Direct C-C Bond Formation from Alkanes Using Ni-Photoredox Catalysis

Article abstract of DOI:10.1021/jacs.8b09191

A method for direct cross coupling between unactivated C(sp³)-H bonds and chloroformates has been accomplished via nickel and photoredox catalysis. A diverse range of feedstock chemicals, such as (a)cyclic alkanes and toluenes, along with late-stage intermediates, undergo intermolecular C-C bond formation to afford esters under mild conditions using only 3 equiv of the C-H partner. Site selectivity is predictable according to bond strength and polarity trends that are consistent with the intermediacy of a chlorine radical as the hydrogen atom-abstracting species.

Full text of DOI:10.1021/jacs.8b09191

Subscriber access provided by Kaohsiung Medical University
Communication
Direct C–C Bond Formation from Alkanes Using Ni-Photoredox Catalysis
Laura K. G. Ackerman, Jesus I. Martinez Alvarado, and Abigail G. Doyle
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b09191 • Publication Date (Web): 11 Oct 2018
Downloaded from http://pubs.acs.org on October 11, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Direct C–C Bond Formation from Alkanes Using Ni-Photoredox Ca-
talysis
Laura K. G. Ackerman‡, Jesus I. Martinez Alvarado‡, Abigail G. Doyle*
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
†Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States.
Supporting Information Placeholder
A. C–C bond formation from hydrocarbons
ABSTRACT: A method for direct cross coupling between un-
activated C(sp3)–H bonds and chloroformates has been accom-
plished via nickel and photoredox catalysis. A diverse range of
feedstock chemicals, such as (a)cyclic alkanes and toluenes,
along with late-stage intermediates, undergo intermolecular C–
C bond formation to afford esters under mild conditions using
only 3 equiv of the C–H partner. Site selectivity is predictable
according to bond strength and polarity trends that are con-
sistent with the intermediacy of a chlorine radical as the hydro-
gen atom-abstracting species.
X
H
C–C bond
step 2
R
oxidation
step 1
hydrocarbons
desired target
few methods reported for a single step operation
B. Prior work: C–H arylation of ethers via Ni/photoredox catalysis
δ
δ
Cl
O
H
O
Ni
Ir
Cl
hυ
aryl chloride
solvent
C. Application to C–H coupling of unactivated alkanes
The development of catalytic methods for functionalization
of unactivated aliphatic C–H bonds represents a prominent
challenge in organic synthesis.1 A variety of useful strategies
have been developed for selective C(sp3)–H oxidation of hydro-
carbons to give C–X bonds (e.g. X= O, N, B, F, or Cl).2 While
valuable in their own right, these products are also frequently
used as precursors for C(sp3)–C bond-forming reactions. Direct
formation of C–C bonds from unactivated hydrocarbons would
thus provide an attractive strategic alternative to this multi-step
sequence (Figure 1A). However, most catalytic methods that ef-
fect intermolecular C–C bond formation of unactivated alkanes
require the use of substrates with coordinating directing groups,
or the use of a substrate in large excess to impart reactivity,
which limits applications at an early and late stage in synthesis.3
Alternatively, Rh-catalyzed C(sp3)–H insertion with donor ac-
ceptor carbenoids represents a powerful methodology for non-
directed C–C bond formation with alkane as the limiting rea-
gent.4 Despite its attributes, the methodology is restricted to the
installation of a specific type of C–C bond. The identification
of alternative strategies that enable the modular installation of
C–C bonds from unactivated alkanes could have a significant
impact on organic synthesis. Here we report that Ni and photo-
redox catalysis represents one such strategy, enabling the gen-
eration of valuable carbonyl derivatives from unactivated
C(sp3)–H bonds via catalytic C–C bond formation with chlo-
roformates.
O
δ
H
δ
H
ArCl
ClCO2Ph
H
PhO
deactivated C–H site
not competitive with CyH
1–3 equiv
activated C–H site
competitive with CyH
Figure 1. Direct C–C bond formation from C(sp3)−H bonds.
