Synthesis of new tropinone derivatives by palladium-catalyzed couplings of 8-azabicyclo[3.2.1]oct-2-enyl nonaflates

Whereas tropinone derived nonaflate 3 was no suitable precursor for Heck-reactions, the related carbamate 7 was an excellent substrate for palladium-catalyzed processes. Nonaflate 7 was either isolated in excellent yield by LDA treatment of ketone 5 followed by trapping with NfF (nonafluorobutanesulfonyl fluoride) or generated in situ by fluoride-catalyzed reaction of silyl enol ether 6 with NfF. The desired 1,3-diene 8 was prepared by conventional Heck-reaction of nonaflate 7 with methyl acrylate in almost quantitative yield. Alternatively, the one-pot nonaflation-Heck protocol starting from silyl enol ether 6 provided 8 in good yield. The couplings of acrylonitrile or phenyl vinyl sulfone were also performed with in situ generated 7 and they afforded the expected 1,3-dienes 9 and 10 in good yields. The Sonogashira-reaction with phenylacetylene also started from silyl enol ether 6 and provided enyne 11 via 7 in good yield. A Diels-Alder reaction of 1,3-diene 8 with N-phenyl maleimide at 100 °C furnished tetracyclic adduct 12 in good yield, with excellent diastereofacial selectivity, but with low endo-exo-selectivity. Nonaflate 14 was easily obtained from the corresponding unsaturated bicyclic ketone 13. It behaved differently in an attempted Heck-reaction and mainly led to fragmentation products 15 and 16, whereas the expected 1,3-diene 17 was formed only as minor component. However, 14 could successfully be used in a Sonogashira-reaction with phenylacetylene to afford compound 18. These transformations demonstrate the great potential of tropinone derived alkenyl nonaflates for diversity oriented syntheses of interesting compounds containing an 8-azabicyclo[3.2.1]octane scaffold.     

A facile stereoselective synthesis of difunctionalized 1,3-dienes containing tin and halogen via hydrozirconation of (Z)-3-(tributylstannyl)alk-3-en-1-ynes

Sonogashira coupling of (E)-α-iodovinylstannanes 1 with (trimethylsilyl)acetylene gave (Z)-1-(trimethylsilyl)-3-(tributylstannyl)alk-3-en-1-ynes 2, which underwent a desilylation reaction to afford (Z)-3-(tributylstannyl)alk-3-en-1-ynes 3 in high yields. (1E,3Z)-1-Halo-3-(tributylstannyl)-substituted 1,3-dienes 5 could be synthesized stereoselectively via hydrozirconation of (Z)-3-(tributylstannyl)alk-3-en-1-ynes 3, followed by trapping with iodine or NBS.     

A short-cut from 1-acetyl adamantane to 2-(1-adamantyl)pyrroles

The oxime of 1-acetyl adamantane 2 is added to acetylene (KOH/DMSO, 70 °C, initial acetylene pressure 13 atm, 30 min) to afford the corresponding O-vinyl oxime 5 in 80% yield. The latter upon heating (DMSO, 120 °C, 1 h) gives 2-(1-adamantyl)pyrrole 3, 1-acetyl adamantane 1, and adamantane (6:3:1 mass ratio), the yield of the pyrrole 3 being 83% (based on 1-acetyl adamantane 1 consumed). Under harsher conditions (NaOH/DMSO, 130 °C, atmospheric pressure of acetylene, 4 h) oxime 2 reacts with acetylene to furnish pyrrole 3, 1-acetyl adamantane 1, 1-vinyl adamantane 9, and adamantane (6:7:3:1 mass ratio), with the isolated yield of pyrrole 3 reaching 34%. Under pressure (NaOH/DMSO, 120 °C, initial acetylene pressure 14 atm, 1 h) the same reaction leads to 2-(1-adamantyl)-1-vinylpyrrole 4 and ketone 1 in 48% (based on consumed ketone 1) and 24% yields, respectively. The pyrrole 4 is easily deprotected to the corresponding 1H-pyrrole 3 in 77% yield by treatment (aqueous MeCN) with Hg(OAc)₂ and NaBH₄.     

