The behaviour of nitrilimines towards ethyl isocyanoacetate

Article abstract of DOI:10.1007/s00706-002-0470-2

Interactions between nitrilimines and the title isocyanide afford, through two competing pathways, 2,3-dihydro-1,2,4-triazines and 1,3-oxazoles. In situ cycloaddition of unreacted nitrilimine with the triazines gives rise to a third class of products, the bicyclic 1,5,6,8a-tetrahydro[1,2,4]triazolo[4,3-d][1,2,4]triazines. Acceptor-free representatives of the latter are prone to triazine ring cleavage, yielding triazolyl ketone hydrazones which served as a structure proof. Substituent effects became apparent upon employment of N-(4-methoxyphenyl)- and N-(4-nitrophenyl)nitrilimines: whereas the former afforded a quinoxaline as the fourth product, triazine formation was totally blocked with the latter, the corresponding oxazole being the sole product. The constitution of acceptor-substituted bicyclic compounds (which failed to give the structure-revealing hydrazones) was established by an X-ray diffraction analysis.

Full text of DOI:10.1007/s00706-002-0470-2

Monatshefte fur Chemie 133, 1165±1175 ꢀ2002)
DOI 10.1007/s00706-002-0470-2
The Behaviour of Nitrilimines
Towards Ethyl Isocyanoacetate
Dietrich Moderhack1;Ã, Ali Daoud1, and Peter G. Jones2
1


Institut fur Pharmazeutische Chemie der Technischen Universitat Braunschweig,
D-38106 Braunschweig, Germany
Institut fur Anorganische und Analytische Chemie der Technischen Universitat Braunschweig,
D-38106 Braunschweig, Germany
2

Received March 5, 2002; accepted March 19, 2002
Published online July 15, 2002 # Springer-Verlag 2002
Summary. Interactions between nitrilimines and the title isocyanide afford, through two competing
pathways, 2,3-dihydro-1,2,4-triazines and 1,3-oxazoles. In situ cycloaddition of unreacted nitrilimine
with the triazines gives rise to a third class of products, the bicyclic 1,5,6,8a-tetrahydro[1,2,4]tri-
azolo[4,3-d][1,2,4]triazines. Acceptor-free representatives of the latter are prone to triazine ring clea-
vage, yielding triazolyl ketone hydrazones which served as a structure proof. Substituent effects became
apparent upon employment of N-ꢀ4-methoxyphenyl)- and N-ꢀ4-nitrophenyl)nitrilimines: whereas the
former afforded a quinoxaline as the fourth product, triazine formation was totally blocked with the
latter, the corresponding oxazole being the sole product. The constitution of acceptor-substituted
bicyclic compounds ꢀwhich failed to give the structure-revealing hydrazones) was established by an
X-ray diffraction analysis.
Keywords. Cyclizations; Heterocycles; Isocyanides; Nitrilimines; X-Ray structure determination.
Introduction
Reactions between nitrilimines and free isocyanides afford, compared to closely
related interactions [1, 2], an unrivalled diversity of products [3±5] ꢀScheme 1).
Depending on the substituents of 1=2 and 3, six different classes of compounds
ꢀ4±6, 8±10) have been obtained until now, excluding 11 [5a] and the respective
dequaternization products of 4 and 5 which occurred in the case of Z ˆ t-Bu [5b].
We expected that employment of an isocyanide 3 bearing a strongly activated ꢀ-
methylene group would give rise to further product classes.
Results and Discussion
When equimolar amounts of 1 ꢀQ ˆ Ar ˆ Ph) and the title isocyanide were heated
with an excess of triethylamine in boiling benzene ꢀi.e. under the conditions
Ã
Corresponding author. E-mail: d.moderhack@tu-bs.de

1166
D. Moderhack et al.
Scheme 1
applied previously [4, 5]), a mixture of products was obtained that did not show
any of the types obtained before ꢀScheme 1). Instead, we isolated three new com-
ponents provisionally denoted as A, B, and C. Mass spectra revealed that A and C
each contained one molecule of nitrilimine and isocyanide, whereas with B the
proportion was 2:1. According to NMR data ꢀone-proton signals at 6.49 and
8.31 ppm; carbon doublets at 69.8 and 150.2 ppm), component A could represent
a dihydrotriazine such as 13a or 17 ꢀQ ˆ Ar ˆ Ph), with an enhanced likelihood for

Reactions of Nitrilimines with Isocyanoacetate
1167
Scheme 2
the ®rst of these constitutions ꢀScheme 2). Treatment of this material with addi-
tional nitrilimine 2a gave a derivative that was identical to B and therefore assigned
structure 14a ꢀcf. Ref. [6]) or 18 ꢀQ ˆ Ar ˆ Ph). Whereas spectroscopic differentia-
tion between these isomers seemed ambiguous, the key evidence came from che-
mical transformation: we observed that, on keeping the CDCl3 solution for several
hours, a one-proton singlet developed at 10.59 ppm which obviously originated
from a phenylhydrazono group. We thereupon heated a fresh sample of B in
chloroform for 12 h and indeed obtained in high yield the known triazolyl ketone
hydrazone 16a [7] ꢀthe CHCOOEt fragment of the triazine half-ring eluded

