Cobalt-Catalyzed Stereoretentive Hydrogen Isotope Exchange of C(sp3)-H Bonds

Article abstract of DOI:10.1021/acscatal.7b02051

Cobalt dialkyl complexes bearing α-diimine ligands proved to be active precatalysts for the nondirected, C(sp³)-H selective hydrogen isotope exchange (HIE) of alkylarenes using D₂ gas as the deuterium source. Alkylarenes with a variety of substitution patterns and heteroatom substituents on the arene ring were successfully labeled, enabling high levels of incorporation into primary, secondary, and tertiary benzylic C(sp³)-H bonds. In some cases, the HIE proceeded with high diastereoselectivity and application of the cobalt-catalyzed method to enantioenriched substrates with benzylic stereocenters provided enantioretentive hydrogen isotope exchange at tertiary carbons.

Full text of DOI:10.1021/acscatal.7b02051

Subscriber access provided by BOSTON UNIV
Letter
Cobalt-Catalyzed Stereoretentive Hydrogen
Isotope Exchange of C(sp3)–H Bonds
W. Neil Palmer, and Paul J. Chirik
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02051 • Publication Date (Web): 28 Jul 2017
Downloaded from http://pubs.acs.org on July 28, 2017
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 free 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 accessible to all
readers and 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.
ACS Catalysis 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
ACS Catalysis
1
2
3
4
5
6
7
8
9
Cobalt-Catalyzed Stereoretentive Hydrogen Isotope Exchange of
C(sp3)–H Bonds
W. Neil Palmer and Paul J. Chirik*
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, U. S. A.
Keywords: cobalt, deuterium, α-diimine, hydrogen isotope exchange, isotopic labeling, C–H activation
ABSTRACT: Cobalt dialkyl complexes bearing α-diimine ligands proved to be active pre-catalysts for the non-directed, C(sp3)–H selective
hydrogen isotope exchange (HIE) of alkylarenes using D2 gas as the deuterium source. Alkylarenes with a variety of substitution patterns and
heteroatom substituents on the arene ring were successfully labeled, enabling high levels of incorporation into primary, secondary, and ter-
tiary benzylic C(sp3)–H bonds. In some cases, the HIE proceeded with high diastereoselectivity and application of the cobalt-catalyzed
method to enantioenriched substrates with benzylic stereocenters provided enantioretentive hydrogen isotope exchange at tertiary carbons.
Hydrogen isotope exchange (HIE) of C–H bonds promoted by
transition metal catalysts is a valuable tool for the preparation of isotop-
ically labeled organic molecules. HIE is particularly useful for studying
mechanisms of C–H bond activation1 and for late-stage deuterium (2H,
or D) or tritium (3H, or T) labeling of pharmaceuticals.2 The selective
incorporation of deuterium into an active pharmaceutical ingredient
(API) can significantly alter its metabolism2d,3 and is a common strate-
gy for the design of new therapeutics.2d,3b,c,4 The radiolabeling of APIs
with tritium is essential in preclinical adsorption, distribution, metabo-
lism, and excretion (ADME) studies,2a,c and preferred conditions gen-
erally use T2 gas at low pressures rather than T2O in order to facilitate
safe handling by minimizing radioactivity-to-volume ratio and produc-
tion of radioactive waste.2a,c
Most transition metal-catalyzed HIE methods using D2 or T2 gas are
selective for C(sp2)–H bonds of arenes and heteroarenes,5 owing to the
established oxidative addition preferences of reduced metal complex-
es.6 The most commonly used catalysts for HIE are homogeneous
iridium complexes that typically rely on interaction with directing
groups in the substrate to promote selective C(sp2)–H HIE.7 Our la-
boratory recently reported a bis(N-heterocyclic-carbene)pyridine
pincer iron-catalyst that exhibited highly predictable, sterically driven
C(sp2)–H site selective HIE that is orthogonal to that observed with
iridium (Scheme 1A).8
without epimerization using D2O under microwave radiation.13c Enan-
tioretentive HIE of α-C–H bonds of chiral primary amines was recent-
ly demonstrated with heterogeneous ruthenium catalysts13d,e and D2
gas or homogeneous ruthenium catalysts and D2O (Scheme 1B).13f
Non-directed, stereoretentive labeling of C–H bonds at tertiary carbon
centers, however, has not been demonstrated. Here we present a
method that uses an α-diimine cobalt(II) dialkyl precatalyst to pro-
mote preferential C(sp3)–H HIE in the presence of C(sp2)–H sites
using D2 gas. The earth abundant metal catalyst is also active for ter-
tiary centers (Scheme 1B), enabling enantioretentive reactions and
making it appealing for late-stage isotope labeling of APIs.
