Yb(OTf)3-catalyzed reactions of 5-alkylidene Meldrum's acids with phenols: one-pot assembly of 3,4-dihydrocoumarins, 4-chromanones, coumarins, and chromones

[reaction: see text] The Yb(OTf)3-catalyzed annulation reactions of phenols with 5-alkylidene Meldrum's acids enabled the synthesis of structurally diverse heterocycles in high isolated yields. A series of 4-substituted 3,4-dihydrocoumarins, 2,2-disubstituted 4-chromanones, coumarins, and 2-substituted chromones were readily and efficiently assembled, including the naturally occurring coumarins citropten, scoparone, and ayapin. Addition of phenols to biselectrophilic 5-alkylidene Meldrum's acids proceeded through two distinct multibond-forming modes: Friedel-Crafts C-alkylation/O-acylation and Friedel-Crafts C-acylation/O-alkylation. The regioselectivity of the catalytic annulation reaction was controlled by the degree of substitution on the alkylidene moiety.     

Meldrum's acids as acylating agents in the catalytic intramolecular Friedel-Crafts reaction

[reaction: see text] The intramolecular Friedel-Crafts acylation of aromatics with Meldrum's acid derivatives catalyzed by metal trifluoromethanesulfonates is reported. Meldrum's acids are easily prepared, functionalized, handled, and purified. The synthesis of polysubstituted 1-indanones from benzyl Meldrum's acids was investigated thoroughly, and it was shown that a variety of catalysts were effective, while accommodating a diversity of functional groups under mild conditions. The scope, limitations, and functional group tolerance (terminal alkene and alkyne, ketal, dialkyl ether, dialkyl thioether, aryl methyl ether, aryl TIPS and TBDPS ethers, nitrile- and nitro-substituted aryls, alkyl and aryl halides) for a variety of 5-benzyl (enolizable Meldrum's acids) and 5-benzyl-5-substituted Meldrum's acids (quaternized Meldrum's acids), forming 1-indanones and 2-substituted-1-indanones, respectively, are delineated. This method was further applied to the synthesis of 1-tetralones, 1-benzosuberones, and the potent acetylcholinesterase inhibitor donepezil. Rate of cyclization as a function of ring size was established for various benzocyclic ketones via competition experiments: 1-tetralones form faster than both 1-indanones and 1-benzosuberones, and 1-benzosuberones cyclize faster than 1-indanones.     

Carbon-based leaving group in substitution reactions: functionalization of sp3-hybridized quaternary and tertiary benzylic carbon centers

Lewis acid promoted substitution reactions employing Meldrum's acid and 5-methyl Meldrum's acid as carbon-based leaving groups are described which transform unstrained quaternary and tertiary benzylic C(sp(3))-C(sp(3)) bonds into C(sp(3))-X bonds (X = C, H, N). Importantly, this reaction has a broad scope in terms of both suitable substrates and nucleophiles with good to excellent yields obtained (typically >90%).     

Catalytic enantioselective protonation of nitronates utilizing an organocatalyst chiral only at sulfur

The highly enantioselective protonation of nitronates formed upon the addition of α-substituted Meldrum's acids to terminally unsubstituted nitroalkenes is described. This work represents the first enantioselective catalytic addition of any type of nucleophile to this class of nitroalkenes. Moreover, for the successful implementation of this method, a new type of N-sulfinyl urea catalyst with chirality residing only at the sulfinyl group was developed, thereby enabling the incorporation of a diverse range of achiral diamine motifs. Finally, the Meldrum's acid addition products were readily converted to pharmaceutically relevant 3,5-disubstituted pyrrolidinones in high yield.     

Scandium triflate-catalyzed intramolecular Friedel-Crafts acylation with Meldrum's acids: insight into the mechanism

The intramolecular Friedel-Crafts acylation of arenes with Meldrum's acid derivatives catalyzed by Sc(OTf)₃ was reported as a mild and general entry into functionalized 1-indanones. Mechanistic investigations were undertaken to determine the rate-determining step in the acylation sequence using Meldrum's acid, as well as to examine the role of the Lewis acid catalyst. Enolizable Meldrum's acid derivatives react via an acyl ketene intermediate under thermal conditions, while quaternized Meldrum's acid derivatives are thermally stable and only act as effective Friedel-Crafts acylating agents in the presence of a Lewis acid catalyst. The acylation was postulated to proceed through direct acylation of a Lewis acid-activated carbonyl. In the catalytic Friedel-Crafts acylation of Meldrum's acids, triflic acid appeared to be the active catalytic species, with Sc(OTf)₃ serving as a very mild and convenient reagent for its delivery.     

