A straightforward synthesis of 2-aminobenzothiazoles from Herz compounds

Article abstract of DOI:10.1039/c1ob05398a

2-Aminobenzothiazoles are readily synthesised from anilines, sulfur monochloride and isocyanides. The key step consists of an iodine-catalysed insertion of isocyanides into the S-S bond of hydrolysed Herz salts, with concomitant extrusion of sulfur monoxi

Full text of DOI:10.1039/c1ob05398a

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PAPER
A straightforward synthesis of 2-aminobenzothiazoles from Herz
compounds†‡
Ana G. Neo, Rosa M. Carrillo and Carlos F. Marcos*
Received 14th March 2011, Accepted 5th April 2011
DOI: 10.1039/c1ob05398a
2-Aminobenzothiazoles are readily synthesised from anilines, sulfur monochloride and isocyanides.
The key step consists of an iodine-catalysed insertion of isocyanides into the S–S bond of hydrolysed
Herz salts, with concomitant extrusion of sulfur monoxide.
materials chemistry, and as starting materials in the synthesis of
Introduction
diverse heterocycles.10 These compounds can be readily synthe-
sised by reacting several organic precursors with the powerful
sulfur transfer reagent sulfur monochloride.10a For example, 4,5-
dichloro-1,2,3-dithiazolium chloride (Appel salt) is conveniently
prepared in this way from chloroacetonitrile,11 while neutral fused
1,2,3-dithiazoles can be obtained from cyclic ketone oximes12 or
unsaturated cyclic 1-amino-2-carbonitriles.13
2-Aminobenzothiazoles are recognised as an important class
of heterocyclic compounds, which exhibit remarkable biologi-
cal activities. For example, they have been proposed as anti-
tumour agents,1 and inhibitors of leukotriene and tromboxane
biosynthesis.2 Importantly, they have also shown neuroprotec-
tant activity, and hence suggested for the treatment of chronic
neurodegenerative disorders such as amyotrophic lateral sclerosis3
and Huntington’s disease.4 On the other hand, they have shown
a wide range of applications as reaction intermediates, and their
chemistry has been recently revised.5
However, the available strategies for the synthesis of these
compounds are rather limited. Unsubstituted aminobenzothia-
zoles can be obtained by oxidative ortho-thiocyanation of anilines
followed by in situ cyclisation.6 Alternatively, N-alkyl and N-
aryl-2-aminobenzothiazoles are usually synthesised by oxidative
cyclisation of substituted arylthioureas7 or, more conveniently,
by intramolecular C–S cross-coupling of ortho-iodo or ortho-
bromo arylthioureas catalysed by palladium8 or copper.9 In any
case, the precursor thioureas are in turn synthesised from aryl or
alkylamines and noxious isothiocyanates.
Besides, the Herz reaction14 makes use of sulfur monochloride
to transform anilines (1) into 1,2,3-benzodithiazolium chlorides
(2), commonly called Herz compounds. Some derivatives of
Herz salts have found important applications as new materials,15
and have also been used as intermediates in the synthesis of
other heterocycles. For example, they can be hydrolysed to 2-
aminobenzenethioles, which upon condensation with aromatic
aldehydes or acid chlorides give 2-arylbenzothiazoles.
The chemistry of monocyclic 1,2,3-dithiazole compounds, has
been extensively studied. Hence, Appel salt is known to react with
nucleophiles with cleavage of the dithiazole ring and elimination of
one or two sulfur atoms.10b However, although Herz salts have been
known for almost a century, examples of their direct condensation
with other reagents are very scarce. For instance, treatment of
Herz salts (2) with excess of nitrous acid was reported to give
1,2,3-benzothiadiazoles.16 On the other hand, malononitrile17 and
amines18 have been reported to react with the benzene ring of
1,2,3-benzodithiazolium chlorides (2) in low to moderate yields.
