A General Strategy for Aliphatic C-H Functionalization Enabled by Organic Photoredox Catalysis

Article abstract of DOI:10.1021/jacs.8b00592

Synthetic transformations that functionalize unactivated aliphatic C-H bonds in an intermolecular fashion offer unique strategies for the synthesis and late-stage derivatization of complex molecules. Herein we report a general approach to the intermolecular functionalization of aliphatic C-H bonds using an acridinium photoredox catalyst and phosphate salt under blue LED irradiation. This strategy encompasses a range of valuable C-H transformations, including the direct conversions of a C-H bond to C-N, C-F, C-Br, C-Cl, C-S, and C-C bonds, in all cases using the alkane substrate as the limiting reagent. Detailed mechanistic studies are consistent with the intermediacy of a putative oxygen-centered radical as the hydrogen atom-abstracting species in these processes.

Full text of DOI:10.1021/jacs.8b00592

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A General Strategy for Aliphatic C–H Functionalization
Enabled by Organic Photoredox Catalysis
Kaila A. Margrey, William L. Czaplyski, David A Nicewicz, and Erik J. Alexanian
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b00592 • Publication Date (Web): 09 Mar 2018
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Journal of the American Chemical Society
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A General Strategy for Aliphatic C–H Functionalization Ena-
bled by Organic Photoredox Catalysis
Kaila A. Margrey,† William L. Czaplyski,† David A. Nicewicz,* and Erik J. Alexanian*
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Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
Supporting Information Placeholder
unactivated C–H sites (Figure 1). While this approach consti-
tutes a two-step diversification of unactivated C–H bonds, we
ABSTRACT: Synthetic transformations that functionalize unac-
tivated, aliphatic C–H bonds in an intermolecular fashion offer
sought a strategy that would facilitate the direct, one-step conver-
unique strategies for the synthesis and late-stage derivatizations
sion of aliphatic C–H bonds into a variety of functional groups.
of complex molecules. Herein, we report a general approach to
Such a modular system for radical-mediated aliphatic C–H func-
the intermolecular functionalization of aliphatic C–H bonds us-
tionalization would decouple the C–H abstraction step from the
ing an acridinium photoredox catalyst and phosphate salt under
radical trapping step, allowing different products to be accessed
blue LED irradiation. This strategy encompasses a range of valu-
simply by substitution of the added radical trapping agent.
able C–H transformations, including the direct conversions of a
Common Approach to C–H Functionalization:
C–H bond to C–N, C–F, C–Br, C–Cl, C–S, and C–C bonds, in
new reaction system developed
for each transformation
reagent
reagent
reagent
R
R
R
all cases using the alkane substrate as the limiting reagent. De-
tailed mechanistic studies are consistent with the intermediacy
of a putative oxygen-centered radical as the hydrogen atom ab-
stracting species in these processes.
initiator or
catalyst system
site selectivities inherent to
each system
+
R
H
excess substrate or material
recycling often necessary
C–H Diversification via Alkyl Xanthates: Alexanian (2016)
O
one
step
F3C
tBu
S
S
diverse C–H
functionalization
products
N
S
+
OEt
R
H
OEt
The strategic functionalization of the ubiquitous, unactivated
aliphatic carbon–hydrogen (C–H) bond unlocks unique strate-
gies for the synthesis of natural products, pharmaceuticals, agro-
chemicals, and materials.1 For example, in the context of drug
discovery, late-stage C–H functionalization allows for expedient
access to structural analogs of targets, which can result in bol-
stered physicochemical properties and structure-activity relation-
ships (SARs) without the need for de novo synthesis.2 Both the
abundance and the low reactivity of these C–H bonds also pre-
sent major challenges in the development of site-selective, inter-
molecular functionalization reactions.
R
CF3
S
1 equiv
This Approach:
photoredox-catalyzed
site-selective
C–H abstraction
R
R
R
R
R
R
direct C–H
diversification
R
H
R
range of radical
trapping agents
acridinium catalyst
phosphate base
455 nm LEDs
1 equiv
Figure 1. Approaches to site-selective, intermolecular C–H function-
alization.
