Chemoselectivity of Multicomponent Condensations of Barbituric Acids, 5-Aminopyrazoles, and Aldehydes

Abstract

Multicomponent cyclocondensations between 5-aminopyrazoles, barbituric acids, and aromatic aldehydes under conventional thermal heating, microwave irradiation, or ultrasonic irradiation were studied and the temperature regime was found to be the main factor in controlling their chemoselectivity. At high temperatures the starting materials react in two different ways yielding pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidines or their dihydro analogues depending on the nature of the N-substituent in the 5-aminopyrazole. Treatment at room temperature results in a new four-component reaction giving previously undisclosed heterocyclic compounds, 4,6-diaryl-1,4,6,7-tetrahydro-2′H-spiro[pyrazolo[3,4-b]pyridine-5,5′-pyrimidine]s. Facile multipurpose three-component selective procedures to new spiroheterocycles are proposed.

The efficient synthesis of organic compounds by an ‘ideal procedure’ [¹] is one of the most important objectives in modern synthetic chemistry for drug discovery and related fields. Organic reactions should preferably be facile and fast and the resulting products should be easily and rapidly purified. Multicomponent reactions [²] and the application of ‘non-classical’ conditions, like controlled microwave [³] and ultrasonic [4] irradiation, are powerful tools in modern chemistry for the optimization of reactions and the efficient preparation of new target compounds. The use of these methods and their combinations in high-throughput organic synthesis has become particularly popular within the last fifteen years and numerous examples of such condensations for the construction of heterocycles with interesting properties have been reported in the literature. [²-4]

The importance of azolopyrimidines in medicinal chemistry is widely known: many of these fused nitrogen heterocycles are known as cardiovascular vasodilators, calcium channel blocking agents, and potassium channel inhibitors and openers. [5] An interesting class of such heterocycles is the azolopyridopyrimidines, which possess antimycobacterial, fungicidal, anticancer, and antihistamic activities and they are effective as central analgetics and for the treatment of insomnia. [6] Some derivatives of pyrazolopyridines have been also found to be useful in agriculture [7] and for coloring wool, silk, and polyamides. [8]

A facile and widespread synthetic approach to azolopyridines and pyrimidines is the multicomponent cyclocondensation of aminoazoles with CH-acids and carbonyl compounds, which sometimes can lead to the formation of several different reaction products; [9] their selectivity may be efficiently tuned by application of microwave and ultrasonic irradiation. [9e] [h] [i] However, the multicomponent synthesis of pyrazolopyridopyrimidines involving barbituric acid as a building block has not been described in the literature and only unsuccessful attempts at similar condensations have been communicated. [¹0] The usual way to pyrazolopyridopyrimidines is by the modification of vicinal aminocarbonitriles or aminoamides of azolopyridines, obtained by three-component reaction of aminoazole, aldehyde, and malononitrile or cyanoacetamide (Scheme 1). [¹¹] This method allows the synthesis of diverse types of the target heterocycles, but cannot be conducted as an efficient one-pot procedure. Another way includes reaction of 5-aminopyrazole-4-carbaldehydes with active methylene compounds, for example barbituric acids and cyclic 1,3-diketones, and leads to pyrazolopyridopyrimidines in high yields. [¹²] However, this route does not give the possibility of introducing substituents into the pyridine ring (Scheme 1).

Four-component condensations involving two equivalents of barbituric acid and one equivalent of aldehyde and ammonia leading to the formation of dihydropyridine ring are also known. [¹³]

Therefore, in the present work the multicomponent reactions of 5-aminopyrazoles 1, barbituric acids 2, and aromatic aldehydes 3 were studied under conventional heating, microwave irradiation, or ultrasonic irradiation at various temperatures. It was established that the three-component reaction of 5-amino-3-methyl-1-phenyl-1H-pyrazole (1a) with barbituric acids 2a,b and aldehydes 3a-h in boiling N,N-dimethylformamide for 30 minutes gave heteroaromatized 4-arylpyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidines 4a-l (Scheme 2, Table 1). The work-up procedure was simple and consisted of the addition of ethanol to the reaction mixture, filtration, and drying on air at room temperature, which allowed the target heterocycles 4a-l to be obtained in 50-95% yields with purity ˜95% according to ^¹H NMR.

From the other hand, it was unexpectedly found that refluxing of the equimolar mixture of N-unsubstituted 3-methyl- and 3-phenyl-5-aminopyrazoles 1d,e with barbituric acids 2a-c and aromatic aldehydes 3a-d,f-h,j in N,N-dimethylformamide for 30 minutes after an identical work up procedure led to 4-aryl-4,9-dihydropyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidines 5a-i in 50-90% yields (Scheme 2, Table 1). It should be noted that in case of compound 5b impurities of the corresponding hetero­aromatized heterocycle (˜5%) were also observed in the ^¹H NMR spectrum.

As the possible reason for the different reaction products in the case of aminoazoles 1a and 1d,e, we considered the influence of the N-phenyl substituent which enlarges the electron-donor properties of the aminoazole moiety and this can result in easier oxidation of the pyridine ring. The multicomponent reactions involving barbituric acid 2a, aldehyde 3g, and 5-amino-3-methyl-1-(4-nitrophenyl)-1H-pyrazole (1b), containing a nitrophenyl electron-withdrawing substituent, however, also led to oxidized heterocycle 4j. The reaction with participation of 5-amino-1,3-dimethyl-1H-pyrazole (1c), barbituric acids 2a,c, and aldehydes 3e,i gave the same result, compounds 4k and 4l were the sole isolated products after cooling and addition of ethanol to the reaction mixture.

Application of controlled microwave irradiation (temperatures from 150 to 190 ˚C) to carry out multicomponent reaction involving N-unsubstituted pyrazoles 1d,e did not give positive results, as it was expected, and led to complicated mixtures of several inseparable products. However, using the microwave field to promote the reaction of 5-aminopyrazoles 1a-c with barbituric acids and aldehydes was successful. It was established that three-component reactions of aromatic aldehydes 3a-i and barbituric acids 2a-c with aminopyrazoles 1a-c can be efficiently carried out under microwave irradiation in ethanol instead of N,N-dimethylformamide at 170 ˚C for five minutes. The most preferable microwave-assisted procedure for the synthesis of pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidines 4, from the viewpoint of yields and purity of the target compounds. consisted of the treatment of the starting building blocks in N,N-dimethylformamide under microwave irradiation at 190 ˚C for three minutes.

Surprisingly, it was observed that the multicomponent reaction involving 4-(methylsulfanyl)benzaldehyde (3b), 5-amino-3-methyl-1-phenyl-1H-pyrazole (1a), and barbituric acid 2a in boiling N,N-dimethylformamide sometimes passed in an unusual manner yielding, according to ^¹H NMR and mass spectra, hitherto undisclosed 3-methyl-4,6-bis[4-(methylsulfanyl)phenyl]-1-phenyl-1,4,6,7-tetrahydro-2′H-spiro[pyrazolo[3,4-b]pyridine-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione (6a).

Taking into account our previous results in tuning the chemoselectivity of multicomponent reactions with participation of similar starting compounds by application of high-temperature microwave-assisted and low-temperature ultrasonic-promoted procedures [9e] [h] [i] we tried to carry out this four-component cyclocondensation under sonication at room temperature. It was found that treatment of two equivalent of aromatic aldehyde 3b,e,g with one equivalent of barbituric acid 2a-c and aminopyrazoles 1a,d in N,N-dimethylformamide in ultrasonic bath for three hours yielded spiro compounds 6a-f in 63-98% yields (Method A, Scheme 3, Table 2).

It was additionally established that simple intensive stirring of the same starting compounds in N,N-dimethyl­formamide at room temperature with magnetic stirring for 2-3 hours also allowed the target spiroheterocycles 6a-f to be obtained in lower yields. It is interesting that a recent report [9h] found that multicomponent condensations of 5-aminopyrazoles with cyclic 1,3-diketones and aldehydes under ultrasonic irradiation at room temperature yielded Biginelli-type dihydropyrimidines, which were not observed in our case. On the other hand, the formation of similar spiro compounds was described for the four-component treatment of barbituric acid, urea, and aldehydes. [¹4]

A main disadvantage of the new four-component reaction is the impossibility of introducing two different substituents R⁴ in positions 4 and 6. To avoid this limitation we developed a two-component procedure consisted of the reaction of arylidenebarbituric acids 7a,b and azometh­ines 8a,b; treatment of these compounds in N,N-dimethylformamide under sonication for three hours yielded spiroheterocycles 6g,h (Method B, Scheme 3, Table 2).

However, this method requires the preliminary synthesis of two starting compounds (6 and 7) and this makes the procedure less efficient and facile. Taking into account such inconveniences, two additional three-component synthetic pathways to target compounds 6 were elaborated.

