Aryliodoazide synthons: A different approach for diversified synthesis of 2-aminothiazole, 1,3-thiazole, and 1,3-selenazole scaffolds

Article abstract of DOI:10.1021/acscombsci.9b00045

Several straightforward and practical processes have been established for the construction of 2-aminothiazoles, 1,3-thiazoles and 1,3-selenazoles from aryliodoazides. These strategies successfully proceed with a wide spectrum of substituted thioamides and its derivatives producing the resulting five-membered heterocycles obtained in satisfactory yields. The unique features of these protocols are operational simplicity and highly functional group tolerance, which make them convenient and practical routes for the preparation of various libraries of 2-aminothiazoles, 1,3-thiazoles, and 1,3-selenazoles.

Full text of DOI:10.1021/acscombsci.9b00045

Subscriber access provided by UNIV AUTONOMA DE COAHUILA UADEC
Technology Note
Aryliodoazide Synthons: A Different Approach for Diversified Synthesis
of 2-Aminothiazole, 1,3-Thiazole and 1,3-Selenazole Scaffolds
Sahar Majnooni, Joseph Duffield, Jessica Price, Ahmad Reza
Khosropour, Hassan Zali Boeini, and M. Hassan Beyzavi
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.9b00045 • Publication Date (Web): 04 Jun 2019
Downloaded from http://pubs.acs.org on June 5, 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 19
ACS Combinatorial Science
1
2
3
4
5
6
7
8
9
Table of Contents Graphic
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
Title: Aryliodoazide Synthons: A Different Approach for Diversified Synthesis of 2-
Aminothiazole, 1,3-Thiazole and 1,3-Selenazole Scaffolds
Authors: Sahar Majnooni, Joseph Duffield, Jessica Price, Ahmad Reza Khosropour,
Hassan Zali-Boeini, M. Hassan Beyzavi
S
N3
Ar3
N
Ar1
I
Ar2
CsF, 100 oC
N
S
C
O
KOtBu
PEG 200, 80 oC
Se
KOtBu
PEG 200, 80 oC
Ar4
H
N
Ar3
N
N
N
Ar2
Ar1
O
Ar1
S
S
Ar4
N
Ar1
31 examples
Se
18 examples
20 examples
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 2 of 19
1
2
3
4
5
6
7
8
9
Aryliodoazide Synthons: A Different Approach for
Diversified Synthesis of 2-Aminothiazole, 1,3-
Thiazole and 1,3-Selenazole Scaffolds
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
‡
‡
Sahar Majnooni,† Joseph Duffield, Jessica Price, Ahmad Reza Khosropour,*,†,‡
Hassan Zali-Boeini,*,† M. Hassan Beyzavi,*,‡
†Department of Chemistry, University of Isfahan, Isfahan 81746-73441, Iran
‡Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas
72701, United States
*Corresponding authors e-mails: khosropour@chem.ui.ac.ir; akhosrop@uark.edu;
hzaliboeini@gmail.com; beyzavi@uark.edu
ABSTRACT: Several straightforward and practical processes have been established for the
construction of 2-aminothiazoles, 1,3-thiazoles and 1,3-selenazoles from aryliodoazides. These
strategies successfully proceed with a wide spectrum of substituted thioamides and its derivatives
producing the resulting five-membered heterocycles obtained in satisfactory yields. The unique
features of these protocols are operational simplicity, and highly functional group tolerance that
make them convenient and practical routes for the preparation of various libraries of 2-
aminothiazoles, 1,3-thiazoles and 1,3-selenazoles.
ACS Paragon Plus Environment

Page 3 of 19
ACS Combinatorial Science
1
2
3
4
KEYWORDS: Iodoazide; Isothiocyanate; 2-Aminothiazole; 1,3-Thiazole; 1,3-Selenazole;
5
6
Thioamide; Selenoamide
7
8
9
Over the past decade, 1,3-thiazoles especially 2-amino-1,3-thiazoles were widely recognized as a
vital, five-membered heterocycles. The 1,3-thiazole motif is one of the backbones of many
bioactive natural products, such as vitamin B1 (thiamine),1 micrococcin,2 and thiostrepton.3
Thiazole containing compounds are known for their broad medicinal and biological activities,
including antitumor,4 anticancer,5 antiviral,6 anti-inflammatory,7 antitubercular,8 antibacterial,9
antifungal,10 antimalarial,11 antihypertensive,12 and anti-HIV (Figure 1, A).13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
S
Ph
S
OH
O
H
N
H
O
N
N
N
N
H
O
O
Ph
Ritonavir (inhibitor of HIV protease )
A
OH
N
OH
O
N
N
S
H
Cl
O
N
N
S
NH2
S
N
N
H
N
N
N
NH
N
H
S
B
D
C
O
O
Anti inflammatory agent
Anticancer agent
Antidepressant agent
O
NH2
Se
O
HO
N
Se
N
O
Cl
N
OH
HO
5-Chloroacetyl-2-piperidino-1,3-selenazole
(anti-melanogenic agent)
Selenazofurin (antiviral agent)
F
E
Figure 1. Selected examples of biologically active and medicinal thiazole and selenazole
containing molecules.
