Switchable and Scalable Heteroarylation of Primary Amines with 2-Chlorobenzothiazoles under Transition-Metal-Free and Solvent-Free Conditions

Article abstract of DOI:10.1021/acs.joc.1c01019

2-Aminobenzothiazoles comprise a valuable structural motif, which prevails in versatile natural products and biologically active compounds. Herein, a switchable and scalable C-N coupling protocol was developed for the synthesis of these compounds from 2-chlorobenzothiazoles and primary amines. Gratifyingly, this protocol was achieved under transition-metal-free and solvent-free conditions. Moreover, introducing an appropriate amount of NaH completely switched the selectivity from mono- toward di-heteroarylation, and further investigations provided a rationale for this new finding. Furthermore, gram-scale synthesis of representative products 3a and 4a was realized by applying operationally simple and glovebox-free procedures, which revealed the practical usefulness of this work. Finally, evaluation of the quantitative green metrics provided evidence that our protocol was superior over the literature ones in terms of green chemistry and sustainability.

Full text of DOI:10.1021/acs.joc.1c01019

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Article
Switchable and Scalable Heteroarylation of Primary Amines with
2‑Chlorobenzothiazoles under Transition-Metal-Free and Solvent-
Free Conditions
Hua Cheng,⊥ Yan-Qiu Zhu,⊥ Peng-Fei Liu, Kai-Qiang Yang, Jin Yan, Wei Sang, Xiao-Sheng Tang,
Rui Zhang,* and Cheng Chen*
Cite This: J. Org. Chem. 2021, 86, 10288−10302
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Supporting Information
ACCESS
ABSTRACT: 2-Aminobenzothiazoles comprise a valuable structural
motif, which prevails in versatile natural products and biologically active
compounds. Herein, a switchable and scalable C−N coupling protocol was
developed for the synthesis of these compounds from 2-chlorobenzothia-
zoles and primary amines. Gratifyingly, this protocol was achieved under
transition-metal-free and solvent-free conditions. Moreover, introducing an
appropriate amount of NaH completely switched the selectivity from
mono- toward di-heteroarylation, and further investigations provided a
rationale for this new finding. Furthermore, gram-scale synthesis of
representative products 3a and 4a was realized by applying operationally
simple and glovebox-free procedures, which revealed the practical
usefulness of this work. Finally, evaluation of the quantitative green
metrics provided evidence that our protocol was superior over the
literature ones in terms of green chemistry and sustainability.
halides,28−36 triflates,32 or triazenes37 efficiently afforded the
aminated products. Besides, treatment of amines with
unsubstituted benzothiazole38−42 or 2-substituted benzothia-
zoles43−52 also enabled the efficient formation of the desired
products (Scheme 1a). It was observed that all of the above
reactions went through one amination sequence to furnish the
mono-heteroarylation products. In our previous work, the
corresponding di-heteroarylation products, namely, tertiary
amines bearing two benzothiazole units, were selectively
prepared from 2-chlorobenzothiazoles and primary aromatic
amines for the first time. Interestingly, switchable mono- vs di-
heteroarylation was realized via a ligand-controlled Pd-
catalyzed strategy (Scheme 1b).53 Inspired by the above
work, we herein aimed to develop a greener and more
practical synthetic approach for these molecules. Gratifyingly,
a transition-metal-free and solvent-free protocol was obtained
to afford either mono- or di-heteroarylation products in a
selective manner (Scheme 1c). It was found that heating the
two reactants in the absence of any base or additive
INTRODUCTION
■
Benzothiazole and its derivatives are an important class of
heterocyclic compounds which have potential applications in
numerous areas such as organic chemistry, pharmaceutical
industry, and materials science.1−4 Among these compounds,
2-aminobenzothiazoles have been widely distributed in a
number of bioactive molecules.5 For example, riluzole is an
antispasmodic drug mainly used for prolonging the life of
patients with amyotrophic lateral sclerosis (ALS).6,7 Talar-
ozole, an all-trans retinoic acid metabolism blocking agent
(RAMBA), can improve the level of endogenous all-trans
retinoic acid (RA) in cells. Accordingly, it is commonly used
as an effective drug to treat psoriasis, acne, and some other
keratinization disorders.8,9 Besides, compounds bearing the 2-
aminobenzothiazole unit also demonstrate anti-tobacco
mosaic virus (TMV) activity,10 antifungal activity,11 anti-
mosquito properties against Anopheles arabiensis,12 and
antibacterial activity.13 Due to the diverse biological and
pharmaceutical properties of 2-aminobenzothiazoles, expedi-
ent synthetic approaches have been developed for accessing
these compounds.
Received: April 30, 2021
Published: July 21, 2021
Among the versatile synthetic methods, we paid great
attention to traditional C−N cross-coupling strategies,14−25
which have been utilized to access 2-aminobenzothiazoles via
the direct functionalization of the benzothiazole framework.
For instance, the C−N cross-coupling of 2-aminobenzothia-
zole (or its derivatives) with boronic acids,26,27 aryl
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Scheme 1. Design Strategy of This Work: (a) Literature Reports; (b) Previous Work; and (c) This Work
exclusively gave rise to the mono-heteroarylation products,
whereas the involvement of an appropriate amount of NaH
completely switched the selectivity to the di-heteroarylation
counterparts. To further demonstrate the practical potential of
our protocol, we carried out gram-scale reactions and
optimized the workup procedures. It was also worth
emphasizing that the green metrics were calculated to be
superior over those of the literature approaches, which
implicated the green and sustainable aspects of the current
protocol.
tions were conducted (as listed in Table 1). To our delight,
Pd was found to be unnecessary for this coupling, with 59% of
4a, 12% of 3a, and 16% of unreacted 1a being observed in the
absence of a Pd salt (entry 1). Since organic solvents are the
major source of wastes in organic synthesis, we then
attempted the same reaction under a solvent-free condition
(entry 2). Interestingly, an even better result was obtained in
comparison with the toluene-containing reaction (entry 2 vs
entry 1). From the perspectives of green chemistry and
sustainability, we decided to continue the optimizations
without any solvent. Next, different bases were screened to
evaluate their effects on the reaction conversion and 4a/3a
selectivity (entries 3−20). Among various metal salts, stronger
RESULTS AND DISCUSSION
■
2-Chlorobenzothiazole (1a) and aniline (2a) were selected as
the two reactants for optimizations of the reaction conditions
(Table S1 in the Supporting Information, Table 1). Our
research commenced with the selected conditions in our
previous work (as listed in Table S1 in the Supporting
Information).53 In the presence of Pd(OAc)2, NaH, and
toluene, Xantphos (or an N-heterocyclic carbene precursor)
provided 3a (or 4a) as the major product (entries 1 and 2),
while a ligandless condition led to 51% of 4a and 5% of 3a
(entry 3). With an aim to identify a greener and more
practical protocol for this transformation, further optimiza-
bases including LDA (pKaH = 35.7), tert-butoxides (pKaH
=
17.0), and hydroxides (pKaH = 15.7) could deliver di-
heteroarylation product 4a to some extent, but they were
not as effective as NaH (entries 3−9 vs entry 2). In contrast,
weaker bases such as carbonates (pKaH = 10.3) and acetates
(pKaH = 4.76) mainly provided mono-heteroarylation product
3a in low to moderate yield (entries 10−15). Subsequently,
organic bases such as 2,2′-bipyridine (bpy), 1,10-phenanthro-
line (1,10-phen), pyridine (pyr), 1,4-diazabicyclo[2.2.2]octane
(DABCO), and diisopropylethylamine (DIPEA) were also
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a
Table 1. Optimization of Reaction Conditions
c
yield (%)
b
entry
base
NaH
NaH
pKaH
solvent
toluene
3a
4a
1a (mmol)
d
d
e
1
2
3
4
5
6
7
8
∼36
∼36
12
3
4
2
5
59
71
65
41
62
57
28
8
18
3
4
5
2
5
0
0
0
0
0
0
5
0.16
0.05
0.08
0.45
0.18
0.16
0.57
0.76
0.42
0.82
0.62
0.72
0.56
0.68
0.62
0.18
0.26
0.15
0.18
0.23
0.00
LDA
35.7
17.0
17.0
17.0
15.7
15.7
15.7
10.3
10.3
10.3
4.76
4.76
4.76
4.23
5.12
5.23
8.60
10.5
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
LiOtBu
NaOtBu
KOtBu
LiOH
NaOH
KOH
Na2CO3
K2CO3
Cs2CO3
LiOAc
NaOAc
KOAc
bpy
14
8
10
11
6
29
10
31
21
25
71
65
76
62
67
86
9
10
11
12
13
14
15
16
17
18
19
20
21
1,10-phen
pyr
DABCO
DIPEA
a
A mixture of 1a (1.00 mmol), 2a (1.00 mmol), a base (1.00 mmol) or no base, and solvent (2.5 mL) was heated at 120 °C under argon for 12 h.
b
c
pKaH represents the pKa values of the conjugate acids.54 NMR yield using 1,3,5-trimethoxybenzene as an internal standard (average of two
d
e
consistent runs). In tetrahydrofuran (THF). In water.
attempted (entries 16−20). It was found that only 3a could
be obtained in 62−76% yield, probably due to their weak
basicity (pKaH = 4.23−10.5), which could not stimulate the
proceeding of the second amination. To our delight, the C−N
coupling proceeded smoothly under the base-free condition,
affording 86% of 3a and 5% of 4a (entry 21). It was obvious
that the intrinsic basicity of the added bases was crucial for
this transformation. Moreover, they could also serve as
additives to interfere the interaction of the two reactants,
thus decreasing the viscosity of the reaction mixture so that
the reaction efficiency was affected. Therefore, it could be
more understandable that the stronger bases stimulated the
formation of di-heteroarylation product 4a (entries 2−9), and
the reaction without a base or additive was more efficient than
those promoted by the weaker bases (entry 21 vs entries 10−
20). Finally, the NaH-promoted and base-free conditions were
selected for further investigations, respectively (entries 2 and
21).
