Palladium(0)-Catalyzed Carbonylative Synthesis of N-Acylsulfonamides via Regioselective Acylation

Article abstract of DOI:10.1021/acs.joc.9b00740

N-Acylsulfonamides represent an important bioisostere of carboxylic acids that allow for greater molecular elaboration and enhanced hydrogen bonding capabilities. Herein, we present a mild and convenient palladium(0)-catalyzed synthesis of N-acylsulfonamides via the carbonylative coupling of sulfonyl azides and electron-rich heterocycles. The reaction proceeds via in situ generation of a sulfonyl isocyanate followed by regioselective acylation of an indole or pyrrole nucleophile. This approach has been used to synthesize 34 indole- and pyrrole-substituted N-acylsulfonamides in yields of up to 95%. Importantly, this process is ligand-free and compatible with an ex situ solid CO source and requires only slightly elevated temperatures, making it a highly attractive method for the preparation of this important class of compounds. This study further investigated the possibility of labeling N-acylsulfonamides with carbon-11 to facilitate biological evaluation and in vivo studies with positron emission tomography.

Full text of DOI:10.1021/acs.joc.9b00740

Subscriber access provided by UNIV OF WESTERN ONTARIO
Article
Palladium(0)-Catalyzed Carbonylative Synthesis of
N-Acylsulfonamides via Regioselective Acylation
Luke Steven Schembri, Jonas Eriksson, and Luke R. Odell
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00740 • Publication Date (Web): 08 May 2019
Downloaded from http://pubs.acs.org on May 8, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
Palladium(0)-Catalyzed Carbonylative Synthesis of N-
Acylsulfonamides via Regioselective Acylation
7
8
Luke S. Schembri, Jonas Eriksson and Luke R. Odell*
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
Department of Medicinal Chemistry, Uppsala Biomedical Center, Uppsala University, P. O. Box 574, SE-751 23
Uppsala, Sweden
ABSTRACT
N-Acylsulfonamides represent an important bioisotere of carboxylic acids that allow for greater
molecular elaboration and enhanced hydrogen bonding capabilities. Herein, we present a mild
and convenient palladium(0)-catalyzed synthesis of N-acylsulfonamides via the carbonylative
coupling of sulfonyl azides and electron-rich heterocycles. The reaction proceeds via in situ
generation of a sulfonyl isocyanate followed by regioselective acylation of an indole or pyrrole
nucleophile. This approach has been used to synthesize 34 indole and pyrrole-substituted N-
acylsulfonamides in yields of up to 95%. Importantly, this process is ligand-free, compatible
with an ex situ solid CO-source and requires only slightly elevated temperatures making it a
highly attractive method for the preparation of this important class of compounds. This study
further investigated the possibility of labelling N-acylsulfonamides with carbon-11 to facilitate
biological evaluation and in vivo studies with positron emission tomography.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 38
1
2
3
4
GRAPHICAL ABSTRACT
5
6
H
O
O
O
S
S
7
8
9
R1
N
R2
N
H
N-
N
O
R3
R2
O
O
O
O
N+
Pd(OAc)2
CO
R3
C
S
S
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R1
R1
N
N
R3
O
O
O
Sulfonyl
Mo(CO)6
N
Isocyanate
R1
R2
N
H
Ligand Free
Regioselective
Low CO-pressure
Ex situ CO source
Mild and convenient
COOH bioisostere
34 examples
Up to 95% yield
INTRODUCTION
N-Acylsulfonamides are a useful carboxylic acid bioisostere; they are hydrolytically and
enzymatically stable,1 and possess a similar pKa range and greater hydrogen bonding capability
compared to carboxylic acids. However, unlike carboxylic acids, they can be further elaborated
to modulate both physicochemical2 and biological properties.3,4 Figure 1 shows this bioisostere
is indeed already present in a variety of currently marketed drugs, drug candidates and
pharmacological tools, in particular, the anti-Hepatitis C drugs beclabuvir,5 asunaprevir,5
danoprevir,6 paritaprevir,7 and glecaprevir,8 with the latter given as a combination with
pibrentasvir to treat all forms of Hepatitis C. It is also present in a number of antibacterials,9
anti-cancer agents,10,11 and anti-platlet aggregating agents.12
ACS Paragon Plus Environment

Page 3 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
O
O
O
O
S
O
S
N
O
NH
H
N
NH
O
O
O
HN
O
O
O
N
H
N
O
O
O
N
N
N
O
F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
N
NH
NH
H
O
O
N
H
H
O
O
S
O
N
Cl
Asunaprevir
Beclabuvir
Danoprevir
F
F
O
S
O
N
N
O
O
NH
O
N
H
O
H
N
O
N
O
HN
O
H
O
O
O
S
N
O
S
O
NH
NH HN
O
N
O
O
O
H
O
HN
N
N
F
F
O
Paritaprevir
Glecaprevir
Anti-bacterial Agent
Cl
Cl
Cl
S
O-
O N+
O
O
O
S
O
O
N
N
O
O
Cl
Br
O
NH
HN
S
NH
S
S
O
N
O
O
Cl
O
O
H
O
S
Cl
Cl
N
NH
N
H
Anti-platlet aggregating agent
(Human Prostaglandin EP3
antagonist)
Anti-cancer agents Venetoclax (Bcl-2 inhibitor, left) and LY573636 (right)
Figure 1. Marketed drugs and pre-clinical compounds containing the acylsulfonamide moiety.
Their prevalence has therefore spurred interest in the discovery of novel and reliable synthetic
methods for their preparation. The most commonplace method is coupling acyl chlorides with
sulfonamides13 or carboxylic acids with sulfonamides with the aid of coupling reagents such as
EDCI.14 There has however, been a shift away from these methods as acyl chlorides can be
difficult to handle, often requiring strictly anhydrous conditions to avoid hydrolysis. While
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 38
1
2
3
4
5
6
7
8
9
coupling reagents can give satisfactory yields, they can lead to excessive waste and certain by-
products such as DCU can be difficult to remove. Reactive sulfonyl isocyanates have also been
employed but their hydrolytic instability also lends itself to handling difficulties and
consequently, a lack of derivatives that are commercially available.15
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
Recently, sulfonyl azides have been employed instead of sulfonamides, which can be easily
synthesized from their corresponding sulfonyl chlorides16 or amides.17 This has resulted in the
development of new methods including reactions with alkynes18 and, interestingly, carboxylic
acids via an in situ formed selenocarboxylate.19 Shangguan and coworkers have also discovered
a simple method of reacting thioacids with sulfonyl azides in good yields.20 More recently,
Fang et al described a novel method involving the catalytic coupling of carboxylic acids and
sulfonyl azides by Co(CO)8 with a rather broad substrate scope but requiring harsher
conditions.21
Palladium-catalyzed carbonylative syntheses are a convenient means of preparing a range of
carbonyl derived functional groups such as carbamates, ureas, amides and imides.22 This
approach is particularly useful for preparing isotopically labelled target molecules by
employing isotopically modified carbon monoxide (i.e. labelled with carbon-11, carbon-13 or
carbon-14).23–25 The carbonylative synthesis of acylsulfonamides via the coupling of aryl
halides with alkyl and aryl sulfonamides has been previously reported (Scheme 1).26,27
However these methods employ harsh conditions, lead to the formation of halide salt waste and,
in the work of Schnyder et al,27 involve the use of palladium ligands and elevated CO-pressures.
Based on previous efforts on the carbonylative coupling of sulfonyl azides,28–31 we envisioned
an efficient route to 3-acyl indole and 2-acyl pyrrole derivatives via the in situ formation and
subsequent capture of a sulfonyl isocyanate intermediate by an electron-rich heterocycle. A
literature survey revealed precedent for the direct reaction between sulfonyl azides and indoles
through a cycloaddition and subsequent ring-opening cascade32 or a palladium-catalyzed N-
ACS Paragon Plus Environment

