Convenient microwave-assisted synthesis of 5-functionalized 1,2,4-triazolium ylides starting from N′,N′-disubstituted carbohydrazonamides

Article abstract of DOI:10.1002/ejoc.200800788

5-Functionalized 1,2,4-triazolium ylides have been prepared in good yields and in very short reaction times by reacting N′,N′-disubstituted carbohydrazonamides with 1,1′-carbonylbis(1,2,4-triazole), 1,1′-thiocarbonyldiimidazole or diphenyl N-cyanimidocarb

Full text of DOI:10.1002/ejoc.200800788

FULL PAPER
DOI: 10.1002/ejoc.200800788
Convenient Microwave-Assisted Synthesis of 5-Functionalized 1,2,4-Triazolium
Ylides Starting from NЈ,NЈ-Disubstituted Carbohydrazonamides
Mehdi Khankischpur[a] and Thomas Kurz*[b]
Keywords: Ylides / Nitrogen heterocycles / Cyclization / Microwave-assisted synthesis
5-Functionalized 1,2,4-triazolium ylides have been prepared
in good yields and in very short reaction times by reacting
NЈ,NЈ-disubstituted carbohydrazonamides with 1,1Ј-carbon-
ylbis(1,2,4-triazole), 1,1Ј-thiocarbonyldiimidazole or diphenyl
N-cyanimidocarbonate under microwave irradiation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
3 by treating N-(α-chlorobenzylidene)carbamoyl chloride
with 1,1-dimethylhydrazine.[3,5] A literature search revealed
that only one 1,1-dialkyl-5-thioxo-1,2,4-triazolium ylide 4
has previously been described. This compound was pre-
pared in only 24% yield by the treatment of phenyl N3,N3-
dimethylcarbazimidate with thiophosgene in benzene.[4] The
reaction of N3,N3-dimethylcarbazimidate with N-(p-tolyl-
sulfonyl)isocyanide dichloride furnished an N-tosylimino
derivative in 60% yield.[4] However, no synthetic protocol is
given for the preparation. Interestingly, the related 5-cyan-
imino-functionalized 1,2,4-triazolium ylides 5 have not
been described before. We now report the synthesis of vari-
ous 5-functionalized 1,2,4-triazolium ylides 3–5 by the
treatment of NЈ,NЈ-disubstituted carbohydrazonamides 2
with diphenyl N-cyanimidocarbonate, 1,1Ј-carbonylbis-
(1,2,4-triazole) and 1,1Ј-thiocarbonyldiimidazole under
microwave irradiation.
Introduction
The steadily increasing number of novel drug targets de-
mands the rapid synthesis and modification of biologically
active compounds. Of the methods used in drug design, mi-
crowave-assisted synthesis represents a promising method
to meet these requirements.[1] Microwave irradiation often
leads to substantial reductions in reaction times and to high
yields.[1] In addition, several reactions that do not occur by
conventional heating can be conducted under microwave ir-
radiation. To the best of our knowledge the microwave-as-
sisted synthesis of heterocyclic betaines has not been pre-
viously reported. Whereas syndnonimines, such as Molsido-
mine, are well-known nitric oxide donors, 1,1-dialkyl-5-oxo-
1,2,4-triazolium ylides 3 have been described as herbicides
and fungicides (Figure 1).[2,3] Interestingly, only one publi-
cation refers to the related 5-thioxo- and 5-tosylimino deriv-
atives.[4] Relatively few synthetic strategies exist for the
preparation of 1,1-dialkyl-5-oxo-1,2,4-triazolium ylides
3.[3–6] The known methods are multistep syntheses or re-
quire the use of phosgene.[3–6] Commonly, the yields are
only low-to-moderate and relatively long reaction times are
necessary.[4–6] 1,1-Dialkyl-5-oxo-1,2,4-triazolium ylides 3
have already been synthesized by the treatment of phenyl
N-(chlorocarbonyl)-1-chlorocarbonimidate with 1,1-dialk-
ylhydrazines (four examples) and by carbonylation of amid-
razones with phosgene or chloroformates in the presence of
a tertiary amine.[4,6] Another strategy utilizes N-meth-
oxycarbonyl-substituted thiocarbamates and 1,1-disubsti-
tuted hydrazines as starting materials, whereas Takahashi et
al. synthesized two 1,1-dialkyl-5-oxo-1,2,4-triazolium ylides
Figure 1. Heterocyclic betaines Molsidomine and 3.
Results and Discussion
Substrates 2a–f were prepared according to a modified
procedure starting from known imidate hydrochlorides 1
and 1,1-disubstituted hydrazines (Scheme 1).[7] The micro-
wave-assisted ring-closing reactions of the starting materials
2a–f were conducted in microwave pressure-tubes at 100 W
in DCM at moderate temperatures (Table 1). Previously un-
reported 5-cyanoimino-functionalized 1,2,4-triazolium
ylides 5a–f were synthesized in good yields of 64–92%
[a] Institute of Pharmacy, University of Hamburg,
Bundesstr. 45, 20146 Hamburg
E-mail: khanki@chemie.uni-hamburg.de
[b] Institute of Pharmaceutical and Medicinal Chemistry,
Heinrich-Heine-Universität Düsseldorf,
Universitätsstr. 1, 40255 Düsseldorf, Germany
E-mail: Thomas.Kurz@uni-duesseldorf.de
Eur. J. Org. Chem. 2008, 6029–6033
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M. Khankischpur, T. Kurz
FULL PAPER
within only 2–3 min by treatment of compounds 2a–f with
Next, amidrazones 2a–f were treated with 1.2 equiv. of
1.2 equiv. of diphenyl N-cyanimidocarbonate (Scheme 1).[8] 1,1Ј-carbonylbis(1,2,4-triazole) and 1,1Ј-thiocarbonyldi-
Compounds 5a–f are characterized by a strong C=N ab- imidazole, respectively to afford 1,2,4-triazolium ylides 3a–
sorption band at 1641–1662 cm–1 and a sharp band of the f and 4a–f, again within only 2–3 min and in high yields
cyano group at 2189–2195 cm–1. The X-ray crystal structure (Scheme 1, Table 1). Completion of the carbonylation reac-
of compound 5b shows E configuration with regard to the tion was monitored by IR spectroscopy and was ac-
C=N double bond (Figure 2).
companied by the appearance of a strong C=O absorption
band at 1767–1774 cm–1. In all cases a simple work up pro-
cedure followed by recrystallization from appropriate sol-
vents furnished compounds 3–5 as analytically pure and so-
lid products. The structures of all novel compounds were
1
elucidated by H and 13C NMR, IR spectroscopy and ele-
mental analysis (see the Exp. Sect.).
