Generation of azomethine imine and metal-free formal 1,3-dipolar cycloaddition of imine with PhIO: Reaction, scope, and synthesis

Article abstract of DOI:10.1039/b924761k

Generation of azomethine imine and its scope in regioselective 1,3-dipolar cycloaddition (DC) of imine with PhIO toward highly substituted Δ²-1,2,4-triazoline, 1,2,4-triazole, and their fused, chiral, and sugar-based analogues are demonstrated. The Royal Society of Chemistry.

Full text of DOI:10.1039/b924761k

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Generation of azomethine imine and metal-free formal 1,3-dipolar
cycloaddition of imine with PhIO: reaction, scope, and synthesisw
Dilip K. Maiti,* Nirbhik Chatterjee, Palash Pandit and Sandip K. Hota
Received (in Cambridge, UK) 24th November 2009, Accepted 16th January 2010
First published as an Advance Article on the web 10th February 2010
DOI: 10.1039/b924761k
Generation of azomethine imine and its scope in regioselective
1,3-dipolar cycloaddition (DC) of imine with PhIO toward
highly substituted D2-1,2,4-triazoline, 1,2,4-triazole, and their
fused, chiral, and sugar-based analogues are demonstrated.
Scheme 1 Generation of azomethine imine and its applications.
Huisgen’s 1,3-DC reaction has found versatile applications in
organic synthesis. The powerful synthetic tool is capable of
constructing bonds in a regio- and stereocontrolled way to
furnish designed ubiquitous carbocyclic and heterocyclic
functional molecules.1 Cycloaddition reactions involving
nitrogenous parent 1,3-dipoles like nitrile oxide, nitrone, and
azomethine ylide are often investigated. Relatively less effort
has been devoted for the generation and application of the
azomethine imine ylides, although there is wide scope for
efficient access to many valuable heterocycles. Olefins are often
used for 1,3-DC reactions, where as utilization of a hetero-
dipolarophile like the imine has received less attention. Metal-
catalysts are usually employed for the cycloaddition of imines.2
Azomethine imines are generated by Huisgen’s route3a
involving condensation of aldehydes with designed
1,2-disubstituted hydrazines having certain restrictions,3c and
subsequently cycloaddition under heating and metal Lewis
acid3d catalyzed conditions furnish pyrazolidines and other
heterocycles. Until now, there are only a few scattered methods
for azomethine imine, for example, 1,4-silatropic shift of
a-silylnitrosoamines under heating conditions.3b However, a
more important and useful transformation of simple starting
materials like aldohydrazones to the desired azomethine imine
ylides, and their oxidative intermolecular [3 + 2]-cycloaddition
with imines under mild and metal-free reaction conditions
toward regioselective synthesis of D2-1,2,4-triazoline, triazole
and their chiral, sugar-based, and fused analogues, to the best
of our knowledge, have never been realized.
absolute regioselective way, leading to an important family of
heterocycles, D2-1,2,4-triazoline (5a, entries 6–8).6 We have found
that the choice of substituent Ts (X, entries 8-10) has a significant
impact on the progress of the reaction. In the ongoing program
to search for new low molecular mass scaffolds for self-
aggregated organic architectures,5,7 the one pot transformation
of the synthon 5a into the 3,4,5-trisubstituted-1,2,4-triazole (6a)
was also achieved rapidly in excellent yield (95%) by the
treatment of NBS (entries 11–13). However, treatment of HOBt8
or base even under heating conditions could not undergo
aromatisation with the loss of Ts.
The metal-free benign synthetic protocol developed under
the neutral and milder reaction conditions is also an alternative
approach to the nitrile imine cycloaddition reaction which is
often performed utilizing unstable chloro- and bromoaldo-
hydrazone precursors at higher temperature in the presence of
base.6 As part of developing a general strategy towards novel
N-heterocycles by avoiding the isolation of unstable imine
precursors (2), corresponding functionalized aldehydes (3) and
primary aliphatic or aromatic amines (4) were taken together
and stirred at ambient temperature for 6.5 h to prepare the
imines (2) in situ (Scheme 2). Adoption of the multicomponent
one pot strategy9 provides great advantages over the linear
multistep syntheses owing to the minimization of time, waste
and manpower, and also reduction of impact on the environment
and hazards. The proposed mechanistic explanation for the
complete regiocontrolled cycloaddition is that PhIO herein
acts as a strong Lewis acid to coordinate with the nitrogen
atom of the N-tosyl aldohydrazone (1) leading to the forma-
tion of azomethine imine ylide (I, Scheme 2), where Ts
stabilizes the negative charge. It follows the unidirectional
formal [3 + 2]-cycloaddition pathways with the imine (2)
involving the lone pair to afford the five-member heterocycles
(II). Relative to the metal catalyzed 1,3-DC reaction it has the
advantage of rapid construction of the double bond to access
the D2-1,2,4-triazolines (5) involving reductive elimination of
the hypervalentiodane moiety from the putative cycloadduct
(II). However, generation of a nitrile imine1a,6 as a key
intermediate from 1 by PhIO and the subsequent 1,3-DC with
2 toward 5 cannot be avoided. Removal of the Ts with
formation of the double bond (N2QC3) by NBS leads to the
desired heterocycles (6).
