A novel, simple and efficient synthesis of 3-amino-benzo[d]imidazo[2,1-b] thiazole derivatives via a multicomponent procedure

Article abstract of DOI:10.1002/jccs.200800043

3-Amino-benzo[d]imidazo[2,1-b]thiazoles were synthesized in moderate to good yields in the presence of NH₄Cl via a one pot procedure. All the products were characterized by ¹H NMR, IR, HRMS.

Full text of DOI:10.1002/jccs.200800043

292
Journal of the Chinese Chemical Society, 2008, 55, 292-296
A Novel, Simple and Efficient Synthesis of
3-Amino-benzo[d]imidazo[2,1-b]thiazole Derivatives via a
Multicomponent Procedure
Chang Sun (
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering
), Shun-Jun Ji* (
) and Yu Liu (
)
Suzhou (Soochow) University, Hengyi Road, Suzhou Industrial Park, Suzhou 215123, P. R. China
3-Amino-benzo[d]imidazo[2,1-b]thiazoles were synthesized in moderate to good yields in the pres-
ence of NH4Cl via a one pot procedure. All the products were characterized by 1H NMR, IR, HRMS.
Keywords: 3-Amino-benzo[d]imidazo[2,1-b]thiazoles; 2-Amino-benzothiazol; Isocyanide;
Multi-component reaction.
INTRODUCTION
Multicomponent reaction (MCR) is one in which
burn,5 Bienaymé6 and Groebke,7 which enabled the ready
synthesis of imidazo[1,2-a]azines by the acid-catalyzed
condensation of aldehyde, isocyanide and 2-aminoazine.
To the best of our knowledge, there are no reports about
synthesis of heterocycles bearing benzo[d]imidazo[2,1-
b]thiazoles in one pot. So we apply benzothiazole in the
Groebke reaction.
Since the first report9 on an Ugi reaction promoted by
ammonium chloride in toluene, there have been a number
of reports10-11 describing the successful use of this condi-
tion. Therefore, we determined to test its applicability to
the MCR-based synthesis of 3-amino-benzo[d]imidazo-
[2,1-b]thiazole derivatives.
three or more starting materials react together in a single
vessel to form a product which incorporates portions of all
the components.1 MCRs are highly efficient,2 not only due
to their convergent nature, but also because of superior
atom economy,3 and straightforward experimental proce-
dures. MCRs involving isocyanides are the most versatile
in terms of the number and variety of compounds which
can be generated.4
Benzothiazoles are an important class of pharmaceu-
tical compounds which exhibit a wide spectra of biological
activities. They have shown activities associated with
emergent and re-emergent human and cattle infectious dis-
eases (AIDS, hepatitis B and C, tuberculosis, bovine viral
diarrhoea) or associated with drug-resistant cancers (leu-
kaemia, carcinoma, melanoma, MDR tumors) for which no
definitive cure or efficacious vaccine is available at pres-
ent.5 Meanwhile imidazo[1,2-a]azines have emerged as
versatile drug templates in broad areas of medicinal chem-
istry, ranging from cardiac stimulation, and anti-inflamma-
tory, antiulcer, and anti-viral based therapies.
RESULTS AND DISCUSSION
Our studies were initiated with 2-amino-benzothi-
azole which upon treatment with a stoichiometric amount
of piperonal and t-butyl isocyanide afforded the product 4f
in 73% yield (Scheme I).
The formation of 4f was confirmed by their spectro-
scopic analysis. Thus, the IR spectra of compounds 4f mea-
sured in potassium bromide pellets show one bond for NH
group at 3352 cm-1. In the 1H NMR spectra of compound 4f
Recently, a variety of MCRs were described by Black-
Scheme I

Study of MCRs Based on Isocyanides
J. Chin. Chem. Soc., Vol. 55, No. 2, 2008 293
Table 1. Synthesis of compound 4
Entry
Ra
Product Yield (%)b Entry
Ra
Product Yield (%)b
1
2
3
4
5
6
7
8
9
C6H5
4-CH3C6H4
4-OHC6H4
4-CH3OC6H4
4-OH-3-OCH3C6H3
3,4-OCH2OC6H3
4-ClC6H4
2,4-Cl2C6H3
2-Pyridyl
4a
4b
4c
4d
4e
4f
59
63
58
54
74
73
74
74
63
10
11
12
13
14
15
16
17
18
4-(N,N-2CH3)-C6H4
4-NO2C6H4
3-NO2C6H4
2-Thienyl
3-Thienyl
i-Propyl
n-C6H13
n-C8H17
benzyl
4j
60
79
74
66
57
57
76
72
44
4k
4l
4m
4n
4o
4p
4q
4r
4g
4h
4i
a Represents the moiety on aldehydes.
