Enantioselective Radical Construction of 5-Membered Cyclic Sulfonamides by Metalloradical C-H Amination

Article abstract of DOI:10.1021/jacs.9b08894

Both arylsulfonyl and alkylsulfonyl azides can be effectively activated by the cobalt(II) complexes of D₂-symmetric chiral amidoporphyrins for enantioselective radical 1,5-C-H amination to stereoselectively construct 5-membered cyclic sulfonami

Full text of DOI:10.1021/jacs.9b08894

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Article
Enantioselective Radical Construction of 5-Membered
Cyclic Sulfonamides by Metalloradical C-H Amination
Yang Hu, Kai Lang, Chaoqun Li, Joseph B. Gill, Isaac Kim, Hongjian Lu, Kimberly B.
Fields, McKenzie Marshall, Qigan Cheng, Xin Cui, Lukasz Wojtas, and X. Peter Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b08894 • Publication Date (Web): 17 Oct 2019
Downloaded from pubs.acs.org on October 20, 2019
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Enantioselective Radical Construction of 5-Membered Cyclic
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Sulfonamides by Metalloradical C H Amination
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Yang Hu,§,† Kai Lang,§,‡ Chaoqun Li,† Joseph B. Gill,† Isaac Kim,‡ Hongjian Lu,† Kimberly B. Fields,†
McKenzie Marshall,† Qigan Cheng,† Xin Cui,† Lukasz Wojtas† and X. Peter Zhang*,‡
‡ Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
† Department of Chemistry, University of South Florida, Tampa, Florida 33620-5250, United States
ABSTRACT: Both arylsulfonyl and alkylsulfonyl azides can be effectively activated by the cobalt(II) complexes of D2-symmetric chiral
amidoporphyrins for enantioselective radical 1,5-C–H amination to stereoselectively construct 5-membered cyclic sulfonamides. In addi-
tion to C–H bonds with varied electronic properties, the Co(II)-based metalloradical system features chemoselective amination of allylic
C–H bonds and is compatible with heteroaryl groups, producing functionalized 5-membered chiral cyclic sulfonamides in high yields with
high enantioselectivities. The unique profile of reactivity and selectivity of the Co(II)-catalyzed C–H amination is attributed to its underly-
ing stepwise radical mechanism, which is supported by several lines of experimental evidence.
Besides arylsulfonyl azides, such enhancement might even enable
INTRODUCTION
the activation of the more challenging alkylsulfonyl azides for
productive C–H amination. Furthermore, considering the availa-
bility of D2-symmetric chiral amidoporphyrins with tunable elec-
tronic, steric and chiral environments,8e,9b,10a,11a-c the Co(II)-
catalyzed C–H amination could be potentially rendered as an en-
antioselective radical process (Scheme 1). While the correspond-
ing a-Co(III)-aminyl radical intermediates I generated from
metalloradical activation of sulfonyl azides were anticipated to
undergo 1,5-H-atom abstraction, it was unclear if the two prochi-
ral faces of the C-centered radical in the resulting e-Co(III)-alkyl
radical intermediates II could be effectively discriminated for
controlling enantioselectivity of the C–N bond formation during
the succeeding 5-exo-tet radical cyclization (Scheme 1). If appro-
priate chiral amidoporphyrin ligands could be identified to
achieve the enantiocontrol, such asymmetric catalytic process for
radical C–H amination would be desirable as it allows for stere-
oselective construction of 5-membered cyclic sulfonamides (also
known as sultams), which are both medicinally important and
synthetically useful (Figure 1),13 from readily available sulfonyl
azides.
Radical reactions have been increasingly exploited as new syn-
thetic tools, which are complementary to ionic reactions, for mo-
lecular construction of organic compounds.1 With the aim at ad-
dressing the outstanding issues in controlling reactivity and stere-
oselectivity of radical species,2 metalloradical catalysis (MRC)
has been recently introduced as a conceptually different approach
to explore the catalytic application of open-shell metalloradical
complexes for both initiation and regulation of homolytic radical
reactions.3,4,5 To this end, cobalt(II) complexes of porphyrins
([Co(Por)]), as stable 15e metalloradicals, have demonstrated the
capability of activating organic azides and diazo compounds to
generate the fundamentally new a-Co(III)-aminyl radicals and a-
Co(III)-alkyl radicals, respectively, upon the release of N2.3,6,7
While the N-centered and C-centered organic radicals are stabi-
lized by the Co(III) complexes, they retain the ability to undergo
common reactions of free radicals, such as radical addition and H-
atom abstraction. More importantly, the reactivity and selectivity
of these and subsequent radical reactions can be effectively con-
trolled by the environment of the porphyrin ligands, leading to
new catalytic radical processes for stereoselective organic trans-
formations.8,9,10,11,12 In particular, Co(II)-based metalloradical
catalysis (Co(II)-MRC) has been successfully applied to intramo-
lecular radical C–H amination with different types of organic
azides as radical precursors.8 Previously, the Co(II) complex of
tetraphenylporphyrin, [Co(TPP)], was shown to catalyze intramo-
lecular C–H amination of arylsulfonyl azides to generate 5-
membered cyclic sulfonamides, but required elevated reaction
temperature.8a Subsequent employment of amidoporphyrins as
supporting ligands has enhanced the catalytic activity of the
Co(II)-based metalloradical system for intramolecular C–H ami-
nation of sulfamoyl azides, even at lower temperature.8b,8e This
ligand-accelerated catalysis is attributed to the potential hydrogen-
bonding interactions between the S=O acceptor of the sulfonyl
unit and the N–H donor of the amide moiety of the porphyrin
ligand in the a-Co(III)-aminyl radical intermediates.8b,8e Assum-
ing the similar ligand acceleration effect, we hoped to enhance the
Co(II)-catalyzed system for 1,5-C–H amination of sulfonyl azides
by employing amidoporphyrins as supporting ligands (Scheme 1).
Scheme 1. Intramolecular Radical C(sp3)–H Amination of
Sulfonyl Azides via Co(II)-Based Metalloradical Catalysis
H
N3
H
H
O
H
R1
N
O
O
R1
S
S
O
Co(II)-MRC
N2
+
R2
R2
H
N3
H
H
N
O
O
R1
O
H
R1
S
N
N
N
N
CoII
S
O
[Co(Por*)]
R2
radical
substitution
radical
activation
R2
N2
Enantioselective
C–N Bond
Formation?