To attain either 3a or 4a in excellent yield, further
optimizations were conducted (as listed in Table 2). At the
outset, the ratios of 1a/2a were changed (entries 1−10). For
the base-free reactions, compared with the ratio of 1.00:1.00,
1.00:0.75−0.50 led to lower 3a/4a selectivity (entries 3−4),
whereas 1.00:1.25−1.50 exclusively provided 3a in excellent
yield (entries 5 and 6), with 1.00:1.25 being identified as the
optimized ratio (entry 5). In the case of the NaH-involving
reactions, gradually increasing the ratio from 1.00:1.00 to
1.50:0.50 facilitated the formation of 4a (entries 2, 7−10).
Specifically, the ratio of 1.25:0.50 was enough to reach the
maximum yield (entry 9). Subsequently, the effect of the
reaction temperatures was also investigated (entries 5, 9, 11−
14). About mono-heteroarylation, lowering the temperature
from 120 to 100 °C led to a comparable result (entry 11 vs
entry 5), while further reducing it to 80 °C gave rise to 3a in
only 68% yield (entry 12). Therefore, 100 °C was regarded as
the most suitable temperature for the selective formation of 3a
(entry 11). For di-heteroarylation, altering the reaction
temperature from 120 to 100 °C exclusively gave 4a, but
with a reduced yield of 78% (entry 13). Unfortunately, a
mixture of 3a and 4a was observed if an even lower
temperature of 80 °C was used (entry 14). These results
illustrated that selective formation of 3a or 4a was realized
under transition-metal-free and solvent-free conditions, with
entry 9 and entry 11 as the optimized conditions for the
mono- and di-heteroarylation, respectively.
After the optimized reaction conditions were achieved, the
substrate scope and limitation of this protocol were explored
(as shown in Scheme 2). At the beginning, the reactions of 1a
and various anilines were attempted. For the base-free
situation, electron-rich products 3b−f were delivered in
excellent yield, while electron-deficient counterparts 3g−n
were afforded in a lower yield of 45−85%. In particular, 4-
(trifluoromethyl)aniline (2l) and 4-aminobenzonitrile (2m)
produced desired products 3l and 3m in 62 and 45% yield,
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Table 2. Further Screening of Other Parameters
a
yield (%)
entry
x
y
base
T
3a
4a
1a (mmol)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.25
1.50
1.00
1.00
1.25
1.25
1.00
1.00
0.75
0.50
1.25
1.50
0.75
0.50
0.50
0.50
1.25
1.25
0.50
0.50
120
120
120
120
120
120
120
120
120
120
100
80
86
3
5
0.00
0.05
0.18
0.21
0.00
0.00
0.08
0.00
0.16
0.39
0.00
0.23
0.39
0.45
NaH
71
26
37
0
0
73
83
45
32
95
96
0
0
0
0
NaH
NaH
NaH
NaH
b
92 (90 )
92
0
0
78
52
b
95 (92 )
68
0
26
NaH
NaH
100
80
a
b
NMR yield using 1,3,5-trimethoxybenzene as an internal standard (average of two consistent runs). Isolated yield.
respectively. It seemed that para substituents of anilines had a
significant impact on the NaH-promoted reactions. Among
the selected electron-donating groups, Me and OMe gave rise
to the di-arylation products (4b−c) in 91−94% yield. In
contrast, the bulkier iPr, tBu, and NMe2 groups resulted in the
expected products (4d−f) in 68−76% yield, with the
concurrent formation of the mono-heteroarylation counter-
parts (3d−f) in 12−21% yield. As for the investigated
electron-deficient groups, two consecutive amination sequen-
ces occurred to give products 4g−m in 21−85% yield. The
only exception was the reaction of 1a with 4-nitroaniline (2n),
which only afforded mono-heteroarylation product 3n in 75%
yield. In the case of potentially bioactive substructures such as
Ph,55 OPh,56−58 or NHPh53 as a para substituent, 3o−q (or
4o−q) were isolated in moderate to high yield under the base-
free (or NaH-promoted) condition. Afterward, the influence
of the substituent positions on the C−N coupling reactions
was evaluated. Under the base-free condition, 3-methylaniline
(2r) and 2-methylaniline (2s) displayed comparable reactivity
with 4-methylaniline (2b). Conversely, 2s exhibited lower
reactivity than 2b and 2r under the NaH-promoted condition,
with the formation of 4s in only 52% yield. Moreover,
incorporation of different R1 groups into the benzothiazole
framework was attempted. For electron-rich groups such as
Me and OMe, excellent yield of mono-heteroarylation
products 3t−u and moderate yield of di-arylated counterparts
4t−u were obtained for the above-mentioned conditions,
respectively. If an electron-withdrawing group (Cl) was used,
56% of 3v and 21% of 4v were delivered for the base-free case,
whereas only 4v was isolated in 52% yield for the NaH-
promoted case. Probably, the activated substrate (1v)
facilitated the second amination process under the mono-
heteroarylation condition to give a certain amount of di-
heteroarylation product 4v. In our previous work, only 4w was
isolated under either mono- or di-heteroarylation condition
for the highly activated substrate (1w) bearing an electron-
deficient ester group as R1.53 Interestingly, the current
protocol resulted in 3w in 93% yield under the base-free
condition and 4w in 85% yield under the NaH-promoted
condition. Pleasingly, under the base-free condition, excellent
yield and selectivity of 3w retained even with an excess
amount of 1a or at an elevated temperature (as detailed in
Table S2, Supporting Information). Apart from aromatic
primary amines, aliphatic substrates 2x−z were also
compatible. Under the base-free condition, desired products
3x−z were obtained in 91−93% yield. As for the NaH-
mediated condition, 63−74% of 4x−z and 15−16% of 3x−z
were isolated. Finally, heteroaromatic primary amine 2a′ was
tried, and only mono-heteroarylation product 3a′ was
obtained (25% under the base-free condition and 75%
under the NaH-promoted condition).
To rationalize this switchable C−N coupling protocol,
additional experiments were carried out. Initially, the reaction
progress was monitored at regular time intervals under both
conditions (as described in Figure 1). In the absence of a
base, 71% of 3a was detected after 1 h. The yield of 3a
increased simultaneously to 92% by elongating the reaction
time to 12 h, while a further increase of the period resulted in
a constant yield of 3a (Figure 1a). It was worth mentioning
that no formation of 4a was detected at all of the tested
periods. A similar phenomenon was found for the NaH-
mediated reactions, in which the yield of 4a was gradually
increased until a plateau was reached, without the observation
of mono-heteroarylation counterpart 3a (Figure 1b). The
results uncovered the excellent selectivity for both conditions.
To further clarify this point, control experiments were carried
out using 1a and 3a as the two coupling reagents (Scheme 3).
Expectedly, no reaction occurred for the base-free strategy,
whereas 88% of 4a was isolated for the NaH-containing
process. Furthermore, the influence of the NaH amounts on
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Scheme 2. Substrate Exploration
Figure 1. Reaction progress monitored under the (a) base-free and (b) NaH-promoted conditions.
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Scheme 3. Treatment of 1a with 3a under either Base-Free or NaH-Promoted Condition
Figure 2. Product distribution between 3a and 4a applying different NaH amounts with the 1a/2a ratios of (a) 1.00:1.00, and (b) 1.00:0.50.
Scheme 4. Gram-Scale Production of (a) 3a and (b) 4a; (c) Synthesis of Bioactive Compound 3b′
the product selectivity was investigated (as shown in Figure
2). At a 1a/2a ratio of 1.00:1.00 (exact ratio for mono-
heteroarylation), 86% of 3a and 5% of 4a were obtained
without NaH. Nevertheless, adding 0.25−1.00 mmol of NaH
into the reaction mixture led to the formation of 4a with good
selectivity, while even more amounts (1.25−1.50 mmol)
resulted in complicated reaction mixtures with lower 4a/3a
selectivity (Figure 2a). In the case of a 2.00:1.00 ratio (exact
ratio for di-heteroarylation), 37% of 4a could be obtained,
together with 32% of 3a without NaH. Compared with the
1.00:1.00 ratio, a similar tendency was found if varying
amounts of NaH were added (Figure 2b). Even though 4a
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Table 3. Comparison of the Green Metrics between Our Work and the Reported Synthetic Approaches for the Mono-
Heteroarylation Reactions
ref
AE (%)
E-factor (kg/kg)
CE (%)
RME (%)
MI (kg/kg)
MP (%)
ref 46
ref 49
ref 49
ref 53
86.1
86.1
86.1
86.1
86.1
1.1
19.9
8.1
11.9
0.4
51.3
63.6
26.0
86.0
82.5
47.7
59.1
25.9
74.1
72.8
2.1
20.9
9.1
12.9
1.4
47.7
4.8
11.0
7.8
a
b
this work
72.8
a
b
Via Cu catalysis. Via Pd catalysis.
could be generated in the absence of NaH, an appropriate
amount of this base was beneficial for acquiring 4a with
excellent selectivity, which is consistent with our previous
observation.25
From the perspective of industrial application, scalability of
a protocol is a key factor. Therefore, gram-scale reactions to
produce 3a and 4a were performed (as depicted in Scheme
4). For the preparation of 3a, the identical procedure as the 1
mmol scale reaction was initially adopted (Scheme 4a).
However, the hydrochloride salt of 3a, which was never
observed for the smaller-scale reaction, was occasionally
obtained. Therefore, 1 M NaOH was added after the reaction
to neutralize this possibly generated salt, delivering 3a (2.06
g) in 91% yield. As for the gram-scale synthesis of 4a, a
modified procedure was applied due to the potential risk
caused by the considerably increased amount of NaH
(Scheme 4b). Initially, 2a (5.0 mmol, 0.46 mL) was added
dropwisely into a stirred mixture of 1a (12.5 mmol, 1.63 mL)
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Figure 3. Green metrics for di-heteroarylation utilizing different methodologies: (a) the approach described in ref 53 and (b) this work.
and NaH (0.4 g, 10 mmol, 60% dispersed in mineral oil) at 0
°C. After 1 h, the temperature was increased to 50 °C and the
resulting mixture was vigorously stirred at this temperature for
1 h. Subsequently, the mixture was stirred at 80 °C for 2 h
and then at 120 °C for another 12 h. Finally, a similar workup
procedure with the standard one was utilized to afford desired
product 4a (1.56 g) in 87% yield. It was worth mentioning
that both reactions were operationally simple and glovebox-
free. Furthermore, the suitability of this protocol for bioactive
molecules was also attempted. Pleasingly, compound 3b′ (a
potential anticancer agent)59 was successfully prepared using
the newly developed protocol (Scheme 4c).
solvents and transition-metal catalysts, the E-factor values of
this protocol (0.8−2.1, Figure 3b) are much lower than those
in the literature (13.1−42.9, Figure 3a). Besides, this NaH-
mediated process displayed significantly better performance
than the reported synthetic route regarding the MI and MP
values, which reflect the relationship between the product
mass and the total input mass. Based on these findings, we
envisioned that both mono- and di-heteroarylation processes
in the present work were greener and more sustainable than
the reported ones.
