Visible-light-promoted site-specific and diverse functionalization of a c(sp3)-c(sp3) bond adjacent to an arene

Article abstract of DOI:10.1021/acscatal.0c01495

We report here a strategy for inert C-C bond functionalization. Site-specific cleavage and functionalization of a saturated C(sp3)-C(sp3) bond via a visible-light-induced radical process have been achieved. The general features of this reaction are as follows. (1) Both linear and cyclic C(sp3)-C(sp3) bonds with a vicinal arene can be specifically functionalized. (2) One carbon is converted into a ketone, and another can be tunably converted into nitrile, peroxide, or halide. (3) The typical conditions include 1.0 mol % of Ru(bpy)3Cl2, 1.0 or 5.0 equiv of Zhdankin reagent, white CFL (24 W), open flask, and room temperature. These reactions offer powerful tools to modify carbon skeletons that are intractable by conventional methods. Good selectivity and functional group tolerance, together with mild and open air conditions, make these transformations valuable and attractive.

Full text of DOI:10.1021/acscatal.0c01495

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Article
A Visible-Light-Promoted Site-Specific and Diverse
Functionalization of the C(sp3)–C(sp3) Bond Adjacent to Arene
Yaxin Wang, Nengyong Wang, Jianyou Zhao, Minzhi Sun, Huichao You, Fang Fang, and Zhong-Quan Liu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c01495 • Publication Date (Web): 14 May 2020
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Page 1 of 13
ACS Catalysis
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A Visible-Light-Promoted Site-Specific and Diverse Functionalization of
the C(sp3)–C(sp3) Bond Adjacent to Arene
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Yaxin Wang, Nengyong Wang, Jianyou Zhao, Minzhi Sun, Huichao You, Fang Fang, and Zhong-Quan
Liu*
College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
ABSTRACT: We reported here a strategy for inert C-C bond functionalization. Site-specific cleavage and functionalization of
saturated C(sp3)-C(sp3) bond via a visible-light-induced radical process was achieved. The general features of this reaction are: 1)
Both linear and cyclic C(sp3)-C(sp3) bonds with a vicinal arene can be specifically functionalized; 2) One carbon is converted into
ketone, and the another can be tunably converted into nitrile, peroxide or halide; 3) The typical conditions includes: 1.0 mol%
Ru(bpy)3Cl2, 1.0 or 5.0 equivalent of Zhdankin reagent, white CFL (24 W), open flask and room temperature. These reactions offer
a powerful tool to modify carbon skeletons that are intractable by conventional methods. Good selectivity and functional group
tolerance, together with mild and open air conditions make these transformations valuable and attractive.
KEYWORDS: free radical, carbon-carbon bond activation, visible-light-initiation, nitrogenation, peroxidation, chlorination
Next, we began to evaluate this hypothesis by using a
hypervalent iodine (Zhdankin reagent 110) under photo-
irradiation,11 which had been proved to be highly efficient for
selective C(sp3)-H functionalization.12
INTRODUCTION
Efficient carbon-carbon (C-C) bond activation would have a
profound impact on various fields such as drug synthesis,1
petrochemical industry,2 degradation of polymers3 and
biomass conversions,4 etc. Despite its tremendous potential
and urgent demand, the low reactivity and discrimination of
carbon-carbon bonds make it challenging to be activated
selectively, especially for C(sp3)-C(sp3) bonds.5
Therefore, the selective C(sp3)-C(sp3) bond cleavage reaction
of cyclohexylbenzene 2 was examined in the presence of
Zhdankin reagent BIN3 1 and photocatalyst Ru(bpy)3Cl2,
under white CFL irradiation, at room temperature and exposed
to air13 (Table 1). To our surprise, deconstructive nitrogenation
product 3 of cyclic alkane by the C(sp3)-C(sp3) bond cleavage
was obtained in 16% yield when 2.0 equivalent of 1, 1 mol%
Ru(bpy)3Cl2 and dichloromethane (DCM) as solvent were
applied (entry 1). Interestingly, deconstructive peroxidation of
cyclic alkane product 6 by the C(sp3)-C(sp3) bond cleavage
was obtained in 53% yield when EtOAc instead of DCM was
applied as solvent (entry 2). These results prompted us to
evaluate the effect of different solvents. Finally, we found that
the yield of 3 was improved to 68% when HFIP as solvent and
5.0 equivalent of 1 were used (entry 5). The solvent HFIP not
only could completely dissolve Ru(bpy)3Cl2 and high-valent
iodine reagent (BIN3), but also well stabilized free radicals
intermediate, which made the reaction went smoothly.
