HETEROCYCLES

Paper | Special issue | Vol. 84, No. 1, 2012, pp. 555-567
Received, 7th May, 2011, Accepted, 13th June, 2011, Published online, 21st June, 2011.
DOI: 10.3987/COM-11-S(P)22

■ Oxaheterocycles: Di- and Trioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-diones and Dibenzo[a,c]cycloheptene-3-carbonitriles

Hardesh K. Maurya, Ramendra Pratap, Vishnu K. Tandon,* Pushyamitra Mishra, Brijesh Kumar, and Vishnu Ji Ram*

Department of Chemistry, University of Lucknow, Lucknow, U.P. 226007, India

Abstract

An efficient and convenient synthesis of 9-aryl-11,12-dihydro-13H-5,8-dioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-diones and 9-aryl-11,12-dihydro-5,8,13-trioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-diones has been delineated through base catalyzed condensation-cyclization of 4-methylsulfanyl-2-oxo-2,5,6,7-tetrahydro-1-oxadibenzo[a,c]cycloheptene-3-carbonitriles and 4-methylsulfanyl-2-oxo-5,6-dihydro-2H-1,7-dioxadibenzo[a,c]cycloheptene-3-carbonitriles with aryl methyl ketone separately. We have also reported the synthesis of 2-aryl-4-sec-amino-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-carbonitriles through ring transformationof 4-sec-amino-2-oxo-2,5,6,7-tetrahydro-1-oxadibenzo[a,c]cycloheptene-3-carbonitriles with aryl methyl ketones in the presence of powdered KOH/NaOH in DMF. We have successfully synthesized 4-aryl-2-(piperidin-1-yl)-5,6-dihydro-7-oxadibenzo[a,c]cycloheptene-1-carbonitriles as isomeric products through ring transformation of 6-aryl-4-sec-amino-2H-pyran-2-one-3-carbonitriles by 3,4-dihydro-2H-benzo[b]oxepin-5(2H)-ones.

INTRODUCTION
An extensive literature survey revealed that the chemistry of 5,8-dioxa- and 5,8,13-trioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-diones remains to be explored. The only report available so far on these oxaheteroarenes is the synthesis1 of pyrano[3,4-c]chromene-4,5-dione (I) and benzo[h]pyrano[3,4-c]chromene-1,12-dione (II) with their anticancer,2 antibacterial,3 photochemical4 and luminescence5 properties. As evident from the topography of these molecules, it seems obvious that pharmacological and optical properties are possibly due to the presence of pyranopyrandione substructure. This inspired us to design newer class of molecules with pyranopyrandione substructure fused with 6, 7, 8, 9-tetrahydro-5H-benzocycloheptene and 2,3,4,5-tetrahydrobenzo[b]oxepine rings resulting III a, b for better efficacy as antimicrobial agents (Figure 1).

Recently, we have reported6 the non-regioselective synthesis of pyranopyrandiones from the reaction of 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carbonitrile with aryl acetones. However, under analogous conditions, reaction of 1 and aryl methyl ketone gave 4,6-diarylpyran-2-ylidene-2-acetonitrile (2) 6b in lieu of compounds like 3-methyl-4,6-diarylpyrano[3,4-c]pyran-1,8-dione (3) (Scheme 1). This discrepancy is possibly due to difference in the hardness of carbanion generated in situ from ketones.

Thus, unpredictability of the course of reactions aroused considerable interest to explore the chemistry of rigid analogs of biaryl systems as depicted in Scheme 2.

RESULTS AND DISCUSSION
The chemistry of rigid analogs of biaryl systems 7, 10, prepared through base induced reaction of 4-methylsulfanyl-2-oxo-2,5,6,7-tetrahydro-1-oxadibenzo[a,c]cycloheptene-3-carbonitrile (6a), 4-methyl sulfanyl-2-oxo-5,6-dihydro-2H-1,7-dioxadi-benzo[a,c]cycloheptene-3-carbonitriles (6b-e) and 4-sec-amino-2-oxo-2,5,6,7-tetrahydro-1-oxadibenzo[a,c]cycloheptene-3-carbonitriles (9) by aryl methyl ketone separately is delineated in Scheme 2.
However, in all the cases reaction of 6a and 6b-e with aryl methyl ketone exclusively gave 9-aryl-11,12-dihydro-13H-5,8-dioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-dione (7a,b) and 9-aryl-11,12-dihydro-5,8,13-trioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-dione (7c-j) respectively.