(SET)/deprotonation process for electron-rich amines or a H-
atom abstraction (HAT) step for electron-poor amines and
ethers. Thus far, successful substrates in these coupling reac-
tions have required C–H bonds proximal to functional groups.
For example, we recently disclosed a strategy for the arylation
of ethereal C(sp3)−H bonds via the photocatalytic generation of
chlorine radical from Ni (Figure 1B).5c Although chlorine radi-
cal is capable of abstracting C–H bonds of unactivated alkanes
(HCl BDFE 97 kcal/mol; cyclohexane BDFE 91 kcal/mol),7 we
found that the cross coupling of cyclohexane with aryl chlorides
was only feasible in moderate yield using a large excess of sub-
strate (44% yield at 10 equiv).
Guided by this result, we set out to develop a catalytic
C(sp3)−H cross-coupling reaction of unactivated alkanes using
substrate in stoichiometric quantities. A principal concern in the
development of such a process was identifying conditions in
which the unactivated alkane would undergo preferential HAT
in the presence of cross-coupled product. For arylation reac-
tions, the benzylic C(sp3)–H bond of the product is considerably
weaker than the starting material C–Hs (BDFE of 80 versus 90–
95 kcal/mol),7 which could lead to overfunctionalization or un-
productive consumption of the chlorine radical. Since chlorine
radical is an electrophilic hydrogen atom acceptor, we antici-
pated that use of an electron-deficient coupling partner such as
Over the past several years, Ni and photoredox catalysis has
emerged as a modular strategy for the construction of C(sp3)−C
bonds from C(sp3)–H partners.5,6 Under this manifold, Ni cata-
lysts are proposed to intercept and functionalize carbon-cen-
tered radicals generated from C–H bonds via one of two distinct
pathways:
an
oxidative
single
electron
transfer
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
a chloroformate would discourage competitive HAT on the ba-
sis of polar effects in free-radical chlorination (Figure 1C).8 The
application of chloroformates in a C(sp3)–H functionalization
reaction was appealing as it would deliver direct access to car-
bonyl derivatives, arguably the most versatile functional groups
in synthesis. Moreover, chloroformates are abundant, inexpen-
sive reagents that undergo facile oxidative addition to Ni.9
Table
1.
Optimization
of
Reaction
Conditions.a
Ir photocatalyst 3 (0.5 mol%)
Ni(cod)2 (4 mol%)
1
2
3
4
5
6
O
H
dtbbpy (5.2 mol%)
O
PhO
11
O
PhO
Cl
PhO
OPh
K3PO4, Na2WO4
PhH (0.1 M), 34 C, 48 h
34 W Blue LEDs
•2H2O
º
3 equiv
12
13
Yield 12 (%)b
Yield 13 (%)c
Entry
Deviation from standard conditions
According to our prior mechanistic studies5c,10a and literature
precedent,10b–d a hypothesized catalytic cycle for the C(sp3)−H
functionalization is displayed in Figure 2. We envisioned that
(dtbbpy)Ni0 (1), would undergo oxidative addition to a chlo-
roformate derivative to generate (dtbbpy)NiII[(CO)OR](Cl)
(2).9b-c,11 Concurrently, visible light irradiation of the photocata-
lyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (3) would enable a long-lived
excited species 4 that serves as a potent single electron oxidant
(t= 2.3 µs, *E1/2(IrIII/IrII) = +1.21 vs. SCE in MeCN) for
NiIIRCl.12,13 Subsequent visible light irradiation of transient
(dtbbpy)NiIII[(CO)OR](Cl) (5) would effect photoelimination of
chlorine radical, followed by rapid hydrogen atom abstraction of
the aliphatic substrate to generate a carbon-centered radical (7).
