Microwave-Enhanced On-Water Amination of 2-Mercaptobenzoxazoles to Prepare 2-Aminobenzoxazoles

Article abstract of DOI:10.1021/acs.joc.8b01824

In this work, we developed a catalyst-free amination of 2-mercaptobenzoxazoles on water under microwave irradiation. The product, 2-aminobenzoxazoles, was successfully produced via direct amination with various amines in moderate to high yields. The formal synthesis of Suvorexant, a medication for the treatment of insomnia, was accomplished using a developed amination process. The reaction was completed in an hour at 100-150 °C in a microwave reactor without the use of external catalyst or additive. Key benefits of this process include an on-water reaction, short reaction time, being scalable and catalyst-free, and use of 2-mercaptobenzoxazoles as an inexpensive starting material having low environmental impact in its preparation.

Full text of DOI:10.1021/acs.joc.8b01824

Subscriber access provided by University of South Dakota
Article
Microwave-Enhanced On-Water Amination of 2-
Mercaptobenzoxazoles to Prepare 2-Aminobenzoxazoles
Theeranon Tankam, Jakkrit Srisa, Mongkol Sukwattanasinitt, and Sumrit Wacharasindhu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01824 • Publication Date (Web): 07 Sep 2018
Downloaded from http://pubs.acs.org on September 7, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
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 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
MicrowaveꢀEnhanced OnꢀWater Amination of 2ꢀ
Mercaptobenzoxazoles to Prepare 2ꢀAminobenzoxazoles
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
Theeranon Tankam, Jakkrit Srisa, Mongkol Sukwattanasinitt and Sumrit Wacharasindhu*
NanotecꢀCU Center of Excellence on Food and Agriculture, Department of Chemistry, Faculty of
Science, Chulalongkorn University Bangkok 10330, Thailand
Sumrit.w@chula.ac.th
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 25
ToC Image:
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
Abstract
In this work, we developed a catalyst free amination of 2
microwave irradiation The product, 2 aminobenzoxazoles, were successfully produced via direct
amination with various amines in moderate to high yields The formal synthesis of Suvorexant, a
medication for the treatment of insomnia, was accomplished, using developed amination process The
reaction was completed in an hour at 100 150 C in a microwave reactor without the use of external
catalyst or additive Key benefits of this process include an onꢀwater reaction, short reaction time,
scalable, catalyst free, and use of 2 mercaptobenzoxazoles as an inexpensive starting material having
ꢀ
mercaptobenzoxazoles on water under
.
ꢀ
.
.
ꢀ
̊
.
ꢀ
low environmental impact in its preparation.
KEYWORDS: Nucleophilic aromatic substitution; on water; catalystꢀfree; microwave; amination
2
ACS Paragon Plus Environment

Page 3 of 25
The Journal of Organic Chemistry
Introduction
2ꢀaminobenzoxazoles are ubiquitous motifs in pharmaceutical compounds as they possess broad
1
2
3
4
spectrum of biological activities. Some therapeutically important agents have been constructed from this
scaffold such as KDR inhibitor 1 (tyrosine Kinase inhibitor with anticancer activity)1 and 5ꢀHT3 receptor
agonist 2 (treatment of Diarrhea)2 (Scheme 1). There are several approaches to convert 2ꢀaminophenol
(4) into 2ꢀaminobenzoxazoles (7) however, each process has specific drawbacks. For example, 2ꢀ
aminobenzoxazole (7) can be synthesized from SNAr displacement of 2ꢀsubstitiuted benzoxazoles3ꢀ6
(SO2Me, CCl3, Br and Cl). Although this is a very efficient route, the process requires multiple
preparation steps and uses toxic halogenated reagents which often produces undesirable byꢀproducts
during the reaction. Recently, direct C–H amination of benzoxazole (5) into target amino compound (7)
was introduced, utilizing transition metal catalyst such as Cu, Ag, Mn and Co in just one step.7ꢀ11
Although this reaction has high atom economy, but toxic metals are used. Another important method is
direct synthesis from 2ꢀaminophenol (4) with either isocyanate or isocyanide as amine surrogates.
Although the reaction is mild and can be operated in one step but the preparation of isocyanate reagent
requires a strong oxidizing agent12ꢀ13 while starting from isocyanide needs Pd(0) as catalyst in the
reaction.14 Moreover, direct synthesis of 2ꢀaminobenzoxazoles (7) utilizing tertramethyl orthocabonate
to generate reactive 2ꢀmetoxy benzoxazoles in situ from 2ꢀaminophenol (4) has been reported. Although
the reaction can be performed in one pot without the use of metal or any strong oxidizing agent but
tertramethyl orthocabonate reagent is required in large amount as solvent in the reaction.15 From process
chemistry perspective, the use of hazardous reagent, toxic metal and harmful organic solvent would
increase operating cost in large scale production of pharmaceuticals as extra safety protocols and metal
removal step are needed. Therefore, a mild, scalable and metalꢀfree approach for 2ꢀaminobenzoxazole
synthesis would be highly desirable.
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
Recently, our group become interested in the use of 2ꢀmercaptobenzoxazole (6) as a starting
material for the synthesis of 2ꢀaminobenzoxazoles (7). Although an extra step is required for the
preparation of starting material 6 from 2ꢀaminophenol 4, but the process is relatively green and
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 25
economical involving the reaction between amino phenol and carbon disulfide in methanol/water
reflux.16 Many reagents are commercially available at low cost. We successfully performed amination of
2ꢀmercaptobenzoxazoles (6) with amine into 2ꢀaminobenzoxazoles (7) using Rose Bengal as a
photocatalyst under irradiation by visible light. Regardless of its many benefits, disadvantages of this
reaction are use of acetonitrile as organic solvent, long reaction time and use of a strong organic base
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
(DBU).17
Cl
HN
N
O
Cl
O
N
N
O
NH
N
O
N
N
H
O
CH3
5-HT3 Receptor Agonist
2
KDR Inhibitor
1
Previous works
R1R2NCS
N
R1R2NH
X
H
R
N C N
X = SO2Me, CCl3, Cl
Chloroform or acetonitrile
O
3
Microwave
irradiation
N
N
O
R1
R2
NH2
OH
R1R2NH
R2N+C-
N
metal or strong oxidant
acetonitrile
O
5
5% Pd(PPh3)4
Dioxane
7
4
R1R2NH
N
R1R2NH
R1R2NH
water
SH
C(OCH3)4
10% RB, DBU
white LED
acetonitrile
HOAc
O
6
Microwave
irradiation
N
SH
O
6
This work
Scheme 1. 2ꢀAminobenzoxazole derivatives with biological activities and synthetic approaches
Water is the solvent of choice for green synthesis as its low cost, nonꢀtoxic and nonꢀ
flammable.18ꢀ19 An onꢀwater reaction whereby water is used as the sole solvent without any additive, has
recently received numerous attention as it is convenient to perform and interesting reactivity has been
observed in several cases.20ꢀ42 In view of this new development, herein we report an efficient onꢀwater
route for the preparation of 2ꢀaminobenzoxazole (7) using 2ꢀmercaptobenzoxazoles (6) and
corresponding amines as starting materials. The reaction was accelerated with microwave and performed
without any catalyst, oxidizing agent or extra additive. Our method, when combined with typical
synthesis of starting material 2ꢀmercaptobenzoxazoles (6), which required only CS2 and 2ꢀaminophenol
(4) in EtOH/H2O, offers a convenient and economical route for the preparation of 2ꢀaminobenzoxazole
(7).
4
ACS Paragon Plus Environment

