Three-Component Alkene Difunctionalization by Direct and Selective Activation of Aliphatic C?H Bonds

Article abstract of DOI:10.1002/anie.202014632

Catalytic alkene difunctionalization is a powerful strategy for the rapid assembly of complex molecules and has wide range of applications in synthetic chemistry. Despite significant progress, a compelling challenge that still needs to be solved is the installation of highly functionalized C(sp³)-hybridized centers without requiring pre-activated substrates. We herein report that inexpensive and easy-to-synthesize decatungstate photo-HAT, in combination with nickel catalysis, provides a versatile platform for three-component alkene difunctionalization through direct and selective activation of aliphatic C?H bonds. Compared with previous studies, the significant advantages of this strategy are that the most abundant hydrocarbons are used as feedstocks, and various highly functionalized tertiary, secondary, and primary C(sp³)-hybrid centers can be easily installed. The practicability of this strategy is demonstrated in the selective late-stage functionalization of natural products and the concise synthesis of pharmaceutically relevant molecules including Piragliatin.

Full text of DOI:10.1002/anie.202014632

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Three-Component Alkene Difunctionalization via Direct and
Selective Activation of Aliphatic C-H Bonds
Authors: Sheng Xu, Herong Chen, Zhijun Zhou, and Wangqing Kong
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202014632
Link to VoR: https://doi.org/10.1002/anie.202014632

10.1002/anie.202014632
Angewandte Chemie International Edition
RESEARCH ARTICLE
Three-Component Alkene Difunctionalization via Direct and
Selective Activation of Aliphatic C-H Bonds
Sheng Xu, Herong Chen, Zhijun Zhou and Wangqing Kong*
Abstract: Catalytic alkene difunctionalization is a powerful strategy
for the rapid assembly of complex molecules and has wide range of
applications in synthetic chemistry. Despite significant progress, a
compelling challenge that still needs to be solved is to install highly
functionalized C(sp3)-hybridized centers without requiring pre-
activated substrates. We herein report that inexpensive and easy-to-
synthesize decatungstate photo-HAT, in combination with nickel
catalysis, provides a versatile platform for three-component alkene
difunctionalization through direct and selective activation of aliphatic
C-H bonds. Compared with previous studies, the significant
advantages of this strategy are that the most abundant hydrocarbons
are used as feedstocks, and various highly functionalized tertiary,
secondary and primary C(sp3)-hybrid centers can be easily installed.
The practicability of this strategy is demonstrated in the selective late-
stage functionalization of natural products and the concise synthesis
of pharmaceutically relevant molecules including Piragliatin.
examples are restricted to perfluoroalkyl or tertiary (3o) alkyl
radicals, and the secondary (2o) and primary (1o) alkyl variants are
very limited. (3) Super-stoichiometric metal reductants or
expensive photocatalysts are usually required (Scheme 1A).
Although the use of natural carboxylic acids or alcohols as C(sp3)-
coupling partners can increase the overall efficiency of bond
formation by expanding the range of potential feedstocks, the
direct functionalization of the C-H bond which is the most
abundant linkage in organic molecules, is clearly a more ideal and
promising way for building carbon-carbon and carbon-heteroatom
bonds. In pursuing methods for difunctionalization of alkenes,[3d,6]
we aspired to develop a redox-neutral and auxiliary-free strategy
for difunctionalization of alkene with unactivated aliphatic C-H
bonds as substrates. Such method would allow the direct late-
stage functionalization of natural products and medicinally
relevant molecules, thereby providing an efficient means for rapid
diversification of lead molecules without the need for de novo
synthesis.
In this context, tetrabutylammonium decatungstate (TBADT) is a
versatile, inexpensive and easy-to-synthesize hydrogen atom
transfer (HAT) photocatalyst, which can generate carbon-
centered radicals from strong C-H bonds by near-ultraviolet-light
irradiation, and has been widely used in many useful C(sp3)-H
Introduction
Alkenes are simple and abundant bulk commodity feedstocks in
organic synthesis. Catalytic difunctionalization of alkenes
represents a versatile platform for rapid construction of complex
multifunctional molecules through the regioselective installation of
two different carbon fragments across the C-C double bond.[1] The
traditional two-electron difunctionalization of alkenes relies on the
use of excessive amounts of preformed organometallic reagents,
which preclude the introduction of sensitive functional groups.[2]
Recently, radical-based difunctionalization of alkenes by Ni-
catalyzed reductive cross-coupling[3] or Ni/photoredox dual
catalysis[4] has experienced a great surge of development.