We were also interested to prepare 2-aryl-4-methylsulfanyl-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-carbonitrile (8a) from the reaction of 6a with aryl methyl ketone but failed to isolate the right product. Thus, a different synthetic strategy was followed to obtain product analogous to 8 by introducing a sec-amino substituent in place of methylsulfanyl group at position 4 of the lactone (6a) for preferential attack at position C11b for the ring transformation reactions.
The precursors, 4-methylsulfanyl-2-oxo-2,5,6,7-tetrahydro-1-oxadibenzo[a,c]cycloheptene-3-carbonitrile (6a) and 4-methylsulfanyl-2-oxo-5,6-dihydro-2H-1,7-dioxadibenzo[a,c]cycloheptene-3-carbonitriles (6b-e) were prepared from the base induced condensation-cyclization of 6,7,8,9-tetrahydrobenzocyclo-hepten-5-one (4a) or 3,4-dihydro-2H-benzo[b]oxepin-5(2H)-ones7,8 (4b), with methyl 2-cyano-3,3-dimethylthioacrylate separately in the presence of powdered KOH or NaOH in DMF. The use of NaOH as a base in the preparation of 6 was found yield wise superior (15-20%) compared to KOH, Scheme 2 (Table 1). 4-sec-Amino-2-oxo-2,5,6,7-tetrahydro-1-oxadibenzo[a,c]cycloheptene-3-carbonitriles (9), required for the construction of 4-sec-amino-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-carbonitrile (10) were obtained by amination9 of 6a with different sec-amine in boiling ethanol (Scheme 2).

The molecular make up of 4-methylsulfanyl-2-oxo-2,5,6,7-tetrahydro-1-oxadibenzo[a,c]cycloheptene-3-carbonitrile (6a) and 4-methylsulfanyl-2-oxo-5,6-dihydro-2H-1,7-dioxadibenzo[a,c]cycloheptene-3-carbonitriles (6b-e) revealed the presence of three electrophilic sites C2, C4, and C11b in which the latter is likely most electron deficient due to extended conjugation and the presence of an electron-withdrawing CN substituent at position 3 of the lactone ring. However, the electrophilicity of C11b is not enough compared to C4 for preferential nucleophilic attack, possibly due to the presence of methylene bridge at C4a of the lactone. The only option to direct the carbanion attack at C11b was to introduce sec-amino function at C4 to reduce its electrophilicity. Under this situation C11b position of the lactone ring becomes susceptible to attack by carbanion, generated in situ either from 6,7,8,9-tetrahydrobenzocycohepten-5-one (4a) or 3,4-dihydro-2H-benzo[b]oxepin-5(2H)-ones (4b) in the presence of powdered KOH/NaOH and DMF. The progress of the reaction was clearly evident by evolution of carbon dioxide bubbles. The completion of reaction was monitored by silica gel coated TLC plates. Thus, an equimolar mixture of 4-methylsulfanyl-2-oxo-2,5,6,7-tetrahydro-1-oxadibenzo[a,c]cycloheptene-3-carbonitrile (6a) or 4-methylsulfanyl-2-oxo-5,6-dihydro-2H-1,7-dioxadibenzo[a,c]cycloheptene-3-carbonitriles (6b-e) and aryl methyl ketone was separately stirred with anhydrous powdered KOH in DMF for 8-18 h at room temperature. Thereafter, the reaction mixture was poured onto crushed ice with vigorous stirring followed by neutralization with 10% aqueous HCl. The resulting precipitate was filtered, washed with water and dried. The crude product was purified by silica gel column chromatography which exclusively gave 9-aryl-11,12-dihydro-13H-5,8-di-oxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-diones (7a,b) and 9-aryl-11,12-dihydro-5,8,13-trioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-dione (7c-j) (Table 2) without any trace formation of expected 2-aryl-4-methylsulfanyl-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-carbonitriles (8).

A different protocol was followed for the preparation of 2-aryl-4-sec-amino-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-carbonitriles (10) by using 4-sec-amino-2-oxo-2,5-tetrahydro-1-oxadibenzo[a,c]cycloheptene-3-carbonitriles (9) as a precursor. Thus, an equimolar mixture of 9 and aryl methyl ketone in the presence of powdered KOH in DMF was stirred for 6-8 h at room temperature. Usual work up and silica gel column chromatography exclusively gave 2-aryl-4-sec-amino-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-carbonitrile (10) in moderate yield. The initial step in the synthesis of 7 is the attack of a carbanion, generated in situ from aryl methyl ketone at C4 of the lactone (6), followed by ring closure involving enolate of the ketone intermediate and CN function. The cyclic imine intermediate so formed is hydrolysed to yield 7. However, the first step in the synthesis of 10 is the formation of Michael adduct with aryl methyl ketone which underwent ring opening in situ followed by recyclization involving C3 of 9 and carbonyl function of aryl methyl ketone. A plausible mechanism of the reaction is illustrated in Scheme 3.

A different synthetic strategy was followed for the construction of 4-aryl-2-methylthio-5,6-dihydro-7- oxadibenzo[a,c]cycloheptene-1-carbonitriles and 4-aryl-2-(piperidin-1-yl)-5,6-dihydro-7-oxadibenzo[a,c]cycloheptene-1-carbonitriles (12a,b), a structural isomers of 8b through the ring transformation of 1b by 4. However, the interaction of 1a with 4 did not follow the same course of reaction and the products isolated were characterized10 as 2-(4-aryl-6,7-dihydro-5H-1,7-dioxadibenzocycloheptene-2-ylidene)-acetonitriles (11a,b) (Scheme 4).

