Sulfonamide-Directed Chemo- and Site-Selective Oxidative Halogenation/Amination Using Halogenating Reagents Generated in Situ from Cyclic Diacyl Peroxides

Article abstract of DOI:10.1021/acs.joc.8b00243

The combination of cyclic diacyl peroxides with commercially available halide salts as a unique halogenating system is utilized in Hofmann-L?ffler-Freytag-type reaction. This strategy allows for the formation of N-chloroamides, δ-brominated products, and

Full text of DOI:10.1021/acs.joc.8b00243

Subscriber access provided by - Access paid by the | UCSB Libraries
Article
Sulfonamide-Directed Chemo- and Site-Selective
Oxidative Halogenation/Amination Using Halogenating
Reagents Generated in situ from Cyclic Diacyl Peroxides
Denghu Chang, Rong Zhao, Congyin Wei, Yuan Yao, Yang Liu, and Lei Shi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00243 • Publication Date (Web): 27 Feb 2018
Downloaded from http://pubs.acs.org on February 27, 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.
The Journal of Organic Chemistry 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 45
The Journal of Organic Chemistry
1
2
3
4
5
6
Sulfonamide-Directed Chemo- and Site-Selective Oxidative
Halogenation/Amination Using Halogenating Reagents
7
8
9
Generated in situ from Cyclic Diacyl Peroxides
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
Denghu Chang,ab Rong Zhao,ab Congyin Wei,ab Yuan Yao,b Yang Liub and Lei Shi*abc
a. Shenzhen Graduate School, Harbin Institute of Technology, Shenzhen 518055, China.
b. MIIT Key Laboratory of Critical Materials Technology for New Energy Conversion and Storage,
School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin 150001,
China
c. State Key Laboratory of ElementoꢀOrganic Chemistry, Nankai University, Tianjin 300071,
China
Eꢀmail: lshi@hit.edu.cn
Homepage: http://homepage.hit.edu.cn/pages/shilei
Abstract
The combination of cyclic diacyl peroxides with commercially available halide salts
as a unique halogenating system is utilized in HofmannꢀLӧfflerꢀFreytagꢀtype reaction.
This strategy allows for the formation of N–chloroamides, δꢀbrominated products and
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 45
1
2
3
4
5
6
7
8
even biologically relevant pyrrolidines under mild conditions in moderate to excellent
yields. Meanwhile, the preliminary structure of the in situ formed brominating reagent
is investigated by NMR and UV/Vis analysis.
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
Introduction
Nitrogenꢀcentered radical species including neutral
Nꢀcentered radicals and
radical ions as very attractive synthetic intermediates are usually used to effect
intramolecular cyclization, rapid additions to olefin, and 1,5ꢀH abstraction in
the synthesis of nitrogenꢀcontaining compounds,1 which can be traced back to
the historical HofmannꢀLӧfflerꢀFreytag (HLF) reaction in the early 1880s.2
However, the generation of nitrogenꢀcentered radical species seriously relies on
preꢀfunctionalization of the corresponding nitrogenꢀcontaining precursors.1,3
These functional groups are then activated with a radical initiator,
transitionꢀmetal catalyst at elevated temperature, UV light, or strong acid to
generate the resulting radical intermediates through homolytic cleavage of
various N‒O, N‒S, N‒N, N‒X, and N‒H bonds. On the other hand, the
subsequent reactions of nitrogenꢀcentered radical species have yet to reach a
satisfactory level of maturity of carbon counterparts,4 in spite of their potential
in the field of alkaloid and heterocyclic synthesis.
Gratifyingly, it was found that the electronꢀdeficiency of the nitrogenꢀcentered radical
is increased by installing an electronꢀwithdrawing group, such as a sulfonyl or
carbonyl group, on the nitrogen and Suárez5 discovered that for sulfonamides in situ
formed IOAc can be used for HLF reaction. This approach allows the in situ formed
ACS Paragon Plus Environment

Page 3 of 45
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
nitrogen‒halogen bond from a strong oxidant and a halogen source to be cleaved
homolytically under mild conditions compatible with the stability of the protective
groups most frequently used in synthetic organic chemistry. In this regard, Fan,6
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
González
and
Herrera7
independently
reported
an
iodineꢀmediated
HofmannꢀLӧfflerꢀFreytagꢀtype reaction of sulfonamides in the presence of a
stoichiometric amount of PhI(OAc)2. Yu8 showed that a similar formation of
pyrrolidine could be accompanied by the subsequent iodination through consecutive
C−H homolysis. Recently, Muñiz developed iodineꢀcatalyzed9a,9b (or
Nꢀiodosuccinimideꢀpromoted9c) visibleꢀlightꢀinitiated amination reactions of remote
C(sp3)‒H bonds. Meanwhile, Tiefenbacher10 extended the Suárezꢀmodified HLF
reaction through the in situ generation of the electronꢀdeficient trifluoroethyl amidyl
radicals. More recently, Nagib11 employed a triiodide strategy that expanded the scope
of the corresponding Suárez modification to enable the direct amination of secondary
C(sp3)‒H bonds. Alternatively, the transitionꢀmetal catalysis12ꢀ15 and visibleꢀlight
photocatalysis16,17 have also emerged as a useful and powerful complement for the
remote C(sp3)‒H bond functionalization of amides, but still some drawbacks exist that
limit practicability and largeꢀscale applicability.
Organic peroxides have received attention as capable reagents for practical
organic synthesis owing to their high reactivity, and generally low cost and low
toxicity of reagents and byproducts.18 Specifically, cyclic organic peroxides as
a really interesting class of compounds are more thermal stable than acyclic
peroxides sharing similarities in atom connectivity, which exhibited the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 45
1
2
3
4
5
6
7
8
9
dichotomy of ionic and radical mechanisms and constituted the key
pharmacophore unit of some antiꢀmalarial drugs (artemisinin, yingzhaosu A et
al.).18
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Proposed halogenating reagents.
Inspired by the enzymeꢀcatalyzed oxidative halogenation in nature19 and our
continuing interest and efforts in the utilization of cyclic peroxides,20 we are
intrigued
by
the
possibility
of
complementing
the
existing
HofmannꢀLӧfflerꢀFreytagꢀtype processes by the combination of cyclic diacyl
peroxides and diverse halide salts. We speculated that such proposed
halogenating reagents (Figure 1) could increase the efficiency of
HofmannꢀLӧfflerꢀFreytagꢀtype reactions by two potential pathways: increasing
the reactivity of halogenating reagent by the existence of the intramolecular
benzoates, or influencing the conformation of the substrates to favor reactivity
and selectivity by intermolecular force. To our delight, our halide saltsꢀenabled
divergent oxidative halogenation/amination of a diverse array of easily
available sulfonamides proceeded at room temperature in moderate to excellent
yields to afford
N–chloroamides, δꢀbrominated products and even biologically
relevant pyrrolidines in a predictable and controllable fashion (Scheme 1). To
ACS Paragon Plus Environment

