An Efficient and Chemoselective Synthesis of 1,6-Naphthyridines and Pyrano[3,2-c]pyridines under Microwave Irradiation

Abstract

A series of 1,6-naphthyridines and pyrano[3,2-c]pyridines were selectively synthesized via microwave-assisted reactions controlled by the nature of the solvent. This has resulted in an efficient and promising synthetic method for constructing the 1,6-naphthyridine and pyrano[3,2-c]pyridine skeletons.

Chemoselectivity is a key issue to be controlled in organic synthesis. In particular, chemoselectivity is synthetically useful because it gives one of several products selectively from the same substrate without the need to separate the products from a product mixture. It continues to be developed as organic synthesis strives for ever-increasing levels of efficiency. As a result, many studies have focused on the chemoselectivity of reactions. [¹] In recent years, many reports have dealt with the control of chemoselectivity of reactions with metal catalysts, [¹a-e] while solvent-dependent chemoselective reactions have been researched in relatively few papers. [¹g-i] Despite these achievements, the development of highly solvent-dependent chemoselective reactions is still of current interest.

Various naphthyridine and pyrano[3,2-c]pyridine derivatives have received considerable attention over the past years because of their wide range of biological activities, including antitumor, anti-inflammatory and antifungal properties. [²-4] Furthermore, compounds incorporating naphthyridine are useful in the treatment of hypertension, myocardial infarction, hyperlipidemia, cardiac arrhythmia and rheumatoid arthritis. [5-8] Therefore, a number of reports for the synthesis of these molecules have been published, such as (a) the reaction of dibenzylidene-4-piperidones with cyanoacetamide (or malononitrile) using piperidine as catalyst [²] [³] and (b) the use of piperidone via multiple steps to obtain the target compounds. [5] However, these methods suffer from time-consuming and complex synthetic paths. Thus, the development of a simple and rapid method for the synthesis of these heterocyclic compounds is strongly desired.

In the context of our interest in the design and development of useful tactics and strategies for the synthesis of heterocyclic compounds, [9] we were pleased to find that 1,6-naphthyridine and pyrano[3,2-c]pyridine derivatives can be efficiently synthesized via microwave-assisted chemoselective reactions controlled by the nature of the solvent (Scheme  [¹] ). To the best of our knowledge, the solvent-dependent chemoselective synthesis of 1,6-naphthyridines and pyrano[3,2-c]pyridines has been seldom investigated.

Choosing an appropriate solvent is of crucial importance not only for successful microwave-promoted syntheses but also for the effective control of chemoselective reactions. In order to choose the optimum solvent, the microwave-assisted reaction of equimolar amounts of chalcone 1b (R^¹ = 4-Tol, R^² = Me) and malononitrile (2) in the presence of ammonium acetate was examined at 110 ˚C, using acetic acid, ethanol, ethylene glycol, water or N,N-di­methylformamide as solvent. All the reactions were carried out under microwave irradiation (initial power: 150 W, maximum power: 200 W). The results of the screening of these solvents are presented in Table  [¹] (entries 1-5). When ethylene glycol, water or ethanol was selected as the solvent, compound 3b was obtained as the main product and only a small quantity of 4b was formed. In contrast, when acetic acid was used as the solvent, 4b was obtained in 92% yield (entry 4). Moreover, only the product 3b was obtained in N,N-dimethylformamide (entry 5). It is worth noting that the reaction could therefore be controlled to exclusively yield 4b or 3b by varying the reaction medium (Scheme  [¹] ).

Thus, the question is, why is there selective formation of product 4 in acetic acid and selective formation of product 3 in N,N-dimethylformamide? The chemoselectivity of the reaction could be attributed to the acidity of the reaction solution. In acetic acid, the reactive position of intermediate 5 is the ketone carbonyl, which is attacked by an NH₂ group to form the intermediate product 6, which cyclizes to ultimately afford compound 4. In N,N-dimethylformamide, however, the intermediate of the addition is the enol 8, which cyclizes to yield compound 3. The suggested pathways for the formation of compounds 4 and 3 are illustrated in Scheme  [²] and Scheme  [³] , respectively.

Furthermore, a study on the effect of the acidity of the reaction solution was conducted with the same substrate 1b (see Table  [¹] , entries 6-12). Increasing the proportion of N,N-dimethylformamide in the mixed solvent acetic acid-N,N-dimethylformamide to a ratio of 1:1 and 1:2 resulted in a higher yield of product 3b, to 6% and 55%, respectively (entries 8 and 9). When the volume/volume ratio of the mixed solvent was increased to 1:3, compound 3b was obtained as the main product (entry 10). Moreover, when chalcone 1b was reacted with an equimolar amount of malononitrile (2) and excess ammonium acetate in the mixed solvent formic acid-N,N-dimethylformamide (1:3), the yield of product 3b was 74%, while the yield of product 4b was 13% (entry 12). However, when the formic acid of the mixed solvent was replaced with trifluoroacetic acid, only product 4b was obtained (entry 11). These results indicate that the acidity of the solvent has obvious effects on the formation of products 3b and 4b.

In a further study, the microwave-assisted reaction of equimolar amounts of chalcone 1b and malononitrile (2) was carried out in N,N-dimethylformamide without ammonium acetate, which resulted in 3b in good yield. Therefore, ammonium acetate plays an unessential role in the synthesis of the pyrano[3,2-c]pyridines.

The effect of temperature on the reaction using the same reagents, in N,N-dimethylformamide and in acetic acid, at temperatures ranging from 80 to 140 ˚C, in increments of 10 ˚C, was investigated. The results are summarized in Table  [²] . The yield of product 4b was increased and the reaction time was shortened when the temperature was increased from 80 to 110 ˚C (entries 1-4); however, further temperature increase from 120 to 140 ˚C failed to improve the yield of product 4b (entries 5-7). Therefore, 110 ˚C was chosen as the most suitable temperature for the synthesis of 4b. In addition, we found that the most suitable temperature for the synthesis of 3b is 120 ˚C (Table  [²] , entry 5).

Under these optimized chemoselectivity conditions, a series of 1,6-naphthyridines 4 and pyrano[3,2-c]pyridines 3 were selectively synthesized via the reaction of chalcones 1, malononitrile (2) and ammonium acetate in an appropriate solvent under microwave irradiation. The results, summarized in Table  [³] , show that this protocol could be applied not only to chalcones with either an electron-withdrawing­ group (such as a nitro or a halide group) or an electron-donating group (such as an alkoxy group, entries 3 and 12), but also to chalcones with a heterocyclic group (such as the 2-thienyl group, entry 9). Therefore, we concluded that the electronic nature of the chalcone substituents has no significant effect on this reaction.

