Copper-catalyzed one-pot coupling reactions of aldehydes (ketones), tosylhydrazide and 2-amino(benzo)thiazoles: An efficient strategy for the synthesis of N-alkylated (benzo)thiazoles

Article abstract of DOI:10.1002/aoc.5124

An efficient and practical C–N bond formation methodology for the synthesis of N-alkylated (benzo)thiazoles was developed, via the copper-catalyzed one-pot two-step reactions of 2-amino(benzo)thiazoles and aldehydes (ketones) with tosylhydrazide. This cross-coupling reaction proceeded smoothly and tolerated a broad range of functional groups (46 examples). A variety of functionalized N-alkylated (benzo)thiazoles were obtained in moderate to high yields. Notably, gram-scale synthesis of fanetizole (anti-inflammatory drug) was also realized through this protocol.

Full text of DOI:10.1002/aoc.5124

Received: 8 November 2018
DOI: 10.1002/aoc.5124
Revised: 26 June 2019
Accepted: 27 June 2019
F U L L P A P E R
Copper‐catalyzed one‐pot coupling reactions of aldehydes
(ketones), tosylhydrazide and 2‐amino(benzo)thiazoles: An
efficient strategy for the synthesis of N‐alkylated (benzo)
thiazoles
Zengyang Xie1
Cunde Wang2
| Ruijiao Chen1 | Mingfang Ma1 | Lingdong Kong1 | Jun Liu1 |
1 Laboratory of New Antitumor Drug
Molecular Design & Synthesis, College of
Basic Medicine, Jining Medical University,
Jining 272067, China
2 School of Chemistry and Chemical
Engineering, Yangzhou University,
Yangzhou 225002, China
An efficient and practical C–N bond formation methodology for the synthesis of
N‐alkylated (benzo)thiazoles was developed, via the copper‐catalyzed one‐pot
two‐step reactions of 2‐amino(benzo)thiazoles and aldehydes (ketones) with
tosylhydrazide. This cross‐coupling reaction proceeded smoothly and tolerated
a broad range of functional groups (46 examples). A variety of functionalized
N‐alkylated (benzo)thiazoles were obtained in moderate to high yields. Notably,
gram‐scale synthesis of fanetizole (anti‐inflammatory drug) was also realized
through this protocol.
Correspondence
Zengyang Xie, Laboratory of New
Antitumor Drug Molecular Design &
Synthesis, College of Basic Medicine,
Jining Medical University, Jining 272067,
China.
KEYWORDS
C–N bonds, copper‐catalyzed, N‐(alkylamino)azoles, tosylhydrazones
Email: xiezyjnmc@126.com Cunde Wang,
School of Chemistry and Chemical
Engineering, Yangzhou University,
Yangzhou 225002, China.
Email: wangcd@yzu.edu.cn
Funding information
National Natural SciencXML firste Foun-
dation of China, Grant/Award Number:
21807041; Natural Science Foundation of
Shandong Province, Grant/Award Num-
ber: ZR2016BL06; NSFC cultivation pro-
ject of Jining Medical University, Grant/
Award Number: JYP2018KJ10; Youth
Support Foundation of Jining Medical
University, Grant/Award Number:
JYFC2018KJ057
1 | INTRODUCTION
the N‐alkylation of primary amines to higher amines is
especially important and interesting because N‐alkylated
The formation of C–N bonds has attracted considerable
attention since the resulting products occur in various
compounds of enormous practical importance, ranging
from agrochemicals and pharmaceuticals to functional
materials.[1] Among these C–N bond forming reactions,
amines are usually used as key intermediates for the prep-
aration of other valuable compounds like additives, dyes,
polymers and bioactive compounds.[2]
One such class of N‐alkylated amines are 2‐N‐
(alkylamino)azoles which exhibit various physiological
Appl Organometal Chem. 2019;e5124.
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© 2019 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.5124

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XIE ET AL.
FIGURE 1 Examples of bioactive 2‐N‐(alkylamino)azoles
SCHEME 1 Various synthesis
strategies for 2‐N‐(alkylamino)
benzothiazoles
and pharmacological activities. For example, 4,5,6,7‐
tetrahydrobenzo[1,2‐d]thiazole derivative I can be used
as a DNA gyrase inhibitor,[3] fanetizole (II) is an anti‐
inflammatory drug,[4] compound III exhibits good Rho
kinase inhibition potency with Ki = 1.1 μM,[5] the 2‐(2,4‐
dioxo‐1,3‐thiazolidin‐5‐yl)acetamide analogue IV is found
to show significant antioxidant activity,[6] while another
2‐N‐(alkylamino)benzothiazole analogue V has been
reported to function as blocker of N‐type calcium chan-
nel,[7] and compound VI is a potent HCV NS5A inhibitor
(EC50 = 4.6 nM) and is undergoing preclinical trials for
the treatment of HCV infection[8] (Figure 1).
Considering the importance of 2‐N‐(alkylamino)
azoles, a number of methods have been developed for
their synthesis (Scheme 1). The successful protocols for
the synthesis of 2‐N‐(alkylamino)azoles involve
aminations of halobenzothiazoles with alkylamines[9] or
cross‐coupling reactions between aminazoles and aryl
halides,[10] the direct oxidative couplings of azoles with
amines[11] or formamides,[12] intramolecular cyclization of
N‐arylthioureas[13] or ortho‐halophenylthioureas,[14] con-
densation of isothiocyanates with amines,[15] Cu‐catalyzed
condensation of sodium hydrosulfide with carbodiimide,[16]
Cu‐catalyzed/mediated three‐component condensation
reactions,[17] aerobic oxidative cyclization/dehydrogenation
of thioureas and cyclohexanones[18] and metal‐catalyzed
N‐alkylation of aminazoles with alcohols.[19] Although the
above procedures are generally practical and versatile, some
of them still have various limitations such as the use of noble
metals and additives, a longer reaction time, a limited sub-
strate scope and the generation of many unwanted wastes.
Therefore, it would be of great importance to develop a
novel protocol based on an inexpensive metal catalyst for
the synthesis of 2‐N‐(alkylamino)azoles.
Tosylhydrazones which are easily obtained through
the condensation of tosylhydrazides with carbonyl com-
pounds, are valuable intermediates and have been suc-
cessfully used in organic synthesis for over 60 years.[20]
The pioneering studies were of two well‐known name
reactions called Shapiro reaction and Bamford‐Stevens
reaction, both of which showed great applications in the
preparation of alkenes. In recent years, the use of
tosylhydrazones as important building blocks to achieve
complex compounds has attracted more attention. Tre-
mendous efforts were made by Barluenga et al.,[21] Wang
and co‐workers[22] and others, who contributed valuable
work on employing tosylhydrazones as versatile coupling
partners to form various chemical bonds, including C–