Page 5 of 45
The Journal of Organic Chemistry
1
2
3
4
5
6
the best of our knowledge, this is the first example of the cyclic diacyl
peroxideꢀhalide salt combinations as an efficient halogenating reagent system
7
8
9
being exploited in the generation of
N‒haloamides and the subsequent
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
application to facilitate remote C(sp3)‒H bromination and pyrrolidine synthesis.
Scheme 1. Direct remote C(sp3)‒H functionalization.
Results and Discussion
Our initial efforts to realize the HofmannꢀLӧfflerꢀFreytagꢀtype transformation
commenced
with
the
reaction
of
4ꢀmethylꢀ ꢀ(4ꢀphenylbutyl)benzenesulfonamide 1a with commercially
N
available TBACl (Tetrabutyl ammonium chloride) as a halogen source. The
choice of sulfonamidates as protecting groups were made for their certain
application in amino and amino acid chemistry.21 Moreover, they also played
positive roles in avoiding overꢀoxidation of the amino group during the
formation of the haloamide intermediate, and controlling the stability of the
N
ꢀcentered radical during the HAT process. Although the direct δꢀC(sp3)–H
chlorination or pyrrolidine formation was not obtained even in the presence of
blue lightꢀemitting diodes (LEDs) irradiation, it is interesting to note that an in
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 45
1
2
3
4
5
situ formation of 2a was efficiently achieved in good yield (92%) using the
combination of TBACl and PPO (phthaloyl peroxide).22
6
7
8
Encouraged by the aboveꢀmentioned results, we began to explore the generality
9
of the
protecting groups with the results summarized in Table 1. Satisfyingly, in
addition to the ꢀtosylated amines, mesylꢀ, 2,4,6ꢀtriisopropylbenzenesulfonyl
and more easily removable nosylꢀprotected amines were perfectly compatible,
with this reaction to provide the desired products in 83ꢀ95% yields (2a-c 2h).
Various aliphatic sulfonamides (1d-g 1i-k) bearing an alkyl substituent in
different position participated well in the ꢀchlorination reactions, affording a
variety of useful ꢀchlorosulfonamide products. Notably, the optically active
ꢀTsꢀisoleucine (1l) and chiral camphorsulfonyl protected amine (1m) could
Nꢀchlorination in a variety of aliphatic amines containing different
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
,
,
N
N
N
also go through the transformation smoothly with complete retention at the
stereogenic centers. Furthermore, trifluoroethyl carbamate (1n) and aliphatic
amide (1o) were investigated, and no conversions could be observed (by TLC
and NMR) probably due to their lower activity. In agreement with a previously
reported literature,23 the expected benzylic δꢀamination of the corresponding
chloramine 2a can be further achieved in 80% yield with as little as 0.1 mol %
of photocatalyst (Scheme 2).
Table 1. Scope of N–H chlorination.a
ACS Paragon Plus Environment

Page 7 of 45
The Journal of Organic Chemistry
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
a
Conditions: A solution of 1 (0.1 mmol), PPO (1.2 equiv) and TBACl (1.2 equiv) in DCE (2 mL) was stirred at
b
room temperature under N2 for 12 h; PPO = phthaloyl peroxide; TBACl = tetrabutyl ammonium chloride. gram
scale, 81% yield of 2a (1.35 g) was obtained.
Scheme 2. Cyclization of NꢀCl sulfonamide 2a.
After an extensive survey of varying oxidants, bases, photocatalysts, bromine
sources and other reaction parameters, it was found that the combination of
3,4ꢀdichlorophthaloyl peroxide and TBAB (Tetrabutylammonium bromide)
with visible light irradiation facilitated the desired bromination of remote
C(sp3)–H bonds to give the δꢀbrominated product 4a in 63% yield.22 With the
optimized conditions in hand, substrates of this δꢀbrominated protocol were
investigated and the results are presented in Table 2. Our metalꢀfree and
visibleꢀlight promoted approach is not limited to secondary C(sp3)−H bonds
(
3b-f) but is also suitable for the bromination of primary nonactivated methyl
groups (3g). Unlike previous work,14 only δꢀbromination of substrates
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 45
1
2
3
4
5
6
7
8
9
containing both δꢀ and εꢀmethylene C(sp3)−H bonds were observed. On the
other hand, δꢀbrominated reaction mainly occurred at the δꢀmethylene
C(sp3)−H bond (4h') rather than the δꢀmethyl one (4h) due to significant
electronic effects. In addition, αꢀester substituted substrates furnished the
corresponding products in a slightly low yields. For example, δꢀbromination of
Lꢀnorleucine derivatives (3i) using this protocol afforded the expected product
4i in 26% yield. More interestingly, a series of αꢀaryl, δꢀbromo sulphonamides
were obtained under the standard reaction conditions in moderate to good
yields (4j-n), in which the potentially reactive arenes and benzylic C(sp3)−H
bonds remained intact. It is noteworthy that although δꢀbromination of
C(sp3)−H bonds with alkyl amide substrates have been realized by using
stoichiometric N–Br precursors24 or transitionalꢀmetal catalyst,14 our
photoꢀinduced δꢀC(sp3)–H bromination of sulfonamide substrates is
operationally simple and does not require costly transitionꢀmetal or external
radical initiators.
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
Table 2. Scope of δꢀC(sp3)–H bromination.a
ACS Paragon Plus Environment

Page 9 of 45
The Journal of Organic Chemistry
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
a Conditions: A mixture of 3 (0.1 mmol), 3,4ꢀdichlorophthaloyl peroxide (1.2 equiv), TBAB (1.2 equiv) and AcOH
(0.2 mL) in DCE (2 mL) was irraditated by blue LED strips at room temperature under N2 for 12 h; TBAB =
tetrabutylammonium bromide. b obtained as a mixture of diastereomers (1:1). c product mixture (4h:4h' = 1:2) was
obtained after purification. d obtained as a mixture of diastereomers (2:1).
Table 3. Optimization of δꢀC(sp3)ꢀH cyclization.a
entry
MX
TBAB
TBAB
TBAI
NaI
base
ꢀꢀꢀ
yield (%)
1
2
20
30
0
NaHCO3
ꢀꢀꢀ
3
4
ꢀꢀꢀ
30
50
64
91
5
KI
ꢀꢀꢀ
6
CsI
ꢀꢀꢀ
7b
CsI
K2HPO4
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 45
1
2
3
4
5
6
7
8
9
8b
CsI
CsI
CsI
CsI
CsI
CsI
CsI
CsI
Na2HPO4
NaH2PO4
NaOAc
K2CO3
NaOH
63
64
99
90
75
92
82
13
9b
10b
11b
12b
13b
14b
15c
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
K3PO4
NaHCO3
ꢀꢀꢀ
a Conditions: A mixture of 5a (0.1 mmol), phthaloyl peroxide (1.2 equiv), MX (1.2 equiv) and base (1.2 equiv) in
b
DCE (2 mL) was irraditated by blue LED strips at room temperature under N2 for 24 h. phthaloyl peroxide (2
equiv). c CsI (0.2 equiv).
Further attempts to arrive at the final pyrrolidine formation of 6a using the
combination of TBAI (Tetrabutylammonium iodide) and PPO as iodinating
agent resulted in no conversion even under visibleꢀlight irradiation.
Interestingly enough, by replacing the counterions from Bu4N+ to Na+, K+ and
Cs+ under blueꢀLED irradiation, a direct δꢀamination product 6a was obtained
in 30%, 50% and 64% yields, respectively (Table 3, entries 4ꢀ6). It showed that
the reaction efficiency was significantly affected by changing counter cations of
the iodides, and CsI was the most effective reagent. This indicated that the base
of the carboxylate of the in situ formed halide active intermediate had important
effect on the reaction. To our delight, after screening of different bases, the
employment of 1.2 equivalent NaOAc dramatically improved the yield of 6a to
ACS Paragon Plus Environment

