A unified photoredox-catalysis strategy for C(sp3)-H hydroxylation and amidation using hypervalent iodine

Article abstract of DOI:10.1039/c7sc02773g

We report a unified photoredox-catalysis strategy for both hydroxylation and amidation of tertiary and benzylic C-H bonds. Use of hydroxyl perfluorobenziodoxole (PFBl-OH) oxidant is critical for efficient tertiary C-H functionalization, likely due to the enhanced electrophilicity of the benziodoxole radical. Benzylic methylene C-H bonds can be hydroxylated or amidated using unmodified hydroxyl benziodoxole oxidant Bl-OH under similar conditions. An ionic mechanism involving nucleophilic trapping of a carbocation intermediate by H₂O or CH₃CN cosolvent is presented.

Full text of DOI:10.1039/c7sc02773g

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EDGE ARTICLE
A Unified PhotoredoxꢀCatalysis Strategy for
C(sp3)−H Hydroxylation and Amidation Using
Hypervalent Iodine
Cite this: DOI: 10.1039/x0xx00000x
GuoꢀXing Li,a Cristian A. MoralesꢀRivera,b Fang Gao,a Yaxin Wang,a Gang He,a
Peng Liu,*b and Gong Chen*a,c
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
We report a unified photoredoxꢀcatalysis strategy for both hydroxylation and amidation of
tertiary and benzylic CꢀH bonds. Use of hydroxyl perfluorobenziodoxole (PFBlꢀOH) oxidant
is critical for efficient tertiary CꢀH functionalization, likely due to the enhanced
electrophilicity of the benziodoxole radical. Benzylic methylene CꢀH bonds can be
hydroxylated or amidated using unmodified hydroxyl benziodoxole oxidant BlꢀOH under
similar conditions. An ionic mechanism involving nucleophilic trapping of a carbocation
intermediate by H2O or CH3CN cosolvent is presented.
www.rsc.org/
A) Radical C(sp3)−H oxygenation using hypervalent iodine
Introduction
[I]
tBuOOH
C
H
H
C
H
C
O
Methods for efficient and selective alkyl CꢀH oxidation could
streamline the synthesis of fine chemicals, natural products, and
drug metabolites.1,2 Despite rapid advances in the development
of metalꢀcatalyzed reactions3 and reagents,4 synthetically
useful C(sp3)ꢀH oxygenation chemistry is still in great
demand.5,6 Recently, radical reactions mediated by hypervalent
iodine (III) reagents have emerged as viable means to
oxygenate C(sp3)ꢀH bonds under mild conditions.7ꢀ11 Ochiai
first reported the oxidation of activated C(sp3)ꢀH bonds of
benzyl and allyl ethers to the corresponding esters using
butylperoxy benziodoxole (BlꢀOO Bu, ) via Hꢀabstraction by
benziodoxole radical Bl
(Scheme 1A).9 Maruoka elegantly
demonstrated the use of acyclic iodane reagents and in the
H-abstraction
Ochiai
O
OOtBu
O
I
I
O
O
Bl , 2
OAc
Bl-OOtBu, 1
Maruoka
AcO
O
I
I
TfO
OOtBu
TfO
N
I
I
O2N
O
Ph
Ph
3
4
5
6
tꢀ
B) This work
t
1
H2O
or
ꢀ
2
C
OH
[I]
photoredox
3
5
C
C
C
H
H-abstraction
CH3CN
selective oxidation of unactivated methylene CꢀH bonds of
simple alkanes to the corresponding ketones, effected by more
reactive iodanyl radical intermediates
C
NHAc
ionic pathway
O
4 . Notably,
and 6 10
I
OH
F
O
Maruoka’s oxygenation reactions proceed with a selectivity for
secondary over tertiary CꢀH bonds. Herein, we report an
efficient and broadly applicable photoredoxꢀcatalysis strategy
for the selective hydroxylation of tertiary and benzylic CꢀH
bonds using hydroxyl benziodoxoles as oxidant and H2O as
cosolvent and hydroxylation reagent. This reaction system can
be easily modulated to achieve tertiary and benzylic CꢀH
amidation with high efficiency and selectivity using CH3CN as
coꢀsolvent and amidation reagent.
OH
O
I
R
R
PFBl-OH
F
(2.5 equiv)
F
F
F
H
R'
or
O
F
R
CFL (23 W)
R'
F
NHAc
[Ru(bpy)3]Cl2 (2.5 mol%)
HFIP/H2O (or HFIP/CH3CN)
30 oC, Ar, 20 h
F
PFBl
R'
O
I
OH
O
Bl-OH
(2 equiv)
H
OH
NHAc
R
Bl
or
Ar
R
Ar
R
Ar
same as above
C(sp3)−H oxygenation and amination with
Results and Discussion
Scheme
1
hypervalent iodine (III).