Increasing amount of 1 led to an increased yield of
deconstructive nitrogenation product 3 (entries 3-6). A series
of control experiments were carried out and proved that
oxygen would play a significant role in C(sp3)-C(sp3) bond
cleavage. The desired product 3 was not observed under the
nitrogen atmosphere (entry 8), while the cleavage reaction
could undergo smoothly in air or oxygen atmosphere (entry 5
vs entry 7), indicating oxygen was necessary but its
concentration had little effect on the reaction. The light had a
Considerable advances in selective activation of C(sp2)-C(sp3)
bonds have been made in the past decades.6 As demonstrated
in Scheme 1A, there are mainly three types of C(sp2)-C(sp3)
bonds that can be activated effectively: Ccarbonyl-C(sp3),6a Caryl
-
C(sp3)6b-6e and Cvinyl-C(sp3).6f However, specific cleavage of
C(sp3)-C(sp3) bond was limited in one category: one or two C-
atoms must be adjacent to a heteroatom (N or O) (Scheme
1B)7-9. Herein we report the secondary model for C(sp3)-C(sp3)
bond cleavage and functionalization (Scheme 1C).
Inspired by previous reports1b,1d,1h,1p,1q,7 and our efforts8,9 on C-
C bond activation, we envisioned that a novel type of C(sp3)-
C(sp3) bond scission would be achieved via the following
pathway (Scheme 1C). Firstly,
a site-specific H-atom
abstraction by an appropriate primary radical would afford a
C-centered radical a, which then could capture one mole of O2
leading to a peroxide radical b. Subsequently, an alkoxyl
radical c would be formed via HAT (Hydrogen Atom Transfer)
and homolysis. Finally, a β-fragmentation of c followed by
SH2 (Homolytic Bimolecular Substitution) would achieve
deconstructive functionalization of alkanes.
RESULTS AND DISCUSSION
remarkable
impact
on
this
reac-
Selective cleavage of inert C(sp3)-C(sp3) bond for
deconstructive nitrogenation of cyclohexylbenzene.
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1
2
3
Scheme 1. Advances in selective activation of C(sp2)-C(sp3) and C(sp3)-C(sp3) bonds6-9.
4
5
C(sp2)-C(sp3) bond cleavage
C(sp3)-C(sp3) bond cleavage
B
A
6
7
8
9
C(carbonyl)-C(sp3):
General model:
O
O
X
O
X
HAT
Cat. [Rh], Lig.
R''
R''
R
10
11
12
13
14
15
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17
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19
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53
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58
59
60
M
R
or -e-, -H+
R''
R'
R
R
R
R'
M catalyst
Ar
oxidative addition
(X = OH, OR1, NR1R2)
Ar
H
C(aryl)-C(sp3):
Selected examples:
cat. [Ag]
H
X
Schmidt
rearragement
O
N3
R
[O]
N3
Halide source
R N
Ar
R
N
Ar
R
R
N
Ar
R'
H
R'
Ar
R
R'
R'
(X= F, Cl, Br)
C(vinyl)-C(sp3):
O
N
O
O
a) -scission
b) HAT
cat. TM, air
or TBN, O2
O3, [Fe]
R N
R
OR
C
C(sp3)-C(sp3) bond activation without strain or activating functionality
O
this work
FG
Ar
n
Ar
n
H
SH2
FG = CN, O,
X...
O
I N3
2+
Ru(bpy)3
O
O
N3
visible light
Ar
n
d
HAT
BIN3 1
-scission
HN3
HAT
homolysis
O2
Ar
Ar
n
n
Ar
OO
n
O
c
a
b
Table 1. Selective cleavage of inert C(sp3)-C(sp3) bond for deconstructive functionalization of cyclohexylbenzene.