Addition of this radical to NiII would result in 8, followed by re-
ductive elimination of the ester product. Single electron transfer
from the reducing IrII (10) to NiI (9) would allow for regeneration
7
8
9
none
1
2
66
44
0
28
33
48
27
17
34
17
32
19
22
25
35
11
1 equiv of cyclohexane
no photocatalyst
no ligand
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
3
5
no nickel
no light
0
6
0
7
26 °C
40 °C
46
55
39
62
8
no Na2WO4
no Na2WO4
•
2H2Od
9
•
2H2Od, 72h
10
11
12
13
Na2SiO3
•
5H2O instead of Na2WO4•2H2O,
57
58
17
d
no K3PO4
no K3PO4, no Na2WO4•2H2O
a K3PO4 (2 equiv); Na2WO4•2H2O (1 equiv). b Yields deter-
mined by H NMR using 4-fluoroanisole as an external stand-
1
of
both
the
Ni
and
photoredox
catalysts.13
c
ard. Yield determined by GC analysis based on consumption
ClCO2R
O
chloroformate
of 2 equiv of chloroformate for production of 1 equiv of DPC.d
3 equiv of base used.
LnNi0
RO
1
Cl
LnNiII
IrII
SET
9
10
that sodium tungstate is acting as a base15 rather than as a pre-
cursor to higher-order tungstates, which could function as pho-
tocatalysts and hydrogen atom acceptors.16 For example, at 72
hours, a reaction without sodium tungstate proceeds to compa-
rable yield as a reaction in its presence (entries 1 and 10). Fur-
thermore, use of near-UV light, which enables access to the
charge-transfer excited states of higher-order tungstates, leads
to low reaction efficiency (Table S9). In all cases, the mass bal-
ance can be attributed to the formation of diphenyl carbonate
(13), a byproduct primarily generated from the reaction of chlo-
roformate with base (Table S4).
CO2R
ester
reductant
2
LnNiI
IrIII
3
SET
*IrIII
oxidant
4
hυ
8
Cl
LnNiIII CO2R
5
LnNiIII CO2R
hυ
7
6
Cl
LnNiII CO2R
LnNiII CO2R
HAT
With these optimized conditions established, we set out to
examine the scope of the C–H cross-coupling reaction (Figure
3). In exploring the chloride-containing coupling partner, we
observed that both p-fluoro and p-methoxy derivatives of phe-
nyl chloroformate are effective for C–H functionalization of cy-
clooctane (15 and 16). More notably, the use of acid chlorides
in place of a chloroformate delivered aromatic and aliphatic ke-
tones 17 and 18 in 55 and 52% yield, respectively, under iden-
tical conditions.17,18 Additionally, 4-morpholine carbonyl chlo-
ride afforded amide 19 in 15% yield, demonstrating that this
methodology could be adopted for direct amidation.
H
B
+
hydrocarbon
B•HCl
Figure 2. Proposed photoelimination mechanism for ester for-
mation from hydrocarbons. 3 = Ir[dF(CF3)ppy]2(dtbbpy)PF6;
dF(CF3)ppy = 2 (2,4-difluorophenyl)-5-(trifluoromethyl)pyri-
dine; dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine.