2R
2R
MRC
1R
1R
O
O
S
S
H
H
α-Co(III)-
Aminyl
Radicals
ε-Co(III)-
Alkyl
Radicals
H
O
N
H
N
N
CoIII
II
O
N
N
N
N
CoIII
I
radical
abstraction
N
N
N
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Ph
Me
O
O
O
O
O
R1
O
S
O
N
S
H
O
O
O
H
O
N
Cl
H
OH
Bz
N
O
N
O
S
S
N
N
N
N
O
HN
H
N
S
Et
O
O
OH
H
Ph
O
O
H
Papain Inhibitor
(W2 Malaria)
Hydroflumethiazide
Calpain Inhibitor
HIV Integrase Inhibitor
Histamine H3 Antagonist
MMP Inhibitor
7
8
9
O
O
H
H
S
O
OH
O
O
O
H
O
O
NH2
O
O
OMe
N
N
S
CN
CF3
O
O
S
O
S
N
O
S
N
N
CON(H)OH
H
F
H
HO
N
S
O
O
Me
NHOH
O
O
10
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O
O
N
H
Ph
NH
HN
Me
Potent AR Antagonist
Me
Sultiame
Selective Tumor
Necrosis Factor Inhibitor
Selective Tumor
Necrosis Factor Inhibitor
HIV-1 Inhibitor
Anticonvulsant Drug
O
O
OH
O
O
O
S
N
O
NH HN
S
N
H
N
O
O
S
S
Me
O
NH
O
O
N
Me
O
O
Cl
O
O
S
N
Me
N
Camphorsultam
Chiral Auxiliary
for the Asymmetric
Synthesis
Me
N
N
N
H
O
O
H
lysosomal
Acidification Inhibitor
Anti-Inflammatory Drug Candidate
Blood Factor XIa Inhibitor
Figure 1. Selective Examples of Bioactive and Synthetically Useful Molecules Containing Cyclic Sulfonamide Motifs.
Catalytic intramolecular C(sp3)–H amination, especially its en-
antioselective variant, represents an attractive strategy for the
construction of N-heterocyclic structures.14 Despite considerable
advancements in recent years,15,16,17 so far, there are only two
previous reports on stereoselective formation of chiral cyclic sul-
fonamides via asymmetric intramolecular C–H amination.18 While
the first catalytic system based on Rh(II)2 complexes of chiral
tetracarboxylates achieved only moderate asymmetric induc-
tion,18a the more recent Ir(III)-based system with the use of chiral
salens could catalyze intramolecular amination of arylsulfonyl
azides to form benzofused cyclic sulfonamides with high enanti-
oselectivity.18b However, the Ir(III)-catalyzed amination was
mainly restricted to arylsulfonyl azides with only one example of
cyclic alkylsulfonyl azide.18b Evidently, there is still a need to
develop new catalytic systems, especially using base metal cata-
lysts, for asymmetric intramolecular C–H amination that is gener-
ally applicable for stereoselective synthesis of valuable chiral
cyclic sulfonamides with diverse structural features. Herein, we
wish to report the development of Co(II) complexes of D2-
symmetric chiral amidoporphyrins ([Co(D2-Por*)]) as effective
metalloradical catalysts for enantioselective radical 1,5-C–H ami-
nation of sulfonyl azides. In addition to arylsulfonyl azides, the
Co(II)-catalyzed asymmetric system is also applicable to the more
challenging alkylsulfonyl azides with different types of C–H
bonds, generating chiral 5-membered cyclic sulfonamides in high
yields with high enantioselectivities. As additional practical at-
tributes associated with the use of organic azides, the Co(II)-based
amination system can be operated under neutral and nonoxidative
conditions without the need of any additives, generating the envi-
ronmentally benign N2 gas as the only byproduct. Furthermore,
we present several lines of experimental evidence that shed light
on the unique radical mechanism of this metalloradical system for
C–H amination.
nitrobenzenesulfonyl azide (1a), which was shown to be a chal-
lenging substrate for the existing Ir(III)-based system because of
the presence of the electron-withdrawing nitro group,18b was cho-
sen as a test substrate for the Co(II)-based metalloradical system
(Table 1). Based on the previously established conditions,8a it was
found that the first-generation chiral metalloradical catalyst
[Co(P1)] (P1 = 3,5-DitBu-ChenPhyrin)11a could effectively cata-
lyze the intramolecular amination reaction of azide 1a, generating
5-membered benzofused cyclic sulfonamide 2a as the exclusive
product in nearly quantitative yield with low but significant
asymmetric induction (Table 1; entry 1). Switching to the catalyst
[Co(P2)] (P2 = 2,6-DiMeO-ChenPhyrin) bearing the same chiral
amide units but with more sterically-hindered achiral meso-aryl
groups led to only slight improvement in the enantioselectivity
while maintaining the quantitative yield (Table 1; entry 2). On the
hypothesis that the low asymmetric induction may be attributed to
the relative flexibility of the chiral arms in ChenPhyrin catalysts,
we decided to test Co(II) complex of D2-symmetric chiral ami-
doporphyrins containing chiral amide units with increased con-
formational rigidity. Indeed, with the use of [Co(P3)] (P3 = 3,5-
DitBu-ZhuPhyrin) as the catalyst, which was previously shown to
possess a more rigid conformation as a result of the unique intra-
molecular O•••H–N hydrogen-bonding interactions in the (S)-(-)-
2-tetrahydrofurancarboxamide units,11b asymmetric induction was
significantly improved without affecting the excellent yield (Table
1; entry 3). Encouraged by the positive outcome, the catalyst
[Co(P4)] (P4 = 2,6-DiMeO-ZhuPhyrin),11b which incorporates
more sterically bulky achiral meso-aryl groups into the structure
to further enhance the rigidity of the chiral environment, was em-
ployed for the amination reaction. Gratifyingly, the desired 1,5-C–
H amination product 2a was produced with 84% ee in still quanti-
tative yield (Table 1; entry 4). The enantioselectivity with
[Co(P4)] could be further improved by lowering the reaction tem-
perature (Table 1; entries 5 and 6). However, a much lower yield
was observed along with the higher enantioselectivity for the reac-
tion at 40 °C (entry 6). Among various solvents screened (see
Table S1 in SI), chloroform was identified as the optimal medium
for enantioselectivity (Table 1; entry 7). In chloroform, when the
reaction was performed at 50 °C with 4 mol % of [Co(P4)], the
desired benzofused cyclic sulfonamide 2a was produced in 96%
yield with 92% ee (Table 1; entry 8).
