Sulfur-mediated synthesis of unsymmetrically substituted: N -aryl oxalamides by the cascade thioamidation/cyclocondensation and hydrolysis reaction

Article abstract of DOI:10.1039/d0ob00811g

A facile and straightforward synthesis of unsymmetrically substituted N-aryl oxalamides from 2,2′-biphenyldiamines, 2-chloroacetic acid derivatives, elemental sulfur, and water has been developed. This protocol is distinguished by efficiency in water under metal-free conditions for N-aryl oxalamides bearing a side-chain NH2-group; it can be adapted for scale-up synthesis. The scope and limitations of this transformation have been investigated.

Full text of DOI:10.1039/d0ob00811g

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: T. A. Tikhonova,
N. V. Ilment, K. A. Lyssenko, I. V. Zavarzin and Y. Volkova, Org. Biomol. Chem., 2020, DOI:
10.1039/D0OB00811G.
Volume 15
Number 47
21 December 2017
Pages 9945-10124
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
Accepted Manuscripts are published online shortly after acceptance,
rsc.li/obc
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
ISSN 1477-0520
PAPER
I . J. Dmochowski et al.
Oligonucleotide modifi cations enhance probe stability for
shall the Royal Society of Chemistry be held responsible for any errors
single cell transcriptome in vivo analysis (TIVA)
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
rsc.li/obc

Page 1 of 21
Organic & Biomolecular Chemistry
Sulfur-Mediated Synthesis of Unsymmetrically Substituted N-Aryl Oxalamides by the Cascade
View Article Online
DOI: 10.1039/D0OB00811G
Thioamidation/Cyclocondensation and Hydrolysis Reaction
Tatyana A. Tikhonova,a Nikita V. Ilment,a Konstantin A. Lyssenko,b,c Igor V. Zavarzin,a and Yulia A.
Volkovaa*
a
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp.,
119991, Moscow, Russian Federation, e-mail address: yavolkova@gmail.com
b
G.V. Plekhanov Russian University of Economics, 36 Stremyanny Per., Moscow 117997, Russian
Federation
c
Department of Chemistry, M.V. Lomonosov Moscow State University, 119991 Moscow, Russian
Federation
R1
one-pot
R1
1) S8
, base
O
H
+
O
NH2
R1
O
N
2) H2 , H
N
H
R2
+
Cl
R2
H2N
N
H2N
O
up to 85% yield
H
R1
R1 = H, Me, Br
R2 = H, Ar, Alk, Het
good scale-up potential and broad substrate scope
efficiency in water media ease of operation
Abstract. A facile and straightforward synthesis of unsymmetrically substituted N-aryl oxalamides from
2,2'-biphenyldiamines, 2-chloroacetic acid derivatives, elemental sulfur, and water has been developed.
This protocol is distinguished by efficiency in water under metal-free conditions for N-aryl oxalamides
bearing a side-chain NH2-group; it can be adapted for scale-up synthesis. The scope and limitations of
this transformation have been investigated.
1

Organic & Biomolecular Chemistry
Page 2 of 21
View Article Online
DOI: 10.1039/D0OB00811G
Introduction
Oxalamides are important structural subunits found in a variety biologically active agents, including
a number of natural products (e.g., nitrogen-containing volatiles1) and commonly used drugs (e.g.,
Ambenonium2 acting as a cholinesterase inhibitor). In particular, unsymmetrically substituted N-aryl
oxalamides have attracted much attention as promising chelating ligands in catalysis,3-12 medically
relevant compounds,13-16 and as building blocks for antiferromagnetic systems17 and supramolecular
architectures (Figure 1).18 19
O
O
F
F
H
H
O
N
N
O
F
F
H
N
N
H
N
O
O
H
O
CO2H
Caspase Inhibitor
Ligand in catalysis
O
O
O
H
H
N
EtO
N
N
N
NMe2
H
H
O
O
O
Ligand for polynuclear copper(II) complexes
Figure 1. Importance of unsymmetrically substituted N-aryl oxalamides.
Unsymmetrically substituted N-aryl oxalamides can be constructed by the two-step treatment of
2-chloro-2-oxoacetates with amines12, 20 or by the copper(II)-catalyzed photocatalytic amidation of
1,3-ketoamides (Figure 2).21 The known method suffers from drawbacks, such as dry solvents, harsh
conditions, and a limited substrate scope. The metal catalyst or additive contaminants are often difficult
to separate, thereby requiring procedures for product purification. Moreover, the synthesis of
oxalamides bearing NH2 substituents, which are important intermediates in organic synthesis and
promising ligands for metals, is a challenging problem within these approaches. Additional synthetic
steps, such as protection/deprotection22 and reduction of nitro23 or diazo groups,24 are commonly
required for the synthesis of oxalamides containing a side-chain amino group. Therefore, the
development of an efficient and simple synthetic approach to arbitrarily substituted oxalamides,
particularly those bearing an NH2 group, is highly desirable.
2

Page 3 of 21
Organic & Biomolecular Chemistry
Previous works:
a)
View Article Online
DOI: 10.1039/D0OB00811G
R1
O
R1
OX
O
base
Cl
H
R2NH2
+
NH2
+
N
N
R2
O
X = Me, Et
-XOH
H
O
[ref. 12,20]
b)
R1
R1
O
O
[Cu], [Ox], LED light
O
H
R3NH2
+
N
R2
N
R2 = Me, Ph
-R2CO2H
N
R3
H
H
O
[ref. 21]
This work:
R1
one-pot
R1
1) S8
, base
O
H
2) H2O, H+
N
O
NH2
N
H
R2
Cl
+
R2
H2N
N
R1 = H, Me, Br
R2 = H, Ar, Alk, Het
H2N
O
H
R1
R1
61-85%
Figure 2. Synthetic approaches to unsymmetrically substituted N-aryl oxalamides.
On the other hand, elemental sulfur-mediated reactions with amines offer a powerful route with
excellent functional group tolerance, allowing a decrease in the number of synthetic steps and producing
structurally diverse products. A number of reports published in the past decade demonstrate the utility of
elemental sulfur in reactions with amines and C-H acids for the synthesis of thioamides,25-27 α-
ketothioamides,28 and 2-amino-2-thioxoacetamides.29 To the best of our knowledge, examples of
elemental sulfur-promoted synthesis of oxalamides are as yet unknown. Recently, our group has
disclosed the Willgerodt-type30 three-component reaction of 2-chloroacetamides with amines and sulfur
as a highly efficient approach to thioamides and N-heterocycles.31-33 Particularly we have shown that
synthesis of 2-carboxamide-substituted dibenzo[1,3]diazepines can be achieved by sulfur-mediated
cyclocondensation of 2,2'-biphenyldiamines with 2-chloroacetic acid derivatives.33 Herein, we propose
an extension this reaction for the construction of unsymmetrically substituted N-aryl oxalamides bearing
a side-chain NH2 group (Figure 2). We developed a novel strategy to synthesize oxalamides through the
sulfur-mediated reaction of 2,2'-biphenyldiamines with 2-chloroacetamides and water. Additionally,
some transformations of oxalamides giving valuable linear and cyclic products were performed.
Results and Discussion
Initially, we studied the reaction of 2,2'-biphenyldiamine (1a) with 2-chloroacetamide 2a in the
presence of sulfur and water (Table 1). Based on our previous results,32, 33 we expected that the classical
Willgerodt–Kindler reaction30 would resulted in the assembly of thioamide 4a. However, by serendipity,
we found that reaction in water-containing DMF gave oxalamide 3a as the major product (Table 1). The
reaction was performed using 3.0 equiv. of S8, 1.1 equiv. of water, and 1.0 equiv. of Et3N on heating for
o
6 h, since the reactions at rt were found to be inefficient (entries 1, 2). The reaction in DMF at 90 C
3

Organic & Biomolecular Chemistry
Page 4 of 21
gave product 3a in 49% yield (entry 4), while the product yields decreased to 7% and 25% at 60 oC and
View Article Online
o
DOI: 10.1039/D0OB00811G
110 C, respectively (entries 3, 5). Other polar aprotic solvents, such as 1,4-dioxane and DMSO, proved
o
to be less efficient at 90 C (entries 6, 7). The screening of solvents also showed that the reactions in
non-polar (n-hexane, CHCl3) and polar protic solvents (CH3CN, EtOH) were inefficient (entries 8–11).
We were pleased to find that refluxing a mixture of compounds 1a and 2a in water in the presence of
10.0 equiv. of triethylamine followed by heating in a DMF/water mixture in the presence of 10 mol% of
TsOH gave oxalamide 3a as the major product in 64% yield (entry 12).
Table 1. Optimization of the reaction conditions.a)
O
S
H
H
Br
NH2
N
N
O
S8, H2O
N
N
H2N
H
H
Cl
+
H2N
O
H2N
O
N
Br
Br
additive
solvent, T o
H
C
4a
1a
2a
3a
not detected
Add.,
equiv
Yield of
3a, %b)
Base,
equiv
S8,
2a,
H2O,
Reaction
time, h
Entry
Solvent
T, oС
equiv equiv equiv
1
2
DMF
DMF
-
-
-
-
-
-
-
-
-
-
-
-
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
0.1
1.0
5.0
3.0
3.0
3.0
0.0
3.0
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2.0
2.0
2.0
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
-
Rt
Rt
6
6
-
>5
7
Et3N (1.0)
Et3N (1.0)
Et3N (1.0)
Et3N (1.0)
Et3N (1.0)
Et3N (1.0)
Et3N (1.0)
Et3N (1.0)
Et3N (1.0)
Et3N (1.0)
3
DMF
60
6
4
DMF
90
6
49
25
9
5
DMF
110
6
6
1,4-dioxane
DMSO
90
6
7
90
6
33
-
8
n-hexane
CHCl3
90
6
9
90
6
-
10
11
12
13
14
15
16
17
18
19
20
a)
CH3CN
EtOH
90
6
-
90
6
-
H2O/DMF
H2O/ DMF
H2O/DMF
H2O/DMF
H2O/DMF
H2O/DMF
H2O/DMF
H2O/DMF
Et3N (10.0) TsOH (0.1)
Et3N (10.0) TsOH (0.1)
Et3N (10.0) TsOH (0.1)
Et3N (10.0) TsOH (0.1)
100/140
100/140
100/140
100/140
100/140
100/140
100/140
100
4/5
4/5
4/5
4/5
4/5
4/5
4/5
5
64
<5
29
47
<5
40
78c)
-
-
-
-
Et3N (0.5)
Et3N (5.0)
TsOH (0.1)
TsOH (0.1)
-
-
Et3N (10.0) TsOH (0.1)
Et3N (10.0) TsOH (0.1)
-
-
H2O/DMFd) Et3N (10.0) TsOH (0.1)
-
100/140
4/10
72
Reaction conditions: 2,2'-biphenyldiamine (1a) (50 mg, 0.27 mmol), 2-bromo-N-(4-
bromophenyl)acetamide (2a), S8, base, solvent (2.5 mL). b) Determined by 1H NMR with internal standard.
с) Isolated yield. d) Water was not removed after first step.
A decrease in the amount of Et3N (from 10.0 equiv. to 0.5 equiv.) and S8 (from 3.0 equiv. to 10 mol%)
proved to be considerably less efficient under similar conditions (entries 13–17). Besides, the reaction
4