Representative work from the groups of Nevado,[3b,3g,3i,4g]
Molander,[4c,4e,4h] Chu,[3c] Aggarwal,[4j] Martin,[4i] Koh[3j] etc. has
proved the synthetic potential of this method. A very attractive
aspect of this versatile transformation is that relatively stable
C(sp3)-hybridized electrophiles or nucleophiles could be
incorporated to replace highly reactive organometallic reagents.[5]
Despite tremendous progress has been made, there are still some
considerable limitations. (1) Most approaches rely heavily on pre-
activated alkyl substrates, such as alkyl halides, alkyl silicates,
alkyl trifluoroborates, oxalate esters or α-silyl amines. Pre-
functionalization leads to additional steps and waste generation,
and lowers efficiency and atomic economy. (2) The reported
functionalization
reactions,[7]
including
oxidations,[8]
dehydrogenations,[9] azidation,[10] amination,[11] fluorinations,[12]
and conjugate additions.[13] Very recently, a dual decatungstate-
HAT and nickel catalysis enabling the direct arylation of C-H
bonds had been developed by the MacMillan group.[14]
Nevertheless, the majority of these catalytic processes are
essentially confined to two-component cross-couplings.[15]
Inspired by these precedents and our ongoing interest in nickel-
catalyzed difunctionalization of alkenes,[3d,6] we sought to
combine nickel catalysis with decatungstate photo-HAT, and
provide a new protocol for three-component difunctionalization of
alkenes. The successful implementation of this strategy is
expected to complement existing approaches and offers a
straightforward access to functionalized complex molecules from
the most abundant hydrocarbon feedstocks. However,
modulating the matching reactivity of the three involved
components is extremely challenging (see below for further
discussion).
Herein, we report that by merging nickel catalysis and
decatungstate photo-HAT, three-component difunctionalization of
alkenes can be achieved through direct activation of aliphatic C-
H bonds. This strategy exhibits good selectivity and broad
substrate scope, and is compatible with various functionalized
tertiary (3o), secondary (2o) and primary (1o) alkyl radicals, which
is unprecedented in previous reports. The utility of this strategy
was demonstrated in selective late-stage functionalization of
complex natural products and the concise synthesis of
[a]
S. Xu, H. Chen, Z. Zhou, Prof. Dr. W. Kong
The Center for Precision Synthesis (CPS), Institute for Advanced
Studies (IAS), Wuhan University, Wuhan, 430072 (P. R. China)
E-mail: wqkong@whu.edu.cn
Supporting information for this article is given via a link at the end of
the document. ((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/anie.202014632
Angewandte Chemie International Edition
RESEARCH ARTICLE
pharmaceutically relevant molecules including Piragliatin
(Scheme 1B).
obstacle that cannot be ignored is the dehalogenation of aryl
halides and the nickel-catalyzed Heck reaction of aryl bromides
and alkenes (Scheme 2).
Scheme 2. Proposed Mechanism and Synthesis Challenges.
Scheme 1. Catalytic Three-Component Difunctionalization of Alkenes.
Our study commenced with the three-component coupling
reaction of cyclohexane (1), 4-bromo-1,1'-biphenyl (2) and methyl
acrylate (3). In the presence of 2 mol% of photocatalyst TBADT,
10 mol% of Ni(bpy)Br2, K3PO4 in MeCN and exposure to near-
ultraviolet light (10 W LEDs), the desired product 4 was isolated
in 23% yield (entry 1, Table 1). As expected, the selective
formation of 4 is challenged by many side reactions, such as the
direct Csp3-Csp2 cross-coupling (5), Giese-type hydroalkylation
(6), and debromination of aryl bromide 2. Unlike nickel-catalyzed
reductive cross-coupling reactions,[3] the electronegativity of the
substituents on the ligand backbone had little effect on the
selectivity and reactivity (entries 2-4), whereas phenanthroline
(L5), bisoxazole (L6), and terpyridine (L7) completely suppressed
the desired reaction (entries 5-7). The key to success lies in the
discovery that the use of acetone instead of acetonitrile as a
solvent could dramatically improve the selectivity of the reaction,
Results and Discussion
Based on the previous studies,[14] a hypothesized catalytic cycle
was proposed as shown in Scheme 2. Photoexcitation of TBADT
produces its excited state A, which can abstract a hydrogen atom
from unactivated hydrocarbon substrates, thereby providing
reduced decatungstate B and carbon-centered radical G1•.