Conclusions
In conclusion, we have developed an efficient, fast and
convenient method for the microwave-assisted preparation
of various 5-functionalized 1,2,4-triazolium ylides. The syn-
thesis of 5-cyanoimino-functionalized 1,2,4-triazolium
ylides (5) has not been reported before. The first compre-
hensive method for the synthesis of 1,1-dialkyl-5-thioxo-
1,2,4-triazolium ylides 4 has been described. Phosgene and
thiophosgene have been successfully replaced by 1,1Ј-car-
bonylbis(1,2,4-triazole) and 1,1Ј-thiocarbonyldiimidazole in
the synthesis of the 1,2,4-triazolium ylides 3 and 4, respec-
tively.
Scheme 1. Synthesis of 1,2,4-triazolium ylides.
Table 1. Microwave synthesis of 1,2,4-triazolium ylides 3–5.[a]
Entry R1
R2
R3
Compound
(% yield)[b]
1
cyclohexyl
–(CH2)2O(CH2)2-
3a (82)
3b (87)
3c (89)
3d (84)
3e (90)
3f (81)
4a (69)
4b (86)
4c (77)
4d (76)
4e (78)
4f (74)
5a (92)
5b (82)
5c (86)
5d (75)
5e (87)
5f (64)
2
3
4
5
6
7
3,4-(CH3O)2-C6H3CH2
3,4-Cl2-C6H3CH2
4-Cl-C6H4CH2
4-Cl-C6H4CH2
2-thienylmethyl
cyclohexyl
CH3
CH3
CH3
CH3
–(CH2)5–
–(CH2)2NCH3(CH2)2–
–(CH2)2O(CH2)2–
–(CH2)2O(CH2)2–
Experimental Section
General: Melting points: Electrothermal 9100 melting-point appa-
ratus, uncorrected values. IR: ATI Genesis Series FT-IR spectrom-
eter; KBr pellets unless otherwise stated. NMR: Bruker AMX 400
spectrometer (400 MHz for 1H; 100 MHz for 13C). NMR spectra
were recorded in [D6]DMSO solution with tetramethylsilane as the
internal standard. Elemental analysis: Heraeus CHN-O-Rapid in-
strument. Microwave-assisted synthesis: CEM microwave model
Discover. Thin-layer chromatography (TLC): Kieselgel 60 F254
(Macherey–Nagel) sheets; column chromatography: Kieselgel 60.
Imidate hydrochlorides used for the synthesis of 2a–f were prepared
starting from the corresponding nitriles in accord with the standard
Pinner synthesis.[7]
8
9
3,4-(CH3O)2-C6H3CH2
3,4-Cl2-C6H3CH2
4-Cl-C6H4CH2
4-Cl-C6H4CH2
2-thienylmethyl
cyclohexyl
3,4-(CH3O)2-C6H3CH2
3,4-Cl2-C6H3CH2
4-Cl-C6H4CH2
4-Cl-C6H4CH2
2-thienylmethyl
CH3
CH3
–(CH2)5–
10
11
12
13
14
15
16
17
18
CH3
CH3
–(CH2)2NCH3(CH2)2–
–(CH2)2O(CH2)2–
–(CH2)2O(CH2)2–
CH3
CH3
–(CH2)5–
CH3
CH3
–(CH2)2NCH3(CH2)2–
–(CH2)2O(CH2)2–
[a] Microwave-assisted synthesis of compounds 3–5 was carried out
by using a CEM Corporation Focused Microwave System, Model
Discover. Parameters for the synthesis of compounds 3–5: Discover
mode; power: 100 W; ramp time: 1 min; hold time 2–3 min; tem-
perature: 50 °C; pressure: 4 bar; PowerMax cooling. [b] Isolated
yields.
CCDC-662796 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Synthesis of NЈ,NЈ-Disubstituted Carbohydrazonamides: Substrates
2a–f were synthesized by a modified literature procedure.[7] The
appropriate NЈ,NЈ-disubstituted hydrazine (18 mmol) was added
dropwise to a suspension of the imidate hydrochloride salt
(15 mmol) in dry dichloromethane (20 mL) and the reaction mix-
ture was stirred at room temperature for 8 h. Afterwards, the sol-
vent was evaporated and the remaining residue was quenched with
an ice-cooled, saturated aqueous solution of potassium carbonate
(15 mL). The mixture was extracted with ethyl acetate (2ϫ30 mL)
and the combined organic layers were dried with Na2SO4, filtered
and concentrated in vacuo. The remaining residues were crys-
tallized from Et2O/hexane to afford 2a–f as solid compounds.
Figure 2. X-ray crystal structure of compound 5b.