Furthermore, 2-aminothiazole as a derivative of this azoles, exhibits various medicinal and
biological activities which have been utilized widely in the treatment of depression (Figure 1, B),14
inflammation (Figure 1, C),15 schizophrenia,16 tuberculosis,17 Parkinson’s disease,18 ulcers,19 and
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 4 of 19
1
2
3
4
5
6
7
8
9
HIV infections.20 Moreover, some of them have shown potent anti-tumor and anti-cancer activities
(Figure 1, D).21 On the other hand, 1,3-selenazoles, as seleno-analoges of 1,3-thiazoles, have also
been studied extensively due to their potential pharmacological and biological behaviours
including antibacterial,22 antitumor,23 anticancer,24 antimicrobial,25 antiviral,26 and anti-
melanogenic activity (Figure 1, E and F).27
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
In spite of the significance and the unique behaviors of these compounds, limited synthetic
approaches have been introduced for the preparation of these scaffolds in the literature.28
Fundamentally, the Hantzsch reaction,29 which consists of the condensation of α-halocarbonyl
with thioamides or selenoamides, is the main path for the synthesis of these heterocycles. Despite
widespread use of this approach, it suffers from utilizing hazardous solvents, harsh reaction
conditions, low diversity and/or expensive starting materials.28,29 Therefore, devising a new and
practical alternative protocol for the synthesis of diverse thiazoles and its derivatives to overcome
these problems is highly desirable.
Among the numerous nitrogen sources, haloazides, specifically iodoazides, have attracted
attention as an effective compound for the C–N bond formation. These precursors have been
utilized as useful synthons to prepare a new class of nitrogen-containing molecules such as vinyl
azides,30 triazoles,31 N-vinyl amides,32 pyrroles and pyridines.33 The iodoazide scaffold could be
obtained via azidoiodination of olefins utilizing I2–NaN3,34 PhI(OAc)2/TMSN3/Et4NI,35
IPy2BF4/TMSN3,36 NaN3/NaI/CAN37 and NaN3/KI/oxone/wet Al2O3.38
To circumvent the challenges of the current synthetic methods of these useful heterocycles, we
developed a practical strategy for the preparation of azoles through a base-promoted reaction of
aryliodoazides.
ACS Paragon Plus Environment

Page 5 of 19
ACS Combinatorial Science
1
2
3
4
5
6
7
8
9
The synthesis of 2-aminothiazoles was the first target. The simplest aryliodoazide, 1-(1-azido-2-
iodoethyl)benzene 1{1}, and phenyl isothiocyanate 2{1} were used to optimize reaction conditions
and screen solvent and base effects (SI, Table S1).
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
With the optimized reaction conditions in hand, we probed the efficiency and generality of this
protocol using a series of aryl iodoazides and isothiocyanates as shown in Figure 2.
Iodoazides 1:
N3
N3
N3
N3
N3
{6}
N3
Cl
Cl
I
I
I
I
I
I
H3CO
Br
Cl
{2}
{1}
{3}
{4}
{5}
Isothiocyanates 2:
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
OCH3
I
{8}
Cl
Br
{7}
NO2
{9}
CH3
{2}
{6}
{1}
{5}
{4}
S
{3}
Thioamides 4:
S
N
S
S
N
N
N
O
O
O
O
H3CO
{4}
{2}
{1}
{3}
S
S
S
S
H3CO
H3CO
H3CO
H3CO
N
N
N
N
O
O
O
O
Cl
(H3C)2N
{8}
{7}
{5}
{6}
OCH3
S
S
Cl
O
N
N
N
O
O
{9}
{10}
S
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 6 of 19
1
2
3
4
Selenoamides 5:
5
6
7
8
Se
Se
N
Se
Cl
Se
N
N
N
O
O
O
O
9
O
H3CO
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
{2}
{1}
Se
{3}
Se
{4}
Se
Se
Cl
Br
N
O
N
N
N
N
O
O
O
Br
{8}
{5}
{7}
{6}
Se
Figure 2. The diversity of reagents screened.