Page 5 of 21
Organic & Biomolecular Chemistry
with 2.0 equiv. of 2-chloroacetamide 2a afforded product 3a in a yield of 78% (entry 18) versus 64%
View Article Online
DOI: 10.1039/D0OB00811G
when using 1.1 equiv of compound 2a. In the absence of elemental sulphur reaction didn’t occur and product
3a was not detected (entry 19). Based on the above results, we developed a one-pot two-step procedure
using the following reaction conditions: 1) 1.0 equiv. of diamine, 3.0 equiv. of sulfur, 10 equiv. of Et3N,
o
2 equiv. of 2-chloroacetamide in water at reflux for 4 h; 2) 10 mol% TsOH in DMF at 140 C for 5 h.
Four-fifth of water was removed by decantation after the first step; otherwise, the product yield slightly
decreased and the longer reaction time of the second was required (entry 20).
In order to evaluate the scope of this procedure, we performed the reaction of 2-chloroacetamides 2
with 2,2'-biphenyldiamines 1 (Table 2). This method proved to be quite general with respect to
2-chloroacetamides 2. Compounds bearing both electron-withdrawing groups (4-Br, 4-Cl, 2-Cl, 2,4-Cl2,
4-I, 4-CF3, 4-NO2) and electron-donating substituents (3-Me, 4-Me, 2,4-Me2) on the benzoyl group were
tolerated under the reaction conditions. Products 3a-j were isolated in 61–78% yields. Unfunctionalized
product 3h was obtained from 2-chloro-N-phenylacetamide (2h) in 69% isolated yield. Compound 3k
derived from 2-chloro-N-(naphthalen-1-yl)acetamide (2k) was synthesized in 77% yield. In addition,
benzyl-substituted chloroacetamide 2l, as well as N-heptyl-substituted compound 2m, produced desired
products 3l and 3m in 85% and 40% yields, respectively. The reaction can also be performed with
unsubstituted chloroacetamide, namely, 2-chloroacetamide 2n, giving product 3n in 80% yield. It is
worthy of note that 2-chloroacetic acid and its esters, such as ethyl chloroacetate, did not produce target
products under the optimized conditions. Dihydrodibenzo[d,f][1,3]diazepine-6-thione was isolated in
quantitative yield in these reactions.33
Substituted biphenyldiamines 1 proved to be competent substrates and smoothly produced
polysubstituted oxalamides 3. The reaction of compounds 1b and 1c bearing 5,5'-Br2 and 5,5'-Me2
substituents, respectively, afforded products 3o–q in 58–70% yields.
5

Organic & Biomolecular Chemistry
Page 6 of 21
View Article Online
DOI: 10.1039/D0OB00811G
Table 2. Reaction scope.a),b)
R1
R1
O
1. S8, Et3N
H
N
H2O, reflux, 4 h
R2
O
NH2
R1
N
H
Cl
R2
+
H2N
H2N
O
N
2. H2O, TsOH
DMF, 140-150 o
5-12 h
H
C
R1
1a
2a-n
3a-n
Cl
Br
Cl
Cl
Cl
I
CF3
HN
HN
HN
HN
HN
HN
O
O
O
O
O
O
O
O
O
O
O
O
NH
NH
NH
NH
NH
NH
H2N
H2N
H2N
H2N
H2N
H2N
3d
3e
3f
, 74%
, 70%
, 71%
3b
3c
, 55%
, 76%
3a
, 78%
Me
Me
O2N
HN
HN
HN
HN
HN
HN
O
O
O
O
O
O
O
O
O
O
O
O
NH
NH
NH
NH
NH
NH
H2N
H2N
H2N
H2N
H2N
H2N
3g
3h
3i
3j
3k
3l
, 85%
, 68%
, 69%
, 61%
, 73%
Me
, 77%
Me
Cl
Cl
n-C7H15
H
O
HN
HN
HN
HN
O
HN
O
O
O
O
O
O
O
O
NH
NH
NH
NH
NH
Me
Br
Br
Me
Br
Br
H2N
H2N
H2N
H2N
H2N
3n
, 80%
3m
3o
3p
3q
, 65%
, 40%
, 70%
, 58%
a) Reaction conditions: 1) 2,2'-biphenyldiamine 1 (0.8 mmol, 1.0 equiv), S8 (614 mg, 2.4
mmol, 3.0 equiv), Et3N (1.12 mL, 8.0 mmol, 10.0 equiv), 2-chloroacetamide 2 (1.6 mmol,
2.0 equiv), water (5 mL), reflux, 4 h; 2) 10 mol% TsOH, DMF (4 mL), 140–150 oC, 5–12 h.
b) Isolated yield.
Moreover, the exploration of the reaction scope was initiated in relation to 2-haloacetophenones
(Scheme 1). 2-Bromo-1-phenylethanone (5a), 1-(benzo[d][1,3]dioxol-5-yl)-2-bromoethanone (5b),
and 2-bromo-1-(3-nitrophenyl)ethanone (5c) were used as reagents, which are readily available in
inventory and are able to significantly increase the efficiency of the developed method. In the
reactions of 2,2'-biphenyldiamine (1a) with 2-bromoacetophenones 5a,b under standard conditions,
target ketoamides 6a,b were isolated in reasonable yields. By contrast, target product 6c was not
detected in the reaction of diamide 5 with nitro-substituted acetophenone 5c. This was attributed to
side decomposition processes in the first step.
6

Page 7 of 21
Organic & Biomolecular Chemistry
O
1. S8, Et3N
NH2
Ar
O
H2O, reflux, 4-7 h
N
View Article Online
DOI: 10.1039/D0OB00811G
H2N
H
+
Br
H2N
O
Ar
2. H2O, TsOH
DMF, 140 oC, 12 h
1a
5a-c
6a-c
NO2
O
O
O
O
O
N
N
N
H
H
O
H
H2N
O
H2N
H2N
O
6a
, 25%
6b
, 50%
6c
, -%
Scheme 1. Synthesis of ketoamides 11
The structure of oxalamide 3 was established by single-crystal X-ray diffraction study of
representative compounds 3b and 3c (Figure 3). The CCDC 1942001 and 1941999 contain the
supplementary crystallographic data for compounds 3b and 3c. The data can be obtained free of charge
from the Cambridge Crystallographic Data Centre.
A)
B)
Figure 3. X-ray molecular structures of compounds 3b (A) and 3c (B) with displacement ellipsoids
(p=50%).
As shown in Scheme 2, this method can easily be scaled up without loss in the yield regardless of
the 2-chloroacetamide substitution (Scheme 1). Thus, the treatment of 2,2'-biphenyldiamine (1a) (1.0 g,
5.4 mmol) with N-benzyl-2-chloroacetamide (2l) (2.0 g, 10.9 mmol) and sulfur at reflux under
optimized conditions gave oxalamide 3l in 71% yield (1.3 g, recrystallization from EtOH) (line a).
2-Chloroacetamide (2n) (1.0 g, 10.8 mmol) also smoothly reacted with diamine 1a (1.0 g, 5.4 mmol)
and sulfur on heating in DMF to form product 3n in 72% yield (1.0 g, recrystallization from EtOH) (line
b).
7

Organic & Biomolecular Chemistry
Page 8 of 21
a)
O
H
1. S8, Et3N
N
NH2
O
Bn
N
H
View Article Online
H2O, reflux, 6 h
H2N
O
Cl
Bn
H2N
DOI: 10.1039/D0OB00811G
N
H
2. H2O, TsOH
DMF, 140 oC, 8 h
Bn = CH2Ph
1a
1.0 g
2l
2.0 g
3l
, 71%
1.3 g
b)
O
S8 (3 eq)
NH2
NH2
N
H
O
H2O (2 eq)
H2N
H2N
O
Cl
NH2
Et3N (3 eq)
DMF, 90 oC, 6 h
1a
2n
3n
, 72%
1.0 g
1.0 g
1.0 g
Scheme 2. Scale-up experiments.
N-Aryl-substituted oxalamides bearing a side-chain NH2 group 3 are valuable compounds since they
can provide access to other functionalized linear and cyclic products. Scheme 3 shows examples of their
transformations. The acylation of compound 3i with 4-methoxybenzoyl chloride gave polyamide 7 in
76% isolated yield (line a). The stepwise nitrosation of oxalamides 3l with sodium nitrite and the
treatment with potassium iodide afforded side-chain iodo-substituted oxalamide 8 in 81% yield (line b).
The synthesis of carbazole 9 was accomplished in 74% yield by the treatment with sodium nitrite and
ethanol (line c). The foregoing demonstrates that the new method provides a feasible route to
structurally interesting and potentially useful functionalized oxalamides and carbazoles and offers new
opportunities for the ligand development in medicinal chemistry and materials science.
a)
O
O
H
H
N
N
Tol
N
N
H
An COCl
Tol
H
H
H2N
O
O
N
An
Py, CH2Cl2
rt, 2.5 h
O
3i
7
, 76%
An = pMeOC6H4
Tol = pMeC6H4
b)
1. HCl, NaNO2,
H2O/acetone,
0 oC, 1 h
O
O
H
N
H
N
N
H
Bn
N
Bn
H
H2N
O
I
O
2. KI, H2O/acetone,
overnight
3l
8
, 81%
Bn = CH2Ph
c)
1. HCl, NaNO2,
H2O/acetone,
0 oC, 1 h
O
H
N
O
N
N
H
Bn
Bn
NH
H2N
O
2. EtOH, rt, overnight
O
3l
9
, 74%
Bn = CH2Ph
Scheme 3. Chemical transformations of oxalamides 3.
Additional experiments were performed to gain insights into the reaction mechanism (Scheme 4). It
was shown that the reactions of mono-N-protected biphenyldiamines 10a,b bearing tosyl and benzyl
substituents with 2-chloroacetamide 2b did not afford oxalamides 11a,b under optimized conditions,
revealing the importance of the presence of two NH2 groups in biphenyldiamines for the reaction to
occur (line a). Moreover, previously33 we found that the short-term treatment of 2,2'-biphenyldiamine
o
(1a) with 2-chloroacetamide 2b in dry DMF at 60 C furnished thioamide 4b (line b). The latter was
8