Addition of the resulting radical G1• to an alkene would afford
radical adduct D, which can be intercepted by Ni(0) species to
generate alkyl-Ni(I) intermediate E. Oxidative addition of Ni(I)
species
E with aryl bromide affords an alkyl-Ni(III)-aryl
intermediate F, which undergoes reductive elimination to deliver
the desired difunctionalization product and Ni(I) species G. A final
single-electron transfer between Ni(I) species
decatungstate C regenerates the reduced decatungstate B and
active Ni(0) catalyst, thereby closing both catalytic cycles.
G
and
which is favorable for product
4 rather than Giese-type
Compared with tertiary (3o) alkyl radicals, secondary (2o) and
primary (1o) alkyl radicals are much less stable and have much
less steric hindrance. Therefore, products of competitive direct
arylation of aliphatic C-H bonds are unavoidable for secondary
(2o) and primary (1o) alkyl radicals.[13a] Photocatalytic scission of
strong aliphatic C-H bonds generates nucleophilic alkyl radicals,
which can be effectively captured by electron-deficient alkenes,
leading to the corresponding Giese addition products.[14a] Another
hydroalkylation 6 (compare entry 8 with entry 3). The effect of the
reaction concentration was further investigated (entries 11-12).
To our delight, the three-component cross-coupling reaction
proceeded optimally at high concentration, providing the desired
product 4 in 71% yield, and only trace amounts of by-product 5
and 6 were observed (entry 12). Reducing the amount of alkene
from 3 equiv. to 1.5 equiv., the yield of 4 only slightly decreased
(63%, entry 13). In addition, reducing the C-H nucleophile to 5
This article is protected by copyright. All rights reserved.

10.1002/anie.202014632
Angewandte Chemie International Edition
RESEARCH ARTICLE
equiv. could still obtain the target product 4 in 61% yield (entry 14).
Finally, control experiments confirmed that the reaction did not
proceed in the absence of nickel-precatalyst, TBADT or light
(entries 15-17).
Table 1. Optimization of the reaction conditions[a]
yield of
yield of
yield of
4 (%)[b]
5 (%)[b]
6 (%)[b]
entry
Ni(L)Br2
solvent
1
2
L1
L2
L3
L4
L5
L6
L7
L3
L3
L3
L3
L3
L3
L3
-
MeCN
MeCN
23
20
35
22
30
30
32
36
27
54
3
MeCN
15
4
MeCN
18
5
MeCN
no reaction
no reaction
no reaction
13
6
MeCN
7
MeCN
8
acetone
DCM
57
17
9
no reaction
noreaction
6
10
DMSO
acetone
acetone
acetone
acetone
acetone
acetone
acetone
11[c]
12[d]
13[d,e]
14[d,f]
15[d]
16[d,g]
17[d,h]
66
71
63
61
13
8
< 2
11
5
12
7
no reaction
no reaction
no reaction
L3
L3
[a] Reactions conditions: 1 (2 mmol), 2 (0.2 mmol), 3 (0.6 mmol), Ni(L)Br2 (10
mol%), TBADT (2 mol%), K3PO4 (0.4 mmol) in solvent (2 mL) at 30 °C under
irradiation of LEDs (10 W, 390 nm) for 12 hours. [b] Yields of isolated products.
[c] Acetone (1 mL). [d] Acetone (0.5 mL) [e] 1.5 equivalents of alkene 3 were
used. [f] 5 equivalents of cyclohexane were used. [g] Without TBADT. [h]
Without light.
With the optimized reaction conditions in hand, the diversity of aryl
halide coupling partners was firstly evaluated (Scheme 3). The
reaction with aryl iodide gave 4 in 15% yield, while aryl chloride
and aryl triflate were inactive. Aryl bromides containing various
synthetic valuable functional groups, such as ether (8, 18),
fluoride (9, 15 and 16), cyano (10), trifluoromethyl (11) and ester
(12), were all tolerated in the Ni/photo-HAT process. Notably, the
presence of chlorine (13 and 16) or borate (14) on the aromatic
ring did not interfere with the reaction efficiency, thus providing a
wealth of new opportunity for further functionalizations. Naphthyl
bromide was perfectly accommodated to furnish 19 in 73% yield.
Interestingly, alkenyl bromide was also found to be applicable to
this reaction, albeit in lower yield (20). Various heterocyclic
bromides were examined. Dibenzofuran (21), carbazole (22),
dibenzothiophene (23), indole (24), quinoline (25), furan (26) and
thiophene (27) were successfully incorporated into the
corresponding products in satisfactory yields. Moreover, both
electron-rich and electron-deficient bromopyridines were
efficiently transformed into the corresponding products 28-30 in
useful efficiency.
Scheme 3. Scope of Aryl and Heteroaryl Halides.
