Efficient synthesis and applications of 2-substituted azulene derivatives: towards highly functionalized carbo- and heterocyclic molecules

An efficient synthesis of 2-substituted azulene derivatives (3-6) was accomplished from ethyl 2-oxo-2H-cyclohepta[b]furan-3-carboxylate 1 and its derivative 2, which in turn were prepared from readily available tropolone. Compounds 1 and 2 were utilized to construct densely functionalized benz[a]azulene and azulene-furan frameworks (16-25, 29-34, 37, 38).     

[4+2] Cycloaddition reactions of 4-sulfur-substituted 2-pyridones with electron-deficient dienophiles

[4+2] Cycloaddition reactions of 4-(phenylthio)-1-tosyl-2-pyridone (6a) and 4-(phenylsulfonyl)-1-tosyl-2-pyridone (6b) with electron-deficient dienophiles 7 (N-methylmaleimide, N-phenylmaleimide, and methyl acrylate) gave new isoquinuclidine products 8-10. The N-tosyl group of 6a and 6b was also efficiently converted to N-alkyl derivatives 6c-f, which showed different stereoselectivity toward reactions with dienophiles 7. Several other dienophiles 15 (dimethyl acetylenedicarboxylate, methyl vinyl ketone, ethyl vinyl ether, and methyl methacrylate) were found not to react with 6a or 6b, but led to the formation of tosyl migration products 4-(phenylthio)-O-tosyl-pyridinol (16a) and 4-(phenylsulfonyl)-O-tosyl-2-pyridinol (16b), respectively. The reactivity, regioselectivity, and stereoselectivity of the cycloaddition reactions were also compared with semi-empirical calculations.     

Aryl-2,3-oxaphosphabicyclo[2.2.2]octene derivatives—the precursors of oxoarylphosphine oxides (aryl metaphosphonates)

The Baeyer-Villiger oxidation of 7-phosphanorbornene 7-oxides with sterically demanding substituents on the phosphorus atom (4a-d) by m-chloroperbenzoic acid afforded the title products (5a-d) as a mixture of two regioisomers (A and B). Isomer A, the result of thermodynamic control, was stable, while isomer B, the product of kinetic control, underwent decomposition and/or epoxidation. Single crystal X-ray analysis of P-(2,4,6-triisopropylphenyl) oxaphosphabicyclooctene (5Ac) was not only useful in the evaluation of its structure, but, for the first time in the literature, a low-coordinated arylmetaphosphonate (15c) formed by fragmentation on X-ray irradiation could also be detected. The precursors (5Aa-c) were utilized in the thermoinduced and UV light-mediated fragmentation-related phosphorylations of alcohols. Beside the well-known elimination-addition mechanism via the metaphosphonate intermediate (15), a novel addition-elimination route involving a species with a pentavalent pentacoordinated phosphorus atom (16) was also substantiated.     

Cycloaddition reactions of cross-conjugated enaminones

A detailed study on the cycloaddition reactions of cross-conjugated enaminones 1 and 9 with dimethyl acetylenedicarboxylate (DMAD) and ketenes is described. The reactions provide a variety of pyran (4, 11), pyran-2-one 14 and pyrrol-3-ylidene 8 derivatives having great pharmacological and medicinal significance. Moreover, the preferred formation of product 8 over 7 has been explained on the basis of molecular dynamics (MD) simulations performed on the intermediate 5 in the gas phase. The synthetic potential of enaminones 9 has further been explored by treating them with Lawesson's reagent (LR) and trapping the in situ generated enaminothiones 16 with some acrylates 17 leading to the formation of thiopyran derivatives 19. To the best of our knowledge, this is the first report in which cross-conjugated enaminothiones 16 have been utilized in cycloaddition reactions.     