Previously, we discovered a visible lightꢀpromoted method for
This journal is © The Royal Society of Chemistry 2013
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VJieowuArrtnicalelONnlainme e
ARTICLE
DOI: 10.1039/C7SC02773G
these results, we questioned whether the reaction with the
corresponding hydroxyl benziodoxole could offer CꢀH
hydroxylation product under similar conditions.
Table 1 Tertiary CꢀH hydroxylation of 7 with hydroxyl benziodoxoles
Bl reagents
O
[Ru(bpy)3]Cl2 (2.5 mol%)
As shown in Table 1, we commenced the investigation of
O
BzO
H
OH
tertiary CꢀH hydroxylation of
7 with BlꢀOH 13 under the
CFL (23 W)
solvents, 30 oC, Ar, 36 h
8
7
irradiation of CFL (23 W) using [Ru(bpy)3]Cl2 as photocatalyst
o
in hexafluoroisopropanol (HFIP) at 30 C. Our previous work
has shown that BlꢀOH 13 can be used to generate Blꢀ2 under
similar conditions for a Minisciꢀtype CꢀH alkylation reaction of
Nꢀheteroarenes with alkyl boronic acids.15,16 However,
entr reagents (equiv)
y
solvents
yield (%)a
8
1
2
3
4
5
6
7
8
9
Bl-N3 11 (2)
HFIP
<1b
<2
29
32
38
46
51
25
18
64c
55
29
<2
<2
BI-OH 13 (2)
HFIP
subjecting
7
,
13, and [Ru(bpy)3]Cl2 to CFL irradiation produced
, with
largely unconsumed (entry 2). However, adding H2O to the
Bl-OH 13 (2)
HFIP/H2O (26/1)
HFIP/H2O (26/1)
HFIP/H2O (26/1)
HFIP/H2O (26/1)
HFIP/H2O (26/1)
HFIP/H2O (26/1)
HFIP/H2O (26/1)
HFIP/H2O (26/1)
HFIP/H2O (10/1)
HFIP/H2O (26/1)
only trace amount of the desired hydroxylation product
7
8
4FBI-OH 14 (2)
4CF3BI-OH 15 (2)
TFBI-OH 16 (2)
PFBI-OH 17 (2)
4MOBI-OH 18 (2)
BI-OAc 12 (2)
reaction increased the yield of
8
to 29% (entry 3). Our previous
is delocalized on
is more stable than
The stability of Bl may explain the
observed weak reactivity for Hꢀabstraction and the low
conversion of 7 17,18
We speculated that installation of electronꢀ
work has indicated that the spin density of Bl
both O and I atoms and that Bl
benzoyloxy radical BzOꢀ15
ꢀ
ꢀ
.
ꢀ
10 17 (2.5)
11 17 (2.5)
.
12 17 (2.5), O2 (1 atm)
13 17 (2.5), Ir(ppy)3 (2.5 mol%)
withdrawing groups on the aryl motif of Bl would increase its
electrophilicity, and enhance its Hꢀabstraction reactivity. As
HFIP/H2O (26/1)
14 17 (2.5), [Ru(bpz)3](PF6)2 (2.5 HFIP/H2O (26/1)
mol%)
shown in entries 4ꢀ7, BlꢀOH analogs 14ꢀ17 with different
15 17 (2.5), in darkness
HFIP/H2O (26/1)
<2
40
4
electronꢀwithdrawing groups were prepared and evaluated (see
Supporting Information for more details).19 We were pleased to
find that these BlꢀOH analogs provided improved results, and
16 17 (2.5), [Ru(bpy)3]Cl2 (1 mol%) HFIP/H2O (26/1)
17 17 (2.5)
18 17 (2.5)
19 17 (2.5)
20 17 (2.5)
21 13 (2.5)
HFIP
DMSO/H2O (26/1)
<2
HFIP/ CH3CN (26/1)d <2 (+ 10% of 10)
HFIP/ CH3CN (4/3)d <2 (+ 56% of 10)e
HFIP/ CH3CN (4/3)d <2 (+ 8% of 10)
hydroxyl perfluorobenziodoxole (PFBlꢀOH, 17) gave the best
20,21
yield.
