Hydroalkylation of Unactivated Olefins via Visible-Light-Driven Dual Hydrogen Atom Transfer Catalysis

Article abstract of DOI:10.1021/jacs.1c05852

Radical hydroalkylation of olefins enabled by hydrogen atom transfer (HAT) catalysis represents a straightforward means to access C(sp3)-rich molecules from abundant feedstock chemicals without the need for prefunctionalization. While Giese-type hydroalkylation of activated olefins initiated by HAT of hydridic carbon-hydrogen bonds is well-precedented, hydroalkylation of unactivated olefins in a similar fashion remains elusive, primarily owing to a lack of general methods to overcome the inherent polarity-mismatch in this scenario. Here, we report the use of visible-light-driven dual HAT catalysis to achieve this goal, where catalytic amounts of an amine-borane and an in situ generated thiol were utilized as the hydrogen atom abstractor and donor, respectively. The reaction is completely atom-economical and exhibits a broad scope. Experimental and computational studies support the proposed mechanism and suggest that hydrogen-bonding between the amine-borane and substrates is beneficial to improving the reaction efficiency.

Full text of DOI:10.1021/jacs.1c05852

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Hydroalkylation of Unactivated Olefins via Visible-Light-Driven Dual
Hydrogen Atom Transfer Catalysis
Guangyue Lei,§ Meichen Xu,§ Rui Chang, Ignacio Funes-Ardoiz,* and Juntao Ye*
Cite This: J. Am. Chem. Soc. 2021, 143, 11251−11261
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ABSTRACT: Radical hydroalkylation of olefins enabled by hydrogen atom transfer (HAT) catalysis represents a straightforward
means to access C(sp3)-rich molecules from abundant feedstock chemicals without the need for prefunctionalization. While Giese-
type hydroalkylation of activated olefins initiated by HAT of hydridic carbon−hydrogen bonds is well-precedented, hydroalkylation
of unactivated olefins in a similar fashion remains elusive, primarily owing to a lack of general methods to overcome the inherent
polarity-mismatch in this scenario. Here, we report the use of visible-light-driven dual HAT catalysis to achieve this goal, where
catalytic amounts of an amine-borane and an in situ generated thiol were utilized as the hydrogen atom abstractor and donor,
respectively. The reaction is completely atom-economical and exhibits a broad scope. Experimental and computational studies
support the proposed mechanism and suggest that hydrogen-bonding between the amine-borane and substrates is beneficial to
improving the reaction efficiency.
associated with the turnover of the borane catalyst using
organic peroxides as the radical initiator.
INTRODUCTION
■
Hydrogen atom transfer (HAT) is a key elementary step in
free-radical reactions and biological transformations.1,2 With
the rapid development of visible-light-mediated photocatal-
ysis,3,4 photoinduced H atom abstraction has evolved into a
powerful strategy for building molecular complexity from
readily available substrates without the need for prefunction-
alization.1 As the selectivity of HAT events is mainly governed
by enthalpy and polar effects,5,6 high levels of efficiency and
regioselectivity could be achieved by fine-tuning bond
dissociation energy (BDE) and philicity of the HAT catalyst.
To date, most of the H atom abstracting radicals that derive
from indirect HAT catalysts7 and direct HAT catalysts such as
diaryl ketones,8 decatungstate anion,9 eosin Y,10 and uranyl
cation,11 have electrophilic character (Figure 1A).1j,6b Con-
sequently, substrate activation via H atom abstraction is largely
limited to those containing hydridic R−H (R = C, Si, B, etc.)