1168
D. Moderhack et al.
isolation). This ®nding clearly pointed to structure 14a ꢀand thereby to 13a). The
remaining 1:1 product ꢀC) did not show an ester group; it was easily recognized as
15a by means of the carbon doublet at 99.8 ppm which is typical of 4-unsubstituted
5-alkoxy-1,3-oxazoles [8].
In order to discover to what extent these reactions are susceptible to nitrilimine
substituents, we studied the behaviour of the hydrazonoyl chlorides 1b±g. It was
found that replacing the C-phenyl group of 1a with a donor or acceptor group had
no major effect ꢀexamples 1b,e±g); using the N-ꢀ4-methoxyphenyl) and N-ꢀ4-nitro-
phenyl) representatives 1c and 1d, however, resulted in conspicuous deviations.
Thus, employment of 1c led to a fourth component: the quinoxaline 9c ꢀformed
through the respective cycloadduct 7). This derivative, in contrast to the congeners
of Scheme 1 where X equals H or Me [4], was obtained in substantial amounts. In
fact, an earlier study of the behaviour of 2c towards cyclohexyl isocyanide had
demonstrated that quinoxaline formation is generally favoured by this particular
nitrilimine. Thus, a derivative 9 ꢀX ˆ MeO, Z ˆ c-C6H11, Ar0 ˆ Ph) had been iso-
lated in 25% yield ꢀalong with 10% of the appropriate salt 5 and 6% of the pyrazole
6) [5b], whereas from 2a there had been a mere 2% of 9 ꢀbesides 34% of 5 and
29% of 6) [4]. A carbodiimide of type 8, however, which in addition to the 6-
methoxyquinoxaline 9 had then been obtained in more than 40% yield ꢀ8: Z ˆ
c-C6H11, Ar ˆ 4-MeOC6H4) [5b], was not found in the present case ꢀZ ˆ
CH2COOEt, Ar ˆ 4-MeOC6H4), evidently because of instability ꢀcf. Ref. [9]). In
complete contrast to the foregoing experiment, the reaction with the acceptor-sub-
stituted analogue 1d failed to give the triazine 13d ꢀand, consequently, the cycload-
duct 14d); the only compound detectable was the oxazole 15d which could be
isolated in almost 90% yield. This ®nding is rationalized as follows ꢀScheme 3).
We assume that the products 13 and 15 arise from a joint precursor, the linear
adduct 19. To form the triazine ꢀ13) as a ®nal product, this intermediate cyclizes to
the triazolium ylide 20 ꢀcf. Ref. [4]); the latter is not protonated to yield the
respective salt 4 ꢀby the triethylammonium chloride present in the reaction mix-
ture) but, as a consequence of the acidic side chain, tautomerizes to the triazolium
N-methanide 21. Species of this kind have been reported to ring-open rapidly to
give a triazahexatriene ꢀakin to 22), which in turn reverts to the triazine in question
ꢀand to a 1-aminoimidazole corresponding to the non-observed material 23) [10].
We sought to prove the sequence 21 ! 22 ! 13 using authentic 21 ꢀQ ˆ Ar ˆ Ph),
but efforts to prepare the necessary salt 4 ꢀZ ˆ CH2COOEt) under the conditions
suitable for this class of compounds [3] remained unrewarded. To afford the ox-
azole ꢀ15), the intermediate 19 undergoes deprotonation to give the conjugated
nitrile ylide 24 which then cyclizes in the usual way ꢀcf. Ref. [11]). The ®rst of
these steps competes with the kinetically controlled ring closure to 20 so as to
impede triazine formation if the N±Ar moiety of 19 is insuf®ciently nucleophilic.
This is apparently the case with Ar ˆ 4-O2NC6H4.
Regarding an alternate pathway to 13, one might consider an attack of the
carbanion of 12 at the terminal N atom of the nitrilimine ꢀallenic structure); how-
ever, this mode appears less plausible since involvement of anionized 12 should
preferentially give the isomeric triazine 17, in particular with the nitrilimine 2d
whose allenic structure is disfavoured ꢀcf. Ref. [12]).

Reactions of Nitrilimines with Isocyanoacetate
1169
Scheme 3
As mentioned above, structural proof for the triazolotriazine 14a was provided
by its conversion to the triazolyl ketone hydrazone 16a, simply achieved through
heating the bicyclic compound in chloroform. Hence, we were tempted to check
the remaining derivatives for this noteworthy behaviour and treated 14b,c,e±g
accordingly. But whereas 14b gave the expected hydrazone 16b very readily and
also 14c ring-opened easily, the acceptor-substituted derivatives 14e±g could not
be induced to react in this manner and decomposed under more stringent condi-
tions. Since the failure to give 16e±g ꢀi.e. the former products 11 [5a]) aroused our
suspicion that these cycloadducts might belong to the type 18, we performed an X-
ray analysis of the representative 14e ꢀsee below). This, however, established the
originally proposed constitution 14e. The inertness of 14e±g towards triazine ring
opening obviously originates in the presence of an acceptor group at Cꢀ8): we
found that the model compound 14h ꢀprepared from the triazine 13g and 1a) also
failed to yield a hydrazone of type 16.
Crystal structure of 14e ꢀFig. 1)
The dimensions of the ring system are rather similar to those measured for
a congener, i.e. 1-ꢀ4-nitrophenyl)-3,6,8,8a-tetraphenyl-1,5,6,8a-tetrahydro[1,2,4]-
triazolo[4,3-d][1,2,4]triazine [6]; the angle Nꢀ4)±Cꢀ8a)±Nꢀ1) is narrow, whereas

1170
D. Moderhack et al.
Fig. 1. X-Ray crystal structure of 14e
Nꢀ7)±Cꢀ8)±Cꢀ8a) is wide ꢀ100.21ꢀ7) and 124.65ꢀ8)ꢀ, respectively), and the bond
2
3
Ê
Cꢀ8)±Cꢀ8a) ꢀ1.5295ꢀ14) A) is long for a Cꢀsp )±Cꢀsp ) bond. The bridgehead
angles are 122.00ꢀ8)ꢀ ꢀCꢀ3)±Nꢀ4)±Cꢀ5)) and 112.11ꢀ8)ꢀ ꢀCꢀ8)±Cꢀ8a)±Nꢀ1)), with
torsion angles of 99.65ꢀ8)ꢀ ꢀCꢀ3)±Nꢀ4)±Cꢀ8a)±Cꢀ8)) and À 155.08ꢀ8)ꢀ ꢀCꢀ5)±
Nꢀ4)±Cꢀ8a)±Nꢀ1)). The crystal packing involves a number of short C±H Á Á Á O
contacts that could be classi®ed as hydrogen bonds, notably Cꢀ8a)±
Hꢀ8a) Á Á Á Oꢀ4) and Cꢀ23)±Hꢀ23) Á Á Á Oꢀ2) with H Á Á Á O distances and C±H Á Á Á O
ꢀ
Ê
angles of 2.36, 2.48 A and 147, 146 , respectively.
Experimental
M.p.: Ko¯er microscope; elemental analysis: CHN Analyzer 1106 Carlo Erba ꢀthe data were
in accordance with the calculated values); IR: PU-9800 FTIR; NMR: Bruker DRX-400 ꢀ400.1
1
and 100.6 MHz for H and 13C); UV=Vis: Philips PU-8730; ¯uorescence: Kontron SFM 25; MS
ꢀEI, 70 eV): Finnigan MAT 90.
Hydrazonoyl chlorides 1a±d [13], 1e, f [14], and 1g [15] and the isocyanide 12 [16] were prepared
according to ꢀor by adopting) literature procedures.
Reaction of the hydrazonoyl chlorides 1a±g with ethyl isocyanoacetate ꢀ12);
general procedure
To a stirred solution of the appropriate hydrazonoyl chloride 1 ꢀ5mmol) and 0.57g 12 ꢀ5mmol) in
25cm3 of anhydrous benzene, 2.5cm3 of triethylamine ꢀca. 18mmol) were added. The mixture was
heated under re¯ux for 1 h, cooled to room temperature, and diluted with 25cm3 of light petroleum
followed by work-up as detailed below.
a) Runs with 1a±c: After standing for 2±3 h, the triethylammonium chloride was ®ltered off, and the
®ltrate was concentrated in vacuo. The residue was chromatographed on silica gel ꢀCH2Cl2 as
eluent) to yield, successively, the 1,3-oxazoles 15a±c, the tetrahydro[1,2,4]triazolo[4,3-d]-
[1,2,4]triazines 14a±c, the dihydro-1,2,4-triazines 13a±c and, in the case of 1c, the quinoxaline 9c
which was accompanied by some 13c.