XIE ET AL.
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C,[23] C–S,[24] C–N,[25] C–O,[26] C–P,[27] C–B,[28] C–Sn,[29]
C–Si[30] and N–N[31] bonds. Despite many significant
achievements, developing more efficient C–N bond for-
mation methodologies utilizing tosylhydrazones is still
required because this may offer new chances for the syn-
thesis of bioactive compounds.
efficient strategy for the synthesis of N‐alkylated (benzo)
thiazoles through Cu‐catalyzed one‐pot two‐step reac-
tions of carbonyl compounds (aldehydes and ketones),
tosylhydrazide and 2‐amino(benzo)thiazoles. More inter-
estingly, the anti‐inflammatory drug fanetizole can also
be synthesized successfully using our catalysis system.
Given the importance of 2‐N‐(alkylamino)azoles and
unique reaction characteristics of tosylhydrazones, as
well as our continuing studies of the formation of chem-
ical bonds,[32] we made further exploration of the N‐
alkylation of primary amines. Herein, we report a more
2 | RESULTS AND DISCUSSION
At the outset of this study, the cross‐coupling reaction
of 2‐aminobenzothiazole (2) and tosylhydrazone
TABLE 1 Optimization of reaction conditions for synthesis of 3aa
Entry
Catalyst (mol%)
Base (equiv.)
Solvent
Yield (%)b
1
—
t‐BuOLi (2.0)
t‐BuOLi (2.0)
t‐BuOLi (2.0)
t‐BuOLi (2.0)
t‐BuOLi (2.0)
t‐BuOLi (2.0)
t‐BuOLi (2.0)
t‐BuOLi (2.0)
NaOH (2.0)
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
1,4‐Dioxane
Toluene
Trace
51
2
Cu(OAc)2 (15)
CuSO4·5H2O (15)
Cu(acac)2 (15)
Cu(NO3)2·3H2O (15)
CuCl (15)
CuI (15)
3
22
4
60
5
35
6
47
7
68
8
CuO (15)
CuI (15)
19
9
15
10
11
12
13
14
15
16
17
18
19
20
21
22c
23d
24e
25d
26d
27d
CuI (15)
Cs2CO3 (2.0)
K2CO3·0.5 H2O (2.0)
Na2CO3 (2.0)
KOH (2.0)
Trace
Trace
33
CuI (15)
CuI (15)
CuI (15)
Trace
0
CuI (15)
t‐BuONa (2.0)
t‐BuOK (2.0)
—
CuI (15)
0
CuI (15)
0
CuI (15)
t‐BuOLi (1.0)
t‐BuOLi (3.0)
t‐BuOLi (2.0)
t‐BuOLi (2.0)
t‐BuOLi (2.0)
t‐BuOLi (2.0)
t‐BuOLi (2.0)
t‐BuOLi (2.0)
t‐BuOLi (2.0)
t‐BuOLi (2.0)
t‐BuOLi (2.0)
30
CuI (15)
66
CuI (10)
57
CuI (5)
40
CuI (20)
69
CuI (15)
34
CuI (15)
82
CuI (15)
78
CuI (15)
75
CuI (15)
DMSO
0
CuI (15)
DMF
Trace
aReaction conditions: 1a (0.6 mmol), tosylhydrazide (0.6 mmol), solvent (4 ml) at 50°C for 2 h; then 2 (0.4 mmol), catalyst, base under heating at 80°C for 3 h.
bIsolated yields. cReaction carried out at 60°C. d100°C. e120°C.

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XIE ET AL.
generated in situ from 4‐chlorobenzaldehyde (1a) with
tosylhydrazide was selected as a model to explore the
reaction conditions. The reaction was performed
through a one‐pot strategy in two steps. Tosylhydrazone
was easily prepared at 50°C for 2 h in 1,4‐dioxane,
followed by addition of 2, catalyst and base into the
resulting mixture without isolation of the intermediate,
and the resulting solution was then heated at 80°C for
another 3 h. It was found that only a trace amount of
the desired product 3a was detected under catalyst‐free
conditions (Table 1, entry 1). Seven types of simple cop-
per salts were examined, and we found that all of them
were favorable for this cross‐coupling reaction; the best
result was obtained when CuI was used as catalyst
(Table 1, entry 7). Subsequently, with the catalyst CuI,
the effects of various bases on the reaction were tested,
with t‐BuOLi affording the best yield, while other bases
like NaOH, Cs2CO3, K2CO3·0.5H2O, Na2CO3, KOH, t‐
BuONa and t‐BuOK resulted in lower yields (Table 1,
entries 7 and 9–15). It should be noted that no target
compound 3a was detected in the absence of base
which demonstrated that a base is indispensable to this
transformation (Table 1, entry 16). Further studies on
the base loading indicated that 2 equiv. of t‐BuOLi
was optimal.
In addition, the effects of catalyst loading, reaction
temperature and solvents were also investigated. When
the CuI catalyst loading was reduced from 15 to 10 and
then 5 mol%, the yield of 3a was lowered from 68 to 57
and 40%, respectively (Table 1, entries 7, 19, 20). But no
further improvement of yield was observed when the
CuI loading was raised to 20 mol% (Table 1, entry 21).
Furthermore, decreasing the reaction temperature to
60°C led to reduced yields of 3a (Table 1, entry 22). To
our delight, the yield was increased to 82% when the reac-
tion was carried out at 100°C, while the yield did not
increase when the reaction temperature reached 120°C
(Table 1, entries 23 and 24). Finally, through the exami-
nation of various solvents, the use of 1,4‐dioxane as a sol-
vent was found to be the most appropriate choice
compared with toluene, dimethylsulfoxide (DMSO) and
dimethylformamide (DMF).
With the optimized reaction conditions in hand, we
then examined the substrate scope of this transformation.
Firstly, the N‐alkylation of 2 with various aldehydes was
evaluated. As evident from Table 2, benzaldehydes bear-
ing electron‐donating substituents on the aromatic ring
gave better yields of the products than those having
electron‐withdrawing substituents (Table 2, 3g–i versus
3a–f). This cross‐coupling reaction was not sensitive to
TABLE 2 Substrate scope for the various aldehydes
The reaction was performed with 1 (0.6 mmol) and tosylhydrazide (0.6 mmol) in 1,4‐dioxane (4 ml) at 50°C for 2 h. Then 2 (0.4 mmol), CuI (15 mol%) and t‐
BuOLi (2.0 equiv.) were added. The resulting solution was stirred at 100°C for another 3 h. Yields refer to isolated yields.

