Thiocyanation and 2-Amino-1,3-thiazole Formation in Water Using Recoverable and Reusable Glycosylated Resorcin[4]arene Cavitands

Article abstract of DOI:10.1021/acs.joc.0c01150

A family of three spatially directional resorcin[4]arene cavitand glycoconjugates (RCGs) have been applied as efficient recoverable and reusable inverse phase transfer catalysts for eco- A nd environmentally friendly thiocyanation and 2-amino-1,3-thiazole formation reactions in water. The results show that RCGs (1 mol %) were capable of hosting and catalyzing various water-insoluble bromo/thiocyanato substrates in water without the use of any co-organic solvents. The recoverability and reusability of RCG catalytic systems, that is, RCG1 and RCG3, were also examined upon a simple extraction of the desired products using DCM or ethyl acetate, followed by subjecting the recovered aqueous solution containing the RCG catalysts to the next reaction cycles.

Full text of DOI:10.1021/acs.joc.0c01150

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Article
Thiocyanation and 2-amino-1,3-thiazole formation in water using
recoverable and reusable glycosylated resorcin[4]arene cavitands
Ali A Husain, and Kirpal S. Bisht
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01150 • Publication Date (Web): 17 Jul 2020
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The Journal of Organic Chemistry
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Thiocyanation and 2-amino-1,3-thiazole formation in water
using recoverable and reusable glycosylated resorcin[4]arene
cavitands
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Ali A. Husain, Kirpal S. Bisht*a
aDepartment of Chemistry, University of South Florida, 4202 East Fowler Avenue, CHE 202, Tampa, Fl, 33620, USA
Supporting Information Placeholder
ABSTRACT: A family of three spatially directional resorcin[4]arene cavitand glycoconjugates (RCGs) have been applied as efficient
recoverable and reusable inverse phase transfer catalysts for eco- and environmentally friendly thiocyanation and 2-amino-1,3-thiazole
formation reactions in water. The results show that RCGs (1 mol%) were capable to host and catalyze various water-insoluble
bromo/thiocyanato substrates in water without the use of any co-organic solvents. The recoverability and reusability of RCG catalytic
systems, i.e., RCG1 and RCG3, were also examined upon a simple extraction of the desired products using DCM or ethyl acetate, followed
by subjecting the recovered aqueous solution containing the RCG catalysts for the next reaction cycles.
salt.6 All of these reactions were carried out in hazardous
organic solvents, suffer from harsh reaction conditions, poor
INTRODUCTION
1,3-thiazole ring, among heterocyclic ring systems, is uniquely
functional group tolerance, limited starting materials and
important because of its presence in many natural products and
involve tedious workup because of the reagents used.
biomolecules possessing wide range of pharmacological
Considering the importance of the 2-aminothiazole heterocyclic
activities. Biological importance of thiazoles has led this ring
core, it is desirable and challenging to develop efficient and
system to be explored as a suitable heterocyclic core in design
green catalyst along with new routes for the construction of
and development of novel therapeutic agents.1 Structural
such thiazole moiety. Incidentally, β-cyclodextrin (β-CD),7
modifications around the thiazole ring has been exploited for its
lipase8 (biocatalyst) and Cu(I)-catalyst,9 have also been utilized
role as an important pharmacophore in many clinically used
in the synthesis of thiazole heterocycles.
drugs.2 Among different synthetic derivatives of 1,3-thiazoles,
H
O
2-amino-1,3-thiazoles are an attractive moiety in medicinal
chemistry with a wide spectrum of biological activities.2-3 Many
marketed drugs, such as abafungin (antifungal agent)
nitazoxanide (antiparasitic agent), meloxicam (anti-
inflammatory agent), and dasatinib (antineoplastic agent)
contain the 2-amino thiazole heterocyclic core (Figure 1).
The Hantzsch reaction, which uses α-halocarbonyl com-
pounds to couple with thioureas or thioamides, has been one of
the widely used methods for the synthesis of 2-aminothiazoles.4
Reactions directly starting from ketones, phenyl acetylene or
styrene with thioureas have been also reported for synthesis of
2-aminothiazole substrates.5 As well, modified version of the
Hantzsch thiazole synthesis has been reported by α-halogenated
ketones with amines in the presence of potassium thiocyanate
N
N
O
O
OAc
N
S
O
OH
S
S
O2N
O
N
N
S
N
S
N
H
H
H
N
H2N
Nitrazoxanide
Sulfathiazole
Meloxicam
O
O
H
S
N
NO2
OH
N
Acinitriazole
O
S
O
N
N
H
H
N
N
N
N
O
N
S
NH
Fanetizole
NH
S
N
N
N
NH
Abafungin
Dasatinib
Cl
Figure 1. A few marketed 2-amino-1,3-thiazole drugs.
