D.; Lastecoueres,
D.; Vincent, J.-M. Copper(I)-photocatalyzed trifluoromethylation of
alkenes. Chem. Commun. 2015, 51, 9571. (f) Kawamura, S.; Sodeoka,
M. Perfluoroalkylation of unactivated alkenes with acid anhydrides as
the perfluoroalkyl source. Angew. Chem., Int. Ed. 2016, 55, 8740.
(9) (a) Yang, Z.; Zhou, J. Palladium-catalyzed, asymmetric
Mizoroki−Heck reaction of benzylic electrophiles using phosphor-
amidites as chiral ligands. J. Am. Chem. Soc. 2012, 134, 11833.
(b) Standley, E. A.; Jamison, T. F. Simplifying nickel(0) catalysis: an
air-stable nickel precatalyst for the internally selective benzylation of
terminal alkenes. J. Am. Chem. Soc. 2013, 135, 1585.
(10) Ye, S.; Xiang, T.; Li, X.; Wu, J. Metal-catalyzed radical-type
transformation of unactivated alkyl halides with C−C bond formation
under photoinduced conditions. Org. Chem. Front. 2019, 6, 2183.
(11) For selected reviews, see: (a) Davies, J.; Morcillo, S. P.;
Douglas, J. J.; Leonori, D. Hydroxylamine derivatives as nitrogen-
radical precursors in visible-light photochemistry. Chem. - Eur. J. 2018,
24, 12154. (b) Yin, W.; Wang, X. Recent advances in iminyl radical-
mediated catalytic cyclizations and ring-opening reactions. New J.
Chem. 2019, 43, 3254. (c) Xiao, T.; Huang, H.; Anand, D.; Zhou, L.
Iminyl-radical-triggered C−C bond cleavage of cycloketone oxime
derivatives: generation of distal cyano-substituted alkyl radicals and
their functionalization. Synthesis 2020, 52, n/a DOI: 10.1055/s-0039-
1690844. For some seminal work, see: (d) Boivin, J.; Fouquet, E.;
Zard, S. Z. Ring opening induced by iminyl radicals derived from
cyclobutanones: new aspects of tin hydride cleavage of S-phenyl
sulfenylimines. J. Am. Chem. Soc. 1991, 113, 1055. (e) Nishimura, T.;
Yoshinaka, T.; Nishiguchi, Y.; Maeda, Y.; Uemura, S. Iridium-
catalyzed ring cleavage reaction of cyclobutanone O-benzoyloximes
providing nitriles. Org. Lett. 2005, 7, 2425.
(12) (a) Yang, H.-B.; Selander, N. Divergent iron-catalyzed coupling
of O-acyloximes with silyl enol ethers. Chem. - Eur. J. 2017, 23, 1779.
(b) Gu, Y.-R.; Duan, X.-H.; Yang, L.; Guo, L.-N. Direct C−H
cyanoalkylation of heteroaromatic N-oxides and quinones via C−C
bond cleavage of cyclobutanone oximes. Org. Lett. 2017, 19, 5908.
(c) Ai, W.; Liu, Y.; Wang, Q.; Lu, Z.; Liu, Q. Cu-catalyzed redox-
neutral ring cleavage of cycloketone O-acyl oximes: chemodivergent
access to distal oxygenated nitriles. Org. Lett. 2018, 20, 409. (d) Ding,
D.; Wang, C. Nickel-catalyzed reductive electrophilic ring opening of
cycloketone oxime esters with aroyl chlorides. ACS Catal. 2018, 8,
11324. (e) Zheng, M.; Li, G.; Lu, H. Photoredox- or metal-catalyzed
in situ SO2-capture reactions: synthesis of β-ketosulfones and
allylsulfones. Org. Lett. 2019, 21, 1216. (f) Tian, L.; Gao, S.; Wang,
R.; Li, Y.; Tang, C.; Shi, L.; Fu, J. Copper-catalyzed ring-opening
C(sp3)−N coupling of cycloketone oxime esters: access to 1°, 2° and
3° alkyl amines. Chem. Commun. 2019, 55, 5347. (g) Wang, T.; Wang,
Y.-N.; Wang, R.; Zhang, B.-C.; Yang, C.; Li, Y.-L.; Wang, X.-S.
Enantioselective cyanation via radical-mediated C−C single bond
cleavage for synthesis of chiral dinitriles. Nat. Commun. 2019, 10,
5373.
