Epimerization of Tertiary Carbon Centers via Reversible Radical Cleavage of Unactivated C(sp3)-H Bonds

Article abstract of DOI:10.1021/jacs.8b05753

Reversible cleavage of C(sp³)-H bonds can enable racemization or epimerization, offering a valuable tool to edit the stereochemistry of organic compounds. While epimerization reactions operating via cleavage of acidic C(sp³)-H bonds, such as the Cα-H of carbonyl compounds, have been widely used in organic synthesis and enzyme-catalyzed biosynthesis, epimerization of tertiary carbons bearing a nonacidic C(sp³)-H bond is much more challenging with few practical methods available. Herein, we report the first synthetically useful protocol for the epimerization of tertiary carbons via reversible radical cleavage of unactivated C(sp³)-H bonds with hypervalent iodine reagent benziodoxole azide and H₂O under mild conditions. These reactions exhibit excellent reactivity and selectivity for unactivated 3° C-H bonds of various cycloalkanes and offer a powerful strategy for editing the stereochemical configurations of carbon scaffolds intractable to conventional methods. Mechanistic study suggests that the unique ability of N₃^? to serve as a catalytic H atom shuttle is critical to reversibly break and reform 3° C-H bonds with high efficiency and selectivity.

Full text of DOI:10.1021/jacs.8b05753

Subscriber access provided by UNIV OF CAMBRIDGE
Article
Epimerization of Tertiary Carbon Centers via Reversible
Radical Cleavage of Unactivated C(sp3)-H Bonds
Yaxin Wang, Xiafei Hu, Cristian A. Morales-Rivera, Guo-
Xing Li, Xin Huang, Gang He, Peng Liu, and Gong Chen
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b05753 • Publication Date (Web): 08 Jul 2018
Downloaded from http://pubs.acs.org on July 8, 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 7
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Epimerization of Tertiary Carbon Centers via Reversible Radical
Cleavage of Unactivated C(sp3)-H Bonds
Yaxin Wang,1# Xiafei Hu,1# Cristian A. Morales-Rivera,3 Guo-Xing Li,1 Xin Huang,1 Gang He,1,2* Peng Liu,3* and
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
Gong Chen1,2,4
*
1State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
2Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
3Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
4Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
ABSTRACT: Reversible cleavage of C(sp3)-H bonds can enable racemization or epimerization, offering a valuable tool to edit the stereochem-
istry of organic compounds. While epimerization reactions operating via cleavage of acidic C(sp3)-H bonds, such as the Ca-H of carbonyl
compounds, have been widely used in organic synthesis and enzyme-catalyzed biosynthesis, epimerization of tertiary carbons bearing a non-
acidic C(sp3)-H bond is much more challenging with few practical methods available. Herein, we report the first synthetically useful protocol
for the epimerization of tertiary carbons via reversible radical cleavage of unactivated C(sp3)-H bonds with hypervalent iodine reagent benzio-
doxole azide and H2O under mild conditions. These reactions exhibit excellent reactivity and selectivity for unactivated 3o C-H bonds of various
cycloalkanes and offer a powerful strategy for editing the stereochemical configurations of carbon scaffolds intractable to conventional methods.
Mechanistic study suggests that the unique ability of N3• to serve as a catalytic H atom shuttle is critical to reversibly break and reform 3o C-H
bond with high efficiency and selectivity.
A) Epimerization via cleavage of acidic C(sp3)-H bond
INTRODUCTION
R1
R3
R2
H
Methods for the selective functionalization of alkyl C-H bonds
have been greatly advanced over the past few decades, offering
streamlined strategies for the synthesis and modification of complex
molecules.1-4 A wide range of reactions have been developed to trans-
form C(sp3)-H bonds into different functional groups.5-9 However,
reactions featuring reversible cleavage of unactivated C(sp3)-H
bonds have received much less attention. Racemization or epimeri-
zation via reversible cleavage of C(sp3)-H bonds might offer an in-
valuable tool for editing the stereochemistry of organic compounds.
Additionally, exchanging C(sp3)-H bonds with C-deuterium bonds
may provide valuable deuterated compounds for biomedical appli-
O
R1
O(H)
R3
R1
R2
R3
R2
O
H
enolization
B) Epimerization of Ile residue in peptide by radical SAM peptide epimerase
NH2
N
N
N
N
H-S
O
CH2
5'-dA
HO
HO
H
H
Cys
5'-dA
N
N
N
H
H
H
O
O
O
[4Fe-4S]
SAM
D-allo-Ile
cations.10,11 Epimerization reactions of tertiary Ca of carbonyl com-
pounds via cleavage of their acidic C(sp3)-H bonds have been rou-
tinely used in the synthesis of complex molecules, and in catalytic
process such as dynamic kinetic resolution (Scheme 1A). Similar
enolization mechanisms have also been widely used by enzyme epi-
merases for the biosynthesis of natural products.12 Compared with
acidic C(sp3)-H bonds, epimerization of tertiary carbons bearing
non-acidic C(sp3)-H bonds is much more challenging. Interestingly,
recent biochemical studies have shown that [4Fe-4S]-cluster radical
S-adenosyl-L-methionine (SAM) epimerases invert the stereocen-
ters of amino acid or sugar units through radical-mediated path-
ways.13, 14 For example, an epimerase selectively converts an L-Ile
L-Ile
C) Epimerization strategy via radical cleavage of nonacidic 3o C−H bond
A-H
A
D
D-H
H
R1
R2
R1
R3
R2
R3
R1
R3
R2
H
A
:
H acceptor D-H : H donor
D) This work: selective epimerization of nonacidic 3o C−H of cyclic alkanes
R
O
R
H
O
I
H
N3
R
1 (2-3 equiv)
unactivated
3o C-H
efficient; selective;
simple to operate;
compatible with
amino acid residue of a peptide to D-allo-Ile via abstraction of Ca-
EtOAc(or PhCl) / H2O
BIN3
1
35-50 o
C
H by a 5’-deoxyadenosyl radical (5’-dA•) and quenching of the car-
bon radical intermediate by a thiol group of an enzyme cysteine res-
idue (Scheme 1B).13 Radical-mediated C(sp3)-H cleavage reactions
could potentially provide a unique solution to epimerize tradition-
ally “unepimerizable” tertiary carbon centers in organic synthesis.
