Synthesis of 4-aryl-5,5-dimethyl-5H-1,2,3-triazoles and 4-aryl-3-cyano-5,5-dimethyl Δ1-pyrazolines by cycloaddition of 2-diazopropane with iminoethers and propenenitriles

Article abstract of DOI:10.1016/j.tetlet.2006.06.161

A regiospecific 1,3-dipolar cycloaddition of 2-diazopropane 3 to iminoethers 1a-c, carried out at 0 °C, afforded in two steps the corresponding 4-aryl-5,5-dimethyl-5H-1,2,3-triazoles 5a-c. Under the same conditions, 3-arylpropenenitriles 2a-d led to 3-cya

Full text of DOI:10.1016/j.tetlet.2006.06.161

Tetrahedron Letters 47 (2006) 6685–6687
Synthesis of 4-aryl-5,5-dimethyl-5H-1,2,3-triazoles and
4-aryl-3-cyano-5,5-dimethyl D1-pyrazolines by cycloaddition of
2-diazopropane with iminoethers and propenenitriles
Baya Toumi and Abdallah Harizi*
De´partement des Sciences Fondamentales, Institut Supe´rieur des Technologies Me´dicales de Tunis, 9,
Avenue du Docteur Z. Essafi Tunis 1006, Tunisia
Received 16 December 2005; revised 17 May 2006; accepted 29 June 2006
Available online 1 August 2006
Abstract—A regiospecific 1,3-dipolar cycloaddition of 2-diazopropane 3 to iminoethers 1a–c, carried out at 0 °C, afforded in two
steps the corresponding 4-aryl-5,5-dimethyl-5H-1,2,3-triazoles 5a–c. Under the same conditions, 3-arylpropenenitriles 2a–d led to
3-cyano-5,5-dimethyl D1-pyrazolines 6a–d. Products 4–6 were obtained in good yields (69–85%).
Ó 2006 Elsevier Ltd. All rights reserved.
1,2,3-Triazoles have found wide application in organic
synthesis1 as well as in medicine, agriculture and indus-
try.2 Among many synthetic methods for the prepara-
tion of 1,2,3-triazoles, 1,3-dipolar cycloaddition of
organic azides to alkynes is the most versatile tool for
the construction of the triazole ring.2–4 In addition,
5,5-dimethyl D1-pyrazolines have been prepared by the
reaction of 2-diazopropane with a,b-unsaturated
ketones.6,7
Treatment of iminoethers 1a–c13 with 2-diazopropane 35
in dry dichloromethane at 0 °C gave 5-aryl-5-methoxy-
4,4-dimethyl-4,5-dihydro-1H-1,2,3-triazoles 4a–c.14 It
is conceivable6,7 that the cycloaddition starts by the
attack of the carbanion of 3 on the C@N double bond
of the iminoether to give compounds 4, which can be
converted by loss of methanol into the corresponding
4-aryl-5,5-dimethyl-5H-1,2,3-triazoles 5a–c15 in satisfac-
tory yields (69–85%). A possible mechanism of this
reaction is shown in Scheme 1.
Recently, a few examples of cycloaddition of 2-diazo-
propane5 to a,b-unsaturated ketones have been stud-
ied.6–9 To the best of our knowledge, 1,3-dipolar
cycloaddition of 2-diazopropane to iminoethers and
propenenitriles has not been developed.
4-Aryl-3-cyano-5,5-dimethyl D1-pyrazolines 6a–d17 were
obtained by 1,3-dipolar cycloaddition of 3-arylpropene-
nitriles 2a–d16 and 2-diazopropane 3 in dry dichloro-
methane at 0 °C in good yields (72–84%). The
proposed mechanism is shown in Scheme 2.
In continuation of our studies on the reactivity of
iminoethers and their use as synthons in organic synthe-
sis,10–12 we report here a novel synthesis of 5-aryl-
5-methoxy-4,4-dimethyl-4,5-dihydro-1H-1,2,3-triazoles
4a–c and 4-aryl-3-cyano-5,5-dimethyl D1-pyrazolines
6a–d arising from a regiospecific 1,3-dipolar cycloaddi-
tion of 2-diazopropane 3, respectively, to iminoethers
1a–c and 3-arylpropenenitriles 2a–d. Refluxing
compounds 4a–c in methanol afforded the correspond-
ing 4-aryl-5,5-dimethyl-5H-1,2,3-triazoles 5a–c.
At low temperature (À60 °C), D3-(1,3,4)-oxadiazolines
and D1-pyrazolines have been previously prepared by
cycloaddition of 2-diazopropane to a,b-unsaturated
ketones.6–8 In our case, we obtained only compounds
6a–d in modest yields (28–34%) without any secondary
product (Scheme 2).