CONCLUSION
In conclusion, we have developed a novel, simple and economical route for the synthesis of various 9-aryl-11,12-dihydro-13H-5,8-dioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-diones (7a,b), 9-aryl-11,12-dihydro-5,8,13-trioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-diones (7c-j) from the reaction of 4-methylsulfanyl-2-oxo-2,5,6,7-tetrahydro-1-oxadibenzo[a,c]cycloheptene-3-carbonitrile (6a) and 4-methylsulfanyl-2-oxo-5,6-dihydro-2H-1,7-dioxadibenzo[a,c]cycloheptene-3-carbonitriles (6b-e) separately with aryl methyl ketone. A new protocol for the construction of 2-aryl-4-sec-amino-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-carbonitrile (10) has also been developed from the reaction of 9 with aryl methyl ketone in the presence of KOH/NaOH in DMF through C-C insertion, not reported so far. The protocol provides an efficient and concise route for the preparation of new class of annelated oxaheterocycles, reported for the first time.

EXPERIMENTAL
Materials and methods: The reagents and the solvents used in this study were of analytical grade and used without further purification. The melting points were determined on an electrically heated Townson Mercer melting point apparatus and are uncorrected. Commercial reagents were used without purification. 1H and 13CNMR spectra were measured on a Bruker WM-300 (300 MHz) using CDCl3 and DMSO-d6 solvents. Chemical shift are reported in parts per million shift (δ-value) from Me4Si (δ 0 ppm for 1H) or based on the middle peak of the solvent (CDCl3) (δ 77.00 ppm for 13CNMR) as the internal standard. Signal patterns are indicate as s, singlet; d, doublet; dd, double doublet; t, triplet; m, multiplet. Coupling constant (J) are given in Hertz. Infrared (IR) spectra were recorded on a Perkin-Elmer AX-1 spectrophotometer in KBr disc and reported in wave number (cm-1). Fast-atomic bombardment (FAB) and ESIMS spectrometers were used for mass spectra analysis. 13C NMR for all compounds is not reported due to poor solubility of compounds in DMSO-d6.
General procedure for the synthesis of 4-methylsulfanyl-2-oxo-2,5,6,7-tetrahydro-1-oxadibenzo[a,c]cycloheptene-3-carbonitrile (6a) and 4-methylsulfanyl-2-oxo-5,6-dihydro-2H-1,7-dioxadibenzo[a,c]cycloheptene-3-carbonitriles (6b): A mixture of 6,7,8,9-tetrahydrobenzocyclohepten-5-one or 3,4-dihydro- 2H-benzo[b]oxepin-5(2H)-one 4 (1 mmol) and methyl 2-cyano-3,3-dimethylthioacrylate 5 (1 mmol) in DMSO (8 mL) was stirred in the presence of powdered KOH (2 mmol) for 5 h and the reaction mixture was poured onto crushed ice with vigorous stirring. The aqueous suspension was neutralized with 10% HCl (5 mL) and the precipitate obtained was filtered, washed with water and purified on silica gel column, using DCM as eluent.
4-Methylsulfanyl-2-oxo-2,5,6,7-tetrahydro-1-oxadibenzo[a,c]cycloheptene-3-carbonitrile (6a): Light yellow amorphous solid; yield: 65%; mp 166-67 ºC; 1H NMR (400 MHz, DMSO-d6): δ 2.17 (t, J = 6.8 Hz, 2H, CH2), 2.34 (t, J = 6.8Hz, 2H, CH2), 2.65 (t, J = 6.8Hz, 2H, CH2), 2.95 (s, 3H, SCH3), 7.40-7.59 (m, 3H, ArH), 7.60 (d, J = 7.2 Hz, 1H, ArH); 13C NMR (100 MHz, DMSO-d6): δ 17.4, 23.5, 30.5, 32.8, 93.9, 114.9, 115.9, 126.8, 127.9, 129.4, 131.5, 131.5, 141.0, 157.5, 158.3, 168.7; HRMS (EI, 70 eV) Calcd for C16H13NO2S: 283.0669 (M+). Found: 283.0658.
4-Methylsulfanyl-2-oxo-5,6-dihydro-2H-1,7-dioxadibenzo[a,c]cycloheptene-3-carbonitrile (6b): White powder; yield: 59%; mp 194 ºC; IR (KBr): 2937, 2212 (CN), 1725 (C=O), 1582, 1488, 1276, 1185, 1126, 1065, 1009, 828, 771, 672, 562 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.95 (t, J = 6 Hz, 2H), 3.01 (s, 3H, SCH3), 4.50 (t, 2H, J= 6 Hz, OCH2), 7.08 (m, 1H, ArH), 7.21 (m, 1H, ArH), 7.45 (m, 1H, ArH), 7.95 (m, 1H, ArH); MS (ESI): m/z 286 (M++1); HRMS (EI, 70 eV) Calcd for C15H11NO3S: 285.0460 (M+). Found: 285.0451.