XIE ET AL.
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TABLE 3 Substrate scope for various 2‐amino(benzo)thiazoles and different aldehydes
The reaction was performed with 1 (0.6 mmol) and tosylhydrazide (0.6 mmol) in 1,4‐dioxane (4 ml) at 50°C for 2 h. Then 4 (0.4 mmol), CuI (15 mol%) and t‐
BuOLi (2.0 equiv.) were added. The resulting solution was stirred at 100°C for another 3 h. Yields refer to isolated yields.
the steric effects of substituents in aldehydes and gave
good yields. Unsubstituted benzaldehyde and 1‐
naphthaldehyde were suitable coupling partners which
delivered the corresponding products with 80 and 89%
yields, respectively (Table 2, 3j and 3k). Most interest-
ingly, the reactions could mildly occur with heteroatom‐
containing aldehydes, where the corresponding products
3l and 3m could be achieved in satisfactory yields.
Finally, aliphatic aldehydes (phenylacetaldehyde and
butyraldehyde) can also be coupled to 2 under our exper-
imental conditions to afford products 3n and 3o.
Next, the N‐alkylation of various 2‐amino(benzo)thia-
zoles with several different aldehydes was then examined,
and the results are summarized in Table 3. It was found
that the reaction could be influenced by the substituent
group on substrates, as 2‐aminobenzothiazoles with 6‐
CH3 group (Table 3, 5e) gave higher yields than the 6‐F
and 6‐Cl counterparts (Table 3, 5f and 5g). Among the
four kinds of 2‐aminobenzothiazoles, 2‐amino‐6‐
bromobenzothiazole provided the corresponding product
with the lowest yield when coupled with benzaldehyde
(Table 3, 5d). Moreover, the scope of non‐benzo‐fused 2‐
aminothiazoles with aldehydes were also screened, and
the corresponding N‐alkylated thiazoles were obtained
in good yields (Table 3, 5j–n).
Compared with aldehyde‐derived N‐tosylhydrazones,
the N‐tosylhydrazones derived from ketones are less
effective in the cross‐coupling reaction, probably as a
result of the steric hindrance of ketones.[33] To expand
the utility of this protocol, the N‐alkylation of non‐
benzo‐fused 2‐aminothiazoles with various ketones was
also studied (Table 4). Once again, all the reactions
proceeded well and provided the target products in good
yields. It is noteworthy that the reaction yield was some-
what affected by the position of substituents in ketones
(8b versus 8c; 8f versus 8g; 8l versus 8m). We also found
the reactivity of 4‐methylthiazol‐2‐amine was much bet-
ter which gave slightly higher yield than 5‐
methylthiazol‐2‐amine (8h versus 8k; 8i versus 8m; 8j
versus 8o). To our delight, aliphatic ketone showed good
reactivity under the reaction conditions, and ideal yield
was obtained when cyclohexanone was used as the sub-
strate (Table 4, 8p).
Next, to demonstrate the synthetic value of this cross‐
coupling, further experiment concerning a gram‐scale syn-
thesis of fanetizole was carried out with 4‐phenylthiazol‐2‐

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XIE ET AL.
TABLE 4 Substrate scope for various 2‐aminothiazoles and different ketones
The reaction was performed with 6 (0.6 mmol) and tosylhydrazide (0.6 mmol) in 1,4‐dioxane (4 ml) at 50°C for 2 h. Then 7 (0.4 mmol), CuI (15 mol%) and t‐
BuOLi (2.0 equiv.) were added. The resulting solution was stirred at 100°C for another 3 h. Yields refer to isolated yields.
SCHEME 2 A gram‐scale synthesis of
anti‐inflammatory drug II
amine and phenylacetaldehyde (Scheme 2). Gratifyingly,
the reaction proceeded smoothly under the optimized con-
ditions and 1.11 g of the desired anti‐inflammatory drug II
was obtained in moderate yield.
Based on the above experimental results and related
reports,[22d, 23u] two possible reaction pathways for the
synthesis of N‐alkylated (benzo)thiazoles were proposed,
as shown in Scheme 3. At the beginning, tosylhydrazones
are easily formed by coupling carbonyl compounds with
tosylhydrazide, which undergo thermal decomposition
to generate diazo compounds in the presence of t‐BuOLi.
Then, the reaction of diazo compounds and copper salt
leads to the formation of copper–carbene species A.[25b]
In one possible pathway (left side, red line), the coordina-
tion reaction of deprotonated 2‐amino(benzo)thiazoles
with copper atom on species A might proceed to produce
the intermediate B, followed by migratory insertion to
generate the intermediate C, which can finally be con-
verted to the product D with release of the Cu(I) catalyst.
SCHEME 3 Possible reaction pathways for one‐pot synthesis of
N‐alkylated (benzo)thiazoles

XIE ET AL.
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Another possibility is that nucleophilic attack of 2‐
amino(benzo)thiazoles on A leads to the generation of
intermediates E and F, the latter undergoing a proton
transfer process to give the final product (right side,
blue line).
stirred at 50°C for 2 h. Then, 2‐amino(benzo)thiazole
(0.4 mmol), CuI (15 mol%) and t‐BuOLi (2.0 equiv.) were
added. The resulting solution was then stirred vigorously
at 100°C for another 3 h in a sealed vessel. After comple-
tion of the reaction (monitored by TLC), the contents
were cooled to room temperature and diluted with
dichloromethane (20 ml). The mixture was washed with
brine (3 × 10 ml), dried over anhydrous Na2SO4, filtered
and concentrated to give the crude product. The residue
was then subjected to flash chromatocstrphy on silica
gel (petroleum ether–ethyl acetate mixtures) to afford
the target N‐alkylated (benzo)thiazoles.
3 | CONCLUSIONS
In summary, we have developed a practical and efficient
Cu‐catalyzed coupling reaction of 2‐amino(benzo)thia-
zoles and aldehydes (ketones) with tosylhydrazide to con-
struct C–N bonds. This reaction proceeded in a one‐pot
two‐step process and afforded various N‐alkylated
(benzo)thiazoles with moderate to good yields. A wide
range of substrates, the use of readily available reagents
and gram‐scale synthesis application were salient features
of the presented protocol. Further research concerning bio-
logical evaluations of these synthesized compounds is
ongoing in our laboratory.
4.2.1 | N‐(4‐Chlorobenzyl)benzo[d]thiazol‐
2‐amine (3a)[19c]
1
Yield: 90.1 mg (82%). H NMR (400 MHz, d6‐DMSO) δ
8.54 (t, J = 5.7 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.45–
7.33 (m, 5H), 7.22 (t, J = 7.7 Hz, 1H), 7.03 (t,
J = 7.5 Hz, 1H), 4.59 (d, J = 5.8 Hz, 2H). 13C NMR
(100 MHz, d6‐DMSO) δ 166.6, 152.8, 138.6, 132.0, 130.9,
129.7, 128.8, 126.1, 121.6, 121.5, 118.6, 46.9.
4 | EXPERIMENTAL
4.1 | General information
4.2.2 | N‐(3‐Chlorobenzyl)benzo[d]thiazol‐
2‐amine (3b)[19e]
1H NMR and 13C NMR spectra were recorded with a
Bruker Avance III HD 400 MHz spectrometer in
DMSO‐d6 solution (Supporting information). High‐
resolution electrospray ionization mass spectra (HR‐ESI‐
MS) were recorded using a Thermo Scientific LTQ
Orbitrap XL equipped with an ESI probe operating in
positive‐ion mode with direct infusion. TLC analyses
were performed on commercial glass plates bearing a
0.25 mm layer of Merck silica gel 60F254. Silica gel (200–
300 mesh) was used for column chromatocstrphy. Unless
otherwise noted, materials obtained from commercial
suppliers were used without further purification. Solvents
1
Yield: 93.4 mg (85%). H NMR (400 MHz, d6‐DMSO) δ
8.56 (t, J = 5.6 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.46–
7.30 (m, 5H), 7.22 (t, J = 7.6 Hz, 1H), 7.03 (t,
J = 7.5 Hz, 1H), 4.62 (d, J = 5.7 Hz, 2H). 13C NMR
(100 MHz, d6‐DMSO) δ 166.6, 152.7, 142.2, 133.5, 130.9,
130.8, 127.5, 127.4, 126.5, 126.1, 121.6, 121.5, 118.7, 46.9.
4.2.3 | N‐(2‐Chlorobenzyl)benzo[d]thiazol‐
2‐amine (3c)[19e]
1
Yield: 89 mg (81%). 1H NMR (400 MHz, d6‐DMSO) δ 8.54
(t, J = 5.6 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.48 (t,
J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.35–7.31 (m,
2H), 7.22 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H),
4.67 (d, J = 5.6 Hz, 2H). 13C NMR (100 MHz, d6‐DMSO)
δ 166.4, 152.7, 136.4, 132.8, 130.9, 129.8, 129.5, 129.4,
127.8, 126.0, 121.6, 121.5, 118.7, 45.4.
were freshly distilled prior to use. Chemical shifts for H
NMR are expressed in parts per million (ppm) relative
to tetramethylsilane (0.0 ppm). Chemical shifts for 13C
NMR are expressed in ppm relative to DMSO‐d6
(39.52 ppm). Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quar-
tet, m = multiplet, dd = doublet of doublets), coupling
constant (Hz) and intecstrtion. All reactions were carried
out under air unless noted.
4.2.4 | N‐(4‐Fluorobenzyl)benzo[d]thiazol‐
2‐amine (3d)[19c]
4.2 | General procedure for synthesis of N‐
alkylated (benzo)thiazoles
1
Yield: 72.3 mg (70%). H NMR (400 MHz, d6‐DMSO) δ
8.51 (t, J = 5.6 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.46–
7.36 (m, 3H), 7.25–7.15 (m, 3H), 7.02 (t, J = 7.5 Hz, 1H),
4.58 (d, J = 5.7 Hz, 2H). 13C NMR (100 MHz, d6‐DMSO)
A
mixture of aldehyde (ketone) (0.6 mmol) and
tosylhydrazide (0.6 mmol) in 1,4‐dioxane (4 ml) was