Additionally, to demonstrate the purely nonthermal microwave effects, the same temperature was applied under classical heating conditions to the synthesis of some examples of compounds 3 and 4. The results for six compounds are listed in Table  [4] . A comparison with the data in Table  [³] for the corresponding compounds indicates that the reaction was efficiently promoted by microwave irradiation, and the reaction time was strikingly shortened from hours required under traditional heating conditions to minutes; the yields were also obviously increased under the microwave irradiation conditions.

The structures of all the synthesized compounds were established on the basis of their spectroscopic data. The IR spectrum of compound 4b showed strong absorptions at 3330 and 3214 cm^-¹ due to the NH₂ group, and at 2219 cm^-¹ due to the CN group. The ^¹H NMR spectrum of 4b showed a broad singlet at δ = 6.71 due to the NH₂ protons and a singlet at δ = 7.92 due to the =CH proton. In the IR spectrum of compound 3b, the appearance of absorption peaks at 3389, 3295 and 2178 cm^-¹ due to the NH₂ group and the CN triple bond, and the disappearance of the band at 1685-1710 cm^-¹ due to the C=O group of the starting chalcone, confirmed the formation of product. The appearance of a broad singlet at δ = 6.76 due to the NH₂ protons and a singlet at δ = 6.87 due to the =CH proton in the ^¹H NMR spectrum provided further confirmation. Moreover, the structure of 4i was also established by X-ray crystallography (Figure  [¹] ). [¹0]

In summary, we have demonstrated an efficient and practical method for the synthesis of a wide range of 1,6-naphthyridines and pyrano[3,2-c]pyridines under mild conditions. Most distinctively, we have shown that the reaction could be controlled to exclusively yield specific products by varying the reaction medium. In light of its operational simplicity, simple purification procedure and good yields, this protocol is superior to the existing methods.

All microwave-assisted reactions were performed in a monomodal Emrys™ Creator from Personal Chemistry, Uppsala, Sweden. Melting points were determined in open capillaries and are uncorrected. IR spectra were recorded on an FT-IR Tensor 27 spectrometer using KBr pellets. ^¹H NMR spectra were measured on a Bruker DPX 400 MHz spectrometer using TMS as internal standard and DMSO-d ₆ as solvent. HRMS (ESI) data were determined using a micrOTOF-Q II HPLC/MS instrument (Bruker). X-ray crystallographic analysis was performed with a Siemens SMART CCD and a Siemens P4 diffractometer.

Chalcones 1; General Procedure

In a 50-mL reaction vial, a mixture of the 4-piperidone (10 mmol), the appropriate aldehyde (20 mmol), 10% NaOH (1 mL) and 95% EtOH (30 mL) was stirred at r.t. for 0.5-2 h. The separated solid was collected by filtration.

1,6-Naphthyridines 4; General Procedure Using Microwave Irradiation­

In a 10-mL reaction vial, the 3,5-dibenzylidene-4-piperidone 1 (1 mmol), malononitrile (2; 1 mmol), NH₄OAc (6 mmol) and AcOH (2 mL) were mixed, and then the vial was capped. The mixture was irradiated at 200 W (initial power: 150 W, maximum power: 200 W) at 110 ˚C for the time given in Table  [³] . Upon completion of the reaction (monitored by TLC), the mixture was cooled to r.t. and then poured into H₂O (70 mL); filtration gave the crude product, which was further purified by recrystallization (95% EtOH) to give pure product.

2-Amino-8-benzylidene-5,6,7,8-tetrahydro-6-methyl-4-phenyl-1,6-naphthyridine-3-carbonitrile (4a)

IR (KBr): 3355, 3212, 2214, 1621, 1556, 1446, 1424, 1370, 1262, 1120, 923, 893, 770, 719, 698 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.97 (s, 1 H, =CH), 7.54-7.44 (m, 5 H, ArH), 7.40-7.37 (m, 5 H, ArH), 6.74 (s, 2 H, NH₂), 3.57 (s, 2 H, CH₂), 3.13 (s, 2 H, CH₂), 2.21 (s, 3 H, CH₃).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₁N₄: 353.1766; found: 353.1788.

2-Amino-5,6,7,8-tetrahydro-6-methyl-8-(4-methylbenzylidene)-4-(4-methylphenyl)-1,6-naphthyridine-3-carbonitrile (4b)

IR (KBr): 3330, 3214, 2219, 1626, 1555, 1513, 1449, 1426, 1362, 1265, 1125, 923, 907, 810, 737, 703 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.92 (s, 1 H, =CH), 7.34 (d, J = 8.0 Hz, 2 H, ArH), 7.27-7.24 (m, 6 H, ArH), 6.71 (s, 2 H, NH₂), 3.55 (s, 2 H, CH₂), 3.12 (s, 2 H, CH₂), 2.39 (s, 3 H, CH₃), 2.34 (s, 3 H, CH₃), 2.20 (s, 3 H, CH₃).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 160.45, 157.94, 139.12, 138.20, 132.51, 131.59, 130.18, 129.79, 129.51, 129.34, 129.27, 129.22, 128.08, 127.62, 126.80, 116.06, 91.57, 54.43, 54.08, 44.79, 20.92.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₅N₄: 381.2079; found: 381.2093.

2-Amino-5,6,7,8-tetrahydro-8-(4-methoxybenzylidene)-4-(4-methoxyphenyl)-6-methyl-1,6-naphthyridine-3-carbonitrile (4c)

IR (KBr): 3356, 3226, 2214, 1632, 1605, 1552, 1510, 1460, 1428, 1361, 1262, 1175, 1126, 1027, 927, 901, 838, 787, 744 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.90 (s, 1 H, =CH), 7.33 (d, J = 8.8 Hz, 4 H, ArH), 7.08 (d, J = 8.4 Hz, 2 H, ArH), 7.02 (d, J = 8.8 Hz, 2 H, ArH), 6.67 (s, 2 H, NH₂), 3.83 (s, 3 H, OCH₃), 3.80 (s, 3 H, OCH₃), 3.56 (s, 2 H, CH₂), 3.15 (s, 2 H, CH₂), 2.22 (s, 3 H, CH₃).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.64, 158.90, 157.97, 152.64, 152.41, 131.12, 130.72, 129.72, 128.55, 127.96, 127.29, 117.60, 116.92, 114.13, 114.04, 88.95, 56.02, 55.66, 55.18, 54.78, 45.26.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₅N₄O₂: 413.1978; found: 413.2001.