Page 5 of 25
The Journal of Organic Chemistry
Result and discussion
We selected the reaction between 2-mercaptobenzoxazole (6) and n-butylamine as a
1
2
3
4
representative catalyst-free amination onꢀwater reaction for the optimization study (Table 1). When the
5
6
7
8
̊
reaction was performed at 100 C for 24 hours in conventional heat (oil bath), all starting materials were
9
consumed to produce 7a in 85% yield (Table 1, entry 1). Reducing reaction time to 1 hour under
conventional heat resulted in almost no reaction (Table 1, entry 2). Switching to microwave reactor, the
reaction was completed within 1 hour providing the desired amination product in 91 % yield (Table 1,
entry 3). This observation clearly demonstrated the acceleration of amination by microwave irradiation.
The increase in reaction rate and yield observed under microwave treatment is probably caused by an
increase in efficiency of energy transfer and more even distribution of heat by microwave irradiation.
This also leads to higher pressure and temperature generated rapidly during the reaction, thereby
decreasing the hydrophobic effects. A notable decrease in hydrophobic effects enable the reaction to
proceed “in water” without requiring organic solvents.24ꢀ25 The reduction of the reaction temperature and
time resulted in incomplete conversion of thiol 6 and lower yield of 7a (Table 1, Entry 4 and 5). The
amount of butyl amine nucleophile could be reduced from 3.0 to 1.5 equivalent without significant drop
of the yield (Table 1 Entry 6), and this amount was used for further study. We would like to emphasize
here that this onꢀwater reaction significantly simplified the product isolation. After the reaction, the
crude products were separated as a top layer on the water surface (Figure S1) using only small amount of
ethyl acetate and pasture pipette to transfer to silica gel column for further chromatography. This reduces
the use of organic solvent for extraction. The reaction at 1 gram scale required higher reaction
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
temperatures of 150 ̊C and prolonged reaction time of 2 hour to ensure the completion of the reaction the
gave 7a in 81% isolated yield (Table 1, Entry 7). This result suggested that the process may be upscaled
with a proper microwave reactor (Table 1, Entry 7).
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 25
Table 1. Optimization of the reaction conditiona
1
2
3
4
5
Water
N
O
N
O
SH
NH
H2N
Temp, Time
Microwave irradiation
6
7a
6
7
8
9
Entry Temp (
̊
Yieldb
85
1c
2c
3
100
100
100
80
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
0
91
4d
5d
6e
7f
69
100
100
150
37
90
81
aReaction conditions: 2ꢀmercaptobenzoxazole
(1.0 equiv. 50 mg) and nꢀbuthylamine (3.0
equiv.) in water (0.55 M) under microwave
irradiation. bIsolated yield after silica gel
chromatography.
heat.
dIncomplete reaction. enꢀbuthylamine (1.5
equiv.) in water (1.1 M). f 1 gram of 6
With the optimized reaction conditions in hand, we next studied the scope of this amination by
subjecting a panel of amines to 2ꢀaminobenzoxazoles derivatives (7a-l, 8a, ,9a, 10a). As shown in
Scheme 2, primary and secondary amines such as benzylamine, N-benzylmethylamine, piperidine and
morpholine reacted smoothly with 6 under the optimized conditions, giving the desired products (7b-e)
in good to excellent yields (80ꢀ89%). For ethanolamine, which contains both N and O nucleophilic
atoms, only CꢀN bond formation occurred selectively, affording 7f in 85% yield. Unfortunately, a less
reactive nucleophile such as aniline failed to react. However, aromatic amines containing electron
donating group such as 4ꢀaminophenol, pꢀtoluidine and 1,4ꢀphenylenediamine reacted with 6 at 150 ̊C to
provide the corresponding products (7hꢀj) in moderate yields (48ꢀ66%). Stearic hindrance on ortho
position of 1,2ꢀphenylenediamine had little effect on the reaction yield as 7k was obtained in satisfactory
yield (58%). Interestingly, the reaction between 6 and piperazine exclusively gave the double amination
6
ACS Paragon Plus Environment

Page 7 of 25
The Journal of Organic Chemistry
product 7l in good yield. The reactions of substituted 2ꢀmercaptobenzoxazoles such as 8 (methoxy), 9
(fluoro) and 10 (chloro) with nꢀbutylamines also proceeded smoothly to afford the desired products 8a,
9a and 10a in moderate to good yields (56ꢀ79%).
1
2
3
4
5
6
7
8
9
Scheme 2. Substrate scope of aminationa
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
aReaction conditions :2ꢀmercaptobenzoxazole (1.0 equiv. 100 mg) and
equiv.) in water (1.1 M) under microwave irradiation. b150
nꢀbuthylamine (1.5
̊C
With these promising results in hand, we demonstrated the formal synthesis of Suvorexant,
Merck’s drug for the treatment of insomnia, using our microwaveꢀenhanced onꢀwater amination process
In Merck’s process, the key intermediate 10f were prepared via threeꢀstep synthesis starting from
condensation of aminophenol 4f with trimethyl orthoformate followed by bromination. Then SNAr
displacement of 2ꢀbromoꢀbenzoxazole with ethanolamine provided the alcohol 10f in 80% yields
.
(Scheme 3)43
10f We successfully performed amination using our method to convert commercially available 6ꢀ
chloroꢀ2ꢀmercaptobenzoxazole (10) into 10f in moderate yields As mentioned above, commercially
available chloro 10 can also be prepared from corresponding aminophenol 4f via simple condensation
.
Using our developed method, we were able to intercept the synthesis of a key intermediate
.
.
with carbon disulfide in water/EtOH16
.
Therefore, combining above process with our method, the
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 25
preparation of 10f from 4f could be carried out with rather mild reagents and in a safe solvent
waterEtOH without the need of metal or additive, thereby offering a more sustainable and more
economical method for industrial large scale production
1
2
3
4
5
6
(
/
)
-
.
7
8
9
Scheme3. Formal Synthesis of Suvorexant
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
Merk process
Cl
NH2
OH
CS2, EtOH:water 80 oC
4f
ref.16
1.p-TsOH, HC(OMe)3
2.LiHMDS, THF. hexane
then NBS, THF
3.
OH
H2N
80% overall yield ref.43
Our process
OH
Cl
OH
Cl
N
O
N
H2N
SH
NH
O
water, microwave
100 oC 30 min, 57%
10f
10
commercially
avialable
4 steps
ref.43
Cl
N
O
N
O
N
N
N
Suvorexant
N
To shed light on the mechanism, several mechanistic experiments were conducted (Scheme 4).
We performed our reaction using 2ꢀ(methylthio)benzo[d]oxazole (11) as a starting material under the
optimized condition. No product 7a was observed and only starting material 11 was recovered. This
result suggusted that simple SNAr is precluded, as SMe group in 11 is considered as better leaving group
than SH moetiey in 6. Moreover, when bidentate amine such as N,N’ꢀdiethylethylenediamineas were
used as a nucleophile, aminophenol 4 was isolated as the sole product in 69% yield (Scheme 4, eq. 2).
It indicated that the reaction perhaps proceeded through the ring-opening mechanism.44 In addition,
when oꢀphenolicthiourea 13b was subjected to the reaction condition without external amine, the
cyclized product 7b were obtained in good yield indicating that the 13b could serve as the intermediate
8
ACS Paragon Plus Environment