Page 9 of 21
Organic & Biomolecular Chemistry
quantitatively converted into dibenzo[d,f][1,3]diazepine 1233 at reflux in water in the presence of
View Article Online
DOI: 10.1039/D0OB00811G
triethylamine (line c). In the presence of water and the acid catalyst (TsOH) in DMF, compound 12
underwent ring opening to form oxalamide 3b in a quantitative yield (line d).
a)
O
H
optimized conditions
O
N
NH2
N
R
H
Cl
R2
H
H
N
N
H
N
O
PG
PG = Bn, Ts
R = pClC6H4
PG
11a,b
10a,b
2b
, -%
b)
S
H
N
S8 (3 eq)
O
NH2
N
H
R
Et3N (3 eq)
Cl
R
H2N
H2N
O
N
H
DMF, 60 oC, 3 h
R = pClC6H4
1a
2b
4b
, 27%
c)
S
H
N
N
HN
O
R
Et3N (3 eq)
N
H
R
H2N
O
H2O, reflux, 2 h
R = pClC6H4
NH
4b
12
, 90%
d)
O
H2O (10 eq)
H
N
N
HN
O
R
TsOH (10 mol %)
N
R
H
H2N
O
NH
DMF, 120 oC, 7 h
R = pClC6H4
12
3b
, 91%
Scheme 4. Studies of the reaction pathway.
Based on the literature precedents30, 33, 34 and experimental data, we propose a tentative mechanism
for the sulfur-mediated reaction of 2,2'-biphenyldiamine with 2-chloroacetic acid derivatives and water
(Scheme 5). The process is initiated by the activation of 2,2'-biphenyldiamine A with elemental sulfur
via the formation of highly nucleophilic polysulfide B. The Willgerodt–Kindler-type thioamidation of
chloride C with intermediate B gives oxoethanethioamide D. Previously described33 the intramolecular
ring closure of D followed by hydrogen sulfide elimination affords 2-carboxy-substituted
dibenzo[d,f][1,3]diazepine E. Finally, compound E undergoes acid-catalyzed ring opening reaction with
water giving oxalamide F.
9

Organic & Biomolecular Chemistry
Page 10 of 21
O
Cl
RHN
View Article Online
DOI: 10.1039/D0OB00811G
NH2
NHn
S
S8
C
H2N
H2N
S
n
-HCl, [S]
S-
A
B
n = 0-6
,
S
N
NHR
NHR
O
AdN
N
H
H2N
O
-H2S
NH
E
D
O
NHR
H2O, H+
N
H
H2N
O
F
Scheme 5. Proposed mechanistic pathway.
The alternative nucleophilic substitution of chlorine in C with 2,2'-biphenyldiamine A followed by
Willgerodt reaction to get the product F seems less plausible.27 After heating of a suspension of diamine
1 and sulfur in water resulted in an intense yellow-brown color of the solid and liquid phases (see some
pictures in Supporting Information, S-4). The intense coloration is attributed to highly reactive partially
water-soluble polysulfides (B, Scheme 5), resulting from S−S bond scission via the stepwise
nucleophilic attack on S8 rings by amine. Heating of this mixture with 2-chloroacetamide 2 resulted in
the formation of brown “packed” gummy and discoloration of the aqueous phase, which is indicative of
1
the consumption of polysulfides. According to the H NMR spectra, the solid phase is enriched with
dibenzo[d,f][1,3]diazepine intermediates (E). Thus, the removal of E from the reaction medium prevents
multiple side processes, primarily such as diazepine ring opening with active N- and S-nucleophiles.
Following the developed protocol, the dilution with DMF led to homogenization of the reaction mixture,
while the addition of TsOH promotes the ring-opening reaction of dibenzo[d,f][1,3]diazepines
intermediates with water (see some pictures in Supporting Information, S-4).
Conclusion
In conclusion, we demonstrated that the cascade thioamidation/cyclocondensation/hydrolysis reaction
provides an easy route to unsymmetrically substituted N-aryl oxalamides starting from
2,2'-biphenyldiamines, 2-chloroacetoamides, sulfur, and water. The new strategy significantly expands
the synthetic scope of available N-aryl oxalamides bearing a side-chain NH2 group. Due to operational
simplicity, this protocol may be useful in pharmacological research and the design of materials and
ligands for application in metal complex-catalyzed reactions. Further investigation and extension of the
results are currently underway.
Experimental Section
10

Page 11 of 21
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/D0OB00811G
General Information
NMR spectra were acquired at room temperature; the chemical shifts δ were measured in ppm relative
to the solvent (1Н: CDCl3, δ = 7.27 ppm, DMSO-d6, δ = 2.50 ppm; 13C: CDCl3, δ = 77.00 ppm, DMSO-
d6, δ = 39.50 ppm). Splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; dd, double doublet. The coupling constants (J) are in Hertz. The structures of all compounds
13
were established using 1D NMR (1H, C) spectroscopy. High-resolution mass spectra (HRMS) were
obtained using electrospray ionization (ESI) with Q-TOF detection and electron ionization (EI)
techniques. IR spectra were obtained either as potassium bromide pellets or as liquid films between two
potassium bromide pellets with an infrared spectrometer. Melting points (mp) are uncorrected.
Analytical thin layer chromatography (TLC) was carried out on silica gel plates (silica gel 60 F254
aluminum supported plates); the visualization was accomplished with an UV lamp (365 nm). Column
chromatography was performed on silica gel 60 (230-400 mesh). 2,2'-Biphenyldiamine, sulfur,
2-chloroacetic acid, 2-bromoacetophenones, p-toluenesulfonic acid, triethylamine, sodium nitrite,
potassium iodide, and 4-methoxybenzoyl chloride were commercially available and were used without
additional purification. All reactions were carried out using freshly distilled and dry solvents. Parent 2-
chloroacetamides were prepared according to published procedures.35 5,5'-Dimethyl-[1,1'-biphenyl]-
2,2'-diamine36,
5,5'-dibromo-[1,1'-biphenyl]-2,2'-diamine37,
N-(2'-amino-[1,1'-biphenyl]-2-yl)-4-
methylbenzenesulfonamide,38 and N2-benzyl-[1,1'-biphenyl]-2,2'-diamine39 were synthesized according
to literature procedures.
General procedure for the synthesis of N1-(2'-amino-[1,1'-biphenyl]-2-yl)oxalamides 3. 2-
Chloroacetamide 2 (1.6 mmol, 2.0 equiv) or 2-bromoacetophenone 5 (1.6 mmol, 2.0 equiv) was added
o
portionwise at 100 C (oil bath) during 2 h to the mixture of 2,2'-biphenyldiamine 1 (0.8 mmol, 1.0
equiv), sulfur (614 mg, 2.4 mmol, 3.0 equiv), and triethylamine (1.12 mL, 8.00 mmol, 10.0 equiv) in
water (5 mL). The mixture was stirred for 4-7 h at reflux until the complete conversion of 2,2'-
biphenyldiamine (TLC monitoring). The reaction mixture was cooled to room temperature and 4/5 parts
of water were decanted. To the residue DMF (4 mL) and TsOH monohydrate (15 mg, 0.08 mmol, 10
o
mol%) were added. The resulting solution was heating at 140-150 С (silicon oil bath) for 5-12 h.
Reaction mixture was cooled to room temperature, diluted with water (15 mL) and extracted with ethyl
acetate (3 × 15 mL). Combined organic layer was washed with water (5 × 15 mL) and dried over
Na2SO4. Solvent was removed under reduced pressure and product was isolated by column
chromatography (eluent: petroleum ether - EtOAc, 4:1  3:1).
N1-(2'-Amino-[1,1'-biphenyl]-2-yl)-N2-(4-bromophen-yl)oxalamide (3a). Yield 78% (256 mg),
yellow solid, mp 220-222 °C; Rf = 0.27 (petroleum ether - EtOAc, 3:1); 1H NMR (300 MHz, CDCl3): δ
9.85 (s, 1H), 9.33 (s, 1H), 8.31 (d, J = 8.10 Hz, 1H), 7.54 (d, J = 8.89 Hz, 2H), 7.48 - 7.45 (m, 3H), 7.41
11

Organic & Biomolecular Chemistry
Page 12 of 21
13
– 7.25 (m, 3H), 7.13 (d, J = 7.43 Hz, 1H), 6.99 – 6.88 (m, 2H), 3.68 (br. s, 2H); C NMR (75 MHz,
View Article Online
DOI: 10.1039/D0OB00811G
CDCl3): δ 157.6 (CO), 157.5 (CO), 143.3 (C), 135.4 (C), 134.0 (C), 132.2 (2 × CH), 131.1 (CH), 130.9
(CH), 130.6 (C), 129.9 (CH), 128.8 (CH), 126.1 (CH), 122.9 (C), 121.5 (CH), 121.3 (2 × CH), 119.6
(CH), 118.1 (C), 116.2 (CH); IR (KBr) 3402 (s), 3385 (s), 3181 (s), 1635 (s), 1497 (w), 1483 (s), 1446
(s), 1292 (w), 1138 (w), 862 (w), 754 (s) cm−1; HRMS (ESI/Q-TOF) 410.0495, calcd. for
+
C20H17BrN3O2 ([M+H]+) 410.0499.
N1-(2'-Amino-[1,1'-biphenyl]-2-yl)-N2-(4-chlorophen-yl)oxalamide (3b). Yield 76% (222 mg),
1
yellow solid, mp 202-205 °C; Rf = 0.27 (petroleum ether - EtOAc, 3:1); H NMR (300 MHz, DMSO-
d6): δ 11.02 (s, 1H), 10.07 (s, 1H), 8.15 (d, J = 8.05 Hz, 1H), 7.84 (d, J = 8.86 Hz, 2H), 7.52 – 7.43 (m,
1H), 7.40 (d, J = 8.86 Hz, 2H), 7.33 – 7.31 (m, 2H), 7.17 (dd, J = 8.05, 7.62 Hz, 1H), 7.00 (dd, J = 8.12,
7.62 Hz, 1H), 6.93 (d, J = 8.12 Hz, 1H), 6.74 (d, J = 7.33 Hz, 1H), 3.35 (br. s, 2H); 13C NMR (75 MHz,
CDCl3): δ 157.6 (CO), 157.5 (CO), 143.3 (C), 134.9 (C), 134.1 (C), 131.1 (CH), 130.9 (CH), 130.6 (C),
130.5 (C) 129.9 (CH), 129.2 (2 × CH), 128.8 (CH), 126.1 (CH), 122.9 (C), 121.5 (CH), 120.9 (2 × CH),
119.6 (CH), 116.2 (CH); IR (KBr) 3469 (s), 3390 (s), 3318 (s), 2924 (s), 1679 (w), 1522 (s), 1494 (s),
+
1305 (w), 1100 (w), 829 (w), 762 (s) cm−1; HRMS (ESI/Q-TOF) 366.0990, calcd. for C20H17ClN3O2
([M+H]+) 366.1003.
N1-(2'-Aamino-[1,1'-biphenyl]-2-yl)-N2-(2-chlorophen-yl)oxalamide (3c). Yield 55% (161 mg),
1
yellow solid, mp 177-180 °C; Rf = 0.27 (petroleum ether - EtOAc, 3:1); H NMR (300 MHz, DMSO-
d6): δ 10.31 (s, 1H), 10.11 (s, 1H), 8.15 (d, J = 8.16 Hz, 1H), 7.85 (d, J = 7.89 Hz, 1H), 7.56 (d, J = 7.33
Hz, 1H), 7.52 – 7.43 (m, 1H), 7.40 – 7.33 (m, 3H), 7.27 (dd, J = 7.89, 6.58 Hz, 1H), 7.17 (dd, J = 8.16,
6.58 Hz, 1H), 7.00 (d, J = 6.62 Hz, 1H), 6.89 (d, J = 7.83 Hz, 1H), 6.72 (dd, J = 7.83, 6.47 Hz, 1H), 4.87
(br. s, 2H); 13C NMR (75 MHz, DMSO-d6): δ 158.5 (CO), 157.6 (CO), 145.5 (C), 134.4 (C), 133.8 (C),
132.1 (C), 131.6 (CH), 131.2 (CH), 129.9 (CH), 129.6 (CH), 128.5 (CH), 128.3 (CH), 127.7 (CH),
126.7 (C), 126.4 (CH), 124.9 (CH), 123.0 (C), 122.3 (CH), 117.9 (CH), 116.4 (CH); IR (KBr) 3413 (s),
3332 (s), 3231 (s), 1676(s), 1508 (w), 1440 (s), 1054 (w), 1032 (w), 753 (s) cm−1; HRMS (ESI/Q-TOF)
+
366.0996, calcd. for C20H17ClN3O2 ([M+H]+) 366.1003.
N1-(2'-Amino-[1,1'-biphenyl]-2-yl)-N2-(3,4-dichloroph-enyl)oxalamide (3d). Yield 70% (224 mg),
yellow solid, mp 199-203 °C; Rf = 0.28 (petroleum ether - EtOAc, 3:1); 1H NMR (300 MHz, CDCl3): δ
9.84 (s, 1H), 9.34 (s, 1H), 8.30 (d, J = 8.24 Hz, 1H), 7.92 (s, 1H), 7.48 (dd, J = 8.24, 7.60 Hz, 1H), 7.42
13
– 7.29 (m, 5H), 7.13 (d, J = 6.38 Hz, 1H), 6.97 – 6.91 (m, 2H), 3.69 (br. s, 2H); C NMR (75 MHz,
CDCl3): δ 157.6 (CO), 157.3 (CO), 143.3 (C), 136.3 (C), 135.7 (C), 133.9 (C), 133.2 (C), 131.2 (CH),
130.9 (CH), 130.7 (CH), 130.6 (C), 129.9 (CH), 128.8 (CH), 126.2 (CH), 122.9 (C), 121.6 (CH), 121.4
(CH), 119.7 (CH), 118.9 (CH), 116.3 (CH); IR (KBr) 3435 (s), 3320 (s), 1683 (s), 1512 (s), 1494 (s),
1446 (s), 1390 (w), 1153 (w), 878 (w), 755 (s) cm−1; HRMS (ESI/Q-TOF) 401.0622, calcd. for
+
C20H16Cl2N3O2 ([M+H]+) 401.0614.
12

