Light-Promoted Bromine-Radical-Mediated Selective Alkylation and Amination of Unactivated C(sp3)–H Bonds

Article abstract of DOI:10.1016/j.chempr.2020.04.022

C–H functionalization has provided new opportunities to construct organic molecules in an atom- and step-economic manner, facilitating the derivatization of complex pharmaceutical compounds. However, because of the intrinsically high bond dissociation ene

Full text of DOI:10.1016/j.chempr.2020.04.022

ll
Article
Light-Promoted Bromine-Radical-Mediated
Selective Alkylation and Amination of
Unactivated C(sp3)–H Bonds
Penghao Jia, Qingyao Li, Wei
Chuen Poh, Heming Jiang,
Haiwang Liu, Hongping Deng,
Jie Wu
chmjie@nus.edu.sg
HIGHLIGHTS
Photo-mediated selective
alkylation and amination of
unactivated C(sp3)–H bonds
Generation of bromine radical as
the HAT agent in a catalytic and
metal-free manner
Excellent selectivity toward
tertiary C(sp3)–H bonds
Stop-flow microtubing (SFMT)
reactors enabling enhanced
reactivity
A visible-light-induced highly selective alkylation and amination of unactivated
C(sp3)–H bonds via the synergistic effects of an organo-photoredox catalyst and a
bromine-based hydrogen atom transfer agent has been developed by applying
CH2Br2 as both the solvent and the bromine radical source. Our study offers a new
paradigm for the direct synthesis of valuable compounds from abundant alkane
feedstocks in a convenient and metal-free manner.
Jia et al., Chem 6, 1–11
July 9, 2020 ª 2020 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2020.04.022

Please cite this article in press as: Jia et al., Light-Promoted Bromine-Radical-Mediated Selective Alkylation and Amination of Unactivated C(sp3)–
H Bonds, Chem (2020), https://doi.org/10.1016/j.chempr.2020.04.022
ll
Article
Light-Promoted Bromine-Radical-Mediated
Selective Alkylation and Amination
of Unactivated C(sp3)–H Bonds
Penghao Jia,1,2 Qingyao Li,1 Wei Chuen Poh,1 Heming Jiang,3 Haiwang Liu,1 Hongping Deng,1,4
and Jie Wu1,5,6,
*
SUMMARY
The Bigger Picture
Substantial effort is currently being devoted to selective C(sp3)–H
bond functionalization, and photocatalysis has presented enormous
potential opportunities in this research field. Here, we developed
a visible-light-induced functionalization of unactivated C(sp3)–H
bonds via the synergistic effects of an organo-photoredox catalyst
and a bromine-based hydrogen atom transfer agent. By applying
CH2Br2 as both the solvent and the bromine radical source, the alkyl-
ation and amination of tertiary C(sp3)–H bonds were achieved in a
highly selective fashion. This study represents the first example of
selective activation of unactivated alkanes by bromine radicals in a
catalytic and metal-free manner. Good reactivity was achieved by
using a sealed microtubing reactor or by adding a proper amount
of water. This highly selective C(sp3)–H functionalization protocol
offers a new paradigm for the direct synthesis of valuable com-
pounds from abundant alkane feedstocks in a convenient and green
manner.
C–H functionalization has
provided new opportunities to
construct organic molecules in an
atom- and step-economic
manner, facilitating the
derivatization of complex
pharmaceutical compounds.
However, because of the
intrinsically high bond
dissociation energies and the
ubiquity of similar C–H bonds in
unfunctionalized alkanes, the
selective functionalization of inert
C(sp3)–H bonds represents one of
the most challenging but
attractive goals in chemical
synthesis. In this context, we
developed highly selective
alkylation and amination of
tertiary C(sp3)–H bonds through
the combination of a photoredox
catalyst and CH2Br2 as a hydrogen
atom transfer agent. Bromine
radical is among the weakest but
most selective hydrogen atom
transfer (HAT) agents. This mild
photocatalytic process will inspire
new perspectives for the
INTRODUCTION
Methods for C–H functionalization serve as a versatile toolbox for the modification of
organic molecules in an atom- and step-economical manner. However, most re-
ported successful approaches are limited to activated C(sp3)–H bonds (e.g., a-oxy,
a-amino, benzylic, and allylic C–H bonds).1 Because of the intrinsically high bond
dissociation energies (BDEs) and the ubiquity of similar inert C–H bonds in unacti-
vated alkanes, the selective functionalization of inert C(sp3)–H bonds represents
one of the most attractive goals in organic synthesis. Strategies involving enzymes,2
metal complexes,3,4 carbenoids,5 and radicals6–10 have been developed to achieve
selective C(sp3)–H functionalizations. Given that radicals can inherently distinguish
aliphatic C–H bonds on the basis of the difference of their BDEs and polarity,9
they offer unique advantages for selective C–H functionalizations with readily acces-
sible feedstocks under mild conditions.11–13
synthesizing value-added
chemicals directly from
commodity alkane feedstocks by
taking full advantage of the merits
of bromine radicals to activate
tertiary C(sp3)–H bonds in a highly
selective fashion.
