Metal-Free Synthesis of 2-Aminobenzothiazoles via Iodine-Catalyzed and Oxygen-Promoted Cascade Reactions of Isothiocyanatobenzenes with Amines

Article abstract of DOI:10.1021/acs.joc.7b01683

In this paper, a highly efficient and sustainable synthesis of 2-aminobenzothiazoles through the cascade reactions of isothiocyanatobenzenes with primary or secondary amines by using iodine as a catalyst and oxygen as an oxidant is presented. Mechanistically, the formation of the title compounds involves the in situ formation of the required benzothiourea intermediate followed by its intramolecular cross dehydrogenative coupling of a C(sp²)-H bond and a S-H bond. To our knowledge, this should be the first example in which 2-aminobenzothiazoles are efficiently prepared from simple and cheap isothiocyanates and amines under metal-free conditions by using iodine as a catalyst and molecular oxygen as an oxidant with water as the byproduct. Compared with literature protocols, this method eliminates the use of ortho-halo-substituted precursors, expensive transition-metal catalysts, and hazardous oxidants.

Full text of DOI:10.1021/acs.joc.7b01683

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Article
Metal-free synthesis of 2-aminobenzothiazoles via
iodine-catalyzed and oxygen-promoted cascade
reactions of isothiocyanatobenzenes with amines
Yuanshuang Xu, Bin Li, Xinying Zhang, and Xuesen Fan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01683 • Publication Date (Web): 16 Aug 2017
Downloaded from http://pubs.acs.org on August 16, 2017
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Metal-free synthesis of 2-aminobenzothiazoles via iodine-catalyzed and oxygen-
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promoted cascade reactions of isothiocyanatobenzenes with amines
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Yuanshuang Xu, Bin Li, Xinying Zhang*, and Xuesen Fan*
School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Henan
Province for Green Manufacturing of Fine Chemicals, Henan Key Laboratory of Organic
Functional Molecule and Drug Innovation, Key Laboratory of Green Chemical Media and
Reactions, Ministry of Education, Henan Normal University, Xinxiang, Henan 453007, China
E-mail: xinyingzhang@htu.cn; xuesen.fan@htu.cn
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Abstract: In this paper, a highly efficient and sustainable synthesis of 2-aminobenzothiazoles
through the cascade reactions of isothiocyanatobenzenes with primary or secondary amines by
using iodine as a catalyst and oxygen as an oxidant is presented. Mechanistically, the formation of
the title compounds involves the in situ formation of the required benzothiourea intermediate
followed by its intramolecular cross dehydrogenative coupling of a C(sp2)−H bond and a S−H
bond. To our knowledge, this should be the first example in which 2-aminobenzothiazoles are
efficiently prepared from simple and cheap isothiocyanates and amines under metal free conditions
by using iodine as a catalyst and molecular oxygen as an oxidant with water as the byproduct.
Compared with literature protocols, this method eliminates the use of ortho-halo-substituted
precursors, expensive transition metal catalyst, and hazardous oxidant.
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INTRODUCTION
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2-Aminobenzothiazole constitutes an essential building block of numerous compounds with a
broad spectrum of medicinal and pharmaceutical activities such as anti-inflammatory, anti-
microbial, anti-tumor, neuroprotective, anti-convulsant, anti-infective, and HIV-1 protease
inhibiting, etc.1 In addition, 2-aminobenzothiazoles have also been frequently used as key
intermediates in the synthesis of fine chemicals.2 Due to their importance, a number of elegant
methods for the synthesis of 2-aminobenzothiazoles have been established (Scheme 1),3 which
mainly include: 1) condensation of 2-aminothiophenols with isothiocyanates;4 2) Cu-, or phen-
catalyzed cyclization of o-halobenzothioureas;5 3) stoichiometric amount of PhCH2NMe3Br3-
promoted6 or transition metal-catalyzed7 cyclization of benzothioureas; 4) Pd-catalyzed amination
of 2-halobenzothiazoles;8 5) Cu-catalyzed condensation of carbodiimide with sodium
hydrosulfide;9 6) iodine-catalyzed condensation and aromatization of cyclohexanone with
thiourea;10 7) Cu-mediated aerobic three-component reaction of diaminodiaryl disulfide, copper
cyanide and an electrophile,11 etc. While these literature protocols are generally efficient and
reliable, some of them still suffer from the need for pre-functionalization of commercial substrates,
the use of toxic reagents, expensive metal catalysts and ligands, and the production of hazardous
by-products. Therefore, the development of environmentally and economically more sustainable
synthetic methods toward 2-aminobenzothiazoles is still highly desirable.
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In recent years, iodine-catalyzed or promoted organic reactions have attracted much attention.
This is not only due to the inexpensive and green nature of molecular iodine, but also owing to its
high efficiency.12 In particular, the combination of a catalytic amount of iodine with an added
oxidant has been widely used in various oxidative carbon−carbon and carbon−heteroatom bonds
forming reactions.13 Meanwhile, cross dehydrogenative coupling (CDC) between the inert
C−H/X−H bonds is an appealing strategy in organic synthesis as it provides easy accesses to
complex molecules from simple starting materials in a single operation without pre-introduction of
special leaving groups. As this strategy can significantly reduce the number of reaction steps, costs,
and the amount of wastes, it perfectly fulfills part of the criteria of green chemistry.14 Inspired by
those pioneering studies as mentioned above, and as a continuation of our recent interest in
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developing novel methods for the preparation of heterocyclic compounds,15 we have designed a
one-pot synthesis of 2-aminobenzothiazoles directly from the reactions of the commercially
available and inexpensive isothiocyanatobenzenes with amines through the in situ formation of a
benzothiourea intermediate followed by its intramolecular CDC reaction promoted by a
combination of a catalytic amount of iodine with a terminal oxidant (Scheme 1). Herein, we report
our detailed study in this aspect.
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Scheme 1. Different synthetic routes to 2-aminobenzothiazoles
RESULTS AND DISCUSSION
Our study was initiated by treating isothiocyanatobenzene (1a) with aniline (2a) in the presence
of 0.2 equiv of I2 and 2 equiv of di-tert-butyl perioxide (DTBP) in chlorobenzene (PhCl) at 120 ºC
for 12 h. To our delight, from this reaction the desired N-phenylbenzo[d]thiazol-2-amine (3a) was
obtained in a yield of 81% (Table 1, entry 1). Then, different oxidants such as tert-butyl
hydroperoxide (TBHP), H2O2, oxone, O2 and air were tested. We were pleased to find that with
oxygen as the oxidant, 3a could be obtained in 82% yield (entries 1-6). This is a highly promising
result on behalf of green and sustainable chemistry since molecular oxygen is considered as an
ideal terminal oxidant due to its inexpensive and environmentally friendly characters.16 While high
yields could also be obtained by using peroxides such as DTBP and H2O2 as the oxidant, this type
of oxidants may suffer from the potential risk of uncontrollable explosive radical reactions.
Therefore, we chose O2 as the oxidant for further screening of the reaction conditions. Among
various solvents thus tried, PhCl was found to be more efficient than toluene, DMF and dioxane
(entries 7-9 vs 5). In a further aspect, different reaction temperatures were tried, and those higher
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or lower than 120 ºC gave diminished yields of 3a (entries 10-11). Reducing the amount of I2 from
0.2 to 0.1 equiv resulted in a sharp decrease in the efficiency, and increasing its amount to 0.5
equiv did not improve the yield of 3a obviously (entries 12-13). Interestingly, further study
showed that when the reaction of 1a with 2a was carried out in the presence of 1.0 equiv of I2
under nitrogen, 3a was obtained in a yield of 68% (entry 14). Finally, a control experiment
indicated that in the absence of iodine, the formation of 3a was not observed (entry 15).
