Synthesis of heteroaromatic 3,3 ′ -bridged biscarbenes of the 1,2,4-triazole series and their properties

The stable 3,3’-bridged biscarbenes, 1,4 - and 1,3-bis[1-alkyl-4-phenyl-1,2,4-triazol-5-yliden-3-yl]benzenes ( 5 а ,b,d ) and 1,3-bis[1-(1-adamantyl)-4-phenyl-1,2,4-triazol-5-yliden-3-yl]butane ( 5c ) have been prepared. Treatment of 5b with copper (I) chloride in tetrahydrofuran/acetonitrile solution and cobalt (II) chloride in acetonitrile or acetonitrile/toluene solution afforded the biscarbene copper (I) complex 8 . The reactions of 5d with diphenyldiazomethane and sulfur resulted in the novel bisthione 6 and bisazine ( 7 ) derivatives, respectively. The X-ray crystal structures of 5d, 8 were determined.


Results and Discussion
The syntheses of biscarbenes of the 1,2,4-triazole series were carried out in three steps: (1) the bis-1,2,4-triazoles 2а-с were obtained by ring transformations of the bis-1,3,4-oxadiazoles 1а-с with anilines; (2) subsequent quaternization of the 1,2,4-triazoles 2а-с with 1-bromoadamantane or tert-butyl iodide afforded the bis-1,2,4-triazolium salts 3а-d; (3) finally, the bis-1,2,4-triazol-5-ylidenes 5а-d were prepared by deprotonation of salts 3а-d by treatment with bases.The first stage of the process has already been described 7 and involves the ring transformation of arylenbis-1,3,4-oxadiazoles 1а,b and butylen-bis-1,3,4-oxadiazole 1с with aniline trifluoroacetate in оdichlorobenzene at 200 ºС thus affording bistriazoles 2a-с.In the absence of acids this reaction is slow and accompanied by contamination of the product with colored impurities.However, in the presence of trifluoroacetic acid the colored impurities are not observed and reaction yields of up to 95 % of the bistriazole 2а were obtained.The isolated yield of triazole 2b is lower (46 %) than that of 2a (95 %) due to washing of the product with aqueous alkalis.In the case of the ring transformation of 1,4-butylen-bis-1,3,4-oxadiazole with p-bromoaniline the yield of bistriazole 2с was markedly reduced (27 %).This is probably due to the various nucleophilic transformations of the system.Similar observations have been reported for aliphatic derivatives of 1,3,4-oxadiazoles. 8The use of aniline hydrochloride or hydrobromide gives similar results.However in this methodology it is the sublimation of the aniline salts that is responsible for decreased yields.In the present method the use of the polar solvent о-dichlorobenzene (2.50 D), was effective in terms of providing a high reaction rate due to azeotropic removal of water from the reaction mixture at the process temperature.
The second stage of the process is the quaternization of bistriazoles 2а-с by treatment with 1bromoadamantane, tert-butyl iodide, or benzyl chloride.These reactions proceed efficiently in acetic acid, 5,9 thus allowing decreased base-promoted elimination of hydrogen halide from the alkylating agent. 10he use of 1-adamantyl-or tert-butyl halides for the quaternization reaction serves two purposes.First, it is known that these substituents provide steric protection of the carbene center.2][13] In the present work it was observed that triazole quaternization with the indicated tertiary alkyl reagents resulted in the exclusive formation of the 1-isomeric salts.On the other hand, NMR studies indicate that primary alkylating reagents such as dimethylsulfate and benzyl chloride give mixtures of the isomeric 1-or 2-substituted salts in which the 1-isomers predominate.However, it was found that the benzyl substituted salt 3e contains mainly the 1-isomer after recrystallization.

Scheme 1
The compositions and structures of compounds 2а-с and 3а-d were established on the basis of elemental analyses and 1 Н NMR spectroscopy.Product purities were estimated by NMR spectroscopy and thin layer chromatography (TLC).The 1 Н NMR spectra of these compounds feature signals for the aromatic protons CHN in the range δ 8.3-9.0 ppm and the protons for the benzene nuclei resonate in the range δ 7.1-8.4ppm.It is interesting to note that the signals for the CHN protons of bistriazoles 2а,b are significantly downfield relative to those of the monotriazoles by ∆δ 0.5-0.7 ppm.This observation is presumably due to conjugation of the triazole and phenylene rings in the bistriazole molecules discussed above.Support for this conclusion stems from the weak influence of the triazole rings in bistriazole 2c with respect to the resonance of the CHN protons observed at δ 8.17 ppm.In the cases of compounds 3а-e the CHN proton signals also fall in the characteristic range of δ 10.4-10.8ppm.