RESULTS AND DISCUSSION
Asymmetric 1,5-C–H Amination of Arylsulfonyl Az-
ides. As the initial efforts for this project, we focused on identi-
fication of a suitable D2-symmetric chiral amidoporphyrin ligand
to support the Co(II)-based catalytic system for intramolecular C–
H amination with potential asymmetric induction. 2-Ethyl-5-
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Table 1. Ligand Effect on Co(II)-Based Metalloradical System
desired 2i, but in a relatively lower yield with moderate enantiose-
for Asymmetric 1,5-C–H Amination of Arylsulfonyl Azidea
lectivity (Table 2; entry 9).
2
3
4
5
6
7
8
9
H
N3
Table 2. [Co(P4)]-Catalyzed Enantioselective 1,5-C–H Amina-
H
H
O
H
N
O
O
Me
tion of Arylsulfonyl Azidesa
S
S
Me
O
[Co(Por*)] (2 mol %)
H
N2
+
N3
H
H
O
H
R1
N
O
O
R1
S
S
O
1a
O2N 2a
O2N
[Co(P4)] (4 mol %)
N2
+
temp (°C)
entry
solvent
yield (%)
ee (%)
catalyst
R2
R2
[Co(P1)]
[Co(P2)]
[Co(P3)]
1
2
80
80
80
chlorobenzene
chlorobenzene
chlorobenzene
99
99
99
28
32
49
1
2
H
N
H
N
H
O
H
O
H
O
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
N
3
S
S
S
Me
(R) Me
Me
O
O
O
[Co(P4)]
[Co(P4)]
[Co(P4)]
[Co(P4)]
[Co(P4)]
4
80
60
40
60
50
chlorobenzene
chlorobenzene
chlorobenzene
chloroform
99
99
63
70
96
84
86
88
89
92
5
6
(1.0 mmol)b
(X-ray)c
entry 3:a (+)-2c
O2N
MeO2C
NC
entry 2:a (+)-2b
93% yield; 93% ee
7
8b
entry 1: (+)-2a
96% yield; 92% ee
75% yield; 90% ee
chloroform
H
O
H
Me
Me
Me
Me
Me
Me
Me
Me
H
H
O
O
N
N
S
H
H
H
H
S
O
H
H
Me
N
[Co(P1)]
O
(S)
(S)
(S)
(S)
O
O
S
O
O
Me
(P1 = 3,5-DitBu-ChenPhyrin)
O
Me
O
H
N
N
H
H
N
N
H
O
N
N
N
N
N
N
N
N
N
O
Me
Me
[Co(P2)]
H
N
N
H
entry 4:d (+)-2d
94% yield; 90% ee
entry 5:d (+)-2e
96% yield; 90% ee
H
entry 6:d (+)-2f
H
N
N
H
O
(P2 = 2,6-DiMeO-ChenPhyrin)
90% yield; 88% ee
O
O
O
O
(S)
(S)
(S)
(S)
H
H
H
H
H
H
O
H
O
H
N
N
Me
Me
Me
Me
Me
Me
Me
Me
S
S
O
H
N
Me
O
O
H
(S)
H
(S)
H
(S)
H
(S)
S
[Co(P3)]
O
O
O
(P3 = 3,5-DitBu-ZhuPhyrin)
O
O
O
O
O
O
O
O
O
N
H
H
H
N
N
H
H
N
O
N
N
MeO2C
N
N
N
N
Br
N
entry 7:d (+)-2g
entry 8:d (+)-2h
entry 9:d,e (⎯)-2i
73% yield; 68% ee
N
O
[Co(P4)]
H
N
N
H
N
N
H
99% yield; 88% ee
88% yield; 60% ee
O
(P4 = 2,6-DiMeO-ZhuPhyrin)
O
O
O
O
O
(S)
O
(S)
(S)
(S)
a Reactions were carried out in chloroform at 50 °C for 48 h on 0.10 mmol
scale under N2; [1] = 0.25 M; Isolated yields; Enantiomeric excess deter-
H
H
H
H
a Reactions were carried out for 18 h on 0.10 mmol scale under N2; [1a] =
0.25 M; Isolated yields; Enantiomeric excess determined by chiral HPLC.
b 4 mol % catalyst for 48 h.
b
c
mined by chiral HPLC. 1.0 mmol scale. Absolute configuration deter-
mined by X-ray analysis. d At 80 °C. e In chlorobenzene.
Asymmetric 1,5-C–H Amination of Alkylsulfonyl Az-
ides. Subsequent experiments indicated that asymmetric intra-
molecular C–H amination of alkylsulfonyl azides behaves differ-
ently from arylsulfonyl azides, presumably due to the flexible
nature of the linear alkyl chain. As illustrated in Table 3 with
substrate 3-phenylpropylsulfonyl azide (3a), catalyst [Co(P4)]
was much less effective in catalyzing the reaction of this alkyl-
sulfonyl azide, affording the 5-membered cyclic sulfonamide 4a
in only 10% yield although with 90% ee (Table 3; entry 1). Cata-
lyst [Co(P1)] was found to be much more effective for this reac-
tion, generating 4a in 97% yield but with only 48% ee (Table 3;
entry 2). When the second-generation metalloradical catalyst
[Co(P5)] (P5 = 3,5-DitBu-QingPhyrin)11c was used, the enantiose-
lectivity of this heterocyclization reaction was increased to 69%
ee while maintaining an excellent yield of 99%. These results
prompted us to develop new metalloradical catalysts with com-
bined features of these existing catalysts. This effort led to the
design and synthesis of D2-symmetric chiral amidoporphyrin 2,6-
DiMeO-Qing(4’-Me)Phyrin (P6). Its cobalt(II) complex [Co(P6)],
whose structure was established by X-ray crystallographic analy-
sis, was found to be a superior metalloradical catalyst for asym-
metric C–H amination of alkylsulfonyl azide 3a. The [Co(P6)]-
catalyzed reaction displayed both high efficiency and excellent
stereoselectivity, affording cyclic sulfonamide 4a in 92% yield
with 94% ee (Table 3; entry 4). With [Co(P6)] as the optimized
catalyst, further solvent evaluation was performed for intramolec-
ular C–H amination of the alkylsulfonyl azide (see Table S2 in
Supporting Information (SI)). Among various solvents evaluated,
benzene was identified as the optimal medium as it gave the high-
est enantioselectivity (Table 3; entries 4–6).
The metalloradical catalyst [Co(P4)] was shown to be generally
effective for asymmetric intramolecular C–H amination of various
arylsulfonyl azides under the optimized conditions (Table 2).