complex substrate
a catalytic
H atom shuttle
N3
Scheme 1. Epimerization of tertiary carbon via reversible cleavage
of tertiary C-H bonds.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 7
H
To achieve such transformations with useful efficiency, the sequence
H
N3
1
2
3
4
5
6
7
8
of H abstraction by a suitable radical H atom acceptor (A•) and
quenching of the tertiary C-radical by suitable H atom donor (D-H)
must be developed (Scheme 1C). Herein, we report an efficient and
synthetically useful protocol for epimerizing tertiary carbons via rad-
ical cleavage of non-acidic 3o C(sp3)-H bonds with hypervalent io-
dine reagent benziodoxole azide and H2O under mild conditions
(Scheme 1D).
H
Ara
H
H
3
2-cis
2-trans
en- Reagents (equiv), reaction time, temp
try
Solvents
DCE
2-trans
(2-cis) %
3 %
1
2
1 (2), BzOOBz (0.1), 24 h, 80 oC
<1 (36)
<1 (8)
62
90
1 (2), Fe(OAc)2 (0.1), PyBOX (0.1), 24 h, CH3CN
23 oC
1 (2), Ru(bpy)3Cl2 (0.1%), VL, 24 h, 35 oC HFIP
1 (2), Ru(bpy)3Cl2 (0.1%), Bu3SnH (1), VL, HFIP
24 h, 35 oC
1 (2), Bu3SnH (1), 24 h, 35 oC
1 (2), Bu3SnH (1), 24 h, 35 oC
1 (2), Bu3SnH (2), 24 h, 35 oC
1 (2), Ph2P(=O)H (1), 24 h, 35 oC
1 (2), Et3SiH (1), 24 h, 35 oC
3
4
<1 (3)
95
52
RESULTS AND DISCUSSION
9
35 (13)
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
Epimerization of cis-decalin
5
6
7
8
9
HFIP
7 (34)
75 (7)
10 (89)
89 (2)
80 (19)
91 (2)
1 (92)
84 (7)
59
17
<1
9
Radical reactions can provide simple and efficient means to selec-
tively cleave 3o and activated 2o C-H bonds of organic compounds
due to their relatively weak bond dissociation energy (BDE).15-20 In
the absence of activated 2o C-H bonds, 3o C-H bonds could poten-
tially serve as a unique set of targets for selective radical C(sp3)-H
functionalization of complex substrates. While conventional radical
C-H cleavage reactions often require relatively harsh conditions, re-
cent studies have shown radical reactions can take place under much
milder conditions.21-23 Compared with the large number of studies
on various radical-mediated functionalizations of 3o C-H bonds, epi-
merization reactions of tertiary carbons via reversible cleavage of un-
activated 3o C-H bonds have been sporadically studied, mostly more
than thirty years ago.24-29 While pioneering works by Mazur,24, 25 Ko-
chi,26 Hill,27 and others have demonstrated the feasibility of such a
transformation, their methods demand relatively harsh operating
conditions such as strong UV irradiation, high temperature or use of
toxic reagents (e.g. HgBr2), and exhibit narrow substrate scope.