[4+2] Cyclization reactions of chiral Cβ-substituted Fischer alkenyl carbene complexes: efficient synthesis of enantiopure cyclohexenone and norbornene derivatives

Chiral alkenyl carbene complexes of tungsten(0) 1 and 2, readily available from the chiral pool, undergo the [4+2] cycloaddition with the Danishefsky diene to provide enantiopure 4-alkenyl-2-cyclohexenone adducts 5 and 7 with high stereoselectivity after treatment of the primary cycloadducts 4 and 6 with TBAF. Cyclopentadiene also cycloadds to carbenes 1 and 2 affording the expected norbornene metal carbene complexes 10 and 12 with remarkable diastereo and face selectivity. Oxidative removal of the metal pentacarbonyl fragment leads to the ester derivatives 11 and 13. The X-ray structure analysis of two cycloadducts derived from carbenes 1 and 2 has been performed.     

In situ 1,3-dipolar azide cycloaddition reaction: synthesis of functionalized d-glucose based chiral piperidine and oxazepine analogues

Functionalized furanose-fused piperidines 4-6 and oxazepines 15-17, useful precursors for structurally unique bioactive nucleosides as well as for potential glycosidase inhibitors, have been synthesized by the application of 1,3-dipolar azide cycloaddition (DAC) reaction on d-glucose based substrates. The strategy works well even with the nucleoside analogue 8, affording the bicyclic nucleoside analogues 11 and 12.     

Synthesis of 4-(2-arylvinyl)-8-hydroxyquinolines via anhydrous Heck coupling reaction and the PL properties of their Al complexes

Anhydrous Heck coupling between 2 and eight different arylvinyl compounds using 3 mol % of PdCl₂/2PPh₃ catalyst system occurs selectively at position-4 of 2 affording 4-(2-arylvinyl)-8-tosyloxyquinolines 3 in good to high yields. The tosyloxy protecting group showed high stability under anhydrous coupling conditions. Deprotection of the resulting 4-arylvinyl-8-tosyloxyquinolines produced 4-(2-arylvinyl)-8-hydroxyquinolines 4 in high yields. The aluminium complexes of the resulting 8-hydroxyquinolines have been synthesized and their photoluminescence (PL) properties have been studied. One of the complexes with a 2,4,6-trimethoxystyryl substituent at position-4 of the quinolate shows higher relative PL quantum yield than the other complexes due to the minimization of the cis-trans photoisomerization in solution.     

Silyl stabilized azanes: reactions of lithiumbis(trimethylsilyl)hydrazine with trialkyltin halides

Lithium 1,2-bis(trimethylsilyl)hydrazine (1a) reacts with Me₃SnCl, Et₃SnBr and Bu₃SnCl to form bis(trimethylsilyl)(trimethylstannyl)hydrazine (2a), (triethylstannyl)bis(trimethyl silyl)hydrazine (2b) and (tributylstannyl)bis(trimethylsilyl)hydrazine (2c), respectively. Compounds 2a and 2b undergo disproportionation at room temperature to form bis(trimethylsilyl)bis(trimethylstannyl)hydrazine (3a) and bis(triethylstannyl)bis(trimethylsilyl)hydrazine (3b). In contrast, 2c is highly stable and can withstand such a reaction up to 150 °C. The monostannylated products, 2a, 2b and 2c do not get lithiated at NH and instead undergo transmetallation in their reaction with RLi or Li to form lithiumbis(trimethylsilyl)hydrazine (1a).     

Mg-promoted reductive coupling of aromatic carbonyl compounds with trimethylsilyl chloride and bis(chlorodimethylsilyl) compounds

Mg-promoted reductive coupling of aromatic carbonyl compounds (1) with chlorosilanes, such as trimethylsilyl chloride (TMSCl:2), 1,2-bis(chlorodimethylsilyl)ethane (3) and 1,5-dichlorohexamethyltrisiloxane (4), in N,N-dimethylformamide (DMF) at room temperature brought about selective and facile reductive formation of both of carbon-silicon and oxygen-silicon bonds to give the corresponding α-trimethylsilylalkyl trimethylsilyl ethers (5) and cyclic siloxanes (6), (7) in moderate to good yields, respectively. The present facile and selective coupling may be initiated through electron transfer from Mg metal to aromatic carbonyl compounds (1).     