CONCLUSIONS
■
Finally, the green and sustainable level of this protocol was
examined using the quantitative green metrics, which include
atom economy (AE), E-factor, carbon efficiency (CE),
reaction mass efficiency (RME), mass intensity (MI), and
mass productivity (MP).60,61 Accordingly, the above-men-
tioned green metrics of this work and the literature protocols
were calculated (as detailed in Tables S3 and S4 in the
Supporting Information). For mono-heteroarylation, com-
pound 3a was selected as an example to elucidate the
calculated parameters (as listed in Table 3). AE is a theoretical
number that only considers the substances in the chemical
equation. Since these methods contain the same equation, an
identical value of 86.1% was determined for all of them.
Meanwhile, the E-factor, which takes the generated wastes
from all of the reagents into account, was examined. To our
delight, the E-factor in this work is much lower than the
literature approaches, implying that our process exhibited less
negative influence on the environment aspect. This result was
evidently attributed to the solvent-free and base-free features
of our process. Compared with the CE and RME values from
the literature, comparable or better results were obtained for
the present work, demonstrating good efficiency of the current
mono-heteroarylation process. In addition, the values of the
other mass-related metrics (MI and MP) also exhibited the
advantage of this base-free process over the reported ones in
terms of greenness and sustainability. With regard to di-
heteroarylation, these parameters of the only literature
example and the present work were also presented (as
shown in Figure 3). For the same reason, the AE values for
each product are identical. It appeared that the two protocols
possessed similar CE and RME values, which indicated that
they have comparable efficiency. Due to the absence of
In summary, a switchable and scalable protocol was developed
for the C−N cross-coupling of 2-chlorobenzothiazoles and
primary amines. Notably, this protocol was realized in the
absence of transition metals and solvents. After screening of
various reaction conditions, the base-free and NaH-promoted
conditions were identified to selectively deliver the desired
mono- and di-heteroarylation products, respectively. Further-
more, additional investigations were performed to provide the
rationale for this switchable C−N coupling protocol. The
experimental results advocated the essence of NaH (with a
suitable amount) in completely tuning the selectivity from
mono- to di-heteroarylation. To demonstrate the practical
value of the newly developed protocol, gram-scale synthesis of
3a and 4a was accomplished in a facile and efficient manner,
without the necessity of using a glovebox for reaction setup. In
view of the quantitative green metrics, both mono- and di-
heteroarylation processes of this protocol displayed relatively
greener and more sustainable levels than the literature
processes.
EXPERIMENTAL SECTION
General Information. All of the reactions were carried out using
■
standard Schlenk techniques unless otherwise mentioned. Nuclear
magnetic resonance (NMR, including H NMR, 13C NMR, and 19F
1
NMR) spectra were recorded on a Bruker Avance 500 spectrometer
in CDCl3 or DMSO-d6, with tetramethylsilane (TMS) as an internal
reference. Multiplicities were designated using the following
abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, p =
pentet, hept = heptet, m = multiplet, dd = doublet of doublets, dt =
doublet of triplets, td = triplet of doublets, ddd = doublet of doublets
of doublets. Melting points were taken on a Buchi M-560 melting
point apparatus without calibration. High-resolution mass spectrom-
etry (HRMS) analyses were done with a Thermo Fisher Q Exactive
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1
UHMR Orbitrap instrument. Ultrasonic radiation was performed
with a Kunshan Shumei KQ-50E ultrasonic cleaner. All of the
common reagents, including 2-chlorobenzothiazoles and primary
amines, were purchased from commercial suppliers and used as
received. The pKaH values of LDA,62 bpy,54 1,10-phen,54 pyr,54
DABCO,63 and DIPEA64 could be found from the corresponding
references, while those of the other bases were derived from the
following link: https://organicchemistrydata.org/hansreich/
resources/pka/#pka_general.
General Procedures for the C−N Cross-Coupling of 2-
Chlorobenzothiazoles and Primary Amines. Under the Base-
Free Condition. 2-Chlorobenzothiazole or its derivative (1, 1.00
mmol) and a primary amine (2, 1.25 mmol) were added into a 25
mL Schlenk flask, which was then capped with a rubber septum. The
flask was subjected to three cycles of evacuation-backfilling with
argon and heated at 100 °C for 12 h. Subsequently, the resultant
solid was washed with cold hexane (3 × 5 mL) to afford the mono-
heteroarylation products (3). If the products were not pure enough,
column chromatography (hexane/ethyl acetate = 7:1−3:1) was
required to deliver the desired pure products. For the gram-scale
reaction, a mixture of 1a (1.3 mL, 10.0 mmol) and 2a (1.2 mL, 12.5
mmol) was heated at 100 °C for 12 h. After the reaction, 1 M NaOH
(10 mL) was slowly added while stirring and the suspension was
placed under ultrasonic radiation for 30 min. The resultant solid was
collected via vacuum filtration, washed with cold hexane (3 × 10
mL), and dried in an oven to afford product 3a in 91% yield (2.06 g,
9.10 mmol).
Under the NaH-Promoted Condition. The procedure was similar
to that under the base-free condition, with a mixture of 1 (1.00
mmol), NaH (40.0 mg, 1.00 mmol, 60% dispersed in mineral oil),
and 2 (1.25 mmol) being heated at 120 °C for 12 h. For the workup
process, the reaction was quenched with ice water (10 mL,
dropwise). Subsequently, the resultant solid was collected, washed
with water (3 × 5 mL) and cold hexane (3 × 5 mL), and dried in an
oven to afford the di-heteroarylation products (4). For the impure
products, column chromatography (hexane/ethyl acetate = 20:1−
4:1) was required to deliver the desired pure products. For the gram-
scale reaction, an optimized procedure was adopted due to the
potential risk from the larger amount of NaH. At 0 °C, 2a (1.14 mL,
12.5 mmol) was added dropwisely to a stirred mixture of 1a (1.30
mL, 10.0 mmol) and NaH (0.40 g, 10.0 mmol), and the mixture was
stirred at this temperature for 1 h, then at 50 °C for 1 h, 80 °C for 2
h, and 120 °C for 12 h. After the reaction, ice water (25 mL) was
added dropwisely while stirring and the suspension was placed under
ultrasonic radiation for 1 h. The resultant solid was collected via
vacuum filtration and washed with water (3 × 15 mL) and cold
hexane (3 × 15 mL) to afford product 4a in 87% yield (1.56 g, 4.35
mmol).
Calculations of NMR Yield and Green Metrics. After the
reaction was completed, the Schlenk flask was cooled down to room
temperature (for the reaction using LiOtBu, NaOtBu, KOtBu, LDA,
or NaH as a promoter, ice water was added dropwise to quench the
reaction). Subsequently, 1,3,5-trimethoxybenzene (84.0 mg, 0.5
mmol) and CDCl3 (∼3.0 mL) were added, with 0.5 mL of the
upper solution being transferred to an NMR tube for NMR analysis.
Besides, the green metrics of the selected references and this work
were calculated based on the literature methods.60,61
mg, under the base-free condition). H NMR (500 MHz, CDCl3) δ
8.87 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H),
7.40−7.33 (m, 2H), 7.30 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 7.8 Hz,
2H), 7.12 (t, J = 7.6 Hz, 1H), 2.37 (s, 3H). 13C{1H} NMR (126
MHz, CDCl3) δ 165.7, 151.5, 137.3, 134.5, 130.1, 129.9, 126.0,
122.1, 121.1, 120.8, 119.1, 20.9. HRMS (ESI): calcd for C14H13N2S
[M + H]+: 241.0794; found: 241.0793.
N-(4-Methoxyphenyl)benzo[d]thiazol-2-amine (3c). The crude
product was purified by column chromatography (hexane/ethyl
acetate = 7:1). White solid, mp 161.6−162.6 °C. Isolated yield: 93%
(238.4 mg, under the base-free condition). 1H NMR (500 MHz,
CDCl3) δ 8.96 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 8.0 Hz,
1H), 7.41 (d, J = 8.8 Hz, 2H), 7.28 (t, J = 7.7 Hz, 1H), 7.10 (t, J =
7.6 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H). 13C{1H} NMR
(126 MHz, CDCl3) δ 167.1, 157.4, 151.7, 133.0, 129.9, 126.0, 124.1,
121.9, 120.8, 118.9, 114.8, 55.5. HRMS (APCI): calcd for
C14H13N2OS [M + H]+: 257.0743; found: 257.0740.
N-(4-Isopropylphenyl)benzo[d]thiazol-2-amine (3d). The crude
product was purified by column chromatography (hexane/ethyl
acetate = 7:1). White solid, mp 245.8−247.2 °C. Isolated yield: 92%
(246.9 mg, under the base-free condition). 1H NMR (500 MHz,
CDCl3) δ 8.71 (s, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 8.2 Hz,
1H), 7.40 (d, J = 8.5 Hz, 2H), 7.34−7.28 (m, 1H), 7.26 (dd, J = 6.8,
1.8 Hz, 2H), 7.13 (td, J = 7.6, 1.3 Hz, 1H), 2.93 (hept, J = 6.8 Hz,
1H), 1.27 (d, J = 6.9 Hz, 6H). 13C{1H} NMR (126 MHz, CDCl3) δ
165.3, 151.5, 145.4, 137.5, 130.0, 127.5, 126.1, 122.2, 120.8, 120.6,
119.2, 33.6, 24.0. HRMS (APCI): calcd for C16H17N2S [M + H]+:
269.1107; found: 269.1104.
