Study of reactions of lactim ethers with cyanoacetohydrazide

Article abstract of DOI:10.1007/s11172-006-0466-x

Main pathways in reactions of lactim ethers with cyanoacetic acid hydrazide depend on the ring size of the starting lactim ether. Five-membered O-methylbutyrolactim produces pre-dominantly 3-amino-4-(pyrrolidin-2-ylidene)-4, 5-dihydropyrazol-5-one, whereas condensation of six-and seven-membered lactim ethers (O-methylvalero-and O-methylcaprolactim, respectively) affords the corresponding polymethylenetriazoles as the major products.

Full text of DOI:10.1007/s11172-006-0466-x

Russian Chemical Bulletin, International Edition, Vol. 55, No. 9, pp. 1636—1641, September, 2006
1636
Study of reactions of lactim ethers
with cyanoacetohydrazide
D. B. Nilov and V. G. Granikꢀ
State Scientific Center of Antibiotics,
3a ul. Nagatinskaya, 117105 Moscow, Russian Federation.
Fax: +7 (095) 231 4284. Eꢀmail: nilov22@hotmail.com
Main pathways in reactions of lactim ethers with cyanoacetic acid hydrazide depend on the
ring size of the starting lactim ether. Fiveꢀmembered Oꢀmethylbutyrolactim produces preꢀ
dominantly 3ꢀaminoꢀ4ꢀ(pyrrolidinꢀ2ꢀylidene)ꢀ4,5ꢀdihydropyrazolꢀ5ꢀone, whereas condensaꢀ
tion of sixꢀ and sevenꢀmembered lactim ethers (Oꢀmethylvaleroꢀ and Oꢀmethylcaprolactim,
respectively) affords the corresponding polymethylenetriazoles as the major products.
Key words: Oꢀmethylbutyrolactim, Oꢀmethylvalerolactim, Oꢀmethylcaprolactim, cyanoꢀ
acetohydrazide, lactim ethers, enamines, triazoles, pyrazolone.
Earlier, it has been demonstrated1 that the reaction
group but at the primary amino group. The structure of
the resulting cyclic amidrazone 6a (which was isolated
as a mixture of the syn and anti isomers in a ratio of
approximately 1 : 1) was unambiguously established by
NMR spectroscopy, mass spectrometry, and elemental
analysis.
of Oꢀmethylbutyrolactim (1a) with cyanoacetic acid
Nꢀacetylhydrazide (2) occurs at the active methylene
group followed by cyclization of the resulting enamine 3
to give 3ꢀaminoꢀ4ꢀ(pyrrolidinꢀ2ꢀylidene)ꢀ4,5ꢀdihydroꢀ
pyrazolꢀ5ꢀone (4) (Scheme 1).
1
The aim of the present study was to investigate the
reactions of lactim ethers with Nꢀunsubstituted cyanoꢀ
acetohydrazide (5) and reveal the dependence of the reꢀ
action pathway on the ring size of the starting lacꢀ
tim ethers. We studied the reactions with Oꢀmethylꢀ
butyroꢀ (1a), Oꢀmethylvaleroꢀ (1b), and Oꢀmethylꢀ
caprolactims (1c). It should be noted that the chemistry
of lactim ethers is characterized as an important line of
investigation associated with the synthesis of various types
of organic, primarily heterocyclic, compounds, and conꢀ
sequently, the development of new approaches to investiꢀ
gation of the reactions of lactim ethers is a topical
problem.2
It is known that condensation of lactim ethers with
compounds containing the active methylene group genꢀ
erally affords enamines, whereas condensation with comꢀ
pounds containing the primary amino group produces
amidines.2,3 It is also known that many properties of enamꢀ
ines and amidines produced in these reactions are to a
great extent determined by the ring size of lactim ether
(fiveꢀ, sixꢀ, or sevenꢀmembered) used in condensation.4
Heating of lactim ether 1a with hydrazide 5 in DMF
gave rise to the final product, viz., pyrazolone 4, which
was also isolated in the reaction of 1a with Nꢀacetyl deꢀ
rivative 2. However, this reaction performed under milder
conditions (heating at 35—40 °C for 2—3 min) afforded
the condensation product not at the active methylene
The H NMR spectrum of compound 6a shows two
sets of signals. For example, the protons of the NH groups
give signals at δ 6.80 and 9.75 along with strongly broadꢀ
ened signals at lower field (approximately at δ 7.25
and 10.10). A singlet for the methylene protons of the
CH2CN groups exists as a standard signal (at δ 3.84) and a
broadened signal (at δ 3.44). The signals for the methylꢀ
ene protons at position 3 of the pyrrolidine ring at δ 2.34
(a triplet) and 2.48 (a broadened triplet) can also be idenꢀ
tified. The signals for the methylene protons at positions 4
and 5 of both isomers appear as multiplets at δ 1.19
and 3.44, respectively.
