Cyclisation reactions of 2-substituted benzoylphosphonates with trialkyl phosphites via nucleophilic attack on a carbonyl-containing ortho substituent

Dimethyl 2-acetoxy- and dimethyl 2-benzoyloxy-benzoylphosphonate undergo cyclisation and deoxygenation in the presence of excess trimethyl phosphite to give dimethyl (3-methyl-1-benzofuran-2-yl)phosphonate and dimethyl (3-phenyl-1-benzofuran-2-yl)phosphonate, respectively. The reaction pathway has been shown to involve phosphite attack on initially formed tricyclic dioxaphospholane intermediates with the subsequent loss of two molecules of trimethyl phosphate. In the absence of additional trimethyl phosphite the initially formed tricyclic dioxaphospholane intermediates lose one molecule of trimethyl phosphate and then undergo a novel rearrangement to give β-ketophosphonates. The mechanism for this reaction helps explain some previously reported epoxide rearrangements. In contrast, the initially formed anionic intermediate from the reaction of dimethyl 2-benzoyloxymethylbenzoylphosphonate with trimethyl phosphite undergoes decomposition to give a carbene intermediate which is trapped by the trimethyl phosphite to give an ylidic phosphonate.     

Reactions of Dimethyl Heteroaroylphosphonates with Trialkyl Phosphite in the Presence of Proton Donors

Abstract

We have previously shown that substituted bcnzoylphosphonates (1; Ar ? X-Ph) react with trimethyl phosphite to give anionic intermediates which in the absence of electrophiles decompose to give carbene intermediates (3). The nature of the subsequent reaction products depends on the type and position of the substituents on the aromatic ring.ll1 When proton donors are present the initially formed anionic intermediates (2) give the quasi-phosphonium salts (4) which usually decompose to give the phohphonate-phosphates (5). although for the case of (1; Ar ? 4-MeOPh) formation of the phosphonates (6) was observed.     

Synthesis and selected reactions of ethyl 5-(1-chloroethyl)-2-methylfuran-3-carboxylate

Ethyl 2-methylfuran-3-carboxylate is smoothly chloroethylated at 0°C in the 5 position of the ring. The resulting halide alkylates secondary amines but eliminates HCl with sodium diethyl phosphite under the Michaelis-Becker reaction conditions and with trimethyl phosphite under the Arbuzov reaction conditions. In the reaction with sodium diethyl phosphite, small amounts of 5-[1-(diethoxyphosphoryl)ethyl]furan-3-carboxylate and 5-ethylfuran-3-carboxylate are formed. In the Arbuzov reaction at a 1: 1.22 furan: trimethyl phosphite molar ratio, methyl 2,4-dimethyl-1-methoxy-1-oxo-1λ⁵-1,2-dihydrophospheto[3,2-b]furan-5-carboxylate was isolated.     

Reactions of 5-Functionalyzed 2-(1-Haloethyl)furans with Sodium Diethylphosphite and Trialkyl Phosphites

5-(1-Haloethyl)furan-2-carboxylic acid derivatives react with sodium dialkyl phosphite, tri-alkyl phosphite in two directions to form phosphonates and alkenes. The alkene fraction in the reaction pro-ducts diminishes as the electron-acceptor power of the 2-substituent in the ring increases in going from dialkylamide to ether and then to nitrile. 5-Bromoethyl-2-cyanofuran reacts with sodium diethyl phosphite to give no other products than those formed by halogenophilic attack, implying a significant withdrawal of the electron density from the bromine atom in this compound.     

Studies of the Reactions of 2-Substituted Dimethyl Benzoylphosphonates with Trimethyl Phosphite

Abstract

Dimethyl benzoylphosphonates (1) react with trimethyl phosphite to give anionic intermediates (2) which decompose to give carbenes (3) and trimethyl phosphate [1]. When suitable ortho-substituents are present on the benzoylphosphonate, intramolecular carbene insertion reactions can occur to give cyclic systems. With alkyl substitutents, where the length of the chain provides a choice of cyclisation pathways, insertion into an appropriate C[sbnd]H bond to give a 5-membered ring has been found to be the preferred option. We have therefore been investigating the behaviour of systems, such as (4), where insertion into a C[sbnd]H bond to give a 5-membered ring is prevented.     