side products:
Ru(bpy)3Cl2 (y mol%)
BIN3
additive (z equiv)
Ph
OH
1
(x equiv)
HO
Ph
4
O
O
CN
Ph
4
5
Ph
solvent
2
3
light, atmosphere
Conditionsa
O
Ph
OOH Ph
4
4
O
O
6
7
Entry
Reagent (equiv), atmosphere,
light sources, reaction time, temp
Solvent
3 (%)
Side products
(%)
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ACS Catalysis
1
2
BIN3 (2), Ru(bpy)3Cl2 (0.01), Air,
white CFL (24 W), 24h, 30 oC
BIN3 (2), Ru(bpy)3Cl2 (0.01), Air,
white CFL (24 W), 24h, 30 oC
BIN3 (2), Ru(bpy)3Cl2 (0.01), Air,
white CFL (24 W), 24h, 30 oC
BIN3 (3), Ru(bpy)3Cl2 (0.01), Air,
white CFL (24 W), 24h, 30 oC
BIN3 (5), Ru(bpy)3Cl2 (0.01), Air,
white CFL (24 W), 24h, 30 oC
BIN3 (6), Ru(bpy)3Cl2 (0.01), Air,
white CFL (24 W), 24h, 30 oC
BIN3 (5), Ru(bpy)3Cl2 (0.01), O2,
white CFL (24 W), 24h, 30 oC
BIN3 (5), Ru(bpy)3Cl2 (0.01), N2,
white CFL (24 W), 24h, 30 oC
BIN3 (5), Ru(bpy)3Cl2 (0.01), Air,
white CFL (24 W), 12h, 30 oC
BIN3 (5), Ru(bpy)3Cl2 (0.01), Air,
blue leds (24 W), 12h, 30 oC
DCM
16
18
65(4)
<10 (5,6,7)
53b(6)
1
2
3
4
5
6
7
8
EtOAc
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
<10 (4,5,7)
35(7)
3
37
<10 (4,5,6)
39(7)
9
10
11
12
13
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60
4
52
<10 (4,5,6)
15(7)
5
68 (63b)
75 (68 b)
66
<10 (4,5,6)
15(7)
6
<10 (4,5,6)
15(7)
7c
8
<10 (4,5,6)
<10 (7)
<10
51
<10 (4,5,6)
<10 (7)
9
<10 (4,5,6)
<10 (7)
10
11
12
50
<10 (4,5,6)
<10 (7)
BIN3 (5), Ru(bpy)3Cl2 (0.01), Air,
darkness, 12h, 30 oC
<10
19
<10 (4,5,6)
<10 (7)
BIN3 (5), Air,
white CFL (24 W),12h, 30 oC
<10 (4,5,6)
1
[a] Yields are based on H-NMR analysis of reaction mixture on a 0.2 mmol scale at a 0.1 M concentration unless specified otherwise
using ACS grade solvents under an air atmosphere (open reactions). Source of light: 24 W white Compact Fluorescent Lamp (white CFL)
or 24 W blue LEDs. [b] Isolated yield. [c] Oxygen bubbling reaction.
tion, since no reaction occurred in darkness (entry 11), while
irradiation of blue LED or white CFL gave similar results
(entry 9 vs entry 10). Visible light irradiation in the absence of
Ru(bpy)3Cl2 also gave a small amount of 3 (entry 12), because
the weak “I-N” bond could be homolyzed by light irradiation.
these substrates was very high with oxygenation occurring at
the benzylic site because of relatively lower bond dissociation
energy (BDE) of benzyl C-H than others and the stability of
the resulting benzyl radical. In general, highly selective
C(sp3)-C(sp3) bond cleavage reactions worked well for lots of
phenyl substituted cycloalkanes (8-19) and benzocycloalkanes
(20-28). Cyclic alkanes of different sizes were all compatible
with this system (3, 8 and 9). Cyclic alkanes with electron-rich
as well as electron-deficient aromatic cores could smoothly
afford deconstructive nitrogenation products under standard
conditions (14, 16-19). In addition, the electron density of the
benzene in the substrate had little effect on the reaction (3 vs
Substrate Scope and Selectivity.
Selective cleavage of inert C(sp3)-C(sp3) bond for
deconstructive nitrogenation of cycloalkanes.
With the optimized conditions in hand, subsequently, a variety
of cyclic alkanes without ring strain or activated groups were
investigated. As shown in Scheme 2, the regioselectivity of
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Page 4 of 13
16 vs 19). However, this reaction system was not applicable to groups, including Bn, halogen, ester, ketone, ether, sulfonate,
1
2
alkyl substituted heteroarenes such as alkyl pyridine, alkyl
furan and alkyl thiophene (see more details in SI). Functional
chain alkanes and naphthalene, were well tolerated. However,
the electron density on cycloalkanes greatly affected the prod-
3
4
5
Scheme 2. Selective cleavage of inert C(sp3)-C(sp3) bond for deconstructive nitrogenation of cycloalkanes.
6
7
8
9
N
Ru(bpy)3Cl2 (1 mol%)
+
BIN3
O
white CFL (24 W)
HFIP, 30 o
open air a
Ar
1
n
Ar
C
n
n = 1, 2, 3...
