Abstract

In order to improve redundant synthetic processes, the integration of a solventless reaction has proved to be useful for gaining high reaction mass efficiency (RME) as well as reducing the amount of solvents. This concept was applied to synthesis of PA-824, a potential antituberculosis drug. Thus, the solventless ring-opening reaction of glycidyl silyl ether with dinitroimidazole was connected to succeeding solution reactions. The ring-opening of glycidol followed by selective silylation of the primary hydroxy group under solventless conditions was also feasible. As a consequence, the overall yield of the target compound was nearly tripled, and thus the RME values were increased more than 2.5 times while the amount of necessary solvents was decreased to less than 1/3.

A variety of arylethynylsilanes (Ar-CCC₆H₄CC)_nSiMe_4−n were prepared successfully by reaction of the corresponding chlorosilanes Me_4−nSiCl_n with ArCCC₆H₄CCM (M=Li, MgBr), which was prepared by treatment of ethynyl(diarylethyne)s ArCCC₆H₄CCH with BuLi or MeMgBr. The ethynyl(diarylethyne)s were readily prepared in good yields by the double-elimination method: addition of lithium hexamethyldisilazide to a mixture of ArCH₂SO₂Ph, TMSCCC₆H₄CHO, and ClP(O)(OEt)₂, followed by desilylation. In the tetrakis(arylethynyl)silanes (ArCCC₆H₄CC)₄Si thus prepared, through-space conjugation of four triple bonds on the silicon atom emerges as a result of participation of the silicon orbitals in the acetylenic π orbitals. This participation enhances the emissive quantum yields of arylethynylsilanes with an increase in the number of arylethynyl moieties on silicon: quantum yields of emission (Φ_F) of 0.72 for (MeOC₆H₄CCC₆H₄CC)₄Si, 0.53 for (MeOC₆H₄CCC₆H₄CC)₂SiMe₂, and 0.47 for MeO-C₆H₄CCC₆H₄CCSiMe₃ were obtained. Although this enhancement effect was also observed in the phenylethynylarylsilane (MeOC₆H₄CCC₆H₄)₂SiMe₂, the bis(arylethynyl)disilane (MeOC₆H₄CCC₆H₄CC-SiMe₂)₂ exhibited non-enhanced emission.

New types of enantiopure compounds were synthesized to gain better insight into the structural features of phenylene ethynylene cyclophynes. Besides the previously obtained meta-substituted arylene ethynylenes, 1, ortho-connected phenylene ethynylene units were incorporated to give cyclophynes with ortho/meta and ortho/ortho connection modes, 2 and 3. Furthermore, a diphenylethyne component was also accommodated in 4. Both ab initio calculations and NMR spectra suggest a large amount of strain for 2 but less strain for 3 and 1 a, the latter having the smallest ring size among cyclophynes with the meta/meta connection mode. The CD spectra of 2 and 3 showed a characteristic shoulder at around 340 nm, similar to the case of 1 a. This implies that the aromatic acetylene bonds cross over each other in the double-helical structure. These results indicate that chirality information is useful for probing the persistency of molecular shape.

The reactions of 1,3-dichloro-1,1,3,3-tetrabutyldistannoxane and dialkyltin dihalides with silver perfluorooctanesulfonate provided the corresponding sulfonates as hydrates. The number of water molecules (n) of hydration was dependent on the conditions. The distannoxane derivative was identified as n from 0.5 to 6, while in the hydrated mononuclear species and DMSO complexes n varied widely from 4 to 13. ¹¹⁹Sn NMR spectroscopy and conductivity measurements indicated the ionic dissociation of these compounds in solution. These compounds exhibited unusually high solubility in polar organic solvents. The ionic dissociation together with facile hydration probably causes the unusual solubility. The Lewis acidity of these compounds was found to be high among organotin derivatives on the basis of ESR spectra of superoxide/metal-ion complexes. In contrast to well-known organotin triflates, these compounds suffered no hydrolysis upon storage in open air. The high catalytic activity of the distannoxane 1 was exemplified for various carbon–carbon bond-forming reactions, such as Mukaiyama–aldol as well as -Michael reactions and allylation of aldehydes.

A variety of diaryl acetylenes were obtained in good yields when lithium hexamethyldisilazide was added to a solution of arylmethyl sulfone, aryl aldehyde, and chlorodiethylphosphate in THF. In this one-shot process, a number of transformations such as aldol reaction, phosphorylation of aldolate, and double elimination of the resulting β-substituted sulfone proceeded successively to afford the desired acetylenes. The one-shot process was accelerated by the substitution of halogen atoms on the phenyl groups, and unsymmetrically substituted diaryl acetylenes were obtained without contamination of the dehalogenated products. Diaryl acetylenes with other substituents such as CF₃, ethoxycarbonyl, dimethylamino, TMS-acetylene groups, as well as pyridinyl and thienyl moieties were also accessible with this method. However, methoxy-substituted compounds were obtained in moderate yields under the same conditions, but the yields were increased when lithium diisopropylamide was used instead.