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XIE ET AL.
δ 166.6, 161.8 (d, JCF = 242.4 Hz), 152.9, 135.6 (d,
JCF = 3.0 Hz), 130.9, 129.9 (d, JCF = 8.2 Hz), 126.0,
121.5, 121.4, 118.6, 115.6 (d, JCF = 21.3 Hz), 46.9.
(d, J = 8.0 Hz, 1H), 7.29–7.08 (m, 5H), 7.01 (t,
J = 7.5 Hz, 1H), 4.54 (d, J = 5.6 Hz, 2H), 2.28 (s, 3H).
13C NMR (100 MHz, d6‐DMSO) δ 166.7, 152.9, 136.6,
136.3, 130.9, 129.4, 127.9, 127.0, 126.0, 121.4, 118.5, 47.4,
21.2.
4.2.5 | N‐(4‐Bromobenzyl)benzo[d]thiazol‐
2‐amine (3e)[19c]
Yield: 97 mg (76%). 1H NMR (400 MHz, d6‐DMSO) δ 8.55
(t, J = 5.6 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.46–7.33 (m,
5H), 7.22 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 4.59
(d, J = 5.8 Hz, 2H). 13C NMR (100 MHz, d6‐DMSO) δ
166.6, 152.8, 142.4, 131.1, 130.3, 126.9, 126.1, 122.2,
121.6, 121.5, 118.7, 46.9.
4.2.10 | N‐Benzylbenzo[d]thiazol‐2‐amine
(3j)[19c]
1
Yield: 76.9 mg (80%). H NMR (400 MHz, d6‐DMSO) δ
8.53 (t, J = 5.4 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.39–
7.33 (m, 5H), 7.29–7.19 (m, 2H), 7.02 (t, J = 7.5 Hz, 1H),
4.60 (d, J = 5.7 Hz, 2H).13C NMR (100 MHz, d6‐DMSO)
δ 166.6, 152.8, 138.6, 132.0, 130.9, 129.7, 128.8, 126.0,
121.5, 121.4, 118.6, 46.9.
4.2.6 | N‐(3‐Bromobenzyl)benzo[d]thiazol‐
2‐amine (3f)[19e]
1
Yield: 100.9 mg (79%). H NMR (400 MHz, d6‐DMSO) δ
4.2.11 | N‐(Naphthalen‐1‐ylmethyl)
benzo[d]thiazol‐2‐amine (3k)[19c]
8.55 (t, J = 5.4 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.54
(d, J = 7.7 Hz, 2H), 7.39–7.29 (m, 3H), 7.27–7.18 (m,
1H), 7.03 (t, J = 7.5 Hz, 1H), 4.57 (d, J = 5.5 Hz, 2H).
13C NMR (100 MHz, d6‐DMSO) δ 166.5, 152.7, 142.4,
131.1, 130.9, 130.4, 130.3, 126.9, 126.1, 122.2, 121.6,
121.5, 118.7, 46.9.
1
Yield: 103.4 mg (89%). H NMR (400 MHz, d6‐DMSO) δ
8.59 (t, J = 4.5 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.98
(d, J = 7.7 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.69 (d,
J = 7.8 Hz, 1H), 7.63–7.54 (m, 3H), 7.49 (t, J = 7.5 Hz,
1H), 7.44 (d, J = 7.9 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H),
7.04 (t, J = 7.5 Hz, 1H), 5.09 (d, J = 4.9 Hz, 2H). 13C
NMR (100 MHz, d6‐DMSO) δ 166.5, 152.9, 134.5, 133.8,
131.5, 130.9, 129.0, 128.3, 126.9, 126.4, 126.1, 126.0,
125.9, 124.0, 121.5, 121.4, 118.6, 45.9.
4.2.7 | N‐(4‐Methoxybenzyl)benzo[d]
thiazol‐2‐amine (3g)[19c]
1
Yield: 97.3 mg (90%). H NMR (400 MHz, d6‐DMSO) δ
8.43 (s, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.38 (d,
J = 7.8 Hz, 1H), 7.31 (d, J = 8.5 Hz, 2H), 7.21 (t,
J = 7.7 Hz, 1H), 7.01 (t, J = 7.9 Hz, 1H), 6.91 (d,
J = 8.5 Hz, 2H), 4.51 (d, J = 5.5 Hz, 2H), 3.72 (s, 3H).
13C NMR (100 MHz, d6‐DMSO) δ 166.6, 158.9, 152.9,
131.2, 130.9, 129.3, 127.0, 126.0, 121.4, 118.5, 114.2, 55.5,
47.2.
4.2.12 | N‐(Furan‐2‐ylmethyl)benzo[d]
thiazol‐2‐amine (3l)[34]
1
Yield: 63.6 mg (69%). H NMR (400 MHz, vd6‐DMSO) δ
8.44 (t, J = 5.0 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.62
(d, J = 6.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.23 (t,
J = 7.6 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.39 (d,
J = 19.0 Hz, 2H), 4.58 (d, J = 5.3 Hz, 2H). 13C NMR
(100 MHz, d6‐DMSO) δ 166.3, 152.7, 152.2, 142.9, 130.1,
126.0, 121.6, 121.5, 118.7, 111.0, 108.0, 54.9.
4.2.8 | N‐(2‐Methylbenzyl)benzo[d]
thiazol‐2‐amine (3h)[13a]
1
Yield: 87.5 mg (86%). H NMR (400 MHz, d6‐DMSO) δ
8.38 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.36 (dd, J = 26.7,
7.2 Hz, 2H), 7.24–7.17 (m, 4H), 7.02 (t, J = 7.5 Hz, 1H),
4.58 (d, J = 4.6 Hz, 2H), 2.34 (s, 3H). 13C NMR
(100 MHz, d6‐DMSO) δ 166.5, 152.9, 136.9, 136.4, 130.9,
130.5, 128.3, 127.7, 126.3, 126.0, 121.4, 118.5, 45.9, 19.1.
4.2.13 | N‐(Thiophen‐3‐ylmethyl)benzo[d]
thiazol‐2‐amine (3m)
1
Yield: 72.9 mg (74%). H NMR (400 MHz, d6‐DMSO) δ
8.43 (t, J = 4.9 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.51–
7.39 (m, 3H), 7.22 (t, J = 7.7 Hz, 1H), 7.14 (d,
J = 4.8 Hz, 1H), 7.06–7.00 (m,, 1H), 4.58 (d, J = 5.3 Hz,
2H). 13C NMR (100 MHz, d6‐DMSO) δ 166.5, 152.9,
140.1, 130.9, 127.5, 126.9, 126.5, 126.0, 121.4, 121.3,
118.6, 43.2. HRMS (ESI) calcd for C12H10N2S2 [MH+]:
247.0358; found: 247.0361.
4.2.9 | N‐(4‐Methylbenzyl)benzo[d]
thiazol‐2‐amine (3i)[19c]
1
Yield: 89.5 mg (88%). H NMR (400 MHz, d6‐DMSO) δ
8.46 (t, J = 5.5 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.38

