Iron-catalyzed tandem reactions of 2-halobenzenamines with isothiocyanates leading to 2-aminobenzothiazoles

Article abstract of DOI:10.1002/adsc.200900450

A highly practical method for the synthesis of 2-aminobenzothiazoles has been developed through an iron-catalyzed tandem reaction. The present tandem process allows the assembly of a wide range of 2-aminobenzothiazoles by the reactions of 2-halobenzenamin

Full text of DOI:10.1002/adsc.200900450

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DOI: 10.1002/adsc.200900450
Iron-Catalyzed Tandem Reactions of 2-Halobenzenamines with
Isothiocyanates Leading to 2-Aminobenzothiazoles
Jing-Wen Qiu,a Xing-Guo Zhang,a Ri-Yuan Tang,a Ping Zhong,a
and Jin-Heng Lia,b,*
a
College of Chemistry and Materials Science, Wenzhou University, Wenzhou 325035, Peopleꢀs Republic of China
Fax : (+86)-577-8836-8607; phone: (+86)-577-8836-8607; e-mail: jhli@hunnu.edu.cn
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education), Hunan Normal
b
University, Changsha 410081, Peopleꢀs Republic of China
Received: June 30, 2009; Published online: September 23, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900450.
Abstract: A highly practical method for the synthe-
sis of 2-aminobenzothiazoles has been developed
through an iron-catalyzed tandem reaction. The
present tandem process allows the assembly of a
wide range of 2-aminobenzothiazoles by the reac-
tions of 2-halobenzenamines with isothiocyanates.
procedure for the synthesis of benzothiazoles using o-
bromoarylthioamide substrates and the Pd2A(dba)3/o-
biphenylP(t-Bu)2 catalytic system. Very recently, Wu
CTHUNGTRENNUNG
AHCTUNGTRENNUNG
and co-workers described a practical copper-catalyzed
tandem reaction between 2-halobenzenamines and
isothiocyanates to prepare 2-aminobenzothiozoles.[7]
However, the utility and applicability of this reaction
was limited due to the expensive catalyst system and/
or the prefunctionalization of starting materials. To
overcome these drawbacks, the development of a con-
cise route using both commercially available materials
and an inexpensive catalytic system remains a chal-
lenging area for exploration.
Keywords: 2-aminobenzothiazoles; cross-coupling;
2-halobenzenamines; iron; isothiocyanates; tandem
reactions
The transition metal-catalyzed cross-coupling reac-
2-Aminobenzothiazoles, an important topical benzo- tion of aryl halides with sulfur nucleophiles has
thiozole scaffold, are broadly found in bioorganic and emerged as a powerful method for the formation of
medicinal chemistry[1] with applications in drug dis- carbon-sulfur bonds.[8,9] Among the reactions, palladi-
covery and development for the treatment of various um, nickel or copper catalysts combined with a ligand
diseases, such as diabetes,[2] epilepsy,[3] and tuberculo- display high activity. From industrial and environmen-
sis.[4] Therefore, considerable effort has been made in tal points of view, however, the development of a
the development of efficient strategies for their con- cheap, efficient and environmentally benign catalyst
struction.[5] The transition metal-catalyzed, particular- for the synthesis of sulfur-containing compounds is
ly palladium or copper, intramolecular cyclization of still desirable. Recently, Bolm and co-workers suc-
2-bromobenzothiaoureas is one of the most common cessfully developed a novel FeCl3-catalyzed S-aryla-
and efficient methods [Eq. (1) in Scheme 1].[6] For ex- tion reaction of aryl iodides with thiols.[10] As a part
ample, Castillꢁn and co-workers firstly reported a of our continuing interest in the use of iron cata-
lysts,[11] herein we report a new facile and efficient
iron-catalyzed tandem protocol for the synthesis of 2-
aminobenzothiazoles involving an S-arylation process
[Eq. (2) in Scheme 1].[12,13]
The reaction between 2-iodophenylamine (1a) and
phenyl isothiocyanate (2a) was investigated to opti-
mize the reaction conditions, and the results are sum-
marized in Table 1. Initially, a series of iron catalysts
were tested (entries 1–4). While 2-iodophenylamine
(1a) was treated with phenyl isothiocyanate (2a), FeF3
and 2,2,6,6-tetramethyl-3,5-heptanedione (L1) to
Scheme 1. The synthesis of 2-aminobenzothiazoles.