Reactions of Nitrilimines with Isocyanoacetate
1171
b) Runs with 1e±g: The residue was chromatographed as above to afford, successively, the derivatives
14e±g, 15e±g ꢀinverse order!), and 13e±g; this procedure was followed by fractional crystallization
in order to achieve complete separation of 14 from 15.
c) Run with 1d: After standing for 2±3 h, the solid was ®ltered off and washed with light petroleum
and H2O to give the derivative 15d; the organic ®ltrate was concentrated to dryness, and the residue
was chromatographed as above to yield a second crop of 15d.
Recrystallization of the products was effected as indicated below. The intermediary dihydro-1,2,4-
triazines 13b,c,e±g ꢀca. 0.1±0.2g; coloured oils) could not be obtained analytically pure; they were
1
identi®ed by the following pairs of one-proton H NMR signals ꢀCDCl3) which match those of 13a
ꢀsee below): ꢁ ˆ 6.47 ꢀs)=8.27 ꢀs) ppm ꢀ13b), 6.26 ꢀs)=8.26 ꢀd, J ˆ 0.7 Hz) ppm ꢀ13c), 6.42 ꢀd, J ˆ
1.1 Hz)=8.39 ꢀd, J ˆ 1.1 Hz) ppm ꢀ13e), 6.39 ꢀs)=8.38 ꢀd, J ˆ 0.9 Hz) ppm ꢀ13f), 6.39 ꢀd, J ˆ
0.9 Hz)=8.32 ꢀd, J ˆ 0.9 Hz) ppm ꢀ13g; further signals of this compound: 1.28 ꢀt, J ˆ 7 Hz, 3H),
1.39 ꢀt, J ˆ 7 Hz, 3H), 4 .25 ꢀq, J ˆ 7 Hz, 2H), 4 .38 ꢀq, J ˆ 7 Hz, 2H), 7.33=7.52 ꢀAA0BB0,
N ˆ 9 Hz, 4H) ppm).
Ethyl ꢀꢀ6-methoxy-3-phenylquinoxalin-2-yl)amino)acetate ꢀ9c; C19H19N3O3)
Yield: 0.31g ꢀ18%); m.p.: 125±127ꢀC ꢀEtOH); pale yellow prisms; IR ꢀKBr): ꢂmax ˆ 3336,
1
1742 cmÀ 1; H NMR ꢀCDCl3): ꢁ ˆ 1.29 ꢀt, J ˆ 7 Hz, 3H), 3.90 ꢀs, 3H), 4.22 ꢀq, J ˆ 7 Hz, 2H), 4.31
ꢀd, J ˆ 5.3 Hz, 2H), 5.56 ꢀt, J ˆ 5.3Hz, 1H), 7.26 ꢀdd, J ˆ 2.8 and 9 Hz, 1H), 7.33 ꢀd, J ˆ 2.8Hz, 1H),
7.48±7.57 ꢀm, 3H), 7.65 ꢀd, J ˆ 9 Hz, 1H), 7.77±7.79 ꢀm, 2H) ppm; 13C NMR ꢀCDCl3): ꢁ ˆ 14.2 ꢀq),
43.3 ꢀt), 55.6 ꢀq), 61.3 ꢀt), 107.7 ꢀd), 121.7 ꢀd), 127.0 ꢀd), 128.4 ꢀd, 2C), 129.3 ꢀd, 2C), 129.6 ꢀd), 136.5
ꢀs), 136.7 ꢀs), 138.2 ꢀs), 146.2 ꢀs), 148.3 ꢀs), 157.2 ꢀs), 171.0 ꢀs) ppm; UV=Vis ꢀEtOH): ꢃmax
ꢀlog") ˆ 261 ꢀ4.14), 392 ꢀ3.81) nm; ¯uorescence ꢀEtOH): ꢃmax ˆ 461 nm ꢀexcitation wavelength:
‡
365 nm); MS: m=z ꢀ%) ˆ 337 ꢀM ), 264ꢀ100).
Ethyl 2,6-diphenyl-2,3-dihydro-1,2,4-triazine-3-carboxylate ꢀ13a; C18H17N3O2)
Yield: 0.36g ꢀ23%); sticky oil; IR ꢀneat): ꢂmax ˆ 1741cmÀ 1; 1H NMR ꢀCDCl3): ꢁ ˆ 1.24ꢀt, J ˆ 7 Hz,
3H), 4.21 ꢀq, J ˆ 7 Hz, 2H), 6.49 ꢀs, 1H), 7.13±7.17 ꢀm, 1H), 7.34±7.44 ꢀm, 7H), 7.78±7.80 ꢀm, 2H),
8.31 ꢀd, J ˆ 0.7 Hz, 1H) ppm; 13C NMR ꢀCDCl3): ꢁ ˆ 14.0 ꢀq), 62.1 ꢀt), 69.8 ꢀd), 117.2 ꢀd, 2C), 123.9
ꢀd), 124.4 ꢀd, 2C), 128.6 ꢀd), 128.8 ꢀd, 2C), 129.1 ꢀd, 2C), 133.7 ꢀs), 139.0 ꢀs), 143.9 ꢀs), 150.2 ꢀd),
‡
167.7 ꢀs) ppm; MS: m=z ꢀ%) ˆ 307 ꢀM , 10), 234 ꢀ100).
Ethyl 1,3,6,8-tetraphenyl-1,5,6,8a-tetrahydro[1,2,4]triazolo[4,3-d][1,2,4]triazine-
5-carboxylate ꢀ14a; C31H27N5O2)
Yield: 0.64g ꢀ51%); m.p.: 110±113ꢀC ꢀMeOH); prisms; IR ꢀKBr): ꢂmax ˆ 1733 cmÀ 1
;
1H NMR
ꢀCDCl3): ꢁ ˆ 1.16 ꢀt, J ˆ 7 Hz, 3H), 4.12±4.27 ꢀm, 2H), 5.85 ꢀs, 1H), 6.37 ꢀs, 1H), 6.86±6.98 ꢀm, 6H),
7.12±7.18 ꢀm, 4H), 7.33±7.37 ꢀm, 3H), 7.44±7.48 ꢀm, 3H), 7.63±7.68 ꢀm, 4H) ppm; 13C NMR ꢀCDCl3):
ꢁ ˆ 14.0 ꢀq), 62.3 ꢀt), 67.1 ꢀd), 73.4 ꢀd), 115.2 ꢀd, 2C), 116.8 ꢀd, 2C), 121.9 ꢀd), 122.0 ꢀd), 126.4 ꢀs), 127.8
ꢀd, 2C), 128.0 ꢀd, 2C), 128.3 ꢀd, 2C), 128.7 ꢀd, 2C), 128.8 ꢀd), 128.9 ꢀd, 2C), 129.1 ꢀd, 2C), 130.7 ꢀd),
‡
136.1 ꢀs), 144.9 ꢀs), 148.1 ꢀs), 155.2 ꢀs), 166.6 ꢀs) ppm; MS: m=z ꢀ%) ˆ 501 ꢀM , 2), 222 ꢀ100).
Ethyl 3,8-bis-ꢀ4-methoxyphenyl)-1,6-diphenyl-1,5,6,8a-
tetrahydro[1,2,4]triazolo[4,3-d][1,2,4]triazine-5-carboxylate ꢀ14b; C33H31N5O4)
1
Yield: 0.61 g ꢀ43%); m.p.: 167±170ꢀC ꢀMeOH); needles; IR ꢀKBr): ꢂmax ˆ 1736 cmÀ 1; H NMR
ꢀCDCl3): ꢁ ˆ 1.17 ꢀt, J ˆ 7 Hz, 3H), 3.80 ꢀs, 3H), 3.84 ꢀs, 3H), 4.12±4.27 ꢀm, 2H), 5.83 ꢀs, 1H),
6.27 ꢀd, J ˆ 0.8Hz, 1H), 6.84±7.03 ꢀm, 10H), 7.15±7.20 ꢀm, 4H), 7.58 ꢀpart of AA0BB0, N ˆ 9 Hz,
2H), 7.62 ꢀpart of AA0BB0, N ˆ 9 Hz, 2H) ppm; 13C NMR ꢀCDCl3): ꢁ ˆ 14.0 ꢀq), 55.2 ꢀq), 55.4 ꢀq),