Heterocycles 6a,d-h were obtained by treatment of azomethines 8a-e with barbituric acids 2a-c and corresponding aromatic aldehydes 3a,b,g,e at room temperature under sonication or simple stirring of the reaction mixture for three hours in 55-70% yields (Method C, Scheme 3, Table 2). The most convenient and effective procedure for the synthesis spiro[pyrazolo[3,4-b]pyridine-5,5′-pyrimidine]s 6 consists of the three-component reaction of arylidenebarbituric acids 7a-e, 5-aminopyrazoles 1a,d,e, and aldehydes 3b,e,g under ultrasonic irradiation or with magnetic stirring at ambient conditions (Method D, Scheme 3, Table 2).

It should be noted that in Methods B and C if the reaction mixture is refluxed, instead of ultrasonication or stirring at room temperature, this leads to decomposition of azo­methines 8 and formation of two isomeric products with reverse location of the R⁴ and R⁵ substituents (see result of X-ray analysis for compound 6h).

In addition, it was established that compounds 6a-h under both refluxing in boiling N,N-dimethylformamide and microwave­ irradiation at 150-180 ˚C could not be rearranged into pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidines 4 or 5 and only numerous products of decomposition were found after the above-mentioned treatments.

The structures of heterocycles of type 4, 5, and 6 were established by elemental analyses in combination with MS and NMR spectroscopic data and X-ray diffraction analysis. The ^¹H NMR spectra of pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidines 4a-l are very simple and exhibit the signals of pyrimidine NH and terminal functional groups as well as of aryl rings. However, even together with information obtained from MS and ^¹³C NMR spectra these data did not give structure proof of the compounds synthesized. Finally X-ray diffraction analysis carried out for heterocycle 4a showed that it has a structure of 4-(4-ethylphenyl)-3-methyl­-1-phenyl-1H-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyr­imidine-5,7(6H,8H)-dione (Figure 1).

^¹H NMR spectra of heterocyclic compounds 5a-i together with signals of functional groups and aromatic rings contain two additional singlets at ca. δ = 5 and 11-12 assigned to methylene and amino groups of dihydropyridine moiety, respectively.

MS spectra and elemental analysis of compounds 6a-h showed that these heterocycles contain fragments of two molecules of aromatic aldehyde, one pyrimidine and one pyrazole ring. ^¹H NMR spectra exhibit the following signals: singlets of methylene protons and amino group of tetrahydropyridine ring at δ = ˜4.8, 4.9, and 6.0-6.5, respectively, pyrimidine NH singlets at δ = 10-12 (for compounds 6a-d,g), multiplets of aromatic rings, and necessary signals of other functional groups. ^¹³C NMR spectra of other signals contain a signal for the spiro-carbon at δ = ca. 65. All this data allowed us to suggest the spiroheterocyclic structure for compounds 6a-h. Finally, this structure was proved by X-ray diffraction data obtained for crystal of 6h obtained in boiling N,N-dimethylformamide (Figure 2).

In summary, the article describes the development of chemoselective cyclocondensations based on multicomponent treatment between 5-aminopyrazoles, barbituric acids, and aromatic aldehydes. It was established that temperature was the main factor in controlling the direction of the reaction studied. Under reflux or microwave irradiation at high temperatures (170-190 ˚C) the starting materials react in two different ways, in the case of N-substituted aminopyrazoles the reaction yields pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidines or their dihydro analogues when the N-substituent is absent. Sonication of the same reaction mixture or simple stirring at room temperature leads to a new four-component reaction yielding previously undisclosed heterocyclic compounds, 4,6-diaryl­-1,4,6,7-tetrahydro-2′H-spiro[pyrazolo[3,4-b]pyridine-5,5′-pyrimidine]s.

Melting points were obtained on a standard melting point apparatus in open capillary tubes. The ^¹H and ^¹³C NMR spectra were recorded in DMSO-d ₆ at 400 and 200 MHz (100 and 50 MHz for ^¹³C) on Jeol Lambda 400 and Varian Mercury VX-200 spectrometers. LR-MS were measured on a GC-MS Varian 1200L (ionizing voltage 70 eV). Elemental analysis was made on a EuroVector EA-3000. TLC analyses were performed on pre-coated (silica gel 60 HF₂₅₄) plates.

Sonication was carried out with help of standard ultrasonic bath producing irradiation at 44.2 kHz in round-bottom flasks equipped with a condenser.

Microwave experiments were performed using the Emrys^TM Creator­ EXP and Emrys^TM Initiator reactors from Biotage AB (Uppsala, Sweden) possessing a single-mode microwave cavity producing controlled irradiation at 2.45 GHz. Experiments were carried out in sealed microwave process vials using high absorbance level settings and IR temperature monitoring. Reaction times reflect irradiation times at the set reaction temperature (fixed hold times).

All solvents and chemicals were obtained from standard commercial vendors and were used without any further purification.

The synthesis of the starting 5-aminopyrazoles 1a-e were carried out by the described procedures. [¹5] Arylidenebarbituric acids 7a-e and Schiff bases 8a-e obtained according known methods. [¹6] [¹7]

X-ray Diffraction Analysis of Compounds 4a and 6h

The colorless crystals of 4a 2 (C₂₃H₁₉N₅O₂)˙C₃H₇NO˙C₆H₆O) are triclinic. At -173 K, a = 11.522(6), b = 13.364(8), c = 16.369(4) Å, α = 79.58(4)˚, β = 84.30(4)˚, γ = 63.27(6)˚, V = 2214(2) Å^³, Mr = 914.03, Z = 2, space group P1, d _calc = 1.371 g/m^³, µ (MoKα) = 0.093 mm^-¹, F(000) = 964. Intensities of 13853 reflections (7323 independent, R _int = 0.037) were measured on the ‘Xcalibur-3’ diffractometer (graphite monochromated MoKα radiation, CCD detector, ω-scanning, 2Θ_max = 50˚).

The colorless crystals of 6h (C₃₂H₃₁N₅O₄S) are triclinic. At 293 K, a = 8.180(1), b = 10.823(2), c = 17.503(3) Å, α = 107.23(1)˚, β = 94.75(1)˚, γ = 96.92(1)˚, V = 1457.7(4) Å^³, Mr = 581.68, Z = 2, space group P1, d _calc = 1.325 g/m^³, µ (MoKα) = 0.157 mm^-¹, F(000) = 612. Intensities of 9458 reflections (4877 independent, R _int = 0.032) were measured on the ‘Xcalibur-3’ diffractometer (graphite monochromated MoKα radiation, CCD detector, ω-scanning, 2Θ_max = 50˚).

The structures were solved by direct method using SHELXTL package. [¹8] The restrains for the bond lengths (Csp^³-Csp^³ 1.54 Å, C_Ar-O 1.37 Å, Csp^³-O 1.42 Å, C_Ar-S 1.77 Å, Csp^³-S 1.79 Å) in the disordered fragments were applied in the refinement of the structures. Positions of the hydrogen atoms were located from electron density difference maps and refined by ‘riding’ model with U _iso = nU _eq of the carrier atom (n = 1.5 for methyl group and n = 1.2 for other hydrogen atoms). The hydrogen atom of the structure 6h participating in the formation of the hydrogen bond was refined in isotropic approximation.

Full-matrix least-squares refinement of the structures against F2 in anisotropic approximation for non-hydrogen atoms using 7155 (4a), 4824 (6h) reflections was converged to: wR ₂ = 0.081 (R ₁ = 0.042 for 2690 reflections with F > 4σ(F), S = 0.708) for structure 4a and wR ₂ = 0.194 (R ₁ = 0.066 for 2842 reflections with F > 4σ(F), S = 0.926) for structure 6h. [¹9]

4-Aryl-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidines 4a-l; General Procedure

A mixture of 5-aminopyrazole 1a-c (1.30 mmol, 1 equiv), barbituric acid 2a-c (1.30 mmol, 1 equiv), and aromatic aldehyde 3a-i (1.3 mmol, 1 equiv) in DMF (2 mL), contained in a round-bottom flask equipped with condenser, was refluxed for 30 min. The mixture was cooled and EtOH (20 mL) was added. The mixture was allowed to stand and then filtered to give a solid product that was washed with EtOH and dried on air at r.t.

4-Aryl-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidines 4a-l; General Procedure for Microwave-Assisted Reactions

A mixture of 5-aminopyrazole 1a-c (1.30 mmol, 1 equiv), barbituric acid 2a-c (1.30 mmol, 1 equiv), and aromatic aldehyde 3a-i (1.3 mmol, 1 equiv) in DMF (2 mL), contained in a sealed microwave vial, was heated in a single mode microwave reactor at 190 ˚C for 3 min with magnetic stirring. The mixture was cooled to r.t. by compressed air and EtOH (20 mL) was added. The mixture was allowed to stand and then filtered to give a solid product which was washed with EtOH and dried on air at r.t.