bonds and electron-neutral aliphatic C−H bonds because of a
polarity-matching effect.6 To make electron-deficient C−H
bonds amenable to H atom abstraction, nucleophilic radicals
resulting from hydridic HAT reagents with appropriate bond
strength are required. In this regard, Roberts’ seminal electron
paramagnetic resonance (EPR) studies demonstrated that
nucleophilic amine- and phosphine-boryl radicals are com-
petent for selective abstraction of electron-deficient C−H
bonds.6a Nevertheless, synthetic reactions catalyzed by these
ligated boranes remain rare,12 mainly due to the challenges
Radical hydroalkylation of olefins represents a straightfor-
ward approach for the construction of C(sp3)−C(sp3) bonds
from abundant feedstock chemicals.13 Given the nucleophilic
character of most carbon-centered radicals, their addition to
olefins is largely limited to polarity-matched, electron-deficient
olefins (Giese reaction)13a and styrene derivatives as their
addition to unactivated olefins is often too sluggish to be
synthetically useful.14 In Giese-type reactions, following the
radical addition, reduction of the radical adduct by a protic
HAT catalyst then furnishes the hydroalkylation product via
sequential single-electron transfer/proton transfer (SET/PT)
or HAT (Figure 1B).4i In contrast, hydroalkylation of
unactivated olefins enabled by HAT catalysis remains under-
explored,15 although protocols relying on SET reduction or
oxidation of prefunctionalized radical precursors such as
organic halides and diazo compounds have been docu-
mented.16 In order to generate electrophilic alkyl radicals
Received: June 6, 2021
Published: July 16, 2021
https://doi.org/10.1021/jacs.1c05852
J. Am. Chem. Soc. 2021, 143, 11251−11261
© 2021 American Chemical Society
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Figure 1. Strategies for hydroalkylation of activated and unactivated olefins via photoinduced hydrogen atom transfer (HAT) catalysis. (A)
Commonly used HAT catalysts are mostly electrophilic and thus generate nucleophilic radicals upon HAT. (B) Well-established Giese-type
hydroalkylation of activated olefins initiated by HAT of hydridic carbon−hydrogen bonds. (C) Hydroalkylation of unactivated olefins with
substrates bearing electron-deficient C−H bonds using a nucleophilic HAT catalyst. (D) This work, hydroalkylation of unactivated olefins via
visible-light-driven dual HAT catalysis. EWG, electron-withdrawing group; El•, electrophilic radical; Nu•, nucleophilic radical.
directly from C−H bonds, a hydridic HAT catalyst that can
easily form a nucleophilic H atom abstracting radical is
required (Figure 1C). However, the terminating HAT event
between the nucleophilic radical adduct and the hydridic HAT
reagent is polarity-mismatched. This renders oxidation of the
radical adduct to a carbocation more favorable due to the low
catalysis is the key to this dual HAT strategy. Given that recent
studies have demonstrated that N-heterocycle carbene
(NHC)-boryl radicals could easily be generated from NHC-
boranes under photoinduced HAT or single-electron oxida-
tion,20,21 we initiated our study by evaluating NHC-borane
complex NHC-BH3 as the hydridic HAT catalyst using various
thiols (not shown) as the protic HAT catalyst for the reaction
of 4-phenyl-1-butene 1 and dimethyl malonate 2 (Table 1).
Unfortunately, only thiol−ene reaction22 byproducts were
formed in most cases without any detectable desired product,
presumably due to the relative low BDE of the B−H bond
(70−80 kcal/mol)23 as compared to the acidic C−H bond of 2
(BDE = 93 kcal/mol).24 Gratifyingly, when quinuclidine-
borane QB1, which has a much stronger B−H bond (BDE =
100 kcal/mol, see Figure 5A) and was utilized by Roberts as H
atom abstractor under high-energy UV irradiation using
peroxides as initiators,12 was tested in the presence of 2,4,6-
triisopropylbenzenethiol (TRIPSH), the desired hydroalkyla-
tion product 3 was obtained in 45% yield using [Ir(dF(CH3)-
ox
oxidation potential of the alkyl radical [E1/2 = 0.47 V versus
saturated calomel electrode (SCE) in MeCN for 2-propyl
radical],17 which typically leads to vicinal difunctionalized
products18 or substituted olefins.19 To overcome this
fundamental limitation, we questioned whether a dual HAT
catalysis strategy, that is, a combination of a hydridic and a
protic HAT catalyst, could circumvent the problem. In
particular, we hypothesized that synergistic action of a ligated
borane6a,20 and a thiol could potentially enable atom-
economical radical hydroalkylation of unactivated olefins
with substrates bearing electron-deficient C−H bonds, thereby
avoiding the use of prefunctionalized radical precursors (Figure
1D). Herein, we report the successful execution of this design
plan.