EtOAc (E)
E
E
E
<1
7
10 1 (2), 7 (1), 24 h, 35 oC
11 1 (2), 24 h, 35 oC
12 1 (2), 24 h, 35 oC
E
E (dry)
E
7
8
(+ 1% H2O (H))c
13 1 (2), 24 h, 35 oC
14 1 (2), 24 h, 35 oC
15 1 (2), 24 h, 35 oC
16 1 (1), 24 h, 35 oC
17 1 (0.5), 7 d, 35 oC
18 1 (0.1), 7 d, 50 oC
19 1 (0.1), HOAc (0.2), 7 d, 50 oC
20 5 (2), 24 h, 35 oC
21 6 (2), 24 h, 35 oC
22 1 (2), 24 h, air, 35 oC
23 1 (2), 24 h, in darkness, 35 oC
E/H (9:1)
97 (<1)
87 (2)
95 (2)
90 (9)
95 (4)
69 (30)
80 (19)
0 (100)
0 (100)
0 (95)
97 (1)
<1
10
3
DCE/H (9:1)
PhCl/H (9:1)
E/H (9:1)
<1
<1
<1
<1
0
E/H (9:1)
E/H (9:1)
E/H (9:1)
E/H (9:1)
E/H (9:1)
0
(4d)
E/H (9:1)
E/H (9:1)
1
In 1996, Zhdankin reported that the reaction of simple alkanes
with azidobenziodoxole (BIN3, 1) in the presence of radical initiator
benzoyl peroxide (BzOOBz) at elevated temperature led to selective
azidation of 3o C−H bonds (see reaction of model substrate cis-de-
calin 2-cis in entry 1 ofTable 1).30 Recently, Hartwig discovered that
Fe/PyBOX catalysts promote similar C(sp3)−H azidation of more
complex substrates at room temperature (entry 2).31 Subsequently,
we developed a visible light (VL)-promoted method to affect selec-
tive 3o C−H azidation with photosensitizer Ru(bpy)3Cl2 in hex-
afluoroisopropanol (HFIP) solvent (entry 3).32, 33 Our visible light-
promoted azidation reaction likely starts with the formation of N3•
or benziodoxole (Bl•) radicals via single electron transfer (SET) ac-
tivation of BIN3.34-38 These radicals abstract a H atom from 3o C-H
bond to form a tertiary C-radical, which then reacts with BIN3 to give
the azidation product. In this VL-promoted system, we noted that
C-H halogenation products were obtained in high yield and selectiv-
ity when in the presence of halide salts, such as LiCl.32 This success-
ful modulation of the hypervalent-iodine mediated radical reaction
pathway prompted us to attempt C-H epimerization using a combi-
nation of H donor (D-H)39 and BIN3. As shown in entry 4, we were
pleased to see that the desired epimerization product trans-decalin
2-trans was obtained in 35% yield when 1 equiv of H-donor Bu3SnH
was included in the reaction mixture. Interestingly, a small amount
of 2-trans was formed in the absence of photosensitizer and VL irra-
diation (entry 5). The yield of 2-trans was improved to 75% when
EtOAc solvent was used (entry 6). Use of excess of Bu3SnH (2 equiv)
gave lower yield (entry 7). Use of other H-donors such as
Ph2P(=O)H, Et3SiH, and Hantzsch ester 7 also gave 2-trans in mod-
erate to excellent yield along with small amount of azidation byprod-
uct 3 (entries 8-10). As seen in entry 11, only trace amount of 2-
trans was formed in dry EtOAc solvent in the absence of H-donors.
O
O
O
O
O
O
EtO2C
CO2Et
Me
I
I
I
N3
OH
OAc
Me
N
H
7
BlOH 5
BlN3
1
BlOAc 6
Table 1. Epimerization of cis-decalin with BIN3. a) Yields are based
on GC-MS analysis of reaction mixture on a 0.1 mmol scale at a 0.2
M concentration using ACS grade solvents under Ar atmosphere un-
less specified otherwise. Source of VL: 18 W compact fluorescent
lamp. b) 2 M concentration. c) EtOAc solvent with 1% of H2O (~3
equiv) was used. d) 3o C-H hydroxylation side product 4 was ob-
tained in 4% yield. E: EtOAc, H: H2O.
Surprisingly, a clean epimerization with almost complete suppres-
sion of azidation was observed when a mixture of EtOAc/H2O (9:1)
was used (entry 13). A mixture of PhCl/H2O gave comparable re-
sults. (entry 15). The use of 0.1 equiv of BIN3 over an extended re-
action time (7 days) at 50 oC led to 69% yield of 2-trans, suggesting
a catalytic pathway in the BIN3-mediated epimerization reaction
(entry 18). In contrast to BIN3, other benziodoxole reagents such as
hydroxybenziodoxole BIOH 5 and acetoxybenziodoxole BIOAc 6
exhibit no reactivity (entries 20, 21). A trial conducted under an air
atmosphere gave only trace amount of C-H hydroxylation side prod-
uct 4 (entry 22). Irradiation with visible light had no impact on the
epimerization reaction (entry 23).
Substrate scope and selectivity
With the optimized conditions in hand, we next explored the
scope of this BIN3/H2O-mediated C-H epimerization reaction with
representative mono-, bicyclic and acyclic alkanes bearing suitable 3o
C(sp3)-H bonds (Scheme 2). In general, the efficiency of the
ACS Paragon Plus Environment

Page 3 of 7
Journal of the American Chemical Society
A) Bicyclic alkanes
1
2
3
4
5
6
7
1 (2 equiv)
EtOAc/H2O (9/1)
35 oC, 24 h
1 (3)d
PhClb
48 hg
1 (2)a
EtOAca
H
H
H
H
H
H
OBz
24 ha
H
H
H
H
OBz
OBz
9-cis
H
standard
conditionsa
H
OBz
9-trans