Page 5 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
arylation process33 both of which presented potential synthetic challenges. Herein we describe
the development of palladium catalyzed synthesis of acylsulfonamides via the carbonylative
acylation of indole and pyrrole nucleophiles with sulfonyl azides (Scheme 1). Notably, the
reaction allows mild and efficient access to new chemical space, is more environmentally
benign compared to previous carbonylation methods relying on the use of aryl halides, is
compatible with low CO-pressures and convenient ex situ CO-generation and does not require
the addition of base or external palladium ligands. To the best of our knowledge, this is also the
first example of the carbonylation of an azide substrate with a carbon-based nucleophile.
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 1. Previous and present work on the carbonylative synthesis of N-acylsulfonamides
and known reactions between indoles and sulfonyl azides.
Previous Work
PdCl2(PPh3)2, PPh3, NEt3
5 bar CO, 120 °C, 15 h
(a)
(b)
O
O
O
O
R1
O
Or
+
S
Ar
X
S
NH2
R1
N
Ar
Pd(OAc)2, Mo(CO)6
DBU, 110 °C, 15 min
H
O
O
N
O
N
R1
S
Pd(TFA)2
PPh3, 40 °C
H
N
N-
HN
DMSO
R2 = H
O
O
O
N+
S
S
+
R2
R1
R1
R2 = Ar
N
R2
N
R3
N
N
R3
R3
Current Work
H
O
O
O
S
S
(c)
R2
R1
N
H
N
R3
N-
Pd(OAc)2
40 °C, 20 h
O
O
O
N
O
O
N+
R2
C
S
R3
S
R1
R1
N
N
Mo(CO)6
CO
R3
O
O
O
N
Ex situ CO source
Low CO-pressure
Regioselective
Mild and convenient
R1
R2
N
H
RESULTS AND DISCUSSION
The optimization of reaction conditions (Table 1) began using tosyl azide (1a) and 1-
methylindole (2a) as model substrates with Pd(OAc)2 as the catalyst and MeCN as the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 38
1
2
3
4
5
6
7
8
solvent/ligand.29 The reaction setup followed that of our previous studies: a two-chamber setup
was employed consisting of a carbonylation chamber and a CO-generation chamber to produce
CO gas ex situ via DBU mediated ligand displacement with Mo(CO)6.
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
Pleasingly, this led to the formation of the desired product in 56% yield (entry 1). During our
initial investigations, formation of the competing indolin-2-imine side-product 3a´32 was
observed (LCMS analysis) even prior to the addition of catalyst. In order to overcome this
problem, it was necessary to mix the azide and indole in the final stages of the reaction set-up.
This practical adjustment coupled with a modulations of reagent stoichiometry (entries 2 and
3) led to a significant improvement in yield, with the best result obtained using a slight excess
of 1a (85%, entry 2). An increase in CO concentration was trialed with no improvement (entry
4) and a reduction in catalyst loading (entry 5) led to a slight decline in yield. The use of mixed
solvent systems for the carbonylation chamber (entries 6 and 7) were also investigated. While
the use of MeCN was thought to be required as a ligand for the palladium-catalysed
carbonylative coupling process, the complete loss of reactivity when THF was used as a co-
solvent was surprising. Accordingly, the use of 1,4-dioxane as a solvent also afforded no
product (not shown). Surveying of different temperatures (entries 8 to 10) resulted in a marked
decrease in yield to 14% when performed at room temperature and no significant change for an
increase in temperature to 65 °C. This did however, afford the option of increasing the reaction
temperature during analogue synthesis when employing less-reactive substrates. Finally, the
use of anhydrous MeCN (entry 11) in the carbonylation chamber led to the formation of 3a in
an improved in yield of 95%. This is likely due to suppression of the competing hydrolytic
degradation of the sulfonyl isocyanate intermediate due to the absence of water.
ACS Paragon Plus Environment

Page 7 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
Table 1. Optimization of reaction conditionsa
7
8
9
O
O
O
O
O
O
O
S
Pd(OAc)2
S
S
N
N
N
N3
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
Me
H
Me
conditions
N
Me
Me
Me
e
1a
2a
3a
3a´
entry
1
2
time (h)
20
temp (oC)
1a equiv
1
2a equiv
solvent
yield (%)b
40
40
40
40
40
40
40
65
40
rt
1
1
1.3
1
1
1
1
1
1
1
MeCN
MeCN
MeCN
MeCN
MeCN
56
85
75
85
80
-
20
20
20
20
20
20
20
20
1.3
1
3
4c
5d
6
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1:9 MeCN:THF
1:1 MeCN:THF
MeCN
7
8
9
10
11
-
84
85
14
95
MeCN
MeCN
20
20
40
1
Dry MeCN
a Reagents and conditions: (a) Carbonylation chamber 1: N-methylindole (0.5 mmol), Tosyl azide (1.3 equiv), 5
mol% Pd(OAc)2, 2 mL solvent; CO-generation chamber: Mo(CO)6 (0.6 equiv), DBU (1.5 equiv), MeCN (2 mL).
b Isolated yield. c 0.8 equiv and 2.4 equiv of Mo(CO)6 and DBU used respectively. d 2 mol% Pd(OAc)2.
The reaction conditions in entry 11 were employed for the synthesis of a small library of
analogues and, in all cases, purification was achieved by column chromatography or
recrystallization without the need for a laborious workup. Initially, the scope and limitations
of the indole component was examined using a set of substrates with varying electronic and
steric properties (Table 2). Substitution on the heterocyclic nitrogen (3a-3f) gave yields that
correlated well with electronic effects and the more electron-rich analogues 3a and 3b gave
high yields of 95% and 89%, respectively. The introduction of an electron-withdrawing acyl
group completely abolished reactivity (3d) as did the presence of a Boc-group (not shown).
Substitution with a phenyl group in entry 3c resulted in an interesting middle ground where,
unlike other electron deficient indoles, the reaction proceeded to completion and the desired
product was isolated in good yield of 68%. Pleasingly, the presence of a free N-H group was
also well-tolerated with indole and 6-methyl indole affording acylsulfonamides 3e and 3f in
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 38
1
2
3
4
5
6
95% and 70% yields, respectively. This may be due to the absence of a strong base, which could
lead to deprotonation of the nitrogen, thereby increasing its nucleophilicity.34
7
8
9
Varying the methyl group position resulted in no discernable difference in the reaction outcome
(3g to 3k). Notably, the introduction of a bulky 2-phenyl substituent was also well-tolerated
and the highly sterically congested 3l was obtained in 84% yield. Indoles containing electron-
donating groups (3m and 3n) performed well as substrates, giving yields of 77% and 76%
respectively. A similar yield was also obtained in the presence of a moderately electron-
withdrawing chloro group (3o, 79%). In accordance with their decreased nucleophilicity,
substrates bearing strongly electron-withdrawing nitro- and cyano- groups were found to be
less reactive furnishing 3p and 3q in moderate yields. Unfortunately, the carbonylative coupling
of 7-aza indole (3r) did not result in product formation, even under more forcing reaction
conditions.
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. Substrate scope for the synthesis of indole analoguesa,b
O
O
O
O
O
R3
R2
S
R3
S
N
N3
+
N
R1
H
N
R1
R2
Me
Me
1a
2a-r
3a-r
O
O
O
O
O
O
O
O
O
S
S
S
N
N
N
H
H
H
N
Bn
N
Ph
N
Me
Me
Me
Me
Me
Me
d
c
3b
3c
, 68%
, 89%
3a
, 95%, 87%
O
Me
O
O
O
O
O
O
O
O
S
S
S
N
N
N
H
H
H
N
Ac
N
H
N
Me
H
3d
3e
, 95%
, -
3f
, 70%
Me
Me
O
O
O
O
O
O
O
O
O
S
S
N
S
N
N
H
H
N
Me
H
N
Me
Me
Me
N
Me
Me
Me
Me
3g
, 89%
3h
, 90%
O
3i
, 91%
O
O
O
O
O
O
O
O
Me
S
S
S
N
N
N
H
H
H
Me
N
N
Me
N
Me
Me
Ph
3l
, 84%
Me
Me
3j
3k
, 90%
, 78%
ACS Paragon Plus Environment

Page 9 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
OMe
MeO
O
O
O
O
Cl
O
O
O
O
O
S
S
N
S
N
N
H
H
N
Me
H
N
Me
Me
N
Me
Me
Me
3o
, 79%
3n
, 76%
3m
, 77%
NO2
CN
O
O
O
O
O
O
O
O
O
S
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
S
S
N
H
H
N
N
Me
H
Me
N
N
Me
Me
Me
Me
3r
, trace
e
3p
, 38%
3q
, 26%
a Reagents and conditions: (a) Carbonylation chamber: Indole (0.5 mmol), Tosyl azide (1.3 equiv), 5 mol%
Pd(OAc)2, Dry MeCN (2 mL); CO-generation chamber: Mo(CO)6 (0.6 equiv), DBU (1.5 equiv), MeCN (2 mL);
N2, 40oC, 20 h. b Isolated yields. c 1.03 mmol scale d 9 days. e Nitroindole (3 equiv) and tosyl azide (1 equiv).
Next, we turned our attention to exploring the scope of the reaction with respect to the sulfonyl
azide component (Table 3). Importantly, the majority of these analogues could be easily
purified from their reaction mixtures by filtration followed by precipitation or recrystallization.
With the exception of the bromo analogue 4f, the reaction was generally compatible with
sulfonyl azides containing electron-donating (4a, 4b, 4d) or electron-withdrawing groups (4e,
4g, 4h, 4i, 4j) to give the corresponding acylsulfonamides in good to excellent yields (56% -
92%). The presence of an ortho-chloro substituent (4g) was also well-tolerated, however the
introduction of two ortho-isopropyl groups (4c) was deleterious for the reaction indicating an
upper-limit for acceptance of steric bulk. Pleasingly, heteroaryl azides were also found to be
productive substrates affording moderate to good yields of the diheterocyclic derivatives 4k, 4l
and 4m. The presence of a basic and potentially coordinating nitrogen (4m and 4n) was
detrimental to the reaction and, in the case of 4n, only trace amounts of the pyridine derivative
4n were observed (LCMS analysis). Notably, the reaction scope could be extended beyond aryl
sulfonyl azides with aliphatic and benzylic sulfonyl azides returning good yields of the
corresponding sp3-carbon linked products (4o, 4p, 4q and 4r). Finally, we explored the use of
alkyl and aryl azide containing substrates, however no conversion to the desired products was
observed under our reaction conditions. This is somewhat surprising given the successful
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 38
1
2
3
4
5
6
carbonylative coupling of azide derivatives and may be due to more electron-deficient nature
of sulfonyl azides.35–37
7
8
9
Table 3. Sulfonyl azide scope for the synthesis of acylsulfonamidesa,b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
O
O
(a)
S
S
R1
+
R1
N
N3
N
H
N
Me
Me
1b-s
2a
4a-r
O
O
iPr
O
O
O
O
O
O
O
O
O
MeO
MeO
S
S
S
N
N
H
N
H
H
N
N
N
Me
MeO
MeO
iPr
Br
iPr
Me
Me
4a
4b
4c
, 75%
O
, 71%
, -
O
O
O
O
O
O
S
S
S
N
H
N
N
H
H
N
N
Me
N
AcHN
Me
Me
4e
4f
, trace
4d
, 77%
, 56%
Cl
O
O
O
O
O
O
O
O
O
Cl
Cl
S
S
F3C
S
N
N
N
H
H
H
N
Me
N
Me
NC
4g
4i
, 73%
, 89%
O
O
O
O
O
O
O
O
O
S
S
S
N
N
N
Cl
H
H
H
S
S
N
Me
N
N
O2N
Me
Me
Cl
4j
4k
4l
, 79%
O
, 81%
O
, 89%
O
O
O
O
O
O
O
S
S
Me
S
N
N
N
N
H
H
H
N
Me
N
N
N
N
Me
4m
Me
Me
Me
4n
4o
, 73%
, 44%
, trace
O
O
O
O
O
O
O
O
O
Me
S
MeO
S
S
N
N
N
H
H
H
O
N
Me
N
N
Me
Me
4p
4q
, 73%
, 70%
4r
, 93%
a Reagents and conditions: (a) Carbonylation chamber: 1-methylindole (0.5 mmol), sulfonyl azide (1.3 equiv), 5
mol% Pd(OAc)2, Dry MeCN (2 mL); CO-generation chamber: Mo(CO)6 (0.6 equiv), DBU (1.5 equiv), MeCN (2
mL); N2, 40oC, 20 h. b Isolated yields.
To further extend the scope of the developed method, the use of pyrrole nucleophiles was
investigated (Table 4). Pyrroles bearing N-methyl and N-phenyl groups were efficiently
coupled with tosyl azide and the target compounds 6a and 6b were obtained in good yields.
Similarly, a free N-H group was also well tolerated (6c), however the introduction of an
electron-withdrawing formyl group (6d) completely abolished reactivity. Finally, the ambident
nucleophile 6e was used to explore chemoselectively and resulted in almost exclusive formation
ACS Paragon Plus Environment

