A Novel Ring Expansion of Pyrimidines to 1 , 2 , 4-Triazepines

A base-promoted ring expansion of 3-amino-4-hydroxyhexahydropyrimidine-2-thiones into 2,4,5,6tetrahydro-3H-1,2,4-triazepine-3-thiones has been developed. Experimental data and DFT calculations showed that the reaction proceeded through fast formation of intermediate acyclic isomers of pyrimidines followed by their slow cyclization into triazepines. The starting hydroxypyrimidines were prepared by reaction of α,β-unsaturated ketones or β-alkoxy ketones with HNCS followed by treatment of the obtained β-isothiocyanato ketones with hydrazine.

It was demonstrated that isothiocyanate 1 reacts with hydrazine hydrate under heating in water in the presence of mineral acid to yield pyrimidine derivative 2 (Scheme 1). 10 Later it was reported that the product of this reaction is not the pyrimidine 2 but triazepine 3 which can also be prepared by reaction of isothiocyanate 1 with hydrazine hydrate in refluxing benzene using a Dean-Stark trap.5e In contrast, under the given conditions 5e,10 we obtained 3-aminopyrimidine-2-thione 4 as the major compound, and the amount of triazepinethione 3 did not exceed 5% and 15%, respectively (according to 1 H NMR spectra of the isolated crude products).This indicates that rapid cyclization of the intermediate thiosemicarbazide 5 into pyrimidine derivative 4 is followed by its slow transformation into triazepinethione 3 via ring expansion with nitrogen insertion.Therefore, results of the reaction of isothiocyanato ketones with hydrazines do not appear to be so clear as reported previously. 2,5,10Indeed, the initially formed 4-(γ-oxoalkyl)thiosemicarbazides (e.g., 5) can undergo various transformations, including cyclization into 1,2,4-triazepine-3-thiones, derivatives of pyrimidine, fused heterocyclic systems, macrocyclic compounds, etc. 11 Based on the reported data and our experience, we hypothesized that 3-amino-4hydroxyhexahydropyrimidine-2-thiones obtained by the reaction of β-isothiocyanato ketones with hydrazines can serve as starting compounds for the preparation of 2,4,5,6-tetrahydro-3H-1,2,4triazepine-3-thiones.Here, we report the synthesis of 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones by base-promoted ring expansion of 3-amino-4-hydroxyhexahydropyrimidine-2-thiones, a plausible pathway of this transformation based on experimental data and DFT calculations, and oxidative transformation of the obtained 1,2,4-triazepine-3-thiones into the corresponding 3-oxo derivatives.Two preparative procedures for the synthesis of β-isothiocyanato ketones are also reported.

Results and discussion
Preparation of β-isothiocyanato aldehydes and ketones was the first step of the triazepine synthesis.
These isothiocyanates have been the focus of considerable attention since 1946, 12 and they have found a broad application as versatile precursors in organic synthesis. 1315b Therefore, in each particular case, careful optimization of reaction conditions should be carried out.As a consequence it is not surprising that the number of β-isothiocyanato aldehydes and ketones described still remains somewhat limited.For the present study, isothiocyanates 6a-j were chosen as a starting material (Scheme 2, Table 1).Among them, only compounds 6a,j could be considered to be synthetically available.As for other isothiocyanates, their synthesis was either not reported previously (for 6d,h,i), 17 or they were obtained only as crude products (for 6e-g), 5a,18,19 or procedures for their preparation were far from optimal (for 6b,c).15c,20 Two alternative methods were used for the synthesis of starting isothiocyanates 6a-j.The first method was based on the addition of HNCS to unsaturated carbonyl compounds 7a-j, and the second was our original method involving the reaction of HNCS with β-alkoxy ketones 8a-d (Scheme 2).