Our investigation began with the reaction of phenyl chlo-
roformate ($0.16/g)9 with cyclohexane (Table 1). Use of this
coupling partner under our previously reported conditions (10%
Ni, 2% Ir, 10 equiv cyclohexane, 2 equiv K3PO4, in 0.04 M ben-
zene) delivered 12 in only 14% yield (Figure S3). Upon exten-
sive investigation, we identified conditions that delivered ester
12 in 66% yield after 48 hours using only 0.5 mol% Ir photo-
catalyst 3 and 4 mol% Ni (entry 1).14 Whereas 1 equiv. of alkane
may be used, highest yields are obtained using a ratio of 3:1 al-
kane:chloroformate (entry 2). Control reactions demonstrated
that the C(sp3)−H functionalization process requires the presence
of both Ni and Ir catalysts, as well as light, and that consistent
reaction temperatures were critical to obtaining high yields (en-
tries 3–8). Notably, the addition of sodium tungstate, and to a
lesser extent, sodium silicate, provided moderate rate accelera-
tions (entries 1 vs 9 and 11). Preliminary data suggests
In our investigation of the C–H coupling partner, we first
evaluated unfunctionalized alkanes. Cyclic alkyl hydrocarbons
with ring sizes from 5 to 15 underwent C–C bond formation,
transforming inert substrates to easily modified products in
good yield (12, 20–22). Tetramethylsilane which possesses one
of the strongest C(sp3)−H bonds (BDFE = 96 kcal/mol)7 was
functionalized in 51% yield (24). Examination of the function-
alization of acyclic alkanes revealed a trend amongst various
C(sp3)−H sites consistent with the influence of BDFE on rate of
C–H abstraction. Pentane was preferentially functionalized at
the internal secondary positions in 68% combined yield (25
a:b:g 1:8:4.6). Analogously, 2-methyl butane exhibited prefer-
ential functionalization at the tertiary position in 53% combined
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
1
2
3
4
Ir photocatalyst 3 (0.5 mol%)
Ni(cod)2 (4 mol%), dtbbpy (5.2 mol%)
O
O
H
% Yielda
Selectivity
+
R
R
Cl
K3PO4 (2 equiv), Na2WO4
•2H2O (1 equiv), PhH (0.1 M)
34 W Blue LEDs, 34–40 ºC, 48 h
3 equiv
functionalized C(sp3)
PhO2C
-H
5
6
7
8
acyl derivatives
O
O
O
O
R
Boc
N
PhO2C
O
O
O
O
PhO2C
NBoc
PhO2C
O
C8H15
C8H15
N
C8H15
O
C8H15
O
t-Bu
14 R= H 75%
15 R= F 62%
16 R=OMe 68%
18 52%
19 15%
17 55%
42 60%
43 48%
41 55%
40 50%
9
CH3
O
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
unactivated C(sp3)
-H
β
CH3
PhO2C
PhO2C
CH3
PhO2C
β
γ
α
PhO2C
PhO2C
H3C
β
γ
β
γ
PhO2C
PhO2C
CH3
O
n
CH3
PhO2C
Si
CH3
24 51%b,c,d
CN
CH
δ
3
α
O
44 73%b
CH3
47 85%b
β:γ:δ 2.1:5.4:1
20 n=1, 48%
12 n=2, 60%
21 n=3, 70%
22 n=11, 50%
46 63%b
β:γ 1.9:1
45 79%b
23 46%b
β 1.3:1
25 68%b,c
α:β:γ 1:8:4.6
3.4:1 dr
α
:
OPh
O
O
benzylic C(sp3)
PhO2C
-H
CH3
γ
O
β
δ
CH3
β
N
PhO2C
N
PhO2C
γ
α
α
PhO2C
CH3
β
PhO2C
H3C CH3
α
H3C CH3
γ
O
γ
O
PhO2C
H3C
PhO2C
β
CH3
β
CH
δ
α
3
CH3
29 41%
26 50%b,c
α:β 1:3.5
δ
27 53%b,c
50 57%b
α:β:γ:δ 1:3:20.5:4
CH3
28 55%b
48 60%b
β:γ:δ 1:4.2:1.4
δ
49 56%b
O
α:β:γ:δ 1.3:9:6.3:1
α:β:γ:δ 1:4.5:18:4.5
β
CH3
α
CH3
H3C
PhO2C
PhO2C
H
H
H
H
H
H
H
H
CO2Ph
CO2Ph
PhO2C
γ
PhO2C
CH3
R
PhO2C
β
NC
30 R=CN 70%b α:β 13:1
31 R=CF3 45%b α:β 14:1
32 R=H 69%b α:β 22:1
Cl
O
α
O
H3C
O
O
33 R=F 73%b α:β 13.6:1
34 R=O(p-FPh) 63%b α:β 30.5:1
35 R=OPh 66%b α:β 32:1
52 18%f
36 60%
37 60%
38 60%b
39 64%
51 40%b
α:β:γ 1:1.6:3.1 (1.8:1 dr)
Figure 3. a Isolated yield of all isomers expressed as an average of two runs. Hydrocarbon substrates worked effectively at 34 °C (+5
°C), whereas hydrocarbons containing amines, ketones, or ethers, worked optimally at 40 °C (+5 °C). b 1H NMR yield of all isomers
expressed as an average of two runs using 4-fluoroanisole as an external standard. c 6 equiv of C–H substrate used. d Yield reported
post-desilylation. Less than 5% of other isomers detected. f 1H NMR yield expressed as a single run reported on 0.08 mmol scale
e
with 1.8 C−H equivalents of [5]-ladderane using 12 W blue LEDs.