In this context, the emergence of photocatalysis has provided enormous opportu-
nities for C(sp3)–H functionalization. In general, four fundamental pathways have
been applied for photo-promoted C–H functionalization: photoredox catalysis,14,15
direct hydrogen atom transfer (HAT) photocatalysis,10,16,17 proton-coupled electron
transfer (PCET),18 and synergistic combinations of photoredox with HAT catal-
ysis12,13,19–30 (Figure 1A). Among these strategies, the synergistic merger of photo-
redox with HAT catalysis, which mainly relies on photoredox-induced N,19–22
O,12,13,23,24 and S25,26 radicals to promote subsequent HAT transformations, offers
Chem 6, 1–11, July 9, 2020 ª 2020 Elsevier Inc.
1

Please cite this article in press as: Jia et al., Light-Promoted Bromine-Radical-Mediated Selective Alkylation and Amination of Unactivated C(sp3)–
H Bonds, Chem (2020), https://doi.org/10.1016/j.chempr.2020.04.022
ll
Article
A
General methods for photo-mediated C-H functionalization
PC
base
PC
C
H
photoredox
PCET
C
C
C
H
S
PC
N
O
X
PC
HAT
HAT
photoredox
direct photo-HAT
B
C
Our previous work using chlorine radical as the HAT catalyst
Cl
PC
CN
CN
CN
CN
good reactivity
moderate/poor selectivity
+
Ar
x
H
Ar
This work: bromine radical as the HAT catalyst
good reactivity
highly selective towards 3° C(sp3)-H
EWG
R
R
EWG
R1
R1
Br
PC
or
R2O2C
or
+
H
metal-free, additive-free
H
N
R2O2C
N
C-H alkylation & amination
N
CO2R2
R
N
CO2R2
Figure 1. Strategies for C–H Functionalization under Visible-Light Irradiation
the largest reaction scope. Moreover, the use of halogen radicals as HAT agents for
C–H functionalization has also been reported. For instance, Doyle’s research group
and our research group developed catalytic methods for the generation of chlorine
radicals by photolysis of a NiIII chloride intermediate to achieve C(sp3)–H cross
coupling27,28 and selective vinylation29 with activated C(sp3)–H substrates, respec-
tively. Our group and Barriault’s group recently demonstrated an alternative cata-
lytic pathway for generating chlorine radicals by a single-electron oxidation of chlo-
ride ions (Figure 1B).30,31 The developed chlorine radical-based protocol showed
good reactivity toward a series of unactivated C(sp3)–H bonds, even ethane was effi-
ciently activated. However, when substrates with more than one reactive site were
involved, the selectivity was low to moderate probably due to the high reactivity
of chlorine radicals.30 Notably, Barriault et al. have demonstrated an obviously
enhanced regioselectivity favoring the activated tertiary C(sp3)–H bond of a cyclo-
pentyl methyl ether substrate by using pyridine as the solvent to attenuate the
high reactivity of the chlorine atom.31 In classical photo-promoted halogenation re-
actions, hydrogen atom abstraction based on bromine radicals requires a higher
activation energy than that required with chlorine radicals, enabling more selective
transformations.32–34 However, this is limited to bromination using stoichiometric
Br2.35–38 Recent developments using bromine radicals as a HAT catalyst are mainly
based on photo-activation of an in situ formed metallic bromide intermediate and
the substrates are limited to activated alkanes.39–41
1Department of Chemistry, National University of