The initial exploration for generation of the azomethine
imine dipolar complex (I, Scheme 1) focused on the application
of efficient metal Lewis acid catalysts4 (entries 1–5, Table 1) on
aldohydrazone (1a) but were in vain. Gratifyingly, attempting
with the organic oxidant iodosobenzene (PhIO), utilized for
our previous studies to generate 1,3-dipoles,1c,5a generated the
dipolar complex (I, Scheme 1), and also rapidly (2.5 h) drove
the formal [3 + 2]-DC reaction with the imine (2a) in an
Department of Chemistry, University of Calcutta, University College
of Science, 92, A. P. C. Road, Kolkata-700009, India.
E-mail: maitidk@yahoo.com; Fax: +91-33-2351-9755;
Tel: +91-33-2350-9937
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, NMR spectra, crystallographic
data in CIF file and self-assembled materials. See DOI: 10.1039/
b924761k
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Table 1 Development and optimization of the reactiona
Entry
Reagents
Ag(OTf)b
1a/5a, X
Reaction conditions
Conversion
5a/6a,Yield(%)
1
2
3
4
5
6
7
8
1a, Ts
1a, Ts
1a, Ts
1a, Ts
1a, Ts
1a, Ts
1a, Ts
1a, Ts
1a, CO2Et
1a, 2,4-C6H3(NO2)2
5a, Ts
5a, Ts
5a, Ts
CH2Cl2, MgSO4, rt, 22 h
CH2Cl2, MgSO4, rt, 25 h
CH2Cl2, MgSO4, rt, 24 h
CH2Cl2, MgSO4, rt, 28 h
CH2Cl2, MgSO4, rt, 24 h
THF, MgSO4, rt, 10 h
Me2CO, MgSO4, rt, 10 h
CH2Cl2, MgSO4, rt, 2.5 h
CH2Cl2, MgSO4, rt, 3 h
CH2Cl2, MgSO4, rt, 24 h
MeOH, rt, 24 h
No reaction
No reaction
No reaction
No reaction
No reaction
80%
85%
100%
100%
5a, —
5a, —
5a, —
5a, —
b
Cu(OTf)2b
Yb(OTf)3
Sc(OTf)3
b
b
Ni(OAc)2
5a, —
PhIOc
PhIOc
PhIOc
PhIOc
PhIOc
HOBtd
NBSd
5a, 62f
5a, 65f
5a, 81f
Dimerization
5a, —
9
10
11
12
13
No reaction
15%
100%
6ae, —
6a, 95
6a, 48
CH2Cl2, MgSO4, rt, 2 h
ClCH2CH2Cl, 50 1C, 8 h
gButOK
60%
a
b
c
d
e
Isolated yield of the compounds 5a and 6a. Catalytic load (15 mol%). Two mole. Stoichiometric amount. Not isolated. Along with 6a
f
g
(9%). Three mole.
reported for 3,4,5-trisubstituted-1,2,4-triazoles involving
multistep reactions.12
The azomethine imine dipolar complex (I) can also be
trapped even with the CQN bond of aromatic N-heterocycles
like pyridines (7a,b) and quinoline (7c) via an absolute regio-
selective Huisgen [3 + 2] cycloaddition. To the best of our
knowledge, this novel intermolecular approach towards rapid
(2.0–2.5 h) access to the fused 1,2,4-triazoles (8, Scheme 3) is
unknown in the literature. The extremely fast reaction rate can
be explained by the involvement of a cascade chemical process
of the highly reactive species I with the imine bond possessing
Scheme 2 Possible pathway of the one pot synthesis.
strong electron density towards generation of the fused
The isolated yield was uniformly high (81–89%) for each
cycloadduct III and followed by reductive elimination of
individual case (entries 1–12, Table 2). Electron-rich and
electron-deficient functional groups present in aromatic sub-
stituents were tolerated by the robust synthetic approach.
Unfortunately, use of activated amine (4d) and 2-hydroxy-
phenylhydrazone (1h) towards formation of desired cycloadducts
(5) were unsuccessful due to the strong chelation of PhIO with
the corresponding carbanion and the phenolic-OH (entries
13,14). Substituted-1,2,4-triazoles (6) have found diverse
applications as antifungal, antiviral and anticancer drugs,10
materials,11b metal–ligand architectures11c and synthons.11a
So far, only a limited number of synthetic approaches are
Scheme 3 Intermolecular 1,3-DC with aromatic-N-heterocycles.