Herz compounds (2) can also be hydrolysed in mild conditions
to stable 3H-1,2,3-benzodithiazole 2-oxides (3),14b,19 which some-
times can be advantageously used in further reactions.20
In this work, we propose an alternative synthesis of 2-
aminobenzothiazoles from 1,2,3-benzodithiazoles, byreplacement
of the S(2) atom with a C-NHR group (Scheme 1).
Scheme 1 Proposed retro-synthetic strategy for 2-aminobenzothiazoles.
Due to their unusual physical and chemical properties, 1,2,3-
dithiazoles have been recognised as valuable building blocks in
Results and discussion
As a result of our double interest in the chemistry of isocyanides21
and the use of sulfur monochloride22 for the synthesis of
heterocycles, we decided to explore the reaction of 3H-1,2,3-
benzodithiazole 2-oxides (3) with isocyanides (4). We envis-
aged that isocyanides could insert in the dithiazole ring, with
extrusion of sulfur monoxide to yield N-alkyl- or N-aryl-2-
benzothiazolylamines (5).
Laboratorio de Qu´ımica Orga´nica y Bioorga´nica (L.O.B.O.). Dept. Qu´ımica
Orga´nica e Inorga´nica. Facultad de Veterinaria. Universidad de Ex-
tremadura, 10071, Ca´ceres, Spain. E-mail: cfernan@unex.es
† Dedicated to the Memory of Antonio Ferna´ndez del Riego, who was
professor of chemistry and oceanographer in the city of Vigo, Spain.
‡ Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra. See DOI: 10.1039/c1ob05398a
4850 | Org. Biomol. Chem., 2011, 9, 4850–4855
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For that purpose, aniline 1a was made to react with excess
S2Cl2 in the classic Herz conditions,14b to yield the corresponding
Herz salt 2a (Scheme 2). Hydrolysis20 of crude 2a in 5% aqueous
sodium acetate readily gave 3H-1,2,3-benzodithiazole 2-oxide
(3a). Attempts to react sulfoxide 3a with cyclohexyl isocyanide
(4a), either at room temperature or in refluxing dichloroethane
only allowed the recovery of untransformed starting materials.
Scheme 3 Proposed mechanism of the reaction between isocyanides and
3H-1,2,3-benzodithiazole 2-oxides.
Table 1 Synthesis of benzo-1,2,3-ditiazole 2-oxides (3)
Entry
ArNH2
Method
3 (% yield)
1
2
3
4
5
4-Cl(C6H4)NH2
Aa
Aa
Bb
Bb
Bb
3a20 (72)
3b20 (39)
3c28 (38)
3d (34)
2,4-Cl2(C6H3)NH2
4-CH3O(C6H4)NH2
4-CF3(C6H4)NH2
2-naphthylamine
Scheme 2 Synthesis of 2-aminobenzothiazoles from anilines.
In order to activate the dithiazole ring for the attack of the
isocyanide, we investigated the catalytic use of Lewis acids, such
as Sc(OTf)3. Unfortunately, they showed no significant effects on
promoting the reaction.
In recent years, molecular iodine has received attention as
a mild and readily available catalyst for a variety of organic
transformations. Its catalytic activity has been attributed to its
moderate Lewis acidity and oxidising capacity.23 Furthermore,
iodine has shown to activate disulfides for the sulfenylation of
indoles.24 Hence we decided to investigate the effect of iodine on
the reaction of benzodithiazole oxides with isocyanides.
Interestingly, when a catalytic amount of iodine was added to an
equimolar mixture of 6-chloro-3H-1,2,3-benzodithiazole 2-oxide
(3a) and cyclohexyl isocyanide (4a) in dichloroethane, the required
benzothiazolylamine (5a) was cleanly obtained as the sole product,
after standing 24 h at room temperature (Scheme 2). The reaction
could be accelerated by the use of microwave radiation; however
this causes a considerable detriment in the yield.