Nucleophilic reactivities of benzenesulfonyl-substituted carbanions

Kinetics of the reactions of four benzenesulfonyl-stabilized carbanions (1a-d)- with reference electrophiles (quinone methides 2 and diarylcarbenium ions 3) have been determined in dimethyl sulfoxide solution at 20 degrees C in order to derive the reactivity parameters N and s according to the linear free-energy relationship logk(20 degrees C) = s(N + E) (eqn (1)). The additions of (1a-d)- to ordinary Michael acceptors (e.g., benzylidene Meldrum's acid 4a, benzylidenebarbituric acids 5a-c, and benzylidene-indan-1,3-diones 6a-d) were also studied kinetically and found to be 5-24 times slower than predicted by eqn (1).     

Palladium-catalyzed asymmetric addition of pronucleophiles to allenes

Simple additions are the most atom economic way to effect alkylations. The ability to effect the hydrocarbonation of allenes asymmetrically then becomes a highly efficient alkylation protocol. The first example of such a protocol involves the ability of a palladium(0) catalyst derived from palladium trifluoroacetate dimer and the bis-2-diphenylphosphinobenzamide of trans-1,2-diamininocyclohexane to catalyze additions to benzyloxyalkene. Various substituted Meldrum's acids including hydroxy Meldrum's acid react well in the presence of 1 mol % trifluoroacetic acid to give one regioisomer with ee's ranging from 82 to 99%. Switching to azlactones to access unusual quarternary amino acids requires somewhat more basic conditions. Thus, use of 2 mol % potassium alpha-butoxide and 20 mol % hippuric acid leads to a smooth reaction to produce a simple regiosomer. This nucleophile raises the question of facial selectivity with respect to both the nucleophile and the electrophile. Excellent diastereoselectivity (dr 13-20:1) and enantioselectivity (85-94% ee) are obtained. Thus, a new approach for asymmetric allylic alkylations of carbon pronucleophiles by simple additions provides a very efficient, more atom economic strategy for asymmetric C-C bond formation.     

Palladium-catalyzed asymmetric quaternary stereocenter formation

An efficient palladium catalyst is presented for the formation of benzylic quaternary stereocenters by conjugate addition of arylboronic acids to a variety of β,β-disubstituted carbocyclic, heterocyclic, and acyclic enones. The catalyst is readily prepared from PdCl(2), PhBOX, and AgSbF(6), and provides products in up to 99% enantiomeric excess, with good yields. Based on this strategy, (-)-α-cuparenone has been prepared in only two steps.     

Facile synthesis of alpha-substituted acrylate esters

Treatment of 5-monosubstituted Meldrum's acids with dimethylmethyleneimmonium iodide (Eschenmoser's iodide salt) in methanol gives alpha-substituted acrylate methyl esters in good yields. Easy access to 5-monosubstituted Meldrum's acids allowed us to synthesize a wide variety of alpha-substituted acrylate methyl esters. The reaction conditions are mild and tolerate many functional groups commonly used in organic synthesis; thus, this new method has potential as an alternative to conventional preparative methods for alpha-substituted acrylate esters.     

Chemistry of amidrazones—II : Synthesis and cyclisation of 1-thioacylamidrazones

1-Thioaroylamidrazones are formed by the action of carboxymethyl dithioates on unsubstituted amidrazones; they are cyclised by acids to 2,5-disubstituted 1,3,4-thiadiazoles. 1-(Ethoxythiocarbonyl)amidrazones are similarly accessible by the use of ethoxythiocarbonylthioacetic acid. They yield 3-ethoxy (or hydroxy)-5-substituted-1,3,4-thiadiazoles under the influence of acids, but are cleaved into smaller fragments by alkalis.     

A novel route to 5-substituted 3-isoxazolols. Cyclization of N, O-DiBoc beta-keto hydroxamic acids synthesized via acyl Meldrum's acids

3-Isoxazolols are most often synthesized from a beta-keto ester and hydroxylamine. This cyclization typically gives rise to a major byproduct, the corresponding 5-isoxazolone. We have found that N, O-diBoc-protected beta-keto hydroxamic acids can be synthesized and cyclized to 5-substituted 3-isoxazolols without formation of any byproduct. We present a novel and versatile three-step procedure in which carboxylic acid derivatives are converted into acyl Meldrum's acids which, upon aminolysis with N, O-bis(tert-butoxycarbonyl)hydroxylamine, lead to the N, O-diBoc-protected beta-keto hydroxamic acids. These hydroxamic acid analogues were then, upon treatment with hydrochloric acid, cyclized to the corresponding 5-substituted 3-isoxazolols.     