Scheme 1. C–H bond selectivity in non-directed transi-
tion metal-catalyzed HIE and methods for enantiore-
tentive HIE of C(sp3)–H bonds.
A. Non-directed HIE of alkylarenes using D2 gas.
D
R
C(sp2)-H
selective
Fe (ref 8)
D
R
D
D2
+
D
D
heterogeneous
Pd, Ni
(refs 9,10)
R
C(sp3)-H
selective
Co (this work)
Selective C(sp3)–H HIE in the presence of C(sp2)–H bonds but in
the absence of directing groups is rare and presents an unmet need for
labeling of drug-like molecules. Precedent exists with heterogeneous
Pd,9 Pt, Rh, Ni,10 and Co11 catalysts but these methods often require
the use of D2O or other deuterated solvents.6 HIE of benzylic C–H
bonds of essentially unfunctionalized alkylarenes has been reported
using Pd/C6,9 or Raney Ni6,10 with D2 gas (Scheme 1A), but can require
multiple iterations of catalyst pre-treatment with D2 in order to obtain
optimal isotopic enrichment.12
B. Enantioretentive HIE of C-H bonds at stereocenters.
D
NH2
Me
D2O
(R = NH2)
Ru (ref 13f)
α-chiral
amines
R
D
D2
(R = Me)
3° chiral
centers
Co (this work)
Few examples of stereoretentive or enantioretentive C(sp3)–H iso-
tope exchange have been reported.13 The deuteration of α-C–H bonds
of β-chiral alcohols by ruthenium was reported to proceed without loss
of enantiopurity.13a Stereoretentive HIE β- to primary amines in phe-
nylalanine derivatives was also described using Pd/C and D2 gas.13b In
both of these examples, increased reaction temperature resulted in
epimerization. Raney Ni has been used to deuterate carbohydrates
Our laboratory recently reported α-diimine cobalt14 and nickel15 di-
alkyl and bis(carboxylate) complexes that are active for the polyboryla-
tion of C(sp3)-H bonds in alkylarenes, a shift from the sterically driven
C(sp2)-H selectivity more commonly observed with iridium16 and
other cobalt borylation catalysts.17 These observations motivated ex-
ploration of these catalysts in HIE reactions not only for applications in
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 5
late stage deuteration and tritiations but also to gain mechanistic in-
sight into the origin of selectivity toward C(sp3)–H functionalization.
C y-
Scheme 3. HIE of alkylarenes using pre-catalyst 2 and
D2.a
1
2
The N-alkyl-substituted α-diimine cobalt dialkyl complex,
(
3
4
5
6
7
8
9
ADI)Co(CH2SiMe3)2 (1, Scheme 2A), was selected for initial HIE
reactions due to its superior performance in catalytic benzylic C(sp3)–
H borylation.14 Stirring a dodecane solution of toluene (4) with 5
mol% of 1 under 4 atm of D2 for 24 hours at 80 °C resulted in deuteri-
um labeling at multiple C–H positions (Scheme 2B). The highest de-
gree of incorporation occurred at the benzylic C–H bonds (>95%), but
the m- and p- positions were also deuterated (11% and 14%, respec-
tively). Arene reduction (12%) to methylcyclohexane was also ob-
served. From these data, it is evident that 1 preferentially activates and
functionalizes benzylic C(sp3)–H sites, consistent with observations
from C-H borylation, but also accesses C(sp2)–H positions, a mode of
reactivity not previously observed during C-B bond forming catalysis
with this precatalyst.14
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
Scheme 2. α-Diimine cobalt complexes used in this
work and their performance in catalytic HIE of toluene
using D2.