A 64% isolated yield of 8 was obtained when 2.5
equiv of 17 was used (entry 10). Regarding the optimization of
this hydroxylation reaction, we note: 1) addition of H2O is
critical to obtain high yield (see entries 10 vs 17). 2) 17 has
high polarity and only dissolves well in polar solvents such as
HFIP, DMSO, DMF; HFIP gives significantly better results
than other solvent tested; 3) under O2 atmosphere, the reaction
gave significantly diminished yield (entry 12); 4) in the dark,
the reaction gave no product (entry 15); 5) Only trace amount
(<3% yield) of methylene CꢀH hydroxylation side product was
detected. Interestingly, when the reaction was performed in
mixed HFIP/CH3CN solvents (4/3) under similar conditions we
obtained 56% yield of the CꢀH aminated product 10 with
excellent selectivity (entry 20).
N3
NHAc
BzO
BzO
9
10
O
N3
I
O
I
OAc
O
O
I
OH
I
OH
F
O
O
O
O
BI-N3, 11
4FBI-OH, 14
Bl-OAc, 12
BI-OH, 13
O
I
OH
O
I
OH
O
I
OH
O
I
OH
F
O
F
O
O
O
F
F
F
CF3
4CF3BI-OH, 15
OMe
4MOBI-OH, 18
F
F
TFBI-OH, 16
PFBl-OH, 17
With optimized conditions in hand, we investigated the
substrate scope of this CꢀH hydroxylation reaction (Scheme 2).
In general, the reaction proceeds with excellent selectivity for
tertiary CꢀH bonds and in good yield. Common functional
groups including CN, iodo, esters, amide, imide and pyridine
(a) Isolated yield on a 0.2 mmol scale, c ~ 50 mM, ACS grade of
HFIP was used. (b) 58% of 9 was obtained. (c) 8% of 7 was
recovered. (d) anhydrous HFIP and CH3CN dried over 4 Å
molecular sieves were used. (e) c ~ 30 mM, ~10% of 7 was
recovered. See SI for more screening results.
moiety are tolerated. When reaction of
7 was performed in a
mixture of HIFP and H218O (97% of 18O), 18Oꢀlabelled product
tertiary CꢀH azidation using Zhdankin reagent BlꢀN3 11 (see
entry 1, Table 1), [Ru(bpy)3]Cl2 photosensitizer, and household
compact fluorescent lamp (CFL) irradiation. 12ꢀ14 We proposed
a radical chain mechanism for this azidation reaction, beginning
19 was obtained. C–H hydroxylation of sulbactam and
thalidomide derivatives (see 27 and 28) bearing βꢀlactam and
imide groups proceeded in good yield. 28 was obtained in 60%
yield on a gram scale. Both steric and electronic factors
influence the reactivity of tertiary CꢀH bonds. For instance,
tertiary CꢀH hydroxylation took place selectively at the more
distal 3o carbon of 29. Hydroxylation of the sterically hindered
and electronꢀpoor tertiary CꢀH bond of phthaloyl valine methyl
ester gave 32 in moderate yield. In comparison, CꢀH
with formation of Bl radical
11 by a photoexcited Ru(II)* species. Bl
abstracts a H atom from the substrate (e.g. 4ꢀmethylpentyl
benzoate ), forming tertiary alkyl radical intermediate, which
reacts with 11 to give CꢀH azidation product and regenerate
radical , propagating a radical chain reaction. Encouraged by
2
via single electron reduction of
ꢀ
2
then selectively
7
2
2 | J. Name., 2012, 00, 1-3
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hydroxylation of leucine methyl ester 34 provided lactone such as iodo, ketone, amide, even pinacolyl boronate ester (see
product 33 in 52% yield. Moreover, short peptide substrates 42). Electronꢀdeficient arenes are less reactive and require the
(see 35 and 36) can be CꢀH hydroxylated on the Leu residue use of 4 equiv of BlꢀOH 13 (see 41). Electronꢀrich substrates
with excellent selectivity under standard conditions.
give good yield with 1.5 equiv of BlꢀOH (see 38). Reaction of
ibuprofen methyl ester gave 43 in 64% yield without the
formation of tertiary CꢀH hydroxylated product. The same
reaction in H218O gave 18Oꢀlabelled product 44. Reaction of
natural product celestolide gave product 45 in excellent yield.