2][13][14] Note, however, that 3e forms colored ylidic compounds and does not produce a carbene.In the case of biscarbene 5а, the procedure was modified in order to increase the reaction selectivity and enhance the yield.The reaction of potassium tert-butoxide with bistriazolium salt 3а in toluene solution (Procedure A) leads to high overall yields (up to 100 %) of unpurified product 5а that features significant quantities of impurities that are insoluble in aromatic solvents (up to 30 %).The use of potassium hexamethylsilazanide (Procedure B) affords carbene 5а in good yield (65 %) and is suitable for use for subsequent synthesis without additional purification.
However, the best result was achieved by conducting the deprotonation of salt 3а with potassium tert-butoxide in a toluene-methanol solvent mixture (Procedure C). 5,14 In this case the initially isolated products are methoxyazolines 4 which are formed by methanol addition to the carbenes.However, compounds 4 are readily converted into the corresponding carbenes by heating in vacuum.This approach is reminiscent of the Enders' method. 15However, in this case, namely in the presence of sodium methoxide and the absence of toluene, the reaction does not proceed to completion.Furthermore, the decomposition of the azoline in the present procedure is effected very easily and does not require several hours of heating in vacuo.In the present case the yield of biscarbene 5а is 85 % and the product purity is high.
The preparation of the isomeric biscarbene 1,3-bis(1-adamantyl-4-phenyl-1,2,4-triazol-5yliden-3-yl)benzene 5b from the corresponding salt by treatment with potassium tert-butoxide in toluene solution (Procedure А) results in a 64 % yield of a product that is contaminated with the corresponding bisazolium tert-butoxide.However, because triazolium salt 3b is considerably more soluble in organic solvents than 3a it seemed appropriate to employ a different method of deprotonation.Indeed, the use of sodium hydride in acetonitrile solution (Procedure D) 5,14 resulted in samples of the biscarbene that were precipitated from the reaction mixture.The ratio of the solubilities of salts 3a and 3b is close to that for the biscarbenes.However, in contrast to the p-isomer 5а, the m-phenylenbiscarbene 5b is not only more soluble in aromatic solvents, but also soluble in saturated hydrocarbons.Carbene 5d was also prepared by method D due to the higher solubility of the precursor salt 3d in acetonitrile.
Compound 5c was prepared in order to study the influence of the phenylene bridge on the stability of biscarbenes.In this case the carbene moieties are separated by an aliphatic bridge comprising four carbon atoms.Deprotonation of the precursor was effected by treatment with potassium tert-butoxide in toluene solution (Procedure А) and the desired product was isolated in 77 % yield.
The 1 Н NMR spectra of compounds 5а-d include the resonances for the adamantyl (5а-c), tert-butyl (5d) and aromatic protons.No signals were detected for the hydrolysis products of the carbenes (formyldiamines and azolium hydroxides) thus confirming the anhydrous nature of the reaction conditions.The adamantyl methylene resonances for the protons closest to the nitrogen atoms of carbenes 5а-c are downfield shifted (δ 2.57-2.62ppm) with respect to other signals for this group and even for bis-cation salts 3а-c (δ 2.24-2.29 ppm) that feature typical electron withdrawing ring systems.Similar chemical shift values have not been observed for other adamantyl proton signals of carbenes: they are typically upfield relative to those of the bis-cation salt resonances (∆δ 0.1-0.3ppm).Presumably, the adamantyl protons are deshielded because of their proximity to the carbene electron pair.A similar observation has been made in the case of monocarbenes of the 1,2,4-triazole series. 14The most important NMR spectral feature of biscarbenes 5а-d is the characteristic 13 C resonance of the carbene carbon, which is observed in the range δ 203-208 ppm.3][14] This trend is attributable to increased conjugation due to the presence of an aromatic bridge.The IR spectrum of biscarbene 5a provided no evidence for the presence of hydrolysis products.
Biscarbenes 5а-d are stable compounds that are unchanged upon storage for several months in the absence of moisture and oxygen.This distinguishes them from some other biscarbene systems that tend to undergo dimerization. 16In fact, crystalline samples of biscarbenes 5a-d undergo little change after several days of exposure to the atmosphere.
