Regioselective synthesis of a new [1,2,3]-triazoles directly from imidates

Article abstract of DOI:10.1002/jhet.5570430238

A one pot synthetic approach to the novel [1,2,3]-triazoles system, by 1,3-dipolar cycloaddition of 2-diazopropane to the imidates 2, is described. The structures of the obtained adducts have been assigned by means of spectroscopic measurements.

Full text of DOI:10.1002/jhet.5570430238

Mar-Apr 2006
499
Regioselective Synthesis of a New [1,2,3]-triazoles
Directly from Imidates
N. Hamdi* , C. Fischmeister , P. H. Dixneuf , A. Romerosa Nievas
(a)
(b)
(b)
(c)
(a) Institut National de Recherche: Analyse physico- chimique, Technopôle de Sidi Thabet 2020, Tunisie.
(b) Institut de Chimie de Rennes, UMR 6509 CNRS - Université de Rennes, campus de Beaulieu, 35042
Rennes, France.
(c ) Dpto.Quimica Fisica, Bioquimica y Quimica Inorganica Universidad de Almeria (España).
Received June 27, 2005
A one pot synthetic approach to the novel [1,2,3]-triazoles system, by 1,3-dipolar cycloaddition of 2-diazo-
propane to the imidates 2, is described. The structures of the obtained adducts have been assigned by means
of spectroscopic measurements.
J. Heterocyclic Chem., 43, 499 (2006).
1. Introduction.
of new [1,2,3]-triazoles by regioselective 1,3-dipolar
cycloaddition of the versatile 2-diazopropane 1 to imidates
2.To the best of our knowledge, this reaction has never
been reported before.
[1,2,3]-Triazoles have found wide use in pharmaceuti-
cals agrochemicals, dyes, photographic materials and cor-
rosion inhibition etc. [1]. For exemple, there are numerous
examples in the literature including anti-HIV activity [2],
antimicrobial activity against Gram-positive bacteria [3]
and selective adrenergic receptor agonism by means of tri-
azole compounds [4]. Several methods have been
described for the synthesis of [1,2,3]-triazoles. Among
them, the most important and useful one is the cycloaddi-
tion of azides with alkynes [5]. However, this reaction usu-
ally needs elevated temperatures and also forms a mixture
of 1,4 and 1,5 regioisomers when unsymmetrical alkynes
are employed. Recently, studies on 1,4 versus 1,5 regiose-
lectivity were reported. Sharpless used Cu (I) salt as a cat-
alyst to promote the reaction of azide with terminal
alkynes in order to generate 1,4–substituted products with
high regioselectivity [6]. Meldal [7] also regioselectivity
synthesized 1,4–substituted [1,2,3]-triazoles by 1,3-dipolar
reactions of azides with polymer-supported terminal
alkynes. The initial regioselective 1,3 dipolar addition of
diazopropane to imidates 2 constitutes a novel route for the
synthesis of [1,2,3]-triazoles. We now report the synthesis
2. Results and Discussion.
2.1 Preparation and Properties of Imidates 2.
Imidates 2 were prepared in two steps by first reacting
nitrile derivatives with various alcohols. The condensation
of the obtained iminoester with appropriate acetyl chloride
resulted in the formation of the title compounds 2a-c
(Figure 2).
Figure 2
The characterizations of compounds 2a-c are given in
the experimental section. The structures of the products
were elucidated by means of spectroscopic analysis.2.2
Cycloaddition Reaction of 2-Diazopropane with Imidates
2a-c. Synthesis of [1,2,3]-triazoles.
The 2-diazopropane 1 reacts at 0 °C in dichloromethane
with the imidate 2a to give exclusively the adduct 3a after
10 h of reaction. This compound results from the regiose-
lective 1,3-dipolar cycloaddition of the 2-diazopropane to
the imidate C=N bond (Figure 3).
Figure 1

