Tandem transformations of 1,2,4-triazol-5-ylidenes into 5-amidino-1,2,4-triazoles

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Results and Discussion
The most widely used approach for the synthesis of stable carbenes, published originally by Arduengo et al., 12 involves the deprotonation of imidazolium salts with potassium tert-butoxide in THF solution.The method used here (procedure A) differs from that of Arduengo et al. in that, after the deprotonation reaction, the resulting dispersion is evaporated to dryness and the carbene product is separated from the inorganic salt by repeated THF or toluene extractions.This modification allows the azolium alkoxide decomposition to the carbene and alcohol to be carried out in high yield.The yield of 1a is typically 81% while the yields of compounds 1b-d are somewhat smaller (57 -74%).
A lesser-used method (procedure B) involves conducting the deprotonation reactions in aromatic solvents.Details of this procedure can be found in references 13 and 14.In the presence of alcohol three types of products can be formed, namely azolium alkoxides 14 or their undissociated forms, alkoxyazolines 9 and H-complexes NHC…HOAlk.
Semi-empirical calculations using the РМ-3 method revealed that the energies of the alkoxyazoline and the isomeric Н-bond complex are almost equal in isopropyl alcohol solution.In the solvents methanol and tert-butanol, the alkoxyazolines become favored by 24 -25 kcal/mol.The complete decomposition of the indicated intermediate 3 (X = i-PrO) occurs readily by removal of the toluene under reduced pressure to afford carbene 1a in high yields (~ 81%).Thus, the role of alcohol in this modification of the carbene synthesis avoids the isolation of the intermediates and protects the carbene center upon deprotonation.The related transformation was carried out in two steps by Enders and co-workers 9 and was completed by decomposition of the pure methoxytriazoline.
The new compounds were characterized by elemental analysis, 1 Н and 13 С NMR spectroscopy.The Crystals of carbene 1a suitable for X-ray diffraction study were grown from toluene solution.A depiction of the molecular structure of 1a is presented in Fig. 1.
The bond angle at the carbene carbon atom С(1) of 1a (100.7°) is larger than that for 4, but the same as that for the Enders carbene within experimental error (100.6 deg).The aromatic rings attached to С(2) and N(1) are less twisted relative to the heterocyclic ring than in the case of carbene 4. The C(2)-C(3) bond order of p = 1.279 is notably larger than that for N(1)-C(9) (p = 1.236) but both values are closer to each other in comparison with those for carbene 4, for which p = 1.310 and 1.224, respectively.
-29.9(2) -140.1 (2)   In order to estimate the thermal stabilities of carbenes 1a-d, these compounds were heated in small amounts of decane or 1,3,5-triethylbenzene.As shown in Scheme 1, an unusual thermal autotransformation took place to afford the amidinotriazoles 5a-d.The product yields varied considerably depending on the reaction conditions.The highest yields were realized in the temperature range 130-170 °С.For example, heating the sample at 170 °С for 8 h resulted in a 28% yield of triazole 5a, while heating at 150 °С for 10 h afforded a 49% yield of 5a, and heating at 130 °С for 38 h and 140 °С for 8 h caused the yield of 5a to increase to 70%.Below 130 °С the rate of the reaction is very slow.The use of the mildest set of conditions does not result in a quantitative yield of the product 5a.Nevertheless, in the case of triazole 5c a high yield was achieved (81%).
It is clear that the end product of this induced transformation results from the interaction of the thermal decomposition product, carbodiimide 6, with the starting carbene 1, followed by stabilization due to dealkylation of the zwitterionic intermediate 7 to form additionally isobutene.This carbene transformation is feasible only when the rate of the interaction 1 + 6 is significantly greater than the rate of thermal decomposition of carbene 1→6 + ArCN, otherwise a significant amount of carbodiimide would remain or only carbodiimide 6 and nitriles would be produced.Nevertheless, at elevated temeperatures (approximately 170 °C) the carbenes 1 probably undergo cleavage by a rapid intramolecular process such that there is insufficient time for reaction with carbodiimides 6 to take place via an intermolecular process.In this case, the major products of the reaction are nitriles and carbodiimides, 6.