The scope with respect to the aliphatic C-H coupling partners was
assessed next (Scheme 4). A wide range of hydrocarbons proved
to be competent coupling partners for the three-component cross-
coupling reaction. Cycloalkanes with five to eight carbon atoms
proceeded smoothly to provide the corresponding products 31, 4
and 32 in 60-73% yields. For linear alkane, n-pentane and 1-
bromobutane were likewise successful, and preferentially
functionalized of the less sterically demanding 2-position (33-34,
40% and 57% yield, respectively). Due to the high BDEs of the
primary C-H bonds, 2,3-dimethylbutane was selectively
functionalized on the secondary C-H bonds (35, 62% yield).
Bridged bicyclic alkanes were also suitable substrates.
Norbornane was exclusively functionalized on the ethylene bridge
(36, 78% yield), while the sterically hindered tertiary C-H bonds
were almost no reactivity despite their relatively low BDEs. On the
contrary, the functionalization of adamantane occurred
This article is protected by copyright. All rights reserved.

10.1002/anie.202014632
Angewandte Chemie International Edition
RESEARCH ARTICLE
predominantly on the sterically hindered tertiary C-H bonds of the
bridgehead (37).
functionalized at the distal to the electron-withdrawing carbonyl
moiety (47 and 48, 54% and 58% yield, respectively). TMS3SiH,
which is prone to form a silyl radical, underwent three-component
coupling reaction to obtain the desired organosilicon compound
49 in moderate yield with only 3 equiv. of TMS3SiH.
Importantly, this protocol is not limited to electronically neutral,
unactivated hydrocarbons. Various α-heteroatom C-H bonds can
also be functionalized with excellent regioselectivity. Ethers were
functionalized at the α-oxy position in moderate to good yields
with excellent regioselectivity (38-41). Notably, alkyl bromide was
compatible with this dual catalytic system, thus opening avenues
for further derivatizations (39, 65% yield). Tert-butyl methyl ether
was also effective substrate (41). As O-tert-butyl can be easily
removed,[16] it constitutes a route to α-aryl, γ-hydroxybutyrates. In
addition to oxygen-containing nucleophiles, Boc-protected
pyrrolidine, piperidine and piperidin-4-one were also competent
substrates and selectively functionalized on the α-amino position
in good efficiencies (42-44, 66-82% yield). Primary α-amino C-H
Subsequently, the applicability of alkenes was also explored.
Acrylates with different substituents were studied (50-51).
Remarkably, a complex acrylate derivative of estrone was readily
difunctionalized (52, 55% yield), thus demonstrating the potential
of this methodology in late-stage functionalization of complex
molecules. In addition to methyl acrylate, other electron-deficient
olefins have also been investigated. Acrylonitriles are compatible
with this dual catalytic system and provided the desired products
in moderate yields (53 and 54, 58% and 54% yield, respectively).
Notably, the resulting α-aryl-γ-amino-substituted nitrile can be
easily converted into highly valuable 1,4-diamines. The more
challenging α, β-unsaturated ketones are also tolerated with this
three-component coupling reaction, thereby providing the
corresponding products 55 and 56 in 51% and 50% yield,
respectively. Interestingly, the less electron-deficient 1,1-
disubstituted acrylamide afforded the oxindole 57 bearing a
quaternary carbon center in 28% yield. However, vinyl boronic
ester and vinyl sulfone could not delivery any desired products
(58 and 59).
nucleophiles,
N-methyl-N-phenylaniline
and
N-Boc
dimethylamine were also transformed into the desired products in
moderate yields (45 and 46, 51% and 54% yield, respectively). As
N-Boc is easily deprotected, it constitutes a route to N-
unprotected α-aryl, γ-amino acid derivatives, which are unique
structural motifs in pharmaceutical compounds.[17] This strategy
can serve as a powerful supplement, since the previously
reported method failed to obtain target product.[18] Strikingly,
ketone was also found to be effective substrate for this
transformation, providing product that was selectively
This article is protected by copyright. All rights reserved.

10.1002/anie.202014632
Angewandte Chemie International Edition
RESEARCH ARTICLE
Scheme 4. Substrate Scope of Unactivated C-H Bonds and Alkenes. 10 equivalents of aliphatic C-H coupling partners were used for products 31~37, and 5
equivalents for products 38~48. Blue bonds denote sites where the corresponding regioisomer are observed. All yields are isolated yields. d.r., diastereomeric ratio;
r.r., regioisomeric ratio. [a] 1.4:1 r.r. [b] 1:1 d.r. [c] 20:1 r.r. [d] 1.2:1 r.r. [e] L2 was used as ligand.
