Nitrilimine cycloadditions to the cyano group in aqueous media

Article abstract of DOI:10.3987/COM-05-10331

Dipolar cycloadditions between nitrilimines (2) and the cyano group of activated nitriles (3) were exploited in aqueous sodium hydrogencarbonate as reaction media in the presence of a surfactant. Short reaction times and mild conditions were experienced a

Full text of DOI:10.3987/COM-05-10331

HETEROCYCLES, Vol. 65, No. 5, 2005
1183
HETEROCYCLES, Vol. 65, No. 5, 2005, pp. 1183 - 1188
Received, 13th January, 2005, Accepted, 25th February, 2005, Published online, 1st March, 2005
NITRILIMINE CYCLOADDITIONS TO THE CYANO GROUP IN
AQUEOUS MEDIA
Giorgio Molteni* and Paola Del Buttero
Università degli Studi di Milano, Dipartimento di Chimica Organica e Industriale,
via Golgi 19, 20133 Milano, Italy
Abstract – Dipolar cycloadditions between nitrilimines (2) and the cyano group
of activated nitriles (3) were exploited in aqueous sodium hydrogencarbonate as
reaction media in the presence of a surfactant. Short reaction times and mild
conditions were experienced affording 1-aryl-5-substituted 1,2,4-triazoles.
INTRODUCTION
Nitrilimine cycloadditions to nitriles constitutes a valuable entry to 1,5-disubstituted 1,2,4-triazoles.1 This
regioselective reaction occurs in cases where the cyano function is activated by conjugation or by an
oxygen atom in the α position.2,3 The reported reaction conditions are usually severe, since prolonged
times in boiling benzene or in boiling neat nitrile dipolarophile are required.
Recently, we developed an efficient and mild nitrilimine cycloaddition protocol onto a variety of alkenyl
dipolarophiles in aqueous media.4 Some advantages over usual procedures are concerned to this method:
(i) reaction rates can be significantly increased; (ii) product separation can often be achieved by simple
filtration of the crude reaction mixture; (iii) environmentally-friendly procedures can be successfully
elaborated. We present here the first investigation on the behavior of variously substituted nitrilimines (2)
onto cyano dipolarophiles (3) in aqueous media.
RESULTS AND DISCUSSION
Nitrilimine intermediates (2) were generated in situ from the corresponding hydrazonoyl chloride (1) in
aqueous 5% sodium hydrogencarbonate at room temperature in the presence of tetrahexylammonium
chloride (THAC) as the catalyst (see Scheme). Reaction times, product yields and eluants are collected in
the Table. 1-Aryl-5-substituted 1,2,4-triazoles (4) were formed as the only regioisomers which were fully
characterised by analytical and spectroscopic methods (see EXPERIMENTAL). As can be inferred from
the Table, in the case of Entries a-j product isolation was actually achieved by filtration of reaction crudes

1184
HETEROCYCLES, Vol. 65, No. 5, 2005
Scheme
COOMe
N
COOMe
Cl
MeOOC
N
N
N
1
1
R
R
N
N
NH
N
5% aq. NaHCO3
THAC, rt
3
R
R
R
1
2
4
R = H, Me, F, Cl, NO2
1
R = COOEt, COOBn, CCl3
Table. Cycloaddition between nitrilimines (2) and cyano dipolarophiles (3) in aqueous 5%
sodium hydrogencarbonate.
________________________________________________________________________________________________________________
Entry
R
R1
Time
(min)
Products and yields (%) Eluant
_______________________________
1
4
________________________________________________________________________________________________________________
__
__
__
__
__
__
__
__
__
__
__
__
__
__
__
__
__
__
__
__
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
H
Me
F
Cl
NO2
H
Me
F
Cl
NO2
H
Me
F
COOEt
COOEt
COOEt
COOEt
COOEt
COOBn
COOBn
COOBn
COOBn
COOBn
CCl3
45
45
45
50
120
50
55
40
40
105
240
180
220
280
360
79
78
95
82
59
76
74
84
74
67
46
41
49
56
24
37
39
34
27
65
AcOEt/Hexane 7:3
AcOEt/Hexane 7:3
CHCl3/Hexane 20:1
CHCl3
CCl3
CCl3
CCl3
CCl3
Cl
NO2
CHCl3
________________________________________________________________________________________________________________
while in the case of Entries k-o chromatographic workup was needed. The extent of the cycloaddition was
somewhat dependent on the electronic features of both nitrilimines (2) and nitriles (3). For a given cyano
dipolarophile, the cycloaddition outcome was less satisfactory with electron-poor nitrilimine (R = NO2);
this behavior reflects the usual HOMO-dipole (LUMO-dipolarophile) control of nitrilimine
cycloadditions.5 On the other hand, conjugated nitriles (R1 = COOEt, COOBn) gave better results as
compared with unconjugated one (R1 = CCl3). Notwithstanding 1,3-dipolar cycloadditions are regarded as