3e14b,19 (76)
a Representative procedure (Method A): To an ice-cooled solution of the
aniline (1, 10 mmol) in of glacial acetic acid (1.6 mL), S2Cl2 (10 mmol)
is cautiously added. The mixture is stirred at rt 30 min and then heated
at 80 ◦C 4 h. The solution is cooled, toluene (25 mL) is added, and the
resulting precipitate is filtered and washed with dry dichloromethane to
yield the corresponding Herz compound (2).14b The Herz compounds,
as obtained previously, are suspended in 5% aqueous NaOAc (25 mL).
The mixture is stirred 30 min at rt, filtered, washed with water and dried
under vacuum to yield the benzo-1,2,3-dithiazole 2-oxides (3).20 b Method
B: Same as Method A, except that the Herz reaction is carried out in
dry dichloroethane (24 mL);29 Herz salts (2) precipitate in dichloroethane
without the need to add toluene, and hence are directly obtained by
filtration.
Table 2 Synthesis of 2-aminobenzothiazoles (5)
(% yield)
Entry
3
Isocyanide (4)
5
MWb
rta
We hypothesise that the reaction mechanism consists in an initial
insertion of the isocyanide into the S–S bond, followed by loss
of sulfur monoxide. However, neither a concerted process, nor
a ring opening-ring closure mechanism can be totally ruled out.
According to our hypothesis, the insertion of isocyanide (4) on
benzodithiazole oxide (3) would give a six-membered heterocyclic
intermediate (6), which would suffer a subsequent transannular
nucleophilic attack to give thiaziridine oxide 7. This would
readily extrude sulfur monoxide, yielding the observed 2-amino-
benzothiazole (5; Scheme 3). Although the insertion of isocyanides
into the S–S bonds is a quite unusual process,25 iodine has been
reported to catalyse the cleavage of S–S bonds,24 and probably
plays a fundamental role in this initial step. On the other hand, the
formation of thiirane intermediates is a common mechanism of
sulfur extrusion, accepted in processes such as the Eschenmoser
coupling26 and in some ring contraction reactions.22b,27
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3b
3b
3c
3c
3d
3d
3d
3e
3e
3e
C6H11NC
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
—
30
12
9
18
12
28
28
53
—
—
27
—
—
69
47
55
45
34
26
58
57
60
52
78
54
40
79
tBuNC
PhCH2NC
2,5-(CH3)2C6H3NC
C6H11NC
tBuNC
C6H11NC
tBuNC
9
C6H11NC
10
11
12
13
14
tBuNC
2,5-(CH3)2C6H3NC
C6H11NC
tBuNC
2,5-(CH3)2C6H3NC
a Procedure at room temperature: To a solution of 3 (0.5 mmol) in dry
dichloromethane (3 mL) isocyanide (4, 0.5 mmol) and I2 (10% mol) are
added. The mixture is stirred at rt 24 h. Workup and purification by column
chromatography gives 5. b Procedure under microwave irradiation: Same
as at room temperature, except that the mixture was irradiated at 100 W
(max) and 100 ◦C in a closed vial during 20 min.
To study the scope of the reaction we prepared different 3H-
1,2,3-benzodithiazole 2-oxides (3) through the Herz-hydrolysis
sequence (Table 1). Hydrolysed Herz compounds 3a–e were then
condensed with different alkyl and aryl isocyanides (4a–d). In
all the cases, the expected 2-aminobenzothiazoles (5a–n) were
consistently obtained in moderate to good yields. The results are
summarised in Table 2.
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In conclusion, we have developed a novel and convenient synthe-
sis of 2-aminobenzothiazoles by the reaction of Herz compounds
with isocyanides. The target heterocycles can be readily obtained
in just 3 reaction steps from simple para-substituted anilines. To
the best of our knowledge this is the first time the insertion of
an isocyanide into a S–S bond has been used in the synthesis of
heterocycles.