500
N. Hamdi, C. Fischmeister, P. H. Dixneuf, A. Romerosa Nievas
Vol. 43
reacts with ketones with inverse regioselectivity (with regards
to imidates 2) to yield oxadiazolines [9,10] (Figure 4).
In conclusion, we have been successful in developing a
new method for the synthesis of [1,2,3]-triazoles by regios-
elective 1,3-dipolar cycloaddition of 2- diazopropane with
imidates 2 in good yields. Further studies on this reaction
and its application in organic synthesis are in progress.
EXPERIMENTAL
General Remarks.
Figure 3
NMR spectra were recorded at room temperature on a
1
13
BRUKER AC 300 MHz ( H and C), with TMS as an internal
standard. Signal assignments were based on HMBC and NOESY
experiments. The IR spectra were recorded on a Bruker FT-IR
1
The structure of compound 3a was determined by H
and C NMR spectroscopy as well as 2D NMR experi-
ments. The H NMR spectrum shows two singlets at 1.92
ppm and at 1.97 ppm for the methyl protons and at 3.81
13
-1
IFS 28 in the region between 4000 and 400 cm , (KBr).
1
Elemental analyses were performed at the National Institute of
Research and Physicochemical Analysis in Tunisia. Melting
points were determined on a Buchi apparatus and are uncor-
rected. TLC was performed on aluminium backed plates coated
with silica gel 60 with F254 indicator. Column chromatography
was carried out using silica gel 60. 2-Diazopropane 1 was pre-
pared according to the Staudinger method [11] and conserved in
ethereal solution at –78 °C. The mode of filling of the column
chromatography and the procedure are described by D. F. Taber
[12] and W. C. Still [13].
13
ppm for the methoxylic protons. C NMR showed a sig-
nal at 50.2 ppm corresponding to the methoxy groups and
the aromatic carbon resonances appeared between 126.4
ppm and 143.2 ppm.
The methyl protons correlate with C and with the car-
bon C consistent with the neighbourghing C -C connec-
tion. The NOESY spectrum shows a nOe correlation
between the methoxylic protons and the methyl protons.
Under similar conditions, reaction of imidate 2b with 2-
diazopropane performed at 0 ºC in dichloromethane, was
completed in less than 10 hours and gave mainly product
3b. As before, the structure of 3b was determined via a
detailed mono and bidimensional NMR study.
5
4
4
5
General Procedure for the Preparation of Imidate 2a-c.
To a 250 ml round bottom flask, simple imidate (0.1 mole),
Et N (0.11 mole) and 150 ml of anhydrous ether were added 0.11
3
mole of the correspond acetyl chloride. The mixture was stirred
at r.t for 12 h. The resulting solid was collected by filtration and
recrystallized from cyclohexane.
We also investigated the reaction of imidate 2c with 2-
diazopropane to get the corresponding regioisomer 3c.
Data from the elemental analysis indicated that the calcu-
lated and observed values are within the acceptable limits
Methyl benzene carboximidoate ( 2a).
This compound was obtained as white oil in 75 % yield; IR
-1
1
νcm (KBr): 1658 (C=N); 3384 (NH). H NMR (300 MHz,
CDCl ) δ: 3.75 (s, 3H, O-CH ); 5.50 (s, 1H, NH); 7.17-7.74
3
3
(
0.4%) and have been found to be in conformity with
13
(m,5H,H
); 126.45-129.2(C
.). C NMR (75.47 MHz, CDCl ) δ: 55.3 (O-CH
arom
3 3
13
assigned structure. Furthermore the C NMR spectrum in
); 161.6 (C=N).
arom
CDCl is also in agreement with this structure and shows
3
Anal. Calcd. for C H NO: C, 71.11; H, 6.66; N, 10.37; O,
8
9
the absence of signal corresponding to the iminic carbone
of the starting imidate 2c at 160 ppm [8].
11.86. Found. C, 71.1; H, 6.6; N, 10.4; O, 11.9.
3-Amino-N-(methoxyphenylmethylene)benzamide (2b).
This compound was obtained as a yellow crystalline solid in 70
These results show for the first time, the reactivity of the
double bond C=N with the 2-diazopropane that constitutes an
efficient route for the preparation of new heterocyclic sys-
tems. In all cases, the reaction is periselective: - only the dou-
ble bond C=N is affected - and regiospecific - diazo carbon
attacks the quaternary carbon of the imidate 2 and not the dou-
ble bond C=O (substrates 2b and 2c). Indeed diazopropane
-1
1
% yield, mp 122 °C, IR νcm , KBr): 1672 (C=N), 1690 (CO); H
NMR (300 MHz, CDCl ): δ 3.82 (s, 3H, O-CH ); 6.30-7.32 ,9H,
3
3
13
H
.), 8.40 (s, 2H, NH ); C NMR (75.47 MHz, CDCl ): δ
53.9 (O-CH ); 124.5-138.5(C
arom
2
3
);160.5 (C=N); 168.1 (CO).
3
arom
Anal. Calcd. for C H N O : C, 70.86; H, 5.51; N, 11.02;
15 14
2 2
O, 12.60. Found: C, 70.80; H, 5.5; N, 10.80; O, 12.9.
Methyl-N-butyryl Benzene Carboximidoate (2c).
This compound was obtained as a yellow crystalline solid in 70
-1
% yield, m.p 120°C, IR νcm (KBr): 1655 (C=N); 1690 (CO).
1
H NMR (300 MHz, CDCl ) δ: 1.15 (t,3H ); 2.33 ( q, 2H) ; 3.80
3
13
(s,3H ); 7.45 (m,5H ). C NMR (75.47 MHz, CDCl ) δ: 13.1
(CH ); 18.7 (CH -CH ); 40.9 (CH -CO); 54.6 (O-CH ); 126.5-
3
3
2
3
2
3
Figure 4
129.7(C
); 160.6 (C=N); 173.9 (CO).
arom