Page 11 of 38
The Journal of Organic Chemistry
1
2
3
4
of sulfonyl urea derivative 6é, indicating a significant preference for aminocarbonylation30 over
5
6
pyrrole acylation under these conditions.
7
8
9
Table 4. Exploring pyrrole derived nucleophilesa,b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
O
O
(a)
S
S
R2
N3
+
N
H
N
N
Me
O
R1
5a e
Me
R1
6a-é
R2
O
1a
-
O
O
O
H
O
O
O
O
O
S
S
S
N
N
N
H
Me
H
H
N
N
N
N
Ph
Me
Me
Me
6a
6b
6c
, 77%
, 76%
, 84%
O
O
O
O
S
N
H
O
Me
S
N
N
H
H
H
N
N
N
Me
S
Me
Me
O
O
O
O
NH2
H
6é
6d
, 46%
, -
6e
, -
a Reagents and conditions: (a) Carbonylation chamber: 1-methylindole (0.5 mmol), sulfonyl azide (1.3 equiv), 5
mol% Pd(OAc)2, Dry MeCN (2 mL); CO-generation chamber: Mo(CO)6 (0.6 equiv), DBU (1.5 equiv), MeCN (2
mL); N2, 40oC, 20 h. b Isolated yields.
Based on our previous studies29,30,38 and the work of others,35–37 a plausible reaction mechanism
is depicted in Figure 2. Firstly, the Pd(II) pre-catalyst is reduced to the active Pd(0) species,
presumably under the action of CO.39 This is supported by control reactions conducted in the
absence of or with sub-stoichiometric amounts of CO, which led to no product formation or
incomplete conversion to the acyl sulfonamide product and direct N-heteroarylation,
respectively. Oxidative addition of the palladium center to the sulfonyl azide substrate generates
the nitrene intermediate (A in Figure 2) and carbon monoxide coordination followed by
migratory insertion leads to the key sulfonyl isocyanate intermediate (B in Figure 2). Finally,
nucleophilic attack by an indole or pyrrole derivative generates the final acyl sulfonamide
products. Control experiments support the intermediacy of a sulfonyl isocyante as the reaction
of tosyl amide with N-methylindole led to no product formation while the direct reaction of
tosyl isocyanate with 1-methylindole gave acyl sulfonamide 3a in 68% yield.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 38
1
2
3
4
5
6
O
O
O
S
R1
Pd(OAc)2
CO
N
H
N
R2
O
S
N3
R1
7
8
9
O
Pd(0)Ln
H
N2
N
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
R2
O
O
S
R1
LnPd
N
R1
O
C
N
S
O
O
PdLn
B
A
O
CO
C
O
S
L Pd
N
R1
O
Figure 2. Plausible mechanism for the synthesis of N-acylsulfonamides. L = MeCN or CO
A brief investigation into the utility of the method for isotopic labelling was performed by
employing [11C]CO to synthesize the acyl sulfonamide [11C]3a (Figure 3). Compounds labelled
with carbon-11, a positron emitting radionuclide with a half-life of 20.4 min, could be used as
radiotracers in biomedical research and clinical routine with positron emission tomography
(PET). Carbonylation with [11C]CO differs from the standard transition-metal-catalyzed
carbonylation as the rapid physical decay of the radionuclide necessitate very short reaction
times, typically less than 10 min, so as to not compromise radiochemical yields. This
prerequisite is helped by the minute quantities of [11C]CO employed in labelling reactions,
typically in the range of 10-50 nmol. The high molar activity (GBq/µmol) of cyclotron produced
carbon-11 and the high sensitivity of PET scanners, enables administration of labelled
compounds at trace quantities (a few nanomoles), for most compounds well below the
pharmacologically active dose. The labelling reactions are optimized with regards to [11C]CO,
and all other reagents, including the catalyst, are employed in large excess de facto, ruling out
a propagating catalytic cycle.
ACS Paragon Plus Environment

Page 13 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
O
Pd2(dba)3
PPh3
O
O
O
O
11C
S
S
[11C]CO
N3
N
+
+
N
H
N
Me
THF, 5 min
130°C
Me
Me
Me
1a
2a
[
11C]3a
10-15%
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
Figure 3. Synthesis of [11C]3a by palladium mediated (0.67 equiv Pd2(dba)3 relative to 1a)
carbonylation with [11C]CO.
The optimized reaction conditions for 3a were used as the starting point and [11C]CO was
transferred to the reaction vial in a stream of xenon. The remarkable solubility of the transfer
gas in the reaction solvent facilitated high recovery of [11C]CO at ambient pressure conditions
while using a non-vented vial.28,40–43 Initially, the desired product [11C]3a was not observed but
when increasing the temperature to 90°C or 120°C the product was detectable by radio-HPLC
analysis. However, at these elevated temperatures the reaction mixture was heterogeneous and
accurate quantification was not possible due to low recovery of radioactive material from the
HPLC column. It was also suspected that due to the minute amounts of [11C]CO used, it could
be partially consumed in a process where Pd(II) was reduced to Pd(0)-species via the water-
gas-shift-reaction.44,45 This result was in agreement with control reactions conducted with sub-
stoichiometric amounts of isotopically unmodified CO and further studies with Pd(II) pre-
catalysts was therefore abandoned.
Instead, the reaction was carried out using a Pd(0) source (Pd2(dba)3) and PPh3 as a ligand at
120°C for 5 min. Gratifyingly, compound [11C]3a was obtained in 2.4% radiochemical yield
and when the temperature was increased to 140°C, the yield was slightly improved (5.2%),
however this was accompanied by palladium black precipitation. At 130°C the product was
obtained in 10% and 15% radiochemical yield (n=2) with good product selectivity (57% and
73%) and moderate conversion of [11C]CO (18% and 21%). The compound was identified by
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 38
1
2
3
4
5
6
7
8
9
analytical radio-UV-HPLC and co-elution of [11C]3a (radio trace) with the reference compound
3a (UV-trace). In comparison with the method optimized for CO, the substochiometric amounts
of [11C]CO required the Pd(II)-precatalyst to be exchanged for a catalytically active Pd(0)-
complex and the reaction temperature significantly increased for the reaction kinetics to match
the short timeframe given by the half-life of carbon-11. Importantly, the identified labelling
conditions provide sufficient quantities of [11C]3a to enable pre-clinical PET evaluation and
are excellent starting point for further investigations into the synthesis of 11C-labelled N-
acylsulfonamides.46 Moreover, this is to the best of our knowledge, the first reported example
of a C-H bond acylation reaction using [11C]CO.
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, a mild and convenient method for the carbonylative synthesis of valuable acyl
sulfonamide products has been developed. The combination of in situ isocyanate generation
from a convenient solid CO-source, ligand-free catalyst system and regioselective acylation
make this an attractive synthetic strategy. Moreover, its efficiency has been demonstrated
through the synthesis of 34 analogues in yields of up to 95% using a diverse array of indoles,
pyrroles and sulfonyl azides. The methodology was also successfully modified for carbon-11
labelling, exemplified by [11C]3a which was obtained in 10-15% radiochemical yield. This
work further highlights the utility of sulfonyl azides in carbonylative syntheses and provides a
valuable tool for the synthesis of this important and pharmaceutically relevant class of
compounds.
ACS Paragon Plus Environment