Page 11 of 45
The Journal of Organic Chemistry
1
2
3
4
99% without a further overꢀoxidation or elimination (Table 3, entry 10). The
5
6
7
reaction also worked well for
Nꢀnosylamidyl group (Table 4, 6b, 99%).
8
9
Substrates with βꢀalkyl substituted sulfonamides reacted with the combination
of PPO and CsI to form pyrrolidines 6c and 6h in 99% and 98% yields.
Meanwhile, different substituents in the paraꢀsubstituted aryl group were well
tolerated (6d-g), and either electronꢀwithdrawing (F, Cl) or electronꢀdonating
(Me, OMe) substituents on the aromatic ring were all competent partners in this
reaction showing that electronic factors played only a minor role. Gratifyingly,
the formation of product 6i demonstrated the applicability of our present
amination conditions to the nonfunctionalized tertiary C(sp3)–H bonds (99%).
In parallel, this protocol could also be applied to an allylic amination reaction
of 5j without consumption of the free double bond, albeit in only 29% yield.
Finally, amination of C(sp3)–H bond adjacent to a heteroatom was carried out in
presence of visible light irradiation at room temperature to provide the
exclusive diastereoselective formation of 6k (80%). To further reveal its
synthetic potential, a camphorsulfonyl amide (5l) was investigated, however no
desired product (6l) was detected. It is interesting to note that when linear
sulfonamides (5m and 5n) were employed as substrates, the reactions took
place smoothly to deliver interrupted δꢀiodination intermediates (6m and 6n) as
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
major products.
Table 4. Scope of δꢀC(sp3)–H Cyclization.a
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 45
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
a
Conditions: A solution of 3 (0.1 mmol), PPO (2 equiv), CsI (1.2 equiv) and NaOAc (1.2 equiv) in DCE (2 mL)
was irraditated by blue LED strips at room temperature under N2 for 24 h. b PPO (1.2 equiv) and without NaOAc.
To gain some insights into the reaction mechanism, a series of control reactions
were conducted. NMR spectra of the combination of TBAB with phthaloyl
peroxide definitely revealed an in situ formation of the corresponding
brominated reagent (formed upon mixing PPO with 1 equiv of TBAB; Figure 2,
blue line). Moreover, under the optimized conditions, 4a and 6a were not
observed in the presence of TEMPO, BHT and other common radical
scavengers, which revealed that the reaction might occur through a radical
process.22 Importantly, when TBAB or CsI was employed, the reactions did not
proceed smoothly in the absence of light, which highlighted an essential role of
photoirradiation in this 1,5ꢀHAT process. Finally, we have also investigated a
preformed stoichiometric N–Br precursor to this reaction conditions (Scheme
3) and the desired δꢀbrominated product was observed (4d, 85%).
Figure 2. 1H NMR analysis of a proposed brominating reagent.
ACS Paragon Plus Environment

Page 13 of 45
The Journal of Organic Chemistry
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
Scheme 3. δꢀC(sp3)ꢀH bromination of Nsꢀsulfonamide 3d.
As expected, the initial reaction between the halogen sources and the cyclic
diacyl peroxides should lead to formation of the corresponding halogenating
reagents. To confirm this hypothesis, UV/Vis and Cyclic Voltammetry (CV)
measurements were performed with TBAX (Tetrabutylammonium halides) and
cyclic diacyl peroxides (Figure 3).22 It was observed that PPO did not absorb
above λ = 310 nm (black line), and the resulting chlorinating reagent (formed
upon mixing PPO with 1 equiv of TBACl) exhibited a similar absorption (red
line). In contrast, addition of TBAB or TBAI induced an intense and a strong
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 45
1
2
3
4
5
6
7
8
9
bathochromic shift up to λ = 340 nm (blue line) and 480 nm (green line)
respectively, probably due to the formation of a more photosensitive molecule.
Figure 3. UV/Vis Experiment of PPO with TBAX (1 equiv) in DCE.
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
Meanwhile, tetrabutylammonium 2ꢀcarboxybenzoate was successfully isolated
from our standard chlorination and bromination conditions as a byproduct. The
corresponding structure of the byproduct was established unambiguously by
single crystal Xꢀray diffraction analysis.25
On the basis of the above results, a prelimilary mechanism of δꢀbromination
was depicted in Scheme 4. With phthaloyl peroxide as oxidant, TBAB is
converted to the proposed brominating reagent, followed by
Nꢀhalogenation to
afford the labile N–X specie. ꢀhalosulfonamides, the parents of
N
Nꢀcentered
radicals, might strike a suitable balance between reactivity and stability to offer
a controlled reactivity profile. Upon irradiation, the weak N–Br bond is broken
and form a nitrogenꢀcentered radical, which can undergo 1,5ꢀH abstraction
(BDE: N–Cl = 79.8 kcalmolꢀ1; N–Br = 67.1 kcalmolꢀ1; N–I = 38.0 kcalmolꢀ1).26
ACS Paragon Plus Environment

Page 15 of 45
The Journal of Organic Chemistry
1
2
3
4
5
6
Then, the key radical recombination gives rise to δꢀbromo amides (4c),
reminiscent of the earlier reported transformations.9a,9c,23
7
8
9
Scheme 4. Plausible mechanism of δꢀbromination.
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
Conclusion
In summary, we have developed
a
new strategy for the
HofmannꢀLӧfflerꢀFreytagꢀtype chemistry using the combination of cyclic
diacyl peroxides with halides as an in situ source of haloamines. Typical
functional groups such as methyl, methoxy, fluoro, chloro, and ester were well
tolerated under the reaction conditions. We viewed this transformation as
particularly attractive due to the versatility of the
N–chloroamides,
δꢀbrominated products, as well as the construction of the valuable pyrrolidines
motif. The other performance of this unique halogenating system is currently
under investigation.
Experimental Section
Unless otherwise noted, all reagents were purchased from commercial sources and
used without further purification. All reactions were monitored by TLC and visualized
by UV lamp (254 nm)/or by staining with a solution of 10 g phosphomolybdic acid
and 100 mL EtOH followed by heating. Flash column chromatography was performed
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 45
1
2
3
4
5
6
7
8
9
using 230ꢀ400 mesh silica gel. 1H NMR (400 MHz) and 13C NMR (150 MHz) spectra
were obtained on Bruker AVꢀ400 or Bruker AVꢀ600 instrument in CDCl3. Chemical
shifts are reported in ppm from tetramethylsilane with the solvent resonance as the
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
1
internal standard. Data for H NMR spectra are reported as follows: chemical shift
(ppm, referenced to protium; s = singlet, d = doublet, t = triplet, dd = doublet of
doublets, td = triplet of doublets, m = multiplet, coupling constant (Hz), and
integration). The following abbreviations were used to designate chemical shift
multiplicities: s = singlet, d = doublet, t = triplet, m = multiplet. HRꢀESIꢀMS spectra
were recorded on a Bruker Esquire LC mass spectrometer using electrospray
ionization.
Representative Procedure for Phthaloyl Peroxide Synthesis.20a To a solution of
phthaloyl chloride (0.40 g, 1.5 mmol, 1.0 equiv) in DCM (25 mL) was added solid
sodium percarbonate (Aldrich available H2O2: 20ꢀ30%) (0.34 g, 2.2 mmol, 1.5 equiv)
in one portion. The heterogeneous reaction mixture was stirred vigorously for 3 h
(rapid stirring is required). The reaction mixture was filtered through Celite and
concentrated to provide the phthaloyl peroxide as a white solid.
CAUTION: Peroxides are dangerous and the synthesis and handling of the cyclic
peroxides should be conducted by experienced practitioners of organic synthesis using
appropriate safety equipment.
General Protection Procedure.9a,11,14 A DCM solution (25 mL) of free amine (5
o
mmol) in round bottom flask was cooled to 0 C. Triethylamine (0.76 mL, 5.5 mmol,
1.1 equiv) and dimethylaminopyridine (61.1 mg, 0.5 mmol, 0.1 equiv) were added
ACS Paragon Plus Environment