Specific Features of Reactions of Halomethyl Derivatives of Alkyl 5-Isobutylfuran-3-carboxylates with Trimethyl Phosphite and Sodium Diethyl Phosphite

Ethyl 5-isobutyl-2-methylfuran-3-carboxylate is selectively brominated with N-bromosuccin-imide by the methyl group to give an unstable bromide. The latter on heating or in the presence of bases un-dergoes dehydrobromination accompanied by rearrangement, leading to a (2'2-dimethylvinyl)furan derivative.Phosphorylation of this bromide with trimethyl phosphite gives a 2-dimethoxyphosphorylmethyl derivativeand a product containing the phosphonate group to the isobutyl radical. Chloromethylation of the startingester proceeds in the 4 position of the furan ring. The resulting chloride undergoes phosphorylation underconditions of the Michaelis-Becker reaction to give the corresponding 4-(dialkoxyphosphorylmethyl)furan'and under the action of trimethyl phosphite a mixture of the same phosphonate, a dehalogenation producthaving a dimethylvinyl fragment. Bromination of the 4-chloromethyl derivative with N-bromosuccinimideinvolves the 2-methyl group. The dihalide reacts with trimethyl phosphite by way of reduction of the bromomethyl group to give 4-chloromethyl- or 4-dimethoxyphosphorylmethyl derivatives, as well as analogous dehydrohalogenation products containing a 5-dimethylvinyl fragment. A scheme describing the sequence of formation of these products in the course of the reaction is offered.     

Ethynylation of 2-(furan-2-yl)- and 2-(thiophen-2-yl)pyrroles with acylbromoacetylenes in the Al2O3 medium: relative reactivity of heterocycles

2-(Furan-2-yl)- and 2-(thiophen-2-yl)pyrroles are readily ethynylated with acylbromoacetylenes in the solid Al₂O₃ medium (no solvent, room temperature, 1 h) to afford 5-(furan-2-yl)- and 5-(thiophen-2-yl)-2-acylethynylpyrroles in 39–74% yields. In the case of 2-(furan-2-yl)pyrroles, an alternative ethynylation of the furan ring takes place, the ratio of the furan and pyrrole ring ethynylation products being 1:5–7. No ethynylation of the thiophene ring as well as ethynylation of both heterocycles in a one molecule has been detected. Thus the reactivity of the heterocycles towards the ethynylation system (acylbromoacetylenes/Al₂O₃) falls in the order: pyrrole>furan>thiophene.     

Synthesis and aminomethylation of 2-isobutyl-3-and 4-diethoxyphosphorylmethylfurans

Synthetic procedure for preparing 2-isobutyl-3-and 4-furancarboxylic acyl chlorides is developed. Reduction of these compounds with lithium alumohydride leads to corresponding alcohols which under treating with thionyl chloride in the presence of pyridine form chloromethyl derivatives. The latter compounds are phosphorylated with sodium diethyl phosphite under the Michaelis-Becker reaction conditions to give corresponding phosphonates. Reaction of compounds obtained with dimethyl(chloromethyl)amine proceeds at the free α-position of the furan ring and delivers aminophosphonates. These substances do not evolve dimethylamine even under the conditions of vacuum distillation (145–150°C, 1 mm Hg).     

Doyle-Kirmse reaction of allylic sulfides with diazoalkane-free (2-furyl)carbenoid transfer

[reaction: see text] In the presence of rhodium catalyst, (2-furyl)carbenoids generated from conjugated ene-yne-carbonyl compounds 1 efficiently undergo carbene transfer reactions with allylic sulfides followed by [2,3]sigmatropic rearrangement of sulfur ylides to give furan-containing sulfides in good yields. When diallyl sulfide is employed, heteroatom-containing polycyclic compounds are obtained by sequential intramolecular Diels-Alder cyclization reaction with a constructed furan ring as an enophile.     