The products of the carbene decomposition were isolated from the mother liquor following the isolation of compound 5a.Based on 1 Н and 13 С NMR spectroscopic data, TLC, and gas chromatography assays, the products of the carbene cleavage are carbodiimide 6 and benzonitrile.The conclusion concerning the formation of carbodiimide 6 was confirmed by carrying out the reaction of the mother liquor components with carbene 1a at 100 °С, i.e. under the conditions in which carbene 1a is not decomposed.The isolation of amidinotriazole 5a in 47% yield (part of compound 5a was not isolated from the reaction mixture) also supports the formation of carbodiimide 6 and the proposed pathway for the reaction.The related carbenes 1bd (R = H) react via a similar pathway to afford 51 -81% yields of triazoles 5b-d.However, it should be noted that the reaction of compound 1b proceeds at higher temperatures (150-170 °С).The structures of the triazoles 5a-d were established on the basis of 1 Н NMR and 13 С NMR spectroscopic data.The triazoles 5a,c,d were characterized by mass spectrometry and the structure of compound 5a was determined by X-ray crystallography.The 1 Н NMR spectra of triazoles 5a-d show resonances for the tert-butyl (δ 1.62-1.66ppm) and aromatic protons (δ 6.1 -7.6 ppm).The N(5)-H proton NMR signals were observed in the same range as those of the aromatic protons; nevertheless, in the cases of compounds 5a,c,d a broadened signal was detected at δ 6.45 -6.59 ppm.This resonance disappeared in the presence of triethylamine or upon heating due to the acceleration of proton exchange, thus confirming the proposed assignment.The 13  ] corresponding to the monomers (m/z 554, 632 and 588, respectively).The presence of benzonitrile in the reaction mixture was evidenced by direct comparison of its physical properties ( 1 H NMR spectrum, boiling point, refractive index) with those of an authentic sample; the evolution of isobutene was confirmed by a 1 H NMR spectroscopic assay of a CDCl 3 solution of the gaseous products).
Crystals of triazole 5a suitable for X-ray diffraction study were grown from octane or decane solution.The X-ray analysis of compound 5a confirms the presence of an uncharged triazole nucleus and the absence of a tert-butyl group at the triazole nucleus that was present in the structure of starting carbene 1a (Fig. 2 and 3).A noteworthy redistribution of the electron density in the triazole ring is apparent from the metrical parameters of the amidine fragment (r C=N 1.280 Å, C-N 1.347 Å, С(15)-N(5) 1.402 Å).The N(4)H proton of the amidine group does not form a hydrogen bond with triazole nitrogen atom N(3).It is interesting to note that the strongest interaction of the aromatic rings with the conjugated triazole and amidine fragments is observed for the arylamidine group.For the C(15)-N(5) bond p = 1.414.The bond orders for the other aromatic groups on the triazole ring are not increased as much: C(9)-N(1) p = 1.155, for C(21)-C(1) p = 1.112, and for C(2)-C(3) p = 1.299 due to twisting of the various rings with respect to each other.Note that the aryl groups attached to the 3,4 positions are twisted by 34.5° and 55.1°, respectively, with respect to the plane of the triazole ring.The amidine fragment is twisted by 54.4° with respect to the plane of the triazole ring.
The nature of the carbodiimide that is formed plays an important role in the successful outcome of the reaction.In this case, the alkylarylcarbodiimides 6 are obtained that react readily with the carbene to afford amidinotriazoles 5 at elevated temperatures.When the reaction of diphenylcarbodiimide with carbene 1a was carried out, the same process was more facile and the resulting zwitterionic compound reacted rapidly with another molecule of carbodiimide 6 to form the triazolo-spiro-imidazolidine 8 even at room temperature.This type of transformation is well known in the case of the reactions of carbenes with isocyanates or isothiocyanates 2,11 but not in the case of carbodiimides.Given the foregoing, aliphatic derivatives of carbodiimides should react even slower than alkylarylcarbodiimides.In fact, an aliphatic analogue of 6, dicyclohexylcarbodiimide, does not form stable products with carbene 1a unless the temperature exceeds 100 °C.Nevertheless, the more active imidazol-2-ylidenes react with carbodiimides to give zwitterionic compounds of type 7. 17  In order to explore the reactivity of carbene 1a with electrophiles other than carbodiimides, the reactions of this carbene with acetonitrile and diphenyldiazomethane were carried out.In both cases the reaction occurred rather rapidly at room temperature to afford 36% and 75% yields of cyanomethylazoline and azine 10, respectively.It should be noted that the related 1-ARKAT USA, Inc.
adamantyl-3,4-diarylsubstituted 1,2,4-triazol-5-ylidenes react with acetonitrile more slowly (at 100 °C for several hours or only slightly at room temperature for 1-2 days). 10,13According to our data 16,18 benzimidazol-2-ylidenes and aromatic-substituted imidazol-2-ylidenes undergo facile insertion reactions (even at room temperature) reminiscent of carbene 1a.Subsequently, Arduengo and co-workers have shown that 4,5-dihydroimidazol-2-ylidenes (but not 1,3diadamantylimidazol-2-ylidene) undergo C-H insertion reactions with acetonitrile. 19The reaction of the 4,4′-bridged bistriazol-5-ylidene with diphenyldiazomethane in toluene solution (in which it is only slightly soluble) proceeds at 50 °C for 10 h. 20The formation of the related azines from imidazol-2-ylidenes has also been described. 21he transformation 1→5 requires strictly anhydrous and oxygen-free conditions.Bubbling triplet oxygen into a THF solution of pure carbene 1a at ambient temperature results in the formation of triazolone 11a as the major product (isolated yield 58%) (Scheme 2).This result is both interesting and unusual because Denk and co-workers 22 noted that the related imidazol-2ylidenes are rather stable to oxygen.Moreover, the first triazolylidene of Enders 23 only reacts with oxygen in refluxing toluene after 24 h.A plausible explanation for the facile transformation of 1a with oxygen is that the reaction proceeds via a triplet-like transition state.Consistent with this proposal, semi-empirical PM-3 calculations reveal that the triplet state of 1a is strongly destabilized.