Synthesis of 1,4-disilacyclohexa-2,5-dienes

Title compounds of the type 2,3,5,6-tetraphenyl-1,4-di-X-1,4-di-Y-1,4-disilacyclohexa-2,5-diene wherein X=Y=NMe₂ (4); X=NMe₂, Y=Cl (cis, trans-5); X=NMe₂, Y=Me [(trans)-6] and X=t-Bu, Y=Cl (trans-8) were synthesized from Si₂(NMe₂)₅Cl, sym-Si₂(NMe₂)₄Cl₂, sym-Si₂(NMe₂)₄Me₂, and sym-Si₂Cl₄(t-Bu)₂, respectively, in the presence of diphenylacetylene at 200 °C. Similarly the analogous title compound from the combination of 1-phenyl-1-propyne and Si₂(NMe₂)₅Cl [X=Y=NMe₂ (cis and trans-7) was synthesized. In all cases where cis/trans diastereomers could arise from two different silicon substituents (5, 6, 8) the trans isomer was the sole or dominant product. Evidence for the intermediacy of the silylene Si(NMe₂)₂ in these reactions was gained from a trapping experiment. Compound 4 upon treatment with SiCl₄, SiBr₄ or PI₃ provided the corresponding 1,1,4,4-tetrahalo derivatives 9a-c, respectively. Treatment of 4 with MeOH or PhOH gave the 1,1,4,4-tetramethoxy and tetraphenoxy analogues 9d and 9e, respectively. The tetrachloro derivative 9a upon LAH reduction led to the corresponding tetrahydro compound 10, while the reaction of 9a with H₂O gave the tetrahydroxy derivative 11. Allowing (trans)-6 to react with SiCl₄ provided a ca. 1:1 cis/trans ratio of the derivative 12 in which X=Cl, Y=Me, and possible pathways that rationalize this loss of stereochemistry are proposed. Synthesis of trans-13 in which X=t-Bu, Y=H was achieved by LAH reduction of 8. All of the title compounds except 8 experience free phenyl rotation at room temperature. At −30 °C this rotation in 8 is essentially halted. The molecular structures of 4, 8, 9c, 9e, 10 and 13 were determined by X-ray crystallography.     

Cycloaddition of methyl 2-(2,6-dichorophenyl)-2H-azirine-3-carboxylate to electron-rich 2-azadienes

tert-Butyldimethylsililoxy-2-aza-1,3-butadienes react with 2H-azirine 3 leading to Diels-Alder cycloadducts in moderate yields. The reactions are endo- and regioselective with the azirine being added by its less hindered face. There is only one product in the case of 1b, 4b. There are two isomers (4 and 5) from 1a, 1c and 1d. A different result was obtained with the diene 1e. Diene 1e formed products 4e and 8. Some of compounds 4 and 5 have been hydrolysed leading to functionalised aziridines 7. Compound 8 gave aziridine 9.     

Efficient synthesis of cephalotaxine- and deoxyharringtonine analogues by a trimethylaluminium-mediated domino reaction

The synthesis of cephalotaxine- and cephalotaxine amide analogues 14a-c and 16a-c as well as of the deoxyharringtonine analogues 5a,b was performed employing a trimethylaluminium-mediated domino reaction of 9a-c and 8 to give the spirocyclic compounds 7a-c, which was followed by a palladium catalyzed α-arylation.     

An expedient method for the synthesis of 6-substituted uracils under microwave irradiation in a solvent-free medium

Condensation of malonic acid 1 and ureas 2a-f proceeds smoothly in the presence of acetic anhydride 3 under microwave irradiation in solvent-free conditions to give 6-hydroxy-uracils 4 in excellent yields. Under identical conditions, the condensation of cyanoacetic acid 5 and ureas 2a,b,g and h in the presence of acetic anhydride 3, followed by cyclization in the presence of sodium hydroxide affords 6-amino-uracils 6 in high yields. The work-up procedures are simple and products need no purification.     

Tandem enlargement of the tetrahydropyridine ring in 1-aryl-tetrahydroisoquinolines using activated alkynes—a new and effective synthesis of benzoazocines

Tetrahydroisoquinolines 3a-e underwent piperidine ring enlargement under the action of activated alkynes, giving benzoazocines 4, 5 and 7-11 in high yields.     

One-pot synthesis of macrocyclic compounds possessing two cyclobutane rings by sequential inter- and intramolecular [2+2] photocycloaddition reactions

Sensitized photocycloaddition reactions of 6,6′-dimethyl-4,4′-[1,3-bis(methylenoxy)phenylene]-di-2-pyrone (1) with electron-poor α,ω-diolefins such as ethylene diacrylate (2a) and polyoxyethylene dimethacrylates (2b-d) afforded site- and stereoselective macrocyclic dioxatetralactones (3a-d) and (4b) having 18- to 25-membered rings across the C5-C6 and C5′-C6′ double bonds, or C5-C6 and C3′-C4′ double bonds in 1, respectively. Similar photoreactions of 1 with electron-rich α,ω-diolefins such as poly(ethylene glycol)divinyl ether (2e and 2f) afforded crown ether-type macrocyclic compounds (5e and 5f) having 18- and 21-membered rings across the C3-C4 and C3′-C4′ double bonds in 1, respectively. The stereochemical features of 3b, 5e-xx, and 5e-nn were determined by the X-ray crystal analysis. The reaction mechanism was inferred by MO methods.     