Firstly, it is worth noting that the same high yield and enantiose-
lectivity for formation of benzofused cyclic sulfonamide 2a could
also be obtained when the reaction with 1a was scaled up 10 times
to 1.0 mmol (Table 2; entry 1). In addition to the nitro group, the
Co(II)-based metalloradical amination could also be effectively
applied to 2-ethylarenesulfonyl azides bearing other electron-
withdrawing substituents such as cyano (1b) and ester (1c)
groups, allowing for high-yielding production of functionalized
benzofused cyclic sulfonamides 2b and 2c in a highly asymmetric
manner (Table 2; entries 2 and 3). The absolute configuration of
the newly-generated chiral center in 2c was established as (R) by
X-ray crystal structural analysis. At a slightly elevated tempera-
ture (80 °C), 2-ethylbenzenesulfonyl azide (1d) and its derivatives
containing different aryl substituents such as electron-donating
alkyl (1e) and amino (1f) groups as well as halogen (1g) atoms
were also suitable substrates for the amination system, giving the
corresponding 5-membered benzofused cyclic sulfonamides 2d–
2g in high yields with high enantioselectivities (Table 2; entries
4–7). The complete regioselectivity at the benzylic C–H position
by [Co(P4)]-catalyzed amination was further highlighted with the
high-yielding formation of 5-membered benzofused cyclic sulfon-
amide 2h from 2-pentyl-5-(methoxycarbonyl)benzenesulfonyl
azide (1h), albeit with lower enantioselectivity (Table 2; entry 8).
The 6-membered benzofused cyclic sulfonamide from potential
amination of the homobenzylic C–H bonds in 1h was not ob-
served. As expected, C–H bonds at bis-benzylic positions could
also be aminated by [Co(P4)] as exemplified with the reaction of
2-benzyl benzenesulfonyl azide (1i), resulting in formation of the
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Table 3. Ligand Effect on Co(II)-Catalyzed Asymmetric 1,5-
C–H Amination of Alkylsulfonyl Azides 3aa
mation of 5-membered cyclic sulfonamide 4n as the major prod-
ucts (66% yield) with the 6-membered cyclic sulfonamide 5n as
the minor product (18% yield) from the reaction of azide 3n illus-
trated that the metalloradical catalyst [Co(P6)] could regioselec-
tively aminate the stronger homobenzylic over the weaker ben-
zylic C–H bonds (Table 4; entry 13). The regioselective amination
of stronger (bishomobenzylic) over weaker C–H bonds (homo-
benzylic and benzylic) by [Co(P6)] was also clearly demonstrated
from the formation of 5-membered cyclic sulfonamide 4o as the
major product (65% yield) with the 6-membered cyclic sulfona-
mide 5o as the minor product (25% yield) without observation of
any 7-membered product from the reaction of azide 3o (Table 4;
entry 14). This remarkable regioselectivity indicated that the cor-
responding a-Co(III)-aminyl radicals I (Scheme 1) inside the
catalyst [Co(P6)] was positioned to have a kinetic preference for
1,5- over 1,6- and 1,7-H abstraction.
H
H
H
H
O
N3
N
[Co(Por*)] (2 mol %)
S
S
O
N2
+
O
O
3a
4a
entry
catalyst
[Co(P4)]
[Co(P1)]
[Co(P5)]
[Co(P6)]
[Co(P6)]
[Co(P6)]
yield (%)
ee (%)
90
solvent
benzene
1
2
3
4
5
6
10
benzene
97
48
benzene
99
69
benzene
92
94
9
chlorobenzene
chloroform
95
91
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
95
84
Me
Me
Me
Me
(R)
(R)
(R)
(R)
H
H
H
H
(R)
(R)
(R)
(R)
O
O
O
O
H
N
N
H
O
H
N
N
H
O
N
N
N
N
N
N
N
N
O
H
N
N
H
H
N
N
H
Table 4. [Co(P6)]-Catalyzed Enantioselective 1,5-C–H Amina-
O
O
O
O
O
(R)
(R)
Me
tion of Alkylsulfonyl Azidesa
(R)
(R)
Me
(R)
(R)
Me
(R)
(R)
Me
H
H
H
H
H
H
H
H
O
N3
N
[Co(P6)] (2 mol %)
S
R
X-Ray Structure of [Co(P6)]
[Co(P6)]
(P6 = 2,6-DiMeO-Qing(4’-Me)Phyrin)
S
[Co(P5)]
(P5 = 3,5-DitBu-QingPhyrin)
N2
+
R
O
O
O
3
4
a Reactions were carried out at 40 °C for 18 h on 0.25 mmol scale under
N2; [3a] = 0.10 M; Isolated yields; Enantiomeric excess determined by
chiral HPLC.
H
N
H
N
H
N
Br
H
Cl
O
H
O
H
O
S
O
S
S
O
O
OMe
entry 1: (⎯)-4b
88% yield; 95% ee
entry 2: (⎯)-4c
96% yield; 96% ee
entry 3: (⎯)-4d
Cl
95% yield; 96% ee
The new metalloradical catalyst [Co(P6)] proved to be general-
ly effective for asymmetric intramolecular C–H amination of
alkylsulfonyl azides as demonstrated with reactions of different
propylsulfonyl azide derivatives 3 under the optimized conditions
(Table 4). Like the amination reaction of 3a, the [Co(P6)]-based
catalytic system performed equally well for 3-arylpropylsulfonyl
azides 3b–3c with various aryl substituents at the ortho-, meta- or
para-positions, producing the corresponding 5-membered cyclic
sulfonamides 4b–4c in high yields with excellent enantioselectivi-
ties (Table 4; entries 1–3). Resembling the [Co(P4)]-based cata-
lytic system for arylsulfonyl azides 1 (Table 2), the [Co(P6)]-
catalyzed amination could also be applicable for electron-deficient
C–H bonds, as exemplified with enantioselective formation of the
desired cyclic sulfonamides 4e and 4f from azide substrates bear-
ing electron-withdrawing aryl substituents such as trifluoromethyl
(3e) and nitro (3f) groups (Table 4; entries 4–5). The absolute
configuration of the newly-generated chiral center in cyclic sul-
fonamide 4f was established as (S) by X-ray crystal structural
analysis. Additionally, indane-derived substrate 3g was success-
fully desymmetrized by [Co(P6)]-based amination to give cis-
fused cyclic sulfonamide 4g in moderate yield with good enanti-
oselectivity (Table 4; entry 6). Alkylsulfonyl azides derived from
indole (3h) and thiophene (3i) could also be intramolecularly
aminated to furnish the desired heteroarene-containing cyclic
sulfonamides 4h and 4i, respectively (Table 4; entries 7 and 8).