Page 9 of 25
The Journal of Organic Chemistry
in the reaction (Scheme 4, eq. 3)
.
Finally, the addition of Pb(NO3)2 into the reaction resulted in the
1
2
3
4
5
formation of PbS as confirm by EDX-XRD (Figure S2). With unpleasent smell after the reaction and the
isolation of PbS, hydrogensulfide was likely liberated in the reaction.
6
7
8
9
Scheme 4. Control Experiments
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
water 1.1 M
100 oC, 1h
CH3
N
O
N
S
NH
(1)
(2)
H2N
Microwave irradiation
O
11
7a, 0%
N
water 1.1 M
100 oC, 1h
NH2
HN
NH
SH
O
OH
Microwave irradiation
6
4, 69 %
S
N
water 1.1 M
100 oC, 1h
H
N
(3)
NH
OH
N
H
Microwave irradiation
O
13b
7b, 64 %
With the above experiments, we then proposed the mechanism of this amination as seen in
scheme 5. Initially, the addition of amine into 2ꢀmercaptobenzoxazole (6) generates adduct 12 as an
intermediate. The ring opening of oxazole motif provides the o-phenolicthiourea intermidate 13 which
in turn cyclize and lose hydrogensulfide as a byꢀproduct during ringꢀclosing process to provide the
product 7. The proposed mechanism is also supported by experiment motioned above as shown in
scheme 4 (eq. 2). When N,N’ diethylethylenediamine were used as nucleophile, the cyclization of
intermediate 13 into 7 was prevented. It appears that nucleophilic attack from N atom occurred instead,
resulting in the synthesis of product 4, that was separated in good yield.
Scheme 5. Plausible mechanism
R
S
N
R
R
R
R
R
H
N
N
N
O
N
NH
OH
H
SH
SH
O
6
13
12
R
HS
N
R
R
N
O
R
N
N
-H2S
OH
7
14
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 25
To extend the scope this onꢀwater amination, we switched the starting matrial into 4ꢀ
mercaptoquinazoline (16) to prepare 4ꢀaminoquinazolines (17) which is also an important scaffold
composing in many therapeutic agents.45 The classical methods to prepare 4ꢀaminoquinazolines (17)
rely on the displacement of amine via SNAr with either corresponding halogenated46 or phosponium
quinazolines which are derived from 4ꢀhydroxyquinazoline starting material (15).47 However, toxic and
expensive reagent are required in those methods. Herein, 4ꢀmercaptoquinazoline (16) was prepared from
4ꢀhydroxyquinazoline (15) using Lawesson’s reagent (scheme 6).48 The microwaveꢀenhanced “on
water” amination of 16 proceeded smoothly with various amines including nꢀbutylamine, piperidine and
morpholine giving the 4ꢀaminoquinazolines 17a-c in excellent yields (78ꢀ87%).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 6. Amination of 4ꢀmercaptoquinazoline 16a
R1
R2
R1
R2
N
SH
N
OH
H
Water 1.1 M
N
Lawesson's reagent
N
N
100 oC, 1 h.
Microwave irradiation
Pyridine, 150 oC, 0.5 h.
Microwave irradiation
85%
N
N
17a-c
N
16
15
O
NH
N
N
N
N
N
N
N
17a, 87%
N
17b, 84%
17c, 78%
aReaction conditions: 4ꢀmercaptoquinazoline (1
(11 M)under microwave irradiation
.
0 equiv. 100 mg) and n-buthylamine (1.5 equiv.) in water
.
.
Conclusions
In summary, we developed a novel microwave-enhanced onꢀwater amination reaction and
applied it to the synthesis of 2-aminobenzoxazoles. We employed 2-mercaptobenzoxazole derivatives as
starting materials due to its low cost, wide availability and low environmental impact in its preparation.
The amination reaction of 2-mercaptobenzoxazole was conducted on water under microwave irradiation
10
ACS Paragon Plus Environment

Page 11 of 25
The Journal of Organic Chemistry
without any additive or catalyst to yield various 2-aminobenzoxazoles in moderate to good yields. We
also successfully extended this method to 4ꢀmercaptoquinazoline, allowing us to access 4ꢀ
aminoquinazolines. In addition, a formal synthesis of Suvorexant, a major pharmaceutical ingredient in
sleeping pills, was accomplished using this newly developed reaction. Our preliminary result also
indicated that the reaction can be successfully scale up to one gram providing an alternative highly atom
economical process for chemical industries. Further studies on microwave-enhanced on water amination
reaction to more challenging and important amino heterocycles are currently on-going and will be
reported in due course.
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
Experimental Section
Materials and methods
All chemicals were obtained from commercial suppliers (Sigma Aldrich, Fluka, or Merck) and
were used without further purify cation. All solvents were used directly without drying .Analytical thinꢀ
layer chromatography (TLC) was performed on Kieselgel F254 preꢀcoated plastic TLC plates from EM
Science . Visualization was performed with a 254 nm ultraviolet lamp. Column chromatography was
1
13
carried out with silica gel (60, 230–400 mesh) from ICN Silitech. The H and C NMR spectra were
recorded on a Varian Mercury 400 or Bruker Avance 400 for 1H (400 MHz) and Bruker Avance 400 for
13C (100 MHz) in CDCl3, CD3CO2, CD3OD or CD3SO2 solution. Mass spectrometry was performed
with a MicroTOF Bruker mass spectrometer and triple quadrupole GC/MS from Agilent technologies.
Microwave reactions were performed with CEM Discover. All microwave reactions were performed in
a sealed tube reaction condition, and the reaction temperatures were monitored by an internal probe and
the temperature was maintained in each experiment.
General procedure for synthesis of 2-aminobenzoxazoles (General Procedure A)
In 10 mL microwave vessel, a mixture of 2ꢀmercaptobenzoxazole (1.0 equiv., 0.661 mmol) and
amine (1.5 equiv., 0.992 mmol) was suspended in 0.6 mL of water followed by sealing of the vessel and
heating to to 100
̊
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 25
100 ̊C in 120 s and was maintained at 100 ̊C for 1 hour. The reaction was cooled to room temperature
1
2
3
4
5
6
7
8
and then added 1 mL of ethyl acetate. The organic layer was transferred using posture pipet and
evaporated under reduced pressure to give the crude product, which was further purified by column
chromatography (eluted with ethyl acetate/hexane1:4) to afford the desired compound.
9
General procedure for synthesis of 4-aminoquinazolines (General Procedure B)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In 10 mL microwave vessel, a mixture of 4ꢀmercapquinazoline (1.0 equiv., 0.617 mmol) and
amine (1.5 equiv., 0.926 mmol) was suspended in 0.6 mL of water followed by sealing of the vessel and
heating to to 100
̊
100 C in 120 s and was maintained at 100
̊
̊
and then added 1 mL of ethyl acetate. The organic layer was transferred using posture pipet and
evaporated under reduced pressure to give the crude product, which was further purified by column
chromatography (eluted with ethyl acetate/hexane 1:2) to afford the desired compound.
N-butylbenzo[d]oxazole-2-amine (7a)17 Synthesized according to General Procedure A using 2ꢀ
mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and nꢀbutylamine (98 µL, 0.992 mmol) in water (0.6
1
mL) to afford 7a (113 mg, 0.595 mmol, 90%) as a yellow solid; H NMR (400 MHz, CDCl3): δ ppm
7.28 (m, 1H), 7.18 (m, 1H), 7.12 (t, J = 7.8 Hz, 1H), 6.99 (t, J = 7.8 Hz, 1H), 3.43 (t, J = 7.2 Hz, 2H),
1.61 (m, 2H), 1.36 (m, 2H), 0.89 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ ppm 161.6, 147.9,
140.5, 124.4, 121.3, 115.6, 109.0, 43.0, 31.7, 19.9, 13.7. IR (ATR, cmꢀ1): 3158, 3064, 2947, 2925, 2864,
1693, 1583, 1461, 1353, 1328, 1243, 944, 725, 693.GCꢀMS: m/z: 189.9 [M]+ (calcd for [C11H14N2O]+
190.11).
N-benzylbenzo[d]oxazol-2-amine (7b)49 Synthesized according to General Procedure A using 2ꢀ
mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and benzylamine (108 µL, 0.992 mmol) in water (0.6
mL) to afford 7b (118 mg, 0.529 mmol, 80%) as a white solid;1H NMR (400 MHz, CD3OD): δ ppm
7.27ꢀ6.92 (m, 9H), 4.47 (s, 2H). 13C NMR (100 MHz, CD3OD): δ ppm 164.3, 149.7, 143.6, 139.7,
12
ACS Paragon Plus Environment