values ranging from –0.5 to –1.0).20 These results explain the
high regioselectivity in esterification for products 29, 37–39.
yield (27 a:b:g:d 1.3:9:6:3.1). An Evans–Polanyi plot (Ea =
a∆G° + b) for 2-methylbutane shows a linear correlation with
an a value of 0.44, comparable to tabulated a values for HAT
with chlorine radical (aCl = 0.45) (Figure 4a).8c Thus, while the
C–H esterification results in mixtures of regioisomeric products
for these substrates, the site selectivity is predictable.
When functionalized cyclic and acyclic substrates were sub-
mitted to the reaction conditions, selectivity trends reflected an
interplay of polarity effects and radical stability. Cyclic amides
and ethers, from a four-membered azetidine to a twelve-mem-
bered crown ether were successfully converted to a-amino and
a-oxy esters 40 and 43 under the dual catalytic conditions.17d,e
Cyclic hydrocarbons with electron-withdrawing functionality,
like cyclopentanone and cyclopentylcarbonitrile, underwent C–
C bond formation with predictable and high levels of selectivity,
furnishing the b-functionalized product 44 and g-functionalized
product 45 in 73 and 79% yields. For an acyclic ketone, selec-
tivity for g functionalization increased when that site changed
from a primary to a secondary position (46 vs 47: 22% vs 54%
yield). Similarly, a preference for the g position increased be-
tween 49 and 50 when that site was changed from a secondary
position to a tertiary position. Synthetically, these examples of-
fer complementarity to arylations of similar substrates under Pd
catalysis, where regioselectivity is ligand/or directing group-de-
pendent.21 Likewise, the Martin laboratory recently described a
method for Ni-catalyzed carboxylation of halogenated aliphatic
hydrocarbons that affords C–C bond formation at two com-
pletely distinct positions of an aliphatic chain to that favored in
this methodology.22
Since toluene and alkyl benzenes are abundant and inexpen-
sive commodity chemicals, we also examined their use as sub-
strates for the esterification reaction (28–39). Notably, the Stahl
and Liu groups have recently reported Cu-catalyzed arylation
reactions of alkyl benzenes with boronic acid derivatives that
provide efficient access to diarylalkanes, albeit requiring a large
excess of substrate or alkyl benzenes with extended aromatic
systems.19 For the esterification reaction, we were pleased to
find that toluene and its acyclic as well as cyclic derivatives un-
derwent C–C bond formation in good yields. The influence of
the polar effect is evidenced in the site selectivity of these reac-
tions. For a series of p-substituted ethyl benzenes, the ratio of
benzylic to methyl functionalization decreases with electron-
withdrawing substituents (30–35). Furthermore, a Hammett-
Brown analysis of the relative rate of benzylic functionalization
across this series (determined by competition experiments, see
SI) reveals that electron-rich substrates undergo C–C bond for-
mation faster than electron-poor substrates (Figure 4B). Indeed,
the small r value is consistent with a highly exothermic abstrac-
tion step and reports on free-radical chlorination of toluenes (r
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
REFERENCES
(1) For recent reviews: (a) Hartwig, J. F.; Larsen, M. A. ACS Cent. Sci.