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Table 1. Screening conditions for the synthesis of 2-amino-
benzothiazole (3).[a]
Table 2. FeF3-catalyzed tandem reactions of 2-iodoaniline
(1a) with isothiocyanates.[a]
Entry Substrate 2
t [h] Yield [%] (Product)
1
2
2b
2c
2
2
81 (4)
82 (5)
Entry [Fe] (mol%)
Base
Solvent Ligand Yield
[%]
1
FeF3 (10)
FeF3 (10)
FeCl3 (10)
Cs2CO3
Cs2CO3
Cs2CO3
DMSO L1
DMSO L1
DMSO L1
DMSO L1
DMSO L1
51
53
35
48
trace
30
70
61
38
35
86
82
75
77
35
25
3
4
5
6
7
2d
2e
2f
2g
2h
2
2
2
2
2
70 (6)
96 (7)
71 (8)
79 (9)
60 (10)
2[b]
3
4
5
6
7
8
9
Fe
Fe
2A
ACHTUNGTRENNUNG
FeF3 (10)
FeF3 (10)
FeF3 (10)
FeF3 (10)
FeF3 (10)
FeF3 (10)
FeF3 (10)
FeF3 (5)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Et3N
DMSO
–
DMSO L2
DMSO L3
DMSO L4
DMSO L2
DMSO L2
10
11
12
13c)
8
9
2i
2j
4
4
51 (11)
41 (12)
DABCO DMSO L2
Et3N
Et3N
Et3N
Et3N
DMSO L2
DMSO L2
14[c,d] FeF3 (5)
[a]
Reaction conditions: 1 (0.2 mmol), 2 (0.22 mmol), FeF3
(10 mol%), 1,10-phenanthroline (L2) (20 mol%), and
Et3N (2.0 equiv.) in DMSO (2 mL) at 808C.
15
16
FeF3 (10)
FeF3 (10)
MeCN
L2
Toluene L2
[a]
Reaction conditions: 1 (0.2 mmol), 2 (0.22 mmol), [Fe]
(10 mol%), ligand (20 mol%), base (2.0 equiv.) in solvent
(2 mL) at 808C for 4 h.
For 24 h.
10 mol% of L2 was added.
For 12 h.
and the results are summarized in Table 2 and
Table 3. As showed in Table 2, a variety of isothiocya-
nates 2 were investigated by reacting with 2-iodoani-
line (1a), FeF3 and L2. The results demonstrated that
several functional groups, such as methyl, methoxy,
[b]
[c]
[d]
afford the target product 3 in 51% yield (4 h) or 53% chloro, acetyl and nitro groups, on the aryl moiety
yield (24 h) (entries 1 and 2), both FeCl3 and were tolerated well, and both electron-rich and elec-
Fe
(SO4)3 reduced the yield to some extent (entries 3 tron-poor aryl isothiocyanates underwent the tandem
(NO2)3 has no activity (entry 5). reaction successfully in moderate to good yields (en-
and 4). Moreover, FeAHCTUNGTRENNUNG
Subsequently, the effect of ligands was examined (en- tries 1–6). 4-Methylphenyl isothiocyanate (2b), for ex-
tries 6–9). We found that without ligand the yield of 3 ample, was treated with 2-iodoaniline (1a) to afford
was decreased to 30% (entry 6). Thus, three other li- the target product 4 in 81% yield (entry 1), and 4-ni-
gands were evaluated, and 1,10-phenanthroline (L2) trophenyl isothiocyanate (2g) provided the corre-
was found to be the most effective (entries 7–9). sponding product 9 in 79% yield (entry 6). Substrate
Among the bases examination, it turned out that 2c, bearing an ortho-methylphenyl group, could also
Et3N was the best base (entries 1 and 10–12). In the react with 2-iodoaniline (1a) smoothly in 82% yield
presence of FeF3, L2 and Et3N, amine 1a underwent (entry 2). To our delight, alkyl isothiocyanate were
the reaction with phenyl isothiocyanate (2a) smoothly also suitable substrates for the tandem reactions
to give an 86% yield (entry 11). Finally, both the (entry 7–9). Benzyl isothiocyanate (2h), for instance,
amount of Fe catalyst and the effect of solvent were was treated with 2-iodoaniline, FeF3 and L2 to afford
tested (entries 13–16). The yield of 3 was reduced to the desired 10 in 60% yield (entry 7).
some extent even after prolonging the reaction using
Multi-substituted anilines 1b–1h were subsequently
a 5 mol% loading of FeF3 (entries 13 and 14), and investigated to react with isothiocyanates under the
both MeCN and toluene were inferior to DMSO (en- standard conditions (Table 3). We were pleased to
tries 15 and 16).
find that the standard conditions were compatible
The scope of both 2-halobenzenamines and isothio- with various 2-halobenzenamines 1b–1h bearing
cyanates was explored under the standard conditions, chloro, fluoro, methyl, ester and trifluoromethyl
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Iron-Catalyzed Tandem Reactions of 2-Halobenzenamines with Isothiocyanates
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Table 3. FeF3-catalyzed tandem reactions of 2-haloanilines (1) with isothiocyanates (2).[a]
Entry
1
Substrate 1
Substrate 2
t (h)
Yield [%] (Product)
1b
1b
1c
1c
1d
1d
1e
2a
2b
2a
2k
2g
2b
2l
4
2
4
4
2
2
2
98 (13)
2
3
4
5
6
7
85 (14)
86 (15)
76 (16)
80 (17)
97 (18)
79 (19)
8
1f
2a
2
95 (20)
9
1g
1g
1h
2e
2c
2l
8
8
8
67 (21)
58 (22)
73 (19)
10
11[b]
[a]
Reaction conditions: 1 (0.2 mmol), 2 (0.22 mmol), FeF3 (0.05 equiv.), 1,10-phenanthroline (0.2 equiv.), NEt3 (2.0 equiv.) in
DMSO (2 mL) at 808C for 2–8 h.