The signals for the methylene carbon atoms of the
pyrrolidine ring belonging to different isomers at δ 21.7
and 21.8 (position 4), 28.5 and 29.0 (position 3), and 45.0
and 45.1 (position 5) and the signals for the methylene
carbon atoms at the cyano group (at δ 23.1 and 24.3) can
be identified from the 13C NMR, HSQC, and HMBC
spectra. The signals for the carbon atoms of the nitrile
group are observed at δ 116.4 and 117.0; of the C=N
group, at δ 154.9 and 160.7; and of the carbonyl group, at
δ 158.0 and 162.9.
Based on the structure of amidrazone 6a, heating of
this compound would be expected to give 3ꢀcyanomethylꢀ
4,5ꢀtrimethyleneꢀ1,2,4ꢀtriazole (7a). However, refluxing
of a solution of compound 6a in DMF leads to considerꢀ
able resinification. Nevertheless, only compound 4 was
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1577—1582, September, 2006.
1066ꢀ5285/06/5509ꢀ1636 © 2006 Springer Science+Business Media, Inc.

Reactions of lactim ethers with cyanoacetohydrazide Russ.Chem.Bull., Int.Ed., Vol. 55, No. 9, September, 2006
1637
Scheme 1
n = 2 (b), 3 (c)
Reagents and conditions: i. DMF, 40 °C, ii. DMF, refluxing, iii. DMF, heating.
isolated from the solution, although in low yield. All charꢀ
acteristics, including the spectroscopic parameters, of this
compound are completely identical to those of the prodꢀ
uct prepared by condensation of Oꢀmethylbutyrolactim
(1a) with Nꢀacetyl derivative 2.
Intermediates 6b,c were not isolated when other lacꢀ
tim ethers 1b,c were used in condensation with hydrꢀ
azide 5. Both these reactions afforded polymethyleneꢀ
triazoles 7b,c in high yields.
ment, including the presumed transition state (TS), are
presented in Scheme 2.
To our knowledge, such transformations in reactions
involving activated forms of lactams, among which are
lactim ethers,2 were not described in the literature.
As mentioned above, the main pathway in the reacꢀ
tions of sixꢀ and sevenꢀmembered lactim ethers 1b,c
with hydrazide 5 (Scheme 3) gives rise to triazole derivaꢀ
tives.5
It should be noted that direct cyclization of a mixture
of isomers 6a giving rise to pyrazole derivative 4 cannot be
performed, and enamine 8 would be required for this
reaction. However, acylamidrazones 6a were prepared in
high yield, and the reaction of Oꢀmethylbutyrolactim 1a
with hydrazide 5 did not produce noticeable amounts of
enamine 8. In our opinion, the differences observed in
condensation of lactim ethers with cyanoacetohydrazide
are associated with the ratio of the reaction rates of the
triazole cyclization and the amidineꢀenamine rearrangeꢀ
ment during heating for intermediates containing a fiveꢀ
membered saturated ring. Possible steps of this rearrangeꢀ
Presumably, the construction of fused systems involvꢀ
ing fiveꢀ and sixꢀmembered (or sevenꢀmembered) rings is
energetically more favorable than the construction of sysꢀ
tems involving two fiveꢀmembered rings and occurs more
rapidly, resulting in the predominant formation of triazole
bicyclic compounds 7b,c. By contrast, the reaction inꢀ
volving Oꢀmethylbutyrolactim produces nonannulated
pyrazole derivative 4.
Study of solutions of the reactions mixtures in acetoꢀ
nitrile by LCꢀmass spectrometry demonstrated that simiꢀ
lar reaction pathways are observed for all lactim ethers,
although occurring to a different extent.

1638
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 9, September, 2006
Nilov and Granik
Scheme 2
(which account for a total of 59% of the substance). Apꢀ
parently, structure 6a or 4 should be assigned to the former
mass; structure 9 or supposedly 10a, to the latter mass.