Furthermore, the Co(II)-based system was shown to be capable of
catalyzing intramolecular amination of allylic C–H bonds
chemoselectively without any complication from the competitive
intramolecular aziridination of C=C bonds. For example, sulfonyl
azides 3j–3l derived from both terminal and internal olefins could
be chemoselectively aminated at the allylic C–H positions,
providing the corresponding vinyl-substituted cyclic sulfonamides
4j–4l in high yields with high enantioselectivities (Table 4; entries
9–11). The [Co(P6)]-based system could be also extended for
amination of non-activated C–H substrates such as sulfonyl azides
3m–3o, affording the 5-membered cyclic sulfonamides 4m–4o in
good yields (Table 4; entries 12–14). While the asymmetric in-
duction was low for these reactions, the enantioselectivities of 4n
and 4o were significantly higher than 4m, indicating the positive
effect of distal phenyl substituent. More importantly, the for-
H
H
H
(X-ray)b
H
O
N
O
H
O
H
N
N
S
S
S
O
O
O
(S)
CF3
NO2
entry 4: (⎯)-4e
94% yield; 96% ee
entry 5: (⎯)-4f
89% yield; 93% ee
entry 6: (+)-4g
62% yield; 80% ee
H
H
H
O
H
N
O
H
O
H
S
N
N
S
S
S
O
O
O
N
Boc
entry 7: (⎯)-4h
entry 8: (⎯)-4i
entry 9:c,d (+)-4j
98% yield; 99% ee
93% yield; 92% ee
92% yield; 93% ee
H
H
H
H
H
N
O
O
N
O
H
N
S
S
S
O
Me
O
O
Br
entry 10:c (⎯)-4k
entry 11:c (⎯)-4l
entry 12:c,d 4m
98% yield; 90% ee
83% yield; 82% ee
74% yield; 7% ee
H
N
H
H
H
H
O
H
H
O
H
N
O
O
N
N
O
S
S
S
S
( )2
O
O
O
entry 13:e
entry 14:d,e
4n
5n
4o
5o
66% yield; 44% ee
18% yield; 20% ee 65% yield; 36% ee
25% yield; 26% ee
a Reactions were carried out in benzene at 40 °C for 18 h on 0.25 mmol
scale under N2; [3] = 0.10 M; Isolated yields; Enantiomeric excess deter-
mined by chiral HPLC. b Absolute configuration determined by X-ray
analysis. c Carried out on 0.10 mmol scale at 0 °C for 24 h using 5 mol %
[Co(P6)] in PhCl. d Enantiomeric excess determined via derivatization. e
Carried out for 48 h.
Mechanistic Studies of 1,5-C–H Amination of Sul-
fonyl Azides. The profile of reactivity and selectivity exhibited
by the Co(II)-based system for 1,5-C–H amination is consistent
with the proposed stepwise radical mechanism that involves the
a-Co(III)-aminyl radicals I and e-Co(III)-alkyl radicals II as the
key intermediates (Scheme 1).6 To obtain direct evidence for the
proposed mechanism, a set of mechanistic experiments was car-
ried
out
(Scheme
2).
First,
mono-deuterated
3-
phenylpropylsulfonyl azide 3aD was used as the substrate to de-
termine the kinetic isotopic effect (KIE) for the Co(II)-catalyzed
intramolecular C–H amination (Scheme 2A). Using the Co(II)
complex of D2h-symmetric amidoporphyrin 3,5-DitBu-
IbuPhyrin,9a [Co(P7)], as an achiral catalyst, the reaction of azide
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Journal of the American Chemical Society
3aD provided a mixture of cyclic sulfonamides 4aH and 4aD,
erization of the locked endocyclic C=C bond, the fact that (Z)-4p
2
which resulted from 1,5-C–H and 1,5-C–D amination, respective-
ly, in 75% combined yield. Analysis of the product mixture by
1H-NMR provided a value of 17.0 for intramolecular KIE. This
high value of primary KIE agrees well with the proposed step of
C–H bond cleavage via H-atom abstraction by a-Co(III)-aminyl
radical intermediate I (Scheme 1). Furthermore, in an effort to
directly detect the radical intermediate I, 3-nitrobenzenesulfonyl
azide (1j), which resembles azide 1a but lacks C(sp3)–H bonds for
further H-atom abstraction, was chosen to react with [Co(P1)] for
the generation of the corresponding a-Co(III)-aminyl radical I1j
(Scheme 2B). The isotropic EPR spectrum of the reaction solution
of [Co(P1)] with 1j was recorded at room temperature (Scheme
2B; see SI for details), displaying the well-resolved signals that
are characteristic of a-Co(III)-aminyl radicals.6a-b In accord with
the spin translocation from the Co(II) ion to the N atom during the
step of metalloradical activation of the azide (Scheme 1), the ob-
served isotropic g value of 2.00499 evidently indicated the exist-
ence of organic radicals. Furthermore, the experimental spectrum
was obtained in 95% yield with low but significant enantioselec-
tivity (14% ee) implies the intermediacy of the tertiary allylic
radicals II(Si)-3p and II(Re)-3p resulted from 1,5-H-atom abstraction
from the racemic tertiary C–H bond. Furthermore, the catalytic
reaction of azide 3q by [Co(P7)] was performed to probe the ex-
istence of the corresponding e-Co(III)-alkyl radical II3q through
ring-opening (Scheme 3D). Besides the construction of cyclic
3
4
5
6
7
8
9
Scheme 2. Kinetic Isotope Effect of Catalytic 1,5-C–H Amina-
tion and Spectroscopic Detection of α-Co(III)-Aminyl Radical
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
A) Determination of Intramolecular Kinetic Isotope Effect
H
O
D
O
O
O
N
N3
S
Ph
H
H
N
N
N
N
H
H
O
O
O
S
N
N
N
4aH
+
Co
N
[Co(P7)] (2 mol %)
H
C6H6; 40 °C; -N2
D
O
D
H
Ph
3aD
75% yield; kH/kD = 17.0
O
N
S
Ph
O
[Co(P7)]
(P7 = 3,5-DitBu-IbuPhyrin)
4aD
could be fittingly simulated on the basis of couplings by both 14
N
B) Detection of α-Co(III)-Aminyl Radical Intermediate
(I = 1) and 59Co (I = 7/2) with hyperfine coupling constants of
39.9 MHz and 4.9 Hz, respectively. Moreover, a-Co(III)-aminyl
radical I1j from the reaction mixture of [Co(P1)] with azide 1j
could also be detected by high-resolution mass spectrometry
(HRMS) with ESI ionization. The obtained spectrum (Scheme 2B;
see SI for details) clearly revealed a signal corresponding to
[Co(P1)(NSO2C6H4NO2)]+ (m/z = 1539.6703), which resulted
from the neutral a-Co(III)-aminyl radical I1j by the loss of one
electron. Both the exact mass and the pattern of isotope distribu-
tion determined by ESI-HRMS matched nicely with those calcu-
lated from the formula [Co(P1)(NSO2C6H4NO2)]+.