Page 15 of 38
The Journal of Organic Chemistry
1
2
3
4
EXPERIMENTAL
5
6
7
General information. Analytical thin-layer chromatography (TLC) was performed on silica
8
9
gel 60 F-254 plates and visualized with UV light. Flash column chromatography was performed
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
13
on silica gel 60 (40-63 µm). H and C{1H} spectra were recorded at 400 and 100 MHz,
respectively. The chemical shifts for 1H NMR and 13C{1H} NMR are referenced to TMS via
residual solvent signals (1H: CD3OD at 3.31 ppm, CDCl3 at 7.26 ppm and DMSO-d6 at 2.50
ppm; 13C{1H}: CD3OD at 49.0 ppm, CDCl3 at 77.16 ppm and DMSO-d6 at 39.52 ppm).
Analytical HPLC/ESI-MS was performed using electrospray ionization (ESI) and a C18
column (50×3.0 mm, 2.6 µm particle size, 100 Å pore size) with CH3CN/H2O in 0.05% aqueous
HCOOH as mobile phase at a flow rate of 1.5 ml/min. LC purity analyses were run using a
gradient of 5-100% CH3CN/H2O in 0.05% aqueous HCOOH as mobile phase at a flow rate of
1.5 ml/min for 5 mins unless otherwise stated on a C18 column. High resolution molecular
masses (HRMS) were determined on a mass spectrometer equipped with an ESI source and
time-of-flight (TOF) or Fourier transform-ion cyclotron resonance mass analyzer as indicated.
General Procedure for the Synthesis of sulfonyl azides as exemplified by the synthesis of
methyl 3-(azidosulfonyl)propanoate (1r): A solution of methyl 3-(chlorosulfonyl)propanoate
(312 mg, 1.67 mmol) in acetone (10 mL) was added dropwise to a solution of sodium azide
(173 mg, 2.66 mmol) in water (3 mL) in a round-bottom flask. After 20 h, the solution was
added to water (30 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers
were washed with water (25 mL) followed by saturated NaHCO3 solution (25 mL), dried with
brine and MgSO4, filtered and the resulting solution evaporated in vacuo to give methyl 3-
1
(azidosulfonyl)propanoate as a clear oil (259 mg, 80%). H NMR (CDCl3) δ 3.75 (s, 3H), 3.66
(t, J = 7.3 Hz, 2H), 2.91 (t, J = 7.3 Hz, 2H); 13C{1H} NMR (CDCl3) δ 170.0 (C), 52.8 (CH2),
51.1 (CH2), 28.4 (CH3); HRMS (ESI-FT ICR) m/z: [M + Na]+ Calcd for C4H7N3O4SNa
216.0050: Found 216.0049.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 38
1
2
3
4
5
6
7
8
2,3,4-trichlorobenzenesulfonyl azide (1h): Yellow liquid (274 mg, 66%). 1H NMR (CDCl3)
δ 7.99 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 8.7 Hz, 2H); 13C{1H} NMR (CDCl3) δ 141.2 (C), 136.9
(C), 135.46 (C), 133.2 (C), 129.4 (CH), 128.7 (CH).
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
1-Methyl-1H-imidazole-4-sulfonyl azide (1n): Clear crystals (435 mg, 82%). 1H NMR
13
(CDCl3) δ 7.62 (d, J = 1.3 Hz, 1H), 7.57 (d, J = 1.0 Hz, 1H), 3.80 (s, 3H); C{1H} NMR
(CDCl3) δ 140.0 (CH), 139.0 (C), 125.7 (CH), 34.4 (CH3); M.P: 60 – 62 °C; HRMS (ESI-FT
ICR) m/z: [M + Na]+ Calcd for C4H5N5O2SNa 210.0056: Found 210.0057.
General Procedure for the Synthesis of N-Acylsulfonamides as exemplified by the
synthesis of 1-methyl-N-tosyl-1H-indole-3-carboxamide (3a): N-Methylindole (53.4 mg,
0.407 mmol) and tosyl azide (104 mg, 0.529 mmol) were weighed in separate vials. Palladium
(II) acetate (4.5 mg, 0.02 mmol) was added to the reaction chamber of an oven-dried H-tube
(carbonylation chamber) and Mo(CO)6 (65.6 mg, 0.248 mmol) to the CO generating chamber
(CO-generation chamber). The azide and indole were then added to carbonylation as a solution
in dry acetonitrile (2 mL), both chambers were then capped and the entire system purged twice
with N2 gas. 1,8-Diazabicyclo(5.4.0)undec-7-ene (93 µL, 0.622 mmol) was finally added as an
MeCN solution (2 mL) via syringe to commence CO generation. The reaction was then stirred
vigorously at 40oC for 20 h. The contents of the carbonylation chamber were then purified by
column chromatography (30 to 75% EtOAc in pentane and 0.1% HCOOH) to give the product
as light-orange crystals (127 mg, 95%. 1.03 mmol scale 295 mg, 87%). 1H NMR (DMSO-d6)
δ 11.85 (br s, 1H), 8.35 (s, 1H), 7.94 – 7.83 (m, 1H), 7.94 – 7.83 (m, 2H), 7.55 – 7.48 (m, 1H),
7.46 – 7.38 (m, 2H), 7.25 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 7.17 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H),
3.84 (s, 3H), 2.38 (s, 3H); 13C{1H} NMR (DMSO-d6) δ 161.6 (C), 143.7 (C), 137.5 (C), 136.9
(C), 135.4 (CH), 129.4 (2×CH), 127.6 (2×CH), 126.5 (C), 122.8 (CH), 121.8 (CH), 120.8 (CH),
110.8 (CH), 106.5 (C), 33.4 (CH3), 21.1 (CH3); mp: 195 – 197 °C; HRMS (ESI-TOF) m/z: [M
- H]- Calcd for C17H15N2O3S 327.0803: Found 327.0802; LC purity (254 nm) = >99%.
ACS Paragon Plus Environment

Page 17 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
1-Benzyl-N-tosyl-1H-indole-3-carboxamide (3b): Purified by column chromatography (30 to
75% EtOAc in pentane and 0.1% HCOOH) and recrystalisation from hot minimal MeCN to
give the product as pale yellow crystals (140 mg, 89%). 1H NMR (DMSO-d6) δ 11.94 (s, 1H),
8.49 (s, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.43
(d, J = 8.3 Hz, 2H), 7.38 – 7.27 (m, 5H), 7.24 – 7.12 (m, 2H), 5.48 (s, 2H), 2.38 (s, 3H);13C{1H}
NMR (DMSO-d6) δ 161.6 (C), 143.8 (C), 137.4 (C), 136.8 (C), 136.2 (C), 134.9 (CH), 129.4
(2×CH), 128.7 (2×CH), 127.8 (CH), 127.6 (2×CH), 127.5 (2×CH), 126.6 (C), 122.9 (CH),
121.9 (CH), 120.9 (CH), 111.1 (CH), 107.1 (C), 49.8 (CH2), 21.1 (CH3); mp: 233 – 234 °C;
HRMS (ESI-TOF) m/z: [M - H]- Calcd for C23H19N2O3S 403.1116: Found 403.1121; LC purity
(254 nm) = >99%.
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
1-Phenyl-N-tosyl-1H-indole-3-carboxamide (3c): Was stirred at 40 °C for 9 days instead of 20
h. Purified by column chromatography (20:80:0.1 to 50:50:0.1 Pentane:EtOAc:HCOOH)
followed by recrystalisation in hot MeCN to give the product as white crystals (116 mg, 68%).
1H NMR (DMSO-d6) δ 12.00 (br s, 1H), 8.71 (s, 1H), 8.14 – 8.06 (m, 1H), 7.93 (d, J = 8.3 Hz,
2H), 7.69 – 7.61 (m, 4H), 7.56 – 7.49 (m, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.31 – 7.23 (m, 2H),
13
2.39 (s, 3H); C{1H} NMR (DMSO-d6) δ 161.6 (C), 143.9 (C), 137.8 (C), 137.2 (C), 135.7
(C), 134.3 (CH), 130.1 (2×CH), 129.5 (2×CH), 127.9 (CH), 127.7 (2×CH), 127.0 (C), 124.3
(2×CH), 123.9 (CH), 122.7 (CH), 121.3 (CH), 111.2 (CH), 108.9 (C), 21.1 (CH3); M.P: 206 –
208 °C; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C22H17N2O3S 389.0960: Found 389.0972;
LC purity (254 nm) = 98%.
N-Tosyl-1H-indole-3-carboxamide (3e): Purified by column chromatography (30 to 75%
EtOAc in pentane and 0.1% HCOOH) to give the product as a dark brown solid (120 mg, 95%).
1H NMR (DMSO-d6) δ 11.94 (s, 1H), 11.84 (s, 1H), 8.38 (d, J = 3.2 Hz, 1H), 7.98 (d, J = 7.8
Hz, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.48 – 7.39 (m, 3H), 7.18 (ddd, J = 8.2, 7.2, 1.3 Hz, 1H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 38
1
2
3
4
5
6
7
8
9
7.12 (ddd, J = 8.0, 7.1, 1.1 Hz, 1H), 2.38 (s, 3H); 13C{1H} NMR (DMSO-d6) δ 161.9, 143.7,
137.5, 136.2, 131.7 (CH), 129.4 (2×CH), 127.6 (2×CH), 126.1 (C), 122.8 (CH), 121.5 (CH),
120.7 (CH), 112.2 (CH), 107.6 (C), 21.1 (CH3); HRMS (ESI-TOF) m/z: [M - H]- Calcd for
C16H13N2O3S 313.0647: Found 313.0643; LC purity (254 nm) = >99%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Methyl-N-tosyl-1H-indole-3-carboxamide (3f): Purified by column chromatography
(65:30:5:0.1 Pentane:EtOAc:Toluene:HCOOH) to give the product as a purple oil (100 mg,
70%). 1H NMR (DMSO-d6) δ 11.87 (s, 2H), 8.08 (d, J = 3.1 Hz, 1H), 7.90 (d, J = 8.3 Hz, 2H),
7.43 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.1 Hz, 1H), 7.11 – 7.02 (m, 1H), 6.85 (d, J = 7.2 Hz, 1H),
2.43 (s, 3H), 2.39 (s, 3H); 13C{1H} NMR (DMSO-d6) δ 162.4 (C), 143.6 (C), 137. (2×C), 136.9
(C), 132.2 (CH), 130.6 (C), 129.4 (2×CH), 127.5 (2×CH), 124.2 (C), 123.0 (CH), 122.8 (CH),
109.9 (CH), 109.6 (C), 21.7 (CH3), 21.1 (CH3); HRMS (ESI-TOF) m/z: [M - H]- Calcd for
C17H15N2O3 327.0803: Found 327.0792; LC purity (254 nm) = >99%.
1,2-Dimethyl-N-tosyl-1H-indole-3-carboxamide (3g): Purified by column chromatography (30
to 75% EtOAc in pentane and 0.1% HCOOH) to give the product as a beige solid (126 mg,
89%). 1H NMR (DMSO-d6) δ 11.64 (br s, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7.80 – 7.74 (m, 1H),
7.52 – 7.46 (m, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.23 – 7.16 (m, 2H), 3.67 (s, 3H), 2.56 (s, 3H),
2.39 (s, 3H); 13C{1H} NMR (DMSO-d6) δ 163.2 (C), 144.1 (C), 143.6 (C), 137.7 (C), 136.1
(C), 129.4 (2×CH), 127.7 (2×CH), 125.3 (C), 121.9 (CH), 121.1 (CH), 119.7 (CH), 110.1 (CH),
105.7 (C), 29.6 (CH3), 21.1 (CH3), 11.8 (CH3); HRMS (ESI-TOF) m/z: [M - H]- Calcd for
C18H17N2O3S 341.0960: Found 341.0963; LC purity (254 nm) = >99%.
1,4-Dimethyl-N-tosyl-1H-indole-3-carboxamide (3h): Purified by column chromatography (30
to 75% EtOAc in pentane and 0.1% HCOOH) and recrystalisation from minimal MeCN to give
the product as colorless crystals (144 mg, 87%). 1H NMR (DMSO-d6) δ 11.89 (s, 1H), 8.10 (s,
1H), 7.92 – 7.86 (m, 2H), 7.46 – 7.40 (m, 2H), 7.32 (dt, J = 8.3, 0.9 Hz, 1H), 7.14 (dd, J = 8.3,
ACS Paragon Plus Environment

