Novel solid-phase parallel synthesis of N-substituted-2-aminobenzo [d]thiazole derivatives via cyclization reactions of 2-iodophenyl thiourea intermediate resin

Article abstract of DOI:10.1021/co300112b

A novel solid-phase methodology has been developed for the synthesis of N-alkyl, N-acyl, and N-sulfonyl-2-aminobenzo[d]thiazole derivatives. The key step in this procedure involves the preparation of polymer-bound 2-aminobenzo[d]thiazole resins 5 by cyclization reaction of 2-iodophenyl thiourea resin 3. The resin-bound 2-iodophenyl thiourea 3 is produced by addition of 2-iodophenyl isothiocyanate 2 to the amine-terminated linker amide resin 1. These core skeleton 2-aminobenzo[d]thiazole resins 5 undergo functionalization reactions with various electrophiles, such as alkyl halides, acid chlorides, and sulfonyl chlorides to generate N-alkyl, N-acyl, and N-sulfonyl-2-aminobenzo[d]thiazole resins 6, 7, and 8, respectively. Finally, N-alkyl, N-acyl, and N-sulfonyl-2-aminobenzo[d]thiazole derivatives 9, 10, and 11 are then generated in good yields and purities by cleavage of the respective resins 6, 7, and 8 using trifluoroacetic acid (TFA) in dichloromethane (DCM).

Full text of DOI:10.1021/co300112b

Research Article
pubs.acs.org/acscombsci
Novel Solid-Phase Parallel Synthesis of N‑Substituted-2-aminobenzo
[d]thiazole Derivatives via Cyclization Reactions of 2‑Iodophenyl
Thiourea Intermediate Resin
Seul-Gi Kim, Se-Lin Jung, Gee-Hyung Lee, and Young-Dae Gong*
Center for Innovative Drug Library Research, Department of Chemistry, College of Science, Dongguk University, 26 Pildong 3-ga,
Jung-gu, Seoul 100-715, Korea
S
* Supporting Information
ABSTRACT: A novel solid-phase methodology has been
developed for the synthesis of N-alkyl, N-acyl, and N-sulfonyl-
2-aminobenzo[d]thiazole derivatives. The key step in this
procedure involves the preparation of polymer-bound 2-
aminobenzo[d]thiazole resins 5 by cyclization reaction of 2-
iodophenyl thiourea resin 3. The resin-bound 2-iodophenyl
thiourea 3 is produced by addition of 2-iodophenyl isothiocyanate 2 to the amine-terminated linker amide resin 1. These core
skeleton 2-aminobenzo[d]thiazole resins 5 undergo functionalization reactions with various electrophiles, such as alkyl halides,
acid chlorides, and sulfonyl chlorides to generate N-alkyl, N-acyl, and N-sulfonyl-2-aminobenzo[d]thiazole resins 6, 7, and 8,
respectively. Finally, N-alkyl, N-acyl, and N-sulfonyl-2-aminobenzo[d]thiazole derivatives 9, 10, and 11 are then generated in
good yields and purities by cleavage of the respective resins 6, 7, and 8 using trifluoroacetic acid (TFA) in dichloromethane
(DCM).
KEYWORDS: 2-5 aminobenzothiazole-based libraries, solid-phase synthesis, 2-aminobenzo[d]thiazole resins, Suzuki coupling reaction
linker that can be cleaved from resins by using nucleophilic
substitution reactions with amines.8 We have utilized this
general methodology to produce amine-functionalized 2-
aminobenzoxazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, and
thiazole libraries through consecutive oxidation and amine-
promoted cleavage of thioether linkages produced in carbon
disulfide mediated reactions of the Merrifield resin.9 However,
our developed method suffered a limitation in that we could
not efficiently introduce various substituents such as amine,
amides, sulfone amides, and urea on the 2-position of
benzo[d]oxazole core skeleton by nucleophilic substitution
reaction at the last cleavage step, as shown in Scheme 1 (resin i
→ compound I). The nucleophile substitution reaction of the
last cleavage step could only proceed with various amine
nucleophiles, and not with alcohols or thiols. Moreover, we
could not obtain the 2-aminobenzothiazole core skeleton using
our developed solid-phase synthesis.9 As a result of these
limitations, we undertook an investigation aimed at developing
efficient and simple parallel synthesis methods to produce
various N-alkyl, N-acyl, and N-sulfonyl-2-aminobenzo[d]-
thiazole derivatives by a new type of solid-phase linker which
can be used to introduce various electrophile substituents on
the 2-position of benzothiazole at the last cleavage step. Herein
we report our recent progress on this project which includes
the first solid-phase synthesis protocol for N-alkyl, N-acyl, and
INTRODUCTION
■
Heterocyclic skeletons serve as ideal scaffolds on which
pharmacophores can be appended to yield potent and selective
drugs.1 The development of unique five-membered heterocyclic
core skeletons, is especially important to drug discovery
research areas. In this respect, the potential of the benzothiazole
scaffold to serve as a privileged structure for the generation of
drug-like libraries in drug-discovery programs has been amply
demonstrated in medicinal chemistry.2 Although, benzothiazole
derivatives are of particular interest in medicinal chemistry3
and, consequently, have been the targets of several solution4
and solid-phase5 synthesis studies, the solid-phase synthesis of
benzothiazoles with sufficiently high levels of diversity has not
been reported in the drug discovery research area. Especially,
the efficient solid-phase syntheses of N-substituted-2-
aminobenzo[d]thiazoles using the Merrifield backbone resin
have not been reported for the construction of drug-like
libraries Therefore, we have previously concentrated our efforts
on describing a facile and rapid solid-phase strategy for the
preparation of a small molecule library based on the
benzothiazole scaffold. As a result, we reported a useful method
for the solid-phase synthesis of 2-aminobenzo[d]oxazole
derivatives using thioether linkage as the safety-catch linker.6
In our developed processes, the choice of the linker that serves
to attach the library scaffold to the polymer support is critical.
As a result, a variety of elegant linking methods have been
developed (i.e., safety-catch linkers7) that enable additional
diversity to be introduced into the products during the cleavage
reactions. The sulfone linker is an example of a safety-catch
Received: September 14, 2012
Revised: November 20, 2012
Published: November 20, 2012
© 2012 American Chemical Society
29
dx.doi.org/10.1021/co300112b | ACS Comb. Sci. 2013, 15, 29−40

ACS Combinatorial Science
Research Article
Scheme 1. Strategy Used to Make Various N-alkyl, N-acyl, and N-sulfonyl-2-aminobenzo[d]thiazole Libraries
a
Scheme 2. Solid-Phase Synthesis Route to the Various N-alkyl, N-acyl, and N-sulfonyl-2-benzo[d]thiazole Derivatives
a
Reagents and conditions: (i) 2-iodophenyl isothiocyanate (or 2,4-diiodophenyl isothiocyanate), Et3N, DCM, r.t., 0.5 h.; (ii) Cs2CO3, CuI(I), 1,4-
dioxane, 70 °C, 1.5 h.; (iii) R1B(OH)2, K3PO4, Pd(PPh3)4, 1,4-dioxane:H2O = 9:1, 15 h.; (iv) Alkyl halides, BuOK, NMP, 60 °C, 24 h.; (v) Acyl
t
halides, pyridine, 40 °C, 12 h.; (vi) sulfonyl halides, pyridine, 40 °C, 12 h.; (vii) TFA:DCM (1:4), 50 °C, 12 h.; and (viii) TFA:DCM (5:95), 50 °C,
3 h.
N-sulfonyl-2-aminobenzo[d]thiazole derivatives 9, 10, and 11
(Scheme 1; resin ii → compound II) via cyclization reactions of
a 2-iodophenyl thiourea resin 3 by addition of 2-iodophenyl
isothiocyanate to a terminated amine resin 1 and followed by
functionalization of 2-aminobenzo[d]thiazole and cleavage on
respective resins 6, 7, and 8 under trifluoroacetic acid (TFA)
condition. We believe our efficient approach is suitable for the
construction of drug-like N-alkyl, N-acyl, and N-sulfonyl-2-
aminobenzo[d]thiazole libraries 9, 10, and 11, respectively, in a
high throughput manner.
RESULTS AND DISCUSSION
■
The overall synthetic strategy used to prepare the target N-
alkyl, N-acyl, and N-sulfonyl-2-aminobenzo[d]thiazole ana-
30
dx.doi.org/10.1021/co300112b | ACS Comb. Sci. 2013, 15, 29−40

ACS Combinatorial Science
Research Article
Figure 1. ATR-FTIR spectra on single beads of 2-aminobenzo[d]thiazole resins 1 (a), 3a (b), 5a (c), 5b (d), 6a (e), 7a (f), and 8a (g).
a
Table 1. Results of the Cyclization Condition Optimization
entry
route
base
TEA
additive
solvent
time (h)
temp. (°C)
yields of 13 (%)
1
A
A
A
A
A
A
B
B
C
C
C
THF
pyridine
THF
24
24
24
24
24
24
24
12
6
80
80
70
60
60
60
40
90
90
90
70
trace
trace
11
24a
34d
FeCl3
HgO, S
44e
THF
8
54e
HgO, S
1,4-dioxane
THF
6
610
EDC·HCl
TBAB/CuBr
trace
trace
11
74f
DMSO
84j,k
94g
Cs2CO3
K2CO3
1,4-dioxane
DMF
CuCl2·H2O
trace
30
104j,k
114l−o
Cs2CO3
Cs2CO3
1,4-dioxane
1,4-dioxane
12
1
CuI
62
a
Reagents: (A) 2-aminothiophenol; (B) 2-iodoaniline; (C) 2-Iodophenyl isothiocyanate.
logues 9, 10, and 11 is outlined in Scheme 2. The initial solid
phase synthesis route that we developed to prepare substances
containing the benzothiazole scaffold involved the formation of
the intermediate 2-aminobenzo[d]thiazole resins 4 and 5 from
solid-supported 2-iodophenyl thiourea linker 3, which was
derived from the amine-terminated resin 1 with 2-iodophenyl
isothiocyanate 2. Next cyclization reaction of intermediate
thiourea resin 3 in the presence of cesium carbonate (Cs2CO3)
and copper(I) iodide (CuI) produced the solid bound 2-
aminobenzo[d]thiazole 4 and 5 as the key intermediate resin.
Subsequently, N-alkylation, N-acylation, and N-sulfonylation
reactions of the 2-amino group proceeded to afford respective
resins 6, 7, and 8 for effective diversification with various
electrophiles. Toward further diversification, we tried to apply
Suzuki coupling reaction. In the results, we successfully
introduced phenyl and substituted phenyl groups on the
31
dx.doi.org/10.1021/co300112b | ACS Comb. Sci. 2013, 15, 29−40