Page 13 of 21
Organic & Biomolecular Chemistry
N1-(2'-Amino-[1,1'-biphenyl]-2-yl)-N2-(4-iodophenyl)-oxalamide (3e). Yield 71% (260 mg), yellow
View Article Online
1
DOI: 10.1039/D0OB00811G
solid, mp 227-228 °C; Rf = 0.28 (petroleum ether - EtOAc, 3:1); H NMR (300 MHz, DMSO-d6): δ
10.97 (s, 1H), 10.05 (s, 1H), 8.16 (d, J = 8.06 Hz, 1H), 7.70 – 7.62 (m, 4H), 7.54 – 7.40 (m, 1H), 7.33 –
7.32 (m, 2H), 7.17 (dd, J = 8.06, 6.59 Hz, 1H), 7.00 (d, J = 7.64 Hz, 1H), 6.90 (d, J = 7.85 Hz, 1H), 6.72
(dd, J = 7.64, 6.59 Hz, 1H), 4.85 (br. s, 2H); 13C NMR (75 MHz, DMSO-d6): δ 159.7 (CO), 152.9 (CO),
138.0 (C), 137.9 (CH), 131.5 (C), 131.1 (C), 130.2 (C), 129.6 (C), 129.1 (CH), 128.5 (CH), 127.8 (C),
125.8 (CH), 125.4 (CH), 123.2 (CH), 123.0 (CH), 122.1 (CH), 121.3 (CH), 117.9 (CH), 116.3 (CH),
109.9 (CH); IR (KBr) 3445 (s), 3361 (s), 3309 (s), 1675 (s), 1514 (s), 1394 (s), 1304 (s), 1004 (w), 826
+
(w), 746 (s) cm−1; HRMS (ESI/Q-TOF) 458.0360, calcd. for C20H17IN3O2 ([M+H]+) 458.0355.
N1-(2'-Amino-[1,1'-biphenyl]-2-yl)-N2-(4-(trifluoro-methyl)phenyl)oxalamide (3f). Yield 74% (236
1
mg), yellow solid, mp 183-184 °C; Rf = 0.25 (petroleum ether - EtOAc, 3:1); H NMR (300 MHz,
CDCl3): δ 9.92 (s, 1H), 9.64 (s, 1H), 8.26 (d, J = 7.99 Hz, 1H), 7.77 (d, J = 8.49 Hz, 2H), 7.58 (d, J =
8.49 Hz, 2H), 7.55 – 7.16 (m, 4H), 7.16 – 7.04 (m, 1H), 7.03 – 6.80 (m, 2H), 3.71 (br. s, 2H); 13C NMR
(75 MHz, CDCl3): δ 157.9 (CO), 157.5 (CO), 143.3 (C), 139.4 (C), 134.0 (C), 131.1 (CH), 130.9 (CH),
130.9 (C), 129.9 (CH), 128.7 (CH), 126.4 (C), 126.3 (C), 126.3 (CH), 126.2 (CH), 123.0 (CF3, JC,F
=
261.4 Hz), 121.8 (CH), 119.8 (3 × CH), 119.7 (CH), 116.3 (CH); IR (KBr) 3463 (s), 3371 (s), 3274 (s),
1660 (s), 1517 (s), 1328 (s), 1115 (s), 1064 (s), 851 (w), 757 (s) cm−1; HRMS (ESI/Q-TOF) 400.1263,
+
calcd. for C21H17F3N3O2 ([M+H]+) 400.1267.
N1-(2'-Amino-[1,1'-biphenyl]-2-yl)-N2-(2-nitrophenyl)-oxalamide (3g). Yield 68% (205 mg), yellow
1
solid, mp 210-212 °C; Rf = 0.27 (petroleum ether - EtOAc, 3:1); H NMR (300 MHz, CDCl3): δ 12.15
(s, 1H), 9.73 (s, 1H), 8.76 (d, J = 8.07 Hz, 1H), 8.42 (d, J = 8.17 Hz, 1H), 8.29 (d, J = 8.44 Hz, 1H),
7.67 (dd, J = 8.44, 7.37 Hz, 1H), 7.49 (dd, J = 8.17, 7.37 Hz, 1H), 7.43 – 7.24 (m, 2H), 7.20 (dd, J =
8.56, 7.19 Hz, 1H), 7.14 (d, J = 7.44 Hz, 1H), 6.98 – 6.89 (m, 2H), 6.87 – 6.79 (m, 1H), 3.69 (br. s,
2H);13C NMR (75 MHz, CDCl3): δ 157.9 (CO), 157.4 (CO), 143.4 (C), 139.2 (C), 136.2 (C), 134.2 (C),
131.1 (CH), 130.9 (CH), 130.5 (C), 129.9 (CH), 128.9 (CH), 128.8 (CH), 126.2 (CH), 125.9 (CH),
122.9 (C), 121.5 (CH), 120.4 (CH), 119.6 (CH), 116.9 (CH), 116.2 (CH), 21.4 (CH3); IR (KBr) 3468
(s), 3370 (s), 3268 (s), 1666 (s), 1512 (s), 1327 (s), 1110 (s), 1060 (s), 854 (w), 758 (s) cm−1; HRMS
+
(ESI/Q-TOF) 377.1252, calcd. for C20H17N4O4 ([M+H]+) 377.1244.
N1-(2'-Amino-[1,1'-biphenyl]-2-yl)-N2-phenyloxalamide (3h). Yield 69% (183 mg), yellow solid, mp
145-148 °C; Rf = 0.20 (petroleum ether - EtOAc, 3:1); 1H NMR (300 MHz, CDCl3): δ 9.88 (s, 1H), 9.44
(s, 1H), 8.32 (d, J = 8.10 Hz, 1H), 7.65 – 7.58 (m, 3H), 7.44 (dd, J = 8.10, 6.94 Hz, 1H), 7.40 – 7.22 (m,
4H), 7.21 – 7.09 (m, 2H), 6.93 (d, J = 7.45 Hz, 1H), 6.88 (d, J = 7.78 Hz, 1H), 3.70 (br. s, 2H);13C NMR
(75 MHz, CDCl3): δ 157.9 (CO), 157.6 (CO), 143.5 (C), 136.4 (C), 134.2 (C), 131.1 (CH), 130.9 (CH),
130.7 (C), 129.9 (CH), 129.1 (2 × CH), 128.8 (CH), 125.9 (CH), 125.3 (CH), 122.9 (C), 121.6 (CH),
119.9 (2 × CH), 119.5 (CH), 116.3 (CH); IR (KBr) 3459 (s), 3374 (s), 3275 (s), 1662 (s), 1511 (s), 1325
13