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9 of 14
139.5, 131.9, 128.8, 127.8, 127.5, 118.9, 113.4, 106.0, 55.9,
47.6.
4.2.14 | N‐Phenethylbenzo[d]thiazol‐2‐
amine (3n)[19k]
1
Yield: 73.3 mg (72%). H NMR (400 MHz, d6‐DMSO) δ
4.2.19 | N‐Benzyl‐6‐bromobenzo[d]thiazol‐
2‐amine (5d)[15b]
8.09 (t, J = 5.2 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.39
(d, J = 7.9 Hz, 1H), 7.33–7.25 (m, 4H), 7.23–7.19 (m,
2H), 7.01 (t, J = 7.5 Hz, 1H), 3.62–3.57 (m, 2H), 2.92 (t,
J = 7.3 Hz, 2H). 13C NMR (100 MHz, d6‐DMSO) δ
166.4, 153.2, 139.8, 130.8, 129.2, 128.8, 126.6, 126.0,
121.4, 121.3, 118.5, 45.8, 35.1.
Yield: 83 mg (65%). 1H NMR (400 MHz, d6‐DMSO) δ 8.64
(t, J = 5.1 Hz, 1H), 7.92 (s, 1H), 7.39–7.29 (m, 7H), 4.59 (d,
J = 5.4 Hz, 2H). 13C NMR (100 MHz, d6‐DMSO) δ 167.3,
152.1, 139.1, 133.1, 131.4, 128.9, 127.9, 127.6, 123.9, 119.9,
112.8, 47.7.
4.2.15 | N‐Butylbenzo[d]thiazol‐2‐amine
(3o)[19k]
4.2.20 | N‐(4‐Chlorobenzyl)‐6‐
methylbenzo[d]thiazol‐2‐amine (5e)[19f]
1
Yield: 43.7 mg (53%). H NMR (400 MHz, d6‐DMSO) δ
7.97 (t, J = 5.1 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.36
(d, J = 7.8 Hz, 1H), 7.22–7.17 (m, 1H), 7.01–6.97 (m,
1H), 3.37–3.33 (m, 2H), 1.60–1.53 (m, 2H), 1.40–1.32 (m,
2H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, d6‐
DMSO) δ 166.6, 153.2, 130.0, 125.9, 121.3, 121.2, 118.4,
44.1, 31.3, 20.1, 14.1.
1
Yield: 93.6 mg (81%). H NMR (400 MHz, d6‐DMSO) δ
8.43 (t, J = 5.8 Hz, 1H), 7.48 (s, 1H), 7.41–7.33 (m, 4H),
7.26 (d, J = 8.1 Hz, 1H), 7.03 (d, J = 8.1, 1H), 4.56 (d,
J = 5.9 Hz, 2H), 2.31 (s, 3H). 13C NMR (100 MHz, d6‐
DMSO) δ 165.9, 150.7, 138.7, 132.0, 130.9, 130.7, 129.7,
128.8, 127.1, 121.4, 118.3, 46.9, 21.2.
4.2.16 | N‐Benzyl‐4‐methylbenzo[d]
thiazol‐2‐amine (5a)[19f]
4.2.21 | N‐(4‐Chlorobenzyl)‐6‐
fluorobenzo[d]thiazol‐2‐amine (5f)
1
1
Yield: 71.2 mg (70%). H NMR (400 MHz, d6‐DMSO) δ
Yield: 72.6 mg (62%). H NMR (400 MHz, d6‐DMSO) δ
8.51 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.45–7.31 (m, 4H),
7.27 (t, J = 7.0 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 6.92 (t,
J = 7.5 Hz, 1H), 4.59 (d, J = 5.4 Hz, 2H), 2.45 (s, 3H).
13C NMR (100 MHz, d6‐DMSO) δ 166.1, 151.9, 139.5,
130.3, 128.8, 128.1, 127.7, 127.5, 126.7, 121.3, 118.9, 47.9,
18.6.
8.53 (t, J = 5.8 Hz, 1H), 7.62 (d, J = 8.8, 1H), 7.41–7.33
(m, 5H), 7.08–7.03 (m, 1H), 4.58 (d, J = 5.8 Hz, 2H). 13C
NMR (100 MHz, d6‐DMSO)
δ
166.5, 157.7 (d,
JCF 236.7 Hz), 149.5, 138.5, 132.1, 131.9 (d,
=
JCF = 11.2 Hz), 129.7, 128.8, 119.1 (d, JCF = 8.8 Hz),
113.4 (d, JCF = 23.6 Hz), 108.4 (d, JCF = 27.2 Hz), 46.9.
HRMS (ESI) calcd for C14H10ClFN2S [MH+]: 293.0310;
found: 293.0316.
4.2.17 | N‐Benzyl‐6‐methylbenzo[d]
thiazol‐2‐amine (5b)[19c]
4.2.22 | N‐(4‐Chlorobenzyl)‐6‐
1
chlorobenzo[d]thiazol‐2‐amine (5g)[19f]
Yield: 83.4 mg (82%). H NMR (400 MHz, d6‐DMSO) δ
8.40 (t, J = 5.8 Hz, 1H), 7.47 (s, 1H), 7.39–7.33 (m, 4H),
7.28–7.23 (m, 2H), 7.03 (d, J = 8.1, 1H), 4.58 (d,
J = 5.8 Hz, 2H), 2.32 (s, 3H). 13C NMR (100 MHz, d6‐
DMSO) δ 166.0, 150.8, 139.5, 130.9, 130.6, 128.8, 127.9,
127.5, 127.1, 121.4, 118.3, 47.7, 21.2.
1
Yield: 81.6 mg (66%). H NMR (400 MHz, d6‐DMSO) δ
8.66 (t, J = 5.8 Hz, 1H), 7.82 (d, J = 2.2 Hz, 1H), 7.40–
7.33 (m, 5H), 7.25–7.22 (m, 1H), 4.59 (d, J = 5.8 Hz,
2H). 13C NMR (100 MHz, d6‐DMSO) δ 167.2, 151.8,
138.3, 132.6, 132.1, 129.7, 128.8, 126.2, 125.3, 121.2,
119.5.46.9.
4.2.18 | N‐Benzyl‐6‐methoxybenzo[d]
thiazol‐2‐amine (5c)[19c]
4.2.23 | N‐(4‐Methoxybenzyl)‐4‐
1
methylbenzo[d]thiazol‐2‐amine (5h)[19f]
Yield: 85.4 mg (79%). H NMR (400 MHz, d6‐DMSO) δ
8.29 (t, J = 5.4 Hz, 1H), 7.39–7.23 (m, 7H), 6.82 (d,
J = 8.7 Hz, 1H), 4.56 (d, J = 5.5 Hz, 2H), 3.73 (s, 3H).
13C NMR (100 MHz, d6‐DMSO) δ 165.1, 154.8, 146.9,
1
Yield: 96.7 mg (85%). H NMR (400 MHz, d6‐DMSO) δ
8.43 (t, J = 5.7 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.34