We hypothesized that highly oxidizing acridinium photoredox
catalyst 1 (E1/2(cat*/cat•) = +2.08 V vs SCE)13 could be used to
oxidatively generate heteroatom-centered radicals capable of ab-
stracting unactivated aliphatic C–H bonds. Coupled with the use
of a sulfonyl group transfer reagent, we conjectured that the C–
H functionalization could be rendered catalytic. To this end, we
screened a variety of anionic, inorganic bases using acridinium
photooxidant 1, sulfonyl azide 3, and cyclooctane as a substrate.14
We found that the use of either K3PO4 in 1,2-dichloroethane
(DCE) or a DCE/pH 8 phosphate buffer system led to produc-
tive C–H azidation. Following further optimization, we discov-
ered that the use of K3PO4 in 1,1,1,3,3,3-hexafluoroisopropanol
(HFIP) was the most efficient system for this transformation.
Recent efforts have led to a variety of useful intermolecular C–
H transformations of unactivated alkanes, notably including
many that use the hydrocarbon substrate as limiting reagent. Sev-
eral methods for C–H oxidation,3 halogenation,4 and azidation5
have been reported, but new reaction systems are typically re-
quired to promote each transformation (Figure 1). Additionally,
a photoredox manifold has been used by MacMillan to achieve
C–H alkylation6 and arylation7 of C–H bonds at positions acti-
vated via hyperconjugation, such as those adjacent to π systems
or heteroatoms.8,9 To date, there are few reports detailing the use
of photoredox catalysis to functionalize unactivated, aliphatic C–
H bonds.10
With these conditions in hand, we explored the substrate
scope of the C–H azidation, with the alkane substrate as limiting
reagent in all cases (Figure 2). Cyclic hydrocarbons provided az-
ides 4–6 in moderate to good yields (57–70%). Trans-decalin af-
forded secondary azides 7 in 57% combined yield, with regiose-
lectivity for the secondary C–H sites. Adamantane underwent az-
idation exclusively at the more sterically accessible tertiary C–H
site to give azide 8 in 75% yield.
Previous efforts in the Alexanian group led to the develop-
ment of N-haloamide and N-xanthylamide reagents enabling site-
selective C–H halogenation11 and xanthylation,12 respectively, of
unactivated aliphatic C–H bonds with substrate as limiting rea-
gent. The alkyl xanthate products arising from the latter reaction
can be transformed into a variety of derivatives, enabling net C–
S, C–C, C–N, C–D, and C–O bond constructions from
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Page 2 of 5
Me
1 (R1 = tBu, R2 = H):
E1/2(Acr*/Acr•) = + 2.08 V vs SCE
E1/2(Acr+/Acr•) = – 0.57 V vs SCE
catalyst 1 (5 mol %)
sulfonyl azide 3 (3 equiv)
K3PO4 (1.1 equiv)
1
2
3
4
5
6
7
8
SO2N3
Me
R2
R2
Me
R–N3
R–H
455 nm LEDs,
HFIP (0.1 M), 20 h
F3C
2 (R1 = R2 = OMe):
E1/2(Acr*/Acr•) = + 1.65 V vs. SCE
E1/2(Acr+/Acr•) = – 0.82 V vs. SCE
N
R1
R1
sulfonyl azide
1 equiv
BF4
3
R2
R2
N3
N3
tBu
OPiv
N3
N3
Me
N3
N3
N3
Me
N3
C2
C3
9
4
5
6
7
8
9
10
51% yielda
11
45% yielda
dr 1.4:1
58% yielda
57% yielda
72% yielda
57% yielda (1.4:1 C3:C2)
75% yielda
46% yielda
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H
H
Me
NH2
O
Me
N3
Me
H
Me
Me
Me
N3
N3
Me
Me
N3
Me
Me
MeO
Me
AcO
BzO
Me
H
12
40% yielda
1.3:1 site selectivity
phentermine
psychostimulant
13
71% yield
14
73% yield, 4:1 site selectivity
15
91% yield, 3:1 site selectivity
Me
Me
N3
Me
Me
N3
Me
Me
N3
Me
Me
N3
Me
Me
N3
N
H
O
Me
PhthN
Me
Br
Me
HO
Me
PhO
Me
H
H
H
H
16
72% yield, 3:1 site selectivity
17 18
67% yield, 3:1 site selectivity 63% yield, 2.7:1 site selectivity
19
31% yield,a 2.1:1 site selectivity
20
39% yield, 3:1 site selectivity
Figure 2. Products of C–H azidations using 0.1 mmol substrate. Yields refer to isolated yields. aNMR yield with hexamethyldisiloxane (HMDS)
as an internal standard.