Singapore, 3 Science Drive 3, Singapore 117543,
Singapore
2School of Chinese Materia Medica, Tianjin
University of Traditional Chinese Medicine, 10
Poyanghu Road, West Area, Tuanbo New Town,
Jinghai District, Tianjin 301617, China
3Laboratory of Computational Chemistry & Drug
Design, State Key Laboratory of Chemical
Oncogenomics, Peking University Shenzhen
Graduate School, Shenzhen 518055, China
4Jiangsu Key Laboratory of Pesticide Science and
Department of Chemistry, College of Sciences,
Nanjing Agricultural University, Nanjing 210095,
China
In line with our ongoing interest in photo-promoted C–H functionalization,15,17,29,30,42–44
here, we developed a bromine-radical-mediated highly selective alkylation and amina-
tion of unactivated C(sp3)–H bonds with excellent efficiency in a metal-free and addi-
tive-free manner, by using an organo-photoredox catalyst in conjunction with CH2Br2,
whichservesasboththe bromine radicalprecursorandthesolvent(Figure1C). Thisstudy
represents the first example of functionalization of unactivated alkanes promoted by
bromine radicals in a catalytic and metal-free fashion. Excellent selectivity for tertiary
5National University of Singapore (Suzhou)
Research institute No. 377 Lin Quan Street,
Suzhou Industrial Park, Suzhou, Jiangsu 215123,
China
6Lead Contact
*Correspondence: chmjie@nus.edu.sg
https://doi.org/10.1016/j.chempr.2020.04.022
2
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Please cite this article in press as: Jia et al., Light-Promoted Bromine-Radical-Mediated Selective Alkylation and Amination of Unactivated C(sp3)–
H Bonds, Chem (2020), https://doi.org/10.1016/j.chempr.2020.04.022
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Article
Table 1. Optimization of the Conditions
Entry
Solvent
HXa
Cat.
Combined
Yield (%)b
Selectivity
(2:20)c
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
1
CH3CN
CH3CN
CHCl3
HCl
HBr
HBr
HBr
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Mes-Acr+ClO4
Mes-Acr+ClO4
Mes-Acr+ClO4
Mes-Acr+ClO4
Mes-Acr+ClO4
Mes-Acr+ClO4
Mes-Acr+ClO4
44
22
86
66
77
0
1:3
6:1
4:1
7:1
9:1
N/A
6:1
9:1
N/A
N/A
9:1
6:1
9:1
9:1
2
3
4
CH2Br2
CH2Br2
CHBr3
5
6
7
Br(CH2)2Br
CH2Br2
CH2Br2
CH2Br2
CH2Br2
Acetone
CH2Br2
CH2Br2
81
76
0
ꢁ
TPP+BF4
8
9
[Ir(dF-CF3ppy)2(dtbpy)]PF6
4CzIPN
10
11d
12f
13g
14g,h
0
Mes-Acr+ClO4
Mes-Acr+ClO4
Mes-Acr+ClO4
Mes-Acr+ClO4
84 (80)e
54
29
76
ꢁ
ꢁ
ꢁ
ꢁ
Reaction conditions: a mixture of 1 (0.2 mmol), methylcyclopentane (1 mmol), HX (0.04 mmol) and cat.
(0.004 mmol) in 2 mL of solvent was injected into a SFMT reactor (volume = 1.5 mL). The reaction was con-
ducted at 50ꢀC under 18 W blue LED irradiation for 48 h, unless otherwise stated.
a0.2 M HX solution in CH3CN was used.
bYields based on analysis of the crude 1H NMR spectra using 1,3,5-trimethoxybenzene as an internal stan-
dard.
cSelectivity was determined by analysis of the crude 1H NMR spectra.
d1 mL of CH2Br2 (0.2 M) was used, and the reaction was conducted for 24 h.
eIsolated yields.
f10 equiv of CH2Br2 was used.
gReaction conducted in a sealed batch reactor (10-mL volume).
h20 equiv of H2O was added.
C–H bonds was obtained. Bromine radical is among the weakest but most selective HAT
agents because of the low BDE of HBr (87 kcal/mol), and its usage in a catalytic transfor-
mation enriches the toolbox of HAT catalysis.