ACS Combinatorial Science
Research Article
Table 2. Yields and Purities of the N-alkyl Benzothiazole Derivatives 9
a
b
Four-step overall yields from BAL resin 1 (loading capacity of resin 1 is 1.16 mmol/g). All of the purified products were checked by LC/MS.
Five-step overall yields from BAL resin 1 (loading capacity of resin 1 is 1.16 mmol/g).
c
benzothiazole ring 4. Finally, the desired N-alkyl-, and N-acyl-,
From our results we determined an efficient cyclization
condition in which 2-aminobenzo[d]thiazole resins 4 and 5
were afforded by cyclization of 2-iodophenyl thiourea resin 3 in
the presence of Cs2CO3, CuI(I) at 70 °C for 1.5 h in 1,4-
dioxane (Table 1 entry 11). The reaction protocol was
modified from several known conditions.4l−o This process led
to the formation of the 2-aminobenzo[d]thiazole resins 4 and
5, whose single bead FTIR spectrum contained imine stretching
bands at 1541 cm−1 and the absence of the thiourea band of
resin 3 at 1585 cm−1(Figure 1, 5a(c)).
and N-sulfonyl-2-aminobenzo[d]thiazole derivatives 9, 10, and
11 were smoothly obtained by cleavage from the N-substituted
resins 6, 7, and 8, respectively, under the condition of dilute
TFA in good yields and purities (Scheme 2).
For the solid-phase parallel synthesis methodology, we
selected the backbone amide linker (BAL) resin 1 as a polymer
support since the amino group in the BAL resin 1 is suitable for
the introduction of 2-iodophenyl isothiocyanate 2 through an
addition reaction in the presence of Et3N under mild condition,
which can also serve as an efficient 2-iodophenyl thiourea linker
3 as a key intermediate resin. The progress of this addition
reaction was monitored by using attenuated total reflection
Fourier transform infrared (ATR-FTIR) spectroscopy to
measure the growth of typical thiourea infrared-bands at 1585
cm−1 (Figure 1, 3a(b)). We then attempted to obtain the 2-
aminobenzo[d]thiazole core skeleton resin 5 by cyclization
reaction in the presence of various bases (Et3N, pyridine,
K2CO3 etc.) and activation reagents (TBAB, FeCl3, HgO, and
CuCl2, etc.) based on known benzothiazole synthesis methods.4
However, we could not obtain the desired resin-bound 2-amio
benzo[d]thiazole 4 and 5 core skeletons since the known
reaction conditions of benzoxazoles were not suitable for solid-
phase reactions. Therefore, our concern focused on the
development of a resin-bound benzothiazole cyclization
reaction under convenient reaction conditions (Table 1).
For the first diversification, we tried to introduce various
electrophiles on the 2-amino group of benzo[d]thiazole core
skeleton resins 4 and 5 using alkyl halides, acid chlorides, and
sulfonyl chlorides. Initially, alkylation reaction of the 2-amino
group on 2-aminobenzo[d]thiazole resins 4 and 5 provided the
desired N-alkyl-2-benzo[d]thiazole resin 6 by reaction with
t
alkyl halides in the presence of BuOK at 60 °C for 24 h in N-
methylpyrrolidone solvent.
In this step, the progress of this reaction (R2 = Bn) was
monitored by ATR-FTIR spectroscopy, which revealed the
disappearance of the band at 1545 cm−1 (Figure 1, 5a (d)). In
the last step, the N-alkyl benzothiazole derivatives 9 was formed
and cleaved from the resin 6 by treatment of TFA: DCM (1:4)
at 50 °C for 12 h. The proton nuclear magnetic resonance (1H
NMR) spectroscopic properties of 9a, following purification by
passing through a short plug of silica, were identical to those of
32
dx.doi.org/10.1021/co300112b | ACS Comb. Sci. 2013, 15, 29−40

ACS Combinatorial Science
Research Article
Chart 1. Building Block for Amine Capping
Chart 2. Building Block for Suzuki Coupling
the corresponding substances produced by using solution-phase
synthesis routes. As shown by the data given in Table 2, the
desired various N-alkyl-2-aminobenzo[d]thiazole derivatives 9
can be produced by this five-step route in high overall yields
and purities. We successfully introduced various alkyl building
blocks (Charts 1 and 2) on the 2-amino groups of the simple
benzothiazole core skeleton ring (9a-9m) as well as R1-
substituted benzothiazole derivatives (9n-9p) by Suzuki
coupling.
easily gives the N-acyl-2-aminobenzo[d]thiazole derivatives 10
cleaved from the resin 7 by treatment of TFA:DCM (5:95) at
50 °C for 3 h. As shown by the data given in Table 3, various
N-acyl-2-aminobenzo[d]thiazole derivatives 10 can be pro-
duced by introduction of various acid chloride building blocks
on the 2-amino groups of the simple benzothiazole core
skeleton ring (10a−10n) as well as R1-substituted benzothia-
zole derivatives (10o−10t) by Suzuki coupling which were
obtained in five-step overall yields and high purities.
Next, the acylation reaction of 2-aminobenzo[d]thiazole
resins 4 and 5 produced N-acyl-2-benzo[d]thiazole resin 7 with
various acid chlorides in pyridine at 40 °C for 12 h. This
progress step (R3 = Ph) was also monitored by ATR-FTIR
spectroscopy, which revealed the disappearance of the band at
1545 cm−1 and the appearance of an amide band at 1664 cm−1
(Figure 1, 7a(e)). This N-acyl-2-aminobenzo[d]thiazole resin 7
Finally, we tried to introduce a sulfonyl functional group on
the 2- position of 2-aminobenzo[d]thiazole. The sulfonylation
reaction of the 2-aminobenzo[d]thiazole resins 4 and 5
provided the desired N-sulfonyl-2-aminobenzo[d]thiazole
resin 8 by reaction with sulfonyl chlorides in pyridine at 40
°C for 12 h. The progress of this reaction (R4 = Ph) was
monitored by ATR-FTIR spectroscopy (Figure 1, 8a(g)),
33
dx.doi.org/10.1021/co300112b | ACS Comb. Sci. 2013, 15, 29−40

ACS Combinatorial Science
Research Article
Table 3. Yields and Purities of the N-acyl-2-benzothiazole Derivatives 10
a
b
Four-step overall yields from BAL resin 1 (loading capacity of resin 1 is 1.16 mmol/g). All of the purified products were checked by LC/MS.
Five-step overall yields from BAL resin 1 (loading capacity of resin 1 is 1.16 mmol/g).
c
which revealed the disappearance of the band at 1545 cm−1 and
In each case, the desired 6-aryl-N-alkylamino-2-benzo[d]-
thiazole 9n, 6-aryl-N-acylamino-2-benzo[d]thiazole 10o, and
6-aryl-N-sulfonylamino-2-benzo[d]thiazole 11l, products are
cleaved from the respective resins by subsequent treatment
with TFA:DCM. As shown by the data given in Tables 2, 3, and
4, various 6-aryl-N-alkylamino-2-benzo[d]thiazole (9n∼9p in
Table 2), 6-aryl-N-acylamino-2-benzo[d]thiazole (10o∼10t in
Table 3), and 6-aryl-N-sulfonylamino-2-benzo[d]thiazole
(11l∼11p in Table 4), derivatives can be produced by this
five-step route in high overall yields and purities.
the appearance of sulfonamide band at 1162 cm−1. This N-
sulfonyl-2-aminobenzo[d]thiazole resin 8 easily gives the N-
sulfonyl-2-aminobenzo[d]thiazole derivatives 11 cleaved from
resin 8 by treatment of TFA:DCM (5:95) at 50 °C for 3 h.
Although the sulfonylation affords lower yields compared to the
alkylations and acylations, as shown by the data given in Table
4, various N-sulfonyl-2-aminobenzo[d]thiazole derivatives 11
(11a−11q) can be produced by this four or five-step route in
fair yields.
To introduce additional diversification into this method-
ology, the aryl group containing 6-aryl-2-aminobenzo[d]-
thiazole resin 5 was introduced by treatment with arylboronic
acid in the presence of K3PO4 and Pd(PPh3)4 in 1,4-
dioxane:H2O (9:1) for 15 h. Functionalization of the 6-aryl-2-
aminobenzo[d]thiazole resin 5 can be promoted by reactions
with alkyl halides, acid chlorides or sulfonyl chlorides using
conditions (iv), (v), and (vi) in Scheme 2 respectively to
generate the corresponding substituted 6n, 7n, and 8n resins.
In this research, an efficient solid-phase methodology has
been developed for the synthesis of 2-aminobenzothiazole-
based libraries. This solid-phase synthesis route provided much
more efficient generation of various 2-substituted alkyl/acyl/
sulfonyl benzothiazole-based libraries 9, 10, and 11 than the
standard solid-phase synthesis methods for benzothiazole
derivatives. The key diversification step commences with a 2-
aminobenzo[d]thiazole core skeleton resin 5 and relies on the
alkylation, acylation, or sulfonylation of the 2 position on the 2-
34
dx.doi.org/10.1021/co300112b | ACS Comb. Sci. 2013, 15, 29−40