1172
D. Moderhack et al.
62.2 ꢀt), 67.0 ꢀd), 73.3 ꢀd), 113.7 ꢀd, 2C), 114.5 ꢀd, 2C), 114.9 ꢀd, 2C), 117.1 ꢀd, 2C), 118.5 ꢀs), 121.7
ꢀd), 121.9 ꢀd), 128.7 ꢀd, 2C), 128.9 ꢀd, 2C), 129.3 ꢀd, 4C), 144.5 ꢀs), 145.0 ꢀs), 148.5 ꢀs), 155.2 ꢀs),
‡
160.1 ꢀs), 161.4ꢀs), 166.8 ꢀs) ppm; MS: m=z ꢀ%) ˆ 561 ꢀM , 3), 251 ꢀ100).
Ethyl 1,6-bis-ꢀ4-methoxyphenyl)-3,8-diphenyl-1,5,6,8a-
tetrahydro[1,2,4]triazolo[4,3-d][1,2,4]triazine-5-carboxylate ꢀ14c; C33H31N5O4)
Yield 0.43 g ꢀ31%); m.p.: 109±112ꢀC ꢀMeOH); prisms; IR ꢀKBr): ꢂmax ˆ 1731cmÀ 1
;
1H NMR
ꢀCDCl3): ꢁ ˆ 1.14ꢀt, J ˆ 7 Hz, 3H), 3.72 ꢀs, 3H), 3.73 ꢀs, 3H), 4.09±4.23 ꢀm, 2H), 5.67 ꢀs, 1H),
6.26 ꢀs, 1H), 6.69±6.76 ꢀoverlapping parts of AA0BB0, 4H), 6.84 ꢀpart of AA0BB0, N ˆ 9 Hz, 2H),
6.93 ꢀpart of AA0BB0, N ˆ 9 Hz, 2H), 7.32±7.34ꢀm, 3H), 7.46±7.53 ꢀm, 3H), 7.59±7.62 ꢀm, 2H),
7.68±7.70 ꢀm, 2H) ppm; 13C NMR ꢀCDCl3): ꢁ ˆ 14.0 ꢀq), 55.5 ꢀq, 2C), 62.1 ꢀt), 68.7 ꢀd), 74.3 ꢀd),
114.0 ꢀd, 2C), 114.2 ꢀd, 2C), 118.1 ꢀd, 2C), 122.2 ꢀd, 2C), 126.7 ꢀs), 127.3 ꢀd, 2C), 127.9 ꢀd, 2C), 128.2
ꢀd, 2C), 128.6 ꢀd), 129.1 ꢀd, 2C), 130.6 ꢀd), 135.9 ꢀs), 139.3 ꢀs), 142.1 ꢀs), 144.9 ꢀs), 155.3 ꢀs), 155.4 ꢀs),
‡
156.4ꢀs), 166.7 ꢀs) ppm; MS: m=z ꢀ%) ˆ 561 ꢀM , 2), 251 ꢀ15), 134ꢀ100).
Ethyl 3,8-diacetyl-1,6-diphenyl-1,5,6,8a-tetrahydro[1,2,4]triazolo[4,3-d][1,2,4]triazine-
5-carboxylate ꢀ14e; C23H23N5O4)
Yield: 0.58g ꢀ54%); m.p.: 133±136ꢀC ꢀMeOH); yellow prisms; IR ꢀKBr): ꢂmax ˆ 1754, 1672cmÀ 1
;
1H NMR ꢀCDCl3): ꢁ ˆ 1.22 ꢀt, J ˆ 7 Hz, 3H), 2.35 ꢀs, 3H), 2.50 ꢀs, 3H), 4.23 ꢀq, J ˆ 7 Hz, 2H), 6.67
ꢀs, 1H), 7.04ꢀm c, 1H), 7.13 ꢀmc, 1H), 7.32±7.41 ꢀm, 7H), 7.47±7.49 ꢀm, 2H) ppm; 13C NMR ꢀCDCl3):
ꢁ ˆ 13.9 ꢀq), 24.6 ꢀq), 26.7 ꢀq), 62.9 ꢀt), 65.1 ꢀd), 70.1 ꢀd), 116.0 ꢀd, 2C), 116.8 ꢀd, 2C), 122.6 ꢀd), 124.1
ꢀd), 128.6 ꢀd, 2C), 129.4ꢀd, 2C), 139.1 ꢀs), 143.4ꢀs), 143.5 ꢀs), 145.9 ꢀs), 165.6 ꢀs), 190.1 ꢀs), 195.5 ꢀs)
‡