Steric course of some cyclopropanation reactions of L-threo-hex-4-enopyranosides

Completely protected 4-deoxy-α-L-threo-hex-4-enopyranosides 1c,d undergo the dichlorocarbene addition affording exclusively diastereomeric adducts 5c,d with the cyclopropane ring anti to the C-3 alkyloxy substituent, while the reaction with 3-unprotected derivatives 1a,b affords a mixture of syn and anti derivatives. Under the Simmons-Smith cyclopropanation adducts 2a-d with a syn stereochemistry are obtained. Starting from 5b, the cyclopropanated sugar 3b is obtained by reduction with LiAlH₄, thus the two diastereomers 2b and 3b can be stereoselectively obtained through the two different pathways. For a useful comparison, 4-deoxy-β-L-threo-hex-4-enopyranoside 1e was also subjected to the above two cyclopropanation methods affording the expected cycloadduct 2e and a diastereomeric mixture of dichlorocycloadducts 4e and 5e (4e/5e=2.8:1).     

Synthesis of an octasubstituted galactose zinc(II) phthalocyanine

4,5-Bis(1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl)phthalonitrile (3) was prepared by S_NAr reaction of diacetone galactose 1 and 4,5-difluorophthalonitrile (2) in 96% yield. Cyclotetramerization of 3 was achieved via its isoindoline derivative 4, affording the peripherally octasubstituted galactose zinc(II) phthalocyanine 5 in 29% yield. Deprotection of 5 gave the highly water soluble octasubstituted galactose zinc(II) phthalocyanine 6 in 81% yield which will be applied as a photosensitizer in photodynamic therapy.     

New efficient synthesis of pyrimido[1,6-c]quinazolin-4-ones by a Biginelli 3CC/Staudinger/aza-Wittig sequence

Dihydropyrimidinone azides 1, obtained from trimethylsilyl chloride-catalyzed Biginelli reaction of 2-azidobenzaldehyde, ethyl acetoacetate, and urea (or thiourea) at room temperature, reacted with triphenylphosphine to give iminophosphorane 2. A tandem aza-Wittig reaction of iminophosphorane 2 with isocyanate, acyl chloride or CS₂ in the presence of K₂CO₃ or NEt₃ generated pyrimido[1,6-c]quinazolin-4-ones 4, 6 or 8 in moderate to good yield.     

Synthesis and characterizations of N,N,N′,N′-tetrakis (diphenylphosphino)ethylendiamine derivatives: Use of palladium(II) complex as pre-catalyst in Suzuki coupling and Heck reactions

Oxidation of N,N,N′,N′-tetrakis(diphenylphosphino)ethylendiamine (1) with elemental sulfur and selenium gives the corresponding sulfide and selenide, respectively, [(Ph₂P(E))₂NCH₂CH₂N(P(E)Ph₂)₂] (E: S 1a, Se 1b). Complexes of 1 [(M₂Cl₄){(Ph₂P)₂NCH₂CH₂N(PPh₂)₂}] (M: Ni(II) 1c, Pd(II) 1d, Pt(II) 1e) were prepared by the reaction of 1 with NiCl₂ or [MCl₂(COD)] (M = Pd, Pt). The new compounds were characterized by NMR, IR spectroscopy and elemental analysis. The catalytic activity of Pd(II) complex 1d was tested in the Suzuki coupling reaction and Heck reaction. The palladium complex 1d catalyses the Heck reaction between styrene and aryl bromides as well as Suzuki coupling reaction between phenylboronic acid and arylbromides affording stilbenes and biphenyls in high yield, respectively.     

Synthesis of the fungal natural product (−)-xylariamide A

The first synthesis of the fungal natural product (−)-xylariamide A 1 is reported. N,O-Bis(trimethylsilyl)acetamide induced coupling of d-tyrosine with (E)-but-2-enedioic acid 2,5-dioxo-pyrrolidin-1-yl ester methyl ester 5 produced the dechloro natural product 6, which was subsequently monochlorinated using oxone and KCl to yield synthetic 1. (−)-Xylariamide A 1, (+)-xylariamide A 2 and (−)-dechloroxylariamide A 6 displayed no cytotoxic or antimicrobial activity.     