1
2
3
4
2016, 2, 281; (b) He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J. -Q.
Chem. Rev. 2017, 117, 8754; (c) Gutekunst, W. R.; Baran, P. S. Chem.
Soc. Rev. 2011, 40, 1976; (d) Yamaguchi, J.; Yamaguchi, A. D.; Itami,
K. Angew. Chem. Int. Ed. 2012, 51, 8960.
(2) For selected examples: (a) Newhouse, T.; Baran, P. S. Angew.
Chem. Int. Ed. 2011, 50, 3362; (b) Liu, W.; Groves, J. T. Acc. Chem.
Res. 2015, 48, 1727; (c) Chen, M. S.; White, M. C. Science 2010, 327,
566; (d) Czaplyski, W. L.; Na, C. G.; Alexanian, E. J. J. Am. Chem.
Soc. 2016, 138, 13854; (e) Michaudel, Q.; Thevenet, D.; Baran, P. S.
J. Am. Chem. Soc. 2012, 134, 2547; (f) Chiappini, N. D.; Mack, J. B.
C.; Du Bois, J. Angew. Chem. Int. Ed. 2018, 130, 5050; (g) Larsen, M.
A.; Cho, S. H.; Hartwig, J. J. Am. Chem. Soc. 2016, 138, 762.
(3) (a) Engle, K. M. ; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res.
2012, 45, 788; (b) Tang, S.; Wang, P.; Li, H.; Lei, A. Nat. Commun.
2016, 7, 11676; (c) Shao, B.; Bagdasarian, A. L.; Popov. S.; Nelson, H.
M. Science 2017, 355, 1403; (d) Choi, G. J.; Zhu, Q.; Miller, D. C.; Gu,
C. J.; Knowles, R. R. 2016, 539, 268; (d) Chu, J. C. K.; Rovis, T. Na-
ture 2016, 539, 272; A recent report described two examples of C–C
bond formation using 1 equivalent of cyclooctane: (e) Margrey, K. A.;
Czaplyski, W. L.; Nicewicz, D. A.; Alexanian, E. J. J. Am. Chem. Soc.
2018, 140, 4213.
(4) (a) Liao, K.; Pickel, T. C.; Boyarskikh, V.; Bacsa, J.; Musaev, D.
G.; Davies, H. M. L. Nature 2018, 551, 609; (b) Liao, K.; Negretti, S.;
Musaev, D. G.; Basca, J.; Davies, H. M. L. Nature 2016, 533, 230.
(5) (a) Zuo, Z. W.; Ahneman, D. T.; Chu, L. L.; Terrett, J. A.; Doyle,
A. G.; MacMillan, D. W. C. Science 2014, 345, 437; (b) Shaw, M. H.;
Shurtleff, V. W.; Terrett, J. A.; Cuthbertson, J. D.; MacMillan, D. W.
C. Science 2016, 352, 1304; (c) Shields, B. J.; Doyle, A.G. J. Am.
Chem. Soc. 2016, 138, 12719; (d) Heitz, D. R.; Tellis, J. C.; Molander,
G. A. J. Am. Chem. Soc. 2016, 138, 12715. (e) Shen, Y.; Gu, Y.; Mar-
tin, R. J. Am. Chem. Soc. 2018, 140, 12200–12209.
5
6
7
8
9
Figure 4. C(sp3)−H abstraction selectivity profile. (a) Evans–
Polanyi relationship for 27; (b) Hammett Plot for ethylbenzene
derivatives. See SI for -OPh Hammett-Brown value (s+).
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
Application of this method to late-stage functionalization
was also evaluated. Sclareolide, a model system for selective
C(sp3)−H oxidations, led to 51 in 40% combined yield at the
most electron-rich and sterically-accessible methylene sites,
which is orthogonal to reactivity exhibited by most transition
metal-based catalysts.23 Additionally, a ladderane core, the de-
rivatives of which are notoriously challenging to access, gave
52 in a modest 18% yield at 1.8 equivalents of substrate. The
closest reaction analog, a Mn(TMP)Cl catalyst system, deliv-
ered 40% of the chlorinated species and requires additional
steps to access a C−C bond.24
In summary, this reaction provides a general strategy to ac-
cess carbonyl derivatives directly from unactivated C(sp3)–H
bonds that is amenable both to early and late stage synthesis.