ppm; MS: m=z ꢀ%) ˆ 433 ꢀM , 7), 177 ꢀ95), 104ꢀ100).
Ethyl 3,8-diacetyl-1,6-bis-ꢀ4-methylphenyl)-1,5,6,8a-
tetrahydro[1,2,4]triazolo[4,3-d][1,2,4]triazine-5-carboxylate ꢀ14f; C25H27N5O4)
Yield: 0.65 g ꢀ56%); m.p.: 134±137ꢀC ꢀMeOH); yellow prisms; IR ꢀKBr): ꢂmax ˆ 1750, 1675,
1
1661 cmÀ 1; H NMR ꢀCDCl3): ꢁ ˆ 1.22 ꢀt, J ˆ 7 Hz, 3H), 2.31 ꢀs, 6H), 2.33 ꢀs, 3H), 2.48 ꢀs, 3H),
4.22 ꢀq, J ˆ 7 Hz, 2H), 6.64ꢀs, 1H), 7.12±7.25 ꢀm, 6H), 7.29 ꢀs, 1H), 7.36 ꢀpart of AA 0BB0, N ˆ 9 Hz,
2H) ppm; 13C NMR ꢀCDCl3): ꢁ ˆ 13.9 ꢀq), 20.7 ꢀq, 2C), 24.5 ꢀq), 26.6 ꢀq), 62.8 ꢀt), 65.3 ꢀd), 70.3 ꢀd),
116.1 ꢀd, 2C), 117.3 ꢀd, 2C), 129.1 ꢀd, 2C), 129.9 ꢀd, 2C), 132.4ꢀs), 133.8 ꢀs), 138.9 ꢀs), 141.0 ꢀs), 141.4
‡
ꢀs), 145.6 ꢀs), 165.6 ꢀs), 189.9 ꢀs), 195.4 ꢀs) ppm; MS: m=z ꢀ%) ˆ 461 ꢀM , 7), 191 ꢀ100), 118 ꢀ95).
Triethyl 1,6-bis-ꢀ4-bromophenyl)-1,5,6,8a-tetrahydro[1,2,4]triazolo[4,3-d][1,2,4]triazine-
3,5,8-tricarboxylate ꢀ14g; C25H25Br2N5O6)
Yield: 1.12g ꢀ69%); m.p.: 109±113ꢀC ꢀMeOH); yellow prisms; IR ꢀKBr): ꢂmax ˆ 1746, 1708cmÀ 1
;
1H NMR ꢀCDCl3): ꢁ ˆ 1.22 ꢀt, J ˆ 7 Hz, 3H), 1.23 ꢀt, J ˆ 7 Hz, 3H), 1.33 ꢀt, J ˆ 7 Hz, 3H), 4.09±4.24
ꢀm, 2H), 4.26 ꢀq, J ˆ 7 Hz, 2H), 4.33 ꢀq, J ˆ 7 Hz, 2H), 6.57 ꢀs, 1H), 7.11 ꢀs, 1H), 7.24=7.40 ꢀAA0BB0,
N ˆ 9 Hz, 4 H), 7.31=7.46 ꢀAA0BB0, N ˆ 9 Hz, 4H) ppm; 13C NMR ꢀCDCl3): ꢁ ˆ 13.9 ꢀq, 2C), 14.0 ꢀq),
61.4ꢀt), 62.8 ꢀt), 63.1 ꢀt), 65.0 ꢀd), 70.3 ꢀd), 114.9 ꢀs), 116.7 ꢀs), 117.5 ꢀd, 2C), 118.1 ꢀd, 2C), 131.5 ꢀd,
2C), 132.2 ꢀd, 2C), 132.5 ꢀs), 141.8 ꢀs), 142.6 ꢀs), 143.4 ꢀs), 158.3 ꢀs), 162.3 ꢀs), 165.3 ꢀs) ppm; MS:
‡
m=z ꢀ%) ˆ 649=651=653 ꢀM , 5), 255=257 ꢀ100), 182=184ꢀ79).
ꢀ5-Ethoxy-1,3-oxazol-2-yl)-phenyl-ketone phenylhydrazone ꢀ15a; C18H17N3O2)
1
Yield: 0.32 g ꢀ21%); m.p.: 109±112ꢀC ꢀEtOH); yellow needles; IR ꢀKBr): ꢂmax ˆ 1598cmÀ 1; H
NMR ꢀCDCl3): ꢁ ˆ 1.40 ꢀt, J ˆ 7 Hz, 3H), 4 .12 ꢀq, J ˆ 7 Hz, 2H), 6.33 ꢀs, 1H), 6.89±6.93 ꢀm, 1H),