This article is protected by copyright. All rights reserved.

10.1002/anie.202014632
Angewandte Chemie International Edition
RESEARCH ARTICLE
We next investigated the feasibility of this protocol for the late-
stage functionalization of complex molecules. As shown in
Scheme 5a, under our reaction conditions, a number of naturally
occurring complex stereo-defined scaffolds were successfully
functionalized at carbon sites where lack adaptive functional
handles. Camphene, a terminal-alkene-containing nature product
was found to be an effective substrate, and preferentially
functionalized of the less sterically hindered secondly C-H bonds
(60). Tropinone, an interesting scaffold found in a variety of
natural products and drugs,[19] was also readily used in this
protocol, providing the desired product 61 in moderate yield with
excellent site selectivity. The sesquiterpene lactone Sclareolide
contains two tertiary C-H bonds and six methylene sites, and
could also be functionalized on the C ring to furnish product 62 in
78% yield.
To further demonstrate the practicability of this protocol in the field
of medicinal chemistry, application of this approach to the concise
synthesis of pharmaceutically relevant molecules was performed.
Our first target is to synthesize the lead compound 64, an
archetypal glucokinase activator (GKA), which can improve
glycemic control administered a single oral dose.[20] The previous
method used to synthesize the lead compound 64 requires seven
steps, involving the preparation of arylpropionic acid or ester,
followed by alkylation with cyclopentylmethyl iodide, hydrolysis
and amidation with the corresponding aminoheterocycle.[21] Our
synthesis strategy started from commercially available
cyclopentane, methyl acrylate and 4-bromo-2-chloro-1-
(methylsulfonyl)benzene. The three-component cross-coupling
protocol proceeded smoothly, producing the precursor 63 in 45%
yield. Hydrolysis of methyl ester followed by amidation with 2-
aminopyrazine provided the desired GKA lead compound 64
(Scheme 5b).
Another important goal is to synthesize Piragliatin 66, which is a
clinically advanced drug candidate for the treatment of type 2
diabetes (T2D).[22] Excitingly, starting with commercially available
cyclopentenone, benzyl acrylate and 4-bromo-2-chloro-1-
fluorobenzene, the three-component cross-coupling reaction
could react smoothly to obtain the key precursor 65 in 48% yield
(d.r = 1/1). Note that the prior synthesis of Pilagliptin and its
diastereomer required 12 steps and the overall yield was low.[22]
Compound 65 can be converted into Piragliaptin in two steps
(hydrolysis and amidation); Thus, the synthesis of Piragliatin 66
can now be accomplished in only 3 steps and in good overall yield
(Scheme 5c). To the best of our knowledge, this is the shortest
synthesis of Piragliatin in the multitude of reported procedures to
date.
Scheme 5. Functionalization of Natural Products and Application to Concise
Synthesis of Piragliatin.
A variety of mechanistic experiments were designed to shed light
on the reaction mechanism (more details see the Supporting
Information). The three-component coupling reaction was
strongly inhibited in the presence of TEMPO or BHT
(Supplementary Fig. 4), which points towards
a radical
mechanism. We further synthesized the 4-CF3C6H4Ni(II) complex
67 and studied the catalytic efficiency of the complex. No
detectable amount of 11 was observed in the stoichiometric
reaction of complex 67 with cyclohexane and methyl acrylate
(Scheme 6a). One possible reason is the instability of complex 67
in the absence of aryl bromide and its strong absorption in the
visible light region.[23] However, using 10 mol% of Ar-Ni(II)
complex 67 instead of Ni(dtbbpy)Br2 as the catalyst, the desired
product 11 could be obtained in 43% yield (Scheme 6b). Taken
together, these results indicate that the Ar-Ni(II) complex may not
be a reactive species in the catalytic cycle, and the generated α-
carbonyl radical D in Scheme 2 was recombined with Ni(0)
species rather than Ar-Ni(II) complex.
This article is protected by copyright. All rights reserved.

10.1002/anie.202014632
Angewandte Chemie International Edition
RESEARCH ARTICLE
Cárdenas, C. Nevado, J. Am. Chem. Soc. 2019, 141, 13812; h) H. Tu, F.
Wang, L. Huo, Y. Li, S. Zhu, X. Zhao, H. Li, F. Qing, L. Chu, J. Am. Chem.
Soc. 2020, 142, 9604; ig) X. Wei, W. Shu, A. García-Domínguez, E.
Merino, C. Nevado, J. Am. Chem. Soc. 2020, 142, 13515; j) T. Yang, X.
