Direct N-alkylation of amino-azoles with alcohols catalyzed by an iridium complex/base system

Article abstract of DOI:10.1039/c1cc14861c

The direct and regioselective N-alkylation of amino-azoles to the corresponding 2-N-(alkylamino)azoles using various alcohols as alkylating agents with good to excellent yields has been accomplished by an iridium complex/base system.

Full text of DOI:10.1039/c1cc14861c

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COMMUNICATION
Direct N-alkylation of amino-azoles with alcohols catalyzed by an
iridium complex/base systemw
Feng Li,* Haixia Shan, Lin Chen, Qikai Kang and Po Zou
Received 6th August 2011, Accepted 10th November 2011
DOI: 10.1039/c1cc14861c
The direct and regioselective N-alkylation of amino-azoles to the
corresponding 2-N-(alkylamino)azoles using various alcohols
as alkylating agents with good to excellent yields has been
accomplished by an iridium complex/base system.
Amino-azoles are very important structural units in many
natural products and other biologically active compounds.
In particular, 2-N-(alkylamino)azoles exhibit a wide range of
Scheme 2 Direct N-alkylation of amino-azoles with alkyl halides and
alcohols.
pharmacological and physiological activities. For example, some
of them are used as anti-inflammatory agents (Fanetizole A),
UDP-galactopyranose mutase inhibitors (B),1a k and m opioid
amines,3a–c chloramines3d or formamides3e provide another
access to 2-N-(alkylamino)azoles.3f These procedures generally
suffer from high catalyst loadings, more stoichiometric amounts
of oxidants or other additives, and low yields.
receptors (C)1b and small-molecule somatostatin receptor
subtype 5 (SST5R) antagonists (D)1c (Scheme 1). Traditionally,
2-N-(alkylamino)azoles are prepared by cyclocondensation
reactions of two functionalized precursors (e.g. Hantszch
aminothiazole synthesis). Transition metal-catalyzed cyclization
reactions have been developed for the preparation of 2-N-
(alkylamino)azoles, including cyclizations of ortho-halobenzo-
thioureas,2a–c benzothioureas,2d,e or domino condensation/
coupling/cyclization of ortho-haloanilines, carbon disulfide and
alkylamines.2f However, these procedures are only available for
the synthesis of benzo-fused 2-N-(alkylamino)azoles. Transi-
tion metal-catalyzed direct oxidative couplings of azoles with
The direct N-alkylation of amino-azoles is apparently one of
the most simple methods for the preparation of 2-N-(alkyl-
amino)azoles. However, such reactions with alkyl halides as
alkylating agents afford 3-alkyl-2-imino-azolines other than
2-N-(alkylamino)azoles because the endocyclic nitrogen is
more basic than the exocyclic one (Scheme 2, left).4 Recently,
much attention has been paid to the N-alkylation of amines
with alcohols as environmentally benign alkylating agents
instead of alkyl halides based on a transition metal-catalyzed
‘‘hydrogen autotransfer (or hydrogen-borrowing) process’’.5,6
Very recently, we demonstrated the regioselective N-alkylation
of 2-aminobenzothiazoles to 2-(N-benzylamino)benzothia-
zoles using benzyl alcohols as alkylating agents catalyzed by
a copper/base system.7 However, only activated benzylic
alcohols could be utilized as alkylating agents and the type
of amino-azoles is also limited to 2-aminobenzothiazoles in the
presence of the above catalytic system, and thus the synthetic
potential is significantly restricted. As part of a continuing
interest in exploring regioselective N-alkylation reactions,
herein we wish to report a general and efficient method for the
preparation of 2-N-(alkylamino)azoles via direct N-alkylation
of amino-azoles with various alcohols catalyzed by an iridium
complex/base system (Scheme 2, right) and the mechanistic
studies are also presented.
Scheme 1 Representative molecules of 2-N-(alkylamino)azoles.
Initial efforts focused on the N-alkylation of 2-aminobenzo-
thiazole 1a with 1-butanol 2a to explore the feasibility of the
reaction. When the reaction was carried out in the presence of
[Cp*IrCl2]2 (0.2 mol%) at 150 1C for 12 h, no product was
observed (Table 1, entry 1). In most cases, the reaction
occurred and afforded the desired product 3aa by the addition
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
w Electronic supplementary information (ESI) available: Experimental
procedures and analytical data for N-alkylated products. See DOI:
10.1039/c1cc14861c
c
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Table 1 N-Alkylation of 2-aminobenzothiazole 1a with 1-butanol 2a
under various conditionsa
Similarly, the N-alkylation with branched aliphatic primary
alcohols 2d and 2e afforded the desired products 3ad and 3ae
in high yields. Functionalized alcohols, such as 2-methoxyethanol
2f and 2-(phenylthio)ethanol 2g, were utilized to afford the
corresponding products 3af and 3ag in 86% and 91% yields,
respectively. Further, reactions with non-benzylic aromatic
alcohols, such as 2-phenylethanol 2h and 3-phenylpropanol
2i, showed high activities and the desired products 3ah and
3ai were obtained in 94% and 96% yields, respectively. The
N-alkylation with benzyl alcohol 2j, and benzylic alcohols bearing