In order to find the best conditions for the synthesis of
compounds 4 and 6, we examined the reaction under
various conditions by changing the temperature and
the solvent; we found that the best yields were obtained
at 0 °C when we used an excess of 2-diazopropane 3
freshly prepared and conserved in ethylbenzene at
À78 °C.
Keywords: 2-Diazopropane; Iminoethers; 3-Arylpropenenitriles; 1,2,3-
Triazoles; D1-Pyrazolines.
*
Corresponding author. Tel.: +216 71 260 400; fax: +216 71 260
460; e-mail: aharizitn@yahoo.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.161

6686
B. Toumi, A. Harizi / Tetrahedron Letters 47 (2006) 6685–6687
N 2
3
N
R
Me
Me
Me
Me
OMe
H
N
C
N
1
CH2Cl2
0 ºC
4
+
H
N
N
5
OMe
R
4a-c
1a-c
3
Me
Me
5
N1
MeOH / Δ
4
R
(-MeOH)
N2
N
3
5a-c
b
1, 4, 5
a
c
R
H
p-Me o-Me
Scheme 1.
R
1N
N 2
Me
Me
CN
X
Me
Me
3
OMe
C
C
CH2Cl2
5
+
4
N
0 ˚C
H
N
X
CN
R
6a-d
3
2a-d
2, 6
R
a
Cl
b
H
c
CH3
d
OCH3
X
CN
CO2Et CSNH2
CSNH2
Scheme 2.
The reactions of Schemes 1 and 2 were conducted until
TLC indicated that the starting materials 1 or 2 had
been completely converted. The purification of 4–6
was performed by silica gel column chromatography
(chloroform/ethyl acetate: 8/2).
correlated with the methyl protons Ha. The stereo-
chemistry of compounds 4a–c and 6a–d is illustrated
in Scheme 3.
In conclusion, we have described a new synthesis of
5-aryl-5-methoxy-4,4-dimethyl-4,5-dihydro-1H-1,2,3-
triazoles 4a–c which afforded the corresponding 4-aryl-
5,5-dimethyl-5H-1,2,3-triazoles 5a–c and 4-aryl-3-cya-
no-5,5-dimethyl D1-pyrazolines 6a–d by 1,3-dipolar
cycloadditions of 2-diazopropane 3 with iminoethers
1a–c and 3-aryl-2-active propenenitriles 2a–d, respec-
tively. Irradiation of compounds 4, 5 and 6 to obtain
substituted azacyclopropanes, azacyclopropenes and
cyclopropylnitriles, respectively, is under investigation.
The structures of compounds 4, 5 and 6 were assigned
1
on the basis of their IR, H and 13C NMR and mass
spectrometry. The structures of the isolable intermedi-
ates 4a–c were deduced from the analysis of HMBC
spectra, which indicated that the methyl protons Ha
and Hb correlate with carbon atoms C4 and C5 via
3
2J and J coupling, whereas the methoxy protons He
correlate with carbon atom C5. The analysis of their
NOESY spectra showed an NOE between the methoxy
protons Hc and methyl protons Hb, while methyl
protons Ha correlated with the aromatic proton Hd.
The HMBC spectra of D1-pyrazolines 6a–d indicated
that the methyl protons Ha and Hb correlate with
carbon atoms C5 (2J) and C4 (3J). Proton H4 exhibited
3
1
N
2
2
a
a
Me
Me
N
N
N
Me
Me
4
3
b
b
1
5
CN
4
H
H
5
N
d
d
H
X
OMe
c
H
R
2
nOe
correlations with carbons C3, C5, CN and CO via J
R
3
nOe
and J coupling constants. The NOESY spectrum of
4a-c
6a-d
6a–d showed only an NOE between proton H4 and
the methyl proton Hb, while the aromatic proton Hd
Scheme 3.

B. Toumi, A. Harizi / Tetrahedron Letters 47 (2006) 6685–6687
6687
removed under reduced pressure and the remaining
residue was recrystallized from methanol to give 5a.
Compound 5a: Yield: 82%; mp 158 °C; IR (CHCl3): 1625,
References and notes
1. (a) Katritzky, A. R.; Lan, X.; Fan, W.-Q. Synthesis 1994,
445–450; (b) Katritzky, A. R.; Jiang, J.; Greenhill, J. V. J.
Org. Chem. 1993, 58, 1987–1991.