Page 13 of 25
The Journal of Organic Chemistry
128.5, 128.4, 125.1, 122.1, 116.5, 109.7, 47.4. IR (ATR, cmꢀ1): 3279, 3057, 2918, 2867, 1663, 1544,
1
2
3
1454, 1335, 1248, 949, 736.ESIꢀMS: m/z: 225.14 [M+H]+ (calcd for [C11H13N2O2]+ 225.10).
4
5
6
7
8
9
N-benzyl-N-methylbenzo[d]oxazol-2-amine (7c)49 Synthesized according to General Procedure A
using 2ꢀmercaptobenzoxazole 6 (100 mg, 0.661 mmol) and Nꢀbenzylmethylamine (128 µL, 0.992
mmol) in water (0.6 mL) to afford 2e (127 mg, 0.535 mmol, 81%)as a white solid; 1H NMR (400 MHz,
CDCl3): δ ppm 7.42ꢀ7.05 (m, 9H), 4.79 (s, 2H)3.16 (s, 3H). 13C NMR (100 MHz, CDCl3): δ ppm 162.8,
148.9, 143.2, 136.1, 128.8, 127.5, 124.0, 120.4, 116.2, 108.8, 53.9, 35.1. IR (ATR, cmꢀ1): 3110, 2918,
1640, 1578, 1232, 1128, 931, 736. ESIꢀMS: m/z: 239.12 [M+H]+ (calcd for [C11H13N2O2]+ 239.12).
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-(piperidin-1-yl)benzo[d]oxazole (7d)17 Synthesized according to General Procedure A using 2ꢀ
mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and piperidine (98 µL, 0.992 mmol) in water (0.6 mL) to
afford 7d (117 mg, 0.582 mmol, 88%)as a white solid; 1H NMR (400 MHz, CDCl3): δ ppm 7.26 (d,J =
8.0 Hz, 1H), 7.15 (d,J = 8.0 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H), 3.59 (m, 4H),
1.61 (m, 6H). 13C NMR (100 MHz, CDCl3): δ ppm 162.5, 148.7, 143.4, 123.8, 120.3, 116.0, 108.5,
46.2, 25.2. IR (ATR, cmꢀ1):2926, 2855, 1636, 1576, 1459, 1243, 737.ESIꢀMS: m/z: 203.12 [M+H]+
(calcd for [C13H11N2O2]+ 203.12).
2-morpholinobenzo[d]oxazole (7e)17 Synthesized according to General Procedure A using 2ꢀ
mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and morpholine (86 µL, 0.992 mmol) in water (0.6 mL)
1
to afford 7e (120 mg, 0.588 mmol, 89%)as a colorless solid; H NMR (400 MHz, CDCl3): δ ppm 7.40
(m, 1H), 7.28 (m, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 3.84 (m, 4H), 3.73 (m, 4H). 13C
NMR (100 MHz, CDCl3): δ ppm 161.8, 148.6, 142.1, 124.2, 121.2, 116.4, 108.9, 66.2, 45.8. IR (ATR,
cmꢀ1): 2960, 2914, 2873, 1636, 1574, 1454, 1286, 1105, 797, 739.ESIꢀMS: m/z: 205.11 [M+H]+ (calcd
for [C11H13N2O2]+ 205.10).
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 25
2-(benzo[d]oxazol-2-ylamino)ethanol (7f)17 Synthesized according to General Procedure A using 2ꢀ
mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and ethanolamine (113 µL, 0.992 mmol) in water (0.6
1
2
3
4
5
6
1
mL) to afford 7f (100 mg, 0.561 mmol, 85%)as a white solid; H NMR (400 MHz, CD3OD): δ ppm
7
8
7.26 (m, 2H), 7.16 (d, J = 8.0 Hz, 1H),7.04 (t, J = 8.0 Hz, 1H), 3.77 (t, J = 4.0 Hz, 2H),3.52 (t, J = 4.0
9
13
Hz, 2H). C NMR (100 MHz, CD3OD): δ ppm 164.4, 149.7, 143.6, 125.0, 122.0, 116.4, 109.7, 61.5,
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
46.2. IR (ATR, cmꢀ1): 3369, 3301, 2915, 2844, 2568, 1750, 1460, 1267, 1026.ESIꢀMS: m/z: 179.09
[M+H]+ (calcd for [C11H13N2O2]+ 179.08).
4-(benzo[d]oxazol-2-ylamino)phenol (7h)50 Synthesized according to General Procedure A using 2ꢀ
mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and 4ꢀaminophenol (108 mg, 0.992 mmol) in water (0.6
mL) to afford 7h (108 mg, 0.476 mmol, 48%)as a brown solid; 1H NMR (400 MHz, (CD3)3SO): δ ppm
10.25 (s, 1H), 9.18 (s, 1H), 7.51 (d, J = 7.8 Hz, 2H), 7.43 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H),
13
7.19 (m, 1H), 7.08 (m, 1H), 6.77 (d, J = 7.8 Hz, 2H). C NMR (100 MHz, (CD3)3SO): δ ppm 158.7,
152.9, 147.2, 142.8, 130.0, 123.5, 121.1, 119.7, 116.3, 115.4, 108.5. IR (ATR, cmꢀ1):3375, 3298, 3279,
3047, 2922, 1763, 1634, 1573, 1505, 1460, 1216, 891, 733. ESIꢀMS: m/z: 221.17 [M+H]+ (calcd for
[C13H11N2O2]+ 227.08).
N-(p-tolyl)benzo[d]oxazol-2-amine (7i)50 Synthesized according to General Procedure A using 2ꢀ
mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and pꢀtoluidine (106 mg, 0.992 mmol) in water (0.6 mL)
to afford 7i (75.5 mg, 0.337 mmol, 51%) as a yellow solid;1H NMR (400 MHz, (CD3)3SO): δ ppm7.64
13
(d, J = 7.8 Hz, 2H), 7.46 (m, 2H), 7.19ꢀ7.12 (m, 4H), 2.28 (s, 3H). C NMR (100 MHz, (CD3)3SO): δ
ppm 158.1, 147.0, 142.5, 136.2, 131.0, 129.3, 123.9, 121.4, 117.6, 116.4, 108.8, 20.3. IR (ATR, cmꢀ1):
ESIꢀMS: m/z: 225.10 [M+H]+ (calcd for [C13H11N2O2]+ 225.10).
N1-(benzo[d]oxazol-2-yl)benzene-1,2-diamine (7j)50 Synthesized according to General Procedure A
using 2ꢀmercaptobenzoxazole 6 (100 mg, 0.661 mmol) and 1,2ꢀphenylenediamine (107 mg, 0.992
14
ACS Paragon Plus Environment