N-(4-(tert-Butyl)phenyl)benzo[d]thiazol-2-amine (3e).53 The
crude product was purified by column chromatography (hexane/
ethyl acetate = 7:1). White solid, mp 136.1−137.6 °C. Isolated yield:
91% (257.0 mg, under the base-free condition). 1H NMR (500 MHz,
CDCl3) δ 8.70 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 8.1 Hz,
1H), 7.41 (s, 4H), 7.32 (t, J = 7.7 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H),
1.34 (s, 9H). 13C{1H} NMR (126 MHz, CDCl3) δ 165.2, 151.5,
147.5, 137.2, 129.9, 126.4, 126.1, 122.2, 120.8, 120.2, 119.2, 34.4,
31.4. HRMS (ESI): calcd for C17H19N2S [M + H]+: 283.1263;
found: 283.1262.
N1-(Benzo[d]thiazol-2-yl)-N4,N4-dimethylbenzene-1,4-diamine
(3f). The crude product was purified by column chromatography
(hexane/ethyl acetate = 5:1). White solid, mp 187.0−188.2 °C.
1
Isolated yield: 85% (229.0 mg, under the base-free condition). H
NMR (500 MHz, CDCl3) δ 8.20 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H),
7.49 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 7.5
Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.76 (d, J = 8.4 Hz, 2H), 2.98 (s,
6H). 13C{1H} NMR (126 MHz, CDCl3) δ 168.0, 152.1, 149.0,
130.2, 129.0, 125.9, 124.8, 121.7, 120.7, 118.9, 113.2, 40.7. HRMS
(APCI): calcd for C15H16N3S [M + H]+: 270.1059; found: 270.1055.
N-(4-Iodophenyl)benzo[d]thiazol-2-amine (3g). The crude prod-
uct was purified by column chromatography (hexane/ethyl acetate =
7:1). Light pink solid, mp 208.9−209.6 °C. Isolated yield: 65%
(228.9 mg, under the base-free condition). 1H NMR (500 MHz,
DMSO-d6) δ 10.58 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.74−7.55 (m,
5H), 7.33 (t, J = 7.4 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H). 13C{1H}
NMR (126 MHz, DMSO-d6) δ 161.7, 152.4, 140.9, 138.0, 130.5,
126.4, 123.0, 121.6, 120.4, 119.9, 85.3. HRMS (APCI): calcd for
C13H10IN2S [M + H]+: 352.9604; found: 352.9602.
N-(4-Bromophenyl)benzo[d]thiazol-2-amine (3h). The crude
product was purified by column chromatography (hexane/ethyl
acetate = 7:1). White solid, mp 219.0−219.8 °C. Isolated yield: 81%
(247.2 mg, under the base-free condition). 1H NMR (500 MHz,
DMSO-d6) δ 10.61 (s, 1H), 7.82 (dd, J = 7.9, 1.2 Hz, 1H), 7.80−
7.76 (m, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H),
7.34 (td, J = 7.8, 1.3 Hz, 1H), 7.18 (td, J = 7.6, 1.1 Hz, 1H).
13C{1H} NMR (126 MHz, DMSO-d6) δ 161.7, 152.4, 140.4, 132.2,
130.5, 126.4, 123.0, 121.6, 120.1, 119.8, 113.7. HRMS (APCI): calcd
for C13H10BrN2S [M + H]+: 304.9743; found: 304.9740.
Characterization Data for Compounds 3 and 4. N-
Phenylbenzo[d]thiazol-2-amine (3a).53 The crude product was
purified by column chromatography (hexane/ethyl acetate = 7:1).
White solid, mp 158.9−160.0 °C. Isolated yield: 92% (208.2 mg,
1
under the base-free condition). H NMR (500 MHz, DMSO-d6) δ
10.48 (s, 1H), 7.90−7.74 (m, J = 10.0 Hz, 3H), 7.62 (d, J = 7.7 Hz,
1H), 7.46−7.28 (m, 3H), 7.20−7.10 (m, 1H), 7.10−6.98 (m, 1H).
13C{1H} NMR (126 MHz, DMSO-d6) δ 162.1, 152.6, 141.1, 130.5,
129.4, 126.3, 122.7, 122.5, 121.5, 119.7, 118.3. HRMS (ESI): calcd
for C13H11N2S [M + H]+: 227.0638; found: 227.0637.
N-(p-Tolyl)benzo[d]thiazol-2-amine (3b).53 The crude product
was purified by column chromatography (hexane/ethyl acetate =
7:1). White solid, mp 182.4−182.9 °C. Isolated yield: 90% (216.3
N-(4-Chlorophenyl)benzo[d]thiazol-2-amine (3i). The crude
product was purified by column chromatography (hexane/ethyl
acetate = 7:1). White solid, mp 205.0−206.1 °C. Isolated yield: 80%
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(208.6 mg, under the base-free condition). 1H NMR (500 MHz,
CDCl3) δ 7.65 (d, J = 5.5 Hz, 1H), 7.63 (d, J = 5.8 Hz, 1H), 7.52−
7.47 (m, 2H), 7.38−7.34 (m, 3H), 7.19 (t, J = 7.6 Hz, 1H). 13C{1H}
NMR (126 MHz, CDCl3) δ 163.0, 151.4, 138.3, 130.0, 129.5, 129.1,
126.3, 122.9, 120.9, 120.8, 119.8. HRMS (APCI): calcd for
C13H10ClN2S [M + H]+: 261.0248; found: 261.0247.
N-(4-Phenoxyphenyl)benzo[d]thiazol-2-amine (3p).53 The crude
product was purified by column chromatography (hexane/ethyl
acetate = 4:1). White solid, mp 158.2−159.5 °C. Isolated yield: 87%
(277.0 mg, under the base-free condition). 1H NMR (500 MHz,
CDCl3) δ 8.41 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 8.1 Hz,
1H), 7.48 (d, J = 8.7 Hz, 2H), 7.39−7.28 (m, 3H), 7.19−7.09 (m,
2H), 7.06 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H). 13C{1H}
NMR (126 MHz, CDCl3) δ 165.2, 157.3, 154.1, 151.6, 135.2, 130.0,
129.8, 126.1, 123.3, 122.7, 122.3, 120.8, 120.0, 119.3, 118.7. HRMS
(ESI): calcd for C19H15N2OS [M + H]+: 319.0900; found: 319.0898.
N1-(Benzo[d]thiazol-2-yl)-N4-phenylbenzene-1,4-diamine (3q).53
The crude product was purified by column chromatography
(hexane/ethyl acetate = 3:1). White solid, mp 182.0−183.4 °C.
N-(4-Fluorophenyl)benzo[d]thiazol-2-amine (3j).53 The crude
product was purified by column chromatography (hexane/ethyl
acetate = 7:1). White solid, mp 202.2−202.6 °C. Isolated yield: 82%
(200.3 mg, under the base-free condition). 1H NMR (500 MHz,
DMSO-d6) δ 10.51 (s, 1H), 7.81 (t, J = 7.0 Hz, 3H), 7.59 (d, J = 8.0
Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 8.5 Hz, 2H), 7.16 (t, J
= 7.5 Hz, 1H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 162.1, 157.8
(d, J = 238.5 Hz), 152.5, 137.6, 130.4, 126.4, 122.8, 121.5, 119.8 (d,
J = 7.7 Hz), 119.7, 116.0 (d, J = 22.3 Hz). 19F{1H} NMR (471 MHz,
CDCl3) δ −117.6. HRMS (ESI): calcd for C13H10FN2S [M + H]+:
245.0543; found: 245.0542.
1
Isolated yield: 72% (228.5 mg, under the base-free condition). H
NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.05 (s, 1H), 7.76 (d,
J = 7.7 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 7.9 Hz, 1H),
7.30 (t, J = 7.5 Hz, 1H), 7.20 (t, J = 7.5 Hz, 2H), 7.11 (d, J = 7.7 Hz,
3H), 7.02 (d, J = 7.8 Hz, 2H), 6.76 (t, J = 7.1 Hz, 1H). 13C{1H}
NMR (126 MHz, DMSO-d6) δ 162.5, 152.8, 144.8, 138.6, 134.3,
130.4, 129.6, 126.3, 122.3, 121.4, 119.9, 119.3, 119.2, 119.0, 116.0.
HRMS (ESI): calcd for C19H16N3S [M + H]+: 318.1059; found:
318.1059.
N-(4-(Trifluoromethoxyl)phenyl)benzo[d]thiazol-2-amine (3k).
The crude product was purified by column chromatography
(hexane/ethyl acetate = 7:1). White solid, mp 172.8−173.2 °C.
1
Isolated yield: 85% (263.7 mg, under the base-free condition). H
NMR (500 MHz, CDCl3) δ 8.27 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H),
7.61 (d, J = 8.1 Hz, 1H), 7.59−7.54 (m, 2H), 7.36 (t, J = 7.7 Hz,
1H), 7.25 (d, J = 9.1 Hz, 2H), 7.19 (t, J = 7.6 Hz, 1H). 13C{1H}
NMR (126 MHz, CDCl3) δ 163.5, 151.4, 145.1, 138.5, 130.0, 126.3,
122.8, 122.3, 120.9, 120.8, 120.5 (q, J = 259.6 Hz), 119.7. 19F{1H}
NMR (471 MHz, CDCl3) δ −58.1. HRMS (APCI): calcd for
C14H10F3N2OS [M + H]+: 311.0460; found: 311.0455.
N-(m-Tolyl)benzo[d]thiazol-2-amine (3r).53 The crude product
was purified by column chromatography (hexane/ethyl acetate =
7:1). White solid, mp 122.6−123.7 °C. Isolated yield: 91% (218.7
1
mg, under the base-free condition). H NMR (500 MHz, CDCl3) δ
9.37 (s, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.29
(d, J = 7.6 Hz, 4H), 7.13 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 6.3 Hz,
1H), 2.37 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 165.4,
151.2, 139.9, 139.6, 129.7, 129.4, 126.0, 125.3, 122.2, 121.3, 120.8,
119.1, 117.5, 21.5. HRMS (ESI): calculated for C14H13N2S [M +
H]+: 241.0794; found: 241.0793.
N-(4-(Trifluoromethyl)phenyl)benzo[d]thiazol-2-amine (3l).53
The crude product was purified by column chromatography
(hexane/ethyl acetate = 7:1). White solid, mp 191.4−192.7 °C.