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In recent years, we have developed a new catalytic systems
based on the spatial directionality of the resorcin[4]arene
cavitand glycoconjugates (RCGs)10 (Figure 2). The multiple β-
D-glucopyranose units on the cavitand rigid cores remarkably
provide a “pseudo-saccharide” cavity, which we have found is
able to host a variety of organic guests and catalyze chemical
reactions in water. Similar to the cyclodextrin, the RCGs are
efficient catalysts in various organic reactions in water, namely;
Page 2 of 8
thiocyanation, 2-amino-1,3-thiazole formation, Cu(I)-catalyzed
azide-alkyne coupling (CuAAC) and impart stereoselectivity in
one-pot three-components Mannich-type reactions (Figure
3).10a Also, we have recently reported on the formation of 1,4-
disubstituted 1,2,3-triazoles in water catalyzed by octavalent
resorcin[4]arene glycoconjugate RG.10b
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Figure 2. Structures of RCGs, β-CD and compound 14.10a
Figure 3. Different organic transformations catalyzed by RCG3 in water.10a
In this manuscript, we focus our interest extending the
thiocyanation and 2-amino-1,3-thiazole formation in water
using RCGs. In here, β-cyclodextrin (β-CD) and compound
1410a that is composed of a flexible “non-directional”
pentaerythritol core which lacks the rigidity and spatial
directionality were used for comparison (Figure 2). While
RCG1 is composed of short saccharide covalent linkers on its
upper rim, RCG3 and RCG5 consist of more flexible and
bulkier covalent spacers, respectively, on their macrocyclic
upper cores (Figure 2).
RESULTS AND DISCUSSION
Molecules containing thiocyanate moieties have received a
great interest in the field of organosulfur chemistry.11 They are
known to have insecticidal12 and biocidal13 activities and are
found in some anticancer natural products derived from
cruciferous vegetables.14 Also, thiocyanates are used as a key-
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intermediate in various organic transformations,15 especially,
Owing to the observed catalytic efficiencies of RCG1 and
RCG3 in catalyzing the thiocyanation reaction of benzyl
bromide in water, we further investigated their performance in
thiocyanations of various alkyl/aryl halides and thiazole
formation reaction along with their catalytic reusability studies.
For example, in Table 1, we summarized the thiocyanation
reactions for various hydrophobic alkyl and aryl bromides in
water using RCG1 catalyst.
1
2
3
4
5
6
7
8
the α-thiocyanato carbonyl containing ketones which are
applied as starting materials in the synthesis of 2-amino-1,3-
thiazole substrates. Considering the thermally instability of the
thiocyanate ion and its tendency to rearrange to
isothiocyanate,16 number of methods have been sought to
develop new strategies to achieve the thiocyanate substrates in
quantitative yields by using phase transfer catalysts (PTCs),17
microwave assistance,18 or ionic liquids (ILs).19
Accordingly, we investigated the thiocyanate formation in
water catalyzed by RCGs, β-CD and model compound 14.
Figure 4 summarizes optimization process for the thiocyanation
reaction of benzyl bromide (1.0 mmol) with potassium
thiocyanate (1.1 equiv.) in 10 mL of water. Duplicate reactions
were performed in the presence or in the absence of the added
catalysts (1 mol%) only in 5 min at different temperatures, i.e.,
25, 50, 80 0C (Figure 4).
Table 1. Synthesis of alkyl/aryl thiocyanate using RCG1.a
9
KSCN , RCG1
10
11
12
13
14
15
16
17
18
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RSCN
2a-18a
RBr
H2O, 80 0
C
Entry
1
Product
Structure
Time
(min)
30
Conv.
(%)b
91
2a
3a
SCN
2
3
SCN
30
30
92
98
KSCN (1.1 equiv), cat. (1 mol%)
H2O, 80 0
Br
SCN
Br
MeO
C
4a
SCN
1a
1 mmol
94
96
4
5
5a
6a
60
30
97
96
SCN
100
25 °C
50 °C
80 °C
O
80
60
40
20
0
67
SCN
46
O
6
7
7a
8a
35
35
99
95
SCN
22
MeO
O
15
SCN
O
8
9
9a
20
30
96
98
no cat.
14
beta-CD RCG1
RCG3
RCG5
SCN
EtO
O
Figure 4. Conversion (%) of benzyl thiocyanate 1a at 80 0C
10a
with/without the additive catalysts.
EtO
SCN
SCN
10
11
11a
12a
35
25
99
93
From the results in Figure 4, it was observed that thiocyanation
proceeded poorly at 25 C with/without the added catalysts
0
O
O
(<10% conv.). Although, raising the temperature to 50 0C
showed a slight improvement but yields were still less than
20%. At a higher reaction temperature, i.e., 80 0C, much higher
yields were observed in the presence of the added catalysts.