O2N
Me
Me
Me
Me
Me
Me
Me
Me
O2N
H
H
H
H
(S)
(S)
(S)
(S)
O
O
O
O
O
O
S
N
O
O
H
N
H
N
N
H
N
H
S
1j
N3
N
N
N
N
N
N
N
N
Co
Co
C6H6; RT; -N2
H
N
N
H
H
N
N
H
O
O
O
O
(S)
(S)
(S)
(S)
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
[Co(P1)]
α-Co(III)-Aminyl Radical I1j
g-value
giso = 2.00499 (exp)
iso = 2.00409 (sim)
Aiso(Co) = 4.9 MHz
Aiso(N) = 39.9 MHz
Further experiments were designed to trap and probe the e-
Co(III)-alkyl radical intermediates II generated from the subse-
quent step of 1,5-H-atom abstraction by a-Co(III)-aminyl radical
intermediates I (Scheme 1). To this end, the amination of allylic
C–H bonds of azide (E)-3k by [Co(P6)] was performed in the
presence of TEMPO (Scheme 3A). Remarkably, even in the pres-
ence of a large excess of TEMPO (5.0 equiv), the 5-membered
cyclic sulfonamide (E)-4k was still produced as the major product
in 72% yield, indicating highly facile formation of the C–N bond
g
via 5-exo-tet radical cyclization of e-Co(III)-allylic radical II(E)-3k
.
Concomitantly, the reaction produced (E)-5k as a minor product
in 10% yield, which was presumably formed from the TEMPO-
trapped intermediate III(E)-3k. The fact that there was no asymmet-
ric induction in (E)-5k while observing significant enantioselec-
tivity for (E)-4k in 72% ee indicates markedly different environ-
ment for the C–O and C–N bond formation processes. The exist-
ence of e-Co(III)-allylic radical intermediates II could be further
probed via olefin isomerization during the catalytic reaction of
azide (Z)-3k by [Co(P6)] (Scheme 3B). Like the reaction of (E)-
3k, the 1,5-amination of allylic C–H bonds of (Z)-3k resulted in
exclusive formation of (E)-4k in 86% yield with 82% ee without
forming any (Z)-4k, representing a rare example of enantioselec-
tive allylic C–H amination with diastereoconvergence. This result
suggests that the C–N bond formation via 5-exo-tet radical cy-
clization occurred much faster in the isomerized radical II(E)-3k
than the initially-formed e-Co(III)-allylic radical II(Z)-3k, presuma-
bly due to the steric difference between the (E)- and (Z)-olefin
units. When the cyclohexene-based azide 3p that contains an en-
docyclic (Z)-olefin was employed as the substrate, the 1,5-
amination of the racemic tertiary allylic C–H bond could be effec-
tively catalyzed by [Co(P6)] to afford the spirobicyclic product
(Z)-4p in an excellent yield (Scheme 3C). While the (Z)-
configuration of the olefin was retained owing to incapable isom-
m/z =1539.6703 (exp)
m/z = 1539.6778 (sim)
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1
2
3
4
5
6
7
8
corresponding small-scale reaction (Table 3; entry 4). To show-
sulfonamide 4q in 50% yield from e-Co(III)-alkyl radical II3q, the
reaction produced sulfonamide 6q in 30% yield directly from a-
Co(II)-aminyl radical I3q. Additionally, detailed analysis of the
case its synthetic utility, the resulting enantioenriched cyclic sul-
fonamide 4a was employed as the key chiral synthon for the syn-
thesis of compound 7a in view of recent attention to the broad
enzyme inhibitory properties of enantiopure fused-cyclic sulfon-
amides.13,19 As depicted in Scheme 4B, the fused-tricyclic sulfon-
amide 7a could be effectively synthesized from 4a through a 4-
step sequence of N-methylation,13m selenylation,20 elimination21
and Diels-Alder reactions22 in an overall 64% yield without the
erosion of the original enantiomeric purity. The stereochemistry
of the endo-stereoisomer 7a was unambiguously established by
X-ray structural analysis (Scheme 4B).
1
reaction mixture by H NMR revealed the formation of acyclic
sulfonamide 5q as the third product in 5% yield. The identity of
product 5q was further confirmed through an independent synthe-
sis (see SI). Compound 5q was likely originated from homoallylic
radical intermediate III3q that was generated from ring-opening of
the cyclopropylcarbinyl radical II3q. Collectively, these experi-
mental results (Schemes 2 and 3) provided convincing evidences
for the proposed stepwise radical mechanism of the Co(II)-
catalyzed 1,5-C–H amination of sulfonyl azides (Scheme 1).