(100 MHz, CDCl3) d 13C NMR (101 MHz, CDCl3) d 139.49 (C),
128.37 (C), 126.76 (CH), 123.00 (CH), 122.73 (C), 114.08 (CH);
MS (EI) m/z (%) 207 (M+, 13), 205 (M+, 29), 190 (66), 188 (100),
171 (22), 158 (28), 154 (93); HRMS (EI) Calcd for C6H4ClNOS2:
204.9423. Found: 204.9426.
4,6-Dichloro-3H-benzo[d][1,2,3]dithiazole 2-oxide (3b)
(Method A, 39%) obtained as a violet solid; mp 109–112 ◦C dec.
(lit.20 129.5–130.5 ◦C dec.); IR (cm-1) 3451, 1634, 1457, 1142; 1H
NMR (400 MHz, CDCl3) d 8.08 (bs, 1H), 7.30 (d, J = 1.7 Hz, 1H),
7.26 (d, J = 1.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) d 137.42
(C), 128.21 (C), 126.42 (CH), 123.78 (C), 121.62 (CH), 118.86 (C);
MS (EI) m/z (%) 241 (M+, 24), 239 (M+, 31), 224 (95), 222 (100),
166 (6), 164 (8), 158 (14), 156 (30).
Experimental section
General Techniques
Melting points are uncorrected. IR spectra were recorded in
KBr pellets. Proton and carbon-13 nuclear magnetic resonance
(1H NMR or 13C NMR) spectra were obtained on 400 MHz
and 500 MHz spectrometers. Mass spectra (MS) were recorded
using Electronic Impact (EI, 70 eV) or Chemical Ionization
with CH4. Commercial reagents and solvents were used as
received with the exception of CH2ClCH2Cl and CH2Cl2 that were
distilled from P2O5. Experiments under microwave irradiation
were performed using a microwave reactor designed for synthetic
chemistry (Discover from CEM). Liquid reagents were measured
using positive-displacement micropipettes with disposable tips and
pistons. Thin layer chromatography was performed on aluminium
plates coated with silica gel, using 254 nm UV light or a mixture
of p-anisaldehyde (2.5%), acetic acid (1%) and H2SO4 (3.4%) in
95% ethanol as developer.
6-Methoxy-3H-benzo[d][1,2,3]dithiazole 2-oxide (3c)
(Method B, 38%) obtained as a violet solid; mp 86–90 ◦C (lit. 115–
◦
◦
1
118 C,28 150 C20); IR (cm-1) 3444, 1634, 1486, 1225, 1103; H
NMR (400 MHz, CDCl3) d 8.23 (bs, 1H), 6.99 (d, J = 8.7 Hz, 1H),
6.91 (d, J = 2.4 Hz, 1H), 6.72 (dd, J = 8.7, 2.4 Hz, 1H), 3.78 (s,
3H); 13C NMR (101 MHz, CDCl3) d 156.12 (C), 134.88 (C), 122.49
(C), 114.34 (CH), 113.08 (CH), 108.16 (CH), 55.98 (CH3); MS (EI)
m/z (%) 201 (M+, 21), 184 (100), 169 (49), 141 (38); HRMS (EI)
Calcd for C7H7NO2S2: 200.9918. Found: 200.9924.
6-(Trifluoromethyl)-3H-benzo[d][1,2,3]dithiazole 2-oxide (3d)
◦
Synthesis of benzo-1,2,3-dithiazole 2-oxides (3)
(Method B, 34%) obtained as a violet solid; mp 126–128 C; IR
(cm-1) 3134, 1334, 1180, 1138, 1080, 830; H NMR (400 MHz,
1
Benzo-1,2,3-dithiazole 2-oxides were prepared substantially fol-
lowing the procedure developed by Herz:14b
CDCl3) d 8.06 (s, 1H), 7.71 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.04
(d, J = 8.4 Hz, 1H); 13C-NMR (101 MHz, CDCl3) d 143.23 (C),
125.82 (q, J = 33.2 Hz, C), 124.22 (q, J = 3.5 Hz, CH), 123.35 (q,
J = 271.94 Hz, C), 121.65 (C), 120.87 (q, J = 3.9 Hz, CH), 113.15
(CH); MS (EI) m/z (%) 239 (M+, 12), 222 (93), 203 (12), 189 (15),
172 (16), 149 (28), 71 (100); HRMS (EI) Calcd for C7H4F3NOS2:
238.9686. Found: 238.9687.
Method A. To a cooled (ice-water bath) solution of the aniline
(1, 10 mmol) in of glacial acetic acid (1.6 mL), sulfur monochloride
(10 mmol) is cautiously added. The mixture is stirred at rt
30 min and then heated at 80 ◦C 4 h. The solution is cooled,
toluene (25 mL) is added, and the resulting precipitate filtered
and washed with dry dichloromethane to yield the corresponding
Herz compound (2). The Herz compounds, as obtained previously,
are hydrolyzed following the procedure described by Sawhney.20
Accordingly, they are suspended in 5% aqueous NaOAc (25 mL).
The mixture is stirred 30 min at rt, filtered, washed with water and
dried under vacuum to yield the benzo-1,2,3-dithiazole 2-oxides
(3).
Method B. To a cooled (ice-water bath) solution of the aniline
(1, 10 mmol) in dry dichloroethane (24 mL), sulfur monochloride
(10 mmol) is cautiously added. The mixture is stirred at rt
30 min and then heated at 80 ◦C 4 h. The solution is cooled
and filtered. The solid is washed with dry dichloromethane to
yield the corresponding benzo-1,2,3-dithiazolium chloride (Herz
compound, 2). The Herz compounds, as obtained previously, are
hydrolyzed following the same procedure as in method A to give
the benzo-1,2,3-dithiazole 2-oxides (3).
3H-Naphtho[2,1-d][1,2,3]dithiazole 2-oxide (3e)
(Method◦B, 76%) obtained as a violet solid; mp 136–139 ◦C (lit.14b,19
142–143 C); IR (cm-1) 3446, 3219, 1620, 1096, 1081, 811, 740; 1H
NMR (500 MHz, CDCl3) d 7.88 (d, J = 8.2 Hz, 1H), 7.77 (bs,
1H), 7.74 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.58 (t,
J = 7.6 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H);
13C NMR (101 MHz, CDCl3) d 137.54 (C), 130.36 (C), 128.89
(C), 128.68 (CH), 127.95 (CH), 127.55 (CH), 124.73 (CH), 124.35
(CH), 114.40 (C), 113.90 (CH); MS (EI) m/z (%) 221 (M+, 13),
204 (100), 172 86), 171 (5), 146 (12), 145 (10), 102 (14); HRMS
(EI) Calcd for C10H7NOS2: 220.9969. Found: 220.9968.
Synthesis of 2-aminothiazoles (5)
To a solution of benzo-1,2,3-dithiazole 2-oxide (3, 0.5 mmol) in
dry dichloromethane (3 mL) isocyanide (4, 0.5 mmol) and I2
(10% mol) are added. The mixture is stirred at rt 24 h (Method
A) or, alternatively, subjected to microwave irradiation at 100 W
(max) and 100 ◦C, for 20 min, in a closed vial (Method B). Water
(10 mL) is then added, and the resulting mixture extracted with
CH2Cl2 (3 ¥ 15 mL). The combined organic phases are dryed
6-Chloro-3H-benzo[d][1,2,3]dithiazole 2-oxide (3a)
◦
(Method A, 72%) obtained as a violet solid; mp 91–96 C (dec.)
◦
(lit.20 113–114 C); IR (cm-1) 3445, 1605, 1465, 1102, 810; H
NMR (400 MHz, CDCl3) d 7.70 (bs, 1H), 7.39 (d, J = 2 Hz, 1H),
7.15 (dd, J = 8.5, 2 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H); 13C-NMR
1
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(Na2SO4) and concentrated, and the residue is purified by flash
column chromatography (SiO2, hexane : EtOAc gradient) to give
compound 5.
156 (16); HRMS (EI) Calcd for C13H14Cl2N2S: 300.0255. Found:
300.0265.