PFBI-OH 17 (2.5 equiv)
[Ru(bpy)3]Cl2 (2.5 mol%)
OH
R'
H
R
R
CFL (23 W)
HFIP/H2O (26/1), Ar, 30 oC, 24 ha
R'
O
OH
OH
OH
R2
18OH
O
BI-OH 13 (2 equiv)
[Ru(bpy)3]Cl2 (2.5 mol%)
H
H
O
BzO
BzO
R2
R2
R1
R1
22, 54% {80%} [36 h]
20 (R = I), 67% {84%}
21 (R = CN), 63% {82%}
R
19, 61% [36 h]
(88% incorporation of 18O)b
CFL (23 W)
HFIP/H2O(9/1), Ar, 30 oC, 10 ha
NPhth
ketone
tBu
OH
OH
OH
OH
OH
PhthN
N
HO
O
24, 57% {73%}
23, 77%
25, 81% [10 h]
I
37
N
O
S
MeO
H
OH
O
O
H
71% (+ 8% of ketone 37'
using 2 equiv of 13) [10 h]
O
38, 82% (10%)c
39, 76% (<5%) [16 h]d
OH
N
N
44% (+24% of 37' using 4 equiv of 13) [24 h]
40% (+22% of 37' using 2 equiv of 17)b [6 h]
N
OH
PhthN
O
O
O
OH
28, 62%
60% (3 mmol scale)c
O
O
OH
OH
26, 74%
27, 65%
OBz
5
OBz
O
dr: 1/1
B
OH
3
7
O
MeOOC
OBz
HO
OH
O
3
7
41, 57% (9%) [16 h]d
42, 50% (<5%)d
40, 78% (6%)
29, 80%d
30, 52% {62%}e
31, 58% {75%} [36 h]
18OH
O
OH
OH
HO
H
COOMe
COOMe
O
PhthN
CO2Me
PhthN
PhthN
CO2Me
43, 64% (10%)
44, 60%f
(93% incorporation of 18O)
O
32, 29% {80%} [36 h]
45, 90% (<5%)c
58% (5 mmol scale)e
33, 52% {88%} [36 h]f
34
HO
O
H
Scheme 3 Substrate scope of benzylic CꢀH hydroxylation with
BlꢀOH 13. (a) Isolated yield on a 0.2 mmol scale under
standard conditions, c ~ 45 mM, yield of ketone byꢀproduct was
O
H
O
O
N
Gly-Asp-Leu
N
PhthN
N
H
PhthN
OMe
O
O
COOMe
given in parentheses. (b) 2 equiv of PFBIꢀOH 17 was used. (c)
1.5 equiv of 13 was used. (d) 4 equiv of 13 was used. (e) 5
mmol scale, 20 h. (f) H218O (97% 18O) was used.
35, 44% {90%} [36 h]
36, 39% {76%} [36 h]
Scheme 2 Substrate scope of tertiary CꢀH hydroxylation with
PFBlꢀOH 17. (a) Isolated yield on 0.2 mmol scale under the
As shown in Scheme 4, by simply switching to the
HFIP/CH3CN solvents, this hydroxyl benziodoxoleꢀmediated
reaction system provides an excellent method for C(sp3)ꢀH
amidation, which remains a challenging transformation for CꢀH
functionalization chemistry.24,25 Tertiary CꢀH amidation with
PFBlꢀOH 17 and benzylic CꢀH amidation with BlꢀOH 13
proceeded with yields and regioꢀselectivity similar to the
corresponding CꢀH hydroxylations carried out in HFIP/H2O
solvents. Unactivated methylene CꢀH bonds were generally
unreactive with either 13 or 17. However, cycloalkanes such as
cyclohexane were efficiently amidated with 17 (see 51),
probably due to their slightly more activated CꢀH bonds and
more favorable kinetics.25b Product 54 carrying a benzamide
group was obtained in good yield using HFIP/PhCN solvent
under similar conditions. Generally, the competing CꢀH
hydroxylation reactions were well suppressed (<2% yield) in
HFIP/nitrile solvents.
standard conditions,
c ~ 50 mM. For reaction with < 85%
conversion of starting material, yields based on recovered SM
(BRSM) were given in braces. (b) H218O (97% 18O) was used.
(c) 3 mmol scale, 46 h. (d) C3 hydroxylation product < 5%. (e)
No C3 hydroxylation product was detected. (f) no free OH
product was obtained.