Chen, W. Rao, M. Koh, Chem. 2020, 6, 738; k) X. Wang, X. Lu, S. He,
Y. Fu, Chem. Sci. 2020, 11, 7950.
[4]
a) K. Skubi, T. V. Blum, T. P. Yoon, Chem. Rev. 2016, 116, 10035; b) J.
Twilton, C. Le, P. Zhang, M. H. Shaw, R. W. Evans, D. W. C. MacMillan.
Nat. Rev. Chem. 2017, 1, 0052; c) A. Lipp, S. O. Badir, G. A. Molander,
Angew. Chem. Int. Ed. DOI: 10.1002/anie.202007668; d) C. Zhu, H. Yue,
L. Chu, M. Rueping, Chem. Sci. 2020, 11, 4051; e) S. O. Badir, G. A.
Molander, Chem. 2020, 6, 1327; f) L. Guo, H. Tu, S. Zhu, L. Chu, Org.
Lett. 2019, 21, 4771; g) A. Garcίa-Domίnguez, R. Mondal, C. Nevado,
Angew. Chem. Int. Ed. 2019, 58, 12286; h) M. W. Campbell, J. S.
Compton, C. B. Kelly, G. A. Molander, J. Am. Chem. Soc. 2019, 141,
20069; i) S. Sun, Y. Duan, R. S. Mega, R. J. Somerville, R. Martin, Angew.
Chem. Int. Ed. 2020, 59, 4370; j) R. S. Mega, V. K. Duong, A. Noble, V.
K. Aggarwal, Angew. Chem. Int. Ed. 2020, 59, 4375.
Scheme 6. Mechanistic Study.
Conclusion
[5]
a) C. E. I. Knappke, S. Grupe, D. Gartner, M. Corpet, C. Gosmini, A.
Jacobi von Wangelin, Chem. Eur. J. 2014, 20, 6828; b) D. A. Everson, D.
J. Weix, J. Org. Chem. 2014, 79, 4793; c) S. Z. Tasker, E. A. Standley,
T. F. Jamison, Nature 2014, 509, 299; d) T. Moragas, A. Correa, R.
Martin, Chem. Eur. J. 2014, 20, 8242; e) J. Gu, X. Wang, W. Xue, H.
Gong, Org. Chem. Front. 2015, 2, 1411; f) D. J. Weix, Acc. Chem. Res.
2015, 48, 1767; g) X. Wang, Y. Dai, H. Gong, Top. Curr. Chem. 2016,
374, 43.
In conclusion, a three-compoent difunctionalization of alkenes
enabled by dual decatungstate photo-HAT/nickel catalysis has
been realized. The advantage of this strategy is that unactivated
hydrocarbons can be used as alkylating agents without requiring
the use of pre-activated radical precursors. This protocol is further
characterized by the unprecedented tolerance of highly
functionalized tertiary, secondary and primary alkyl radicals,
which was reluctant to cooperate in previous reports. Moreover,
the utility of this strategy is demonstrated in the selective late-
stage functionalization of complex natural products and the
concise synthesis of pharmaceutically relevant molecules
including Piragliatin.
[6]
[7]
a) T. Ma, Y. Chen, Y. Li, Y. Ping, W. Kong, ACS Catal. 2019, 9, 9127; b)
Y. Ping, K. Wang, Q. Pan, Z. Ding, Z. Zhou, Y. Guo, W. Kong, ACS Catal.
2019, 9, 7335; c) S. Xu, K. Wang, W. Kong, Org. Lett. 2019, 21, 7498; d)
Y. Li, Z. Ding, A. Lei, W. Kong, Org. Chem. Front. 2019, 6, 3305.
a) C. L. Hill, Synlett. 1995, 127; b) C. Tanielian, Coord. Chem. Rev. 1998,
178-180, 1165; c) M. D. Tzirakis, I. N. Lykakis, M. Orfanopoulos, Chem.
Soc. Rev. 2009, 38, 2609; d) S. Protti, M. Fagnoni, D. Ravelli,
ChemCatChem. 2015, 7, 1516; e) D. Ravelli, S. Protti, M. Fagnoni, Acc.
Chem. Res. 2016, 49, 2232; (f) L. Capaldo, D. Ravelli, Eur. J. Org. Chem.
2017, 2056; g) D. Ravelli, M. Fagnoni, T. Fukuyama, T. Nishikawa, I. Ryu,
ACS Catal. 2018, 8, 701.
Acknowledgements
[8]
[9]
a) F. Lévesque, D. A. DiRocco, M. Reibarkh, Y. Ji, L. A. Joyce, J. F.
Dropinski, H. Sheng, B. D. Sherry, I. W. Davies, Angew. Chem. Int. Ed.
