PLEASE SCROLL DOWN FOR ARTICLE

This article was downloaded by: [University of Witwatersrand]On: 10 November 2008Access details: Access Details: [subscription number 789273259]Publisher Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,37-41 Mortimer Street, London W1T 3JH, UK

Synthetic CommunicationsPublication details, including instructions for authors and subscription information:http://www.informaworld.com/smpp/title~content=t713597304

Regioselective Synthesis of 1,8-Naphthyridinone-Annulated Oxygen and SulfurHeterocycles by Tri-n-butyl Tinhydride-Mediated Aryl Radical CyclizationK. C. Majumdar a; R. Islam a

a Department of Chemistry, University of Kalyani, Kalyani, India

Online Publication Date: 01 January 2008

To cite this Article Majumdar, K. C. and Islam, R.(2008)'Regioselective Synthesis of 1,8-Naphthyridinone-Annulated Oxygen and SulfurHeterocycles by Tri-n-butyl Tinhydride-Mediated Aryl Radical Cyclization',Synthetic Communications,38:23,4053 — 4067

To link to this Article: DOI: 10.1080/00397910802238759

URL: http://dx.doi.org/10.1080/00397910802238759

Full terms and conditions of use: http://www.informaworld.com/terms-and-conditions-of-access.pdf

This article may be used for research, teaching and private study purposes. Any substantial orsystematic reproduction, re-distribution, re-selling, loan or sub-licensing, systematic supply ordistribution in any form to anyone is expressly forbidden.

The publisher does not give any warranty express or implied or make any representation that the contentswill be complete or accurate or up to date. The accuracy of any instructions, formulae and drug dosesshould be independently verified with primary sources. The publisher shall not be liable for any loss,actions, claims, proceedings, demand or costs or damages whatsoever or howsoever caused arising directlyor indirectly in connection with or arising out of the use of this material.

Regioselective Synthesis of 1,8-Naphthyridinone-Annulated Oxygen and Sulfur Heterocycles by

Tri-n-butyl Tinhydride–Mediated ArylRadical Cyclization

K. C. Majumdar and R. IslamDepartment of Chemistry, University of Kalyani, Kalyani, India

Abstract: The tin hydride–mediated cyclizations of a number of ethers, sulfides,and sulfones under mild, neutral conditions have been investigated. While the2-bromobenzyloxy ethers were prepared in 62–65% yields by the alkylation of4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one with 2-bromobenzyl bromidesin refluxing acetone in the presence of anhydrous potassium carbonate, thesulfides were derived from 4-mercapto-1-phenyl-1,8-naphthyridin-2(1H)-oneand 2-bromobenzyl bromides in 82–84% yields by a phase-transfer catalysis(PTC) reaction. The corresponding sulfones were prepared by treatment of thesulfides with m-CPBA in refluxing dichloromethane. The ethers, sulfides, andthe sulfones were treated with nBu3SnH-AIBN to give regioselectively1,8-naphthyridinone-annulated oxygen and sulfur heterocycles in 70–78% yields.

Keywords: Azobisisobutyronitrile(AIBN), 6-endo-trig, 4-mercapto-1-phenyl-1,8-naphthyridin-2(1H)-one, radical cyclization, sulfur heterocycle, tributyltin hydride

INTRODUCTION

In recent years, aryl radical cyclization has been developed as a powerfultool for constructing the carbo- and heterocyclic compounds in organicsynthesis.[1] Although oxygen- and nitrogen-containing radical cycliza-tions have been studied intensively,[2–4] an examination of the literature

Received April 2, 2008.Address correspondence to K. C. Majumdar, Department of Chemistry,

University of Kalyani, Kalyani 741235, W. B., India. E-mail: kcm_ku@yahoo.co.in

Synthetic Communications1, 38: 4053–4067, 2008

Copyright # Taylor & Francis Group, LLC

ISSN: 0039-7911 print=1532-2432 online

DOI: 10.1080/00397910802238759

4053

Downloaded By: [University of Witwatersrand] At: 20:38 10 November 2008

reveals only scattered examples of the synthesis of sulfur-based hetero-cycles via radical cyclization.[5] This includes cyclizations with a sulfurfunctionality in the hexynyl chain at 3-[6] and 4- positions[7] and an exam-ple of a sulfonylated radical in the 2-position.[8] Several useful radicalcyclizations with a sulfur functionality located a to the radical center havealso been reported, but these give a cyclic product with the sulfur func-tionality external to the ring.[9] The alkyl radical cyclized predominantlyto the smaller five-membered ring rather than the larger six-membered ring because of the stereoelectronically more favorabletransition state in the former 5-exo-cyclization, though it resulted in anunstable primary radical intermediate. For a stabilized radical, thispreference is reversed.[10,11] For example, N-(o-bromobenzyl)enamideprecursors[10a] exclusively undergo 6-endo-trig cyclization to give thetetrahydroisoquinolone derivatives via the intermediate stabilizedradicals. Many other examples have been reported where the radicalsadjacent to the carbonyl group[12] or benzylic position[13] are stabilizedand preferentially gave the useful 6-endo products. In the course of ourstudies on the [3,3]-sigmatropic rearrangement, we observed an unusualformation of [6,6]-pyranopyrans and [6,6]-pyranothiopyrans in the caseof substrates containing 3-hydroxycoumarin,[12] 5-hydroxyuracil,[13] and4-mercaptocoumarin.[14] We investigated whether the synthesis of the[6,6]-ring system could be achieved by nBu3SnH-mediated cyclization.

Naphthyridinone and their derivatives are known to possess a widerange of medicinal and biological properties and are also active againstvarious organisms. They are used for diagnosis of and therapy for humandiseases including AIDS; for combating exo- and endo-parasites in agri-culture; as preservatives and ingredients in cutting fluids; and as ligandsin analytical chemistry.[15a,b] Some 2,3-fused furo- and 3,4-fused pyra-no[1,8]naphthyridinones possess antiallergic, anti-inflammatory, andcytoprotective activity.[15] Several methodologies for the construction offive- or six-membered oxygen and nitrogen heterocycles fused atthe 3,4-position of [1,8]naphthyridinone moiety are available in theliterature,[15f] but no report on the synthesis of six-membered sulfurheterocycles fused at the 3,4-position is available in literature. In thiscontext, we report an efficient radical-based approach for the synthesisof 1,8-naphthyridinone-annulated oxygen and sulfur containing hetero-cyclic compounds. Here we report the results of our investigation.

RESULTS AND DISCUSSION

We initiated our study with different 4-(20-bromobenzyloxy)-1-phenyl-1,8-naphthyridin-2(1H)-one 3a,b derivatives. The compounds

4054 K. C. Majumdar and R. Islam

Downloaded By: [University of Witwatersrand] At: 20:38 10 November 2008

4-(20-bromobenzyloxy)-1-phenyl-1,8-naphthyridin-2(1H)-ones 3a,b wereprepared in 62–65% yields by the reaction of different substituted2-bromobenzyl bromides 2a,b with 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (1) in refluxing acetone in the presence of anhydrous K2CO3

for 20–22 h (Scheme 1). Compounds 3a,b were characterized from theirelemental analyses and spectroscopic data.

The substrate 3a was refluxed in degassed dry toluene under nitrogenwith tri-n-butyltin hydride in the presence of a catalytic amount ofazobisisobutyronitrile (AIBN) for 2 h to give product 4a (yield 78%) asthe only isolable product (Scheme 1). The 1H NMR spectrum of the pro-duct 4a displayed a two-proton singlet at d 5.38 due to�OCH2, andtwelve aromatic protons appeared as multiplets at d 7.14 to d 8.77. The13C chemical shifts of compound 4a were assigned by a distortionlessenhancement polarization transfer (DEPT) experiment. The multiplicitieswere also established by a DEPT experiment. DEPT showed 13 proto-nated carbons, among which were 12>CH–, and one –CH2–. The massspectrum of compound 4a showed a molecular ion peak at m=z 326 (Mþ).Encouraged by the result, other starting material 3b was also similarlytreated to afford the cyclic product 4b in 70% yield.

Scheme 1. Reagents and conditions: (i) dry acetone, K2CO3, reflux, 20–22 h; (ii)Bu3SnH, AIBN, dry toluene, reflux, 2 h.

Regioselective Synthesis of Oxygen and Sulfur Heterocycles 4055

Downloaded By: [University of Witwatersrand] At: 20:38 10 November 2008

As there are no such report on the synthesis of sulfur heterocyclesfused at the 3,4-position of the [1,8]naphthyridinone moiety, we turnedour attention to radical mediated synthesis of sulfur heterocycles. Thestarting materials 4-(20-bromobenzylthio)-1-phenyl-1,8-naphthyridin-2(1H)-ones 6a,b were prepared in 82–84% yields by the phase-transfer-catalyzedalkylation of 4-mercapto-1-phenyl-1,8-naphthyridin-2(1H)-one 5 withdifferent substituted 2-bromobenzyl bromides 2a,b in dichloromethaneand 1% aqueous NaOH solution in the presence of benzyltriethylammo-nium chloride (BTEAC) at room temperature for 8–10 h. The otherstarting materials, 4-(20-bromobenzylsulfonyl)-1-phenyl-1,8-naphthyridin-2(1H)-ones 7a,b, were prepared by the oxidation of 6a,b with 2 equivalentsof m-CPBA in dichloromethane (Scheme 2). Compounds 6a,b and 7a,b

were characterized from their elemental analyses and spectroscopic data.The substrates 6a,b were also similarly treated with Bu3SnH and

AIBN to give exclusively the tetracyclic compounds 8a,b in 70–75% yield(Scheme 3). We also subjected 4-(20-bromobenzylsulfonyl)-1-phenyl-1,8-naphthyridin-2(1H)-ones 7a,b to radical cyclization under similar reac-tion conditions by treatment with Bu3SnH and AIBN to give exclusively

Scheme 2. Reagents and conditions: (i) BTEAC, 1% aq. NAOH, dichloro-methane, rt, 8–10 h; (ii) m-CPBA (2 equivalents), dichloromethane, reflux, 4 h.

4056 K. C. Majumdar and R. Islam

Downloaded By: [University of Witwatersrand] At: 20:38 10 November 2008

the tetracyclic compounds 9a,b. In the case of substrates 3a,b and 6a,b,only the 6-endo-cyclized oxidized products were obtained exclusively,and in the case of the sulfonyl substrates 7a,b (X¼SO2), only the reduced6-endo-cyclization products 9a,b were obtained. The structure of the com-pound 9a was readily confirmed by 1H NMR spectroscopy, which exhib-ited one proton doublet at d 4.64 (J¼6 Hz) and another proton doublet atd 4.71 (J¼6 Hz) due to ring juncture protons Hd and Hc respectively. Thestereochemistry of the ring fusion of the cyclic system can be surmisedfrom the molecular model (Dreiding model), which shows a strain-freecis-arrangement, and also from the small coupling constant of 9a

(J¼6 Hz). The two SO2CH2 protons appear as two proton doublet eachat d 4.42 (J¼16 Hz) and 4.50 (J¼16 Hz).

The formation of products 4, 8, and 9 from the substrates 3, 6, and 7

may be easily explained by the generation of an aryl radical 10 in the tri-n-butyltin hydride and AIBN-mediated reaction. The aryl radical 10 mayundergo cyclization by two different modes: a 6-endo trig-cyclization[11]

to afford the heterocyclic radical 13 (pathway a, Scheme 4) or a 5-exotrig-cyclization to give spiro heterocyclic radical[16] 11 (pathway b,Scheme 4) with a subsequent neophyl rearrangement. It is very clear fromthe present study that the intermediate tertiary radical 13 is much morestabilized by the adjacent pyridine ring as compared to the intermediate11 which is stabilized by an adjacent carbonyl group. However, for thecompounds 6 and 7, the 5-exo-cyclization to form the spiro heterocyclicradical 11 followed by a neophyl rearrangement is highly unlikely at thepresent instance. It is known that b-fragmentation of alkylthiyl radicalsare very fast[17] (108 s�1) compared to neophyl-type rearrangements,which are much slower[18] (about 103–104 s�1). Therefore, neophyl rear-rangement of radical 11 could not compete with the b-fragmentationreaction, which would lead to another product. In case of compounds

Scheme 3. Reagents and conditions: (i) nBu3SnH, AIBN, dry toluene, reflux,2–4 h.

Regioselective Synthesis of Oxygen and Sulfur Heterocycles 4057

Downloaded By: [University of Witwatersrand] At: 20:38 10 November 2008

6 and 7, the other reason for the formation of a six-membered productmay be the greater polarization of the sulfur atom.[19] The 6-endo-ringclosure of the sulfonyl-based radicals 10 (X¼SO2), in which the highregioselectivity is believed to be controlled by a combination of bothsteric factor and FMO interaction, leads to the reduced cyclic sulfo-nes[2b–d] 9a,b. The presence of a highly electronwithdrawing SO2 groupattached to the radical center confers considerable electrophilic characteronto the radical and favors the 6-endo product. The relatively more stableheterocyclic radical 13 may form a conjugated double bond to yield theproducts 4 and 8 (a,b) by an unknown mechanism (i.e., an oxidation stepin Bu3 SnH-mediated cyclizations).[20] In the case of 7a,b (X¼SO2), onlyreduced products are obtained as isolable products, which lead todihydro heterocyclic ring 9a,b (Scheme 4).

It is interesting to note that regioselectively six-membered heterocyc-lic rings are formed in all the cases at the present instance. In conclusion,we have successfully extended the Bu3SnH mediated radical cyclization

Scheme 4. Mechanistic pathway of the radical cyclization.

4058 K. C. Majumdar and R. Islam

Downloaded By: [University of Witwatersrand] At: 20:38 10 November 2008

for the synthesis of oxygen, sulfur, and sulfone containing six-memberedheterocyclic compounds. The methodology described here is mild andinteresting in its simplicity.

EXPERIMENTAL

Melting points were determined in an open capillary and are uncorrected.IR spectra were recorded on a Perkin-Elmer L 120-000A spectrometer(nmax in cm�1) on KBr disks. 1H NMR (400 MHz, 500 MHz) and 13CNMR (125.7 MHz) spectra were recorded on a Varian-400 FT-NMRand Bruker DPX-500 spectrometers in CDCl3 (chemical shifts in d) withTMS as internal standard. Silica gel [(60–120 mesh), Spectrochem, India]was used for chromatographic separation. Silica gel G [E-Merck (India)]was used for thin-layer chromatography (TLC). Petroleum ether refers tothe fraction boiling between 60–80 �C. Compounds 1 and 5 were preparedaccording to the published procedure.[15c,21]

General Procedure for the Preparation of 4-(20-Bromobenzyloxy)-

1-phenyl-1,8-naphthyridin-2(1H)-ones 3a,b

A mixture of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one 1 (0.47 g,2 mmol), 2-bromobenzyl bromide 2a (0.50 g, 2 mmol) or 2-bromo-5-methoxy benzyl bromide 2b (0.56 g, 2 mmol), and anhydrous potassiumcarbonate (3 g) was refluxed in dry acetone (100 ml) on a water bathfor 20–22 h. The reaction mixture was then cooled and filtered, and thesolvent was removed. The residual mass was subjected to column chro-matography over silica gel using petroleum ether–ethyl acetate (4:1) aseluant to give compounds 3a,b, which were then recrystallized fromchloroform–petroleum ether.

Compound 3a

Yield: 0.52 g, 65%; solid; mp 216–218 �C; IR (KBr) nmax: 2938, 1694,1618, 1584 cm�1; dH (400 MHz, CDCl3): 5.29 (s, 2H, –OCH2), 6.24 (s,1H,¼CH), 7.14–7.16 (m, 1H, ArH), 7.25–7.29 (m, 3H, ArH), 7.39–7.41(m, 1H, ArH), 7.47–7.49 (t, 1H, J¼7.3 Hz, ArH), 7.54–7.58 (t, 3H,J¼7.8 Hz, ArH), 7.62–7.64 (m, 1H, ArH), 8.32–8.33 (d, 1H, J¼7.8 Hz,ArH), 8.46–8.47 (dd, 1H, J¼1.4 Hz, 4.4 Hz, ArH); m=z¼408, 406 (Mþ).Anal. calcd for C21H15BrN2O2: C, 61.93; H, 3.71; N, 6.88. Found: C,62.07; H, 3.79; N, 6.84%.

Regioselective Synthesis of Oxygen and Sulfur Heterocycles 4059

Downloaded By: [University of Witwatersrand] At: 20:38 10 November 2008

Compound 3b

Yield: 0.53 g, 62%; solid; mp 182–184 �C; IR (KBr) nmax: 2940, 1651,1610, 1497 cm�1; dH (400 MHz, CDCl3): 3.82 (s, 3H, –OCH3), 5.24 (s,2H, –OCH2), 6.22 (s, 1H,¼CH), 6.81–6.83 (d, 1H, J¼8.7 Hz, ArH),7.09 (d, 1H, J¼2.8 Hz, ArH), 7.13–7.16 (dd, 1H, J¼4.6 Hz, 7.7 Hz,ArH), 7.25–7.28 (m, 2H, ArH), 7.48–7.58 (m, 4H, ArH), 8.30–8.32 (d,1H, J¼7.8 Hz, ArH), 8.46–8.47 (dd, 1H, J¼1.3 Hz, 4.4 Hz, ArH);m=z¼438, 436 (Mþ). Anal. calcd. for C22H17BrN2O3: C, 60.43; H, 3.92;N, 6.41. Found: C, 60.64; H, 3.89; N, 6.51%.

General Procedure for the Preparation of 4-(20-Bromobenzylthio)-

1-phenyl-1,8-naphthyridin-2(1H)-ones 6a,b

A solution of BTEAC (0.25 g, 0.9 mmol) in 1% aqueous NaOH (50 ml)was added to a mixture of 4-mercapto-1-phenyl-1,8-naphthyridin-2(1H)-one 5 (0.50 g, 2 mmol) and 2a,b (0.50 g, 0.56 g, 2 mmol) in dichlor-omethane (50 ml) was added and the mixture was stirred for a period of8–10 h. This was then diluted with water (100 ml) and extracted withdichloromethane (2� 50 ml). The dichloromethane extract was washedsuccessively with 2 N HCl (2� 50 ml), brine (2� 50 ml), and H2O(50 ml) and dried (Na2SO4). Dichloromethane was removed, and the resi-dual mass was purified by column chromatography over silica gel. Theproduct was obtained by eluting the column with petroleum ether–ethylacetate (4:1).

Compound 6a

Yield: 0.69 g, 82%; solid; mp 176–178 �C; IR (KBr) nmax: 2967, 1653, 1578,1437 cm�1; dH (400 MHz, CDCl3): 4.40 (s, 2H, –SCH2), 6.68 (s, 1H,¼CH),7.12–7.14 (dd, 1H, J¼4.6 Hz, 7.8 Hz, ArH), 7.18–7.34 (m, 4H, ArH), 7.48–7.63 (m, 5H, ArH), 8.17–8.18 (d, 1H, J¼7.8 Hz, ArH), 8.44 (d, 1H,J¼3.2 Hz, ArH); m=z¼424, 422 (Mþ). Anal. calcd. for C21H15BrN2OS:C, 59.58; H, 3.57; N, 6.62. Found: C, 59.75; H, 3.62; N, 6.71%.

Compound 6b

Yield: 0.75 g, 84%; solid; mp 190–192 �C; IR (KBr) nmax: 2936, 1640,1581, 1430 cm�1; dH (400 MHz, CDCl3): 3.79 (s, 3H, –OCH3), 4.35 (s,2H, –SCH2), 6.66 (s, 1H,¼CH), 6.74–6.77 (dd, 1H, J¼2.8 Hz, 8.7 Hz,

4060 K. C. Majumdar and R. Islam

Downloaded By: [University of Witwatersrand] At: 20:38 10 November 2008

ArH), 7.05 (d, 1H, J¼2.8 Hz, ArH), 7.12–7.15 (dd, 1H, J¼4.6 Hz, 7.9 Hz,ArH), 7.24–7.27 (m, 2H, ArH), 7.48–7.50 (m, 2H, ArH), 7.54–7.58 (t, 2H,J¼7.6 Hz, ArH), 8.16–8.19 (dd, 1H, J¼1.4 Hz, 7.8 Hz, ArH), 8.43–8.45(dd, 1H, J¼1.4 Hz, 4.4 Hz, ArH); m=z¼454, 452 (Mþ). Anal. calcd. forC22H17BrN2O2S: C, 58.28; H, 3.78; N, 6.18. Found: C, 58.18; H, 3.94;N, 6.32%.

General Procedure for the Preparation of 4-(20-Bromobenzylsulfonyl)-1-phenyl-1,8-naphthyridin-2(1H)-ones 7a,b

A solution of m-CPBA [0.17 g, 0.5 mmol (50%)] in dichloromethane(30 ml) was slowly added to a well-stirred solution of the sulfides 6a,b

(0.25 mmol) in dichloromethane (30 ml). The reaction mixture wasrefluxed for 4 h. The resulting solution was then washed with 10% aqu-eous Na2CO3 (3� 25 ml) and brine (25 ml) and dried (Na2SO4). Removalof the solvent furnished the product. These were recrystallized fromchloroform–petroleum ether to give pure compounds 7a,b.

Compound 7a

Yield: 0.11 g, 93%; solid; mp 218–220 �C; IR (KBr) nmax: 3076, 1655, 1581,1427 cm�1; dH (400 MHz, CDCl3): 4.74 (s, 2H, –SO2CH2), 7.04–7.07 (dd,1H, J¼4.6 Hz, 8.1 Hz, ArH), 7.18–7.25 (m, 3H, ArH), 7.37–7.41 (m, 2H,ArH), 7.42 (s, 1H,¼CH), 7.49–7.53 (m, 1H, ArH), 7.56–7.62 (m,3H, ArH), 8.43–8.45 (dd, 1H, J¼1.4 Hz, 4.4 Hz, ArH), 8.53–8.55 (dd,1H, J¼1.4 Hz, 8 Hz, ArH); m=z¼456, 454 (Mþ). Anal. calcd. forC21H15BrN2O3S: C, 55.39; H, 3.32; N, 6.15. Found: C, 55.63; H, 3.49;N, 6.24%.

Compound 7b

Yield: 0.11 g, 95%; solid; mp 220–222 �C; IR (KBr) nmax: 2926, 1659, 1584,1430 cm�1; dH (500 MHz, CDCl3): 3.83 (s, 3H, –OCH3), 4.69 (s, 2H,–SO2CH2), 6.74–6.77 (dd, 1H, J¼3 Hz, 8.8 Hz, ArH), 7.08–7.10 (dd, 1H,J¼4.6 Hz, 8.1 Hz, ArH), 7.12 (d, 1H, J¼2.9 Hz, ArH), 7.22–7.28 (m,2H, ArH), 7.44 (s, 1H,¼CH), 7.50–7.53 (t, 1H, J¼7.4 Hz, ArH), 7.57–7.60 (m, 2H, ArH), 8.45–8.46 (dd, 1H, J¼1.5 Hz, 4.5 Hz, ArH), 8.60–8.62 (dd, 1H, J¼1.5 Hz, 8.1 Hz, ArH); m=z¼486, 484 (Mþ). Anal. calcd.for C22H17BrN2O4S: C, 54.44; H, 3.53; N, 5.77. Found: C, 54.63;H, 3.51; N, 5.83%.

Regioselective Synthesis of Oxygen and Sulfur Heterocycles 4061

Downloaded By: [University of Witwatersrand] At: 20:38 10 November 2008

General Procedure for the Preparation of Compounds4(a,b), 8(a,b), and 9(a,b)

Tributyltin hydride (0.08 g, 0.3 mmol) was added all at once under nitro-gen to a magnetically stirred solution of 3a–f (0.2 mmol) and azobisisobu-tyronitrile (AIBN) (0.01 g) in dry degassed toluene (5 ml). The mixturewas heated at reflux for 2–4 h, and then the solvent was removed underreduced pressure. The residue was dissolved in ether (10 ml) and stirredwith a 10% aqueous potassium fluoride solution (10 ml) for 45 min.The white precipitate was separated by filtration, and the aqueous phasewas extracted with ether (10 ml). The combined ether extract was washedwith brine and dried over anhydrous Na2SO4. The residual mass afterremoval of the solvent was subjected to column chromatography usingpetroleum ether–ethyl acetate (9:1) as eluent to give products 4a,b,

8a,b, and 9a,b.

Compound 4a

Yield: 0.04 g, 78%; solid; mp 246–248 �C; IR (KBr) nmax: 2924, 1643,1611, 1578 cm�1; dH (400 MHz, CDCl3): 5.38 (s, 2H, –OCH2), 7.14–7.19 (m, 2H, ArH), 7.29–7.38 (m, 4H, ArH), 7.49–7.53 (t, 1H, J¼7.2 Hz,ArH), 7.58–7.62 (t, 2H, J¼7.2 Hz, ArH), 8.33–8.35 (d, 1H, J¼7.5 Hz,ArH), 8.47–8.49 (m, 1H, ArH), 8.75–8.77 (d, 1H, J¼7.7 Hz, ArH); dC

(125.7 MHz, CDCl3): 70.07, 109.08, 111.44, 118.51, 124.26, 126.05,128.18, 128.61, 128.70, 128.87, 129.22, 129.54, 129.92, 132.26, 137.71,150.43, 151.37, 157.74, 162.48; m=z¼326 (Mþ). Anal. calcd. forC21H14N2O2: C, 77.29; H, 4.32; N, 8.58. Found: C, 77.42; H, 4.39;N, 8.54%.

Compound 4b

Yield: 0.04 g, 70%; solid; mp 284–286 �C; IR (KBr) nmax: 2933, 1649,1633, 1610, 1583 cm�1; dH (400 MHz, CDCl3): 3.83 (s, 3H, –OCH3),5.34 (s, 2H, –OCH2), 6.69 (s, 1H, ArH), 6.86–6.89 (dd, 1H, J¼2.1 Hz,8.7 Hz, ArH), 7.14–7.15 (dd, 1H, J¼4.7 Hz, 7.7 Hz, ArH), 7.30–7.32 (d,2H, J¼7.4 Hz, ArH), 7.48–7.51 (t, 1H, J¼7.2 Hz, ArH), 7.55–7.60 (t,2H,J¼7.4 Hz, ArH), 8.29–8.30 (d, 1H, J¼6.6 Hz, ArH), 8.44 (d, 1H,J¼3 Hz, ArH), 8.72–8.75 (d, 1H, J¼8.8 Hz, ArH); m=z¼356 (Mþ). Anal.calcd. for C22H16N2O3: C, 74.15; H, 4.53; N, 7.86. Found: C, 74.05; H,4.67; N, 7.92%.

4062 K. C. Majumdar and R. Islam

Downloaded By: [University of Witwatersrand] At: 20:38 10 November 2008

Compound 8a

Yield: 0.04 g, 75%; solid; mp 238–240 �C; IR (KBr) nmax: 3061, 2921,1648, 1582, 1448 cm�1; dH (500 MHz, CDCl3): 3.95 (s, 2H, –SCH2),7.17–7.20 (dd, 2H, J¼4.6 Hz, 7.7 Hz, ArH), 7.33–7.34 (m, 4H, ArH),7.49–7.52 (t, 1H, J¼7.3 Hz, ArH), 7.58–7.61 (t, 2H, J¼7.5 Hz, ArH),8.35–8.37 (d, 1H, J¼7.6 Hz, ArH), 8.43–8.45 (m, 1H, ArH); m=z¼342(Mþ). Anal. calcd. for C21H14N2OS: C, 73.66; H, 4.12; N, 8.18. Found:C, 73.84; H, 4.17; N, 8.30%.

Compound 8b

Yield: 0.04 g, 70%; solid; mp 252–254 �C; IR (KBr) nmax: 2925, 1647,1606, 1582, 1441 cm�1; dH (500 MHz, CDCl3): 3.85 (s, 3H, –OCH3),3.92 (s, 2H, –SCH2), 6.78–6.79 (d, 1H, J¼2.4 Hz, ArH), 6.84–6.87 (dd,1H, J¼2.6 Hz, 8.8 Hz, ArH), 7.16–7.19 (dd, 1H, J¼4.6 Hz,7.9 Hz, ArH), 7.32–7.33 (d, 2H, J¼7.3 Hz, ArH), 7.49–7.52 (t, 1H,J¼7.4 Hz, ArH), 7.58–7.61 (t, 2H, J¼7.8 Hz, ArH), 8.32–8.34 (dd, 1H,J¼1.4 Hz, 7.9 Hz, ArH), 8.42–8.44 (m, 2H, ArH); m=z¼372 (Mþ). Anal.calcd. for C22H16N2O2S: C, 70.95; H, 4.33; N, 7.52. Found: C, 71.18; H,4.45; N, 7.43%.

Compound 9a

Yield: 0.05 g, 74%; solid; mp 210–212 �C; IR (KBr) nmax: 2921, 1695,1590, 1492 cm�1; dH (500 MHz, CDCl3): 4.42–4.45 (d, 1H, J¼16 Hz,–SO2CH), 4.50–4.53 (d, 1H, J¼16 Hz, –SO2CH), 4.64–4.65 (d, 1H,J¼6 Hz, –CCHd), 4.71–4.73 (d, 1H, J¼6 Hz, –CCHc), 7.07–7.10 (dd,1H, J¼4.9 Hz, 7.4 Hz, ArH), 7.22–7.24 (m, 1H, ArH), 7.29–7.30 (d,2H, J¼7.4 Hz, ArH), 7.38–7.41 (m, 4H, ArH), 7.47–7.50 (m, 2H, ArH),7.75–7.78 (dd, 1H, J¼1.5 Hz, 7.4 Hz, ArH), 8.33–8.34 (dd, 1H, J¼1.6 Hz,Hz, 4.9 Hz, ArH); m=z¼376 (Mþ). Anal. calcd. for C21H16N2O3S: C,67.00; H, 4.28; N, 7.44. Found: C, 67.10; H, 4.25; N, 7.61%.

Compound 9b

Yield: 0.05 g, 72%; solid; mp 243–245 �C; IR (KBr) nmax: 2924, 1659,1584, 1463 cm�1; dH (500 MHz, CDCl3): 3.82 (s, 3H, –OCH3), 4.44–4.46 (d, 1H, J¼16 Hz, –SO2CH), 4.49–4.51 (d, 1H, J¼16 Hz, –SO2CH),4.71–4.73 (d, 1H, J¼6 Hz, –CCHd), 4.77–4.79 (d, 1H, J¼6 Hz, –CCHc),6.76–6.78 (d, 1H, J¼2.4 Hz, ArH), 6.88–6.91 (dd, 1H, J¼2.6 Hz,

Regioselective Synthesis of Oxygen and Sulfur Heterocycles 4063

Downloaded By: [University of Witwatersrand] At: 20:38 10 November 2008

8.8 Hz, ArH), 7.16–7.19 (dd, 1H, J¼4.6 Hz, 7.8 Hz, ArH), 7.28–7.30 (d,2H, J¼7.4 Hz, ArH), 7.48–7.51 (t, 1H, J¼7.8 Hz, ArH), 7.58–7.61 (t,2H, J¼7.8 Hz, ArH), 8.30–8.32 (dd, 1H, J¼1.6 Hz, 7.8 Hz, ArH), 8.43–8.45 (m, 2H, ArH); m=z¼406 (Mþ). Anal. calcd. for C22H18N2O4S: C,65.01; H, 4.46; N, 6.89. Found: C, 65.25; H, 4.69; N, 6.77%.

ACKNOWLEDGMENT

We thank the CSIR (New Delhi) and the DST (New Delhi) for financialassistance. One of us (R. I.) is thankful to CSIR (New Delhi) for a seniorresearch fellowship.

REFERENCES

1. (a) Giese B. Radicals in Organic Synthesis: Formation of Carbon–CarbonBonds: Pergamon: New York, 1986: (b) Ishibashi, H.; Ohata, K.; Niihara,M.; Sato, T.; Ikeda, M. Regiochemistry in aryl radical cyclisations (5-exoversus 6-endo) of N-vinylic 2-iodobenzamides. J. Chem. Soc., Perkin Trans.I 2000, 547; (c) Parsons, A. F.; Williams, D. A. J. Radical cyclisationreactions leading to polycyclics related to the amaryllidaceae and erythrinaalkaloids. Tetrahedron 2000, 56, 7217; (d) Curran, D. P. The designand application of free radical chain reactions in organic synthesis, part 1.Synthesis 1988, 417; (e) Curran, D. P. The design and application of freeradical chain reactions in organic synthesis, part 2. Synthesis 1988, 489; (f)Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Radical reactions in natural pro-duct synthesis. Chem. Rev. 1991, 91, 1237; (g) Renaud, P.; Sibi, M. (Eds.)Radicals in Organic Synthesis; Wiley-VCH: Weinheim, 2001; vols. 1 and 2;(h) Majumdar, K. C.; Basu, P. K. Formation of five- and six-memberedheterocyclic ring by radical cyclization. Heterocycles 2002, 57, 2413; (i)Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P. Formation of five-and six-membered heterocyclic rings under radical cyclisation conditions.Tetrahedron 2005, 61, 10603.

2. (a) Ishibashi, H.; Kato, I.; Takeda, Y.; Kogure, M.; Tamura, O. 6-Endo-trigand 5-exo-trig selective aryl radical cyclisations of N-(o-bromobenzyl)enamides. Chem. Commun. 2000, 1527; (b) Della, E. W.; Graney, S. D. Ringclosure of 2-thia- and 2-sulfonyl-5-hexenyl radicals. Tetrahedron Lett. 2000,41, 7987; (c) Della, E. W.; Graney, S. D. Regioselectivity of ring closure of2-thia- and 2-sulfonyl-5-methyl-5-hexenyl radicals. Org. Lett. 2002, 4, 4065;(d) Della, E. W.; Graney, S. D. The Regiochemistry of cyclization ofa-sulfenyl-, a-sulfinyl-, and a-sulfonyl-5-hexenyl radicals: Procedures leadingto regioselective syntheses of cyclic sulfones and sulfoxides. J. Org. Chem.2004, 69, 3824.

4064 K. C. Majumdar and R. Islam

Downloaded By: [University of Witwatersrand] At: 20:38 10 November 2008

3. Serra, A. C.; Da Silva Correa, C. M. M. An interesting rearrangement ofunsaturated sulphonate and thiosulphonate esters. Tetrahedron Lett. 1991,32, 6653.

4. Ponaras, A. A.; Zaim, O. Radical cyclizations of 2-(x-haloalkylthio)enonesto thiapolycycloalkanones. Tetrahedron Lett. 2000, 41, 2279.

5. Vacher, B.; Samat, A.; Allouche, A.; Laknfli, A.; Baldy, A.; Chanon, M.5-(Endo)-isopropylsulfonyl-5-(Exo)-phenyl-2-norbornene: X-ray and mole-cular mechanics assessment of the high efficiency of this new radical clock.Tetrahedron 1988, 44, 2925.

6. Ke, B.-W.; Lin, C.-H.; Tsai, Y.-M. Generation and intramolecular cyclizationof a-sulfinyl and a-sulfonyl radicals. Tetrahedron 1997, 53, 7805.

7. Capella, L.; Montevecchi, P. C.; Navacchia, M. L. Radical sequentialprocesses promoted by 1,5-radical translocation reaction: Formation and[3þ 2] anulation of alkenesulfanyl radicals. J. Org. Chem. 1996, 61, 6783.

8. Cid, M. M.; Dominguez, D.; Castedo. L.; Va’zquez-Lopez, E. M. Synthesisof phenethylenamides and their radical cyclization to 3-benzazepines. Tetra-hedron 1999, 55, 5599.

9. Ahmad-Juhan, S. A.; Whiting, D. A. Synthesis of (�)-trimethylpeltogynol via6-endo radical cyclisation. J. Chem. Soc., Perkin Trans. 1990, 1, 418.

10. Sato, T.; Nakamura, N.; Ikeda, K.; Okada, M.; Ishibashi, H.; Ikeda, M.Formation of five-membered lactams by 5-endo-trigonal radical cyclisationsof 2-chloro-N-(cycloalk-1-enyl)acetamides: New synthesis of erythrinaneskeleton. J. Chem. Soc., Perkin Trans. 1992, 1, 2399.

11. (a) Majumdar, K. C.; Mukhopadhyay, P. P. Regioselective synthesis of 2H-benzopyrano[3,2-c]quinolin-7(8H)-ones by radical cyclization. Synthesis2003, 97; (b) Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P.; Sarkar,S; Ghosh, S. K.; Biswas, P. Regioselective synthesis of 1H,3H,6H[2]benzo-pyrano[4,3-d]pyrimidine-2,4-diones and 12H-benzopyrano[3,2-c][1]benzo-pyran-5-ones by radical cyclization. Tetrahedron, 2003, 59, 2151; (c)Majumdar, K. C.; Mukhopadhyay, P. P. C–C bond formation by radicalcyclization: Synthesis of pyrimidine-annulated heterocycles. Synthesis 2003,920; (d) Majumdar, K. C.; Biswas, A.; Mukhopadhyay, P. P. Carbon–Carbon bond formation by radical cyclisation: Regioselective synthesis ofcoumarin-annulated sulfur heterocycles. Synthesis 2003, 2385; (e) Majumdar,K. C.; Mukhopadhyay, P. P.; Biswas, A. Regioselective synthesis of quino-lone-annulated sulfur heterocycles by aryl radical cyclization. TetrahedronLett. 2005, 46, 6655.

12. Majumdar, K. C.; Das, U. Studies in pyrimidine-annelated heterocycles bytandem cyclization: Regioselective synthesis of [6,6]pyranopyran by intramo-lecular [1,6] Michael addition. J. Org. Chem. 1998, 63, 9997.

13. Majumdar, K. C.; Chatterjee, P.; Saha, S. Regioselective synthesis of [6c,12b-cis]-6c,7,12,13-tetrahydro-1H-chromeno[3¼B4,4¼B4:4,5]pyrano[2,3-c]chromen-1-ones via unusual [1,6] Michael addition. Tetrahedron Lett. 1998, 39, 7147.

14. Majumdar, K. C.; Kundu, U. K.; Ghosh, S. K. Studies in sigmatropic rear-rangement: Synthesis of a [6,6]pyranothiopyran ring system by sequentialClaisen rearrangement and pyridine hydrotribromide mediated regioselective‘‘6-endo’’ cyclization. Org. Lett. 2002, 4, 2629.

Regioselective Synthesis of Oxygen and Sulfur Heterocycles 4065

Downloaded By: [University of Witwatersrand] At: 20:38 10 November 2008

15. (a) Litvinov, V. P.; Roman, S. V.; Dyachenko, V. D. Naphthyridines:Structure, physicochemical properties, and general methods of synthesis.Russ. Chem. Rev. 2000, 69(3), 201–220; (b) Litvinov, V. P. Chemistry andbiological activities of 1,8-naphthyridines. Russ. Chem. Rev. 2004, 73(7),637–669; (c) Sherlock, M. H.; Kaminski, J. J.; Tom, W. C.; Lee, J. F.; Wong,S. C.; Kreutner, W.; Bryant, R. W.; McPhail, A. T. Antiallergy agents, 1:Substituted 1,8-naphthyridin-2(1H)-ones as inhibitors of SRS-A release. J.Med. Chem. 1988, 31, 2108–2121; (d) Santilli, A. A.; Scotese, A. C.; Bauer,R. F.; Bell, S. C. N-Substituted 1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolines and 3-phenylpiperidines: Effects on central dopamine and sigmareceptors. J. Med. Chem. 1987, 30, 2270; (e) Chen, K.; Kuo, S. C.; Hsieh,M. C.; Merger, A.; Lin, C. M.; Hamel, E.; Lee, K. H. Antitumor agents,178: Synthesis and biological evaluation of substituted 2-aryl-1,8-naphthyri-din-4(1H)-ones as antitumor agents that inhibit tubulin polymerization. J.Med. Chem. 1997, 40, 3049; (f) Sherlock, M. H. Substituted 1,8-naphthyridi-nones, useful as anti-allergic agents. US, Patent No. 4,596,809, June 24, 1986.

16. (a) Ishibashi, H.; Kawanami, H.; Nakagawa, H.; Ikeda, M. Sulfur-controlled6-exo aryl radical cyclisation of N-ethenyl-2-(2-bromophenyl)acetamides:Synthesis of (�)-tetrahydropalmatine and saulatine. J. Chem. Soc., PerkinTrans. 1997, 1, 2291; (b) Abeywickrema, A. N.; Beckwith, A. L. J.; Gerba,S. Consecutive ring closure and neophyl rearrangement of some alkenylarylradicals. J. Org. Chem. 1987, 52, 4072.

17. Chatgilialoglu, C.; Altieri, A.; Fischer, H. The kinetics of thiyl radical-induced reactions of monounsaturated fatty acid esters. J. Am. Chem. Soc.2002, 124, 12816.

18. Studer, A.; Bossart, M. Radical aryl migration reactions. Tetrahedron 2001,57, 9649.

19. (a) Struble, D. A.; Beckwith, A. L.; Gream, G. A. Cyclization of 4-(1-cyclohexenyl) butyl radical. Tetrahedron Lett. 1968, 3701; (b) Beckwith, A.L.; Schiesser, C. H. Regio- and stereo-selectivity of alkenyl radical ringclosure: A theoretical study. Tetrahedron 1985, 41, 3925; (c) Spellmeyer, D.C.; Houk, K. N. Force-field model for intramolecular radical additions. J.Org. Chem. 1987, 52, 959; (d) Giese, B. Formation of CC bonds by additionof free radicals to alkenes. Angew. Chem., Int. Ed. Engl. 1983, 22, 753.

20. (a) Rosa, A. M.; Lobo, A. M.; Branco, P. S.; Prabhakar, S.; Sa-da-Costa, S.M. New syntheses of the amaryllidacaea alkaloids vasconine assoanine,oxoassoanine, pratosine and ismine by radical cyclisation. Tetrahedron1997, 53, 299; (b) Aldabbagh, F.; Bowman, W. R. Radical cyclisation ontoimidazoles and benzimidazoles. Tetrahedron Lett. 1997, 38, 3793; (c) Curran,D. P.; Ko, S.-B.; Josien, H. Cascade radical reactions of isonitriles: A second-generation synthesis of (20S)-camptothecin, topotecan, irinotecan, andGI-147211C. Angew. Chem. Int. Ed. Engl. 1995, 34, 2683; (d) Bowman, W.R.; Cloonan, M. O.; Krintel, S. L. Synthesis of heterocycles by radical cyclisa-tion. J. Chem. Soc., Perkin Trans. 2001, 1, 2885; (e) Bowman, W. R.; Mann,E.; Parr, J. Bu3SnH-mediated oxidative radical cyclisations: Synthesis of6H-benzo[c]chromen-6-ones. J. Chem. Soc., Perkins Trans. 2000, 1, 2991;

4066 K. C. Majumdar and R. Islam

Downloaded By: [University of Witwatersrand] At: 20:38 10 November 2008

(f) Comins, D. L.; Hong, H.; Jianhua, G. Asymmetric synthesis of camp-tothecin alkaloids: A nine-step synthesis of (S)-camptothecin. TetrahedronLett. 1994, 35, 5331; (g) Rosa, A. M.; Lobo, A. M.; Branco, P. S.; Prabhakar,S.; Pereira, A. M. D. L. Synthesis of phenanthridines by radical Caryl-Caryl

coupling. Tetrahedron 1997, 53, 269; (h) Harrowven, D. C.; Nunn, M. I.T.; Blumire, N. J.; Fenwick. D. R. The first total synthesis of toddaquinoline,an alkaloid from Toddalia asiatica. Tetrahedron 2001, 57, 4447.

21. Majumdar, K. C.; Islam, R. Chemoselective synthesis of thieno[3,2-c][1,8]naphthyridin-4(5H)-ones by tandem cyclization. Heteroatom Chem.2007, 18, 87.

Regioselective Synthesis of Oxygen and Sulfur Heterocycles 4067

Downloaded By: [University of Witwatersrand] At: 20:38 10 November 2008