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XIE ET AL.
(d, J = 8.6 Hz, 2H), 7.05 (d, J = 7.3 Hz, 1H), 6.95–6.88 (m,
1H), 6.65 (s, 1H), 4.38 (d, J = 5.6 Hz, 2H), 2.18 (s, 3H). 13
C
NMR (100 MHz, d6‐DMSO) δ 168.0, 140.0, 135.9, 128.7,
127.8, 127.3, 119.9, 47.8, 12.1. HRMS (ESI) calcd for
C11H12N2S [MH+]: 205.0794; found: 205.0796.
3H), 4.49 (d, J = 5.8 Hz, 2H), 3.73 (s, 3H), 2.45 (s, 3H). 13
C
NMR (100 MHz, d6‐DMSO) δ 165.9, 158.9, 151.8, 131.3,
130.3, 129.5, 127.7, 126.7, 121.2, 118.8, 114.2, 55.5, 47.4,
18.6.
4.2.29 | N‐(4‐Chlorobenzyl)‐4‐
phenylthiazol‐2‐amine (5n)
4.2.24 | N‐(4‐Methoxybenzyl)‐6‐
chlorobenzo[d]thiazol‐2‐amine (5i)[19f]
1
Yield: 103.5 mg (86%). H NMR (400 MHz, d6‐DMSO) δ
1
Yield: 91.4 mg (75%). H NMR (400 MHz, d6‐DMSO) δ
8.20 (t, J = 5.9 Hz, 1H), 7.81 (d, J = 7.2 Hz, 2H), 7.44–
7.34 (m, 6H), 7.25 (t, J = 7.2 Hz, 1H), 7.07 (s, 1H), 4.50
(d, J = 5.9 Hz, 2H). 13C NMR (100 MHz, d6‐DMSO) δ
168.6, 150.4, 138.9, 135.3, 131.9, 129.9, 128.9, 128.7,
127.8, 126.1, 101.8, 47.5. HRMS (ESI) calcd for
C16H13ClN2S [MH+]: 301.0561; found: 301.0568.
8.54 (t, J = 5.6 Hz, 1H), 7.80 (d, J = 6.0 Hz, 1H), 7.37–
7.21 (m, 4H), 6.91 (d, J = 8.6 Hz, 2H), 4.50 (d,
J = 5.6 Hz, 2H), 3.72 (s, 3H). 13C NMR (100 MHz, d6‐
DMSO) δ 167.2, 158.9, 151.9, 132.6, 130.9, 129.3, 126.1,
125.1, 121.1, 119.4, 114.3, 55.4, 47.2.
4.2.25 | N‐Benzylthiazol‐2‐amine (5j)[35]
4.2.30 | N‐(1‐Phenylethyl)thiazol‐2‐amine
(8a)
Yield: 57 mg (75%). 1H NMR (400 MHz, d6‐DMSO) δ 8.05
(t, J = 5.4 Hz, 1H), 7.33–7.30 (m, 4H), 7.26–7.23 (m, 1H),
7.00 (d, J = 3.2 Hz, 1H), 6.61 (d, J = 3.4 Hz, 1H), 4.43 (d,
J = 5.8 Hz, 2H). 13C NMR (100 MHz, d6‐DMSO) δ 169.5,
139.8, 139.2, 128.7, 127.8, 127.3, 106.8, 48.2.
1
Yield: 62.1 mg (76%). H NMR (400 MHz, d6‐DMSO) δ
8.08 (d, J = 7.4 Hz, 1H), 7.37–7.29 (m, 4H), 7.21 (t,
J = 7.2 Hz, 1H), 6.95 (s, 1H), 6.56 (s, 1H), 4.78–4.71 (m,
1H), 1.42 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, d6‐
DMSO) δ 168.6, 145.4, 139.2, 128.7, 127.2, 126.5, 106.6,
54.4, 23.9. HRMS (ESI) calcd for C11H12N2S [MH+]:
205.0794; found: 205.0797.
4.2.26 | N‐(4‐Bromobenzyl)thiazol‐2‐amine
(5k)
1
Yield: 94.7 mg (88%). H NMR (400 MHz, d6‐DMSO) δ
4.2.31 | N‐(1‐o‐Tolylethyl)thiazol‐2‐amine
8.08 (t, J = 5.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.29
(d, J = 8.4 Hz, 2H), 6.99 (d, J = 3.6 Hz, 1H), 6.62 (d,
J = 3.6 Hz, 1H), 4.40 (d, J = 5.9 Hz, 2H). 13C NMR
(100 MHz, d6‐DMSO) δ 169.3, 139.4, 139.1, 131.6, 130.0,
120.3, 107.0, 47.4. HRMS (ESI) calcd for C10H9BrN2S
[MH+]: 268.9743; found: 268.9748.
(8b)
1
Yield: 64.6 mg (74%). H NMR (400 MHz, d6‐DMSO) δ
8.08 (d, J = 7.4 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.17–
7.07 (m, 3H), 6.94 (d, J = 3.6 Hz, 1H), 6.53 (d,
J = 3.6 Hz, 1H), 4.97–4.90 (m, 1H), 2.36 (s, 3H), 1.38 (d,
J = 6.8 Hz, 3H). 13C NMR (100 MHz, d6‐DMSO) δ
168.6, 143.5, 139.2, 135.1, 130.5, 126.9, 126.6, 125.1,
106.5, 50.7, 22.5, 19.1. HRMS (ESI) calcd for C12H14N2S
[MH+]: 219.0950; found: 219.0953.
4.2.27 | N‐Benzyl‐4‐methylthiazol‐2‐amine
(5l)
1
Yield: 62.1 mg (76%). H NMR (400 MHz, d6‐DMSO) δ
7.93 (t, J = 5.8 Hz, 1H), 7.33 (d, J = 4.4 Hz, 4H), 7.27–
7.22 (m, 1H), 6.15 (s, 1H), 4.40 (d, J = 5.9 Hz, 2H), 2.08
(s, 3H). 13C NMR (100 MHz, d6‐DMSO) δ 168.8, 148.2,
139.8, 128.7, 127.8, 127.3, 100.6, 48.1, 17.8. HRMS (ESI)
calcd for C11H12N2S [MH+]: 205.0794; found: 205.0797.
4.2.32 | N‐(1‐p‐Tolylethyl)thiazol‐2‐amine
(8c)
1
Yield: 74.2 mg (85%). H NMR (400 MHz, d6‐DMSO) δ
8.01 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.10
(d, J = 8.0 Hz, 2H), 6.94 (d, J = 3.6 Hz, 1H), 6.54 (d,
J = 3.6 Hz, 1H), 4.72–4.65 (m, 1H), 2.25 (s, 3H), 1.40 (d,
J = 6.9 Hz, 3H). 13C NMR (100 MHz, d6‐DMSO) δ
168.8, 142.3, 139.1, 136.2, 129.2, 126.4, 106.5, 54.2, 23.9,
21.1. HRMS (ESI) calcd for C12H14N2S [MH+]: 219.0950;
found: 219.0951.
4.2.28 | N‐Benzyl‐5‐methylthiazol‐2‐amine
(5m)
Yield: 58 mg (71%). 1H NMR (400 MHz, d6‐DMSO) δ 7.82
(t, J = 5.2 Hz, 1H), 7.32 (d, J = 4.4 Hz, 4H), 7.26–7.21 (m,