A. α-Diimine cobalt precatalysts.
iPr
iPr
N
N
N
SiMe3
iPr
iPr
iPr
iPr
N
Co
N
Co
N
Co
SiMe3
SiMe3
Me3Si
iPr
iPr
1
2
3
(
iPrDI)Co(η3-C3H5)
(
CyADI)Co(CH2SiMe3)2
(
iPrDI)Co(CH2SiMe3)2
B. Catalytic HIE of toluene.a
[% Bn]
D
D
[% m]
[% p]
D
D
cat. [Co], D2
+
Dn
dodecane
temp., 24 h
D
4
4
[% m] D
% Bn : % m : % p
reduction
(12%)
(8%)
[Co]: 1 (5%, 4 atm D2, 80 °C);
> 95% : 11% : 14%
2 (10%, 1 atm D2, 50 °C); > 95% : 11% : 15%
3 (5%, 4 atm D2, 80 °C); 6% : 0% : 0%
(0%)
aReactions conducted with 0.55 mmol of toluene in 0.55 mL of dodecane for 24
hours. Catalyst loading, pressure of D2 gas, and reaction temperature included in
parentheses. See SI for details.
aReactions conducted with 0.55 mmol of alkylarene, 10 mol% of 2, and 1 atm of
D2 in 0.55 mL of heptane or dodecane solvent at 50 °C for 24 hours. Percent
deuterium incorporation at the carbon position indicated in brackets. See SI for
details. bArene reduction observed. See SI for details. cReaction carried out at 80
Because arene reduction could be deleterious in the context of late
stage HIE, the pre-catalyst and reaction conditions were modified to
minimize this pathway (see SI, Table S1). Optimal conditions were
identified that employed 10 mol% of the N-aryl substituted α-diimine
cobalt dialkyl complex, (iPrDI)Co(CH2SiMe3)2 (2, Scheme 2A),14
at 50 °C and 1 atm of D2 (Scheme 2B). Under these conditions, high
levels (>95%) of deuterium incorporation into the benzylic C–H
bonds was observed with less arene reduction (8%). The related cobalt
η3-allyl complex, (iPrDI)Co(η3-C3H5) (3, Scheme 2A),18 was also
evaluated but only provided trace levels of deuterium incorporation
(Scheme 2B), highlighting the importance of the cobalt(II) dialkyl pre-
catalyst for entry into the catalytic HIE manifold.
With optimized conditions using cobalt pre-catalyst 2 established,
the generality of the method was investigated with a series of substitut-
ed methylarenes. The HIE protocol was selective for the benzylic C–H
bonds of p-, m-, o-, and polysubstituted methylarenes (Scheme 3A)
and proved tolerant of heteroatom substituents on the arene, including
fluoro (5), methoxy (6, 12), and dimethylamino (7) functional
groups. For m-tolylboronic acid pinacol ester (8), an elevated tempera-
ture (80 °C, 4 atm D2) was required to observe deuterium incorpora-
tion, but also provided a large degree of C(sp2)–H labeling and a signif-
icant amount (53%) of reduced arene.19
f
°C. d5 mol% of 2 used. eCPME used as the solvent. Run with 0.34 mmol of
substrate.