RESULTS
Investigation of Reaction Conditions
We commenced our study by employing the previously established HCl-based HAT
protocol.30 The reaction was more efficient and reliable when taking advantage of our
recently developed stop-flow microtubing (SFMT) reactor45 instead of conventional
batch reactors. Benzylidene malononitrile 1, as the Michael acceptor, and methylcy-
clopentane, as the C–H coupling partner, were irradiated with an 18 W blue Light
Emitting Diode (LED) strip at 50ꢀC in an SFMT reactor (Table 1). With the optimized
HCl-based HAT protocol, in which Mes-Acr+ClO4ꢁ was used as the photoredox cata-
lyst and HCl was used as the HAT catalyst precursor in CH3CN, moderate reactivity
with almost no selectivity between the tertiary and secondary C–H bonds was
observed (entry 1). Then, HBr was used in place of the HCl to test the effect of the
bromine radical (Table 1, entry 2, and Table S1). A promising selectivity of 6:1 favor-
ing the tertiary C–H bond was observed, but the reactivity was retarded. Using halo-
genated solvents instead of CH3CN provided significantly improved results (Table 1,
entries 3 and 4, and Table S2). CH2Br246 turned out to be the optimal choice, as it af-
forded the products with 66% yield and 7:1 selectivity. Conducting the reaction in
CH2Br2 without HBr provided an improved outcome, where 77% yield of the products
Chem 6, 1–11, July 9, 2020
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H Bonds, Chem (2020), https://doi.org/10.1016/j.chempr.2020.04.022
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Article
were obtained with a selectivity of 9:1 favoring alkylation of the tertiary C–H bond (Ta-
ble1, entry 5). Other bromine-containing solvents were evaluated (Table S3). No re-
action occurred in CHBr3 (Table 1, entry 6). Br(CH2)2Br afforded products in a yield
similar to that achieved in CH2Br2 with a slightly lower selectivity (entry 7). Examina-
tion of other photocatalysts revealed that only photocatalysts with strong oxidative
power, such as 2,4,6-tri(p-tolyl)pyrylium tetrafluoroborate (TPP+BF4ꢁ) could effec-
tively promote the reaction (entry 8), whereas no reaction occurred with [Ir(dF-
CF3ppy)2(dtbpy)]PF6
or
1,2,3,5-tetrakis-(carbazol-9-yl)-4,6-dicyanobenzene
(4CzIPN) (Table 1, entries 9 and 10, and Table S4). Further optimization revealed
that the reaction yield could be improved to 80% isolated yield by running the reac-
tion at 0.2 M in CH2Br2 for 24 h (Table 1, entry 11, and Table S5). Attempted efforts to
use CH2Br2 as a reagent instead of a solvent resulted in less effective results. 54% of
products was obtained with 6:1 selectivity by using 10 equiv of CH2Br2 in acetone (Ta-
ble 1, entry 12, and Table S3). Notably, when switching the reaction vessel from the
SFMT reactor to a sealed batch reactor (10-mL volume), the efficiency decreased
significantly (29% yield, Table 1, entry 13), indicating that volatile active species
might be involved in the reaction process.30 However, by adding 20 equiv of water
into the reaction mixture in a sealed tube reactor, 76% yield of the products could
be obtained (Table 1, entry 14, and Table S6), enabling a convenient batch setup
to obtain useful efficiency.
Comparison between the Cl- and Br- Radical-Based Photo-HAT Protocols
To further demonstrate the difference in reactivity and selectivity between the optimized
Br-radical-based photo-HAT protocol and the previously established Cl-radical-based
method,30 a series of comparative experiments with various unactivated alkanes were
conducted. The results are summarized in Scheme 1. In general, the bromine-radical-
based photo-HAT protocol showed no reactivity toward primary C–H bonds and
much lower reactivity with secondary C–H bonds compared with the chlorine radical-
based protocol (entries 1–4). However, bromine radicals displayed excellent reactivity
and selectivity for tertiary C–H bonds, whereas chlorine radicals showed almost no
selectivity between different types of C–H bonds (entries 5–10). Even with activated al-
kanes, such as cyclopentyl methyl ether, the bromine-radical-based protocol still pro-
vided much better selectivity for tertiary over primary C–H bonds (entries 11–12).
Substrate Scope for C–H Alkylation
A wide range of unactivated alkanes were effective under the optimal conditions and
provided the alkylation products in generally good selectivities (Scheme 2). Both cy-
clic and acyclic unfunctionalized alkanes afforded the corresponding products in
good yields (2–12). Steric hindrance has little effect on the reactivity, and even 2,3-di-
methylbutane gave product 9 in good yield. The selectivity is mainly controlled by the
ratio between the number of tertiary C–H bonds and secondary C–H bonds present in
the substrate. When there were more secondary C–H bonds present in the substrate,
the selectivity was decreased to some extent (3, 4, and 8). Alkanes bearing remote
electron-withdrawing functional groups were subsequently evaluated (13–27).