HETEROCYCLES, Vol. 65, No. 5, 2005
1185
solvent-insensitive processes,6 we experienced a dramatic increase of reaction rates compared with
available literature data.3 In order to account for the observed rate enhancements, our mechanistic picture7
implies that the hydrophobic effect8 gives rise to close association of organic reactants. Nitrilimine
intermediate should be generated into the organic aggregate, which is characterised by a high local
concentration of the dipolarophile. In this context, THAC acts as a genuine phase transfer catalyst driving
the basic agent from the bulk aqueous media into the organic aggregate. As a limitation in scope, it needs
to be added that nitrilimines (2) fail to react with alkyl nitriles (methyl cyanide, benzyl cyanide) and
benzonitrile in the above conditions. This is not surprising, however, in the light of the known poor
reactivity of unactivated nitriles as dipolarophiles.9 As concluding remarks, some advantages concerned
to the present aqueous media cycloaddition protocol should be pointed out: (i) cleaner and faster
transformations were experienced compared to non-aqueous synthesis; (ii) reaction conditions were mild
and (iii) the use of organic solvents was suppressed in the cycloaddition reaction.
EXPERIMENTAL
Melting points were determined with a Büchi apparatus in open tubes and are uncorrected. IR spectra
were recorded with a Perkin-Elmer 1725 X spectrophotometer. MS spectra were determined with a
1
VG-70EQ apparatus. H NMR (300 MHz) spectra were taken with a Bruker AMX 300 instrument (in
CDCl3 solutions at room temperature). Chemical shifts are given as ppm from tetramethylsilane and J
values are given in Hz.
Nitriles (3) were used as purchased by Aldrich without any further purification. Hydrazonoyl chlorides
(1) were synthesised according to literature procedures.10
Cycloaddition between hydrazonoyl chlorides (1) and nitriles (3) in aqueous sodium hydrogen
carbonate; General Procedure. A mixture of hydrazonoyl chloride (1) (1.0 mmol), the appropriate
nitrile (3) (10.0 mmol), THAC (38 mg, 0.1 mmol) and aqueous 5% sodium hydrogencarbonate (5.0 mL)
was stirred at rt for the time indicated in the Table.
In the case of Entries a-j the mixture was filtered; the solid material was washed with water (25 mL) and
dried. Subsequent crystallisation gave pure 4a-j.
1-Phenyl-3-methoxycarbonyl-5-ethoxycarbonyl-1,2,4-triazole (4a) (79%) as pale yellow needles having
mp 119-120°C (from hexane/toluene); IR (nujol): 1740 (cm-1); 1H-NMR: 1.37 (3H, t, J=6.7), 3.93 (3H, s),
4.38 (2H, q, J=6.7), 7.3-7.5 (5H, m); MS: 275 m/z (M+). Anal. Calcd for C13H13N3O4: C, 56.72; H, 4.76;
N, 15.27. Found: C, 56.77; H, 4.78; N, 15.32.
1-(4-Methylphenyl)-3-methoxycarbonyl-5-ethoxycarbonyl-1,2,4-triazole (4b) (78%) as colorless needles