Methylarenes with substituents in the 4-position, including p-xylene
(9), 4-phenyltoluene (10), and 4-tert-butyltoluene (11), also under-
went cobalt-catalyzed C(sp3)–H HIE, although the latter two exhibited
comparatively low levels of deuterium incorporation, possibly due to
steric effects disfavoring coordination of the substrate to the cobalt
catalyst prior to C–H activation. With p-cymene (14), incorporation at
the tertiary benzylic C–H position (93%) was only slightly higher than
at the primary methyl group (86%). At elevated temperature and pres-
sure (80 °C, 4 atm D2), use of 5 mol% of 2 to label 4-methyl-
benzylboronic acid pinacol ester (13) provided a higher degree of
deuterium incorporation α- to boron (93%) than in the methyl posi-
tion (60%). This result is consistent with the apparent activating effect
of a [BPin] substituent toward C–H functionalization previously ob-
served in the context of benzylic C–H borylation14,15,20 and with the
formation of stabilized α-boryl organometallic intermediates previous-
ly invoked in transition metal catalysis.21 This effect implies that the
increased acidity of C–H bonds α- to boron substituents22 coincides
with increased rates of C–H functionalization by transition metals.
ACS Paragon Plus Environment

Page 3 of 5
ACS Catalysis
Cobalt-catalyzed HIE was also applied to arenes with additional me-
1
2
3
4
5
6
7
thyl groups. A high degree of deuterium incorporation was observed in
the benzylic C–H positions of mesitylene (15). At elevated tempera-
tures and pressures (80 °C, 4 atm D2) in cyclopentylmethyl ether
(CPME), isotope exchange was even successful with hexamethylben-
zene (16), providing a modest amount of deuterium incorporation
(23%) after 24 hours and demonstrating compatibility of the method
with ethereal solvents.
Substrates with secondary and tertiary benzylic C–H bonds also
highlight the unique selectivity of the cobalt-catalyzed method
(Scheme 3B). Selective incorporation of deuterium into the secondary
benzylic C–H bonds of ethylbenzene (17), benzylboronic acid pinacol
ester (18), and benzyltriethoxysilane (19) was observed using stand-
ard conditions. In the isotope exchange reaction with benzylcyclopro-
pane (20), incorporation was observed in the benzylic as well as the m-
and p-positions. Importantly, no evidence for cyclopropane ring-
opening was observed. This result is consistent with either a non-
radical mechanism for C–H activation, or a benzylic hydrogen atom
abstraction and rapid radical rebound to a cobalt intermediate occur-
ring at a rate greater than the rate of cyclopropane ring-opening.23
Alkylarenes with longer alkyl chains terminated by boronate (21) or
amine (22) substituents were also preferentially deuterated in the
benzylic position. Branched alkylarenes exhibited high selectivity for
tertiary benzylic C(sp3)–H bonds under standard catalytic conditions.
With racemic tert-butyldimethylsilyl (TBS) protected 3-phenylbutanol
(23-(rac)) and 2-phenyl-3-methylbutane (25-(rac)), the benzylic
C–H bonds were exclusively labeled. With sec-butylbenzene (24-
(rac)), 9% of the homobenzylic methyl group was deuterated.
Bicyclic alkylarenes were also subjected to cobalt-catalyzed HIE.
With tetralin (26) and indan (27), the benzylic methylene positions
were selectively labeled and accompanied by a small degree of incorpo-
ration into the arene C(sp2)–H bonds. These substrates have proven
challenging for benzylic C–H borylation with both α-diimine cobalt14
and nickel15 catalysts. These HIE results demonstrate that C(sp3)–H
functionalization of these substrates is possible in a similar catalytic
regime, suggesting that C–B bond formation may be the challenging
step that limits substrate scope in those protocols. The pinacol ester of
1-indanylboronic acid (28-(rac)) underwent deuteration at elevated
temperature and pressure (80 °C, 4 atm D2) using 5 mol% of 2, result-
ing in preferential incorporation into the α-boryl benzylic position
(>95%) than the benzylic methylene site (56%), again consistent with
an apparent [BPin] activating effect.14,15,20
8
9
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
aReactions conducted with 0.55 mmol of alkylarene, 10 mol% of 2, and 1 atm of
D2 in 0.55 mL of heptane solvent at 50 °C for 24 hours. Percent deuterium
incorporation at the carbon position indicated in brackets. See SI for details.
bEnantiomeric excess (ee) determined by chiral gas chromatography. See SI for
details.