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Table 1. Optimization studies for the preparation of 3a a
entry
1
catalyst (equiv)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.1)
I2 (0.5)
I2 (1.0)
none
oxidant (equiv)
solvent
PhCl
t/°C
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yield (%)b
81
DTBP (2)
2
TBHP (2)
PhCl
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3
H2O2 (2)
PhCl
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4
oxone (2)
O2
PhCl
trace
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5
PhCl
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air
PhCl
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O2
toluene
DMF
dioxane
PhCl
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O2
trace
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O2
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O2
67
O2
PhCl
75
O2
PhCl
32
O2
PhCl
84
N2
PhCl
68
O2
PhCl
0
a Reaction conditions: 1a (0.55mmol), 2a (0.5 mmol), O2 or N2 (balloon, 1 atm),
solvent (3 mL), 12 h. b Isolated yield.
With the optimized reaction conditions in hands, the scope and generality of this 2-
aminobenzothiazole-forming reaction were studied. For this purpose, the reactions of diversely
substituted isothiocyanatobenzenes (1) with aromatic amines (2) were firstly studied, and the
results were listed in Table 2. It turned out that 1 and 2 bearing either an electron-donating group
(EDG) such as methyl or methoxy, or an electron-withdrawing group (EWG) such as fluoro,
chloro or trifluoromethyl on the phenyl ring underwent this reaction smoothly to give 3a-3j in
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yields ranging from 56-90%, and the electronic nature of the phenyl moiety rendered an obvious
effect in that substrates bearing EDG generally gave higher yields than those bearing EWG. This is
exemplified by the preparation of 3b, 3c vs 3d, 3e, 3f. Meanwhile, it was observed that para-,
meta- and ortho-substituted 1 and 2 worked well for this reaction, and meta-substituted substrate
cyclized regioselectively to give the sterically less hindered isomer (3g and 3h). Finally, it was
found that naphthalen-1-amine and 1-isothiocyanatonaphthalene could take part in this reaction
smoothly to give 3k in a yield of 78%.
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Table 2. Substrate scope for the preparation of 3 (I) a, b
3a, 82%
3d, 64%
3b, 85%
3e, 69%
3c, 84%
3f, 62%
3h, 73%
3g, 76%
3i, 90%
3k, 78%
3j, 56%
a Reaction conditions: 1 (0.55mmol), 2 (0.5 mmol), I2 (0.1 mmol), O2 (balloon, 1 atm), PhCl (3 mL),
120 ºC, 12 h. b Isolated yield.
Next, the scope of the amine substrates (2) was extended from aromatic primary amines to alkyl
primary amines, and the results were listed in Table 3. We were delighted to observe that when
diversely substituted isothiocyanates (1) were reacted with propan-1-amine, the corresponding
products 3l-3o could be obtained in yields ranging from 62% to 75%. Next, a variety of
isothiocyanates (1) were let to react with phenylmethanamine. It was shown that functional groups
such as methyl, methoxy, chloro, bromo and trifluoromethyl attached on the phenyl moiety in 1
were well tolerated, and both electron-rich and electron-poor phenylisothiocyanates underwent this
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cascade reaction successfully to give 3p-3w in moderate to good yields. To our delight, o-
methylphenylisothiocyanate was found to be also suitable for this reaction to give the
corresponding product (3u) in a yield of 74%. Next, (3-fluorophenyl)methanamine, o-
tolylmethanamine and (2-chlorophenyl)methanamine reacted with 1a smoothly to give 3x-3z in
moderate yields. When 1-phenylethan-1-amine was reacted with diversely substituted
isothiocyanates, the corresponding reactions afforded 3aa-3ee in 41-68% yields. Notably, from the
reaction of naphthalen-1-ylmethanamine, 3ff could be obtained in a yield of 56%.
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Table 3. Substrate scope for the preparation of 3 (II) a, b
3l, 68%
3o, 62%
3n, 71%
3q, 67%
3m, 75%
3p, 61%
3r, 60%
3t, 50%
3s, 55%
3w, 55%
3z, 56%
3v, 50%
3y, 53%
3u, 74%
3x, 56%
3cc, 58%
3aa, 61%
3bb, 64%
3dd, 41%
3ff, 56%
3ee, 68%
a Reaction conditions: 1 (0.55mmol), 2 (0.5 mmol), I2 (0.1 mmol), O2 (balloon, 1 atm), PhCl (3
mL), 120 ºC, 12 h. b Isolated yield.
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To further expand the substrate scope, morpholine (4a), an alkyl secondary amine, was treated
with 1a under the standard reaction conditions used for the synthesis of 3 (Table 1, entry 5). From
this reaction, the expected product 5a was obtained in 29% yield (Scheme 2, 1). To improve the
efficiency, several parameters possibly affecting this reaction were screened. After some trials and
errors, we were delighted to find that 5a could be obtained in 63% yield by treating the mixture of
1a and 4a with 0.5 equiv of iodine in PhCl under oxygen at 120 ºC for 14 h (Scheme 2, 2).
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Scheme 2. Synthesis of 5a under different reaction conditions
Next, the suitability of other secondary amines for this reaction was studied, and the results
were listed in Table 4. It was found that in addition to morpholine, thiomorpholine, pyrrolidine,
piperidine or functinalized piperidine could also take part in this reaction successfully to give a
series of hybrid compounds (5a-5h) containing both the benzothiazole scaffold and another kind
of heterocyclic unit with potential biological and material significance.
Table 4. Substrate scope for the preparation of 5 a, b
5c, 49%
5f, 48%
5a, 63%
5b, 58%
5e, 55%
5d, 52%
5g, 51%
5h, 62%
a Reaction conditions: 1 (0.55mmol), 4 (0.5 mmol), I2 (0.25mmol), O2 (balloon, 1
atm), PhCl (3 mL), 120 ºC, 14 h. b Isolated yield.
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Furthermore, we noted that Patel et al have recently reported an interesting intramolecular
arylthiolation of benzothioureas through Pd-catalyzed C−H bond activation or C−X bond
breakage.7d In that elegant study, they observed that the reaction of 1-chloro-2-isothiocyanato-
benzene with morpholine went through both the C−H bond activation and the C−Cl bond breakage
pathways to give a mixture of 4-(4-chlorobenzo[d]thiazol-2-yl)morpholine (5i) and 4-
(benzo[d]thiazol-2-yl)morpholine (5a) in yields of 71% and 15%, respectively (Scheme 3, 1).
When 1-bromo-2-isothiocyanatobenzene was used, on the other hand, the reaction exclusively
followed a dehalogenative route to give 5a in an excellent yield of 96%. Meanwhile, the formation
of 4-(4-bromobenzo[d]thiazol-2-yl)morpholine (5j) was not observed (Scheme 3, 2). To compare
our method with Patel’s protocol, we carried out the reactions of 1-chloro-2-isothiocyanato-
benzene and 1-bromo-2-isothiocyanatobenzene with morpholine under the promotion of I2 and O2.
It turned out that both of them exclusively underwent the C−H bond functionalization pathway to
give 5i (Scheme 3, 3) and 5j (Scheme 3, 4) in moderate yields. Meanwhile, the formation of 5a,
derived from C−Cl or C−Br bond cleavage, was not observed. These results tell that the method
developed in this paper could be considered as a complementary tool to Patel’s protocol.
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Scheme 3. Different reaction versions of 1-halo-2-isothiocyanatobenzene with morpholine
Based on the above observation and previous reports,13 a plausible mechanism accounting for
the formation of 3a from the reaction of 1a with 2a is proposed in Scheme 4. Initially, 1a
condenses with 2a to afford 1,3-diphenylthiourea (A). Then, A reacts with iodine to afford
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intermediate B through the formation of a S−I bond. Next, an intramolecular attack of the π
electron of the nucleophilic benzene ring onto the electrophilic S in B forms an arenium σ-
complex (C). Finally, an extrusion of H+ from C assisted by I– as a base leads to the formation of
3a via intermediate D. Meanwhile, oxidation of the in situ formed HI by molecular oxygen
regenerates I2 for the next cycle of the reaction.
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Scheme 4. Proposed reaction mechanism accounting for the formation of 3a
To verify the proposed reaction mechanism, some control experiments were carried out. First,
1a was treated with 2a in PhCl at 70 ºC for 2h. From this reaction, 1,3-diphenylthiourea, the
proposed intermediate A as shown in Scheme 4, was obtained in a yield of 92% (Scheme 5, 1).