2-Amino-8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-5,6,7,8-tetrahydro-6-methyl-1,6-naphthyridine-3-carbonitrile (4d)

IR (KBr): 3288, 3159, 2210, 1624, 1571, 1555, 1493, 1453, 1422, 1368, 1274, 1260, 1183, 1129, 1089, 1010, 917, 901, 847, 834, 818, 739 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.91 (s, 1 H, =CH), 7.61 (d, J = 8.4 Hz, 2 H, ArH), 7.50 (d, J = 8.4 Hz, 2 H, ArH), 7.44-7.39 (m, 4 H, ArH), 6.80 (s, 2 H, NH₂), 3.54 (s, 2 H, CH₂), 3.13 (s, 2 H, CH₂), 2.22 (s, 3 H, CH₃).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 158.36, 152.46, 134.44, 133.73, 133.25, 133.10, 131.59, 131.44, 130.25, 129.89, 129.09, 128.84, 115.95, 112.72, 110.85, 90.17, 52.55, 51.79, 42.37, 30.69.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₁₉Cl₂N₄: 421.0987; found: 421.1007.

2-Amino-8-(4-fluorobenzylidene)-4-(4-fluorophenyl)-5,6,7,8-tetrahydro-6-methyl-1,6-naphthyridine-3-carbonitrile (4e)

IR (KBr): 3273, 3146, 2215, 1625, 1602, 1558, 1505, 1452, 1423, 1362, 1265, 1224, 1160, 1105, 1012, 917, 848, 829, 798, 736 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.92 (s, 1 H, =CH), 7.47-7.41 (m, 4 H, ArH), 7.38 (t, J = 8.8 Hz, 2 H, ArH), 7.28 (t, J = 8.8 Hz, 2 H, ArH), 6.76 (s, 2 H, NH₂), 3.54 (s, 2 H, CH₂), 3.13 (s, 2 H, CH₂), 2.22 (s, 3 H, CH₃).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 162.36 (^¹ J _C,F = 245 Hz), 161.48 (^¹ J _C,F = 245 Hz), 157.88, 152.30, 151.83, 132.51, 132.45, 131.66, 131.58, 130.65, 130.57, 127.10, 117.68, 116.56, 115.85, 115.65, 115.44, 89.32, 55.24, 54.58, 45.17.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₁₉F₂N₄: 389.1578; found: 389.1586.

2-Amino-8-(4-bromobenzylidene)-4-(4-bromophenyl)-5,6,7,8-tetrahydro-6-methyl-1,6-naphthyridine-3-carbonitrile (4f)

IR (KBr): 3366, 3206, 2210, 1614, 1569, 1543, 1488, 1453, 1429, 1358, 1259, 1192, 1114, 1069, 1009, 891, 842, 818, 782, 738 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.89 (s, 1 H, =CH), 7.75 (d, J = 8.4 Hz, 2 H, ArH), 7.64 (d, J = 8.4 Hz, 2 H, ArH), 7.37-7.32 (m, 4 H, ArH), 6.82 (s, 2 H, NH₂), 3.53 (s, 2 H, CH₂), 3.12 (s, 2 H, CH₂), 2.22 (s, 3 H, CH₃).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₁₉Br₂N₄: 508.9976; found: 508.9964.

2-Amino-5,6,7,8-tetrahydro-6-methyl-8-(4-nitrobenzylidene)-4-(4-nitrophenyl)-1,6-naphthyridine-3-carbonitrile (4g)

IR (KBr): 3374, 3302, 2210, 1623, 1595, 1558, 1501, 1488, 1451, 1429, 1343, 1266, 1109, 1013, 925, 861, 850, 817, 785, 724 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.39 (d, J = 8.4 Hz, 2 H, ArH), 8.28 (d, J = 8.8 Hz, 2 H, ArH), 8.03 (s, 1 H, =CH), 7.74 (d, J = 8.8 Hz, 2 H, ArH), 7.66 (d, J = 8.4 Hz, 2 H, ArH), 6.95 (s, 2 H, NH₂), 3.60 (s, 2 H, CH₂), 3.15 (s, 2 H, CH₂), 2.23 (s, 3 H, CH₃).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₁₉N₆O₄: 443.1468; found: 443.1491.

2-Amino-5,6,7,8-tetrahydro-6-methyl-8-(3-nitrobenzylidene)-4-(3-nitrophenyl)-1,6-naphthyridine-3-carbonitrile (4h)

IR (KBr): 3379, 3284, 2212, 1625, 1556, 1526, 1449, 1352, 1264, 1097, 916, 859, 822, 808, 743, 717, 701 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.39 (d, J = 8.0 Hz, 1 H, ArH), 8.29 (s, 1 H, ArH), 8.20 (d, J = 8.4 Hz, 1 H, ArH), 8.15 (s, 1 H, ArH), 8.03 (s, 1 H, =CH), 7.92-7.84 (m, 3 H, ArH), 7.75 (t, J = 8.4 Hz, 1 H, ArH), 6.90 (s, 2 H, NH₂), 3.61 (s, 2 H, CH₂), 3.22-3.14 (m, 2 H, CH₂), 2.23 (s, 3 H, CH₃).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 157.85, 151.94, 150.56, 147.95, 147.87, 137.52, 136.60, 135.70, 135.09, 134.90, 130.58, 130.17, 126.02, 124.07, 123.71, 123.23, 122.33, 117.10, 116.25, 89.60, 54.78, 54.23, 44.99.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₁₉N₆O₄: 443.1468; found: 443.1460.

2-Amino-6-benzyl-5,6,7,8-tetrahydro-4-(2-thienyl)-8-(2-thien­ylmethylene)-1,6-naphthyridine-3-carbonitrile (4i)

IR (KBr): 3275, 3201, 2207, 1621, 1556, 1454, 1412, 1352, 1267, 1215, 1088, 1067, 935, 855, 750, 716 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.07 (s, 1 H, =CH), 7.80 (d, J = 5.2 Hz, 1 H, ArH), 7.73 (d, J = 5.2 Hz, 1 H, ArH), 7.29-7.25 (m, 5 H, ArH), 7.23 (m, 2 H, ArH), 7.21-7.16 (m, 2 H, ArH), 6.81 (s, 2 H, NH₂), 3.70 (s, 2 H, CH₂), 3.63 (s, 2 H, CH₂), 3.33 (s, 2 H, CH₂).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 158.24, 153.04, 145.23, 138.97, 137.55, 134.08, 130.68, 129.57, 129.41, 129.27, 128.94, 128.80, 128.15, 128.11, 127.62, 127.13, 121.38, 118.33, 116.61, 89.28, 60.67, 53.13, 52.20.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₁N₄S₂: 441.1207; found: 441.1192.