Page 17 of 45
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
into the above mixture. A DCM solution (5 mL) of sulfonyl chloride (5.5 mmol, 1.1
equiv) was then added slowly. The solution was allowed to slowly warm to room
temperature overnight. Once complete, the reaction was quenched with 1M HCl. The
aqueous layer was washed with DCM. Combined organic phases were dried with
anhydrous Na2SO4, concentrated under reduced pressure, and purified by flash
column chromatography (silica gel, petroleum ether/EtOAc 10:1 to 2:1).
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
4ꢀMethylꢀNꢀ(4ꢀphenylbutyl)benzenesulfonamide (1a, 5a).9a 1H NMR (400 MHz,
Chloroformꢀd) δ 7.78 (d, J = 7.9 Hz, 2H), 7.46 – 7.06 (m, 7H), 4.95 (t, J = 6.2 Hz,
1H), 2.96 (q, J = 6.7 Hz, 2H), 2.57 (t, J = 7.5 Hz, 2H), 2.44 (s, 3H), 1.65 – 1.58 (m,
2H), 1.55 – 1.49 (m, 2H). 13C{1H} NMR (150 MHz, Chloroformꢀd) δ 143.4, 141.9,
136.9, 129.7, 128.4, 128.3, 127.1, 125.8, 43.0, 35.3, 29.1, 28.2, 21.6.
4ꢀNitroꢀNꢀ(4ꢀphenylbutyl)benzenesulfonamide (1b, 5b).11 1H NMR (400 MHz,
Chloroformꢀd) δ 8.36 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 7.31 – 7.25 (m,
2H), 7.23 – 7.16 (m, 1H), 7.15 – 7.07 (m, 2H), 4.60 (brs, 1H, NH), 3.06 (q, J = 6.7 Hz,
2H), 2.60 (t, J = 7.3 Hz, 2H), 1.73 – 1.39 (m, 4H). 13C{1H} NMR (150 MHz,
Chloroformꢀd) δ 150.0, 146.0, 141.4, 128.4, 128.3, 128.2, 126.0, 124.4, 43.3, 35.2,
29.2, 28.1.
Nꢀ(4ꢀphenylbutyl)methanesulfonamide (1c).11 1H NMR (400 MHz, Chloroformꢀd) δ
7.36 – 7.28 (m, 2H), 7.24 – 7.20 (m, 3H), 4.92 (brs, 1H, NH), 3.17 – 3.11 (m, 2H),
2.92 (s, 3H), 2.67 (t, J = 7.5 Hz, 2H), 1.79 – 1.44 (m, 4H). 13C{1H} NMR (150 MHz,
Chloroformꢀd) δ 142.0, 128.5, 128.4, 125.9, 43.1, 40.0, 35.4, 29.6, 28.3.
4ꢀMethylꢀNꢀpentylbenzenesulfonamide (1d, 3b).11 1H NMR (400 MHz, Chloroformꢀd)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 45
1
2
3
4
5
6
7
8
9
δ 7.76 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 4.64 (brt, 1H, NH), 2.92 (q, J =
6.8 Hz, 2H), 2.43 (s, 3H), 1.45 (t, J = 7.1 Hz, 2H), 1.32 – 1.17 (m, 4H), 0.97 – 0.72
(m, 3H). 13C{1H} NMR (150 MHz, Chloroformꢀd) δ 143.4, 137.1, 129.8, 127.2, 43.3,
29.3, 28.8, 22.2, 21.6, 14.0.
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
1
Nꢀpentylmethanesulfonamide (1e). H NMR (600 MHz, Chloroformꢀd) δ 4.89 (brs,
1H, NH), 3.05 (q, J = 6.5 Hz, 2H), 2.90 (s, 3H), 1.56 –1.47 (m, 2H), 1.35 – 1.25 (m,
4H), 0.84 (t, J = 6.5 Hz, 3H). 13C{1H} NMR (150 MHz, Chloroformꢀd) δ 43.3, 39.9,
29.7, 28.7, 22.2, 14.0. HRMS (ES+) Calculated for C6H15NNaO2S+ [M+Na]+:
188.0716, found: 188.0726.
1
Nꢀheptylꢀ4ꢀmethylbenzenesulfonamide (1f, 5n). H NMR (600 MHz, Chloroformꢀd) δ
7.77 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 5.02 (t, J = 6.3 Hz, 1H), 2.92 – 2.89
(m, 2H), 2.42 (s, 3H), 1.46 – 1.41 (m, 2H), 1.30 – 1.11 (m, 8H), 0.84 (t, J = 7.2 Hz,
3H).
13C{1H} NMR (150 MHz, Chloroformꢀd) δ 143.2, 137.0, 129.7, 127.1, 43.2, 31.6,
29.5, 28.7, 26.5, 22.5, 21.5, 14.0. HRMS (ES+) Calculated for C14H23NNaO2S+
[M+Na]+: 292.1342, found: 292.1349.
Nꢀheptylꢀ4ꢀnitrobenzenesulfonamide (1g, 3c, 5m). 1H NMR (400 MHz, Chloroformꢀd)
δ 8.39 (d, J = 8.8 Hz, 2H), 8.08 (d, J = 8.9 Hz, 2H), 4.83 (t, J = 6.1 Hz, 1H), 3.03 (q, J
= 6.8 Hz, 2H), 1.53 – 1.46 (m, 2H), 1.29 – 1.23 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H).
13C{1H} NMR (150 MHz, Chloroformꢀd) δ 150.0, 146.0, 128.3, 124.4, 43.4, 31.6,
29.7, 28.7, 26.4, 22.5, 14.0. HRMS (ES+) Calculated for C13H21N2O4S+ [M+H]+:
301.1217, found: 301.1219.
ACS Paragon Plus Environment

Page 19 of 45
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2,4,6ꢀTriisopropylꢀNꢀpentylbenzenesulfonamide (1h). 1H NMR (600 MHz,
Chloroformꢀd) δ 7.16 (s, 2H), 4.38 (brs, 1H, NH), 4.17 (q, J = 6.8 Hz, 2H), 2.96 (m,
2H), 2.90 (q, J = 6.9 Hz, 1H), 1.26 (m, 24H), 0.83 (m, 3H). 13C{1H} NMR (150 MHz,
Chloroformꢀd) δ 152.7, 150.4, 132.4, 123.9, 42.9, 34.3, 29.7, 29.5, 28.9, 25.0, 23.7,
22.3, 14.0. HRMS (ES+) Calculated for C20H36NO2S+ [M+H]+: 354.2461, found:
354.2462.
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
Nꢀ(2ꢀethylhexyl)ꢀ4ꢀmethylbenzenesulfonamide (1i). 1H NMR (400 MHz,
Chloroformꢀd) δ 7.78 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 5.13 (t, J = 6.3 Hz,
1H), 2.82 (t, J = 6.0 Hz, 2H), 2.41 (s, 3H), 1.42 – 1.02 (m, 9H), 0.84 – 0.75 (m, 6H).
13C{1H} NMR (150 MHz, Chloroformꢀd) δ 143.2, 137.0, 129.6, 127.1, 45.7, 39.1,
30.6, 28.6, 23.8, 22.9, 21.5, 14.0, 10.7. HRMS (ES+) Calculated for C15H26NO2S+
[M+H]+: 284.1679, found: 284.1678.
Nꢀ(heptanꢀ2ꢀyl)ꢀ4ꢀmethylbenzenesulfonamide (1j). 1H NMR (400 MHz, Chloroformꢀd)
δ 7.79 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 4.52 (d, J = 8.0 Hz, 1H), 3.45 –
3.18 (m, 1H), 2.44 (s, 3H), 1.52 – 0.93 (m, 11H), 0.83 (t, J = 7.0 Hz, 3H). 13C{1H}
NMR (150 MHz, Chloroformꢀd) δ 143.1, 138.3, 129.6, 127.0, 50.0, 37.4, 31.4, 25.2,
22.5, 21.8, 21.5, 14.0. HRMS (ES+) Calculated for C14H23NNaO2S+ [M+Na]+:
292.1342, found: 292.1342.
Nꢀ(4ꢀmethylhexanꢀ2ꢀyl)ꢀ4ꢀnitrobenzenesulfonamide (1k). 1H NMR (400 MHz,
Chloroformꢀd) δ 8.34 (d, J = 8.5 Hz, 2H), 8.10 (d, J = 6.6 Hz, 2H), 5.39 – 5.33 (m,
1H), 3.45 – 3.40 (m, 1H), 1.48 – 0.88 (m, 8H), 0.83 – 0.56 (m, 6H). Major isomer in
13C{1H} NMR (150 MHz, Chloroformꢀd) δ 149.8, 147.4, 128.2, 124.4, 48.7, 44.7,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 45
1
2
3
4
5
6
30.9, 29.3, 22.5, 18.9, 11.0. HRMS (ES+) Calculated for C13H21N2O4S+ [M+H]+:
301.1217, found: 301.1217.
7
8
9
Methyl tosylꢀLꢀisoleucinate (1l).23 1H NMR (400 MHz, Chloroformꢀd) δ 7.72 (d, J =
8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 5.07 (d, J = 10.0 Hz, 1H), 3.80 (dd, J = 10.0,
5.5 Hz, 1H), 3.45 (s, 3H), 2.44 (s, 3H), 1.84 – 1.68 (m, 1H), 1.49 – 1.39 (m, 1H), 1.24
– 1.05 (m, 1H), 0.98 – 0.82 (m, 6H). 13C{1H} NMR (150 MHz, Chloroformꢀd) δ
171.8, 143.6, 136.6, 129.5, 127.3, 60.2, 52.1, 38.4, 24.6, 21.5, 15.3, 11.2.
1ꢀ((1S,4S)ꢀ7,7ꢀdimethylꢀ2ꢀoxobicyclo[2.2.1]heptanꢀ1ꢀyl)ꢀNꢀpentylmethanesulfonamid
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
1
e (1m). H NMR (400 MHz, Chloroformꢀd) δ 5.16 (t, J = 6.1 Hz, 1H), 3.41 (d, J =
15.1 Hz, 1H), 3.21 – 3.10 (m, 2H), 2.92 (d, J = 15.1 Hz, 1H), 2.41 (d, J = 18.6 Hz,
1H), 2.28 – 2.21 (m, 1H), 2.15 (t, J = 4.6 Hz, 1H), 2.06 – 1.91 (m, 3H), 1.60 (q, J =
7.2 Hz, 2H), 1.50 – 1.33 (m, 1H), 1.42 – 1.25 (m, 4H), 1.04 (s, 3H), 0.93 – 0.90 (m,
6H). 13C{1H} NMR (150 MHz, Chloroformꢀd) δ 217.1, 59.2, 49.2, 48.8, 43.8, 43.0,
42.8, 29.7, 28.8, 27.0, 26.7, 22.3, 19.9, 19.5, 14.0. HRMS (ES+) Calculated for
C15H27NNaO3S+ [M+Na]+: 324.1604, found: 324.1607.
1
Nꢀ(2,2,2ꢀtrifluoroethyl)pentanamide (1n). H NMR (400 MHz, Chloroformꢀd) δ 5.68
(brs, 1H, NH), 3.92 (m, 2H), 2.25 (t, J = 7.6 Hz, 2H), 1.64 (m, 2H), 1.36 (m, 2H),
0.92 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (150 MHz, Chloroformꢀd) δ 173.8, 124.1 (q, J
= 233.2 Hz), 40.4 (q, J = 34.9 Hz), 36.0, 27.5, 22.2, 13.7. HRMS (ES+) Calculated for
C7H13F3NO+ [M+H]+: 184.0944, found: 184.0939.
Nꢀtosyltetradecanamide (1o). 1H NMR (400 MHz, Chloroformꢀd) δ 8.79 (s, 1H), 7.97
(d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 2.46 (s, 3H), 2.26 (t, J = 7.5 Hz, 2H),
ACS Paragon Plus Environment