Different functional groups, such as ester, amide, benzoate, acetate, benzenesulfo-
nate, free acid, bromine, and nitrile groups were well tolerated. Excellent regioselec-
tivity for tertiary C–H bonds was observed in all these cases. Under basic conditions,
bromide product 19 underwent a facile intramolecular SN2-type cyclization to give
cyclohexane derivative 20. To further demonstrate the synthetic value of this proto-
col, we tested an amino acid derivative and a 3b-androsterone derivative, and alkyl-
ation products 26 and 27 were obtained in 63% and 41% yields, respectively, with
excellent selectivity. Substrates with multiple reactive sites were also investigated.
Several derivatives of dihydrocitronellol with two tertiary C–H sites were applied
4
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H Bonds, Chem (2020), https://doi.org/10.1016/j.chempr.2020.04.022
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Article
R
CN
CN
Mes-Acr ClO4 (2 mol%)
Ph
Conditions 1: HCl (5 mol%), CH3CN/DCE (7/1, 0.1 M)
Conditions 2: CH2Br2 (0.2 M)
+
R-H
Ph
NC
solvent, 50 °C
18 W blue LED, 24 h
SFMT reactors
CN
combined
combined
R-H
R-H
(x equiv.)
entry
1
entry
7
conditions
selectivityb
-
conditions
selectivityb
yields (%)a
yields (%)a
(x equiv.)
(2 equiv.)
(10 equiv.)
1
98
1
43
63
1
2
C1/C2 = 2/1
(5 equiv.)
-
C /C > 20/1
1
2
2
2
35
85
8
9
2
1
1
2
(5 equiv.)
2
3
1
1
3
4
5
1
2
1
C1/C2/C3 = 1/2/1
C1/C2/C3 = 0/2/1
nd
8
1
OBz
(2 equiv.)
(5 equiv.)
2
3
1
10
11
OBz
2
1
59
43
64
60
> 20:1
(5 equiv.)
(5 equiv.)
2
1
1
O
C /C +C = 1/3
1
2
3
C1/C2 = 1/1
C1/C2 = 3/1
2
3
(5 equiv.)
(5 equiv.)
2
1
1
O
12
6
2
2
80
C1/C2+C3 = 9/1
89
2
3
(5 equiv.)
(5 equiv.)
Scheme 1. Comparison between Cl- and Br-Radical-Based Photo-HAT Protocols
aYields based on analysis of the crude 1H NMR spectra using 1,3,5-trimethoxybenzene as an internal standard.bSelectivity was determined by analysis of
the crude 1H NMR spectra.
(28–31). Moderate to good selectivities were obtained at the remote and more elec-
tron-rich tertiary C–H bonds. A 3:1 selectivity between the tertiary C–H bond and the
primary C–H bond adjacent to an oxygen atom was observed when cyclopentyl
methyl ether was used as the substrate (32). However, when a substrate bearing
both benzylic and tertiary C–H bonds was applied, full selectivity for the benzylic
site was observed (33). This protocol was highly selective for the most hydridic C–H
bond in the adamantanecarboxylate derivative possessing multiple tertiary C–H
bonds (34). For the scope of alkenes, a series of electron-deficient alkenes were
tested. Dicyanides containing electron-rich or electron-deficient aryl rings or alkyl
chains were all suitable substrates (35–39). Alkenes possessing ketone or ester moi-
eties were good candidates for this transformation, affording the corresponding
products (40–44) with moderate to good selectivities. This alkylation could also
perform well under the optimized batch conditions (Table 1, entry 14), with slightly
lower efficiency obtained than that in the SFMT reactor (2, 5, 7, 15, 28, 37).