Reactions of Nitrilimines with Isocyanoacetate
1173
7.28±7.42 ꢀm, 7H), 7.76±7.79 ꢀm, 2H), 12.66 ꢀs, 1H) ppm; 13C NMR ꢀCDCl3): ꢁ ˆ 14.5 ꢀq), 68.3 ꢀt),
99.8 ꢀd), 113.8 ꢀd, 2C), 121.2 ꢀd), 125.5 ꢀs), 127.8 ꢀd), 128.1 ꢀd, 2C), 128.2 ꢀd, 2C), 129.2 ꢀd, 2C), 136.3
‡
ꢀs), 144.3 ꢀs), 148.7 ꢀs), 158.2 ꢀs) ppm; MS: m=z ꢀ%) ˆ 307 ꢀM , 100), 234ꢀ84).
ꢀ5-Ethoxy-1,3-oxazol-2-yl)-ꢀ4-methoxyphenyl)-ketone phenylhydrazone ꢀ15b; C19H19N3O3)
Yield: 0.13 g ꢀ8%); m.p.: 112±114ꢀC ꢀEtOH); yellow needles; IR ꢀKBr): ꢂmax ˆ 1598 cmÀ 1; 1H NMR
ꢀCDCl3): ꢁ ˆ 1.43 ꢀt, J ˆ 7 Hz, 3H), 3.84ꢀs, 3H), 4.17 ꢀq, J ˆ 7 Hz, 2H), 6.36 ꢀs, 1H), 6.88±6.93 ꢀm,
1H), 6.95=7.71 ꢀAA0BB0, N ˆ 9 Hz, 4H), 7.28±7.30 ꢀm, 4H), 12.54 ꢀs, 1H) ppm; 13C NMR ꢀCDCl3):
ꢁ ˆ 14.5 ꢀq), 55.3 ꢀq), 68.3 ꢀt), 99.8 ꢀd), 113.57 ꢀd, 2C), 113.63 ꢀd, 2C), 120.9 ꢀd), 125.3 ꢀs), 128.9 ꢀs),
‡
129.2 ꢀd, 2C), 129.3 ꢀd, 2C), 144.4 ꢀs), 148.7 ꢀs), 158.2 ꢀs), 159.4 ꢀs) ppm; MS: m=z ꢀ%) ˆ 337 ꢀM ,
60), 264ꢀ100).
ꢀ5-Ethoxy-1,3-oxazol-2-yl)-phenyl-ketone ꢀ4-methoxyphenyl)hydrazone ꢀ15c; C19H19N3O3)
Yield: 0.11 g ꢀ7%); m.p.: 111±114ꢀC ꢀEtOH); yellow needles; IR ꢀKBr): ꢂmax ˆ 1603 cmÀ 1; 1H NMR
ꢀCDCl3): ꢁ ˆ 1.44 ꢀt, J ˆ 7 Hz, 3H), 3.79 ꢀs, 3H), 4.18 ꢀq, J ˆ 7 Hz, 2H), 6.36 ꢀs, 1H), 6.88=7.25
ꢀAA0BB0, N ˆ 9 Hz, 4H), 7.31±7.35 ꢀm, 1H), 7.39±7.43 ꢀm, 2H), 7.76±7.78 ꢀm, 2H), 12.59 ꢀs, 1H)
ppm; 13C NMR ꢀCDCl3): ꢁ ˆ 14.5 ꢀq), 55.6 ꢀq), 68.3 ꢀt), 99.7 ꢀd), 114.7 ꢀd, 2C), 114.8 ꢀd, 2C), 124.4
ꢀs), 127.6 ꢀd), 128.0 ꢀd, 2C), 128.1 ꢀd, 2C), 136.4ꢀs), 138.2 ꢀs), 148.8 ꢀs), 154.6 ꢀs), 158.1 ꢀs) ppm; MS:
‡
m=z ꢀ%) ˆ 337 ꢀM , 70), 264ꢀ100).
ꢀ5-Ethoxy-1,3-oxazol-2-yl)-phenyl-ketone ꢀ4-nitrophenyl)hydrazone ꢀ15d; C18H16N4O4)
Yield: 1.53g ꢀ87%); m.p.: 202±206ꢀC ꢀacetone); deep yellow needles; IR ꢀKBr): ꢂmax ˆ 1596cmÀ 1
;
1H NMR ꢀCDCl3): ꢁ ˆ 1.47 ꢀt, J ˆ 7 Hz, 3H), 4.22 ꢀq, J ˆ 7 Hz, 2H), 6.43 ꢀs, 1H), 7.31=8.19 ꢀAA0BB0,
N ˆ 9 Hz, 4H), 7.42±7.48 ꢀm, 3H), 7.75±7.78 ꢀm, 2H), 13.04 ꢀs, 1H) ppm; 13C NMR ꢀCDCl3): ꢁ ˆ 14.5
ꢀq), 68.6 ꢀt), 100.1 ꢀd), 112.9 ꢀd, 2C), 125.9 ꢀd, 2C), 128.3 ꢀd, 2C), 128.4ꢀd, 2C), 128.8 ꢀd), 129.8 ꢀs),
‡
135.2 ꢀs), 141.1 ꢀs), 147.8 ꢀs), 149.4 ꢀs), 158.8 ꢀs) ppm; MS: m=z ꢀ%) ˆ 352 ꢀM , 100), 279 ꢀ93).
1-ꢀ5-Ethoxy-1,3-oxazol-2-yl)-1-ꢀphenylhydrazono)propan-2-one ꢀ15e; C14H15N3O3)
1
Yield: 0.34g ꢀ25%); m.p.: 103±104ꢀC ꢀEtOH); yellow needles; IR ꢀKBr): ꢂmax ˆ 1684cm À 1; H
NMR ꢀCDCl3): ꢁ ˆ 1.46 ꢀt, J ˆ 7 Hz, 3H), 2.56 ꢀs, 3H), 4.23 ꢀq, J ˆ 7 Hz, 2H), 6.29 ꢀs, 1H), 7.06±
7.11 ꢀm, 1H), 7.34±7.39 ꢀm, 4H), 13.38 ꢀs, 1H) ppm; 13C NMR ꢀCDCl3): ꢁ ˆ 14.8 ꢀq), 26.2 ꢀq), 68.7
ꢀt), 99.1 ꢀd), 115.4 ꢀd, 2C), 124.0 ꢀd), 125.0 ꢀs), 129.7 ꢀd, 2C), 142.8 ꢀs), 147.7 ꢀs), 159.0 ꢀs), 194.8 ꢀs)
‡
ppm; MS: m=z ꢀ%) ˆ 273 ꢀM , 100), 200 ꢀ38).
1-ꢀ5-Ethoxy-1,3-oxazol-2-yl)-1-ꢀꢀ4-methylphenyl)hydrazono)propan-2-one
ꢀ15f; C15H17N3O3)
1
Yield: 0.41 g ꢀ29%); m.p.: 128±129ꢀC ꢀEtOH); yellow needles; IR ꢀKBr): ꢂmax ˆ 1673cmÀ 1; H
NMR ꢀCDCl3): ꢁ ˆ 1.46 ꢀt, J ˆ 7 Hz, 3H), 2.34ꢀs, 3H), 2.56 ꢀs, 3H), 4.24ꢀq,
J ˆ 7 Hz, 2H), 6.29
ꢀs, 1H), 7.17=7.28 ꢀAA0BB0, N ˆ 8 Hz, 4H), 13.37 ꢀs, 1H) ppm; 13C NMR ꢀCDCl3): ꢁ ˆ 14.5 ꢀq), 20.8
ꢀq), 25.9 ꢀq), 68.5 ꢀt), 98.8 ꢀd), 115.1 ꢀd, 2C), 124.3 ꢀs), 130.0 ꢀd, 2C), 133.5 ꢀs), 140.3 ꢀs), 147.6 ꢀs),
‡
158.7 ꢀs), 194.6 ꢀs) ppm; MS: m=z ꢀ%) ˆ 287 ꢀM , 100), 214ꢀ56).
Ethyl ꢀꢀ4-bromophenyl)hydrazono)ꢀ5-ethoxy-1,3-oxazol-2-yl)acetate ꢀ15g; C15H16BrN3O4)
Yield: 0.29g ꢀ15%); m.p.: 96±97ꢀC ꢀEtOH); yellow needles; IR ꢀKBr): ꢂmax ˆ 1715cmÀ 1; 1H NMR
ꢀCDCl3): ꢁ ˆ 1.42 ꢀt, J ˆ 7 Hz, 3H), 1.47 ꢀt, J ˆ 7 Hz, 3H), 4.24 ꢀq, J ˆ 7 Hz, 2H), 4.39 ꢀq, J ˆ 7 Hz,