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Starting material
Product
Starting material
Product
CN
O
O
CN
MeO
MeO
b
b
8a
14a
8
9
14
75% (58% )
60% (52% )
CN
O
O
I
I
CN
9a
b
b
15a
16a
15
70% (64% )
40% (33% )
CN
OCOPh
O
O
O
O
OCOPh
CN
b
b
10a
trans
10
10
16
trans 72%(66% )
67% (59% )
b
10b
cis
cis 76%(71% )
CN
CN
O
O
Cl
COOCH2Ph
Cl
COOCH2Ph
PhH2COOC
17a
PhH2COOC
b
b
11
17
11a
54% (37% )
49% (39% )
O
O
CN
O
O
S
O
S
O
Cl
EtO
EtO
O
O
b
c
b
18a
11'
18
16% (16% )
58% (52% )
CN
O
O
O
O
OH
59% (O2 balld)
57% (40% )
R = Ph, n = 1, 65%;
R = Ph, n = 2, 62% ;
b
19a
12
19
20,
21,
22,
23,
24,
25,
26,
27,
28,
12a
13a
e
R = o-Me-Ph, n = 1, 28%;
R = m-Me-Ph, n = 1, 62%;
R = p-Me-Ph, n = 1, 51%
R = p-OMe-Ph, n = 1, 50%
R = p-Br-Ph, n = 1, 47%
R = p-I-Ph, n = 1, 57%
R
O
CN
R
O
Br
Br
CN
n
n
b
13
66% (56% )
20a-27a
R = Naphthalene, n = 52%
Starting material
Product
O
Starting material
Product
Ph
O
Ph
CN
H
O
O
H
H
H
H
H
H
CN
H
H
H
H
PhOCO
H
PhOCO
PhOCO
H
PhOCO
(or OMe)
f
(or OMe)
33a Epiandrosterone derivative
33
48%
f
29
30
58%
52% (-OMe)
29a
30a
(-OCOPh)
(-OMe)
f
Estrone derivative
CN
OCOPh
OCOPh
OCOPh
OCOPh
CN
O
H
H
H
H
O
H
H
H
H
H
H
H
PhOCO
PhOCO
Ph
H
H
f
f
31a Estradiol derivative
34a Androstanolone derivative
34
56%
31
56%
CN
H
HO
H
OH
O
H
H
H
MeO
MeO
34
X-Ray
CCDC 1977526
f
32a Ethynylestradiol
32
53%
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ACS Catalysis
[a] Isolated yield on 0.2 mmol scale, t = 24 h; [b] Isolated yield on 0.2 mmol scale, t = 12 h; [c] Side product 11' was formed in 16%
isolated yield; [d] O2 ball instead of air is applied; [e] About 21% of ketone byproduct from benzyl oxidation of substrate was formed, see
SI. [f] t = 48 h.
1
2
3
4
Scheme 3. Selective cleavage of inert C(sp3)-C(sp3) bond of linear alkanes.
5
6
7
Ru(bpy)3Cl2 (1 mol%)
R3 R2
O
1
BIN3 (1.0 or 5.0 equiv)
R1
8
9
Ar
white CFL (24 W)
HFIP, 30 oC, 12h
open air a
Ar
R1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Starting material
Product
Ph
Starting material
Product
Starting material
Product
Ph
Ph
O
n-Pr
O
R''
R''
b
c e
35a
35
35% (75% )
OCOPh
OCOPh
n-Pr
O
41a
b
e
45
46
R' = COOCH2Ph, 51% (59% )
R' = COOEt, 59%
41
45a
46a
71%
O
Br
Br
COOCH2Ph
O
Ibuprofen derivatives
O
b
36a
36
30% (70% )
Ph
Ph
Ph
Ph
42a
e
42
53%
Br
Br
O
O
CHO
O
H
CHO
H
b
COOMe
36aa
36
25% (68% )
COOMe
e, f
47a Methyl Dehydroabietate
47
30%
43a
43
52%
O
R'
R'
O
37a-40a
MeO
b
37
38
39
40
R' = i-Pr, 31% (68% )
MeO
OMe
O
H
COOMe
d
O
O
R' = CHO, 20% (RSM 55% )
H
e
R' = OCOPh, 76%
COOMe
e
e
44a Hexestrol
derivative
44
34%
e
R' = COOCH2Ph, 69%
47'
47
78%
1
[a] Isolated yield on 0.2 mmol scale, t = 12 h; [b] Yields are based on H-NMR analysis; [c] Isolated as a N-(t-butyl)benzamide after
treatment with t-BuOAc, AcOH and H2SO4, See SI. [d] RSM is the short for of recovery starting material. [e] BIN3 = 5.0 equiv; [f] Side
products from benzyl oxidation and azidation of substrates were formed, See SI.