Repeating the procedure with enantiopure arylindan (>98% ee (S))
replicated the diastereoselectivity observed with the racemic substrate
and the enantiopurity of the starting material was preserved in the
deuterated product (>98% ee (S), 29-(S), Scheme 4B), demonstrat-
ing that this HIE protocol proceeds with high levels of enantiospecifici-
ty (es).24 With (S)-1-methyltetralin (92% ee (S), 30-(S)), stereo-
chemical integrity was again conserved (>98% es) with high levels of
deuterium incorporation into the tertiary benzylic stereocenter (92%),
as well as the benzylic methylene (81%). With the acyclic substrate
(R)-2-phenyl-3-methylbutane (72% ee (R), 25-(R)), enantiospecific
HIE (>98% es) was achieved with a high degree (93%) of deuterium
labeling of the tertiary benzylic C–H bond.
In summary, a cobalt-catalyzed method for the selective C(sp3)–H
hydrogen isotope exchange of alkylarenes with D2 gas has been discov-
ered that proceeds with stereoretention when applied to enantioen-
riched substrates. The enhanced scope and functional group tolerance
of this HIE method compared to the previous C(sp3)–H borylation
method with the same catalysts14 implies that the latter protocol is
limited not by C–H activation but rather by C–B bond formation.
Studies to improve the scope of C(sp3)–H HIE and borylation and to
develop alternative C(sp3)–H functionalization methods are currently
in progress.
The deuteration of tertiary benzylic C(sp3)–H bonds inspired ex-
ploration of HIE in enantioenriched substrates containing tertiary
benzylic stereocenters. Initial experiments were conducted with race-
mic substrates to verify the applicability of the method to this class of
substrates. With 1 atm of D2 and 10 mol% of 2 at 50 °C, racemic 1-(4′-
methoxyphenyl)indan (29-(rac)) was successfully labeled (Scheme
4A). Incorporation was preferred on the face of the saturated ring anti-
to the aryl substituent, consistent with a mechanism in which selectivi-
ty is controlled by pre-coordination of the arene to the cobalt catalyst
intermediate resulting in diastereoselective C(sp3)–H activation.
Scheme 4. Diastereoselective and enantioretentive HIE
of benzylic C–H bonds using precatalyst 2 and D2.a
ASSOCIATED CONTENT
Supporting Information
Complete experimental details including pre-catalyst optimization
studies, and characterization data for deuterated products. This materi-
al is available free of charge via the Internet at http://pubs.acs.org.
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 5
(13) (a) Takahashi, M.; Oshima, K.; Matsubara, S. Chem. Lett.
AUTHOR INFORMATION
2005, 34, 192-193. (b) Maegawa, T.; Akashi, A.; Esaki, H.; Aoki, F.; Sajiki,
H.; Hirota, K. Synlett. 2005, 845-847. (c) Cioffi, E. A.; Bell, R. H.; Le, B.
Tetrahedron: Asymmetry 2005, 16, 471-475. (d) Taglang, C.; Martínez-
Prieto, L. M.; del Rosal, I.; Maron, L.; Poteau, R.; Philippot, K.; Chaudret,
B.; Perato, S.; Lone, A. S.; Puente, C.; Dugave, C.; Rousseau, B.; Pieters, G.
Angew. Chem. Int. Ed. 2015, 54, 10474-10477. (e) Jere, F. T.; Miller, D.