While a number of methods for oxidation of benzylic
methylene groups to ketones have been developed,22 practical
methods for CꢀH hydroxylation of these methylene groups to
benzyl alcohols are sparse.23 As shown in Scheme 3, we
subjected 4ꢀethylphenyliodide to our standard CꢀH
hydroxylation conditions with PFBlꢀOH 17, and obtained the
alcohol product 37 in 40% yield along with 22% of ketone 37’
and other unidentified byꢀproducts. We were delighted to find
that use of 2 equiv of BlꢀOH 13 under the same conditions gave
37 in 71% yield along with 8% of ketone. More ketone 37’
(24%) was obtained when 4 equiv of BlꢀOH was used for
extended reaction time (24 h). This BlꢀOH mediated benzylic
CꢀH hydroxylation exhibited excellent chemoꢀselectivity and
broad substrate scope. The reaction tolerates functional groups
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H
NHAc
PFBI-OH 17 (2.5 equiv) [conditions A]
or BI-OH 13 (2.0 equiv) [conditions B]a
R
R
R'
R'
[Ru(bpy)3]Cl2 (2.5 mol%)
CFL (23 W)
HFIP/CH3CN, Ar, 30 oC, 10-24 h
H
NHAc
Ar
R
Ar
R
NPhth
NHAc
NHAc
MeOOC
PhthN
46, 67% [A]
47, 71% [A]
48, 60% [A]
AcHN
O
O
O
NHAc
NHAc
N
O
NHAc
F3C
N
H
51, 63% [A]b
49, 71% [A]
NHAc
50, 64% [A]
NHAc
NHBz
OBz
2
COOMe
I
54, 62% [B]c
53, 74% [B]
52, 67% [B]
Scheme 4 C(sp3)ꢀH amidation with 13 or 17. (a) Conditions A for
tertiary CꢀH amidation, HFIP/CH3CN (4/3), c ~ 30 mM, 24 h;
conditions B for benzylic CꢀH amidation, HFIP/CH3CN (8/3), c ~ 35
mM, 10 h. anhydrous HFIP and CH3CN dried over 4 Å molecular
sieves were used. Isolated yield on a 0.2 mmol scale. (b) 1 equiv of
cyclohexane was used, 0.5 mmol scale. (c) PhCN was used as
cosolvent, HFIP/PhCN (8/5), c ~ 30 mM, 10 h.
As shown in Scheme 5A, two CꢀO bond forming
mechanisms were initially considered for this CꢀH
hydroxylation reaction: nucleophilic trapping of a carbocation
intermediate with H2O (pathway
with the hydroxyl benziodoxole reagents (pathway
contrast to the large quantum yield observed in our
previously reported visible lightꢀpromoted C−H azidation
reaction with BlꢀN3 11 12
a small (0.85, measured by Yoon’s
method26) of the C−H hydroxylation reaction of
with PFBlꢀ
a
) or a radical chain reaction
b
).23c In
Φ
,
Φ
7
OH 17 suggested a nonꢀradical chain mechanism (see SI for
details). The dependence of the reactivity on the H2O coꢀ
solvent and the formation of amidation product in the presence
Scheme
5
Mechanistic consideration of C(sp3)ꢀH
functionalization with PFBlꢀOH. DFT calculations were
performed at the M06ꢀ2X/6ꢀ311++G(d,p)ꢀ
SDD/SMD(HFIP)//M06ꢀ2X/6ꢀ31+G(d)ꢀSDD level of theory.
All energies are in kcal/mol. See Supporting Information of
DFT calculations with BlꢀOH
of CH3CN product strongly support ionic pathway
a. Sternꢀ
Volmer experiments confirmed that the excited state of
photocatalyst [Ru(bpy)3]Cl2 can be quenched by the addition of
PFBlꢀOH 17, while no obvious luminescence change of the
photocatalyst was observed in the presence of substrate
SI for details).27
7 (see
This mechanism is supported by density functional theory
(DFT) calculations using t-butane as a model substrate (Scheme
The mechanism of tertiary CꢀH hydroxylation with PFBlꢀOH
17 likely begins with single electron transfer (SET) from
5B). The initial SET reduction of PFBlꢀOH 17 to PFBl
significantly more exergonic than the SET with BlꢀOH 13 to
Bl (∆ = –4.9 kcal/mol with PFBlꢀOH 15 vs –0.9 kcal/mol
with BlꢀOH 13).28,29 With its spin density delocalized over the
O and I atoms, PFBl 55 undergoes facile Hꢀabstraction of t-
butane through an Oꢀcentered transition state (TS1) with a ∆G‡
of 16.6 kcal/mol to give This Hꢀabstraction process is
Buꢀ30
promoted by the electronꢀdeficient perfluoroaryl group. The
corresponding Hꢀabstraction with Bl requires a noticeably
higher barrier of 18.2 kcal/mol (see SI). The subsequent
oxidation of Bu by Ru(III) to butyl cation is highly
ꢀ55 is
photoexcited Ru(II)* to PFBlꢀOH 17, generating radical PFBl
55. Radical 55 abstracts a H atom from alkane substrate
forming tertiary carbon radical II
Ru(III) species, forming tertiary carbocation intermediate III
ꢀ
I,
ꢀ
2
G
.