In the presence of moisture two major side products are formed, namely triazolones 11 and triazoles 2 (Scheme 3).The possible reason for this observation relates to the facile disproportionation of the intermediate 5-hydroxy-5H-triazoline 12 into the corresponding triazolone 11b and 5H-triazoline 13, followed by further decomposition of the latter to form isobutane and triazole 2c.The related thermal disproportionation 12→11 + 13 has been recognized earlier in the case of a benzimidazole series. 14

N
Both side products, the bromo-substituted compounds 11b and 2c, were isolated from the resulting reaction mixture in small quantities and characterized by mass spectrometry (11b, m/z [MH + ] 452; 2c, m/z [MH + ] 380).The related compound 13b was synthesized independently by the reduction of salt 3d with sodium borohydride in methanol solution.Refluxing 13b in toluene or xylene solution causes transformation to the triazole 2d due to intramolecular reduction of the tert-butyl group and isobutane elimination.

Conclusions
In summary, we have demonstrated a new autotransformation of stable carbenes 1→6→7→5 that relates to tandem transformations.This is the first observation of such a tandem process in a stable carbene series.The mechanism of this reaction involves an induced reaction due to the formation of the carbodiimides 6, followed by further interaction of the latter with carbene 1 to afford the zwitterionic intermediates 7 which are stabilized under the reaction conditions by isobutene elimination to form amidinotriazoles (7→ 5 + i-C 4 H 8 ).The first stage of the tandem reaction (1→6→7→5) probably proceeds via thermal transformation of the singlet carbenes 1 1 to the triplet triazolylidenes 1 3 which decompose rapidly to benzonitriles and carbodiimides (1 1 →1 3 →6→7→5).Semi-empirical (PM-3) calculations reveal that in a triplet state triazolylidene 1a undergoes decomposition to benzonitrile and carbodiimide.In this process, the N(1)-N(2) and C(3)-N(4) bonds are broken, while in the case of the related triphenylsubstituted 1,2,4-triazol-5-ylidene, only the C(3)-N(4) bond is ruptured.For the related tetrazol-5-ylidenes, the PM-3 method also predicts decomposition of the molecule into nitrogen and carbodiimide.In fact, tetrazol-5-ylidenes undergo facile in situ decomposition via this route to carbodiimides and nitrogen even at room temperature. 24The present 1,2,4-triazol-5-ylidene reaction is initiated in a similar fashion, but at significantly higher temperatures.

Experimental Section
General Procedures.All experiments with the 1,2,4-triazol-5-ylidenes 1a-d were carried out under an argon atmosphere.All solvents were dried by standard methods prior to use. 1 H and 13 C NMR chemical shifts are reported relative to tetramethylsilane (TMS, δ = 0.00) as the internal standard.Mass spectra were measured on an Agilent 1100 Series chromatomass spectrometer (APCI, 3 kV).The chromatography was carried out on a Zorbax SB Cl8 column with a 95.5% acetontrile mixture that contained 0.1% of formic acid.Thin-layer chromatography was ARKAT USA, Inc.
С NMR spectrum featured the characteristic resonances for the triazole ring carbon atoms C(1) and C(2) in the range δ 147.4 -150.4 ppm and signals for the phenylimino C(15) -N(5) atom (δ 151.8-152.8ppm) (see Fig. 2 for the atom numbering scheme).Also noteworthy are the chemical shifts of the ipso-carbon atoms, C(9)-N(1), of the N-aromatic quaternary atoms (δ 143.2-143.6 ppm).The C-amidine resonances for compounds 5a-d are estimated to be in the range δ 124.7 -125.7 ppm.The mass spectra of compounds 5a,c,d exhibit the molecular ions [M + ] or [MH +
C NMR spectra, the signals for the tert-butyl carbon atoms fall in the ranges δ 27.3 -29.5 and δ 57.3 -59.2 ppm, which are diagnostic for all the indicated compounds.The 13 C resonances for the C(3) atoms (δ 151.0, 144.2 and 152.4 ppm) and the C(5) atoms (δ 79.4,149.6 and 159.9 ppm) are characteristic for compounds 9,10, and 11a.The signals for the Ph 2 C atoms of azine 10 (153.4 ppm) were also detected.