ppy)2(dtbbpy)]BArF (PC) as the photocatalyst (entry 2),
4
with the rest of the mass balance being unreacted starting
materials. Inspired by recent advances in hydrogen bond-
assisted photoinduced radical reactions,1c,25 we envisioned that
introduction of a hydrogen bond donor in the amine-borane
complex might accelerate the desired HAT due to hydrogen
RESULTS AND DISCUSSION
■
Reaction Development. At the outset of our inves-
tigation, we recognized that identification of a ligated borane
that can generate nucleophilic boryl radical under photoredox
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a
to yield the products in 81−93% yields. Of note, nitriles such
as ethyl cyanoacetate (13), malonitrile (14), and β-ketonitrile
(15) all reacted well to give the desired products in good yields
despite the fact that addition of amine-boryl radicals to nitrile
groups has been documented.27 Furthermore, no over-
oxidation of radical adducts or α,α-dialkylation of the 1,3-
dicarbonyl derivatives was observed under the reaction
conditions, highlighting the mildness of the current protocol
compared to conventional chemical oxidation conditions28 or
alkylation with alkyl halides under basic conditions. Simple
carboxylic esters such as methyl propionate is not reactive
under the conditions, presumably due to the difficulty in
generating the corresponding weakly electrophilic carbon
radical under our conditions (vide infra).
The scope of the olefin was then examined and a high level
of functional group tolerance was observed. Mono- or
disubstituted unactivated olefins bearing a free hydroxyl
(17), tosylate (18), chloro (19), carboxylic ester (20), ketone
(21), ether (22), silyl (23), boronate (24), amide (25), cyano
(26, 27), and carbamate (28, 29) groups were all well
tolerated, providing the desired products in 59−96% yields.
Olefins with alkyl rings of various size (30−33), electron-rich
carbazole (34), or electron-deficient arenes (35−37) all
underwent the reaction smoothly. While Minisci-type
borylation of pyridines was achieved using an amine-borane
very recently,29 no such reactivity was observed under our
conditions, and the desired product 37 was obtained in 70%
yield. Internal olefins such as cis-cyclooctene and 2,3-dimethyl-
but-2-ene were also amenable, giving rise to the products 38
and 39 in 95% and 76% yields, respectively. As expected, the
reactions of 2-methylbut-2-ene with dimethyl malonate or N-
phenylcarbamoylacetate afforded the products 40 and 41 as
mixtures of regioisomers. When 1,5-hexadiene was subjected to
the reaction conditions, 1,6-dialkylated product 42 was
obtained in 78% yield. To further illustrate the utility of the
present method, a diverse range of structurally complex olefins
derived from drug molecules, natural products, and materials
precursors were examined (Figure 3). To our delight, the
existing functional groups and structural complexity exerted a
negligible influence on the efficiency of the reaction, leading to
potentially valuable products 43−67 in moderate to excellent
yields. The structure of product 54 was confirmed by X-ray
diffraction analysis. The practicability of the methodology was
further demonstrated by the synthesis of 38, 63, and 66 on
preparative scales. Overall, the current dual HAT-enabled
hydroalkylation protocol exhibits much broader substrate
scope with higher functional group tolerance compared to
existing oxidant- or base-promoted approaches.28,30
Table 1. Reaction Optimization
b
entry
borane
H atom donor
yield (%)
1
2
3
4
5
6
7
NHC-BH3
QB1
QB2
QB3
QB4
QB5
QB5
QB5
−
TRIPSH
TRIPSH
TRIPSH
TRIPSH
TRIPSH
TRIPSH
(TRIPS)2
(TRIPS)2
(TRIPS)2
−
0
45
75
46
45
89
92 (91)
91
7
c
d
8
9
10
11
QB5
−
QB5
QB5
18
0
0
−
e
12
f
(TRIPS)2
(TRIPS)2
13
0
a
Reaction conditions: All reactions were carried out with 1 (0.2
mmol), 2 (0.8 mmol), PC (1 mol %), borane (20 mol %), TRIPSH
(10 mol %) or (TRIPS)2 (5 mol %), and PhCF3 (0.5 mL) unless
otherwise noted. The reactions were irradiated with a 40-W Kessil
b
blue LED under nitrogen atmosphere for 48 h. Yields were
determined by 1H NMR analysis of the crude reaction mixture.
c
d
e
f
Isolated yield. Benzene as the solvent. Without PC. Without light.
BArF : tetrakis[3,5-bis(trifluoromethyl)-phenyl]borate.
4
bonding interaction with the carbonyl group of the substrate.
