Regioselective N-alkylation of 2-aminobenzothiazoles with benzylic alcohols

Article abstract of DOI:10.1039/c1cc10604j

The preparation of 2-(N-alkylamino)benzothiazoles via regioselecive N-alkylation of 2-aminobenzothiazoles has been accomplished by using benzylic alcohols as alkylating agents.

Full text of DOI:10.1039/c1cc10604j

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COMMUNICATION
Regioselective N-alkylation of 2-aminobenzothiazoles with benzylic
alcoholsw
Feng Li,* Haixia Shan, Qikai Kang and Lin Chen
Received 31st January 2011, Accepted 4th March 2011
DOI: 10.1039/c1cc10604j
The preparation of 2-(N-alkylamino)benzothiazoles via regioselecive
N-alkylation of 2-aminobenzothiazoles has been accomplished
by using benzylic alcohols as alkylating agents.
basic endocyclic nitrogen, affording N-endosubstituted
3-alkyl-2-iminobenzothiazolines as products (Scheme 1, left).10
Herein, we wish to describe our efforts towards regioselective
N-alkylation of 2-aminobenzothiazoles to N-exosubstituted
2-(N-alkylamino)benzothiazoles using alcohols as alkylating
agents (Scheme 1, right). The copper/base was selected as the
catalytic system here because it is cost-effective and has
emerged for the N-alkylation of sulfonamides with alcohols.2e,f
Initially, the N-alkylation of 2-aminobenzothiazole 1a with
benzyl alcohol 1b was chosen as a model to explore the
feasibility of the reaction. The reaction was carried out in the
presence of a copper salt (1 mol%) and NaOH (20 mol%) at
130 1C. When Cu(II) source was used as the catalyst, only low to
moderate yields of the desired product 1c were obtained
(Table 1, entries 1–3). The reaction proceeded to afford 1c with
The N-alkylation of amines is one of the most fundamental
and important C–N bond-forming transformations in organic
synthesis.1 Traditionally, the N-alkylation of amines was
performed with alkyl halides using stoichiometric bases.
Recently, much attention has been paid to the N-alkylation
of amines with alcohols as alkylating agents based on transition
metal-catalyzed ‘‘hydrogen autotransfer (or hydrogen-borrowing)
process’’.2 Such methods are apparently attractive because of
highly atom efficiency and the formation of water as the only
side product. However, most studies were focused on using
alcohols as benign alkylating agents instead of alkyl halides.3
The potential of alcohols as alkylating agents other than alkyl
halides on regioselectivity remains unrealized.
2-(N-alkylamino)benzothiazoles are very important structural
units in many biologically active compounds,4 and they also
exhibit a wide range of pharmacological and physiological
activities.5 As a result, several transition metal-catalyzed
methods have been developed for the preparation of
2-(N-alkylamino)benzothiazoles, including cyclization of
ortho-halobenzothioureas,6 oxidative C–H funcationalization
of benzothioureas,7 and oxidative decarbonylative coupling of
benzothiazoles with formamides.8 However, these procedures
usually suffer from the multistep preparation of the starting
materials, use of expensive metal catalysts and low functional
group tolerance. Very recently, Ma and co-workers reported
an Ullmann-type three-component method available for the
synthesis of 2-(N-alkylamino)benzothiazoles from easily
accessible 2-haloanilines in the presence of stoichiometric or
excess amount of copper salts and bases.9 The preparation of
2-(N-alkylamino)benzothiazoles via simple N-alkylation of
2-aminobenzothiazoles is still a challenge in organic synthesis.
It was well documented that the N-alkylation of
2-aminobenzothiazoles with alkyl halides occurs on the most
Scheme 1 Regioselective N-alkylation of 2-aminobenzothiazoles with
alkyl halides and alcohols.
Table 1 N-alkylation of 2-aminobenzothiazole 1a with benzyl alcohol 1b
under various conditionsa
Entry
Cu source
Base
Yield%b
1
2
3
4
5
6
7
8
CuCl2Á2H2O
CuBr2
Cu(OAc)2
CuCl
CuBr
Cul
CuCl
CuCl
CuCl
CuCl
CuCl
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
KOH
Na2CO3
K2CO3
tBuONa
tBuOK
27
66
75
96
94
93
80
10
21
43
37
School of Chemical Engineering, Nanjing University of Science and
Technology, Nanjing 210094, P. R. China.
E-mail: fengli@mail.njust.edu.cn; Fax: +86-25-84431939;
Tel: +86-25-84317316
9
10
11
a
w Electronic supplementary information (ESI) available: Experimental
procedures and analytical data for 1–20c. See DOI: 10.1039/
c1cc10604j
Reaction conditions: 1 mmol amine, 1.2 mmol alcohol, 0.01 mmol
b
Cu source, 0.2 mmol base, 130 1C, 12h. Isolated yield.
c
5058 Chem. Commun., 2011, 47, 5058–5060
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almost quantitative yields when Cu(I) source was used as the
catalyst (entries 4–6). Among Cu(I) sources, CuCl was chosen as
the catalyst for further research (entry 4). Using KOH, Na2CO3,