Page 19 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7.2 Hz, 1H), 6.91 (dt, J = 7.2, 1.0 Hz, 1H), 3.81 (s, 3H), 2.43 (s, 3H), 2.39 (s, 3H); 13C{1H}
NMR (DMSO-d6) δ 162.1 (C), 143.6 (C), 137.4 (C), 137.4 (C), 136.0 (CH), 130.8 (C), 129.4
(2×CH), 127.5 (2×CH), 124.6 (C), 123.3 (CH), 122.8 (CH), 108.5 (C), 108.2 (CH), 33.2 (CH3),
21.5 (CH3), 21.1 (CH3); mp: 117 – 119 °C; HRMS (ESI-TOF) m/z: [M - H]- Calcd for
C18H17N2O3S 341.0960: Found 341.0968; LC purity (254 nm) = >99%.
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
1,5-Dimethyl-N-tosyl-1H-indole-3-carboxamide (3i): Purified by column chromatography (30
to 75% EtOAc in pentane and 0.1% HCOOH) and recrystalisation from minimal hot MeCN to
1
give the product as a light-orange solid (150 mg, 91%). H NMR (DMSO-d6) δ 11.80 (br s,
1H), 8.28 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.78 (s, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.39 (d, J =
8.7 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 3.80 (s, 3H), 2.38 (s, 3H), 2.36 (s, 3H); 13C{1H} NMR
(DMSO-d6) δ 161.6 (C), 143.7 (C), 137.5 (C), 135.3 (CH), 135.3 (C), 130.8 (C), 129.4 (2×CH),
127.6 (2×CH), 126.8 (C), 124.2 (CH), 120.5 (CH), 110.4 (CH), 106.0 (C), 33.4 (CH3), 21.1
(CH3), 21.0 (CH3); HRMS (ESI-TOF) m/z: [M - H]- Calcd for C18H17N2O3S 341.0960: Found
341.0956; LC purity (254 nm) = >99%.
1,6-Dimethyl-N-tosyl-1H-indole-3-carboxamide (3j): Purified by column chromatography (30
to 75% EtOAc in pentane and 0.1% HCOOH) to give a light-brown solid (149 mg, 90%). 1H
NMR (DMSO-d6) δ 11.82 (br s, 1H), 8.27 (s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 8.1 Hz,
1H), 7.41 (d, J = 8.1 Hz, 2H), 7.30 (s, 1H), 7.00 (d, J = 8.2 Hz, 1H), 3.79 (s, 3H), 2.40 (s, 3H),
2.37 (s, 3H); 13C{1H} NMR (DMSO-d6) δ 161.6 (C), 143.7 (C), 137.5 (C), 137.3 (C), 134.9
(CH), 132.2 (C), 129.4 (2×CH), 127.6 (2×CH), 124.3 (C), 123.5 (CH), 120.5 (CH), 110.5 (CH),
106.4 (C), 33.3 (CH3), 21.3 (CH3), 21.0 (CH3); HRMS (ESI-TOF) m/z: [M - H]- Calcd for
C18H17N2O3S 341.0960: Found 341.0957; LC purity (254 nm) = >99%.
1,7-Dimethyl-N-tosyl-1H-indole-3-carboxamide (3k): Purified by column chromatography (30
to 75% EtOAc in pentane and 0.1% HCOOH) to give a light-brown solid (129 mg, 78%). 1H
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 38
1
2
3
4
5
6
7
8
9
NMR (DMSO-d6) δ 11.78 (s, 1H), 8.23 (s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.84 (d, J = 7.8 Hz,
1H), 7.41 (d, J = 8.3 Hz, 2H), 7.00 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 7.1 Hz, 1H), 4.06 (s, 3H),
2.69 (s, 3H), 2.37 (s, 3H); 13C{1H} NMR (DMSO-d6) δ 161.5 (C), 143.7 (C), 137.5 (C), 136.9
(CH), 135.5 (C), 129.4 (2×CH), 127.6 (C), 127.6 (2×CH), 125.3 (CH), 122.3 (C), 121.9 (CH),
118.9 (CH), 105.9 (C), 37.4 (CH3), 21.0 (CH3), 18.9 (CH3); HRMS (ESI-TOF) m/z: [M - H]-
Calcd for C18H17N2O3S 341.0960: Found 341.0966; LC purity (254 nm) = >99%.
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-Methyl-2-phenyl-N-tosyl-1H-indole-3-carboxamide
(3l):
Purified
by
column
chromatography (30 to 75% EtOAc in pentane and 0.1% HCOOH) and recrystalisation from
minimal MeCN to give the product as pale yellow crystals (167 mg, 84%). 1H NMR (DMSO-
d6) δ 11.02 (s, 1H), 7.82 – 7.72 (m, 3H), 7.59 (d, J = 8.1 Hz, 1H), 7.56 – 7.47 (m, 3H), 7.45 –
7.35 (m, 4H), 7.31 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.25 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 3.59 (s,
13
3H), 2.41 (s, 3H); C{1H} NMR (DMSO-d6) δ 162.5 (C), 144.0 (C), 143.8 (C), 137.1 (C),
136.5 (C), 130.7 (2×CH), 129.5 (C), 129.3 (3×CH), 128.3 (2×CH), 127.6 (2×CH), 125.5 (C),
122.8 (CH), 121.6 (CH), 120.0 (CH), 110.9 (CH), 107.2 (C), 31.0 (CH3), 21.1 (CH3); mp: 181
– 183 °C; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C23H19N2O3S 403.1116: Found 403.1106;
LC purity (254 nm) = >99%.
5-Methoxy-1-methyl-N-tosyl-1H-indole-3-carboxamide (3m): Purified by column
chromatography (30 to 75% EtOAc in pentane and 0.1% HCOOH) to give the product as dark
brown solid (112 mg, 80%). 1H NMR (DMSO-d6) δ 11.84 (br s, 1H), 8.32 (s, 1H), 7.92 (d, J =
8.4 Hz, 2H), 7.51 (d, J = 2.5 Hz, 1H), 7.46 – 7.34 (m, 3H), 6.87 (dd, J = 8.9, 2.5 Hz, 1H), 3.79
(s, 3H), 3.74 (s, 3H), 2.35 (s, 3H); 13C{1H} NMR (DMSO-d6) δ 161.7 (C), 155.5 (C), 143.7
(C), 137.6 (C), 135.5 (CH), 131.9 (C), 129.5 (2×CH), 127.6 (2×CH), 127.4 (C), 112.9 (CH),
111.6 (CH), 106.1 (C), 102.3 (CH), 55.3 (CH3), 33.5 (CH3), 21.0 (CH3); HRMS (ESI-TOF)
m/z: [M - H]- Calcd for C18H17N2O4S 357.0909: Found 357.0920; LC purity (254 nm) =
>99%.
ACS Paragon Plus Environment