(13) (a) Li, L.; Chen, H.; Mei, M.; Zhou, L. Visible-light promoted
γ-cyanoalkyl radical generation: three-component cyanopropylation/
etherification of unactivated alkenes. Chem. Commun. 2017, 53,
11544. (b) Wang, P.-Z.; Yu, X.-Y.; Li, C.-Y.; He, B.-Q.; Chen, J.-R.;
Xiao, W.-J. A photocatalytic iminyl radical-mediated C−C bond
cleavage/addition/cyclization cascade for the synthesis of 1,2,3,4-
tetrahydrophenanthrenes. Chem. Commun. 2018, 54, 9925. (c) Zhao,
B.; Chen, C.; Lv, J.; Li, Z.; Yuan, Y.; Shi, Z. Photoinduced
fragmentation-rearrangement sequence of cycloketoxime esters. Org.
Chem. Front. 2018, 5, 2719. (d) Lu, B.; Cheng, Y.; Chen, L.-Y.; Chen,
J.-R.; Xiao, W.-J. Photoinduced copper-catalyzed radical amino-
carbonylation of cycloketone oxime esters. ACS Catal. 2019, 9, 8159.
(e) Chen, J.; Wang, P.-Z.; Lu, B.; Liang, D.; Yu, X.-Y.; Xiao, W.-J.;
Chen, J.-R. Enantioselective radical ring-opening cyanation of oxime
esters by dual photoredox and copper catalysis. Org. Lett. 2019, 21,
9763. (f) Yu, X.-Y.; Chen, J.; Chen, H.-W.; Xiao, W.-J.; Chen, J.-R.
(23) The improvement in the E:Z ratio is probably attributed to the
coordination of 2,6-di-tert-butylpyridine to the organometallic
intermediate, which would enhance the steric effect. However, the
corresponding yield is slightly decreased. In addition, a catalytic
amount (0.5 equiv) would give an inferior E:Z ratio compared to that
with 1.0 equiv of 2,6-di-tert-butylpyridine.
(24) The disfavor of a six-membered metallacyclic intermediate
showed an inherent distinction between copper and palladium or
F
https://dx.doi.org/10.1021/acs.orglett.0c00963
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
nickel: (a) O’Duill, M. L.; Matsuura, R.; Wang, Y.; Turnbull, J. L.;
Gurak, J. A., Jr.; Gao, D.-W.; Lu, G.; Liu, P.; Engle, K. M. Tridentate
directing groups stabilize 6-membered palladacycles in catalytic alkene
hydrofunctionalization. J. Am. Chem. Soc. 2017, 139, 15576. (b) Liu,
Z.; Ni, H.-Q.; Zeng, T.; Engle, K. M. Catalytic carbo- and
aminoboration of alkenyl carbonyl compounds via 5- and 6-
membered palladacycles. J. Am. Chem. Soc. 2018, 140, 3223.
(c) Derosa, J.; van der Puyl, V. A.; Tran, V. T.; Liu, M.; Engle, K.
M. Directed nickel-catalyzed 1,2-dialkylation of alkenyl carbonyl
compounds. Chem. Sci. 2018, 9, 5278. (d) Peng, J.-B.; Wu, F.-P.; Li,
D.; Geng, H.-Q.; Qi, X.; Ying, J.; Wu, X.-F. Palladium-catalyzed
regioselective carbonylative coupling/amination of aryl iodides with
unactivated alkenes: efficient synthesis of β-aminoketones. ACS Catal.
2019, 9, 2977.
transfer mechanisms in copper(II)-mediated aerobic C-H oxidation. J.
Am. Chem. Soc. 2013, 135, 9797.
(25) For selected examples of palladium-catalyzed directed
functionalization of unactivated alkenes, see: (a) Gurak, J. A., Jr.;
Yang, K. S.; Liu, Z.; Engle, K. M. Directed, regiocontrolled
hydroamination of unactivated alkenes via protodepalladation. J.
Am. Chem. Soc. 2016, 138, 5805. (b) Liu, M.; Yang, P.; Karunananda,
M. K.; Wang, Y.; Liu, P.; Engle, K. M. C(alkenyl)−H activation via
six-membered palladacycles: catalytic 1,3-diene synthesis. J. Am.
