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Radical-mediated cyclization reaction — Regioselective synthesis of pyrimidine- and coumarin-annulated [6,6]-fused oxygen heterocycles Krishna C. Majumdar, Pradip Debnath, and Pradip K. Maji
Abstract: The n-Bu3SnH-AIBN mediated aryl radical cyclization of various 8-[(2-bromophenoxy)methyl]-1,3-dimethyl2,3,4,6-tetrahydro-1H-pyrano[3,2-d]pyrimidine-2,4-diones and 1-[(2-bromophenoxy)methyl]-3,5-dihydropyrano[2,3c]coumarins was investigated with the formation of [6,6]-fused oxygen heterocycles as a single regioisomer. Key words: n-Bu3SnH-AIBN, aryl radical cyclization, 6-endo-trig, oxygen heterocycles, coumarin derivatives, pyrimidine derivatives Résumé : On a effectué une étude le la régiochimie de la cyclisation arylique radicalaire catalysée par le n-Bu3SnAIBN de diverses 8-[2-bromophénoxy]méthyl-1,3-diméthyl-2,3,4,6-tétrahydro-1H-pyrano[3,2-d]pyrimidine-2,4-diones et de 1-[(2-bromophénoxy)méthyl]-3,5-dihydropyrano[2,3-c]coumarines qui conduit à la formation d’hétérocycles oxygénés à fusion [6,6] sous la forme d’un seul régioisomère. Mots-clés : n-Bu3Sn-AIBN, cyclisation arylique radicalaire, 6-endo-trig, hétérocycles oxygénés, dérivés de la coumarine, dérivés de la pyrimidine. [Traduit par la Rédaction]
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Introduction Coumarin and its derivatives are important heterocyclic compounds that are found in many natural products (1), many of that exhibit remarkable physiological and biological activities (2). Many compounds containing the coumarin skeleton have shown antihelmintic, hypnotic, insecticidal, anti-coagulant, and antifungal properties (3). Some pyrimidine derivatives are active against cancer (4), viral disease (5), and the AIDS virus (6). Several efforts have been made to synthesize them. In the interest of synthesizing new coumarin and pyrimidine ring systems of biological interest, we previously reported the synthesis of several novel fiveand six-membered coumarin- and pyrimidine-annulated heterocycles by the application of sigmatropic rearrangements (7) and radical cyclization strategy (8). In recent years, intramolecular aryl radical cyclization has revolutionized the construction of various types of cyclic compounds via carbon–carbon bond-forming processes (9). In particular, the intramolecular addition of carbon-centered radical intermediates to arene and aromatic heterocycles has gained considerable prominence (10). It provides a mild and often high-yielding route to condensed aromatic ring systems. It has been rationalized that a stereoelectronically fa-
vored 5-exo cyclization is generally preferred over a 6-endo cyclization in those systems having an alkenic bond at the 5position relative to the radical center. However, regiochemistry of the radical cyclization can be influenced, and even reversed, to favor the formation of six-membered rings by factors other than stereoelectronic control (11). The extensive investigations of the 5-hexenyl radical revealed that there are three factors, namely the substitution pattern at C5, vinyl radical cyclization, and ring strain, that can direct 6endo cyclization over 5-exo cyclization (12). In this context, we recently reported the synthesis of pyrone- and coumarinannulated [6,6]-fused sulfur and oxygen heterocycles, respectively, based on the regioselective 6-endo-trig radical cyclization, wherein a mixture of diastereoisomers was obtained in some cases (13). More recently, we have shown that n-Bu3SnH-mediated cyclization of sulfur and sulfone precursors derived from coumarin afforded a mixture of [6,6]-fused and (or) spiro heterocycles (14). All these previous investigations have influenced us to undertake a study of the radical cyclization on o-bromoaryl enol ethers, using 8[(2-bromophenoxy]methyl]-1,3-dimethyl-2,3,4,6-tetrahydro1H-pyrano[3,2-d]pyrimidine-2,4-diones 5a–5f, and 1-[2bromophenoxy) methyl]-3,5-dihydropyrano[2,3-c]coumarin 5g–5l as the starting materials, with a view to synthesize the
Received 22 February 2008. Accepted 23 April 2008. Published on the NRC Research Press Web site at canjchem.nrc.ca on 11 July 2008. K.C. Majumdar1, P. Debnath, and P.K. Maji. Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India. 1
Corresponding author (e-mail:
[email protected]).
Can. J. Chem. 86: 846–854 (2008)
doi:10.1139/V08-087
© 2008 NRC Canada
Majumdar et al. Scheme 1. Reagents and conditions: (i) K2CO3, NaI, acetone, reflux, 6–10 h; (ii) chlorobenzene, reflux, 3–5 h.
847 Scheme 2. Reagents and conditions: (i) Toluene (0.01 mol/L), nBu3SnH, AIBN, reflux, 3.5 h.
Scheme 3.
polycyclic pyrimidine and coumarin derivatives, respectively. Here, we report the results of our investigation.