ACS Combinatorial Science
Research Article
Table 4. Yields and Purities of the N-sulfonyl-2-aminobenzothiazole Derivatives 11
a
b
Four-step overall yields from BAL resin 1 (loading capacity of resin 1 is 1.16 mmol/g). All of the purified products were checked by LC/MS.
c
Five-step overall yields from BAL resin 1 (loading capacity of resin 1 is 1.16 mmol/g).
aminobenzo[d]thiazole ring. To introduce additional diversifi-
cation into this methodology, the aryl group containing 6-aryl-
2-amino-benzothiazole resin 5 was introduced by Suzuki
coupling reaction. This strategy, based on an efficient solid-
phase sequence, enables the construction of a large library and
is potentially applicable for the preparation of other drug-like
N-alkyl/acyl/sulfonyl-2-aminobenzo[d]thiazole ring systems.
Finally, the calculated physicochemical properties of members
of the library constructed by using this approach are well
distributed within reasonable orally acceptable drug-like ranges.
Further studies in this area are underway, the results of which
will be reported in due course.
column chromatography was carried out on Merck silica gel 60
(230−400 mesh). The crude products were purified by high
1
throughput chromatography using Isorea One (Biotage). H
NMR and carbon nuclear magnetic resonance (13C NMR)
spectra were recorded in δ units relative to deuterated solvent
as an internal reference using a Varian 400 MHz, Bruker 400
and 500 MHz NMR instrument. Liquid chromatography-
tandem mass spectrometry (LC-MS/MS/Agilent6460 Triple
Quad LC/MS) analysis was performed on an electrospray
ionization (ESI) mass spectrometer with photodiode-array
detector (PDA) detection. LC-MS/MS area percentage purities
of all products were determined by LC peak area analysis
(Poroshell 120 EC-C18 column, 4.6 mm × 100 mm, 2.7
Micron; PDA detector at 245 nm; 70% CH3CN/H2O). High-
resolution mass spectrometry fast-atom bombardment (HRMS-
FAB) spectra were obtained using an API 4000Q TRAP LC-
MS/MS system (Applied Biosystems).
EXPERIMENTAL PROCEDURES
■
General Procedure for Synthesis. All chemicals were
reagent grade and used as purchased. Reactions were
monitored by thin layer chromatography (TLC) analysis
using Merck silica gel 60 F-254 thin layer plates or attenuated
ATR-FTIR analysis using Identify IR (Smiths Detection). Flash
Representative Procedure for 2-Iodophenyl Thiourea
Resin 3a. To a suspension of BOMBA resin 1 (5 g, 5.8 mmol,
35
dx.doi.org/10.1021/co300112b | ACS Comb. Sci. 2013, 15, 29−40

ACS Combinatorial Science
Research Article
loading 1.16 mmol/g) in DCM (60 mL) was added
successively triethylamine (TEA; 0.81 mL, 5.8 mmol), and 2-
iodophenyl isothiocyanate 2 (0.64 g, 16 mmol) at 0 °C. The
suspension was shaken for 0.5 h at room temperature under a
nitrogen atmosphere. 2-Iodophenyl thiourea resin 3a was
filtered and washed with DCM (×2), MeOH (×2), DCM (×2)
and dried under high vacuum. Resin 3a was obtained as a
orange solid. Single-bead ATR-FTIR: 1585, 1504, 1282, 957,
820, 732 cm−1.
Representative Procedure for 2-Aminobenzo[d]-
thiazole Resin 5a. To a suspension of 2-iodophenyl thiourea
resin 3a (6.4 g, 5.8 mmol) in 1,4-dioxane (65 mL) was added
Cs2CO3 (7.5 g, 23.2 mmol), and CuI (0.22 g, 1.16 mmol). The
mixture was shaken for 1.5 h at 70 °C. The suspension was
filtered, and the precipitate containing the 2-aminobenzo[d]-
thiazole resin 5a was washed with water, MeOH (×3), and
DCM (×3) and dried under high vacuum. Resin 5a was
obtained as a dark yellow solid. Single-bead ATR-FTIR: 1542,
1492, 1450, 1419, 1375, 750, 725 cm−1.
Representative Procedure for the Suzuki Coupling
Reaction. Formation of 6-Phenyl-2-aminobenzo[d]-
thiazole Resin 5b. To a suspension of 6-iodo-2-aminobenzo
[d]thiazole resin 4a was added successively K3PO4 (1.4 g, 6.8
mmol), phenylboronic acid (0.8 g, 6.8 mmol) in 1,4-
dioxane:H2O (9:1), and Pd(PPh3)4 (0.2 g, 0.2 mmol) was
added under nitrogen atmosphere. The suspension was shaken
for 15 h at 80 °C. 6-Phenyl-2-aminobenzo[d]thiazole resin 5b
was filtered and washed with water, MeOH (×3), and DCM
(×3) and dried under high vacuum. Resin 5b was obtained as a
dark brown solid. Single-bead ATR-FTIR: 1527, 1506, 1493,
1450, 1419, 872, 758, 698 cm−1.
DCM (×3) and dried under high vacuum. Resin 7a was
obtained as a yellow-orange solid. Single-bead ATR-FTIR:
1719, 1655(CO), 1502, 1492, 1450, 1376, 1253, 972 cm−1.
Representative Procedure for the Third-Generation
Sulfonylation Reaction Step vi, the Preparation of N-
benzenesulfonyl-2-aminobenzo[d]thiazole Resin 8a. To
a suspension of 2-aminobenzo[d]thiazole resin 5a (150 mg,
0.15 mmol) in pyridine (4 mL) was added benzenesulfonyl
chloride (0.18 mL, 1.5 mmol) and catalytic amounts of DMAP.
The mixture was shaken for 12 h at 40 °C. N-benzenesulfonyl-
2-aminobenzo[d]thiazole resin 8a was filtered and washed with
water, MeOH (×3), and DCM (×3) and dried under high
vacuum. 8a was obtained as a yellow-orange solid. Single-bead
ATR-FTIR: 1676, 1603, 1503, 1492, 1445, 1362, 1270 cm−1.
Representative Procedure for the Cleavage Step vii:
the Preparation of N-benzyl-2-aminobenzo [d]thiazole
9a from Resin 6a. A mixture of N-benzyl-2-aminobenzo
[d]thiazole resin 6a(150 mg, 0.15 mmol) and 3 mL of cleavage
cocktail (TFA:DCM = 1:4, v/v) was shaken at 50 °C for 12 h.
The resin was filtered, and the filtrate was concentrated in
vacuum to give a residue that was dissolved in DCM. The
organic filtrates were neutralized by adding saturated NaHCO3
solution. The filtrate was washed with water and dried over
MgSO4. The solution was concentrated under reduced
pressure, and the residue was purified by column silica gel
chromatography to afford 9a (14 mg, 45%, four-step overall
yield from BOMBA resin, loading capacity 1.16 mmol/g) as a
1
white solid. mp 161−162 °C; H NMR (400 MHz, CDCl3) δ
7.57 (dd, J = 7.9, 0.7 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.42−
7.38 (m, 2H), 7.38−7.26 (m, 4H), 7.11−7.04 (m, 1H), 6.24 (s,
1H), 4.63 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 167.5,
152.3, 137.5, 130.5, 128.8, 127.9, 127.7, 126.0, 121.6, 120.8,
119.0, 49.4; LC-MS/MS (ESI): m/z = 241.0 [M+1]+. HRMS
(EI): [M+1]+ calcd for C14H13N2S, 241.0794; found, 240.963.
Representative Procedure for the First-Generation
Alkylation Reaction Step iv, the Preparation of N-
benzyl-2-aminobenzo[d]thiazole Resin 6a. To a suspen-
sion of 2-aminobenzo[d] thiazole resin 5a (150 mg, 0.15
1
N-(4-methylbenzyl)-2-aminobenzo[d]thiazole (9b). H
t
NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.8 Hz, 1H), 7.52 (d, J
= 8.0 Hz, 1H), 7.33−7.26 (m, 3H), 7.17 (d, J = 7.8 Hz, 2H),
7.08 (t, J = 7.6 Hz, 1H), 5.77 (s, 1H), 4.59 (s, 2H), 2.35 (s,
3H); LC-MS/MS (ESI): m/z = 255.0 [M+1]+.
mmol) in NMP (4 mL) was added BuOK (168 mg, 1.5
mmol). After shaking for 1 h, benzyl chloride (0.17 mL, 1.5
mmol) was added to the mixture which was then shaken for 24
h at 60 °C. N-benzyl-2-aminobenzo[d]thiazole resin 6a was
filtered and washed with water, MeOH (×3), and DCM (×3)
and dried under high vacuum. Resin 6a was obtained as a
yellow-orange solid. Single-bead ATR-FTIR: 1682, 1534, 1504,
1493, 1450, 1376 cm−1.
Representative Procedure for the First-Generation
Alkylation Reaction Step iv, Preparation of 6-Phenyl-N-
benzyl-2-aminobenzo[d]thiazole Resin 6n. To a suspen-
sion of 6-phenyl-2-aminobenzo[d] thiazole resin 5b (150 mg,
0.14 mmol) in 1,4-dioxane (4 mL) were added LiHMDS (234
mg, 1.4 mmol). After shaking for 1 h, benzyl chloride (0.17 mL,
1.5 mmol) was added to the mixture which was then shaken for
24 h at 60 °C. 6-Phenyl-N-benzyl-2-aminobenzo[d]thiazole
resin 6n was filtered and washed with water, MeOH (×3), and
DCM (×3) and dried under high vacuum. Resin 6n was
obtained as a dark brown solid. Single-bead ATR-FTIR: 1682,
1534, 1504, 1493, 1450, 1376 cm−1.
Representative Procedure for the Second-Generation
Acylation Reaction Step v, the Preparation of N-
benzoyl-2-aminobenzo[d]thiazole Resin 7a. To a suspen-
sion of 2-aminobenzo[d]thiazole resin 5a (150 mg, 0.15 mmol)
in pyridine (4 mL) was added benzoyl chloride (0.17 mL, 1.5
mmol) and catalytic amounts of DMAP. The mixture was
shaken for 12 h at 40 °C. N-benzoyl-2-aminobenzo [d]thiazole
resin 7a was filtered and washed with water, MeOH (×3), and
N-(4-methoxybenzyl)-2-aminobenzo[d]thiazole (9c).
1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.9 Hz, 1H),
7.50 (d, J = 8.1 Hz, 1H), 7.37−7.26 (m, 3H), 7.08 (t, J = 7.6
Hz, 1H), 6.89 (d, J = 8.6 Hz, 2H), 5.84 (s, 1H), 4.56 (s, 2H),
3.80 (s, 3H); LC-MS/MS (ESI): m/z = 271.0 [M+1]+.
1
N-(4-fluorobenzyl)-2-aminobenzo[d]thiazole (9d). H
NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.9 Hz, 1H), 7.53 (d, J
= 8.0 Hz, 1H), 7.37 (dd, J = 8.5, 5.4 Hz, 2H), 7.33−7.27 (m,
1H), 7.13−6.99 (m, 3H), 5.70 (s, 1H), 4.62 (s, 2H); LC-MS/
MS (ESI): m/z = 259.0 [M+1]+.
1
N-(4-chlorobenzyl)-2-aminobenzo[d]thiazole (9e). H
NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.8 Hz, 1H), 7.49 (d, J
= 8.0 Hz, 1H), 7.31−7.26 (m, J = 7.7 Hz, 1H), 7.13−7.07 (m, J
= 7.6 Hz, 1H), 6.02 (s, 1H), 4.62 (s, 2H); LC-MS/MS (ESI):
m/z = 274.9 [M+1]+.
N-(4-trifluoromethylbenzyl)-2-aminobenzo[d]thiazole
1
(9f). H NMR (400 MHz, CDCl3) δ 7.66−7.56 (m, J = 11.8,
8.1 Hz, 3H), 7.55−7.46 (m, J = 13.4, 8.1 Hz, 3H), 7.33−7.26
(m, 1H), 7.14−7.07 (m, J = 11.0, 4.2 Hz, 1H), 6.12 (s, 1H),
4.72 (s, 2H); LC-MS/MS (ESI): m/z = 309.0 [M+1]+.
N-(4-cyanobenzyl)-2-aminobenzo[d]thiazole (9g). 1H
NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.3 Hz, 2H), 7.59 (d, J
= 7.9 Hz, 1H), 7.52 (dd, J = 8.2, 2.8 Hz, 3H), 7.34−7.27 (m, J =
7.7 Hz, 1H), 7.15−7.09 (m, J = 7.6 Hz, 1H), 5.86 (s, 1H), 4.75
36
dx.doi.org/10.1021/co300112b | ACS Comb. Sci. 2013, 15, 29−40