The reaction was also carried out in EtOH (2 mL) at 150 ˚C for 5 min. In this case the precipitate formed was filtered after cooling of the mixture without addition of any other solvent.

4-(4-Ethylphenyl)-3-methyl-1-phenyl-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidine-5,7(6 H ,8 H )-dione (4a)

Colorless solid; mp >300 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.25 (t, J = 7.5 Hz, 3 H, CH₃), 1.70 (s, 3 H, CH₃), 2.69 (q, J = 7.5 Hz, 2 H, CH₃), 7.17-8.24 (m, 9 H_arom), 11.28 (s, 2 H, NH).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 161.8, 153.2, 151.4, 150.7, 150.3, 145.5, 143.7, 139.1, 133.7, 129.5, 128.0, 127.3, 126.3, 120.7, 114.2, 104.2, 28.5, 16.0, 14.4.

MS (EI, 70 eV): m/z (%) = 397 (100) [M⁺], 398 (29.5), 396 (26.8).

Anal. Calcd for C₂₃H₁₉N₅O₂: C, 69.51; H, 4.82; N, 17.62. Found: C, 69.48; H, 4.78; N, 17.60.

3-Methyl-4-[4-(methylsulfanyl)phenyl]-1-phenyl-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidine-5,7(6 H ,8 H )-dione (4b)

Colorless solid; mp >300 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.80 (s, 3 H, CH₃), 2.54 (s, 3 H, SCH₃), 6.24-8.25 (m, 9 H_arom), 11.16 (s, 1 H, NH), 11.76 (s, 1 H, NH).

MS (EI, 70 eV): m/z (%) = 415 (100) [M⁺], 416 (38.5), 417 (13.3).

Anal. Calcd for C₂₂H₁₇N₅O₂S: C, 63.60; H, 4.12; N, 16.86. Found: C, 63.63; H, 4.09; N, 16.84.

3-Methyl-4-(4-nitrophenyl)-1-phenyl-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidine-5,7(6 H ,8 H )-dione (4c)

Yellow solid; mp >300 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.74 (s, 3 H, CH₃), 7.29-8.35 (m, 9 H_arom), 11.27 (s, 1 H, NH), 11.86 (s, 1 H, NH).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 161.8, 152.8, 150.3, 150.0, 147.5, 147.3, 144.7, 138.5, 137.8, 134.5, 129.4, 129.2, 126.1, 123.0, 122.8, 120.4, 113.4, 103.9, 14.2.

MS (EI, 70 eV): m/z (%) = 414 (100) [M⁺], 415 (23.5).

Anal. Calcd for C₂₁H₁₄N₆O₄: C, 60.87; H, 3.41; N, 20.28. Found: C, 60.91; H, 3.45; N, 20.30.

4-(4-Cyanophenyl)-3-methyl-1-phenyl-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidine-5,7(6 H ,8 H )-dione (4d)

Colorless solid; mp >300 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.71 (s, 3 H, CH₃), 7.28-8.23 (m, 9 H_arom), 11.24 (s, 1 H, NH), 11.83 (s, 1 H, NH).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 161.3, 152.5, 150.0, 149.8, 148.2, 144.4, 141.2, 138.4, 131.3, 129.0, 128.7, 125.8, 120.3, 118.6, 112.8, 110.7, 103.4, 39.5, 13.7.

MS (EI, 70 eV): m/z (%) = 394 (100) [M⁺], 395 (25.9), 393 (24.1).

Anal. Calcd for C₂₂H₁₄N₆O₂: C, 67.00; H, 3.58; N, 21.31. Found: C, 66.98; H, 3.61; N, 21.29.

4-(4-Methoxyphenyl)-3-methyl-1-phenyl-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidine-5,7(6 H ,8 H )-dione (4e)

Colorless solid; mp >300 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.76 (s, 3 H, CH₃), 3.82 (s, 3 H, OCH₃), 6.98-8.24 (m, 9 H_arom), 11.11 (s, 1 H, NH), 11.70 (s, 1 H, NH).

MS (EI, 70 eV): m/z (%) = 399 (100) [M⁺], 398 (40.6), 400 (16.6).

Anal. Calcd for C₂₂H₁₇N₅O₃: C, 66.16; H, 4.29; N, 17.53. Found: C, 66.13; H, 4.33; N, 17.51.

3-Methyl-1-phenyl-4-(2,4,5-trimethoxyphenyl)-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidine-5,7(6 H ,8 H )-dione (4f)

Yellow solid; mp 276-277 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.87 (s, 3 H, CH₃), 3.64 (s, 6 H, 2 OCH₃), 3.87 (s, 3 H, OCH₃), 6.78-8.24 (m, 7 H_arom), 11.10 (s, 1 H, NH), 11.63 (s, 1 H, NH).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 161.4, 153.0, 150.3, 150.1, 149.8, 148.2, 145.4, 142.5, 138.7, 129.3, 126.0, 120.5, 115.6, 114.2, 113.5, 104.6, 97.9, 56.4, 56.2, 55.8, 13.5.

MS (EI, 70 eV): m/z (%) = 459 (100) [M⁺], 428 (47.8), 460 (26.2), 444 (18.5).

Anal. Calcd for C₂₄H₂₁N₅O₅: C, 62.74; H, 4.61; N, 15.24. Found: C, 62.77; H, 4.60; N, 15.22.

4-(4-Ethylphenyl)-3-methyl-1-phenyl-7-thioxo-1,6,7,8-tetrahydro-5 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidin-5-one (4g)

Colorless solid; mp 281-282 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.25 (t, J = 7.8 Hz, 3 H, CH₃), 1.74 (s, 3 H, CH₃), 2.7 (q, J = 7.8 Hz, 2 H, CH₃), 7.19-8.30 (m, 9 H_arom), 12.27 (s, 1 H, NH), 13.10 (s, 1 H, NH).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 176.2, 159.2, 151.9, 151.3, 150.1, 145.6, 144.0, 139.0, 133.2, 129.5, 128.1, 127.3, 126.2, 120.4, 115.0, 105.9, 28.5, 15.9, 14.4.

MS (EI, 70 eV): m/z (%) = 413 (100) [M⁺], 414 (30.9), 412 (25.1), 384 (17.8).

Anal. Calcd for C₂₃H₁₉N₅OS: C, 66.81; H, 4.63; N, 16.94. Found: C, 66.85; H, 4.60; N, 16.96.

4-(4-Chlorophenyl)-3-methyl-1-phenyl-7-thioxo-1,6,7,8-tetra­hydro-5 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidin-5-one (4h)

Yellow solid; mp 297-298 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.82 (s, 3 H, CH₃), 7.32-8.34 (m, 9 H_arom), 12.35 (s, 1 H, NH), 13.2 (s, 1 H, NH).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 175.9, 159.1, 151.5, 149.7, 149.2, 145.1, 138.6, 134.5, 133.0, 129.7, 129.2, 127.7, 126.0, 120.1, 114.3, 105.6, 14.1.

MS (EI, 70 eV): m/z (%) = 419 (100) [M⁺], 420 (32.2), 421 (23.9).

Anal. Calcd for C₂₁H₁₄ClN₅OS: C, 60.07; H, 3.36; N, 16.68. Found: C, 60.04; H, 3.32; N, 16.66.

4-(3,4-Dihydroxyphenyl)-3-methyl-1-phenyl-7-thioxo-1,6,7,8-tetrahydro-5 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidin-5-one (4i)

Yellow solid; mp >300 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.85 (s, 3 H, CH₃), 6.50-8.25 (m, 8 H_arom), 9.03 (s, 1 H, OH), 9.10 (s, 1 H, OH), 11.10 (s, 1 H, NH), 11.70 (s, 1 H, NH).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 165.7, 161.5, 153.0, 151.7, 150.5, 150.3, 150.0, 145.4, 144.7, 138.8, 129.3, 126.8, 120.4, 119.0, 115.6, 115.0, 114.1, 104.0, 89.1, 80.3, 14.0.

MS (EI, 70 eV): m/z (%) = 417 (100) [M⁺], 416 (26.8), 415 (18.9).

Anal. Calcd for C₂₁H₁₅N₅O₃S: C, 60.42; H, 3.62; N, 16.78. Found: C, 60.45; H, 3.60; N, 16.77.

4-(4-Chlorophenyl)-3-methyl-1-(4-nitrophenyl)-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidine-5,7(6 H ,8 H )-dione (4j)

Yellow solid; mp >300 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.71 (s, 3 H, CH₃), 7.3-8.55 (m, 8 H_arom), 11.26 (s, 1 H, NH), 11.88 (s, 1 H, NH).