Synthesis of 3,4-disubstituted isoquinolines via palladium-catalyzed cross-coupling of 2-(1-alkynyl)benzaldimines and organic halides

The palladium-catalyzed cross-coupling of readily available N-tert-butyl-2-(1-alkynyl)benzaldimines and aryl, allylic, benzylic, alkynyl halides, as well as a vinylic halide, provides a valuable new route to 3,4-disubstituted isoquinolines with aryl, allylic, benzylic, 1-alkynyl, and vinylic substituents, respectively, in the 4-position. The reaction appears to require an aryl group on the end of the acetylene furthest from the imine functionality. The reaction conditions have been optimized, and reasonably good yields have been obtained.     

(R)-(+)-N-methylbenzoguanidine ((R)-NMBG) catalyzed kinetic resolution of racemic secondary benzylic alcohols with free carboxylic acids by asymmetric esterification

(R)-(+)-N-Methylbenzoguanidine ((R)-NMBG) was found to function as an efficient acyl-transfer catalyst for the kinetic resolution of racemic secondary benzylic alcohols in the presence of achiral carboxylic acids and pivalic anhydride. The use of a tertiary amine in this reaction is not necessary to attain good chemical yields of the products. It was determined that diphenylacetic acid could be employed as the most suitable acyl donor for achieving a high enantioselectivity for the kinetic resolution of the racemic secondary benzylic alcohols having normal aliphatic alkyl chains at the C-1 positions. On the other hand, a less-hindered carboxylic acid, such as 3-phenylpropanoic acid, functioned as a better acyl donor for the kinetic resolution of racemic secondary benzylic alcohols having branched aliphatic alkyl chains at the C-1 positions.     

A convenient synthesis of coumarin-3-carboxylic acids via Knoevenagel condensation of Meldrum's acid with ortho-hydroxyaryl aldehydes or ketones

Coumarin-3-carboxylic acids were obtained in high yields with excellent purity from ortho-hydroxybenzaldehydes and Meldrum's acid after a 2 h reflux in ethanol. The less reactive ketones were first reacted with alcoholic ammonia to form ketimines, which were then condensed with Meldrum's acid to generate 4-alkylcoumarin-3-carboxylic acids in moderate yields.     

Experimental and theoretical investigation of reversible interconversion, thermal reactions, and wavelength-dependent photochemistry of diazo Meldrum's acid and its diazirine isomer, 6,6-dimethyl-5,7-dioxa-1,2-diaza-spiro[2,5]oct-1-ene-4,8-dione

The photochemical or thermal decomposition of diazo Meldrum's acid (1) in methanolic solutions yields ketoester 3a, the product of the Wolff rearrangement, while products produced from the singlet carbene were not detected. This observation, combined with the analysis of activation parameters for the thermal decomposition of 1, as well as with the results of DFT B3PW91/6-311+G(3df,2p) and MP2/aug-cc-pVTZ//B3PW91/6-311+G(3df,2p) calculations, allows us to conclude that the Wolff rearrangement of 1 is a concerted process. The outcome of the photolysis of diazo Meldrum's acid depends on the wavelength of irradiation. Irradiation with 254 nm light results in an efficient (Phi(254) = 0.34) photo-Wolff reaction, while at 355 nm, the formation of diazirine 2 becomes the predominant process (Phi(350) = 0.024). This unusual wavelength selectivity indicates that Wolff rearrangement and isomerization originate from different electronically excited states of 1. The UV irradiation of diazirine 2 leads to the loss of nitrogen and the Wolff rearrangement, apparently via a carbene intermediate. This process is accompanied by a reverse isomerization to diazo Meldrum's acid. Triplet-sensitized photolysis of both isomers results in the formation of Meldrum's acid, the product of a formal reduction of 1 and 2. Mild heating of diazirine 2 produces quantitative yields of diazo Meldrum's acid. The activation parameters for thermal reactions of diazo 1 and diazirino 2 isomers were determined in aqueous and dioxane solutions.     