When A was treated with I2 in PhCl under an oxygen atmosphere at 120 ºC for 10 h, 3a was
obtained in a yield of 90% (Scheme 5, 2). These results tell that A should be a key intermediate in
the formation of 3a from the reaction of 1a and 2a.
Scheme 5. Control experiments (I)
Next, using 2 equiv of butylated hydroxytoluene (BHT) as a free-radical trap was found to have
no obvious negative effect on the transformation of A toward 3a (Scheme 6, 1). Moreover, when
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2 equiv of BHT were added directly to the reaction of 1a with 2a under standard reaction
conditions, 3a could still be obtained in a yield of 80% (Scheme 6, 2), suggesting that a radical
reaction pathway might be excluded.
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Scheme 6. Control experiments (II)
To clarify whether an iodine-catalyzed intramolecular aromatic electrophilic substitution is
involved in the formation of 3, an intermolecular competing experiment was carried out. Thus, a
mixture of 1,3-bis(4-methoxyphenyl)thiourea (6, 0.5 mmol) and 1,3-bis(4-(trifluoromethyl)-
phenyl)thiourea (7, 0.5 mmol) were treated with 0.1 mmol of I2 under an oxygen atmosphere at
120 ºC for 4 h. From this reaction, 3c, formed from the reaction of 6, was obtained in 37% yield.
Meanwhile, 3f, formed from the reaction of 7, was obtained only in trace amount (Scheme 7).
These results indicate that substrate bearing an EDG on the phenyl ring undergoes the cyclization
much more rapidly than that bearing an EWG. The higher reactivity of the electron-richer substrate
is in consistent with the proposed aromatic electrophilic substitution mechanism with the
formation of an arenium σ-complex.
Scheme 7. An intermolecular competing experiment
Furthermore, an intramolecular competing experiment was also tried. Thus, 1-(4-methoxy-
phenyl)-3-(4-(trifluoromethyl)phenyl)thiourea (8) was subjected to I2 and O2 in PhCl at 120 ºC for
4 h. From this reaction, 5-methoxy-N-(4-(trifluoromethyl)phenyl)benzo[d]thiazol-2-amine (9) was
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formed in a yield of 38% through the annulation onto the electron-richer benzene ring attached
with a methoxy group. Meanwhile, the formation of another possible regioisomer, N-(4-
methoxyphenyl)-5-(trifluoromethyl)benzo[d]thiazol-2-amine (10) was not found (Scheme 8). This
is in consistent with what has been observed in the intermolecular competing experiment as shown
in Scheme 7, and should be considered as another positive evidence in supporting the proposed
reaction mechanism as shown in Scheme 4.
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Scheme 8. An intramolecular competing experiment
Finally, in order to check the suitability of this new synthetic method in an enlarged scale, 11
mmol of 1a was treated with 10 mmol of 2a under standard reaction conditions. From this reaction,
3a was obtained in a yield of 71% (Scheme 9).
Scheme 9. Gram-scale synthesis of 3a
CONCLUSION
In summary, a molecular iodine-catalyzed and oxygen-oxidized synthesis of 2-amino
benzothiazoles from the cascade reaction of isothiocyanatobenzenes with amines has been
developed. Compared with literature reports, notable features of this novel method include: 1)
accomplished in the absence of any metal catalyst, 2) starting from commercially available and
inexpensive materials, 3) eliminating the need of ortho-halo substituted precursors and the use of
hazardous oxidant, 4)broad substrate scope, and 5) high efficiency and excellent sustainability.
With these advantages, this method is expected to find wide applications in related areas.
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EXPERIMENTAL SECTION
1. General Methods.
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Commercial reagents were used without further purification. Melting points were recorded with
a micro melting point apparatus and uncorrected. The 1H NMR spectra were recorded at 400 MHz
or 600 MHz. The 13C NMR spectra were recorded at 100 MHz or 150 MHz. The 19F NMR spectra
were recorded at 565 MHz. Chemical shifts were expressed in parts per million (δ) downfield from
the internal standard tetramethylsilane, and were reported as s (singlet), d (doublet), t (triplet), dd
(doublet of doublet), m (multiplet), br s (broad singlet), etc. The coupling constants J were given
in Hz. High resolution mass spectra (HRMS) were obtained via ESI mode by using a MicrOTOF
mass spectrometer. The conversion of starting materials was monitored by thin layer
chromatography (TLC) using silica gel plates (silica gel 60 F254 0.25 mm), and components were
visualized by observation under UV light (254 and 365 nm).
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2. A typical procedure for the synthesis of 3a and spectroscopic data of 3a-3ff
To a 10 mL schlenk tube were added isothiocyanatobenzene (1a, 66 uL, 0.55 mmol), aniline (2a,
46 uL, 0.5 mmol), I2 (25.4 mg, 0.1 mmol) and PhCl (3 mL). The mixture was then strirred at 120
ºC under an oxygen atmosphere for 12 h. Upon completion, the resulting mixture was quenched
with saturated aqueous solution of Na2S2O3 (10 mL), and extracted with EtOAc (10 mL  3). The
combined organic phase was washed with water and brine, dried over anhydrous Na2SO4, and
evaporated under reduced pressure. The residue was purified by column chromatography on silica
gel with petroleum ether/ethyl acetate (10:1) as the eluent to give 3a (92.8 mg, 82%). 3b-3ff were
obtained in a similar manner.
N-Phenylbenzo[d]thiazol-2-amine (3a): Eluent: petroleum ether/ethyl acetate (10:1); white solid
(92.8 mg, 82%), mp 156-157 ºC (lit.17 158-159 ºC). 1H NMR (400 MHz, CDCl3) δ: 7.11-7.19 (m,
2H), 7.30 ( t, J = 7.6 Hz, 1H), 7.40 ( t, J = 7.6 Hz, 2H), 7.48-7.54 (m, 3H), 7.61 (d, J = 8.4 Hz, 1H),
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9.52 (br s, 1H). C NMR (100 MHz, CDCl3) δ: 119.2, 120.7, 120.9, 122.3, 124.5, 126.2, 129.6,
129.8, 140.1, 151.3, 165.4. MS: m/z 227 [M+H]+.
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6-Methyl-N-(p-tolyl)benzo[d]thiazol-2-amine (3b): Eluent: petroleum ether/ethyl acetate (10:1);
white solid (108.1 mg, 85%), mp 163-164 ºC (lit.17 165-166 ºC). 1H NMR (400 MHz, DMSO-d6) δ:
2.27 (s, 3H), 2.35 (s, 3H), 7.10-7.16 (m, 3H), 7.46 ( d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.66 ( d, J =
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8.4 Hz, 2H), 10.28 (s, 1H). C NMR (100 MHz, DMSO-d6) δ: 20.4, 20.8, 117.8, 118.7, 120.8,
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126.9, 129.3, 130.0, 130.8, 131.3, 138.3, 150.1, 160.9. MS: m/z 255 [M+H]+.
6-Methoxy-N-(4-methoxyphenyl)benzo[d]thiazol-2-amine (3c): Eluent: petroleum ether/ethyl
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acetate (10:1); white solid (120.3 mg, 84%), mp 156-157 ºC. H NMR (400 MHz, DMSO-d6) δ:
3.73 (s, 3H), 3.76 (s, 3H), 6.88-6.95 (m, 3H), 7.40 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.67 (d, J =
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8.8 Hz, 2H), 10.10 (s, 1H). C NMR (100 MHz, DMSO-d6) δ: 55.2, 55.5, 105.3, 113.3, 114.1,
119.2, 119.3, 131.0, 134.2, 146.3, 154.4, 155.0, 160.3. HRMS calcd for C15H15N2O2S: 287.0849
[M+H]+ , found: 287.0854.