As shown in Table 1, various aryliodozides 1 with functionalized Ar1 were applied to study the
substrate scope. Although both electron-withdrawing and electron-donating moieties on the
iodoazide had little effect on the overall reaction, better results were achieved in the presence of
electron-rich substituents. Additionally, it was observed that regardless of the presence of either
electron-donating or electron-withdrawing groups all arylisothiocyanates screened produced the
desired product in good yields.
Table 1. Synthesis of 2-Aminothiazoles from Various Iodoazides and Isothiocyanatesa
Ar2
HN
N N N
CsF (1.0 mmol)
100 oC, Solvent-free
+ Ar2
N
C
S
S
N
Ar1
I
Ar1
1
2
Ar1
C6H5
C6H5
C6H5
C6H5
C6H5
3
Entry Compounds
Ar2
C6H5
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
4-MeC6H4
Yieldb (%)
1
3{1,1}
3{1,2}
3{1,6}
3{1,7}
3{1,9}
3{2,2}
3{3,1}
67
65
69
70
72
65
69
2
3
4
5
6
7
4-MeC6H4
4-MeOC6H4
C6H5
ACS Paragon Plus Environment

Page 7 of 19
ACS Combinatorial Science
1
2
3
4
5
6
7
8
9
8
9
3{3,2}
3{3,4}
3{3,6}
3{3,7}
3{4,1}
3{4,2}
3{4,3}
3{4,4}
3{4,5}
3{4,6}
3{4,7}
3{5,1}
3{5,2}
3{5,3}
3{5,5}
3{5,6}
3{5,7}
3{6,1}
3{6,2}
3{6,3}
3{6,5}
3{6,6}
3{6,7}
3{6,8}
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeC6H4
68
66
70
72
64
63
61
60
57
66
67
63
61
60
54
65
66
63
62
60
55
65
67
66
3-MeOC6H4
4-ClC6H4
4-BrC6H4
C6H5
4-MeC6H4
4-EtC6H4
3-MeOC6H4
1-Naphthyl
4-ClC6H4
4-BrC6H4
C6H5
4-MeC6H4
4-EtC6H4
1-Naphthyl
4-ClC6H4
4-BrC6H4
C6H5
4-MeC6H4
4-EtC6H4
1-Naphthyl
4-ClC6H4
4-BrC6H4
4-IC6H4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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-ClC6H4
4-ClC6H4
2,4-Cl2C6H3
2,4-Cl2C6H3
2,4-Cl2C6H3
2,4-Cl2C6H3
2,4-Cl2C6H3
2,4-Cl2C6H3
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
aReaction conditions: 1 (1 mmol), 2 (1 mmol), CsF (1 mmol), were heated at 100 C for 10 h.
o
bYield of isolated product.
It is noteworthy that 1-naphthyl group as bulky aryl-substituents was also found to be suitable for
this conversion and an acceptable quantity of the corresponding products was obtained
(compounds 3{4,5}, 3{5,5}, and 3{6,5}).
In order to investigate the selectivity in the synthesis of 2-aminothiazoles, the competition between
aliphatic and aromatic isothiocyanates was also examined. Phenyl isothiocyanate, as the aromatic
derivative, and benzyl isothiocyanate, as the aliphatic derivative, were reacted with 1-(1-azido-2-
iodoethyl)benzene in an equimolar ratio. Under both optimal and increased temperature or reaction
time, the benzyl isothiocyanate derived product was not produced. Furthermore, to explore the full
scope of this procedure, we substituted phenyl isothiocyanate with phenyl isocyanate and found
that the reaction failed and the phenyl isocyanate was recovered entirely. Both of these competition
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 8 of 19
1
2
3
4
5
6
reactions confirm that the electrophilicity of the sp-carbon could be a key factor for this
transformation.
7
8
9
Based on the observed results, a plausible mechanism was suggested in Scheme 1. First, the azide
group of iodoazide 1 attacks to isothiocyanate 2 to form intermediate A which undergoes an
intramolecular addition generating intermediate B. Subsequently, intermediate B is converted to
intermediate C by releasing N2 via the abstraction of benzylic hydrogen with F– as a base.