Presumably, compounds 9 and 10a are generated through
condensation of Oꢀmethylbutyrolactim at the primary
amino group of pyrazole derivative 4 and at the active
methylene group of compounds 6a, respectively (regardꢀ
less of whether the cis or trans isomer is involved in this
reaction).
The second peak involves compounds with masses 215
and 300 (which account for a total of 29% of the subꢀ
stance), which, presumably, have structures 12a and 11a,
respectively. Compound 12a is of interest because it is a
trimethylenetriazole derivative, i.e., has a bicyclic strucꢀ
ture generated in the reactions with sixꢀ and sevenꢀmemꢀ
bered lactim ethers. Although we failed to preparatively
isolate compound 12a in the reaction with Oꢀmethylꢀ
butyrolactim, the fact of its formation is essential, beꢀ
cause this is evidence for the similarity of the general
scheme for the reactions of all lactim ethers with cyanoꢀ
acetic acid hydrazide.
Scheme 3
The above conclusion is confirmed by analysis of the
chromatogram of the reaction mixture obtained by the
reaction of Oꢀmethylvalerolactim with cyanoacetohydrꢀ
azide, the reaction products being detected by mass specꢀ
trometry. This reaction produces triazole 7b (M+ 162) as
the major product, but the chromatogram contains also
impurity peaks with a mass 243 (12b) and with masses 261
and 342, which, apparently, belong respectively to comꢀ
pounds 10b and 11b, (Scheme 4) containing no triazole
rings.
n = 2 (b), 3 (c)
For Oꢀmethylbutyrolactim, the chromatogram of the
reaction mixture shows two dominating peaks. One peak
includes primarily compounds with masses 166 and 233
In conclusion, it should be noted that compounds
7b,c are characterized by very high CH acidity of the
methylene group due to the electronꢀwithdrawing propꢀ
erties of the nitrile group and the triazolyl fragment. Heatꢀ
ing of these compounds with lactim ethers 1a—c gave rise
to the corresponding enaminonitriles 12b—g in high yields
(Scheme 5).
Using compound 12c as an example, it was demonꢀ
strated that brief heating in 25% sulfuric acid leads to
saponification of the cyano group to form the correspondꢀ
ing carboxylic acid (13), which under these conditions
undergoes decarboxylation giving rise to 3ꢀ[(azepanꢀ
2ꢀylidene)methyl]ꢀ5,6,7,8ꢀtetrahydro[1,2,4]triazoꢀ
lo[4,3ꢀa]pyridine (14). On the whole, this behavior is not

Reactions of lactim ethers with cyanoacetohydrazide Russ.Chem.Bull., Int.Ed., Vol. 55, No. 9, September, 2006
1639
Scheme 4
typical of usual enaminonitriles and is, apparently, attribꢀ
uted to the strong electronꢀwithdrawing effect of the
triazolyl group (see Scheme 5).
It should be noted that compounds 12 can be prepared
also by refluxing of twofold excesses of lactim ethers 1b,c
with hydrazide 5 in DMF.
To conclude, it should be noted that the pathway in
the reactions of lactim ethers with Nꢀunsubstituted
cyanoacetohydrazide substantially depends on the lactam
ring size. New polymethylenetriazoles were synthesized
based on the aboveꢀdescribed processes.
Experimental
1
The H NMR spectra were recorded on Varian Unity+400,
Bruker DRX500, and Bruker AM360 spectrometers in DMSOꢀd6
with Me4Si as the internal standard. The mass spectra were
obtained on a Finnigan SSQꢀ710 instrument using a direct inlet
system; the ionization chamber temperature was 180 °C; the
ionizing electron energy was 70 eV. The LCꢀmass spectra
(LC/MS) were recorded on an Agilent Technologies 1100 inꢀ
strument. The IR spectra were measured on a PerkinꢀElmer 599
spectrometer as Nujol mulls and on a Specord M82 spectromꢀ
eter in KBr pellets (1 mg/200 mg of KBr). The course of the
reactions was monitored and the purity of the compounds was
checked by chromatography on Silufol UVꢀ254 plates; the spots
in the chromatograms were visualized with UV light. The meltꢀ
ing points were determined on a Boetius hotꢀstage apparatus.
The physicochemical characteristics, elemental analysis data,
Scheme 5
1
and H NMR spectroscopic data are given in Table 1.
