Access to 2-alkyl chromanones via a conjugate addition approach

The introduction of alkyl substituents at C-2 of chromanones via conjugate addition of silyl enol ethers to a variety of chromenones is reported. In most cases racemic 2-alkyl chromanones were obtained in good yield in the presence of TMSOTf. The copper(II)-promoted conjugate addition of silyl enol ethers to chromenones was also carried out, albeit in low yields and no selectivity. Reliable syntheses of the chromenones via acylation of the corresponding β-diketo-compounds are also described.     

Indium-mediated beta-allylation,beta-propargylation,and beta-allenylation onto alpha,beta-unsaturated ketones: reactions of in-situ-generated 3-tert-butyldimethylsilyloxyalk-2-enylsulfonium salts with in-situ-generated organoindium reagents

3-tert-Butyldimethylsilyloxyalk-2-enylsulfonium salts, generated in situ from the reaction of alpha,beta-enones with dimethyl sulfide in the presence of TBSOTf, underwent a novel nucleophilic substitution with allylindiums to give silyl enol ethers of delta,epsilon-alkenyl ketones in good yields, which correspond to formal Michael addition products. In a similar manner, 1,4-propargylation of propargylindiums onto the sulfonium salts produced the corresponding silyl enol ethers of delta,epsilon-alkynyl ketones in good yields. Organoindium reagents derived from gamma-substituted propargyl bromide and indium afforded the corresponding silyl enol ethers of beta-allenyl ketones in good yields. The reaction proceeds via an addition-substitution mechanism involving the formation of allylic sulfonium salts. The presence of the intermediate sulfonium salt was confirmed by observation of the low-temperature (1)H NMR spectra.     

In situ generation of Mes2Mg as a non-nucleophilic carbon-centred base reagent for the efficient one-pot conversion of ketones to silyl enol ethers

Treatment of commercially available MesMgBr with 1,4-dioxane produces the key Mes(2)Mg reagent in situ which then mediates the deprotonation of ketones to deliver trimethylsilyl enol ethers, at readily accessible temperatures and without any nucleophilic addition, in an expedient and high yielding one-pot process.     

Tandem asymmetric conjugate addition--silylation of enantiomerically enriched zinc enolates. Synthetic importance and mechanistic implications

[formula: see text] The zinc enolates, resulting from the copper-catalyzed enantioselective conjugate addition of dialkyl zinc reagents to cyclic and acyclic enones, could be trapped, quantitatively, as silyl enol ethers with TMSOTf in apolar solvents or with TMSCI and NEt3. These enantiomerically enriched silyl enol ethers were submitted to four synthetic transformations to show their synthetic utility. The zinc enolates obtained from acyclic enones were found to be configurationally stable, as shown by the stereochemistry of the silyl enol ethers.     

Synthesis of bicyclo[4.n.1]alkanones

Cyclic beta-keto ester monoanions react with 1,4-dihalobutenes to give C-alkylated products which subsequently undergo a stereoselective SN2' O-alkylation reaction to yield functionalized enol ethers. When the starting material was ethyl cyclopentanone carboxylate, the C-alkylated product, treated with a base, directly afforded the functionalized bicyclo[4.2.1]nonanone. The enol ethers were submitted to a flash vacuum thermolysis (FVT) reaction to readily afford functionalized bicyclo[4.n.1]alkanones (n = 3, 4). This reaction sequence was applied to the synthesis of a functionalized tricyclo[7.4.1.0(1,5)]tetradecanone, which represents an analogue to the tricyclic core of ingenol.     

alpha-Nitration of Ketones via Enol Silyl Ethers. Radical Cations as Reactive Intermediates in Thermal and Photochemical Processes