10-Methyl-4-methylsulfanyl-2-oxo-5,6-dihydro-2H-1,7-dioxadibenzo[a,c]cycloheptene-3-carbonitrile(6c): Yellow powder; yield: 55%; mp 180 ºC; IR (KBr): 3020, 2929, 2221 (CN), 1720 (C=O), 1589, 1489, 1216, 1129, 1039, 830, 760, 669, 493 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.36 (s, 3H, Me), 2.92 (t, J = 6 Hz, 2H), 3.01 (s, 3H, SCH3), 4.47 (t, 2H, J= 6 Hz, OCH2), 7.00 (d, 1H, J=9, Hz, ArH), 7.26 (d, J=9, 1H, ArH), 7.70 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3): 18.20, 20.61, 27.80, 29.65, 74.62, 93.67, 114.55, 115.77, 121.83, 122.32, 129.62, 133.44, 134.35, 155.44, 155.90, 158.11; MS (ESI): m/z 300 (M++1), 301 (M++2); HRMS (EI, 70 eV) Calcd for C16H13NO3S: 299.06161 (M+). Found: 299.0628.
10-Methoxy-4-methylsulfanyl-2-oxo-5,6-dihydro-2H-1,7-dioxadibenzo[a,c]cycloheptene-3-carbonitrile(6d): Yellow amorphous solid; yield: 65%; mp 178 ºC; IR (KBr): 2956, 2216 (CN), 1722 ( C=O), 1585, 1489, 1271, 1212, 1037, 840, 761, 668, 502 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.87 (t, J = 6 Hz, 2H), 3.01 (s, 3H, SCH3), 3.83 (s, 3H, OCH3), 4.47 (t, 2H, J= 6 Hz, OCH2), 7.03 (s, 1H, ArH), 7.28 (d, J = 9 Hz, 2H, ArH); 13C NMR (75 MHz, CDCl3): δ 18, 27, 55, 75, 93, 112 (2C), 114, 115, 120, 123, 124, 150, 155, 158, 168; MS: m/z 315 (M+); HRMS (ESI) Calcd for C16H13NO4S: 316.0626 (M++1). Found: 316.0633.
8,10-Dimethyl-4-methylsulfanyl-2-oxo-5,6-dihydro-2H-1,7-dioxadibenzo[a,c]cycloheptene-3-carbonitrile(6e): Yellow amorphous solid; yield: 65%; mp 210 ºC; IR (KBr): 2936, 2887, 2217 (CN), 1698 (C=O), 1602, 1561, 1485, 1307, 1271, 1226, 1071, 1017, 958, 851, 782, 755, 669, 501 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.35 (s, 3H, Me), 2.43 (s, 3H, Me), 2.71 (t, J = 6 Hz, 2H), 3.02 (s, 3H, SCH3), 4.43 (t, 2H, J= 6 Hz, OCH2), 6.81 (s, 1H, ArH), 6.93 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3): δ 17.81, 20.37, 21.39, 25.11, 77.87, 93.57, 114.66, 115.27,120.84, 122.49, 128.62, 139.18, 143.66, 155.65, 157.94, 158.32, 167.48; MS (ESI): m/z 314 (M++1); HRMS (EI, 70 eV) Calcd for C17H15NO3S: 313.0773 (M+). Found: 313.0761.
General procedure for the synthesis of 9-aryl-11,12-dihydro-13H-5,8-dioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-diones (7a,b) and 9-aryl-11,12-dihydro-5,8,13-trioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-diones (7c): A mixture of 4-methylsulfanyl-2-oxo-2,5,6,7-tetrahydro-1- oxadibenzo[a,c]cycloheptene- 3-carbonitrile 6 (1.0 mmol) and aryl methyl ketone (1.1 mmol) and powdered KOH (1.2 mmol) in DMF (10 mL) was stirred at room temperature for 8-18 h. After completion, reaction mixture was poured onto crushed ice and neutralized with 10% HCl. The crude product obtained was filtered, washed with water and finally purified by a silica gel column chromatography using 25% EtOAc in hexane.
9-(4-Bromophenyl)-11,12-dihydro-13H-5,8-dioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-dione (7a): White leaflet solid; mp 252 oC; yield: 40%; IR (KBr): 2926, 2855, 1780 (C=O), 1704 (C=O), 1596, 1461, 1351 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 2.30-2.35 (m, 2H, CH2), 2.42-2.45 (m, 2H, CH2), 2.60-2.62 (m, 2H, CH2), 7.19-7.21 (m, 1H, ArH), 7.38-7.76 (m, 4H, ArH), 8.0 (d, J = 8.4 Hz, 2H, ArH), 8.1 (d, J = 8.4 Hz, 2H, ArH); HRMS (EI, 70 eV) Calcd for C23H15BrO4: 434.0154 (M+). Found: 434.0155.