2017, 56, 15274; b) G. Laudadio, S. Govaerts, Y. Wang, D. Ravelli, H. F.
Koolman, M. Fagnoni, S. W. Djuric, T. Noël, Angew. Chem. Int. Ed. 2018,
57, 4078.
Financial support from the “1000-Youth Talents Plan”, NSFC (No.
21702149) and Wuhan University is greatly appreciated.
Keywords: nickel-catalysis • three-component reactions •
alkene difunctionalization • aliphatic C-H bonds • dual catalysis
J. G. West, D. Huang, E. J. Sorensen, Nat. Commun. 2015, 6, 10093.
[10] C. R. Zwick, H. Renata, J. Org. Chem. 2018, 83, 7407.
[11] I. Ryu, A. Tani, T. Fukuyama, D. Ravelli, S. Montanaro, M. Fagnoni, Org.
Lett. 2013, 15, 2554.
[1]
a) J. S. Zhang, L. Liu, T. Chen, L. B. Han, Chem. Asian J. 2018, 13, 2277;
b) R. K. Dhungana, S. Kc, P. Basnet, R. Giri, Chem. Rec. 2018, 18, 1314;
c) J. Derosa, O. Apolinar, T. Kang, V. T. Tran, K. M. Engle, Chem. Sci.
2020, 11, 4287; d) Y. Ping, W. Kong, Synthesis. 2020, 52, 979.
[12] a) S. D. Halperin, H. Fan, S. Chang, R. E. Martin, R. Britton, Angew.
Chem. Int. Ed. 2014, 53, 4690; b) S. D. Halperin, D. Kwon, M. Holmes,
E. L. Regalado, L. Campeau, D. A. DiRocco, R. Britton, Org. Lett. 2015,
17, 5200.
[2]
a) L. Liao, R. Jana, K. B. Urkalan, M. S. Sigman, J. Am. Chem. Soc. 2011,
133, 5784; b) J. W. Gu, Q. Q. Min, L. C. Yu, X. G. Zhang, Angew. Chem.
Int. Ed. 2016, 55, 12270; c) L. Zhang, G. J. Lovinger, E. K. Edelstein, A.
A. Szymaniak, M. P. Chierchia, J. P. Morken, Science 2016, 351, 70; d)
T. Qin, J. Cornella, C. Li, L. R. Malins, J. T. Edwards, S. Kawamura, B.
D. Maxwell, M. D. Eastgate, P. S. Baran, Science 2016, 352, 801; e) B.
Shrestha, P. Basnet, R. K. Dhungana, S. Kc, S. Thapa, J. M. Sears, R.
Giri, J. Am. Chem. Soc. 2017, 139, 10653; f) P. Gao, L. A. Chen, M. K.
Brown, J. Am. Chem. Soc. 2018, 140, 10653; g) J. Derosa, R. Kleinmans,
V. T. Tran, M. K. Karunananda, S. R. Wisniewski, M. D. Eastgate, K. M.
Engle, J. Am. Chem. Soc. 2018, 140, 17878; h) P. Basnet, S. Kc, R. K.
Dhungana, B. Shrestha, T. J. Boyle, R. Giri, J. Am. Chem. Soc. 2018,
140, 15586; i) M. Chierchia, P. Xu, G. J. Lovinger, J. P. Morken, Angew.
Chem. Int. Ed. 2019, 58, 14245; j) J. Derosa, V. T. Tran, M. N. Boulous,
J. S. Chen, K. M. Engle, J. Am. Chem. Soc. 2017, 139, 10657.
[13] a) G. Laudadio, Y. Deng, K. van der Wal, D. Ravelli, M. Nuño, M. Fagnoni,
D. Guthrie, Y. Sun, T. Noël, Science 2020, 369, 92; b) J. J. Murphy, D.
Bastida, S. Paria, M. Fagnoni, P. Melchiorre, Nature 2016, 532, 218.
[14] a) I. B. Perry, T. F. Brewer, P. J. Sarver, D. M. Schultz, D. A. DiRocco,
D. W. C. MacMillan, Nature 2018, 560, 70; b) P. J. Sarver, V. Bacauanu,
D. M. Schultz, D. A. DiRocco, Y. Lam, E. C. Sherer, D. W. C. MacMillan,
Nat. Chem. 2020, 12, 459; c) H. Cao, Y. Kuang, X. Shi, K. Wong, B. Tan,
J. Kwan, X. Liu, J. Wu, Nat. Commun. 2020, 11, 1956.
[15] P. Fan, Y. Lan, C. Zhang, C. Wang, J. Am. Chem. Soc. 2020, 142, 2180.