Notably, in the reaction catalyzed by RCG1 and RCG3 at 80
0C, nearly quantitative yield of 94% and 96%, respectively, of
benzyl thiocyanate 1a was observed. While 46%, 22% and 15%
yields were obtained for reactions catalyzed by β-CD,
compound 14 and blank (no added catalyst), respectively.
Significantly, among the RCG catalysts tested, RCG1/RCG3
were preferred compared to the RCG5 (67% yield) suggesting
that the nature of the covalent linkers, i.e.; flexibility and steric
hindrance, has a major influence on the construction of pseudo-
saccharide cavity and thus on their catalytic efficiencies. Also,
the results revealed RCGs to be more efficient catalysts than β-
CD (rigid saccharide macrocycle) in facilitating the
thiocyanation of benzyl bromide in water. The lack of
significant catalytic activity in the reaction with the added non-
directional glyco-pentaerythritol 14 suggested the importance
of spatial directionality provided by the cavitand rigid core in
facilitating the formation of the pseudo-saccharide cavity for
catalysis.
EtO
OEt
SCN
12
13
14
15
13a
14a
15a
16a
50
40
45
40
96
92
95
83
SCN
SCN
NCS
SCN
SCN
NCS
NCS
SCN
SCN
SCN
16
17
17a
18a
15
45
85
98
aReaction condition: aryl/alkyl bromide (1.0 mmol), KSCN (1.1 mmol) and
RCG1 (1 mol%), H2O (10 mL), 80 C, Determined by H-NMR for the
crude reaction mixture after extraction with DCM.
0
b
1
It was evident from the results that a variety of water-insoluble
alkyl/benzyl bromide derivatives were well tolerated in water
and within 30 minutes more than 90% product yields were
observed. The catalyst was tolerant of cyclic/acylic and
aromatics along with different functionalities, including
unsaturation, carbonyl containing ester and ketone
functionalities.
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The recoverability and reusability of RCG1 was investigated
Page 4 of 8
different among the RCGs (only 23% when RCG5 was
applied) suggesting a definite role for the spatial directionality
imparted by the cavitand core along with the covalent linkers
between the cavitand and the glycoside units in the formation
of the pseudo-saccharide bucket site required for catalysis.
RCG3 robustness in catalyzing the formation of 2-
aminothiazole in water upon the reaction of α-thiocyanato
propiophenone (1.0 mmol) with a variety of substituted aniline
derivatives (1.1 equiv.) was evaluated (Table 2).
1
2
3
4
5
6
7
8
for the thiocyanation reaction. In the reaction of benzyl bromide
catalyzed by RCG1, after extracting the formed benzyl
thiocyanate 1a with DCM, the recovered aqueous phase
containing RCG1 was subjected to the next thiocyanation
reaction cycle to evaluate its residual catalytic efficiency
(Figure 5). Most impressively, RCG1 catalyst retained most of
its catalytic activity over five extraction and catalytic cycles
resulting in >80% yield of the benzyl thiocyanate 1a. Such
result indicates that RCG1 can be practically recovered and
reused.
9
Table 2. Scoping the thiazole formation using RCG3.a
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13
14
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S
O
NH
94
91
SCN
NH2
RCG3
N
100
80
60
40
20
0
89
88
R
86
+
H2O, 80 0
C
R
2b-17b
Conv. (%)b
98
Entry
1
Product
2b
Structure
S
NH
NH
OH
N
S
N
2
3
3b
4b
97
98
HO
S
NH
N
run 1
run 2
run 3
run 4
run 5
Figure 5. Reusability of RCG1 for thiocyanation of benzyl
bromide in water.
OH
S
4
5
5b
6b
97
96
NH
OMe
N
Since thiocyanates are a key-intermediate (starting material)
in the synthesis of thiazoles, the condensation of α-thiocyanato
ketone with aniline in water was investigated (Figure 6) for the
synthesis of 2-aminothiazole 1b. The reaction between α-
thiocyanato propiophenone (1.0 mmol) and aniline (1.1 mmol)
with/without the additive catalysts (1 mol%, RCGs, β-CD and
model compound 14) were carried out in 10 mL of water at 80
0C in 1 hr and results are shown in Figure 6.
S
NH
N
MeO
S
6
7b
98
NH
N
OMe
S
7
8
8b
9b
98
99
NH
N
S
N
O
NH
SCN
NH2
S
N
cat. (1 mol%)
H2O, 80 0C
NH
+
1b
1 mmol
1.1 equiv.
S
9
10b
11b
23
35
NH
Cl
100
80
60
40
20
0
N
82
S
N
10
NH
65
Cl
Br
S
N
11
12
12b
13b
28
31
NH
NH
23
S
N
17
6
5
Br
F
S
N
13
14
14b
15b
88
NH
NH
no cat.