Intramolecularly donor-stabilized silenes: Part 5. Generation and conversion of 1-[2,6-bis(alkoxymethyl)phenyl]- and 1-(8-alkoxynaphthyl)-1,2,2-tris(trimethylsilyl)silenes

1-(8-Methoxy-1-naphthyl)-1,2,2-tris(trimethylsilyl)silene (10) and the 1-[2,6-bis(alkoxymethyl)phenyl]-1,2,2-tris(trimethylsilyl)silenes (12a-d) were generated by the reaction of (dichloromethyl)tris(trimethylsilyl)silane (1) with two molar equivalents of 8-methoxy-1-naphthyllithium or 2,6-bis(alkoxymethyl)phenyllithium (8a-d), respectively, but proved to be unstable. 10 was trapped with excess of the applied naphthyllithium reagent to give 1,1-bis(8-methoxy-1-naphthyl)-1-[bis(trimethylsilyl)methyl]-2,2,2-trimethyldisilane (11); and 12a-d underwent spontaneous conversions and formed two types of substituted 2-oxa-1-silaindane derivatives (13a,b and 14b-d). Whereas silenes with an intramolecular amine coordination are thermally stable compounds which can be isolated, the intramolecular coordination of an ether group to the electrophilic silene silicon atom does not provide a comparable stabilization to the SiC system and the respective derivatives generated were converted into resultant products.     

Asymmetric synthesis of the tricyclic core of cyathin diterpenoids via intramolecular Heck reaction

The enantioselective synthesis of the ketones 3 which displays the carbon core of NGF-inducing cyathane diterpenes is described. The key tricyclic trienone 22 was assembled in 13 steps from Michael adduct (R)-8a via intramolecular Heck cyclization of the chiral triflate 21. The trienone 22 was further elaborated into ketone 3 through trimethylaluminum-promoted expansion of the C-ring with trimethylsilyldiazomethane.     

Three-component synthesis of 2-imino-1,4-benzoxazines

A series of 2-imino-1,4-benzoxazines (8a-e) were prepared by the one-pot, three-component, condensation of salicylaldehyde (4), various ortho-aminophenols (5), and 2,6-dimethylphenylisonitrile (6). The structures of four of the crystalline benzoxazine derivatives (8b-e) were unambiguously established by X-ray analysis.     

Synthesis of 4-substituted azepino[3,4-b]indole-1,5-diones

Mono- or dibromo derivatives 2 and 3 were prepared by an efficient two-step route from 10-methyl-azepino[3,4-b]indole-1,5-dione 1. Elimination reaction on 2 gave access to 4-bromo-10-methyl-2H,10H-azepino[3,4-b]indole-1,5-diones 4. Finally, 4-substituted 10-methyl-2H,10H-azepino[3,4-b]indole-1,5-diones 6-14 were synthesised in good yields from 4 via palladium-mediated cross-coupling reactions.     

Novel regiochemistry in the aqueous singlet oxygen ene reactions of carboxylic acid salts: a comparison of substrate structure

The singlet oxygen (¹Δ_g) photooxidations of angelic acid salt (1), tiglic acid salt (2), 2,3-dimethyl-2-butenoic acid salt (3), 3-ethoxycarbonyl-5,6-dihydro-2-methyl-4H-pyrane acid salt (4), cis-3-hexenoic acid salt (5), and trans-3-hexenoic acid salt (6) were conducted in deuterated water. The major and minor ene allylic hydroperoxide products were quantified and indicate that the allylic hydrogen geminal to the carboxylate group is preferentially abstracted in 1-4, whereas the allylic hydrogen α to the carboxylate is slightly favored for 5 and 6. We have attributed the observed regiochemistry in 1-4 to stabilizing hydrogen bonding interactions between the solvent and the perepoxide, which leads to the major ene product.     