Page 21 of 45
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1.58 – 1.54 (m, 2H), 1.43 – 1.10 (m, 21H), 0.90 (t, J = 6.8 Hz, 3H). 13C{1H} NMR
(150 MHz, Chloroformꢀd) δ 171.2, 145.1, 135.6, 129.6, 128.3, 36.3, 31.9, 29.7, 29.6,
29.6, 29.4, 29.4, 29.2, 28.8, 24.3, 22.7, 21.7, 14.2. HRMS (ES+) Calculated for
C21H36NO3S+ [M+H]+: 382.2411, found: 382.2413.
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
1
4ꢀNitroꢀNꢀpentylbenzenesulfonamide (3a). H NMR (400 MHz, DMSOꢀd6) δ 8.48 –
8.35 (m, 2H), 8.04 (d, J = 8.8 Hz, 2H), 7.95 (brt, 1H, NH), 2.79 (m, 2H), 1.45 – 1.28
(m, 2H), 1.27 – 1.13 (m, 4H), 0.89 – 0.71 (m, 3H). 13C{1H} NMR (150 MHz,
DMSOꢀd6) δ 149.4, 146.2, 128.0, 124.5, 42.5, 28.6, 28.1, 21.5, 13.7. HRMS (ES+)
Calculated for C11H16N2NaO4S+ [M+Na]+: 295.0723, found: 295.0730.
1
Nꢀ(heptanꢀ2ꢀyl)ꢀ4ꢀnitrobenzenesulfonamide (3d). H NMR (400 MHz, Chloroformꢀd)
δ 8.37 (d, J = 8.8 Hz, 2H), 8.10 (d, J = 8.8 Hz, 2H), 4.94 (d, J = 8.3 Hz, 1H), 3.43 –
3.36 (m, 1H), 1.39 (q, J = 6.8 Hz, 2H), 1.30 – 1.11 (m, 6H), 1.08 (d, J = 6.5 Hz, 3H),
0.82 (t, J = 6.9 Hz, 3H). 13C{1H} NMR (150 MHz, Chloroformꢀd) δ 149.9, 147.2,
128.2, 124.3, 50.7, 37.4, 31.3, 25.2, 22.5, 21.9, 13.9. HRMS (ES+) Calculated for
C13H20N2NaO4S+ [M+Na]+: 323.1036, found: 323.1035.
4ꢀNitroꢀNꢀ(nonanꢀ5ꢀyl)benzenesulfonamide (3e).14 1H NMR (400 MHz, Chloroformꢀd)
δ 8.37 (d, J = 8.4 Hz, 2H), 8.09 (d, J = 8.4 Hz, 2H), 4.73 (d, J = 8.7 Hz, 1H), 3.31 (q,
J = 7.0 Hz, 1H), 1.53 – 1.25 (m, 4H), 1.23 – 0.92 (m, 8H), 0.80 (t, J = 6.7 Hz, 6H).
13C{1H} NMR (150 MHz, Chloroformꢀd) δ 149.8, 147.4, 128.2, 124.2, 54.8, 34.8,
27.4, 22.4, 13.9.
4ꢀNitroꢀNꢀ(tridecanꢀ7ꢀyl)benzenesulfonamide (3f). 1H NMR (400 MHz, Chloroformꢀd)
δ 8.37 (d, J = 8.4 Hz, 2H), 8.09 (d, J = 8.4 Hz, 2H), 4.72 (d, J = 8.7 Hz, 1H), 3.30 (q,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 45
1
2
3
4
5
6
7
8
9
J = 7.0 Hz, 1H), 1.53 – 1.10 (m, 20H), 0.85 (t, J = 7.1 Hz, 6H). 13C{1H} NMR (150
MHz, Chloroformꢀd) δ 149.8, 147.4, 128.2, 124.2, 54.9, 35.2, 31.6, 29.0, 25.3, 22.5,
14.0. HRMS (ES+) Calculated for C19H33N2O4S+ [M+H]+: 385.2156, found:
385.2159.
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
1
Nꢀ(heptanꢀ4ꢀyl)ꢀ4ꢀnitrobenzenesulfonamide (3g). H NMR (400 MHz, Chloroformꢀd)
δ 8.37 (d, J = 8.4 Hz, 2H), 8.09 (d, J = 8.4 Hz, 2H), 4.80 (d, J = 8.7 Hz, 1H), 3.37 –
3.30 (m, 1H), 1.58 – 1.10 (m, 8H), 0.80 (t, J = 7.3 Hz, 6H). 13C{1H} NMR (150 MHz,
Chloroformꢀd) δ 149.8, 147.4, 128.2, 124.3, 54.4, 37.3, 18.5, 13.8. HRMS (ES+)
Calculated for C13H21N2O4S+ [M+H]+: 301.1217, found: 301.1219.
Nꢀ(2ꢀethylhexyl)ꢀ4ꢀnitrobenzenesulfonamide (3h). 1H NMR (400 MHz, Chloroformꢀd)
δ 8.37 (d, J = 7.0 Hz, 2H), 8.08 (d, J = 7.0 Hz, 2H), 5.16 (t, J = 6.3 Hz, 1H), 2.92 (t, J
= 6.2 Hz, 2H), 1.42 – 1.14 (m, 9H), 0.88 – 0.75 (m, 6H). 13C{1H} NMR (150 MHz,
Chloroformꢀd) δ 150.0, 145.9, 128.3, 124.4, 46.0, 39.2, 30.5, 28.6, 23.7, 22.8, 14.0,
10.6. HRMS (ES+) Calculated for C14H23N2O4S+ [M+H]+: 315.1373, found:
315.1377.
Methyl 2ꢀ((4ꢀnitrophenyl)sulfonamido)hexanoate (3i). 1H NMR (400 MHz,
Chloroformꢀd) δ 8.36 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H), 5.44 (d, J = 9.3 Hz,
1H), 4.01 (q, J = 7.6 Hz, 1H), 3.56 (s, 3H), 1.92 – 1.60 (m, 2H), 1.35 – 1.27 (m, 4H),
0.89 – 0.86 (m, 3H). C{1H} NMR (150 MHz, Chloroformꢀd) δ 171.9, 150.1, 145.7,
13
128.5, 124.3, 55.9, 52.7, 33.0, 27.0, 22.0, 13.8. HRMS (ES+) Calculated for
C13H19N2O6S+ [M+H]+: 331.0959, found: 331.0957.
4ꢀNitroꢀNꢀ(1ꢀphenylheptyl)benzenesulfonamide (3j). 1H NMR (400 MHz,
ACS Paragon Plus Environment