14
beta-CD RCG1
RCG3
RCG5
Figure 6. Conversion (%) of thiazole 1b at 80 0C with/without the
additive catalysts.
S
N
N/A
Like observations made during the thiocyanation reaction,
poor conversions (<17%) were observed with compound 14, β-
CD or in absence of an additive catalyst. Expectedly, RCG1
and RCG3 led to highest conversions of 65% and 82%,
respectively. Noticeably again, the catalytic efficiency was
NO2
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S
N
15
16b
N/A
NH
1
2
3
4
5
CF3
aReaction condition: 8a (1.0 mmol), aniline derivatives (1.1 mmol) and
RCG3 (1 mol%), H2O (10 mL), 1 hr, 80 0C, bConv. (%) for the crude
reaction mixture after extraction with ethyl acetate.
6
7
8
9
From the results, it was observed that the condensation
occurred with ease and with excellent yields (>95% conv.)
when electron-donor substituted anilines (entries 1-8) were
used. However, halogenated aniline gave lower yields (23-35%,
entries 9-12) with exception of 4-fluoroaniline which gave 88%
conversion (entry 13). The strongly electron withdrawing, i.e.,
4-nitro- and 4-trifluoromethylaniline, were found to be
unreactive (entries 14 & 15).
10
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13
14
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60
Figure 7. Proposed reaction mechanism for the one-pot thiazole
formation in water catalysed by RCG3.
Since, the RCGs can effectively catalyze the thiocyanation
and thiazole formation, it was logical to extend their catalytic
capability to a one-pot three component coupling reaction for
the formation of 2-aminothiazoles (Scheme 1). The one-pot
reaction essentially is a combination of two artificial synthetic
steps; (i) formation of α-thiocyanato carbonyl containing
Moreover, we also examined the recoverability and reusability of
RCG3, after extraction of formed 2-aminothiazole product 1b with
ethyl acetate, the aqueous phase containing RCG3 catalyst was
recovered (Figure 8). The aqueous solution was then directly
subjected without further purification for the next thiazole
formation reaction cycle to evaluate its residual catalytic efficiency,
which was significantly maintained for five extraction/reaction
cycles (>65%, Figure 8).
0
ketones within 30 minutes at 80 C, followed by (ii) direct
addition of aniline derivatives on the reaction mixture at 80 0C
for the synthesis of the targeted 2-aminothiazole compounds
(Figure 7). It was observed from all reactions that RCG3
successfully catalyzed the one-pot thiazole formation in water
of various 2-amino-1,3-thiazoles in good to high yield, i.e., 66-
87 %, Scheme 1.
100
82
79
75
72
80
60
40
20
0
69
Scheme 1. One-pot thiocyanation/thiazole formation using RCG3
R'
S
O
NH
(i) KSCN, RCG3, H2O, 30 min, 80 0
(ii) aniline derivative, 1 hr, 80 0
C
Br
R'
N
C
R
18 examples
S
N
S
S
N
S
OH
NH
NH
NH
NH
N
N
HO
3b (85%)
OH
2b (83%)
4b (82%)
1b (71%)
S
S
N
S
N
OMe
NH
NH
NH
run 1
run 2
run 3
run 4
run 5
N
MeO
OMe
S
훼
Figure 8. Reusability of RCG3 for thiazole formation of -
thiocyanato propiophenone in water.
6b (82%)
NH
5b (84%)
7b (87%)
S
S
N
S
N
NH
NH
NH
N
N
In conclusion, resorcin[4]arene cavitand glycoconjugates
(RCGs) were found to be excellent, recoverable and reusable
inverse phase transfer catalysts in thiocyanation and 2-amino-1,3-
thiazole formation reactions in aqueous condition. Such method
can be substantially practicable in a green approach for the
synthesis of thiocyanate and thiazole species in an ideal reaction
medium, water. RCGs were found to have several advantages,
including low catalytic loading (1 mol%), eco-friendly aqueous
reaction condition, significantly shorter reaction time,
recyclability, and reusability along with high yield desired
products.
F
8b (79%)
14b (66%)
NH
9b (83%)
OH
17b (81%)
S
N
S
S
NH
NH
N
N
OH
HO
19b (85%)
20b (89%)
18b (86%)
S
S
S
S
NH
NH
NH
NH
N
N
N
N
F
F
24b (70%)
21b (83%)
23b (73%)
22b (81%)
aReaction condition: (i) alpha-bromo propiophenone (1.0 mmol), KSCN (1.1 mmol), H2O (10 mL),
30 min, 80 0C; (ii) aniline derivatives (1.1 mmol) and
bIsolated yield.