9-Thiophen-2-yl-11,12-dihydro-13H-5,8-dioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-dione (7b): White leaflet solid; mp 220 oC; yield: 60%; IR (KBr): 2925, 2853, 1781 (C=O), 1703 (C=O), 1593, 1460, 1352 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 2.25-2.28 (m, 2H, CH2), 2.45-2.50 (m, 2H, CH2), 2.63-2.67 (m, 2H, CH2), 7.20-7.22 (m, 1H, ArH), 7.40-7.46 (m, 4H, ArH), 7.60-7.62 (m, 1H, ArH), 7.73-7.80 (m, 1H, ArH), 8.10-8.12 (m, 1H, ArH); 13C NMR (100 MHz, CDCl3): δ 22.64, 31.93, 33.65, 63.47, 97.03, 100.23, 103.21, 113.00, 126.53, 126.69, 127.97, 128.22, 129.19, 129.40, 129.58, 130.22, 133.31, 140.81, 140.93, 144.14; MS: m/z 360 (M+), 345, 331, 316; HRMS (EI, 70 eV) Calcd for C21H14O4S: 362.0613 (M+). Found: 362.0602.
3-Methoxy-9-phenyl-11,12-dihydro-5,8,13-trioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-dione (7c): Yellow amorphous solid; yield: 67%; mp >290 oC; IR (KBr): 3058, 2935, 1763 (C=O), 1701 (C=O), 1628, 1560, 1492 cm-1; 1H NMR (CDCl3, 300 MHz): δ 3.00 (t, J=6 Hz, 2H, CH2), 3.86 (s, 3H, OCH3), 4.54 (t, J=6 Hz, 2H, OCH2), 6.86 (s, 1H), 7.04 (s, 1H, ArH), 7.27 (s, 1H, ArH), 7.54 (m, 4H, ArH), 7.97 (m, 2H, ArH); MS (ESI): m/z 388 (M+); HRMS (ESI) Calcd for C23H16O6: 389.0980 (M++1). Found 389.0973.
9-(4-Chlorophenyl)-3-methoxy-11,12-dihydro-5,8,13-trioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-dione (7d): Yellow powder; yield: 52%; mp >290 oC; IR (KBr): 3201, 3113, 2941, 1763 (C=O), 1701 (C=O), 1623, 1520, 1488, 1468, 1446 cm-1; 1H NMR (CDCl3, 300 MHz): δ 3.03 (t, J=6, 2H, CH2), 3.81 (s, 3H, OCH3), 4.49 (t, J=6 Hz, 2H, OCH2), 7.13 (m, 2H, ArH), 7.30 (s, 1H), 7.49 (s, 1H, ArH), 7.68 (d, J=8.1 Hz, 2H, ArH), 8.15 (d, J=8.1 Hz, 2H, ArH); MS (ESI): m/z 423 (M+); HRMS (ESI) Calcd for C23H15ClO6: 423.0606 (M++1). Found: 423.0615.
3-Methoxy-9-p-tolyl-11,12-dihydro-5,8,13-trioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-dione (7e): Yellow amorphous solid; yield: 47%; mp 256 oC; IR (KBr): 2934, 1763 (C=O), 1696 (C=O), 1619, 1555, 1486, 1380, 1264, 1204, 1100, 1039, 818 cm-1; 1H NMR (CDCl3, 300 MHz): δ 2.41 (s, 3H, Me), 3.03 (bs, 2H, CH2), 3.81 (s, 3H, OCH3), 4.49 (bs, 2H, OCH2), 7.13 (m, 2H, ArH), 7.31 (s, 1H), 7.41 (m, 3H, ArH), 8.04 (d, J=7.2 Hz, 2H, ArH); MS (ESI): m/z 402 (M+); HRMS (ESI) Calcd for C24H18O6: 403.1137 (M++1). Found 403.1145.
3-Methoxy-9-pyridin-4-yl-11,12-dihydro-5,8,13-trioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-dione (7f): Yellow amorphous solid; yield: 46%; mp >290 oC; IR (KBr): 3052, 2934, 1763 (C=O), 1702 (C=O), 1633, 1566, 1497, 1405, 1272, 1207, 1088, 1025, 818, 783 cm-1; 1H NMR (CDCl3, 300 MHz): δ 3.06 (bs, 2H, CH2), 3.81 (s, 3H, OCH3), 4.51 (bs, 2H, OCH2), 7.14 (bs, 2H, ArH), 7.32 (s, 1H), 7.66 (s, 1H, ArH), 8.04 (bs, 2H, ArH), 8.83 (bs, 2H, ArH); MS (ESI): m/z 389 (M+); HRMS (ESI) Calcd for C22H15NO6: 390.0933 (M++1). Found: 390.0921.
3-Methoxy-9-naphthalen-1-yl-11,12-dihydro-5,8,13-trioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-dione (7g): Yellow powder; yield: 42%; mp 272 oC; IR (KBr): 3046, 2959, 1769 (C=O), 1713 (C=O), 1571, 1491, 1381, 1246, 1212, 1099, 1041, 938, 793, 769 cm-1; 1H NMR (CDCl3, 300 MHz): δ 3.00 (bs, 2H, CH2), 3.82 (s, 3H, OCH3), 4.45 (bs, 2H, OCH2), 7.13 (m, 2H, ArH), 7.25 (s, 1H), 7.36 (s, 1H, ArH), 7.67 (m, 3H, ArH), 7.94 (m, 1H, ArH), 8.09 (m, 1H, ArH), 8.20 (m, 1H, ArH), 8.29 (m, 1H, ArH); MS (ESI): m/z 438 (M+); HRMS (ESI) Calcd for C27H18O6: 439.1137 (M++1). Found: 439.1120.
9-(4-Chlorophenyl)-11,12-dihydro-5,8,13-trioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-dione (7h): Yellow powder; yield: 41%; mp 290 oC; IR (KBr): 3090, 2931, 2891, 1764 (C=O), 1702 (C=O), 1580, 1492, 1401, 1258, 1214, 1094, 1008, 824, 769, cm-1; 1H NMR (CDCl3, 300 MHz): δ 3.06 (bs, 2H, CH2), 4.54 (bs, 2H, OCH2), 6.83 (s, 1H), 7.10 (d, J=7.8 Hz, 1H, ArH), 7.21 (m, 1H, ArH), 7.44 (d, J=6.9Hz, 1H, ArH), 7.51 (d, J=8.1Hz, 2H, ArH), 7.91 (d, J=8.1Hz, 2H, ArH), 8.19 (d, J=8.1Hz, 1H, ArH); MS (ESI): m/z 392 (M+); HRMS (ESI) Calcd for C23H13ClO5: 393.0485 (M++1). Found: 393.0479.