Results and discussion As radical precursors for our present study, we have prepared 8-[(2-bromophenoxy)methyl]-1,3-dimethyl-2,3,4,6tetrahydro-1H-pyrano[3,2-d]pyrimidine-2,4-diones (5a–5f) and 1-[(2-bromophenoxy)methyl]-3,5-dihydropyrano[2,3-c]coumarins (5g–5l), by the thermal rearrangement of 1,3-dimethyl 5-(4aryloxybut-2-ynyloxy) uracils (4a–4f) and 3-(4-aryloxybut2-ynyl)coumarins (4g–4l) in 81%–89% and 84%–90% yields, respectively. The compounds 4a–4l were, in turn, prepared by the classical alkylation of 1,3-dimethyl-5hydroxy uracil (1) or 3-hydroxycoumarin (2) with different 1-aryloxy-4-chlorobut-2-ynes (3a–3f) according to our earlier published procedure (7) (Scheme 1). As our aim was to synthesize [6,6]-fused oxygen heterocycles, we examined the scope of C–C bond formation of compounds 5 by n-Bu3SnH–AIBN (azobis-isobutylnitrile) mediated radical cyclization. Compound 5a, when heated with n-Bu3SnH (1.1 equiv.) and AIBN (0.5 equiv.) in dry benzene at 80 °C for 5 h, yielded a solid product. The 1H NMR spectrum of the product revealed that the cyclization did not occur. Only the halogen-reduced product was obtained. However, by changing the solvent to toluene under the same reaction conditions, we were able to obtain regioselectivly the cyclized product 6a in 89% yield. It has already been established that a very high level of diastereoselectivity could be obtained when the concentration of the reactant is reduced from 0.1 to 0.01 mol/L (15). These observations have been attributed to the reversibility of the cyclization and the decreased availability of the tin hydride. We then tried to carry out the cyclization reaction in highly dilute conditions. The conditions for the n-Bu3SnHAIBN procedure were optimized for the six-membered radical cyclizations of the substrates 5. Substrate 5a (0.01 mol/L) was refluxed in degassed dry toluene under nitrogen atmosphere with n-Bu3SnH (1.0 equiv.) for 3.5 h. The cyclization of 5a under dilute conditions gave 6a in 81% yield (Scheme 2). The high field 1H NMR (500 MHz in CDCl3) spectrum of the compound 6a displayed one proton double triplet at δ 3.28 (J = 3.8 Hz and 11.6 Hz) and another
one proton double triplet at δ 3.36 (J = 3.8 Hz and 11.7 Hz), owing to ring-juncture protons. The stereochemistry of the ring-juncture protons can be surmised from the molecular model (Dreiding model), which showed a strain-free cisarrangement. Compared with the literature results (7,13), the small coupling constant value (J = 3.8 Hz) of the ring juncture protons of 6a also indicated the cis stereochemistry. On the basis of this promising result, the tin hydride mediated cyclization of the precursors 5a–5f was conducted. The results are summarized in Table 1. From Table 1 it is observed that other substrates 5b–5f give exclusively the [6,6] pyranopyran derivatives 6b–6f in 76%–89% yields. Encouraged by the results of radical cyclization of pyrimidines, we have investigated similar radical cyclization reactions of substrates containing a coumarin moiety. Substrate 5g was subjected to radical cyclization under the aforesaid reaction conditions. Unfortunately, we were unable to obtain any cyclized product because the starting material decomposed under the reaction conditions. However, by changing the solvent to benzene and lowering the reaction temperature to 75 °C, we eliminated the decomposition of the starting material. It was observed that when the substrates 5g–5l were treated with n-Bu3SnH (1.0 equiv) and AIBN in benzene, cyclization proceeded affording the cyclized product 6g–6l in 75%–90% yields (Table 1). The formation of the products 6 from 5 may be explained by the generation of aryl radical 7, which may undergo either a 5-exo trig or a 6-endo-trig cyclization at the double bond of the pyran moiety as described in Scheme 3. A 6endo-trig cyclization of radical 7 may produce the intermediate radical 8 while a 5-exo-trig cyclization may give the © 2008 NRC Canada
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Can. J. Chem. Vol. 86, 2008 Table 1. Tin hydride-mediated radical cyclization of compounds 5a–5l.
spirocyclic radical 9 (not isolated), followed by neophyl rearrangement (16) to radical intermediate 10. Abstraction of a hydrogen from n-Bu3SnH by radical intermediate 7 may give the [6,6]-fused cyclized products 6. Aryl radical cyclization normally gives a high 5-exo : 6endo ratio indicating a stronger preference for exo cyclization than for alkyl radical cyclization. However, suitably substituted 5-hexenyl radicals are known to undergo 6endo cyclization to give six-membered rings. It is interesting to note that six-membered rings are formed regioselectively in all cases we have studied at present. Earlier we had reported the synthesis of the [6,6]pyranopyrans by sequential Claisen rearrangement of the 4-aryloxy-2-ynyloxy derivatives of uracil and coumarin (7). This radical cyclization protocol is found to give the polycyclic heterocycles in better yields under mild conditions.
Conclusion In conclusion, we have successfully extended the nBu3SnH mediated radical cyclization reaction to the regioselective synthesis of coumarin- and pyrimidineannulated [6,6]-fused heterocycles. The process is quite general and regioselective and afforded the desired products in good-to-excellent yields. The mildness of the reaction conditions and high level of regioelectivity allow this radical cyclization to serve as a powerful synthetic tool for the preparation of complex aromatic heterocycles.
Experimental Melting points were determined in an open capillary and are uncorrected. IR spectra were recorded on a © 2008 NRC Canada
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849 Table 1 (concluded).
Note: Reagent conditions: n-Bu3SnH, AIBN, toluene, reflux, 3–4 h; n-Bu3SnH, AIBN, benzene, 75 °C, 3–4 h.
PerkinElmer L 120-000A spectrometer (νmax in cm–1) on KBr disks. 1H NMR (300 MHz, 400 MHz, and 500 MHz) and 13C NMR (125.7 MHz) spectra were recorded on a Bruker DPX-300, Varian-400 FT–NMR, Bruker DPX-500 and spectrometer in CDCl3 (chemical shift in δ) with TMS as internal standard. Silica gel [(60–120 mesh), Spectrochem, India] was used for chromatographic separation. Petroleum ether refers to the fraction boiling between 60 and 80 °C.