Organic & Biomolecular Chemistry
Page 14 of 21
(s), 1112 (s), 1070 (s), 848 (w), 754 (s) cm−1; HRMS (ESI/Q-TOF) 354.1202, calcd. for C20H17N3O2Na+
View Article Online
([M+Na]+) 354.1213.
DOI: 10.1039/D0OB00811G
N1-(2'-Amino-[1,1'-biphenyl]-2-yl)-N2-(p-tolyl)oxala-mide (3i). Yield 61% (168 mg), yellow solid,
mp 208-210 °C; Rf = 0.22 (petroleum ether - EtOAc, 3:1); 1H NMR (300 MHz, CDCl3): δ 9.85 (s, 1H),
9.30 (s, 1H), 8.35 (d, J = 8.08 Hz, 1H), 7.53 - 7.44 (m, 3H), 7.35 (dd, J = 7.47, 6.11 Hz, 1H), 7.31 - 7.25
(m, 2H), 7.17 - 7.14 (m, 3H), 6.94 (d, J = 7.47 Hz, 1H), 6.90 (d, J = 8.15 Hz, 1H), 3.69 (br. s, 2H), 2.34
(s, 3H); 13C NMR (75 MHz, CDCl3): δ 158.0 (CO), 157.3 (CO), 143.5 (C), 135.0 (C), 134.3 (C), 133.8
(C), 131.1 (CH), 130.9 (CH), 130.5 (C), 129.9 (CH), 129.6 (2 × CH), 128.8 (CH), 125.9 (CH), 122.9
(C), 121.5 (CH), 119.8 (2 × CH), 119.5 (CH), 116.2 (CH), 20.9 (CH3); IR (KBr) 3368 (s), 3317 (s),
3034 (s), 1675 (s), 1522 (s), 1494 (s), 1445 (s), 1303 (w), 818 (w), 752 (s) cm−1; HRMS (ESI/Q-TOF)
+
346.1557, calcd. for C21H20N3O2 ([M+H]+) 346.1550.
N1-(2'-Amino-[1,1'-biphenyl]-2-yl)-N2-(m-tolyl)oxal-amide (3j). Yield 73% (202 mg), yellow solid,
mp 169-171 °C; Rf = 0.23 (petroleum ether - EtOAc, 3:1); 1H NMR (300 MHz, CDCl3): δ 9.84 (s, 1H),
9.27 (s, 1H), 8.35 (d, J = 8.13 Hz, 1H), 7.50 – 7.48 (m, 2H), 7.45 – 7.21 (m, 5H), 7.13 (d, J = 7.43 Hz,
1H), 6.99 (d, J = 7.53 Hz, 1H), 6.94 (d, J = 7.55 Hz, 1H), 6.92 – 6.89 (m, 1H), 3.69 (br. s, 2H), 2.35 (s,
3H);13C NMR (75 MHz, CDCl3): δ 157.9 (CO), 157.4 (CO), 143.4 (C), 139.2 (C), 136.2 (C), 134.2 (C),
131.1 (CH), 130.9 (CH), 130.5 (C), 129.9 (CH), 128.9 (CH), 128.8 (CH), 126.2 (CH), 125.9 (CH),
122.9 (C), 121.5 (CH), 120.4 (CH), 119.6 (CH), 116.9 (CH), 116.2 (CH), 21.4 (CH3); IR (KBr) 3463
(s), 3374 (s), 3271 (s), 1670 (s), 1515 (s), 1327 (s), 1121 (s), 1068 (s), 857 (w), 750 (s) cm−1; HRMS
+
(ESI/Q-TOF) 346.1546, calcd. for C21H20N3O2 ([M+H]+) 346.1550.
2-((2'-Amino-[1,1'-biphenyl]-2-yl)amino)-N-(naphthal-en-2-yl)acetamide (3k). Yield 77% (234 mg),
1
yellow solid, mp 200-203 °C; Rf = 0.25 (petroleum ether - EtOAc, 3:1); H NMR (300 MHz, DMSO-
d6): δ 10.97 (s, 1H), 10.03 (s, 1H), 8.27 (d, J = 8.07 Hz, 1H), 7.99 - 7.95 (m, 1H), 7.88 – 7.84 (m, 2H),
7.60 – 7.48 (m, 5H), 7.35 – 7.33 (m, 2H), 7.13 (dd, J = 8.12, 6.70 Hz, 1H), 7.01 (d, J = 7.52 Hz, 1H),
6.85 (d, J = 8.12 Hz, 1H), 6.71 (dd, J = 8.07, 6.70 Hz, 1H), 4.83 (br. s, 2H);13C NMR (75 MHz, DMSO-
d6): δ 159.7 (CO), 158.1 (CO), 145.6 (C), 134.8 (C), 134.1 (C), 132.7 (C), 131.8 (C), 131.5 (CH), 131.1
(CH), 129.5 (CH), 128.7 (C), 128.6 (CH), 128.5 (CH), 127.2 (CH), 126.7 (2 × CH), 126.1 (CH), 125.8
(CH), 123.5 (CH), 123.2 (CH), 122.8 (C), 121.9 (CH), 117.8 (CH), 116.3 (CH); IR (KBr) 3441 (s), 3344
(s), 1684 (s), 1523 (s), 1496 (s), 1446 (s), 1304 (w), 1158 (w), 856 (w), 772 (s) cm−1; HRMS (ESI/Q-
+
TOF) 382.1545, calcd. for C24H20N3O2 ([M+H]+) 382.1550.
N1-(2'-Amino-[1,1'-biphenyl]-2-yl)-N2-benzyloxalamide (3l). Yield 85% (234 mg), yellow solid, mp
173-177 °C; Rf = 0.26 (petroleum ether - EtOAc, 3:1); 1H NMR (300 MHz, CDCl3): δ 9.73 (s, 1H), 8.34
(d, J = 8.18 Hz, 1H), 7.83 (t, J = 5.95 Hz, 1H), 7.45 (dd, J = 8.18, 6.56 Hz, 1H), 7.36 – 7.31 (m, 8H),
7.12 (d, J = 7.47 Hz, 1H), 6.94 (d, J = 7.44 Hz, 1H), 6.89 (d, J = 7.77 Hz, 1H), 4.48 (d, J = 5.95 Hz,
13
2H), 3.66 (br. s, 2H); C NMR (75 MHz, CDCl3): δ 159.8 (CO), 157.6 (CO), 143.5 (C), 136.8 (C),
14

Page 15 of 21
Organic & Biomolecular Chemistry
134.4 (C), 131.0 (CH), 130.9 (CH), 130.2 (C), 129.9 (CH), 128.8 (2 × CH), 128.8 (CH), 127.9 (3 × CH),
View Article Online
DOI: 10.1039/D0OB00811G
125.7 (CH), 122.8 (C), 121.2 (CH), 119.5 (CH), 116.2 (CH), 43.9 (CH2); IR (KBr) 3431 (s), 3335 (s),
1670 (s), 1523 (s), 1448 (s), 1307 (s), 1004 (s), 748 (w), 698 (s) cm−1; HRMS (ESI/Q-TOF) 346.1552,
+
calcd. for C21H20N3O2 ([M+H]+) 346.1550.
N1-(2'-Amino-[1,1'-biphenyl]-2-yl)-N2-heptyloxalamide (3m). Yield 40% (112 mg), yellow solid, mp
165-168 °C; Rf = 0.20 (petroleum ether - EtOAc, 3:1); 1H NMR (300 MHz, DMSO-d6): δ 9.83 (s, 1H),
8.98 (t, J = 5.85 Hz, 1H), 8.16 (d, J = 8.11 Hz, 1H), 7.45 (m, 1H), 7.29 – 7.27 (m, 2H), 7.24 – 7.06 (m,
1H), 6.95 (d, J = 7.58 Hz, 1H), 6.87 (d, J = 7.94 Hz, 1H), 6.70 (dd, J = 7.58, 6.86 Hz, 1H), 4.70 -4.76
(m, 2H), 3.15 – 2.96 (m, 2H), 1.56 – 1.35 (m, 2H), 1.19 – 1.26 (m, 8H), 0.85 (t, J = 6.70 Hz, 3H); 13C
NMR (75 MHz, DMSO-d6): δ 159.9 (CO), 158.1 (CO), 145.6 (C), 134.7 (C), 131.4 (CH), 131.0 (CH),
129.5 (CH), 128.5 (2 × CH), 125.9 (CH), 122.6 (C), 121.7 (C), 117.7 (CH), 116.2 (CH), 31.6 (CH2),
29.0 (CH2), 28.8 (CH2), 26.7 (CH2), 22.5 (2 × CH2), 14.4 (CH3); IR (KBr) 3461 (s), 3380 (s), 3271 (s),
1664 (s), 1512 (s), 1327 (s), 1112 (s), 1067 (s), 852 (w), 754 (s) cm−1; HRMS (ESI/Q-TOF) 354.2169,
+
calcd. for C21H28N3O2 ([M+H]+) 354.2176.
N1-(2'-Amino-[1,1'-biphenyl]-2-yl)oxalamide (3n). Yield 80% (163 mg), yellow solid, mp 199 °C; Rf
1
= 0.20 (petroleum ether - EtOAc, 3:1); H NMR (300 MHz, DMSO-d6): δ 9.74 (s, 1H), 8.27 (s, 1H),
8.11 (d, J = 8.12 Hz, 1H), 7.94 (s, 1H), 7.50 – 7.37 (m, 1H), 7.31 - 7.27 (m, 2H), 7.16 (dd, J = 8.12, 6.91
Hz, 1H), 6.95 (d, J = 8.24 Hz, 1H), 6.85 (d, J = 7.53 Hz, 1H), 6.71 (dd, J = 8.24, 6.91 Hz, 1H), 4.71 (br.
13
s, 2H); C NMR (75 MHz, DMSO-d6): δ 162.2 (CO), 158.4 (CO), 145.5 (C), 134.7 (C), 131.6 (C),
131.4 (CH),131.0 (CH), 129.6 (CH), 128.5 (CH), 125.9 (CH), 122.7 (CH), 121.9 (CH), 117.8 (CH),
116.2 (CH); IR (KBr) 3455 (s), 3375 (s), 3328 (s), 1692 (s), 1623 (s), 1582 (s), 1447 (s), 1304 (w), 761
+
(s) cm−1; HRMS (ESI/Q-TOF) 256.1084, calcd. for C14H14N3O2 ([M+H]+) 256.1081.
N1-(2'-Amino-5,5'-dimethyl-[1,1'-biphenyl]-2-yl)-N2-phenyloxalamide (3o). Yield 70% (201 mg),
yellow solid, mp 165-167 °C; Rf = 0.21 (petroleum ether - EtOAc, 3:1); 1H NMR (300 MHz, CDCl3): δ
9.84 (s, 1H), 9.24 (s, 1H), 8.38 (d, J = 8.12 Hz, 1H), 7.88 (d, J = 8.72 Hz, 1H), 7.48 (dd, J = 7.75, 6.46
Hz, 1H), 7.41 – 7.22 (m, 3H), 7.13 (d, J = 6.46 Hz, 1H), 7.03 (m, 2H), 6.96 – 6.90 (m, 1H), 6.89 (d, J =
7.75 Hz, 1H), 3.68 (br. s, 2H), 2.31 (s, 6H); 13C NMR (75 MHz, CDCl3): δ 158.1 (CO), 157.3 (CO),
143.4 (C), 135.3 (C), 134.3 (C), 131.8 (C), 131.2 (CH), 131.1 (CH), 130.9 (CH), 130.4 (C), 129.9 (CH),
128.8 (CH), 128.2 (C), 127.4 (CH), 125.9 (CH), 122.9 (C), 121.3 (CH), 121.3 (CH), 119.5 (CH), 116.2
(CH), 20.9 (CH3), 17.36 (CH3); IR (KBr) 3444 (s), 3393 (s), 1682 (s), 1510 (s), 1383 (s), 1130 (s), 1023
+
(s), 814 (w), 479 (s) cm−1; HRMS (ESI/Q-TOF) 360.1694, calcd. for C22H22N3O2 ([M+H]+) 360.1707.
N1-(2'-Amino-5,5'-dibromo-[1,1'-biphenyl]-2-yl)-N2-(2,3-dimethylphenyl)oxalamide (3p). Yield
1
58% (239 mg), yellow solid, mp 115-117 °C; Rf = 0.25 (petroleum ether - EtOAc, 3:1); H NMR (300
MHz, CDCl3): δ 9.76 (s, 1H), 9.23 (s, 1H), 8.25 (d, J = 8.56 Hz, 1H), 7.73 (d, J = 8.56 Hz, 1H), 7.62 (d,
J = 7.76 Hz, 1H), 7.51 (s, 1H), 7.36 (d, J = 7.76 Hz, 1H), 7.25 (s, 1H), 7.13 (dd, J = 8.00, 7.71 Hz, 1H),
15