II can be oxidized by the
,
ꢀ
and regenerating the photocatalyst. Finally, tertiary carbocation
intermediate III is attacked by H2O to give hydroxylated
product IV. Trapping of III by CH3CN can give the amidated
t
.
product
V
following a Ritter reactionꢀtype mechanism.25b We
ꢀ
2
speculate that BlꢀOH mediated benzylic CꢀH hydroxylation and
amidation proceeds through a similar mechanism, involving
cleavage of benzylic CꢀH bond with less electrophilic Blꢀ2.
t
ꢀ
t
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7SC02773G
3 For selected metalꢀcatalyzed C(sp3)ꢀH oxygenation reactions, see: (a)
M. S. Chen and M. C. White, Science, 2007, 318, 783; (b) Y.ꢀH.
Zhang and J.ꢀQ. Yu, J. Am. Chem. Soc., 2009, 131, 14654; (c) M.
Zhou, N. D. Schley and R. H. Crabtree, J. Am. Chem. Soc., 2010, 132,
12550; (d) E. McNeill and J. Du Bois, J. Am. Chem. Soc., 2010, 132,
10202; (e) M. Lee and M. S. Sanford, J. Am. Chem.
Soc., 2015, 137, 12796.
exothermic. Finally, the
tbutyl cation is trapped with H2O,
providing BuOH. Taken together, the DFT calculations
t
indicated the perfluorinated analogue PFBlꢀOH promotes both
the initial SET reduction and the Hꢀabstraction steps in the
catalytic cycle of the tertiary CꢀH hydroxylation.
4 For selected CꢀH hydroxylation with dioxiranes and oxaziridines, see:
(a) D. Yang, M.ꢀK. Wong, X.ꢀC. Wang and Y.ꢀC. Tang, J. Am. Chem.
Soc., 1998, 120, 6611; (b) B. H. Brodsky and J. Du Bois, J. Am.
Chem. Soc., 2005, 127, 15391; (c) K. Chen, J. M. Richter and P. S.
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Brodsky and J. Du Bois, Angew. Chem., Int. Ed., 2009, 48, 4513; (e)
S. Kasuya, S. Kamijo and M. Inoue, Org. Lett., 2009, 11, 3630; (f) A.
M. Adams and J. Du Bois, Chem. Sci., 2014, 5, 656.
Conclusions
In summary, we have developed a unified photoredoxꢀ
catalysis strategy for both C(sp3)ꢀH hydroxylation and
amidation using hydroxyl benziodoxole oxidant. This strategy
allows the selective functionalization of tertiary and benzylic
methylene CꢀH bonds under mild conditions. These reactions
exhibit excellent substrate scope, and offer an efficient and
convenient method for lateꢀstage derivatization of complex
substrates. Distinct from the radical chain mechanism invoked
for our previous tertiary CꢀH azidation reaction with azido
benziodoxole, we propose a new productꢀforming pathway:
photoredox catalyzed formation of a carbocation intermediate,
followed by nucleophilic trapping with H2O or nitrile
cosolvent. Further expansion of the nucleophile scope and the
functionalization of unactivated methylene CꢀH bonds using
this reaction system are currently under investigation.
5 For other selected methods for C(sp3)ꢀH oxygenation: (a) X. Li, X.
Che, G.ꢀH. Chen, J. Zhang, J.ꢀL. Yan, Y.ꢀF. Zhang, L.ꢀS. Zhang, C.ꢀP.
Hsu, Y. Q. Gao and Z.ꢀJ. Shi, Org. Lett., 2016, 18, 1234; (b) J.
Ozawa, M. Tashiro, J. Ni, K. Oisaki and M. Kanai, Chem. Sci., 2016,
7, 1904.
6 For a photoredoxꢀcatalyzed sulfonateꢀdirected C(sp3)ꢀH hydroxylation,
see: A. Hollister, E. S. Conner, M. L. Spell, K. Deveaux, L. Maneval,
M. W. Beal and J. R. Ragains, Angew. Chem., Int. Ed., 2015, 54,
7837.
7 For selected reviews on hypervalent iodine, see: (a) “Hypervalent
Iodine ChemistryꢀModern Developments in Organic Synthesis”: T.
Wirth, M. Ochiai, V. V. Zhdankin, G. F. Koser, H. Tohma and Y.
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J. Waser, Angew. Chem., Int. Ed., 2016, 55, 4436.
8 (a) R. Samanta, K. Matcha and A. P. Antonchick, Eur. J. Org. Chem.,
2013, 5769; (b) T. Dohi and Y. Kita, ChemCatChem, 2014, 6, 76; (c)
L. Bering and A. P. Antonchick, Chem. Sci., 2017, 8, 452.
9 M. Ochiai, T. Ito, H. Takahashi, A. Nakanishi, M. Toyonari, T. Sueda,
S. Goto and M. Shiro, J. Am. Chem. Soc., 1996, 118, 7716.
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Marouka, Angew. Chem., Int. Ed., 2013, 52, 8657; (b) S. A. Moteki,
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Chem., 2014, 3, 932.