To our delight, a dramatic increase in the yield of 3 was indeed
observed when readily available 3-quinuclidinol−borane QB2
was utilized (75%, entry 3). Boranes QB3 with the hydroxyl
group protected or QB4 derived from 3-(hydroxymethyl)-
quinuclidine proved to be less effective (entries 4 and 5),
indicating the hydroxyl group and its position play a pivotal
role. Further evaluation of substituent effect on the
quinuclidinol scaffold led to the identification of borane QB5
as the optimal hydridic HAT catalyst and the yield of product
3 was increased to 89% (entry 6, see section 2 of the
Supporting Information). Interestingly, replacing the thiol with
5 mol % of easy-to-handle and odorless bis(2,4,6-triisopropyl-
phenyl) disulfide [(TRIPS)2] provided 3 in 91% yield upon
isolation (entry 7).26 Same efficiency was observed when
benzene was used as the solvent (entry 8). Notably, control
experiments confirmed that visible light and photocatalyst are
indispensable while the absence of the borane catalyst or the
disulfide resulted in a significant decrease in the yield of 3
(entries 9−13).
Mechanistic Investigations. Next, we turned our
attention to investigate the mechanism of the reaction. The
radical nature of the reaction was first confirmed by a series of
experiments (Figure 4A). A radical trapping experiment with
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) completely
shut down the reactivity with two radical adducts 68 and 69
being detected by high resolution mass spectrometry (HRMS),
indicating the involvement of the electrophilic malonyl radical
and the thiyl radical, respectively. Radical clock experiment
using α-cyclopropyl-styrene 70 provided the ring-opened
product 71 in 67% yield as a mixture of E/Z isomers.
Similarly, bicyclic terpene β-pinene also afforded the ring-
opened product 72 in 69% yield. Stern−Volmer luminescence
quenching experiments showed that the disulfide efficiently
quenches the excited state of the iridium photocatalyst while
Reaction Scope. With the optimal conditions in hand, we
explored the scope and limitations of the reaction (Figure 2). A
diverse array of active methylene compounds was found to be
suitable alkyl radical precursors. In addition to 1,3-diesters (4−
6), triethylmethanetricarboxylate (7), β-ketoester (8), β-
ketoamide (9), carbamoylacetates with a free NH2 (10), an
N-alkyl (11) or an N-aryl (12) group all showed high reactivity
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Figure 2. Hydroalkylation of unactivated olefins enabled by dual HAT catalysis. Reaction conditions: olefin (0.2 mmol), active methylene
compound (0.4 or 0.8 mmol), PC (1 mol %), QB5 (20 mol %), and (TRIPS)2 (5 mol %) in PhCF3 (0.5 mL), irradiation with a 40-W Kessil blue
LED at room temperature for 48 h unless otherwise noted; Isolated yields are reported. see Supporting Information for experimental details.
aReaction performed with QB5 (40 mol %). bDiastereomeric ratio (d.r.) and regioisomeric ratio (r.r.) were determined by 1H NMR and GC-MS or
c
LC-MS analysis of the crude reaction mixture. Reaction performed on 2 mmol scale.
IV/III*
all the other components or combinations do not (Figure S13
by the excited-state of the photocatalyst Ir(III)* (E1/2
=
−0.92 V vs SCE in MeCN)32 is unlikely to be operative. On
red
in the SI). Given the reduction potential of (TRIPS)2 (E1/2
=
−1.78 V vs SCE in MeCN),31 SET reduction of the disulfide
the basis of literature precedents,22c,26a we attributed the
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Figure 3. Hydroalkylation of complex olefins derived from natural products or drugs. See Figure 2 and SI for reaction conditions.
strong phosphorescence quenching to an energy transfer event
between the Ir(III)* and the disulfide. Moreover, cyclic
voltammetry studies indicate that SET oxidation of the amine-
darkness for the reaction of 1 and 2 revealed that constant
irradiation is required as no conversion was observed in the
dark period (Figure S14 in the SI). Moreover, the quantum
yield of the reaction between 1 and 2 was determined to be
0.32. Collectively, these results indicate that radical chain
propagation, if present, is not the major pathway for the
current hydroalkylation reaction.
ox
borane catalyst QB5 (Ep/2 = +1.27 V vs SCE in MeCN, see
SI for details) by the excited-state of the photocatalyst Ir(III)*
III*/II
(E1/2
= +0.97 V vs SCE in MeCN)32 is not
thermodynamically favorable, suggesting a reductive quenching
pathway is unlikely to be operative. Conducting light on/off
experiments with alternating periods of irradiation and
On the basis of the above mechanistic studies, a plausible
mechanism was proposed (Figure 4B). Upon blue light
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Figure 4. Mechanistic studies. (A) Radical trap and radical clock reactions. (B) Proposed reaction mechanism. (C) 1H NMR titration experiments
using QB5 and dimethyl malonate 2. The resonance signal corresponding to the hydroxyl group of QB5 (indicated with a red arrow) is downfield
shifted upon increasing concentrations of dimethyl malonate 2 (bottom to top). (D) Job plot indicates the formation of a complex between QB5
and dimethyl malonate 2 with 1:1 stoichiometry.