b Isolated yields and all products were characterized by IR, 1H NMR, HRMS and Mp.
measured in CDCl3 were observed the signal of CH3 groups
at 1.06 ppm, the signal of NH group group at 3.13 ppm, and
the aromatic proton signals at 6.86-8.34 ppm. The structure
of the product of 4f was further characterized by X-ray
analysis (Fig. 1).12
moderate to good yields. As shown in Table 1, we can see
that a series of aromatic aldehydes bearing either elec-
tron-withdrawing or electron donating groups perform
equally well in the reaction. Additionally, aliphatic and
heterocyclic aldehydes deliver the corresponding products
in good yields.
Next, we continued investigating the MCRs involv-
ing 1, 3 with different aldehydes to obtain corresponding
products. To our delight, in all these cases, the reactions
proceeded smoothly to give the corresponding products in
Mechanistically the following scheme may be in-
voked to explain the formation of product 4. A probable
mechanism which accounts for most of the observed results
involves a (nonconcerted) [4+1] cycloaddition between the
protonated Schiff base (which holds both the electrophile
and nucleophile) and the isocyanide (which behaves as a
vinylidene carbenoid). A subsequent prototropic shift
gives the final aromatic fused 3-amino-benzo[d]imidazo-
[2,1-b]thiazoles (Scheme II).
In order to confirm the proposed mechanism, we car-
ried out the reaction of 5 and 3 in toluene under similar con-
ditions. The target compound 4g was obtained with yields
similar to the one-pot reaction. The fact supported the pro-
posed mechanism (Scheme III).
Fig. 1. The crystal structure of 4f.
In conclusion, we have developed an easy and facile
Scheme II Plausible mechanism for the reaction of isocyanide and aldehyde with 2-amino-benzothiazole

294 J. Chin. Chem. Soc., Vol. 55, No. 2, 2008
Sun et al.
Scheme III
7.20-7.65 (m, 7H, ArH), 8.35 (d, J = 8, 1H, ArH). 13C NMR
(75 MHz, CDCl3): d = 21.6, 30.3, 56.8, 114.9, 124.1, 124.4,
125.6, 127.9, 128.4, 129.3, 130.6, 132.6, 134.0, 136.9,
141.4, 144.0. HRMS [Found: m/z, 336.1469 (M+), Calcd.
for C23H21N3S, 336.1456].
one-pot synthesis of 3-amino-benzo[d]imidazo[2,1-b]thia-
zoles by the reaction of 2-aminobenzothiazole, aldehydes
and isocyanide. The application of these compounds in me-
dicinal chemistry is in progress in our lab.
EXPERIMENTAL SECTION
General
2-(4-Hydroxyphenyl)-3-(N-t-butyl)-amino-benzo[d]imi-
dazo[2,1-b]thiazole 4c
Mp 263-265 °C. IR (KBr) (vmax/cm-1): 3449.8, 3341.8,
2971.3, 1597.6, 1489.5, 1458.7. 1H NMR (400 MHz, DMSO-
d6): d = 0.98 (s, 9H, CH3), 4.62 (s, 1H, NH), 6.76-8.37 (m,
8H, ArH), 9.35 (s, 1H, OH). 13C NMR (75 MHz, DMSO-
d6): d = 29.7, 65.1, 114.7, 1177, 120.8, 125.4, 128.7, 131.5,
131.7, 152.8, 156.2, 156.3, 166.4, 166.5, 167.0. HRMS
[Found: m/z, 337.1293 (M+), Calcd. for C19H19N3OS,
337.1249].
Melting points were recorded on an electrothermal
1
digital melting point apparatus and are uncorrected. H
NMR and 13C NMR (75 MHz) spectra were recorded on a
Varian Mercury MHz spectrometer in CDCl3 or DMSO-d6.