6-Fluoro-N-(4-fluorophenyl)benzo[d]thiazol-2-amine (3d): Eluent: petroleum ether/ethyl acetate
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(10:1); white solid (83.9 mg, 64%), mp 228-230 ºC. H NMR (400 MHz, DMSO-d6) δ: 7.12-7.22
(m, 3H), 7.55-7.59 (m, 1H), 7.71 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.77-7.81 (m, 2H), 10.49 (s,
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1H). C NMR (100 MHz, DMSO-d6) δ: 107.9 (d, JC-F = 27.6 Hz), 113.3 (d, JC-F = 24.0 Hz),
115.5 (d, 2JC-F = 22.6 Hz), 119.3 (d, 3JC-F = 7.3 Hz), 119.8 (d, 3JC-F = 8.7 Hz), 131.1 (d, 3JC-F = 10.9
Hz), 137.0 (d, 4JC-F = 2.2 Hz), 148.7, 157.3 (d, 1JC-F = 237.2 Hz), 157.9 (d, 1JC-F = 236.4 Hz), 161.5
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(d, JC-F = 1.4 Hz). 19F NMR (565 MHz, DMSO-d6) δ: -120.24, -120.89. HRMS calcd for
C13H9F2N2S: 263.0449 [M+H]+ , found: 263.0459.
6-Chloro-N-(4-chlorophenyl)benzo[d]thiazol-2-amine (3e): Eluent: petroleum ether/ethyl
acetate (10:1); white solid (101.8 mg, 69%), mp 226-227 ºC (lit.17 228-229 ºC). H NMR (400
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MHz, DMSO-d6) δ: 7.33 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.58(d, J =
8.4 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.93 (s, 1H), 10.69 (s, 1H). 13C NMR (100 MHz, DMSO-d6)
δ: 119.3, 120.3, 120.8, 125.7, 126.1 126.3, 128.8 131.7, 139.3, 150.8, 162.0. MS: m/z 295, 297
[M+H]+.
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6-(Trifluoromethyl)-N-(4-(trifluoromethyl)phenyl)benzo[d]thiazol-2-amine
(3f):
Eluent:
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petroleum ether/ethyl acetate (10:1); white solid (112.3 mg, 62%), mp 152-153 ºC. H NMR (400
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8.02 (d, J = 8.4 Hz, 2H), 8.35 (s, 1H), 11.15 (s, 1H). C NMR (150 MHz, DMSO-d6) δ: 118.4,
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119.5 (q, 3JC-F = 4.4 Hz), 120.2, 122.9 (q, 2JC-F = 31.7 Hz), 123.427 (q, 3JC-F = 3.2 Hz), 123.434 (q,
2JC-F = 31.8 Hz), 124.9 (q, 1JC-F = 270.2 Hz), 125.1 (q, 1JC-F = 270.2 Hz), 126.8 (q, 3JC-F = 4.4 Hz),
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131.3, 143.9, 155.1, 164.5. F NMR (565 MHz, DMSO-d6) δ: -59.57, -60.16. HRMS calcd for
C15H9F6N2S: 363.0385 [M+H]+, found: 363.0387.
5-Methoxy-N-(3-methoxyphenyl)benzo[d]thiazol-2-amine (3g): Eluent: petroleum ether/ethyl
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acetate (10:1); yellowish solid (108.8 mg, 76%), mp 157-158 ºC. H NMR (400 MHz, CDCl3) δ:
3.77 (s, 3H), 3.80 (s, 3H), 6.70 (d, J = 6.8 Hz, 1H), 6.77 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 7.05 (d,
J = 7.2 Hz, 1H), 7.10 (s, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 9.53 (br s, 1H). 13C
NMR (100 MHz, CDCl3) δ: 55.4, 55.5, 103.4, 106.2, 109.9, 111.2, 112.6, 121.1, 121.3, 130.3,
141.2, 152.4, 159.1, 160.7, 166.3. HRMS calcd for C15H15N2O2S: 287.0849 [M+H]+, found:
287.0854.
5-Fluoro-N-(3-fluorophenyl)benzo[d]thiazol-2-amine (3h): Eluent: petroleum ether/ethyl acetate
(10:1); white solid (95.6 mg, 73%), mp 177-179 ºC. 1H NMR (600 MHz, DMSO-d6) δ: 6.84 (t, J =
7.8 Hz, 1H), 7.03 (t, J = 9.0 Hz, 1H), 7.36-7.49 (m, 3H), 7.80-7.83 (m,1H), 7.90 (d, J = 12.0 Hz,
1H ), 10.79 (s, 1H). 13C NMR (150 MHz, DMSO-d6) δ: 105.3 (d, 2JC-F = 26.3 Hz), 106.6 (d, 2JC-F
=
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25.1 Hz), 109.0 (d, JC-F = 20.9 Hz), 110.5 (d, JC-F = 24.2 Hz), 114.2, 122.5 (d, JC-F = 9.8 Hz),
126.1, 130.9 (d, 3JC-F = 8.9 Hz), 142.5 (d, 3JC-F = 10.8 Hz), 153.5 (d, 3JC-F = 12.0 Hz), 161.9 (d, 1JC-
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= 237.5 Hz), 163.0 (d, JC-F = 239.6 Hz), 164.0. F NMR (565 MHz, DMSO-d6) δ: -111.54, -
F
116.69. HRMS calcd for C13H9F2N2S: 263.0449 [M+H]+ , found: 263.0459.
4-Methyl-N-(o-tolyl)benzo[d]thiazol-2-amine (3i): Eluent: petroleum ether/ethyl acetate (10:1);
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white solid (114.5 mg, 90%), mp 131-133 ºC (lit.18 130-132 ºC). H NMR (400 MHz, CDCl3) δ:
2.26 (s, 3H), 2.39 (s, 3H), 6.97 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 7.17 (t, J = 7.6 Hz,
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1H), 7.23-7.27 (m, 2H), 7.37 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 8.83 (br s, 1H). C
NMR (100 MHz, CDCl3) δ: 17.9, 18.3, 118.4, 122.0, 124.9, 126.7, 126.9, 127.3, 128.8, 130.0,
131.3, 133.1, 138.7, 151.0, 167.0. MS: m/z 255 [M+H]+.
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4-Chloro-N-(2-chlorophenyl)benzo[d]thiazol-2-amine (3j): Eluent: petroleum ether/ethyl acetate
(30:1); white solid (82.3 mg, 56%), mp 116-118 ºC. 1H NMR (400 MHz, CDCl3) δ: 6.97-7.03 (m,
2H), 7.24-7.34 (m, 3H), 7.43 (dd, J1 = 7.6 Hz, J2 = 0.8 Hz, 1H), 7.86 (s, 1H), 8.16 (d, J = 8.4 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ: 119.3, 120.3, 123.4, 123.8, 124.7, 126.6, 128.1, 129.7, 131.5,
136.3, 148.7, 162.9. HRMS calcd for C13H9Cl2N2S: 294.9858 [M+H]+ , found: 294.9866.
N-(Naphthalen-1-yl)naphtho[1,2-d]thiazol-2-amine (3k): Eluent: petroleum ether/ethyl acetate
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(10:1); purple solid (127.3 mg, 78%), mp 179-181 ºC. H NMR (600 MHz, DMSO-d6) δ: 7.45-
7.63 (m, 6H), 7.70 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.90 (t, J = 7.8 Hz, 2H), 8.34 (d, J
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= 7.8 Hz, 1H), 8.43 (d, J = 6.0 Hz, 1H), 8.50 (d, J = 8.4 Hz, 1H), 10.56 (s, 1H). C NMR (100
MHz, CDCl3) δ: 118.7, 121.6, 121.9, 122.6, 123.7, 125.2, 125.5, 125.9, 126.0, 126.70, 126.74,
126.8, 127.1, 128.0, 128.7, 128.9, 132.2, 134.7, 136.0, 147.5, 168.3. HRMS calcd for C21H15N2S:
327.0950 [M+H]+, found: 327.0951.