75%
2-cis
2-trans
97%
8-cis
22%
8-trans
77%
(+ 76% of 8-trans,
2% of 8-N3)j
(+ <1% of 2-cis,
<1% of 2-N3)j
(+ 14% of 8-cis,
(18% of 9-cis,
6% of 9-N3)k
c
j
9% of 8-N3
)
8
9
B) Monocyclic alkanes
1 (3)d
PhClb
50 oCf, 48 hg
1 (3)d
PhClb
48 hg
1 (3)d
PhClb
3 dh
H
H
H
nBu
H
H
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
H
tBu
BzO
H
BzO
tBu
BnO2C
tBu
nBu
tBu
H
TsO
H
CO2Bn
10-cis
OTs
12-cis
H
11-cis
H
H
10-trans
11-trans
57% (50%l)
12-trans
55% (50%l)
34%
6%
44%
66%
(+ 65% of 12-trans,
<1% of 12-N3)k
(+ 93% of 10-trans,
<1% of 10-N3)k
(+ 55% of 11-trans,
<1% of 11-N3)k
(+ 42% of 11-cis,
<1% of 11-N3)k
(+ 33% of 10-cis,
<1% of 10-N3)k
(+ 45% of 12-cis,
<1% of 12-N3)k
1 (3)d
PhClb
3 dh
1 (3)d
1 (3)d
H
H
Et3SiH (2)e
5 di
BzO
H
BzO
H
H
PhthN
BzHN
BzHN
PhthN
H
H
H
H
H
14-cis
5%
H
H
15-cis
51%
15-trans
14-trans
58 (50%l)
13-cis
3%
13-trans
73% (68%l)
26% (21%l)
(+ 72% of 15-cis,
2% of 15-N3)k
(+ 69% of 14-trans,
<1% of 14-N3)k, m
(+ 96% of 13-trans,
<1% of 13-N3)k
(+ 9% of 14-cis,
<1% of 14-N3)k, m
(+ 47% of 15-trans,
2% of 15-N3)k
(+ 16% of 13-cis,
c k
10% of 13-N3
)
1 (3)d
PhClb
50 oCf, 48 hg
1 (3)d
PhClb
1 (3)d
PhClb
50 oCf, 48 hg
OBz
H
OBz
H
BzO
OBz
H
OBz
H
OBz
50 oCf, 3 dh
OBz
H
H
H
H
OBz
H
OBz
H
OBz
OBz
H
16-trans
H
OBz
17-trans
17-cisn
18-trans
18-cis
2%
16-cis
8%k
18%
65%
56%
2%
(+ 96% of 18-trans,
<1% of 18-N3)k
(+ 78% of 18-cis,
3% of 18-N3)k
(+ 29% of 17-cis,
5% of 17-N3)k
(+ 90% of 16-trans,
2% of 16-N3)k
(+ 42% of 16-cis,
2% of 16-N3)k
(+ 95% of 17-trans,
2 % of 17-N3)k
1 (3)d
50 oCf
48 hg
1 (3)d
5 di
H
H
H
O
O
H
H
H
H
2
H
O
5
O
+
H
O
N
H
O
N
BzO
H
BzO
BzO
H
H
O
H
O
H
19-III
16%k
19-I
19-II
65%k
20-trans
65% (60%l)
20-cis
30% (26%l)
(+ 60% of 20-trans, 10% of 20-N3)k
(+ 18% of 19-I, <1 of 19-N3)k
c,p k
(+ 23% of 20-cis, 10% of 20-N3
)
C) Other substrates
1 (3)d
3 dh
1 (3)d
48 hg
N3
OBz
H
OBz
*
BzO
Ph
*
H
BzO
H
Ph
racemization
21-R
H
21-S
(enantiopure)
22-N3
75% (cis/trans ~ 1:1)
H
22%
22
c
o
(+ 25% of 22 (of same cis/trans ratio))j
(+ 61% of 21-S, 16% of 21-N3
)
(cis/trans: 1:3.6)
H
1 (2)a
PhClb
OBz
O
CO2Bn
O
Ph
H
OBz
decomposition
H
H
OBn
H
+
BnO2C
H
(>90% SM consumed)
H
H
24-cis
(>95% SM recovered)a
23-cis
(>95% SM recovered)a
~20%
byproduct
25-cis
Scheme 2. Substrate scope of BIN3/H2O-mediated 3o C-H epimerization. a) Standard reaction conditions: 0.1 mmol of alkane, 0.2 mmol of
BIN3, EtOAc/H2O (0.45/0.05 mL), 35 oC, Ar, 24 hours unless specified otherwise. b) EtOAc is replaced with PhCl. c) More azidation byprod-
uct is formed in PhCl/H2O than in EtOAc/H2O. d) BIN3 (3 equiv). e) Additional Et3SiH (2 equiv). Significant oxidation at NH-adjacent 3o
C-H occurred in the absence of Et3SiH. f) Reaction temperature: 50 oC. g) t = 48 h. h) t = 3 d. i) t = 5 d, j) Yields are based on GC-MS analysis.
k) Yields are based on 1H-NMR analysis. l) Isolated yield. m) about 20% of benzamide byproduct was formed. n) A cis/trans (3/1) mixture was
used. o) Yields are analyzed by chiral HPLC. p) azidation of 3o C-H bond. SM: starting material.
epimerization reactions correlates well with the relative thermody-
namic stability of the corresponding epimers. Reactions of epimers
with small free energy difference are bidirectional and give similar
product distribution from either epimer starting material, indicating
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 7
the ability to reach epimerization equilibrium (see 8, 11). Reactions
modified conditions with the addition of 0.1 equiv of Et3SiH. Reac-
tion of androstanediol derivative 28 gave C14-epimer 29 in 65% iso-
lated yield. The epimerization of pregnanediol dibenzoate 30 took
place at either C5 or C14 position to give a diastereomeric mixture of
31 (23%) and 32 (57%). The structures of epimerization products
have been confirmed by X-ray crystallography.
1
2
3
4
5
6
7
8
of epimers with large free energy difference are unidirectional, pre-
dominantly giving the more stable epimer (see 2, 9). The site and
chemo-selectivity of this C-H epimerization is strongly influenced
by the BDE of C-H bonds and electronic effects. Electron-rich 3o C-
H bonds of cyclic alkanes are most reactive, forming only small
amount of azidation byproducts (typically less than 5%). Electron-
withdrawing groups such as alkoxylcarbonyl (e.g. CO2Bn) and car-
boxylate oxygen (e.g. BzO) not only diminish the epimerization re-
activity of neighboring 3o C-H bonds but also lead to more C-H az-
idation byproduct. Compared to electronic effects, steric effects ap-
pear to have a less significant impact on the reactivity (see 10, 12).