A two-step four-component queuing cascade involving a Heck coupling, π-allylpalladium trapping and Diels-Alder reaction

Palladium-catalyzed cross-coupling of bicyclopropylidene (1) with iodoethene (11) in the presence of a secondary amine 12 provides allylidenecyclopropanes 13 which undergo immediate Diels-Alder reactions upon addition of dienophiles 14-18 to provide 8-(1′-aminoethyl)-substituted spiro[2.5]oct-7-ene derivatives 23a-26a in 29-66% yield. The same one-pot, two-step queuing cascade can be carried out with other iodoalkenes including cyclic ones and with cyclic dienophiles such as N-arylmaleinamides 19-22 and N-phenyl-triazolinedione 37 to furnish highly substituted spiro[2.5]oct-4-enes and spirocyclopropanated heterobicycles 47a-49a, 41a-46a (17-50%). Spirocyclopropanated heterobicycles such as 55, 56 (25 and 38% yield, respectively) can also be obtained by an inter-intra-intra-intermolecular version of this queuing cascade involving 1-hydroxyethyl- and 1-aminoethyl-substituted iodoethenes 53, 54.     

The first one-pot Alder-ene-reductive amination sequence

Alkyne allyl alcohols 1 are cycloisomerized under Pd catalysis to give (4-alkylidene tetrahydrofuran-3-yl) acetaldehydes 2 in good yields. These mild reaction conditions are fully compatible with a subsequent reductive amination with secondary amines and formic acid. Thus, the cycloisomerization-reductive amination sequence of yne allyl alcohols 1 and secondary amines 3 furnishes β-amino ethyl alkylidene tetrahydrofurans 4 in moderate to good yields in a one-pot fashion.     

Unusual sulfanylation through ring transformation of arene-tethered 2H-pyran-2-ones by in situ built Michael adduct

A novel synthesis of highly functionalized alkylsulfanylmethyl arenes 8a-m through the ring transformation of 6-aryl-4-methyl/ethylsulfanyl-2H-pyran-2-one-3-carbonitriles 1a-j, by reaction with methyl vinyl ketone 2, is delineated and illustrated. To ascertain the course of reaction, 3-arylsulfanylmethyl-2-methyl-6-methylsulfanyl-4-phenylbenzonitriles 8k-m were also prepared from the reaction of 1 with 4-arylsulfanyl-butan-2-ones 7c,d.     

Synthesis and crystal structures of dinuclear zinc complexes with the 1,3-bis(2-pyridylmethyl)acetamidinato ligand

The reaction of an equimolar mixture of N,N′-bis(2-pyridylmethyl)acetamidine (1) and di(tert-butyl)phosphane with dimethylzinc yields dinuclear bis(methylzinc) bis(2-pyridylmethyl)acetamidinate di(tert-butyl)phosphanide (2). A similar protocol allows the preparation of bis(alkylzinc) bis(2-pyridylmethyl)acetamidinate tert-butylamide [zinc-bound methyl (3) or trimethylsilylmethyl group (4)]. The reactions of 3 and 4 with diphenylsilane lead to the formation of insoluble dimeric bis(alkylzinc) N,N′-bis(2-pyridylmethyl)acetamidinate hydrides [zinc-bound methyl (5) or trimethylsilylmethyl group (6)]. These zinc hydrides decompose once dissolved under formation of elemental zinc thus hampering catalytic applications. Molecular structures of [(1)ZnCl₂] as well as of the zinc complexes 2 to 6 are discussed.     

Synthesis of bridged nicotinates having [n](2,5)pyridinophane skeletons (n=8-14)

Synthesis of various bridged nicotinates 6 having [n](2,5)pyridinophane skeletons (n=8-14) was accomplished by the unique pyridine-formation reaction of methyl propiolate with a series of formyl-substituted (vinylimino)phosphoranes 5, which were prepared from the corresponding cycloalkanones 1 via Vilsmeier-Haack formylation giving chloro-substituted cycloalkenals 2, their thermal and photochemical transformation to formyl azirines 4, and the following ring-opening reactions with triphenylphosphine. The HPLC analysis of [11](2,5)pyridinophane derivatives, (S_p,S)-14 and (R_p,S)-14, showed that these diastereomers rapidly epimerize themselves at room temperature and that their planar-chirality was thermodynamically less stable as compared to the corresponding [11](2,5)cyclophane systems.