9-(4-Chlorophenyl)-1,3-dimethyl-11,12-dihydro-5,8,13-trioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-dione (7i): White leaflet solid; yield: 45%; mp >290 oC; IR (KBr): 3089, 2943, 1762 (C=O), 1701 (C=O), 1591, 1500, 1428, 1400, 1286, 1207, 1121, 1071, 1001, 891, 827, 801 cm-1; 1H NMR (CDCl3+DMSO-d6, 300 MHz): δ 2.36 (s, 3H, 8-Me), 2.48 (s, 3H, 10-Me), 2.72 (bs, 2H, CH2), 4.51 (bs, 2H, OCH2), 6.84 (s, 1H, ArH), 6.87 (s, 1H, ArH), 6.95 (s, 1H), 7.52 (d, J=8.1Hz, 2H, ArH), 7.93 (d, J=8.1Hz, 2H, ArH); MS (ESI): m/z 420 (M+); HRMS (ESI) Calcd for C24H17ClO5: 421.0798 (M++1). Found: 421.0782.
9-(4-Chlorophenyl)-3-methyl-11,12-dihydro-5,8,13-trioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-6,7-dione (7j): White leaflet solid; yield: 40%; mp >290 oC; IR (KBr): 3092, 2968, 1763 (C=O), 1704 (C=O), 1617, 1562, 1489, 1400, 1307, 1255, 1216, 1086, 1090, 1029, 886, 823 cm-1; 1H NMR (DMSO-d6, 300 MHz): δ 2.36 (s, 3H, 8-Me), 3.08 (bs, 2H, CH2), 4.50 (bs, 2H, OCH2), 7.06 (d, J=8.1Hz, 1H, ArH), 7.36 (d, J=8.4Hz, 1H, ArH), 7.48 (s, 1H), 7.70 (m, 3H, ArH), 8.15 (d, J=8.1Hz, 2H, ArH); MS (ESI): m/z 406 (M+); HRMS (EI, 70 eV) Calcd for C23H15ClO5S: 406.0608 (M+). Found: 406.0614.
General procedure for the synthesis of 4-sec-amino-2-oxo-2,5,6,7-tetrahydro-1-oxadibenzo[a,c]cycloheptene-3-carbonitriles (9): A mixture of 6 (1 mmol) and sec-amine (1.1 mmol) was refluxed in absolute EtOH for 6 h. During this period precipitate separated out which was filtered after cooling, washed with cold EtOH and finally crystallized with acetone.
4-(Piperidin-1-yl)-2-oxo-2,5,6,7-tetrahydro-1-oxadibenzo[a,c]cycloheptene-3-carbonitrile (9a): Light yellow amorphous solid; yield: 60%; mp 168 ºC; 1H NMR (400 MHz, DMSO-d6): δ 1.65 (bs, 6H, CH2), 2.09 (t, J = 6.8 Hz, 2H, CH2), 2.22 (t, J = 6.8 Hz, 2H, CH2), 2.65 (t, J = 6.8 Hz, 2H, CH2), 3.53-3.54 (m, 4H, NCH2), 7.36-7.47 (m, 3H, ArH), 7.53-7.56 (m, 1H, ArH); 13C NMR (100 MHz, DMSO-d6): δ 22.78, 24.67, 26.0, 31.3, 33.9, 52.9, 53.0, 77.7, 99.5, 111.8, 117.2, 126.8, 127.9, 129.3, 131.4, 132.0, 141.5, 159.8, 161.8, 167.4; HRMS: (CI) Calcd for C20H20N2O2: 320.1525 (M+). Found: 320.1539.
4-(Morpholin-4-yl)-2-oxo-2,5,6,7-tetrahydro-1-oxadibenzo[a,c]cycloheptene-3-carbonitrile (9b): Light yellow amorphous solid; yield: 70%; mp 175 ºC; 1H NMR (400 MHz, DMSO-d6): δ 2.10 (t, J = 6.8 Hz, 2H, CH2), 2.22 (p, J = 6.8 Hz, 2H, CH2), 2.65 (t, J= 6.8 Hz, 2H, CH2), 3.63 (t, J = 4.8 Hz, 4H, NCH2), 3.94 (t, J = 4.8 Hz, 4H, OCH2), 7.37-7.47 (m, 3H, ArH), 7.54-7.56 (m, 1H, ArH); 13C NMR (100 MHz, DMSO-d6): δ 24.65, 31.2, 33.9, 51.9, 66.4, 78.1, 111.5, 117.2, 126.8, 127.9, 129.3, 131.5, 131.8, 141.5, 160.2, 161.5, 166.9; HRMS (CI) Calcd for C19H18N2O3: 322.1317 (M+). Found for m/z 322.1312.
General procedure for the synthesis of 2-aryl-4-sec-amino-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-carbonitrile (10): An equimolar mixture of 9 (1 mmol) and aryl methyl ketone was stirred in DMF (8 mL) in the presence of powdered KOH (1.5 mmol) at room temperature for 6-8 h. Thereafter, the reaction mixture was poured onto crushed ice and the precipitate separated was filtered, washed with water and dried. The crude product was purified by silica gel column chromatography using 25% EtOAc in hexane.
2-(4-Bromophenyl)-4-piperidin-1-yl-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-carbonitrile (10): Viscous liquid; yield: 40%; 1H NMR (400 MHz, CDCl3): δ 2.23-2.24 (m, 2H, CH2), 2.42-2.45 (m, 2H, CH2), 2.60-2.62 (m, 2H, CH2), 3.20-3.51 (m, 6H, CH2), 3.88-3.92 (m, 4H, CH2), 7.17 (s, 1H), 7.23-7.37 (m, 2H, ArH), 7.42-7.45 (m, 2H, ArH), 7.58-7.60 (m, 2H, ArH), 7.42-7.45 (m, 2H, ArH); 13C NMR (100 MHz, CDCl3): δ 22.67, 25.29, 25.50, 26.92, 31.35, 31.60, 32.75, 34.67, 67.81, 109.42, 118.04, 123.02, 126.80, 127.0, 128.3, 128.7, 128.9, 130.5, 131.8, 137.28, 137.95, 139.3, 139.5, 144.1, 147.7, 153.2; MS (CI): m/z 456 (M+), 458 (M++2); HRMS (CI) Calcd for C27H25BrN2: 456.1201 (M+). Found: 456.1190.