Enantiodivergent synthesis of cytotoxic styryl lactones from d-xylose. The first total synthesis of (+)- and (−)-crassalactone C

Enantiodivergent total syntheses of both (+)- and (−)-enantiomers of goniofufurone, 7-epi-goniofufurone and crassalactone C have been accomplished starting from d-xylose. The key steps of the synthesis of 7-epi-(+)-goniofufurone were a stereo-selective addition of phenyl magnesium bromide to a protected dialdose, and a stereospecific furano-lactone ring formation by reaction of a related hemiacetal derivative with Meldrum's acid. Synthesis of both (+)-goniofufurone and (+)-crassalactone C required a configurational inversion at C-5 in the common intermediate that was efficiently achieved under the standard Mitsunobu conditions, or alternatively through a sequential oxidation of the benzylic hydroxyl group followed by a stereo-selective reduction with borohydride. A similar approach was then applied to the synthesis of the unnatural (−)-enantiomers of goniofufurone, 7-epi-goniofufurone and crassalactone C, as well as two novel, conformationally constrained analogues of both (+)- and (−)-goniofufurone. Their in vitro antiproliferative activities against a number of human tumour cell lines were recorded and compared with those observed for the parent natural products.     

Synthesis, Structure, and Alkylation of N-Methylmorpholinium 5-[2-Cyanoethyl-1-(4-hydroxy-3-methoxyphenyl)-2-thiocarbamoyl]-2,2-dimethyl-6-oxo-1,3-dioxa-4-cyclohexen-4-olate

N-Methylmorpholinium 5-[2-cyanoethyl-1-(4-hydroxy-3-methoxyphenyl)-2-thiocarbamoyl]-2,2-dimethyl-6-oxo-1,3-dioxa-4-cyclohexen-4-olate was obtained from the reaction of 4-hydroxy-3-methoxybenzaldehyde with cyanothioacetamide and Meldrum's acid in the presence of N-methylmorpholine. The molecular and crystal structure of the title compound have been established and its alkylation has been studied.     

Preparation and improved stability of N-Boc-alpha-amino-5-acyl Meldrum's acids,a versatile class of building blocks for combinatorial chemistry

The preparation of novel N-Boc-alpha-amino-5-acyl Meldrum's acids is described. The synthetic inaccessibility and instability of several of these products have led to the development of a protocol that allows the synthesis of their corresponding 4-(dimethylamino)pyridine (DMAP) salts (5-AMA-DMAP's), which exhibit superior stability compared to that of the free 5-AMA. A simple and expedient ion-exchange method was developed for the quantitative removal of DMAP to liberate the synthetically useful DMAP-free form when needed.     

Total synthesis of (+/-)-taiwaniaquinol B via a domino intramolecular friedel-crafts acylation/carbonyl alpha-tert-alkylation reaction

The first synthesis of taiwaniaquinol B, a 6-nor-5(6-->7)abeoabietane-type diterpenoid exhibiting the uncommon fused 6-5-6 tricyclic carbon skeleton, was accomplished in 15 steps. A Lewis acid-promoted tandem intramolecular Friedel-Crafts/carbonyl alpha-tert-alkylation reaction was exploited as the core strategy for the synthesis of the sterically congested 1-indanone-containing tricyclic structure. This multiple carbon-carbon bond forming reaction exploits the unique reactivity of Meldrum's acid. The facile precursor synthesis makes this a useful methodology for the expedient modification and assembly of sterically congested 1-indanone-containing ring systems.     

Studies on the synthesis of (-)-gymnodimine. Subunit synthesis and coupling

Two principal subunits of the marine algal toxin (-)-gymnodimine were synthesized. A trisubstituted tetrahydrofuran representing C10-C18 of the toxin was prepared via a highly stereoselective iodine-mediated cyclization of an acyclic alkene bearing a bis-2,6-dichlorobenzyl (DCB) ether. The formation of a cis-2,5-disubstituted tetrahydrofuran in this process conforms to a stereodirecting effect by the DCB group proposed by Bartlett and Rychnovsky. A cyclohexene subunit corresponding to the C1-C8, C19-C24 portion of gymnodimine was synthesized via Diels-Alder cycloaddition of a 1,2,3-trisubstituted diene to a symmetrical dienophile obtained from Meldrum's acid. Differentiation of carbonyl groups in the cycloadduct was made by an intramolecular reaction with a neighboring alcohol to form a gamma-lactone. Linkage of the two subunits at C18-C19 was accomplished by using a B-alkyl Suzuki coupling in which a borane prepared from the pendent alkenyl chain of the cyclohexene domain was reacted with the (E)-iodoalkene attached at C16 of the tetrahydrofuran sector. Subsequent transformations positioned functional groups in the coupled product for a future macrocyclization event that would close the 15-membered ring of gymnodimine.