Considering the prevalence and importance of nitrogen-containing molecules in natural
products and pharmaceutical compounds, developing methods for the direct and selec-
tive C(sp3)–H amination of unactivated alkanes is of great importance.47 After a simple
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H Bonds, Chem (2020), https://doi.org/10.1016/j.chempr.2020.04.022
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Article
Mes-Acr ClO4 (2 mol%)
EWG
R
+
R-H
EWG
R'
CH2Br2 (0.2 M), 50 °C, 24 h
18 W Blue LED
R'
SMFT reactors
yielda, selectivityb
unactivated alkanes
Ph
Ph
NC
CN
2, 80%, 9:1
(76%, 9:1)c
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
CN
CN
4, 69%, 5:1d
CN
CN
CN
CN
CN
CN
9, 63%, > 20:1
CN
CN
5, 95%, > 20:1d
(67%, > 20:1)c,d
3, 66%, 4:1d
6, 67%, 6:1d
7, 82%, 8:1
(79%, 8:1)c
8, 69%, 5:1
10, 84%, > 20:1 11, 81%, > 20:1
12, 72%, 10:1, dr = 2:1
alkanes possessing an electron withdrawing group
O
O
Br
OBz
CN
Ph
OBz
NPhth
CO2Me
CN
CN
Ph
K2CO3
Ph
Ph
Ph
Ph
Ph
Ph
DMSO
NC
NC
NC
NC
NC
NC
NC
CN
CN
CN
CN
CN
CN
CN
14, 74%, >20:1d
19, 73%,15:1d
20
, 87%
13, 75%, > 20:1d
17, 61%, > 20:1
15, 64%, > 20:1
(52%, > 20:1)c,e
16, 66%, > 20:1d
18, 87%, > 20:1
O
OBz
OAc
NPhth
H
OSO2Ph
CO2H
OBz
O
H
H
CO2Me
Ph
Ph
NC
O
Ph
Ph
Ph
Ph
Ph
NC
NC
NC
NC
CN
NC
NC
CN
CN
CN
CN
CN
CN
27, 41%, > 20:1
21, 73%, > 20:1
22, 68%, > 20:1
23, 75%, > 20:1
24, 86%, > 20:1, dr = 1:1 25, 73%, > 20:1, dr = 2:1d
26, 63%, > 20:1, dr = 1:1
H
alkanes bearing multiple reaction sites
scope of alkenes
Br
NPhth
OBz
H
CO2Me
H
H
H
H
H
H
H
O
O
O
Ph
Cl
Ph
Ph
OMe
Ph
NC
CN
NC
NC
NC
Ph
Ph
Ph
NC
Ph
CN
CN
CN
NC
NC
NC
CN
NC
CN
CN
CN
CN
36, 73%, 7:1d
35, 84%, 7:1
28, 71%, 9:1, dr = 1:1
(60%, 9:1, dr = 1:1)c
31, 52%, 5:1, dr = 1:1
34, 58%, > 20:1d
32, 88%, 3:1 33, 91%, > 20:1, dr = 1:1
29, 65%, 4:1, dr = 1:1 30, 62%, 5:1, dr = 1:1
F
CO2Et
O
Ph
Ph
O
CO2Et
CO2Me
NC
CN
EtO2C
NC
NC
EtO2C
MeO2C
CO2Et
42, 45%, 9:1
CN
Br
CN
Ph
CN
CN
Ph
44, 64%, 9:1
37, 82%, 7:1
(57%, 7:1)c,e
38, 80%, 6:1
41, 41%, 6:1, dr = 2:1d
43, 58%, 4:1
40, 58%, 3:1, dr = 2:1
39, 72%, 6:1
Scheme 2. Scope of the Selective Alkylation of Unactivated C–H Bonds
Reaction conditions: a mixture of the alkene (0.2 mmol), C–H partner (1 mmol), and Acr-Mes+ClO4ꢁ (0.004 mmol) in 1 mL of CH2Br2 (0.2 M) was injected
into the SFMT reactors (volume = 0.75 mL). The reaction was performed at 50ꢀC under 18 W blue LED irradiation for 24 h, unless otherwise noted (see
Figure S1).
aCombined isolated yields of all the isomers.bSelectivity of the major isomer relative to all minor isomers, determined by analysis of the crude 1H NMR
spectra.cReaction conducted in a sealed batch reactor (10-mL volume) with H2O (4 mmol) as an additive for 24 h (see Figure S2).d10 equiv of the C–H
substrate was used.eReaction was conducted for 48 h.
optimization based on the established alkylation protocol, we found that by using TPP+-
ꢁ
BF4 as the photoredox catalyst, and dialkyl azodicarboxylates as the aminating
reagent, a series of unactivated C(sp3)–H bonds could be aminated in a selective manner
(Scheme3).TheaminationproceededwellwithhighselectivityforthetertiaryC–Hbonds
of an alkane substrate with azodicarboxylates bearing different ester groups (45–47).
Various acyclic and cyclic alkanes were shown to be suitable substrates and afforded hy-
drazine derivatives 48–50 with good to high selectivities. Excellent selectivities were ob-
tained with alkane substrates bearing remote electron-withdrawing groups (51–55). This
protocol offers a direct and convenient route for the amination of unactivated C(sp3)–H
bonds with high selectivity toward tertiary C–H bonds in a metal-free, additive-free, and
step-economical manner.