ucts. Benzyl carboxylate substituted cyclohexylbenzene under
optimal conditions obtained not only deconstructive
nitrogenation product, but also another product produced by
deconstructive hydroxylation intermediate proceeding
intramolecular transesterification (11 and 11’). Moreover,
more electron- deficient 4-Ph-cyclohexanone was totally
converted into deconstructive hydroxylation product under
oxygen atmosphere. It might be possible to control C(sp3)-
C(sp3) bond cleavage reaction product by controlling electron
density on cyclic alkanes (12). Large steric hindrance heavily
reduced the reaction yield (22 vs 23 vs 24). When substrate
contained two cyclohexanes, only one ring-opening product
was obtained (19).
epiandrosterone, and androstanolone derivatives) to achieve
inert C(sp3)-C(sp3) bond cleavage of steroid molecules. To our
delight, steroid compounds with different skeletons could
smoothly undergo selective C(sp3)-C(sp3) bond cleavage
reactions to obtain corresponding deconstructive nitrogenation
product in moderate yields (Scheme 2 29-34). Additionally,
common functional groups such as Bz, ester, tertiary alcohol
and alkynyl on steroid molecules were well compatible.
Importantly, for carbon skeletons that did not participate in the
reaction, the original stereo configurations were still
maintained (34 X-Ray). We predicted that there would be two
products formed via different C(sp3)-C(sp3) bond cleavage of
androstanolone derivatives. However, it is extremely
interesting that only one configurational deconstructive
nitrogenation product was observed in the C(sp3)-C(sp3) bond
cleavage reaction of compound 34 (34 X-Ray). This protocol
of oxidative C(sp3)-C(sp3) cleavage of alkanes might have
profound implications of synthesis,14 since it offers facile
approaches to many valuable compounds. For instance, oxo
nitriles derived from 1-arylcyclic alkanes have been used to
synthesize of isoquinoline derivatives14a-14d and produce α-
hydroxyketones which are present in a multitude of natural
Selective cleavage of inert C(sp3)-C(sp3) bond for
deconstructive nitrogenation of steroids derivatives.
The selective C-C bond cleavage reactions have been
successfully applied in skeletal modification of steroids
derivatives. However, most of these transformations undergo
β-fragmentation of alkoxy radical, which limits substrates
greatly.1 Therefore, we further applied our strategy in a series
of complex steroids (eg. estrone, estradiol, ethynylestradiol,
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products.14e-14h Furthermore, these oxo nitriles are utilized as
of cyclopentylbenzene product was formed in 12% yield under
key intermediates to synthesize vinylnitriles.14i
standard light-promoted conditions for 1 hour. And as reaction
time increased, the yield of compound 60 decreased while the
yield of compound 8 increased. In addition, possible
intermediate 60 with Ru(bpy)3Cl2 or without Ru(bpy)3Cl2 in
HFIP at room temperature and under visible light irradiation
for 12 hours in the absence of BIN3 could not form target
product 8 (Scheme 6B). As expected, deconstructive azidation
of cyclopentylbenzene product could easily form compound 8
in the yield of 47% (Scheme 6C). The above research results
indicated that deconstructive azidation of cyclopentylbenzene
product might be an intermediate in deconstructive
nitrogenation of cyclopentylbenzene by C(sp3)-C(sp3) bonds
cleavage. Hydroperoxycyclohexyl benzene V-1 was prepared
according to the literature16. A series of experiments were
carried out to investigate the mechanism for the peroxide V-1
transformation (Scheme 6D). Hydroperoxycyclohexyl benzene
V-1 is unstable and was underwent homolysis and β-
fragmentation to give compound 5 in the yield of 5% in the air
and darkness for a long time (Scheme 6D, entry 1). Light and
photosensitizer Ru(bpy)3Cl2 could accelerate the conversion of
peroxide (entry 1 vs entry 2 and entry1 vs entry 3). When the
reaction time increased, the yield of compound 5 decreased
and the yield of compound 6 increased (entry 3 and entry 5).
Compound 3 could be obtained by the reaction of peroxide
and BIN3 with Ru(bpy)3Cl2 or without Ru(bpy)3Cl2 in a
nitrogen atmosphere under white CFL irradiation at room
temperature (entry 6 and entry 7).
1
2
3
4
5
6
7
8
9
Selective cleavage of inert C(sp3)-C(sp3) bond in linear
alkanes.