6030
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Eur. J. Org. Chem. 2008, 6029–6033

Microwave-Assisted Synthesis of 1,2,4-Triazolium Ylides
Recrystallization from EtOAc/hexane provided analytically pure
products.
ane (5 mL) and 1,1Ј-carbonylbis(1,2,4-triazole) (394 mg, 2.4 mmol)
were added to a 10-mL microwave glass pressure-tube equipped
with a magnetic stirrer bar. The tube was closed with a silicon
septum and the reaction mixture was subjected to microwave irradi-
ation for 2–3 min. The reaction mixture was cooled to room tem-
perature and transferred to a round-bottomed flask. The solvent
was evaporated, ethyl acetate (20 mL) was added and the mixture
was washed with a saturated aqueous solution of sodium hydrogen
carbonate (3ϫ5 mL). The organic layer was dried with Na2SO4,
filtered, and the solvent was evaporated. The remaining residue was
crystallized from Et2O/hexane. Recrystallization from THF/hexane
provided compounds 3a–f as analytically pure solids. Microwave
parameters for compounds 3a–f: Discover mode; power: 100 W;
ramp time: 1 min; hold time: 2–3 min; temperature: 50 °C; pressure:
4 bar; PowerMax cooling mode.
NЈ-(Morpholin-4-yl)cyclohexanecarboimidamide (2a): Colourless so-
1
lid; yield 60% (1.9 g), m.p. 116.3 °C. H NMR: δ = 1.11–1.96 (m,
11 H, cyclohexyl, C6H11), 2.43 (s, 4 H, 3,5-H), 3.63 (s, 4 H, 2,6-H),
5.72 (s, 2 H, NH2) ppm. 13C NMR: δ = 25.96 (cyclohexyl, C-1),
26.14 (cyclohexyl, C-2,6), 30.46 (cyclohexyl, C-3,5), 42.27 (cyclo-
hexyl, C-4), 54.87 (C-3,5), 66.21 (C-2,6), 163.04 (C=N) ppm. IR: ν
˜
= 3408 (NH2), 1610 (C=N) cm–1. C11H21N3O (211.31): calcd. C
62.53, H 10.02, N 19.89; found C 62.39, H 9.98, N 19.53.
(1Z)-2-(3,4-Dimethoxyphenyl)-NЈ,NЈ-dimethylethanehydrazonamide
1
(2b): Colourless solid; yield 65% (2.3 g), m.p. 68.1 °C. H NMR: δ
3
= 2.26 [s, 6 H, N(CH3)2], 3.16 (s, 2 H, 2-H), 3.71 [d, JH,H
=
2.54 Hz, 6 H, 3,4-(CH3O)2-Ph], 5.76 (s, 2 H, NH2), 6.77–6.86 (m,
2 H, 5Ј,6Ј-H), 6.92 (d, 3JH,H = 1.78 Hz, 1 H, 2Ј-H) ppm. 13C NMR:
δ = 39.06 (C-2), 46.84 [N(CH3)2], 55.64, 55.88 [3,4-(CH3O)2-Ph],
112.07, 112.61, 120.73 (C-2Ј, C-5Ј, C-6Ј), 130.89, 147.66, 148.78
2-Cyclohexyl-4-oxo-8-oxa-1,3,5-triazaspiro[4.5]dec-1-en-5-ium-3-ide
(3a): Colourless solid; yield 82 % (389 mg), m.p. 115.0 °C. 1H
NMR: δ = 1.18–1.83 (m, 10 H, cyclohexyl, C5H10), 2.32–2.39 (m,
1 H, cyclohexyl, CH), 2.80–2.83 (d, 3JH,H = 12.46 Hz, 2 H, morph-
oline, 3-H), 3.36–3.43 (m, 2 H, morpholine, 5-H), 3.93–4.04 (m, 4
H, morpholine, 2,6-H) ppm. 13C NMR: δ = 25.34 (cyclohexyl, C-
3,5), 25.85 (cyclohexyl, C-4), 29.56 (cyclohexyl, C-2,6), 39.22 (cy-
clohexyl, C-1), 55.66 (C-7,9), 62.37 (C-6,10), 170.39 (C-2), 187.29
(C-1Ј, C-3Ј, C-4Ј), 158.25 (C-1) ppm. IR: ν = 3318 (NH ), 1639
˜
2
(C=N) cm–1. C12H19N3O2 (237.30): calcd. C 60.74, H 8.07, N
17.71; found C 60.69, H 8.15, N 17.33.
(1Z)-2-(3,4-Dichlorophenyl)-NЈ-(piperidin-1-yl)ethanimidamide (2c):
Colourless solid; yield 61% (2.6 g), m.p. 126.0 °C. 1H NMR: δ =
1.35 (s, 2 H, piperidine, 4-H), 1.53–1.59 (m, 4 H, piperidine, 3,5-
H), 2.44 (s, 4 H, piperidine 2,6-H), 3.29 (s, 2 H, 2-H), 6.03 (br. s,
2 H, NH2), 7.27–7.29 (m, 1 H, 6Ј-H), 7.54–7.56 (m, 2 H, 2Ј,5Ј-
H) ppm. 13C NMR: δ = 24.02 (piperidine, C-4), 25.51 (piperidine,
C-3,5), 38.20 (C-2), 55.51 (piperidine, C-2,6), 129.21, 130.61, 130.82
(C-6Ј, C-5Ј, C-2Ј), 130.94, 134.68 (C-3Ј, C-4Ј, C-1Ј), 157.51 (C-
(C-4) ppm. IR: ν = 1773 (C=O) cm–1. C H N O (237.30): calcd.
˜
12 19
3
2
C 60.74, H 8.07, N 17.71; found C 60.56, H 8.30, N 17.63. Hold
time: 2.5 min.
3-(3,4-Dimethoxybenzyl)-1,1-dimethyl-5-oxo-1,5-dihydro-1,2,4-tri-
azol-1-ium-4-ide (3b): Colourless solid; yield 87% (458 mg), m.p.