Crystals of biscarbene 5d suitable for X-ray diffraction study were grown from a 1:1 toluenetetrahydrofuran solution.To analyze the structure we used not only the metrical parameters of the molecule (bond lengths and angles) but also the bond orders calculated using the linear dependence of bond lengths and bond orders (p) in model compounds (ethane С-С, 1.534 А; ethylene C=C, 1.337 А; methylamine С-N, 1.474 А; methylenimine С=N, 1.300 А; hydrazine N-N, 1.449 А and azomethane N=N, 1.254 А) (Figure 1, Table 1) in a similar fashion to that described previously. 6For comparison of the X-ray data one mononuclear carbene 1-tert-butyl-3-phenyl-4-(4-bromophenyl)-1,2,4-triazol-5-ylidene А was also used, as described in reference 17.The molecular structure of 5d features an overall trans conformation and the phenylene link is twisted by 30° with respect to the triazole rings.The bond order between the carbene nucleus and the central phenylene link is р 1.310.The N(4)-phenyl nucleus is twisted by 59° thus decreasing the bond order to р 1.190.The inner angle at the carbene carbon atom (100.4°) is in agreement with the data for an analogous mononuclear carbene with a tert-butyl group. 17The С(5)-N(1) bond order in the triazole ring is 1.753 (cf., for the mononuclear analogue A, р is 1.799).The other cyclic bonds have bond orders that are similar to those for mononuclear analogues -С(5)-N(4) -1.511, С(3)-N(4) -1.523, multiple bond С(3)=N(2) 1.977 (for A -1.494, 1.546 and 1.966, respectively).similar to the mononuclear compound А, in bistriazolylidene 5d the cyclic bonds are significantly delocalized and the bond order of the С(5)-N(1) bond is indicative of an appreciable contribution of the ylidic resonance form of a triazolylidene ring.It should be noted that despite the almost identical twist angles of the phenylene group in mono-and biscarbenes with N-tert-butyl substituents, the spectral properties and chemical reactivities of these species differ appreciably.For example, the biscarbenes are distinctly less reactive toward electrophiles and more stable upon storage.
In order to evaluate the reactivity patterns of bistriazolylidenes, their reactions with sulfur (a known trap for carbenes), diphenyldiazomethane, and copper (I) salts were investigated.Bisthione 6 is formed easily and in 93 % yield upon treatment of carbene 5d with sulfur in toluene solution at 25 °С.The reaction of biscarbene 5d with diphenyldiazomethane results in exclusive formation of the yellow colored azine 7. Nucleophilic substitution of nitrogen in diazocompounds to form the corresponding bisdiphenylmethylenbisazolines was not observed.The interaction of biscarbene 5b with CuCl affords the corresponding biscarbene complex 8 (Scheme 3).The preparation of copper complexes of type 8 in acetonitrile solution is accompanied by the formation of unidentified green colored products, the formation of which is significantly decreased if the reaction is carried out in a 1:1 mixture of acetonitrile and THF.The carbene complex with CuI of type 8 was also isolated initially in almost quantitative yield.However, when attempts were made to recrystallize these compounds from polar, high boiling solvents (DMF, DMSO), they underwent complete transformation to dark-colored products.In the case of the copper chloride complex 8 the impurities can be completely separated by filtration through silica gel using a 10:1 mixture of chloroform and methanol.The compositions and structures of compounds 6-8 were established by elemental analysis, and 1 Н and 13 С NMR spectroscopy.The purities of the new compounds were estimated by 1 Н NMR spectroscopy and TLC.
The 1 Н NMR spectrum of thione 6 features the anticipated resonances for the aromatic and adamantyl protons and are downfield with respect to those for biscarbene 5d.The appropriate resonances for the aromatic and methyl protons of azine 7 were evident in the 1 Н NMR spectrum.The 1 Н NMR spectrum of complex 8 shows a weakened influence of the carbene carbon on the shielding of the adamantyl СН 2 group connected to a triazole ring (∆δ 0.23 ppm).The chemical shift is close to those of triazolium salts (δ 2.24-2.29 ppm).In the 13 С NMR spectrum of copper complex 8 the carbene resonance is upfield of that for carbene 5b (∆δ 31 ppm, up to 176 ppm) and falls within the typical range for metal carbene complexes.