Eventually, the desired product is generated by tautomerization of C.
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. Proposed Mechanism for the Synthesis of 3.
Ar2
Ar2
N
N
S
Ar2
N2
S
N2
N
N
C
N2
N
N
S
-I
2
Ar1
I
Ar1
I
H
Ar1
A
1
B
F
N2
Ar2
Ar2
HN
N
C
S
N
N
S
Ar1
Ar1
H
3
Inspired by these results, we envisioned the investigation into the synthesis of other 1,3-thiazoles
as well as corresponding 1,3-selenazoles. Accordingly, the reaction of iodoazide 1{1} with
thioamide 4{1} in the presence of base was chosen as the model reaction. Optimization of the
reaction parameters is summarized in SI, Table S2.
Based on the results, we focused our attention on the investigation of substituent influence in this
transformation. Thioamides bearing a variety of substituents (Figure 2) were reacted with three
ACS Paragon Plus Environment

Page 9 of 19
ACS Combinatorial Science
1
2
3
4
5
6
7
8
9
types of iodoazide in PEG-200 using KOtBu as the base and the corresponding products were
obtained in good to excellent yields (Table 2). In this reaction, the electron density on the phenyl
ring of thioamides slightly affected their reactivity. As expected, thioamides with electron-
donating group showed more reactivity than those electron-withdrawing groups. The best result
was observed when electron-donating groups like –CH(CH3)2, –OCH3 and –N(CH3)2 were placed
in the para position of phenyl moiety (compounds 6{1,3}, 6{1,4} and 6{1,7} respectively).
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. Synthesis of Thiazole and Selenazole Derivatives a
Ar3
X
N N N
KOtBu (1.0 mmol)
N
X
Ar3
+
N
PEG, 80 oC
Ar1
I
O
1
Ar1
6, 7
4, 5
6
X=S,
X: S, Se
7
X=Se,
Entry
1
2
3
4
5
6
7
8
Compounds Ar1
C6H5
C6H5
Ar3
C6H5
4-MeC6H4
Yieldb (%)
83
85
84
88
86
87
88
79
76
79
87
80
81
83
85
83
6{1,1}
6{1,2}
6{1,3}
6{1,4}
6{1,5}
6{1,6}
6{1,7}
6{1,8}
6{1,9}
6{1,10}
6{3,1}
6{4,1}
6{4,2}
6{4,3},
6{4,4}
6{4,5}
6{4,6}
6{4,7}
6{4,8}
6{4,9}
6{1,1}
7{1,2}
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
C6H5
4-CH(CH3)2C6H4
4-MeOC6H4
3,4-(MeO)2C6H3
3,4,5-(MeO)2C6H3
4-N(CH3)2C6H4
4-ClC6H4
3-ClC6H4
O(CH₂CH₂)₂NCSC6H4
C6H5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
C6H5
4-MeC6H4
4-CH(CH3)2C6H4
4-MeOC6H4
3,4-(MeO)2C6H3
3,4,5-(MeO)2C6H3
4-N(CH3)2C6H4
4-ClC6H4
3-ClC6H4
C6H5
4-MeC6H4
84
85
74
73
88
89
C6H5
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 10 of 19
1
2
3
4
5
6
7
8
9
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
7{1,3}
7{1,4}
7{1,5}
7{1,6}
7{1,7}
7{1,8}
7{3,2}
7{3,3}
7{3,5}
7{4,1}
7{4,2}
7{4,3},
7{4,4},
7{4,5},
7{4,6},
7{4,7},
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
2-ClC6H4
3-ClC6H4
3-BrC6H4
4-BrC6H4
O(CH₂CH₂)₂NCSC6H4
4-MeC6H4
4-MeOC6H4
3-ClC6H4
91
81
82
84
85
80
91
94
87
83
84
90
80
81
83
85
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
C6H5
4-MeC6H4
4-MeOC6H4
2-ClC6H4
3-ClC6H4
3-BrC6H4
4-BrC6H4
aReaction conditions: 1 mmol of 1 and 1 mmol of 4 or 6 in the presence of 1mmol of KOtBu in
2ml of PEG-200 as solvent at 80oC for 7 h .b Yield of isolated product.