IR spectra were obtained on a Nicolet FT-IR500 spectro-
photometer using KBr pellets. High resolution mass spec-
tra were obtained using a GCT-TOF instrument.
Typical experimental procedure
To a mixture of 2-aminobenzothiazole (0.5 mmol)
and an aldehyde (0.5 mmol) was added solid ammonium
chloride (1 mmol) and isocyanide (0.6 mmol) in toluene (5
mL). The reaction mixture was brought to reflux for 2 days,
the solvent was removed under reduced pressure and the
crude product was purified by chromatography to afford
the pure product 4.
2-(4-Methoxyphenyl)-3-(N-t-butyl)-amino-benzo[d]imi-
dazo[2,1-b]thiazole 4d
Mp 159-162 °C. IR (KBr) (vmax/cm-1): 3419.0, 3295.5,
1
2963.6, 1489.5, 1250.3, 1180.8. H NMR (400 MHz,
CDCl3): d = 1.05 (s, 9H, CH3), 2.15 (s, 1H, NH), 3.84 (s,
3H, CH3), 6.94 (s, 1H, ArH), 6.96 (s, 1H, ArH), 7.29-7.62
(m, 5H, ArH), 8.33 (d, J = 8, 1H, ArH). 13C NMR (75 MHz,
CDCl3): d = 30.3, 55.6, 56.7, 114.0, 114.8, 124.2, 124.4,
125.6, 128.0, 128.2, 129.3, 130.6, 134.1, 141.3, 144.0,
159.0. HRMS [Found: m/z, 351.1479 (M+), Calcd. for
C20H21N3OS, 351.1405].
2-Phenyl-3-(N-t-butyl)-amino-benzo[d]imidazo[2,1-b]-
thiazole 4a
Mp 176-178 °C. IR (KBr) (vmax/cm-1): 3318.6, 3063.9,
1
2971.3, 2932.7, 1674.7, 1535.8. H NMR (400 MHz,
CDCl3): d = 1.05 (s, 9H, CH3), 3.22 (s, 1H, NH), 7.42-8.37
(m, 9H, ArH). 13C NMR (75 MHz, CDCl3): d = 30.3, 57.0,
115.0, 124.3, 124.6, 125.7, 127.4, 128.1, 128.6, 128.7,
130.7, 134.1, 135.6, 141.5, 144.3. HRMS [Found: m/z,
321.1302 (M+), Calcd. for C19H19N3S, 321.1300].
2-(4-Methylphenyl)-3-(N-t-butyl)-amino-benzo[d]imi-
dazo[2,1-b]thiazole 4b
Mp 195-197 °C. IR (KBr) (vmax/cm-1): 3372.7, 3164.3,
1620.7, 1528.1, 1427.8. 1H NMR (400 MHz, CDCl3): d =
1.05 (s, 9H, CH3), 3.22 (s, 1H, NH), 2.38 (s, 3H, CH3),
2-(4-Hydroxy-3-methoxyphenyl)-3-(N-t-butyl)-amino-
benzo[d]imidazo[2,1-b]thiazole 4e
Mp 224-226 °C. IR (KBr) (vmax/cm-1): 3326.3, 2963.6,
1597.6, 1481.8, 1250.3. 1H NMR (400 MHz, CDCl3): d =
1.05 (s, 9H, CH3), 3.16 (s, 1H, NH), 3.98 (s, 3H, CH3), 5.67
(s, 1H, OH), 6.92-7.66 (m, 6H, ArH), 8.33 (d, J = 8, 1H,
ArH). 13C NMR (75 MHz, DMSO-d6): d = 35.1, 60.8, 61.1,
117.1, 119.7, 120.5, 125.8, 129.9, 131.1, 133.1, 134.5,
138.6, 146.0, 147.7, 151.0, 162.5. HRMS [Found: m/z,
367.1369 (M+), Calcd. for C20H21N3O2S, 367.1354].

Study of MCRs Based on Isocyanides
J. Chin. Chem. Soc., Vol. 55, No. 2, 2008 295
2-(3,4-Methylenedioxyl)phenyl-3-(N-t-butyl)amino-
benzo[d]imidazo[2,1-b]thiazole 4f
149.9. HRMS [Found: m/z, 364.1784 (M+), Calcd. for
C21H24N4S, 364.1722].