irradiation, the disulfide undergoes photolytic homolysis to
afford aryl thiyl radical I, which could be readily reduced
(E[PhS•/PhS−] = 0.16 V vs SCE)33 by the excited state of the
IV/III*
polarity-matched HAT with the electron-deficient C−H bond
of substrates to afford electrophilic carbon radical III.6a
Intermolecular addition to unactivated olefins then occurs
with high levels of anti-Markovnikov regioselectivity to provide
nucleophilic alkyl radical adduct IV, which is reduced by the in
situ generated aryl thiol via another polarity-matched HAT
event to provide the final hydroalkylation product and close
the dual HAT catalytic cycle. Given the relatively low BDEs of
the S−H bond of thiophenols (BDE = 80.4 kcal/mol for 2,4,6-
trimethylbenzenethiol)24 and the high BDEs of B−H bonds of
amine-boranes (BDE = 100 kcal/mol for QB5), an alternative
pathway involving HAT between the thiyl radical and the
photocatalyst Ir(III)* (E1/2
= −0.92 V vs SCE in
MeCN)32 to provide aryl thiolate II and the oxidized form
of the photocatalyst. The resulting strongly oxidizing Ir(IV)
species (E1/2IV/III = +1.51 V vs SCE in MeCN)32 then engages
ox
in oxidation with the amine-borane catalyst QB5 (Ep/2
=
+1.27 V vs SCE in MeCN), either via a SET oxidation/
deprotonation sequence or a concerted oxidative proton-
coupled electron transfer (PCET) process, to afford the boryl
radical. In turn, this nucleophilic boryl radical undergoes
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Figure 5. Density functional theory (DFT) calculations. (A) Bond dissociation energy (BDE) of the B−H bond of amine-borane catalysts and of
the α-C−H bonds of selected substrates. (B) Boryl radical formation via direct oxidation of the borane catalyst or via a H-bonding assisted adduct
formation/oxidation sequence. (C) HAT transition state (TS) for the formation of electrophilic carbon radical using boryl radical. (D) Transition
states for the terminating HAT step using a thiol or the substrate as the H atom donor. Calculations were performed at the CPCM (benzene)
M06/6-311++G(3d,2p)//M06/6-31+G(d,p) level of theory. See SI for details. All energies are given in kcal mol−1. The values of the geometry
information are given in Ångstroms.
amine-borane catalyst to generate the boryl radical is less
favorable on thermochemical grounds. In addition, preliminary
studies indicate that another pathway involving the formation
of a boryl sulfide,34 if present, is of minor importance for the
observed reactivity (see SI for details).
using different borane catalysts or substrates, we performed
density functional theory (DFT) calculations at the CPCM
(benzene) M06/6-311++G(3d,2p)//M06/6-31+G(d,p) level
of theory (Figure 5, see SI for details). We began the
calculations by calculating BDEs of the B−H bonds of the
borane catalysts QB1−QB5 and of the α-C−H bonds of
selected substrates. It was found that bond strengths are not
correlated with the catalytic efficiency shown in Table 1 as all
these borane catalysts have essentially the same BDE of the B−
H bond (∼100 kcal/mol). In addition, the unreactive methyl
propionate has a lower BDE of the α-C−H bond (90.4 kcal/
mol) than that of the reactive substrate 2 (93.9 kcal/mol)
(Figure 5A). We then turned to calculate the formation of the
boryl radical by using QB2 as the hydridic HAT catalyst due to
its lower conformational space (Figure 5B). It was found that
the borane catalyst shows a well-structured hydrogen-bonding
platform that favors adduct formation with the malonate,
In seeking to examine the hydrogen bonding between the
1
amine-borane catalyst and the substrates, H NMR titration
experiments were performed and the resonance signal
corresponding to the hydroxyl moiety of QB5 was downfield
shifted upon increasing concentrations of dimethyl malonate 2
(Figure 4C), indicating an O−H···O hydrogen bond might
exist with the carbonyl of the malonate being the H-bond
acceptor. Moreover, Job plot analysis indicates the formation
of a complex between QB5 and dimethyl malonate 2 with 1:1
stoichiometry (Figure 4D).