87.4 °C. 1H NMR: δ = 2.96 [s, 6 H, N(CH3)2], 3.56 [s, 2 H, 3,4-
1) ppm. IR: ν = 3379 (NH ), 1628 (C=N) cm–1. C13H17Cl2N3
3
˜
(CH3O)2-PhCH2], 3.72 [d, JH,H = 1.79 Hz, 6 H, 3,4-(CH3O)2-Ph],
2
6.78–6.80 (m, 1 H, 2Ј-H), 6.86–6.88 (m, 2 H, 5Ј,6Ј-H) ppm. 13C
NMR: δ = 35.58 [3,4-(CH3O)2-PhCH2], 47.66 [N(CH3)2], 55.41,
55.52 [3,4-(CH3O)2-Ph], 111.86, 112.90, 121.02 (C-5Ј, C-2Ј, C-6Ј),
127.85, 147.65, 148.55 (C-1Ј, C-4Ј, C-3Ј), 170.01 (C-3), 181.88 (C-
(286.21): calcd. C 54.56, H 5.99, N 14.68; found C 54.24, H 6.05,
N 14.62.
(1Z)-2-(4-Chlorophenyl)-NЈ,NЈ-dimethylethanehydrazonamide (2d):
Colourless solid; yield 62% (2.0 g), m.p. 136.0 °C. 1H NMR: δ =
2.25 [s, 6 H, N(CH3)2], 3.23 (s, 2 H, 2-H), 5.86 (s, 2 H, NH2), 7.29–
7.35 (m, 4 H, 4-Cl-Ph) ppm. 13C NMR: δ = 38.78 (C-2), 46.81
[N(CH3)2], 128.39, 130.63 (C-3Ј,5Ј, C-2Ј,6Ј), 131.18, 137.64 (C-4Ј,
5) ppm. IR: ν = 1773 (C=O) cm–1. C H N O (263.30): calcd. C
˜
13 17
3
3
59.30, H 6.51, N 15.96; found C 59.12, H 6.62, N 15.65. Hold time:
2 min.
C-1Ј), 157.65 (C-1) ppm. IR: ν = 3287 (NH ), 1653 (C=N) cm–1.
2-(3,4-Dichlorobenzyl)-4-oxo-1,3,5-triazaspiro[4.5]dec-1-en-5-ium-3-
ide (3c): Colourless solid; yield 89% (556 mg), m.p. 116.0 °C. 1H
NMR: δ = 1.51–2.00 (m, 6 H, 7,8,9-H), 2.86–2.89 (m, 2 H, 6-H),
3.23–3.30 (m, 2 H, 10-H), 3.73 (s, 2 H, 3,4-Cl2-PhCH2), 7.30–7.33
(m, 1 H, 2Ј-H), 7.56–7.61 (m, 2 H, 5Ј,6Ј-H) ppm. 13C NMR: δ =
20.76 (C-8), 21.02 (C-7,9), 35.00 (3,4-Cl2-PhCH2), 56.61 (C-6,10),
129.34 (C-4Ј), 129.52, 130.35 (C-6Ј, C-5Ј), 130.71 (C-3Ј), 131.14 (C-
˜
2
C10H14ClN3 (211.70): calcd. C 56.74, H 6.67, N 19.85; found C
56.64, H 6.70, N 19.73.
(1Z)-2-(4-Chlorophenyl)-NЈ-(4-methylpiperazin-1-yl)ethanimidamide
1
(2e): Colourless solid; yield 62% (2.5 g), m.p. 146.5 °C. H NMR:
δ = 2.14 (s, 4 H, 4-Me-piperazine, 3,5-H), 2.40 (br. s, 4 H, 4-Me-
piperazine, 2,6-H), 3.25 (s, 2 H, 2-H), 3.37 (s, 3 H, NCH3), 5.87 (s,
2 H, NH2), 7.29–7.35 (m, 4 H, 4-Cl-Ph) ppm. 13C NMR: δ = 38.75
(C-2), 46.01 (NCH3), 53.97 (4-Me-piperazine, C-3,5), 54.68 (4-Me-
piperazine, C-2,6), 128.40, 130.62 (C-3Ј,5Ј, C-2Ј,6Ј), 131.20, 137.59
2Ј), 136.88 (C-1Ј), 171.04 (C-2), 181.48 (C-4) ppm. IR: ν = 1774
˜
(C=O) cm–1. C14H15Cl2N3O (312.20): calcd. C 53.86, H 4.84, N
13.46; found C 53.87, H 4.90, N 13.26. Hold time: 2 min.
3-(4-Chlorobenzyl)-1,1-dimethyl-5-oxo-1,5-dihydro-1,2,4-triazol-1-
ium-4-ide (3d): Colourless solid; yield 84% (524 mg), m.p. 131.5 °C.
1H NMR: δ = 2.96 [s, 6 H, N(CH3)2], 3.66 (s, 2 H, 4-Cl-PhCH2),
7.31–7.38 (m, 4 H, 4-Cl-Ph) ppm. 13C NMR: δ = 35.70 (4-Cl-
PhCH2), 48.08 [N(CH3)2], 128.61 (C-3Ј, C-5Ј), 131.41 (C-2Ј, C-6Ј),
(C-4Ј, C-1Ј), 158.04 (C-1) ppm. IR: ν = 3375 (NH ), 1634
˜
2
(C=N) cm–1. C13H19ClN4 (266.78): calcd. C 58.53, H 7.18, N 21.00;
found C 58.24, H 7.27, N 20.79.
(1Z)-NЈ-Morpholin-4-yl-2-(2-thienyl)ethanimidamide (2f): Pale-yel-
1
low solid; yield 56% (1.9 g), m.p. 87.0 °C. H NMR: δ = 2.50 (s, 4
131.74, 134.95 (C-1Ј, C-4Ј), 170.38 (C-3), 181.83 (C-5) ppm. IR: ν
˜
= 1771 (C=O) cm–1. C11H12ClN3O (237.69): calcd. C 55.59, H 5.09,
N 17.68; found C 55.41, H 5.45, N 17.31. Hold time: 2 min.