1174D. Moderhack et al.
2H), 6.33 ꢀs, 1H), 7.27=7.44 ꢀAA0BB0, N ˆ 9 Hz, 4H), 13.27 ꢀs, 1H) ppm; 13C NMR ꢀCDCl3): ꢁ ˆ 14.3
ꢀq), 14.5 ꢀq), 61.3 ꢀt), 68.5 ꢀt), 99.5 ꢀd), 115.8 ꢀs), 116.7 ꢀd, 2C), 117.6 ꢀs), 132.2 ꢀd, 2C), 141.9 ꢀs),
‡
147.5 ꢀs), 158.6 ꢀs), 162.8 ꢀs) ppm; MS: m=z ꢀ%) ˆ 381=383 ꢀM , 100), 308=310 ꢀ24).
Diethyl 6-ꢀ4-bromophenyl)-1,3-diphenyl-1,5,6,8a-tetrahydro-
[1,2,4]triazolo[4,3-d][1,2,4]triazine-5,8-dicarboxylate ꢀ14h; C28H26BrN5O4)
To a stirred solution of crude 0.38g 13g ꢀ1mmol) and 0.23g 1a ꢀ1mmol) in 15cm3 of anhydrous
benzene, 0.5 cm3 of triethylamine ꢀca. 3 mmol) were added. The mixture was heated under re¯ux for
1 h, cooled to room temperature, diluted with 15cm3 of light petroleum and, after ®ltration of the
triethylammonium chloride, concentrated in vacuo. The residue was chromatographed on silica gel
ꢀCH2Cl2 as eluent) and recrystallized from MeOH.
1
Yield: 0.24 g ꢀ42%); m.p.: 145±146ꢀC; yellow prisms; IR ꢀKBr): ꢂmax ˆ 1735, 1694cm À 1; H
NMR ꢀCDCl3): ꢁ ˆ 1.24ꢀt, J ˆ 7 Hz, 3H), 1.32 ꢀt, J ˆ 7 Hz, 3H), 4.19±4.36 ꢀm, 4H), 5.77 ꢀs, 1H), 6.36
ꢀs, 1H), 6.77=7.29 ꢀAA0BB0, N ˆ 9 Hz, 4H), 6.97±7.01 ꢀm, 1H), 7.28±7.33 ꢀm, 2H), 7.44±7.55 ꢀm, 7H)
ppm; 13C NMR ꢀCDCl3): ꢁ ˆ 14.0 ꢀq), 14.1 ꢀq), 61.5 ꢀt), 63.1 ꢀt), 66.5 ꢀd), 71.0 ꢀd), 116.1 ꢀd, 2C),
116.5 ꢀs), 117.4ꢀd, 2C), 121.6 ꢀd), 125.8 ꢀs), 127.7 ꢀd, 2C), 128.7 ꢀd, 2C), 129.2 ꢀd, 2C), 131.0 ꢀd),
132.1 ꢀd, 2C), 134.2 ꢀs), 142.5 ꢀs), 148.3 ꢀs), 155.4 ꢀs), 162.6 ꢀs), 165.4 ꢀs) ppm; MS: m=z
‡
ꢀ%) ˆ 575=577 ꢀM , 27), 255=257 ꢀ90), 221 ꢀ100), 182=184ꢀ89).
Ring opening of triazolotriazines 14a±c; general procedure
A solution of the appropriate triazolotriazine 14 ꢀ0.5mmol) in 50 cm3 of CHCl3 was heated under
re¯ux for 12 h ꢀdaylight!) whereupon the solvent was removed in vacuo. In the case of 14a,b, the
residue was treated with the minimum amount of EtOH to allow crystallization of the phenylhydra-
zones 16a,b which were collected by ®ltration ꢀdata see below). In the case of 14c, the residue was
chromatographed on silica gel ꢀCH2Cl2 as eluent) to give an oil which, after treatment with EtOH, left
an inhomogeneous solid showing an intense singlet at 10.44 ppm in its 1H NMR spectrum ꢀCDCl3).
Attempts to isolate the product failed.
ꢀ1,3-Diphenyl-1H-1,2,4-triazol-5-yl)-phenyl-ketone phenylhydrazone ꢀ16a; C27H21N5)
Yield: 0.17 g ꢀ82%); m.p.: 179±180ꢀC ꢀEtOH) ꢀRef. [7]: 181±182ꢀC); pale yellow needles; the IR, 1H
and 13C NMR data were consistent with the literature data [7].
ꢀ4-Methoxyphenyl)-ꢀ3-ꢀ4-methoxyphenyl)-1-phenyl-1H-1,2,4-triazol-5-yl)-ketone
phenylhydrazone ꢀ16b; C29H25N5O2)
Yield: 0.22 g ꢀ93%); m.p.: 164±166ꢀC ꢀEtOH); pale yellow prisms; 1H NMR ꢀCDCl3): ꢁ ˆ 3.70 ꢀs, 3H),
3.89 ꢀs, 3H), 6.64=7.03 ꢀAA0BB0, N ˆ 9 Hz, 4H), 6.89±6.94 ꢀm, 1H), 7.15±7.37 ꢀm, 10H), 7.42±7.55
ꢀm, 1H), 8.22 ꢀpart of AA0BB0, N ˆ 9 Hz, 2H), 10.18 ꢀs, 1H) ppm; 13C NMR ꢀCDCl3): ꢁ ˆ 55.2 ꢀq),
55.4ꢀq), 113.56 ꢀd, 2C), 113.61 ꢀd, 2C), 114.2 ꢀd, 2C), 121.0 ꢀd), 122.8 ꢀs), 123.9 ꢀd, 2C), 127.7 ꢀd,
2C), 128.1 ꢀd, 2C), 128.5 ꢀd), 128.7 ꢀs), 128.9 ꢀd, 2C), 129.3 ꢀd, 2C), 129.6 ꢀs), 137.4ꢀs), 144.1 ꢀs),
‡
146.8 ꢀs), 159.4 ꢀs), 161.0 ꢀs), 161.9 ꢀs) ppm; MS: m=z ꢀ%) ˆ 475 ꢀM , 92), 4 74 ꢀ100).
Crystal structure determination of 14e
Crystal data: C23H23N5O4, M ˆ 433.46, triclinic, space group Pꢀ À 1), a ˆ 9.1925ꢀ6), b ˆ 10.0014ꢀ6),
Ê 3
ꢀ
ꢀ
Ê
c ˆ 12.3904ꢀ8) A, ꢀ ˆ 68.551ꢀ3), ꢄ ˆ 85.026ꢀ3), ꢅ ˆ 85.468ꢀ3) , U ˆ 1054.9A , Z ˆ 2, T ˆ À 140 C.
Data collection: A crystal of ca. 0.3Â0.23Â0.2 mm was used to record 13938 intensities on a Bruker