N-tert-Butyl-4,6-dichlorobenzo[d]thiazol-2-amine (5f)
6-Chloro-N-cyclohexylbenzo[d]thiazol-2-amine (5a).
(Method A, 26%; Method B, 12%) obtained as a yellow oil; IR
(Method A, 69%) obtained as a white solid; mp 98–101 ◦C; IR
(cm-1) 3205, 3019, 2925, 2856, 1593, 1568, 1524, 1446, 1213, 807;
1H NMR (400 MHz, CDCl3) d 7.55 (d, J = 2.1 Hz, 1H), 7.42 (d,
J = 8.6 Hz, 1H), 7.25 (dd, J = 8.6, 2.1 Hz, 1H), 5.45 (bs, 1H), 3.62–
3.49 (m, 1H), 2.33–1.04 (m, 10H); 13C NMR (101 MHz, CDCl3) d
166.98 (C), 149.79 (C), 130.70 (C), 126.68 (C), 126.56 (CH), 120.55
(CH), 118.86 (CH), 55.00 (CH), 33.06 (CH2), 25.36 (CH2), 24.64
(CH2); MS (EI) m/z (%) 266 (M+, 14), 184 (100), 149 (12); HRMS
(EI) Calcd for C13H15ClN2S: 266.0644. Found: 266.0652.
(cm-1) 3417, 2970, 1593, 1538, 1433, 1388, 1258, 1219, 837; H
1
NMR (500 MHz, CDCl3) d 7.47 (s, 1H), 7.36 (s, 1H), 6.55 (bs, 1H),
1.54 (s, 9H); 13C NMR (101 MHz, CDCl3) d 165.06 (C), 147.40
(C), 132.29 (C), 126.39 (C), 126.27 (CH), 123.46 (C), 118.77 (CH),
53.57 (C), 28.86 (CH3); MS (EI) m/z (%) 274 (M+, 10), 218 (74),
156 (13), 141 (13), 71 (100); HRMS (EI) Calcd for C11H12Cl2N2S:
274.0098. Found: 274.0102.
N-Cyclohexyl-6-methoxybenzo[d]thiazol-2-amine (5g)
N-tert-Butyl-6-clorobenzo[d]thiazol-2-amine (5b)
(Method A, 58%; Method B, 28%) obtained as a white solid; mp
◦
98–100 C; IR (cm-1) 3422, 2928, 2853, 1604, 1542, 1471, 1246,
(Method A, 47%; Method B, 30%) obtained as a white solid; mp
827; 1H NMR (400 MHz, CDCl3) d 7.44 (d, J = 8.8 Hz, 1H), 7.14
(d, J = 2.4 Hz, 1H), 6.90 (dd, J = 8.8, 2.5 Hz, 1H), 5.23 (bs, 1H),
3.83 (s, 3H), 3.63–3.49 (m, 1H), 2.21–1.17 (m, 10H); 13C NMR
(101 MHz, CDCl3) d 164.99 (C), 155.02 (C), 146.64 (C), 131.28
(C), 119.05 (CH), 113.36 (CH), 105.47 (CH), 55.92 (CH3), 54.37
(CH), 33.36 (CH2), 25.51 (CH2), 24.73 (CH2); MS (EI) m/z (%)
262 (M+, 39), 191 (10), 180 (100), 165 (89); HRMS (EI) Calcd for
C14H18N2OS: 262.1140. Found: 262.1141.
84–87 ◦C; IR (cm-1) 3420, 3270, 3227, 3035, 2966, 2932, 1592, 1563,
1
1530, 1447, 1363, 1258, 1214, 811; H NMR (400 MHz, CDCl3)
d 7.54 (d, J = 2.1 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.24 (dd, J =
8.6, 2.2 Hz, 1H), 5.20 (s, 1H), 1.50 (s, 9H); 13C NMR (101 MHz,
CDCl3) d 164.59 (C), 151.16 (C), 131.90 (C), 126.59 (C), 126.14
(CH), 120.11 (CH), 119.64 (CH), 53.61 (C), 29.04 (CH3); MS (EI)
m/z (%) 240 (M+, 23), 218 (19), 184 (100), 149 (14); HRMS (EI)
Calcd for C11H13ClN2S: 240.0488. Found: 240.0490.