To better distinguish the substitution effect on the reaction, we decided to carry out a set of
additional examination. As illustrated in Table 2, by utilizing of 4{10} as a di-thioamide substrate,
only 6{1,10} was obtained selectively. Next, we decided to extend the scope of this protocol
through the synthesis of selenazoles by utilizing selenoamides (Figure 2) instead of thioamides
with the previously optimized reaction conditions (Table 2).
As depicted in Table 2, the reaction of iodoazides 1 with the variety of selenoamides 5 proceeded
efficiently utilizing KOtBu as the base in PEG-200 to obtain the corresponding products in good
to excellent yields.
As shown in Table 2, similar to the thioamides, the reactivity of the selenoamides was influenced
slightly by the substituted effects on the phenyl ring. Also, it was illustrated that by utilizing 5{8},
7{1,8} as a mono-selenazole was obtained selectively in high yield. During our investigation, we
found that selenoamides perform similar to the corresponding thioamides with more reactivity.
Meanwhile, investigating the reactivity of iodoazides revealed that the electron-donating groups
ACS Paragon Plus Environment

Page 11 of 19
ACS Combinatorial Science
1
2
3
4
5
6
(e.g. OCH3) increased the efficiency of the reaction (compounds 7 {3,2},7 {3,3} and 7 {3,5}
respectively).
7
8
9
In order to develop the scope of this reaction, we decided to employ this method in the synthesis
of 1,3-oxazoles and 1,3-imidazoles. The reaction of iodoazide 1{1} with two types of substrates:
morpholino(phenyl)methanone (X=O)and morpholino (phenyl) methanimine (X=NH) was carried
out under the optimized condition (SI, Scheme S1). Unfortunately, these reactions did not proceed
to form the desired products. These results demonstrated that the progress of this reaction was
directly related to the nucleophilicity of the substrates.
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
Finally, to expand the utility of this method, the selectivity was studied more by carrying out the
competitive
reaction
of
1-(1-azido-2-iodoethyl)benzene
1{1}
with
morpholino(phenyl)methanethione 4{1} and morpholino(phenyl)methaneselenone 5{1} in
equimolar ratios under optimized condition (SI, Scheme S2). This investigation illustrated the
increased reactivity of selenoamides in comparison to thioamides and the corresponding selenazole
was produced in good selectivity. This observation may be due to the more nucleophilicity of the
selenoamide in contrast to the thioamide. Moreover, this result indicated that the strength of the
nucleophile was the key factor in this transformation.
Based on the aforementioned results, the plausible mechanism is proposed in Scheme 2. Initially,
the thio/selenoamide reacts with the iodoazide via SN2 reaction to form A. Subsequently, via 5-
exo-dig reaction through azide attack on iminium part, the intermediate B is achieved. Through
abstraction of proton by KOtBu and releasing nitrogen gas, C is produced. Finally, by
aromatization of C and the elimination of morpholine molecule the desired product is obtained.
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 12 of 19
1
2
3
4
5
6
7
8
9
Scheme 2. Proposed Reaction Mechanism
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
X
Ar2
N
N
X
N
Ar2
Ar2
N
N2
N2
N
O
X
N2
N
H
Ar1
Ar1
I
-I-
H
Ar1
KOtBu
O
A
B
X=S, Se
N2
Ar2
Ar2
N
X
N
X
N
Ar1
Ar1
H
HN
O
C
In conclusion, we designed practical strategy to access diversified 2-aminothiazole, 1,3-
thiazole and 1,3-selenazole scaffolds. The significant feature of these methods is utilizing
aryliodoazides as the versatile reagent, which can participate in the reaction with a wide variety
of aryl isothiocyanates, thioamides or selenoamides. Utilizing solvent free conditions for the
synthesis of 2-aminothiazoles or PEG-200 as a non-toxic solvent for 1,3-thiazole and 1,3-
selenazole preparations could be considered as advantages of these protocols. In
addition, high diversity in the presented methodologies and the use of inexpensive starting
materials are other significant advantages. These new procedures give promising approaches
ACS Paragon Plus Environment

Page 13 of 19
ACS Combinatorial Science
1
2
3
4
5
to attain useful 5-membered nitrogen containing heterocycles. Furthermore, we envision that the
6
7
protocols with aryliodoazides are capable to furnish various N-heterocycles with medicinal and
8
9
biological activities.