J.; Jackson, J. E. Org. Lett. 2003, 5, 527-530. (f) Hale, L. V. A.; Szymczak,
N. K. J. Am. Chem. Soc. 2016, 138, 13489-13492.
(14) Palmer, W. N.; Obligacion, J. V.; Pappas, I.; Chirik, P. J. J. Am.
Chem. Soc. 2016, 138, 766-769.
(15) Palmer, W. N.; Zarate, C.; Chirik, P. J. J. Am. Chem. Soc. 2017,
139, 2589-2592.
1
2
3
4
5
6
7
8
Corresponding Author
* pchirik@princeton.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
An NSF GOALI (CHE-1564379) is acknowledged for financial sup-
port. WNP also acknowledges Eli Lilly for partial support through a
graduate fellowship.
9
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
(16) (a) Ishiyama, T.; Miyaura, N. Pure Appl. Chem. 2006, 78,
1369-1375. Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2003, 680, 3-
11. (c) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hart-
wig, J. F. Chem. Rev. 2010, 110, 890-931. (d) Hartwig, J. F. Acc. Chem.
Res. 2012, 45, 864-873.
(17) (a) Obligacion, J. V.; Semproni, S.; Chirik, P. J. J. Am. Chem.
Soc. 2014, 136, 4133-4136. (b) Schaefer, B. A.; Margulieux, G. W.; Small,
B. L.; Chirik, P. J. Organometallics 2015, 34, 1307-1320. (c) Obligacion, J.
V.; Semproni, S. P.; Pappas, I.; Chirik, P. J. J. Am. Chem. Soc. 2016, 138,
10645-10653. (d) Léonard, N. G.; Bezdek, M. J.; Chirik, P. J. Organometal-
lics 2017, 36, 142-150. (e) Obligacion, J. V.; Bezdek, M. J.; Chirik, P. J. J.
Am. Chem. Soc. 2017, 139, 2825-2823.
(18) Palmer, W. N.; Diao, T.; Pappas, I.; Chirik, P. J. ACS Catal.
2015, 5, 622-626.
(19) The electron-deficient nature of the substrate may favor arene
reduction compared to toluene under identical reaction conditions (20%,
see SI, Table S1) and may also account for a lack of HIE at 50 °C due to less
reversible substrate coordination to the catalyst.
REFERENCES
(1)
(a) Burwell Jr., R. L. Acc. Chem. Res. 1969, 2, 289-296. (b)
Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507-514. (c) Jones, W. D.
Acc. Chem. Res. 2003, 36, 140-146. (d) Lersch, M.; Tilset, M. Chem. Rev.
2005, 105, 2471-2526.
(2)
(a) Voges, R.; Heys, J. R.; Moenius, T. Preparation of Com-
pounds Labeled with Tritium and Carbon-14; John Wiley and Sons, Inc.:
New York, 2009. (b) Isin, E. M.; Elmore, C. S.; Nilsson, G. N.; Thompson,
R. A.; Weidolf, L. Chem. Res. Toxicol. 2012, 25, 532-542. (c) Lockley, W.
J. S.; McEwen, A.; Cooke, R. J. Labelled Comp. Radiopharm. 2012, 55,
235-257. (d) Gant, T. G. J. Med. Chem. 2014, 57, 3595-3611.
(3)
(a) Belleau, B.; Burba, J.; Pindell, M.; Reiffenstein, J. Science
1961, 133, 102-104. (b) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529-
2591. (c) Katsnelson, A. Nature Med. 2013, 19, 656.
(4)
1075. (b) Halford, B. Chem. Eng. News 2016, 94, 32-36.
(5) (a) Junk, T.; Catallo, W. J. Chem. Soc. Rev. 1997, 26, 401-406.
(a) Timmins, G. S. Expert Opin. Ther. Pat. 2014, 24, 1067-
(20) Shimada, S.; Batsanov, A. S.; Howard, J. A. K.; Marder, T. B.
Angew. Chem. Int. Ed. 2001, 40, 2168-2171.