1
Isolated yield: 62% (182.5 mg, under the base-free condition). H
N-(o-Tolyl)benzo[d]thiazol-2-amine (3s).53 The crude product
was purified by column chromatography (hexane/ethyl acetate =
7:1). White solid, mp 119.8−121.1 °C. Isolated yield: 84% (201.9
NMR (500 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.00 (d, J = 8.3 Hz,
2H), 7.87 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.68 (d, J =
8.0 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H).
13C{1H} NMR (126 MHz, DMSO-d6) δ 161.6, 152.2, 144.4, 130.6,
126.8 (q, J = 3.8 Hz), 126.5, 125.1 (q, J = 270.8 Hz), 123.3, 122.2
(q, J = 31.9 Hz), 121.7, 120.2, 117.9. 19F{1H} NMR (471 MHz,
CDCl3) δ −61.9. HRMS (ESI): calcd for C14H10F3N2S [M + H]+:
295.0511; found: 295.0510.
4-(Benzo[d]thiazol-2-ylamino)benzonitrile (3m). The crude
product was purified by column chromatography (hexane/ethyl
acetate = 4:1). White solid, mp 198.2−199.4 °C. Isolated yield: 45%
(113.1 mg, under the base-free condition). 1H NMR (500 MHz,
DMSO-d6) δ 10.99 (s, 1H), 7.98 (d, J = 8.7 Hz, 2H), 7.88 (d, J = 7.8
Hz, 1H), 7.82 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.38 (t, J
= 7.7 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H). 13C{1H} NMR (126 MHz,
DMSO-d6) δ 161.3, 152.1, 144.9, 134.0, 130.6, 126.6, 123.5, 121.8,
120.3, 119.8, 118.1, 103.7. HRMS (APCI): calcd for C14H10N3S [M
+ H]+: 252.0590; found: 252.0586.
1
mg, under the base-free condition). H NMR (500 MHz, CDCl3) δ
8.92 (s, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.37
(d, J = 8.0 Hz, 1H), 7.34−7.21 (m, 4H), 7.08 (t, J = 7.5 Hz, 1H),
2.36 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 167.4, 151.6,
138.3, 132.7, 131.3, 130.0, 127.2, 126.5, 126.0, 124.5, 121.9, 120.8,
118.7, 17.9. HRMS (ESI): calcd for C14H13N2S [M + H]+: 241.0794;
found: 241.0793.
6-Methyl-N-phenylbenzo[d]thiazol-2-amine (3t).53 The crude
product was purified by column chromatography (hexane/ethyl
acetate = 7:1). White solid, mp 166.5−167.3 °C. Isolated yield: 91%
(218.7 mg, under the base-free condition). 1H NMR (500 MHz,
CDCl3) δ 8.39 (s, 1H), 7.48 (dd, J = 7.7, 4.6 Hz, 3H), 7.43 (s, 1H),
7.39 (t, J = 7.5 Hz, 2H), 7.14 (t, J = 7.0 Hz, 2H), 2.41 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 163.6, 149.3, 139.9, 132.3,
130.0, 129.5, 127.4, 124.1, 120.8, 119.9, 119.0, 21.3. HRMS (ESI):
calcd for C14H13N2S [M + H]+: 241.0794; found: 241.0792.
6-Methoxy-N-phenylbenzo[d]thiazol-2-amine (3u).53 The crude
product was purified by column chromatography (hexane/ethyl
acetate = 5:1). White solid, mp 115.5−116.6 °C. Isolated yield: 90%
(230.7 mg, under the base-free condition). 1H NMR (500 MHz,
CDCl3) δ 8.60 (s, 1H), 7.53−7.44 (m, 3H), 7.43−7.35 (m, 2H),
7.19−7.10 (m, 2H), 6.93 (dt, J = 8.8, 1.9 Hz, 1H), 3.83 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 162.7, 155.7, 145.6, 140.0,
130.9, 129.5, 123.9, 119.8, 119.8, 113.9, 105.1, 55.9. HRMS (ESI):
calcd for C14H13N2OS [M + H]+: 257.0743; found: 257.0742.
6-Chloro-N-phenylbenzo[d]thiazol-2-amine (3v).53 The crude
product was purified by column chromatography (hexane/ethyl
acetate = 7:1). White solid, mp 191.0−191.8 °C. Isolated yield: 56%
of 3v (146.0 mg) and 21% of di-heteroarylation counterpart 4v (45.0
N-(4-Nitrophenyl)benzo[d]thiazol-2-amine (3n). The crude
product was purified by column chromatography (hexane/ethyl
acetate = 7:1). Yellow solid, mp 225.7−227.0 °C. Isolated yield: 85%
(230.6 mg, under the base-free condition) and 75% (101.7 mg, under
1
the NaH-promoted condition). H NMR (500 MHz, CDCl3) δ 8.28
(d, J = 9.1 Hz, 2H), 7.78 (dd, J = 8.5, 3.9 Hz, 3H), 7.72 (d, J = 7.9
Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H). 13C{1H}
NMR (126 MHz, CDCl3) δ 160.3, 151.3, 145.3, 142.5, 130.4, 126.6,
125.7, 123.8, 121.0, 120.8, 117.3. HRMS (APCI): calcd for
C13H10N3O2S [M + H]+: 272.0488; found: 272.0486.
N-([1,1′-Biphenyl]-4-yl)benzo[d]thiazol-2-amine (3o). The crude
product was purified by column chromatography (hexane/ethyl
acetate = 7:1). White solid, mp 224.0−224.5 °C. Isolated yield: 56%
(169.3 mg, under the base-free condition). 1H NMR (500 MHz,
CDCl3) δ 7.70−7.55 (m, 8H), 7.45 (t, J = 7.7 Hz, 2H), 7.39−7.32
(m, 2H), 7.18 (t, J = 7.6 Hz, 1H). 13C{1H} NMR (126 MHz,
CDCl3) δ 163.5, 151.5, 140.4, 138.9, 137.0, 130.2, 128.8, 128.2,
127.2, 126.8, 126.2, 122.7, 120.9, 119.9, 119.7. HRMS (APCI): calcd
for C19H15N2S [M + H]+: 303.0950; found: 303.0948.
1
mg, under the base-free condition). H NMR (500 MHz, CDCl3) δ
8.07 (s, 1H), 7.59 (s, 1H), 7.49 (dd, J = 8.6, 3.3 Hz, 3H), 7.41 (t, J =
7.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H).
13C{1H} NMR (126 MHz, CDCl3) δ 164.3, 150.2, 139.4, 131.3,
129.6, 127.7, 126.7, 124.6, 120.5, 120.2, 120.1. HRMS (ESI): calcd
for C13H10ClN2S [M + H]+: 261.0248; found: 261.0247.
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Article
Ethyl 2-(phenylamino)benzo[d]thiazole-6-carboxylate (3w). The
crude product was purified by column chromatography (hexane/
ethyl acetate = 7:1). White solid, mp 155.5−156.0 °C. Isolated yield:
93% (277.5 mg, under the base-free condition). 1H NMR (500 MHz,
CDCl3) δ 8.87 (s, 1H), 8.34 (d, J = 1.6 Hz, 1H), 8.02 (dd, J = 8.5,
1.7 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.53−7.49 (m, 2H), 7.44 (t, J
= 7.9 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H),
1.40 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 167.4,
166.3, 155.1, 139.3, 129.8, 129.7, 127.9, 125.1, 124.5, 122.9, 120.8,
118.6, 60.9, 14.4. HRMS (APCI): calcd for C16H15N2O2S [M + H]+:
299.0849; found: 299.0844.
123.5, 121.2, 120.7. HRMS (APCI): calcd for C20H14N3S2 [M + H]+:
360.0624; found: 360.0617.
N-(Benzo[d]thiazol-2-yl)-N-(p-tolyl)benzo[d]thiazol-2-amine
(4b).53 The crude product was purified by column chromatography
(hexane/ethyl acetate = 5:1). White solid, mp 189.1−190.4 °C.
Isolated yield: 91% (169.9 mg, under the NaH-promoted condition).
1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.1 Hz, 2H), 7.71 (d, J =
7.9 Hz, 2H), 7.43 (s, 4H), 7.39 (t, J = 7.7 Hz, 2H), 7.26−7.23 (m,
2H), 2.50 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 163.0,
150.1, 140.1, 139.2, 132.5, 131.1, 129.0, 126.0, 123.4, 121.2, 120.7,
21.5. HRMS (APCI): calcd for C21H16N3S2 [M + H]+: 374.0780;
found: 374.0776.
N-Benzylbenzo[d]thiazol-2-amine (3x). The crude product was
purified by column chromatography (hexane/ethyl acetate = 5:1).
White solid, mp 163.2−163.9 °C. Isolated yield: 93% (223.5 mg,
N-(Benzo[d]thiazol-2-yl)-N-(4-methoxyphenyl)benzo[d]thiazol-
2-amine (4c). The crude product was purified by column
chromatography (hexane/ethyl acetate = 4:1). White solid, mp
206.5−207.3 °C. Isolated yield: 94% (183.1 mg, under the NaH-
1
under the base-free condition). H NMR (500 MHz, CDCl3) δ 7.57
(dd, J = 7.9, 1.3 Hz, 1H), 7.47 (dd, J = 8.1, 1.1 Hz, 1H), 7.40 (d, J =
7.0 Hz, 2H), 7.35 (t, J = 7.3 Hz, 2H), 7.33−7.26 (m, 2H), 7.08 (td, J
= 7.6, 1.2 Hz, 1H), 6.17 (s, 1H), 4.63 (s, 2H). 13C{1H} NMR (126
MHz, CDCl3) δ 167.4, 152.3, 137.4, 130.5, 128.8, 127.9, 127.7,
126.0, 121.6, 120.8, 119.0, 49.4. HRMS (APCI): C14H13N2S [M +
H]+: calcd for 241.0794; found: 241.0791.
1
promoted condition). H NMR (500 MHz, CDCl3) δ 7.80 (d, J =
8.1 Hz, 2H), 7.72 (dd, J = 7.9, 1.2 Hz, 2H), 7.46 (d, J = 8.9 Hz, 2H),
7.39 (ddd, J = 8.3, 7.2, 1.2 Hz, 2H), 7.26−7.23 (m, 2H), 7.12 (d, J =
8.9 Hz, 2H), 3.92 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
163.3, 160.4, 150.2, 134.5, 132.5, 130.5, 126.1, 123.4, 121.2, 120.7,
115.6, 55.6. HRMS (APCI): calcd for C21H16N3OS2 [M + H]+:
390.0729; found: 390.0726.