Reactions of Nitrilimines with Isocyanoacetate
1175
SMART 1000 CCD diffractometer ꢀMoKꢀ radiation, 2ꢆmax ˆ 60ꢀ). Structure re®nement: The structure
was re®ned anisotropically on F2 ꢀprogram SHELXL-97 [17]) to wR2 ˆ 0.117, R1 ˆ 0.040 for 292
parameters and 6080 unique re¯ections. The hydrogens were re®ned using a riding model or rigid
methyl groups. The data have been deposited at the Cambridge Crystallographic Data Centre ꢀdeposi-
tion No. CCDC 173739).
References
[1] Nitrilimines ꢀ2) ‡ metal-coordinated isocyanides: Hiraki K, Fuchita Y, Morinaga S ꢀ1978) Chem
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[2] 1,3-Dipoles ꢀother than 2) ‡ free isocyanides ꢀ3): Moderhack D ꢀ1985) Synthesis 1083 ꢀsee p
1090f)
[3] Moderhack D, Lorke M ꢀ1987) Heterocycles 26: 1751; Moderhack D ꢀ1989) Liebigs Ann Chem
1271
[4] Moderhack D, Lorke M, Ernst L, Schomburg D ꢀ1994) Chem Ber 127: 1633
[5] a) Moderhack D, Daoud A, Jones PG ꢀ2000) J Prakt Chem 342: 707; b) Moderhack D, Daoud A
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[6] For a precedent of the process 13a ! 14a, see: Butler RN, Duffy JP, McArdle P, Cunningham D
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ꢀM) 0935
[7] Moderhack D ꢀ1996) Liebigs Ann 777
ꢀ
[8] L'abbe G, Ilisiu A-M, Dehaen W, Toppet S ꢀ1993) J Chem Soc Perkin Trans 1 2259
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Perkin Trans 2 613
[10] Butler RN, Duffy JP, Cunningham D, McArdle P, Burke LA ꢀ1990) J Chem Soc Chem Commun
882; Butler RN, Duffy JP, Cunningham D, McArdle P, Burke LA ꢀ1992) J Chem Soc Perkin
Trans 1 147; Butler RN, McDonald PD, McArdle P, Cunningham D ꢀ1994) J Chem Soc Perkin
Trans 1 1653
[11] Taylor EC, Turchi IJ ꢀ1979) Chem Rev 79: 181; Chupp JP, Leschinsky KL ꢀ1980) J Heterocycl
Chem 17: 705; Chupp JP, Leschinsky KL ꢀ1980) J Heterocycl Chem 17: 711; Bossio R,
Marcaccini S, Pepino R ꢀ1986) Heterocycles 24: 2003
[12] Houk KN, Yamaguchi K ꢀ1984) Theory of 1,3-Dipolar Cycloadditions. In: Padwa A ꢀed) 1,3-
Dipolar Cycloaddition Chemistry, vol 2. Wiley, New York, p 407
[13] Rector DL, Folz SD, Conklin RD, Nowakowski LH, Kaugars G ꢀ1981) J Med Chem 24: 532
[14] Dieckmann W, Platz L ꢀ1905) Ber Dtsch Chem Ges 38: 2986
[15] Anderson Bowack D, Lapworth A ꢀ1905) J Chem Soc 87: 1854
[16] Hartman GD, Weinstock LM ꢀ1980) Org Synth 59: 183
[17] Sheldrick GM ꢀ1997) SHELXL-97, A Program for Re®ning Crystal Structures, Univ Gottingen,

Germany