MS (EI, 70 eV): m/z (%) = 448 (100) [M⁺], 450 (38.6), 449 (32.8).

Anal. Calcd for C₂₁H₁₃ClN₆O₄: C, 56.20; H, 2.92; N, 18.72. Found: C, 56.18; H, 2.89; N, 18.71.

4-(4-Methoxyphenyl)-1,3-dimethyl-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidine-5,7(6 H ,8 H )-dione (4k)

Yellow solid; mp 288-289 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.70 (s, 3 H, CH₃), 3.81 (s, 3 H, OCH₃), 3.86 (s, 3 H, NCH₃), 6.95-7.19 (m, 4 H_arom), 11.02 (s, 1 H, 1 NH), 11.60 (s, 1 H, 1 NH).

MS (EI, 70 eV): m/z (%) = 337 (100) [M⁺], 336 (50.6), 338 (13.2).

Anal. Calcd for C₁₇H₁₅N₅O₃: C, 60.53; H, 4.48; N, 20.76. Found: C, 60.51; H, 4.47; N, 20.74.

1,3,6,8-Tetramethyl-4-(4-methylphenyl)-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidine-5,7(6 H ,8 H )-dione (4l)

Yellow solid; mp 221-223 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.68 (s, 3 H, CH₃), 2.39 (s, 3 H, CH₃), 3.14 (s, 3 H, CH₃), 3.66 (s, 3 H, CH₃), 3.94 (s, 3 H, CH₃), 7.09-7.27 (m, 4 H_arom).

MS (EI, 70 eV): m/z (%) = 349 (100) [M⁺], 348 (60.9), 350 (23.8).

Anal. Calcd for C₁₉H₁₉N₅O₂: C, 65.32; H, 5.48; N, 20.04. Found: C, 65.29; H, 5.51; N, 20.05.

4-Aryl-4,9-dihydro-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidines 5a-i; General Procedure

A mixture of 5-aminopyrazole 1d,e (1.30 mmol, 1 equiv), barbituric acid 2a-c (1.30 mmol, 1 equiv), and aromatic aldehyde 3a-d,f-h,j (1.3 mmol, 1 equiv) in DMF (2 mL), contained in a round-bottom flask equipped with condenser, was refluxed for 30 min. The mixture was cooled and EtOH (20 mL) was added. The mixture was allowed to stand and then filtered to give the solid product, which was washed with EtOH and dried on air at r.t.

4-(4-Ethylphenyl)-3-methyl-4,9-dihydro-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidine-5,7(6 H ,8 H )-dione (5a)

Colorless solid; mp >300 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.1 (t, J = 7.5 Hz, 3 H, CH₃), 1.88 (s, 3 H, CH₃), 2.5 (q, J = 7.5 Hz, 2 H, CH₂), 4.82 (s, 1 H, 4-CH), 6.98-7.07 (m, 4 H_arom), 8.71 (s, 1 H, NH), 9.94 (s, 1 H, NH), 10.44 (s, 1 H, 9-NH), 11.80 (s, 1 H, 1-NH).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.4, 150.5, 147.3, 145.1, 141.3, 127.6, 103.0, 87.3, 34.7, 28.2, 16.0, 10.0.

MS (EI, 70 eV): m/z (%) = 323 (23.4) [M⁺], 218 (100), 175 (26.6).

Anal. Calcd for C₁₇H₁₇N₅O₂: C, 63.15; H, 5.30; N, 21.66. Found: C, 63.17; H, 5.27; N, 21.63.

3,6,8-Trimethyl-4-[4-(methylsulfanyl) phenyl]-4,9-dihydro-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidine-5,7(6 H ,8 H )-dione (5b)

Colorless solid; mp 195-196 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.90 (s, 3 H, CH₃), 2.38 (s, 3 H, SCH₃), 3.04 (s, 3 H, NCH₃), 3.44 (s, 3 H, NCH₃), 4.94 (s, 1 H, 4-CH), 7.03-7.14 (m, 4 H_arom), 9.8 (s, 1 H, 9-NH), 11.92 (s, 1 H, 1-NH).

MS (EI, 70 eV): m/z (%) = 369 (15.9) [M⁺], 246 (100), 247 (15.3), 137 (15.20).

Anal. Calcd for C₁₈H₁₉N₅O₂S: C, 58.52; H, 5.18; N, 18.96. Found: C, 58.55; H, 5.20; N, 18.93.

3-Methyl-4-(4-nitrophenyl)-4,9-dihydro-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidine-5,7(6 H ,8 H )-dione (5c)

Yellow solid; mp >300 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.86 (s, 3 H, CH₃), 5.05 (s, 1 H, 4-CH), 7.4-8.1 (m, 4 H_arom), 8.92 (s, 1 H, NH), 10.08 (s, 1 H, NH), 10.55 (s, 1 H, 9-NH), 11.92 (s, 1 H, 1-NH).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.4, 155.2, 150.4, 147.6, 146.1, 145.6, 136.4, 129.1, 123.7, 101.5, 86.2, 35.5, 9.9.

MS (EI, 70 eV): m/z (%) = 340 (22.6) [M⁺], 218 (100), 175 (38.7), 338 (51.1).

Anal. Calcd for C₁₅H₁₂N₆O₄: C, 52.94; H, 3.55; N, 24.70. Found: C, 52.91; H, 3.52; N, 24.69.

4-(4-Cyanophenyl)-3-methyl-4,9-dihydro-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidine-5,7(6 H ,8 H )-dione (5d)

Colorless solid; mp >300 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.85 (s, 3 H, CH₃), 4.98 (s, 1 H, 4-CH), 7.33-7.68 (m, 4 H_arom), 8.87 (s, 1 H, NH), 10.04 (s, 1 H, NH), 10.53 (s, 1 H, 9-NH), 11.90 (s, 1 H, 1-NH).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.4, 153.2, 150.5, 147.8, 145.7, 136.3, 132.4, 128.9, 119.5, 109.0, 101.7, 86.3, 35.6, 9.9.

MS (EI, 70 eV): m/z (%) = 320 (16.5) [M⁺], 218 (100), 175 (34.6), 219 (12.6).

Anal. Calcd for C₁₆H₁₂N₆O₂: C, 60.00; H, 3.78; N, 26.24. Found: C, 59.97; H, 3.81; N, 26.23.

3-Methyl-4-(2,4,5-trimethoxyphenyl)-4,9-dihydro-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidine-5,7(6 H ,8 H )-dione (5e)

Colorless solid; mp >300 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.85 (s, 3 H, CH₃), 3.55 (s, 3 H, OCH₃), 3.72 (s, 6 H, 2 OCH₃), 5.11 (s, 1 H, 4-CH), 6.52-6.58 (m, 2 H_arom), 8.61 (s, 1 H, NH), 9.88 (s, 1 H, NH), 10.37 (s, 1 H, 9-NH), 11.68 (s, 1 H, 1-NH).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.3, 150.8, 150.6, 148.3, 147.8, 145.9, 143.3, 135.5, 128.1, 114.3, 103.1, 99.8, 86.8, 57.3, 57.1, 56.3, 28.6, 9.8.

MS (EI, 70 eV): m/z (%) = 385 (50.0) [M⁺], 354 (100), 153 (65.5), 168 (60.4).

Anal. Calcd for C₁₈H₁₉N₅O₅: C, 56.10; H, 4.97; N, 18.17. Found: C, 56.14; H, 4.95; N, 18.16.

4-(3,4-Dihydroxyphenyl)-3-methyl-4,9-dihydro-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidine-5,7(6 H ,8 H )-dione (5f)

Colorless solid; mp >300 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.90 (s, 3 H, CH₃), 4.68 (s, 1 H, 4-CH), 6.4-6.54 (m, 3 H_arom), 8.49 (s, 1 H, OH), 8.65 (s, 1 H, OH), 8.70 (s, 1 H, NH), 9.91 (s, 1 H, NH), 10.45 (s, 1 H, 9-NH), 11.78 (s, 1 H, 1-NH).

MS (EI, 70 eV): m/z (%) = 325 (40.7) [M⁺], 110 (100), 174 (67.7), 217 (88.3).

Anal. Calcd for C₁₅H₁₃N₅O₄: C, 55.05; H, 4.00; N, 21.40. Found: C, 55.02; H, 4.03; N, 21.38.