an electron-donating group 2k and an electron-withdrawing
group 2l afforded the corresponding products 3aj–3al in
93%–97% yields. In the case of the secondary alcohol with high
steric hindrance 2m, the desired product 3am was successfully
obtained in 80% yield.
Entry
Catalyst
Base
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Ir(cod)Cl]2
—
—
n.d.
n.d.
n.d.
35
90
95
92
93
90
n.d.
NaHCO3
Na2CO3
K2CO3
Cs2CO3
NaOH
KOH
NaOtBu
NaOH
NaOH
The N-alkylation of a variety of amino-azoles 1b–m with 2a
was then investigated. As shown in Table 3, the N-alkylation of
2-aminobenzothiazoles bearing one or two electron-donating
substituents 1b–d gave the corresponding products 3ba–3da in
88–97% yields. Similarly, reactions of 2-aminobenzothiazoles
bearing a halogen atom 1e–g afforded the desired products
3ea–3ga in 85–92% yields. The aminobenzothiazole bearing an
electron-withdrawing substituent 1h was also converted into the
corresponding product 3ha in 90% yield. Further, the N-alkylation
of non-benzo-fused 2-aminothiazoles 1i–k gave the desired
products 3ia–3ka in excellent yields. The reaction was also
applied to amino-oxazoles 1l–m, affording the corresponding
products 3la and 3ma in 92% and 86% yields, respectively.
It is noteworthy that apart from the desired products
2-N-(alkylamino)azoles, no isomer 3-alkyl-2-iminoazolines and
over-alkylated 2-(N-dialkylamino)azoles were formed in all
a
Reaction conditions: 1 mmol 1a, 5 mmol 2a, 0.2 mol% catalyst,
b
0.2 mmol base, 150 1C, 12 h. Isolated yield.
of a base (entries 2–8). Among the tested bases, NaOH was
found to be the most effective and the product 3aa was
obtained in 95% yield. Using [Ir(cod)Cl]2 as an alternative
catalyst, the reaction afforded 3aa in 90% yield (entry 9). No
reaction took place in the presence of NaOH alone, indicating
that the combination of the iridium complex and a base is
necessary for the reaction (entry 10).
To expand the scope of the reaction, the N-alkylation of 1a
with various alcohols 2b–m was examined under the optimal
conditions (Table 1, entry 6), and the results are summarized in
Table 2. The N-alkylation with other linear aliphatic primary
alcohols, such as 1-hexanol 2b and 1-octanol 2c, gave the
corresponding products 3ab–3ac in 93% and 86% yields.
Table 3 N-Alkylation of amino-azoles with 1-butanol 2aa,b
Table 2 N-Alkylation of 2-aminobenzothiazole 1a with various
alcoholsa,b
a
a
Reaction conditions: 1 mmol amine, 5 mmol alcohol, 0.2 mol%
b
Reaction conditions: 1 mmol amine, 5 mmol alcohol, 0.2 mol%
b
c
c
[Cp*IrCl2]2, 0.2 mmol NaOH, 150 1C, 12 h. Isolated yield. 1 mmol
NaOH. 0.4 mmol NaOH.
[Cp*IrCl2]2, 0.2 mmol NaOH, 150 1C, 12 h. Isolated yield. 1 mmol
NaOH. 0.4 mmol NaOH.
d
d
c
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cases. In addition, a stoichiometric amount of base was
required in a few cases to obtain the N-alkylated products in
high yields.
broad substrate scope. Further studies to expand the application
of the synthetic strategy are currently underway.
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. This project is also supported by the State Key
Laboratory of Fine Chemicals, Dalian University of Technol-
ogy (Grant No. KF0911).
To obtain the information about the reaction mechanism,
the condensation of an amino-azole with an aldehyde, and
hydrogen transfer between the resulting imine and alcohol were
undertaken. The reaction of 4,5-diphenylthiazol-2-amine with
benzaldehyde at 150 1C for 12 h gave (Z)-N-benzylidene-4,5-
diphenylthiazol-2-amine in 45% yield as only product [eqn (1)].
Further, the reaction of the resulting (Z)-N-benzylidene-4,5-
diphenylthiazol-2-amine with benzyl alcohol in the presence of
[Cp*IrCl2]2 (0.2 mol%) and NaOH (20 mol%) was carried out
for 12 h to afford almost stoichiometric amounts of N-benzyl-
4,5-diphenylthiazol-2-amine and benzaldehyde [eqn (2)].
Notes and references
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ð2Þ
Based on these experimental results, a plausible mechanism
is proposed to account for the regioselective N-alkylation of
amino-azoles catalyzed by the iridium complex/base system
(Scheme 3). Accompanied by the catalytic cycle of iridium, the
alcohol is first dehydrogenated to form the aldehyde, followed
by the condensation of the resulting aldehyde with amino-azole
to afford an imine intermediate, which is hydrogenated to
afford the N-alkylated product. Obviously, the regioselectivity
of the reaction may be attributed to that the exocyclic nitrogen
is favored over the endocyclic one in the process of the con-
densation with aldehyde.
In summary, a simple, efficient and general method for the
preparation of 2-N-(alkylamino)azoles via direct N-alkylation
of amino-azoles with alcohols has been accomplished by
the [Cp*IrCl2]2/NaOH system. The procedure is apparently
attractive from a synthetic point of view because of high atom
efficiency, the formation of water as only side product, and
7 F. Li, H. Shan, Q. Kang and L. Chen, Chem. Commun., 2011,
47, 5058.
Scheme 3 Plausible mechanism for the direct N-alkylation reaction.
c
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Chem. Commun., 2012, 48, 603–605 605