(1 mol%), H2O (10 mL), 1 hr, 80 0C,
RCG3
EXPERIMENTAL SECTION
General
1H- and 13C-NMR spectra were recorded on a Bruker DRX-250 and
Inova 400 spectrometers. Sample concentrations were about 10 %
(w/v) in CDCl3 and DMSO-d6 and the J values are given in Hz. The
mass spectral analyses were performed on an Aligent Technologies
6540 UHD Accurate-Mass Q-TOF LC/MS.
Materials
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All reagents were used with no further purification unless otherwise
specified. 2-, 3- 4-amino phenols and 4-anisidine were re-
crystallized out from (3:7) ethyl acetate/hexane solvents.
5-methyl-N,4-diphenylthiazol-2-amine (1b). Yellow solid in 218
mg (82 %); 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.6 Hz, 2H),
7.39 (t, J = 7.5 Hz, 2H), 7.21-7.32 (m, 5H), 7.01 (t, J = 7.1 Hz, 1H),
2.44 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ 161.2, 145.9,
140.5, 134.9, 129.3, 128.5, 128.3, 127.4, 122.7, 118.0, 166.5, 12.3.
2-((5-methyl-4-phenylthiazol-2-yl)amino)phenol (2b). Brown
1
2
3
4
General procedure for the synthesis of resocrcin[4]arene
cavitands
glycoconjugates
(RCGs). All
glycosylated
resorcin[4]arene cavitands were prepared following the typical
5
1
solid (276 mg, 98 %); H NMR (400 MHz, DMSO-d6) δ 9.27 (s,
procedure reported previously.10a
6
7
8
9
1H), 8.14 (d, J = 8.9 Hz, 1H), 7.64 (t, J = 7.4 Hz, 2H), 7.44 (t, J =
7.5 Hz, 2H), 7.32 (t, J = 7.3 Hz, 2H), 6.85 (t, J = 7.3 Hz, 1H), 6.80
(m, 1H), 2.40 (s, 3H); 13C{H} NMR (100 MHz, DMSO-d6) δ 160.3,
146.2, 144.6, 135.2, 129.4, 128.3, 127.9, 127.0, 122.0, 119.2,
118.7, 116.5, 11.9. HRMS (ESI) m/z: (M + H)+ Calcd for
C16H15N2OS+ 283.0900; Found 283.0907.
Resorcin[4]arene Cavitand Glycoconjugate 1 (RCG1).10a Pale
yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 8.08 (s, 4H), 7.67
(s, 4H), 5.99 (d, J = 7.0 Hz, 4H), 5.31 (s, 8H), 4.84 (d, J = 12.11
Hz, 4H), 4.61 (d, J = 12.11 Hz, 4H), 4.61 (t, J = 8.1 Hz, 4H), 4.26
(d, J = 7.7 Hz, 8H), 3.71 (d, J = 10.3 Hz, 4H), 3.48 (dd, J = 6.2,
11.7 Hz, 4H), 3.13-3.16 (m, 8H), 3.06 (t, J = 8.8 Hz, 4H), 2.99 (t, J
= 8.4 Hz, 4H), 2.36 (m, 8H), 1.40 (m, 8H), 1.25 (m, 24H), 0.84 (t,
J = 6.6 Hz, 12H); 13C{H} NMR (125 MHz, DMSO-d6) δ 153.6,
143.9, 138.5, 125.4, 123.3, 122.0, 102.6, 77.4, 77.1, 73.8, 70.6,
61.8, 61.6, 43.7, 37.5, 31.8, 29.4, 28.1, 22.6, 14.3.
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3-((5-methyl-4-phenylthiazol-2-yl)amino)phenol (3b). Brown
1
solid (273 mg, 97 %); H NMR (400 MHz, DMSO-d6) δ 9.07 (s,
1H), 7.64 (d, J = 7.7 Hz, 2H), 7.42-7.45 (m, 4H), 7.22 (t, J = 7.2
Hz, 1H), 6.73 (d, J = 8.7 Hz, 2H), 2.39 (s, 3H); 13C{H} NMR (100
MHz, DMSO-d6) δ 160.8, 152.5, 145.7, 135.8, 133.9, 128.7, 128.4,
127.4, 119.5, 115.9, 12.4.