Azidation of benzylic C–H bonds was also successful, as the
functionalization of propylbenzene afforded azide 9 in moderate
yield. Tert-butylcyclohexane and cis-4-methylcyclohexyl pivalate
reacted exclusively at the tertiary C–H sites in 51% and 45%
yield, respectively, despite the presence of additional secondary
C–H bonds. The azidation of isobutylbenzene delivered tertiary
azide 12 in moderate yield; this product serves as a precursor to
the psychostimulant pharmaceutical phentermine.
Having demonstrated an efficient C–H azidation, we investi-
gated the use of other reagents to develop a modular C–H func-
tionalization. Using cyclooctane as substrate, we sought to access
a diverse array of C–H functionalizations (Figure 3). In these
studies, we used DCE as solvent with pH 8 phosphate buffer ra-
ther than K3PO4 to ensure complete solubility of all reagents. Sev-
eral strategies for aliphatic C–H fluorination have been devel-
oped, often involving ultraviolet irradiation or transition metal
catalysts.4b–f Using our catalytic photoredox approach, substitut-
ing N-fluorobenzenesulfonimide (NFSI) for the sulfonyl azide de-
livered fluorocyclooctane in moderate yield. We could also ex-
tend our strategy to C–H bromination or chlorination by using
diethyl bromomalonate or N-chlorosuccinimide, respectively.
Trifluoromethylthiol group installation has proven to be useful
in medicinal chemistry owing to the beneficial effects this moiety
has on molecular polarity and lipophilicity.16 The use of a radical
trifluoromethylthiolating reagent developed by Shen17 enabled
C–H trifluoromethylthiolation of cyclooctane in low yield, pos-
sibly due to product instability under the reaction conditions.
We note that in each system, both the phosphate base and pho-
tocatalyst were necessary for productive reactivity.14 In all cases,
these transformations proceed simply by changing the radical
trap reagent; although these reactions are not fully optimized,
they provide proof-of-concept for the modularity of our ap-
proach.
We next sought to examine the site selectivity of the C–H az-
idation using acyclic substrates with multiple reactive sites. Me-
thyl 6-methylheptanoate produced tertiary azide 13 in 71% yield
as a single regioisomer. However, methyl hexanoate, a substrate
containing several electronically deactivated secondary C–H
bonds but no tertiary sites, did not undergo functionalization
with this system, consistent with a strong sensitivity to the BDE
of the C–H bonds in the substrate. In order to examine the elec-
tronic site selectivity of the C–H azidation further, we surveyed
several derivatives of dihydrocitronellol, each containing two ter-
tiary C–H sites. In all cases, azidation was favored at the site distal
to the other functionality present, with no secondary C–H func-
tionalization observed. Acetate and benzoate esters delivered
products 14 and 15 in 73% and 91% yield respectively, with
good levels of regioselectivity. Derivatives containing protected
primary amines and halide substituents provided similar site se-
lectivities, affording 16 and 17 in good yields. Dihydrocitronellol
itself was also a competent substrate, producing 18 in 63% yield
with no detectable oxidation of the free alcohol, highlighting the
mild conditions associated with the system. Azidation of a sub-
strate bearing a phenoxy group, which could be competitively ox-
idized by the acridinium catalyst, proceeded to give 19, albeit in
lower yield and selectivity. We also studied the C–H azidation of
a substrate containing a nitrogen heterocycle, which can be prob-
lematic for C–H functionalizations involving high-valent metal-
oxo systems.15 The azidation of a pyridyl ketone substrate deliv-
ered 20 in moderate yield, further highlighting the functional
group compatibility of our catalytic system.