(b) Atzrodt, J.; Derdau, V.; Fey, T.; Zimmermann, J. Angew. Chem. Int.
Ed. 2007, 46, 7744-7765. (c) Lockley, W. J. S.; Heys, J. R. J. Labelled
Comp. Radiopharm 2010, 53, 635-644.
(21)
(a) Pereira, S.; Srebnik, M. Tetrahedron Lett. 1995, 36, 1805-
1808. (b) Joannou, M. V.; Moyer, B. S.; Meek, S. J. J. Am. Chem. Soc.
2015, 137, 6176-6179. (c) Joannou, M. V.; Moyer, B. S.; Goldfogel, M. J.;
Meek, S. J. Angew. Chem. Int. Ed. 2015, 54, 14141-14145. (d) Endo, K.;
Ohkubo, T.; Hirokami, M.; Shibata, T. J. Am. Chem. Soc. 2010, 132,
11033-11035. (e) Sun, C.; Potter, B.; Morken, J. P. J. Am. Chem. Soc.
2014, 136, 6534-6537.
(22) (a) Rathke, M. W.; Kow, R. J. Am. Chem. Soc. 1972, 94, 6854-
6856. (b) Matteson, D. S.; Moody, R. J. J. Am. Chem. Soc. 1977, 29, 3196-
3197. (c) Matteson, D. S.; Moody, R. J. Organometallics 1982, 1, 20-28.
(23) The rate constant of cyclopropane ring-opening of the corre-
sponding cyclopropylbenzyl radical was previously determined to be 2.7 x
105 s-1 at 22 °C in hexane solution: Masnovi, J.; Samsel, E. G.; Bullock, R. M.
J. Chem. Soc., Chem. Commun. 1989, 1044-1045.
(6)
(a) Jones, W. D.; Feher, F. J. Acc. Chem. Res. 1989, 22, 91-100.
(b) Xue, X.-S.; Ji, P.; Zhou, B.; Cheng, J.-P. Chem. Rev. 2017, 117, 8622-
8648.
(7)
(a) Hesk, D.; Das, P. R.; Evans, B. J. Labelled Comp. Radio-
pharm. 1995, 36, 497-502. (b) Herbert, J. M. J. Labelled Comp. Radio-
pharm. 2010, 53, 658-661. (c) Nilsson, G. N.; Kerr, W. J. Labelled Comp.
Radiopharm. 2010, 53, 662-667. (d) Brown, J. A.; Cochrane, A. R.; Irvine,
S.; Kerr, W. J.; Mondal, B.; Parkinson, J. A.; Paterson, L. C.; Reid, M.; Tut-
tle, T.; Andersson, S.; Nilsson, G. N. Adv. Synth. Catal. 2014, 356, 3551-
3562.
(8) Yu, R. P.; Hesk, D.; Rivera, N.; Pelczer, I.; Chirik, P. J. Nature
2016, 529, 195-199.
(9) Atkinson, J. G.; Luke, M. O.; Stuart, R. S. Can. J. Chem. 1967,
45, 1511-1518.
(10) Heys, J. R. J. Labelled Comp. Radiopharm. 2010, 53, 716-721.
(11) Tsukinoki, T.; Ishimoto, K.; Mukumoto, M.; Suzuki, M.; Kawa-
ji, T.; Nagano, Y.; Tsuzuki, H.; Mataka, S.; Tashiro, M. J. Chem. Res. Syn-
op. 1996, 1, 66-67.
(12) Azran, J.; Shimoni, M.; Buchman, O. J. Catal. 1994, 148, 648-
653.
(24) Percent “es”, or enantiospecificity, indicates the percentage of
the reaction that proceeds with enantioretention and is defined as: % es =
(% ee of product) / (% ee of starting material) * 100.
ACS Paragon Plus Environment

Page 5 of 5
ACS Catalysis
1
2
3
4
5
6
7
8
9
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
ACS Paragon Plus Environment