Page 15 of 25
The Journal of Organic Chemistry
mmol) in water (0.6 mL) to afford 7j (86.2 mg, 0.383 mmol, 58%) as a yellow solid;1H NMR (400
MHz, (CD3)3SO): δ ppm12.53 (s, 1H), 8,98 (s, 1H), 7.13 (m, 4H), 6.63 (m, 1H), 6.58 (m, 1H), 6.54 (m,
1H), 6.40 (m, 1H).13C NMR (100 MHz, (CD3)3SO): δ ppm 168.1, 144.0, 136.4, 132.2, 122.3, 119.5,
116.5, 114.5, 114.4, 109.5. IR (ATR, cmꢀ1): ESIꢀMS: m/z: 226.10 [M+H]+ (calcd for [C13H11N2O2]+
226.10).
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
N1-(benzo[d]oxazol-2-yl)benzene-1,4-diamine (7k)50 Synthesized according to General Procedure A
using 2ꢀmercaptobenzoxazole 6 (100 mg, 0.661 mmol) and 1,4ꢀphenylenediamine (107 mg, 0.992
mmol) in water (0.6 mL) to afford 7k (98.1 mg, 0.436 mmol, 66%) as a brown solid;1H NMR (400
MHz, (CD3)3SO): δ ppm10.05 (s, 1H), 7.36 (m, 4H), 7.17 (m, 1H), 7.05 (m, 1H), 6.61 (d, J = 8.0 Hz,
1H). 13C NMR (100 MHz, (CD3)3SO): δ ppm158.8, 147.1, 144.2, 142.9, 127.9, 123.7, 120.8, 119.7,
115.9, 114.2, 108.5. IR (ATR, cmꢀ1): ESIꢀMS: m/z: 226.10 [M+H]+ (calcd for [C13H11N2O2]+ 226.10).
1,4-bis(benzo[d]oxazol-2-yl)piperazine (7l)50 Synthesized according to General Procedure A using 2ꢀ
mercaptobenzoxazole 6 (100 mg, 0.661 mmol) and piperazine (85 mg, 0.992 mmol) in water (0.6 mL)
to afford 7l (75 mg, 0.234 mmol, 71%) as a yellow solid; 1H NMR (400 MHz, CDCl3): δ ppm 7.44 (d, J
= 8.0 Hz, 2H), 7.32 (d,J = 8.0 Hz, 2H), 7.24 (t, J = 8.0 Hz, 2H), 7.12 (t, J = 8.0 Hz, 2H), 3.93 (m, 8H).
13C NMR (100 MHz, CDCl3): δ ppm 167.8, 161.3, 148.6, 124.4, 121.5, 116.5, 109.1, 45.2. IR (ATR,
cmꢀ1): ESIꢀMS: m/z: 321.16 [M+H]+ (calcd for [C13H11N2O2]+ 321.14).
N-butyl-5-methoxybenzo[d]oxazol-2-amine (8a)17 Synthesized according to General Procedure A
using 5ꢀmethoxybenzoxazoleꢀ2ꢀthiol 8 (100 mg, 0.552 mmol) and nꢀbutylamine (98 µL, 0.992 mmol) in
water (0.6 mL) to afford 8a (68 mg, 0.309 mmol, 56%) as a brown solid; 1H NMR (400 MHz, CDCl3):
δ ppm 7.03 (d, J = 8.0 Hz, 1H), 6.86 (d,J = 4.0 Hz, 1H), 6.53 (dd, J = 8.0, 4.0 Hz, 1H), 3.73 (s, 1H),
3.40 (t, J = 8.0 Hz, 2H), 1.59 (m, 2H)1.35 (m, 2H), 0.89(t, J = 8.0 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 162.8, 157.1, 143.4, 142.9, 108.6, 107.3, 101.4, 55.9, 42.1, 31.8, 19.9, 13.7.IR (ATR, cmꢀ1):
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 25
3044, 2925, 2867, 1699, 1596, 1435, 1155, 949, 785.ESIꢀMS: m/z: 221.13 [M+H]+(calcd for
1
2
3
[C13H11N2O2]+ 221.13).
4
5
6
7
8
9
N-butyl-5-fluorobenzo[d]oxazol-2-amine (9a)17 Synthesized according to General Procedure A using
5ꢀfluorobenzoxazoleꢀ2ꢀthiol (100 mg, 0.591 mmol) 9 and nꢀbutylamine (98 µL, 0.992 mmol) in water
(0.6 mL) to afford 9a (92 mg, 0.443 mmol, 75%) as a yellow solid; 1H NMR (400 MHz, CDCl3): δ ppm
7.04 (dd,J = 8.0, 4.0 Hz, 1H), 6.95 (dd, J = 8.0, 4.0 Hz, 1H), 6.65 (t, J = 8.0 Hz, 1H), 5.72 (brs, 1H)3.40
(t, J = 8.0 Hz, 2H), 1.59 (m, 2H)1.37 (m, 2H), 0.88(t, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
ppm 167.8, 161.3, 148.6, 124.4, 121.5, 116.5, 109.1, 45.2. IR (ATR, cmꢀ1): 2951, 2925, 2867, 1692,
1583, 1454, 1245, 1145, 1129, 968, 839, 736.ESIꢀMS: m/z: 209.11 [M+H]+ (calcd for [C13H11N2O2]+
209.11).
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-butyl-5-chlorobenzo[d]oxazol-2-amine (10a)17 Synthesized according to General Procedure A
using 5ꢀchlorobenzoxazoleꢀ2ꢀthiol 10 (100 mg, 0.591 mmol) and nꢀbutylamine (98 µL, 0.992 mmol) in
1
water (0.6 mL) to afford 10a (105 mg, 0.467 mmol, 79%) as a white solid; H NMR (400 MHz,
CDCl3): δ ppm 7.30 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H), 5.62 (brs, 1H) 3.47 (t, J = 8.0 Hz, 2H), 1.66 (m,
13
2H), 1.43 (m, 2H) 0.96 (t, J = 8.0 Hz, 3H). C NMR (100 MHz, CDCl3): δ ppm 163.0, 147.0, 144.0,
129.3, 120.6, 116.2, 109.2, 42.9, 31.7, 19.9, 13.7. IR (ATR, cmꢀ1): 3158, 3064, 2947, 2925, 2864, 1693,
1583, 1461, 1353, 1328, 1243, 944, 725. ESIꢀMS: m/z: 225.08 [M+H]+ (calcd for [C13H11N2O2]+
225.08).
2-(5-chlorobenzo[d]oxazol-2-ylamino)ethanol (10f)17 Synthesized according to General Procedure A
using 5ꢀfluorobenzoxazoleꢀ2ꢀthiol 9 (100 mg, 0.591 mmol) and nꢀbutylamine (98 µL, 0.992 mmol) in
water (0.6 mL) to afford 10f (71 mg, 0.337 mmol, 57%) as a white solid; 1H NMR (400 MHz, CD3OD):
δ ppm 7.21 (d,J = 8.0 Hz, 1H), 7.20 (s, 1H), 6.99 (d, J = 8.0 Hz, 1H), 3.75 (t, J = 4.0 Hz, 2H), 3.50 (t, J
16
ACS Paragon Plus Environment