CH3
CH3
BlN3 (3 equiv)
(Et3SiH 0.1 equiv)
CH3
H
CH3
H
8
O
O
H
D
C
14
9
B
14
A
3
EtOAc/H2O (9/1)
35 oC, 6 d
H
5
H
H
OBz
H
OBz
H
27b
9
26 androsterone
40%a (+ 50% of 26) without Et3SiH
72%a (+ 25% of 26) with Et3SiH
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
CH3
As shown in Scheme 2A and 2B, the epimerization of 5- and 6-
membered mono- and bicyclic alkanes generally works well. While
the reactions of 1,4 or 1,2-disubstituted cyclohexanes (10-14, 16)
favor the formation of more stable trans isomers, the reaction of 1,3-
disubstituted cyclohexane 15 slightly favors the more stable cis-iso-
mer 15-cis. Functional groups such as benzoate (9), benzyl ester
(10), phthalimide (13), BocNH (20), and tosyl (12) were tolerated.
Free OH, SH, NH2 and CO2H groups are incompatible with the re-
action conditions. Epimerization of isomenthol benzoate 19-I takes
place at either C5 or C2 position to give a mixture of 19-II (65%) and
19-III (16%). The epimerization of Boc-protected phenylalanine
ester 20-cis selectively occurs at the 3o C-H bonds of cyclohexane
without reaction at the acidic Ha of the amino acid. In comparison,
epimerization reactions of 20-cis under the known UV-irradiation
conditions with acetone, HgBr2, or polyoxometalate gave much
lower yield.40 Reaction of 14-cis bearing a secondary amide group
BzNH under standard conditions gave a complex mixture. However,
the reaction was improved with the addition of 2 equiv of Et3SiH.
Including Et3SiH in the reaction mixture improved the epimeriza-
tion performance in some cases (see Scheme 3). The lack of reactiv-
ity observed with 23-cis and 24-cis indicates that electron-withdraw-
ing CO2Bn and BzO groups deactivate their adjacent 3o C-H bond
(Scheme 2C).41 Accordingly, the epimerization of 10-15 should oc-
cur at the more electron-rich 3o C-H bonds highlighted in green. Re-
actions in EtOAc/H2O usually gave less C-H azidation byproduct
than in PhCl/H2O (see 8 and 13). The epimerization reactivity of
electronically deactivated substrates can be slightly improved with
PhCl /H2O solvents (see 9 and 17 bearing two electron-withdraw-
ing OBz groups). Compared with cyclohexane 16 and cyclopentane
17, the lower epimerization efficiency of 18 may be caused by the
higher BDE of the cyclobutane 3o C-H bonds. No epimerization re-
action was observed for the corresponding cyclopropane substrate
due to its even higher 3o C-H BDE. These OBz-protected substrates
were easily prepared in two steps from the corresponding commer-
cially available carboxylic acids.42 Compared with the clean epimeri-
zation reactions of benzyloxycarbonyl, benzoate and tosylate sub-
strates (e.g. 10, 11, 12), a trial with benzyl ether 25-cis gave a com-
plex mixture and benzaldehyde byproduct, presumably caused by
oxidation of the benzylic C-H bond. As indicated by the slow race-
mization of 21-S, 3o C-H bonds of acyclic alkanes are less reactive
than the 3o C-H bonds of cyclic alkanes. In 22, the target 3o benzylic
C-H bond gave mostly azidation byproduct 22-N3 possibly due to
the low H abstraction reactivity of the corresponding benzyl radical
intermediate.
CH3
OBz
CH3
H
CH3
H
BlN3 (3 equiv)
H
OBz
AcO
AcO
14
EtOAc/H2O (9/1)
50 oC, 4 d
3
5
H
H
H
H
H
28 3β-androstanediol
29
76%a (65%c)
(+ 23% of 28)
OBz
CH3
CH3
5
H
BlN3 (3 equiv)
Et3SiH (0.1 equiv)
14
H
H
H
EtOAc/H2O (9/1)
50 oC, 4 d
OBz
30 pregnanediol
OBz
CH3
OBz
CH3
CH3
H
H
CH3
H
H
H
14
+
(+ 10% of 30)
5
H
H
OBz
H
31, 23%c
32, 57%c
OBz
x-ray
x-ray
Scheme 3. 3o C-H epimerization of steroids. Reactions are con-
ducted on a 0.1 mmol scale. a) Yields are based on 1H-NMR analysis.
b) Structure of its oxime derivative was confirmed by X-ray crystal-
lography. c) Isolated yield. See SI for detailed X-ray structures.
Mechanistic Studies
Control experiments and density functional theory (DFT) calcu-
lations have been carried out to understand the mechanism of this
BIN3/H2O-mediated C(sp3)-H epimerization reaction. As outlined
in Scheme 1C, a radical 3o C-H epimerization reaction would re-
quire efficient H-abstraction by a H-acceptor (A•) as well as selec-
tive quenching of the resulting carbon radical intermediate by a H-
donor (D-H). Ideally, A• should not react with D-H, avoiding non-
productive consumption of donor and acceptor.43-48 Furthermore,
competing reaction pathways of the carbon radical intermediates
need to be suppressed to achieve clean epimerization. 1) Previous
studies have shown that BIN3 is uniquely effective at initiating the C-
H activation step through the formation of H-acceptor Bl•33 or N3•
via dissociative SET or homolytic cleavage of I-N bond (Scheme
4A).32 In this reaction system, homolytic I-N cleavage of BIN3 is ex-
pected to occur at ambient temperature in the absence of light irra-
diation. This is supported by the DFT calculations that indicated a
very small BDE of 27.8 kcal/mol for the Bl-N3 bond (eq 1), com-
pared to the calculated I-O BDEs for Bl-OH 5 and Bl-OAc 6 (42.3
and 42.5 kcal/mol, respectively). More importantly, H-N3 has a
As shown in Scheme 3, this epimerization protocol has been suc-
cessfully applied to steroid substrates bearing multiple 3o C-H bonds.