Site selectivity is predictable, arising from hydrogen atom ab-
straction by chlorine radical, and affords a synthetic comple-
ment to alternative approaches for achieving C–C bond for-
mation from alkanes. Our future efforts will be directed at elu-
cidating the mechanism of this process and developing strate-
gies to control the site-selectivity of C(sp3)–H functionaliza-
tion.
(6) While this manuscript was in preparation, a method for the arylation
of unactivated alkane substrates (5 equiv) using Ni/photoredox was re-
ported by the MacMillan lab: Perry, I. B.; Brewer, T. F.; Sarver, P. J.;
Schultz, D. M.; DiRocco, D. A.; MacMillan, D. W. C. Nature 2018,
560, 70.
(7) See supporting information for details.
(8) (a) Kochi, J. K., Ed. Free Radicals, Wiley-Interscience, New York,
1973; (b) Tedder, J. M. Tetrahedron 1982, 38, 313; (c) Afanas'ev, I. B.
Russian Chemical Reviews 1971, 40, 216.
ASSOCIATED CONTENT
(9) Price based on the purchase of phenyl chloroformate from
Oakwood chemical on April 19, 2018; (b) Zheng, M.; Xue, W.; Xue,
T.; Gong, H. Org. Lett. 2016, 18, 6152; (c) Otsuka, S.; Nakamura, A.;
Yoshida, T.; Naruto, M.; Ataka, K. J. Am. Chem. Soc. 1973, 95, 3180.
(10) (a) Shields, B. J.; Kudisch, B.; Scholes, G. D.; Doyle, A. G. J. Am.
Chem. Soc. 2018, 140, 3035; (b) Hwang, S. J.; Powers, D. C.; Maher,
A. G.; Anderson, B. L.; Hadt, R. G.; Zheng, S.-L.; Chen, Y.-S.; Nocera,
D. G. J. Am. Chem. Soc. 2015, 137, 6472; (c) Hwang, S. J.; Anderson,
B. L.; Powers, D. C.; Maher, A. G.; Hadt, R. G.; Nocera, D. G. Organ-
ometallics 2015, 34, 4766; (d) Mondal, P.; Pirovano, P.; Das, A.; Far-
quhar, E. R.; McDonald, A. R. J. Am. Chem. Soc. 2018, 140, 1834.
(11) See Supporting Information for spectroscopic, computational, and
stoichiometric experiments that probe this proposed catalytic cycle.
(12) Ep = 0.4 V vs SCE in MeCN for (dtbbpy)Ni(COPh)Cl.
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website. Experimental procedures, computational data,
and characterization and spectral data for new compounds.
AUTHOR INFORMATION
Corresponding Author
*agdoyle@princeton.edu
Author Contributions
‡L.K.G.A. and J.I.M.A. contributed equally.
(13) Lowry, M. S.; Goldsmith, J. I.; Slinker, J. D.; Rohl, R.; Pascal, R.
A.; Malliaras, G. G.; Bernhard, S. Chem. Mater. 2005, 17, 5712.
Notes
The authors declare no competing financial interest.
(14) When chlorobenzene was submitted to the optimized reaction con-
ditions no product was detected at 3 equiv. of cyclohexane. See Figure
S8.
ACKNOWLEDGMENTS
(15) Lassner, E.; Schubert, W. -D. Tungsten Properties, Chemistry,
Technology of the Element, Alloys, and Chemical Compounds; Kluwer
Academic/ Plenum Publishers: New York, 1999; (b) (1) Barré, T.;
Arurault, L.; Sauvage, F. X. Spectrochim. Acta - Part A Mol. Biomol.