Page 17 of 25
The Journal of Organic Chemistry
13
= 4.0 Hz, 2H). C NMR (100 MHz, CDCl3): δ ppm 165.4, 148.4, 145.3, 130.4, 121.6, 116.3, 110.5,
1
2
3
61,4, 46.2. IR (ATR, cmꢀ1): ESIꢀMS: m/z: 213.04 [M+H]+ (calcd for [C13H11N2O2]+ 213.04).
4
5
6
7
8
9
2-(methylthio)benzo[d]oxazole (11)49 2ꢀmercaptobenzoxazole 6 (200 mg, 1.32 mmol) and
iodomethane (187 mg, 1.32 mmol) were stirred in ethyl acetate (10 mL) at room temperature for 1 hour.
The reaction mixture was then quenched with water (10 mL) and extracted with EtOAc. The residues
were dried with Na2SO4 and evaporated under reduced pressure to give the crude product, which was
further purified by column chromatography (eluted with ethyl acetate/hexane) to afford 3 (194 mg, 1.17
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
mmol, 89%) as a yellow liquid: H NMR (400 MHz, CDCl3): δ ppm 7.60 (d,J = 8.0 Hz, 1H), 7.42 (d,J
= 8.0 Hz, 1H), 7.26 (m, 2H), 2.76 (s, 3H).
1-benzyl-3-(2-hydroxyphenyl)thiourea (13b)50 Benzylisothiocyanate (200 mg, 1.342 mmol) and 2ꢀ
aminophenol (220 mg, 2.02 mmol) were stirred in ethyl acetate (10 mL) at room temperature for 30
minutes. The solvent was evaporated and crude solid was then washed with hexane several times to
afford 5 (215 mg, 0.833mmol, 62%) as a white solid;1H NMR (400 MHz, (CD3)3CO): δ ppm7.53 (m,
1H), 7.24ꢀ7.38 (m, 5H), 7.07 (m, 1H), 6.95 (m, 1H), 6.84 (m, 1H), 4.87 (s, 2H).
quinazoline-4-thiol (16)48 4ꢀ hydroxyquinazoline (15) (500 mg, 3.42 mmol) and Lawesson’s reagent
(2,075 mg, 5.13 mmol) in pyridine (5 mL) was heated under microwave irradiation 150 °C for 30
minutes. After cooling, water (100 mL) was added to the reaction mixture, and the precipitated yellow
solid was filtered. The solid was redissolved in 3 M NaOH solution (10 mL × 3). The aqueous solution
was neutralized with 1 M HCl solution (15 mL × 3) until complete precipitation occurred. After
filtration, yellow solid was then rinsed with MeOH and dried to afford 16 (493 mg, 3.04 mmol, 85%) as
a yellow solid: 1 H NMR (CDCl3, 400 MHz) δ 13.8 (brs, 1H,), 8.52 (d, J = 8.0 Hz, 1H,), 8.11 (s, 1H),
7.84 (d, J = 4.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H).
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 25
4-(n-butylamino)quinazoline (17a)17 Synthesized according to General Procedure B using 4ꢀ
mercaptoquinazoline 16 (100 mg, 0.617 mmol) and nꢀbutylamine (91 µL, 0.926 mmol) in water (0.6
1
2
3
4
5
6
1
mL) to afford 17a (108 mg, 0.595 mmol, 87%) as a yellow solid; H NMR (400 MHz, CDCl3): δ ppm
7
8
8.59 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.67 (m, 2H), 7.37 (m, 1H), 5.92 (s, 1H), 3.59 (m, 2H), 1.64 (m,
9
13
2H), 1.41 (m, 2H), 0.91 (d, J = 7.5 Hz, 3H). C NMR (100 MHz, CDCl3): δ ppm 159.5, 155.2, 149.1,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
132.5, 128.3, 125.9, 120.8, 115.0, 41.0, 31.4, 20.3, 13.8. ESIꢀMS: m/z: 202.14 [M+H]+ (calcd for
[C12H16N3]+ 202.13).
4-(piperidin-1-yl)quinazoline (17b)17 Synthesized according to General Procedure B using 4ꢀ
mercaptoquinazoline 16 (100 mg, 0.617 mmol) and piperidine (91 µL, 0.926 mmol) in water (0.6 mL) to
afford 17b (110 mg, 0.518 mmol, 84%) as a yellow liquid; 1H NMR (400 MHz, CDCl3): δ ppm 8.72 (s,
1H), 7.90 (m, 2H), 7.74 (m, 1H), 7.46 (m, 1H), 3.76 (m, 4H), 1.81 (m, 4H). 13C NMR (100 MHz,
CDCl3): δ ppm 164.9, 153.8, 151.2, 132.2, 127.9, 125.4, 125.1, 116.7, 51.0, 26.0, 24.3. ESIꢀMS: m/z:
214.14 [M+H]+ (calcd for [C13H14N3]+ 214.13).
4-(quinazolin-4-yl)morpholine (17c)17 Synthesized according to General Procedure B using 4ꢀ
mercaptoquinazoline 16 (100 mg, 0.617 mmol) and morpholine (91 µL, 0.926 mmol) in water (0.6 mL)
1
to afford 17c (103 mg, 0.481 mmol, 78%) as a yellow solid; H NMR (400 MHz, CDCl3): δ ppm 8.75
13
(s, 1H), 7.94(m, 1H) 7.88 (m, 1H), 7.75 (m, 1H), 7.47 (m, 1H), 3.90 (m, 4H), 3.80 (m, 4H). C NMR
(100 MHz, CDCl3): δ ppm 164.6, 153.8, 151.4, 132.7, 128.6, 125.7, 127.4, 116.4, 66.8, 50.3. ESIꢀMS:
m/z: 216.12 [M+H]+ (calcd for [C13H14N3]+ 216.11).
ASSOCIATED CONTENT
18
ACS Paragon Plus Environment