Resorcin[4]arene Cavitand Glycoconjugate 3 (RCG3).10a Pale
yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 8.20 (s, 4H), 5.68
(d, J = 6.2 Hz, 4H), 7.55 (s, 4H), 4.51 (s, 8H), 4.56-4.68 (m, 16H),
4.25 (d, J = 7.7 Hz, 4H), 4.25 (d, J = 7.7 Hz, 4H), 4.25 (m, 12H),
4.10 (m, 4H), 3.93 (m, 4H), 3.68 (d, J = 9.9 Hz, 4H), 3.46 (dd, J =
5.9, 11.7 Hz, 4H), 3.15-3.19 (m, 8H), 3.08 (t, J = 9.2 Hz, 4H), 3.00
(t, J = 8.7 Hz, 4H), 2.33 (m, 8H), 1.26 (m, 24H), 1.40 (m, 8H), 0.85
(t, J = 6.6 Hz, 12H); 13C{H} NMR (125 MHz, DMSO-d6) δ 153.7,
144.0, 138.1, 125.4, 124.6, 122.4, 103.4, 99.6, 77.5, 77.1, 73.7,
70.5, 67.9, 63.8, 61.8, 61.6, 50.1, 37.3, 31.9, 29.8, 29.4, 28.2, 22.6,
14.3.
4-((5-methyl-4-phenylthiazol-2-yl)amino)phenol (4b). Brown
1
solid (276 mg, 98 %); H NMR (400 MHz, DMSO-d6) δ 9.07 (s,
1H), 7.64 (d, J = 7.7 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.41 (m,
1H), 7.31 (d, J = 7.1 Hz, 1H), 6.73 (d, J = 8.5 Hz, 2H), 2.39 (s, 3H);
13C{H} NMR (100 MHz, DMSO-d6) δ 160.4, 152.1, 145.2, 135.3,
133.5, 128.2, 128.0, 126.9, 119.0, 115.4, 115.1, 12.0.
N-(2-methoxyphenyl)-5-methyl-4-phenylthiazol-2-amine (5b).
Yellow solid (287 mg, 97 %); 1H NMR (400 MHz, CDCl3) δ 8.03
(d, J = 6.6 Hz, 1H), 7.70 (d, J = 7.4 Hz, 2H), 7.45 (t, J = 7.5 Hz,
2H), 7.35 (m, 1H), 6.97 (m, 2H), 6.88 (d, J = 7.7 Hz, 1H), 3.88 (s,
3H), 2.49 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ 159.5, 147.2,
146.7, 135.2, 130.1, 128.3, 128.2, 127.4, 121.4, 121.0, 115.7,
101.0, 55.6, 12.2.
N-(3-methoxyphenyl)-5-methyl-4-phenylthiazol-2-amine (6b).
Yellow solid (284 mg, 96 %); 1H NMR (400 MHz, CDCl3) δ 7.63
(d, J = 7.2 Hz, 2H), 7.38 (t, J = 7.3 Hz, 2H), 7.29 (m, 1H), 7.12 (t,
J = 8.2 Hz, 2H), 6.84 (t, J = 2.2 Hz, 1H), 6.69-6.71 (dd, J = 1.7, 8.0
Hz, 1H), 6.53-6.55 (dd, J = 2.1, 8.2 Hz, 1H), 3.71 (s, 3H), 2.45 (s,
3H); 13C{H} NMR (100 MHz, CDCl3) δ 161.3, 160.4, 145.7, 141.8,
134.9, 129.9, 128.4, 128.2, 127.3, 116.5, 110.4, 108.2, 103.7, 55.1,
12.3.
N-(4-methoxyphenyl)-5-methyl-4-phenylthiazol-2-amine (7b).
Brown solid (287 mg, 98 %); 1H NMR (400 MHz, CDCl3) δ 7.56
(d, J = 7.3 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 7.26 (m, 1H), 7.05 (d,
J = 8.7 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 3.77 (s, 3H), 2.38 (s, 3H);
13C{H} NMR (100 MHz, CDCl3) δ 164.2, 156.0, 146.0, 134.1,
128.5, 128.1, 127.2, 122.0, 115.3, 114.4, 55.4, 12.2.
Resorcin[4]arene Cavitand Glycoconjugate 5 (RCG5).10a Pale
yellow solid; 1H NMR (600 MHz, DMSO-d6) δ 8.68 (s, 4H), 7.78
(s, 4H), 7.75 (d, J = 8.5 Hz, 8H), 7.13 (d, J = 8.5 Hz, 8H), 5.86 (d,
J = 7.3 Hz, 4H), 4.90 (d, J = 12.7 Hz, 4H), 4.71 (d, J = 12.7 Hz,
8H), 4.51 (d, J = 7.3 Hz, 4H), 4.31 (d, J = 7.7 Hz, 12H), 3.71 (d, J
= 11.3 Hz, 4H), 3.43-3.47 (m, 4H), 3.16 (m, 8H), 3.06 (t, J = 9.2
Hz, 4H), 3.00 (t, J = 8.3 Hz, 4H), 2.50 (m, 8H), 1.45 (m, 8H), 1.22-
1.33 (m, 24H), 0.88 (t, J = 6.6 Hz, 12H); 13C{H} NMR (125 MHz,
DMSO-d6) δ 158.8, 154.0, 145.3, 138.5, 130.8, 123.0, 122.2, 116.0,
102.7, 99.9, 77.4, 77.1, 73.8, 70.6, 62.0, 61.6, 61.3, 37.3, 31.9, 29.7,
9.3, 28.2, 22.6, 14.3.