11 Y. Zhao and Y. Y. Yeung, Org. Lett., 2010, 12, 2128. A carbonylꢀ
directed methylene CꢀH oxygenation using PhI(OAc)2 and tBuOOH,
yielding ketones, is described.
12 Y. Wang, G.ꢀX. Li, G. Yang, G. He and G. Chen. Chem. Sci., 2016,
7, 2679.
13 (a) V. V. Zhdankin, A. P. Krasutsky, C. J. Kuehl, A. J. Simonsen, J.
K. Woodward, B. Mismash and J. T. Bolz, J. Am. Chem. Soc., 1996,
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14 For selected reviews on photoredox catalysis reactions: (a) J. M. R.
Narayanam and C. R. J. Stephenson, Chem. Soc. Rev., 2011, 40, 102;
(b) T. P. Yoon, M. A. Ischay and J. N. Du, Nature Chem., 2010, 2,
527; (c) C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem.
Rev., 2013, 113, 5322; (d) J. Xie, H. Jin, P. Xu and C. Zhu,
Tetrahedron Lett., 2014, 55, 36.
Acknowledgements
We greatly thank the State Key Laboratory of Elementoꢀ
Organic Chemistry at Nankai University, and NSFC 21421062,
21672105 for financial support of this work. DFT calculations
were performed using supercomputer resources at the Center
for Simulation and Modeling at the University of Pittsburgh,
and the Extreme Science and Engineering Discovery
Environment supported by the National Science Foundation.
Notes and references
a
State Key Laboratory and Institute of ElementoꢀOrganic Chemistry,
College of Chemistry, Collaborative Innovation Center of Chemical
Science and Engineering (Tianjin), Nankai University, Tianjin 300071,
China
Eꢀmail: gongchen@nankai.edu.cn
b
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA
15260, USA. Eꢀmail: pengliu@pitt.edu
c
Department of Chemistry, The Pennsylvania State University, 104
Chemistry Building, University Park, PA 16802, USA. Eꢀmail:
guc11@psu.edu
15 G.ꢀX. Li, C. A. MoralesꢀRivera, Y. Wang, F. Gao, G. He, P. Liu and
G. Chen. Chem. Sci., 2016, 7, 6407.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
16 For use of BlꢀOH in photoredoxꢀpromoted reactions: (a) H. Huang,
G. Zhang, L, Gong, S. Zhang and Y. Chen. J. Am. Chem. Soc., 2014,
136, 2280; (b) H. Tan, H. Li, W. Ji and L. Wang. Angew. Chem., Int.
Ed., 2015, 54, 8374; (c) K. Jia, F. Zhang, H. Huang and Y. Chen. J.
Am. Chem. Soc., 2016, 138, 1514.
17 (a) J. Barluenga, E. CamposꢀGomez, D. Rodriguez, F. Gonzalezꢀ
Bobes and J. M. Gonzalez, Angew. Chem., Int. Ed., 2005, 44, 5851;
(b) refs 9, 13a.
1 (a) T. Newhouse and P. S. Baran, Angew. Chem. Int. Ed. 2011, 50,
3362; (b) M. C. White, Science, 2012, 335, 807; (c) J. Genovino, D.
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2 (a) P. A. Wender, M. K. Hilinski and A. V. W. Mayweg, Org. Lett.,
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E. M. Stang and M. C. White, Nature Chem., 2009, 1, 547.
18 The relatively weak Hꢀabstraction reactivity of Blꢀ is less
consequential in the CꢀH azidation reaction because the reaction
proceeds via a radical chain pathway.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

Chemical Science
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VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C7SC02773G
19 M. Linuma, K. Moriyama and H. Togo, Eur. J. Org. Chem., 2014,
772.
20 For the original report of PFBlꢀOH 17, see: R. D. Richardson, J. M.
Zayed, S. Altermann, D. Smith and T. Wirth, Angew. Chem., Int.
Ed., 2007, 46, 6529. PFBlꢀOH can be readily prepared on the gram
scale in 2 steps from a cheap precursor (2,3,4,5ꢀtetrafluorobenzoic
acid, < $250 per Kg) without column purification. It is a stable solid
which can be stored in dark for 2 months and conveniently handled
under air on the bench top.
21 For a recent use of PFBlꢀOH 17 in photoredoxꢀmediated reaction,
see: K. Jia, Y. Pan and Y. Chen, Angew. Chem., Int. Ed., 2017, 56,
2478.
22 For recent examples of benzylic CꢀH oxygenation to form ketones:
(a) T. Dohi, N. Takenaga, A. Goto, H. Fujioka and Y. Kita, J. Org.