We next sought to develop a C–H alkylation using electron-
poor alkenes as coupling partners. The use of a more reducing
acridinium catalyst 2 and a solvent mixture of DCE and 2,2,2-
trifluoroethanol (TFE) enabled the use of both methyl vinyl ke-
tone and methyl acrylate as radical traps, delivering ketone and
ester products in 76% and 43% yield, respectively. Recent stud-
ies have reported intramolecular C–H alkylations using activated
alkenes and iridium photoredox catalysis proceeding by 1,5-hy-
drogen atom abstraction.18 To the best of our knowledge, this is
the first report of a visible light-mediated, intermolecular unacti-
vated C–H alkylation using the substrate as limiting reagent.19
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In order to shed light on the mechanism, we sought to identify
1
2
3
4
5
6
7
8
the active hydrogen atom abstracting species. We initially fo-
cused on the C–H azidation for these studies. A Stern-Volmer
analysis determined that sulfonyl azide 3 did not quench the ac-
ridinium fluorescence.14 Owing to the acidity of HFIP and the
use of stoichiometric base, we considered that oxidation of the
resultant alkoxide could produce an oxygen-centered radical. We
also found that sodium 1,1,1,3,3,3-hexafluoroisopropoxide in
HFIP did not quench the catalyst excited state.14 We next con-
sidered the role of the base. Although either K3PO4 or pH 8 phos-
phate buffer was competent in these reactions, we were unable
to obtain redox potentials of either substance in MeCN owing to
insolubility or immiscibility. While attempting to study Stern-
Volmer fluorescence quenching with these bases, our efforts
were similarly hampered regardless of the solvent used. To cir-
cumvent this issue, we synthesized a more soluble dibasic phos-
phate 28 from the corresponding phosphoric acid 29.22 We
found that the dibasic phosphate quenched the excited state of
the acridinium and the protonated acid did not (Figure 5), high-
lighting the necessity of the anionic base. Addition of the dibasic
phosphate also leads to a shift in the resonances of the 1H NMR
of acridinium catalyst 1 in CDCl3, suggesting the possibility of
an acridinium-phosphate complex in solution.14
C–H Diversification via Reagent Selection
derivative (R = )
yield (%)
70a
64
catalyst 1 (5 mol %)
trap reagent (3 equiv)
N3
R
F
455 nm LEDs,
DCE/pH 8 phosphate buffer
1 equiv
Br
60
(4:1, 0.1 M), 20 h
Trap Reagents:
Cl
32
SO2N3
PhO2S
SO2Ph
EtO2C
CO2Et
N
F
SCF3
30
Br
F3C
O
76b
43b
OSCF3
C(O)Me
CO2Me
O
O
Me
Me
O
N
9
Me
OMe
Cl
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
Figure 3. Products of modular C–H functionalization using 0.1
mmol substrate. Yields refer to NMR yields with HMDS or fluoro-
a
benzene as an internal standard. See Figure 2 for azidation condi-
tions. bReactions use catalyst 2 and an alternate solvent system, see
Supporting Information for details.
Our studies continued with applications to several complex
substrates with multiple C–H sites (Figure 4). The functionaliza-
tion of (–)-menthol benzoate afforded azide 21 in 54% yield fa-
voring functionalization at the most electron-rich tertiary posi-
tion. Owing to the presence of adamantyl cores in several phar-
maceuticals, we studied the reactivity of these substrates using
several C–H transformations. The azidation of N-phthalimide
protected memantine, an NMDA receptor antagonist used to
treat Alzheimer’s disease, occurred at the tertiary position to de-
liver 22 in 55% yield. Similarly, the fluorination of this substrate
was successful, delivering 23 in 86% yield with complete site se-
lectivity for the tertiary position. A precursor to differin, a topical
retinoid, was transformed to azide 24 in moderate yield despite
the presence of an electron-rich aromatic ring, underscoring the
mild nature of our system. This substrate also coupled effectively
with methyl vinyl ketone, delivering adduct 25 in 45% yield as a
single regioisomer.20 Ibuprofen methyl ester–containing both ter-
tiary and benzylic sites–slightly favored benzylic azidation,
providing a mixture of regioisomers (26) in 57% yield. Other re-
ported strategies for the C–H azidation of this substrate provide
only the benzylic azide,5a highlighting the complementary nature
of our protocol that allows access to new derivatives of important
pharmaceuticals. Steroid 5α-cholestan-3-one, containing 46 ali-
phatic C–H bonds, underwent functionalization at the C17 and
C25 positions providing 27 in 37% yield, with similar site selec-
tivity to that observed by Curci in the context of C–H hydroxyla-
tion.21
O
P
NBu4
PhO
O
O
NBu4
28
O
P
kSV = 150.5 M-1
kq = 1.08 x 1010 (M-1s-1
)
PhO
OH
OH
29
.
.
Figure 5. Stern-Volmer fluorescence quenching of 1 in DCE.