H, morpholine, 3,5-H), 3.46 (s, 2 H, 2-H), 3.65 (s, 4 H, morpholine,
2,6-H), 5.97 (s, 2 H, NH2), 6.92 (d, 3JH,H = 3.56 Hz, 2 H, 3Ј,4Ј-H),
7.31 (t, 3JH,H = 3.30 Hz, 1 H, 5Ј-H) ppm. 13C NMR: δ = 34.17 (C-
2), 54.75 (morpholine, C-3,5), 66.14 (morpholine, C-2,6), 124.76,
125.94, 126.92 (C-5Ј, C-4Ј, C-3Ј), 140.83 (C-2Ј), 157.89 (C-1) ppm.
2-(4-Chlorobenzyl)-8-methyl-4-oxo-1,3,5,8-tetraazaspiro[4.5]dec-1-
en-5-ium-3-ide (3e): Colourless solid; yield 90 % (527 mg), m.p.
1
196.2 °C. H NMR: δ = 2.29 (s, 3 H, NCH3), 2.54–2.61 (m, 2 H,
IR: ν = 3421 (NH ), 1622 (C=N) cm–1. C10H15N3OS (225.31):
˜
2
6-H), 2.88–2.91 (m, 4 H, 7,9-H), 3.30–3.39 (m, 2 H, 10-H), 3.69 (s,
2 H, 4-Cl-PhCH2), 7.32–7.38 (m, 4 H, 4-Cl-Ph) ppm. 13C NMR: δ
= 35.43 (NCH3), 45.14 (4-Cl-PhCH2), 49.57 (C-7,9), 55.83 (C-6,10),
128.23 (C-3Ј,5Ј), 130.88 (C-2Ј,6Ј), 131.35 (C-1Ј), 134.65 (C-4Ј),
calcd. C 53.31, H 6.71, N 18.65; found C 53.45, H 6.73, N 18.34.
Microwave-Assisted Synthesis of Compounds 3a–f. General Pro-
cedure: Compounds 2a–f (2 mmol) dissolved in dry dichlorometh-
Eur. J. Org. Chem. 2008, 6029–6033
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6031

M. Khankischpur, T. Kurz
FULL PAPER
170.23 (C-2), 182.02 (C-4) ppm. IR: ν = 1774 (C=O) cm–1
C14H17ClN4O (292.77): calcd. C 57.44, H 5.85, N 19.14; found C
57.25, H 6.18, N 18.82. Hold time: 2.5 min.
1
.
138.9 °C. H NMR: δ = 3.10 [s, 6 H, N(CH3)2], 3.86 (s, 2 H, 4-Cl-
PhCH2), 7.33–7.40 (m, 4 H, 4-Cl-Ph) ppm. 13C NMR: δ = 33.90
(4-Cl-PhCH2), 51.32 [N(CH3)2], 128.33, 131.16 (C-3Ј,5Ј, C-2Ј,6Ј),
˜
131.59, 133.96 (C-1Ј, C-4Ј), 179.54 (C-3), 198.17 (C-5) ppm. IR: ν
˜
4-Oxo-2-(2-thienylmethyl)-8-oxa-1,3,5-triazaspiro[4.5]dec-1-en-5-
ium-3-ide (3f): Pale-brown solid; yield 81% (407 mg), m.p. 111.0 °C.
1H NMR: δ = 2.87–2.90 (m, 2 H, 6-H), 3.40–3.47 (m, 2 H, 10-H),
3.94 (s, 2 H, 2-thienyl-CH2), 3.98–4.06 (m, 4 H, 7,9-H), 6.95–7.01
(m, 2 H, 3Ј,4Ј-H), 7.39–7.40 (m, 1 H, 5Ј-H) ppm. 13C NMR: δ =
30.80 (2-thienyl-CH2), 55.24 (C-7,9), 61.97 (C-6,10), 125.21, 126.64,
126.75 (C-5Ј, C-4Ј, C-3Ј), 136.85 (C-1Ј), 169.75 (C-2), 181.95 (C-
= 2953, 1557, 1442, 1334 cm–1. C11H12ClN3S (253.76): calcd. C
52.07, H 4.77, N 16.56; found C 51.83, H 4.84, N 16.41. Hold time:
3 min.
2-(4-Chlorobenzyl)-8-methyl-4-thioxo-1,3,5,8-tetraazaspiro[4.5]dec-
1-en-5-ium-3-ide (4e): Colourless solid; yield 78% (482 mg), m.p.
1
209.5 °C. H NMR: δ = 2.32 (s, 3 H, NCH3), 2.66 (s, 2 H, 6-H),
4) ppm. IR: ν = 1767 (C=O) cm–1. C H N O S (251.31): calcd.
˜
2.84–2.97 (m, 4 H, 7,9-H), 3.70 (s, 2 H, 10-H), 3.89 (s, 2 H, 4-Cl-
PhCH2), 7.34–7.40 (m, 4 H, 4-Cl-Ph) ppm. 13C NMR: δ = 34.44
(4-Cl-PhCH2), 45.41 (NCH3), 50.50 (C-7,9), 60.19 (C-6,10), 128.76,
131.49 (C-3Ј,5Ј, C-2Ј,6Ј), 131.98, 134.43 (C-1Ј, C-4Ј), 180.41 (C-2),
11 13
3
2
C 52.57, H 5.21, N 16.72; found C 52.38, H 5.31, N 16.57. Hold
time: 3 min.