3ꢀAminoꢀ4ꢀ(pyrrolidinꢀ2ꢀylidene)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazolꢀ
5ꢀone (4). A mixture of Oꢀmethylbutyrolactim (1a) (5.0 g,
50 mmol), cyanoacetohydrazide (5) (5.0 g, 50 mmol), and DMF
(5 ml) were refluxed with stirring for 2 h. Then the reaction
mixture was cooled, washed with diethyl ether, triturated with
PriOH, and filtered off. The yield of 4 was 3.0 g (36%). The
physicochemical properties of the product are identical to those
of the authentic sample.1
2ꢀ(Pyrrolidinꢀ2ꢀylidene)cyanoacetohydrazide (6a). A mixture
of Oꢀmethylbutyrolactim (1a) (1.0 g, 10 mmol) and cyanoacetoꢀ
hydrazide (5) (1.0 g, 10 mmol) was thoroughly ground and
slightly warmed on a water bath (at 40 °C). The reaction mixꢀ
ture first became liquid and then rapidly solidified. The solid
mixture was triturated with diethyl ether and filtered. Comꢀ
pound 6a was obtained in a yield of 1.61 g (99%).
3ꢀCyanomethylꢀ5,6,7,8ꢀtetrahydro[1,2,4]triazolo[4,3ꢀa]ꢀ
pyridine (7b). A mixture of Oꢀmethylvalerolactim (1b) (2.5 g,
22 mmol) and cyanoacetohydrazide (5) (2.2 g, 22 mmol) in
DMF (2 mL) was refluxed for 1.5 h, cooled, triturated with
diethyl ether, filtered, and successively washed with a 5 : 1 ethyl
acetate—isopropanol mixture and diethyl ether. Compound 7b
was obtained in a yield of 2.75 g (77%).
3ꢀCyanomethylꢀ6,7,8,9ꢀtetrahydroꢀ5Hꢀ[1,2,4]triazoꢀ
lo[4,3ꢀa]azepine (7c). A mixture of Oꢀmethylcaprolactim (1c)
(6.4 g, 50 mmol) and cyanoacetohydrazide (5) (5.0 g, 50 mmol)
in DMF (3 mL) was slightly warmed until dissolution of the
hydrazide started and then kept at room temperature for 12 h.
The mixture was concentrated, and the residue was triturated
with diethyl ether and filtered. Compound 7c was obtained in a
12
m
n
b
2
2
c
3
2
d
1
2
e
1
3
f
2
3
g
3
3
Reagents and conditions: i. DMF, refluxing; ii. 50% H2SO4,
refluxing.

1640
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 9, September, 2006
Nilov and Granik
Table 1. Selected physicochemical characteristics and elemental analysis data for the compounds synthesized
Comꢀ Yield
poꢀ (%)
und (method)
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
1H NMR (δ, (J/Hz))
MS,
m/z
(%)
N
C
H
4
36
99
—
—
—
—
—
—
—
C7H10N4O
C7H10N4O
—
—
166[M]+
166[M]+
6a*
153—163
(decomp.) (H2O)
7b
7c
77
89
136—139
(PhH)
59.27 6.23 35.15 C8H10N4
59.24 6.22 34.55
1.80 (m, 2 H, CH2); 1.90 (m, 2 H, CH2);
2.81 (t, 2 H, CH2, J = 6.41); 3.89 (t, 2 H,
CH2, J = 6.10); 4.29 (s, 2 H, CH2CN)
162[M]+
176[M]+
107—109
(PhH)
61.06 7.16 31.80 C9H12N4
61.34 6.86 31.80
1.58 (m, 2 H, CH2); 1.68 (m, 2 H, CH2);
1.80 (m, 2 H, CH2); 2.88 (t, 2 H, CH2,
J = 5.75); 3.92 (t, 2 H, CH2, J = 5.09);
4.32 (s, 2 H, CH2CN)
12b
12c
59(А)
66(B)
160—163
(PhMe)