2-Amino-6-benzyl-8-benzylidene-5,6,7,8-tetrahydro-4-phenyl-1,6-naphthyridine-3-carbonitrile (4j)

IR (KBr): 3329, 3208, 2223, 1655, 1571, 1533, 1473, 1367, 1331, 1232, 1154, 1100, 932, 892, 766, 736, 698 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.79 (s, 1 H, =CH), 7.49-7.48 (m, 3 H, ArH), 7.39-7.31 (m, 8 H, ArH), 7.18 (m, 1 H, ArH), 7.16 (s, 2 H, NH₂), 7.12-7.10 (m, 3 H, ArH), 3.64 (s, 2 H, CH₂), 3.50 (s, 2 H, CH₂), 3.18 (s, 2 H, CH₂).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 161.21, 160.43, 155.01, 137.38, 135.24, 134.38, 130.64, 129.55, 129.41, 128.82, 128.66, 128.53, 128.34, 128.05, 128.00, 127.55, 127.03, 115.89, 113.99, 112.72, 88.31, 59.81, 51.67.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₅N₄: 429.2074; found: 429.2106.

2-Amino-6-benzyl-5,6,7,8-tetrahydro-8-(3-nitrobenzylidene)-4-(3-nitrophenyl)-1,6-naphthyridine-3-carbonitrile (4k)

IR (KBr): 3365, 3204, 2212, 1616, 1556, 1528, 1455, 1350, 1264, 1101, 1028, 935, 809, 764, 741, 700 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.31 (s, 1 H, ArH), 8.25 (s, 2 H, NH₂), 8.14 (m, 1 H, ArH), 8.02 (s, 1 H, =CH), 7.84 (d, J = 7.6 Hz, 1 H, ArH), 7.72-7.64 (m, 3 H, ArH), 7.14 (s, 7 H, ArH), 3.81 (s, 2 H, CH₂), 3.56 (s, 2 H, CH₂), 3.38 (d, J = 7.2 Hz, 2 H, CH₂).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 157.92, 152.39, 150.78, 147.82, 147.73, 137.45, 137.33, 136.54, 135.62, 134.51, 130.47, 130.03, 128.87, 127.93, 126.97, 126.57, 123.94, 123.53, 123.12, 122.25, 117.39, 116.24, 89.70, 59.76, 52.09, 51.60.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₃N₆O₄: 519.1781; found: 519.1794.

2-Amino-6-benzyl-5,6,7,8-tetrahydro-8-(4-methoxybenzylidene)-4-(4-methoxyphenyl)-1,6-naphthyridine-3-carbonitrile (4l)

IR (KBr): 3378, 3235, 2208, 1640, 1608, 1548, 1501, 1459, 1363, 1297, 1255, 1178, 1029, 908, 830, 757, 736, 700 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.90 (s, 1 H, =CH), 7.29-7.18 (m, 7 H, ArH), 7.16-7.14 (m, 2 H, ArH), 7.03-6.99 (m, 2 H, ArH), 6.96-6.93 (m, 2 H, ArH), 6.63 (s, 2 H, NH₂), 3.81 (s, 3 H, CH₃), 3.78 (s, 3 H, CH₃), 3.68 (s, 2 H, CH₂), 3.52 (s, 2 H, CH₂), 3.30 (s, 2 H, CH₂).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.54, 158.83, 158.03, 153.11, 152.61, 137.76, 131.04, 130.37, 129.67, 128.78, 128.49, 128.37, 128.03, 127.20, 126.97, 117.29, 116.93, 114.05, 113.92, 89.04, 60.44, 55.17, 53.17, 52.35.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₁H₂₉N₄O₂: 489.2291; found: 489.2269.

2-Amino-6-benzyl-8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile (4m)

IR (KBr): 3298, 3213, 2221, 1636, 1562, 1529, 1493, 1474, 1365, 1246, 1225, 1092, 1013, 904, 827, 762, 700 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.75 (s, 1 H, =CH), 7.57 (d, J = 8.4 Hz, 2 H, ArH), 7.44-7.39 (m, 5 H, ArH), 7.31 (d, J = 8.8 Hz, 2 H, ArH), 7.19-7.17 (m, 4 H, ArH and NH₂), 7.12-7.10 (m, 2 H, ArH), 3.60 (s, 2 H, CH₂), 3.51 (s, 2 H, CH₂), 3.19 (s, 2 H, CH₂).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 160.35, 157.71, 137.34, 134.32, 134.06, 133.15, 132.97, 131.25, 129.68, 129.43, 128.85, 128.80, 128.56, 128.03, 127.85, 127.06, 119.58, 115.75, 112.72, 100.94, 59.58, 51.50, 51.32.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₃Cl₂N₄: 497.1295; found: 497.1286.

2-Amino-6-benzyl-8-(4-bromobenzylidene)-4-(4-bromophenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile (4n)

IR (KBr): 3304, 3197, 2222, 1639, 1604, 1566, 1531, 1510, 1474, 1364, 1235, 1160, 1105, 1014, 903, 834, 792, 759, 700 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.71-7.67 (m, 3 H, ArH and =CH), 7.57 (d, J = 8.4 Hz, 2 H, ArH), 7.34 (d, J = 8.4 Hz, 2 H, ArH), 7.30-7.20 (m, 4 H, ArH), 7.19-7.18 (m, 3 H, ArH and NH₂), 7.12-7.10 (m, 2 H, ArH), 3.61 (s, 2 H, CH₂), 3.51 (s, 2 H, CH₂), 3.22 (s, 2 H, CH₂).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₃Br₂N₄: 585.0284; found: 585.0296.