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
Scheme 4. Applications of Co(II)-Catalyzed Enantioselective
1,5-C–H Amination of Sulfonyl Azides
Scheme 3. Trapping and Probing of -Co(III)-Alkyl Radicals
e
after 1,5-H-Atom Abstraction in Co(II)-Catalyzed Amination
A) Gram-Scale Asymmetric Synthesis of 5-Membered Cyclic Sulfonamide
A) Trapping Allylic Radical by TEMPO
H
H
H
H2N
TEMP
H
H
N
H
H
H
[Co(P6)] (2 mol %)
O
SO2
O
N
N3
H
O
N3
TEMPO (5.0 equiv)
S
[Co(P6)] (2 mol %)
S
96% yield
94% ee
+
O
Ph
S
Ph
S
N2
+
O
Ph
O
O
C6H6; 40 °C
-N2
C6H6; 40 °C; 18 h
O
(E)-3k
O
(E)-4k
(E)-5k
10% yield; 0% ee
72% yield; 72% ee
Ph
3a (10 mmol)
4a (1.89 g)
B) Asymmetric Synthesis of Fused-Tricyclic Sulfonamide Target
H
N
Me
N
Me
N
Ph
Ph
MeI; K2CO3
18-crown-6
H
O
H
H
1,5-H-atom
abstraction
O
O
1. LDA; PhSeBr
S
TEMPO
H
S
S
OTEMP
H
N
H
H
NH
O
O
O
O
S
O
S
O S
98% yield
2. 30% H2O2
72% yield
NH
O
O
O
4a
94% ee
6a
94% ee
I(E)-
II(E)-
III(E)-
3k
5a
[Co]
3k
[Co]
3k
[Co]
B) Probing Allylic Radical via Olefin Isomerization
Me
H
N
H
H
O
H
N
Ph
H
H
H
O
O
N
S
Et2AlCl; 80 °C
90% yield
O
H
[Co(P6)] (2 mol %)
6a
94% ee
N3
S
S
+
O
Ph
O
H
+
S
C6H6; 40 °C
-N2
O
O
(E)-4k
86% yield; 82% ee
Ph
7a
(Z)-4k
(Z)-3k
0% yield
Ph
endo:exo = 4:1
> 20:1 d.r.; 94% ee
X-Ray Structure of endo-7a
Ph
1,5-H-atom
abstraction
O S
allylic radical
isomerization
H
N
H
CONCLUSIONS
O
S
H
O
S
Ph
H
NH
NH
O
O
O
I(Z)-
II(Z)-
3k
II(E)-
[Co]
3k
[Co]
3k
[Co]
In summary, we have developed Co(II)-based metalloradical
systems for asymmetric 1,5-C–H amination of both arylsulfonyl
and alkylsulfonyl azides under neutral and nonoxidative condi-
tions. In addition to benzylic C–H bonds with varied steric and
electronic properties, the Co(II)-catalyzed enantioselective radical
amination is highlighted with chemoselective amination of allylic
C–H bonds as well as compatibility with heteroaryl groups, allow-
ing for stereoselective construction of functionalized 5-membered
cyclic sulfonamides in high yields with excellent enantioselectivi-
ties. This work represents, to date, one of the most general and
selective catalytic systems for asymmetric intramolecular C–H
amination of sulfonyl azides. The unique profile of reactivity and
selectivity of the Co(II)-based asymmetric 1,5-C–H amination is
attributed to the underlying stepwise radical mechanism, which is
well supported by several lines of experimental evidence. Practi-
cally, we have demonstrated the Co(II)-based radical C–H amina-
tion protocol can be operated on a multigram-scale under the
same mild conditions without affecting the high yield and excel-
lent enantioselectivity. To showcase its synthetic utility, the
Co(II)-catalyzed enantioselective radical amination has been ap-
plied as the key step for the highly effective synthesis of the
fused-tricyclic sulfonamide molecule.
C) Probing Tertiary Allylic Radical with Substrate Containing Endocyclic (Z)-Olefin
O
O
O
O
S
[Co(P6)] (2 mol %)
S
N3
N
95% yield
14% ee
C6H6; 50 °C; -N2
H
(±)-3p
(Z)-4p
asymmetric
control
σ-bond
1,5-H-atom
abstraction
rotation
H
O
S
O
S
O
S
NH
NH
N
O
O
O
II(Re)-
3p
I3p
II(Si)-
3p
[Co]
[Co]
[Co]
D) Probing Cyclopropylcarbinyl Radical through Ring-Opening
O
O
O
O
O
O
O
O
S
S
S
S
NH2
H
N3
H
NH2
H
N
H
[Co(P7)] (2 mol %)
H
H
+
+
Ph
H
C6H6; 80 °C
-N2
4q
3q
6q
30% yield
5q
5% yield
Ph
Ph
Ph
Ph
50% yield
radical
β-scission
1,5-H-atom
abstraction
Ph
Ph
H
H
O
S
H
H
O
S
O S
N
NH
NH
O
O
O
I3q
II3q
III3q
[Co]
[Co]
[Co]
Scalability and Utility of Co(II)-Catalyzed Asymmet-
ric 1,5-C–H Amination of Sulfonyl Azides. The successful
development of asymmetric intramolecular C–H amination of
both arylsulfonyl and alkylsulfonyl azides via Co(II)-based metal-
loradical catalysis provides a practical method to access optically
active cyclic sulfonamides bearing various functionalities, which
should find applications in research and development of pharma-
ceuticals. To demonstrate the practicality of the Co(II)-based sys-
tem for 1,5-C–H amination, the catalytic reaction of 3-
phenylpropylsulfonyl azide (3a) by [Co(P6)] was scaled up 40
times from 0.25 mmol to 10 mmol under the identical conditions
(Scheme 4A). The desired 5-membered cyclic sulfonamide 4a
was produced in multigram quantities in 96% yield with 94% ee,
which was similar to those (92% yield; 94% ee) obtained from the
ASSOCIATED CONTENT
Supporting Information
Experimental details and analytical data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental details, supplementary figures and spectroscopic
data (pdf)
Crystallography data for 2c, [Co(P6)], 4f and endo-7a (CIF)
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Journal of the American Chemical Society
Huang, H.-M.; McDouall, J. J. W.; Procter, D. J. SmI2-Catalysed
AUTHOR INFORMATION
2
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4
5
6
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Organocobalt Complexes as Sources of Carbon-Centered Radicals for
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(c) Singh, R.; Mukherjee, A., Metalloporphyrin Catalyzed C–H Ami-
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Huang, J. S. Selective Functionalisation of Saturated C–H Bonds with
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Corresponding Author
peter.zhang@bc.edu
Author Contributions
§
These authors contributed equally.
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ACKNOWLEDGMENT
We are grateful for financial support by NIH (R01-GM098777)
and in part by NSF (CHE-1900375).
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(16) For select examples of intramolecular asymmetric C–H amina-
tion, see: (a) Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.; Yu, W.-Y.; Che,
C.-M. Highly Diastereo- and Enantioselective Intramolecular Ami-
dation of Saturated C–H Bonds Catalyzed by Ruthenium Porphyrins.
Angew. Chem., Int. Ed. 2002, 41, 3465–3468. (b) Milczek, E.;
Boudet, N.; Blakey, S. Enantioselective C–H Amination Using Cati-
onic Ruthenium(II)–Pybox Catalysts. Angew. Chem., Int. Ed. 2008,
47, 6825–6828. (c) Wang, H.; Park, Y.; Bai, Z.; Chang, S.; He, G.;
Chen, G. Iridium-Catalyzed Enantioselective C(sp3)–H Amidation
Controlled by Attractive Noncovalent Interactions. J. Am. Chem. Soc.