N-Propylbenzo[d]thiazol-2-amine (3l): Eluent: petroleum ether/ethyl acetate (10:1); white solid
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(65.4 mg, 68%), mp 77-78 ºC (lit.6 79-80 ºC). H NMR (400 MHz, DMSO-d6) δ: 0.94 (t, J = 7.2
Hz, 3H), 1.57-1.66 (m, 2H), 3.32 (q, J = 6.4 Hz, 2H), 7.00 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 8.0 Hz,
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1H), 7.38 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 8.01 (t, J = 4.8 Hz, 1H). C NMR (150
MHz, DMSO-d6) δ: 11.9, 22.5, 46.2, 118.4, 121.2, 121.3, 125.9, 130.7, 153.2, 166.6. MS: m/z 193
[M+H]+.
6-Methyl-N-propylbenzo[d]thiazol-2-amine (3m): Eluent: petroleum ether/ethyl acetate (10:1);
white solid (77.4 mg, 75%), mp 109-110 ºC. 1H NMR (400 MHz, DMSO-d6) δ: 0.92 (t, J = 7.2 Hz,
3H), 1.55-1.64 (m, 2H), 2.30 (s, 3H), 3.29 (q, J = 6.8 Hz, 2H), 7.00 (d, J = 8.4 Hz, 1H), 7.26 (d, J
= 8.0 Hz, 1H), 7.42 (s, 1H), 7.88 (t, J = 5.2 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 11.4, 20.7,
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22.0, 45.7, 117.5, 120.8, 126.4, 129.7, 130.3, 150.6, 165.5. HRMS calcd for C11H15N2S: 207.0950
[M+H]+, found: 207.0950.
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6-Methoxy-N-propylbenzo[d]thiazol-2-amine (3n): Eluent: petroleum ether/ethyl acetate (10:1);
white solid (78.9 mg, 71%), mp 205-206 ºC. 1H NMR (400 MHz, DMSO-d6) δ: 0.93 (t, J = 7.2 Hz,
3H), 1.56-1.65 (m, 2H), 3.29 (q, J = 6.4 Hz, 2H), 3.74 (s, 3H), 6.82 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz,
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1H), 7.28-7.30 (m, 2H), 7.78 (t, J = 4.8 Hz, 1H). C NMR (100 MHz, DMSO-d6) δ: 11.4, 22.0,
45.7, 55.5, 105.5, 112.8, 118.2, 131.2, 146.8, 154.2, 164.6. HRMS calcd for C11H15N2OS:
223.0900 [M+H]+, found: 223.0876.
6-Chloro-N-propylbenzo[d]thiazol-2-amine (3o): Eluent: petroleum ether/ethyl acetate (10:1);
white solid (70.3 mg, 62%), mp 124-126 ºC. 1H NMR (400 MHz, DMSO-d6) δ: 0.93 (t, J = 7.2 Hz,
3H), 1.56-1.65 (m, 2H), 3.32 (q, J = 6.4 Hz, 2H), 7.22 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1H), 7.35 (d, J
= 8.8 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 8.14 (t, J = 5.2 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
δ: 11.3, 21.9, 45.7, 118.7, 120.5, 124.4, 125.6, 131.9, 151.6, 166.7. HRMS calcd for C10H12ClN2S:
227.0404 [M+H]+, found: 227.0414.
N-Benzylbenzo[d]thiazol-2-amine (3p): Eluent: petroleum ether/ethyl acetate (10:1); white solid
(73.3 mg, 61%), mp 157-158 ºC (lit.17 160-161 ºC). 1H NMR (400 MHz, DMSO-d6) δ: 4.60 (d, J =
6.0 Hz, 2H), 7.02 (t, J = 7.6 Hz, 1H), 7.19-7.28 (m, 2H), 7.33-7.39 (m, 5H), 7.66 (d, J = 8.0 Hz,
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1H), 8.50 (t, J = 5.6 Hz, 1H). C NMR (100 MHz, DMSO-d6) δ: 47.2, 118.1, 120.92, 120.95,
125.5, 127.0, 127.4, 128.4, 130.4, 138.9, 152.4, 166.2. MS: m/z 241 [M+H]+.
N-Benzyl-6-methoxybenzo[d]thiazol-2-amine (3q): Eluent: petroleum ether/ethyl acetate (10:1);
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white solid (90.6 mg, 67%), mp 133-134 ºC (lit.7b 136-136.5 ºC). H NMR (400 MHz, CDCl3) δ:
3.78 (s, 3H), 4.58 (s, 2H), 6.49 (br s, 1H), 6.84 (dd, J1 = 8.8 Hz, J2 = 2.8 Hz, 1H), 7.09 (d, J = 2.0
Hz, 1H), 7.26-7.39 (m, 6H). 13C NMR (100 MHz, CDCl3) δ: 49.4, 55.9, 105.4, 113.6, 119.2, 127.7,
127.8, 128.8, 131.4, 137.7, 146.5, 155.2, 166.2. MS: m/z 271 [M+H]+.
N-Benzyl-6-chlorobenzo[d]thiazol-2-amine (3r): Eluent: petroleum ether/ethyl acetate (10:1);
white solid (82.4 mg, 60%), mp 204-205 ºC (lit.19 207-208 ºC). 1H NMR (400 MHz, DMSO-d6) δ:
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= 5.6 Hz, 1H). C NMR (100 MHz, DMSO-d6) δ: 47.2, 118.9, 120.6, 124.7, 125.6, 127.1, 127.4,
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128.4, 132.1, 138.7, 151.4, 166.8. MS: m/z 275 [M+H]+.
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N-Benzyl-6-bromobenzo[d]thiazol-2-amine (3s): Eluent: petroleum ether/ethyl acetate (10:1);
white solid (87.8 mg, 55%), mp 210-211 ºC. 1H NMR (400 MHz, DMSO-d6) δ: 4.59 (d, J = 6.0 Hz,
2H), 7.25-7.38 (m, 7H), 7.91 (s, 1H), 8.63 (t, J = 5.6 Hz, 1H). 13C NMR (150 MHz, DMSO-d6) δ:
47.7, 112.8, 120.0, 123.9, 127.6, 127.9, 128.9, 133.1, 139.1, 152.2, 167.3. HRMS calcd for
C14H12BrN2S: 318.9905 [M+H]+, found: 318.9899.
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N-Benzyl-6-(trifluoromethyl)benzo[d]thiazol-2-amine (3t): Eluent: petroleum ether/ethyl acetate
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(10:1); white solid (77.1 mg, 50%), mp 195-196 ºC (lit.9 192.5- 194.7 ºC). H NMR (400 MHz,
DMSO-d6) δ: 4.65 (d, J = 5.6 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H), 7.34-7.41 (m, 4H), 7.50-7.55 (m,
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2H), 8.14 (s, 1H), 8.89 (t, J = 5.6 Hz, 1H). C NMR (100 MHz, DMSO-d6) δ: 47.3, 117.9, 118.6
(q, 3JC-F = 3.6 Hz), 121.1 (q, 2JC-F = 32.0 Hz), 122.6 (q, 3JC-F = 3.6 Hz), 124.8 (q, 1JC-F = 269.9 Hz),
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127.2, 127.4, 128.4, 131.1, 138.4, 155.4, 168.8. F NMR (565 MHz, DMSO-d6) δ: -59.20. MS:
m/z 309 [M+H]+.
N-Benzyl-4-methylbenzo[d]thiazol-2-amine (3u): Eluent: petroleum ether/ethyl acetate (10:1);
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white solid (94.1 mg, 74%), mp 110-112 ºC (lit.7b 112-113 ºC). H NMR (400 MHz, CDCl3) δ:
2.53 (s, 3H), 4.53 (s, 2H), 6.43 (br s, 1H), 6.96 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 7.2 Hz, 1H), 7.23-
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7.33 (m, 5H), 7.38 (d, J = 7.6 Hz, 1H). C NMR (100 MHz, CDCl3) δ: 18.5, 49.6, 118.4, 121.5,
126.8, 127.6, 127.8, 128.7, 128.8, 130.3, 137.7, 151.4, 167.2. MS: m/z 255 [M+H]+.
