1,10-Phenanthroline-catalyzed tandem reaction of 2-iodoanilines with isothiocyanates in water

Article abstract of DOI:10.1002/adsc.201200175

The 1,10-phenanthroline-catalyzed tandem reaction of 2-iodoaniline with isothiocyanate in water is described, which provides an environmentally benign, efficient and simple route for the preparation of 2-aminobenzothiazoles. The present tandem process shows broad substrate scope in the absence of transition metals and phase-transfer catalysts. Copyright

Full text of DOI:10.1002/adsc.201200175

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DOI: 10.1002/adsc.201200175
1,10-Phenanthroline-Catalyzed Tandem Reaction of
2-Iodoanilines with Isothiocyanates in Water
Wu Zhang,a,* Yun Yue,a Dan Yu,a Lei Song,a Yang-Yang Xu,a Yu-Jie Tian,a
and Yu-Jun Guoa
a
Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based Materials,
College of Chemistry and Materials Science, Anhui Normal University, Wuhu 241000, Peopleꢀs Republic of China
E-mail: zhangwu@mail.ahnu.edu.cn
Received: March 1, 2012; Revised: May 15, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200175.
Abstract: The 1,10-phenanthroline-catalyzed tandem process shows broad substrate scope in the absence
reaction of 2-iodoaniline with isothiocyanate in of transition metals and phase-transfer catalysts.
water is described, which provides an environmental-
ly benign, efficient and simple route for the prepara- Keywords: 2-aminobenzothiazoles; 2-iodoanilines;
tion of 2-aminobenzothiazoles. The present tandem isothiocyanates; 1,10-phenanthroline; tandem reac-
tion; water
Introduction
most powerful and reliable methodologies.[7] Recently,
the direct oxidative coupling between benzothiazoles
The 2-aminobenzothiazole is one of the most impor- and amines,[8] as well as domino three-component re-
tant structural motifs in pharmaceutically active com- actions of carbon disulfides, amines and 2-haloanilines
pounds and natural products.[1] A great amount of have attracted more attention from the viewpoints of
compounds with the skeleton have been applied in atom economy and operational simplicity.[9] Also,
drugs for the treatment of various diseases, such as tu- tandem reactions for the efficient construction of het-
berculosis,[2] tumors,[3] and cancer.[4] Therefore, the de- erocycles are important goals. Recently, several
velopment of efficient methods for constructing 2- groups have reported independently on the construc-
aminobenzothiazoles has received great interest from tion of 2-aminobenzothiazole compounds from 2-hal-
the perspective of medicinal chemistry and organic oanilines and isothiocyanates with the support of
synthesis (Scheme 1). Among them, transition metal- Cu(I) or FeACHTNUTGRNEUNG
(III) catalysts (Scheme 2).[10] We found
catalyzed cross-coupling reactions of 2-halobenzothia- that one component played a crucial role in most of
zoles with amines[5] or 2-aminobenzothiazoles with the synthetic processes: 1,10-phenanthroline (phen)
aryl halides[6] and intramolecular cyclizations of 2-hal- via the analysis and comparison of the detailed reac-
obenzothioureas or benzothioureas represent the tion conditions. At the same time, we found that Shi
and Shirakawa/Hayashi had already reported the
À
direct C H arylation of benzene with aryl halides in
the presence of catalytic amounts of phen and its de-
rivatives without the presence of a transition metal
catalyst.[11]
Arguably most reactions for the synthesis of N-sub-
stituted-2-aminobenzothiazoles were carried out in or-
ganic solvents such as DMSO, DME and toluene.
From the viewpoints of economic and environmental
aspects, it is desirable to avoid any use of hazardous,
contaminated and expensive organic solvents. Water
is considered to be the best solvent for it is cheap,
non-toxic and nonpolluting. Recently, Fan et al. re-
Scheme 1. Efficient synthesis of 2-aminobenzothiazoles.
ported a significant rate acceleration of the tandem
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Scheme 2. Phen was used as ligand for the synthesis of 2-aminobenzothiazoles.
reaction of isothiocyanates with 2-aminothiophenols Table 1. Optimization of the reaction conditions for the
preparation of 3a.[a]
in water compared with commonly used organic sol-
vents.[12]
Herein, we have developed a transition metal-free
synthesis of 2-aminobenzothiazoles from 2-iodoani-
lines and isothiocyanates using phen as catalyst in
water.
Entry
Catalyst
Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
–
NaHCO3
–
KOH
NaOH
K2CO3
Na2CO3
NaHCO3
NEt3
DABCO
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
DMSO
toluene
dioxane
THF
DMF
H2O
H2O
H2O
0[c]
Results and Discussion
phen
phen
phen
phen
phen
phen
phen
phen
bipy
EDA
DMEDA
l-Pro
H2acac
phen
phen
phen
phen
phen
phen
phen
phen
phen
0[c]
trace
trace
41
48
99
64
trace
32
13
0
The reaction between 2-iodoaniline (1a) and phenyl
isothiocyanate (2a) was greatly facilitated leading to
the desired product in high yield. The effects of cata-
lyst, base, solvent, temperature, and reaction time
were investigated, and the results are summarized in
Table 1. In the absence of either phen or base the re-
action fails to generate the desired products and only
intermediates 1-(2-iodophenyl)-3-phenylthiourea were
obtained even after heating for 14 h (entries 1 and 2).