2. Wamhoff, H. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Ed.; Pergamon Press: Oxford-New
York-Toronto-Sydney-Paris-Frankfort, 1984; Vol. 5, pp
670–732.
1
1540 cmÀ1; H NMR (300 MHz, CDCl3): d 1.85 (s, 3H),
1.96 (s, 3H), 7.26–7.80 (m, 5H); 13C NMR (75 MHz,
CDCl3): d 18.4, 25.2, 126.0, 129.3, 133.3, 155.5, 162,7; MS
(EI): m/z (%) 173 (M+, 15), 103 (100), 145 (52), 77(18).
Compound 5b: Yield: 69%; mp 177 °C; IR (CHCl3): 1620,
1
1535 cmÀ1; H NMR (300 MHz, CDCl3): d 1.83 (s, 3H),
1.90 (s, 3H), 2.23 (s, 3H), 7.20–7.76 (m, 4H); 13C NMR
(75 MHz, CDCl3): d 18.6, 25.4, 26.0, 125.3, 127.6, 130.2,
132.4, 154.7, 162.1; MS (EI): m/z (%) 187 (M+, 12), 117
(100), 159 (48), 91 (16). Compound 5c: Yield: 74%; mp
3. Palacios, F.; Aochoa de Retana, A. M.; Pagalday, J.
Heterocycles 1994, 38, 95–101.
4. Elachqar, A.; Hallaoui, A. El.; Roumestant, M. L.;
Viallefont, Ph. Synth. Commun. 1994, 24, 1279–1283.
5. Staudinger, H.; Gaule, A. Chem. Ber. 1916, 49, 1897–1905.
6. Aldersley, M. F.; Dean, F. M.; Mann, B. J. Chem. Soc.,
Perkin Trans. 1 1986, 2217–2222.
7. Newmann, M. F. Angew. Chem. 1968, 80, 42–45.
8. Lachheb, J.; Martin, M. T.; Khemiss, A. Tetrahedron Lett.
1999, 40, 9029–9031.
162 °C; IR (CHCl3): 1628, 1542 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d 1.80 (s, 3H), 1.92 (s, 3H), 2.22 (s,
3H), 7.23–7.80 (m, 4H); 13C NMR (75 MHz, CDCl3): d
17.8, 25.2, 26.4, 125.5, 127.6, 129.8, 133.6, 155.1, 162.0;
MS (EI): m/z (%) 187 (M+, 16), 117 (100), 159 (51), 91
(22).
16. (a) Boullet, F. T.; Foucaud, A. Tetrahedron Lett. 1982, 23,
4927–4928; (b) Brunskill, S. A.; Asish, D.; Ewing, D. F. J.
Chem. Soc., Perkin Trans. 1 1978, 629–633.
9. Hammami, H.; Ben Dhia, Y.; Khemiss, A. J. Soc. Chim.
Tun. 2002, 4, 1539–1543.
10. Harizi, A.; Zantour, H. Synth. Commun. 2002, 32, 387–
392.
11. Harizi, A.; Zantour, H. Phosphorus, Sulfur, Silicon Relat.
Elem. 2004, 179, 1883–1891.
12. Harizi, A.; Romdane, A.; Mighri, Z. Tetrahedron Lett.
2000, 41, 5833–5835.
17. Synthesis of 3-cyano-5,5-dimethyl D1-pyrazolines 6a–d:
For 6a: To a solution of 3-aryl-2-cyanopropenenitrile 2a
(1.88 g, 10 mmol) in 30 mL of dry CH2Cl2 at 0 °C was
added a solution of 2-diazopropane (2.1 g, 30 mmol) in
10 mL of dry CH2Cl2. The reaction mixture was stirred for
6 h at rt, then concentrated and purified by column
chromatography on silica gel (cyclohexane–EtOAc: 8/2) to
afford 3,3-dicyano-5,5-dimethyl-4-parachloro-phenyl D1-
pyrazolines 6a as an oil. Compound 6a: Yield: 82%; IR
13. Huisgen, R. J. Org. Chem. 1976, 41, 403–419.
14. Synthesis of 4,5-dihydro-1H-1,2,3-triazoles 4a–c: For 4a:
To a solution of iminoether 1a (1.35 g, 10 mmol) in 30 mL
of dry CH2Cl2 at 0 °C was added a solution of 2-
diazopropane (2.1 g, 30 mmol) in 10 mL of dry CH2Cl2.