Computational Studies. To gain deeper insights into the
mechanism of the reaction and origins of reactivity differences
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especially at high concentrations (ΔG°add = 1.4 kcal/mol).
Moreover, oxidation of this adduct to form the boryl radical is
much favored as compared to the direct oxidation of the free
borane catalyst (ΔG°ox = 4.6 vs −0.3 kcal/mol), presumably
through an oxidative PCET pathway where the carbonyl group
of the malonate is acting as the base. By contrast, the absence
of the hydroxyl group (QB1) or the H-bond acceptor (a
second carbonyl group) makes the formation of the adduct
much less favored, thereby decelerating the formation of the
boryl radicalthis is in agreement with the observed
diminished reactivities. The thus formed highly nucleophilic
boryl radical then undergoes a fast and polarity-matched HAT
with the electron-deficient C−H bonds of the substrate
(Figure 5C). This HAT step has a free energy barrier of
only 5.1 kcal/mol and also exhibits the formation of H-bond in
the transition state, underscoring the importance of the
pendant hydroxyl group in QB2 (TSHAT1) and allowing for
fast malonyl radical formation. Finally, we explored two
competitive pathways, i.e., thiol catalysis and radical chain
propagation, for the terminating HAT event (Figure 5D).
Interestingly, the activation barrier is significantly lowered
(ΔΔG‡ = 13.0 kcal/mol) by the thiol catalyst as compared to
the radical chain propagation mechanism, where C−H bonds
of another substrate acts as the H atom donor, in line with the
measured quantum yield of the reaction.
Engineering, Shanghai Jiao Tong University, Shanghai
200240, China; orcid.org/0000-0001-6389-9680;
Email: juntaoye@sjtu.edu.cn
Ignacio Funes-Ardoiz − Department of Chemistry, Centro de
Investigación en Síntesis Química (CISQ), Universidad de La
Rioja, 26006 Logrono, Spain; orcid.org/0000-0002-
̃
5843-9660; Email: ignacio.funesa@unirioja.es
Authors
Guangyue Lei − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, Frontiers Science Center for
Transformative Molecules, School of Chemistry and Chemical
Engineering, Shanghai Jiao Tong University, Shanghai
200240, China
Meichen Xu − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, Frontiers Science Center for
Transformative Molecules, School of Chemistry and Chemical
Engineering, Shanghai Jiao Tong University, Shanghai
200240, China
Rui Chang − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, Frontiers Science Center for
Transformative Molecules, School of Chemistry and Chemical
Engineering, Shanghai Jiao Tong University, Shanghai
200240, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c05852
CONCLUSION
■
Author Contributions
In summary, we have developed a dual HAT protocol for the
hydroalkylation of unactivated olefins with substrates contain-
ing electron-deficient C−H bonds. This approach is comple-
mentary with the well-established HAT-initiated Giese-type
hydroalkylation where only hydridic or electron-neutral C−H
bonds and electron-deficient olefins are amenable. This
method obviates the use of prefunctionalized electrophilic
carbon radical precursors and exhibits a broad scope with a
high level of functional group tolerance. Experimental and
computational studies reveal that hydrogen-bonding between
the amine-borane catalyst and substrates is beneficial to
improving the reaction efficiency. We anticipate this H-bond
assisted dual HAT strategy might be extended more broadly to
achieve otherwise challenging reactions in an atom-economical
fashion.
§G.L. and M.X. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We dedicate this paper to the memory of Professor Ei-ichi
Negishi. Financial support from the National Natural Science
Foundation of China (Grant No. 22001163), “Thousand
Youth Talents Plan”, and Shanghai Jiao Tong University
(SJTU) are acknowledged. J.Y. thanks Prof. Xianjie Fang and
Prof. Gang Chen for the generous use of their analytical
instrumentation and Prof. Zhaoguo Zhang for sharing
laboratory space during the initial stage of this project. I.F.A.
thanks the University of La Rioja for financial support and the
computer cluster “Beronia” for providing computational
resources. Dr. Devenderan Ramanathan and Mr. Qinglong
Shi from SJTU are acknowledged for reproducing the
syntheses of compounds 17, 18, 25, and 53.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c05852.
■
sı
REFERENCES
Experimental procedures and product characterization
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■
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Accession Codes
CCDC 2080253 contains the supplementary crystallographic
data of compound 54 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 Authors
Juntao Ye − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, Frontiers Science Center for
Transformative Molecules, School of Chemistry and Chemical
■
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