Highly colored (red) solutions of various enol silyl ethers and tetranitromethane (TNM) are readily bleached to afford good yields of alpha-nitro ketones in the dark at room temperature or below. Spectral analysis show the red colors to be associated with the intermolecular 1:1 electron donor-acceptor (EDA) complexes between the enol silyl ether and TNM. The formation of similar vividly colored EDA complexes with other electron acceptors (such as chloranil, tetracyanobenzene, tetracyanoquinodimethane, etc.) readily establish enol silyl ethers to be excellent electron donors. The deliberate irradiation of the diagnostic (red) charge-transfer absorption bands of the EDA complexes of enol silyl ethers and TNM at -40 degrees C affords directly the same alpha-nitro ketones, under conditions in which the thermal reaction is too slow to compete. A common pathway is discussed in which the electron transfer from the enol silyl ether (ESE) to TNM results in the radical ion triad [ESE(*)(+), NO(2)(*), C(NO(2))(3)(-)]. A subsequent fast homolytic coupling of the cation radical of the enol silyl ether with NO(2)(*)() leads to the alpha-nitro ketones. The use of time-resolved spectroscopy and the disparate behavior of the isomeric enol silyl ethers of alpha- and beta-tetralones as well as of 2-methylcyclohexanone strongly support cation radicals (ESE(*)(+)) as the critical intermediate in thermal and photoinduced electron-transfer as described in Schemes 1 and 2, respectively.     

Rhodium-catalyzed asymmetric 1,4-addition of aryltitanium reagents generating chiral titanium enolates: isolation as silyl enol ethers

The addition of aryltitanium triisopropoxide (ArTi(OPr-i )3) to alpha,beta-unsaturated ketones proceeded with high enantioselectivity (94-99.8% ee) in the presence of 3 mol % of [Rh(OH)((S )-binap)]2 in THF at 20 degrees C to give high yields of the titanium enolates as 1,4-addition products. The titanium enolates were converted into silyl enol ethers by treatment with chlorotrimethylsilane and lithium isopropoxide.     

C-C versus C-O anionic domino cycloalkylation of stabilized carbanions: facile one-pot stereoselective preparation of functionalized bridged bicycloalkanones and cyclic enol ethers

alpha,alpha'-Diactivated cyclic- or acyclic ketones undergo a chemoselective base promoted (K2CO3, DBU) one-pot C-C cycloalkylation, with 1,3- and 1,4-dihalides having a cis-like fixed configuration. This reaction gives highly functionalized bicyclo[3.2.1]octan-9-one and bicyclo[4.2.1]nonan-9-one derivatives, which are easily transformed to seven- and eight-membered rings through a high yield retro-Dieckmann cleavage. Starting from trans-1,4-dibromo-2-butenes, the transformation is governed by stereoelectronic factors and leads, through a chemo- and stereoselective C-O cycloalkylation, to synthetically valuable monocyclic or fused polycyclic functionalized enol ethers of high synthetic value. Semiempirical calculations showed a small difference in energy and the late character of the transition states leading to cis and trans isomers of the corresponding fused polycyclic enol ethers. These results, although minimizing the influence of a destabilizing 1,3-interaction on the outcome of the reaction, are qualitatively in agreement with the experimental results.     

Synthesis of functionalized 4-chlorophenols and 1,4-dihydroquinones by [3+3] cyclization of 1,3-bis-silyl enol ethers with 2-chloro- and 2-acyloxy-3-(silyloxy)alk-2-en-1-ones

Functionalized 4-chlorophenols and 1,4-dihydroquinones were prepared by [3+3] cyclization of 1,3-bis-silyl enol ethers with 2-chloro- and 2-acyloxy-3-(silyloxy)alk-2-en-1-ones.     

Synthetic Studies on and Mechanistic Insight into [W(CO)5(L)]‐Catalyzed Stereoselective Construction of Functionalized Bicyclo[5.3.0]decane Frameworks

Stereoselective preparation of a variety of synthetically useful functionalized bicyclo[5.3.0]decane derivatives was achieved by tandem cyclization of 3‐siloxy‐1,3,9‐triene‐7‐yne derivatives based on the electrophilic activation of alkynes catalyzed by [W(CO)₅(L)]. The reaction proceeded smoothly under photoirradiation, and various substrates were cyclized to give the corresponding bicyclic compounds with up to four chiral centers stereospecifically. Reactions of siloxydienes with a silyl substituent as an equivalent of a hydroxyl group also proceeded with wide generality to afford silyl‐substituted bicyclo[5.3.0]decanes, which were highly useful as synthetic intermediates. Stereochemical studies concerning the silyl enol ether moiety suggested that two types of reaction pathway for the formation of seven‐membered rings were present. The reaction of (Z)‐enol silyl ethers proceeded through Cope rearrangement of cis‐divinylcyclopropane intermediates, and that of (E)‐enol silyl ethers by 1,4‐addition of the dienyl tungsten species at the position δ to the metal atom. In the reactions of siloxydiene derivatives with silyl substituents, all possible diastereomers could be synthesized stereoselectively by changing the geometry of the silyl enol ether and enyne moieties.     

