Synthesis of thiopyrano[2,3-d] pyrimidines and thieno[2,3-d]pyrimidines

The reaction of 4-chloro-5-cyano-2-methylthiopyrimidine (I) with ethyl mercaptosuccinate (II) in refluxing ethanol containing sodium carbonate has afforded diethyl 3-amino-2-(methyl-thio)-7H-thiopyrano[2,3-d]pyrimidine-6,7-dicarboxylate (IV). Displacement of the methylthio group in IV with hydrazine gave the corresponding hydrazino derivative which underwent Schiff base formation with benzaldehyde or 2,6-dichlorobenzaldehyde. Treatment of IV in refluxing acetic anhydride afforded the corresponding diacetylated amino derivative. Partial saponification of IV with sodium hydroxide gave 5-amino-2-(methylthio)-7H-thiopyrano-[2,3-d]pyrimidine 6,7-dicarboxylic acid 6 ethyl ester (VIII). The reaction of 4-amino-6-chloro-5-cyano-2-phenylpyrirnidine (XI) with II resulted in the formation of ethyl 4-amino-6-(ethoxy-carbonyl)-5,6-dihydro-5-amino-2-phenylthieno[2,3-d]pyrimidine-6-acetate (XIII) which when subjected to hydrolysis gave ethyl 4,5-diamino-2-phenylthieno[2,3-d]pyrimidine-6-acetate isolated as the hydrochloride (XIV). Diazotization of IV with sodium nitrite in acetic acid unexpectedly afforded diethyl 5-(acetyloxy)-6,7-dihydro-6-hydroxy-2-(methylthio)-5H-thio-pyrano[2,3-d]pyrimidine-6,7-diearboxylate (XV). Several structural ambiguities were resolved by ir and pmr spectra.     

Synthesis of 2-Methyl-3-acetyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine

For our synthetic work we needed the title compound. Literature survey revealed that 2-amino-4-oxo-4H-[1] benzopyran-3-carboxaldehyde (2-amino-3-formylchro-mone) can undergo condensation with diethyl malonate (or ethyl cyanoacetate) forming ethyl 2-hydroxy(or amino)-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate¹.     

Synthesis of substituted pyrazolo [1,5 — a] pyrimidines

Condensation of 3-amino-4-cyanopyrazole (1) with ethylacetoacetate, ethyl cyanoacetate, diethyl malonate and acetylacetone afforded pyrazolo[1,5-a]pyrimidine derivatives (2—8a). Other compounds (8b—h) of this ring system were obtained by treatment of 1 with arylidenemalononitrile and ethylarylidenecyanoacetate. And the reaction of compound (1) with activated acetylenes yeilded pyrazolo[1,5-a]pyrimidine derivatives (11a—b).     

Reaction of 2-trifluoromethylchromones with cyanoacetic and malonic esters. Synthesis of new benzo[c]coumarin derivatives

Reflux of 2-trifluoromethylchromones with ethyl cyanoacetate and diethyl malonate in ethanol in the presence of sodium ethoxide furnished a number of new benzo[c]coumarin derivatives, which were formed with involvement of two ester molecules.     

Acid-Catalyzed Rearrangements of 5,6-exo-Epoxy-7-oxabicyclo[2.2.1]hept-2-yl Derivatives. Migratory Aptitudes of Acyl vs. Alkyl Groups in Wagner-Meerwein Transpositions

In the presence of HSO₃F/Ac₂O in CH₂CL₂, 2-exo- and 2-endo-cyano-5,6-exo-epoxy-7-oxabicyclo[2.2.1]hept-2-yl acetates ( 6a , b ) gave products derived from the epoxide-ring opening and a 1,2-shift of the unsubstituted alkyl group (σ bond C(3)–C(4)). In contrast, under similar conditions, the 5,6-exo-epoxy-7-oxabicyclo[2.2.1]heptan-2-one ( 6c ) gave 5-oxo-2-oxabicyclo[2.2.1]heptane-3,7-diyl diacetates 20 and 21 arising from the 1,2-shift of the acyl group. Acid treatment of 5,6-exo-epoxy-2,2-dimethoxy-7-oxabicyclo[2.2.1]heptane ( 6d ) and of 5,6-exo-epoxy-2,2-bis(benzyloxy)-7-oxabicyclo[2.2.1]heptane ( 6e ) gave minor products arising from epoxide-ring opening and the 1,2-shift of σ bond C(3)–C(4) and major products ( 25 , 29 ) arising from the 1,3-shift of a methoxy and benzyloxy group, respectively. Under similar conditions, 5,6-exo-epoxy-2,2-ethylenedioxy-7-oxabicyclo[2.2.1]heptane ( 6f ) gave 1,1-(ethylenedioxy)-2-(2-furyl)ethyl acetate ( 32 , major) and a minor product 33 , arising from the 1,2-shift of σ bond C(3)–C(4). The following order of migratory aptitudes for 1,2-shifts toward electron-deficient centers has been established: acyl > alkyl > alkyl α-substituted with inductive electron-withdrawing groups. This order is valid for competitive Wagner-Meerwein rearrangements involving equilibria between carbocation intermediates with similar exothermicities.     

First example of regioselective nucleophilic 1,6-addition of trimethyl(trifluoromethyl)silane to 4H-chromene derivatives

Condensation of 2-trifluoromethylchromone with diethyl malonate, ethyl cyanoacetate, and Meldrum’s acid gave the corresponding methylidene derivatives of 2-trifluoromethyl-4H-chromene. Nucleophilic 1,6-addition of an excess of Me₃SiCF₃ in the presence of Me₄NF to those obtained from the former two compounds afforded 4-substituted 2,2-bis(trifluoromethyl)-2H-chromenes. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1628–1630, September, 2006.     

Synthesis and some transformations of 3-(2,2-dimethyloxan-4-yl)-4-methylpentanenitrile

2,2-Dimethyloxane-4-carbaldehyde reacted with ethyl cyanoacetate to give ethyl 2-cyano-3-(2,2-dimethyloxan-4-yl)prop-2-enoate whose reaction with isopropylmagnesium bromide afforded ethyl 2-cyano-3-(2,2-dimethyloxan-4-yl)-4-methylpentanoate. Elimination of the ester group from the latter led to the formation of 3-(2,2-dimethyloxan-4-yl)-4-methylpentanenitrile.     

Synthesis and antimicrobial activity of imidazo- and pyrimido[2,1-f]-theophyllines

Heating of 8-aminotheophylline with methyl (Z)-2-benzoylamino-3-(dimethylamino)propenoate in acetic acid afforded in a one-pot synthesis a new pyrimido[2,1-f]theophylline derivative. Methylation of this by using CH₃I/NaH furnished in good yield the double methylated derivative. Furthermore, glycosidation of the former with 1-α-bromo-2,3,4,6-tetra-O-acetyl-d-glucose gave the β-glucoside derivative. Reaction of 8-aminotheophylline with [bis(methylthio)methylene]malonitrile, ethyl[bis(methylthio)methylene]cyanoacetate, 1,3-diphenylprop-2-en-1-one, 2-cyano-1,3-diphenylprop-2-en-1-one, 1-(4-nitrophenyl)-3-(dimethylamino)prop-2-ennitrile, 1-phenyl-3-(dimethylamino)prop-2-en-1-one, 2-substituted 3-aryl or heteroarylprop-2-ennitrile and ethyl(arylmethylene)cyanoacetate in N,N-dimethylformamide in the presence of anhydrous potassium carbonate afforded also the corresponding new derivatives of pyrimido-[2,1-f]theophylline. However, 8-aminotheophylline reacted in similar manner with 3-chloropentan-2,4-dione and 2-bromo-1-phenylethanone to give the corresponding imidazo[2,1-f]theophyllines. Furthermore, azo-coupling of one of these with 4-methylphenyldiazonium chloride was performed. The antimicrobial activity of the products has been evaluated. The structures of all new compounds obtained were established by their spectral analyses. Correspondence: Mosselhi A. N. Mosselhi, Department of Chemistry, Faculty of Science, Cairo University, Cairo, Egypt.     

Synthesis and reactions of ethyl 3-acetyl-8-cyano-6,7-dimethylpyrrolo[1,2-a]pyrimidine-4-carboxylate and related compounds

The reactions of 3-acetyl-4-ethoxycarbonyl- or 3,4-diethoxycarbonylpyrrolo[1,2-a]pyrimidine derivatives 7a,b , which were prepared by condensation of the 2-aminopyrrole ( 4 ) with ethyl 3-ethoxymethylene-2,4-dioxovalerate ( 5a ) or ethyl ethoxymethyleneoxaloacetate ( 5b ), with diazomethane are described. Thus, reaction of 7a , with diazomethane gave ethyl 2a-acetyl-7-cyano-2a,3a-dihydro-5,6-dimethyl-3H -cyclopropa[e]pyrrolo[1,2-a]pyrimidine-3a-carboxylate ( 11 ) in 74% yield, which was readily transformed into the 1-pyrrol-2-yl-pyrrole ( 18 ) by treatment with potassium hydroxide. On the other hand, reaction of 7b with diazomethane afforded three products whose structures were assigned as diethyl 7-cyano-2a,3a-dihydro-5,6-dimethyl-3H-cyclopropa[e]pyrrolo[1,2-a]pyrimidine-2a,3a-carboxylate ( 20 ), 6-cyano-7,8-dimethyl-3a,3b,5,9a-tetrahydro-4H -aziridino[c]-1H or 3H-pyrazolo[3,4-e]pyrrolo[1,2-a]pyrimidine-3a,9a-dicarboxylates ( 21,22 ). Ring Transformation of 20 to 25 was not observed.     

Synthesis of cycl[3.2.2]azine and benzo[g]cycl[3.2.2]azine derivatives by use of the [2 + 8] cycloaddition reaction of indolizines and dimethyl acetylenedicarboxylate

The reaction of 1-ethoxycarbonylmethylpyridinium bromides 5a-k with nitro ketene dithioacetal, 1,1-bis-(methylthio)-2-nitroethylene ( 2 ), in the presence of triethylamine in ethanol gave the desired ethyl 2-methyl-thioindolizine-3-carboxylates 3a-k in good yields, along with ethyl 2-methylthio-1-nitroindolizine-3-carboxyl-ates 4a-d . Deesterification of 3 using sodium hydroxide in methanol followed by treatment with polyphosphoric acid gave the corresponding 2-methylthioindolizines 5a-d in good yields. The desulfurization of 5 with Raney-nickel in ethanol occurs smoothly to give the 1,2,3-unsubstituted indolizines 6a-c (a , parent indolizine; b , 8-methylindolzine; c , 6,8-dimethylindolizine). Similarly, pyrrolo[2,1-a]isoquinoline ( 19 ) was also synthesized. These indolizine and pyrrolo[1,2-a]isoquinoline derivatives were allowed to react with dimethyl acetylene to give the corresponding cycl[3.2.2]azine and benzo[g]cycl[3.2.2]azine derivatives in good results.     

Benzopyrans. Part 42. Reactions of 4‐Oxo‐4H‐1‐benzopyran‐3‐carbaldehyde with some active methylene compounds in the presence of ammonia

The title aldehyde 1 in the presence of ammonia gives the pyridine derivatives 9‐11 respectively with acetylacetone, diethyl malonate and ethyl cyanoacetate, and ethyl (or methyl)‐l‐benzopyrano[4,3‐b]pyri‐dine‐3‐carboxylate 22 (or 23 ) with ethyl (or methyl) acetoacetate. Acetylacetone pretreated with ammonia condenses with 1 giving the fused pyridine 24 . Ammonia converts the ester 6 to the pyridine 13 or 14 . Chromic acid oxidation of 22 and 23 affords the coumarinopyridines 25 and 26 , respectively.     

Reactions of 2-(trifluoromethyl)chromones with cyanoacetamides, ethyl cyanoacetate and diethyl malonate. Unexpected synthesis of benzo[c]coumarin derivatives

While 2-(trifluoromethyl)chromones react with cyanoacetamides in the presence of sodium ethoxide to produce 6-(2-hydroxyaryl)-4-(trifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carbonitriles, their reactions with ethyl cyanoacetate and diethyl malonate under the same conditions took an entirely different course and gave novel functionalized derivatives of 6H-benzo[c]chromen-6-one.     

Synthesis of 2(3H)-benzofuranone derivatives by copper (i)-promoted substitution reactions of active methylene carbanions

Activation of soft carbanions by copper(I) in the sub-stitution reaction toward aryl halides and allyl halides was demonstrated. Derivatives of 2(3H)-benzofuranones (2, 14 -18) were prepared in a one-pot procedure by the reaction of copper(I) diethyl malonate with sodium o-bromophenoxide. 2-Hydroxybenzofuran (4) and its 2-amino derivative (5) were obtained by using copper(I) salts of ethyl acetoacetate and ethyl cyanoacetate. The reaction of sodium p-bromophenoxides with copper(I) diethyl malonate yielded p-1,1,2,2-tetracaeboethoxyethylphenols (7, 8). 3-Carboethoxy-3-β-methallyl-2-benzofuranone (14) was converted into spiro[2-benzofuranone-3,3'-(5',5'-dimethyl)-γ-butyrolactone] (22) under acidic conditions. The latter compound was further decarboxylated to give spiro [2-benzofuranone-3,1'-(2',2'-dimethyl)cyclopropane] (23) by the treatment with sodium ethoxide.     

The Diels-Alder Reactivity of 2,2′-Ethylidenebis[3,5-dimethylfuran] and Exploratory Chemistry of the Mono-adducts

In the presence of Me₃Al, 1-cyanovinyl acetate added to 2,2′-ethylidenebis[3,5-dimethylfuran] ( 1 ) to give a 20:10:1:1 mixture of mono-adducts 4,5,6 , and 7 resulting from the same regiocontrol (‘para’ orienting effect of the 5-methyl substituent in 1 ). The additions of a second equiv. of dienophile to 4–7 were very slow reactions. The major mono-adducts 4 (solid) and 5 (liquid) have 2-exo-carbonitrile groups. The molecular structure of 4 (1RS,1′RS,2SR,4SR)-2-exo-cyano-4-[1-(3,5-dimethylfuran-2-yl)ethyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl acetate) was determined by X-ray single-crystal radiocrystallography. Mono-adducts 4 and 5 were saponified into the corresponding 7-oxanorbornenones 8 and 9 which were converted with high stereoselectivity into (1RS,1′SR,4RS,5RS,6RS)-4-[1-(3,5-dimethyl furan-2-yl)ethyl]-6-exo-methoxy-1,5-endo-dimethyl-7-oxabicyclo [2.2.1]heptan-2-one dimethyl acetal ( 12 ) and its (1′RS-stereoisomer 12a , respectively. Acetal hydrolysis of 12a followed by treatment with (t-Bu)Me₂SiOSO₂CF₃ led to silylation and pinacol rearrangement with the formation of (1RS,1′RS,5RS,6RS)-4-[(tert-butyl)dimethy lsilyloxy]-1-(3,5-dimethylfuran-2-yl)ethyl]-5-methoxy-6-methyl-3-methylidene- 2-oxabicyclo[2.2.1]heptane ( 16 ). In the presence of Me₃Al, dimethyl acetylenedicarboxylate added to 12 giving a major adduct 19 which was hydroborated and oxidized into (1RS,1′RS,2″RS,3″RS,4SR,4″RS,5 SR,6SR)-dimethyl 5-exo-hydroxy-4,6-endo-dimethyl-1-[1-(3-exo,5,5-trimeth oxy-2-endo,4-dimethyl-7-oxabicyclo[2.2.1]hept-2-yl)ethyl]-7-oxabicyclo [2.2.1]hept-2-ene-2,3-dicarboxylate ( 20 ). Acetylation of alcohol 20 followed by C?C bond cleavage afforded (1′RS,1″SR,2RS,2′″SR,3RS, 3″SR,4RS,4″SR,5RS)-dimethyl {3-acetoxy-2,3,4,5-tetrahydro-2,4-dimethyl-5-[1-(3-exo,5,5-trimethoxy ?2-endo,4-dimethyl-7-oxabicyclo[2.2.1]hept-1-yl)-ethyl]furan-2,5-diyl} bis[glyoxylate] ( 24 ).     

5,5,6-Trimethylbicyclo[2.2.1]heptan-2-one in the Synthesis of Carbocyclic Analogs of Prostaglandin Endoperoxides

1,3-Dipolar cycloaddition of nitrile oxides to 5,5,6-trimethyl-exo-2-ethynylbicyclo[2.2.1]heptan-endo-2-ol yields the corresponding 2-(isoxazol-5-yl) derivatives. Opening of the isoxazole ring in the latter gives rise to prostanoid precursors with partially built up or completed side chain. 5,5,6-Trimethyl-3-methylenebicyclo[2.2.1]heptan-2-one reacts with nitromethane in the presence of tetramethylguanidine to afford 5,5,6-trimethyl-exo-3-(2-nitroethyl)bicyclo[2.2.1]heptan-2-one which can be converted into the corresponding nitrile oxide by the action of phenyl isocyanate in benzene in the presence of triethylamine as catalyst. 1,3-Dipolar cycloaddition of the nitrile oxide to ethyl 4-pentynoate yields 3-exo-[5-(2-ethoxycarbonylethyl)isoxazol-3-ylmethyl]-5,5,6-trimethylbicyclo[2.2.1]heptan-2-one. Treatment of the latter with hydroxyl amine leads to formation of the corresponding Z-oxime whose reaction with n-hexyl bromide results in transalkylation of the ester group to afford 3-exo-[5-(2-hexyloxycarbonylethyl)isoxazol-3-ylmethyl]-5,5,6-trimethylbicyclo[2.2.1]heptan-2-one oxime.     

Synthesis of pyrido[2,3-<Emphasis Type="Italic">d</Emphasis>]pyrimidin-7(8<Emphasis Type="Italic">H</Emphasis>)-one derivatives from 5-acetyl-4-aminopyrimidines and β-dicarbonyl compounds

Heating of 5-acetyl-4-aminopyrimidine derivatives with ethyl acetoacetate, ethyl benzoylacetate, and diethyl acetone-1, 3-dicarboxylate in the absence of a base gave the corresponding 6-acylpyrido[2, 3-d]pyrimidin-7(8H)-ones. Under analogous conditions, the reaction with ethyl malonate afforded ethyl 7-oxo-7, 8-dihydropyrido[2, 3-d]pyrimidine-6-carboxylates. The pyridone (rather than hydroxypyridine) structures of the pyridopyrimidines obtained were confirmed by IR spectroscopy.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 770–773, March, 2005.     

The Homoconjugated Electron-Releasing Carbonyl Group of 1-Methylbicyclo[2.2.1]hept-5-en-2-one. Regioselective syntheses of 5-chloro- and 6-chloro-1-methylbicyclo[2.2.1]hept-5-en-2-one

Syntheses of (±)-2-exo-cyano-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl acetate ( 1 ) and of (±)-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-one ( 2 ) are reported. The additon of PhSeCl to 1 afforded (±)-5-endo-chloro-2-exo-cyano-1-methyl-6-exo-(phenylselenenyl)-7-oxabicyclo[2.2.1]hept-2-endo-yl acetate ( 6 ), whereas 2 added to PhSeCl with the opposite regioselectivity giving (±)-6-endo-chloro-1-methyl-5-exo-(phenylselenenyl)-7-oxabicyclo[2.2.1]heptan-2-one ( 7 ). These adducts were converted into 5-chloro-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-one ( 9 ) and 6-chloro-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-one ( 10 ), respectively.     

Synthesis,spectroscopic characterization,and in vitro antimicrobial activity of fused pyrazolo[4′,3′:4,5]thieno[3,2-d]pyrimidine

4-Amino-3-methyl-1-phenyl-1H-thieno[2,3-c]pyrazole-5-carboxamide ( 1 ), which had been previously synthesized according to literature, was used for synthesizing pyrazolothieno-pyrimidine ( 2 ) in the presence of triethyl orthoformate and acetic acid. Chlorination of the latter compound upon reflux with phosphorus oxychloride afforded the chloropyrazolothienopyrimidine ( 3 ), which underwent heterocyclization reaction with sodium azide to produce the tetrazolo-pyrazolothienopyrimidine ( 6 ). The chloropyrimidine ( 3 ) reacted with hydrazine hydrate to give the hydrazinopyrimidine derivative ( 4 ), which in turn underwent intramolecular condensation reactions with various 1,3-dicarbonyl compounds, namely ethyl acetoacetate, ethyl benzoylacetate, ethyl cyanoacetate, acetylacetone, diethyl malonate, and ethyl (ethoxymethylene) cyanoacetate, yielding new pyrazolyl pyrazolothienopyrimidine ring systems. Also triazolopyrazolothieno-pyrimidines and benzylidene Schiff's base compounds were obtained as a result of the reactions with carbon disulfide in pyridine and benzaldehyde, respectively. The chemical structures of the newly synthesized compounds were elucidated using elemental and spectroscopic analyses (FT-IR, ¹ H-NMR, ¹³ C-NMR, and mass spectroscopy). Some of the synthesized compounds possess high antibacterial and antifungal activities.     

Reactions of ring-expanded xanthines containing the imidazo[4,5-e][1,4]diazepine ring system

4,5,7,8-Tetrahydro-6H-imidazo[4,5-e][1,4]diazepine-5,8-dione underwent bromination at the 2-position with or without substituents at the 3-, 4- or 7-position, using bromine, N-bromosuccinimide, or acetyl hypobro-mite. The activation of position 6 with an ester functionality, as in 7 , did not alter the site of bromination. The base-catalyzed bromination of the ring-open precursor, diethyl 2-[N-(1-benzyl-5-nitroimidazolyl-4-carbon-yl)amino]malonate ( 5 ), resulted either in introduction of an alkoxy functionality in the above aminomalonate side-chain, yielding 17 when the reaction was quenched with an alcohol, or in degradation of the side-chain, yielding 1-benzyl-5-nitroimidazole-4-carboxamide ( 19 ) when the reaction was quenched with water. Both 17 and 19 are formed by oxidative bromination of 5 via the bromo intermediate 15 . An indirect evidence for the latter was obtained by base-catalyzed methylation of 5 which gave diethyl 2-methyl-2-[N-(1-benzyl-5-nitroimid-azolyl-4-carbonyl)amino]malonate ( 21 ). The base-catalyzed bromination of 5 with N-bromosuccinimide gave rise to two products, the dimer 24a and the monomer 24b that contained the substituted 2,2-diaminomalon-ate side-chain. The structure of 24b was confirmed by single-crystal X-ray diffraction analyses. Reduction of the 5-nitro group of 17 to the corresponding amino derivative 25 , followed by ring-closure with sodium meth-oxide/methanol, yielded three products, a 5:6-fused system 26 and two 5:7 fused systems 27 and 28 . The structures of 26 and 27 were confirmed by single-crystal X-ray diffraction analyses. A tentative reaction pathway for the formation of all three products has been proposed. Hydrolysis of 27 with aqueous hydrochloric acid resulted in ring-opening to form 5-amino-1-benzylimidazole-4-carboxamide ( 40 ). A mechanism for the hydrolysis reaction has been proposed. Catalytic hydrogenation of 5 in acetic acid yielded the aminoimidazo-lone derivative 11 which upon ring-closure with sodium methoxide in methanol produced imidazo[4,5-e][1,4]-diazepine-2,5,8-trione ( 12 ).     

3-exo-tet Cyclization of 2,2-disubstituted 1,3-dihalopropanes with indium in aqueous and ionic liquid solvent system

The 3-exo-tet cyclization of 2,2-disubstituted 1,3-dihalopropanes with In powder in THF solution of 20% H₂O, dioxane solution of 20% H₂O, and ionic liquids, such as [bmim]Br, [bmim]Cl, and [bmin]BF₄, respectively, was efficiently carried out to form the corresponding 1,1-disubstituted cyclopropanes in good yields. The cyclopropanation of 2,2-disubstituted 1,3-dihalopropanes with In powder in ionic liquids, such as [bmim]Br, [bmim]Cl, and [bmin]BF₄, was markedly accelerated compared with that in a THF solution of 20% H₂O and a dioxane solution of 20% H₂O. The mechanism was proposed to involve the radical 3-exo-tet cyclization of the formed 3-halopropyl radical.