ACS Combinatorial Science
Research Article
(s, 2H); 13C NMR (126 MHz, DMSO) δ 166.6, 152.7, 145.6,
132.8, 131.0, 128.5, 126.1, 121.7, 121.5, 119.4, 118.7, 110.2,
47.1; LC-MS/MS (ESI): m/z = 266.0 [M+1]+.
Representative Procedure for the Cleavage Step viii;
Preparation of N-benzoyl-2-aminobenzo [d]thiazole 10a
from Resin 7a. A mixture of N-benzoyl-2-aminobenzo
[d]thiazole resin 7a(150 mg, 0.15 mmol) and 3 mL of cleavage
cocktail (TFA:DCM = 5:95, v/v) was shaken at 50 °C for 3 h.
The resin was filtered, and the filtrate was concentrated in
vacuum to give a residue that was dissolved in DCM. The
organic filtrates were adjusted to pH 5−6 by adding saturated
NaHCO3 solution. The filtrate was washed with water and
dried over MgSO4. The solution was concentrated under
reduced pressure, and the residue was purified by column silica
gel chromatography to afford 10a (19 mg, 49%, four-step
overall yield from BOMBA resin, loading capacity 1.16 mmol/
N-methyl-2-aminobenzo[d]thiazole (9h). 1H NMR (400
MHz, CDCl3) δ 7.59 (dd, J = 7.9, 0.7 Hz, 1H), 7.57−7.52 (m,
1H), 7.33−7.27 (m, 1H), 7.12−7.05 (m, J = 7.8, 1.1 Hz, 1H),
5.65 (s, 1H), 3.11 (s, 3H); LC-MS/MS (ESI): m/z = 165.0 [M
+1]+.
N-allyl-2-aminobenzo[d]thiazole (9i). 1H NMR (400
MHz, CDCl3) δ 7.56 (dd, J = 18.1, 8.0 Hz, 2H), 7.29 (t, J = 7.7
Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 5.98 (ddd, J = 22.0, 10.6, 5.5
Hz, 1H), 5.67−5.46 (m, 1H), 5.35 (d, J = 17.1 Hz, 1H), 5.23
(d, J = 10.3 Hz, 1H), 4.07 (d, J = 5.4 Hz, 2H); LC-MS/MS
(ESI): m/z = 190.9 [M+1]+.
1
g) as a white solid. mp 187−188 °C; H NMR (400 MHz,
N-(cyclopropylmethyl)-2-aminobenzo[d]thiazole (9j).
1H NMR (400 MHz, CDCl3) δ 7.73−7.44 (m, 2H), 7.34−
7.26 (m, 1H), 7.12−7.04 (m, 1H), 5.55 (s, 1H), 3.29 (d, J = 7.1
Hz, 2H), 1.22−1.08 (m, 1H), 0.63−0.54 (m, 2H), 0.34−0.26
(m, 2H); LC-MS/MS (ESI): m/z = 205.1 [M+1]+.
CDCl3) δ 11.68 (s, 1H), 8.00 (d, J = 7.3 Hz, 2H), 7.88−7.80
(m, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H),
7.31−7.26 (m, 1H), 7.25 (d, J = 3.6 Hz, 2H); 13C NMR (101
MHz, CDCl3) δ 165.9, 159.6, 147.9, 133.1, 132.1, 132.0, 129.0,
127.9, 126.1, 124.0, 121.4, 120.7; LC-MS/MS (ESI): m/z =
254.9 [M+1]+. HRMS (EI): [M+1]+ calcd for C14H11N2OS,
255.0587; found, 254.749.
N-(4-methylbenzoyl)-2-aminobenzo[d]thiazole (10b).
1H NMR (400 MHz, CDCl3) δ 11.14 (s, 1H), 7.92−7.86 (m,
2H), 7.86−7.78 (m, 1H), 7.44−7.34 (m, 1H), 7.34−7.27 (m,
2H), 7.23 (d, J = 7.9 Hz, 2H), 2.39 (s, 3H); LC-MS/MS (ESI):
m/z = 269.0 [M+1]+.
N-(4-methoxybenzoyl)-2-aminobenzo[d]thiazole
(10c). 1H NMR (400 MHz, CDCl3) δ 10.90 (s, 1H), 7.96 (d, J
= 8.8 Hz, 2H), 7.89−7.80 (m, 1H), 7.49 (d, J = 7.6 Hz, 1H),
7.38−7.27 (m, 2H), 6.92 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H); LC-
MS/MS (ESI): m/z = 282.9 [M+1]+.
N-(4-fluorobenzoyl)-2-aminobenzo[d]thiazole (10d).
1H NMR (400 MHz, CDCl3) δ 11.42 (s, 1H), 8.05−7.97
(m, 2H), 7.89−7.82 (m, 1H), 7.39−7.29 (m, 3H), 7.14−7.06
(m, 2H); 13C NMR (101 MHz, CDCl3) δ 165.6 (d, J = 255.1
Hz), 165.1, 160.1, 147.4, 131.8, 130.6 (d, J = 9.3 Hz), 128.3 (d,
J = 3.1 Hz), 126.1, 124.2, 121.5, 120.4, 116.2 (d, J = 22.2 Hz);
LC-MS/MS (ESI): m/z = 273.0 [M+1]+.
N-(cyclohexylmethyl)-2-aminobenzo[d]thiazole (9k).
1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.9 Hz, 1H),
7.51 (d, J = 7.8 Hz, 1H), 7.32−7.26 (m, 1H), 7.07 (td, J = 8.1,
1.0 Hz, 1H), 5.45 (s, 1H), 3.25 (d, J = 6.8 Hz, 2H), 1.86−1.60
(m, J = 22.3, 18.4, 10.1 Hz, 7H), 1.32−1.14 (m, 3H), 1.01 (qd,
J = 12.1, 2.9 Hz, 2H); LC-MS/MS (ESI): m/z = 247.0 [M+1]+.
N-(methylethylether)-2-aminobenzo[d]thiazole (9l).
1H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 10.7, 8.0 Hz,
2H), 7.33−7.26 (m, 1H), 7.12−7.05 (m, 1H), 5.61 (s, 1H),
3.70−3.58 (m, 4H), 3.40 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 167.2, 152.4, 130.5, 125.9, 121.6, 120.8, 119.0, 70.8,
58.8, 44.8. LC-MS/MS (ESI): m/z = 209.0 [M+1]+.
N-(3-phenylpropyl)-2-aminobenzo[d]thiazole (9m).
1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.8 Hz, 1H),
7.52 (d, J = 8.1 Hz, 1H), 7.41−7.26 (m, 3H), 7.24−7.16 (m, J =
12.5, 4.2 Hz, 3H), 7.12−7.03 (m, 1H), 5.50 (s, 1H), 3.45 (t, J =
7.0 Hz, 2H), 2.75 (t, 2H), 2.03 (dt, J = 14.4, 7.2 Hz, 2H); LC-
MS/MS (ESI): m/z = 269.1 [M+1]+.
1
6-Phenyl-N-benzyl-2-aminobenzo[d]thiazole (9n). H
N-(4-chlorobenzoyl)-2-aminobenzo[d]thiazole (10e).
1H NMR (400 MHz, CDCl3) δ 11.43 (s, 1H), 7.95−7.90
(m, 2H), 7.88−7.83 (m, 1H), 7.42−7.38 (m, 2H), 7.38−7.29
(m, 3H); 13C NMR (101 MHz, CDCl3) δ 165.2, 160.0, 147.3,
139.5, 131.7, 130.5, 129.4, 129.3, 126.2, 124.2, 121.5, 120.4;
LC-MS/MS (ESI): m/z = 288.9 [M+1]+.
NMR (400 MHz, CDCl3) δ 7.80 (d, J = 1.6 Hz, 1H), 7.61−
7.52 (m, 4H), 7.44−7.31 (m, 8H), 5.89 (s, 1H), 4.66 (s, J = 8.5
Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 167.4, 151.8, 141.1,
137.4, 135.3, 131.3, 128.9, 128.8, 127.9, 127.7, 127.0, 126.9,
125.5, 119.3, 119.1, 49.4; LC-MS/MS (ESI): m/z = 317.0 [M
+1]+. HRMS (EI): [M+1]+ calcd for C20H17N2S, 317.1107;
found, 316.992.
6-(4-Methoxyphenyl)-N-benzyl-2-aminobenzo[d]-
thiazole (9o). 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 1.7
Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.53−7.48 (m, 3H), 7.43−
7.30 (m, 5H), 6.97 (d, J = 8.8 Hz, 2H), 4.65 (s, 2H), 3.85 (s,
3H); 13C NMR (126 MHz, CDCl3) δ 167.3, 158.8, 151.2,
137.4, 134.9, 133.6, 131.2, 128.8, 128.0, 127.9, 127.7, 125.1,
119.0, 118.8, 114.2, 55.4, 49.4; LC-MS/MS (ESI): m/z = 347.0
[M+1]+.
N-(4-trifluoromethylbenzoyl)-2-aminobenzo[d]-
1
thiazole (10f). H NMR (500 MHz, DMSO) δ = 13.19 (s,
1H), 8.35 (d, J = 7.6 Hz, 2H), 8.04 (d, J = 7.8 Hz, 1H), 7.94 (d,
J = 7.7 Hz, 2H), 7.82 (d, J = 7.9 Hz, 1H), 7.50 (t, J = 7.6 Hz,
1H), 7.37 (t, J = 7.5 Hz, 1H); 13C NMR (126 MHz, DMSO) δ
165.36, 159.23, 147.59, 135.85, (q, J = 32.0 Hz), 131.29,
129.28, 126.28, 125.51(q, J = 3.5 Hz), 123.79 (q, J = 272.7 Hz),
123.82, 121.84, 120.10; LC-MS/MS (ESI): m/z = 322.9 [M
+1]+.
N-(4-cyanobenzoyl)-2-aminobenzo[d]thiazole (10g).
1H NMR (400 MHz, CDCl3) δ 10.85 (s, 1H), 8.09 (d, J =
8.5 Hz, 2H), 7.90−7.85 (m, 1H), 7.77 (d, J = 8.5 Hz, 2H),
7.55−7.50 (m, 1H), 7.43−7.33 (m, 2H); LC-MS/MS (ESI):
m/z = 280.0 [M+1]+.
6-(3-Nitrophenyl)-N-benzyl-2-aminobenzo[d]thiazole
(9p). 1H NMR (400 MHz, CDCl3) δ 8.45 (t, J = 2.0 Hz, 1H),
8.17 (ddd, J = 8.2, 2.2, 0.9 Hz, 1H), 7.91 (ddd, J = 7.8, 1.6, 1.0
Hz, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.65−7.52 (m, 3H), 7.45−
7.30 (m, 5H), 5.76 (s, 1H), 4.68 (s, 2H); 13C NMR (126 MHz,
DMSO) δ 167.7, 153.4, 148.9, 142.3, 139.2, 133.3, 132.2, 131.1,
130.9, 128.9, 127.9, 127.6, 125.2, 121.9, 121.1, 120.1, 118.9,
47.7; LC-MS/MS (ESI): m/z = 361.9 [M+1]+.
N-acetyl-2-aminobenzo[d]thiazole (10h). 1H NMR
(400 MHz, CDCl3) δ 10.90 (s, 1H), 7.85 (ddd, J = 7.9, 1.1,
0.5 Hz, 1H), 7.80−7.74 (m, 1H), 7.46 (ddd, J = 8.2, 7.3, 1.2 Hz,
37
dx.doi.org/10.1021/co300112b | ACS Comb. Sci. 2013, 15, 29−40