In the presence of strong inorganic bases such as
KOH and NaOH, only traces of the target product
could be found (entries 3 and 4). To our surprise, the
target product 3a were obtained in 41% and 48%
yield by using weak bases, such as K2CO3 or Na2CO3,
respectively (entries 5 and 6). Further screening of
bases revealed that NaHCO3 was the most efficient
base and the yield could be dramatically improved,
giving an almost quantitative yield (entry 7). Organic
bases such as NEt3 and DABCO were evaluated, too.
However, lower yields were obtained (entries 8 and
9). The catalytic activity of the different ligand-type
organic compounds such as 2,2’-dipyridine, EDA,
DMEDA, l-proline, and acetylacetone (H2acac) were
investigated (entries 10–14). Among these tested or-
ganocatalysts, 1,10-phenanthroline was found to be
uniquely effective. Decreasing the catalyst amount
from 10 to 5 mol% resulted in the decrease of the
yield (entry 15). The effect of the solvent was also in-
vestigated, trace products were obtained in organic
solvents such as DMSO, toluene, 1,4-dioxane, THF
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
0
0
33[d]
trace
trace
trace
trace
trace
35[e]
0[f]
trace[g]
[a]
Reaction conditions: 1a (0.25 mmol), 2a (0.3 mmol), cata-
lyst (10 mol%), base (2.0 equiv.), solvent (4 mL), stirred
under air, 808C, 2 h.
Isolated yield.
14 h.
Phen (5 mol%).
1 h.
[b]
[c]
[d]
[e]
[f]
Room temperature.
608C.
[g]
Thus, the optimal reaction conditions were set to be
and DMF (entries 16–20). It may be due to the poor 10 mol% of phen in the presence of 2 equiv. of
solubility of NaHCO3 in organic solvents. When the NaHCO3 in water for 2 h at 808C. To our delight, this
reaction time was shortened to 1 h, the yield was only phen-catalyzed tandem reaction can be applied to
35% (entry 21). The reaction could not be carried out gram-scale synthesis, a 96% yield was obtained when
at room temperature, and only trace products were 5.48 g (25 mmol) of 2-iodoaniline were used under the
generated even at 608C (entries 22 and 23).
optimized conditions.
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1,10-Phenanthroline-Catalyzed Tandem Reaction of 2-Iodoanilines with Isothiocyanates in Water
With the standard protocol in hand, we started to Fortunately, several typical alkyl isothiocyanates were
investigate the scope and functional group compatibil- also suitable substrates under the standard condition,
ity of the new organocatalytic tandem reaction. The and provided good yields (entries 9–11).
reaction shows very high efficiency and tolerates
Several representative 2-iodobenzenamine deriva-
many functional groups such as alkyl, chloro, cyano, tives were examined. It could be seen that electronic
trifluoromethyl, alkoxy and ester (Table 2). It was effects played a significant role: 2-iodobenzenamines
with electron-donating and weak electron-withdraw-
ing groups such as methyl and chloro on the para po-
Table 2. Tandem reaction between various substituted 1 and
2.[a]
sition proceeded with good to excellent yields (en-
tries 12–19). However, only moderate yields could be
obtained when a strong electron-withdrawing group
such as 4-trifluoromethyl was present (entries 20–22).
Furthermore, the nitro group completely inhibited the
reaction (entry 24).
The yields also depended on the nature of the hal-
ides. Unfortunately, a trace of the corresponding
product was detected when the less active substrate 2-
bromoaniline was investigated (entry 25); and even
no target compound was obtained with 2-chloroani-
line (entry 26).
Entry R1/X
R2
Product 3 Yield [%][b]
1
2
3
4
5
6
7
8
H/I
H/I
H/I
H/I
H/I
H/I
H/I
H/I
4-MeC6H4
2-MeC6H4
2,6-Me2C6H3
3b
3c
3d
98
91
89
73
97
95
81
55
85
74
78
96
98
99
94
83
93
95
82
72
83
61
87
nr
2,6-(i-Pr)2C6H3 3e
4-EtOC6H4
4-ClC6H4
4-CNC6H4
4-CF3C6H4
C6H5CH2
cyclohexyl
n-dodecyl
C6H5
4-MeC6H4
4-EtOC6H4
4-ClC6H4
4-CNC6H4
C6H5
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
A plausible mechanism, which accounts for the for-
mation of the 2-aminobenzothiazoles by a tandem re-
action, is shown in Scheme 3. First, the nucleophilic
9
H/I
H/I
H/I
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
4-Me/I
4-Me/I
4-Me/I
4-Me/I
4-Me/I
4-Cl/I
4-Cl/I
4-Cl/I
4-CF3/I
4-CF3/I
4-CF3/I
4-EtOC6H4
4-CNC6H4
C6H5
4-EtOC6H4
4-CNC6H4
3s
3t
3u
3v
3w
3x
3y
3a
3a
3-CO2Me/I C6H5
4-NO2/I
H/Br
C6H5
C6H5
C6H5
trace
nr
Scheme 3. Plausible mechanism.