Mp 181-183 °C. IR (KBr) (vmax/cm-1): 3352.7, 2963.6,
2-(4-Nitrophenyl)-3-(N-t-butyl)-amino-benzo[d]imida-
1
2894.2, 1481.8, 1373.8, 1234.8. H NMR (400 MHz,
zo[2,1-b]thiazole 4k
CDCl3): d = 1.06 (s, 9H, CH3), 3.13 (s, 1H, NH), 6.00 (s,
2H, CH2), 6.86-8.34 (m, 7H, ArH). 13C NMR (75 MHz,
CDCl3): d = 30.3, 56.7, 101.3, 108.4, 108.7, 114.8, 121.7,
124.2, 124.4, 125.6, 128.1, 129.6, 130.5, 134.0, 141.2,
144.0, 146.9, 147.9. HRMS [Found: m/z, 365.1267 (M+),
Calcd. for C20H19N3O2S, 365.1198].
Mp 202-204 °C. IR (KBr) (vmax/cm-1): 3375.7, 3321.7,
1
2962.9, 1597.2, 1523.9, 1489.2, 1331.0. H NMR (400
MHz, CDCl3): d = 1.11 (s, 9H, CH3), 3.17 (s, 1H, NH),
7.33-8.28 (m, 8H, ArH). 13C NMR (75 MHz, CDCl3): d =
30.5, 57.6, 114.9, 124.1, 124.6, 125.3, 126.0, 128.2, 130.1,
130.8, 133.7, 139.2, 142.1, 145.6, 146.6. HRMS [Found:
m/z, 366.1137 (M+), Calcd. for C19H18N4O2S, 366.1150].
2-(3-Nitrophenyl)-3-(N-t-butyl)-amino-benzo[d]imida-
zo[2,1-b]thiazole 4l
2-(4-Chlorophenyl)-3-(N-t-butyl)-amino-benzo[d]imi-
dazo[2,1-b]thiazole 4g
Mp 180-182 °C. IR (KBr) (vmax/cm-1): 3272, 3241,
2963, 1489, 1204. 1H NMR (400 MHz, CDCl3): d = 1.06 (s,
9H, CH3), 3.26 (s, 1H, NH), 7.23-7.76 (m, 7H, ArH), 8.34-
8.36 (m, J = 8, 1H, ArH). 13C NMR (75 MHz, CDCl3): d =
30.3, 56.9, 114.8, 124.3, 124.7, 125.7, 128.6, 128.7, 129.2,
130.6, 133.0, 133.9, 134.0, 140.3, 144.5. HRMS [Found:
m/z, 355.0976 (M+), Calcd. for C19H18ClN3S ,355.0910].
2-(2,4-Dichlorophenyl)-3-(N-t-butyl)-amino-benzo[d]-
imidazo[2,1-b]thiazole 4h
Mp 184-186 °C. IR (KBr) (vmax/cm-1): 3241.4, 2963.6,
1481.8, 1366.0, 1204.0. 1H NMR (400 MHz, CDCl3): d =
0.98 (s, 9H, CH3), 3.10 (s, 1H, NH), 7.30-7.68 (m, 6H,
ArH), 8.42-8.44 (m, 1H, ArH). 13C NMR (75 MHz, CDCl3):
d = 30.1, 56.4, 115.3, 124.2, 124.8, 125.8, 127.8, 129.7,
130.5, 130.6, 132.9, 133.6, 133.7, 133.9, 134.4, 137.9,
144.6. HRMS [Found: m/z, 389.0576 (M+), Calcd. for
C19H17Cl2N3S, 389.0520].
Mp 157-159 °C. IR (KBr) (vmax/cm-1): 3340.6, 3328.7,
1
2966.7, 1489.5, 1342.9, 1188.5. H NMR (400 MHz,
CDCl3): d = 1.11 (s, 9H, CH3), 3.16 (s, 1H, NH), 7.26-8.80
(m, 8H, ArH). 13C NMR (75 MHz, CDCl3): d = 30.4, 57.0,
114.7, 121.7, 122.3, 124.4, 125.0, 125.8, 129.3, 130.5,
133.5, 137.0, 138.8, 145.0, 148.3. HRMS [Found: m/z,
366.1139 (M+), Calcd. for C19H18N4O2S, 366.1150].