Organic & Biomolecular Chemistry
Page 16 of 21
7.05 (d, J = 7.71 Hz, 1H), 6.78 (d, J = 8.00 Hz, 1H), 3.55 (br. s, 2H), 2.33 (s, 3H), 2.23 (s, 3H); 13C
View Article Online
DOI: 10.1039/D0OB00811G
NMR (75 MHz, CDCl3): δ 158.2 (CO), 157.3 (CO), 142.2 (C), 137.6 (C), 133.9 (C), 133.8 (CH), 133.3
(C), 133.1 (CH), 132.2 (CH), 131.2 (C), 127.9 (CH), 127.8 (C), 126.1 (CH), 123.6 (C), 123.1 (CH),
120.1 (CH), 118.8 (C), 117.9 (CH), 111.4 (C), 29.7 (CH3), 20.6 (CH3); IR (KBr) 3446 (s), 3390 (s),
1680 (s), 1515 (s), 1387 (s), 1124 (s), 1025 (s), 820 (w), 471 (s) cm−1; HRMS (ESI/Q-TOF) 517.9900,
+
calcd. for C22H20Br2N3O2 ([M+H]+) 517.9898.
N1-(2'-Amino-5,5'-dibromo-[1,1'-biphenyl]-2-yl)-N2-(3,4-dichlorophenyl)oxalamide (3q). Yield
1
65% (289 mg), yellow solid, mp 110-111 °C; Rf = 0.24 (petroleum ether - EtOAc, 3:1); H NMR (300
MHz, CDCl3): δ 9.72 (s, 1H), 9.24 (s, 1H), 8.19 (d, J = 8.83 Hz, 1H), 7.91 (s, 1H), 7.62 (d, J = 6.56 Hz,
1H), 7.52 (s, 1H), 7.43 - 7.39 (m, 3H), 7.26 (s, 1H), 6.81 (d, J = 8.83 Hz, 1H), 3.71 (br. s, 2H);13C NMR
(75 MHz, DMSO-d6): δ 158.9 (CO), 157.7 (CO), 145.2 (C), 137.9 (C), 133.9 (C), 133.9 (CH), 133.3
(C), 133.1 (CH), 132.5 (CH), 131.8 (CH), 131.4 (C), 131.1 (CH), 126.9 (C), 124.5 (CH), 123.6 (C),
122.4 (CH), 121.2 (CH), 118.4 (C), 118.3 (CH), 108.2 (C); IR (KBr) 3444 (s), 3393 (s), 1682 (s), 1510
(s), 1383 (s), 1130 (s), 1023 (s), 814 (w), 479 (s) cm−1; HRMS (ESI/Q-TOF) 557.8797, calcd. for
+
C20H14Br2Cl2N3O2 ([M+H]+) 557.8803.
N-(2'-amino-[1,1'-biphenyl]-2-yl)-2-oxo-2-phenylacetamide (6a). Yield 25% (63 mg), yellow solid,
1
mp 166-168 °C; Rf = 0.29 (petroleum ether - EtOAc, 3:1); H NMR (300 MHz, CDCl3): δ 9.36 (br. s,
1H), 8.44 (d, J = 8.18 Hz, 1H), 8.34 (d, J = 7.48 Hz, 2H), 7.66 – 7.59 (m, 1H), 7.54 – 7.44 (m, 4H), 7.39
– 7.31 (m, 2H), 7.15 (d, J = 8.84 Hz, 1H), 6.95 (d, J = 7.48 Hz, 1H), 6.89 (d, J = 8.18 Hz, 1H), 3.68 (br.
s, 2H); 13C NMR (75 MHz, CDCl3): δ 187.4 (CO), 159.3 (CO), 143.5 (C), 134.4 (CH), 133.2 (C), 131.3
(2 × CH), 131.0 (2 × CH), 130.4 (C), 129.8 (CH), 128.8 (CH), 128.5 (2 × CH), 128.1 (C), 125.7 (CH),
+
122.9 (C), 121.6 (CH), 119.5 (CH), 116.1 (CH); HRMS (ESI/Q-TOF) 317.1308, calcd. for C20H17N2O2
([M+H]+) 317.1305.
N-(2'-amino-[1,1'-biphenyl]-2-yl)-2-(benzo[d][1,3]dioxol-5-yl)-2-oxoacetamide (6b). Yield 50% (144
1
mg), yellow solid, mp 175-177 °C; Rf = 0.30 (petroleum ether - EtOAc, 3:1); H NMR (300 MHz,
CDCl3): δ 9.36 (br. s, 1H), 8.42 (d, J = 8.03 Hz, 1H), 8.19 (d, J = 8.33 Hz, 1H), 7.79 (s, 1H), 7.52 – 7.45
(m, 1H), 7.37 (d, J = 7.55 Hz, 1H), 7.34 – 7.29 (m, 1H), 7.28 – 7.25 (m, 1H), 7.14 (d, J = 7.55 Hz, 1H),
13
6.94 - 6.89 (m, 3H), 6.07 (s, 2H), 3.68 (br. s, 2H); C NMR (75 MHz, CDCl3): δ 184.9 (CO), 159.7
(CO), 153.1 (C), 147.9 (C), 143.5 (C), 134.6 (C), 130.9 (CH), 130.3 (C), 129.8 (CH), 129.2 (CH), 128.8
(CH), 127.7 (C), 125.6 (CH), 122.9 (C), 121.5 (CH), 119.4 (CH), 116.0 (CH), 110.5 (CH), 108.1 (CH),
+
101.9 (CH), 29.7 (CH2); HRMS (ESI/Q-TOF) 361.1193, calcd. for C21H17N2O4 ([M+H]+) 317.1199.
Synthesis of N1-(2'-(4-methoxybenzamido)-[1,1'-biphenyl]-2-yl)-N2-(p-tolyl)oxalamide (7). 4-
Methoxybenzoyl chloride (24 mg, 0.15 mmol, 1.1 equiv) was added to the mixture of oxalamide 3i (48
mg, 0.14 mmol, 1.0 equiv) and pyridine (14 μL, 0.18 mmol, 1.3 equiv) in dry CH2Cl2 (1.4 mL). The
mixture was stirred for 2.5 h at rt until the complete conversion of oxalamide (TLC monitoring). The
16

Page 17 of 21
Organic & Biomolecular Chemistry
resulted mixture was concentrated under reduced pressure. Residue was purified by column
View Article Online
DOI: 10.1039/D0OB00811G
chromatography (eluent: petroleum ether - EtOAc, 3:1) to get 51 mg (yield 76%) of colorless solid, mp
1
207 - 209 °C; Rf = 0.31 (petroleum ether - EtOAc, 3:1). H NMR (300 MHz, DMSO-d6): δ 10.76 (s,
1H), 9.65 (s, 1H), 9.59 (s, 1H), 8.03 (d, J = 8.07 Hz, 1H), 7.68 (d, J = 8.42 Hz, 2H), 7.61 (m, 3H), 7.49
(dd, J = 8.07, 7.64 Hz, 1H), 7.37 (m, 2H), 7.25 (d, J = 7.66 Hz, 1H), 7.20 (m, 2H), 7.14 (d, J = 8.42 Hz,
13
2H), 6.94 (d, J = 8.79 Hz, 2H), 3.78 (s, 3H), 2.26 (s, 3H); C NMR (75 MHz, DMSO-d6): δ 165.4
(CO), 162.2 (CO), 158.3 (CO), 158.2 (C), 136.7 (C), 135.3 (C), 134.7 (C), 134.5 (C), 134.3 (C), 132.8
(C), 130.8 (CH), 130.5 (CH), 129.6 (2 × CH), 129.5 (2 × CH), 129.2 (CH), 128.6 (CH), 127.6 (CH),
126.8 (C), 126.6 (CH), 125.5 (CH), 122.9 (CH), 120.9 (2 × CH), 114.0 (2 × CH), 55.8 (CH3), 20.9
(CH3); IR (KBr) 3329 (s), 3302 (s), 1681 (s), 1524 (s), 1440 (s), 1305 (s), 1030 (s), 756 (w), 483 (s)
+
cm−1; HRMS (ESI/Q-TOF) 480.1918, calcd.for C29H26N3O4 ([M+H]+) 480.1905.
Synthesis of N1-(benzyl-N2-(2'-iodo-[1,1'-biphenyl]-2-yl)oxalamide (8). 20%-Water solution of
o
NaNO2 (16 mg, 0.22 mmol, 1.5 equiv) was added portionwise during 5 min at 5 C (ice bath) to the
mixture of oxalamide 3l (50 mg, 0.14 mmol, 1.0 equiv) and HClconc (19 μL, 0.18 mmol, 1.3 equiv) in
o
water/acetone mixture (2.0 mL, 1:1 ratio). The mixture was vigorously stirred for 10 min at 5 C (ice
bath) and 1 h at rt. Solution of KI (47 mg, 0.28 mmol, 2.0 equiv) in water (0.3 mL) was added and
mixture was additionally stirred at rt overnight. The resulted mixture was diluted with ethyl acetate (10
mL), organic layer was washed with saturated water solution of NaHSO3 until color stay persist and
dried over Na2SO4. Solvent was removed under reduced pressure. Residue was purified by column
chromatography (eluent: petroleum ether - EtOAc, 3:1) to get 52 mg (yield 81%) of colorless solid, mp
72 - 75 °C; Rf = 0.30 (petroleum ether - EtOAc, 3:1). 1H NMR (300 MHz, CDCl3): δ 9.06 (s, 1H), 8.42
(d, J = 8.07 Hz, 1H), 8.06 (d, J = 7.34, 1H), 7.83 (t, J = 5.77 Hz, 1H), 7.55 – 7.46 (m, 4H), 7.44 – 7.38
13
(m, 4H), 7.36 – 7.28 (m, 7H), 4.48 (d, J = 5.77 Hz, 2H); C NMR (75 MHz, CDCl3): δ 159.8 (CO),
157.6 (CO), 143.5 (C), 136.8 (C), 134.4 (C), 131.0 (CH), 130.9 (CH), 130.2 (C), 129.9 (CH), 128.8 (2 ×
CH), 128.8 (CH), 127.9 (3 × CH), 125.7 (CH), 122.8 (C), 121.2 (CH), 119.5 (CH), 116.2 (CH), 43.9
(CH2); IR (KBr) 3431 (s), 3335 (s), 1670 (s), 1523 (s), 1448 (s), 1307 (s), 1004 (s), 748 (w), 698 (s)
+
cm−1; HRMS (ESI/Q-TOF) 457.1552, calcd. for C21H18N2O2 ([M+H]+) 457.1550.
Synthesis of N-benzyl-2-(9H-carbazol-9-yl)-2-oxoacetamide (9). HClconc (26 μL, 0.26 mmol, 1.3
equiv) and NaNO2 (21 mg, 0.3 mmol, 1.5 equiv) was added stepwise at 0 oC (ice bath) the suspension of
oxalamide 3l (68 mg, 0.2 mmol, 1.0 equiv) and in water/acetone mixture (2.0 mL, 1:1 ratio). The
o
mixture was stirred for 1 h at 0 C (ice bath), ethanol (40 μL, 0.4 mmol, 2.0 equiv) was added and
mixture was additionally stirred at rt overnight. The resulted mixture was concentrates under reduce
pressure. Residue was purified by column chromatography (eluent: petroleum ether - EtOAc, 5:1  4:1)
to get 49 mg (yield 74%) of colorless solid, mp 157 - 159 °C; Rf = 0.31 (petroleum ether - EtOAc, 3:1).
1H NMR (300 MHz, CDCl3): δ 7.91 (m, 4H), 7.40 (m, 9H), 7.08 (br.s, 1H), 4.71 (d, J = 5.95 Hz, 2H);
17