N-Phenethylbenzo[d]thiazol-2-amine (3y). The crude product
was purified by column chromatography (hexane/ethyl acetate =
5:1). White solid, mp 144.1−144.3 °C. Isolated yield: 91% (231.5
N-(Benzo[d]thiazol-2-yl)-N-(4-isopropylphenyl)benzo[d]thiazol-
2-amine (4d). The crude product was purified by column
chromatography (hexane/ethyl acetate = 7:1). White solid, mp
210.1−210.9 °C. Isolated yield: 73% of 4d (146.6 mg) and 18% of
mono-heteroarylation counterpart 3d (24.2 mg, under the NaH-
1
mg, under the base-free condition). H NMR (500 MHz, CDCl3) δ
7.58 (dd, J = 7.9, 1.2 Hz, 1H), 7.52 (dd, J = 8.1, 1.0 Hz, 1H), 7.34−
7.27 (m, 3H), 7.26−7.21 (m, 3H), 7.08 (td, J = 7.6, 1.2 Hz, 1H),
5.58 (s, 1H), 3.69 (t, J = 6.9 Hz, 2H), 2.99 (t, J = 6.9 Hz, 2H).
13C{1H} NMR (126 MHz, CDCl3) δ 167.2, 152.4, 138.3, 130.4,
1
promoted condition). H NMR (500 MHz, CDCl3) δ 7.80 (d, J =
8.1 Hz, 2H), 7.71 (d, J = 7.8 Hz, 2H), 7.52−7.43 (m, 4H), 7.39 (t, J
= 7.7 Hz, 2H), 7.26−7.22 (m, 2H), 3.06 (hept, J = 7.0 Hz, 1H), 1.37
(d, J = 6.8 Hz, 6H). 13C{1H} NMR (126 MHz, CDCl3) δ 163.1,
150.7, 150.1, 139.4, 132.5, 128.9, 128.5, 126.0, 123.4, 121.2, 120.7,
34.0, 23.9. HRMS (APCI): calcd for C23H20N3S2 [M + H]+:
402.1093; found: 402.1090.
128.8, 128.7, 126.7, 125.9, 121.5, 120.8, 118.9, 46.5, 35.6. HRMS
(APCI): calcd for C15H15N2S [M + H]+: 255.0950; found: 255.0947.
N-Hexylbenzo[d]thiazol-2-amine (3z). The crude product was
purified by column chromatography (hexane/ethyl acetate = 5:1).
White solid, mp 63.1−63.3 °C. Isolated yield: 92% (215.6 mg, under
the base-free condition). 1H NMR (500 MHz, CDCl3) δ 7.58 (d, J =
7.8 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.28 (td, J = 7.8, 1.2 Hz, 1H),
7.07 (td, J = 7.6, 1.1 Hz, 1H), 5.70 (s, 1H), 3.40 (t, J = 7.1 Hz, 2H),
1.68 (p, J = 7.3 Hz, 2H), 1.46−1.36 (m, 2H), 1.34−1.26 (m, 4H),
0.94−0.84 (m, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 167.6,
152.5, 130.4, 125.9, 121.4, 120.7, 118.8, 45.7, 31.4, 29.5, 26.5, 22.5,
14.0. HRMS (APCI): calcd for C13H19N2S [M + H]+: 235.1263;
found: 235.1261.
N-(Benzo[d]thiazol-2-yl)-N-(4-(tert-butyl)phenyl)benzo[d]-
thiazol-2-amine (4e).53 The crude product was purified by column
chromatography (hexane/ethyl acetate = 20:1). White solid, mp
272.7−274.1 °C. Isolated yield: 68% of 4e (141.3 mg) and 21% of
mono-heteroarylation counterpart 3e (29.7 mg, under the NaH-
1
promoted condition). H NMR (500 MHz, CDCl3) δ 7.80 (d, J =
8.1 Hz, 2H), 7.72 (d, J = 7.9 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.46
(d, J = 8.1 Hz, 2H), 7.39 (t, J = 7.7 Hz, 2H), 7.24 (t, J = 5.9 Hz,
2H), 1.43 (s, 9H). 13C{1H} NMR (126 MHz, CDCl3) δ 163.1,
153.0, 150.1, 139.1, 132.5, 128.6, 127.4, 126.0, 123.4, 121.2, 120.7,
35.0, 31.4. HRMS (APCI): calcd for C24H22N3S2 [M + H]+:
416.1250; found: 416.1245.
N-(Pyridin-2-yl)benzo[d]thiazol-2-amine (3a′).53 The crude
product was purified by column chromatography (hexane/ethyl
acetate = 3:1). White solid, mp 238.7−239.4 °C. Isolated yield: 25%
(56.8 mg, under the base-free condition), 75% (85.2 mg, under the
NaH-promoted condition). 1H NMR (500 MHz, DMSO-d6) δ 11.55
(s, 1H), 8.34 (d, J = 5.0 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.76 (t, J
= 7.8 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H),
7.18 (dd, J = 13.4, 7.6 Hz, 2H), 7.00 (t, J = 6.2 Hz, 1H). 13C{1H}
NMR (126 MHz, DMSO-d6) δ 159.8, 152.1, 149.9, 147.0, 138.8,
132.1, 126.2, 122.5, 121.6, 119.6, 117.3, 111.7. HRMS (ESI): calcd
for C12H10N3S [M + H]+: 228.0590; found: 228.0589.
N1,N1-bis(Benzo[d]thiazol-2-yl)-N4,N4-dimethylbenzene-1,4-dia-
mine (4f). The crude product was purified by column chromatog-
raphy (hexane/ethyl acetate = 4:1). White solid, mp 278.7−280.1
°C. Isolated yield: 76% of 4f (153.0 mg) and 12% of mono-
heteroarylation counterpart 3f (16.2 mg, under the NaH-promoted
condition). 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.1 Hz, 2H),
7.70 (d, J = 7.9 Hz, 2H), 7.43−7.33 (m, 4H), 7.23 (t, J = 7.8 Hz,
2H), 6.86 (d, J = 8.5 Hz, 2H), 3.07 (s, 6H). 13C{1H} NMR (126
MHz, CDCl3) δ 163.9, 150.9, 150.4, 132.6, 130.4, 129.7, 125.9,
123.2, 121.2, 120.7, 112.8, 40.3. HRMS (APCI): calcd for
C22H19N4S2 [M + H]+: 403.1046; found: 403.1042.
7-Chloro-N-(2,6-dimethylphenyl)benzo[d]thiazol-2-amine
(3b′).59 The crude product was purified by column chromatography
(hexane/ethyl acetate = 7:1). White solid, mp 196.2−197.5 °C.
1
Isolated yield: 62% (179.0 mg, under the base-free condition). H
NMR (500 MHz, CDCl3) δ 9.07 (s, 1H), 7.27−7.24 (m, 1H), 7.23−
7.19 (m, 2H), 7.19−7.14 (m, 2H), 7.06−7.01 (m, 1H), 2.37 (s, 6H).
13C{1H} NMR (126 MHz, CDCl3) δ 169.7, 153.0, 137.3, 136.5,
130.4, 129.1, 128.7, 126.9, 126.3, 121.2, 116.5, 18.1. HRMS (ESI):
calcd for C15H14ClN2S [M + H]+: 289.0561; found: 289.0560.
N-(Benzo[d]thiazol-2-yl)-N-phenylbenzo[d]thiazol-2-amine
(4a).53 The crude product was purified by column chromatography
(hexane/ethyl acetate = 5:1). White solid, mp 201.9−203.3 °C.
Isolated yield: 90% (161.8 mg, under the NaH-promoted condition).
1H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.1 Hz, 2H), 7.71 (d, J =
N-(Benzo[d]thiazol-2-yl)-N-(4-iodophenyl)benzo[d]thiazol-2-
amine (4g). The crude product was purified by column
chromatography (hexane/ethyl acetate = 20:1). White solid, mp
241.1−241.9 °C. Isolated yield: 75% (182.0 mg, under the NaH-
1
promoted condition). H NMR (500 MHz, CDCl3) δ 7.97 (d, J =
8.1 Hz, 2H), 7.80 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 7.8 Hz, 2H), 7.41
(t, J = 7.7 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 7.5 Hz,
2H). 13C{1H} NMR (126 MHz, CDCl3) δ 162.4, 150.0, 141.3,
139.8, 132.4, 131.3, 126.2, 123.7, 121.3, 120.8, 95.9. HRMS (APCI):
calcd for C20H13IN3S2 [M + H]+: 485.9590; found: 485.9586.
N-(Benzo[d]thiazol-2-yl)-N-(4-bromophenyl)benzo[d]thiazol-2-
amine (4h). The crude product was purified by column
7.9 Hz, 2H), 7.68−7.58 (m, 3H), 7.55 (d, J = 7.4 Hz, 2H), 7.39 (t, J
= 7.7 Hz, 2H), 7.24 (t, J = 7.6 Hz, 2H). 13C{1H} NMR (126 MHz,
CDCl3) δ 162.8, 150.1, 141.7, 132.4, 130.5, 129.9, 129.3, 126.1,
10298
https://doi.org/10.1021/acs.joc.1c01019
J. Org. Chem. 2021, 86, 10288−10302

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
chromatography (hexane/ethyl acetate = 20:1). White solid, mp
(d, J = 7.2 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.51 (t, J = 7.6 Hz,
2H), 7.46−7.37 (m, 3H), 7.30−7.24 (m, 2H). 13C{1H} NMR (126
MHz, CDCl3) δ 162.9, 150.1, 142.8, 140.8, 139.9, 132.5, 129.6,
129.1, 128.9, 128.0, 127.3, 126.1, 123.5, 121.3, 120.8. HRMS
(APCI): calcd for C26H18N3S2 [M + H]+: 436.0937; found:
436.0927.