2-(2-Thiopheneyl)-3-(N-t-butyl)-amino-benzo[d]imida-
zo[2,1-b]thiazole 4m
Mp 155-157 °C. IR (KBr) (vmax/cm-1): 3295.5, 3071.7,
1
2971.3, 1489.5, 13366.0, 1180.8. H NMR (400 MHz,
CDCl3): d = 1.17 (s, 9H, CH3), 3.22 (s, 1H, NH), 7.06-7.66
(m, 6H, ArH), 8.32 (d, J = 8, 1H, ArH). 13C NMR (75 MHz,
CDCl3): d = 30.4, 57.4, 115.0, 124.3, 124.5, 124.6, 124.7,
125.7, 127.6, 128.2, 130.6, 133.9, 136.3, 137.9, 144.7.
HRMS [Found: m/z, 327.0875 (M+), Calcd. for C17H17N3S2,
327.0864].
2-(2-Pyridineyl)-3-(N-t-butyl)-amino-benzo[d]imidazo-
[2,1-b]thiazole 4i
2-(Thiophen-3-yl)-3-(N-t-butyl)-amino-benzo[d]imida-
Mp 142-144 °C. IR (KBr) (vmax/cm-1): 3449.8, 3280.0,
zo[2,1-b]thiazole 4n
1
2971.3, 1589.9, 1497.2, 1196.2. H NMR (400 MHz,
Mp 137-139 °C. IR (KBr) (vmax/cm-1): 3349.8, 3303.2,
2971.3, 1651.6, 1489.5. 1H NMR (400 MHz, CDCl3): d =
1.12 (s, 9H, CH3), 3.09 (s, 1H, NH), 7.26-8.32 (m, 7H,
ArH). 13C NMR (75 MHz, CDCl3): d = 30.4, 56.8, 114.8,
122.0, 124.3, 124.6, 125.6, 125.7, 125.8, 128.2, 130.7,
134.0, 136.3, 137.9, 144.4. HRMS [Found: m/z, 327.0866
(M+), Calcd. for C17H17N3S2, 327.0864].
CDCl3): d = 1.14 (s, 9H, CH3), 5.16 (s, 1H, NH), 7.11-8.53
(m, 8H, ArH). 13C NMR (75 MHz, CDCl3): d = 29.8, 57.5,
115.6, 120.7, 121.5, 124.1, 124.7, 125.5, 130.6, 133.7,
133.8, 136.7, 137.2, 143.8, 148.5, 155.0. HRMS [Found:
m/z, 322.1261 (M+), Calcd. for C18H18N4S, 322.1252].
2-[4-(Dimethylamino)phenyl]-3-(N-t-butyl)-amino-ben-
zo[d]imidazo[2,1-b]thiazole 4j
2-Isopropyl-3-(N-t-butyl)-amino-benzo[d]imidazo[2,1-
Mp 177-178 °C. IR (KBr) (vmax/cm-1): 3419.0, 3341.8,
b]thiazole 4o
1
2971.3 1481.8, 1366.0, 1188.5. H NMR (400 MHz,
Mp 151-153 °C. IR (KBr) (vmax/cm-1): 3342.1, 3241.4,
1
CDCl3): d = 1.06 (s, 9H, CH3), 2.99 (s, 6H, CH3), 3.17 (s,
1H, NH), 6.76 (s, 1H, ArH), 6.78 (s, 1H, ArH), 7.27-7.64
(m, 5H, ArH), 8.34 (d, J = 8, 1H, ArH). 13C NMR (75 MHz,
CDCl3): d = 30.4, 41.0, 56.8, 112.6, 114.9, 123.9, 124.2,
124.3, 125.7, 127.7, 129.0, 130.7, 134.3, 141.9, 143.9,
2963.6, 1632.2, 1481.8, 1366.0, 1211.7. H NMR (400
MHz, CDCl3): d = 1.24 (s, 9H, CH3), 1.32 (d, J = 3, 6H,
CH3), 2.70 (s, 1H, NH), 2.95-3.11 (m, 1H, CH), 7.22-8.27
(m, 4H, ArH). 13C NMR (75 MHz, CDCl3): d = 19.7, 28.8,
35.8, 52.2, 120.6, 122.0, 124.4, 126.7, 132.3, 148.2, 160.4,

296 J. Chin. Chem. Soc., Vol. 55, No. 2, 2008
Sun et al.