Crystals of complex 8 suitable for single-crystal X-ray diffraction experiments were grown from acetonitrile.This study revealed a trans-oriented molecular structure for 8 (Figure 2, Table 2).The triazole ring retains its polarity.For example, the C-N-N-C angle is 0.7 o while that for the second nucleus and previously isolated mononuclear triazole carbenes is -0.1 o . 17The Cu-Cl bond distance in complex 8 (2.10Å) is shorter than that in crystalline copper chloride (2.34 Å), 18 thus evidencing more covalent character for this bond than in the case of complex 8.The Cu-Cl bond distance in 8 is very similar to that in the tetrahydropyrimidin-2-ylidene complex 9.The Сu-C(5) bond in complex 8 is shorter (1.87-1.88Å) than those in the corresponding tetrahydropyrimidin-2-ylidene (1.91 Å) and N-oxazolinylimidazol-2-ylidene 10 (1.90 Å) complexes. 20This observation can be attributed to the greater donor strength of the triazole However, such a suggestion is not in accord with the accepted view of the donor ability of 1,2,4-triazol-5-ylidenes in comparison with those of imidazol-2-ylidenes and especially acyclic carbenes and tetrahydropyrimidines. 19The explanation for this apparent contradiction might be the increased bond order of the Cu-C(5) bond in complex 8 due to back donation of the metal to the heterocyclic nucleus.
Experimental Section General Procedures.All experiments with biscarbenes 5a-d were carried out under a nitrogen or 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 internal standard.IR spectra were measured as Nujol mulls and thin-layer chromatography was performed on silica gel with chloroform or a 10:1 mixture of chloroform and methanol as eluent, followed by 1,4-Bis(1-adamantyl-4-phenyl-1,2,4-triazol-5-yliden-3-yl)benzene (5а).(а) A mixture of the anhydrous salt 3а (1.0 g, 1.25 mmol) and potassium tert-butoxide (0.28 g (2.50 mmol) in anhydrous methanol (10 mL) was stirred under an inert atmosphere for 15 min, then toluene (10 mL) was then added and the resulting mixture was stirred for 15 min.The precipitate that formed was filtered off and the filtrate was evaporated in vacuo.The resulting product was dried for 40 min at 70-80 ºС (0.79 g) and purified by extraction with anhydrous toluene (65 mL).After removing the solvent 0.67 g (85 %) of biscarbene 5а was obtained and recrystallized from toluene solution.mp 208-210 °С (toluene). 1 (b) A mixture of anhydrous salt 3а (0.3 g, 0.36 mmol) and potassium tert-butoxide (0.08 g, 0.72 mmol) was stirred in anhydrous toluene (5 mL) under a nitrogen atmosphere for 1 h.The inorganic salt was filtered off and the filtrate was evaporated in vacuo.The resulting product was triturated with petroleum ether (2 mL), filtered off, dried, and purified (0.16 g) according to Procedure (а).This method resulted in the isolation of 0.13 g (57 % yield) of 5а.
(c) A 15 % solution of potassium hexamethyldisilazanide (1.67 g, 1.26 mmol) was added to a dispersion of salt 3а (0.5 g, 0.63 mmol) in 10 mL of a 50/50 mixture of anhydrous toluene and tetrahydrofuran and stirred under a nitrogen atmosphere for 1 h.The inorganic salt was filtered off and the filtrate was evaporated in vacuo.The resulting product was stirred with petroleum ether (2 mL), filtered off and dried.The product (0.26 g, 65 %) is suitable for further synthetic use without additional purification.1,3-Bis(1-adamantyl-4-phenyl-1,2,4-triazol-5-yliden-3-yl)benzene (5b).(а) A mixture of anhydrous salt 3b (1 g, 1.2 mmol) and potassium tert-butoxide (0.27 g, 2.4 mmol) in toluene solution (12 mL) was stirred under a nitrogen atmosphere for 1 h.The inorganic precipitate was filtered off and the filtrate was evaporated in vacuo.The resulting product was triturated with petroleum ether (2×3 mL), filtered off and dried.Yield of biscarbene 5b 0.49 g (64 %).mp 178-180 °С (acetonitrile).(b) A solution of the anhydrous salt 3b (0.5 g, 0.6 mmol) in acetonitrile (8 mL) was cooled to -45 ºС, then sodium hydride (0.03 g (1.2 mmol) was added and the reaction mixture was heated to room temperature.After completion of the hydrogen evolution the reaction mixture was evaporated in vacuo and the resulting residue was extracted with toluene (5 mL).The toluene was evaporated under reduced pressure and the product was stirred with petroleum ether (2 mL) and dried.Yield 0.26 g (68 %) of biscarbene 5b.