ACS Combinatorial Science
Research Article
1H), 7.34 (ddd, J = 8.3, 7.4, 1.1 Hz, 1H), 2.30 (s, 3H); LC-MS/
MS (ESI): m/z = 193.0 [M+1]+.
6-(4-Methoxyphenyl)-N-benzoyl-2-aminobenzo[d]-
thiazole (10q). 1H NMR (400 MHz, CDCl3) δ 11.10 (s, 1H),
8.05−7.96 (m, J = 5.9, 4.5 Hz, 3H), 7.63−7.54 (m, 3H), 7.53−
7.45 (m, 3H), 7.43 (d, J = 8.5 Hz, 1H), 7.04−6.96 (m, 2H),
3.87 (s, 3H); 13C NMR (126 MHz, DMSO) δ 166.4, 159.3,
159.0, 158.6, 136. 2, 133.4, 133.0, 132.8, 132.4, 129.1, 128.8,
128.4, 125.3, 121.0, 119.5, 114. 9, 55.6; LC-MS/MS (ESI): m/z
= 361.0 [M+1]+.
N-cyclopropanecarbonyl-2-aminobenzo[d]thiazole
(10i). 1H NMR (400 MHz, CDCl3) δ 12.15 (s, 1H), 7.85 (d, J
= 7.4 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.47−7.41 (m, 1H),
7.35−7.29 (m, 1H), 1.77−1.69 (m, 1H), 1.30−1.23 (m, 2H),
1.01−0.94 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 172.9,
160.4, 147.7, 131.9, 126.3, 123.9, 121.7, 120.0, 15.2, 9.5; LC-
MS/MS (ESI): m/z = 219.0 [M+1]+.
6-(4-Methoxyphenyl)-N-acetyl-2-aminobenzo[d]-
1
N-trimethylacetyl-2-aminobenzo[d]thiazole (10j). 1H
NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.83 (d, J = 7.9 Hz,
1H), 7.76 (d, J = 8.1 Hz, 1H), 7.49−7.40 (m, 1H), 7.36−7.28
(m, 1H), 1.36 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 176.6,
158.3, 148.2, 132.2, 126.2, 123.9, 121.4, 120.8, 39.4, 27.2; LC-
MS/MS (ESI): m/z = 235.0 [M+1]+.
thiazole (10r). H NMR (400 MHz, CDCl3) δ 10.70−10.42
(m, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H),
7.64 (dd, J = 8.5, 1.8 Hz, 1H), 7.61−7.54 (m, 2H), 7.01 (d, J =
8.8 Hz, 2H), 3.87 (s, 3H), 2.32 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 168.4, 159.3, 158.8, 146.8, 137.3, 133.2, 132.8, 128.3,
125.7, 120.7, 119.7, 114.4, 55.4, 23.6; LC-MS/MS (ESI): m/z =
299.0 [M+1]+.
1
N-hexanoyl-2-aminobenzo[d]thiazole (10k). H NMR
6-(3-Nitrophenyl)-N-benzoyl-2-aminobenzo[d]-
(400 MHz, CDCl3) δ 10.88 (s, 1H), 7.85 (d, J = 7.4 Hz, 1H),
7.77 (d, J = 8.1 Hz, 1H), 7.49−7.41 (m, 1H), 7.38−7.30 (m,
1H), 2.55−2.39 (m, 2H), 1.71 (dt, J = 14.4, 7.2 Hz, 2H), 1.31−
1.22 (m, 4H), 0.85 (t, J = 6.9 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 171.8, 159.2, 147.9, 132.0, 126.3, 124.0, 121.6, 120.5,
36.5, 31.2, 24.7, 22.2, 13.8; LC-MS/MS (ESI): m/z = 249.0 [M
+1]+.
1
thiazole (10s). H NMR (400 MHz, CDCl3) δ 11.03−10.75
(m, 1H), 8.50 (t, J = 1.9 Hz, 1H), 8.22 (ddd, J = 8.2, 2.2, 0.9
Hz, 1H), 8.10 (d, J = 1.5 Hz, 1H), 8.06−8.00 (m, 2H), 7.97
(ddd, J = 7.7, 1.6, 1.0 Hz, 1H), 7.67−7.58 (m, 3H), 7.52 (dd, J
= 15.5, 7.8 Hz, 3H); 13C NMR (101 MHz, DMSO) δ 166.6,
160.51, 149.2, 149.0, 142.0, 133.8, 133.8, 133.4, 133.2, 132.3,
131.0, 129.1, 128.8, 125.9, 122.4, 121.6, 121.3, 120.9; LC-MS/
MS (ESI): m/z = 376.0 [M+1]+.
N-(3,3-dimethylbutyryl)-2-aminobenzo[d]thiazole
1
(10l). H NMR (400 MHz, CDCl3) δ 10.79 (s, J = 188.0 Hz,
6-(3-Nitrophenyl)-N-acetyl-2-aminobenzo[d]thiazole
(10t). 1H NMR (400 MHz, DMSO) δ 12.44 (s, 1H), 8.52 (t, J
= 1.9 Hz, 1H), 8.46 (s, 1H), 8.22 (dd, J = 7.9, 1.7 Hz, 2H), 7.85
1H), 7.85 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.50−
7.43 (m, 1H), 7.38−7.30 (m, 1H), 2.33 (s, 2H), 0.94 (s, 9H);
13C NMR (101 MHz, CDCl3) δ 170.5, 159.5, 147.7, 131.9,
126.3, 124.0, 121.6, 120.5, 49.8, 31.4, 29.4; LC-MS/MS (ESI):
m/z = 249.1 [M+1]+.
(d, J = 1.0 Hz, 2H), 7.78 (t, J = 8.0 Hz, 1H), 2.23 (s, 3H); 13
C
NMR (126 MHz, DMSO) δ 170.1, 159.6, 149.3, 149.0, 142.1,
133.8, 133.6, 133.1, 131.0, 125.8, 122.4, 121.6, 121.4, 120.8,
40.5, 40.3, 40.2,40.0, 39.8, 39.6, 39.5, 23.3; LC-MS/MS (ESI):
m/z = 314.0 [M+1]+.
N-(2-thienoyl)-2-aminobenzo[d]thiazole (10m). 1H
NMR (400 MHz, CDCl3) δ 8.33 (dd, J = 3.9, 1.0 Hz, 1H),
7.92−7.84 (m, J = 5.2, 4.0 Hz, 2H), 7.78 (dd, J = 5.0, 1.0 Hz,
1H), 7.60 (ddd, J = 8.4, 7.4, 1.1 Hz, 1H), 7.55−7.46 (m, 1H),
7.28 (dd, J = 4.9, 4.0 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ
160.5, 159.8, 147.5, 136.5, 133.1, 132.0, 130.8, 128.3, 126.3,
124.1, 121.5, 120.6; LC-MS/MS (ESI): m/z = 260.9 [M+1]+.
N-(2-quinolinecarbonyl)-2-aminobenzo[d]thiazole
Representative Procedure for the Cleavage Step viii,
Preparation of N-benzenesulfonyl-2-aminobenzo[d]-
thiazole 11a from Resin 8a. A mixture of N-benzenesulfon-
yl-2-aminobenzo [d]thiazole resin 8a(150 mg, 0.15 mmol) and
3 mL of cleavage cocktail (TFA:DCM = 5:95, v/v) was shaken
at 50 °C for 3 h. The resin was filtered, and the filtrate was
concentrated in vacuum to give a residue that was dissolved in
DCM. The organic filtrates were adjusted to pH 5−6 by
saturated adding NaHCO3 solution. The filtrate was washed
with water and dried over MgSO4. The solution was
concentrated under reduced pressure, and the residue was
triturated with ether and the solid was collected to give 11a (12
mg, 27%, four-step overall yield from BOMBA resin, loading
1
(10n). H NMR (400 MHz, CDCl3) δ 11.55 (s, 1H), 8.48−
8.36 (m, 2H), 8.23−8.15 (m, 1H), 7.94 (dd, J = 8.2, 0.8 Hz,
1H), 7.91−7.80 (m, 3H), 7.70 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H),
7.54−7.44 (m, 1H), 7.39−7.31 (m, 1H); 13C NMR (101 MHz,
CDCl3) δ 162.6, 157.4, 148.9, 147.1, 146.4, 138.1, 132.4, 130.8,
129.9, 129.8, 128.9, 127.8, 126.3, 124.0, 121.5, 121.2, 118.7;
LC-MS/MS (ESI): m/z = 306.0 [M+1]+.
1
6-Phenyl-N-benzoyl-2-aminobenzo[d]thiazole (10o).
1H NMR (400 MHz, CDCl3) δ 11.59 (s, 1H), 8.07−7.98
(m, 3H), 7.66−7.59 (m, 2H), 7.56 (t, J = 7.5 Hz, 1H), 7.47
(ddd, J = 23.9, 12.4, 5.0 Hz, 5H), 7.36 (t, J = 7.4 Hz, 1H), 7.30
(d, J = 8.5 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 165.9,
159.7, 147.2, 140.7, 137.5, 133.1, 132.8, 132.0, 129.1, 128.9,
127.9, 127.4, 127.3, 125.7, 120.8, 119.7; LC-MS/MS (ESI): m/
z = 331.0 [M+1]+. HRMS (EI): [M+1]+ calcd for C20H15N2OS,
331.0900; found, 331.001.
capacity 1.16 mmol/g) as an ivory solid. mp 269−270 °C; H
NMR (400 MHz, DMSO) δ 13.22 (s, 1H), 7.91−7.84 (m, 2H),
7.81 (d, J = 7.6 Hz, 1H), 7.64−7.60 (m, 1H), 7.60−7.52 (m,
2H), 7.44−7.36 (m, 1H), 7.32−7.24 (m, 2H); 13C NMR (101
MHz, DMSO) δ 167.5, 142.5, 136.69, 132.9, 129.6, 127.7,
126.3, 125.2, 124.2, 123.2, 113.3; LC-MS/MS (ESI): m/z =
290.9 [M+1]+. HRMS (EI): [M+1]+ calcd for C13H11N2O2S2,
291.0256; found, 290.844.
1
N-toluenesulfonyl-2-aminobenzo[d]thiazole (11b). H
1
6-Phenyl-N-acetyl-2-aminobenzo[d]thiazole (10p). H
NMR (400 MHz, DMSO) δ 13.18 (s, 1H), 7.80 (d, J = 7.5 Hz,
1H), 7.75 (d, J = 8.2 Hz, 2H), 7.43−7.34 (m, 3H), 7.33−7.22
(m, 2H), 2.36 (s, 3H); LC-MS/MS (ESI): m/z = 305.0 [M
+1]+.
N-(4-methoxybenzene)sulfonyl-2-aminobenzo[d]-
thiazole (11c). 1H NMR (400 MHz, DMSO) δ 13.12 (s, 1H),
7.79 (d, J = 8.9 Hz, 3H), 7.42−7.36 (m, 1H), 7.30 (d, J = 7.9
Hz, 1H), 7.27−7.22 (m, 1H), 7.12−7.04 (m, 2H), 3.81 (s, 3H);
NMR (400 MHz, CDCl3) δ 11.15 (s, 1H), 8.05 (d, J = 1.7 Hz,
1H), 7.82 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 8.4, 1.7 Hz, 1H),
7.64 (d, J = 7.3 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.37 (t, J =
7.3 Hz, 1H), 2.32 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
168.5, 159.4, 147.2, 140.6, 137.7, 132.8, 128.9, 127.4, 127.3,
126.0, 120.7, 120.0, 23.6; LC-MS/MS (ESI): m/z = 269.0 [M
+1]+.
38
dx.doi.org/10.1021/co300112b | ACS Comb. Sci. 2013, 15, 29−40