4-(3-Ethoxy-2-hydroxyphenyl)-3-methyl-4,9-dihydro-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidine-5,7(6 H ,8 H )-dione (5g)

Colorless solid; mp >300 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.31 (t, J = 6.9 Hz, 3 H, CH₃), 1.86 (s, 3 H, CH₃), 3.94 (q, J = 6.9 Hz, 2 H, CH₃), 5.2 (s, 1 H, 4-CH), 6.32-6.66 (m, 3 H_arom), 8.78 (s, 1 H, NH), 8.84 (s, 1 H, OH), 10.03 (s, 1 H, NH), 10.60 (s, 1 H, 9-NH), 11.80 (s, 1 H, 1-NH).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 164.6, 150.2, 147.9, 147.5, 146.1, 143.6, 135.7, 134.9, 121.0, 119.4, 110.9, 102.9, 87.1, 64.4, 28.1, 15.3, 9.8.

MS (EI, 70 eV): m/z (%) = 355 (100) [M⁺], 218 (73.2), 110 (75.0), 138 (46.8).

Anal. Calcd for C₁₇H₁₇N₅O₄: C, 57.46; H, 4.82; N, 19.71. Found: C, 57.44; H, 4.80; N, 19.70.

4-(4-Chlorophenyl)-3-phenyl-4,9-dihydro-1 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidine-5,7(6 H ,8 H )-dione (5h)

Colorless solid; mp >300 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 5.25 (s, 1 H, 4-CH), 7.12-7.49 (m, 9 H_arom), 9.06 (s, 1 H, NH), 10.05 (s, 1 H, NH), 10.55 (s, 1 H, 9-NH), 12.66 (s, 1 H, 1-NH).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 162.8, 150.4, 147.5, 146.8, 146.0, 138.3, 130.8, 129.8, 129.5, 129.2, 128.6, 128.1, 126.7, 101.9, 87.4, 31.2.

MS (EI, 70 eV): m/z (%) = 391 (30) [M⁺], 280 (100), 393 (17.0), 237 (19.8).

Anal. Calcd for C₂₀H₁₄ClN₅O₂: C, 61.31; H, 3.60; N, 17.87. Found: C, 61.33; H, 3.57; N, 17.86.

4-(4-Chlorophenyl)-3-phenyl-7-thioxo-1,4,6,7,8,9-hexahydro-5 H -pyrazolo[4′,3′:5,6]pyrido[2,3- d ]pyrimidin-5-one (5i)

Colorless solid; mp >300 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 5.29 (s, 1 H, 4-CH), 7.1-7.49 (m, 9 H_arom), 8.85 (s, 1 H, NH), 10.60 (s, 1 H, NH), 12.02 (s, 1 H, 9-NH), 12.75 (s, 1 H, 1-NH).

MS (EI, 70 eV): m/z (%) = 407 (29.9) [M⁺], 296 (100), 409 (18.8), 219 (28.4).

Anal. Calcd for C₂₀H₁₄ClN₅OS: C, 58.89; H, 3.46; N, 17.17. Found: C, 58.86; H, 3.49; N, 17.14.

4,6-Aryl-1,4,6,7-tetrahydro-2′ H -spiro[pyrazolo[3,4- b ]pyridine-5,5′-pyrimidine]s 6a-f; General Procedure for Method A

A mixture of 5-aminopyrazole 1a,d (1.30 mmol, 1 equiv), barbituric acid 2a-c (1.30 mmol, 1 equiv), and aldehyde 3b,e,g (2.6 mmol, 2 equiv) in DMF (1 mL), contained in a round-bottom flask, was sonicated in ultrasonic bath at r.t. for 3 h. Then EtOH (30 mL) was added and the mixture was allowed to stand; it was filtered to give the solid product, which was washed with EtOH and dried on air at r.t.

This synthesis can be also carried out with intensively magnetic stirring instead of ultrasonication with some lower yields.

4,6-Aryl-1,4,6,7-tetrahydro-2′ H -spiro[pyrazolo[3,4- b ]pyridine-5,5′-pyrimidine]s 6g,h; General Procedure for Method B

A mixture of arylidenebarbituric acid 7a,b (2 mmol, 1 equiv) and appropriate Schiff base 8a,b (2 mmol, 1 equiv) in DMF (1 mL), contained in a round-bottom flask equipped with a condenser, was refluxed for 30 min. The mixture was cooled, EtOH (30 mL) was added, and the mixture was allowed to stand; it was filtered to give the solid product, which was washed with EtOH and dried on air at r.t.

4,6-Aryl-1,4,6,7-tetrahydro-2′ H -spiro[pyrazolo[3,4- b ]pyridine-5,5′-pyrimidine]s 6a,d-h; General Procedure for Method C

A mixture of barbituric acid 2a-c (1.30 mmol, 1 equiv), aromatic aldehyde 3a,b,e,g (1.3 mmol, 1 equiv), and Schiff base 8a-e in DMF (1 mL), contained in a round-bottom flask, was sonicated in an ultrasonic bath at r.t. for 3 h. Then EtOH (30 mL) was added and the mixture was allowed to stand; it was filtered to give the solid product, which was washed with EtOH and dried on air at r.t.

4,6-Aryl-1,4,6,7-tetrahydro-2′ H -spiro[pyrazolo[3,4- b ]pyridine-5,5′-pyrimidine]s 6a,d-h; General Procedure for Method D

A mixture of 5-aminopyrazole 1a,d,e (1.30 mmol, 1 equiv), aromatic aldehyde 3b,e,g (1.3 mmol, 1 equiv), and arylidenebarbituric acid 7a-e in DMF (1 mL), contained in a round-bottom flask, was sonicated in ultrasonic bath at r.t. for 3 h. Then EtOH (30 mL) was added and the mixture was allowed to stand; it was filtered to give the solid product, which was washed with EtOH and dried on air at r.t.

3-Methyl-4,6-bis[4-(methylsulfanyl)phenyl]-1-phenyl-1,4,6,7-tetrahydro-2′ H -spiro[pyrazolo[3,4- b ]pyridine-5,5′-pyrimidine]-2′,4′,6′(1′ H ,3′ H )-trione (6a)

Colorless solid; mp 281-282 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.59 (s, 3 H, CH₃), 2.43 (s, 6 H, 2 SCH₃), 4.71 (d, J = 7.5 Hz, 1 H, 6-CH), 4.88 (s, 1 H, 4-CH), 6.16 (d, J = 7.5 Hz, 1 H, 7-NH), 7.01-7.82 (m, 13 H_arom), 11.11 (br s, 2 H, NH).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 172.3, 167.2, 149.2, 145.5, 144.4, 139.6, 139.2, 137.9, 133.0, 132.2, 129.0, 128.7, 125.5, 125.5, 125.3, 121.0, 102.1, 65.8, 57.3, 46.2, 14.3, 14.2, 13.92.

MS (EI, 70 eV): m/z (%) = 569 (13) [M⁺], 307 (100), 306 (37), 308 (21), 442 (20).

Anal. Calcd For C₃₀H₂₇N₅O₃S₂: C, 63.25; H, 4.78; N, 12.29. Found: C, 63.22; H, 4.80; N, 12.26.

4,6-Bis(4-methoxyphenyl)-3-methyl-1-phenyl-1,4,6,7-tetrahydro-2′ H -spiro[pyrazolo[3,4- b ]pyridine-5,5′-pyrimidine]-2′,4′,6′(1′ H ,3′ H )-trione (6b)

Colorless solid; mp 219-220 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.57 (s, 3 H, CH₃), 3.71 (s, 6 H, 2 OCH₃), 4.68 (d, J = 7.6 Hz, 1 H, 6-CH), 4.84 (s, 1 H, 4-CH), 6.06 (d, J = 7.6 Hz, 1 H, 7-NH), 6.83-7.82 (m, 13 H_arom), 11.02 (s, 1 H, NH), 11.18 (s, 1 H, NH).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 172.9, 167.8, 159.8, 159.2, 149.6, 145.9, 144.8, 140.0, 129.8, 129.3, 128.9, 128.4, 125.6, 121.4, 114.2, 102.8, 66.0, 58.0, 55.6, 55.5, 46.7, 14.3.

MS (EI, 70 eV): m/z (%) = 537 (14) [M⁺], 291 (100), 290 (53), 246 (61), 184 (64).

Anal. Calcd For C₃₀H₂₇N₅O₅: C, 67.03; H, 5.06; N, 13.03. Found: C, 67.05; H, 5.02; N, 13.02.

4,6-Bis(4-chlorophenyl)-3-methyl-1-phenyl-1,4,6,7-tetrahydro-2′ H -spiro[pyrazolo[3,4- b ]pyridine-5,5′-pyrimidine]-2′,4′,6′(1′ H ,3′ H )-trione (6c)

Colorless solid; mp 255-256 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.59 (s, 3 H, CH₃), 4.77 (d, J = 7.3 Hz, 1 H, 6-CH), 4.94 (s, 1 H, 4-CH), 6.35 (d, J = 7.3 Hz, 1 H, 7-NH), 7.06-7.8 (m, 13 H_arom), 11.17 (s, 1 H, NH), 11.36 (s, 1 H, NH).