Spectrosc. 2005, 61, 551.
The authors gratefully acknowledge Jaron Mercer and the
Burns lab for their generous donation of [5]-ladderane; Dr.
István Pelczer for NMR assistance; Lotus Separations; and Ben
J. Shields, Stephen I. Ting, and Eric W. Webb for their helpful
advice. Financial support was provided by NIGMS (R01
GM100985 and R35 GM126986) and an F32 Ruth L Kirschtein
NRSA Fellowship under Award No. 5 F32 GM119364-02
(L.K.G.A.).
(16) (a) Hill, C. L.; Prosser-McCartha, C. M. Photocatalytic and Pho-
toredox Properties of Polyoxometalate Systems. In Photosensitization
and Photocatalysis Using Inorganic and Organometallic Compounds;
Kalyanasundaram, K., Grätzel, M., Eds.; Springer: Dordrecht, 1993; pp
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
307–330. (b) Na2WO4 forms higher order tungstates at temperatures
(20) Russell, G. A.; Williamson, Jr., R. C. J. Am. Chem. Soc. 1964, 86,
2357.
1
above 90 °C.
(21) (a) Zhu, R. -Y.; Li, Z. -Q.; Park, H. S.; Senanayake, C. H.; Yu, J.
-Q. J. Am. Chem. Soc. 2018, 140, 3564; (b) Li, S.; Zhu, R. -Y.; Xiao,
K. -J.; Yu, J. -Q. Angew. Chem. Int. Ed. 2016, 55, 4317; (c) Shao, Q.;
He, J.; Wu, Q. -F.; Yu, J. -Q. ACS Catal. 2017, 7, 7777.
(22) (a) Juliá-Hernández, F.; Moragas, T.; Cornella, J.; Martin, R. Na-
ture, 2017, 545, 84.
(17) Selected examples of ketone synthesis using acyl electrophiles: (a)
Wotal, A. C.; Weix, D. J. Org. Lett. 2012, 14, 1476; (b) Wu, F.; Lu,
W.; Qian, Q.; Ren, Q.; Gong, H. Org. Lett. 2012, 14, 3044; (c) Le, C.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2015, 137, 11938; (d) Joe, C.
L.; Doyle, A. G. Angew. Chem. Int. Ed. 2016, 55, 4040; (e) Amani, J.;
Sodagar, E.; Molander, G. A. Org. Lett. 2016, 18, 732.
(18) Ni-photoredox catalyzed thiocarbonylation and acylation of ethers
has been accomplished in solvent quantities of substrate: (a) Hong S.-
H.; Kang, B. Chem. Sci. 2017, 8, 6613; (b) Sun, Z.; Kumagai, N.; Shi-
basaki, M. Org. Lett. 2017, 19, 3727.
2
3
4
5
6
7
8
9
(23) Zou, L.; Paton, R. S.; Eschenmoser, A.; Newhouse, T. R.; Baran,
P. S.; Houk, K. N. J. Org. Chem. 2013, 78, 4037.
(24) Mercer, J. A. M.; Cohen, C. M.; Shuken, S. R.; Wagner, A. M.;
Smith, M. W.; Moss, III, F. R.; Smith, M. D.; Vahala, R.; Gonzalez-
Martinez, A.; Boxer, S. G.; Burns, N. Z. J. Am. Chem. Soc. 2016, 138,
15845.
(19) (a) Vasilopoulos, A.; Zultanski, S. L.; Stahl, S. S. J. Am. Chem.
Soc. 2017, 139, 7705; (b) Zhang, W.; Chen, P.; Liu, G. J. Am. Chem.
Soc. 2017, 139, 7709.
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
O
δ
O
H
δ
Ni
Ir
PhO
PhO
Cl
Cl
hυ
abundant
carbon source
3 equiv
40 examples
PhO2C
O
PhO2C
PhO2C
PhO2C
CH3
O
CH3
CN
O
ACS Paragon Plus Environment