224.5−225.5 °C. Isolated yield: 83% (181.9 mg, under the NaH-
1
promoted condition). H NMR (500 MHz, DMSO-d6) δ 7.99 (dd, J
= 8.0, 1.1 Hz, 2H), 7.92 (d, J = 8.5 Hz, 2H), 7.76 (d, J = 8.1 Hz,
2H), 7.73 (d, J = 8.5 Hz, 2H), 7.46 (td, J = 7.8, 1.2 Hz, 2H), 7.32
(td, J = 7.7, 1.1 Hz, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ
162.7, 149.9, 141.1, 134.1, 132.3, 126.9, 124.1, 123.9, 122.1, 121.0.
HRMS (APCI): calcd for C20H13BrN3S2 [M + H]+: 437.9729; found:
437.9727.
N-(Benzo[d]thiazol-2-yl)-N-(4-phenoxyphenyl)benzo[d]thiazol-
2-amine (4p).53 The crude product was purified by column
chromatography (hexane/ethyl acetate = 5:1). White solid, mp
217.5−219.0 °C. Isolated yield: 88% (198.7 mg, under the NaH-
N-(Benzo[d]thiazol-2-yl)-N-(4-chlorophenyl)benzo[d]thiazol-2-
amine (4i). The crude product was purified by column
chromatography (hexane/ethyl acetate = 20:1). White solid, mp
197.0−197.6 °C. Isolated yield: 85% (167.4 mg, under the NaH-
1
promoted condition). H NMR (500 MHz, CDCl3) δ 7.80 (d, J =
8.1 Hz, 2H), 7.72 (d, J = 7.9 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H),
7.45−7.35 (m, 4H), 7.28−7.21 (m, 3H), 7.20−7.16 (m, 4H).
13C{1H} NMR (126 MHz, CDCl3) δ 163.1, 158.8, 155.9, 150.1,
1
promoted condition). H NMR (500 MHz, CDCl3) δ 7.79 (d, J =
8.1 Hz, 2H), 7.73 (d, J = 7.8 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.49
(d, J = 8.6 Hz, 2H), 7.41 (t, J = 7.7 Hz, 2H), 7.29−7.22 (m, 2H).
13C{1H} NMR (126 MHz, CDCl3) δ 162.5, 150.0, 140.0, 135.9,
136.1, 132.5, 130.8, 130.0, 126.1, 124.4, 123.5, 121.2, 120.8, 120.1,
119.4. HRMS (APCI): calcd for C26H18N3OS2 [M + H]+: 452.0886;
found: 452.0874.
132.4, 130.8, 130.7, 126.2, 123.7, 121.3, 120.8. HRMS (APCI): calcd
N1,N1-bis(Benzo[d]thiazol-2-yl)-N4-phenylbenzene-1,4-diamine
(4q).53 The crude product was purified by column chromatography
(hexane/ethyl acetate = 5:1). White solid, mp 202.7−203.8 °C.
Isolated yield: 75% (169.0 mg, under the NaH-promoted condition).
1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 8.1 Hz, 2H), 7.73 (d, J =
for C20H13ClN3S2 [M + H]+: 394.0234; found: 394.0234.
N-(Benzo[d]thiazol-2-yl)-N-(4-fluorophenyl)benzo[d]thiazol-2-
amine (4j).53 The crude product was purified by column
chromatography (hexane/ethyl acetate = 20:1). White solid, mp
199.6−201.0 °C. Isolated yield: 72% (135.9 mg, under the NaH-
7.9 Hz, 2H), 7.45−7.30 (m, 6H), 7.26 (s, 2H), 7.24−7.19 (m, 4H),
7.04 (t, J = 7.4 Hz, 1H), 6.12 (s, 1H). 13C{1H} NMR (126 MHz,
DMSO-d6) δ 163.6, 150.1, 145.7, 142.7, 133.0, 132.5, 130.6, 129.8,
126.8, 123.9, 122.0, 121.5, 120.9, 118.8, 116.9. HRMS (APCI): calcd
for C26H19N4S2 [M + H]+: 451.1046; found: 451.1037.
N-(Benzo[d]thiazol-2-yl)-N-(m-tolyl)benzo[d]thiazol-2-amine
(4r).53 The crude product was purified by column chromatography
(hexane/ethyl acetate = 20:1). White solid, mp 194.9−195.8 °C.
Isolated yield: 86% (160.6 mg, under the NaH-promoted condition).
1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.1 Hz, 2H), 7.72 (d, J =
7.9 Hz, 2H), 7.52 (t, J = 7.9 Hz, 1H), 7.40 (t, J = 7.7 Hz, 3H), 7.35
(d, J = 7.0 Hz, 2H), 7.26−7.23 (m, 2H), 2.47 (s, 3H). 13C{1H}
NMR (126 MHz, CDCl3) δ 162.9, 150.1, 141.6, 140.6, 132.5, 130.8,
130.2, 129.7, 126.2, 126.1, 123.4, 121.2, 120.7, 21.5. HRMS (APCI):
calcd for C21H16N3S2 [M + H]+: 374.0780; found: 374.0777.
N-(Benzo[d]thiazol-2-yl)-N-(o-tolyl)benzo[d]thiazol-2-amine
(4s).53 The crude product was purified by column chromatography
(hexane/ethyl acetate = 20:1). White solid, mp 193.4−194.3 °C.
Isolated yield: 52% (97.1 mg, under the NaH-promoted condition).
1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.1 Hz, 2H), 7.73 (d, J =
7.9 Hz, 2H), 7.56−7.44 (m, 4H), 7.40 (t, J = 7.7 Hz, 2H), 7.25 (t, J
= 7.6 Hz, 2H), 2.19 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
162.2, 150.3, 140.6, 137.4, 132.5, 132.2, 130.4, 129.5, 128.1, 126.1,
123.4, 121.2, 120.8, 17.5. HRMS (APCI): calcd for C21H16N3S2 [M
+ H]+: 374.0780; found: 374.0775.
1
promoted condition). H NMR (500 MHz, CDCl3) δ 7.79 (d, J =
8.2 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.53 (dd, J = 8.5, 4.9 Hz, 2H),
7.40 (t, J = 7.7 Hz, 2H), 7.31 (t, J = 8.4 Hz, 2H), 7.25 (t, J = 7.7 Hz,
2H). 13C{1H} NMR (126 MHz, CDCl3) δ 163.1 (d, J = 250.4 Hz),
162.7, 150.0, 137.5 (d, J = 3.2 Hz), 132.4, 131.4 (d, J = 8.9 Hz),
126.2, 123.6, 121.5, 120.8, 117.5 (d, J = 23.0 Hz). 19F{1H} NMR
(471 MHz, CDCl3) δ −110.0. HRMS (APCI): calcd for
C20H13FN3S2 [M + H]+: 378.0529; found: 378.0524.
N-(Benzo[d]thiazol-2-yl)-N-(4-(trifluoromethoxy)phenyl)benzo-
[d]thiazol-2-amine (4k). The crude product was purified by column
chromatography (hexane/ethyl acetate = 20:1). White solid, mp
172.0−172.3 °C. Isolated yield: 76% (168.5 mg, under the NaH-
1
promoted condition). H NMR (500 MHz, CDCl3) δ 7.80 (d, J =
8.1 Hz, 2H), 7.74 (d, J = 7.9 Hz, 2H), 7.64−7.57 (m, 2H), 7.47 (d, J
= 8.7 Hz, 2H), 7.42 (t, J = 7.7 Hz, 2H), 7.28 (d, J = 7.7 Hz, 2H).
13C{1H} NMR (126 MHz, CDCl3) δ 162.5, 150.0, 149.9, 139.7,
132.4, 131.2, 126.3, 123.9, 123.7, 122.6, 121.5, 121.3, 120.8, 119.4,
117.3. 19F{1H} NMR (471 MHz, CDCl3) δ −57.7. HRMS (APCI):
calcd for C21H13F3N3OS2 [M + H]+: 444.0447; found: 444.0441.
N-(Benzo[d]thiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)benzo[d]-
thiazol-2-amine (4l).53 The crude product was purified by column
chromatography (hexane/ethyl acetate = 5:1). White solid, mp
230.7−231.9 °C. Isolated yield: 21% (44.9 mg, under the NaH-
promoted condition). 1H NMR (500 MHz, DMSO-d6) δ 8.11 (d, J =
8.1 Hz, 2H), 8.04 (d, J = 8.1 Hz, 2H), 7.99 (d, J = 7.9 Hz, 2H), 7.75
(d, J = 8.1 Hz, 2H), 7.45 (t, J = 7.7 Hz, 2H), 7.32 (t, J = 7.6 Hz,
2H). 13C{1H} NMR (126 MHz, CDCl3) δ 162.1, 149.9, 144.5,
132.4, 131.8 (q, J = 33.0 Hz), 130.1, 127.6 (q, J = 3.7 Hz), 126.3,
123.8, 123.7 (q, J = 272.6 Hz), 121.3, 120.8. 19F{1H} NMR (471
MHz, DMSO-d6) δ −61.1. HRMS (APCI): calcd for C21H13F3N3S2
[M + H]+: 428.0497; found: 428.0493.
4-(Bis(benzo[d]thiazol-2-yl)amino)benzonitrile (4m). The crude
product was purified by column chromatography (hexane/ethyl
acetate = 10:1). White solid, mp 229.3−230.6 °C. Isolated yield: 60%
(115.3 mg, under the NaH-promoted condition). 1H NMR (500
MHz, CDCl3) δ 7.99−7.89 (m, 2H), 7.79 (d, J = 8.1 Hz, 2H), 7.75
(d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 7.43 (t, J = 7.7 Hz,
2H), 7.29 (t, J = 7.6 Hz, 2H). 13C{1H} NMR (126 MHz, CDCl3) δ
161.8, 149.8, 145.2, 134.3, 132.3, 130.5, 126.4, 124.0, 121.4, 120.9,
117.9, 113.8. HRMS (APCI): calcd for C21H13N4S2 [M + H]+:
385.0576; found: 385.0569.