2-Amino-6-benzyl-5,6,7,8-tetrahydro-8-(4-nitrobenzylidene)-4-(4-nitrophenyl)-1,6-naphthyridine-3-carbonitrile (4o)

IR (KBr): 3343, 3217, 2211, 1594, 1556, 1513, 1455, 1429, 1342, 1260, 1108, 1014, 894, 851, 750, 703 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.33 (d, J = 8.8 Hz, 2 H, ArH), 8.20 (d, J = 8.8 Hz, 2 H, ArH), 8.02 (s, 1 H, =CH), 7.67 (d, J = 8.8 Hz, 2 H, ArH), 7.56 (d, J = 8.8 Hz, 2 H, ArH), 7.20-7.11 (m, 5 H, ArH), 6.99 (s, 2 H, NH₂), 3.71 (s, 2 H, CH₂), 3.52 (s, 2 H, CH₂), 3.28 (s, 2 H, CH₂).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 157.90, 152.30, 151.25, 147.79, 146.15, 142.71, 141.64, 137.43, 135.55, 130.44, 129.96, 128.80, 128.04, 127.02, 126.78, 123.75, 123.57, 117.30, 116.08, 89.46, 59.77, 52.22, 51.78.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₃N₆O₄: 519.1781; found: 519.1767.

Pyrano[3,2- c ]pyridines 3; General Procedure Using Microwave Irradiation

In a 10-mL reaction vial, the 3,5-dibenzylidene-4-piperidone 1 (1 mmol), malononitrile (2; 1 mmol), NH₄OAc (6 mmol) and DMF (2 mL) were mixed, and then the vial was capped. The mixture was irradiated at 200 W (initial power: 150 W, maximum power: 200 W) at 120 ˚C for the time given in Table  [³] . Upon completion of the reaction (monitored by TLC), the mixture was worked up using the procedure given above for the 1,6-naphthyridines 4.

2-Amino-8-benzylidene-5,6,7,8-tetrahydro-6-methyl-4-phenyl-4 H -pyrano[3,2- c ]pyridine-3-carbonitrile (3a)

IR (KBr): 3338, 3284, 2189, 1640, 1619, 1594, 1489, 1453, 1415, 1399, 1326, 1272, 1218, 1171, 1110, 1050, 917, 904, 878, 766, 756, 699 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.43-7.35 (m, 4 H, ArH), 7.31-7.22 (m, 6 H, ArH), 6.93 (s, 1 H, =CH), 6.84 (s, 2 H, NH₂), 4.06 (s, 1 H, CH), 3.48 (d, J = 14.4 Hz, 1 H, CH₂), 3.28 (d, J = 14.4 Hz, 1 H, CH₂), 3.00 (d, J = 16.0 Hz, 1 H, CH₂), 2.57 (d, J = 16.0 Hz, 1 H, CH₂), 2.15 (s, 3 H, CH₃).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.79, 143.49, 139.15, 135.93, 128.96, 128.69, 128.49, 127.60, 127.46, 127.14, 121.43, 120.44, 113.23, 112.71, 55.86, 54.56, 54.08, 44.50, 41.07.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₂N₃O: 356.1758; found: 356.1756.

2-Amino-5,6,7,8-tetrahydro-6-methyl-8-(4-methylbenzylidene)-4-(4-methylphenyl)-4 H -pyrano[3,2- c ]pyridine-3-carbonitrile (3b)

IR (KBr): 3389, 3295, 2178, 1644, 1604, 1511, 1461, 1448, 1416, 1395, 1323, 1269, 1205, 1171, 1101, 1055, 911, 812 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.22 (d, J = 8.0 Hz, 2 H, ArH), 7.17-7.13 (m, 4 H, ArH), 7.09 (d, J = 8.0 Hz, 2 H, ArH), 6.87 (s, 1 H, =CH), 6.76 (s, 2 H, NH₂), 3.99 (s, 1 H, CH), 3.46 (d, J = 14.8 Hz, 1 H, CH₂), 3.28 (d, J = 17.2 Hz, 1 H, CH₂), 2.96 (d, J = 16.4 Hz, 1 H, CH₂), 2.53 (d, J = 17.6 Hz, 1 H, CH₂), 2.31 (s, 3 H, CH₃), 2.29 (s, 3 H, CH₃), 2.14 (s, 3 H, CH₃).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.72, 140.55, 139.08, 136.53, 136.21, 133.09, 129.23, 129.09, 128.92, 127.50, 126.80, 121.28, 120.48, 112.93, 55.99, 54.56, 54.17, 44.52, 40.70, 20.79, 20.65.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₆N₃O: 384.2071; found: 384.2089.

2-Amino-8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-5,6,7,8-tetrahydro-6-methyl-4 H -pyrano[3,2- c ]pyridine-3-carbonitrile (3c)

IR (KBr): 3365, 3289, 2180, 1645, 1605, 1489, 1461, 1449, 1413, 1393, 1321, 1267, 1207, 1169, 1092, 1056, 1014, 986, 911, 817, 737, 697 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.48-7.43 (m, 4 H, ArH), 7.26 (m, 4 H, ArH), 6.92 (s, 2 H, NH₂), 6.89 (s, 1 H, =CH), 4.12 (s, 1 H, CH), 3.46 (d, J = 13.6 Hz, 1 H, CH₂), 3.28 (d, J = 14.8 Hz, 1 H, CH₂), 3.00 (d, J = 16.0 Hz, 1 H, CH₂), 2.55 (d, J = 16.0 Hz, 1 H, CH₂), 2.16 (s, 3 H, CH₃).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.79, 142.43, 139.23, 134.78, 131.76, 131.72, 130.71, 129.47, 128.70, 128.51, 128.13, 120.36, 120.19, 113.25, 55.54, 54.39, 53.92, 44.40, 40.39.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₀Cl₂N₃O: 424.0978; found: 424.0989.

2-Amino-5,6,7,8-tetrahydro-6-methyl-8-(3-nitrobenzylidene)-4-(3-nitrophenyl)-4 H -pyrano[3,2- c ]pyridine-3-carbonitrile (3d)

IR (KBr): 3359, 3267, 2190, 1639, 1596, 1522, 1456, 1416, 1348, 1266, 1174, 1116, 1052, 984, 899, 818, 738, 714, 682 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.19-8.14 (m, 2 H, ArH), 8.09 (s, 1 H, ArH), 8.06 (s, 1 H, ArH), 7.75-7.69 (m, 4 H, ArH), 7.05 (s, 3 H, NH₂ and =CH), 4.41 (s, 1 H, CH), 3.53 (d, J = 14.0 Hz, 1 H, CH₂), 3.28 (d, J = 14.8 Hz, 1 H, CH₂), 3.09 (d, J = 16.4 Hz, 1 H, CH₂), 2.59 (d, J = 16.0 Hz, 1 H, CH₂), 2.17 (s, 3 H, CH₃).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.98, 148.06, 147.94, 145.66, 139.42, 137.45, 135.14, 134.46, 130.48, 130.09, 129.62, 123.37, 122.41, 122.04, 121. 84, 119.98, 119.84, 113.67, 55.07, 54.14, 53.60, 44.25, 40.48.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₀N₅O₅: 446.1459; found: 446.1459.