N-tert-Butyl-6-methoxybenzo[d]thiazol-2-amine (5h)
N-Benzyl-6-clorobenzo[d]thiazol-2-amine (5c)
(Method A, 57%; Method B, 28%) obtained as a white oil; IR
(cm-1) 3375, 2964, 2922, 1605, 1572, 1551, 1469, 1429, 1256, 1213;
1H NMR (400 MHz, CDCl3) d 7.46 (d, J = 8.8 Hz, 1H), 7.14 (d,
J = 2.5 Hz, 1H), 6.90 (dd, J = 8.8, 2.6 Hz, 1H), 5.10 (bs, 1H),
3.83 (s, 3H), 1.50 (s, 9H); 13C NMR (101 MHz, CDCl3) d 163.09
(C), 155.16 (C), 146.46 (C), 131.62 (C), 119.34 (CH), 113.28 (CH),
105.10 (CH), 55.92 (CH3), 53.28 (C), 29.16 (CH3); MS (CI) m/z
(%) 237 (M++ 1, 14), 181 (17), 149 (86), 71 (100); HRMS (CI)
Calcd for C12H17N2OS: 237.1062. Found: 237.1073.
(Method ◦A, 55%; Method B, 12%) obtained as a white solid; mp
180–190 C (lit.30 207–208 ◦C); IR (cm-1) 3441, 2928, 1620, 1574,
1
1448, 1355, 1264, 820, 746; H NMR (400 MHz, CDCl3) d 7.55
(d, J = 1.9 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.74–7.17 (m, 7H),
4.63 (s, 2H); 13C NMR (101 MHz, CDCl3) d 169.03 (C), 134.13
(C), 129.53 (C), 129.19 (CH), 128.75 (CH), 128.37 (CH), 127.82
(CH), 125.80 (C), 125.76 (C), 121.53 (CH), 116.97 (CH), 50.53
(CH2); MS (EI) m/z (%) 274 (M+, 21), 170 (10), 149 (25), 91 (100);
HRMS (EI) Calcd for C14H11ClN2S: 274.0331. Found: 274.0342.
N-Cyclohexyl-6-(trifluoromethyl)benzo[d]thiazol-2-amine (5i)
6-Cloro-N-(2,6-dimethylphenyl)benzo[d]thiazol-2-amine (5d)
(Method ◦A, 60%; Method B, 53%) obtained as a white solid; mp
(Method ◦A, 45%; Method B, 9%) obtained as a white solid; mp
204–207 C; IR (cm-1) 3443, 2920, 1649, 1592, 1522, 1496, 1473,
1445, 1315, 1194, 770; 1H NMR (400 MHz, CDCl3) d 7.46 (s, 1H),
7.31–7.11 (m, 5H), 6.26 (bs, 1H), 2.33 (s, 6H); 13C NMR (101 MHz,
CDCl3) d 169.89 (C), 150.15 (C), 137.20 (C), 136.46 (C), 131.20
(C), 129.07 (CH), 128.67 (CH), 126.91 (C), 126.57 (CH), 120.68
(CH), 118.86 (CH), 18.17 (CH3); MS (EI) m/z (%) 288 (M+, 100),
273 (21), 220 (18), 132 (28); HRMS (EI) Calcd for C15H13ClN2S:
288.0488. Found: 288.0496.
101–102 C; IR (cm-1) 3433, 3236, 2932, 2855, 1639, 1581, 1550,
1
1321, 1274, 1167, 1109; H NMR (400 MHz, CDCl3) d 7.85 (s,
1H), 7.61–7.51 (m, 2H), 5.88 (bs, 1H), 3.65–3.52 (m, 1H), 2.20–
1.18 (m, 10H); 13C NMR (101 MHz, CDCl3) d 168.48 (C), 154.66
(C), 130.25 (C), 125.90 (C), 123.57 (C), 123.46 (q, J = 3.6 Hz, CH),
118.31 (q, J = 4.0 Hz, CH), 54.94 (CH), 33.10 (CH2), 25.35 (CH2),
24.66 (CH2); MS (EI) m/z (%) 300 (M+, 14), 257 (6), 243 (7), 218
(100), 149 (38); HRMS (EI) Calcd for C14H15F3N2S: 300.0908.
Found: 300.0905.
4,6-Dichloro-N-cyclohexylbenzo[d]thiazol-2-amine (5e)
N-tert-Butyl-6-(trifluoromethyl)benzo[d]thiazol-2-amine (5j)
(Method A, 34%; Method B, 18%) obtained as a white solid; IR
(cm-1) 3445, 2931, 2856, 1594, 1554, 1539, 1432, 774; H NMR
(Method A, 52%) obtained as a yellow oil; IR (cm-1) 3421, 2967,
2926, 1577, 1540, 1319, 1288, 1163, 1119, 826; 1H NMR (400 MHz,
CDCl3) d 7.86 (s, 1H), 7.60 (bs, 2H), 6.80 (bs, 1H), 1.56 (s, 9H);
13C NMR (101 MHz, CDCl3) d 166.72 (C), 146.63 (C), 126.63
(C), 125.45 (d, J = 34.2 Hz, C), 124.53 (CH), 122.61 (C), 118.72
(CH), 116.60 (CH), 54.94 (C), 28.38 (CH3); MS (EI) m/z (%)
1
(400 MHz, CDCl3) d 7.47 (s, 1H), 7.34 (s, 1H), 6.14 (bs, 1H), 3.43–
3.32 (m, 1H), 2.15–1.21 (m, 10H); 13C NMR (101 MHz, CDCl3)
d 167.32 (C), 147.08 (C), 131.39 (C), 126.55 (C), 126.44 (CH),
122.98 (C), 119.19 (CH), 55.54 (CH), 32.89 (CH2), 25.24 (CH2),
24.44 (CH2); MS (EI) m/z (%) 300 (M+, 16), 218 (100), 191 (10),
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274 (M+, 14), 218 (100), 191 (8), 149 (18); HRMS (EI) Calcd for
C12H13F3N2S: 274.0752. Found: 274.0753.
Acknowledgements
We thank financial support from Instituto de Salud Carlos III
(PI081234) and Junta de Extremadura and FEDER (PRI07A032
& PRI08A039).
6-(Trifluoromethyl)-N-(2,6-dimethylphenyl)benzo[d]thiazol-2-
amine (5k)
(Method A, 78%) obtained as a yellow solid; mp 246–250 ◦C; IR
(cm-1) 3451, 2859, 1621, 1581, 1560, 1319, 1272, 1160, 1118, 771;
1H NMR (400 MHz, CDCl3) d 7.79 (s, 1H), 7.56 (d, J = 8.5 Hz,
1H), 7.49 (d, J = 8.3 Hz, 1H), 7.34–7.19 (m, 4H), 2.37 (s, 6H);
13C NMR (101 MHz, CDCl3) d 171.33 (C), 152.27 (C), 136.93
(C), 135.75 (C), 129.31 (C), 129.22 (CH), 129.15 (CH), 125.61 (C),
124.46 (q, J = 32.8 Hz, C), 123.82 (CH), 123.80 (q, J = 3.7 Hz,
1H), 118.66 (q, J = 3.9 Hz, 1H), 117.89 (CH), 18.10 (CH3); MS
(EI) m/z (%) 322 (M+, 25), 307 (10), 162 (7), 149 (8), 131 (20),
57 (100); HRMS (EI) Calcd for C16H13F3N2S: 322.0752. Found:
322.0756.
Notes and references
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