Page 23 of 45
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Chloroformꢀd) δ 8.08 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.9 Hz, 2H), 7.13 – 7.08 (m,
3H), 7.04 – 6.95 (m, 2H), 5.53 (d, J = 7.7 Hz, 1H), 4.40 (q, J = 7.5 Hz, 1H), 1.90 –
1.60 (m, 2H), 1.34 – 1.14 (m, 8H), 0.85 (t, J = 6.9 Hz, 3H). 13C{1H} NMR (150 MHz,
Chloroformꢀd) δ 149.4, 146.5, 140.0, 128.5, 128.1, 127.7, 126.6, 123.7, 58.9, 37.5,
31.6, 28.7, 25.9, 22.5, 14.0. HRMS (ES+) Calculated for C19H25N2O4S+ [M+H]+:
377.1530, found: 377.1540.
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
4ꢀNitroꢀNꢀ(1ꢀphenylpentyl)benzenesulfonamide (3k). 1H NMR (400 MHz,
Chloroformꢀd) δ 8.08 (d, J = 8.9 Hz, 2H), 7.72 (d, J = 8.9 Hz, 2H), 7.17 – 7.06 (m,
3H), 7.00 – 6.94 (m, 2H), 5.34 (d, J = 7.6 Hz, 1H), 4.41 (q, J = 7.5 Hz, 1H), 1.89 –
1.65 (m, 2H), 1.36 – 1.10 (m, 4H), 0.85 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (150 MHz,
Chloroformꢀd) δ 149.4, 146.5, 140.0, 128.5, 128.1, 127.7, 126.6, 123.7, 58.9, 37.2,
28.0, 22.2, 13.8. HRMS (ES+) Calculated for C17H21N2O4S+ [M+H]+: 349.1217,
found: 349.1219.
1
Nꢀ(1ꢀ(4ꢀfluorophenyl)pentyl)ꢀ4ꢀnitrobenzenesulfonamide (3l). H NMR (400 MHz,
Chloroformꢀd) δ 8.16 (d, J = 8.9 Hz, 2H), 7.78 (d, J = 8.9 Hz, 2H), 7.00 (dd, J = 8.6,
5.3 Hz, 2H), 6.84 (t, J = 8.6 Hz, 2H), 5.46 (d, J = 7.3 Hz, 1H), 4.39 (q, J = 7.4 Hz,
1H), 1.85 – 1.62 (m, 2H), 1.35 – 1.03 (m, 4H), 0.83 (t, J = 7.1 Hz, 3H). 13C{1H} NMR
(150 MHz, Chloroformꢀd) δ 162.0 (d, J = 246.6 Hz), 149.6, 146.5, 136.1, 128.2 (d, J
= 8.0 Hz), 128.2, 123.8, 115.4 (d, J = 20.9 Hz), 58.1, 37.2, 28.0, 22.1, 13.8. 19F NMR
(376 MHz, Chloroformꢀd) δ ꢀ113.8. HRMS (ES+) Calculated for C17H20FN2O4S+
[M+H]+: 349.1217, found: 349.1219.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 45
1
2
3
4
5
6
7
8
9
1
Nꢀ(1ꢀ(4ꢀchlorophenyl)pentyl)ꢀ4ꢀnitrobenzenesulfonamide (3m). H NMR (400 MHz,
Chloroformꢀd) δ 8.16 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.5 Hz,
2H), 6.96 (d, J = 8.5 Hz, 2H), 5.52 (d, J = 7.3 Hz, 1H), 4.37 (q, J = 7.4 Hz, 1H), 1.86
– 1.60 (m, 2H), 1.33 – 1.04 (m, 4H), 0.82 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (150
MHz, Chloroformꢀd) δ 149.6, 146.4, 138.7, 133.7, 128.7, 128.2, 128.0, 123.9, 58.2,
37.0, 28.0, 22.1, 13.8. HRMS (ES+) Calculated for C17H20ClN2O4S+ [M+H]+:
383.0827, found: 383.0837.
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
Nꢀ(1ꢀ([1,1'ꢀbiphenyl]ꢀ4ꢀyl)hexyl)ꢀ4ꢀnitrobenzenesulfonamide (3n). 1H NMR (400
MHz, Chloroformꢀd) δ 8.09 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H), 7.45 (d, J =
4.3 Hz, 4H), 7.42 – 7.32 (m, 3H), 7.06 (d, J = 8.2 Hz, 2H), 5.26 (t, J = 6.5 Hz, 1H),
4.46 (q, J = 7.4 Hz, 1H), 1.88 – 1.68 (m, 2H), 1.41 – 1.16 (m, 6H), 0.91 – 0.78 (m,
3H). 13C{1H} NMR (150 MHz, Chloroformꢀd) δ 149.5, 146.6, 140.9, 140.1, 138.9,
128.9, 128.2, 127.6, 127.2, 127.1, 126.9, 123.7, 58.6, 37.3, 31.2, 25.6, 22.4, 14.0.
HRMS (ES+) Calculated for C24H27N2O4S+ [M+H]+: 439.1687, found: 439.1688.
Nꢀ(2,2ꢀdimethylꢀ4ꢀphenylbutyl)ꢀ4ꢀmethylbenzenesulfonamide (5c).9a 1H NMR (400
MHz, Chloroformꢀd) δ 7.86 – 7.70 (m, 2H), 7.38 – 7.05 (m, 7H), 4.73 (t, J = 6.9 Hz,
1H), 2.76 (d, J = 6.9 Hz, 2H), 2.62 – 2.46 (m, 2H), 2.44 (s, 3H), 1.59 – 1.47 (m, 2H),
0.95 (s, 6H). 13C{1H} NMR (150 MHz, Chloroformꢀd) δ 143.3, 142.6, 136.9, 129.8,
128.4, 128.3, 127.1, 125.7, 52.8, 41.5, 34.0, 30.3, 25.0, 21.6.
1
Nꢀ(4ꢀ(4ꢀfluorophenyl)ꢀ2,2ꢀdimethylbutyl)ꢀ4ꢀmethylbenzenesulfonamide (5d). H NMR
(400 MHz, Chloroformꢀd) δ 7.78 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.10
(dd, J = 8.2, 5.5 Hz, 2H), 6.93 (t, J = 8.5 Hz, 2H), 5.22 – 4.99 (brm, NH), 2.74 (d, J =
ACS Paragon Plus Environment