MS (EI, 70 eV): m/z (%) = 547 (14.1) [M⁺], 549 (10.1), 294 (100.0), 295 (85.0), 296 (35.0).

Anal. Calcd For C₂₈H₂₁Cl₂N₅O₃: C, 61.55; H, 3.87; N, 12.82. Found: C, 61.51; H, 3.85; N, 12.80.

4,6-Bis(4-chlorophenyl)-3-methyl-1-phenyl-2′-thioxo-1,4,6,7-tetrahydro-2′ H -spiro[pyrazolo[3,4- b ]pyridine-5,5′-pyrimidine]-4′,6′(1′ H ,3′ H )-dione (6d)

Colorless solid; mp 210-211 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.58 (s, 3 H, CH₃), 4.7 (d, J = 7.3 Hz, 1 H, 6-CH), 4.97 (s, 1 H, 4-CH), 6.45 (d, J = 7.3 Hz, 1 H, 7-NH), 7.06-7.8 (m, 13 H_arom), 12.2 (s, 1 H, NH), 12.3 (s, 1 H, NH).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 177.7, 170.2, 164.9, 145.7, 144.6, 139.9, 135.9, 134.8, 131.1, 133.0, 130.4, 129.4, 129.0, 125.8, 121.8, 101.9, 66.5, 58.6, 46.6, 14.4.

MS (EI, 70 eV): m/z (%) = 561 (17) [M⁺], 562 (11), 563 (4.7), 295 (100), 297 (98), 266 (96).

Anal. Calcd For C₂₈H₂₁Cl₂N₅O₂S: C, 59.79; H, 3.76; N, 12.45. Found: C, 59.72; H, 3.74; N, 12.44.

4,6-Bis(4-methoxyphenyl)-1′,3,3′-trimethyl-1,4,6,7-tetrahydro-2′ H -spiro[pyrazolo[3,4- b ]pyridine-5,5′-pyrimidine]-2′,4′,6′(1′ H ,3′ H )-trione (6e)

Yellow solid; mp 225-226 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.52 (s, 3 H, CH₃), 2.74 (s, 3 H, NCH₃), 2.79 (s, 3 H, NCH₃), 3.66 (s, 3 H, OCH₃), 3.68 (s, 3 H, OCH₃), 4.68 (d, J = 7.3 Hz, 1 H, 6-CH), 4.88 (s, 1 H, 4-CH), 5.83 (d, J = 7.3 Hz, 1 H, 7-NH), 6.75-7.06 (m, 8 H_arom), 11.54 (s, 1 H, NH).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.4, 164.6, 162.5, 159.6, 158.7, 152.5, 149.7, 135.3, 131.9, 130.1, 129.0, 128.4, 114.6, 113.7, 100.1, 66.2, 60.4, 55.1, 54.9, 45.8, 28.0, 27.3, 11.2.

MS (EI, 70 eV): m/z (%) = 489 (29.7) [M⁺], 216 (100), 273 (74.6), 274 (68), 490 (20).

Anal. Calcd For C₂₆H₂₇N₅O₅: C, 63.79; H, 5.56; N, 14.31. Found: C, 63.82; H, 5.54; N, 14.30.

4,6-Bis(4-methoxyphenyl)-1′,3′-dimethyl-3-phenyl-1 H -1,4,6,7-tetrahydro-2′ H -spiro[pyrazolo[3,4- b ]pyridine-5,5′-pyrimidine]-2′,4′,6′(1′ H ,3′ H )-trione (6f)

Yellow solid; mp 156-157 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 2.67 (s, 3 H, NCH₃), 2.83 (s, 3 H, NCH₃), 3.49 (s, 3 H, OCH₃), 3.69 (s, 3 H, OCH₃), 4.81 (d, J = 7.3 Hz, 1 H, 6-CH), 5.28 (s, 1 H, 4-CH), 6.02 (d, J = 7.3 Hz, 1 H, 7-NH), 6.40-7.10 (m, 13 H_arom), 12.07 (s, 1 H, NH).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.6, 164.6, 162.5, 159.6, 158.2, 149.6, 129.8, 128.6, 128.5, 128.2, 127.6, 127.1, 126.8, 113.7, 113.0, 99.6, 65.8, 60.6, 55.1, 54.8, 46.4, 35.7, 30.7, 28.1, 27.3.

MS (EI, 70 eV): m/z (%) = 551 (30.8) [M⁺], 277 (100), 273 (70.6), 274 (62.2).

Anal. Calcd For C₃₁H₂₉N₅O₅: C, 67.50; H, 5.30; N, 12.70. Found: C, 67.47; H, 5.33; N, 12.67.

4-(4-Ethylphenyl)-6-(4-methoxyphenyl)-3-methyl-1 H -1,4,6,7-tetrahydro-2′ H -spiro[pyrazolo[3,4- b ]pyridine-5,5′-pyrimidine]-2′,4′,6′(1′ H ,3′ H )-trione (6g)

Yellow solid; mp 219-220 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.11 (t, J = 7.6 Hz, 3 H, CH₃), 1.51 (s, 3 H, CH₃), 2.56 (q, J = 7.6 Hz, 2 H, CH₂), 3.70 (s, 3 H, OCH₃), 4.66 (d, J = 7.3 Hz, 1 H, 6-CH), 4.80 (s, 1 H, 4-CH), 5.78 (d, J = 7.3 Hz, 1 H, 7-NH), 6.79-7.15 (m, 8 H_arom), 9.95 (s, 1 H, NH), 10.85 (s, 1 H, NH), 11.06 (s, 1 H, NH).

MS (EI, 70 eV): m/z (%) = 459 (31) [M⁺], 457 (55), 332 (39.5), 215 (52).

Anal. Calcd For C₂₅H₂₅N₅O₄: C, 65.35; H, 5.48; N, 15.24. Found: C, 65.37; H, 5.51; N, 15.23.

6-(4-Methoxyphenyl)-1′,3,3′-trimethyl-4-[4-(methylsulfan­yl)phenyl]-1-phenyl-1,4,6,7-tetrahydro-2′ H -spiro[pyrazolo[3,4- b ]pyridine-5,5′-pyrimidine]-2′,4′,6′(1′ H ,3′ H )-trione (6h)

Colorless solid; mp 252-253 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.59 (s, 3 H, CH₃), 2.41 (s, 3 H, SCH₃), 2.77 (s, 3 H, NCH₃), 2.84 (s, 3 H, NCH₃), 3.69 (s, 3 H, OCH₃), 4.76 (d, J = 7.3 Hz, 1 H, 6-CH), 4.95 (s, 1 H, 4-CH), 6.24 (d, J = 7.3 Hz, 1 H, 7-NH), 6.80-7.80 (m, 13 H_arom).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.2, 164.9, 159.6, 158.9, 149.6, 145.5, 144.2, 139.6, 138.0, 133.0, 132.8, 132.2, 132.0, 129.0, 128.7, 128.1, 125.6, 125.5, 121.1, 113.8, 101.9, 66.5, 58.6, 55.0, 46.6, 28.2, 27.5, 14.2, 13.9.

MS (EI, 70 eV): m/z (%) = 581 (93) [M⁺], 565 (37.8), 290 (100), 426 (54.9), 306 (40.1).

Anal. Calcd For C₃₂H₃₁N₅O₄S: C, 66.07; H, 5.37; N, 12.04. Found: C, 66.03; H, 5.33; N, 12.03.