Using DABCO as base at 1208C.
[b]
groups. Substrate 1b with a 4-chloro group, for in- benzothiazoles.[15] In the presence of FeF3 and 1,10-
stance, underwent the reaction with isothiocyanate 2a phenanthroline (L2), a variety of 2-halobenzenamines
or 2b, FeF3, and L2, smoothly in good yields (entries 1 and isothiocyanates underwent the tandem reactions
and 2). 4-Methyl-2-iodoaniline 1e was a suitable sub- successfully to afford the corresponding 2-aminoben-
strate under the same conditions (entry 7). It was ob- zothiazoles in moderate to excellent yields. It is note-
served that the tandem reactions of electron-with- worthy that the scope is extended to 2-iodobenzena-
drawing 2-iodobenzenamines 1f and 1g were also suc- mines and 2-bromobenzenamines using an inexpen-
cessful to give the target products in moderate to sive and environmentally benign iron catalytic system.
good yields (entries 8–10). Interestingly, a less active Work to study the detailed mechanism and apply the
substrate, 4-methyl-2-bromoaniline (1h), also dis- iron catalytic system in organic synthesis is currently
played high activity for the tandem reaction with 4- underway.
ethoxyphenyl isothiocyanate (2l) in 73% yield
(entry 11).
In summary, we have developed an iron-catalyzed
tandem reaction method for the synthesis of 2-amino-
Adv. Synth. Catal. 2009, 351, 2319 – 2323
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Jing-Wen Qiu et al.
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Experimental Section
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Typical Experimental Procedure for FeF3-Catalyzed
Tandem Reactions of 2-Halobenzenamines with
Isothiocyanates
A mixture of 2-iodoaniline 1 (0.2 mmol), isothiocyanate 2
(0. 22 mmol), FeF3 (10 mol%), 1,10-phenanthroline (L2,
0.2 equiv.), Et3N (2 equiv.), and DMSO (2 mL) was stirred
at 808C for the indicated time until complete consumption
of starting material as monitored by TLC and GC-MS anal-
ysis. After the reaction was finished, the mixture was poured
into ethyl acetate, and washed with saturated NaCl (10ꢃ
3 mL). After the aqueous layer was extracted with ethyl ace-
tate, the combined organic layers were dried over anhydrous
Na2SO4 and evaporated under vacuum. The residue was pu-
rified by flash column chromatography (hexane/ethyl ace-
tate) to afford the desired product.
N-p-Tolylbenzo[d]thiazol-2-amine (4):[14] White solid, mp
177–1788C (lit.[14] mp 177–1788C); 1H NMR (300 MHz,
DMSO-d6): d=10.36 (s, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.66
(d, J=7.7 Hz, 2H), 7.58 (d, J=8.1 Hz, 1H), 7.31 (d, J=
7.7 Hz, 1H), 7.16–7.11 (m, 3H), 2.27 (s, 3H); 13C NMR (75
MHZ, DMSO-d6): d=162.0, 152.5, 138.5, 131.3, 130.3, 129.7,
126.1, 122.4, 121.3, 119.4, 118.2, 20.7; LR-MS (EI, 70 eV):
m/z (%)=240 (M+, 86), 239 (100), 119 (22).
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c) Iron Catalysis in Organic Chemistry: Reactions and
Applications, (Ed.: B. Plietker), Wiley-VCH, Wein-
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Chem. Soc. Rev. 2008, 37, 1108.
[13] For selected papers, see: a) M. Taillefer, N. Xia, A.
Ouali, Angew. Chem. 2007, 119, 952; Angew. Chem.
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Eur. J. 2008, 14, 6037; c) J. Norinder, A. Matsumoto, N.
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Acknowledgements
We thank the National Natural Science Foundation of China
(No. 20872112), Zhejiang Provincial Natural Science Foun-
dation of China (Nos. Y407116, Y4080169 and Y4080027),
and Program for New Century Excellent Talents in Universi-
ty (No. NCET-06-0711) for financial support. Tang, R.-Y.
also thank Wenzhou University (No. 2007L004) for financial
support.
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Iron-Catalyzed Tandem Reactions of 2-Halobenzenamines with Isothiocyanates
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1a with 2a in the presence of 1,10-phenanthroline (L2)
(0.02 mol% or 0.002 mol%), Et3N (2.0 equiv.), and
DMSO (2 mL): 57% yield (0.01 mol% CuI) and 61%
yield (0.001 mol% CuI). These results suggested that
FeF3 plays the key role in the present reaction, but we
cannot rule out the effect of Cu.
Adv. Synth. Catal. 2009, 351, 2319 – 2323
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