Dihalodiphenylacetylenes are conveniently synthesized by a double elimination reaction of β-substituted sulfones which are readily obtained from halogen-substituted benzyl sulfone and benzaldehyde derivatives. Halogens can be incorporated at any desired positions in the diphenylacetylene skeleton simply by choosing the substitution position of the halogen on the aromatic rings of the starting compounds. The diphenylacetylenes with different halogen substituents thus obtained undergo sequential carbon-carbon bond formations due to the different reactivities of the halogens. Thus, various moieties can be incorporated on the diphenylacetylene skeleton at whichever positions so that a variety of tailor-made phenylene-ethynylenes with regulated structure and composition could be designed.

Die Mischung macht's: Die Reaktion zwischen festen Reaktanten wird beschleunigt und verläuft mit höheren Ausbeuten, wenn die Reaktanten zunächst in Lösung gemischt und diese anschließend zur Trockene eingeengt wird. Auf diese Art gelang die Synthese des gezeigten [2]Rotaxans aus zwei mit den Stoppern versehenen Bausteinen und dem Kronenether.

Auch mal abschalten… Der Shuttle-Prozess von Rotaxanen mit einer zentralen 2,2′-Bipyridineinheit zwischen zwei Bipyridinium-„Stationen“ kann durch Metallionen beeinflusst werden. Die Komplexierung von Cu^I-Ionen an die 2,2′-Bipyridineinheit versetzt das System in den Ruhezustand, durch Dekomplexierung kehrt es wieder in den dynamischen Zustand zurück (siehe Bild).

Action stations: Treatment of rotaxanes containing a 2,2′-bipyridine moiety between two bipyridinium stations with Cu^I ions gives rise to a new type of shuttling process. The switch between static and dynamic states is achieved through complexation of the Cu^I center to the 2,2′-bipyridine unit followed by decomplexation (see picture).

It's all in the mix: The reaction between solid reactants undergoes rate acceleration and results in an increase in yield when the reactants are premixed in solution and then concentrated to dryness. This protocol has been successfully applied to the end-capping synthesis of a [2]rotaxane (see structure).

The high atom efficiency was achieved through addition of Ac₂O in the Sc(OTf)₃-catalyzed allylation of aldehyde with tetraallytin in a 4 : 1 molar ratio.

The synthesis of a variety of organotin compounds with 1H, 1H, 2H, 2H-perfluorooctyl groups is reported, together with an improved method for the corresponding distannoxane. Unique properties of this compound are disclosed in terms of fluorophilicity and activity as a Lewis acid catalyst in comparison with other mono-nuclear derivatives. A new criterion for obtaining high solubility in fluorocarbon solvents is presented. Copyright © 2003 John Wiley & Sons, Ltd.

Novel, practical protocols of transesterification have been advanced with recourse to fluorous biphase technology. The fluoroalkyldistannoxane catalysts enable transesterification in FC-72 solvent to furnish 100% yields of the desired esters by use of reactants ester and alcohol in a 1 : 1 ratio. The catalysts also work in FC-72/organic solvent system as well as in toluene alone. A number of esters and alcohols bearing various functional groups are employable. The catalysts can be totally recovered and reused. More conveniently, the catalyst solution in FC-72 which is separated from the reaction mixture is directly used for the next reaction.

Die „kommerziell erhältliche Chiralität“ der Binaphthyleinheiten und die Effizienz der Kupplungsreaktionen waren für die Synthese der doppelhelicalen Alkinylcyclophane 1 in enantiomerenreiner Form entscheidend. Die einzigartigen Eigenschaften dieser Moleküle wurden durch Einkristallröntgenstrukturanalyse und CD-Spektroskopie zweifelsfrei belegt.

A new method for constructing 5,6,11,12-tetradehydrodibenzo[a,e]cyclooctene is described on the basis of one-pot double elimination protocol. The target molecule, which is the smallest cyclophane with alternate arylene−ethynylene linkage, is synthesized in 61 % yield through oxidative dimerization of ortho-(phenylsulfonylmethyl)benzaldehyde. The initial carbon–carbon bond formation between sp³ carbons followed by stepwise conversion to sp² and finally sp carbons bypasses the difficulty encountered in direct coupling of the sp carbon in the terminal acetylene. The mechanism of this process is discussed. The Wittig–Horner-type coupling is a key reaction employed for the carbon–carbon bond formation. Generation of (E)-vinylsulfone moiety in the first coupling between α-sulfonyl anion and aldehyde functions is crucial for the effective second coupling to complete the cyclization. The syn-elimination of the (E)-vinylsulfone moieties in the cyclized intermediate furnishes the acetylenic bonds.