General procedure for thiocyanation reaction in water.
Alkyl/aryl bromide (1.0 mmol) and KSCN (1.1 equiv./Br) were
added into 10 mL of water. RCG1 (1 mol%) was then added and
the reaction mixture was heated to 80 0C in oil bath. After
completion, the reaction mixture was allowed to cool at room
temperature, followed by extraction the product with DCM (5 mL
x 2) and the combined organic layer was dried over Na2SO4. DCM
was concentrated and NMR spectra were recorded.
General procedure for thiazole formation in water. α-
thiocyanato propiophenone (1.0 mmol) and aniline derivative (1.1
mmol) were added into 10 mL of water. RCG3 (1 mol%) was then
added and the reaction mixture was heated to 80 0C for 1 hr in oil
bath. After completion, the reaction mixture was allowed to cool at
room temperature, followed by extraction the product with ethyl
acetate (5 mL x 2) and the combined organic layer was dried over
Na2SO4. Ethyl acetate was concentrated, and NMR spectra were
recorded.
5-methyl-4-phenyl-N-(o-tolyl)thiazol-2-amine (8b). Yellow
1
solid (274 mg, 98 %); H NMR (400 MHz, DMSO-d6) δ 9.10 (s,
1H), 9.10 (s, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.5 Hz, 2H),
7.42 (t, J = 7.6 Hz, 2H), 7.31 (m, 1H), 7.18 (m, 2H), 6.97 (d, J =
7.6 Hz, 1H), 2.39 (s, 3H), 2.28 (s, 3H); 13C{H} NMR (100 MHz,
DMSO-d6) δ 161.3, 145.1, 139.6, 130.5, 128.6, 128.2, 128.0, 127.0,
126.4, 123.0, 120.7, 116.3, 18.1, 12.0.
5-methyl-4-phenyl-N-(p-tolyl)thiazol-2-amine (9b). Orange
1
solid (277 mg, 99 %); H NMR (400 MHz, CDCl3) δ 7.53 (t, J =
7.8 Hz, 2H), 7.35 (t, J = 7.8 Hz, 2H), 7.25 (m, 1H), 7.14 (d, J = 8.1
Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 2.39 (s, 3H), 2.31 (s, 3H); 13C{H}
NMR (100 MHz, CDCl3) δ 162.1, 145.5, 138.1, 134.8, 132.5,
129.8, 128.4, 128.2, 127.3, 118.7, 115.8, 20.7, 12.2.
General procedure for one-pot thiazole formation in water. α-
bromo propiophenone (1.0 mmol) and potassium thiocyanate (1.1
mmol) were added into 10 mL of water. RCG3 (1 mol%) was then
N-(4-fluorophenyl)-5-methyl-4-phenylthiazol-2-amine (14b).
0
added and the reaction mixture was heated to 80 C for 30 min.
1
Yellow solid (249 mg, 88 %); H NMR (400 MHz, DMSO-d6) δ
Aniline derivative (1.1 mmol) was then added to the solution and
10.08 (s, 1H), 7.67-7.72 (m, 2H), 7.66 (t, J = 8.6 Hz, 2H), 7.44 (t,
J = 7.5 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H), 7.14 (t, J = 8.8 Hz, 2H),
2.41 (s, 3H); 13C{H} NMR (100 MHz, DMSO-d6) δ 159.3, 145.2,
137.9, 135.1, 128.3, 127.0, 118.1, 115.5, 115.3, 11.9.
0
the reaction mixture was ran for 1 hr at 80 C. After completion,
the reaction mixture was allowed to cool at room temperature,
followed by extraction the product with ethyl acetate (5 mL x 2)
and the combined organic layer was then dried over Na2SO4. Ethyl
acetate was concentrated, and NMR spectra were recorded.
N,4-diphenylthiazol-2-amine (17b). Brown solid (204 mg, 81 %);
1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 7.93 (d, J = 6.9
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Hz, 2H), 7.76 (d, J = 7.3 Hz, 2H), 7.43 (m, 2H), 7.36 (m, 2H), 7.30
We are grateful to the NMR and Mass Analysis core facilities
of the Department of Chemistry and the Department of
Sponsored research at the University of South Florida.
1
2
(s, 3H), 6.97 (m, 1H); 13C{H} NMR (100 MHz, DMSO-d6) δ 163.1,
150.1, 141.2, 134.5, 130.0, 128.6, 127.5, 125.7, 121.2, 116.8,
102.8.