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
 ASSOCIATED CONTENT
Supporting Information
Typical experimental procedures, antimicrobial assay and characterization data, including 1H and
13C spectra. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
E-mail: khosropour@chem.ui.ac.ir or akhosrop@uark.edu (A.R.K.), h.zali@chem.ui.ac.ir
(H.Z.B), beyzavi@uark.edu (M.H.B)
ACKNOWLEDGEMENTS
M. H. B. gratefully acknowledges financial support through the startup funds from the University
of Arkansas. A. R. K. and H. Z. B. gratefully thank the Center of Excellence of Chemistry and the
Research Council of the University of Isfahan (CECUI) for financial support of this work.
Notes: The authors declare no competing financial interest.
 REFERENCES
(1) Du, Q.; Wang, H.; Xie, J. Thiamin (Vitamin B1) Biosynthesis and regulation: a rich source
of antimicrobial drug targets?. Int. J. Biol. Sci. 2011, 7,41–52.
(2) Ciufolini, M. A.; Lefranc, D. Micrococcin P1: Structure, biology and synthesis. Nat. Prod.
Rep. 2010, 27, 330–342.
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 14 of 19
1
2
3
4
5
6
7
8
9
(3) Nicolaou, K. C.; Safina, B. S.; Zak, M.; Lee, S. H.; Nevalainen, M.; Bella, M.; Estrada, A.
A.; Funke, C.; Zecri, F, J.; Bulat, S. Total synthesis of thiostrepton. retrosynthetic analysis and
construction of key building blocks. J. Am. Chem. Soc. 2005, 127, 11159–11175.
(4) Esposito, G.; Teta, R.; Miceli, R.; Ceccarelli, L. S.; Sala, G. D.; Camerlingo, R.; Irollo, E.;
Mangoni, A.; Pirozzi, G.; Costantino, V. Isolation and assessment of the in vitro anti-tumor activity
of smenothiazole a and b, chlorinated thiazole-containing peptide/polyketides from the caribbean
sponge, smenospongia aurea. Mar. Drugs. 2015, 13, 444–459.
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) Martins, P.; Jesus, J.; Santos, S.; Raposo, L. R.; Roma-Rodrigues, C.; Baptista, P. V.;
Fernandes, A. R. Heterocyclic anticancer compounds: recent advances and the paradigm shift
towards the use of nanomedicine’s tool box. Molecules. 2015, 20, 16852–16891.
(6) Guzeldemirci, N. U.; Pehlivan, E.; Halamoglu, Z.; Kocabalkanli, A. Synthesis and antiviral
activity evaluation of some new cyclohexylidenehydrazide derivatives of 1,3-thiazole core.
Marmara. Pharm. J. 2016, 20, 207–215.
(7) Sharma, R.; Xavier, F. P.; Vasu, K. K.; Chaturvedi, S. C.; Pancholi, S. S. Synthesis of 4-
benzyl-1,3-thiazole derivatives as potential anti-inflammatory agents: An analogue-based drug
design approach. J. Enzyme. Inhib. Med. Chem. 2009, 24, 890–897.
(8) Lu, X.; Liu, X.; Wan, B.; Franzblau, S. G.; Chen, L.; Zhou, C.; You, Q. Synthesis and
evaluation of anti-tubercular and antibacterial activities of new 4-(2,6-dichlorobenzyloxy)phenyl
thiazole, oxazole and imidazole derivatives. Part 2. Eur. J. Med. Chem. 2012, 49, 164–171.
(9) Ghasemi, B.; Beyzaei, H.; Majidiani, H. A comparative study on the antibacterial effects of
some newly synthesized thiazole, imidazolidine and tetrahydropyrimidine derivatives against
bacillus cereus and salmonella typhimurium. J. Pharm. Sci. 2016, 22, 54–59.
ACS Paragon Plus Environment

Page 15 of 19
ACS Combinatorial Science
1
2
3
4
5
6
7
8
9
(10) Edwards, J. A.; Kemski, M. M.; Rappleye, C. A. Identification of an aminothiazole with
antifungal activity for intracellular histoplasma capsulatum. Antimicrob. Agents Chemother. 2013,
57, 4349–4359.
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
(11) Makam, P.; Thakur, P. K.; Kannan, T. In vitro and in silico antimalarial activity of 2-(2-
hydrazinyl)thiazole derivatives. Eur. J. Pharm. Sci. 2014, 52, 138–145.