A new strategy for constructing enantiopure acetylenic cyclophanes is described on the basis of one-pot double elimination reaction starting from dialdehydes and bis(sulfoximine)s. In this case, the conventional sulfone protocol affords poorer yields of the desired cyclophanes. Thus, arylene–ethynylene moieties with terminal sulfoximine or formyl functions are linked to binaphthyl cores and these building blocks are then subjected to double elimination reaction. The desired macrocycles are obtained in up to 35 % yield. The corresponding Sonogashira coupling fails to afford cyclophanes indicative of effectiveness of the double elimination methodology.

Durch eine vollständig selektive Esterifizierung in Gegenwart des Fluoralkyldistannoxans [{Cl(C₆F₁₃CH₂CH₂)₂SnOSn(CH₂CH₂C₆F₁₃)₂Cl}₂] (1) gelingt die Unterscheidung zwischen primären und sperrigen oder aromatischen Carbonsäuren. Bei einem Carbonsäure/Alkohol-Verhältnis von exakt 1:1 verläuft die Reaktion mit 100% Ausbeute, und der Katalysator kann ohne Aktivitätsverlust regeneriert werden.

A perfectly selective esterification that discriminates between primary and sterically hindered or aromatic carboxylic acids occurs in the presence of the fluoroalkyldistannoxane [{Cl(C₆F₁₃CH₂CH₂)₂SnOSn(CH₂CH₂C₆F₁₃)₂Cl}₂] (1). The reaction gives 100 % yield with a strict 1:1 ratio of the carboxylic acid and alcohol reactants, and the catalyst can be recycled without any loss of activity.

One-pot processes to enantiopure 2-hydroxymethyl-1,4-benzodioxane derivatives have been established under catalysis of CsF. A sequence of O-alkylation of catechols with enantiopure 3-chloro-1,2-propanediol, tosylation of the alcohol, deprotection of the benzyl ether, and intramolecular etherification can be integrated. The O-alkylation is also feasible with enantiopure oxiranes. All reactions, except debenzylation, are catalyzed by a single catalyst, CsF. The hydrogenative deprotection of the benzyl ether with Pd-C is compatible with the CsF-catalyzed reactions. The integrated protocols give rise not only to compaction of the whole processes but also to increases in overall yields.

Deprotection of acetyl esters is effected cleanly by the neutral organotin catalyst, [tBu₂SnOH(Cl)]₂. The mildness of the reaction gives rise to great synthetic versatility and in the process a variety of functional groups are tolerated. Differentiations between primary, secondary, and tertiary alcohols and between acetyl ester and other esters are feasible. No racemization occurs with chiral acetyl esters. Exclusive deprotection of primary acetyl esters in carbohydrates and nucleosides is observed. The crude product thus obtained can be used for further reactions without purification.

Katalysatorrückgewinnung ist nicht nötig bei der durch [{Cl(C₆F₁₃CH₂CH₂)₂SnOSn(C₆F₁₃CH₂CH₂)₂Cl}₂] 1 katalysierten, quantitativ verlaufenden Umesterung in einem „fluorigen“ Zweiphasensystem (siehe Schema). Eine Lösung des dimeren Fluoralkyldistannoxans 1 in FC-72 kann problemlos mehrfach eingesetzt werden, ohne dass der reine Katalysator zwischendurch isoliert werden müsste.

There is no need for the recovery of the catalyst in the fluorous biphasic transesterification catalyzed by [{Cl(C₆F₁₃CH₂CH₂)₂SnOSn(C₆F₁₃CH₂CH₂)₂Cl}₂] (1; see scheme), which results in quantitative conversions and yields. An FC-72 solution of the dimeric fluoroalkyldistannoxane 1 can be recycled repeatedly without having to recover the neat catalyst.

A variety of aromatic hydrocarbons bearing multiple alkyl substituents are accessible with perfect regiocontrol in a one-pot reaction starting from cyclohexenones and their aromatic analogues [Eq. (1)]. The present methodology can be further extended to the synthesis of polycyclic aromatic hydrocarbons. The drawbacks encountered in the Friedel–Crafts reaction are resolved since the reaction proceeds under basic conditions.

Eine Vielzahl von aromatischen Kohlenwasserstoffen mit mehreren Alkylsubstituenten läßt sich unter vollständiger Regiokontrolle in einer Eintopfreaktion aus Cyclohexenon und dessen aromatischen Analoga herstellen [Gl. (1)]. Die vorgestellte Methode kann auch auf die Synthese von polycyclischen aromatischen Kohlenwasserstoffen ausgedehnt werden. Die Nachteile der Friedel-Crafts-Reaktion treten nicht auf, da die Reaktion unter basischen Bedingungen stattfindet.

A novel one-pot process for the synthesis of acetylenes is described that integrates the addition of an α-anion of sulfone to aldehyde, the trapping of the resulting adduct to incorporate a leaving group, and the double elimination of this intermediate.