References

• 1a Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 
  Search in Google Scholar
• 1b Wender PA. Handy ST. Wright DL. Chem. Ind. (London)  1997,  765 
• Multicomponent Reactions   Zhu J. Bienayme H. Wiley-VCH; Weinheim: 2005. 
• 2b Bagley MC. Lubinu MC. Top. Heterocycl. Chem.  2006,  1:  31 
  Search in Google Scholar
• 2c Simon C. Constantieux T. Rodriguez J. Eur. J. Org. Chem.  2004,  4957 
• 2d Orru RVA. de Greef M. Synthesis  2003,  1471 
• 2e Dömling A. Chem. Rev.  2006,  106:  17 
  Search in Google Scholar
• 2f Groenendaal B. Ruijter E. Orru RVA. Chem. Commun.  2008,  5474 
• See, for example:
• 3a Kappe CO. Angew. Chem. Int. Ed.  2004,  43:  6250 
  Search in Google Scholar
• 3b Hayes BL. Aldrichimica Acta  2004,  37:  266 
  Search in Google Scholar
• 3c Roberts BA. Strauss CR. Acc. Chem. Res.  2005,  38:  653 
  Search in Google Scholar
• 3d De La Hoz A. Diaz-Ortiz A. Moreno A. Chem. Soc. Rev.  2005,  34:  164 
  Search in Google Scholar
• 3e Kappe C. O., Stadler A.; Microwaves in Organic and Medicinal Chemistry; Wiley-VCH: Weinheim, 2005
• See, for example:
• 4a Bonrath W. Paz Schmidt R. In Advances in Organic Synthesis   . Bentham Science; Amsterdam: 2005.  Chap. 3. p.81-117  
• 4b Mason TJ. Luche J.-L. In Chemistry Under Extreme or Non-Classical Conditions   van Eldick R. Hubbard CD. John Wiley; Chichester: 1997. 
• 4c Cravotto G. Cintas PJ. Chem. Soc. Rev.  2006,  35:  180 
  Search in Google Scholar
• 4d Mason TJ. Chem. Soc. Rev.  1997,  26:  443 
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• 4e Muravyova EA. Desenko SM. Musatov VI. Knyazeva IV. Shishkina SV. Shishkin OV. Chebanov VA. J. Comb. Chem.  2007,  9:  798 
  Search in Google Scholar
• 5a Huang Z. Ma Q. Bobbitt JM. J. Org. Chem.  1993,  58:  4837 
  Search in Google Scholar
• 5b Vicente J. Chicote MT. Guerrero R. de Arellano MCR. Chem. Commun.  1999,  1541 
• 5c Alajarin R. Avarez-Buila J. Vaquero JJ. Sunkel C. Fau J. Statkov P. Sanz J. Tetrahedron: Asymmetry  1993,  4:  617 
  Search in Google Scholar
• 5d Bossert F. Vater W. Med. Res. Rev.  1989,  9:  291 
  Search in Google Scholar
• 5e Triggle DJ. Langs DA. Janis RA. Med. Res. Rev.  1989,  9:  123 
  Search in Google Scholar
• 5f Tsuda Y, Mishina T, Obata M, Araki K, Inui J, and Nakamura T. inventors; WO  8,504,172. 
• 5g Tsuda Y, Mishina T, Obata M, Araki K, Inui J, and Nakamura T. inventors; JP  61,227,584. 
• 5h Tsuda Y, Mishina T, Obata M, Araki K, Inui J, and Nakamura T. inventors; EP  0,217,142. 
• 5i Atwal KS, Vaccaro W, Lloyd J, Finlay H, Yan L, and Bhandaru RS. inventors; US  2007,099,899. 
• 5j Atwal KS. Moreland S. Bioorg. Med. Chem. Lett.  1991,  1:  291 
  Search in Google Scholar
• 6a Sanghvi YS. Larson SB. Wills RC. Robins RK. Revankar GR. J. Med. Chem.  1989,  32:  945 
  Search in Google Scholar
• 6b Bell MR. Ackerman JH. US 4,920,128,  1990, 
• 6c Farghaly AM. Habib NS. Hazzaa AB. El-Sayed OA. J. Pharm. Sci.  1989,  3:  90 
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• 6d Ganjee A. Adair OO. Queener SF. J. Med. Chem.  2003,  46:  5074 
  Search in Google Scholar
• 6e Rosowsky A. Chen H. Fu H. Queener SF. Bioorg. Med. Chem.  2003,  11:  59 
  Search in Google Scholar
• 6f Dishington AP. Johnson PD. Kettle JG. Tetrahedron Lett.  2004,  45:  3733 
  Search in Google Scholar
• 7 Tseng CP. inventors; US  4,838,925. 
• 8a Hahn WE. Muszynski M. Chem. Stosow.  1986,  30:  421 
  Search in Google Scholar
• 8b Muszynski M. Hahn WE. PL 130681, 1984; Chem. Abstr. 1986,  104, 159328a 
• 9a Chebanov VA. Desenko SM. Curr. Org. Chem.  2006,  10:  297 
  Search in Google Scholar
• 9b Chebanov VA. Sakhno YaI. Desenko SM. Chernenko VN. Musatov VI. Shishkina SV. Shishkin OV. Kappe CO. Tetrahedron  2007,  63:  1229 
  Search in Google Scholar
• 9c Quiroga J. Insuasty B. Hormaza A. Saitz C. Jullian C. J. Heterocycl. Chem.  1998,  35:  575 
  Search in Google Scholar
• 9d Drizin I. Holladay MW. Yi L. Zhang GQ. Gopalakrishnan S. Gopalakrishnan M. Whiteaker KL. Buckner SA. Sullivan JP. Carroll WA. Bioorg. Med. Chem. Lett.  2002,  12:  1481 
  Search in Google Scholar
• 9e Chebanov VA. Saraev VE. Desenko SM. Chernenko VN. Shishkina SV. Shishkin OV. Kobzar KM. Kappe CO. Org. Lett.  2007,  9:  1691 
  Search in Google Scholar
• 9f Gladkov ES. Chebanov VA. Desenko SM. Shishkin OV. Shishkina SV. Dallinger D. Kappe CO. Heterocycles  2007,  63:  469 
  Search in Google Scholar
• 9g Chebanov VA. Sakhno YI. Desenko SM. Shishkina SV. Musatov VI. Shishkin OV. Knyazeva IV. Synthesis  2005,  2597 
• 9h Chebanov VA. Saraev VE. Desenko SM. Chernenko VN. Knyazeva IV. Groth U. Glasnov TN. Kappe CO. J. Org. Chem.  2008,  73:  5110 
  Search in Google Scholar
• 9i Sakhno YaI. Desenko SM. Shishkina SV. Shishkin OV. Sysoyev DO. Groth U. Kappe CO. Chebanov VA. Tetrahedron  2008,  64:  11041 
  Search in Google Scholar
• 10 Shirobokova MG. PhD Thesis   Kharkiv National University; Ukraine: 2001. 
• 11a Aly AA. Phosphorus, Sulfur Silicon Relat. Elem.  2006,  181:  2395 
  Search in Google Scholar
• 11b Wamhoff H. Paasch J. Liebigs Ann. Chem.  1990,  995 
• 11c Hussein AM. El-Emary TI. J. Chem. Res., Synop.  1998,  20 
• 12 Ahluwalia VK. Dahiya A. Garg VK. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  1997,  88 
• 13a Suresh T. Kumar RN. Mohan PS. Heterocycl. Commun.  2003,  9:  203 
  Search in Google Scholar
• 13b Khajuria RK. Sharma SR. Jain SM. Sharma S. Kapil A. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  1993,  981 
• 14a Shaabani A. Bazgir A. Tetrahedron Lett.  2004,  45:  2575 
  Search in Google Scholar
• 14b Drozdz B. Arch. Pharm. (Weinheim, Ger.)  1989,  322:  231 
  Search in Google Scholar
• 14c Saini A. Kumar S. Sandhu JS. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  2004,  43:  2482 
  Search in Google Scholar
• 15a Nam NL. Grandberg II. Sorokin VI. Chem. Heterocycl. Compd. (Engl. Transl.)  2000,  36:  281 ; Khim. Geterotsikl. Soedin. 2000, 342
  Search in Google Scholar
• 15b Desenko SM. Orlov VD. Azaheterocycles Based on Aromatic Unsaturated Ketones   Folio; Kharkov: 1998. 
• 16 Brooker L. G. S. Keyes G. H. Sprague R. H. VanDyke R. H. VanLare E. VanZandt G. White F. L. J. Am. Chem. Soc.  1951,  73:  5326 
  CrossrefSearch in Google Scholar
• 17 Puchala A. Suontamo R. Rasala D. Lysek R. J. Chem. Soc., Perkin Trans. 2  1996,  2383 
  Crossref

Sheldrick G. M. SHELXTL PLUS, PC Version, A system of computer programs for the determination of crystal structure from X-ray diffraction data, Rev.5.1, 1998.

The final atomic coordinates, and crystallographic data for molecules 4a and 6h have been deposited with the Cambridge Crystallographic Data Centre, 12 Union Road, CB2 1EZ, UK [fax: +44 (1223)336033, e-mail: deposit@ccdc.cam.ac.uk] and are available on request quoting the deposition numbers CCDC 706772 for 4a and CCDC 706773 for 6h.