ACS Combinatorial Science
Research Article
13C NMR (101 MHz, DMSO) δ 167.1, 162.6, 137.0, 134.4,
128.4, 127.6, 125.3, 123.9, 123.1, 114.7, 113.3, 56.1; LC-MS/
MS (ESI): m/z = 321.0 [M+1]+.
N-(4-fluorobenzene)sulfonyl-2-aminobenzo[d]-
thiazole 11d. 1H NMR (400 MHz, DMSO) δ 7.96−7.87 (m,
2H), 7.76 (d, J = 7.8 Hz, 1H), 7.41−7.28 (m, 4H), 7.24−7.15
(m, 1H); 13C NMR (101 MHz, DMSO) δ 171.7, 167.6, 164.3
(d, J = 249.9), 139.7 (d, J = 3.1), 129.2 (d, J = 9.3), 127.2,
126.8, 123.4, 122.7, 116.4 (d, J = 22.5), 114.4; LC-MS/MS
(ESI): m/z = 308.9 [M+1]+.
6-(4-Methoxyphenyl)-N-benzenesulfonyl-2-
aminobenzo[d]thiazole 11n. H NMR (400 MHz, DMSO)
1
δ 13.19 (s, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.93−7.84 (m, 2H),
7.69−7.53 (m, 6H), 7.34 (d, J = 8.4 Hz, 1H), 7.08−6.99 (m,
2H), 3.80 (s, 3H); 13C NMR (126 MHz, DMSO) δ 166.9,
158.8, 141.9, 135.7, 132.3, 131.5, 129.0, 127.6, 125.7, 125.6,
125.5, 120.1, 114.4, 113.0, 55.1; LC-MS/MS (ESI): m/z =
397.0 [M+1]+.
6-(4-Methoxyphenyl)-N-methanesulfonyl-2-
1
aminobenzo[d]thiazole 11o. H NMR (400 MHz, DMSO)
δ 12.99 (s, 1H), 8.06 (s, 1H), 7.70−7.55 (m, 3H), 7.36 (d, J =
8.4 Hz, 1H), 7.04 (d, J = 8.6 Hz, 2H), 3.80 (s, 3H), 3.02 (s,
3H); 13C NMR (126 MHz, DMSO) δ 166.9, 159.4, 136.0,
135.6, 132.2, 128.2, 126.3, 125.8, 120.5, 114.9, 113.3, 55.7; LC-
MS/MS (ESI): m/z = 335.0 [M+1]+.
N-(4-chlorobenzene)sulfonyl-2-aminobenzo[d]-
1
thiazole 11e. H NMR (400 MHz, DMSO) δ 13.29 (s, 1H),
7.92−7.85 (m, 2H), 7.82 (d, J = 7.6 Hz, 1H), 7.70−7.60 (m,
2H), 7.45−7.37 (m, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.30−7.24
(m, 1H); 13C NMR (126 MHz, DMSO) δ 167.8, 141.4, 137.6,
136.9, 129.7, 128.2, 127.8, 125.3, 124.2, 123.2, 113.5; LC-MS/
MS (ESI): m/z = 324.9 [M+1]+.
6-(3-Nitrophenyl)-N-benzenesulfonyl-2-aminobenzo-
1
[d]thiazole 11p. H NMR (400 MHz, DMSO) δ 13.33 (s,
1H), 8.46 (s, 1H), 8.31 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.15
(d, J = 7.8 Hz, 1H), 7.92−7.74 (m, 5H), 7.65−7.56 (m, 4H),
7.42 (d, J = 8.4 Hz, 1H); 13C NMR (126 MHz, DMSO) δ
167.7, 148.9, 142.3, 141.4, 137.0, 133.9, 133.6, 133.0, 131.1,
129.7, 126.7, 126.5, 126.3, 122.6, 121.8, 121.5, 113.8; LC-MS/
MS (ESI): m/z = 411.9 [M+1]+.
N-(3-nitrobenzene)sulfonyl-2-aminobenzo[d]thiazole
11f. 1H NMR (400 MHz, DMSO) δ 13.30 (s, 1H), 7.87 (dt, J
= 4.4, 1.3 Hz, 2H), 7.82 (d, J = 7.6 Hz, 1H), 7.68−7.60 (m,
2H), 7.44−7.38 (m, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.31−7.25
(m, 1H); 13C NMR (101 MHz, DMSO) δ 168.3, 148.3, 144.1,
137.0, 132.3, 131.8, 127.8, 127.4, 125.4, 124.4, 123.3, 120.9,
113.7; LC-MS/MS (ESI): m/z = 335.9 [M+1]+.
6-(3-Nitrophenyl)-N-benzenesulfonyl-2-aminobenzo-
1
[d]thiazole 11q. H NMR (400 MHz, DMSO) δ 13.11 (s,
1
N-methanesulfonyl-2-aminobenzo[d]thiazole 11g. H
1H), 8.47 (t, J = 1.9 Hz, 1H), 8.29 (d, J = 1.7 Hz, 1H), 8.23
(dd, J = 8.2, 2.2 Hz, 1H), 8.16 (d, J = 7.9 Hz, 1H), 7.83 (dd, J =
8.4, 1.8 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 8.4 Hz,
1H), 3.04 (s, 3H); 13C NMR (126 MHz, DMSO) δ 166.5,
148.4, 140.8, 135.4, 133.0, 133.0, 130.5, 130.4, 126.1, 122.0,
121.1, 120.8, 112.9, 41.0; LC-MS/MS (ESI): m/z = 349.9 [M
+1]+.
NMR (400 MHz, DMSO) δ 7.77 (d, J = 7.8 Hz, 1H), 7.43−
7.35 (m, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.26−7.18 (m, 1H),
2.99 (s, 3H); 13C NMR (101 MHz, DMSO) δ 166.9, 136.8,
127.6, 125.3, 123.8, 123.1, 113.0; LC-MS/MS (ESI): m/z =
228.9 [M+1]+.
N-butanesulfonyl-2-aminobenzo[d]thiazole 11h. 1H
NMR (400 MHz, DMSO) δ 13.00 (s, 1H), 7.76 (d, J = 7.4
Hz, 1H), 7.41−7.35 (m, 1H), 7.31 (d, J = 7.4 Hz, 1H), 7.26−
7.19 (m, 1H), 3.12−3.02 (m, 2H), 1.67 (ddd, J = 12.3, 10.3, 6.5
Hz, 2H), 1.47−1.32 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H); 13C
NMR (126 MHz, HDMSO) δ 167.2, 138.2, 127.3, 126.0, 123.5,
122.8, 113.4, 53.0, 25.9, 21.4, 14.0; LC-MS/MS (ESI): m/z =
271.0 [M+1]+.
ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental procedures and analytical data of compounds,
along with copies of 1H, 13C NMR, LC-MS, and high
resolution-MS spectra of compounds 9a, 10a, and 11a, and
1H NMR, and LC-MS spectra of compounds 9b−9s, 10b−10u,
and 11b−11q, and ATR-FTIR spectra of resins 1−7. This
material is available free of charge via the Internet at http://
pubs.acs.org.
N-(1-naphthalenesulfonyl)-2-aminobenzo[d]thiazole
11k. 1H NMR (400 MHz, DMSO) δ 13.25 (s, 1H), 8.73 (d, J
= 8.5 Hz, 1H), 8.26 (dd, J = 7.3, 1.2 Hz, 1H), 8.21 (d, J = 8.3
Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.4 Hz, 1H),
7.73 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H), 7.70−7.61 (m, 2H), 7.40−
7.32 (m, 1H), 7.31−7.20 (m, 2H); 13C NMR (101 MHz,
DMSO) δ 167.3, 137.0, 136.7, 134.3, 134.0, 129.2, 128.2, 128.2,
127.9, 127.7, 127.3, 126.0, 125.2, 124.9, 124.1, 123.2, 113.3;
LC-MS/MS (ESI): m/z = 341.0 [M+1]+.
AUTHOR INFORMATION
Corresponding Author
*Tel: 82-2-2260-3206. Fax: 82-2-2290-1349. E-mail: ydgong@
dongguk.edu
Funding
This research was supported by grants from the National
Research Foundation of Korea (2010-0004128) funded by the
Ministry of Education, Science and Technology, and funded by
the Ministry of Knowledge Economy, Korea.
■
6-Phenyl-N-benzenesulfonyl-2-aminobenzo[d]-
1
thiazole 11l. H NMR (400 MHz, DMSO) δ 13.28 (s, 1H),
8.14 (d, J = 1.6 Hz, 1H), 7.91−7.86 (m, 2H), 7.69 (dd, J = 8.4,
1.8 Hz, 1H), 7.68−7.64 (m, 2H), 7.62−7.55 (m, 3H), 7.48 (t, J
= 7.6 Hz, 2H), 7.41−7.35 (m, 2H); 13C NMR (101 MHz,
DMSO) δ 167.6, 142.6, 139.8, 136.6, 136.4, 132.8, 129.6, 129.5,
127.9, 127.1, 126.5, 126.4, 126.3, 121.2, 113.7; LC-MS/MS
(ESI): m/z = 366.9 [M+1]+.
6-Phenyl-N-methanesulfonyl-2-aminobenzo[d]-
thiazole 11m. 1H NMR (400 MHz, DMSO) δ 13.02 (s, 1H),
8.12 (d, J = 1.6 Hz, 1H), 7.73−7.65 (m, 3H), 7.48 (t, J = 7.6
Hz, 2H), 7.42−7.34 (m, 2H), 3.02 (s, 3H); 13C NMR (126
MHz, DMSO) δ 166.0, 164.7, 138.7, 135.2, 135.1, 128.4, 126.8,
126.0, 125.2, 120.1, 112.3; LC-MS/MS (ESI): m/z = 305.0 [M
+1]+.
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) (a) Krchn
̌
ak
́
, V.; Holladay, M. W. Solid Phase Heterocyclic
Chemistry. Chem. Rev. 2002, 102, 61. (b) Thompson, L. A.; Ellman, J.
A. Synthesis and Applications of Small Molecule Libraries. Chem. Rev.
1996, 96, 555. (c) Terrett, N. K.; Gardner, M.; Gordon, D. W.;
Kobylecki, R. J.; Steele, J. Combinatorial Synthesis - The Design of
Compound Libraries and their Application to Drug Discovery.
Tetrahedron 1995, 51, 8135.
39
dx.doi.org/10.1021/co300112b | ACS Comb. Sci. 2013, 15, 29−40

