Synthesis of novel 1-thia-5,9-diaza-spiro[5.5]undec-2-ene and its recyclization to 1,5,9-triaza-spiro[5.5]undec-2-ene and/or spiro(piperidine-4,2’-thieno[2,3-d ]pyrimidine)

An efficient and direct procedure for the synthesis of 1-thia-5,9-diaza-spiro[5.5]undec-2-ene has been described. The base-catalyzed recyclization of the latter has been studied. The structures of the products were proved by elemental analyses, IR, MS, 1 H-and 13 C-NMR spectroscopy.

Next, we moved on to study the alkylation of 3a using dimethyl sulfate, ethyl iodide, and benzyl chloride as alkylating agents under basic conditions (Scheme 2).The reaction proved to involve the sulfur atom, thus affording the S-alkylated derivatives 4-6 (Scheme 2).The structural assignments of compounds 4-6 were confirmed by their spectroscopic data.The distinction between the thiazine and pyrimidine structural types is clearly manifested in the 1 H-and 13 C-NMR spectra.For example, the 1 H NMR spectrum of 4 showed the absence of exocyclic NH proton, and in its 13 C NMR spectrum the resonance of the aminal carbon atom in compound 4 (δ 73.41) are shifted downfield from those of the thioaminal carbon atom in compound 3a.

Scheme 2
According to the literature survey, few examples of Dimroth rearrangements are known which involve the transformation of amino-1,3-thiazines to pyrimidinethiones. 21,35,36From this evidence, the mechanistic picture for the pyrimidine forming process emerged as shown in Scheme 3. Seemingly, a base causes proton abstraction from the nitrogen atom in position 5 and thiazine ring-opening to afford the intermediate A which possesses a thio-keto enolic equilibrium forming intermediate B, which allows free rotation around the single bond affording the E-diastereomer that could close to the pyrimidines 4, 5 and 6, respectively.

Scheme 3
In addition, formation of the pyrimidines 4 and 5 was further confirmed by an alternative synthesis.Thus, the reaction of 7a,b with 4-oxo-piperidine-1-carboxylic acid ethyl ester 2a in boiling ethanol, in the presence of catalytic amounts of p-toluenesulfonic acid (p-TSA) afforded 4 and/or 5 in excellent yields (Scheme 4).The identity of the products prepared in Scheme 4 with those obtained previously in Scheme 2 was confirmed by comparison of their IR and 1 H NMR spectra.

Scheme 4
Treatment of 3a with ethyl bromoacetate and/or bromoacetonitrile, in aq.KOH furnished the spiro-thienopyrimidine derivatives 9a,b (Scheme 5).The structures of 9a,b were established by their correct analyses and compatible spectroscopic data.The IR and 1 H-NMR spectra of 9a revealed the absence of the CN group, signals attributable to the exocyclic NH proton of 3a, and the presence of signal attributable to the NH2 protons at δ 6.85 ppm which exchange with D2O.Furthermore, the fragmentation patterns of the mass spectra of 9a and 9b show molecular ion peaks at m/z 458.70 (M + , 48.3%) and m/z 411.65 (M + , 89.36%), respectively, which are in good agreement with the assigned structure.The structures of 9a,b are rationalized in terms of the initial formation of the intermediate 8, which on subsequent intramolecular cyclization under the reaction conditions affords the final product .

Scheme 5
Similarly, compound 3b was reacted with alkylating reagents such as dimethyl sulfate and ethyl iodide under basic conditions to give the corresponding S-alkylated derivatives 10 and 11 (Scheme 6).

Scheme 6
The molecular formulae of compounds 10 and 11 are supported by elemental analyses and mass spectra that gave the expected molecular ion peaks and their corresponding fragmentation patterns.The IR as well as the 1 H NMR spectra agree with the proposed structures.The reaction of the spirothiazine 3b with benzyl chloride in EtOH in the presence of triethylamine did not afford the expected S-benzylated derivative, but rather the dibenzylated derivative 12 (Scheme 6).Both the mass spectrum and elemental analysis established the molecular formula of 12 as C36H34N4OS.The IR and 1 H-NMR spectra of 12 revealed the absence of NH group and signals attributable to the endo-and exo-cyclic NH protons of 12, respectively.Furthermore, the structure assigned for compound 12 was fully supported by their 13 C NMR.
The alkylation of 3b with ethyl bromoacetate in aq.KOH gave the spiro S-substituted thiopyrimidine 13 (Scheme 7), whose elemental analysis and spectral data are in good agreement with the proposed structure.The IR spectrum revealed the presence of CN group with strong absorption band at 2196, NH group at 3145 and CO (ester group) at 1698 cm -1 .The 1 H NMR of 13 revealed the presence of signals at δ = 3.70 and 8.17 attributable to the SCH2 and NH protons, respectively.Moreover the mass spectrum of 13 exhibited a molecular ion peak at m/z = 476.20 (M + , 52.54%).On the other hand, the alkylation of 3b with bromo-acetonitrile under the previous conditions gave the spiro-thienopyrimidine 13 (Scheme 7).Depending upon the spectroscopic data the structure of compound 14 is undoubtedly confirmed.Thus, the 1 H-NMR of 14 revealed the absence of signals attributable to the exocyclic NH proton of 3b, and the presence of signal attributable to the NH2 protons.The mass spectrum of 14 showed the molecular ion peak m/z = 429.60(M + , 65.59%) corresponding to the molecular formula C14H10N4OS.

Experimental Section
General.Melting points were measured with a Gallenkamp apparatus and are uncorrected.The reactions and purity were monitored by thin layer chromatography (TLC) on aluminum plates coated with silica gel with fluorescent indicator (Merck, 60 F254) using CHCl3 / CH3OH (10:1) as eluent.Infrared spectra were recorded on a Jasco FT/IR-450 Plus spectrophotometer.The NMR spectra were obtained on a JHA-LAA 400 WB-FT spectrometer at 400 MHz for 1 H-NMR, and 100 MHz 13 C, with CDCl3 and DMSO-d6 as solvent.Chemical shifts are quoted in δ and are referenced to TMS or the solvent signal.The mass spectra were recorded on a Trace GC 2000 / Finnegan Mat SSQ 7000 and Shimadzu GCMS-QP-1000EX mass spectrometer at 70 eV.Elemental analyses were measured with a Vario EL III CHNOS Elemental Analyzer, Germany, in the Microanalytical Center of Cairo University.Compounds 1, 37 7a, 38 and 7b, 21 were synthesized using the published procedures.