1186
HETEROCYCLES, Vol. 65, No. 5, 2005
having mp 123-124°C (from hexane/toluene); IR (nujol): 1740 (cm-1); 1H-NMR: 1.35 (3H, t, J=6.7), 2.48
(3H, s), 3.92 (3H, s), 4.36 (2H, q, J=6.7), 7.0-7.4 (4H, m); MS: 289 m/z (M+). Anal. Calcd for
C14H15N3O4: C, 58.12; H, 5.23; N, 14.53. Found: C, 58.16; H, 5.27; N, 14.59.
1-(4-Fluorophenyl)-3-methoxycarbonyl-5-ethoxycarbonyl-1,2,4-triazole (4c) (95%) as colorless needles
having mp 122-123°C (from hexane/toluene); IR (nujol): 1735 (cm-1); 1H-NMR: 1.37 (3H, t, J=6.7), 3.98
(3H, s), 4.43 (2H, q, J=6.7), 7.0-7.3 (4H, m); MS: 293 m/z (M+). Anal. Calcd for C13H12N3O4F: C, 53.24;
H, 4.12; N, 14.33. Found: C, 53.28; H, 4.08; N, 14.29.
1-(4-Chlorophenyl)-3-methoxycarbonyl-5-ethoxycarbonyl-1,2,4-triazole (4d) (82%) as pale yellow
1
needles having mp 130-131°C (from hexane/toluene); IR (nujol): 1735 (cm-1); H-NMR: 1.36 (3H, t,
J=6.7), 3.96 (3H, s), 4.41 (2H, q, J=6.7), 7.2-7.6 (4H, m); MS: 309 m/z (M+). Anal. Calcd for
C13H12N3O4Cl: C, 50.41; H, 3.91; N, 13.57. Found: C, 50.37; H, 3.93; N, 13.61.
1-(4-Nitrophenyl)-3-methoxycarbonyl-5-ethoxycarbonyl-1,2,4-triazole (4e) (59%) as pale yellow needles
1
having mp 150-151°C (from hexane/chloroform); IR (nujol): 1735 (cm-1); H-NMR: 1.38 (3H, t, J=6.7),
4.01 (3H, s), 4.45 (2H, q, J=6.7), 7.4-7.8 (4H, m); MS: 320 m/z (M+). Anal. Calcd for C13H12N4O6: C,
48.75; H, 3.78; N, 17.49. Found: C, 48.72; H, 3.81; N, 17.53.
1-Phenyl-3-methoxycarbonyl-5-benzyloxycarbonyl-1,2,4-triazole (4f) (76%) as pale yellow needles
having mp 134-135°C (from hexane/toluene); IR (nujol): 1740, 1735 (cm-1); 1H-NMR: 3.96 (3H, s), 5.28
(2H, s), 7.2-7.5 (10H, m); MS: 337 m/z (M+). Anal. Calcd for C18H15N3O4: C, 64.09; H, 4.48; N, 12.46.
Found: C, 64.13; H, 4.50; N, 12.42.
1-(4-Methylphenyl)-3-methoxycarbonyl-5-benzyloxycarbonyl-1,2,4-triazole (4g) (74%) as white needles
having mp 137-138°C (from hexane/toluene); IR (nujol): 1745, 1735 (cm-1); 1H-NMR: 2.39 (3H, s), 3.96
(3H, s), 5.31 (2H, s), 7.2-7.4 (9H, m); MS: 351 m/z (M+). Anal. Calcd for C19H17N3O4: C, 64.95; H, 4.88;
N, 11.96. Found: C, 64.91; H, 4.90; N, 12.02.
1-(4-Fluorophenyl)-3-methoxycarbonyl-5-benzyloxycarbonyl-1,2,4-triazole (4h) (84%) as colorless
needles having mp 120-121°C (from hexane/toluene); IR (nujol): 1745, 1735 (cm-1); 1H-NMR: 3.94 (3H,
s), 5.33 (2H, s), 7.1-7.4 (9H, m); MS: 355 m/z (M+). Anal. Calcd for C18H14N3O4F: C, 60.85; H, 3.97; N,
11.83. Found: C, 60.88; H, 4.00; N, 11.87.
1-(4-Chlorophenyl)-3-methoxycarbonyl-5-benzyloxycarbonyl-1,2,4-triazole (4i) (74%) as pale yellow
needles having mp 134-135°C (from hexane/toluene); IR (nujol): 1745, 1735 (cm-1); 1H-NMR: 4.03 (3H,
s), 5.24 (2H, s), 7.2-7.5 (9H, m); MS: 371 m/z (M+). Anal. Calcd for C18H14N3O4Cl: C, 58.15; H, 3.80; N,
11.30. Found: C, 58.19; H, 3.81; N, 11.34.
1-(4-Nitrophenyl)-3-methoxycarbonyl-5-benzyloxycarbonyl-1,2,4-triazole (4j) (67%) as yellow needles
1
having mp 154-155°C (from hexane/chloroform); IR (nujol): 1750, 1735 (cm-1); H-NMR: 4.05 (3H, s),
5.29 (2H, s), 7.2-7.8 (9H, m); MS: 382 m/z (M+). Anal. Calcd for C18H14N4O6: C, 56.55; H, 3.69; N, 14.65