2-Amino-5,6,7,8-tetrahydro-6-methyl-8-(4-nitrobenzylidene)-4-(4-nitrophenyl)-4 H -pyrano[3,2- c ]pyridine-3-carbonitrile (3e)

IR (KBr): 3365, 3293, 2182, 1642, 1593, 1521, 1458, 1418, 1392, 1340, 1273, 1172, 1097, 1055, 907, 868, 809, 716 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.26 (d, J = 8.0 Hz, 4 H, ArH), 7.54 (d, J = 8.8 Hz, 4 H, ArH), 7.06 (s, 2 H, NH₂), 7.03 (s, 1 H, =CH), 4.36 (s, 1 H, CH), 3.53 (d, J = 14.4 Hz, 1 H, CH₂), 3.48-3.43 (m, 1 H, CH₂), 3.08 (d, J = 16.4 Hz, 1 H, CH₂), 2.56 (d, J = 16.4 Hz, 1 H, CH₂), 2.17 (s, 3 H, CH₃).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.91, 150.84, 146.75, 145.93, 142.74, 139.46, 130.70, 130.09, 128.98, 124.10, 123.70, 120.07, 119.95, 114.32, 56.01, 54.75, 54.25, 53.81, 44.30, 40.69.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₀N₅O₅: 446.1459; found: 446.1472.

2-Amino-8-(4-bromobenzylidene)-4-(4-bromophenyl)-5,6,7,8-tetrahydro-6-methyl-4 H -pyrano[3,2- c ]pyridine-3-carbonitrile (3f)

IR (KBr): 3364, 3283, 2181, 1644, 1590, 1486, 1459, 1409, 1391, 1321, 1267, 1169, 1104, 1074, 1010, 910, 895, 828, 814, 734 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.61-7.56 (m, 4 H, ArH), 7.23-7.18 (m, 4 H, ArH), 6.89 (s, 2 H, NH₂), 6.87 (s, 1 H, =CH), 4.11 (s, 1 H, CH), 3.46 (d, J = 14.0 Hz, 1 H, CH₂), 3.26 (d, J = 14.0 Hz, 1 H, CH₂), 3.00 (d, J = 16.4 Hz, 1 H, CH₂), 2.53 (d, J = 16.4 Hz, 1 H, CH₂), 2.16 (s, 3 H, CH₃).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.72, 142.77, 139.18, 135.05, 131.55, 131.36, 130.93, 129.78, 128.11, 120.35, 120.30, 120.18, 120.11, 113.16, 55.39, 54.32, 53.85, 44.33, 40.40.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₀Br₂N₃O: 511.9968; found: 511.9979.

2-Amino-6-benzyl-8-benzylidene-5,6,7,8-tetrahydro-4-phenyl-4 H -pyrano[3,2- c ]pyridine-3-carbonitrile (3g)

IR (KBr): 3299, 3259, 2189, 1639, 1618, 1592, 1491, 1453, 1400, 1374, 1349, 1269, 1218, 1169, 1100, 1075, 1042, 919, 878, 746, 696 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.37-7.32 (m, 4 H, ArH), 7.29-7.25 (m, 2 H, ArH), 7.23-7.19 (m, 4 H, ArH), 7.18-7.16 (m, 3 H, ArH), 7.09-7.07 (m, 2 H, ArH), 6.95 (s, 1 H, =CH), 6.86 (s, 2 H, NH₂), 4.01 (s, 1 H, CH), 3.63 (d, J = 14.4 Hz, 1 H, CH₂), 3.45 (m, 3 H, CH₂), 3.07 (d, J = 16.0 Hz, 1 H, CH₂), 2.69 (d, J = 16.0 Hz, 1 H, CH₂).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.79, 151.99, 150.42, 143.48, 139.47, 137.74, 135.89, 128.87, 128.64, 128.38, 128.00, 127.56, 127.10, 126.91, 121.83, 120.39, 112.87, 108.59, 59.89, 56.05, 52.26, 51.69, 41.07.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆N₃O: 432.2071; found: 432.2081.

2-Amino-6-benzyl-8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-5,6,7,8-tetrahydro-4 H -pyrano[3,2- c ]pyridine-3-carbonitrile (3h)

IR (KBr): 3329, 3279, 2192, 1649, 1598, 1489, 1411, 1395, 1375, 1325, 1265, 1214, 1169, 1091, 1049, 1013, 917, 884, 826, 753, 700 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.43-7.39 (m, 4 H, ArH), 7.23-7.17 (m, 7 H, ArH), 7.07-7.06 (m, 2 H, ArH), 6.92 (s, 1 H, =CH), 6.90 (s, 2 H, NH₂), 4.07 (s, 1 H, CH), 3.61 (d, J = 14.8 Hz, 1 H, CH₂), 3.46-3.42 (m, 3 H, CH₂), 3.06 (d, J = 16.8 Hz, 1 H, CH₂), 2.66 (d, J = 16.0 Hz, 1 H, CH₂).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.78, 142.45, 139.46, 137.69, 134.73, 131.70, 130.62, 129.45, 128.66, 128.60, 128.42, 127.99, 127.74, 126.94, 120.79, 120.19, 112.86, 112.72, 59.65, 55.60, 51.81, 51.61, 40.30.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₄Cl₂N₃O: 500.1291; found: 500.1301.