Microwave-Assisted Synthesis of Compounds 4a–f. General Pro-
cedure: Compounds 2a–f (2 mmol) dissolved in dry dichlorometh-
ane (5 mL) and 1,1Ј-thiocarbonyldiimidazole (428 mg, 2.4 mmol)
were added to a 10 mL glass pressure microwave tube equipped
with a magnetic stirrer bar. The tube was closed with a silicon
septum and the reaction mixture was subjected to microwave irradi-
ation for 2–3 min. The reaction mixture was cooled to room tem-
perature and transferred to a round-bottomed flask. The solvent
was evaporated, ethyl acetate (20 mL) was added and the mixture
was washed with 1  hydrochloric acid (3ϫ5 mL). The organic
layer was dried with Na2SO4, filtered and the solvent was evapo-
rated. The remaining residues were purified by filtration through a
short silica gel column (3 cm) with EtOAc/hexane (1:1) as eluent.
Crystallization from EtOAc/hexane provided 4a–f as analytically
pure solids. Microwave parameters for compounds 4a–f: Discover
mode; power: 100 W; ramp time: 1 min; hold time: 2–3 min; tem-
perature: 50 °C; pressure: 4 bar; PowerMax cooling mode.
199.04 (C-4) ppm. IR: ν = 1560, 1458, 1340 cm–1. C H ClN S
˜
14 17
4
(308.84): calcd. C 54.45, H 5.55, N 18.14; found C 54.13, H 5.65,
N 17.97. Hold time: 2.5 min.
2-(2-Thienylmethyl)-4-thioxo-8-oxa-1,3,5-triazaspiro[4.5]dec-1-en-5-
ium-3-ide (4f): Orange-brown solid; yield 74 % (396 mg), m.p.
1
136.0 °C. H NMR: δ = 2.86 (br. s, 2 H, 6-H), 3.72 (br. s, 2 H, 10-
H), 4.07 (s, 4 H, 7,9-H), 4.14 (s, 2 H, 2-thienyl-CH2), 6.98–7.00 (m,
1 H, 3Ј-H), 7.03–7.04 (m, 1 H, 4Ј-H), 7.42–7.44 (m, 1 H, 5Ј-
H) ppm. 13C NMR: δ = 29.42 (2-thienyl-CH2), 59.15 (C-7,9), 62.46
(C-6,10), 125.50, 126.91, 127.05 (C-5Ј, C-4Ј, C-3Ј), 136.10 (C-2Ј),
179.97 (C-2), 198.25 (C-4) ppm. IR: ν = 1555, 1456, 1331 cm–1.
˜
C11H13N3OS2 (267.37): calcd. C 49.41, H 4.90, N 15.72; found C
49.06, H 5.01, N 15.47. Hold time: 3 min.
Microwave-Assisted Synthesis of Compounds 5a–f. General Pro-
cedure: Compounds 2a–f (2 mmol) dissolved in dry dichlorometh-
ane (5 mL) and diphenyl N-cyanimidocarbonate (572 mg,
2.4 mmol) were added to a 10 mL glass pressure microwave tube
equipped with a magnetic stirrer bar. The tube was closed with a
silicon septum and the reaction mixture was subjected to micro-
wave irradiation for 2–3 min. The reaction mixture was cooled to
room temperature and was transferred to a round-bottomed flask.
The solvent was evaporated, ethyl acetate (20 mL) was added and
the mixture was washed with a saturated aqueous solution of po-
tassium carbonate (3ϫ5 mL). The organic layer was dried with
Na2SO4, filtered and the solvent was evaporated. The remaining
residues were purified by column chromatography with EtOAc/hex-
ane (1:1) as eluent. Crystallization from THF/hexane provided 5a–
f as analytically pure solids. Microwave parameters for compounds
5a–f: Discover mode; power: 100 W; ramp time: 1 min; hold time:
2–3 min; temperature: 50 °C; pressure: 4 bar; PowerMax cooling
mode.
2-Cyclohexyl-4-thioxo-8-oxa-1,3,5-triazaspiro[4.5]dec-1-en-5-ium-3-
ide (4a): Colourless solid; yield 69% (350 mg), m.p. 120.9 °C. 1H
NMR: δ = 1.17–1.91 (m, 10 H, cyclohexyl, C5H10), 2.53–2.60 (m,
1 H, cyclohexyl, CH), 2.80 (br. s, 2 H, 6-H), 3.71 (br. s, 2 H, 10-
H), 4.06 (s, 4 H, 7,9-H) ppm. 13C NMR: δ = 24.81 (cyclohexyl, C-
3,5), 25.37 (cyclohexyl, C-4), 29.08 (C-2,6), 59.13 (C-7,9), 62.48 (C-
6,10), 184.74 (C-2), 197.96 (C-4) ppm. IR: ν = 2928, 2854,
˜
1544 cm–1. C12H19N3OS (253.37): calcd. C 56.89, H 7.56, N 16.58;
found C 56.84, H 7.69, N 16.51. Hold time: 3 min.
3-(3,4-Dimethoxybenzyl)-1,1-dimethyl-5-thioxo-1,5-dihydro-1,2,4-tri-
azol-1-ium-4-ide (4b): Colourless solid; yield 86% (480 mg), m.p.
136.0 °C. 1H NMR: δ = 3.10 [s, 6 H, N(CH3)2], 3.73 [d, J = 2.03 Hz,
6 H, 3,4-(CH3O)2-Ph], 3.76 [s, 2 H, 3,4-(CH3O)2-PhCH2], 6.80–6.83
(m, 1 H, 6Ј-H), 6.88–6.90 (m, 2 H, 5Ј,2Ј-H) ppm. 13C NMR: δ =
34.56 [3,4-(CH3O)2-PhCH2], 51.68 [N(CH3)2], 55.89 [3,4-(CH3O)2-
Ph], 112.26, 113.39, 121.61 (C-5Ј, C-2Ј, C-6Ј), 127.52 (C-1Ј), 148.18,
(4E)-4-(Cyanoimino)-2-cyclohexyl-8-oxa-1,3,5-triazaspiro[4.5]dec-1-
en-5-ium-3-ide (5a): Colourless solid; yield 92 % (481 mg), m.p.
