Table 1: Screening of reaction conditions for the reaction of 2-iodoani-
observed when other copper salts, such as Cu(OAc)2·H2O and
CuSO4·5H2O (Table 1, entries 12 and 13), or the solvents
dioxane and dimethyl sulfoxide (DMSO; entries 14 and 15)
were used.
line, carbon disulfide, and piperidine.[a]
Having optimized the reaction conditions through the use
of CuCl2·2H2O as both the catalyst and the desulfurizing
agent, we explored the scope and limitations of this three-
component reaction. We first examined the reaction of a
number of monosubstituted 2-haloanilines with piperidine as
a coupling partner (Scheme 3). Generally, the reaction
proceeded well with these substrates to deliver the 2,5- and
2,6-disubstituted benzothiazoles 12b–12k in good to excellent
yields. The results demonstrated that both the electronic
features and the orientation of the additional substituent on
the 2-haloaniline have limited influence on this cascade
reaction. 2-Bromoanilines also underwent this transforma-
tion, although they required higher reaction temperatures
than the corresponding iodides, and the products were formed
in slightly lower yields. The synthesis of trisubstituted
benzothiazoles 12l and 12m from two disubstituted
2-haloanilines indicates that this method enables the intro-
duction of functional groups at 4-, 5-, and/or 6-positions of
benzothiazoles.
We further explored the generality of the present method
by varying the secondary amine and found that thiomorpho-
line, Boc-protected piperazine, simple and sterically hindered
acyclic amines, functionalized cyclic amines, as well as
N-methylaniline, were compatible with this process. Thus,
benzothiazoles 12n–12ab were formed in 61–93% yield.
Additionally, the substituted thiazolo[4,5-b]pyridine 12ac was
obtained from 3-iodopyridin-2-amine and piperidine in 74%
yield.
Entry
Catalyst, ligand, additive
T [8C]
Yield of
12a [%][b]
1
2
3
4
5
CuI, l-proline
CuI, l-proline
CuI, l-proline, AgNO3 (1.5 equiv)
CuI, l-proline, CuBr2 (1.5 equiv)
CuBr2 (1.5 equiv)
80
110
110
110
110
110
110
110
90
110
110
110
110
110
110
22[c]
36[d]
74
80
78
88
92
92
84
85
80
88
82
70
70
6
7
CuBr2 (1.0 equiv)
CuCl2·2H2O (1.0 equiv)
CuCl2·2H2O (1.0 equiv)
CuCl2·2H2O (1.0 equiv)
CuCl2·2H2O (1.0 equiv)
CuCl2·2H2O (1.0 equiv)
Cu(OAc)2·H2O (1.0 equiv)
CuSO4·5H2O (1.0 equiv)
CuCl2·2H2O (1.0 equiv)
CuCl2·2H2O (1.0 equiv)
8[e]
9
10[f]
11[g]
12
13
14[h]
15[i]
[a] Reaction conditions: 8a (0.5 mmol), CS2 (0.6 mmol), piperidine
(1 mmol), CuI (0.05 mmol, for entries 1–4), l-proline (0.1 mmol, for
entries 1–4), additive (0.5–0.75 mmol, for entries 3–15), K2CO3
(1.5 mmol), DMF (1 mL), 6 h. [b] Yield of the isolated product. [c] Com-
pound 9a was isolated in 77% yield. [d] Compounds 9a and 11a were
isolated in 8 and 30% yield, respectively. [e] The reaction was carried out
with 0.75 mmol of piperidine. [f] K3PO4 was used as the base. [g] Cs2CO3
was used as the base. [h] DMSO was used as the solvent. [i] Dioxane was
used as the solvent.
808C to give the desired product 12a in 22% yield together
with the simple coupling product 9a in 77% yield (Table 1,
entry 1). The isolation and characterization of 9a provided
direct evidence for the mechanism proposed in Scheme 2. To
facilitate the further conversion of 9a, we increased the
reaction temperature to 1108C. In this case, the yield of 12a
was still low, mainly because of the formation of 11a (Table 1,
entry 2). To solve this problem, we examined the use of
desulfurizing agents to promote the formation of 12a. Indeed,
the yield of 12a was increased to 74% by the addition of silver
nitrate (1.5 equiv; Table 1, entry 3). When CuBr2 was used as
the additive, the yield was further improved to 80% (Table 1,
entry 4). Further exploration indicated that in the presence of
CuBr2, neither CuI nor l-proline was necessary for this
transformation (Table 1, entry 5). A decrease in the amount
of CuBr2 used to 1 equivalent led to further improvement of
the yield (Table 1, entry 6). Exchange of the copper salt for
cheaper CuCl2·2H2O delivered the best result (Table 1,
entry 7). In this case, the amount of piperidine could be
decreased to 1.5 equivalents without alteration of the yield
(Table 1, entry 8). This amount was used in subsequent
studies (but not in the other reactions shown in Table 1).
Under the action of CuCl2·2H2O, the reaction proceeded to
completion even at 908C to produce 12a in 84% yield
(Table 1, entry 9). When the base was changed to K3PO4 or
Cs2CO3, the reaction yield decreased only slightly (Table 1,
entries 7, 10, and 11). A similar slight decrease in the yield was
Another notable characteristic of this reaction is that a
wide range of functional groups, including nitro, keto, ester,
nitrile, methoxy, chloro, and trifluoromethyl substituents,
remain intact under the reaction conditions. This advantage
makes our method a very powerful tool for the assembly of
bioactive benzothiazoles. Indeed, products 12o–12q could be
used for the synthesis of serotonin-receptor modulators,[15]
PDE4 inhibitors,[16] modulators of metabotropic glutamate
receptor 5 (mGluR5),[17] and the anti-HIV agent 1;[1] com-
pound 12w is a precursor for the synthesis of analogues of
sabeluzole with an inhibitory effect on gastric-acid secre-
tion;[18] benzothiazole 12y could be applied to the preparation
of CB2-receptor modulators;[19] whereas benzothiazoles 12z,
12v, and 12aa could be employed for the assembly of the
antibacterial agent 2,[2] PPAR agonist 3,[3] and H3-receptor
ligand 4,[4] respectively.
We next turned our attention to the use of other
N nucleophiles (Scheme 4). When benzylamine was treated
with 2-iodoaniline under the described reaction conditions,
the desired product 12ad was obtained in only 15% yield. We
found that the yield could be improved to 97% if benzyl-
amine was first treated with carbon disulfide at 08C, and the
reaction mixture was heated after the addition of 2-iodoani-
line and CuCl2·2H2O (3.5 equiv). These modified conditions
were found to be suitable for a number of primary amines,
including aliphatic amines with a range of functionality and
electron-rich anilines; the corresponding 2-aminobenzothia-
Angew. Chem. Int. Ed. 2011, 50, 1118 –1121
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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