Reaction of androsterone benzoate 26 selectively gave the C14-epi-
mer 27 with a cis C/D ring juncture in good yield under slightly
ACS Paragon Plus Environment

Page 5 of 7
Journal of the American Chemical Society
Scheme 4. Mechanistic studies.
1
2
A) Selected calculated BDE values and control experiments
B) Proposed reaction mechanism
H2O
3
4
5
6
7
8
9
O
O
BlN3
initiation
Bl
Δ
H = 27.8
O
O
(kcal/mol)
BIOH
I
I
N3
(eq 1)
N3
+
BlN3
1
33
Bl
HN3
N3
H
R
R
ΔH = 93.3
R
H
(kcal/mol)
(or I )
(eq 2)
(eq 3)
(eq 4)
N3
HN3
H
+
+
I
H abstraction
III
II
N3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
radical chain
O
PhCla
I
OH
BlN3
1
+
H2O
HN3
C) DFT calculation of epimerization of 2-cis
35 oC, 30 min
BlOH 5
ΔG
(ΔH)
D
(kcal/mol)
BlN3 (2 equiv)
2-cis
2-cis
PhCl/D2O (9/1)
35 oC, 3 d
D
11.2
(1.5)
34 (>95%)
TS3
TS1
TS2
8.7
(-0.7)
aq. HN3
TS1
(~20 equiv, 0.4 mL)b
HN3
HN3
TS3
N3
2-trans
3.7
(5.0)
(eq 5)
(eq 6)
N3
EtOAc (0.4 mL)
35 oC, 48 h
0.1
(2.0)
0.0
(0.0)
TS2
-2.0
(0.0)
-3.0
(-2.8)
2-cis
aq. HN3
2'
2-trans
H
(~20 equiv, 0.4 mL)b
2''
H
BlOH (5 equiv)
H
2-trans
2-cis
EtOAc/H2 (0.4 mL)
35 oC, 48 h
(>95%)
H
DFT calculations were performed at the M06-2X/6-311++G(d,p)-SDD/SMD(EtOAc)//M06-2X/6-31+G(d)-SDD/SMD(EtOAc) level of
theory, See Supporting Information for more details. a) 64% yield of 5 was formed for forward reaction of 1 (1 equiv) in PhCl/H2O (9/1, H2O
~ 9 equiv). 5% yield of 1 was formed for reverse reaction of 5 (1 equiv) and aq. HN3 (~ 3 equiv) in PhCl/H2O. b) aq. solution of HN3 [~5 M]
is prepared from reacting NaN3 with aq. H2SO4 at rt (see Supporting Information).
BDE of 93.3 kcal/mol, which is very close to the BDE of unactivated
3o C-H bonds (93.3 and 96.1 kcal/mol for 3o C-H of 2-cis and 2-
trans, respectively, Scheme 4C). In comparison, the 2o C-H bonds
of cyclohexane have a larger BDE of 97.5 kcal/mol. The close match
azidation pathway. 4) As outlined in the proposed reaction pathway
in Scheme 4B, this epimerization reaction likely starts with a homo-
lytic cleavage of the residual BIN3, generating Bl•33 and N3•radical.
N3• then selectively cleaves a 3o C-H bond of alkane I forming car-
bon radical II and HN3.38 In additional to the steric hindrance and
C-H bond nucleophilicity, the 1,3-diaxial strain release and torsional
strain factor concerning the tertiary radical transition state would
also influence the reactivity of H abstraction.50-52 Nucleophilic car-
in BDE of H-N3 and unactivated 3o C-H not only renders N3• a com-
petent H-acceptor for 3o C-H bonds but also makes H-N3 a suitable
H-donor to 3o carbon radical intermediates, making N3• an effective
hydrogen atom shuttle for 3o C-H bonds. 2) Although H2O is critical
to the success of this epimerization reaction, H2O is unlikely the im-
mediate H-donor due to the high BDE of H-OH (~ 117.2
kcal/mol).49 Control experiments indicate that BIN3 readily reacts
with H2O to form BlOH 5 and HN3 in EtOAc or PhCl (>60% con-
version in 30 min, eq 3). Furthermore, reacting BlOH with aq. HN3,
prepared by mixing NaN3 with aqueous H2SO4, can also form small
amount of BIN3, suggesting a reversible reaction of BIN3 and H2O.
Reaction of 2-cis using D2O as co-solvent gave the deuterated prod-
uct 34 in excellent yield (eq 4), suggesting DN3 as the deuterium do-
nor. 3) As shown in eq 5, the use of aq. HN3 alone did not give any
epimerization product under the reaction conditions. Similarly,
BlOH alone cannot promote the epimerization reaction (entry 20,
Table 1). However, a combination of BlOH and aq. HN3 is effective
(eq 6). These results suggest that the residual BIN3, rather than HN3
or BlOH, is responsible for the initiation of C-H epimerization.32
Since BIN3 is an excellent azidation reagent for carbon radicals, the
low concentration of BIN3 and the abundance of HN3 in the reaction
system might contribute to the suppression of the competing C-H
53
bon radical II then reacts with the electrophilic H-donor HN3 to
give the epimerization product III or I and regenerate N3•, thus
propagating a radical chain reaction. As shown in Scheme 4C, DFT
calculations of the epimerization of cis-decalin 2-cis show that both
the initial H abstraction by N3• (TS1) and the subsequent quench-
ing of tertiary carbon radical with HN3 (TS3) proceed with low en-
ergy barriers.54-57 The late transition state (r(C-H) = 1.32 Å in TS1)
suggests the rate and selectivity of the C-H abstraction are sensitive
to the BDE of the C-H bonds.57 DFT calculations also indicate the
more sterically hindered Bl• 33 is less effective than N3• at cleaving
the 3o C-H bond of 2-cis (see Supporting Information for details).