ACS Combinatorial Science
Research Article
(2) (a) Sato, Y.; Yamada, M.; Yoshida, S.; Soneda, T.; Ishikawa, M.;
Nizato, T.; Suzuki, K.; Konno, F. Benzoxazole Derivatives as Novel 5-
HT3 Receptor Partial Agonists in the Gut. J. Med. Chem. 1998, 41,
3015. (b) Chen, P.; Cheng, P. T. W.; Alam, M.; Beyer, B. D.; Bisacchi,
G. S.; De. Jneka, T.; Evans, A. J.; Greytok, J. A.; Hermsmeier, M. A.;
Humphreys, W. G.; Jacobs, G. A.; Kocy, O.; Lin, P.-F.; Lis, K. A.;
Marella, M. A.; Ryono, D. E.; Sheaffer, A. K.; Spergel, S. H.; Sun, C.-q.;
Tino, J. A.; Vite, G.; Colonno, R. J.; Zahler, R. Barrish, Aminodiol HIV
Protease Inhibitors. Synthesis And Structure−Activity Relationships
Of P1/P1′ Compounds: Correlation between Lipophilicity and
Cytotoxicity. J. C. J. Med. Chem. 1996, 39, 1991. (c) Meyer, M. D.;
Hancock, A. A.; Tietje, K.; Sippy, K. B.; Prasad, R.; Stout, D. M.;
Arendsen, D. L.; Donner, B. G.; Carroll, W. A. Structure−Activity
Studies for a Novel Series of N-(Arylethyl)-N-(1,2,3,4-tetrahydronaph-
thalen-1-ylmethyl)-N-methylamines Possessing Dual 5-HT Uptake
Inhibiting and α2-Antagonistic Activities. J. Med. Chem. 1997, 40, 1049.
(d) Costanzo, M. J.; Maryanoff, B. E.; Hecker, L. R.; Schott, M. R.;
Yabut, S. C.; Zhang, H.-C.; Andrade-Gordon, P.; Kauffman, J. A.;
Lewis, J. M.; Krishnan, R.; Tulinski, A. Potent Thrombin Inhibitors
That Probe the S1′ Subsite: Tripeptide Transition State Analogues
Based on a Heterocycle-Activated Carbonyl Group1. J. Med. Chem.
1996, 39, 3039.
(3) (a) Gomaa, M. S.; Bridgens, C. E.; Aboraia, A. S.; Veal, G. J.;
Redfern, C. P. F.; Brancale, A.; Armstrong, J. L.; Simons, C. J. Small
Molecule Inhibitors of Retinoic Acid 4-Hydroxylase (CYP26):
Synthesis and Biological Evaluation of Imidazole Methyl 3-(4-(aryl-
2-ylamino)phenyl)propanoates. Med. Chem. 2011, 54, 2778.
(b) D’Angelo, N. D.; Kim, T.-S.; Andrews, K.; Booker, S. K.;
Caenepeel, S.; Chen, K.; D’Amico, D.; Freeman, D.; Jiang, J.; Liu, L.;
McCarter, J. D.; San Miguel, T.; Mullady, E. L.; Schrag, M.;
Subramanian, R.; Tang, J.; Wahl, R. C.; Wang, L.; Whittington, D.
A.; Wu, T.; Xi, N.; Xu, Y.; Yakowec, P.; Yang, K.; Zalameda, L. P.;
Zhang, N.; Hughes, P.; Norman, M. H. Discovery and Optimization of
a Series of Benzothiazole Phosphoinositide 3-Kinase (PI3K)/
Mammalian Target of Rapamycin (mTOR) Dual Inhibitors. J. Med.
Chem. 2011, 54, 1789. (c) Stoppie, P.; Borgers, M.; Borghgraef, P.;
Dillen, L.; Goossens, J.; Sanz, G.; Szel, H.; Van Hove, C.; Van Nyen,
G.; Nobels, G.; Vanden Bossche, H.; Venet, M.; Willemsens, G.; Van
Wauwe, J. R115866 inhibits all-trans-retinoic acid metabolism and
exerts retinoidal effects in rodents. J. Pharmacol. Exp. Ther. 2000, 293,
304. (d) Bradshaw, T. D.; Westwell, a D. The development of the
antitumour benzothiazole prodrug, Phortress, as a clinical candidate.
Curr. Med. Chem. 2004, 11, 1009. (e) Amnerkar, N. D.; Bhusaridig, K.
P. J. Nanomater. Biosci. 2010, 5, 267. (f) Kaplancikli, Z. A.; Altintop, M.
D.; Turan-Zitouni, G.; Ozdemir, A.; Ozic, R.; Akalin, G. Synthesis,
antimicrobial activity and cytotoxicity of novel oxadiazole derivatives. J.
Enzyme Inhib. Med. Chem. 2012, 27, 51. (g) Fawzi, A. B.; Macdonald,
D.; Bendow, L. L.; Smith Torhan, A.; Zhang, H. T.; Weig, B. C.; Ho,
G.; Tulshian, D.; Linder, M. E.; Graziano, M. P. SCH-202676: An
allosteric modulator of both agonist and antagonist binding to G
protein-coupled receptors. Mol. Pharmacol. 2001, 59, 30. (h) Lanza-
fame, A.; Christopoulos, A. Investigation of the interaction of a
putative allosteric modulator, N-(2,3-diphenyl-1,2,4-thiadiazole-5-
(2H)-ylidene) methanamine hydrobromide (SCH-202676), with M1
muscarinic acetylcholine receptors. J. Pharmacol. Exp. Ther. 2004, 308,
830. (i) Castro, A.; Castano, T.; Encinas, A.; Porcal, W.; Gil, C.
Advances in the synthesis and recent therapeutic applications of 1,2,4-
thiadiazole heterocycles. Bioorg. Med. Chem. 2006, 14, 1644.
G.; Li, Z. Yellow HgO as an efficient cyclo-desulfurization agent in the
synthesis of 2-substituted aminobenzoxazoles from N-(2-hydroxy-
phenyl)-N′-phenylthioure. J. Chem. Res. (S) 2001, 138. (f) Guo, Y.-J.;
Tang, R.-Y.; Zhong, P.; Li, J.-H. Copper-catalyzed tandem reactions of
2-halobenzenamines with isothiocyanates under ligand- and base-free
conditions. Tetrahedron Lett. 2010, 51, 649. (g) Ma, D.; Lu, X.; Shi, L.;
Zhang, H.; Jiang, Y.; Liu, X. Domino Condensation/S-Arylation/