139.5 °C. 1H NMR: δ = 1.17–1.90 (m, 10 H, cyclohexyl, C5H10),
2.47–2.55 (m, 1 H, cyclohexyl, CH), 3.21–3.24 (d, 3JH,H = 12.72 Hz,
2 H, 6-H), 3.55–3.62 (m, 2 H, 10-H), 3.48–4.09 (m, 4 H, 7,9-
H) ppm. 13C NMR: δ = 25.16 (cyclohexyl, C-3,5), 25.70 (cyclo-
hexyl, C-4), 29.40 (cyclohexyl, C-2,6), 38.17 (cyclohexyl, C-1),
59.94 (C-7,9), 62.39 (C-6,10), 115.23 [N(CN)], 178.52 (C-2), 184.13
149.00 (C-4Ј, C-3Ј), 180.32 (C-3), 198.45 (C-5) ppm. IR: ν = 1517,
˜
1478, 1261 cm–1. C13H17N3O2S (279.36): calcd. C 55.89, H 6.13, N
15.04; found C 55.55, H 6.14, N 14.92. Hold time: 2.5 min.
2-(3,4-Dichlorobenzyl)-4-thioxo-1,3,5-triazaspiro[4.5]dec-1-en-5-
ium-3-ide (4c): Pale-yellow solid; yield 77 % (505 mg), m.p.
1
139.0 °C. H NMR: δ = 1.52–2.06 (m, 6 H, 7,8,9-H), 2.82 (d, J =
11.80 Hz, 2 H, 6-H), 3.56 (t, J = 12.80 Hz, 2 H, 10-H), 3.93 (s, 2
H, 3,4-Cl2-PhCH2), 7.32–7.35 (m, 1 H, 6Ј-H), 7.59 (d, J = 8.29 Hz,
1 H, 2Ј-H), 7.64 (d, J = 2.01 Hz, 1 H, 5Ј-H) ppm. 13C NMR: δ =
20.71 (C-8), 21.70 (C-7,9), 33.67 (3,4-Cl2-PhCH2), 61.00 (C-6,10),
129.60 (C-4Ј), 129.71, 130.46 (C-6Ј, C-5Ј), 130.82 (C-3Ј), 131.33 (C-
(C-4) ppm. IR: ν = 2193 (CN), 1650 (C=N) cm–1. C13H19N5O
˜
(261.33): calcd. C 59.75, H 7.33, N 26.80; found C 59.73, H 7.36,
N 26.80. Hold time: 3 min.
(5E)-5-(Cyanoimino)-3-(3,4-dimethoxybenzyl)-1,1-dimethyl-1,5-di-
hydro-1,2,4-triazol-1-ium-4-ide (5b): Colourless solid; yield 82%
(471 mg), m.p. 165.4 °C. 1H NMR: δ = 3.24 [s, 6 H, N(CH3)2], 3.72
2Ј), 136.25 (C-1Ј), 179.48 (C-2), 194.60 (C-4) ppm. IR: ν = 2953,
˜
1557, 1442, 1334 cm–1. C14H15Cl2N3S (328.27): calcd. C 51.23, H
4.61, N 12.80; found C 51.11, H 4.79, N 12.66. Hold time: 2.5 min.
3
[s, 2 H, 3,4-(CH3O)2-PhCH2], 3.73 [d, JH,H = 2.26 Hz, 6 H, 3,4-
3-(4-Chlorobenzyl)-1,1-dimethyl-5-thioxo-1,5-dihydro-1,2,4-triazol- (CH3O)2-Ph], 6.81–6.84 (m, 1 H, 6Ј-H), 6.89–6.91 (m, 2 H, 2Ј,5Ј-
1-ium-4-ide (4d): Pale-yellow solid; yield 76 % (386 mg), m.p.
H) ppm. 13C NMR: δ = 34.20 [3,4-(CH3O)2-PhCH2], 51.32
6032
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 6029–6033

Microwave-Assisted Synthesis of 1,2,4-Triazolium Ylides
[N(CH3)2], 55.41, 55.50 [3,4-(CH3O)2-Ph], 111.91, 113.02 (C-5Ј, C- (4E)-4-(Cyanoimino)-2-(2-thienylmethyl)-8-oxa-1,3,5-triazaspiro[4.5]-
2Ј), 114.73 [N(CN)], 121.23 (C-6Ј), 126.81 (C-1Ј), 147.86, 148.63
dec-1-en-5-ium-3-ide (5f): Pale-rose solid; yield 64% (352 mg), m.p.
(C-4Ј, C-3Ј), 178.40 (C-3), 179.01 (C-5) ppm. IR: ν = 2195 (CN),
174.2 °C. 1H NMR: δ = 3.27 (d, 3JH,H = 12.80 Hz, 2 H, 6-H), 3.58–
˜
1655 (C=N) cm–1. C14H17N5O2 (287.32): calcd. C 58.52, H 5.96, N 3.65 (m, 2 H, 10-H), 3.99–4.11 (m, 4 H, 7,9-H), 4.10 (s, 2 H, 2-
24.37; found C 58.52, H 6.13, N 24.25. Hold time: 2.5 min.
thienyl-CH2), 6.98–7.00 (m, 1 H, 3Ј-H), 7.05–7.06 (m, 1 H, 4Ј-H),
7.43–7.45 (m, 1 H, 5Ј-H) ppm. 13C NMR: δ = 29.54 (2-thienyl-
CH2), 59.63 (C-7,9), 61.98 (C-6,10), 114.45 [N(CN)], 125.56,
126.92, 127.16 (C-5Ј, C-4Ј, C-3Ј), 135.72 (C-2Ј), 178.21 (C-2),
(4E)-4-(Cyanoimino)-2-(3,4-dichlorobenzyl)-1,3,5-triazaspiro[4.5]-
dec-1-en-5-ium-3-ide (5c): Colourless solid; yield 86% (578 mg),
m.p. 194.5 °C. 1H NMR: δ = 1.54–2.04 (m, 6 H, 7,8,9-H), 3.23–
178.93 (C-4) ppm. IR:
ν =
˜
2189 (CN), 1641 (C=N) cm–1.