Silyl stabilized azanes: Reactions of mono- and dilithium bis(trimethylsilyl)hydrazide with dichloro- and tetrachlorostannane

SnCl₄ acts primarily as an oxidant and oxidizes monolithium bis(trimethylsilyl) hydrazide 1 to mainly bis(trimethylsilyl)amine, BSA and tris(trimethylsilyl)hydrazine, TrSH and itself get reduced to SnCl₂. Similarly, reaction of SnCl₄ with dilithiumbis(trimethylsilyl) hydrazide 2, oxidizes it to lithium tris(trimethylsilyl)hydrazide, Li-TrSH. Reaction of dichlorostannane (reduction of oxidation state of tin from +4 to +2) with 1 gives a simple substitution reaction and give a pale yellow solid, 1,4-bis(trimethylsilyl)-1,2,4,5-tetraza-3,6-distannacyclohexane, 3b. Whereas, in reaction of 2 with SnCl₂ intermediate stannimine [(Me₃Si)₂N-NSn], tetramerizes and further loses tetrakis(trimethylsilyl)tetrazene, TST to give a cubane compound [(Me₃Si)N-Sn]₄, 4.     

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.     

Cyclization in situ of enose-/ynose-nitrilimines: an expedient approach to the synthesis of chiral glycopyrazoles and pyrazolonucleosides

Intramolecular [3+2] nitrilimine cycloaddition reactions on carbohydrate-derived substrates proceed in a regioselective fashion, affording structurally novel chiral glycopyrazoles (4-6 and 10a-c) in good yields. The products can be subsequently transformed to bicyclic pyrazoles (viz. 11 from 4) or nucleoside analogues (viz. 12 from 4).     

Synthesis of new bicyclic lactam peptidomimetics by ring-closing metathesis reactions

An efficient and versatile synthetic method for the preparation of new fused bicyclic lactams 3a and 3b is described. The spirane cyclopentane nucleus was easily installed by diallylation of the pyroglutamate derivative 18 followed by ring-closing metathesis (RCM). A more practical and stereoselective method for the allylation of the α-methoxy carbamate 21, involving the use of InCl₃ as a Lewis acid, was developed. In the crucial coupling reaction of the diastereomeric mixture of cis- and trans-pirrolidine derivatives 5a and 5b with N-Cbz vinyl phenylalanine only the cis isomer was found to react. An RCM reaction on the dipeptides 25a and 25b followed by catalytic hydrogenation, gave the final epimeric bicyclic lactams 3a and 3b. The same synthetic sequence on the model compound 7, lacking the spiro cyclopentane nucleus, is also reported.     

Silicon-carbon unsaturated compounds. 77. Thermal behavior of cis- and trans-1-silacyclobut-3-ene formed from pivaloyl[tert-butylbis(trimethylsilyl)]silane and tert-butylacetylene

The reaction of tert-butylbis(trimethylsilyl)silyl potassium with pivaloyl chloride gave pivaloyl[tert-butylbis(trimethylsilyl)]silane (1) in 89% yield. The cothermolysis of 1 with tert-butylacetylene at 140 °C for 24 h produced the mixture consisting of cis- and trans-1,2,3-tri(tert-butyl)-2-(trimethylsiloxy)-1-(trimethylsilyl)-1-silacyclobut-3-ene (cis-2 and trans-2) in a ratio of 0.7: 1, in 88% combined yield. The thermolysis of the mixture, cis-2 and trans-2, at 250 °C for 24 h proceeded to give trans-1,2,4-tri(tert-butyl)-1-(trimethylsiloxy)-2-(trimethylsilyl)-1-silacyclobut-3-ene (4) as a single product in 96% yield. Similar treatment of cis- and trans-2 at 190 °C for 15 h afforded silylcyclopropene 3 quantitatively, which underwent further isomerization at 250 °C to give trans-1-silacyclobut-3-ene 4 in quantitative yield.     

Studies on isocyanides: synthesis of tetrazolyl-isoindolinones via tandem Ugi four-component condensation/intramolecular amidation

The Ugi four-component condensation between methyl o-formylbenzoates 1, anilines 2a-c, isocyanides 3, and trimethylsilyl azide (4) afforded the expected Ugi adducts 5a-d, which were cyclized to the title compounds 6a-d upon treatment with sodium ethoxide in ethanol. Starting from aralkyl- or alkylamines 2d-g the Ugi adducts underwent a spontaneous cyclization to tetrazolyl-isoindolinones 6e-j.