As shown in Scheme 3, linear alkanes also underwent
selective C(sp3)-C(sp3) bond cleavage reactions to acquire
corresponding aldehydes or ketones in moderate to good
yields. To investigate another product of C(sp3)-C(sp3) bond
cleavage reaction of linear alkanes, 1,2-diphenylethane was
carried out under the condition B (See SI). After the reaction,
PhCN as another product was detected in the solvent by LC-
MS. Then the reaction mixture was treated with t-BuOAc,
AcOH and H2SO4, proceeding Ritter reaction to obtain N-(t-
Bu)-benzamide in the yield of 28%, which fully proved that
there was benzonitrile product in the C(sp3)-C(sp3) bond
cleavage reaction system of 1,2-diphenylethane. Moreover, we
were delighted to find that many natural products and drug
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
molecules
(eg.
hexestrol,
ibuprofen
and
methyl
dehydroabietate derivatives) containing various kinds of
carbon-carbon bonds still could accurately cleave C(sp3)-
C(sp3) bond to effectively finish their skeletal modification.
Selective cleavage of inert C(sp3)-C(sp3) bond for
deconstructive peroxidation of cycloalkanes.
As shown in Table 1, deconstructive peroxidation product of
cyclohexylbenzene by the C(sp3)-C(sp3) bond cleavage could
be obtained in 53% yield when solvent was EtOAc rather than
HFIP (Table 1, entry 2), which inspired us to evaluate various
cyclic alkanes under conditions E (Scheme 4) (See SI). In
general, cycloalkylbenzene with different sizes (eg.
Scheme 4. Selective cleavage of inert C(sp3)-C(sp3) bond
for deconstructive peroxidation of cycloalkanes.
BIN3 (2.0 equiv)
Ru(bpy)3Cl2 (1 mol%)
OOH
R
R
O
cyclopentylbenzene,
cyclohexylbenzene
and
EtOAc
White CFL (24 W), 30 o
(2 mL)
cycloheptylbenzene) and different aryl substituted cyclic
alkanes had been proved to be suitable substrates and
functional groups including halogen, ketone and linear alkyl
were tolerated.
n
n
C
n = 1, 2, 3
a
open air
, 48 h
OOH
OOH
OOH
O
O
O
Selective cleavage of inert C(sp3)-C(sp3) bond for
deconstructive chlorination of cycloalkanes.
3
2
b
b
b
48
6
53% (R-CN 18% )
58% (R-CN 25% )
49
60% (R-CN 27% )
HOO
To our delight, we found that this reaction system could be
futher modulated to form mainly deconstructive chlorination
of cycloalkanes product by the addition of a chlorine donor. In
Scheme 5, reactions of cyclic alkanes with the Zhdankin
reagent BIN3, Ru(bpy)3Cl2, LiCl as the Cl donor and visible
light irradiation under air at room temperature gave
chlorination products smoothly. These transformations also
featured high selectivity, efficiency and good functional group
tolerance.
HOO
HOO
O
O
O
O
I
4
Br
50
Et
b
b
b
51
54% (R-CN 28% )
56% (R-CN 23% )
52
51% (R-CN 26% )
[a] Isolated yield on 0.2 mmol scale, t = 48 h; [b] Side products
from deconstructive nitrogenation of cyclic alkanes.
Scheme 5. Selective cleavage of inert C(sp3)-C(sp3) bond
for deconstructive chlorination of cycloalkanes.
However, it is worth noting that the competing deconstructive
nitrogenation of cycloalkanes process was not completely
suppressed in both deconstructive peroxidation and
chlorination reaction systems.
Mechanistic Studies.15
In order to reveal the mechanism of the C(sp3)-C(sp3) bond
activation, series of control experiments were carried out
(Scheme 6). As shown in Scheme 6A, deconstructive azidation
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BIN3 (5.0 equiv)
LiCl
Ru(bpy)3Cl2 (1 mol%)
R
(10.0 equiv)
Cl
n
R
1
2
3
4
O
n
HFIP (2 mL)
White CFL (24 W), 30 oC
n = 1, 2, 3
a
open air
, 24 h
5
6
7
8
Cl
Cl
Cl
O
O
O
Br
2
2
b
b
b
53
54
55
58
59% (R-CN 18% )
54% (R-CN 20% )
57% (R-CN 33% )
9
Cl
Cl
Cl
10
11
12
13
14
15
O
O
O
O
Cy
56
OCOPh
b
b
b
57% (R-CN 14% )
57
65% (R-CN 19% )
72% (R-CN 16% )
[a] Isolated yield on 0.2 mmol scale, t = 24 h; [b] Side products
from deconstructive nitrogenation of cyclic alkanes.
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 6. Mechanistic Studies.