Page 21 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
4-Methoxy-1-methyl-N-tosyl-1H-indole-3-carboxamide (3n): Purified by column
chromatography (30 to 75% EtOAc in pentane and 0.1% HCOOH) to give the product as dark
brown crystals (114 mg, 77%). 1H NMR (DMSO-d6) δ 11.83 (br s, 1H), 8.05 (s, 1H), 7.92 (d,
J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.32 – 7.17 (m, 2H), 6.90 (d, J = 7.5 Hz, 1H), 4.08
(s, 3H), 3.79 (s, 3H), 2.39 (s, 3H); 13C{1H} NMR (DMSO-d6) δ 160.1 (C), 150.9 (C), 144.2
(C), 139.0 (C), 137.6 (CH), 136.5 (C), 129.5 (2×CH), 127.7 (2×CH), 123.8 (CH), 112.8 (C),
107.5 (C), 105.4 (CH), 103.4 (CH), 56.3 (CH3), 33.4 (CH3), 21.1 (CH3); mp: 208 – 210 °C;
HRMS (ESI-TOF) m/z: [M - H]- Calcd for C18H17N2O4S 357.0909: Found 357.0923; LC
purity (254 nm) = >99%.
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
6-Chloro-1-methyl-N-tosyl-1H-indole-3-carboxamide
(3o):
Purified
by
column
chromatography (20 to 75% EtOAc in pentane and 0.1% HCOOH) to give the product as a
brown solid (150 mg, 79%). 1H NMR (DMSO-d6) δ 11.96 (br s, 1H), 8.36 (s, 1H), 7.95 (d, J =
8.5 Hz, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 1.8 Hz, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.18
(dd, J = 8.5, 1.9 Hz, 1H), 3.83 (s, 3H), 2.37 (s, 3H); 13C{1H} NMR (DMSO-d6) δ 161.4 (C),
143.8 (C), 137.4 (C), 137.3 (C), 136.3 (CH), 129.4 (2×CH), 127.6 (C and 2×CH as per HMBC),
125.2 (C), 122.1 (2 CH as per HSQC), 110.9 (CH), 106.8 (C), 33.5 (CH3), 21.1 (CH3); HRMS
(ESI-TOF) m/z: [M - H]- Calcd for C17H14ClN2O3S 361.0414: Found 361.0405; LC purity (254
nm) = >99%.
1-Methyl-5-nitro-N-tosyl-1H-indole-3-carboxamide (3p): 3 Equiv of indole used instead of
1:1.3 indole:azide.. Purified by column chromatography (50 to 100% EtOAc in pentane and
0.1% HCOOH) and recrystalisation from minimal MeCN to give the product as green crystals
(58 mg, 38%). 1H NMR (DMSO-d6) δ 12.18 (s, 1H), 8.82 (d, J = 1.7 Hz, 1H), 8.55 (s, 1H), 8.19
– 8.04 (m, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 9.1 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H), 3.92
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 38
1
2
3
4
5
6
7
8
9
(s, 3H), 2.39 (s, 3H); 13C{1H} NMR (DMSO-d6) δ 161.1 (C), 144.0 (C), 142.6 (C), 139.8 (C),
138.8 (CH), 137.0 (C), 129.5 (2×CH), 127.7 (2×CH), 125.8 (C), 118.0 (CH), 117.2 (CH), 111.8
(CH), 108.4 (C), 33.9 (CH3), 21.1 (CH3); mp: 238 – 239 °C; HRMS (ESI-TOF) m/z: [M - H]-
Calcd for C17H14N3O5S 372.0654: Found 372.0644; LC purity (254 nm) = 98%.
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
5-Cyano-1-methyl-N-tosyl-1H-indole-3-carboxamide
(3q):
Purified
by
column
chromatography (25 to 100% EtOAc in pentane and 0.1% HCOOH) to give the product as a
beige solid (46 mg, 26%). 1H NMR (DMSO-d6) δ 12.10 (br, s, 1H), 8.50 (s, 1H), 8.33 (dd, J =
1.5, 0.5 Hz, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.77 – 7.72 (m, 1H), 7.63 (dd, J = 8.6, 1.6 Hz, 1H),
13
7.43 (d, J = 8.0 Hz, 2H), 3.89 (s, 3H), 2.39 (s, 3H); C{1H} NMR (DMSO-d6) δ 161.3 (C),
143.9 (C), 138.6 (C), 137.7 (CH), 137.2 (C), 129.5 (2×CH), 127.6 (2×CH), 126.1 (C), 125.8
(CH), 125.6 (CH), 119.8 (C), 112.5 (CH), 107.3 (C), 104.1 (C), 33.7 (CH3), 21.1 (CH3); HRMS
(ESI-TOF) m/z: [M - H]- Calcd for C18H14N3O3S 352.0756: Found 352.0750; LC purity (254
nm) = >99%.
N-((3,4-Dimethoxyphenyl)sulfonyl)-1-methyl-1H-indole-3-carboxamide (4a): Purified by
column chromatography (50 to 75% EtOAc in pentane and 0.1% HCOOH) to give the product
as maroon crystals (154 mg, 75%). 1H NMR (DMSO-d6) δ 11.75 (s, 1H), 8.33 (s, 1H), 8.03 –
7.96 (m, 1H), 7.62 (dd, J = 8.5, 2.2 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 2.2 Hz, 1H),
7.25 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.21 – 7.14 (m, 2H), 3.84 (s, 3H), 3.84 (s, 3H), 3.83 (s,
13
3H); C{1H} NMR (DMSO-d6) δ 161.6 (C), 152.6 (C), 148.2 (C), 136.9 (C), 135.4 (CH),
131.8 (C), 126.5 (C), 122.8 (CH), 121.8 (CH), 121.7 (CH), 120.8 (CH), 111.1 (CH), 110.8 (CH),
110.2 (CH), 106.6 (C), 55.9 (CH3), 55.8 (CH3), 33.4 (CH3); mp: 172 – 174 °C; HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C18H19N2O5S 375.1015: Found 375.1022; LC purity (254 nm)
= 98%.
ACS Paragon Plus Environment

Page 23 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
N-((4-Methoxyphenyl)sulfonyl)-1-methyl-1H-indole-3-carboxamide (4b): Purified by column
chromatography (30 to 75% EtOAc in pentane and 0.1% HCOOH) to give the product as
brown-green crystals (124 mg, 71%). 1H NMR (DMSO-d6) δ 11.78 (s, 1H), 8.34 (s, 1H), 7.99
(d, J = 7.9 Hz, 1H), 7.98 – 7.90 (m, 2H), 7.51 (d, J = 8.2 Hz, 1H), 7.29 – 7.20 (m, 1H), 7.22 –
7.09 (m, 3H), 3.83 (s, 6H); 13C{1H} NMR (DMSO-d6) δ 162.8 (C), 161.6 (C), 136.9 (C), 135.4
(CH), 131.8 (C), 129.9 (2×CH), 126.5 (C), 122.8 (CH), 121.8 (CH), 120.8 (CH), 114.1 (2×CH),
110.7 (CH), 106.5 (C), 55.7 (CH3), 33.4 (CH3); mp: 177 – 179 °C; HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C17H17N2O4S 345.0909: Found 345.0919; LC purity (254 nm) = 99%.
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-((4-Acetamidophenyl)sulfonyl)-1-methyl-1H-indole-3-carboxamide (4d): Purified by
dissolving the material in minimal DMF, filtering any black solid (Pd black), and precipitating
and washing with MeCN to give the product as a grey solid (104 mg, 56%). 1H NMR (DMSO-
d6) δ 11.82 (br s, 1H), 10.35 (s, 1H), 8.33 (s, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 8.7 Hz,
2H), 7.78 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.1 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 7.5
Hz, 1H), 3.83 (s, 3H), 2.08 (s, 3H); 13C{1H} NMR (DMSO-d6) δ 169.0 (C), 161.7 (C), 143.4
(C), 136.9 (C), 135.4 (CH), 133.9 (C), 128.8 (2×CH), 126.5 (C), 122.7 (CH), 121.8 (CH), 120.8
(CH), 118.3 (2×CH), 110.7 (CH), 106.7 (C), 33.3 (CH3), 24.1 (CH3); HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C18H18N3O4S 372.1018: Found 372.1003; LC purity (254 nm) = >99%.
N-((3-Methoxyphenyl)sulfonyl)-1-methyl-1H-indole-3-carboxamide
(4e):
Purified
by
dissolving the material in acetone, filtering any solid (Pd black), and recrystallizing and
washing with MeCN to give the product as brown crystals, (136 mg, 77%). 1H NMR (DMSO-
d6) δ 11.91 (s, 1H), 8.35 (s, 1H), 8.05 – 7.92 (m, 1H), 7.65 – 7.42 (m, 4H), 7.31 – 7.22 (m, 2H),
7.22 – 7.12 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H); 13C{1H} NMR (DMSO-d6) δ 161.6 (C), 159.1
(C), 141.5 (C), 136.9 (C), 135.6 (CH), 130.3 (CH), 126.5 (C), 122.8 (CH), 121.9 (CH), 120.8
(CH), 119.4 (CH), 118.8 (CH), 112.7 (CH), 110.8 (CH), 106.5 (C), 55.6 (CH3), 33.4 (CH3);
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 38
1
2
3
4
5
mp: 168 – 170 °C; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H17N2O4S 345.0909: Found
345.0902; LC purity (254 nm) = >99%.
6
7
8
9
1-Methyl-N-((2,3,4-trichlorophenyl)sulfonyl)-1H-indole-3-carboxamide (4g): Purified by
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
dissolving the material in acetone, filtering any solid (Pd black), and recrystallizing and
1
washing with MeCN to give the product as opaque white crystals (156 mg, 73%). H NMR
(DMSO-d6) δ 12.54 (br s, 1H), 8.50 (s, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.98 – 7.89 (m, 2H), 7.53
(d, J = 8.2 Hz, 1H), 7.25 (ddd, J = 8.3, 7.2, 1.2 Hz, 1H), 7.16 (ddd, J = 8.0, 7.2, 0.9 Hz, 1H),
13
3.87 (s, 3H); C{1H} NMR (DMSO-d6) δ 161.5 (C), 138.2 (C), 138.0 (C), 137.0 (C), 136.1
(CH), 132.6 (C), 131.1 (CH), 130.7 (C), 129.2 (CH), 126.5 (C), 123.0 (CH), 122.0 (CH), 120.8
(CH), 110.9 (CH), 105.9 (C), 33.5 (CH3); mp: 201 – 203 °C; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C16H12Cl3N2O3S 416.9634: Found 416.9635; LC purity (254 nm) = 95%.
1-Methyl-N-((3-(trifluoromethyl)phenyl)sulfonyl)-1H-indole-3-carboxamide (4h): Purified by
column chromatography (25 to 75% EtOAc in pentane and 0.1% HCOOH) to give the product
as beige crystals (156 mg, 86%). 1H NMR (DMSO-d6) δ 12.14 (br s, 1H), 8.35 (s, 1H), 8.34 –
8.30 (m, 1H), 8.27 (s, 1H), 8.13 – 8.08 (m, 1H), 7.99 – 7.94 (m, 1H), 7.91 (t, J = 7.9 Hz, 1H),
7.53 (d, J = 8.2 Hz, 1H), 7.26 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 7.18 (ddd, J = 8.1, 7.1, 1.1 Hz,
1H), 3.85 (s, 3H); 13C{1H} NMR (DMSO-d6) δ 161.7 (C), 141.5 (C), 137.0 (C), 136.0 (CH),
131.6 (CH), 130.9 (CH), 130.2 (q, J = 3.2 Hz, CH), 130.1 – 129.0 (m, C), 126.4 (C), 124.1 (q,
J = 3.9 Hz, CH), 123.4 (q, J = 274.8 Hz, CF3), 122.9 (CH), 122.0 (CH), 120.7 (CH), 110.9
(CH), 106.2 (C), 33.4 (CH3); mp: 191 – 193 °C; HRMS (ESI-FT ICR) m/z: [M + Na]+ Calcd
for C17H13F3N2O3SNa 405.0491: Found 405.0490; LC purity (254 nm) = >99%.
N-((4-Cyanophenyl)sulfonyl)-1-methyl-1H-indole-3-carboxamide (4i): Purified by filtering and
washing the solid with cold MeCN to give the product as a cream-colored solid (142 mg, 88%).
1H NMR (DMSO-d6) δ 12.20 (br s, 1H), 8.36 (s, 1H), 8.17 (d, J = 8.2 Hz, 2H), 8.12 (d, J = 8.6
ACS Paragon Plus Environment