Organic & Biomolecular Chemistry
Page 18 of 21
13C NMR (75 MHz, CDCl3): δ 163.0 (CO), 161.8 (CO), 137.8 (C), 136.5 (C), 128.9 (2 × CH), 128.8
View Article Online
DOI: 10.1039/D0OB00811G
(C), 128.2 (2 × CH), 128.1 (CH), 127.3 (2 × CH), 126.7 (C), 124.6 (2 × CH), 119.8 (2 × CH), 115.9 (2 ×
CH), 99.9 (C), 43.9 (CH2); IR (KBr) 3329 (s), 3312 (s), 1674 (s), 1524 (s), 1432 (s), 1030 (s), 766 (w),
+
473 (s) cm−1; HRMS (ESI/Q-TOF) 329.1282, calcd.for C21H17N2O2 ([M+H]+) 329.1285.
Scale-up synthesis of N1-(2'-Amino-[1,1'-biphenyl]-2-yl)-N2-benzyloxalamide (3l). N-Benzyl-2-
chloroacetamide (2l) (2.0 g, 10.9 mmol, 2.0 equiv) was added portionwise at 100 oC (oil bath) during 2
h to the mixture of 2,2'-biphenyldiamine (1a) (1.0 g, 5.4 mmol, 1.0 equiv), sulfur (4.1 g, 16.2 ммоль,
3.0 equiv), and triethylamine (7.5 mL, 54.0 mmol, 10.0 equiv) in water (50 mL). The mixture was
stirred for 6 h at reflux until the complete conversion of 2,2'-biphenyldiamine (TLC monitoring). The
reaction mixture was cooled to room temperature and 4/5 parts of water were decanted. To the residue
DMF (40 mL) and TsOH monohydrate (93 mg, 0.54 mmol, 10 mol%) were added. The resulting
o
solution was heating at 140 С (silicon oil bath) for 8 h. Reaction mixture was cooled to room
temperature, diluted with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). Combined
organic layer was washed with water (5 × 30 mL) and dried over Na2SO4. Solvent was removed under
reduced pressure. Product was isolated by recrystallization from ethanol (65 mL) to get 1.3 g (yield
71%) of yellow solid.
Scale-up synthesis of N1-(2'-Amino-[1,1'-biphenyl]-2-yl)oxalamide (3n). Triethylamine (2.2 mL, 16.2
mmol, 3.0 equiv) was added at rt to the solution of 2,2'-biphenyldiamine (1a) (1.0 g, 5.4 mmol, 1.0
equiv) and sulfur (4.1 g, 16.2 mmol, 3.0 equiv) in DMF (10 mL) with water (200 µL, 10.8 mmol, 2
equiv). The mixture was vigorously stirred at rt for 15 min. 2-Chloroacetamide (2n) (1.0 g, 10.8 mmol,
2.0 equiv) was added and mixture was heated at 90 oC (oil bath) for 6 h until the complete conversion of
biphenyldiamine (TLC monitoring). Reaction mixture was cooled to room temperature and diluted with
water (60 mL). Formed precipitate was filtered, washed with water (5 × 30 mL), dried, and dissolved in
acetone (70 ml) to remove sulfur. Filtrate was concentrated under reduced pressure and product was
isolated by recrystallization from ethanol (50 mL) to get 1.0 g (yield 72%) of yellow solid.
Synthesis of 2-((2'-amino-[1,1'-biphenyl]-2-yl)amino)-N-(4-chlorophenyl)-2-thioxoacetamide (4b).
The mixture of 2,2'-biphenyldiamine (1a) (300 mg, 1.63 mmol, 1.2 equiv), and sulfur (1.0 g, 4.08 mmol,
3.0 equiv), triethylamine (0.57 mL, 4.08 mmol, 3.0 equiv) in dry DMF (15 mL) was vigorously stirred
at rt for 15 min. Next 2-chloro-N-(4-chlorophenyl)acetamide (2b) (275 mg, 1.36 mmol, 1.0 equiv) was
added and reaction was stored at 60 ˚С (oil bath) for 3 h until the complete conversion of 2,2'-
biphenyldiamine (TLC monitoring). The resulted mixture was cooled to room temperature, diluted with
water (45 mL) and extracted with EtOAc (3 × 45 mL). Combined organic fractions were washed with
water (5 × 45 mL), dried over Na2SO4.and and concentrated under reduced pressure. The residue was
purified by column chromatography (eluent: petroleum ether - EtOAc, 4:1  3:1) to get 140 mg (yield
27%) of yellow solid, mp 130 − 132 °C (mplit = 130 – 132 °C33); Rf = 0.30 (petroleum ether - EtOAc,
18

Page 19 of 21
Organic & Biomolecular Chemistry
1
3:1). H NMR (300 MHz, CDCl3): δ 11.79 (br.s, 1H), 10.28 (br.s, 1H), 8.65 (d, J = 8.03 Hz, 1H), 7.60
View Article Online
DOI: 10.1039/D0OB00811G
(d, J = 8.83 Hz, 2H), 7.57 – 7.49 (m, 1H), 7.46 (d, J = 3,97 Hz, 2H), 7.33 (d, J = 8.83 Hz, 2H), 7.26 (dd,
J = 7.56, 1.43 Hz, 1H), 7.16 (dd, J = 7.56, 1.43 Hz, 1H), 6.93 (m, 2H), 3.70 (s, 2H); HRMS (ESI/Q-
TOF) 382.0772, calcd. for C20H17ClN3OS+ ([M+H]+) 382.0775.
Synthesis of N-(4-chlorophenyl)-5H-dibenzo[d,f][1,3]diazepine-6-carboxamide (12). The mixture of
thioxoacetamide 4b (50 mg, 0.13 mmol, 1.0 equiv) and triethylamine (54 µL, 0.39 mmol, 3.0 equiv) in
water (5 mL) was refluxed for 2 h until the complete conversion of thioxoacetamide (TLC monitoring).
The resulted mixture was cooled to room temperature and extracted with EtOAc (3 × 10 mL). Organic
layer was dried over Na2SO4 and solvent was removed under reduced pressure. Residue was purified by
column chromatography (eluent: petroleum ether - EtOAc, 4:1  3:1) to get 40 mg (yield 90%) of
1
yellow solid, mp 132 - 134 °C (mplit = 132 -134 °C33); Rf = 0.22 (petroleum ether - EtOAc, 5:1). H
NMR (300 MHz, DMSO-d6): δ 10.59 (br.s, 1H), 8.51 (br.s, 1H), 7.87 (d, J = 8.80 Hz, 2H), 7.44 (d, J =
8.80 Hz, 2H), 7.31 (d, J = 7.34 Hz, 2H), 7.00-7.23 (m, 6H); HRMS (ESI/Q-TOF) 348.0887, calcd. for
C20H15ClN3O+ ([M+H]+) 348.0898.
Acknowledgements
This work was supported by the RFBR grant 18-33-20087.
References
1.
T. Harig, C. Schlawis, L. Ziesche, M. Pohlner, B. Engelen, S. Schulz, Nitrogen-containing
volatiles from marine salinispora pacifica and roseobacter-group bacteria. J. Nat. Prod. 2017, 80, 3289-
3295. DOI: 10.1021/acs.jnatprod.7b00789.
2.
K. Obara, D. Chino, Y. Tanaka, Long-lasting inhibitory effects of distigmine on recombinant
human acetylcholinesterase activity. Biol. Pharm. Bull. 2017, 40, 1739-1746. DOI: 10.1248/bpb.b17-
00351.
3.
Z. Chen, Y. Jiang, L. Zhang, Y.-L. Guo, D. Ma, Oxalic diamides and tert-butoxide: Two types of
ligands enabling practical access to alkyl aryl ethers via Cu-catalyzed coupling reaction. J. Am. Chem.
Soc. 2019, 141, 3541-3549. DOI: 10.1021/jacs.8b12142.
4.
J. Gao, S. Bhunia, K. Wang, L. Gan, S. Xia, D. Ma, Discovery of N-(naphthalen-1-yl)-N′-alkyl
oxalamide ligands enables Cu-catalyzed aryl amination with high turnovers. Org. Lett. 2017, 19, 2809-
2812. DOI: 10.1021/acs.orglett.7b00901.
5.
G. G. Pawar, H. Wu, S. De, D. Ma, Copper (I) oxide/N,N′-bis[(2-furyl)methyl] oxalamide-
catalyzed coupling of (hetero) aryl halides and nitrogen heterocycles at low catalytic loading. Adv.
Synth. Catal. 2017, 359, 1631-1636. DOI: 10.1002/adsc.201700026.
6.
Y. Zhai, X. Chen, W. Zhou, M. Fan, Y. Lai, D. Ma, Copper-catalyzed diaryl ether formation
from (hetero) aryl halides at low catalytic loadings. J. Org. Chem. 2017, 82, 4964-4969. DOI:
10.1021/acs.joc.7b00493.
7.
Org. Lett. 2017, 19, 4864-4867. DOI: 10.1021/acs.orglett.7b02326.
8. M. Fan, W. Zhou, Y. Jiang, D. Ma, CuI/Oxalamide catalyzed couplings of (hetero) aryl chlorides
S. De, J. Yin, D. Ma, Copper-catalyzed coupling reaction of (hetero) aryl chlorides and amides.
and phenols for diaryl ether formation. Angew. Chem. Int. Ed. 2016, 55, 6211-6215. DOI:
10.1002/anie.201601035.
19