3
3.26 (d, JH,H = 11.70 Hz, 2 H, 6-H), 3.43–3.50 (m, 2 H, 10-H),
C12H13N5OS (275.33): calcd. C 52.35, H 4.76, N 25.44; found C
52.12, H 4.93, N 25.19. Hold time: 2.5 min.
3.89 (s, 2 H, 3,4-Cl2-PhCH2), 7.33–7.36 (m, 1 H, 6Ј-H), 7.60 (d,
3
3JH,H = 8.14 Hz, 1 H, 2Ј-H), 7.65 (d, JH,H = 2.04 Hz, 1 H, 5Ј-
H) ppm. 13C NMR: δ = 20.58 (C-8), 21.64 (C-7,9), 34.20 (3,4-Cl2-
PhCH2), 61.64 (C-6,10), 115.18 [N(CN)], 130.09, 130.90 (C-6Ј, C-
5Ј), 131.26 (C-3Ј,4Ј), 131.73 (C-2Ј), 136.35 (C-1Ј), 178.88 (C-2),
Acknowledgments
179.82 (C-4) ppm. IR: ν = 2190 (CN), 1642 (C=N) cm–1
.
˜
C15H15Cl2N5 (336.23): calcd. C 53.59, H 4.50, N 20.83; found C
53.57, H 4.61, N 20.81. Hold time: 2.5 min.
We thank Prof. Dr. J. Kopf for the X-ray crystal structure analysis.
(5E)-3-(4-Chlorobenzyl)-5-(cyanoimino)-1,1-dimethyl-1,5-dihydro-
1,2,4-triazol-1-ium-4-ide (5d): Colourless solid; yield 75% (392 mg),
[1] a) C. O. Kappe, Angew. Chem. Int. Ed. 2004, 43, 6250–6284; b)
B. Wathey, J. Tierney, P. Lidström, J. Westman, Drug Discovery
Today 2002, 7, 373–380.
[2] a) K. Schonafinger, Farmaco 1999, 54, 316–320; b) S. Laurant,
F. Bringaud, P. Hoffmann, J. Heterocycl. Chem. 2003, 40, 943–
947.
1
m.p. 156.3 °C. H NMR: δ = 3.24 [s, 6 H, N(CH3)2], 3.83 (s, 2 H,
4-Cl-PhCH2), 7.34–7.41 (m, 4 H, 4-Cl-Ph) ppm. 13C NMR: δ =
34.47 (4-Cl-PhCH2), 51.74 [N(CH3)2], 115.08 [N(CN)], 128.76 (C-
3Ј,5Ј), 131.59 (C-2Ј,6Ј), 132.06 (C-1Ј), 134.05 (C-4Ј), 178.82 (C-3),
179.01 (C-5) ppm. IR: ν = 2195 (CN), 1662 (C=N) cm–1
.
[3] M. Kouji, H. Jiyunzuo, Sankyo Co., Ltd., JP 58116475, 1983
˜
[Chem. Abstr. 1983, 99, 158441y].
C12H12ClN5 (261.72): calcd. C 55.07, H 4.62, N 26.76; found 55.27,
H 4.78, N 26.84. Hold time: 2.5 min.
[4] K. T. Potts, W. R. Kuehnling, P. Murphy, J. Org. Chem. 1984,
49, 2404–2407.
(4E)-2-(4-Chlorobenzyl)-4-(cyanoimino)-8-methyl-1,3,5,8-tetraaza-
spiro[4.5]dec-1-en-5-ium-3-ide (5e): Colourless solid; yield 87 %
[5] M. Takahashi, K. Takeguchi, S. Imaizum, Synthesis 1982, 155–
156.
1
[6] K. Grohe, Bayer AG, DE 2743976, 1979 [Chem. Abstr. 1979,
91, 91644f].
[7] a) W. Walter, H. Weiss, Justus Liebigs Ann. Chem. 1972, 758,
162–172; b) A. Pinner, Die Imidoäther und ihre Derivate, Op-
penheim, Berlin, 1892.
[8] a) R. L. Webb, S. Labaw, J. Heterocycl. Chem. 1982, 19, 1205–
1206; b) T. Kurz, N. Lolak, D. Geffken, Tetrahedron Lett. 2007,
48, 2733–2735.
(551 mg), m.p. 250 °C (dec.). H NMR: δ = 2.31 (s, 3 H, NCH3),
2.62–2.68 (m, 2 H, 7-H), 2.96 (d, 3JH,H = 12.46 Hz, 2 H, 9-H), 3.28
3
(d, JH,H = 12.21 Hz, 2 H, 6-H), 3.51–3.58 (m, 2 H, 10-H), 3.85 (s,
2 H, 4-Cl-PhCH2), 7.35–7.41 (m, 4 H, 4-Cl-Ph) ppm. 13C NMR: δ
= 34.18 (4-Cl-PhCH2), 44.91 (NCH3), 49.54 (C-7,9), 60.31 (C-6,10),
114.68 [N(CN)], 128.39, 131.05 (C-3Ј,5Ј, C-2Ј,6Ј), 131.67, 133.72
(C-1Ј, C-4Ј), 178.67 (C-2), 178.99 (C-4) ppm. IR: ν = 2189 (CN),
˜
1655 (C=N) cm–1. C15H17ClN6 (316.80): calcd. C 56.87, H 5.41, N
26.53; found 56.74, H 5.53, N 26.42. Hold time: 2.5 min.
Received: August 12, 2008
Published Online: October 31, 2008
Eur. J. Org. Chem. 2008, 6029–6033
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6033