3
4
5
6
7
8
9
2-((4-phenylthiazol-2-yl)amino)phenol (18b). Yellow solid (230
mg, 86 %);1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.49 (s,
1H), 8.30 (s, 1H), 7.89 (d, J = 5.0 Hz, 2H), 7.25-7.29 (m, 2H), 6.88
(m, 3H); 13C{H} NMR (100 MHz, DMSO-d6) δ 164.2, 149.5,
146.3, 134.6, 129.3, 128.6, 127.4, 125.6, 122.3, 119.0, 115.1,
103.2.
3-((4-phenylthiazol-2-yl)amino)phenol (19b). Brown solid (228
mg, 85 %); 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.45
(s, 1H), 7.94 (d, J = 7.3 Hz, 2H), 7.43 (d, J = 7.5 Hz, 2H), 7.39 (s,
1H), 7.31 (t, J = 7.1 Hz, 1H), 7.28 (s, 1H), 7.13 (t, J = 7.8 Hz, 1H),
7.08 (m, 1H), 6.44 (d, J = 7.2 Hz, 1H); 13C{H} NMR (100 MHz,
DMSO-d6) δ 163.1, 158.0, 150.1 142.3, 134.6, 129.7, 128.6, 127.6,
125.8, 108.6, 107.9, 104.1, 102.8.
4-((4-phenylthiazol-2-yl)amino)phenol (20b). Brown solid (239
mg, 89 %); 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.14 (s,
1H), 7.89 (d, J = 7.5 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.41 (t, J =
7.6 Hz, 2H), 7.29 (t, J = 7.3 Hz, 1H), 7.18 (s, 1H), 6.78 (d, J = 8.7
Hz, 2H); 13C{H} NMR (100 MHz, DMSO-d6) δ 164.3, 152.3,
150.1, 134.7, 133.6, 128.6, 127.6, 125.6, 119.3, 115.5, 101.8.
4-phenyl-N-(o-tolyl)thiazol-2-amine (21b). Brown solid (221 mg,
83 %); 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 7.91 (d, J
= 7.3 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H),
7.30 (t, J = 7.3 Hz, 1H), 7.27 (s, 1H), 7.14 (d, J = 8.3 Hz, 2H), 2.26
(s, 3H); 13C{H} NMR (100 MHz, DMSO-d6) δ 163.3, 150.1, 138.8,
134.6, 130.1, 129.4, 128.6, 127.5, 125.6, 120.5, 117.0, 20.4.
4-phenyl-N-(p-tolyl)thiazol-2-amine (22b). Brown solid (215 mg,
81 %); 1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.02 (d, J =
8.0 Hz, 1H), 7.87 (d, J = 7.5 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.27
(d, J = 7.3 Hz, 1H), 7.25 (s, 2H), 7.22 (s, 1H), 7.01 (t, J = 7.2 Hz,
2H), 2.31 (s, 3H); 13C{H} NMR (100 MHz, DMSO-d6) δ 165.4,
149.9, 139.4, 134.7, 130.6, 128.8, 128.5, 127.4, 126.5, 125.6,
123.3, 120.9, 102.8, 18.1.
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N-(3-fluorophenyl)-4-phenylthiazol-2-amine (23b). Yellow
solid (197 mg, 73 %); 1H NMR (100 MHz, DMSO-d6) δ 10.54 (s,
1H), 7.91 (d, J = 7.7 Hz, 2H), 7.83 (d, J = 12.2 Hz, 1H), 7.44 (t, J
= 7.6 Hz, 2H), 7.30-7.39 (m, 4H), 6.78 (t, J = 7.5 Hz, 1H); 13C{H}
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128.7, 127.7, 125.6, 112.7, 107.5, 107.3, 103.6.
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7.92 (d, J = 7.5 Hz, 2H), 7.77-7.80 (m, 2H), 7.42 (t, J = 7.5 Hz,
2H), 7.30 (t, J = 8.4 Hz, 2H), 7.20 (t, J = 8.9 Hz, 2H); 13C{H} NMR
(100 MHz, DMSO-d6) δ 163.2, 150.0, 137.8, 134.5, 128.6 127.6,
125.7, 118.4, 115.6, 115.4, 102.8.
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ASSOCIATED CONTENT
Supporting Information
NMR spectral data for RCG1, RCG3, RCG5 and 2-amino-1,3-
thiazole compounds 1b-9b, 14b, 17b-24b and HRMS (ESI)
spectral data for the unknown thiazole 2b, are included.
Corresponding Author
*E-mail: kbisht@usf.edu
Present Addresses
†Department of Chemistry, University of South Florida, 4202
East Fowler Avenue, CHE 202, Tampa, Fl, 33620, USA
Notes
The authors declare no competing financial interest
ACKNOWLEDGMENT
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