Page 25 of 45
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
6.8 Hz, 2H), 2.54 – 2.45 (m, 2H), 2.43 (s, 3H), 1.65 – 1.41 (m, 2H), 0.93 (s, 6H).
13C{1H} NMR (150 MHz, Chloroformꢀd) δ 161.1 (d, J = 251.6 Hz), 143.3, 138.2 (d, J
=2.6 Hz), 136.9, 129.7, 129.6 (d, J = 7.6 Hz), 127.0, 115.0 (d, J = 20.0 Hz), 52.7, 41.5,
34.0, 29.4, 25.0, 21.5. HRMS (ES+) Calculated for C19H25FNO2S+ [M+H]+: 350.1585,
found: 350.1590.
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
Nꢀ(4ꢀ(4ꢀchlorophenyl)ꢀ2,2ꢀdimethylbutyl)ꢀ4ꢀmethylbenzenesulfonamide (5e).9a 1H
NMR (400 MHz, Chloroformꢀd) δ 7.77 (d, J = 8.0 Hz, 2H), 7.33 – 7.28 (m, 2H), 7.22
(d, J = 8.1 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 4.85 (brt, J = 6.9 Hz, NH), 2.74 (d, J =
6.8 Hz, 2H), 2.52 – 2.46 (m, 2H), 2.44 (s, 3H), 1.57 – 1.42 (m, 2H), 0.93 (s, 6H).
13C{1H} NMR (150 MHz, Chloroformꢀd) δ 143.4, 141.1, 136.9, 131.3, 129.8, 129.7,
128.4, 127.0, 52.7, 41.3, 34.0, 29.6, 25.0, 21.6.
Nꢀ(2,2ꢀdimethylꢀ4ꢀ(pꢀtolyl)butyl)ꢀ4ꢀmethylbenzenesulfonamide (5f).9a 1H NMR (400
MHz, Chloroformꢀd) δ 7.76 (d, J = 8.2 Hz, 2H), 7.39 – 7.25 (m, 2H), 7.18 – 6.95 (m,
4H), 4.64 (d, J = 6.7 Hz, 1H), 2.75 (d, J = 6.9 Hz, 2H), 2.51 – 2.38 (m, 5H), 2.34 (s,
3H), 1.55 – 1.41 (m, 2H), 0.94 (s, 6H). 13C{1H} NMR (150 MHz, Chloroformꢀd) δ
143.3, 139.5, 137.0, 135.2, 129.7, 129.1, 128.2, 127.1, 52.8, 41.7, 34.0, 29.8, 25.0,
21.6, 21.0.
Nꢀ(4ꢀ(4ꢀmethoxyphenyl)ꢀ2,2ꢀdimethylbutyl)ꢀ4ꢀmethylbenzenesulfonamide (5g).9a 1H
NMR (400 MHz, Chloroformꢀd) δ 7.77 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H),
7.07 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 4.73 (t, J = 6.9 Hz, 1H), 3.80 (s,
3H), 2.75 (d, J = 6.9 Hz, 2H), 2.52 – 2.38 (m, 5H), 1.57 – 1.41 (m, 2H), 0.94 (s, 6H).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 45
1
2
3
4
5
6
13C{1H} NMR (150 MHz, Chloroformꢀd) δ 157.7, 143.3, 137.0, 134.6, 129.7, 129.2,
127.1, 113.8, 55.3, 52.8, 41.7, 34.0, 29.3, 25.0, 21.6.
7
8
9
4ꢀMethylꢀNꢀ((1ꢀphenethylcyclohexyl)methyl)benzenesulfonamide (5h).9a 1H NMR
(400 MHz, Chloroformꢀd) δ 7.79 (d, J = 7.8 Hz, 2H), 7.40 – 7.03 (m, 7H), 4.79 – 4.63
(m, 1H), 2.85 (d, J = 6.8 Hz, 2H), 2.44 (s, 5H), 1.65 – 1.55 (m, 2H), 1.55 – 1.19 (m,
10H). 13C{1H} NMR (150 MHz, Chloroformꢀd) δ 143.3, 142.8, 136.9, 129.8, 128.4,
128.4, 127.1, 125.7, 36.1, 33.5, 29.2, 26.1, 21.6, 21.2.
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
4ꢀMethylꢀNꢀ(2,2,4ꢀtrimethylpentyl)benzenesulfonamide (5i).9a 1H NMR (400 MHz,
Chloroformꢀd) δ 7.76 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 4.55 (t, J = 6.8 Hz,
1H), 2.69 (d, J = 6.8 Hz, 2H), 2.45 (s, 3H), 1.71 – 1.55 (m, 1H), 1.12 (d, J = 5.5 Hz,
2H), 0.89 (s, 6H), 0.88 (s, 6H). 13C{1H} NMR (150 MHz, Chloroformꢀd) δ 143.3,
137.0, 129.7, 127.1, 53.9, 48.3, 34.4, 25.3, 25.3, 24.0, 21.5.
Nꢀ(2,2ꢀdimethylhexꢀ5ꢀenꢀ1ꢀyl)ꢀ4ꢀmethylbenzenesulfonamide (5j). 1H NMR (400 MHz,
Chloroformꢀd) δ 7.77 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 3H), 5.81 – 5.71 (m,
1H), 5.05 – 4.87 (m, 2H), 4.74 (t, J = 6.8 Hz, 1H), 2.70 (d, J = 6.8 Hz, 2H), 2.44 (s,
3H), 1.98 – 1.89 (m, 2H), 1.37 – 1.25 (m, 2H), 0.87 (s, 6H). 13C{1H} NMR (150 MHz,
Chloroformꢀd) δ 143.3, 138.9, 137.0, 129.7, 127.1, 114.3, 52.9, 38.5, 33.8, 28.1, 24.8,
21.5. HRMS (ES+) Calculated for C15H24NO2S+ [M+H]+: 282.1522, found: 282.1522.
Nꢀ((1S,2R)ꢀ2ꢀ(benzyloxy)ꢀ2,3ꢀdihydroꢀ1Hꢀindenꢀ1ꢀyl)ꢀ4ꢀmethylbenzenesulfonamide
1
(5k). H NMR (400 MHz, Chloroformꢀd) δ 7.85 (d, J = 8.0 Hz, 2H), 7.47 – 7.13 (m,
11H), 5.61 (d, J = 9.1 Hz, 1H), 4.90 – 4.86 (m, 1H), 4.48 (d, J = 11.6 Hz, 1H), 4.20 (d,
J = 11.6 Hz, 1H), 4.02 – 3.99 (m, 1H), 3.08 (d, J = 16.6, 1H), 2.91 (dd, J = 16.6, 4.9
ACS Paragon Plus Environment