Organic & Biomolecular Chemistry
Page 20 of 21
9.
copper-catalyzed
10.1021/acs.orglett.7b01403.
10. W. Zhou, M. Fan, J. Yin, Y. Jiang, D. Ma, CuI/oxalic diamide catalyzed coupling reaction of
P. S. Fier, K. M. Maloney, Reagent design and ligand evolution for the development of a mild
View Article Online
DOI: 10.1039/D0OB00811G
hydroxylation
reaction.
Org.
Lett.
2017,
19,
3033-3036.
DOI:
(hetero) aryl chlorides and amines. J. Am. Chem. Soc. 2015, 137, 11942-11945. DOI:
10.1021/jacs.5b08411.
11.
under mild conditions. J. Am. Chem. Soc. 2016, 138, 13493-13496. DOI: 10.1021/jacs.6b08114.
12. D. V. Morarji, K. K. Gurjar, Theoretical and experimental studies: Cu(I)/Cu(II) catalytic cycle in
S. Xia, L. Gan, K. Wang, Z. Li, D. Ma, Copper-catalyzed hydroxylation of (hetero) aryl halides
CuI/oxalamide-promoted C–N bond formation. Organometallics 2019, 38, 2502-2511. DOI:
10.1021/acs.organomet.9b00224.
13.
S. D. Linton, T. Aja, R. A. Armstrong, X. Bai, L.-S. Chen, N. Chen, B. Ching, P. Contreras, J.-L.
Diaz, C. D. Fisher, First-in-class pan caspase inhibitor developed for the treatment of liver disease. J.
Med. Chem. 2005, 48, 6779-6782. DOI: 10.1021/jm050307e.
14.
D. Ben-Hail, R. Begas-Shvartz, M. Shalev, A. Shteinfer-Kuzmine, A. Gruzman, S. Reina, V. De
Pinto, V. Shoshan-Barmatz, Novel compounds targeting the mitochondrial protein VDAC1 inhibit
apoptosis and protect against mitochondrial dysfunction. J. Biol. Chem. 2016, 291, 24986-25003. DOI:
10.1074/jbc.M116.744284.
15.
L.-Y. Wang, K. Zheng, Y.-T. Li, Z.-Y. Wu, C.-W. Yan, Synthesis, structure and in vitro
antiproliferative activities of oxamido-bridged dicopper(II) complexes: A comparative study of
experimental evidence and molecular docking of DNA/protein binding. Appl. Organomet. Chem. 2018,
32, e3940. DOI: 10.1002/aoc.3940.
16.
N. Madani, A. M. Princiotto, L. Mach, S. Ding, J. Prevost, J. Richard, B. Hora, L. Sutherland, C.
A. Zhao, B. P. Conn, T. Bradley, M. A. Moody, B. Melillo, A. Finzi, B. F. Haynes, A. B. Smith III, S.
Santra, J. Sodroski, A CD4-mimetic compound enhances vaccine efficacy against stringent
immunodeficiency virus challenge. Nature Comm. 2018, 9, 2363. DOI: 10.1038/s41467-018-04758-9.
17.
S. Weheabby, M. A. Abdulmalic, M. Atzori, R. Sessoli, A. Aliabadi, T. Rüffer, Promotion of
antiferromagnetic exchange interaction in multinuclear copper(II) complexes via fused
oxamato/oxamidato ligands. Dalton Trans. 2018, 47, 16164-16181. DOI: 10.1039/C8DT03691H.
18.
Y. Liu, Y.-Z. Li, G. Liu, B. Liu, L. Hou, Y.-Y. Wang, Five new coordination polymers of s- and
d-block metals: Structural diversities, magnetic properties and luminescence. J. Solid State Chem. 2019,
270, 516-523. DOI: 10.1016/j.jssc.2018.12.026.
19.
Z. Džolić, N. K. Beyeh, M. Cetina, L. Turunen, K. Rissanen, Self-complementary dimers of
oxalamide-functionalized resorcinarene tetrabenzoxazines. Chem. Asian J. 2018, 13, 164-169. DOI:
10.1002/asia.201701426.
20.
J. H. Sellstedt, C. J. Guinosso, A. J. Begany, S. C. Bell, M. Rosenthale, Oxanilic acids, a new
series of orally active antiallergic agents. J. Med. Chem. 1975, 18, 926-933. DOI:
10.1021/jm00243a014.
21.
photocatalyzed umpolung reaction. Chem. Comm. 2019, 55, 3883-3886. DOI: 10.1039/C9CC01079C.
22. C. Rabong, U. Jordis, J. B. Phopase, NXO building blocks for backbone modification of peptides
and preparation of pseudopeptides. J. Org. Chem. 2010, 75, 2492-2500. DOI: 10.1021/jo902518r.
23. I. Borza, É. Bozó, G. Barta-Szalai, C. Kiss, G. Tárkányi, Á. Demeter, T. Gáti, V. Háda, S.
D. Ghosh, R. Nandi, S. Khamarui, S. Ghosh, D. K. Maiti, Selective amidation by a
Kolok, A. Gere, L. Fodor, J. Nagy, K. Galgóczy, I. Magdó, B. Ágai, J. Fetter, F. Bertha, G. M. Keserü,
C. Horváth, S. Farkas, I. Greiner, G. Domány, Selective NR1/2B N-methyl-d-aspartate receptor
antagonists among indole-2-carboxamides and benzimidazole-2-carboxamides. J. Med. Chem. 2007, 50,
901-914. DOI: 10.1021/jm060420k.
24.
J. M. LaLonde, M. Le-Khac, D. M. Jones, J. R. Courter, J. Park, A. Schön, A. M. Princiotto, X.
Wu, J. R. Mascola, E. Freire, J. Sodroski, N. Madani, W. A. Hendrickson, A. B. Smith, Structure-based
design and synthesis of an HIV-1 entry inhibitor exploiting X-ray and thermodynamic characterization.
ACS Med. Chem. Lett. 2013, 4, 338-343. DOI: 10.1021/ml300407y.
20

Page 21 of 21
Organic & Biomolecular Chemistry
25.
(a) T. B. Nguyen, M. Q. Tran, L. Ermolenko, A. Al-Mourabit, Three-component reaction
View Article Online
between alkynes, elemental sulfur, and aliphatic amines: a general, straightfoDrOwI:a1r0d.1,039a/Dn0dOB0a0t8o1m1G
economical approach to thioamides. Org. Lett. 2013, 16, 310-313. DOI: 10.1021/ol403345e. (b) T. B.
Nguyen, P. Retailleau, Sulfur-promoted aminative aromatization of 1,2,3,4-tetrahydrophenazines with
amines: flexible access to 1-aminophenazines. Adv. Synth. Catal. 2018, 360, 12, 2389-2393
DOI:10.1002/adsc.201800260.
26.
(a) T. Guntreddi, R. Vanjari, K. N. Singh, Decarboxylative thioamidation of arylacetic and
cinnamic acids: a new approach to thioamides. Org. Lett. 2014, 16, 3624-3627. DOI:
10.1021/ol501482g. (b) X. Li, Q. Pan, R. Hu, X. Wang, Z. Yang, S. Han, S8-Mediated one-pot synthesis
of thioamides from benzyl chlorides and amines. Asian J. Org. Chem., 2016, 5, 1353-1358.
DOI:10.1002/ajoc.201600385.
27.
T. B. Nguyen, L. Ermolenko, A. Al-Mourabit, Efficient and selective multicomponent oxidative
coupling of two different aliphatic primary amines into thioamides by elemental sulfur. Org. Lett. 2012,
14, 4274-4277. DOI: 10.1021/ol3020368.
28.
B. Eftekhari-Sis, S. V. Khajeh, O. Büyükgüngör, Synthesis of α-ketothioamides via Willgerodt–
Kindler reaction of arylglyoxals with amines and sulfur under solvent-free conditions. Synlett 2013, 24,
977-980. DOI: 10.1055/s-0032-1316897.
29.
Russ. Chem. Bull. 2004, 53, 415-419.
30. D. L. Priebbenow, C. Bolm, Recent advances in the Willgerodt–Kindler reaction. Chem. Soc.
Rev. 2013, 42, 7870-7880. DOI: 10.1039/C3CS60154D.
31. M. Kozlov, A. Komkov, T. Losev, A. Tyurin, A. Dmitrenok, I. Zavarzin, Y. Volkova, Flexible
I. Zavarzin, V. Yarovenko, E. Chernoburova, M. Krayushkin, Synthesis of monothiooxamides.
synthesis of phosphoryl-substituted imidazolines, tetrahydropyrimidines, and thioamides by sulfur-
mediated processes. J. Org. Chem. 2019, 84, 11533-11541. DOI: 10.1021/acs.joc.9b01384.
32.
M. Kozlov, A. Kozlov, A. Komkov, K. Lyssenko, I. Zavarzin, Y. Volkova, Synthesis of
phosphoryl thioamides via three-component reaction of phosphinic chlorides with amines and sulfur.
Adv. Synth. Catal. 2019, 361, 2904-2915. DOI: 10.1002/adsc.201900067.
33.
T. A. Tikhonova, K. A. Lyssenko, I. V. Zavarzin, Y. A. Volkova, Synthesis of
dibenzo[d,f][1,3]diazepines via elemental sulfur-mediated cyclocondensation of 2,2′-biphenyldiamines
with 2-chloroacetic acid derivatives. J. Org. Chem. 2019, 84, 15817-15826. DOI:
10.1021/acs.joc.9b02002.
34.
Catal. 2017, 359, 1066-1130. DOI: 10.1002/adsc.201601329.
35. B. Milevsky, N. Solov’eva, T. Chibisova, V. Yarovenko, E. Zayakin, V. Chernyshev, M.
T. B. Nguyen, Recent advances in organic reactions involving elemental sulfur. Adv. Synth.
Krayushkin, V. Traven, Hydrazones derived from thiooxamohydrazides and 3-formyl-4-
hydroxycoumarin: synthesis, structures, and fragmentation. Russ. Chem. Bull. 2012, 61, 2311-2321.
DOI:10.1007/s11172-012-0325-x.
36.
36.
C. Mei, W. Lu, Palladium (II)-catalyzed oxidative homo-and cross-coupling of aryl
ortho-sp2 C–H bonds of anilides at room temperature. J. Org. Chem. 2018, 83, 4812-4823. DOI:
10.1021/acs.joc.8b00120.
37.
E. Wang, C. Li, Y. Mo, Y. Zhang, G. Ma, W. Shi, J. Peng, W. Yang, Y. Cao, Poly (3,6-
silafluorene-co-2,7-fluorene)-based high-efficiency and color-pure blue light-emitting polymers with
extremely narrow band-width and high spectral stability. J. Mat. Chem. 2006, 16, 4133-4140.
DOI:10.1039/B609250K.
38.
D. J. Cheng, L. Yan, S. K. Tian, M. Y. Wu, L. X. Wang, Z. L. Fan, S. C. Zheng, X. Y. Liu, B.
Tan, Highly enantioselective kinetic resolution of axially chiral BINAM derivatives catalyzed by a
Brønsted acid. Angew. Chem. Int. Ed. 2014, 53, 3684-3687. DOI:10.1002/anie.201310562.
39.
C. Wang, H. Yamamoto, Nickel-catalyzed regio- and enantioselective aminolysis of 3,4-epoxy
alcohols. J. Am. Chem. Soc. 2015, 137, 4308-4311. DOI:10.1021/jacs.5b01005.
21