2019, 141, 7194–7201. (d) Zhou, Z.; Chen, S.; Qin, J.; Nie, X.;
Zheng, X.; Harms, K.; Riedel, R.; Houk, K. N.; Meggers, E. Catalytic
Enantioselective Intramolecular C(sp3)−H Amination of 2-
Azidoacetamides. Angew. Chem., Int. Ed. 2019, 58, 1088–1093. (e)
Xing, Q.; Chan, C.-M.; Yeung, Y.-W.; Yu, W.-Y. Ruthenium(II)-
Catalyzed Enantioselective γ-Lactams Formation by Intramolecular
C–H Amidation of 1,4,2-Dioxazol-5-Ones. J. Am. Chem. Soc. 2019,
141, 3849–3853.
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(17) For a recent example of intermolecular asymmetric C–H ami-
nation, see: Nasrallah, A.; Boquet, V.; Hecker, A.; Retailleau, P.;
Darses, B.; Dauban, P. Catalytic Enantioselective Intermolecular
Benzylic C(sp3)−H Amination. Angew. Chem., Int. Ed. 2019, 58,
8192–8196.
(18) For the first example of asymmetric cyclic sulfonamide for-
mation via intramolecular C–H amination, see: (a) Fruit, C.; Müller,
P. Intramolecular Asymmetric Amidations of Sulfonamides and Sul-
famates Catalyzed by Chiral Dirhodium(II) Complexes. Helv. Chim.
Acta 2004, 87, 1607–1615. For the only example of highly asymmet-
ric benzofused cyclic sulfonamide formation via intramolecular C–H
amination, see: (b) Ichinose, M.; Suematsu, H.; Yasutomi, Y.; Nish-
ioka, Y.; Uchida, T.; Katsuki, T. Enantioselective Intramolecular
Benzylic C−H Bond Amination: Efficient Synthesis of Optically
Active Benzosultams. Angew. Chem., Int. Ed. 2011, 50, 9884–9887.
(19) For select examples of synthesis and bioactivity studies on
chiral fused-cyclic sulfonamides, see: (a) Samarakoon, T. B.; Loh, J.
K.; Rolfe, A.; Le, L. S.; Yoon, S. Y.; Lushington, G. H.; Hanson, P.
R., A Modular Reaction Pairing Approach to the Diversity-Oriented
Synthesis of Fused- and Bridged-Polycyclic Sultams. Org. Lett. 2011,
13, 5148–5151. (b) Yin, X.; Zheng, Y.; Feng, X.; Jiang, K.; Wei, X.-
Z.; Gao, N.; Chen, Y.-C. Asymmetric [5+3] Formal Cycloadditions
with Cyclic Enones through Cascade Dienamine–Dienamine Cataly-
sis. Angew. Chem., Int. Ed. 2014, 53, 6245–6248. (c) Loh, J. K.;
Asad, N.; Samarakoon, T. B.; Hanson, P. R. Modular, One-Pot, Se-
quential Aziridine Ring Opening–SNAr Strategy to 7-, 10-, and 11-
Membered Benzo-Fused Sultams. J. Org. Chem. 2015, 80, 9926–
9941. Also see ref 13t.
(14) For select reviews, see: (a) Park, Y.; Kim, Y.; Chang, S. Tran-
sition Metal-Catalyzed C–H Amination: Scope, Mechanism, and
Applications. Chem. Rev. 2017, 117, 9247–9301. (b) Alderson, J. M.;
Corbin, J. R.; Schomaker, J. M. Tunable, Chemo- and Site-Selective
Nitrene Transfer Reactions through the Rational Design of Silver(I)
Catalysts. Acc. Chem. Res. 2017, 50, 2147–2158. (c) Collet, F.; Les-
cot, C.; Dauban, P. Catalytic C–H Amination: the Stereoselectivity
Issue. Chem. Soc. Rev. 2011, 40, 1926–1936.
(15) For select examples of non-asymmetric intramolecular C–H
amination, see: (a) Huard, K.; Lebel, H. N-Tosyloxycarbamates as
Reagents in Rhodium-Catalyzed C–H Amination Reactions. Chem. -
Eur. J. 2008, 14, 6222–6230. (b) Hennessy, E. T.; Betley, T. A. Com-
plex N-Heterocycle Synthesis via Iron-Catalyzed, Direct C–H Bond
Amination. Science 2013, 340, 591–595. (c) Alderson, J. M.; Phelps,
A. M.; Scamp, R. J.; Dolan, N. S.; Schomaker, J. M. Ligand-
Controlled, Tunable Silver-Catalyzed C–H Amination. J. Am. Chem.
Soc. 2014, 136, 16720–16723. (d) Hong, S. Y.; Park, Y.; Hwang, Y.;
Kim, Y. B.; Baik, M.-H.; Chang, S. Selective Formation of g-Lactams
via C–H Amidation Enabled by Tailored Iridium Catalysts. Science
2018, 359, 1016–1021. (e) Azek, E.; Khalifa, M.; Bartholoméüs, J.;
Ernzerhof, M.; Lebel, H. Rhodium(II)-Catalyzed C−H Aminations
using N-Mesyloxycarbamates: Reaction Pathway and By-Product
Formation. Chem. Sci. 2019, 10, 718–729. (f) Baek, Y.; Betley, T. A.
Catalytic C–H Amination Mediated by Dipyrrin Cobalt Imidos. J.
Am. Chem. Soc. 2019, 141, 7797–7806. For metal-free C(sp3)−H
radical amination, see: (g) Evoniuk, C. J.; Gomes, G. d. P.; Hill, S. P.;
(20) Brattesani, D. N.; Heathcock, C. H. Sulfenylation and
Selenylation of Nitriles. Tetrahedron Lett. 1974, 15, 2279–2282.
(21) Grieco, P. A.; Gilman, S.; Nishizawa, M. A Facile One-Step
Synthesis of Alkyl Aryl Selenides from Alcohols. J. Org. Chem.
1976, 41, 1485–1486.
(22) Wanner, J.; Harned, A. M.; Probst, D. A.; Poon, K. W. C.;
Klein, T. A.; Snelgrove, K. A.; Hanson, P. R. A Dual Metathesis
Route to Oligomeric Sulfonamides. Tetrahedron Lett. 2002, 43, 917–
921.
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