The reaction mixture was stirred for 4 h at rt, then
concentrated and purified by column chromatography on
silica gel (cyclohexane–EtOAc: 8/2) to afford 4,5-dihydro-
1,2,3-triazole 4a as a yellow oil. Compound 4a: Yield:
(CHCl3): 2208, 2195, 1540 cmÀ1 1H NMR (300 MHz,
;
CDCl3): d 1.58 (s, 3H), 1.66 (s, 3H), 4.90 (s, 1H), 7.20–7.67
(m, 4H); 13C NMR (75 MHz, CDCl3): d 23.2, 25.0, 55.1,
90.4, 94.7, 111.2, 112.0, 127.7, 129.5, 133.2, 135.3; MS
(EI): m/z (%) 258 (M+, 2), 152 (100), 236 (68), 56 (60).
Compound 6b: Yield: 84%; IR (CHCl3): 2200, 1745,
1
85%; IR (CHCl3): 3360, 1550 cmÀ1; H NMR (300 MHz,
1
1540 cmÀ1; H NMR (300 MHz, CDCl3): d 1.67 (s, 3H),
CDCl3): d 1.82 (s, 3H), 1.90 (s, 3H), 3.74 (s, 3H), 5.85 (s,
1H), 7.28–7.64 (m, 5H); 13C NMR (75 MHz, CDCl3): d
17.9, 25.1, 53.3, 126.0, 129.2, 132.4, 134.2, 155.3, 162.6;
MS (EI): m/z (%) 205 (M+, 5), 120 (100), 85 (68), 174 (42).
1.78 (s, 3H), 4.10 (q, 2H, J = 7 Hz), 1.18 (t, 3H, J = 7 Hz),
5.42 (s, 1H), 7.21–7.64 (m, 5H); 13C NMR (75 MHz,
CDCl3): d 13.9, 21.5, 24.7, 54.2, 63.6, 93.9, 100.5, 111.4,
115.2, 126.8, 129.3, 134.8, 144.2; MS (EI): m/z (%) 271
(M+, 4), 118 (100), 202 (66), 77 (40). Compound 6c: Yield:
Compound 4b: Yield: 78%; IR (CHCl3): 3365, 1540 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 1.85 (s, 3H), 1.92 (s, 3H),
2.24 (s, 3H), 3.85 (s, 3H), 6.05 (s, 1H), 7.50 (m, 4H); 13C
NMR (75 MHz, CDCl3): d 18.3, 24.2, 25.8, 54.0, 124.4,
128.5, 130.4, 132.5, 154.6, 163.1; MS (EI): m/z (%) 219
(M+, 3), 134 (100), 85 (64), 188 (38), 91 (18). Compound
1
76%; IR (CHCl3): 3420, 2190, 1625, 1538 cmÀ1; H NMR
(300 MHz, CDCl3): d 1.70 (s, 3H), 1.81 (s, 3H), 2.42 (s,
3H), 3.77 (s, 1H), 11.40 (s, 2H), 7.55 (m, 4H); 13C NMR
(75 MHz, CDCl3): d 20.3, 24.1, 26.5, 54.6, 94.2, 99.4,
113.0, 145.8, 126.8, 131.2, 134.2, 143.7; MS (EI): m/z (%)
272 (M+, 5), 132 (100), 216 (67), 56 (63), 105 (52).
Compound 6d: Yield: 72%; IR (CHCl3): 3435, 2110, 1630,
1
4c: Yield: 74%; IR (CHCl3): 3355, 1530 cmÀ1; H NMR
(300 MHz, CDCl3): d 1.80 (s, 3H), 1.88 (s, 3H), 2.20 (s,
3H), 3.75 (s, 3H), 5.85 (s, 1H), 7.45 (m, 4H); 13C NMR
(75 MHz, CDCl3): d 18.0, 24.5, 26.3, 53.7, 125.2, 128.7,
130.2, 131.5, 154.7, 162.9; MS (El): m/z (%) 219 (M+, 6),
134 (100), 85 (57), 188 (44), 91 (23).
1
1535 cmÀ1; H NMR (300 MHz, CDCl3): d 1.66 (s, 3H),
1.75 (s, 3H), 3.80 (s, 3H), 3.58 (s, 1H), 10.83 (s, 2H), 7.50
(m, 4H); 13C NMR (75 MHz, CDCl3): d 20.5, 25.0, 54.7,
55.3, 94.7, 100.2, 112.6, 144.5, 126.0, 130.0, 132.4, 134.5,
143.2; MS (EI): m/z (%) 288 (M+, 4), 148 (100), 232 (63),
56 (47).
15. Synthesis of 4-aryl-5,5-dimethyl-5H-1,2,3-triazoles 5a–c:
For 5a: A solution of compound 4a (0.95 g, 5 mmol) in
20 mL of methanol was refluxed for 12 h. The solvent was