K2CO3, tBuONa or tBuOK as alternative base for the reaction,
decreases in the yield were observed (entries 7–11).
To expand the scope of the reaction, the N-alkylation of 1a
with various alcohols b was examined under the optimal
conditions (Table 1, entry 4), and the results are summarized
in Table 2. Similar to the case of 1b, the N-alkylation of
benzylic alcohols bearing a donating group, such as methyl 2b
and methoxyl 3b, gave the corresponding products 2–3c with
97% and 92% yields, respectively (Table 2, entries 1–2). The
N-alkylation with benzylic alcohols bearing a halogen atom
4–7b proceeded to give the corresponding products 4–7c with
excellent yields as well (entries 3–6). Benzylic alcohols bearing
an electron-withdrawing group, such as trifluoromethyl 8b and
trifluoromethoxy 9b, were successfully utilized to afford the
desired products 8–9c with 85% and 75% yields, respectively
(entries 7–8). Further, reactions with benzylic alcohols bearing
two substituted groups 10–11b showed high activities and the
corresponding products 10–11c were obtained with 81% and
83% yields, respectively (entries 9–10). The reaction was also
applied to 2-pyridylmethanol 12b and 2-naphthalenemethanol
13b, affording the desired products 12–13c with 85% and 80%
yields, respectively (entries 11–12). However, no reaction took
place in the N-alkylation with aliphatic alcohols such as
1-butanol and cyclohenxanol under the same conditions.
The N-alkylation of a variety of substituted 2-aminobenzo-
thiazoles with 1b was then investigated. As shown in Table 3,
the N-alkylation of 2-aminobenzothiazoles bearing one or two
Table
2
N-alkylation of 2-aminobenzothiazole 1a with various
alcoholsa
Entry
1
Alcohol
Product
Yield%b
97
2
3
4
92
94
90
Table 3 N-alkylation of a variety of substituted 2-aminobenzo-
thiazoles with benzyl alcohol 1ba
5
91
6
7
8
98
85
75
Entry Amine
Product
Yield%b
1
92
2
94
3
4
5
88
96
98
9
81
83
10
11
85
80
6
7
a
93
12
87c
a
Reaction conditions: 1 mmol amine, 1.2 mmol alcohol, 0.01 mmol
b
Reaction conditions: 1 mmol amine, 1.2 mmol alcohol, 0.01 mmol
b
c
CuCl, 0.2 mmol NaOH, 130 1C, 12 h. Isolated yield.
CuCl, 0.2 mmol NaOH, 130 1C, 12 h. Isolated yield. 160 1C.
c
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Scheme 2 A possible mechanism for the regioselective N-alkylation
reaction.
electron-donating substituents 2–5a afforded the corres-
ponding products 14–17c with 88–96% yields (Table 3, entries
1–4). Similarly, 2-aminobenzothiazoles bearing a halogen atom
6–7a were also converted into the corresponding products
18–19c with excellent yields (entries 5–6). Further, the N-
alkylation of 2-aminobenzothiazoles bearing an electron-
withdrawing substituent 8a afforded the desired product 20c
with 87% yields, though the elevated reaction temperature was
required (entry 7).
In all case, no side product such as isomer 3-alkyl-
2-iminobenzothiazoline and over-alkylated 2-(N-dialkylamino)-
benzothiazoles was observed. Clearly, the reaction exhibited
complete regioselectivity. It was also noteworthy that the
substituent such as halide, methoxyl, thiomethyl, trifluoromethyl
or trifluoromethoxy group on either benzyl alcohols or 2-amino-
benzothiazoles could be tolerated under this reaction conditions.
Based on the experimental results and the known ‘‘hydrogen
autotransfer (or hydrogen-borrowing) methodologies’’,
a
possible mechanism for the regioselective N-alkylation reac-
tion is as follows (Scheme 2): the alcohols are first dehydro-
genated to form the aldehydes with the generation of copper
hydride species in the presence of bases.11 Obviously, the
exocyclic nitrogens are favored over endocyclic nitrogens in
the process of the condensation of 2-aminobenzothiazoles with
the resulting aldehydes, affording imine intermediates. Finally,
the imine intermediates undergo the transfer hydrogenations
to afford the 2-(N-alkylamino)benzothiazoles with regioselectivity,
and the copper hydride species are also consumed.
In summary, we have developed a simple approach for the
preparation of 2-(N-alkylamino)benzothiazoles via regioselective
N-alkylation of 2-aminobenzothiazoles with benzylic alcohols.
Notably, the research demonstrated new potential of alcohols
as electrophiles. Efforts to elucidate the exact mechanism of
reaction and expand the scope of reaction type are currently
under way in our laboratory.
We are grateful to National Natural Science Foundation of
China (No. 20902046) and Natural Science Foundation of Jiangsu
Province (No. BK2009384) for financial support of this research.
The project is also supported by the State Key Laboratory of
Fine Chemicals, Dalian University of Technology (Grant No.
KF0911).
c
5060 Chem. Commun., 2011, 47, 5058–5060
This journal is The Royal Society of Chemistry 2011