To demonstrate the synthetic utility of the established selective alkylation and ami-
nation methods, the reactions were conducted on a larger scale, and gram quantities
6
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H
TPP BF4 (2 mol%)
RO2C
N
RO2C
N
+
R-H
N
R
CO2R
N
CO2R
CH2Br2 (0.2 M), 50 °C, 24 h
18 W blue LED
yielda, selectivityb
SMFT reactors
H
H
H
N
H
iPrO2C
N
H
H
iPrO2C
N
iPrO2C
N
CO2iP
Boc
N
N
CO2iPr
EtO2C
N
iPrO2C
N
N
CO2iPr
N
Boc
r
N
CO2Et
N
CO2iPr
49, 78%, > 20:1
50, 52%, 5:1
45, 68%, 12:1
46, 60%, 12:1
iPrO2C
CO2iPr
BzO
52, 56%, > 20:1
47, 52%, 9:1
48, 65%, 7:1
H
H
H
H
H
iPrO2C
N
iPrO2C
N
N
iPrO2C
N
iPrO2C
N
N
CO2iPr
N
CO2iPr
N
CO2iPr
N
CO2iPr
N
PhO2SO
MeO2C
NC
53, 49%, > 20:1
AcO
54
55, 55%, > 20:1
51, 56%, > 20:1
, 67%, > 20:1
Scheme 3. Scope of the Selective Amination of Unactivated C–H Bonds
Reaction conditions: a mixture of dialkyl azodicarboxylates (0.2 mmol), C–H partner (1 mmol), and
TPP+BF4ꢁ (0.004 mmol) in CH2Br2 (0.2 M) was injected into an SFMT reactor (volume = 0.75 mL). The
reaction was performed at 50ꢀC under 18 W blue LED irradiation for 24 h.aCombined isolated yield
of all the isomers.bSelectivity of the major isomer compared with all minor isomers, determined by
analysis of the crude 1H NMR spectra.
of the products were obtained with similar yields and the same high selectivity
(Schemes 4 and S1). The scale of the reaction can be further increased by utilizing
SFMT reactors with a larger volume (as illustrated in the synthesis of 2), which high-
lights the practical utility of this strategy.
DISCUSSION
Mechanism Study
A series of control experiments were performed to elucidate the reaction mecha-
nism. The screening of different photocatalysts (Table S4) demonstrated that the
ꢁ
more oxidizing photocatalysts, such as Mes-Acr+ClO4 (E1/2(cat*/cat$)
= +
2.06 V versus saturated calomel electrode (SCE))48 and TPP+BF4 (E1/2(cat*/
cat$) = + 2.31 V versus SCE)49 could effectively promote the reaction, whereas
photocatalysts with higher triplet state energies but lower reductive potentials
ꢁ
than Mes-Acr+ClO4 gave no desired product ([Ir(dF-CF3ppy)2(dtbpy)]PF6 and
ꢁ
fac-Ir(ppy)3).50 These results indicate a redox-initiated process rather than an en-
ergy transfer. Radical trapping experiments were conducted to probe the reaction
intermediates. When the reaction was performed in the presence of ethene-1,1-
diyldibenzene, (2-bromoethene-1,1-diyl)dibenzene (56) was generated (Schemes
5A and S3). Product 56 was also formed when ethene-1,1-diyldibenzene was sub-
jected to the standard reaction conditions in the absence of the starting sub-
strates. No reaction occurred in the absence of Mes-Acr+ClO4ꢁ, which indicated
the generation of Br radicals from CH2Br2 under photoredox conditions. The
Stern-Volmer quenching study further illustrated that CH2Br2 could reductively
quench the excited photocatalyst Mes-Acr+ClO4ꢁ (Figure S4). The strong oxidizing
ꢁ48
ox
ability of Mes-Acr+ClO4
allows it to oxidize CH2Br2 (E1/2 = + 1.62 V versus
SCE, Scheme 5B; Figure S5) via a single-electron oxidation. Density functional the-
ory (DFT) calculations (Scheme S6) illustrated that the CH2Br2 radical cation gener-
ated by the single-electron oxidation of CH2Br2 preferentially undergoes cleavage
to deliver a bromine radical and a bromomethyl cation, which possesses a much
lower free energy barrier (Scheme 5C, 12.6 kcalmolꢁ1, path a) than the generation
of a bromo carbon radical and a bromine cation (133.8 kcalmolꢁ1, path b). The
transient bromine radical is responsible for the abstraction of the hydrogen atom
from the C(sp3)–H partner to produce a tertiary radical and release HBr. The
Chem 6, 1–11, July 9, 2020
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Article
R
CN
CN
Ph
Ph
NC
CN
or
cat. (2 mol%)
or
R-H
+
CH2Br2, 60 °C, 48 h
blue LED
SMFT reactors
H
i
PrO C
N
iPrO2C
N
2
N
R
CO2iPr
N
CO2iPr
OBz
H
iPrO2C
N
N
CO2iPr
Ph
Ph
CN
NC
NC
CN
2
18
48
72%, 1.02 g, 9:1a
63%, 1.98 g, 9:1b
69%, 1.16 g, > 20:1a
60%, 1.13 g, 7:1a
Scheme 4. Gram-Scale Reaction of Alkylation and Amination
aSFMT reactor (volume = 27.2 mL) was used (see Figure S3).bSFMT reactor (volume = 59.3 mL) was
used.