Chem. Soc. 2018, 140, 5805. (c) Wang, H.; Bai, Z.; Jiao, T.; Deng, Z.;
Tong, H.; He, G.; Peng, Q.; Chen, G. Palladium-catalyzed amide-
directed enantioselective hydrocarbofunctionalization of unactivated
alkenes using a chiral monodentate oxazoline ligand. J. Am. Chem. Soc.
2018, 140, 3542. (d) Wang, C.; Xiao, G.; Guo, T.; Ding, Y.; Wu, X.;
Loh, T.-P. Palladium-catalyzed regiocontrollable reductive Heck
reaction of unactivated aliphatic alkenes. J. Am. Chem. Soc. 2018,
140, 9332. (e) Shen, H.-C.; Zhang, L.; Chen, S.-S.; Feng, J.; Zhang,
B.-W.; Zhang, Y.; Zhang, X.; Wu, Y.-D.; Gong, L.-Z. Enantioselective
addition of cyclic ketones to unactivated alkenes enabled by amine/
Pd(II) cooperative catalysis. ACS Catal. 2019, 9, 791. (f) Schreib, B.
S.; Carreira, E. M. Palladium-catalyzed regioselective C−H iodination
of unactivated alkenes. J. Am. Chem. Soc. 2019, 141 (22), 8758.
(g) Jeon, J.; Ryu, H.; Lee, C.; Cho, D.; Baik, M.-H.; Hong, S. Site-
selective 1,1-difunctionalization of unactivated alkenes enabled by
cationic palladium catalysis. J. Am. Chem. Soc. 2019, 141, 10048.
(h) Bai, Z.; Bai, Z.; Song, F.; Wang, H.; Chen, G.; He, G. Palladium-
catalyzed amide-directed hydrocarbofunctionalization of 3-alkena-
mides with alkynes. ACS Catal. 2020, 10, 933.
(26) For selected examples of nickel-catalyzed directed functional-
ization of unactivated alkenes, see: (a) Derosa, J.; Tran, V. T.;
Boulous, M. N.; Chen, J. S.; Engle, K. M. Nickel-catalyzed β,γ-
dicarbofunctionalization of alkenyl carbonyl compounds via con-
junctive cross-coupling. J. Am. Chem. Soc. 2017, 139, 10657. (b) Lv,
H.; Xiao, L.-J.; Zhao, D.; Zhou, Q.-L. Nickel(0)-catalyzed linear-
selective hydroarylation of unactivated alkenes and styrenes with aryl
boronic acids. Chem. Sci. 2018, 9, 6839. (c) Derosa, J.; Kleinmans, R.;
Tran, V. T.; Karunananda, M. K.; Wisniewski, S. R.; Eastgate, M. D.;
Engle, K. M. Nickel-catalyzed 1,2-diarylation of simple alkenyl amides.
J. Am. Chem. Soc. 2018, 140, 17878. (d) Lv, H.; Kang, H.; Zhou, B.;
Xue, X.; Engle, K. M.; Zhao, D. Nickel(0)-catalyzed intermolecular
oxidative Heck arylation driven by transfer hydrogenation. Nat.
Commun. 2019, 10, 5025.
(27) For a copper-catalyzed intramolecular cyclization, see: Shi, P.;
Wang, J.; Gan, Z.; Zhang, J.; Zeng, R.; Zhao, Y. A practical copper-
catalyzed approach to β-lactams via radical carboamination of alkenyl
carbonyl compounds. Chem. Commun. 2019, 55, 10523.
(28) (a) Ling, L.; Chen, J.; Song, J.; Zhang, Y.; Li, X.; Song, L.; Shi,
F.; Li, Y.; Wu, C. From N-benzoylpyridinium imides to pyrazolo[1,5-
a]-pyridines: a mechanistic discussion on a stoichiometric Cu
protocol. Org. Biomol. Chem. 2013, 11, 3894. (b) Dong, J.; Wang,
F.; You, J. Copper-mediated tandem oxidative C(sp2)−H/C(sp)−H
alkynylation and annulation of arenes with terminal alkynes. Org. Lett.
2014, 16, 2884.
(29) For a selected example of bidentate directing-group-stabilized
copper(III) species, see: Suess, A. M.; Ertem, M. Z.; Cramer, C. J.;
Stahl, S. S. Divergence between organometallic and single-electron-
G
https://dx.doi.org/10.1021/acs.orglett.0c00963
Org. Lett. XXXX, XXX, XXX−XXX