5-({4-[(2-Bromo-6-methylphenyl)oxy]but-2-ynyl}oxy)-1,3dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (4a) Yield 91%; colorless solid; mp 161–163 °C (acetonitrile– methanol). IR (KBr, cm–1): 2923, 1707, 1648. 1H NMR (400 MHz, CDCl 3) δH: 2.56 (s, 3H, ArCH 3), 3.61 (s, 6H, -NCH3), 4.94 (s, 2H, -OCH2), 4.99 (s, 2H, -OCH2), 7.51 (m, 3H), 7.76 (s, 1H, C6H). MS m/z: 392, 394 (M+). Anal. calcd. for C17H17N2O4Br: C 51.92, H 4.36, N 12; found: C 52.06, H 4.31, N 7.14.
General procedure for the preparation of compounds 4a–4l The compounds 4a–4l were synthesized according to the earlier published procedure (7).
5-({4-[(2-Bromo-4,6-dimethylphenyl)oxy]but-2-ynyl}oxy)1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (4b): Yield 90%; colorless solid; mp 122–123 °C (acetonitrile– methanol). IR (KBr, cm–1): 2982, 1706, 1642. 1H NMR © 2008 NRC Canada
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(400 MHz, CDCl3) δH: 2.24 (s, 3H, ArCH3), 2.27 (s, 3H, ArCH3), 3.34 (s, 3H, -NCH3), 3.35 (s, 3H, -NCH3), 4.65 (s, 2H, -OCH2), 4.73 (s, 2H, -OCH2), 6.90 (s, 1H), 7.01 (s, 1H), 7.17 (s, 1H, C6H). MS m/z: 406, 408 (M+). Anal. calcd. for C18H19N2O4Br: C 53.08, H 4.70, N 6.88; found: C 53.24, H 4.76, N 6.91. 5-({4-[(2-Bromo-4-methylphenyl)oxy]but-2-ynyl}oxy)-1,3dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (4c) Yield 93%; colorless solid; mp 155–157 °C (acetonitrile– methanol). IR (KBr, cm–1): 2948, 1700, 1642. 1H NMR (400 MHz, CDCl 3 ) δH : 2.27 (s, 3H, ArCH 3 ), 3.22 (s, 3H, -NCH3), 3.36 (s, 3H, -NCH3), 4.73 (s, 2H, -OCH2), 4.76 (s, 2H, -OCH2), 7.08 (s, 1H, C6H), 7.24–7.29 (m, 3H). MS m/z: 392, 394 (M+). Anal. calcd. for C17H17N2O4Br: C 51.92, H 4.36, N 7.12; found: C 51.85, H 4.41, N 7.10. 5-({4-[(1-Bromonaphthalene-2-yl)oxy]but-2-ynyl}oxy)-1,3dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (4d) Yield 87%; colorless solid; mp 118–120 °C (acetonitrile– methanol). IR (KBr, cm–1): 2979, 1701, 1638. 1H NMR (400 MHz, CDCl 3 ) δH : 3.05 (s, 3H, -NCH 3 ), 3.29 (s, 3H, -NCH3), 4.72 (s, 2H, -OCH2), 4.93 (s, 2H, -OCH2), 6.80 (s, 1H, C6H), 7.30 (d, J = 8.9 Hz, 1H), 7.42 (d, J = 7.3 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.76 (m, 2H), 8.20 (d, J = 8.5 Hz, 1H). MS m/z: 428, 430 (M+). Anal. calcd. for C20H17N2O4Br: C 55.96, H 3.99, N 6.53; found: C 56.26, H 4.05, N 6.62. 5-({4-[(2-Bromophenyl)oxy]but-2-ynyl}oxy)-1,3-dimethyl1,2,3,4-tetrahydropyrimidine-2,4-dione (4e) Yield 96%; colorless solid; mp 104–106 °C (acetonitrile– methanol). IR (KBr, cm–1): 2979, 1705, 1639. 1H NMR (400 MHz, CDCl 3 ) δH : 3.32 (s, 3H, -NCH 3 ), 3.35 (s, 3H, -NCH3), 4.72 (s, 2H, -OCH2), 4.80 (s, 2H, -OCH2), 6.86– 6.99 (m, 2H), 7.06 (s, 1H, C6H), 7.47 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H). MS m/z:378, 380 (M+). Anal. calcd. for C16H15N2O4Br: C 50.68, H 3.99, N 7.39; found: C 50.58, H 4.02, N 7.37. 5-({4-[(2-Bromo-3-methylphenyl)oxy]but-2-ynyl}oxy)-1,3dimethyl–1,2,3,4-tetrahydropyrimidine-2,4-dione (4f) Yield 88%; colorless solid; mp 110–111 °C (acetonitrile– methanol). IR (KBr, cm–1): 2950, 1707, 1661. 1H NMR (400 MHz, CDCl 3 ) δH : 2.40 (s, 3H, ArCH 3 ), 3.20 (s, 3H, -NCH3), 3.32 (s, 3H, -NCH3), 4.72 (s, 2H, -OCH2), 4.78 (s, 2H, -OCH2), 6.77–6.84 (m, 1H), 6.92 (s, 1H, C6H), 7.08– 7.12 (m, 1H), 7.35–7.43 (m, 1H). MS m/z: 392, 394 (M+). Anal. calcd. for C17H17N2O4Br: C 51.92, H 4.36, N 7.12; found: C 52.16, H 4.37, N 7.23. 3-({4-[(2-Bromo-6-methylphenyl)oxy]but-2-ynyl}oxy)-2Hchromen-2-one (4g) Yield: 81%; colorless solid; mp 148–149 °C (dichloromethane–hexane). IR (KBr, cm–1): 2920, 1732, 1629. 1H NMR (400 MHz, CDCl3) δH: 2.27 (s, 3H), 4.71 (s, 2H), 4.85 (s, 2H), 6.97 (s, 1H), 7.18–7.43 (m, 7H). MS m/z: 398, 400 (M+). Anal. calcd. for C20H15BrO4: C 60.17, H 3.79; found: C 60.38, H 3.86.