165.3, 176.6. HRMS [Found: m/z, 287.1440 (M+), Calcd.
for C16H21N3S, 287.1456].
novation Project for Graduate Students of Jiangsu Prov-
ince.
2-Hexyl-3-(N-t-butyl)-amino-benzo[d]imidazo[2,1-b]-
thiazole 4p
Received July 2, 2007.
Mp 116-118 °C. IR (KBr) (vmax/cm-1): 3449.8, 3233.7,
2955.9, 1481.8, 1211.7. 1H NMR (400 MHz, CDCl3): d =
0.89 (s, 3H), 1.23 (s, 9H, CH3), 1.62-1.73 (m, 7H), 2.61 (t, J
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Mp 94-96 °C. IR (KBr) (vmax/cm-1): 3449.8, 3233.7,
2925.0, 1481.8, 1366.0. 1H NMR (400 MHz, CDCl3): d =
0.88 (s, 3H), 1.23 (s, 9H, CH3), 1.27-1.35 (m, 8H), 1.74 (s,
3H), 2.61 (t, J = 8.1, 3H), 2.73 (s, 1H, NH), 7.23-8.28 (m,
4H). 13C NMR (75 MHz, CDCl3): d = 14.6, 23.1, 25.5,
28.7, 29.5, 29.6, 29.7, 32.2, 37.0, 67.5, 105.2, 120.9, 122.0,
124.4, 126.7, 132.3, 133.0, 148.2, 172.5. HRMS [Found:
m/z, 357.2235 (M+), Calcd. for C21H31N3S, 357.2239].
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Mp 146-148 °C. IR (KBr) (vmax/cm-1): 3449.8, 3249.2,
2963.6, 1636.2, 1489.5. 1H NMR (400 MHz, CDCl3): d =
1.24 (s, 9H, CH3), 2.66 (s, 1H, NH), 4.07 (s, 2H, CH2),
7.19-8.29 (m, 9H, ArH). 13C NMR (75 MHz, CDCl3): d =
29.8, 30.4. 55.7, 114.6, 124.0, 124.1, 125.4, 126.3, 127.7,
128.7, 128.8, 129.0, 129.1, 133.9, 140.2, 140.5. HRMS
[Found: m/z, 335.1473 (M+), Calcd. for C20H21N3S,
335.1456].
7. Bienaymé, H.; Bouzid, K. Angew. Chem., Int. Ed. 1998, 37,
2234.
8. Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661.
9. Cristau, P.; Vors, J.-P.; Zhu, J. Org. Lett. 2001, 3, 4079.
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D. V.; Krasavin, M. Tetrahedron Lett. 2006, 47, 947.
12. Crystallographic data for the structural analysis have been
deposited with the Cambridge Crystallographic Data Cen-
tre, CCDC No. 631276 for product 4f. Copies of this infor-
mation may be obtained free of charge from The Director,
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (Email:
linstead@ccdc.cam.ac.uk or deposit@ccdc.cam.ac.uk; Fax:
+44 1223 33603). Structural parameters for 4f: data collec-
tion: Rigaku Mercury CCD area detector; radiation: MoKa;
wavelength: l = 0.71070 Å; crystal size: 0.60 ´ 0.60 ´ 0.38
mm3; crystal system: Monoclinic, P 21/c; unit cell: a =
7.8170(10) Å, b = 18.943(2) Å, c = 12.4468(16) Å, a =
90.00o, b = 107.696(3), g = 90.00°.
ACKNOWLEDGMENTS
This work was partially supported by the Key Labo-
ratory of Organic Synthesis of Jiangsu Province at Suzhou
University (No. S8109108), the Natural Science Founda-
tion of Jiangsu Province (BK2006048) and the National
Science Foundation of China (No. 20472062, 20672079),
Nature Science Key Basic Research of Jiangsu Province
for Higher Education (No. 06KJA15007, 05KJB150116),
Jiangsu Provincial Key Laboratory of Fine Petrochemical
Technology (KF0402), and a Research Grant from the In-