Page 27 of 45
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Hz, 1H), 2.48 (s, 3H). 13C{1H} NMR (150 MHz, Chloroformꢀd) δ 142.3, 139.4, 137.9,
137.0, 136.4, 128.7, 127.4, 127.2, 126.8, 126.6, 126.0, 126.0, 123.9, 123.6, 78.0, 70.2,
59.0, 34.9, 20.5. HRMS (ES+) Calculated for C23H24NO3S+ [M+H]+: 394.1471, found:
394.1478.
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
1ꢀ((1S,4S)ꢀ7,7ꢀdimethylꢀ2ꢀoxobicyclo[2.2.1]heptanꢀ1ꢀyl)ꢀNꢀ(4ꢀphenylbutyl)methanesu
lfonamide (5l). 1H NMR (600 MHz, Chloroformꢀd) δ 7.33 – 7.24 (m, 2H), 7.22 – 7.14
(m, 3H), 5.17 (d, J = 6.4 Hz, 1H), 3.37 (d, J = 15.1 Hz, 1H), 3.22 – 3.10 (m, 2H), 2.90
(d, J = 15.0 Hz, 1H), 2.65 (t, J = 7.7 Hz, 2H), 2.39 (d, J = 18.5 Hz, 1H), 2.24 – 2.18
(m, 1H), 2.17 – 1.86 (m, 4H), 1.74 – 1.69 (m, 2H), 1.66 – 1.62 (m, 2H), 1.45 (dt, J =
12.5, 6.2 Hz, 1H), 1.01 (s, 3H), 0.90 (s, 3H). 13C{1H} NMR (150 MHz, Chloroformꢀd)
δ 217.2, 142.0, 128.4, 128.4, 125.8, 59.3, 49.3, 48.9, 43.6, 43.0, 42.8, 35.4, 29.6, 28.4,
27.0, 26.7, 19.9, 19.5. HRMS (ES+) Calculated for C20H29NNaO3S+ [M+Na]+:
386.1760, found: 386.1769.
General Procedure for Synthesis of N-Cl Sulfonamides. To a mixture of an
appropriate sulfonamide (0.1 mmol) and PPO (19.7 mg, 0.12 mmol, 1.2 equiv) in a
standard Schlenk tube, TBACl (33.3 mg, 0.12 mmol, 1.2 equiv) was added. The
mixture was evacuated and backfilled with N2 (3 times). Then, the solvent DCE (2
mL) was added via syringe, and the mixture was stirred for 12 h. Upon completion,
the solvents were removed under reduced pressure and the resulting mixture was
purified by preparative TLC using petroleum ether/EtOAc as the eluent.
Nꢀchloroꢀ4ꢀmethylꢀNꢀ(4ꢀphenylbutyl)benzenesulfonamide (2a).23 Colorless oil (31.1
mg, 92% yield). 1H NMR (600 MHz, Chloroformꢀd) δ 7.73 – 7.71 (m, 2H), 7.29 (d, J
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 45
1
2
3
4
5
6
7
8
9
= 7.9 Hz, 2H), 7.21 – 7.18 (m, 2H), 7.12 – 7.09 (m, 3H), 3.15 (t, J = 6.5 Hz, 2H), 2.56
(t, J = 6.3 Hz, 2H), 2.38 (s, 3H), 1.79 – 1.54 (m, 4H). 13C{1H} NMR (150 MHz,
Chloroformꢀd) δ 145.4, 141.8, 129.8, 129.7, 129.6, 128.4, 128.4, 125.9, 56.4, 35.2,
27.7, 26.5, 21.8. HRMS (ES+) Calculated for C17H21ClNO2S+ [M+H]+: 338.0976,
found: 338.0970.
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
Nꢀchloroꢀ4ꢀnitroꢀNꢀ(4ꢀphenylbutyl)benzenesulfonamide (2b).23 White solid (35.0 mg,
95% yield). 1H NMR (600 MHz, Chloroformꢀd) δ 8.41 (d, J = 8.8 Hz, 2H), 8.10 (d, J
= 8.8 Hz, 2H), 7.35 – 7.12 (m, 5H), 3.30 – 3.28 (m, 2H), 2.67 – 2.65 (m, 2H), 1.74 –
13
1.71 (m, 4H). C{1H} NMR (150 MHz, Chloroformꢀd) δ 151.0, 141.5, 138.8, 130.7,
128.4, 128.4, 126.0, 124.2, 56.5, 35.1, 27.6, 26.4. HRMS (ES+) Calculated for
C16H17ClN2NaO4S+ [M+Na]+: 391.0490, found: 391.0493.
NꢀchloroꢀNꢀ(4ꢀphenylbutyl)methanesulfonamide (2c). Colorless oil (21.7 mg, 83%
yield). 1H NMR (600 MHz, Chloroformꢀd) δ 7.22 – 7.19 (m, 2H), 7.12 – 7.10 (m, 3H),
3.36 (t, J = 6.6 Hz, 2H), 2.97 (s, 3H), 2.58 (t, J = 7.5 Hz, 2H), 1.78 – 1.57 (m, 4H).
13C{1H} NMR (150 MHz, Chloroformꢀd) δ 141.7, 128.4, 126.0, 55.6, 35.2, 33.8, 27.7,
26.6.
HRMS (ES+) Calculated for C11H16ClNNaO2S+ [M+Na]+: 284.0482, found:
284.0489.
Nꢀchloroꢀ4ꢀmethylꢀNꢀpentylbenzenesulfonamide (2d).23 Colorless oil (23.4 mg, 85%
yield). 1H NMR (400 MHz, Chloroformꢀd) δ 7.82 (d, J = 8.4 Hz, 2H), 7.45 – 7.34 (d,
J = 8.4 Hz, 2H), 3.22 (t, J = 6.9 Hz, 2H), 2.47 (s, 3H), 1.69– 1.65 (m, 2H), 1.42 – 1.28
(m, 4H), 0.90 (s, 3H). 13C{1H} NMR (100 MHz, Chloroformꢀd) δ 145.4, 130.1, 129.8,
ACS Paragon Plus Environment

Page 29 of 45
The Journal of Organic Chemistry
1
2
3
4
5
6
129.7, 56.8, 28.3, 26.8, 22.3, 21.8, 14.1. HRMS (ES+) Calculated for
C12H18ClNNaO2S+ [M+Na]+: 298.0639, found: 298.0633.
7
8
9
1
NꢀchloroꢀNꢀpentylmethanesulfonamide (2e). Colorless oil (16.6 mg, 83% yield). 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
NMR (600 MHz, Chloroformꢀd) δ 3.41 (t, J = 7.0 Hz, 2H), 3.06 (s, 3H), 1.75 – 1.73
(m, 2H), 1.36 – 1.34 (m, 4H), 0.90 (t, J = 6.6 Hz, 3H). 13C{1H} NMR (150 MHz,
Chloroformꢀd) δ 55.9, 33.8, 28.1, 26.8, 22.2, 13.9. HRMS (ES+) Calculated for
C6H14ClNNaO2S+ [M+Na]+: 222.0326, found: 222.0332.
NꢀchloroꢀNꢀheptylꢀ4ꢀmethylbenzenesulfonamide (2f). Colorless oil (28.2 mg, 93%
yield). 1H NMR (600 MHz, Chloroformꢀd) δ 7.82 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0
Hz, 2H), 3.21 (t, J = 6.9 Hz, 2H), 2.47 (s, 3H), 1.67 (p, J = 7.0 Hz, 2H), 1.39 – 1.10
(m, 8H), 0.88 (t, J = 6.8 Hz, 3H). 13C{1H} NMR (150 MHz, Chloroformꢀd) δ 145.3,
129.8, 129.7, 129.6, 56.7, 31.7, 28.8, 27.0, 26.0, 22.6, 21.7, 14.1. HRMS (ES+)
Calculated for C14H22ClNNaO2S+ [M+Na]+: 326.0952, found: 326.0947.
NꢀchloroꢀNꢀheptylꢀ4ꢀnitrobenzenesulfonamide (2g). colorless oil (30.0 mg, 90%
yield). 1H NMR (400 MHz, Chloroformꢀd) δ 8.46 (d, J = 8.4 Hz, 2H), 8.16 (d, J = 8.4
Hz, 2H), 3.30 (t, J = 6.9 Hz, 2H), 1.71 (t, J = 7.1 Hz, 2H), 1.43 – 1.25 (m, 8H), 0.90 (t,
J = 6.5 Hz, 3H). 13C{1H} NMR (150 MHz, Chloroformꢀd) δ 151.0, 138.8, 130.7,
124.2, 56.7, 31.6, 28.7, 26.9, 25.9, 22.5, 14.1. HRMS (ES+) Calculated for
C13H19ClN2NaO4S+ [M+Na]+: 357.0646, found: 357.0647.
Nꢀchloroꢀ2,4,6ꢀtriisopropylꢀNꢀpentylbenzenesulfonamide (2h). Colorless oil (34.1 mg,
1
88% yield). H NMR (600 MHz, Chloroformꢀd) δ 7.12 (s, 2H), 4.15 – 4.10 (m, 2H),
3.46 (t, J = 6.9 Hz, 2H), 2.87 – 2.82 (m, 1H), 1.72 – 1.68 (m, 2H), 1.34 – 1.24 (m, 4H),
ACS Paragon Plus Environment