2-Amino-6-benzyl-8-(4-fluorobenzylidene)-4-(4-fluorophenyl)-5,6,7,8-tetrahydro-4 H -pyrano[3,2- c ]pyridine-3-carbonitrile (3i)

IR (KBr): 3334, 3298, 2197, 1650, 1602, 1507, 1417, 1398, 1375, 1267, 1225, 1157, 1091, 916, 831, 780, 756, 697 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.25-7.20 (m, 4 H, ArH), 7.19-7.14 (m, 7 H, ArH), 7.08-7.06 (m, 2 H, ArH), 6.92 (s, 1 H, =CH), 6.83 (s, 2 H, NH₂), 4.05 (s, 1 H, CH), 3.59 (d, J = 14.0 Hz, 1 H, CH₂), 3.45 (s, 2 H, CH₂), 3.40 (d, J = 14.4 Hz, 1 H, CH₂), 3.05 (d, J = 16.0 Hz, 1 H, CH₂), 2.65 (d, J = 16.0 Hz, 1 H, CH₂).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 161.15 (^¹ J _C,F = 257 Hz), 161.00 (^¹ J _C,F = 256 Hz), 153.76, 146.37, 139.63, 139.37, 137.69, 132.32, 132.28, 130.89 (^³ J _C,F = 8 Hz), 129.44 (^³ J _C,F = 8 Hz), 128.62, 127.99, 126.94, 120.86, 120.32, 115.40 (^² J _C,F = 21 Hz), 115.31 (^² J _C,F = 21 Hz), 112.66, 59.75, 55.84, 51.98, 51.57.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₄F₂N₃O: 468.1882; found: 468.1873.

2-Amino-6-benzyl-5,6,7,8-tetrahydro-8-(3-nitrobenzylidene)-4-(3-nitrophenyl)-4 H -pyrano[3,2- c ]pyridine-3-carbonitrile (3j)

IR (KBr): 3337, 3293, 2184, 1647, 1596, 1522, 1465, 1399, 1351, 1263, 1218, 1159, 1085, 914, 815, 739, 695, 685 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.17-8.16 (m, 1 H, ArH), 8.12-8.10 (m, 1 H, ArH), 8.03 (s, 2 H, NH₂), 7.70-7.65 (m, 4 H, ArH), 7.12-7.11 (m, 3 H, ArH), 7.07 (s, 1 H, =CH), 7.06-7.04 (m, 4 H, ArH), 4.35 (s, 1 H, CH), 3.66 (d, J = 14.4 Hz, 1 H, CH₂), 3.54 (d, J = 15.2 Hz, 1 H, CH₂), 3.49-3.34 (m, 2 H, CH₂), 3.13 (d, J = 16.4 Hz, 1 H, CH₂), 2.69 (d, J = 16.0 Hz, 1 H, CH₂).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.78, 142.45, 139.46, 137.69, 134.73, 131.70, 131.09, 130.62, 129.45, 128.66, 128.60, 128.42, 127.99, 127.74, 126.93, 124.02, 120.79, 118.67, 114.22, 112.87, 59.65, 56.01, 55.60, 51.89, 51.81, 51.62, 40.29.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₄N₅O₅: 522.1772; found: 522.1761.

2-Amino-6-benzyl-5,6,7,8-tetrahydro-8-(4-nitrobenzylidene)-4-(4-nitrophenyl)-4 H -pyrano[3,2- c ]pyridine-3-carbonitrile (3k)

IR (KBr): 3329, 3301, 2200, 1650, 1591, 1517, 1421, 1398, 1340, 1269, 1218, 1168, 1108, 920, 895, 859, 811, 748, 700 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.24-8.19 (m, 4 H, ArH), 7.51-7.48 (m, 4 H, ArH), 7.15 (s, 1 H, =CH), 7.14-7.13 (m, 2 H, ArH), 7.08-7.06 (m, 3 H, ArH), 7.05 (s, 2 H, NH₂), 4.31 (s, 1 H, CH), 3.69 (d, J = 14.8 Hz, 1 H, CH₂), 3.53 (d, J = 14.8 Hz, 1 H, CH₂), 3.48 (s, 2 H, CH₂), 3.13 (d, J = 16.4 Hz, 1 H, CH₂), 2.66 (d, J = 15.6 Hz, 1 H, CH₂).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.90, 150.89, 146.73, 145.92, 142.73, 139.70, 137.52, 133.95, 130.34, 130.01, 128.97, 128.57, 127.98, 126.95, 124.03, 123.60, 120.54, 119.90, 113.88, 59.42, 54.85, 51.58, 40.59.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₄N₅O₅: 522.1772; found: 522.1774.

2-Amino-6-benzyl-8-(4-bromobenzylidene)-4-(4-bromophenyl)-5,6,7,8-tetrahydro-4 H -pyrano[3,2- c ]pyridine-3-carbonitrile (3l)

IR (KBr): 3326, 3293, 2196, 1644, 1594, 1485, 1407, 1392, 1373, 1322, 1267, 1170, 1098, 1071, 1010, 917, 887, 815, 749, 696 cm^-¹.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.51-7.48 (m, 4 H, ArH), 7.14-7.12 (m, 5 H, ArH), 7.10 (m, 2 H, ArH), 7.02-7.00 (m, 2 H, ArH), 6.86 (s, 2 H, NH₂), 6.84 (s, 1 H, =CH), 3.99 (s, 1 H, CH), 3.56 (d, J = 14.4 Hz, 1 H, CH₂), 3.40-3.36 (m, 3 H, CH₂), 3.00 (d, J = 16.0 Hz, 1 H, CH₂), 2.60 (d, J = 16.0 Hz, 1 H, CH₂).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.77, 142.87, 139.46, 137.69, 135.06, 131.59, 131.58, 131.34, 130.92, 129.83, 128.60, 128.01, 127.77, 126.93, 120.85, 120.32, 120.23, 112.84, 59.62, 55.48, 51.75, 51.67, 40.36.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₄Br₂N₃O: 588.0281; found: 588.0272.

Acknowledgment

We are grateful for financial support from the National Science Foundation of China (No. 20672090), the Natural Science Foundation of Jiangsu Province (No. BK2006033) and the Six Kinds of Professional Elite Foundation of Jiangsu Province (No. 06-A-039).