Synthesis of isomeric bromo(diethoxyphosphorylmethyl)furans

Series of the previously unknown bromo(diethoxyphosphorylmethyl)furans including four of six possible regioisomers is synthesized. The target products were obtained by bromination of the corresponding (diethoxyphosphorylmethyl)furans or by a four-step synthesis including bromination of isomeric methyl-furancarboxylates, reduction of the products formed to the corresponding alcohols, substitution of hydroxy group with halogen and phosphorylation by the Michaelis-Becker reaction. It was established for the first fime that in the course of bromination of alkyl carboxylates and phosphonates of the furan series under the typical conditions of electrophilic reaction (Br₂ + 10% molar of AlCl₃, chloroform) the substituent enters not only into the heteroring, but also into the side chain. In the case of 5-methyl-2-(diethoxyphosphorylmethyl)furan only the last reaction pathway is observed. It is shown that bromo(chloromethyl)furans react with sodium diethyl phosphite not only according to the Michaelis-Becker scheme leading to phosphonates, but also by the pathway of debromination of the furan ring. The last unexpected reaction may acquire a practical use for removing a substituent protecting the α-position of the furan ring under mild conditions.     

Strain-Induced Ring Expansion Reactions of Calix[3]pyrrole-Related Macrocycles

The recent discovery of calix[3]pyrrole, a porphyrinogen-like tripyrrolic macrocycle, has provided an unprecedented strain-induced ring expansion reaction into calix[6]pyrrole. Here, we synthesized calix[n]furan[3-n]pyrrole (n=1∼3) macrocycles to investigate the reaction scope and mechanism of the ring expansion. Single crystal X-ray analysis and theoretical calculations revealed that macrocyclic ring strain increases as the number of inner NH sites increases. While calix[1]furan[2]pyrrole exhibited almost quantitative conversion into calix[2]furan[4]pyrrole within 5 minutes, less-strained calix[2]furan[1]pyrrole and calix[3]furan were inert. However, N-methylation of calix[2]furan[1]pyrrole induced a ring-expansion reaction that enabled the isolation of a linear reaction intermediate. The mechanism analysis revealed that the ring expansion consists of regioselective ring cleavage and subsequent cyclodimerization. This reaction was further utilized for synthesis of calix[6]-type macrocycles.     

Intermediate carbene formation in the reaction of thioamides with phosphorus (III) derivatives: Quantum chemical investigation

The reactions of perfluoroalkyl thioamides with trimethyl phosphine, trimethyl phosphite, and tris(dimethylamino)phosphine have been analyzed by means of quantum chemical (DFT and MP2) calculations. The reaction seems to proceed via the nucleophilic attack of the electrophilic carbon atom by the phosphorus lone pair with the formation of cyclic or acyclic adducts. The latter releases the thiophosphate molecule forming perfluoroalkylaminocarbene as the short‐lived intermediate. The reaction of the carbene with the second molecule of trialkyl phosphite yields phosphorus ylide. The ylide undergoes a migration of fluorine from carbon to phosphorus. The reactions of perfluoroalkyl thioamides with phosphines and tris(dimethylamino)phosphine probably proceeds differently. Using alkyl thioamides or amides instead of perfluoroalkyl thioamides also makes the reaction less favorable. The only combination of perfluoroalkyl thioamides with trialkyl phosphite fulfills both the kinetic requirements (moderate activation energies and relative energies for intermediates) and the thermodynamic aspects (higher stabilities of the reaction products compared with the starting materials). © 2013 Wiley Periodicals, Inc.     

Catalytic and highly enantioselective Friedel–Crafts type reactions of heteroaromatic compounds with trifluoropyruvate and glyoxylate by a dicationic palladium complex

The highly enantioselective Friedel–Crafts alkylation of furan and thiophene derivatives with trifluoropyruvate, which have never provided the high level of asymmetric induction and yield until now, was achieved by using dicationic palladium complexes as Lewis acid catalysts. Moreover, glyoxylate instead of trifluoropyruvate as an electrophile led to complete change of regioselectivity with 2-trimethylsilylated furan, thiophene, and pyrrole derivatives to give the corresponding heteroarylated products in high yields and enantioselectivities. The respective products with trifluoropyruvate and glyoxylate could also be obtained via sequential catalytic reaction; intramolecular cyclization of alkynyldiols using cationic Au catalyst followed by Friedel–Crafts type reactions using dicationic Pd catalyst.     