6-Methyl-N-(6-methylbenzo[d]thiazol-2-yl)-N-phenylbenzo[d]-
thiazol-2-amine (4t).53 The crude product was purified by column
chromatography (hexane/ethyl acetate = 20:1). White solid, mp
192.2−193.3 °C. Isolated yield: 62% (120.1 mg, under the NaH-
1
promoted condition). H NMR (500 MHz, CDCl3) δ 7.67 (d, J =
8.3 Hz, 2H), 7.65−7.57 (m, 3H), 7.54 (d, J = 7.6 Hz, 2H), 7.50 (s,
2H), 7.20 (d, J = 8.2 Hz, 2H), 2.44 (s, 6H). 13C{1H} NMR (126
MHz, CDCl3) δ 162.1, 148.1, 141.8, 133.3, 132.5, 130.4, 129.8,
129.4, 127.4, 120.8, 120.6, 21.5. HRMS (APCI): calcd for
C22H18N3S2 [M + H]+: 388.0937; found: 388.0930.
6-Methoxy-N-(6-methoxybenzo[d]thiazol-2-yl)-N-phenylbenzo-
[d]thiazol-2-amine (4u).53 The crude product was purified by
column chromatography (hexane/ethyl acetate = 4:1). White solid,
mp 165.4−166.3 °C. Isolated yield: 64% (134.2 mg, under the NaH-
1
promoted condition). H NMR (500 MHz, DMSO-d6) δ 7.77−7.68
(m, 5H), 7.67 (d, J = 8.9 Hz, 2H), 7.61 (d, J = 1.5 Hz, 2H), 7.07
(dd, J = 8.8, 1.5 Hz, 2H), 3.84 (s, 6H). 13C{1H} NMR (126 MHz,
DMSO-d6) δ 161.1, 156.4, 144.2, 141.9, 133.6, 131.0, 130.4, 130.0,
121.5, 115.1, 105.5, 56.1. HRMS (APCI): calcd for C22H18N3O2S2
[M + H]+: 420.0835; found: 420.0827.
N-([1,1′-Biphenyl]-4-yl)-N-(benzo[d]thiazol-2-yl)benzo[d]thiazol-
2-amine (4o). The crude product was purified by column
chromatography (hexane/ethyl acetate = 10:1). White solid, mp
257.0−257.5 °C. Isolated yield: 61% (132.8 mg, under the NaH-
6-Chloro-N-(6-chlorobenzo[d]thiazol-2-yl)-N-phenylbenzo[d]-
thiazol-2-amine (4v).53 The crude product was purified by column
chromatography (hexane/ethyl acetate = 20:1). White solid, mp
1
promoted condition). H NMR (500 MHz, CDCl3) δ 7.85 (d, J =
8.4 Hz, 2H), 7.82 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 7.9 Hz, 2H), 7.71
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J. Org. Chem. 2021, 86, 10288−10302

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Article
244.2−245.3 °C. Isolated yield: 51% (109.2 mg, under the NaH-
promoted condition). 1H NMR (500 MHz, CDCl3) δ 7.73−7.59 (m,
7H), 7.53 (d, J = 6.9 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H). 13C{1H}
NMR (126 MHz, CDCl3) δ 162.8, 148.6, 141.2, 133.6, 130.6, 130.3,
129.2, 129.0, 126.8, 122.1, 120.4. HRMS (APCI): calcd for
C20H12Cl2N3S2 [M + H]+: 427.9844; found: 427.9839.
441053, P. R. China; orcid.org/0000-0001-8786-3068;
Email: rzhangccnu@163.com
Cheng Chen − State Key Laboratory of Advanced Technology
for Materials Synthesis and Processing, Wuhan University of
Technology, Wuhan 430070, P. R. China; orcid.org/
0000-0001-5439-5421; Email: chengchen@whut.edu.cn
Diethyl 2,2′-(phenylazanediyl)bis(benzo[d]thiazole-6-carboxy-
late) (4w).53 The crude product was purified by column
chromatography (hexane/ethyl acetate = 4:1). White solid, mp
239.1−239.9 °C. Isolated yield: 85% (214.0 mg, under the NaH-
Authors
Hua Cheng − Department of Chemical Engineering and Food
Science, Hubei University of Arts and Science, Xiangyang
441053, P. R. China
Yan-Qiu Zhu − Department of Chemical Engineering and
Food Science, Hubei University of Arts and Science,
Xiangyang 441053, P. R. China
Peng-Fei Liu − Department of Chemical Engineering and
Food Science, Hubei University of Arts and Science,
Xiangyang 441053, P. R. China
Kai-Qiang Yang − Department of Chemical Engineering and
Food Science, Hubei University of Arts and Science,
Xiangyang 441053, P. R. China
Jin Yan − Department of Chemical Engineering and Food
Science, Hubei University of Arts and Science, Xiangyang
441053, P. R. China
Wei Sang − State Key Laboratory of Advanced Technology for
Materials Synthesis and Processing, Wuhan University of
Technology, Wuhan 430070, P. R. China
Xiao-Sheng Tang − College of Optoelectronic Engineering,
Chongqing University of Posts and Telecommunications,
Chongqing 400065, P. R. China; School of Materials Science
and Engineering, Zhengzhou University, Zhengzhou 450001,
P. R. China; orcid.org/0000-0003-4402-391X
1
promoted condition). H NMR (500 MHz, CDCl3) δ 8.45 (s, 2H),
8.10 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.6 Hz, 2H), 7.72−7.62 (m,
3H), 7.56 (d, J = 7.0 Hz, 2H), 4.40 (q, J = 7.1 Hz, 4H), 1.42 (t, J =
7.1 Hz, 6H). 13C{1H} NMR (126 MHz, CDCl3) δ 166.2, 165.0,
153.3, 141.1, 132.4, 130.7, 130.4, 129.1, 127.7, 125.8, 123.0, 120.9,
61.1, 14.4. HRMS (APCI): calcd for C26H22N3O4S2 [M + H]+:
504.1046; found: 504.1037.
N-(Benzo[d]thiazol-2-yl)-N-benzylbenzo[d]thiazol-2-amine (4x).
The crude product was purified by column chromatography
(hexane/ethyl acetate = 20:1). White solid, mp 184.9−185.4 °C.
Isolated yield: 64% of 4x (119.5 mg) and 16% of mono-
heteroarylation counterpart 3x (19.2 mg, under the NaH-promoted
condition). 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 8.1 Hz, 2H),
7.77 (d, J = 7.8 Hz, 2H), 7.45−7.40 (m, 4H), 7.33−7.29 (m, 2H),
7.28−7.25 (m, 3H), 5.77 (s, 2H). 13C{1H} NMR (126 MHz,
CDCl3) δ 161.9, 149.8, 135.4, 132.4, 128.7, 127.8, 127.2, 126.2,
123.4, 121.0, 120.9, 54.8. HRMS (APCI): calcd for C21H16N3S2 [M
+ H]+: 374.0780; found: 374.0777.
N-(Benzo[d]thiazol-2-yl)-N-phenethylbenzo[d]thiazol-2-amine
(4y). The crude product was purified by column chromatography
(hexane/ethyl acetate = 20:1). White solid, mp 164.6−165.1 °C.
Isolated yield: 74% of 4y (143.4 mg) and 16% of mono-
heteroarylation counterpart 3y (20.3 mg, under the NaH-promoted
condition). 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 8.0 Hz, 2H),
7.80 (dd, J = 7.9, 1.1 Hz, 2H), 7.45 (t, J = 7.7 Hz, 2H), 7.41 (d, J =
7.1 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.31−7.25 (m, 3H), 4.66−4.57
(m, 2H), 3.33−3.24 (m, 2H). 13C{1H} NMR (126 MHz, CDCl3) δ
161.3, 150.1, 138.0, 132.1, 129.1, 128.7, 126.8, 126.2, 123.3, 121.0,
120.9, 54.4, 33.6. HRMS (APCI): calcd for C22H18N3S2 [M + H]+:
388.0937; found: 388.0932.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01019
Author Contributions
⊥H.C. and Y.-Q.Z. contributed equally to this work.
N-(Benzo[d]thiazol-2-yl)-N-hexylbenzo[d]thiazol-2-amine (4z).
The crude product was purified by column chromatography
(hexane/ethyl acetate = 20:1). White solid, mp 105.4−105.8 °C.
Isolated yield: 63% of 4z (115.8 mg) and 15% of mono-
heteroarylation counterpart 3z (17.6 mg, under the NaH-promoted
condition). 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 8.1 Hz, 2H),
7.80 (d, J = 8.2 Hz, 2H), 7.44 (t, J = 7.7 Hz, 2H), 7.29−7.26 (m,
2H), 4.48−4.40 (m, 2H), 2.05−1.92 (m, 2H), 1.53−1.46 (m, 2H),
1.43−1.30 (m, 4H), 7.84 (d, J = 8.1 Hz, 3H). 13C{1H} NMR (126
MHz, CDCl3) δ 161.5, 150.1, 132.1, 126.1, 123.2, 120.9, 120.8, 52.9,
31.4, 27.3, 26.4, 22.6, 14.0. HRMS (APCI): calcd for C20H22N3S2 [M
+ H]+: 368.1250; found: 368.1249.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by Innovation Team Cultivation
Fund of Hubei University of Arts and Sciences (no.
2020kypyt004), National Undergraduate Innovation and
Entrepreneurship Training Program (201910519006), the
Foundation of Hubei University of Arts and Science (grant
no. 2059057), Scientific Research Program Guiding Project of
Hubei Provincial Department of Education (B2019135), the
fund of the Key Laboratory of Catalysis and Energy Materials
Chemistry of Ministry of Education & Hubei Key Laboratory
of Catalysis and Materials Science (no. CHCL19002),
Research Funds for the National Key Research and Develop-
ment Program of China (grant no. 2018YFB2200500),
National Natural Science Foundation of China (nos.
51775070 and 61975023), and Guangdong Province Interna-
tional Scientific and Technological Cooperation Projects (no.
2020A0505100011). The project was also supported by State
Key Laboratory of Advanced Technology for Materials
Synthesis and Processing (Wuhan University of Technology,
No. 2021-KF-19).
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01019.
Supplementary results; detailed calculated green metrics
and original NMR spectra of all target compounds;
optimization of reaction conditions; and reactions of
ethyl 2-chlorobenzo[d]thiazole-6-carboxylate (1w) and
aniline (2a) under the base-free condition (PDF)
AUTHOR INFORMATION
Corresponding Authors
Rui Zhang − Department of Chemical Engineering and Food
Science, Hubei University of Arts and Science, Xiangyang
■
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