63.89 7.06 28.52 C13H17N5 1.77 (m, 6 H, CH2); 1.91 (m, 2 H, CH2);
64.17 7.04 28.79 2.69 (m, 2 H, CH2); 2.80 (t, 2 H, CH2,
243[M]+
J = 6.41); 3.40 (m, 2 H, CH2); 4.05 (t, 2 H,
CH2, J = 5.97); 10.30 (br.s, 1 H, NH)
93(B)
213—215
(AcOEt—
PriOH, 5 : 1)
65.38 7.31 27.26 C14H19N5 1.60 (m, 2 H, CH2); 1.67 (m, 2 H, CH2);
—
65.34 7.44 27.22
1.74 (m, 4 H, CH2); 1.80 (m, 2 H, CH2);
2.70 (m, 2 H, CH2); 2.89 (t, 2 H, CH2,
J = 6.11); 3.35 (m, 2 H, CH2); 4.22 (t, 2 H,
CH2, J = 4.58); 9.76 (br.s, 1 H, NH)
12d
12e
98(B)
98(B)
252—255
(AcOEt—
62.69 6.73 30.53 C12H15N5 1.80 (m, 2 H, CH2); 1.93 (m, 2 H, CH2);
—
—
62.86 6.60 30.55
2.05 (m, 2 H, CH2); 2.81 (t, 2 H, CH2,
J = 6.41); 3.63 (t, 2 H, CH2, J = 7.02); 4.06
(t, 2 H, CH2, J = 6.10); 9.46 (br.s, 1 H, NH)
PriOH, 3 : 1)
199—201
(AcOEt—
PriOH, 3 : 1)
64.35 7.39 29.00 C13H17N5 1.60 (m, 2 H, CH2); 1.68 (m, 2 H, CH2);
64.17 7.04 28.79
1.80 (m, 2 H, CH2); 2.04 (m, 2 H, CH2);
2.90 (m, 4 H, CH2); 3.59 (t, 2 H, CH2,
J = 7.02); 4.21 (t, 2 H, CH2, J = 4.58);
9.15 (br.s, 1 H, NH)
12f
58(B)
208—210
(AcOEt—
PriOH, 5 : 1)
65.33 7.51 27.23 C14H19N5 1.54 (m, 2 H, CH2); 1.66 (m, 2 H, CH2);
—
65.34 7.44 27.22
1.73 (m, 2 H, CH2); 1.80 (m, 2 H, CH2);
1.92 (m, 2 H, CH2); 2.83 (m, 2 H, CH2);
3.52 (m, 2 H, CH2); 4.08 (t, 2 H, CH2,
J = 6.10); 10.29 (br.s, 1 H, NH)
12g
48(A)
92(B)
184—187
(PhMe)
66.29 7.95 26.25 C15H21N5 1.67 (m, 6 H, CH2); 2.80 (t, 2 H, CH2,
—
66.39 7.80 25.81
J = 5.20); 2.88 (t, 2 H, CH2, J = 5.61);
3.42 (m, 2 H, CH2); 4.15 (t, 2 H, CH2,
J = 4.80); 9.42 (br.t, 1 H, NH)
14*
55
190—193
(AcOEt—
PriOH, 1 : 1)
—
—
—
C13H20N4 1.51 (m, 2 H, CH2); 1.61 (m, 2 H, CH2);
1.77 (m, 2 H, CH2); 1.87 (m, 2 H, CH2);
2.40 (m, 2 H, CH2); 2.74 (t, 2 H, CH2,
J = 6.64); 3.67 (t, 2 H, CH2, J = 6.19);
4.60 (s, 1 H, CH); 8.2 (br.t, 1 H, NH)
232[M]+
* The structure was established by IR and NMR spectroscopy and mass spectrometry.
yield of 7.9 g (89%). 13C NMR (DMSOꢀd6), δ: 19.8, 30.4, 31.0,
33.1, and 34.9 (2 C each, cyclic CH2); 49.9 (2C, CH2CN);
121.3, 150.7, and 163.0 (1 C each).
3ꢀ[(Piperidinꢀ2ꢀylidene)cyanomethyl]ꢀ5,6,7,8ꢀtetraꢀ
hydro[1,2,4]triazolo[4,3ꢀa]pyridine (12b). Method A. A mixture
of cyanoacetohydrazide (5) (1.0 g, 10 mmol), Oꢀmethylvaleroꢀ
lactim (1b) (2.6 g, 23 mmol), and DMF (3 mL) was refluxed
for 4 h, the solvent was evaporated, and the residue was trituꢀ
rated with benzene and filtered off. Compound 12b was obꢀ
tained in a yield of 1.44 g (59%).

Reactions of lactim ethers with cyanoacetohydrazide Russ.Chem.Bull., Int.Ed., Vol. 55, No. 9, September, 2006
1641
Method B. Compound 12b was synthesized analogously to
compound 12d (see below) from 7b (0.81 g, 5 mmol) and
Oꢀmethylvalerolactim (1b) (0.85 g, 7.5 mmol) in a yield of
0.8 g (66%).