References

• 1a Padwa A. Austin DJ. Angew. Chem., Int. Ed. Engl.  1994,  33:  1797 
  Search in Google Scholar
• 1b Seo J. Chui HMP. Heeg MJ. Montgomery J. J. Am. Chem. Soc.  1999,  121:  476 
  Search in Google Scholar
• 1c Organ MG. Arvanitis EA. Dixon CE. Cooper JT. J. Am. Chem. Soc.  2002,  124:  1288 
  Search in Google Scholar
• 1d Davies HML. Panaro SA. Tetrahedron  2000,  56:  4871 
  Search in Google Scholar
• 1e Lebel H. Paquet V. Org. Lett.  2002,  4:  1671 
  Search in Google Scholar
• 1f Hunter R. Hinz W. Richards P. Tetrahedron Lett.  1999,  40:  3643 
  Search in Google Scholar
• 1g Tu S. Jiang B. Zhang Y. Jia R. Zhang J. Yao C. Shi F. Org. Biomol. Chem.  2007,  5:  355 
  Search in Google Scholar
• 1h Wang J. Mason R. Derveer DV. Feng K. Bu XR. J. Org. Chem.  2003,  68:  5415 
  Search in Google Scholar
• 1i Lin M.-Y. Maddirala SJ. Liu R.-S. Org. Lett.  2005,  7:  1745 
  Search in Google Scholar
• 2 El-Subbagh HI. Abu-Zaid SM. Mahran MA. Badria FA. Al-Obaid AM. J. Med. Chem.  2000,  43:  2915 
  CrossrefSearch in Google Scholar
• 3 Hammam AG. Sharaf MA. Abdel-Hafez NA. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  2001,  40:  213 
  Search in Google Scholar
• 4 Gangjee A. Zeng Y. McGuire JJ. Kisliuk RL. J. Med. Chem.  2002,  45:  5173 
  CrossrefSearch in Google Scholar
• 5 El-Kashef HS. Geies AA. Kamal El.-DeanAM. Abdel-Hafez AA. J. Chem. Technol. Biotechnol.  1993,  57:  15 
  Search in Google Scholar
• 6 Haglid F. Ark. Kemi  1967,  26:  489 
  Search in Google Scholar
• 7 Skotnicki JS. inventors; US Patent  4902685.  , (American Home Products Corporation, New York, N.Y.),
• 8 Blagg J, Fray MJ, Lewis ML, Mathias JP, Stefaniak MH, and Stobie A. inventors; PCT Int. Appl. WO  2003076427.  (Pfizer Ltd, UK; Pfizer, USA),
• 9a Tu S. Jia R. Jiang B. Zhang J. Zhang Y. Yao C. Ji S. Tetrahedron  2007,  63:  381 
  Search in Google Scholar
• 9b Tu S. Zhang J. Jia R. Zhang Y. Jiang B. Shi F. Synthesis  2007,  558 

The single-crystal growth was carried out in ethanol at room temperature. X-ray crystallographic analysis was performed with a Siemens SMART CCD and a Siemens P4 diffractometer (graphite monochromator, MoKα radiation, λ = 0.71073 Å). Crystal data for 4i: empirical formula = C₂₅H₂₀N₄S₂, formula weight = 440.57, crystal dimensions = 0.13 × 0.12 × 0.03 mm, monoclinic, space group P2(1)/n, a = 11.0619(12) Å, b = 11.2598(13) Å, c = 17.5329(19) Å, α = 90, β = 93.6620(10), γ = 90, µ = 0.265 mm^-¹, V = 2179.3(4) Å^³, Z = 4, D _c  = 1.343 g/cm^³, F(000) = 920, S = 0.808, R ₁ = 0.0665, wR ₂ = 0.0863.

References

• 1a Padwa A. Austin DJ. Angew. Chem., Int. Ed. Engl.  1994,  33:  1797 
  Search in Google Scholar
• 1b Seo J. Chui HMP. Heeg MJ. Montgomery J. J. Am. Chem. Soc.  1999,  121:  476 
  Search in Google Scholar
• 1c Organ MG. Arvanitis EA. Dixon CE. Cooper JT. J. Am. Chem. Soc.  2002,  124:  1288 
  Search in Google Scholar
• 1d Davies HML. Panaro SA. Tetrahedron  2000,  56:  4871 
  Search in Google Scholar
• 1e Lebel H. Paquet V. Org. Lett.  2002,  4:  1671 
  Search in Google Scholar
• 1f Hunter R. Hinz W. Richards P. Tetrahedron Lett.  1999,  40:  3643 
  Search in Google Scholar
• 1g Tu S. Jiang B. Zhang Y. Jia R. Zhang J. Yao C. Shi F. Org. Biomol. Chem.  2007,  5:  355 
  Search in Google Scholar
• 1h Wang J. Mason R. Derveer DV. Feng K. Bu XR. J. Org. Chem.  2003,  68:  5415 
  Search in Google Scholar
• 1i Lin M.-Y. Maddirala SJ. Liu R.-S. Org. Lett.  2005,  7:  1745 
  Search in Google Scholar
• 2 El-Subbagh HI. Abu-Zaid SM. Mahran MA. Badria FA. Al-Obaid AM. J. Med. Chem.  2000,  43:  2915 
  CrossrefSearch in Google Scholar
• 3 Hammam AG. Sharaf MA. Abdel-Hafez NA. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  2001,  40:  213 
  Search in Google Scholar
• 4 Gangjee A. Zeng Y. McGuire JJ. Kisliuk RL. J. Med. Chem.  2002,  45:  5173 
  CrossrefSearch in Google Scholar
• 5 El-Kashef HS. Geies AA. Kamal El.-DeanAM. Abdel-Hafez AA. J. Chem. Technol. Biotechnol.  1993,  57:  15 
  Search in Google Scholar
• 6 Haglid F. Ark. Kemi  1967,  26:  489 
  Search in Google Scholar
• 7 Skotnicki JS. inventors; US Patent  4902685.  , (American Home Products Corporation, New York, N.Y.),
• 8 Blagg J, Fray MJ, Lewis ML, Mathias JP, Stefaniak MH, and Stobie A. inventors; PCT Int. Appl. WO  2003076427.  (Pfizer Ltd, UK; Pfizer, USA),
• 9a Tu S. Jia R. Jiang B. Zhang J. Zhang Y. Yao C. Ji S. Tetrahedron  2007,  63:  381 
  Search in Google Scholar
• 9b Tu S. Zhang J. Jia R. Zhang Y. Jiang B. Shi F. Synthesis  2007,  558 

The single-crystal growth was carried out in ethanol at room temperature. X-ray crystallographic analysis was performed with a Siemens SMART CCD and a Siemens P4 diffractometer (graphite monochromator, MoKα radiation, λ = 0.71073 Å). Crystal data for 4i: empirical formula = C₂₅H₂₀N₄S₂, formula weight = 440.57, crystal dimensions = 0.13 × 0.12 × 0.03 mm, monoclinic, space group P2(1)/n, a = 11.0619(12) Å, b = 11.2598(13) Å, c = 17.5329(19) Å, α = 90, β = 93.6620(10), γ = 90, µ = 0.265 mm^-¹, V = 2179.3(4) Å^³, Z = 4, D _c  = 1.343 g/cm^³, F(000) = 920, S = 0.808, R ₁ = 0.0665, wR ₂ = 0.0863.