Page 25 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Hz, 2H), 7.99 – 7.92 (m, 1H), 7.56 – 7.50 (m, 1H), 7.26 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 7.18
(ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 3.85 (s, 3H); 13C{1H} NMR (DMSO-d6) δ 161.7 (C), 144.2 (C),
137.0 (C), 136.0 (CH), 133.3 (2×CH), 128.3 (2×CH3), 126.4 (C), 122.9 (CH), 122.0 (CH), 120.7
(CH), 117.6 (C), 115.7 (C), 110.9 (CH), 106.2 (C), 33.4 (CH3); HRMS (ESI-FT ICR) m/z: [M
+ Na]+ Calcd for C17H13N3O3SNa 362.0570: Found 362.0569; LC purity (254 nm) = >99%.
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-Methyl-N-((4-nitrophenyl)sulfonyl)-1H-indole-3-carboxamide (4j): Purified by dissolving
the material in minimal DMF, filtering any black solid (Pd black), and precipitating and
washing with MeCN to give the product as a yellow solid (155 mg, 79%). 1H NMR (DMSO-
d6) δ 12.26 (br s, 1H), 8.51 – 8.43 (m, 2H), 8.37 (s, 1H), 8.30 – 8.19 (m, 2H), 7.95 (d, J = 7.9
Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.30 – 7.23 (m, 1H), 7.22 – 7.13 (m, 1H), 3.86 (s, 3H);
13C{1H} NMR (DMSO-d6) δ 161.7 (C), 150.1 (C), 145.5 (C), 137.0 (C), 136.0 (CH), 129.1
(2×CH), 126.4 (C), 124.5 (2×CH), 122.9 (CH), 122.0 (CH), 120.7 (CH), 110.9 (CH), 106.2 (C),
33.4 (CH3); HRMS (ESI-TOF) m/z: [M - H]- Calcd for C16H12N3O5S 358.0498: Found
358.0503; LC purity (254 nm) = >99%.
N-((4,5-Dichlorothiophen-2-yl)sulfonyl)-1-methyl-1H-indole-3-carboxamide (4k): Purified by
column chromatography (75% EtOAc in pentane and 0.1% HCOOH) followed by
recrystallization and washing with minimal MeCN to give the product as purple crystals (65
mg, 81%). 1H NMR (DMSO-d6) δ 12.44 (br s, 1H), 8.34 (s, 1H), 8.06 (ddd, J = 7.8, 1.4, 0.8 Hz,
1H), 7.91 (s, 1H), 7.56 (ddd, J = 8.2, 1.0, 0.8 Hz, 1H), 7.29 (ddd, J = 8.3, 7.1, 1.4 Hz, 1H), 7.23
(ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 3.86 (s, 3H); 13C{1H} NMR (DMSO-d6) δ 161.9 (C), 138.0 (C),
137.0 (C), 136.1 (CH), 132.0 (CH), 131.2 (C), 126.4 (C), 123.5 (C), 123.0 (CH), 122.1 (CH),
120.8 (CH), 110.9 (CH), 106.2 (C), 33.5 (CH3); mp,: 168 – 170 °C; HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C14H11Cl2N2O3S2 388.9588: Found 388.9590; LC purity (254 nm) = >99%.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 38
1
2
3
4
5
6
7
8
9
1-Methyl-N-(thiophen-2-ylsulfonyl)-1H-indole-3-carboxamide (4l): Purified by dissolving the
material in acetone and minimal DMF, filtering any solid (Pd black), recrystallizing by slow
evaporation of the solution and washing with cold MeCN to give the product as brown crystals,
(145 mg, 89%). 1H NMR (DMSO-d6) δ 12.08 (s, 1H), 8.34 (s, 1H), 8.04 (ddd, J = 7.8, 1.4, 0.8
Hz, 1H), 8.01 (dd, J = 5.0, 1.4 Hz, 1H), 7.85 (dd, J = 3.8, 1.4 Hz, 1H), 7.53 (ddd J = 8.2, 1.0,
0.8 Hz, 1H), 7.27 (ddd, J = 8.2, 7.1, 1.3 Hz, 1H), 7.23 – 7.18 (m, 2H), 3.84 (s, 3H); 13C{1H}
NMR (DMSO-d6) δ 161.6 (C), 140.7 (C), 136.9 (C), 135.6 (CH), 134.1 (CH), 133.8 (CH), 127.3
(CH), 126.5 (C), 122.9 (CH), 121.9 (CH), 120.8 (CH), 110.8 (CH), 106.4 (C), 33.4 (CH3); mp:
214 – 216 °C; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H13N2O3S2 321.0368: Found
321.0368; LC purity (254 nm) = 98%.
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-Methyl-N-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1H-indole-3-carboxamide (4m): Purified
by washing the solid with acetone, recrystallizing in DMSO (0.4 mL) and washing the residual
solid with DCM to give the product as cream-colored crystals (64 mg, 44%). 1H NMR (DMSO-
d6) δ 11.72 (s, 1H), 8.38 (s, 1H), 8.03 – 7.99 (m, 1H), 7.98 (d, J = 1.4 Hz, 1H), 7.75 (d, J = 1.4
Hz, 1H), 7.54 – 7.50 (m, 1H), 7.25 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 7.18 (ddd, J = 8.1, 7.1, 1.1
Hz, 1H), 3.84 (s, 3H), 3.73 (s, 3H); 13C{1H} NMR (DMSO-d6) δ 161.4 (C), 139.3 (CH), 138.6
(C), 136.9 (C), 135.2 (CH), 126.6 (C), 126.5 (CH), 122.7 (CH), 121.7 (CH), 120.9 (CH), 110.7
(CH), 106.8 (C), 33.6 (CH3), 33.4 (CH3); mp: 246 – 248 °C; HRMS (ESI-FT ICR) m/z: [M +
Na]+ Calcd for C14H14N4O3SNa 341.0679: Found 341.0679; LC purity (254 nm) = >99%.
N-(Isopropylsulfonyl)-1-methyl-1H-indole-3-carboxamide (4o): Purified by dissolving the
material in minimal DMF, filtering any black solid (Pd black), and recrystallizing and washing
with MeCN to give the product as light-green crystals (110 mg, 73%). 1H NMR (DMSO-d6) δ
11.37 (s, 1H), 8.38 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.34 – 7.26 (m,
1H), 7.26 – 7.16 (m, 1H), 3.94 – 3.87 (m, 1H), 3.86 (s, 3H), 1.33 (d, J = 6.9 Hz, 6H); 13C{1H}
NMR (DMSO-d6) δ 162.6 (C), 137.0 (C), 135.5 (CH), 126.7 (C), 122.8 (CH), 121.9 (CH), 120.9
ACS Paragon Plus Environment