HETEROCYCLES, Vol. 65, No. 5, 2005
1187
Found: C, 56.58; H, 3.71; N, 14.70.
In the case of Entries k-o the mixture was taken up with chloroform (25 mL). The organic layer was
washed with water (2 x 20 mL), dried over sodium sulfate and evaporated. The residue was
chromatographed on a silica gel column with the eluant reported in the Table. Unreacted 1 was eluted
first, followed by 1,2,4-triazole (4).
1-Phenyl-3-methoxycarbonyl-5-trichloromethyl-1,2,4-triazole (4k) (46%) as pale yellow needles having
mp 90-91°C (from hexane/toluene); IR (nujol): 1735 (cm-1); 1H-NMR: 3.93 (3H, s), 7.2-7.4 (5H, m); MS:
319 m/z (M+). Anal. Calcd for C11H8N3O2Cl3: C, 41.21; H, 2.52; N, 13.11. Found: C, 41.24; H, 2.50; N,
13.14.
1-(4-Methylphenyl)-3-methoxycarbonyl-5-trichloromethyl-1,2,4-triazole (4l) (41%) as pale yellow
needles having mp 94-95°C (from hexane/toluene); IR (nujol): 1730 (cm-1); 1H-NMR: 2.38 (3H, s), 3.98
(3H, s), 7.2-7.4 (4H, m); MS: 333 m/z (M+). Anal. Calcd for C12H10N3O2Cl3: C, 43.08; H, 3.01; N, 12.56.
Found: C, 43.11; H, 2.98; N, 12.60.
1-(4-Fluorophenyl)-3-methoxycarbonyl-5-trichloromethyl-1,2,4-triazole (4m) (49%) as white needles
1
having mp 90-91°C (from hexane/toluene); IR (nujol): 1735 (cm-1); H-NMR: 3.94 (3H, s), 7.0-7.3 (4H,
m); MS: 337 m/z (M+). Anal. Calcd for C11H7N3O2F: C, 39.03; H, 2.08; N, 12.41. Found: C, 38.99; H,
2.05; N, 12.44.
1-(4-Chlorophenyl)-3-methoxycarbonyl-5-trichloromethyl-1,2,4-triazole (4n) (56%) as white needles
1
having mp 98-99°C (from hexane/toluene); IR (nujol): 1735 (cm-1); H-NMR: 3.95 (3H, s), 7.2-7.5 (4H,
m); MS: 354 m/z (M++1). Anal. Calcd for C11H7N3O2Cl4: C, 37.21; H, 1.99; N, 11.84. Found: C, 37.18; H,
2.01; N, 11.89.
1-(4-Nitrophenyl)-3-methoxycarbonyl-5-trichloromethyl-1,2,4-triazole (4o) (24%) as yellow needles
having mp 111-112°C (from hexane/chloroform); IR (nujol): 1740 (cm-1); 1H-NMR: 4.01 (3H, s), 7.4-7.8
(4H, m); MS: 364 m/z (M+). Anal. Calcd for C11H7N4O4Cl3: C, 36.14; H, 1.93; N, 15.32. Found: C, 36.17;
H, 1.90; N, 15.35.
ACKNOWLEDGEMENTS
Thanks are due to MURST and CNR for financial support.
REFERENCES
1. P. Caramella and P. Grünanger, '1,3-Dipolar Cycloaddition Chemistry'; ed. by A. Padwa,
Wiley-Interscience, New York, 1984, Vol. 1, Ch. 3.

1188
HETEROCYCLES, Vol. 65, No. 5, 2005
2. R. Huisgen, M. Seidel, J. Sauer, J. W. McFarland, and G. Wallbillich, J. Org. Chem., 1959, 24, 892.
3. R. Huisgen, R. Grashey, M. Seidel, G. Wallbillich, H. Knupfer, and R. Schmidt, Ann. Chem., 1962,
653, 105.
4. G. Molteni, M. Orlandi, and G. Broggini, J. Chem. Soc., Perkin Trans. 1, 2000, 3742.
5. (a) K. N. Houk, J. Sims, R. E. Duke, R. W. Strozier, and J. K. George, J. Am. Chem. Soc., 1973, 95,
7287; (b) K. N. Houk, J. Sims, C. R. Watts, and L. J. Luskus, J. Am. Chem. Soc., 1973, 95, 7301.
6. R. Huisgen, Angew. Chem., Int. Ed. Engl., 1963, 2, 633.
7. (a) G. Molteni, A. Ponti, and M. Orlandi, New J. Chem., 2002, 26, 1340. (b) A. Ponti and G. Molteni,
New J. Chem., 2002, 26, 1346.
8. R. Breslow, Acc. Chem. Res., 1991, 24, 159.
9. A. I. Meyers and C. J. Sircar, 'The Chemistry of the Cyano Group'; ed. by Z. Rappoport,
Wiley-Interscience, London, 1970, Ch. 8.
10. R = H: R. Fusco and R. Romani, Gazz. Chim. Ital., 1946, 76, 419. R = Me, NO2: M. M. El-Abadelah,
A. Q. Hussein, M. R. Kamal, and K. H. Al-Adhami, Heterocycles, 1988, 27, 917. R = F: M. M.
El-Abadelah, A. Q. Hussein, and H. A. Saadeh, Heterocycles, 1991, 32, 1063. R = Cl: M. T. Cocco, A.
Maccioni, and A. Plumitallo, Il Farmaco, Ed. Sci., 1985, 40, 272.