Page 19 of 25
The Journal of Organic Chemistry
The Supporting Information is available free of charge on the ACS Publications website at
1
2
3
1
13
http://pubs.acs.org. Copies of H, C NMR spectra of compounds 7a-l, 8-10a, 10f, 11, 13b, 16, 17a-c,
4
5
picture of reaction mixture, and spectrum of EDXꢀSEM from PbS.
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
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: Sumrit.w@chula.ac.th
Notes
The authors declare no competing financial interest.
Acknowledgements
This study was financially supported by Thailand Research Fund (RSA6080018 and
RTA6180007) and National Nanotechnology Centre (NANOTEC), NSTDA, Ministry of
Science and Technology, Thailand, through its program of the Centre of Excellence Network.
This work was also partially supported by a Grant for International Research Integration: Chula
Research Scholar and Theeranon Tankam was supported by from Science Achievement
Scholarship of Thailand.
References
[1]
Harmange, J.C.; Weiss, M. M.; Germain, J.; Polverino, A. J.; Borg, G.; Bready, J.; Chen, D.;
Choquette, D.; Coxon, A.; DeMelfi, T.; DiPietro, L.; Doerr, N.; Estrada, J.; Flynn, J.; Graceffa,
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 25
R.F.; Harriman, S.P.; Kaufman, S.; La D.S., Long, A.; Martin, M.W., Neervannan, S.; Patel,
V.F., Potashman, M.; Regal, K.; Roveto, P.M.; Schrag, M.L.; Starnes, C.; Tasker, A.; Teffera,
Y.; Wang, L.; White, R.D.; Whittington, D.A.; Zanon, R. Naphthamides as Novel and Potent
Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors: Design, Synthesis,
and Evaluation. J. Med. Chem. 2008, 51, 1649ꢀ1667.
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
[2]
[3]
[4]
Yoshida, S.; Shiokawa, S.; Kawano, K.; Ito, T.; Murakami, H.; Suzuki, H.; Sato, Y. Orally
Active Benzoxazole Derivative as 5ꢀHT3 Receptor Partial Agonist for Treatment of Diarrheaꢀ
Predominant Irritable Bowel Syndrome. J. Med. Chem. 2005, 48, 7075–7079.
Khajondetchairit, P.; Phuangsawai, O.; Suphakun, P.; Rattanabunyong, S.; Choowongkomon,
K.; Gleeson, M.P. Design, Synthesis, and Evaluation of the Anticancer Activity of 2ꢀAminoꢀ
Arylꢀ7ꢀArylꢀBenzoxazole Compounds. Chem Biol Drug Des. 2017, 90, 987–994.
Lester, R.P.; Bham, T.; Bousfield, T.W.; Lewis, W.; Camp, J.E. Exploring the Reactivity of
2 Trichloromethylbenzoxazoles for Access to Substituted Benzoxazoles. J. Org. Chem. 2016,
81, 12472−12477.
[5]
[6]
[7]
Sherry, B.D.; Chen, J. YꢀC; Mangion, I.K.; Yin, J. A Method for the Synthesis of 2ꢀ
Aminobenzoxazoles. Tet. Lett. 2012, 53, 730–732.
Kumar, R.U. Reddy, K.H.V.; Kumar, B.S.P.A.; G. Satish, G.; Reddy, V.P.; Nageswar, Y.V.D.
Metal Free Amination of 2ꢀChloroazoles in Aqueous Medium. Tet. Lett. 2016, 57, 637–640.
Cho, S.H.; Kim, J.Y.; Lee, S.Y.; Chang, S. SilverꢀMediated Direct Amination of Benzoxazoles:
Tuning the Amino Group Source from Formamides to Parent Amines. Angew. Chem., Int.Ed.
2009, 48, 9127−9130.
[8]
Kim, J.Y.; Cho, S.H.; Joseph, J.; Chang, S. Cobaltꢀ and ManganeseꢀCatalyzed Direct Amination
of Azoles under Mild Reaction Conditions and the Mechanistic Details. Angew. Chem., Int. Ed.
2010, 49, 9899−9903.
20
ACS Paragon Plus Environment

Page 21 of 25
The Journal of Organic Chemistry
[9]
Wang, J.; Hou, JꢀT.; Wen, J.; Zhang, J.; Yu, XꢀQ. IronꢀCatalyzed Direct Amination of Azoles
Using Formamides or Amines as Nitrogen Sources in Air. Chem.Commun. 2011, 47,
3652−3654.
1
2
3
4
5
6
7
8
9
[10] Guo, S.; Qian, B.; Xie, Y.; Xia, C.; Huang, H. CopperꢀCatalyzed Oxidative Amination
of Benzoxazoles via CꢀH and CꢀN Bond Activation: A New Strategy for Using Tertiary Amines
as Nitrogen Group Sources. Org. Lett. 2011, 13, 522ꢀ525.
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] Chen, SꢀC., Lia, N.; Tian, F.; Chai, NꢀN.; He, MꢀY.; Chen, Q. Mild Direct Amination of
Benzoxazoles Using Interpenetrating Cobalt(II)ꢀBased MetalꢀOrganic Framework as an Efficient
Heterogeneous Catalyst. Mol. Catal. 2018, 450, 104ꢀ111.
[12] Carpenter, R.D.; Kurth, M.J. A Rapid and Efficient Route to Benzazole Heterocycles. Nat.
Protoc. 2010, 5, 1731ꢀ1736.
[13] Ghosh, H.; Yella, R.; Nath, J.; Patel, B.K. Desulfurization Mediated by Hypervalent Iodine(III):
A Novel Strategy for the Construction of Heterocycles. Eur. J. Org. Chem. 2008, 6189ꢀ6196.
[14] Liu, B.; Yin, M.; Gao, H.; Wu, W.; Jiang, H. Synthesis of 2 Aminobenzoxazoles and
3 Aminobenzoxazines via PalladiumꢀCatalyzed Aerobic Oxidation of o Aminophenols with
Isocyanides. J. Org. Chem. 2013, 78, 3009ꢀ3020.
[15] Cioffi, C.L.; Lancing, J.J.; Yuksel, H. Synthesis of 2ꢀAminobenzoxazoles Using Tetramethyl
Orthocarbonate or 1,1ꢀDichlorodiphenoxymethane. J. Org. Chem. 2010, 75, 7942ꢀ7945.
[16] Varun, B.V.; Prabhu, K.R. Regioselective Thiolation of Arenes and Heteroarenes: C−H
Functionalization Strategy for C−S Bond Formation. J. Org. Chem. 2014, 79, 9655−9668.
[17] Rattanangkool, E.; Sukwattanasinitt, M.; Wacharasindhu, S. Organocatalytic Visible Light
Enabled SNAr of Heterocyclic Thiols: A MetalꢀFree Approach to 2 Aminobenzoxazoles and
4 Aminoquinazolines J. Org. Chem. 2017, 82, 13256−13262.
[18] Chanda, A.; Fokin, V.V. Organic Synthesis “On Water”. Chem. Rev. 2009, 109, 725–748.
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 25
[19] Butler, R.N.; Coyne, A.G. Water: Nature’s Reaction Enforcers Comparative Effects for Organic
Synthesis “InꢀWater” and “OnꢀWater”. Chem. Rev. 2010, 110, 6302–6337.
[20] Narayan, S.; Muldoon, J.; Finn, M.G.; Fokkin, V.V.; Kolb, H.C.; Sharpless, K.B. “On Water”:
Unique Reactivity of Organic Compounds in Aqueous Suspension. Angew. Chem. Int. Ed. 2005,
44, 3275 –3279.
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
[21] Hoz, A.D.L.; DiazꢀOrtiz, A.; Moreno, A. Microwaves in Organic Synthesis. Thermal and Nonꢀ
Thermal Microwave Effects. Chem. Soc. Rev. 2005, 34, 164ꢀ178.
[22] Robert, B.; Strauss, C.R. Toward Rapid, “Green”, Predictable MicrowaveꢀAssisted Synthesis.
Acc. Chem. Res. 2005, 38, 653–661.
[23] Dallinger, D.; Kappe, C.O. MicrowaveꢀAssisted Synthesis in Water as Solvent. Chem. Rev.
2007, 107, 2563ꢀ2591.
[24] Polshettiwar, V.; Varma, R.S. Aqueous Microwave Chemistry: A Clean and Green Synthetic
Tool for Rapid Drug Discovery. Chem. Soc. Rev. 2008, 37, 1546–1557.
[25] Gawande, M.B.; Bonifacio, V.D.B.; Luque, R.; Brancoa, P.S.; Varma, R.S. Benign by Design:
CatalystꢀFree InꢀWater, OnꢀWater Green Chemical Methodologies in Organic Synthesis. Chem.
Soc. Rev. 2013, 42, 5522ꢀ5551.
[26] Caddick, S. Microwave Assisted Organic Reactions. Tetrahedron 1995, 51, 10403ꢀ10432.
[27] Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Microwave Assisted Organic Synthesis ꢀ A
Review. Tetrahedron 2001, 57, 9225ꢀ9283.
[28] An, J.; Bagnell, L.; Cablewski, T.; Strauss, C.R.; Trainor, R.W. Applications of Highꢀ
Temperature Aqueous Media for Synthetic Organic Reactions. J. Org. Chem. 1997, 62, 2505ꢀ
2511.
[29] Leadbeater, N.E.; M. Marco, M. Rapid and Amenable Suzuki Coupling Reaction in Water Using
Microwave and Conventional Heating. J. Org. Chem. 2003, 68, 888ꢀ892.
22
ACS Paragon Plus Environment