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11 of 14
(m, 1H), 6.10 (s, 1H), 4.75–4.68 (m, 1H), 2.04 (s, 3H),
1.41 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, d6‐DMSO)
δ 168.0, 148.1, 145.3, 128.7, 127.2, 126.5, 100.5, 54.3,
23.9, 17.8. HRMS (ESI) calcd for C12H14N2S [MH+]:
219.0950; found: 219.0953.
4.2.33 | N‐(1‐(2‐Chlorophenyl)ethyl)
thiazol‐2‐amine (8d)
Yield: 85 mg (89%). 1H NMR (400 MHz, d6‐DMSO) δ 8.23
(d, J = 7.3 Hz, 1H), 7.47 (dd, J = 7.7, 1.7 Hz, 1H), 7.40 (dd,
J = 7.9, 1.3 Hz, 1H), 7.33–7.29 (m, 1H), 7.26–7.22 (m, 1H),
6.94 (d, J = 3.6 Hz, 1H), 6.58 (d, J = 3.6 Hz, 1H), 5.13–5.06
(m, 1H), 1.40 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, d6‐
DMSO) δ 168.3, 142.7, 139.3, 132.2, 129.7, 128.9, 128.0,
127.0, 107.0, 51.5, 22.2. HRMS (ESI) calcd for
C11H11ClN2S [MH+]: 239.0404; found: 239.0410.
4.2.38 | 4‐Methyl‐N‐(1‐p‐tolylethyl)thiazol‐
2‐amine (8i)
1
Yield: 69.7 mg (75%). H NMR (400 MHz, d6‐DMSO) δ
7.91 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.11
(d, J = 8.0 Hz, 2H), 6.09 (s, 1H), 4.69–4.62 (m, 1H), 2.26
(s, 3H), 2.03 (s, 3H), 1.39 (d, J = 6.9 Hz, 3H). 13C NMR
(100 MHz, d6‐DMSO) δ 168.1, 148.0, 142.2, 136.2, 129.3,
126.4, 100.5, 54.1, 23.9, 21.1, 17.7. HRMS (ESI) calcd for
C13H16N2S [MH+]: 233.1107; found: 233.1111.
4.2.34 | N‐(1‐(3‐Bromophenyl)ethyl)
thiazol‐2‐amine (8e)
1
Yield: 101.9 mg (90%). H NMR (400 MHz, d6‐DMSO) δ
8.10 (d, J = 4.8 Hz, 1H), 7.55 (s, 1H), 7.39 (dd, J = 16.4,
7.8 Hz, 2H), 7.28 (t, J = 7.8 Hz, 1H), 6.98 (s, 1H), 6.60
(s, 1H), 4.81–4.71 (m, 1H), 1.41 (d, J = 6.9 Hz, 3H).
13C NMR (100 MHz, d6‐DMSO) δ 168.6, 148.5, 139.2,
130.9, 130.0, 129.2, 125.7, 122.2, 107.1, 53.9, 23.8. HRMS
(ESI) calcd for C11H11BrN2S [MH+]: 282.9899; found:
282.9903.
4.2.39 | N‐(1‐(3‐Bromophenyl)ethyl)‐4‐
methylthiazol‐2‐amine (8j)
1
Yield: 95.1 mg (80%). H NMR (400 MHz, d6‐DMSO) δ
8.00 (d, J = 7.8 Hz, 1H), 7.56 (s, 1H), 7.42–7.36 (m, 2H),
7.28 (t, J = 7.8 Hz, 1H), 6.13 (s, 1H), 4.77–4.70 (m, 1H),
2.04 (s, 3H), 1.40 (d, J = 6.9 Hz, 3H). 13C NMR
(100 MHz, d6‐DMSO) δ 167.8, 148.3, 148.1, 130.9, 130.1,
129.2, 125.8, 122.2, 100.9, 53.8, 23.9, 17.7. HRMS (ESI)
calcd for C12H13BrN2S [MH+]: 297.0056; found: 297.0061.
4.2.35 | N‐(1‐(Naphthalen‐1‐yl)ethyl)
thiazol‐2‐amine (8f)
1
Yield: 80.4 mg (79%). H NMR (400 MHz, d6‐DMSO) δ
8.25 (d, J = 7.2 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.94
(d, J = 7.7 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.60–7.45
(m, 4H), 6.92 (d, J = 3.6 Hz, 1H), 6.54 (d, J = 3.6 Hz,
1H), 5.64–5.58 (m, 1H), 1.56 (d, J = 6.8 Hz, 3H). 13C
NMR (100 MHz, d6‐DMSO) δ 168.5, 141.0, 139.1, 133.9,
131.0, 129.2, 127.7, 126.6, 126.0, 123.5, 122.6, 122.5,
106.6, 50.6, 22.9. HRMS (ESI) calcd for C15H14N2S [MH
+]: 255.0950; found: 255.0957.
4.2.40 | 5‐Methyl‐N‐(1‐phenylethyl)
thiazol‐2‐amine (8k)
1
Yield: 62.9 mg (72%). H NMR (400 MHz, d6‐DMSO) δ
7.82 (s, 1H), 7.35–7.28 (m, 4H), 7.20 (t, J = 7.0 Hz, 1H),
6.65 (s, 1H), 4.69 (d, J = 5.6 Hz, 1H), 2.15 (s, 3H), 1.40
(d, J = 6.7 Hz, 3H). 13C NMR (100 MHz, d6‐DMSO) δ
167.9, 145.5, 136.0, 128.7, 127.1, 126.5, 119.5, 54.0, 24.0,
12.1. HRMS (ESI) calcd for C12H14N2S [MH+]: 219.0950;
found: 219.0956.
4.2.36 | N‐(1‐(Naphthalen‐2‐yl)ethyl)
thiazol‐2‐amine (8g)
1
Yield: 89.5 mg (88%). H NMR (400 MHz, d6‐DMSO) δ
8.18 (d, J = 7.4 Hz, 1H), 7.88–7.84 (m, 4H), 7.56–7.45
(m, 3H), 6.94 (d, J = 3.6 Hz, 1H), 6.55 (d, J = 3.6 Hz,
1H), 4.95–4.88 (m, 1H), 1.52 (d, J = 6.9 Hz, 3H). 13C
NMR (100 MHz, d6‐DMSO) δ 168.6, 142.9, 139.2, 133.3,
132.6, 128.4, 128.1, 127.9, 126.6, 126.1, 125.2, 124.8,
106.7, 54.6, 23.8. HRMS (ESI) calcd for C15H14N2S [MH
+]: 255.0950; found: 255.0956.
4.2.41 | 5‐Methyl‐N‐(1‐o‐tolylethyl)thiazol‐
2‐amine (8l)
1
Yield: 61.3 mg (66%). H NMR (400 MHz, d6‐DMSO) δ
7.83 (d, J = 6.7 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.16–
7.06 (m, 3H), 6.59 (s, 1H), 4.91–4.84 (m, 1H), 2.34 (s,
3H), 2.14 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H). 13C NMR
(100 MHz, d6‐DMSO) δ 169.6, 143.6, 135.1, 130.5, 128.7,
126.9, 126.6, 125.1, 121.2, 50.4, 22.5, 19.1, 12.0. HRMS
(ESI) calcd for C13H16N2S [MH+]: 233.1107; found:
233.1111.
4.2.37 | 4‐Methyl‐N‐(1‐phenylethyl)
thiazol‐2‐amine (8h)
1
Yield: 70.7 mg (81%). H NMR (400 MHz, d6‐DMSO) δ
7.96 (d, J = 7.7 Hz, 1H), 7.37–7.29 (m, 4H), 7.23–7.19