Synthesis and reactivity of N-alkyl-2-oxoalkanesulfonamides

A series of N-alkyl-2-oxoalkanesulfonamides have been synthesized by reacting silyl enol ethers with N-alkyl-sulfamoyl chlorides. Their reactivity towards electrophiles was investigated in order to explore the regio-aand stereoselectivity of the process. 2-Oxoalkanesulfonamides were used to prepare 5-(methylsulfamoyl)-1,4-dihydropyridines derivatives.     

One-pot sequential Cu-catalyzed reduction and Pd-catalyzed arylation of silyl enol ethers

[reaction: see text] Enantiomerically enriched beta-substituted diphenylsilyl enol ethers, which can be prepared from Cu-catalyzed asymmetric conjugate reduction, are utilized in the Pd-catalyzed arylation of various aryl bromides. This new method provides a simple route to alpha-arylated cycloalkanones with excellent levels of enantiomeric and diastereomeric purity. The isolation of the intermediate, diphenylsilyl enol ethers is not necessary; the procedure can be carried out in one-pot.     

1,5]-Anion relay/[2,3]-Wittig rearrangement of 3,3-bis(silyl) allyl enol ethers: synthesis of useful vinyl bis(silane) species

The [1,5]-anion relay/[2,3]-Wittig rearrangement of 3,3-bis(silyl) enol allyl ethers has been developed. This reaction provides an efficient method to synthesize versatile vinyl bissilanes, which can be transformed into trisubstituted vinylsilanes through a [1,4]-Brook rearrangement/alkylation protocol using a wide range of electrophiles.     

Chalcogenopyranones from disodium chalcogenide additions to 1,4-pentadiyn-3-ones. The role of enol ethers as intermediates

Enol ethers 9 are formed as a mixture of E- and Z-isomers from the addition of ethanol to 1,4-pentadiyn-3-ones 2 in sodium ethoxide/ethanol. The enol ethers react with disodium chalcogenides to give the corresponding 2,6-disubstituted chalcogenopyranones 1 bearing alkyl, aryl, or heteroaryl substituents in high yield as the only heterocyclic product of reaction. Diynones 2 react with disodium chalcogenides to give mixtures of products in which the chalcogenopyranones 1 are minor components and the dihydrochalcogenophenes 3 are the major products. The addition of hydrogen sulfide to diynone 2b in ethanol gives a product mixture nearly identical to that observed for the addition of disodium sulfide in sodium ethoxide in ethanol to 2b . Intermediates for the addition of hydrogen chalcogenides and disodium chalcogenides to both 2 and 9 are described, which lead to the heterocyclic products.     

Chameleon reactivity of the allene bond of 4-vinylidene-2-oxazolidinone: novel through-space conjugative nucleophilic addition of electron-rich alkenes and hetero-nucleophiles