Overall, the facile activation of BIN3 at ambient temperature, the
proper equilibrium between BIN3 and HN3 in the presence of H2O,
and the unique ability of N3• as a catalytic hydrogen atom shuttle
enable an efficient, selective and clean radical 3o C-H epimerization
under mild conditions.
Conclusion
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
17. Mukherjee, S.; Maji, B.; Tlahuext-Aca, A.; Glorius, F. J. Am. Chem. Soc.
In summary, we have developed the first synthetically useful pro-
2016, 138, 16200.
1
2
3
4
5
6
tocol for radical-mediated C-H epimerization reactions of tertiary
carbon centers, using a hypervalent iodine reagent and H2O under
mild conditions. These reactions show excellent reactivity and selec-
tivity toward unactivated 3o C-H bonds of various cycloalkanes and
offer a powerful tool to edit stereochemical configurations that are
intractable by conventional methods. Using this method, we have
demonstrated easy access to novel steroid scaffolds. We hope that
18. Halperin, S. D.; Fan, H.; Chang, S.; Martin, R. E.; Britton, R. Angew.
Chem. Int. Ed. 2014, 53, 4690.
19. Amaoka, Y.; Nagatomo, M.; Watanabe, M.; Tao, K.; Kamijo, S.; Inoue,
M. Chem. Sci. 2014, 5, 4339.
20. Brodsky, B. H.; Du Bois, J. J. Am. Chem. Soc. 2005, 127, 15391.
21. Yan, M.; Lo, J. C.; Edwards, J. T.; Baran, P. S. J. Am. Chem. Soc. 2016,
138, 12692.
7
8
9
22. Studer, A.; Curran, D. P. Angew. Chem. Int. Ed. 2015, 54, 4436.
23. Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113,
5322.
24. Gorodetsky, M.; Mazur, Y. J. Am. Chem. Soc. 1968, 90, 6540.
25. Mazur, Y. Pure Appl. Chem. 1975, 41, 145.
use of N3• as a catalytic hydrogen atom shuttle for unactivated
C(sp3)-H bonds might facilitate other challenging radical C-H func-
tionalization transformations, such as C-H deuteration and dynamic
kinetic resolution, in future investigations.
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
26. Salomon, R. G.; Kochi, J. K. Tetrahedron Lett. 1973, 4387.
27. Combs-Walker, L. A.; Hill, C. L. J. Am. Chem. Soc. 1992, 114, 938.
28. Augustine, R. L.; Caputo, J. A. J. Am. Chem. Soc. 1964, 86, 2751.
29. Dang, H.-S.; Robert, B. P. Tetrahedron Lett. 2000, 41, 8595.
30. Zhdankin, V. V.; Krasutsky, A. P.; Kuehl, C. J.; Simonsen, A. J.; Wood-
ward, J. K.; Mismash, B.; Bolz, J. T. J. Am. Chem. Soc. 1996, 118, 5192
31. Sharma, A.; Hartwig, J. F. Nature 2015, 517, 600.
32. Wang, Y. X.; Li, G.-X.; Yang, G.; He, G.; Chen, G. Chem. Sci. 2016, 7,
2679.
33. Li, G.-X.; Morales-Rivera, C. A.; Gao, F.; Wang, Y. X.; He, G.; Liu, P.;
Chen, G. Chem. Sci. 2017, 8, 7180.
34. Brand, J. P.; Gonzales D. F., Nicolai, S.; Waser, J. Chem. Commun. 2011,
47, 102.
ASSOCIATED CONTENT
Detailed synthetic procedures, compound characterization, NMR spec-
tra, X-ray crystallographic data, and computational details are provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
equal contribution# from Y.W. and X.H.
Corresponding Author
hegang@nankai.edu.cn, pengliu@pitt.edu, gongchen@nankai.edu.cn,
The authors declare no competing financial interest.
35. Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
36. Dohi, T.; Kita, Y. ChemCatChem. 2014, 6, 76.
37. Li, Y.; Hari, D. P.; Vita, M. V.; Waser, J. Angew. Chem. Int. Ed. 2016, 55,
4436.
ACKNOWLEDGMENT
G.C. and G. H. thanks NSFC-21421062, -21672105, -21725204,
and -91753124 and Laviana for financial support of the experimental
part of this work. P.L. thanks the NSF (CHE-1654122) for financial
support for the computational part of the work. C.A.M.R. acknowl-
edges an NSF research fellowship (DGE-1747452). Calculations
were performed at the Center for Research Computing at the Uni-
versity of Pittsburgh and the Extreme Science and Engineering Dis-
covery Environment (XSEDE) supported by the National Science
Foundation.
38. Antonchick, A. P.; Burgmann, L. Angew. Chem. Int. Ed. 2013, 52, 3267.
39. Gansäuer, A.; Shi, L.; Otte, M.; Huth, I.; Rosales, A.; Sancho-Sanz, I.;
Padial, N. M.; Oltra, J. E. Top. Curr. Chem. 2012, 320, 93.