[16] A. Procopio, P. Costanzo, M. Curini, M. Nardi, M. Oliverio, R. Paonessaa,
Synthesis 2001, 1, 73.
[17] B. N. Desai, K. W. Fowler, R. J. Chorvat, L. G. Frederick, F. R. Hatley, K.
J. Rorig, S. M. Garthwaite, J. Med. Chem. 1998, 31, 2158.
[18] S. Zheng, Z. Chen, Y. Hu, X. Xi, Z. Liao, W. Li, W. Yuan, Angew. Chem.
Int. Ed. 2020, 59, 17910.
[3]
a) C. Yan, Y. Peng, X. Xu, Y. Wang, Chem. Eur. J. 2012, 18, 6039; b) A.
Garcıá-Domίnguez, Z. Li, C. Nevado, J. Am. Chem. Soc. 2017, 139,
6835; c) X. Zhao, H. Tu, L. Guo, S. Zhu, F. L. Qing, L. Chu, Nat. Commun.
2018, 9, 3488; d) K. Wang, Z. Ding, Z. Zhou, W. Kong, J. Am. Chem.
Soc. 2018, 140, 12364; e) D. Anthony, Q. Lin, J. Baudet, T. Diao, Angew.
Chem. Int. Ed. 2019, 58, 3198; f) Y. Jin, C. Wang, Chem. Sci. 2019, 10,
1780; g) W. Shu, A. Garcίa-Domίnguez, M. T. Quirós, R. Mondal, D. J.
[19] G. Grynkiewicz, M. Gadzikowska, Pharmacol. Rep. 2008, 60, 439.
[20] a) J. Grimsby, R. Sarabu, W. L. Corbett, N. Haynes, F. T. Bizzarro, J. W.
Coffey, K. R. Guertin, D. W. Hilliard, R. F. Kester, P. E. Mahaney, L.
Marcus, L. Qi, C. L. Spence, J. Tengi, M. A. Magnuson, L. Chu, C. A.
Mark, T. Dvorozniak, F. M. Matschinsky, J. F. Grippo, Science 2003, 301,
This article is protected by copyright. All rights reserved.

10.1002/anie.202014632
Angewandte Chemie International Edition
RESEARCH ARTICLE
370; b) N. Haynes, W. L. Corbett, F. T. Bizzarro, K. R. Guertin, D. W.
Hilliard, G. W. Holland, R. F. Kester, P. E. Mahaney, L. Qi, C. L. Spence,
J. Tengi, M. T. Dvorozniak, A. Railkar, F. M. Matschinsky, J. F. Grippo,
J. Grimsby, R. Sarabu, J. Med. Chem. 2010. 53, 3618.
[21] J. Zhao, T. Nanjo, E. C. de Lucca Jr, M. C. White, Nat. Chem. 2019, 11,
213.
[22] R. Sarabu, F. T. Bizzarro, W. L. Corbett, M. T. Dvorozniak, W. Geng, J.
F. Grippo, N. Haynes, S. Hutchings, L. Garofalo, K. R. Guertin, D. W.
Hilliard, M. Kabat, R. F. Kester, W. Ka, Z. Liang, P. E. Mahaney, L.
Marcus, F. M. Matschinsky, D. Moore, J. Racha, R. Radinov, Y. Ren, L.
Qi, M. Pignatello, C. L. Spence, T. Steele, J. Tengi, J. Grimsby, J. Med.
Chem. 2012, 55, 7021.
[23] A. W. Rand, H. Yin, L. Xu, J. Giacoboni, R. Martin-Montero, C. Romano,
J. Montgomery, R. Martin, ACS Catal. 2020, 10, 4671.
This article is protected by copyright. All rights reserved.

10.1002/anie.202014632
Angewandte Chemie International Edition
RESEARCH ARTICLE
RESEARCH ARTICLE
Sheng Xu, Herong Chen, Zhijun Zhou,
and Wangqing Kong*
Page No. – Page No.
Three-Component Alkene
Difunctionalization via Direct and
Selective Activation of Aliphatic C-H
Bonds
A photocatalytic three-component alkene difunctionalization method for the direct and selective activation of aliphatic C-H bonds is
developed. The significant advantages of this strategy are that the most abundant hydrocarbons are used as feedstocks, and various
highly functionalized tertiary, secondary and primary C(sp3)-hybrid centers can be easily installed. The practicability of this strategy is
demonstrated in the selective late-stage functionalization of natural products and the concise synthesis of pharmaceutically relevant
molecules including Piragliatin.
This article is protected by copyright. All rights reserved.