General procedure for the synthesis of 2-(4-aryl-6,7-dihydro-5H-1,7-dioxadibenzo[a,c]cycloheptene-2-ylidene)acetonitriles (11): A mixture of 3,4-dihydrobenzo[b]oxepine-5(2H)-ones 4 (1 mmol), 6-aryl-4- methylthio-2-oxo-2H-pyran-3-carbonitriles 1a (1 mmol) and powdered KOH (2 mmol) in DMF (8 mL) was stirred for 3 h.The reaction mixture was poured onto crushed ice with vigorous stirring. The aqueous phase was neutralized with 10% HCl and the precipitate obtained was filtered, washed with water and purified on silica gel column using hexane:DCM mixture (7:3) as eluent.
[4-(4-Chlorophenyl)-10-methoxy-5,6-dihydro-1,7-dioxadibenzo[a,c]cyclohepten-2-ylidene]acetonitrile(11a): Reddish amorphous solid; yield: 55%; mp 200 oC; 1H NMR (300 MHz, CDCl3): δ (Z-isomer, 70%) 2.50 (s, 2H, CH2), 3.89 (s, 3H, OCH3), 4.26 (s, 2H, OCH2), 6.18 (s, 1H, CH), 6.65-7.43 (m, 8H, ArH); δ (E-isomer, 30%) 2.41 (s, 2H, CH2), 3.83 (s, 3H, OCH3), 4.35 (s, 2H, OCH2), 6.65 (s, 1H, CH), 6.65-7.43 (m, 8H, ArH); 13C NMR (75 MHz, CDCl3): δ 31, 55, 65, 72, 110, 112, 115, 116, 117, 118, 119, 122(2C), 129(2C), 135(2C), 146, 150, 151, 155, 164; MS (ESI): m/z 378 (M+), 380 (M++2); HRMS (ESI) Calcd for C22H16ClNO3: 378.0897 (M++1). Found: 378.0889.
2-(10-Methoxy-4-phenyl-5,6-dihydro-5H-1,7-dioxadibenzo[a,c]cycloheptene-2-ylidene)acetonitrile (11b): Reddish amorphous solid; yield: 39%; mp 116 oC; IR (KBr): 2933, 2513, 2223 (CN), 2187, 1637, 1571, 1487, 1399 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.35 (s, 3H, Me), 2.43 (s, 3H, Me), 2.71 (t, 2H, CH2 J=6 Hz), 3.02 (s, 3H, SMe), 4.43 (t, 2H, OCH2, J=6 Hz), 6.81(s, 1H, Ar-H), 6.93 (s, 1H, Ar-H); MS (ESI): m/z 344 (M++1); HRMS (ESI) Calcd for C22H17NO3: 344.1142 (M++1). Found: 344.1138.
General procedure for the synthesis of 4-aryl-2-(piperidin-1-yl)-5,6-dihydro-7-oxadibenzo[a,c]cycloheptene-1-carbonitriles (12): A mixture of 3,4-dihydrobenzo[b]oxepine-5(2H)-ones 4 (1 mmol) and 6-aryl-4-(sec-amino)-2H-pyran-2-one-3-carbonitrile 1b (1 mmol) in DMF (6 mL) was stirred for 3 h in the presence of powdered KOH (2 mmol). After completion of the reaction, content was poured onto crushed ice with vigorous stirring and neutralized with 10% HCl. The precipitate obtained was filtered, washed with water and dried. The crude product was purified through silica gel column using a mixture of hexane: DCM (7:3) as eluent.
2-Methoxy-8-phenyl-10-piperidin-1-yl-6,7-dihydro-5-oxadibenzo[a,c]cycloheptene-11-carbonitrile (12a): White solid; yield: 44%; mp 144 oC; IR (KBr): 3069, 2934, 2850, 2804, 2218 (CN), 1573, 1496, 1439 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.52-1.69 (m, 6H), 3.06 (m, 2H), 3.20 (m, 4H), 3.79 (s, 3H), 4.24 ( m, 2H), 6.97-7.03 (m, 2H), 7.08 (s, 1H), 7.24 (d, 1H, J=3 Hz), 7.38-7.48 (m, 5H); 13C NMR (75 MHz, CDC3): δ 24, 26(2C), 28, 53(2C), 55, 78, 105, 115, 116, 118, 119, 122, 127(2C), 128(3C), 132(2C), 140, 143, 146, 148, 155, 156; MS (ESI): m/z 411 (M++1), 412 (M++2); HRMS (ESI) Calcd for C27H26N2O2: 411.20725 (M++1). Found: 411.20728.
2-Methoxy-8-naphthalen-1-yl-10-piperidin-1-yl-6,7-dihydro-5-oxadibenzo[a,c]cycloheptene-11-carbonitrile (12b): Light yellow solid; yield: 36%; mp 188 oC; IR (KBr): 2938, 2217 (CN), 1640, 1496, 1459 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.60-2.49 (m, 6H), 3.18 (m, 2H), 3.82 (s, 3H), 3.91-4.16 (m, 4H), 4.73 ( m, 2H), 6.80-7.07 (m, 3H), 7.23-7.81 (m, 6H), 7.92-7.94 (m, 2H); MS (ESI): m/z 461 (M++1), 462 (M++2); HRMS (ESI) Calcd for C31H28N2O2: 461.2184 (M++1). Found: 461.2179.