N-Benzyl-4-chlorobenzo[d]thiazol-2-amine (3v): Eluent: petroleum ether/ethyl acetate (10:1);
white solid (68.7 mg, 50%), mp 126-128 ºC. 1H NMR (400 MHz, DMSO-d6) δ: 4.62 (d, J = 5.6 Hz,
2H), 7.01 (t, J = 7.6 Hz, 1H), 7.26-7.32 (m, 2H), 7.36 (t, J = 7.2 Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H),
7.65 (d, J = 8.0 Hz, 1H), 8.83 (t, J = 5.2 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 47.5, 119.9,
121.58, 121.63, 125.7, 127.2, 127.6, 128.4, 131.7, 138.4, 149.1, 167.0. HRMS calcd for
C14H12ClN2S: 275.0404 [M+H]+ , found: 275.0395.
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N-Benzyl-4-bromobenzo[d]thiazol-2-amine (3w): Eluent: petroleum ether/ethyl acetate (10:1);
white solid (87.8 mg, 55%), mp 131-132 ºC. 1H NMR (400 MHz, DMSO-d6) δ: 4.60 (d, J = 6.0 Hz,
2H), 6.93 (t, J = 8.0 Hz, 1H), 7.25-7.29 (m, 1H), 7.35 (t, J = 8.0 Hz, 2H), 7.41-7.45 (m, 3H), 7.67
(d, J = 7.6 Hz, 1H), 8.84 (br s, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 47.5, 110.7, 120.4, 122.0,
127.2, 127.7, 128.4, 128.7, 131.1, 138.4, 150.4, 166.6. HRMS calcd for C14H12BrN2S: 318.9899
[M+H]+, found: 318.9889.
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N-(3-Fluorobenzyl)benzo[d]thiazol-2-amine (3x): Eluent: petroleum ether/ethyl acetate (10:1);
white solid (72.3 mg, 56%), mp 141-143 ºC. 1H NMR (400 MHz, CDCl3) δ: 4.62 (s, 2H), 6.98 (t, J
= 8.0 Hz, 1H), 7.05-7.12 (m, 2H), 7.17 (d, J = 7.2 Hz, 2H), 7.23-7.32 (m, 2H), 7.37 (d, J = 8.0 Hz,
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1H), 7.56 (d, J = 8.0 Hz, 1H). C NMR (100 MHz, CDCl3) δ: 48.8 (d, JC-F = 2.1 Hz), 114.5 (d,
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2JC-F = 21.8 Hz), 114.7 (d, JC-F = 21.1 Hz), 118.8, 120.9, 121.7, 123.1 (d, JC-F = 3.0 Hz), 126.1,
130.3, 130.4 (d, 3JC-F = 8.7 Hz), 140.2 (d, 3JC-F = 6.6 Hz), 152.1, 163.1 (d, 1JC-F = 245.2 Hz), 167.9.
19F NMR (565 MHz, CDCl3) δ: -112.36. HRMS calcd for C14H12FN2S: 259.0700 [M+H]+, found:
259.0707.
N-(2-Methylbenzyl)benzo[d]thiazol-2-amine (3y): Eluent: petroleum ether/ethyl acetate (10:1);
yellowish solid (67.4 mg, 53%), mp 154-155 ºC (lit.7b 157- 158 ºC). 1H NMR (400 MHz, CDCl3) δ:
2.36 (s, 3H), 4.58 (s, 2H), 6.60 (br s, 1H), 7.05 (t, J = 7.6 Hz, 1H), 7.15-7.25 (m, 4H), 7.33-7.36
(m, 2H), 7.55 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 19.1, 47.6, 118.8, 120.9, 121.5,
126.0, 126.4, 128.1, 128.5, 130.3, 130.7, 135.2, 136.6, 152.3, 167.6. MS: m/z 255 [M+H]+.
N-(2-Chlorobenzyl)benzo[d]thiazol-2-amine (3z): Eluent: petroleum ether/ethyl acetate (10:1);
white solid (76.9 mg, 56%), mp 134-135 ºC (lit.20 134.7-135.2 ºC). 1H NMR (400 MHz, CDCl3) δ:
4.71 (s, 2H), 7.03-7.08 (m, 2H), 7.17-7.25 (m, 3H), 7.36-7.40 (m, 2H), 7.47-7.50 (m, 1H), 7.54 (d,
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J = 8.0 Hz, 1H). C NMR (100 MHz, CDCl3) δ: 47.1, 118.8, 120.9, 121.6, 126.0, 127.1, 129.1,
129.5, 129.7, 130.4, 133.6, 135.1, 152.2, 167.9. MS: m/z 275 [M+H]+.
N-(1-Phenylethyl)benzo[d]thiazol-2-amine (3aa): Eluent: petroleum ether/ethyl acetate (10:1);
white solid (77.6 mg, 61%), mp 131-132 ºC (lit.7b 132- 134 ºC). 1H NMR (400 MHz, DMSO-d6) δ:
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(m, 3H), 7.42 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 7.6 Hz, 1H), 8.54 (d, J = 7.6 Hz, 1H). C NMR
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(100 MHz, DMSO-d6) δ: 23.1, 53.4, 118.1, 120.8, 120.9, 125.5, 126.0, 126.8, 128.3, 130.3, 144.4,
152.5, 165.3. MS: m/z 255 [M+H]+.
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6-Methyl-N-(1-phenylethyl)benzo[d]thiazol-2-amine (3bb): Eluent: petroleum ether/ethyl
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acetate (10:1); yellowish solid (85.9 mg, 64%), mp 106-107 ºC. H NMR (400 MHz, CDCl3) δ:
1.57 (d, J = 6.8 Hz, 3H), 2.33 (s, 3H), 4.73 (q, J = 6.8 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 7.09 (br s,
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1H), 7.21-7.26 (m, 1H), 7.28-7.32 (m, 3H), 7.35-7.38 (m, 3H). C NMR (100 MHz, CDCl3) δ:
21.2, 23.8, 55.6, 118.4, 120.9, 126.2, 127.1, 127.6, 128.8, 130.7, 131.1, 143.3, 149.9, 167.1.
HRMS calcd for C16H17N2S: 269.1107 [M+H]+, found: 269.1112.
6-Methoxy-N-(1-phenylethyl)benzo[d]thiazol-2-amine (3cc): Eluent: petroleum ether/ethyl
acetate (10:1); white solid (82.5 mg, 58%), mp 125-127 ºC. 1H NMR (400 MHz, CDCl3) δ: 1.59 (d,
J = 6.4 Hz, 3H), 3.76 (s, 3H), 4.76 (q, J = 6.8 Hz, 1H), 6.68 (br s, 1H), 6.85 (dd, J1 = 8.8 Hz, J2 =
2.4 Hz, 1H), 7.06 (d, J = 2.8 Hz, 1H), 7.24-7.27 (m, 1H), 7.32 (t, J = 7.2 Hz, 2H), 7.38 (d, J = 8.4
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 23.8, 55.5, 55.9, 105.4, 113.5, 119.2, 126.2, 127.6, 128.8,
131.6, 143.2, 146.3, 155.0, 165.9. HRMS calcd for C16H17N2OS: 285.1056 [M+H]+, found:
285.1054.
N-(1-Phenylethyl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine (3dd): Eluent: petroleum ether/
ethyl acetate (10:1); yellowish solid (66.1 mg, 41%), mp 120-122 ºC. 1H NMR (400 MHz, CDCl3)
δ: 1.63 (d, J = 6.8 Hz, 3H), 4.78 (q, J = 6.4 Hz, 1H), 7.21-7.39 (m, 6H), 7.48 (s, 2H), 7.78 (s, 1H).
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13C NMR (100 MHz, CDCl3) δ: 23.5, 55.8, 118.3 (q, JC-F = 3.6 Hz), 118.5, 123.2 (q, JC-F = 3.6
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Hz), 123.4 (q, JC-F = 32.8 Hz), 124.6 (q, JC-F = 269.9 Hz), 126.1, 127.9, 128.9, 130.7, 142.3,
154.5, 169.5. 19F NMR (565 MHz, CDCl3) δ: -60.94. HRMS calcd for C16H14F3N2S: 323.0824
[M+H]+, found: 323.0833.