Chem., 2008, 73, 7365; (b) J.ꢀB. Xia, K. W. Cormier and C. Chen,
Chem. Sci., 2012, 3, 2240.
23 For recent examples of benzylic methylene CꢀH oxygenation to
install NHPI, ONO2, or OTFA groups, see: (a) J. M. Lee, E. J. Park,
S. H. Cho and S. Chang, J. Am. Chem. Soc., 2008, 130, 7824; (b) S.
Kamijo, Y. Amaoka and M. Inoue, Tetrahedron Lett., 2011, 52,
4654; (c) R. Sakamoto, T. Inada, S. Selvakumar, S. A. Moteki and
K. Maruoka, Chem. Commun., 2016, 52, 3758.
24 For selected reviews on CꢀH amination: (a) F. Collet, C. Lescot and
P. Dauban, Chem. Soc. Rev., 2011, 40, 1926; (b) J. L. Roizen, M. E.
Harvey and J. Du Bois, Acc. Chem. Res., 2012, 45, 911.
25 For selected example of intermolecular C(sp3)ꢀH amination: (a) X.ꢀQ.
Yu, J.ꢀS. Huang, X.ꢀG. Zhou and C.ꢀM. Che, Org. Lett., 2000, 2,
2233; (b) Q. Michaudel, D. Thevenet and P. S. Baran, J. Am. Soc.
Chem., 2012, 134, 2547; (c) J. L. Roizen, D. N. Zalatan and J. Du
Bois, Angew. Chem., Int. Ed., 2013, 52, 11343; (d) K. Kiyokawa, T.
Kosaka, T. Kojima and S. Minakata, Angew. Chem., Int. Ed., 2015,
54, 13719; (e) G. Pandey and R. Laha, Angew. Chem., Int. Ed., 2015,
54, 14875; (f) K. Kiyokawa, K. Takemoto and S. Minakata, Chem.
Commun., 2016, 52, 13082.
26 For a leading reference characterizing chain processes in visible light
photoredox catalysis based on the measurements of quantum yield
Φ
: M. A. Crismesia and T. P. Yoon. Chem. Sci. 2015, 6, 5426. A
reaction with >> 1 could only be consistent with a productꢀ
forming chain mechanism..
Φ
27 N. J. Turro, Modern Molecular Photochemistry; Benjamin
/Cummings: Menlo Park, CA, 1978
28 (a) DFT calculations were performed using Gaussian 09, Revision
D.01, M. J. Frisch, et al. Gaussian, Inc., Wallingford CT, 2009.
Geometries were optimized at the M06ꢀ2X/6ꢀ31+G(d)ꢀSDD level of
theory in the gas phase. Single point energies were calculated at the
M06ꢀ2X/6ꢀ311++G(d,p)ꢀSDD level with the SMD solvation model
in HFIP. See SI for computational details. For recent computational
studies on photoredox mediated C–C bond formation reactions, see:
(b) O. Gutierrez, J. C. Tellis, D. N. Primer, G. A. Molander and M.
C. Kozlowski, J. Am. Chem. Soc. 2015, 137, 4896. (c) T. B.
Demissie, K. Ruud and J. H. Hansen, Organometallics 2015, 34,
4218.
29 The experimental redox potentials of E⊖Ru(bpy)
(−0.81 V vs SCE
3+/2+*
3
in MeCN) and ER⊖u(bpy)
(+1.29 V vs SCE in MeCN) were used in
3+/2+
3
the computation of the SET reaction energies with Ru(II)* and
Ru(III). See: C. R. Bock, T. J. Meyer and D. G. Whitten, J. Am.
Chem. Soc. 1975, 97, 2909. For DFT calculations of redox potentials,
see: ref 16 and (b) P. Winget, C. J. Cramer and D. G. Truhlar,
Theor. Chem. Acc. 2004, 112, 217. (c) A. A. Isse, C. Y. Lin, M. L.
Coote and A. Gennaro J. Phys. Chem. B, 2011, 115, 678. (d) H. G.
Roth, N. A. Romero and D. A. Nicewicz, Synlett 2016, 27, 714.
30 Our DFT calculation shows that the Iꢀcentered Hꢀabstraction
pathway from 55 yields a highly unstable hydridoiodane and is much
less favourable (See SI for details).
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7SC02773G
TOC
O
I
OH
F
O
OH
R
R
PFBl-OH
F
F
R'
or
H
(2.5 equiv)
F
R
CFL (23 W)
R'
NHAc
R'
[Ru(bpy)3]Cl2 (2.5 mol%)
HFIP/H2O (or HFIP/CH3CN)
30 oC, Ar