We also examined the reactivity of dibasic phosphate 28 under
the azidation conditions with cyclooctane as substrate (eq 1). The
use of substoichiometric 28 (5 or 20 mol %) produced up to 48%
yield of azide 6, consistent with catalytic activity of the base. How-
ever, the use of stoichiometric 28 led to a diminished yield of
17%. Using methyl 6-methylheptanoate as substrate with 20 mol
% 28 produced azide 13 in 20% yield. Importantly, only func-
tionalization at the tertiary C–H bond occurred, suggesting that
28 and K3PO4 serve the same role in the transformation.
Reactions with Base 28
1 (5 mol %)
N3
3 (3 equiv)
28
C–H Functionalization of Complex Targets
5 mol % 28: 20% yield
20 mol % 28: 48% yield
100 mol % 28: 17% yield
(1)
MeO
NPhth
OBz Me
455 nm LEDs,
HFIP (0.1 M), 20 h
N3
1 equiv
O
6
Me
Me
Me
R
1 (5 mol %)
3 (3 equiv)
Me
O
H
R
Br
28 (20 mol %)
Me
Me
Me
N3
Me
(2)
21
differin precursor
24 R = N3; 40% yielda
N-Phth memantine
22 R = N3; 55% yield
23 R = F; 86% yield
MeO
MeO
455 nm LEDs,
HFIP (0.1 M), 20 h
(–)-menthol benzoate
54% yield
3:1 site selectivity
13
20% yield
C(O)Me
25 R =
45% yield
Me
Me
We provide a mechanistic hypothesis in Figure 6 consistent
with this data. The acridinium photoredox catalyst is excited by
the 455 nm LEDs and can undergo single-electron transfer from
the phosphate salt, generating an oxygen-centered radical. Ab-
straction of the most electron-rich aliphatic C–H bond of the
substrate generates a carbon-centered radical, which, upon trap-
ping by the sulfonyl azide, affords the desired product and a sul-
fonyl radical. Based on previous work in the Nicewicz lab,23 we
Me
Me
C17
Me
H
CO2Me
C25
Me
H
H
N3
Me
Me
H
N3
26
O
ibuprofen methyl ester
57% yield
H
27
5α-cholestan-3-one
37% yield
1:1 C25:C17
1.1:1 site selectivity
Figure 4. Complex products of modular C–H functionalization. For
reaction details see the Supporting Information. Yields refer to iso-
lated yields. aNMR yield with HMDS as an internal standard.
hypothesize that the sulfonyl radical is capable of oxidizing Mes-
24
Ÿ
Acr , regenerating the acridinium catalyst.
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1
2
3
4
5
6
7
8
HO
O
P
OH
O
P
O
P
O
HO
O
H
HO
O
O
O
H
N3
H
SO2
+e–
Mes-Acr•
F3C
SO2N3
Mes-Acr+*
–e– +e–
F3C
9
SO2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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37
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
hv
Mes-Acr+
F3C
Figure 6. Proposed mechanism of the C–H azidation.
The versatility of the current approach in accessing a diverse
array of C–H functionalizations highlights the unique capabili-
ties of organic photoredox catalysis to generate reactive interme-
diates in a controlled manner. The present catalytic system ena-
bles the decoupling of the C–H abstracting species from the C–
X forming step. This allows for the development of a modular
system to access a range of functionalized products directly, thus
obviating the need to develop new methodology for each specific
C–H transformation. We anticipate that the synthetic utility and
mild conditions of this strategy will lead to applications in com-
plex molecule synthesis and late-stage functionalization across a
wide range of contexts.
(9) For examples achieving the same bond formation via mechanisms
that do not involve direct C–H abstraction, see: (a) McNally, A.; Prier,
C. K.; MacMillan, D. W. C. Science 2011, 334, 1114; (b) Zuo, Z.; Ahne-
man, D. T.; Chu, L.; Terrett, J. A.; Doyle, A. G.; MacMillan, D. W. C.
Science 2014, 345, 437; (c) Noble, A.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2014, 136, 11602; (d) Prier, C. K.; MacMillan, D. W. C. Chem. Sci.
2014, 5, 4173; (e) Zhou, R.; Liu, H.; Tao, H.; Yu, X.; Wu, J. Chem. Sci.
2017, 8, 4654.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and spectral
data for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(10) Mukherjee, S.; Maji, B.; Tlahuext-Aca, A.; Glorius, F. J. Am.