The Calpha==Cbeta double bond of allene carbamates 1 serves as an electron acceptor similar to the double bond of conjugated enones by means of a through-space interaction with the N--SO2 bond; the carbamate double bond is thus subject to nucleophilic addition for a wide variety of nucleophiles, which proceeds under mild conditions by heating at 70-100 degrees C. Depending on the kind of nucleophiles, 1 displays three different reaction modes: 1) Typically enol ethers and allylsilanes promote 1,3-sulfonyl migration of 1 and undergo the inverse electron demand Diels-Alder reaction with the 1-aza-1,3-butadiene intermediates II thus formed to furnish bicyclic 2-alkoxy-5-sulfonyltetrahydropyridines 2 and 2-silylmethyl-5-sulfonyltetrahydropyridines 3, respectively, with high regio- and stereoselectivity and retention of configuration of the double bonds of these electron-rich alkenes; 2) silanes (RnSiH4-n, n=1-3) and thiols deliver the hydride and the thiolate at the Cbeta carbon and promote the 1,3-sulfonyl migration, followed by protonation of the thus-formed carbamate anion (Z)-III to provide, for example, (Z)-4 a and (Z)-4 j, respectively; 3) alcohols simply add to the Calpha==Cbeta double bond and provide (E)-6. Usually, the reaction with alcohols is accompanied by the second pathway, giving rise to, for example, (Z)-4 b in addition to (E)-6 b. Phenol engages in the third pathway and provides (E)-6 g exclusively. Heteroaromatics, such as furans and benzofurans follow the first pathway, however, in a different regioselectivity from enol ethers and allylsilanes, delivering the oxygen atom at the 3-position of 5-sulfonyltetrahydropyridines (2 g and 2 h). Indoles, on the other hand, show a dichotomy, equally enjoying the first and the third pathways and provide mixtures of (E)-7 and (E)-8, respectively.     

Synthesis of 6-alkylidene-2,3-benzo-1,4-diaza-7-oxabicyclo[4.3.0]non-2-enes by cyclization of 1,3-bis(silyl enol ethers) with quinoxalines

6-Alkylidene-2,3-benzo-1,4-diaza-7-oxabicyclo[4.3.0]non-2-enes were prepared by cyclization of 1,3-bis(silyl enol ethers) with quinoxaline.     

First anionic silyl migration from sp2 carbon to carbonyl oxygen. Stereospecific allylation of (Z)-beta-trimethylsilyl-alpha,beta-unsaturated ketones

1,4-Silyl migration from sp2 carbon to carbonyl oxygen proceeded by the treatment of (Z)-beta-trimethylsilyl-alpha,beta-unsaturated ketones with copper(I) tert-alkoxide to afford vinylmetal species, which reacted with allylic halides to produce enol trimethylsilyl ethers of beta-alk-2-enyl-alpha,beta-unsaturated ketones with complete retention of configuration.     

Cyclooctanone synthesis via a formal [6+2] cycloaddition reaction of a dicobalt acetylene complex

An efficient formal [6+2] cycloaddition reaction of a new six-carbon unit with enol silyl ether was developed on the basis of a dicobalt hexacarbonyl propargyl cation species. Under the influence of EtAlCl₂, 6-benzoyloxy-2-(triisopropylsilyloxy)-1-hexen-4-yne-dicobalthexacarbonyl reacted with enol triisopropylsilyl ethers to yield 7-(triisopropylsilyloxy)-3-cyclooctyn-1-one-dicobalthexacarbonyl derivatives in good yield. The reactions with cyclic enol silyl ethers as well as acyclic enol silyl ethers exhibited remarkably high diastereoselectivity.     

Lewis base activation of Lewis acids. Catalytic enantioselective addition of silyl enol ethers of achiral methyl ketones to aldehydes

A highly enantioselective addition of silyl enol ethers derived from simple methyl ketones is described. The catalyst system of silicon tetrachloride activated by a chiral bisphosphoramide (R,R)-7 effectively promotes the addition of a variety of unsubstituted silyl enol ethers to aromatic, olefinic, and heteroaromatic aldehydes in excellent yield. [reaction: see text]     

Phorboxazole synthetic studies. 2. Construction of a C(20-28) subtarget, a further extension of the Petasis-Ferrier rearrangement

[formula: see text] In this, the second of two Letters, we describe the efficient assembly of (+)-4, a C(20-28) subtarget for the total synthesis of phorboxazoles A (1) and B (2). The synthesis was achieved in 12 linear steps (20% overall yield) via Petasis-Ferrier rearrangement of an E/Z mixture of trisubstituted enol ethers (15) to assemble the C(22-26) cis-tetrahydropyran. A mechanism for the observed diastereoconvergence of 15 is proposed. In addition, a new tactic for the synthesis of enol ethers (e.g., 15) based on the elegant work of Julia is described.