generated tertiary radical will undergo nucleophilic addition to the Michael
acceptor to furnish a radical adduct, which will be reduced by the reduced form
of the photocatalyst. Protonation of the anion will furnish the final product.
Notably, because the in situ generated HBr (E1/2ox = + 0.76 V versus SCE, Scheme
5B and Figure S6) is more easily oxidized than CH2Br2, HBr might act as a more
reactive bromine radical source during the reaction process. This could explain
why reactions in SFMT reactors were more efficient than those in batch reactors,
as SFMT reactors retained the volatile HBr (boiling point: ꢁ66ꢀC) within the reac-
tion solution (for more detailed mechanism study, see Schemes S2, S4, S5; Figures
S7 and S8).
Conclusion
In conclusion, we have developed visible-light-mediated selective alkylation or
amination of unactivated C(sp3)–H bonds in a highly selective as well as additive-
and metal-free manner. By the synergistic effects of photoredox catalysis with
CH2Br2 as the bromine radical precursor, excellent selectivity for tertiary C(sp3)–
H bonds was achieved with a variety of unactivated C(sp3)–H partners. Stop-flow
microtubing reactors were applied and provided better reactivity than that was
achieved with traditional batch reactors. Our study provides a practical strategy
for using bromine radicals for HAT in a catalytic and mild fashion, which will
shed new light on selective C–H functionalizations using abundant unactivated
alkanes as feedstocks.
EXPERIMENTAL PROCEDURES
Full experimental procedures are provided in the Supplemental Information.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2020.04.022.
ACKNOWLEDGMENTS
We are grateful for the financial support provided by the Ministry of Education
(MOE) of Singapore (MOE2017-T2-2-081), GSK-EDB (R-143-000-687-592), NUS
8
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ll
Article
A
Br
Acr-Mes ClO4 (2 mol%)
(1 equiv.)
Ph
Ph
Ph CH2Br2 (0.2 M), 50 °C
18 W Blue LED
Ph
Ph
Ph
Ph
Br
CN
CN
Acr-Mes ClO4 (2 mol%)
56, 15%
+
Ph
Ph
Ph
CH2Br2 (0.2 M), 50 °C
18 W Blue LED
56, 12%
NR
Ph
No desired product
CH2Br2 (0.2 M), 50 °C
18 W Blue LED
B
C
CH2Br2
HBr
+
*
[Mes-Acr ]
Br
CH2Br
path a ( G = 12.6 Kcal/mol)
Br
path b ( G = 133.8 Kcal/mol)
CH2Br2
Br
CH2Br
+
R
[Mes-Acr+]
n
CH3Br
HBr
R
n
Ph
R
[Mes-Acr+]
n
CN
NC
Ph
CN
CN
R
R
H
n
n
Ph
Ph
NC
NC
CN
CN
Scheme 5. Plausible Mechanism with Supporting Evidence
(A) Radical trapping experiments.
(B) Cyclic voltammetry measurements of CH2Br2 and HBr.
(C) Proposed plausible mechanisms.
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Article
(Suzhou) Research Institute, and National Natural Science Foundation of China
(21702142 and 21871205).
AUTHOR CONTRIBUTIONS
J.W., P.J., and H.D. designed the project and monitored the research progress; P.J.,
Q.L., and W.C.P. conducted the experiments and analyzed the data; P.J. and H.L.
conducted the mechanistic study; H.J. conducted the DFT calculations; J.W. and
P.J. wrote the manuscript and Supplemental Information.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: March 7, 2020
Revised: April 20, 2020
Accepted: April 28, 2020
Published: May 28, 2020
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