ACKNOWLEDGEMENTS
HKM, VKT and VJR are thankful to CSIR, New Delhi, India for financial support [project No-01(2280)/08/EMR-II] and SAIF, CDRI, Lucknow, India for providing spectroscopic data.

References

1. G. A. Greak, S. E. Liew, and S. F. J. Tan, Singapore Nat. Acad. Sci., 1973, 3, 223; J. A. Van Allan, and G. A. Reynolds, J. Heterocycl. Chem., 1971, 8, 803. CrossRef
2. T. Ikekawa, N. Uehara, Y. Maeda, M. Nakanishi, and F. Fukuoka, Cancer Res., 1969, 29, 734; T. Mizuno, Int. J. Med. Mushr, 1999, 1, 9.
3. T. Högberg, M. Vora, S. D. Drake, L. A. Mitscher, and D. T. W. Chu, Acta Chem. Scand.-B, 1984, 38, 359.
4. I. Petkov, Y. Anghelova, and P. Markov, Bulg. Acad. Sci., 1994, 81, 5.
5. P. Nikolov, I. Petkov, and P. Z. Markov, Naturforsch. A. Phys. Sci., 2000, 741.
6. a) R. Pratap, B. Kumar, and V. J. Ram, Tetrahedron, 2006, 62, 8158; CrossRef b) V. J. Ram and A. Goel, Tetrahedron Lett., 1996, 37, 9. CrossRef
7. V. K. Tandon, J. M. Khanna, and N. Anand, Tetrahedron, 1990, 46, 2871. CrossRef
8. V. J. Ram, M. Verma, F. A. Hussaini, and A. Soeb, J. Chem. Res. (S), 1991, 98; V. J. Ram, M. Verma, F. A. Hussaini, and A. Soeb, Liebigs Ann. Chem., 1991, 1229. CrossRef
9. V. J. Ram, M. Nath, P. Srivastava, S. Sarkhel, and P. R. Maulik, J. Chem. Soc., Perkin Trans. 1, 2000, 3719. CrossRef
10. V. K. Tandon, H. K. Maurya, B. Kumar, B. Kumar, and V. J. Ram, Synlett, 2009, 2992. CrossRef