(12) Siddiqui, N.; Arya, S. K.; Ahsanb, W.; Azad, B. Diverse biological activities of thiazoles:
A Retrospect. Int. J. Drug Dev. Res. 2011, 3, 156–164.
(13) Doss, M. L.; Lalitha, K. G. Molecular docking studies of thiazole schiff’s bases as HIV1-
protease inhibitors. J. Curr. Chem. Pharm. Sc. 2011, 1, 52–58.
(14) Debattista, C.; Solvason, H. B.; Breen, J. A. H.; Schatzberg, A. F. Pramipexole
augmentation of a selective serotonin reuptake inhibitor in the treatment of depression, J Clin
Psychopharmacol. 2000, 20, 274–275.
(15) Jayashree, B. S.; Anuradha, D.; Venugopala, N. K. Synthesis and characterization of schiff
bases of 2'-amino-4'-(6-chloro-3-coumarinyl)-thiazole as potential NSAIDs. Asian. J. Chem. 2005,
17, 2093–2097.
(16) Jaen, J. C.; Wise, L. D.; Caprathe, B. W.; Tecle, H.; Bergmeier, S.; Humblet, C. C.;
Heffner, T. G.; Meltzer, L. T.; Pugsley, T. A. 4-(1, 2, 5, 6-Tetrahydro-1-alkyl-3-pyridinyl)-2-
thiazolamines: A novel class of compounds with central dopamine agonist properties. J. Med.
Chem. 1990, 33, 311–317.
(17) Meissner, A.; Boshoff, H. I.; Vasan, M.; Duckworth, B. P.; Barry III, C. E.; Aldrich, C. C.
Structure–activity relationships of 2-aminothiazoles effective against mycobacterium tuberculosis.
Bioorg Med Chem. 2013, 21, 6385–6397.
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 16 of 19
1
2
3
4
5
6
7
8
9
(18) Liu, Z.; Chen, X.; Yu, L.; Zhen, X.; Zhang, A. Synthesis and pharmacological investigation
of novel 2-aminothiazole-privileged aporphines. Bioorg Med Chem 2008, 16, 6675–6681.
(19) Mohareb, R. M.;Zaki, M. Y.; Abbas, N. S. Synthesis, anti-inflammatory and anti-ulcer
evaluations of thiazole, thiophene, pyridine and pyran derivatives derived from androstenedione.
Steroids. 2015, 98, 80–91.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(20) Stefanska, J., Nowicka, G., Struga, M., Szulczyk, D., Koziol, A. E., Augustynowicz-
Kopec, E., Napiorkowska, A.; Bielenica, A.; Filipowski, W.; Filipowska, A.; Drzewiecka, A.;
Giliberti, G.; Madeddu, S.; Boi, S.; Colla, P. L.; Sanna, G. Antimicrobial and anti-biofilm activity
of thiourea derivatives incorporating a 2-aminothiazole scaffold. Chem. Pharm. Bull. 2015, 63,
225–236.
(21) Das, D.; Sikdar, P.; Bairagi, M. Recent developments of 2-aminothiazoles in medicinal
chemistry. Eur. J. Med. Chem. 2016, 109, 89–98.
(22) Mbaveng, A. T.; Ignat, A. G.; Ngameni, B.; Zaharia, V.; Ngadjui, B. T.; Kuete, V. In vitro
antibacterial activities of p-toluenesulfonyl-hydrazinothiazoles and hydrazinoselenazoles against
multi-drug resistant Gram-negative phenotypes. BMC Pharmacol. Toxicol. 2016, 17, 3–10.
(23) Zhao, H. C.; Shi, Y. P.; Liu, Y. M.; Li, C. W.; Xuan, L. N.; Wang, P.; Zhang, K.; Chen.
B. Q. Synthesis and antitumor-evaluation of 1,3-selenazole-containing 1,3,4-thiadiazole
derivatives. Bioorg. Med. Chem. Lett. 2013, 23, 6577–6579.
(24) Xu, B. B.; Shi, P; Guan, Q. Y.; Shi, X.; Zhao, G. L. Synthesis, crystal structure, and
biological activity of a nickel (II) complex constructed by 2-phenyl-4-selenazole carboxylic acid
and 1,10 phenanthroline. J. Coord. Chem. 2013, 66, 2605–2614.
ACS Paragon Plus Environment

Page 17 of 19
ACS Combinatorial Science
1
2
3
4
5
6
7
8
9
(25) Yin, G. Q.; Xia, S.; Bei, S. J.; Liang, Z. G. Antimicrobial, anticancer and DNA binding
studies of transition metal (II) complexes containing 2-phenyl-4-selenazole carboxylic acid. Sci.