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3-({4-[(2-Bromo-4,6-dimethylphenyl)oxy]but-2-ynyl}oxy)2H-chromen-2-one (4h) Yield: 79%; colorless solid; mp 133–134 °C (dichloromethane–hexane). IR (KBr, cm–1): 2928, 1730, 1621. 1H NMR (500 MHz, CDCl3) δH: 2.19 (s, 3H), 2.26 (s, 3H), 4.71 (s, 2H), 4.86 (s, 2H), 6.84 (s, 1H), 7.00–7.10 (m, 2H), 7.27– 7.44 (m, 4H). MS m/z: 412, 414 (M+). Anal. calcd. for C21H17BrO4: C 61.03, H 4.15; found: C 60.17, H 4.10. 3-({4-[(2-Bromo-4-methylphenyl)oxy]but-2-ynyl}oxy)-2Hchromen-2-one (4i) Yield: 69%; colorless solid; mp 107–109 °C (dichloromethane–hexane). IR (KBr, cm–1): 2916, 1731, 1632. 1H NMR (400 MHz, CDCl3) δH : 2.20 (s, 3H), 4.78 (s, 2H), 4.86 (s, 2H), 7.04 (s, 1H), 7.21–7.44 (m, 7H). MS m/z: 398, 400 (M+). Anal. calcd. for C20H15BrO4: C 60.17, H 3.79; found: C 60.40, H 3.85. 3-({4-[(1-Bromonaphthalene-2-yl)oxy]but-2-ynyl}oxy)-2Hchromen-2-one (4j) Yield: 77%; colorless solid; mp 103–105 °C (dichloromethane–hexane). IR (KBr, cm–1): 2916, 1730, 1627. 1H NMR (400 MHz, CDCl3) δH: 4.83 (s, 2H), 4.93 (s, 2H), 6.84 (s, 1H), 7.04–7.14 (m, 10H). MS m/z: 434, 436 (M+). Anal. calcd. for C23H15BrO4: C 63.47, H 3.47; found: C 63.79, H 3.51. 3-({4-[(2-Bromophenyl)oxy]but-2-ynyl}oxy)-2H-chromen2-one (4k) Yield: 78%; colorless solid; mp 128–130 °C (dichloromethane–hexane). IR (KBr, cm–1): 2917, 1734, 1617. 1H NMR (400 MHz, CDCl3) δH: 4.73 (s, 2H), 4.85 (s, 2H), 6.94 (s, 1H), 7.14–7.44 (m, 8H). MS m/z: 384, 386 (M+). Anal. calcd. for C19H13BrO4: C 59.24, H 3.40; found: C 59.36, H 3.37. 3-({4-[(2-Bromo-3-methylphenyl)oxy]but-2-ynyl}oxy)-2Hchromen-2-one (4l) Yield: 80%; colorless solid; mp 163–165 °C (dichloromethane–hexane). IR (KBr, cm–1): 2919, 1739, 1629. 1H NMR (400 MHz, CDCl3) δH: 2.31 (s, 3H), 4.77 (s, 2H), 4.86 (s, 2H), 6.84 (s, 1H), 7.03–7.43 (m, 7H). MS m/z: 398, 400 (M+). Anal. calcd. for C20H15BrO4: C 60.17, H 3.79; found: C 60.03, H 3.88. General procedure for the preparation of compounds 5a–5l. The compounds 5a–l were synthesized according to the earlier published procedure (7). 8-{[(2-Bromo-6-methylphenyl)oxy]methyl}-1,3-dimethyl2,3,4,6-tetrahydro-1H-pyrano[3,2-d]pyrimidine-2,4-dione (5a) Yield 89%; colorless solid; mp 139–141 °C (acetonitrile– methanol). IR (KBr, cm–1): 2957, 1696, 1648. 1H NMR (400 MHz, CDCl 3) δH: 2.23 (s, 3H, ArCH 3), 3.40 (s, 3H, -NCH3), 3.54 (s, 3H, -NCH 3 ), 4.58 (d, J = 4.8 Hz, 2H, -OCH2), 4.71 (s, 2H, -OCH2), 6.30 (t, J = 4.8 Hz, 1H), 7.25– 754 (m, 3H). MS m/z: 392, 394 (M+). Anal. calcd. for C17H17N2O4Br: C 51.92, H 4.36, N 7.12; found: C 52.09, H 4.45, N 7.09. © 2008 NRC Canada
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8-{[(2-Bromo-4,6-dimethylphenyl)oxy]methyl}-1,3dimethyl-2,3,4,6-tetrahydro-1H-pyrano[3,2-d]pyrimidine2,4-dione (5b) Yield 83%; colorless solid; mp 175–177 °C (acetonitrile– methanol). IR (KBr, cm–1): 2942, 1698, 1651. 1H NMR (400 MHz, CDCl3) δH: 2.21 (s, 3H, ArCH3), 2.28 (s, 3H, ArCH3), 3.39 (s, 3H, -NCH3), 3.52 (s, 3H, -NCH3), 4.58 (d, J = 4.8 Hz, 2H, -OCH2), 4.69 (s, 2H, -OCH2), 6.33 (t, J = 4.8 Hz, 1H), 6.92 (s, 1H), 7.20 (s, 1H). MS m/z: 406, 408 (M+). Anal. calcd. for C18H19N2O4Br: C 53.08, H 4.70, N 6.88; found: C 53.36, H 4.54, N 6.93. 8-{[(2-Bromo-4-methylphenyl)oxy]methyl}-1,3-dimethyl2,3,4,6-tetrahydro-1H-pyrano[3,2-d]pyrimidine-2,4-dione (5c) Yield 81%; colorless solid; mp 105–108 °C (acetonitrile– methanol). IR (KBr, cm–1): 3001, 2940, 1693, 1654. 1H NMR (400 MHz, CDCl3) δH: 2.26 (s, 3H, ArCH3), 3.39 (s, 3H, -NCH3), 3.48 (s, 3H, -NCH3), 4.57 (d, J = 4.8 Hz, 2H, -OCH2), 4.83 (s, 2H, -OCH2), 6.26 (t, J = 4.8 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 7.36 (s, 1H). MS m/z: 392, 394 (M+). Anal. calcd. for C17H17N2O4Br: C 51.92, H 4.36, N 7.12; found: C 52.11, H 4.39, N 7.19. 8-{[(1-Bromonaphthlene-2-yl)oxy]methyl}-1,3-dimethyl2,3,4,6-tetrahydro-1H-pyrano[3,2-d]pyrimidine-2,4-dione (5d) Yield 86%; colorless solid; mp 115–117 °C (acetonitrile– methanol). IR (KBr, cm–1): 3009, 1697, 1654. 1H NMR (500 MHz, CDCl 3) δH: 3.40 (s, 3H, -NCH 3), 3.55 (s, 3H, -NCH 3 ), 4.59 (d, J = 4.9 Hz, 2H, -OCH 2 ), 5.02 (s, 2H, -OCH2), 6.32 (t, J = 4.9 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.43 (t, J = 8.5 Hz, 1H), 7.57 (t, J = 8.3 Hz, 1H), 7.77 (m, 2H), 8.20 (d, J = 8.5 Hz, 1H). MS m/z: 428, 430 (M+). Anal. calcd. for C20H17N2O4Br: C 55.96, H 3.99, N 6.53; found: C 55.87, H 4.03, N 6.59. 8-{[(2-Bromophenyl)oxy]methyl}-1,3-dimethyl-2,3,4,6tetrahydro-1H-pyrano[3,2-d]pyrimidine-2,4-dione (5e) Yield 85%; colorless solid; mp 133–135 °C (acetonitrile– methanol). IR (KBr, cm–1): 2929, 1704, 1656. 1H NMR (400 MHz, CDCl 3 ) δH : 3.40 (s, 3H, -NCH 3 ), 3.56 (s, 3H, -NCH3), 4.59 (d, J = 4.8 Hz, 2H, -OCH 2 ), 4.82 (s, 2H, -OCH2), 6.38 (t, J = 4.8 Hz, 1H), 6.90 (t, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H). MS m/z: 378, 380 (M+). Anal. calcd. for C16H15N2O4Br: C 50.68, H 3.99, N 7.39; found: C 50.95, H 3.92, N 7.41. 8-{[(2-Bromo-3-methylphenyl)oxy]methyl}-1,3-dimethyl2,3,4,6-tetrahydro-1H-pyrano[3,2-d]pyrimidine-2,4-dione (5f) Yield 81%; colorless solid; mp 101–104 °C (acetonitrile– methanol). IR (KBr, cm–1): 3012, 2953, 1697, 1654. 1H NMR (400 MHz, CDCl3) δH: 2.40 (s, 3H, ArCH3) 3.39 (s, 3H, -NCH3), 3.47 (s, 3H, -NCH3), 4.58 (d, J = 4.8 Hz, 2H, -OCH2), 4.85 (s, 2H, -OCH2), 6.30 (t, J = 4.8 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H, ArH). MS m/z: 392, 394 (M+). Anal. calcd. for C17H17N2O4Br: C 51.92, H 4.36, N 7.12; found: C 51.99, H 4.38, N 7.23.
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1-[(2-Bromo-6-methylphenyl)oxy]-3,5-dihydropyrano[2,3c]chromen-5-one (5g) Yield: 85%; colorless solid; mp 166–168 °C (dichloromethane – petroleum ether). IR (KBr, cm–1): 2920, 1729, 1608. 1H NMR (500 MHz, CDCl3) δH: 2.29 (s, 3H), 4.80 (d, J = 4.2 Hz, 2H), 4.98 (s, 2H), 6.27 (t, J = 4.3 Hz, 1H), 7.21– 7.64 (m, 7H). MS m/z: 398, 400 (M+). Anal. calcd. for C20H15BrO4: C 60.17, H 3.79; found: C 60.01, H 3.84. 1-[(2-Bromo-4,6-dimethylphenyl)oxy]-3,5dihydropyrano[2,3-c]chromen-5-one (5h) Yield: 90%; colorless solid; mp 145–147 °C (dichloromethane – petroleum ether). IR (KBr, cm–1): 2923, 1725, 1608. 1H NMR (500 MHz, CDCl3) δH: 2.26 (s, 3H), 2.32 (s, 3H), 4.76 (d, J = 4.1 Hz, 2H), 4.99 (s, 2H), 6.23 (t, J = 4.1 Hz, 1H), 7.28–7.53 (m, 6H). MS m/z: 412, 414 (M+). Anal. calcd. for C21H17BrO4: C 61.03, H 4.15; found: C 61.32, H 4.24. 1-[(2-Bromo-4-methylphenyl)oxy]-3,5-dihydropyrano[2,3c]chromen-5-one (5i) Yield: 86%; colorless solid; mp 153–154 °C (dichloromethane – petroleum ether). IR (KBr, cm–1): 2931, 1723, 1611. 1H NMR (500 MHz, CDCl3) δH: 2.30 (s, 3H), 4.78 (d, J = 4.3 Hz, 2H), 4.95 (s, 2H), 6.25 (t, J = 4.0 Hz, 1H), 7.21 (s, 1H), 7.26–7.52 (m, 5H), 8.07 (d, J = 7.9 Hz, 1H). MS m/z: 398, 400 (M+). Anal. calcd. for C20H15BrO4: C 60.17. H 3.79; found: C 60.27, H 3.83. 1-{(1-Bromonaphthalen-2-yl)oxy}-3,5-dihydropyrano[2,3c]chromen-5-one (5j) Yield: 86%; colorless solid; mp 190–192 °C (dichloromethane – petroleum ether). IR (KBr, cm–1): 2864, 1721, 1605. 1H NMR (500 MHz, CDCl3) δH: 4.79 (d, J = 4.6 Hz, 2H), 5.14 (s, 2H), 6.36 (t, J = 4.5 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 7.25–7.28 (m, 1H), 7.36 (dd, J = 1.2, 8.2 Hz, 1H), 7.39–7.60 (m, 3H), 7.79–7.82 (m, 2H), 7.88 (dd, J = 1.0, 8.0 Hz, 1H), 8.22 (d, J = 8.5 Hz, 1H). MS m/z: 434, 436 (M+). Anal. calcd. for C23H15BrO4: C 63.47, H 3.47; found: C 63.54, H 3.50. 1-[(2-Bromophenyl)oxy]-3,5-dihydropyrano[2,3-c]chromen5-one (5k) Yield: 88%; colorless solid; mp 140–141 °C (dichloromethane – petroleum ether). IR (KBr, cm–1): 2907, 1724, 1610. 1H NMR (500 MHz, CDCl3) δH: 4.81 (d, J = 4.1 Hz, 2H), 4.92 (s, 2H), 6.31 (t, J = 4.2 Hz, 1H), 7.20–7.71 (m, 8H). MS m/z: 384, 386 (M+). Anal. calcd. for C19H13BrO4: C 59.24, H 3.40; found: C 59.41, H 3.51. 1-[(2-Bromo-3-methylphenyl)oxy]-3,5-dihydropyrano[2,3c]chromen-5-one (5l) Yield: 84%; colorless solid; mp 169–171 °C (dichloromethane – petroleum ether). IR (KBr, cm–1): 2909, 1720, 1620. 1H NMR (400 MHz, CDCl3) δH: 2.30 (s, 3H), 4.76 (d, J = 4.2 Hz, 2H), 4.93 (s, 2H), 6.27 (t, J = 4.1 Hz, 1H), 7.18– 7.69 (m, 7H). MS m/z: 398, 400 (M+). Anal. calcd. for C20H15BrO4: C 60.17, H 3.79; found: C 60.30, H 3.72. © 2008 NRC Canada
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General procedure for the radical cyclization of compounds 5 A suspension of the compounds 5 (0.30 mmol, 0.01mol/L), n-Bu3SnH (0.08 mL, 0.30 mmol), and AIBN (25 mg) in dry degassed toluene (for 5a–f) or benzene (for 5g–l) were heated for 3–4 h under N2. After the completion of the reaction the solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 (15 mL) and stirred with 10% aqueous KF solution (10 mL) for 1 h. The aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The combined CH2Cl2 extract was washed with water (2 × 20 mL) and then brine solution (1 × 20 mL), and was dried (Na2SO4). The solvent was removed and the residual mass was subjected to column chromatography over silica gel using petroleum ether – ethyl acetate as eluant to give 6a–l. Compounds 6a–f were recrystallized from acetonitrile– methanol mixture and compounds 6g–l were recrystalized from dichloromethane – petroleum ether (60–80 °C). 2,4,7-Trimethyl-1,2,3,4,4b,5,10b,11-octahydrochromeno[3′,4′:4,5]pyrano[3,2-d]pyrimidine-1,3-dione (6a) Yield: 81%; colorless solid; mp 171–172 °C (acetonitrile– methanol). IR (KBr, cm–1): 1655, 1633. 1H NMR (500 MHz, CDCl3) δH: 2.20 (s, 3H, ArCH3), 3.24 (dt, J = 3.8, 11.6 Hz, 1H), 3.36 (dt, J = 3.8, 11.7 Hz, 1H), 3.41 (s, 3H, -NCH3), 3.52 (s, 3H, -NCH3), 3.90 (t, J = 11.2 Hz, 1H), 4.00 (t, J = 11.3 Hz 1H), 4.46 (ddd, J = 1.8, 4.3, 11.6 Hz, 1H), 4.53 (ddd, J = 1.3, 4.3, 11.6 Hz, 1H), 6.87 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H). MS m/z: 314 (M+). Anal. calcd. for C17H18N2O4: C 64.96, H 5.77, N 8.91; found: C 65.18, H 5.85, N 8.99. 2,4,7,9-Tetramethyl-1,2,3,4,4b,5,10b,11octahydrochromeno[3′,4′:4,5]pyrano[3,2-d]pyrimidine-1,3dione (6b) Yield: 86%; colorless solid; mp 190–192 °C (acetonitrile– methanol). IR (KBr, cm–1): 1657, 1633. 1H NMR (500 MHz, CDCl3) δH: 2.21 (s, 3H, ArCH3), 2.32 (s, 3H, ArCH 3), 3.23 (dt, J = 4.4, 11.6 Hz, 2H), 3.41 (s, 3H, -NCH3), 3.51 (s, 3H, -NCH3), 3.90 (t, J = 11.2 Hz, 1H), 3.93 (t, J = 11.4 Hz, 1H), 4.47 (ddd, J = 1.3, 4.1, 11.3 Hz, 1H), 4.55 (ddd, J = 1.8, 4.1, 11.4 Hz, 1H), 6.79 (s, 1H), 6.89 (s, 1H). 13C NMR (75.5MHz, CDCl3): δC 16.2, 20.8, 28.9, 31.3, 31.8, 32.9, 65.7, 67.7, 117.7, 126.7, 127.4, 127.9, 130.7, 131.5, 132.2, 150.8, 151.1, 158.7. MS m/z: 328 (M+). Anal. calcd. for C18H20N2O4: C 65.84. H 6.14, N 8.53; found: C 66.02, H 6.11, N 8.56. 2,4,9-Trimethyl-1,2,3,4,4b,5,10b,11octahydrochromeno[3′,4′:4,5]pyrano[3,2-d]pyrimidine1,3-dione (6c) Yield: 85%; colorless solid; mp 130–132 °C (acetonitrile– methanol). IR (KBr, cm–1): 1651, 1627. 1H NMR (500 MHz, CDCl3) δH: 2.29 (s, 3H, ArCH3), 3.30 (dt, J = 4.4, 11.7 Hz, 2H), 3.41(s, 3H, -NCH3), 3.50 (s, 3H, -NCH3), 3.91 (t, J = 11.2 Hz, 2H), 4.44 (ddd, J = 1.7, 4.5, 11.3 Hz, 2H), 6.78 (d, J = 8.2 Hz, 1H), 6.95 (s, 1H), 7.01 (t, J = 8.1 Hz, 1H). MS m/z: 314 (M+). Anal. calcd. for C17H18N2O4: C 64.96, H 5.77, N 8.91; found: C 65.19, H 5.79, N 8.88.
Can. J. Chem. Vol. 86, 2008
2,4-Dimethyl-1,2,3,4,4b,5,12c,13-octahydrobenzo[5′,6′]chromeno[3′,4′:4,5] pyroano[3,2-d]pyrimidine1,3-dione (6d) Yield: 76%; colorless solid; mp 156–157 °C (acetonitrile– methanol). IR (KBr, cm–1): 1654, 1631. 1H NMR (500 MHz, CDCl3) δH: 3.35 (dt, J = 3.8, 11.0 Hz, 1H), 3.44 (s, 3H, NCH3), 3.54 (s, 3H, -NCH3), 3.88 (dt, J = 3.9, 11.4 Hz, 1H), 4.00 (t, J = 11.4 Hz, 1H), 4.16 (t, J = 11.3 Hz, 1H), 4.57 (dd, J = 2.4, 11.6 Hz, 1H), 4.86 (dd, J = 3.2, 11.8 Hz, 1H), 7.06 (d, J = 8.9 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 8.2 Hz, 1H), 7.71 (t, J = 8.9 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H). MS m/z: 350 (M+). Anal. calcd. for C20H18N2O4: C 68.56, H 5.18, N 8.00; found: C 68.73, H 5.22, N 8.13. 2,4-Dimethyl-1,2,3,4,4b,5,10b,11-octahydrochromeno[3′,4′:4,5]pyrano[3,2-d]pyrimidine-1,3-dione (6e) Yield: 89%; colorless solid; mp 200-202 °C (acetonitrile– methanol). IR (KBr, cm–1): 1651, 1623. 1H NMR (300 MHz, CDCl3) δH: 3.17–3.36 (m, 2H), 3.41 (s, 3H, -NCH3), 3.51 (s, 3H, -NCH3), 4.00 (dt, J = 4.1, 11.1Hz, 2H), 4.47–4.50 (m, 2H), 6.89–7.36 (m, 4H). MS m/z: 300 (M+). Anal. calcd. for C16H16N2O4: C 63.99, H 5.37, N 9.33; found: C 64.08, H 5.45, N 9.49. 2,4,10-Trimethyl-1,2,3,4,4b,5,10b,11octahydrochromeno[3′,4′:4,5]pyroano[3,2-d]pyrimidine1,3-dione (6f) Yield: 81%; colorless solid; mp 144–146 °C (acetonitrile– methanol). IR (KBr, cm–1): 1667, 1624. 1H NMR (500 MHz, CDCl3) δH: 2.35 (s, 3H, ArCH3), 3.24 (dt, J = 4.1, 11.1 Hz, 2H), 3.41(s, 3H, -NCH3), 3.50 (s, 3H, -NCH3), 3.88 (t, J = 11.5 Hz, 1H), 4.01 (t, J = 11.3 Hz 1H), 4.49 (dd, J = 4.3, 11.6 Hz, 1H), 4.56 (dd, J = 1.8, 11.6 Hz, 1H), 6.74–7.14 (m, 3H). MS m/z: 314 (M+). Anal. calcd. for C17H18N2O4: C 64.96, H 5.77, N 8.91; found: C 65.01, H 5.89, N 8.98. 9-Methyl-6c,7,12b,13-tetrahydro-1Hchromeno[3′,4′:4,5]pyrano[2,3-c]chromen-1-one (6g) Yield: 75%; colorless solid; mp 124–125 °C (dichloromethane – petroleum ether). IR (KBr, cm–1): 2919, 1731, 1623. 1H NMR (500 MHz, CDCl3) δH: 2.23 (s, 3H), 3.34 (dt, J = 4.4, 10.4 Hz, 1H), 3.56 (dt, J = 4.0, 11.0 Hz, 1H), 3.97 (t, J = 11.5 Hz, 1H), 4.18 (t, J = 11.6 Hz, 1H), 4.61 (dd, J = 4.5, 12.6 Hz, 1H), 4.74 (dd, J = 2.0, 11.6 Hz, 1H), 6.84–7.10 (m, 3H), 7.33–7.71 (m, 4H). MS m/z: 320 (M+). Anal. calcd. for C20H16O4: C 74.99, H 5.03; found: C 75.23, H 5.18. 9,11-Dimethyl-6c,7,12b,13-tetrahydro-1Hchromeno[3′,4′:4,5]pyrano[2,3-c]chromen-1-one (6h) Yield: 82%; colorless solid; mp 181–183 °C (dichloromethane – petroleum ether). IR (KBr, cm–1): 2921, 1737, 1623. 1H NMR (500 MHz, CDCl3) δH: 2.20 (s, 3H), 2.28 (s, 3H), 3.33 (dt, J = 4.2, 10.2 Hz, 1H), 3.57 (dt, J = 4.1, 11.3 Hz, 1H), 3.93 (t, J = 11.3 Hz, 1H), 4.16 (t, J = 11.7 Hz, 1H), 4.60 (dd, J = 4.3, 11.5 Hz, 1H), 4.71 (dd, J = 2.6, 11.5 Hz, 1H), 6.84 (s, 1H), 6.91 (s, 1H), 7.33–7.70 (m, 4H). MS m/z: 334 (M+). Anal. calcd. for C21H18O4: C 75.43, H 5.43; found: C 75.50, H 5.38. © 2008 NRC Canada
Majumdar et al.