H/Cl
[a]
Reaction conditions: 1 (0.25 mmol), 2 (0.30 mmol), phen
(10 mol%), NaHCO3 (0.5 mmol), H2O (4 mL), stirred
under air at 808C for 2 h.
addition of 2-iodoanilines with NCS forms the inter-
mediates 1-(2-iodophenyl)-3-phenylthiourea in the
presence of base. This step was very easy without any
additional external conditions in water. Second, the
intermediates were converted to the final products
[b]
Isolated yield; nr=no reaction.
found that moderate to excellent yields were achieved through intramolecular cyclization with the aid of
for phenyl isothiocyanates with both electron-donat- phen and NaHCO3. Initially, we suspected that the re-
ing and electron-withdrawing substituents (Table 2, action system could contain trace amounts of metal
entries 1–9). In general, the presence of electron-do- impurities that would induce this transformation. We
nating groups and weak electron-withdrawing groups repeated the reactions with new glassware and mag-
on phenyl isothiocyanates showed excellent efficien- neton; furthermore, we analyzed the reaction aqueous
cies (entries 1, 5, 6, 13–15, 18). However, when phenyl solution obtained after filtration using inductively
isothiocyanates substituted by a strong electron-with- coupled plasma-atomic emission spectroscopy (ICP-
drawing group such as trifluoromethyl were used, AES). The test results demonstrated the absence of
only 55% yield was obtained (entry 8). Besides, iso- Pd, Cu, Fe and other transition metals at the limits of
thiocyanate with a steric hindering substituent at the detection. Therefore we perceive that the reaction
ortho position was tolerated in this reaction (entry 4). mechanism was different from the previously reported
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Wu Zhang et al.
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transition metal-catalyzed mechanism,[10b,d] and the
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scavenger tetramethylpiperidine N-oxide (TEMPO)
was added under the same conditions, and no trace of
desired product could be obtained.
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In summary, phen can effectively catalyze the tandem
reaction of 2-iodoanilines and isothiocyanates to syn-
thesize 2-aminobenzothiazole compounds in excellent
yields. A more environmentally friendly and mild
base was used. It is also noteworthy to point out that
the reactions are carried out in water.
Experimental Section
Typical Experimental Procedure for 1,10-
Phenanthroline-Catalyzed Tandem Reactions of 2-
Iodobenzenamines with Isothiocyanates
A mixture of 2-iodoaniline 1 (0.25 mmol), isothiocyanate 2
(0.30 mmol, 1.2 equiv.), phen (0.025 mmol, 10 mol%),
NaHCO3 (0.5 mmol, 2 equiv.), and H2O (4 mL) was stirred
in air, heating from room temperature to 808C (about
0.5 h), then continued to stir at 808C for 2 h. Then the reac-
tion was stopped and cooled down to room temperature, the
mixture was extracted with ethyl acetate (3ꢂ10 mL), the
combined organic layer was washed with water (2ꢂ10 mL),
then dried over anhydrous MgSO4 and evaporated under
vacuum. The residue was purified by column chromatogra-
phy on silica gel (petroleum ether/ethyl acetate) to afford
the corresponding product 3.
N-Phenylbenzo[d]thiazol-2-amine (3a):[14] White solid; mp
161–1628C (lit. mp 157.2–159.48C). 1H NMR (300 MHz,
CDCl3): d=7.63 (d, J=7.6 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H),
7.50 (d, J=7.6 Hz, 2H), 7.41 (t, J=7.4 Hz, 2H), 7.32 (t, J=
7.3 Hz, 1H), 7.12–7.20 (m, 2H); 13C NMR (75 MHz,
CDCl3): d=165.2, 151.3, 140.0, 129.8, 129.6, 126.2, 124.5,
122.4, 120.9, 120.5, 119.3.
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Acknowledgements
Financial support from the National Natural Science Founda-
tion of China (20972002, 21171006) and Education Depart-
ment of Anhui Province (TD200707) are gratefully acknowl-
edged.
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6 1,10-Phenanthroline-Catalyzed Tandem Reaction of 2-
Iodoanilines with Isothiocyanates in Water
Adv. Synth. Catal. 2012, 354, 1 – 6
Wu Zhang,* Yun Yue, Dan Yu, Lei Song, Yang-Yang Xu,
Yu-Jie Tian, Yu-Jun Guo
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