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XIE ET AL.
8H), 7.05 (s, 1H), 3.54–3.46 (m, 2H), 2.92 (t, J = 7.4 Hz,
2H). 13C NMR (100 MHz, d6‐DMSO) δ 168.6, 150.5,
139.9, 135.4, 129.2, 128.9, 128.8, 127.7, 126.6, 126.1,
101.3, 46.6, 35.2. HRMS (ESI) calcd for C17H16N2S [MH
+]: 281.1107; found: 281.1112.
4.2.42 | 5‐Methyl‐N‐(1‐p‐tolylethyl)thiazol‐
2‐amine (8m)
1
Yield: 58.5 mg (63%). H NMR (400 MHz, d6‐DMSO) δ
7.76 (d, J = 6.9 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.10
(d, J = 8.0 Hz, 2H), 6.59 (s, 1H), 4.67–4.60 (m, 1H), 2.25
(s, 3H), 2.14 (s, 3H), 1.37 (d, J = 6.9 Hz, 3H). 13C NMR
(100 MHz, d6‐DMSO) δ 167.3, 142.5, 136.1, 135.9, 129.2,
126.4, 119.7, 53.9, 24.0, 21.1, 12.0. HRMS (ESI) calcd for
C13H16N2S [MH+]: 233.1107; found: 233.1111.
ACKNOWLEDGEMENTS
Financial support from the National Natural Science
Foundation of China (Grant No. 21807041), the Natural
Science Foundation of Shandong Province (Grant No.
ZR2016BL06), the NSFC cultivation project of Jining
Medical University (Grant No. JYP2018KJ10), and
the Youth Support Foundation of Jining Medical Univer-
sity (Grant No. JYFC2018KJ057) is gratefully
acknowledged.
4.2.43 | N‐(1‐(2‐Chlorophenyl)ethyl)‐5‐
methylthiazol‐2‐amine (8n)
1
Yield: 80.9 mg (80%). H NMR (400 MHz, d6‐DMSO) δ
7.99 (d, J = 7.1 Hz, 1H), 7.46 (dd, J = 7.7, 1.5 Hz, 1H),
7.39 (dd, J = 7.8, 1.2 Hz, 1H), 7.31 (td, J = 7.5, 1.1 Hz,
1H), 7.23 (td, J = 7.6, 1.7 Hz, 1H), 6.59 (s, 1H), 5.07–
5.00 (m, 1H), 2.15 (s, 3H), 1.38 (d, J = 6.9 Hz, 3H). 13C
NMR (100 MHz, d6‐DMSO) δ 166.8, 142.8, 136.2, 132.2,
129.7, 128.8, 127.9, 127.0, 120.3, 51.1, 22.2, 12.0. HRMS
(ESI) calcd for C12H13ClN2S [MH+]: 253.0561; found:
253.0564.
ORCID
Zengyang Xie https://orcid.org/0000-0002-4152-1561
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SUPPORTING INFORMATION
Additional supporting information may be found online
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