4-Methyl-N-(1-phenylethyl)benzo[d]thiazol-2-amine (3ee): Eluent: petroleum ether/ethyl
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acetate (10:1); yellowish oil (91.2 mg, 68%). H NMR (400 MHz, CDCl3) δ: 1.52 (d, J = 6.8 Hz,
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3H), 2.55 (s, 3H), 4.70 (q, J = 6.4 Hz, 1H), 6.16 (br s, 1H), 6.93 (t, J = 7.6 Hz, 1H), 7.07 (d, J =
7.2 Hz, 1H), 7.21-7.24 (m, 1H), 7.29 (t, J = 7.6 Hz, 2H), 7.34 (d, J = 7.6 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ: 18.5, 23.6, 55.6, 118.4, 121.4, 126.2, 126.8, 127.7, 128.7, 128.8, 130.5, 143.0,
151.1, 166.3. HRMS calcd for C16H17N2S: 269.1107 [M+H]+, found: 269.1111.
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N-(Naphthalen-1-ylmethyl)benzo[d]thiazol-2-amine (3ff): Eluent: petroleum ether/ethyl acetate
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(10:1); white solid (81.3 mg, 56%), mp 148-149 ºC (lit.20 150.1- 150.8 ºC). H NMR (400 MHz,
CDCl3) δ: 4.93 (s, 2H), 6.44 (br s, 1H), 6.97 (t, J = 7.6 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.28-7.32
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(m, 2H), 7.38-7.46 (m, 4H), 7.71 (d, J = 8.4 Hz, 1H), 7.76-7.78 (m, 1H), 7.91-7.93 (m, 1H). C
NMR (100 MHz, CDCl3) δ: 47.5, 118.9, 120.9, 121.6, 123.4, 125.5, 126.0, 126.1, 126.5, 126.7,
128.9, 130.4, 131.4, 132.6, 133.9, 152.3, 167.3. MS: m/z 291 [M+H]+.
3. A typical procedure for the synthesis of 5a and spectroscopic data of 5a-5j
To a 10 mL schlenk tube were added isothiocyanatobenzene (1a, 66 uL, 0.55 mmol),
morpholine (4a, 44 uL, 0.5 mmol), I2 (64.5 mg, 0.25 mmol) and PhCl (3 mL). The mixture was
then strirred at 120 ºC under an oxygen atmosphere for 14 h. Upon completion, the resulting
mixture was quenched with saturated aqueous solution of Na2S2O3 (10 mL), and extracted with
EtOAc (10 mL  3). The combined organic phase was washed with water and brine, dried over
anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column
chromatography on silica gel with petroleum ether/ethyl acetate (10:1) as the eluent to give 5a
(69.4 mg, 63%). 5b-5j were obtained in a similar manner.
4-(Benzo[d]thiazol-2-yl)morpholine (5a): Eluent: petroleum ether/ethyl acetate (10:1); white
solid (69.4 mg, 63%), mp 117-118 ºC (lit.7b 119-120 ºC). 1H NMR (400 MHz, CDCl3) δ: 3.62 (t, J
= 4.8 Hz, 4H), 3.83 (t, J = 4.8 Hz, 4H), 7.10 (t, J = 7.6 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.56-7.62
(m, 2H). 13C NMR (100 MHz, CDCl3) δ: 48.5, 66.3, 119.4, 120.8, 121.7, 126.1, 130.6, 152.5,
169.0. MS: m/z 221 [M+H]+.
4-(4-Methylbenzo[d]thiazol-2-yl)morpholine (5b): Eluent: petroleum ether/ethyl acetate (10:1);
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white solid (68.0 mg, 58%), mp 140-142 ºC (lit.18 143-146 ºC). H NMR (400 MHz, CDCl3) δ:
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7.6 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H). C NMR (100 MHz, CDCl3) δ: 18.2, 48.5, 66.3, 118.2,
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121.5, 126.8, 129.3, 130.5, 151.6, 168.1. MS: m/z 235 [M+H]+.
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2-Thiomorpholinobenzo[d]thiazole (5c): Eluent: petroleum ether/ethyl acetate (10:1); white
solid (57.9 mg, 49%), mp 92-94 ºC (lit.21 92-93 ºC). 1H NMR (400 MHz, CDCl3) δ: 2.73-2.76 (m,
4H), 3.95-3.98 (m, 4H), 7.08 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H),
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7.60 (d, J = 7.6 Hz, 1H). C NMR (100 MHz, CDCl3) δ: 26.6, 51.2, 119.1, 120.7, 121.6, 126.1,
130.7, 152.6, 168.1. MS: m/z 237 [M+H]+.
4-Methyl-2-thiomorpholinobenzo[d]thiazole (5d): Eluent: petroleum ether/ethyl acetate (10:1);
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yellowish solid (65.1 mg, 52%), mp 80-82 ºC. H NMR (400 MHz, CDCl3) δ: 2.55 (s, 3H), 2.72-
2.75 (m, 4H), 3.95-3.97 (m, 4H), 6.98 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 7.2 Hz, 1H), 7.43 (d, J = 7.6
Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 18.3, 26.6, 51.1, 118.1, 121.4, 126.8, 129.1, 130.5, 151.7,
167.2. HRMS calcd for C12H15N2S2: 251.0671 [M+H]+, found: 251.0687.
2-(Pyrrolidin-1-yl)benzo[d]thiazole (5e): Eluent: petroleum ether/ethyl acetate (10:1); white
solid (56.2 mg, 55%), mp 101-102 ºC (lit.22 102-103 ºC). 1H NMR (400 MHz, CDCl3) δ: 2.03-2.07
(m, 4H), 3.56 (t, J = 6.0 Hz, 4H), 7.03 (t, J = 7.2 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 7.6
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Hz, 2H). C NMR (100 MHz, CDCl3) δ: 25.7, 49.5, 118.7, 120.66, 120.69, 125.9, 130.8, 153.4,
165.4. MS: m/z 205 [M+H]+.
2-(Piperidin-1-yl)benzo[d]thiazole (5f): Eluent: petroleum ether/ethyl acetate (10:1); white solid
(52.4 mg, 48%), mp 94-95 ºC (lit.22 95-98 ºC). 1H NMR (400 MHz, CDCl3) δ: 1.68 (s, 6H), 3.58-
3.60 (m, 4H), 7.04 (t, J = 7.6 Hz, 1H), 7.25-7.29 (m, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0
Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 24.3, 25.3, 49.6, 118.8, 120.6, 121.1, 125.9, 130.7, 153.0,
168.9. MS: m/z 219 [M+H]+.
8-(Benzo[d]thiazol-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane (5g): Eluent: petroleum ether/ethyl
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acetate (10:1); white solid (70.5 mg, 51%), mp 117-119 ºC (lit.7a 118.5-121 ºC). H NMR (400
MHz, CDCl3) δ: 1.84 (t, J = 5.6 Hz, 4H), 3.75 (t, J = 5.6 Hz, 4H), 4.00 (s, 4H), 7.07 (t, J = 8.0 Hz,
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1H), 7.26-7.31 (m, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H). C NMR (100 MHz,
CDCl3) δ: 34.4, 46.8, 64.5, 106.9, 119.0, 120.7, 121.4, 126.0, 131.0, 152.9, 168.3. MS: m/z 277
[M+H]+.
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8-(6-Methoxybenzo[d]thiazol-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane (5h): Eluent: petroleum
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ether/ethyl acetate (10:1); yellowish solid (95.0 mg, 62%), mp 104-106 ºC. H NMR (400 MHz,
CDCl3) δ: 1.83 (t, J = 5.6 Hz, 4H), 3.71 (t, J = 5.6 Hz, 4H), 3.81 (s, 3H), 4.00 (s, 4H), 6.89 (dd, J1
= 8.8 Hz, J2 = 2.4 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ: 34.3, 46.8, 55.9, 64.5, 105.2, 107.0, 113.6, 119.4, 132.0, 147.1, 155.0, 166.9. HRMS
calcd for C15H19N2O3S: 307.1111 [M+H]+, found: 307.1110.