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60a
A) Trapping of intermediate
D) The mechanistic investigation for the peroxide intermediate transformation
1
2
3
4
5
6
7
8
Ru(bpy)3Cl2 (1 mol%)
or no Ru(bpy)3Cl2 (1 mol%)
BIN3 or no BIN3
HFIP (0.1 M), rt (30 oC)
O
BIN3 (5.0 equiv)
Ru(bpy)3Cl2 (1 mol%)
HOO
N3
3 (-CN)
5 (-OH)
6 (-OOH)
RSM
+
+
HFIP (0.1 M)
White CFL (24 W), Air
rt (30 oC), 1 h
V-1
8a
60
60
12%
10%
b
Entry Reagent (equiv), light sources,
time, atmosphere
3
5
6
(%)
(%)
(%)
(%)
c
60
without BIN3
B) The reaction of intermediate
O
1
2
3
No additives, darkness, 24 h, air
0
0
5
0
0
80
73
O
Ru(bpy)3Cl2 (1 mol%)
or no Ru(bpy)3Cl2
9
CN
No additives, white CFL (24 W), 4 h, air
18
N3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
HFIP (0.1 M)
White CFL (24 W), Air
rt (30 oC), 12 h
Ru(bpy)3Cl2 (0.01), white CFL (24 W),
4 h, air
0
0
19
5
21
35
55
50
8
(not observed)
60
intermediate
4
5
No additives, white CFL (24 W), 24 h, air
Ru(bpy)3Cl2 (0.01), white CFL (24 W),
24 h, air
d
0
8
5
40
0
43
53
60
C) The reaction of intermediate
O
with BIN3
6
7
BIN3 (5), white CFL (24 W), 12 h, N2
33
BIN3 (5.0 equiv)
O
Ru(bpy)3Cl2 (1 mol%)
CN
BIN3 (5), Ru(bpy)3Cl2 (0.01),
white CFL (24 W), 12 h, N2
N3
35
5
0
50
HFIP (2 mL)
White CFL (24 W), Air
rt (30 oC), 12 h
60
intermediate
Yields are based on isolated yield of reaction mixture on a 0.2 mmol scale at a 0.1 M
concentration. Source of light: 24 W white Compact Fluorescent Lamp (white CFL).
RSM is short for recovery of starting material.
8
, 47% (isolated)
E) Plausible mechanism for deconstructive nitrogenation, peroxidation and chlorination of alkanes by selective C(sp3)-C(sp3) bond cleavage
O
I
N3
2+
light / Ru(bpy)3
[Ru(bpy)32+]*
O
I
N3
+
radical initiation
COO
BIN3
1
I
II
OO
O
1.HAT
H
Ar
N
O
O
Ar
O2
Ar
Ar
N3/BI
O
2.homolysis
-scission
Ar
Ar
BIN3
Ar
N3
light / [Ru2+]*
BI
III
IV
V
VI
VIII
X
intermediate
VII
chain propagation
O
Ar
O2
OO
H
OO
O
1.HAT
H
Ar
Path A: LiCl
Path B: BICl
( via in situ substitution
of BIN3 with LiCl)
O
Ar
IX
O2
N3/BI
Ar
Ar
2.homolysis
Ar
-scission
light / [Ru2+]*
O
Ar
Cl
III
IV
V
VI
BI
VII
chain propagation
XI
[a] The mixture of 0.2 mmol 8, 1 mol% Ru(bpy)3Cl2 and 5.0 mmol [IIII] reagents BIN3 at a 0.1 M concentration HFIP under an air
atmosphere and 24 W white CFL irradiation for 1 h, isolated yields are shown; [b] t = 2 h；[c] Intermediate 60 0.2 mmol at a 0.1 M
concentration HFIP under an air atmosphere and 24 W white CFL irradiation for 12 h; [d] Intermediate 60 0.2 mmol at a 0.1 M
concentration HFIP under optimal conditions for 12 h.