Heterocyclization Reactions: Copper-Catalyzed Three-Component
Synthesis of 2-N-Substituted Benzothiazoles. Angew. Chem., Int. Ed.
2011, 50, 1118. (h) Khatik, G. L.; Dube, N.; Pal, A.; Nair, V. A. Highly
Efficient One-Pot Synthesis of 2-Aminobenzoxazoles Using Triflic
Acid as a Cyclodesulfurizing Reagent. Synth. Commun. 2011, 41, 2631.
(i) Qiu, J.-W.; Zhang, X.-G.; Tang, R.-Y.; Zhong, P.; Li, J.-H. Iron-
Catalyzed Tandem Reactions of 2-Halobenzenamines with Isothio-
cyanates Leading to 2-Aminobenzothiazoles. Adv. Synth. Catal. 2009,
351, 2319. (j) Feng, E.; Huang, H.; Zhou, Y.; Ye, D.; Jiang, H.; Liu, H.
Metal-Free Synthesis of 2-Substituted (N, O, C) Benzothiazoles via an
Intramolecular C-S Bond Formation. J. Comb. Chem. 2010, 12, 422.
(k) Vera, M. D. Pelletier, Enhanced Parallel Synthesis Efficiency
through Tandem Pd-Catalyzed S- and N-Arylation Reactions: Single-
Vessel Formation of Aminobenzothiazoles. J. C. J. Comb. Chem. 2007,
9, 569. (l) Shen, G.; Lv, X.; Bao, W. Synthesis of N-Substituted-2-
Aminobenzothiazoles by Ligand-Free Copper(I)-Catalyzed Cross-
Coupling Reaction of 2-Haloanilines with Isothiocyanates. Eur. J.
Org. Chem. 2009, 5897. (m) Ding, Q.; He, X.; Wu, J. Synthesis of 2-
Aminobenzothiazole via Copper(I)-Catalyzed Tandem Reaction of 2-
Iodobenzenamine with Isothiocyanate. J. Comb. Chem. 2009, 11, 587.
(n) Wang, J.; Peng, F.; Jiang, J.-l.; Lu, Z.-j.; Wang, L.-y.; Bai, J.; Pan, Y.
Synthesis of N-benzothiazol-2-yl-amides by a copper-catalyzed intra-
molecular cyclization process. Tetrahedron Lett. 2008, 49, 467.
(o) Joyce, L. L.; Evindar, G.; Batey, R. A. Copper- and palladium-
catalyzed intramolecular C−S bond formation: aconvenient synthesis
of 2-aminobenzothiazoles. Chem. Commun. 2004, 446.
(5) (a) Piscitelli, F.; Ballatore, C.; Smith, A. B. Solid phase synthesis
of 2-aminobenzothiazoles. Bioorg. Med. Chem. Lett. 2010, 20, 644.
(b) Lim, H.-J.; Myung, D.; Lee, I. Y. C.; Jung, M. H. Microwave-
Assisted Synthesis of Benzimidazoles, Benzoxazoles, and Benzothia-
zoles from Resin-Bound Esters. J. Comb. Chem. 2008, 10, 501.
(c) Hioki, H.; Matsushita, K.; Kubo, M.; Kodama, M. Combinatorial
Synthesis of Benzothiazoles and Benzimidazoles Using a Traceless
Aniline Linker. J. Comb. Chem. 2006, 8, 462.
(6) Hwang, J. Y.; Gong, Y.-D. Solid-Phase Synthesis of the 2-
Aminobenzoxazole Library Using Thioether Linkage as the Safety-
Catch Linker. J. Comb. Chem. 2006, 8, 297.
(7) Guillier, F.; Orain, D.; Bradley, M. Linkers and Cleavage
Strategies in Solid-Phase Organic Synthesis and Combinatorial
Chemistry. Chem. Rev. 2000, 100, 2091.
(8) Font, D.; Heras, M.; Villalgordo, J. M. Solution- and Solid-Phase
Parallel Synthesis of 4-Alkoxy-Substituted Pyrimidines with High
Molecular Diversity. J. Comb. Chem. 2003, 5, 311.
(9) (a) Hwang, J. Y.; Choi, H.-S.; Lee, D.-H.; Gong, Y.-D. Solid-
Phase Synthesis of 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Derivatives
via Selective, Reagent-Based Cyclization of Acyldithiocarbazate Resins.
J. Comb. Chem. 2005, 7, 816. (b) Hwang, J. Y.; Choi, H.-S.; Lee, D.-H.;
Yoo., S.-e.; Gong, Y.-D. Solid-Phase Synthesis of 5-Amino-1-
(Substituted Thiocarbamoyl)pyrazole and 1,2,4-Triazole Derivatives
via Dithiocarbazate Linker. J. Comb. Chem. 2005, 7, 136. (c) Lee, I. Y.;
Kim., S. Y.; Lee, J. Y.; Yu, C.-M.; Lee, D. H.; Gong, Y.-D. Solution-
phase parallel synthesis of new 2H-pyrimido-[4,5-e][1,2,4]triazin-3-
ylidenecyanamides. Tetrahedron Lett. 2004, 45, 9319.
(4) (a) U.S. Patent US2006/293281 A1, 2006. (b) Bose, D. S.;
Idrees, M. Hypervalent iodine mediated intramolecular cyclization of
thioformanilides: expeditious approach to 2-substituted benzothia-
zoles. J. Org. Chem. 2006, 71, 8261. (c) Wang, W.; Zhong, W.; Zhou,
R.; Yu, J.; Dai, J.; Ding, Q.; Peng, Y. ChemInform Abstract: Iron-
Catalyzed One-Pot Synthesis of 2-Aminobenzothiazoles from 2-
Aminobenzenethiols and Isothiocyanates under Ligand-Free Con-
ditions in Water. Heterocycles 2010, 81, 2841. (d) Zhang, X.; Jia, X.;
Wang, J.; Fan, X. An economically and environmentally sustainable
synthesis of 2-aminobenzothiazoles and 2-aminobenzoxazoles pro-
moted by water. Green Chem. 2011, 13, 413. (e) Qian, X.; Li, Z.; Song,
(10) (a) Klburn, J. P.; Lau, J.; Jones, R. C. F. 1,3,4-Oxadiazole
formation; a novel solid support strategy. Tetrahedron Lett. 2001, 42,
2583. (b) U.S. Patent US2006/0293281 A1, 2006
40
dx.doi.org/10.1021/co300112b | ACS Comb. Sci. 2013, 15, 29−40