China. Chem. 2013, 56, 588–594.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(26) Ninomiya, M.; Garud, D. R.; Koketsu, M. Biologically significant selenium-containing
heterocycles. Coord. Chem. Rev. 2011, 255, 2968–2990.
(27) Lee, E. H.; Lim, Y. J.; Ha, S. K.; Kang. T. H.; Koketsu, M.; Kang, C.; Kima, S. Y.; Park,
J. H. Inhibitory effects of 5‐chloroacetyl‐2‐piperidino‐1, 3‐selenazole,
a
novel
selenium‐containing compound, on skin melanin biosynthesis. J. Pharm. Pharmacol. 2010, 62,
352–359.
(28) (a) Tang, X.; Zhu, Z.; Qi, C.; Wu, W.; Jiang, H. Copper-Catalyzed Coupling of Oxime
Acetates with Isothiocyanates: A Strategy for 2-Aminothiazoles. Org. Lett. 2016, 18, 180–183. (b)
Facchinetti, V.; Nery, A. C. S.; Avellar, M. M.; Gomes, C. R. B.; de Souza, M. V. N.; Vasconcelos,
T. R. A. Highlights on the synthesis and biological activity of 1,3-selenazoles. Curr. Org. Synth.
2015, 12, 140–149.
(29) Zarnegar, Z.; Sadeghi, M.; Alizadeh, R.; Safai, J. HX-DMSO: A novel liquid halogenating
system for synthesis of 2-aminothiazoles via Csp3-H bond functionalization. J Mol Liq. 2018, 255,
76–79.
(30) Banert, K.; Ihle, A.; Kuhtz, A.; Penk, E.; Saha, B.; Wurthwein, E. U. Generation of highly
strained 2,3-bridged 2H-azirines via cycloaddition reactions of 2-azidobuta-1,3-dienes and
photolysis of the resulting cyclic vinyl azides. Tetrahedron. 2013, 69, 2501–2508.
(31) Devadoss, A.; Chidsey C. E. D. Azide-modified graphitic surfaces for covalent attachment
of alkyne-terminated molecules by “Click” chemistry. J. Am. Chem. Soc. 2007, 129, 5370–5731.
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 18 of 19
1
2
3
4
5
6
7
8
9
(32) Choi, H.; Shirley, H. J.; Hume, P. A.; Brimble, M. A.; Furkert, D. P. Unexpected direct
synthesis of N‐vinyl amides through vinyl azide–enolate [3+ 2] cycloaddition. Angew. Chem. Int.
Ed. 2017, 56, 7420–7424.
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
(33) Aelterman, W.; De Kimpe, N.; Tyvorskii, V.; Kulinkovich, O. Synthesis of 2, 3-
disubstituted pyrroles and pyridines from 3-halo-1-azaallylic anions. J. Org. Chem. 2001, 66, 53–
58.
(34) Terentev, A. O.; Krylov, I. B.; Kokorekin, V. A.; Nikishin, G. I. Facile method for the
synthesis of vicinal azidoiodides by the reaction of the NaN3–I2 system with unsaturated
compounds. Synth. Commun. 2008, 38, 3797–3809.
(35) Kirschning, A.; Hashem, M. A.; Monenschein, H.; Rose, L.; Schoning, K. U. Preparation
of novel haloazide equivalents by iodine (III)-promoted oxidation of halide anions. J. Org. Chem.
1999, 64, 6522–6526.
(36) Barluenga, J.; Alvarez-Perez, M.; Fananas, F. J.; Gonzalez J. M. A smooth and practicable
azido‐iodination reaction of alkenes based on iPy2BF4 and Me3SiN3. Adv. Synth. Catal. 2001, 343,
335–337.
(37) Nair, V.; George, T. G.; Sheeba, V.; Augustine, A. Balagopal, L.; Nair, L. G. A novel
regioselective synthesis of azidoiodides from alkenes using cerium (IV) ammonium nitrate.
Synlett. 2000, 2000, 1597–1598.
(38) Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O. Simple and regioselective
azidoiodination of alkenes using Oxone. Tetrahedron Lett. 2002, 43, 1201–1203.
ACS Paragon Plus Environment

Page 19 of 19
ACS Combinatorial Science
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment