Short synthesis of noscapine, bicuculline, egenine, capnoidine, and corytensine alkaloids through the addition of 1-siloxy-isobenzofurans to imines

A concise diastereotioselective strategy for the synthesis of noscapine, bicuculline, and egenine (1a-c), as well as capnoidine and corytensine (2a,b), was developed using diastereoselective addition of 1-siloxy-isobenzofurans 4a and 4b to iminium ion 5 in a one-pot approach. The synthesis features the use of imine 13 obtained through Bischler-Napieralsky reaction from amine 11. The addition of ionic liquids as addictives in the reactions afforded erythro configuration in major adduct compounds. The synthetic route can also be applied in the total synthesis of promising tubulin binding agent EM105 (3).     

Synthesis of polyfunctionalized furans from 3-acetyl-1-aryl-2-pentene-1,4-diones

The BF₃-catalyzed cyclization of 3-acetyl-1-aryl-2-pentene-1,4-diones 1a-e in the presence of water in boiling tetrahydrofuran gave bis(3-acetyl-5-aryl-2-furyl)methanes 2a-e in 26-79% yields along with a small amount of 3-acetyl-5-aryl-2-methylfurans 3a-e. The exact structure of 2a was determined by X-ray crystallography. The use of a half volume of the solvent for the reaction of 1a resulted in the formation of 2,4-bis(3-acetyl-5-phenyl-2-furfuryl)-3-acetyl-5-phenylfuran (4) together with 2a and 3a. A similar reaction of 1a was carried out in the presence of 3-acetyl-5-(4-methylphenyl)-2-methylfuran (3d) to afford 4-(3-acetyl-5-phenyl-2-furfuryl)-3-acetyl-5-(4-methylphenyl)-2-methylfuran (5) in 49% yield. The BF₃-catalyzed reaction of 1a with 2,4-pentanedione in dry tetrahydrofuran at 23°C gave 3-(3-acetyl-5-phenyl-2-furfuryl)-4-hydroxy-3-penten-2-one (6a) and 3-(3-acetyl-2-methyl-4-phenyl-5-furyl)-4-hydroxy-3-penten-2-one (7a) in 66 and 24% yields, respectively. The product distribution depended on the reaction temperature. A similar reaction of 1b-e also yielded the corresponding trisubstituted furans 6b-e and tetrasubstituted furans 7b-e in good yields. These results suggested the presence of the furfuryl carbocation intermediate A during the reaction. The one-pot synthesis of 6a and 7a was also achieved by a similar reaction using phenylglyoxal. The deoxygenation of 1a with triphenylphosphine gave 3a in 88% yield, while 1a was treated with concentrated hydrochloric acid to yield 3-acetyl-2-chloromethyl-5-phenylfuran (8) which was quantitatively transformed in ethanol into 3-acetyl-2-ethoxymethyl-5-phenylfuran (9) and in water into 3-acetyl-5-phenylfurfuryl alcohol (10), respectively. In addition, the Diels-Alder reaction of cyclopantadiene with 1a gave the corresponding [4+2] cycloaddition products 11 and 12.     

Electrochemical synthesis of 5,6-dihydroxy-2-methyl-1-benzofuran-3-carboxylate derivatives

Electrochemical oxidation of catechols (1a-c) has been studied in the presence of methyl acetoacetate (2a) and ethyl acetoacetate (2b) as nucleophiles in aqueous solution using cyclic voltammetry and controlled-potential coulometry. The results indicate that the quinones derived from catechols (1a-c) participate in Michael addition reactions with 2a and 2b to form the corresponding benzofuran derivatives (3a-f). The electrochemical synthesis of 3a-f has been successfully performed in an undivided cell in good yield and purity. The oxidation mechanism was deduced from voltammetric data and by coulometry at controlled potential. The products have been characterized after purification by IR, ¹H NMR, ¹³C NMR, MS, and single crystal X-ray diffraction.     

An efficient synthesis of benzofurans and their application in the preparation of natural products of the genus Calea

The intramolecular cyclization of the β-substituted olefins methyl 2-aryloxy-3-dimethylaminopropenoates 3a-3f catalyzed by Lewis acids leads to a short and novel synthesis of benzofurans 2a-2f. When the olefins 4-dimethylamino-3-aryloxy-3-buten-2-ones 4a-4f were used, the cyclization process was faster and provided the corresponding substituted 2-acetylbenzofurans 1a-1f. Among the latter, naturally occurring compounds calebertin (1a), caleprunin A (1b), and caleprunin B (1c) were prepared in good overall yields. These benzofurans were also obtained by direct treatment under MW irradiation of the precursors 1-aryloxypropan-2-ones 7a-7c with DMFDMA, followed by addition of the catalyst, resulting in a route that was one step shorter.     

Microwave-assisted manganese(III) acetate based oxidative cyclizations of alkenes with β-ketosulfones

The microwave-assisted synthesis of 5-(4-nitrophenyl)-2-phenyl-4-(phenylsulfonyl)-2,3-dihydrofuran (5a) was performed via manganese(III) acetate based oxidative cyclization of 1-(4-nitrophenyl)-2-(phenylsulfonyl)ethanone (3a) with vinylbenzene (4a). This new protocol was applied to four sulfone derivatives (3a-d), using vinylbenzene (4a) and diphenylethene (4b), affording a series of 2,3-dihydrofurans (5a-d, 6a-d) in moderate to good yields (26-55%). Similar methodology, applied on allylbenzene (4c), surprisingly, led to dehydronaphthalene derivatives (7a-d) in moderate yields. The unexpected mechanism and the role of allylbenzene (4c) are herein discussed.     

Stereoselective synthesis of aminocyclitol moieties of trehazolin and trehalostatin via enyne metathesis protocol

Stereoselective and efficient synthesis of respective aminocyclitol moieties 1a and 2a of trehazolin and trehalostatin as hexaacetates 1b and 2b using ring-closing enyne metathesis as the key reaction is described.     

Facile synthesis of 4-phenylquinolin-2(1H)-one derivatives from N-acyl-o-aminobenzophenones

An efficient synthesis of 4-phenylquinolin-2(1H)-one derivatives has been achieved in a one-pot reaction from N-acyl-o-aminobenzophenones 1a-c (a: acyl=acetyl; b: acyl=propanoyl; c: acyl=heptanoyl) using NaH as a base. Treatment of 1 with NaH provided the quinolones 2a-c with 62-83% yields, whereas the reaction in the presence of alkyl iodide (alkyl=methyl, ethyl, n-octyl) gave the corresponding N-alkylated quinolones 3a-g in 75-95% yields. The alkylation reaction of 4-phenylquinolin-2(1H)-one 2a with alkyl halide gave a mixture of N-alkylated and O-alkylated products. Comparison of IR and NMR data of the N-alkylated and O-alkylated compounds with those of 2a-c indicated that 2a-c exist as the lactam form.     

C11H12 Hydrocarbons—II : Preparation of tricyclo[5.4.0.0]undeca-3,8,10-triene a norbornenone route from cycloheptatriene

A stereoselective 6-step synthesis of the C₁₁H₁₂ hydrocarbon cis,anti,cis-tricyclo[5.4.0.0^2,5]undeca-3,8,10-triene (2a) is described. The dichloro compound 3c was prepared by the selective reduction of 3a with chromous perchlorate-ethylenediamine complex, a general reagent for this type of transformation. Irradiation of 3c produced 6a and 7a in ∼ 7:1 ratio. Reduction of the mixture with sodium produced ketal mixture 6b and 7b. The ketals were hydrolyzed to ketones 6c and 7c and the ketones decarbonylated to 2a and an isomeric hydrocarbon tentatively assigned as homobasketene 2b′. Hydrocarbon 2a was readily obtained pure by a silver nitrate extraction procedure and 2b′ by preparative VPC. It was shown that pure 6c gives only 2a and therefore, 7c is the source of 2b′. The stereochemical assignments, based on both spectral and chemical evidence, are discussed.     

A facile synthesis of (6S,1′S)-(+)-hernandulcin and (6S,1′R)-(+)-epihernandulcin

A facile total synthesis of (+)-hernandulcin (1) was accomplished from (−)-isopulegol in 6 steps with 15% overall yield. Epoxidation of (−)-isopulegol with m-chloroperbenzoic acid followed by opening of the epoxide 3a with prenyl Grignard afforded the tertiary alcohol 4a with correct C-6 and C-1′ stereochemistry as a major product. Oxidation of the secondary alcohol in compound 4a to the ketone 5a was accomplished in high yield by using TPAP and N-methylmorpholine N-oxide. Conversion of the ketone 5a to α,β-unsaturated ketone via organoselenium intermediate gave (+)-hernandulcin (1). This method was also successfully applied to the synthesis of (+)-epihernandulcin (2).     

Synthesis of arylated highly congested indans using a domino sequence

A novel and efficient regioselective synthesis of various arylated highly congested 7-aryl-5-methylsulfanylindan-4-carbonitriles (3a-f), methyl 7-aryl-5-methylsulfanylindan-4-carboxylates (10a-e) and 7-aryl-5-methylsulfanylindan-4-carboxylic acids (11a-e) through base-catalyzed reaction of 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (1a-f) and methyl 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (9a-e) by cyclopentanone (2) has been delineated. The synthetic potential of 2-pyranone was explored further to generate molecular diversity using 6-aryl-4-sec-amino-2-oxo-2H-pyran-3-carbonitriles (7a-h), 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (5a,b) and methyl 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (12a,b) as precursors for the ring transformation by cyclopentanone to assess the effects of substituents on the course of the reaction to obtain highly congested indans, 6,7-diaryl-5-methylsulfanylindan-4-carbonitriles (6a,b), 7-aryl-5-(piperidin-1-yl)indan-4-carbonitriles (8a-h) and methyl 6,7-diaryl-5-methylsulfanylindan-4-carboxylates (13a,b).     

Amberlyst 15 catalyzed synthesis of indole-pyrazole based tri(hetero)arylmethanes

An expedient synthesis of 1,3-diaryl-4-(3,3′-diindolyl)methylpyrazoles 3a-m has been developed using Amberlyst 15 catalyzed condensation of 1,3-diaryl-4-formyl pyrazoles 2 with indoles 1. This reaction was further extended to the synthesis of 4,4′-bis(3,3′-diindolyl)methylphenoxy-alkanes 5a-b by coupling of 4,4′-di(formylphenoxy)alkane 4 with indole 1.     

An efficient and novel synthesis of chromonyl chalcones using recyclable Zn(l-proline)2 catalyst in water

A novel approach was adopted for the synthesis of a series of chromonyl chalcones (3a-o) from 3-formylchromones (1a-c) and different cyclic active methyl compounds (2a-e), employing Zn(l-proline)₂ as a recyclable Lewis acid catalyst in water. In each conversion, the catalyst was successfully recovered and reused several times without significant loss in yield and selectivity. All the newly synthesized compounds were characterized using elemental analysis and spectral data (IR, ¹H NMR, ¹³C NMR and mass spectrometry).     

Regioselective synthesis of 3,4,6,7-tetrahydro-3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones through ascorbic acid catalyzed three-component domino reaction

An efficient, three-component domino reaction of dimedone 1, aromatic aldehydes (2a–o), and 1,3-cyclohexanedione 1a in the regio-selective synthesis of 3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones (3a–o) is reported. The desired product, 3 is efficiently promoted by ascorbic acid as an organo catalyst.     

Synthesis of 5-alkyl(or aryl)pyrrolo[1,2-a]quinoxalin-4(5H)-ones by denitrocyclisation of N-alkyl(or aryl)-1-(2-nitrophenyl)-1H-pyrrole-2-carboxamides. Evidence of a Smiles rearrangement

An efficient method for the synthesis of hitherto unknown alkyl(or aryl)pyrrolo[1,2-a]quinoxalin-4(5H)-ones 8a-g, 16 and 17 has been established. The method is based on the synthesis of the corresponding N-alkyl(or aryl)-1-(2-nitrophenyl)-1H-pyrrole-2-carboxamides 3a-c and 7a-c,e which undergo denitrocyclisation with NaH in DMF in 4.5 or 2 h. When 3a was treated with NaH in DMF for 30 min the product of a Smiles rearrangement, 9, was isolated. Under similar conditions but for 4.5 h 9 was converted into 8a. This confirms the involvement of a Smiles rearrangement during the denitrocyclisation process. Conversion of 3b into isomeric pyrroloquinoxalinones 12 and 13 confirms a process involving two pathways, direct denitrocylisation of 3b and Smiles rearrangement of 3b followed by denitrocylisation, respectively. Furthermore, denitrocylisation of 7d into pyrroloquinoxalinones 16 and 17 suggests that similar cyclisation pathways are followed by N-arylcarboxamides.     

Substituent-induced regioselective synthesis of 1,2-teraryls and pyrano[3,4-c]pyran-4,5-diones from 2H-pyran-2-ones

Substituent-controlled regioselective synthesis of highly functionalized 1,2-teraryls 3a-k has been achieved through ring transformation of 6-aryl-4-(pyrrolidin-1-yl/piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1a-g by aryl acetones 2a-c in the presence of powdered KOH in DMF in very good yield. Under similar reaction conditions, 6-aryl-4-methylsulfanyl-2H-pyran-2-ones 5a-f afforded 1,7-diaryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-diones 6a-j as major products and 3,4-diaryl-2-methyl-6-methylsulfanylbenzonitriles as minor constituents 7a-j.     

An unexpected formation of pyrazolopyrimidines during the attempted to obtain 5-substituted tetrazoles from carbonitriles

In this Letter, we described the synthesis of new 5-(5-amino-1-aryl-1H-pyrazole-4-yl)-1H-tetrazoles 2a–c from 5-amino-1-aryl-1H-pyrazole-4-carbonitriles 1a–c as well as the unexpected 1H-pyrazolo[3,4-d]pyrimidine derivatives 6a–c from 5-amino-1-aryl-3-methyl-1H-pyrazole-4-carbonitriles 4a–c, instead of 5-(5-amino-1-aryl-3-methyl-1H-pyrazole-4-yl)-1H-tetrazoles 5a–c as desired. In an attempt to obtain these tetrazole derivatives containing the methyl group at C3-position in the pyrazole ring, the amino group in 5-amino-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile 4c was protected by the reaction with sodium hydride and di-tert-butyl-dicarbonate (Boc). The tetrazole derivative 5c was synthesized from the protected compound 7c using analogue methodology to obtain 2a–c and 6a–c.     

3-Amino- and 3-acylamido-2-phosphonopyridines: synthesis by Pd-catalyzed P-C coupling, structure and conversion to pyrido[b]-anellated PC-N heterocycles

Palladium catalyzed cross-coupling of 3-amino- and 3-acylamido-2-bromopyridines 1a-f with triethyl phosphite allowed the synthesis of 3-amino- and 3-acylamido pyridine-2-phosphonic acid diethyl esters 2a-f, whereas nickel catalysts, although providing access to related anilido-2-phosphonates, proved inactive. Reduction of the aminophosphonate 2a with LiAlH₄ afforded 3-amino-2-phosphinopyridine (3a), which was cyclocondensed with dimethylformamide dimethyl acetal (DMFA) via phosphaalkene intermediates 4a to the novel pyrido[b]-anellated 1,3-azaphosphole 5a. Reaction of amidophosphonates 2b-f with LiAlH₄ did not result in the expected reductive cyclization, as shown by closely related anilido-2-phosphonates, but led to product mixtures containing N-secondary 3-amino-2-phosphinopyridines 3b-f as the main or major component. The conversion of 3b,d,e with DMFA to 5b,d,e provides first examples of N-substituted pyrido[b]-anellated azaphospholes. Structures were confirmed by multinuclear NMR and X-ray crystallography (for 2c, 3b).     

Formation of bis- and tris[2]catenanes via the cross-catenation of Pd(II)- and Pt(II)-linked coordination rings

We have demonstrated the self-assembly of linear oligo[2]catenanes via selective cross-catenation. A Pd(II)-linked double looped molecule 1 was transformed into the cyclic trimer c-(1)₃ through the catenation. When 1 was treated with a kinetically inert Pt(II)-linked single looped molecule 2a in aqueous media (1:1.2 DMSO/H₂O) at room temperature, linear oligo[2]catenanes of 2a-(1)_n-2a (n=1 and 2) were selectively obtained, because the kinetically inert Pt(II)-linked ring 2a is allowed to thread on only kinetically labile Pd(II)-linked ring of 1. The distribution of the oligomers depends on the monomer ratio of 1 to 2a. When the ratio of 1 to 2a was 1:2, bis[2]catenane 3a (2a-1-2a) was quantitatively assembled. When the ratio of 1 to 2a was 1:1, not only 3a but also tris[2]catenane 4 (2a-1-1-2a) was assembled. The ratio of 3a to 4 was carefully determined to be 1:1 by NMR. The lengths of 3a and 4 in an extended conformation were estimated by MD/MM2 simulation to be 3.6 and 5.4 nm, respectively.     

An efficient substituent dependent synthesis of congested pyridines and pyrimidines

An efficient and versatile synthesis of various congested pyridines 3a-h, 6a,b, 8a-n, 10a-g, and 16a,b, and (pyrimidin-4-yl)acetonitriles 13a-g has been delineated by base catalyzed ring transformation of suitably functionalized 2H-pyran-2-ones 1a-h, 5, 7, and 15 by formamidine acetate 2a, acetamidine hydrochloride 2b, S-methylisothiourea 9a, pyrazol-1-yl-carboxamidine 9b, and arylamidine hydrochloride 12 separately in the presence of powdered KOH in dry DMF.     

Singlet oxygen addition to chiral allylic alcohols and subsequent peroxyacetalization with β-naphthaldehyde: synthesis of diastereomerically pure 3-β-naphthyl-substituted 1,2,4-trioxanes

The synthesis of a series of eight β-naphthyl-substituted 1,2,4-trioxanes 3a-h by a sequence of singlet oxygen ene reaction of allylic alcohols 1a-h and Lewis acid catalyzed peroxyacetalization of the allylic hydroperoxides 2a-h with β-naphthaldehyde is reported. The ene reactions were performed by solid-state photooxygenation in dye-crosslinked polystyrene beads and resulted in mixtures of diastereoisomeric hydroperoxides 2. Boron trifluoride catalyzed peroxyacetalization resulted in the formation of 3, as well as the 1,2,4-trioxanes 4 and 5, which were formed via acid catalyzed β-hydroperoxy alcohol cleavage.