40. For comparative studies of C-H epimerization of 20-cis under other
conditions: 20-trans (3%) + 20-cis (96%) under 365 nm UV irradiation
o
in acetone at 35 C for 3 d (see ref 26); 20-trans (7%) + 20-cis (91%)
under 254 nm UV irradiation with HgBr2 (0.67 equiv) in cyclohexane at
o
35 C for 3 d (see ref 25); 20-trans (15%) + 20-cis (83%) under UV
o
irradiation (365 nm) with decatungstate (1 mol%) in CH3CN at 35 C
o
for 3 d (see ref 27); Complete decomposition 20-cis of at 220 C with
10% Pd/C in toluene for 3 h (see ref 28). See SI for details.
41. The highlighted C-H bond of 24-cis is also deactivated by the adjacent
OBz group.
REFERENCES
1. Godula, K.; Sames, D. Science 2006, 312, 67.
2. Davies, H. M.; Manning, J. R. Nature 2008, 451, 417.
3. Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976.
4. White, M. C. Science 2012, 335, 807.
5. Chen, M. S.; White, M. C. Science 2007, 318, 783.
6. Hartwig, J. F. J. Am. Chem. Soc. 2016, 138, 2.
7. He, J.; Wasa, M.; Chan, K. S. L.; Shao, O.; Yu, J.-Q. Chem. Rev. 2017,
117, 8754.
8. Liu, W.; Huang, X. Y.; Cheng, M. J.; Nielsen, R. J.; Goddard, W. A.;
Groves, J. T. Science 2012, 337, 1322.
9. Le, C.; Liang, Y.; Evans, R. W.; Li, X. M.; MacMillan, D. W. C. Nature
2017, 547, 79.
10. Loh, Y. Y.; Nagao, K.; Hoover, A. J.; Hesk, D.; Rivera, N. R.; Colletti, S.
L.; Davies, I. W.; MacMillan, D. W.C. Science 2017, 358, 1182.
11. Soulard, V.; Villa, G.; Vollmar, D. P.; Renaud, P. J. Am. Chem. Soc. 2018,
140, 155.
12. Tanner, M. E. Acc. Chem. Res. 2002, 35, 237.
13. Benjdia, A.; Guillot, A.; Ruffie, P.; Leprince, J.; Berteau, O. Nat. Chem.
2017, 9, 698.
14. Kudo, F.; Hoshi, S.; Kawashima, T.; Kamachi, T.; Eguchi, T. J. Am.
Chem. Soc. 2014, 136, 13909.
15. Newhouse, T.; Baran, P. S. Angew. Chem. Int. Ed. 2011, 50, 3362.
16. Yi, H.; Zhang, G. T.; Wang, H. M.; Huang, Z. Y.; Wang, J.; Singh, A. K.;
Lei, A. W. Chem. Rev. 2017, 117, 9016.
42. Luo, Y.-R. Comprehensive handbook of chemical bond energies. CRC
Press: Boca Raton, 2007.
43. Heberger, K.; Lopata, A. J. Org. Chem. 1998, 63, 8646.
44. De Vleeschouwer, F.; Van Speybroeck, V.; Waroquier, M.; Geerlings, P.;
De Proft, F. Org. Lett. 2007, 9, 2721.
45. Fisher, H.; Radom, L. Angew. Chem. Int. Ed. 2001, 40, 1340.
46. Mayer, J. M. Acc. Chem. Res. 2011, 44, 36.
47. Capaldo, L.; Ravelli, D. Eur. J. Org. Chem. 2017, 2056.
48. Crossley, S. W. M.; Barabe, F.; Shenvi, R. A. J. Am. Chem. Soc. 2014, 136,
16788.
49. Hioe, J.; Zipse, H. Org. Biomol. Chem. 2010, 8, 3609.
50. Chen, K.; Eschenmoser, A.; Baran, P. S. Angew. Chem. Int. Ed. 2009, 48,
9705.
51. Salamone, M.; Bietti, M. Acc. Chem. Res. 2015, 48, 2895.
52. Salamone, M.; Ortega, V. B.; Bietti, M. J. Org. Chem. 2015, 80, 4710.
53. Workentin, M. S.; Wagner, B. D.; Lusztyk, J.; Wayner, D. D. M. J. Am.
Chem. Soc. 1995, 117, 119.
54. Barluenga, J.; Campos-Gomez, E.; Rodriguez, D.; Gonzalez-Bobes, F.;
Gonzalez, J. M. Angew. Chem. Int. Ed. 2015, 44, 5851.
55. Ochiai, M.; Ito, T.; Takahashi, H.; Nakanishi, A.; Toyonari, M.; Sueda,
T.; Goto, S.; Shiro, M. J. Am. Chem. Soc. 1996, 118, 7716.
56. Lloyd, R. V.; Williams, R. V. J. Phys. Chem. 1985, 89, 15379.
57. Liu, F.; Yang, Z.; Yu, Y.; Mei, Y.; Houk, K. N. J. Am. Chem. Soc. 2017,
139, 16650.
ACS Paragon Plus Environment

Page 7 of 7
Journal of the American Chemical Society
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
R
O
H
R
O
I
R
H
N3
1 (2-3 equiv)
unactivated
3o C-H
efficient; selective;
simple to operate;
compatible with
complex substrate
EtOAc(or PhCl) / H2O
BIN3 1
35-50 oC
a catalytic
H atom shuttle
N3
ACS Paragon Plus Environment