Page 23 of 25
The Journal of Organic Chemistry
[30] Arvela, R.K.; Leadbeater, N.E. Suzuki Coupling of Aryl Chlorides with Phenylboronic Acid in
Water, Using Microwave Heating with Simultaneous Cooling. Org. Lett. 2005, 7, 2101ꢀ2104
[31] Strauss, C.R.; Varma, R.S. Microwaves in Green and Sustainable Chemistry. In Microwave
Methods in Organic Synthesis. Top. Curr. Chem.; Larhed, M., Olofssonq, K., Eds.; Springer
Berlin Heidelberg, 2006; Vol. 266, pp 199ꢀ231.
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
[32] Polshettiwar, V.; Varma, R.S. Greener and Sustainable Approaches to the Synthesis of
Pharmaceutically Active Heterocycles. Curr. Opin. Drug. Discov. Devel. 2007, 10, 723ꢀ737.
[33] Polshettiwar, V.; Varma, R.S. MicrowaveꢀAssisted Organic Synthesis and Transformations
using Benign Reaction Media. Acc. Chem. Res. 2008, 41, 629ꢀ639.
[34] Deng, S.; Zhang, G.; Chen, S.; Xue, Y.; Du, Z.; Wang, P. Rapid and Effective Preparation of a
HPEI Modified Biosorbent Based on Cellulose Fiber with a Microwave Irradiation Method for
enhanced Arsenic Removal in Water. J. Mater. Chem. A 2016, 4, 15851−15860.
[35] Deng, S.; Zhang, G.; Liang, S.; Wang, P Microwave Assisted Preparation of Thioꢀ
Functionalized Polyacrylonitrile Fiber for the Selective and Enhanced Adsorption of Mercury
and Cadmium from Water. ACS Sustainable Chem. Eng. 2017, 5, 6054−6063.
[36] Yamada, Y.M.A.; Arakawa, T.; Hocke, H.; Uozumi, Y. A Nanoplatinum Catalyst for Aerobic
Oxidation of Alcohols in Water. Angew. Chem., Int.Ed. 2007, 46, 704ꢀ706.
[37] Bhattacharjya, A.; Klumphu, P.; Lipshutz, B.H. Kumada–GrignardꢀType Biaryl Couplings on
Water, Nat.Commun. 2015, 6, 8663ꢀ8668.
[38] Chinthakindi, P.K.; Kruger, H.G.; Govender, T.; Naicker, T.; Arvidsson, P.I. OnꢀWater
Synthesis of Biaryl Sulfonyl Fluorides. J. Org. Chem. 2016, 81, 2618−2623.
[39] Souza, G.F.P.D.; Zuben, T.W.V.; Salles, A.G. “On Water” MetalꢀCatalystꢀFree Oxidative
Coupling−Amidation of Amines To Access Imines and Amides. ACS Sustainable Chem. Eng.
2017, 5, 8439ꢀ8446.
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 25
[40] Muthusamy, S.; Gangadurai, C. ‘‘On water” Cascade Synthesis of Benzopyranopyrazoles and
Their Macrocycles. Tet. Lett., 2018, 59, 1501ꢀ1505.
1
2
3
4
5
6
7
8
9
[41] Nam, T.K.; Jang, D.O. Radical “On Water” Addition to the C=N Bond of Hydrazones: A
Synthesis of Isoindolinone Derivatives. J. Org. Chem. 2018, 83, 7373ꢀ7379.
[42] Chakraborti, G.; Paladhi, S.; Mandal, T.; Dash, J. “On Water’’ Promoted UllmannꢀType C−N
BondꢀForming Reactions: Application to Carbazole Alkaloids by Selective N Arylation of
Aminophenols. J. Org. Chem. 2018, 83, 7347ꢀ7359.
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
[43] Mangion, I.K., Sherry, B.D., Yin, J., Fleitz, F.J. Enantioselective Synthesis of a Dual
Orexin Receptor Antagonist. Org. Lett. 2012, 14, 3458ꢀ3461.
[44] Noshita, M.; Shimizu, Y.; Morimoto, H.; Ohshima, T. DiethylenetriamineꢀMediated Direct
Cleavage of Unactivated Carbamates and Ureas Org. Lett. 2016, 18, 6062ꢀ6065.
[45] V. Horn, K.S.; Burda, W.N.; Fleeman, R.; Shaw, L.N.; Manetsch, R. Antibacterial Activity of a
Series of N2, N4 Disubstituted Quinazolineꢀ2,4ꢀdiamines. J. Med. Chem. 2014, 57, 3075ꢀ3093.
[46] Font, M.; Gonzalez, A.; Palop, J.A.; Sanmartin, C. New Insights into the Structural
Requirements for ProꢀApoptotic Agents Based on 2,4ꢀDiaminoquinazoline, 2,4ꢀ
Diaminopyrido[2,3ꢀd] Pyrimidine and 2,4ꢀDiaminopyrimidine Derivatives. Eur. J. Med. Chem.
2011, 46, 3887−3899.
[47] Wan, Z.ꢀK.; Wacharasindhu, S.; Levins, C.G.; Lin, M.; Tabei, K.; Mansour, T.S. The Scope and
Mechanism of PhosphoniumꢀMediated SNAr Reactions in Heterocyclic Amides and Ureas. J.
Org. Chem. 2007, 72, 10194ꢀ10210.
[48] Alexandre, F.; Berecibar, A.; Wrigglesworth, R.; Besson, T. Novel Series of 8Hꢀ
Quinazolino[4,3ꢀb] Quinazolinꢀ8ꢀones via Two Niementowski Condensations. Tetrahedron
2003, 59, 1413ꢀ1419.
[49] Lamani, M.; Prabhu, K.R. IodineꢀCatalyzed Amination of Benzoxazoles: A MetalꢀFree Route to
2ꢀAminobenzoxazoles under Mild Conditions. J. Org. Chem. 2011, 76, 7938ꢀ7944.
24
ACS Paragon Plus Environment

Page 25 of 25
The Journal of Organic Chemistry
[50] Yadav, V.K.; Srivastava, V.P.; Yadav, L.D.S. Iodide Catalyzed Synthesis of 2ꢀ
Aminobenzoxazoles via Oxidative Cyclodesulfurization of Phenolic Thioureas with Hydrogen
Peroxide. Tet. Lett. 2018, 59, 252ꢀ255.
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
25
ACS Paragon Plus Environment