4-(4-Chlorobenzo[d]thiazol-2-yl)morpholine (5i): Eluent: petroleum ether/ethyl acetate (10:1);
white solid (67.5 mg, 53%), mp 110-112 ºC (lit.7f 112-113 ºC). H NMR (400 MHz, CDCl3) δ:
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7.48 (d, J = 8.0 Hz, 1H). C NMR (150 MHz, CDCl3) δ: 48.4, 66.2, 119.3, 122.0, 123.7, 126.4,
131.8, 149.6, 169.0. MS: m/z 255 [M+H]+.
4-(4-Bromobenzo[d]thiazol-2-yl)morpholine (5j): Eluent: petroleum ether/ethyl acetate (10:1);
yellow solid (73.3 mg, 49%), mp 79-80 ºC (lit.7f 81-85 ºC). 1H NMR (400 MHz, CDCl3) δ: 3.64 (t,
J = 5.2 Hz, 4H), 3.82 (t, J = 4.8 Hz, 4H), 6.93 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.52 (d,
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J = 7.6 Hz, 1H). C NMR (150 MHz, CDCl3) δ: 48.4, 66.2, 112.5, 119.9, 122.4, 129.5, 131.1,
150.8, 168.6. MS: m/z 299, 301 [M+H]+.
4. Control experiments (I)
4.1. To a 10 mL reaction tube were added 1a (66 uL, 0.55 mmol), 2a (46 uL, 0.5 mmol) and PhCl
(3 mL). The tube was then sealed, and the mixture was stirred at 70 ºC for 2 h. Upon completion,
the resulting mixture was evaporated under reduced pressure, and the residue was purified by
column chromatography on silica gel with petroleum ether/ethyl acetate (3:1) as the eluent to give
A (105.0 mg, 92%).
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1,3-Diphenylthiourea (A): Eluent: petroleum ether/ethyl acetate (3:1); white solid (105.0 mg,
92%), mp 153-154 ºC (lit.23 154-155 ºC). 1H NMR (400 MHz, CDCl3) δ: 7.17-7.21 (m, 2H), 7.29-
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7.34 (m, 8H), 8.07 (br s, 2H). C NMR (100 MHz, CDCl3) δ: 125.3, 127.1, 129.6, 137.2, 179.8.
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MS: m/z 229 [M+H]+.
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4.2. To a 10 mL schlenk tube were added A (114.2 mg, 0.5 mmol), I2 (25.4 mg, 0.1 mmol) and
PhCl (3.0 mL). Then, the mixture was strirred at 120 ºC under an oxygen atmosphere for 10 h.
Upon completion, the resulting mixture was quenched with saturated aqueous solution of Na2S2O3
(10 mL), and extracted with EtOAc (10 mL  3). The combined organic phase was washed with
water and brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The
residue was purified by column chromatography on silica gel with petroleum ether/ethyl acetate
(10:1) as the eluent to give 3a (101.8 mg, 90%).
5. Control experiments (II)
5.1. To a 10 mL schlenk tube were added A (114.2 mg, 0.5 mmol), I2 (25.4 mg, 0.1 mmol), BHT
(220.4 mg, 1.0 mmol) and PhCl (3 mL). The mixture was then strirred at 120 ºC under an oxygen
atmosphere for 10 h. Upon completion, the resulting mixture was quenched with saturated aqueous
solution of Na2S2O3 (10 mL), and extracted with EtOAc (10 mL  3). The combined organic phase
was washed with water and brine, dried over anhydrous Na2SO4, and evaporated under reduced
pressure. The residue was purified by column chromatography on silica gel with petroleum
ether/ethyl acetate (10:1) as the eluent to give 3a (97.3 mg, 86%).
5.2. To a 10 mL schlenk tube were added isothiocyanatobenzene (1a, 66 uL, 0.55 mmol), aniline
(2a, 46 uL, 0.5 mmol), I2 (25.4 mg, 0.1 mmol), BHT (220.4 mg, 1.0 mmol) and PhCl (3 mL). The
mixture was then strirred at 120 ºC under an oxygen atmosphere for 12 h. Upon completion, the
resulting mixture was quenched with saturated aqueous solution of Na2S2O3 (10 mL), and
extracted with EtOAc (10 mL  3). The combined organic phase was washed with water and brine,
dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by
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column chromatography on silica gel with petroleum ether/ethyl acetate (10:1) as the eluent to
give 3a (90.5 mg, 80%).
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To a 10 mL schlenk tube were added 1,3-bis(4-methoxyphenyl)thiourea (6, 144.2 mg, 0.5
mmol), 1,3-bis(4-(trifluoromethyl)phenyl)thiourea (7, 182.2 mg, 0.5 mmol), I2 (25.4 mg, 0.1 mmol)
and PhCl (5 mL). The mixture was then strirred at 120 ºC under an oxygen atmosphere for 4 h.
Then, the resulting mixture was quenched with saturated aqueous solution of Na2S2O3 (10 mL),
and extracted with EtOAc (10 mL  3). The combined organic phase was washed with water and
brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel with petroleum ether/ethyl acetate (10:1) as the
eluent to give 3c (53.0 mg, 37%).
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7. An intramolecular competing experiment
To a 10 mL schlenk tube were added 1-(4-methoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-
thiourea (8, 163.2 mg, 0.5 mmol), I2 (25.4 mg, 0.1 mmol) and PhCl (3 mL). The mixture was then
strirred at 120 ºC under an oxygen atmosphere for 4 h. Then, the resulting mixture was quenched
with saturated aqueous solution of Na2S2O3 (10 mL), and extracted with EtOAc (10 mL  3). The
combined organic phase was washed with water and brine, dried over anhydrous Na2SO4, and
evaporated under reduced pressure. The residue was purified by column chromatography on silica
gel with petroleum ether/ethyl acetate (10:1) as the eluent to give 9 (61.6 mg, 38%).
6-Methoxy-N-(4-(trifluoromethyl)phenyl)benzo[d]thiazol-2-amine (9): Eluent: petroleum ether/
ethyl acetate (10:1); white solid (61.6 mg, 38%), mp 182-183 ºC. 1H NMR (400 MHz, DMSO-d6)
δ: 3.79 (s, 3H), 6.96 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 7.49 (s, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.70
13
(d, J = 8.8 Hz, 2H), 7.95 (d, J = 8.8 Hz, 2H), 10.72 (s, 1H). C NMR (100 MHz, DMSO-d6) δ:
2
55.6, 105.3, 113.8, 117.1, 120.1, 121.4 (q, JC-F = 32.0 Hz), 124.6 (q, 1JC-F = 269.8 Hz), 126.3 (q,
3JC-F = 3.7 Hz), 131.3, 144.0, 145.7, 155.6, 159.2. 19F NMR (565 MHz, DMSO-d6) δ: -59.98.
HRMS calcd for C15H12F3N2OS: 325.0617 [M+H]+, found: 325.0619.
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8. Gram-scale synthesis of 3a
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5
To a 50 mL round-bottom flask were added 1a (1.31 mL, 11 mmol), 2a (0.91 mL, 10 mmol), I2
6
7
8
o
(0.51 g, 2 mmol) and PhCl (25 mL). The mixture was then strirred at 120 C under an oxygen
9
atmosphere for 12 h. Upon completion, the resulting mixture was quenched with saturated aqueous
solution of Na2S2O3 (10 mL), and extracted with EtOAc (10 mL  3). The combined organic phase
was washed with water and brine, dried over anhydrous Na2SO4, and evaporated under reduced
pressure. The residue was purified by column chromatography on silica gel with petroleum
ether/ethyl acetate (10:1) as the eluent to give 3a (1.60 g, 71%).
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Acknowledgments. We are grateful to the National Natural Science Foundation of China (NSFC)
(grant number 21572047), Program for Innovative Research Team in Science and Technology in
Universities of Henan Province (15IRTSTHN003), and Program for Science and Technology
Innovation Talents in Universities of Henan Province (15HASTIT005) for financial support.
Supporting Information. Copies of 1H, 13C and 19F NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
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