Page 27 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
(CH), 110.8 (CH), 106.5 (C), 52.7 (CH), 33.4 (CH3), 15.6 (2×CH3); mp: 225 – 227 °C; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C13H17N2O3S 281.00960: Found 281.0971; LC purity (254
nm) = 97%.
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
N-(Butylsulfonyl)-1-methyl-1H-indole-3-carboxamide (4p): Purified by dissolving the material
in minimal DMF, filtering any black solid (Pd black), and recrystallizing and washing with
MeCN to give the product as yellow crystals (100 mg, 70%). 1H NMR (DMSO-d6) δ 11.45 (s,
1H), 8.36 (s, 1H), 8.14 – 8.07 (m, 1H) , 7.58 – 7.51 (m, 1H) , 7.29 (ddd, J = 8.2, 7.0, 1.4 Hz,
1H), 7.23 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 3.86 (s, 3H), 3.57 – 3.46 (m, 2H), 1.69 (p, J = 7.5 Hz,
2H), 1.42 (h, J = 7.4 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (DMSO-d6) δ 162.6 (C),
137.0 (C), 135.5 (CH), 126.7 (C), 122.8 (CH), 121.9 (CH), 120.9 (CH), 110.8 (CH), 106.5 (C),
52.4 (CH2), 33.4 (CH3), 25.1 (CH2), 20.7 (CH2), 13.5 (CH3); m: 158 – 159 °C; HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C14H19N2O3S 295.1116: Found 295.1117; LC purity (254 nm)
= 99%.
Methyl 3-(N-(1-methyl-1H-indole-3-carbonyl)sulfamoyl)propanoate (4q): Purified by diluting
the material with 150 mL ether, washing with water (3 × 50 mL), brine, drying with MgSO4
and evaporating the ether to give a cream-colored solid (108 mg, 73%). 1H NMR (DMSO-d6) δ
11.56 (s, 1H), 8.35 (s, 1H), 8.11 (ddd, J = 7.7, 1.4, 0.7 Hz, 1H), 7.56 (ddd, J = 8.1, 1.0, 0.7 Hz,
1H), 7.29 (ddd, J = 8.2, 7.1, 1.4 Hz, 1H), 7.24 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 3.86 (s, 3H), 3.80
(t, J = 7.2 Hz, 2H), 3.58 (s, 3H), 2.81 (t, J = 7.1 Hz, 2H); 13C{1H} NMR (DMSO-d6) δ 170.5
(C), 162.5 (C), 137.0 (C), 135.6 (CH), 126.6 (C), 122.9 (CH), 121.9 (CH), 120.9 (CH), 110.8
(CH), 106.5 (C), 51.9 (CH3), 48.4 (CH2), 33.4 (CH3), 28.2 (CH2); HRMS (ESI-FT ICR) m/z:
[M + Na]+ Calcd for C14H16N2O5SNa 347.0672: Found 347.0671; LC purity (254 nm) = >99%.
N-(Benzylsulfonyl)-1-methyl-1H-indole-3-carboxamide (4r): Purified by dissolving the
material in acetone, filtering any solid (Pd black), and recrystallizing and washing with MeCN
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 38
1
2
3
4
5
6
7
8
9
to give the product as small crystals (151 mg, 91%). 1H NMR (DMSO-d6) δ 11.39 (br s, 1H),
8.28 – 8.13 (m, 2H), 7.55 (d, J = 7.9 Hz, 1H), 7.37 – 7.23 (m, 7H), 4.83 (s, 2H), 3.83 (s, 3H);
13C{1H} NMR (DMSO-d6) δ 163.4 (C), 137.0 (C), 135.3 (CH), 130.7 (2×CH), 129.8 (C), 128.5
(2×CH), 128.3 (CH), 126.8 (C), 122.7 (CH), 121.8 (CH), 121.1 (CH), 110.8 (CH), 107.2 (C),
58.3 (CH2), 33.4 (CH3); mp: 211 – 212 °C; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C17H17N2O3S 329.0960: Found 329.0951; LC purity (254 nm) = >99%.
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-Methyl-N-tosyl-1H-pyrrole-2-carboxamide (6a): Purified by column chromatography (30 to
75% EtOAc in pentane and 0.1% HCOOH) followed by recrystallization in minimal hot ethanol
to give the product as cream-colored crystals (161 mg, 76%). 1H NMR (DMSO-d6) δ 11.85 (s,
1H), 7.88 – 7.82 (m, 2H), 7.44 – 7.40 (m, 2H), 7.19 (dd, J = 4.1, 1.7 Hz, 1H), 7.07 (t, J = 1.9
Hz, 1H), 6.07 (dd, J = 4.1, 2.5 Hz, 1H), 3.70 (s, 3H), 2.38 (s, 3H); 13C{1H} NMR (DMSO-d6)
δ 158.4 (C), 143.9 (C), 137.2 (C), 131.6 (CH), 129.5 (2×CH), 127.6 (2×CH), 122.3 (C), 117.5
(CH), 107.6 (CH), 36.6 (CH3), 21.1 (CH3); mp: 167 – 169 °C; HRMS (ESI-FT ICR) m/z: [M +
Na]+ Calcd for C13H14N2O3SNa 301.0617: Found 301.0617; LC purity (254 nm) = >99%.
1-Phenyl-N-tosyl-1H-pyrrole-2-carboxamide (6b): Purified by dissolving the material in
acetone, filtering any solid (Pd black), recrystallizing by slow evaporation of the
MeCN/acetone solution and washing with cold MeCN to give the product as green crystals,
(120 mg, 84%). 1H NMR (DMSO-d6) δ 12.06 (s, 1H), 7.79 – 7.74 (m, 2H), 7.38 (d, J = 8.0 Hz,
2H), 7.37 – 7.31 (m, 3H), 7.28 (dd, J = 4.0, 1.7 Hz, 1H), 7.21 (dd, J = 2.6, 1.7 Hz, 1H), 7.15 –
7.07 (m, 2H), 6.29 (dd, J = 4.0, 2.7 Hz, 1H), 2.37 (s, 3H); 13C{1H} NMR (DMSO-d6) δ 157.6
(C), 143.9 (C), 139.7 (C), 136.9 (C), 131.2 (CH), 129.5 (2×CH), 128.6 (2×CH), 127.4 (2×CH),
127.3 (CH), 125.4 (2×CH), 123.5 (C), 118.6 (CH), 109.2 (CH), 21.0 (CH3); mp: 208 – 209 °C;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H13N2O3S2 341.0960: Found 341.0971; LC
purity (254 nm) = >99%.
ACS Paragon Plus Environment

Page 29 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
N-Tosyl-1H-pyrrole-2-carboxamide (6c): Purified by column chromatography (30 to 75%
EtOAc in pentane and 0.1% HCOOH) followed by recrystallization in minimal hot ethanol to
give the product as white crystals, (177 mg, 77%). 1H NMR (DMSO-d6) δ 11.96 (s, 1H), 11.72
(s, 1H), 7.91 – 7.82 (m, 2H), 7.45 – 7.39 (m, 2H), 7.13 (ddd, J = 3.9, 2.5, 1.4 Hz, 1H), 7.05 –
6.98 (m, 1H), 6.13 (ddd J = 3.8, 2.5, 2.3 Hz, 1H), 2.38 (s, 3H); 13C{1H} NMR (DMSO-d6) δ
157.9 (C), 144.0 (C), 137.1 (C), 129.4 (2×CH), 127.7 (2×CH), 125.1 (CH), 123.3 (C), 114.9
(CH), 109.6 (CH), 21.1 (CH3); mp: 209 – 211 °C; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C12H13N2O3S 265.0647: Found 265.0649; LC purity (254 nm) = >99%.
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-((2-(1H-pyrrol-1-yl)phenyl)carbamoyl)-4-methylbenzenesulfonamide (6é): Purified by
column chromatography (30 to 50% EtOAc in pentane and 0.1% HCOOH) to give the product
as a cream-colored solid (68.0 mg, 46%). 1H NMR (DMSO-d6) δ 11.15 (br s, 1H), 7.93 (s, 1H),
7.81 – 7.75 (m, 3H), 7.43 (d, J = 8.1 Hz, 2H), 7.32 (ddd, J = 8.3, 7.1, 2.0 Hz, 1H), 7.25 – 7.14
(m, 2H), 6.84 (t, J = 2.1 Hz, 2H), 6.26 (t, J = 2.1 Hz, 2H), 2.40 (s, 3H); 13C{1H} NMR (DMSO-
d6) δ 149.5 (C), 144.0 (C), 136.8 (C), 132.3 (C), 132.0 (C), 129.6 (2×CH), 127.9 (CH), 127.4
(2×CH), 127.1 (CH), 124.8 (CH), 123.1 (CH), 122.0 (2×CH), 109.8 (2×CH), 21.1 (CH3);
HRMS (ESI-FT ICR) m/z: [M + Na]+ Calcd for C18H17N3O3SNa 378.0883: Found 378.0882;
LC purity (254 nm) = >99%.
ACS Paragon Plus Environment