Chem. Soc. 2016, 138, 16200.
AUTHOR INFORMATION
Corresponding Authors
(11) (a) Schmidt, V. A.; Quinn, R. K.; Brusoe, A. T.; Alexanian, E. J.
J. Am. Chem. Soc. 2014, 136, 14389; (b) Quinn, R. K.; Könst, Z. A.;
Michalak, S. E.; Schmidt, Y.; Szklarski, A. R.; Flores, A. R.; Nam, S.;
Horne, D. A.; Vanderwal, C. D.; Alexanian, E. J. J. Am. Chem. Soc. 2016,
138, 696.
(12) Czaplyski, W. L.; Na, C. G.; Alexanian, E. J. J. Am. Chem. Soc.
2016, 138, 13854.
(13) Joshi-Pangu, A.; Lévesque, F.; Roth, H. G.; Oliver, S. F.; Cam-
peau, L.-C.; Nicewicz, D.; DiRocco, D. A. J. Org. Chem. 2016, 81, 7244.
(14) See Supporting Information for details.
(15) Howell, J. M; Feng, K.; Clark, J. R.; Trzepkowski, L. J.; White,
M. C. J. Am. Chem. Soc. 2015, 137, 14590.
(16) Landelle, G.; Panossian, A.; Leroux, F. R. Curr. Top. Med. Chem.
2014, 14, 941.
(17) Shao, X.; Xu, C.; Lu, L.; Shen, Q. Acc. Chem. Res. 2015, 48, 1227.
(18) (a) Choi, G. J.; Zhu, Q.; Miller, D. C.; Gu, C. J.; Knowles, R. R.
Nature 2016, 539, 268; (b) Chu, J. C. K.; Rovis, T. Nature 2016, 539,
272; (c) Chen, D.-F.; Chu, J. C. K.; Rovis, T. J. Am. Chem. Soc. 2017, 139,
14897.
(19) For an example of C–H alkylation mediated by UV irradiation,
see: Kamijo, S.; Takao, G.; Kamijo, K.; Tsuno, T.; Ishiguro, K.; Murafuji,
T. Org. Lett. 2016, 18, 4912.
(20) Alkylation of another substrate containing tertiary C–H bonds
(cis-4-methylcyclohexyl pivalate) using methyl vinyl ketone proceeded in
low yield (17%). Efforts to improve the scope of the alkylation are un-
derway.
(21) Bovicelli, P.; Lupattelli, P.; Mincione, E.; Prencipe, T.; Curci, R.
J. Org. Chem. 1992, 57, 5052.
(22) Under the optimized conditions with K3PO4/HFIP or pH 8 phos-
phate buffer, dibasic phosphate is the most abundant phosphate in so-
lution, with less tribasic and negligible monobasic to be expected.
*eja@email.unc.edu
*nicewicz@email.unc.edu
Author Contributions
†These authors contributed equally to this work.
ACKNOWLEDGMENT
This work was supported by the National Institutes of Health
(NIGMS) Award No. R01 GM 120163 (E.J.A.) and an Eli Lilly
Grantee Award (D.A.N.). This research made use of an Edinburgh
FLS920 emission spectrometer funded by the UNC EFRC: Center
for Solar Fuels, an Energy Frontier Research Center funded by the
U.S. Department of Energy, Office of Science, Office of Basic En-
ergy Sciences under Award Number DE-SC0001011. We thank the
UNC Department of Chemistry Mass Spectrometry Core Labora-
tory for its assistance with MS analysis.
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(23) Perkowski, A.; Nicewicz. D. A. J. Am. Chem. Soc. 2013, 135,
10334.
(24) We cannot completely discount the possibility of free radical
chain processes in these transformations. Further mechanistic studies to
elucidate reaction pathways are underway.
1
2
3
4
5
MeO
6
7
8
9
Modular Access to:
C–H azidation
C–H fluorination
C–H bromination
C–H chlorination
N3
MeO
organic
photoredox-catalyzed
C–H abstraction
direct C–H
diversification
40% yield
MeO
Br
Br
R
C–H trifluoromethylthiolation
C–H alkylation
10
11
12
13
14
15
16
17
18
19
20
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42
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44
45
46
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48
49
50
51
52
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54
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56
57
58
59
60
Br
45% yield
Me
O
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