Table 2 Experimental data for synthesis of 1,2,4-triazoles (6)a
Imine (2)
Aldehyde (3, R2)
Amine (4, R3)
Entry
Aldohydrazone (1, R1)
Reaction time/h
6,Yield (%)
1
2
3
4
5
6
7
8
p-NO2–C6H4(1a)
b-naphthyl(1b)
p-Cl–C6H4(1c)
p-Br–C6H4 (1d)
b-naphthyl(1b)
m-NO2–C6H4(1e)
p-MeO–C6H4(1f)
p-Cl–C6H4(1c)
p-Cl–C6H4(1c)
C6H5(1g)
o-MeO–C6H4(3a)
p-MeO–C6H4(3b)
p-MeO–C6H4(3b)
p-MeO–C6H4(3b)
o-BnO–C6H4(3c)
m-NO2–C6H4(3d)
o-NO2–C6H4(3e)
p-Cl–C6H4(3f)
p-Cl–C6H4(3f)
C6H5(3g)
m-NO2–C6H4(3d)
m-NO2–C6H4(3d)
m-NO2–C6H4(3d)
p-MeO–C6H4(3b)
CH2C6H5(4a)
CH2C6H5(4a)
CH2C6H5(4a)
CH2C6H5(4a)
p-Me–C6H4(4b)
p-Me–C6H4(4b)
p-Me–C6H4(4b)
cyclohexyl(4c)
CH2C6H5(4a)
CH2C6H5(4a)
CH2C6H5(4a)
CH2C6H5(4a)
CHCO2EtBn(4d)
CH2C6H5(4a)
5.0(3.0 + 2.0)
5.0(3.0 + 2.0)
4.0(2.5 + 1.5)
4.0(2.5 + 1.5)
5.0(3.0 + 2.0)
4.5(3.0 + 1.5)
5.0(3.0 + 2.0)
4.5(3.0 + 1.5)
4.5(2.5 + 2.0)
4.5(3.0 + 1.5)
4.5(2.5 + 2.0)
5.0(3.0 + 2.0)
5.0(5.0 + -)
6a, 84
6b, 88
6c, 82
6d, 81
6e, 80
6f, 85
6g, 81
6h, 88
6i,b 82
6j, 89
9
10
11
12
13
14
b-naphthyl(1b)
m-NO2–C6H4(1e)
C6H5(1g)
6k, 82
6l, 88
6mc, —
6nd, —
o-OH–C6H4(1h)
5.0(5.0 + -)
a
b
Isolated yield. Structure determined by XRD. Decomposed. No desired product.
c
d
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Table 3 Experimental data for synthesis of fused-1,2,4-triazole (8)
Entry Aldohydrazone (1) N-Heterocycles (7)
t/h 8, Yield (%)
2.5 8a, 81
1
2
3
4
5
6
p-MeO–C6H4(1f)
p-MeO–C6H4(1f)
p-Cl–C6H4(1b)
b-naphthyl(1a)
p-Br–C6H4 (1d)
p-CHO-C5H4N(7a)
p-COCH3-C5H4N(7b) 2.5 8b, 79
p-CHO-C5H4N(7a)
quinoline(7c)
p-CHO-C5H4N(7a)
2.0 8c, 78
2.0 8d, 80
2.5 8e, 78
2.5 8f, 74
m-NO2–C6H4(1e) p-CHO-C5H4N(7a)
PhI to the fused triazoline intermediate IV. To regain the
aromaticity, the Ts and the fused ring ÀH have been triggered
off automatically affording the fused triazole in excellent yield
(74–81%, Table 3). Thus, NBS is not required. Aldehyde, ketone
and other functional groups are tolerated by the metal-free
benign approach which can be utilized for further modifications.
1,2,4-Triazolo[3,4-a]pyridines and their quinoline analogues have
been the focus of growing attention in the recent past for their
known and potential biological activities.13
Fig. 1 Single crystal X-ray diffraction structure of compound 6i.
neighboring molecules leading to the generation of self-
aggregated low dimensional materials (ESIw).5,7
We acknowledge the financial supports of this work by the
DST (project no. SR/S1/OC-22/2006), CRNN and CSIR
(SRF), India.
In contrast to the literature methods, it has no restriction
regarding placement of the substitution pattern around the
triazole motif (6) by utilizing designed precursors. We have
considerably expanded the scope towards synthesis of the chiral
triazoles14 (6o–q, 1, Scheme 4) from the commercially available
chiral aliphatic amine. Chiral 1,2,4-triazoles are well-known as
drugs and fungicides.10 Azomethine imine bearing the chiral sugar
moieties can also be tolerated in this approach and efficiently
utilized (2–4) for the synthesis of sugar-based 1,2,4-triazoles (6r, s)
and their functionalized fused analogues (8g–i). The unnatural
nucleoside analogues synthesized for the first time are potential
candidates for new drug design and other applications.15
Notes and references
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The structure is determined by means of X-ray diffraction
(6i, Fig. 1) analyses.16 It reveals the outward orientation7,17 of
all the three aromatic substituents located side-by-side and
also strong intermolecular hydrogen bonding between the p-Cl
and o-H atoms (2.87 A) which have significant roles
for creating the gluing non-covalent interactions among the
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16 CCD deposition code of compound 6i: 741300.
17 Observed dihedral angles: N1–C8–C16–C21
=
À142.21;
N1–C9–C10–C15 = +138.21; C8–N1–C6–C5 = +97.91.
Scheme 4 Evaluation of precursor scope.
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2024 | Chem. Commun., 2010, 46, 2022–2024