References

• 1a Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 
  Search in Google Scholar
• 1b Wender PA. Handy ST. Wright DL. Chem. Ind. (London)  1997,  765 
• Multicomponent Reactions   Zhu J. Bienayme H. Wiley-VCH; Weinheim: 2005. 
• 2b Bagley MC. Lubinu MC. Top. Heterocycl. Chem.  2006,  1:  31 
  Search in Google Scholar
• 2c Simon C. Constantieux T. Rodriguez J. Eur. J. Org. Chem.  2004,  4957 
• 2d Orru RVA. de Greef M. Synthesis  2003,  1471 
• 2e Dömling A. Chem. Rev.  2006,  106:  17 
  Search in Google Scholar
• 2f Groenendaal B. Ruijter E. Orru RVA. Chem. Commun.  2008,  5474 
• See, for example:
• 3a Kappe CO. Angew. Chem. Int. Ed.  2004,  43:  6250 
  Search in Google Scholar
• 3b Hayes BL. Aldrichimica Acta  2004,  37:  266 
  Search in Google Scholar
• 3c Roberts BA. Strauss CR. Acc. Chem. Res.  2005,  38:  653 
  Search in Google Scholar
• 3d De La Hoz A. Diaz-Ortiz A. Moreno A. Chem. Soc. Rev.  2005,  34:  164 
  Search in Google Scholar
• 3e Kappe C. O., Stadler A.; Microwaves in Organic and Medicinal Chemistry; Wiley-VCH: Weinheim, 2005
• See, for example:
• 4a Bonrath W. Paz Schmidt R. In Advances in Organic Synthesis   . Bentham Science; Amsterdam: 2005.  Chap. 3. p.81-117  
• 4b Mason TJ. Luche J.-L. In Chemistry Under Extreme or Non-Classical Conditions   van Eldick R. Hubbard CD. John Wiley; Chichester: 1997. 
• 4c Cravotto G. Cintas PJ. Chem. Soc. Rev.  2006,  35:  180 
  Search in Google Scholar
• 4d Mason TJ. Chem. Soc. Rev.  1997,  26:  443 
  Search in Google Scholar
• 4e Muravyova EA. Desenko SM. Musatov VI. Knyazeva IV. Shishkina SV. Shishkin OV. Chebanov VA. J. Comb. Chem.  2007,  9:  798 
  Search in Google Scholar
• 5a Huang Z. Ma Q. Bobbitt JM. J. Org. Chem.  1993,  58:  4837 
  Search in Google Scholar
• 5b Vicente J. Chicote MT. Guerrero R. de Arellano MCR. Chem. Commun.  1999,  1541 
• 5c Alajarin R. Avarez-Buila J. Vaquero JJ. Sunkel C. Fau J. Statkov P. Sanz J. Tetrahedron: Asymmetry  1993,  4:  617 
  Search in Google Scholar
• 5d Bossert F. Vater W. Med. Res. Rev.  1989,  9:  291 
  Search in Google Scholar
• 5e Triggle DJ. Langs DA. Janis RA. Med. Res. Rev.  1989,  9:  123 
  Search in Google Scholar
• 5f Tsuda Y, Mishina T, Obata M, Araki K, Inui J, and Nakamura T. inventors; WO  8,504,172. 
• 5g Tsuda Y, Mishina T, Obata M, Araki K, Inui J, and Nakamura T. inventors; JP  61,227,584. 
• 5h Tsuda Y, Mishina T, Obata M, Araki K, Inui J, and Nakamura T. inventors; EP  0,217,142. 
• 5i Atwal KS, Vaccaro W, Lloyd J, Finlay H, Yan L, and Bhandaru RS. inventors; US  2007,099,899. 
• 5j Atwal KS. Moreland S. Bioorg. Med. Chem. Lett.  1991,  1:  291 
  Search in Google Scholar
• 6a Sanghvi YS. Larson SB. Wills RC. Robins RK. Revankar GR. J. Med. Chem.  1989,  32:  945 
  Search in Google Scholar
• 6b Bell MR. Ackerman JH. US 4,920,128,  1990, 
• 6c Farghaly AM. Habib NS. Hazzaa AB. El-Sayed OA. J. Pharm. Sci.  1989,  3:  90 
  Search in Google Scholar
• 6d Ganjee A. Adair OO. Queener SF. J. Med. Chem.  2003,  46:  5074 
  Search in Google Scholar
• 6e Rosowsky A. Chen H. Fu H. Queener SF. Bioorg. Med. Chem.  2003,  11:  59 
  Search in Google Scholar
• 6f Dishington AP. Johnson PD. Kettle JG. Tetrahedron Lett.  2004,  45:  3733 
  Search in Google Scholar
• 7 Tseng CP. inventors; US  4,838,925. 
• 8a Hahn WE. Muszynski M. Chem. Stosow.  1986,  30:  421 
  Search in Google Scholar
• 8b Muszynski M. Hahn WE. PL 130681, 1984; Chem. Abstr. 1986,  104, 159328a 
• 9a Chebanov VA. Desenko SM. Curr. Org. Chem.  2006,  10:  297 
  Search in Google Scholar
• 9b Chebanov VA. Sakhno YaI. Desenko SM. Chernenko VN. Musatov VI. Shishkina SV. Shishkin OV. Kappe CO. Tetrahedron  2007,  63:  1229 
  Search in Google Scholar
• 9c Quiroga J. Insuasty B. Hormaza A. Saitz C. Jullian C. J. Heterocycl. Chem.  1998,  35:  575 
  Search in Google Scholar
• 9d Drizin I. Holladay MW. Yi L. Zhang GQ. Gopalakrishnan S. Gopalakrishnan M. Whiteaker KL. Buckner SA. Sullivan JP. Carroll WA. Bioorg. Med. Chem. Lett.  2002,  12:  1481 
  Search in Google Scholar
• 9e Chebanov VA. Saraev VE. Desenko SM. Chernenko VN. Shishkina SV. Shishkin OV. Kobzar KM. Kappe CO. Org. Lett.  2007,  9:  1691 
  Search in Google Scholar
• 9f Gladkov ES. Chebanov VA. Desenko SM. Shishkin OV. Shishkina SV. Dallinger D. Kappe CO. Heterocycles  2007,  63:  469 
  Search in Google Scholar
• 9g Chebanov VA. Sakhno YI. Desenko SM. Shishkina SV. Musatov VI. Shishkin OV. Knyazeva IV. Synthesis  2005,  2597 
• 9h Chebanov VA. Saraev VE. Desenko SM. Chernenko VN. Knyazeva IV. Groth U. Glasnov TN. Kappe CO. J. Org. Chem.  2008,  73:  5110 
  Search in Google Scholar
• 9i Sakhno YaI. Desenko SM. Shishkina SV. Shishkin OV. Sysoyev DO. Groth U. Kappe CO. Chebanov VA. Tetrahedron  2008,  64:  11041 
  Search in Google Scholar
• 10 Shirobokova MG. PhD Thesis   Kharkiv National University; Ukraine: 2001. 
• 11a Aly AA. Phosphorus, Sulfur Silicon Relat. Elem.  2006,  181:  2395 
  Search in Google Scholar
• 11b Wamhoff H. Paasch J. Liebigs Ann. Chem.  1990,  995 
• 11c Hussein AM. El-Emary TI. J. Chem. Res., Synop.  1998,  20 
• 12 Ahluwalia VK. Dahiya A. Garg VK. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  1997,  88 
• 13a Suresh T. Kumar RN. Mohan PS. Heterocycl. Commun.  2003,  9:  203 
  Search in Google Scholar
• 13b Khajuria RK. Sharma SR. Jain SM. Sharma S. Kapil A. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  1993,  981 
• 14a Shaabani A. Bazgir A. Tetrahedron Lett.  2004,  45:  2575 
  Search in Google Scholar
• 14b Drozdz B. Arch. Pharm. (Weinheim, Ger.)  1989,  322:  231 
  Search in Google Scholar
• 14c Saini A. Kumar S. Sandhu JS. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  2004,  43:  2482 
  Search in Google Scholar
• 15a Nam NL. Grandberg II. Sorokin VI. Chem. Heterocycl. Compd. (Engl. Transl.)  2000,  36:  281 ; Khim. Geterotsikl. Soedin. 2000, 342
  Search in Google Scholar
• 15b Desenko SM. Orlov VD. Azaheterocycles Based on Aromatic Unsaturated Ketones   Folio; Kharkov: 1998. 
• 16 Brooker L. G. S. Keyes G. H. Sprague R. H. VanDyke R. H. VanLare E. VanZandt G. White F. L. J. Am. Chem. Soc.  1951,  73:  5326 
  CrossrefSearch in Google Scholar
• 17 Puchala A. Suontamo R. Rasala D. Lysek R. J. Chem. Soc., Perkin Trans. 2  1996,  2383 
  Crossref

Sheldrick G. M. SHELXTL PLUS, PC Version, A system of computer programs for the determination of crystal structure from X-ray diffraction data, Rev.5.1, 1998.

The final atomic coordinates, and crystallographic data for molecules 4a and 6h have been deposited with the Cambridge Crystallographic Data Centre, 12 Union Road, CB2 1EZ, UK [fax: +44 (1223)336033, e-mail: deposit@ccdc.cam.ac.uk] and are available on request quoting the deposition numbers CCDC 706772 for 4a and CCDC 706773 for 6h.