Finally, based on the results of control experiments and
previous literatures,10,12a a plausible mechanism was proposed
(Scheme 6E). Firstly, the weak “I–N” bond of BIN3 was
pathways to achieve different C(sp3)-C(sp3) bonds cleavage
and functionalization reactions as following:
10
1) In the deconstructive nitrogenation of alkanes by selective
C(sp3)-C(sp3) bonds cleavage, reaction of radical VII with
BIN3 afforded intermediate X, which could quickly convert to
the product of deconstructive nitrogenation of alkanes. A
series of control experiments were performed to reveal the
mechanism for conversion of the azide into a nitrile. The
desired product was observed without Ru(bpy)3Cl2, indicating
Ru(bpy)3Cl2 was not necessary, but only promoted the
cleaved via single electron reduction of photoexcited Ru(II)*
to form azido radical, which had been studied clearly in
previous reports.10,12a,12v Then selective H-atom abstraction by
N3 radical occurred to form a relatively stable benzyl radical
intermediate IV. Subsequently, IV was trapped by O2, leading
to peroxide radical. Next, HAT followed by homolysis of V
formed alkoxy radical VI, which underwent a β-fragmentation
to give radical VII. Finally, VII could undergo different
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Zhong-Quan Liu - College of Pharmacy, Nanjing University of
Chinese Medicine, Nanjing 210023, China; Email:
liuzhq@lzu.edu.cn
reaction. The BIN3 and visible light irradiation would play a
1
2
3
4
5
6
7
8
significant role in this system. Furthermore, the reaction was
suppressed by adding BHT (2,6-bis(1,1-dimethylethyl)-4-
methylphenol) as a radical scavenger, which suggested that the
process might involve free radical intermediates. Plausible
Authors
Yaxin Wang - College of Pharmacy, Nanjing University of
Chinese Medicine, Nanjing 210023, China;
Email:1120150254@mail.nankai.edu.cn
mechanism for the conversion of intermediate X to nitrile was
18
proposed (more details please see the SI).17,
The radical
Nengyong Wang - College of Pharmacy, Nanjing University of
Chinese Medicine, Nanjing 210023, China;
chain mechanism is supported by the large quantum yield (Φ ≈
19, measured by Yoon's method19) of deconstructive
nitrogenation of cyclohexylbenzene.20
9
Email: 569812902@qq.com
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Jianyou Zhao - College of Pharmacy, Nanjing University of
Chinese Medicine, Nanjing 210023, China;
2) In EtOAc solvent, because the concentration of BIN3 was
extremely low, primary radical VII preferred to react with O2
to achieve deconstructive peroxidation of cycloalkanes.
Email: 974871845@qq.com
3) Two alternative pathways might happen. In Path A, radical
VII directly reacted with LiCl to form the deconstructive
chlorination products. In Path B, radical VII abstracted a Cl-
atom from BICl that was generated via in situ substitution of
BIN3 1 with LiCl to give deconstructive chlorination products.
The control experiments indicated that both BIN3 1 and BICl 1’
are involved in the deconstructive chlorination reaction.
Mixing of BIN3 1 and LiCl in HFIP at rt in the absence of light
could produce BICl 1’ (42% yield in 2 h). Subjecting substrate
8a and 5.0 equivalent of BICl 1’ to the standard light-
promoted conditions did not give any product. Interestingly,
the addition of 1 equivalent of BIN3 1 together with BICl 1’
cleanly restored the deconstructive chlorination reaction (see
more details in SI). It suggests that BICl 1’ cannot be able to
activate the C(sp3)-C(sp3) bond in alkanes effectively, but it is
more reactive than BIN3 1 toward homolytic substitution by
radical intermediate VII.
Minzhi Sun - College of Pharmacy, Nanjing University of
Chinese Medicine, Nanjing 210023, China;
Email: zhima11mm@163.com
Huichao You - College of Pharmacy, Nanjing University of
Chinese Medicine, Nanjing 210023, China;
Email: 1464667258@qq.com
Fang Fang - College of Pharmacy, Nanjing University of Chinese
Medicine, Nanjing 210023, China;
Email: fylffh@163.com
Notes
Dedicated to those who fight against the COVID-19.
ACKNOWLEDGMENT
This project is supported by National Natural Science Foundation
of China (No. 21672089, 21971116).
CONCLUSION
REFERENCES
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converted into nitriles, peroxides or chlorides via cleavage of
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ASSOCIATED CONTENT
Additional experimental procedures and spectroscopic data for all
new compounds are supplied. This material is available free of
charge via the Internet at http://pubs.acs.org.
Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org.
Experimental details, characterization data of compounds, NMR
spectra, and mechanistic discussion (PDF)
X-ray crystallographic data for 34 (CIF)
AUTHOR INFORMATION
Corresponding Author
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(18) For the details of transformation intermediate 60, see the
Supporting Information.
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with Φ>>1 could only be consistent with a product-forming
chain mechanism. The radical chain mechanism is supported by
the large quantum yield (Φ≈19, measured by Yoon's method) of
deconstructive nitrogenation of cyclohexylbenzene. Our
“light/dark” experiment showed that the same deconstructive
nitrogenation of cyclohexylbenzene requires constant irradiation
for product formation, which suggests a relatively short lifetime
of the radical chain process (see more details in SI).
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N
N
BI
3
HFIP
Ar
Site-specific C-C Cleavage
Diverse C-C functionalization
Visible-light initiation
58 examples
O
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9
Ru(bpy)3Cl2
(1 mol%)
Air
, BIN3
OOH
EtOAc
visible light
Ar
Ar
Ar
open air
rt,
O
Open air
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Cl
Cl
Li , BIN3
Excellent FG compatability
HFIP
O
(8.43cmх3.77cm)
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