Scheme 2. Synthesis of β-isothiocyanato carbonyl compounds 6a-j.
β-Alkoxy ketones 8a-d were prepared by directed aldol type condensation of TMS ethers of acetone, cyclopentanone, or cyclohexanone with acetone dimethyl acetal or acetaldehyde diethyl acetal in the presence of ZnCl 2 in AcOEt. 21During the reaction and vacuum distillation, β-alkoxy ketones 8ac partly converted into the corresponding unsaturated ketones 7b,d,h.Compounds 6a-j were synthesized by reacting 7a-j, 8d or mixtures of 7b,d,h and 8a-c with NH 4 SCN in the presence of H 2 SO 4 in water.The ratio of the reagents, the reaction temperature and time were optimized to achieve maximum conversion of starting compounds (92-100% according to 1 H NMR spectra of the crude products) (Table 1).Under improved reaction conditions mesityl oxide (7a) reacted with HNCS (1.05 equiv.)for 15 min upon heating at 70-80 °C to give isothiocyanate 6a in 75% isolated yield (Table 1, entry 1).
Isothiocyanato ketones 6b-e,h,i were prepared using a greater excess of HNCS (1.96-3.01equiv.)and heating at 60 °C for 3-7 hours (entries 2-5, 8, and 9).The same temperature was used for the preparation of isothiocyanate 6g from ketone 7g (entry 7).In contrast, the addition of HNCS to ketone 7f smoothly proceeded at 5 °C for 25 h (entry 6).The amount of isothiocyanate 6f in the isolated crude product significantly decreased within the reaction temperature range of 20-90 °C ( 1 H NMR spectroscopic data).Mild reaction conditions were applied for the synthesis of isothiocyanate 6j from aldehyde 7j (entry 10).Compounds 6c,d,g,h with two stereocenters formed as diastereomeric mixtures (Table 1).The isothiocyanates 6a-j obtained were purified by vacuum distillation.Partial elimination of HNCS proceeded during distillation of 6d,e,f,h to give an admixture of the corresponding unsaturated ketone 7d,e,f,h (3-21%) in the resulting product.The amount of this admixture was taken into account in the following synthetic step.
The reaction between isothiocyanates 6a-j and hydrazine hydrate (1 equiv.)readily proceeded in MeCN or EtOH at room temperature to give the corresponding 3-amino-4-hydroxyhexahydropyrimidine-2-thiones 10a-j in 74-97% yields (Scheme 3, Table 2) via intermediate formation of 4-(γoxoalkyl)thiosemicarbazides 9a-j.Cyclization of the latter with participation of the amino group was not observed.Scheme 3. Reaction β-isothiocyanato carbonyl compounds 6a-j with hydrazine.Reaction of 6b-j with hydrazine afforded pyrimidines as mixtures of two (for 10b,e,f,i,j) or four diastereomers (for 10c,d,g,h).This reaction proceeded under thermodynamic control, which was confirmed by data in entries 3 and 4, and by the presence of acyclic isomers 9b-d,g along with pyrimidines 10b-d,g (entries 2-5, 8) in the isolated products.
Pyrimidines 10a-j were converted into the corresponding 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3thiones 11a-j under the action of bases (Scheme 4).Table 3 shows selected experimental data for this transformation.Scheme 4. Base-promoted ring expansion of pyrimidines 10a-j into triazepines 11a-j.a The crude products obtained by the reaction of 6a-j with N2H4 were used (see Table 2).b Level of conversion according to 1 H NMR spectroscopy of the crude product.c With considerable amount of impurities (about 55 mol%).d With considerable amount of impurities (about 70 mol%).e With considerable amount of impurities (about 66 mol%).f A mixture of 12a (R 1 = H, two isomers, 56:27) and 13a (R 1 = H) in a ratio of 83:17.g Plus 4 mol% of a mixture of 12b and 13b (R 1 = Me).h Plus 5 mol% of a mixture of 12b and 13b (R 1 = Me).i A mixture of 12b and 13b (R 1 = Me) in a ratio of 61:39.j A complex mixture of unidentified products.
Monocyclic pyrimidines 10a-c afforded triazepines 11a-c in 78-93% yields after treatment with aqueous NaOH (0.74-1 equiv.) at room temperature (entries 1-3).Transformation of bicyclic pyrimidines 10d-g into triazepines 11d-g did not proceed under these conditions (entry 10).The use of alcoholic KOH (2.49-2.51equiv.)and heating the reaction mixture at 40 °C for 4 h led to smooth formation of triazepines 11d-g (entries 4-6, 8).For these starting compounds the reaction rate decreased with a decrease in temperature (entry 6 vs entry 7, and entry 8 vs entry 9), and reflux of the reaction mixture led to formation of a considerable amount of impurities (entry 12).No reaction proceeded with pyrimidine 10g under the action of DBU in MeCN at room temperature (entry 11).Transformation of anion A into the anion of acyclic form D proceeds via the transition state TS with low activation energy (electronic energy 0.5 kcal/mol in EtOH, the Gibbs free energy ≈0 kcal/mol in EtOH, 298 K and 1 atm).Further detailed calculations using the OH-anion as a base showed that the complex of anion A with H 2 O obtained after deprotonation of 10a with hydroxide undergoes N3-C4 bond cleavage with an activation barrier of ∆G = 2.4 kcal/mol (EtOH, 298 K, 1 atm) to give the complex of anion D with H 2 O.This reaction proceeds with a ∆G value of -1.1 kcal/mol.The IRC analysis demonstrated that the found transition state connects the desired minima.Anion D after protonation followed by cyclization of the obtained thiosemicarbazide 9a into triazepine 14 and dehydration gives the target product 11a.Formation of triazepine 11a from pyrimidine 10a is a thermodynamically favorable process with ∆G = -12 kcal/mol (EtOH, 298 K, 1 atm).
We suppose that the base-promoted transformation of other pyrimidines 10b-i into the corresponding triazepines 11b-i proceeds via acyclic isomers 9b-i analogously, as described for 10a.
Although the acyclic isomers 9a-i readily form from pyrimidines 10a-i, their conversion into 14a-i proceeding with participation of the most nucleophilic nitrogen of the thiosemicarbazide moiety 22 seems to be slow and strongly dependent on the structure of the starting compound (Table 3).This explains the formation of side products from 10j rather then triazepine 11j, since the aldehyde group in the intermediate acyclic form 9j is highly reactive under strongly basic conditions.

Conclusion
An efficient synthesis of the rare heterocyclic scaffold, 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thione has been developed.The key step of the synthesis is the ring expansion of 3-amino-4-hydroxyhexahydropyrimidine-2-thiones under the action of bases.The proposed reaction pathway based on experimental data and DFT calculations included fast formation of intermediate acyclic isomers followed by their slow cyclization into triazepines.Starting hydroxypyrimidines were prepared by reaction of α,β-unsaturated ketones or β-alkoxy ketones with thiocyanic acid followed by treatment of the obtained β-isothiocyanato ketones with hydrazine.3-Oxo-analogs were readily obtained from triazepine-3-thiones by oxidation with H 2 O 2 .Since various β-alkoxy ketones can be prepared using directed aldol condensation of TMS ethers of ketones and acetals of carbonyl compounds, a large variety of triazepines can be obtained and subsequently modified.We believe that this methodology will be helpful for further research into the chemistry and applications of 1,2,4-triazepines.

Table 1 .
Optimized reaction conditions for the synthesis of β-isothiocyanato carbonyl compounds 6a-j a b NH4SCN/H2SO4/substrate molar ratio.c Bath temperature.d Isolated yield (after vacuum distillation).e After vacuum distillation.