3ꢀ[(Azepanꢀ2ꢀylidene)methyl]ꢀ5,6,7,8ꢀtetrahydro[1,2,4]triꢀ
azolo[4,3ꢀa]pyridine (14). A mixture of compound 12c (0.4 g,
1.6 mmol) and 50% sulfuric acid (3 mL) was refluxed for 15 min,
diluted with water (30 mL), and cooled. Then a concentrated
KOH solution was added dropwise with cooling to pH 12—13.
The precipitate that formed was filtered off and thoroughly
washed with water to remove inorganic impurities. Compound 14
was obtained in a yield of 0.2 g (55%). IR (KBr), ν/cm–1: 3280,
3224 (NH); 1632 (C=N).
3ꢀ[(Azepanꢀ2ꢀylidene)cyanomethyl]ꢀ5,6,7,8ꢀtetraꢀ
hydro[1,2,4]triazolo[4,3ꢀa]pyridine (12c) was synthesized analoꢀ
gously to compound 12d (see below) from polymethylenetriazole
7b and Oꢀmethylcaprolactim (1c). The yield was 93%.
3ꢀ[(Pyrrolidinꢀ2ꢀylidene)cyanomethyl]ꢀ5,6,7,8ꢀtetraꢀ
hydro[1,2,4]triazolo[4,3ꢀa]pyridine (12d). A mixture of comꢀ
pound 7b (0.5 g, 5 mmol), Oꢀmethylbutyrolactim (1a) (0.85 g,
7.5 mmol), and DMF (1 mL) was refluxed with stirring for 1.5 h
and then cooled. The residue was triturated with diethyl ether
and filtered off. Compound 12d was obtained in a yield of
0.69 g (98%).
This study was financially supported by the Federal
Agency for Science and Innovations of the Russian Fedꢀ
eration (Contract No. 1/05).
3ꢀ[(Pyrrolidinꢀ2ꢀylidene)cyanomethyl]ꢀ6,7,8,9ꢀtetrahydroꢀ
5Hꢀ[1,2,4]triazolo[4,3ꢀa]azepine (12e) was synthesized analoꢀ
gously to compound 12d from polymethylenetriazole 7c and
Oꢀmethylbutyrolactim (1a). The yield was 98%.
3ꢀ[(Piperidinꢀ2ꢀylidene)cyanomethyl]ꢀ6,7,8,9ꢀtetrahydroꢀ
5Hꢀ[1,2,4]triazolo[4,3ꢀa]azepine (12f) was synthesized analoꢀ
gously to compound 12d from polymethylenetriazole 7c and
Oꢀmethylvalerolactim (1b). The yield was 58%.
References
1. V. A. Azimov, V. G. Granik, R. G. Glushkov, and L. N.
Yakhontov, Khim. Geterotsikl. Soedin., 1978, 355 [Chem.
Heterocycl. Comp., 1978, 3 (Engl. Transl.)].
2. R. G. Glushkov and V. G. Granik, Adv. Het. Chem., 1970,
12, 185.
3. V. G. Granik, Usp. Khim., 1982, 51, 207 [Russ. Chem. Rev.,
1982, 51, 119 (Engl. Transl.)].
4. S. Petersen and E. Tietze, Chem. Ber., 1957, 90, 909.
5. M. Bonanomi and L. Baiocchi, J. Heterocyclic Chem., 1983,
20, 1657.
3ꢀ[(Azepanꢀ2ꢀylidene)cyanomethyl]ꢀ6,7,8,9ꢀtetrahydroꢀ5Hꢀ
[1,2,4]triazolo[4,3ꢀa]azepine (12g). Method A. Compound 12g
was synthesized analogously to compound 12b (method A) from
cyanoacetohydrazide (8.3 g, 84 mmol) and Oꢀmethylcaprolactim
(1c) (21.3 g, 168 mmol) in a yield of 11.0 g (48%).
Method B. Compound 12g was synthesized analogously to
compound 12d from polymethylenetriazole 7c (0.88 g, 5 mmol)
and Oꢀmethylcaprolactim (1c) (0.95 g, 7.5 mmol) in a yield of
1.25 g (92%).
Received May 26, 2006;
in revised form June 19, 2006