Mar-Apr 2006
Regioselective Synthesis of a New [1,2,3]-triazoles Directly from Imidates
501
Anal. Calcd. for C H NO : C, 70.24; H, 7.31; N, 6.82; O,
15.62; Found: C, 70.2; H, 7.2; N, 6.9; O, 15.7.
MHz, CDCl ) δ: 16.9 (CH ); 19.5(CH ); 21.9(CH ); 22.3
12 15
2
3
3(a)
3(b)
3
(CH -CH ); 33.3 (CH -CO); 55.2 (O-CH ); 83.4 (C ); 102.5
2
3
2
3
4
-1
(C ); 124.2-142.5(C
). IR νcm (KBr): 1625 (N=N); 3020
5
arom
Cycloaddition Reaction of 2-Diazopropane with Imidates 2a-c:
Synthesis of [1,2,3]-Triazoles 3a-c.
(C-C
).
arom
Anal. Calcd. for C H N O : C, 54.27 ; H, 8.54; N, 21.10;
9
17 3 2
To a stirred solution containing (2 mmoles) of imidate 2a-c in
40 ml of anhydrous dichloromethane at 0 °C were added, in small
fractions, 10 ml of a 2.6 M etheral solution of 2-diazopropane
freshly prepared at –60 °C. The reaction was followed by TLC
(hexane- ethyl acetate 1/1 as eluent) and the reaction was main-
tained till the imidate 2a-c had totally reacted. The solution was
allowed to react for 10 hours at 0 °C at which time the solvent
was evaporated under reduced pressure. The obtained [1,2,3]-tri-
azoles were purified either by filtration on a column of silica or
by recristallisation in a mixture of dichloromethane-petroleum
ether to afford 3a-b.
O, 16.08. Found: C, 54.2; H, 8.5; N, 21.2; 0, 16.1.
Acknowledgements.
We are very grateful to the “Junta” of Andalusia in Spain for
generous support of this work through the project AM 56/04. We
are very grateful to the Tunisian Ministry of the Scientific
Research, Technology and the development of competences and
the Spanish agency of international cooperation for generous sup-
port of this work through the project A/2903/05.
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*
Corresponding authors: Email: hamdi_naceur@yahoo.fr ,
Fax: 0021671537688.
1
This compound was obtained as a yellow oil in 70 % yield; H
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NMR (300 MHz, CDCl ) δ: 1.92 (s, 3H, CH ); 1.97 (s, 3H,
CH ); 3.74 (s, 3H, O-CH ); 5.60 ( s, 1H, NH); 7.17-7.74
3
3(a)
3(b)
3
13
(H
.); C NMR (75.47 MHz, CDCl ) δ: 17.9 (CH ); 19.23
); 50.2 (O-CH ); 82.7 (C ); 103.75 (C ); 126.45-
3 4 5
arom
3 3(a)
(CH
143.2(C
3200 (NH); 3020 (C-C
3(b)
-1
). IR νcm (KBr): 1525 (N=N); 3020 (C-C
);
arom
arom
).
arom
Anal. Calcd. for C H N O: C, 64.39; H, 7.31; N, 20.48; O,
11 15
3
7.80. Found: C, 64.3; H, 7.2; N, 20.4; 0, 7.6.
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1
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CH ); 3.90 (s, 3H, O-CH ); 6.30-7.32 (H .); 8.40 (s, 2H,
3
3(a)
3(b)
3
arom
13
NH ); C NMR (75.47 MHz, CDCl ) δ: 17.3 (CH ); 19.3
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2
3
3(a)
(CH
140.5(C
); 57.3(O-CH ); 81.4 (C ); 102.3 (C ); 124.2-
3(b)
3 4 5
); IR νcm (KBr): 1620 (N=N); 3030 (C-C
-1
).
arom
arom
Anal. Calcd. for C H N O : C, 58.06 ; H, 6.45; N, 22.58;
12 15
4 2
O, 12.91.Found : C, 57.8; H, 6.4; N, 22.5; 0, 13.3.
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5-Methoxy-4,4-dimethyl-5-phenyl-1-propionyl-4,5-dihydro-1H-
[1,2,3]-triazole (3c).
This compound was obtained as a yellow crystal in 80 % yield;
1
m.p = 130 °C; H NMR (300 MHz, CDCl ) δ: 0.26 (s, 3H,
[11] H. Staudinger, A. Gaule, Ber., 49, 1897 (1916).
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3
CH ); 1.20 (t, 3H ); 1.28 (s, 3H, CH ) ; 2.30 (q, 2H); 3.85 (s,
3H, O-CH ); 6.30-7.32 (H
3(a)
3(b)
13
); 7.55 (m, 5H). C NMR (75.47
3
arom