11-Methyl-6c,7,12b,13-tetrahydro-1Hchromeno[3′,4′:4,5]pyrano[2,3-c]chromen-1-one (6i) Yield: 76%; colorless solid; mp 141–144 °C (dichloromethane – petroleum ether). IR (KBr, cm–1): 2930, 1735, 1624. 1H NMR (500 MHz, CDCl3) δH: 2.31 (s, 3H), 3.34 (dt, J = 4.4, 10.7 Hz, 1H), 3.59 (dt, J = 4.0, 11.0 Hz, 1H), 3.94 (t, J = 11.3 Hz, 1H), 4.17 (t, J = 11.7 Hz, 1H), 4.61 (dd, J = 4.1, 11.6 Hz, 1H), 4.67 (dd, J = 2.6, 12.6 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 7.00 (s, 1H), 7.03 (d, J = 8.3 Hz, 1H), 7.33–7.46 (m, 3H), 7.65 (d, J = 7.7 Hz, 1H). MS m/z: 320 (M+). Anal. calcd. for C20H16O4: C 74.99, H 5.03; found: C 75.12, H 5.09. 4c,5,12c,13-Tetrahydro-7H-benzo[f]chromeno[4′,3′:5,6]pyrano[4,3-c]chromen-7-one (6j) Yield: 90%; colorless solid; mp 201–202 °C (dichloromethane – petroleum ether). IR (KBr, cm–1): 2916, 1727, 1620. 1H NMR (500 MHz, CDCl3) δH: 3.69 (dt, J = 4.2, 11.3 Hz, 1H), 3.95 (dt, J = 4.1, 11.4 Hz, 1H), 4.20 (t, J = 11.5 Hz, 1H), 4.24 (t, J = 11.5 Hz, 1H), 4.77 (dd, J = 3.7, 11.6 Hz, 1H), 5.00 (dd, J = 3.0, 12.0 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 7.35–7.59 (m, 5H), 7.68 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 6.7 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H). MS m/z: 356 (M+). Anal. calcd. for C23H16O4: C 77.52, H 4.53; found: C 77.76, H 4.63. 6c,7,12b,13-Tetrahydro-1H-chromeno[3′,4′:4,5]pyrano[2,3c]chromen-1-one (6k) Yield: 86%; colorless solid; mp 176–177 °C (dichloromethane – petroleum ether). IR (KBr, cm–1): 2919, 1725, 1621. 1H NMR (500 MHz, CDCl3) δH: 3.38–3.43 (m, 1H), 3.61–3.65 (m, 1H), 3.98 (t, J = 11.4 Hz, 1H), 4.19 (t, J = 11.8 Hz, 1H), 4.62 (dd, J = 4.5, 11.6 Hz, 1H), 4.68 (dd, J = 2.8. 11.6 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H), 7.21–7.46 (m, 5H), 7.65(d, J = 7.8 Hz, 1H). 13C NMR (125 MHz, CDCl3) δc: 30.0, 31.6, 66.0, 68.6, 117.6, 117.8, 118.9, 119.5, 120.9, 121.9, 122.4, 125.4, 129.2, 129.5, 130.4, 140.5, 149.8, 155.3, 156.9. MS: m/z = 306 (M+). Anal. calcd. for C19H14O4: C 74.50, H 4.61; found: C 74.81, H 4.72. 12-Methyl-6c,7,12b,13-tetrahydro-1Hchromeno[3′,4′:4,5]pyrano[2,3-c]chromen-1-one (6l) Yield: 85%; colorless solid; mp 143–145 °C (dichloromethane – petroleum ether). IR (KBr, cm–1): 2917, 1735, 1619. 1H NMR (300 MHz, CDCl3) δH: 2.23 (s, 3H), 3.38– 3.41 (m, 1H), 3.61–3.65 (m, 1H), 3.96 (t, J = 10.9 Hz, 1H), 4.17 (t, J = 11.2 Hz, 1H), 4.62 (dd, J = 3.9, 11.4 Hz, 1H), 4.74 (dd, J = 2.5, 11.2 Hz, 1H), 6.90–7.70 (m, 7H). MS m/z: 320 (M+). Anal. calcd. for C20H16O4: C 74.99, H 5.03; found: C 74.85, H, 5.07.
Acknowledgements We thank the Council of Scientific and Industrial Research (CSIR), New Delhi, and the Department of Science and Technology (DST), New Delhi, for financial assistance. PKM and PD are thankful to the University Grants Commission (UGC), New Delhi, and CSIR for their respective fellowships.
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