Synthesis of a series of aromatic benziporphyrins and heteroanalogues via tripyrrane-like intermediates derived from resorcinol and 2-methylresorcinol

Tripyrrane analogues were prepared by reacting resorcinol or 2-methylresorcinol with 2 equiv of an acetoxymethylpyrrole in the presence of p-toluenesulfonic acid and calcium chloride. Following removal of the benzyl ester protective groups, the resorcinol-derived benzitripyrrane was reacted with a pyrrole dialdehyde to give an aromatic hydroxyoxybenziporphyrin. However, furan and thiophene dialdehydes gave highly insoluble products that could not be fully characterized. The methylresorcinol-derived tripyrrane analogue reacted with pyrrole, furan, thiophene, and selenophene dialdehydes to give unstable porphyrinoids that were further oxidized with [bis(trifluoroacetoxy)iodo]benzene to give stable benziporphyrin derivatives. These oxidized benziporphyrins showed strongly diatropic properties by proton NMR spectroscopy where the differences in chemical shifts (Δδ) were >18 ppm in some cases. The selenophene-derived system was further characterized by X-ray crystallography, and these results showed that one of the pyrrole subunits in this crowded structure was tilted by 21° relative to the mean macrocyclic plane. The tripyrrolic system reacted with silver(I) acetate to give the corresponding silver(III) organometallic complex. Regioselective alkylation with methyl or ethyl iodide and potassium carbonate gave diastereomeric mixtures of N-alkyl derivatives, and the N-ethyl substitution products showed highly diastereotopic characteristics.     

Deprotonative metalation of five-membered aromatic heterocycles using mixed lithium-zinc species

Deprotonation of benzoxazole, benzothiazole, benzo[b]thiophene, benzo[b]furan, N-Boc-protected indole and pyrrole, and N-phenylpyrazole using an in situ mixture of ZnCl(2).TMEDA (0.5 equiv) and lithium 2,2,6,6-tetramethylpiperidide (1.5 equiv) in THF at room temperature is described. The reaction was evidenced by trapping with iodine, regioselectively giving the expected functionalized derivatives in 52-73% yields. A mixture of mono- and disubstituted derivatives was obtained starting from thiazole. Cross-coupling reactions of 2-metalated benzo[b]thiophene and benzo[b]furan with heteroaromatic chlorides proved possible under palladium catalysis. A reaction pathway where the lithium amide and zinc diamide present in solution behave synergically was proposed for the deprotonation reaction, taking account of NMR and DFT studies carried out on the basic mixture.     

3,3]-rearrangements of phosphonium ylides

Allylic phosphonium ylides are readily generated by the combination of an allylic alcohol, a carbene, and a chlorophosphite. Here we demonstrate that these intermediates undergo a thermal [3,3]-rearrangement to provide single isomers of homoallylic phosphonates in good to excellent yields. This new reaction manifold for phosphorus ylides is tolerant of a range of substitution patterns on the reactants and provides access to structurally complex intermediates for the synthesis of enzyme inhibitors, aminophosphonic acids, and natural products.     

The direction of the dipole moments of furan,thiophen, and pyrrole: A controversial question

The report that the dipole moment in the five-membered heterocyclic rings, furan, thiophene, and pyrrole has the positive pole on the heteroatom is contradicted with arguments based on reactivity data, theoretical calculations and moment values of substituted derivatives. In actuality, the dipole moment in furan and thiophene is directed from the ring (positive pole) to the heteroatom (negative pole).     

Highly diastereoselective vinylogous Mukaiyama aldol reaction of α-keto phosphonates with 2-(trimethylsilyloxy)furan catalyzed by Cu(OTf)2

The diastereospecific formation of δ-hydroxyalkylbutenolide phosphonate has been achieved via a vinylogous Mukaiyama aldol reaction. The reaction was performed using α-ketophosphonate 1 and 2-(trimethylsilyloxy)furan 2 mediated by Cu(OTf)(2) and 2,2,2-trifluoroethanol as additive in CH(2)Cl(2). The reaction proceeds rapidly and affords the corresponding 5-(hydroxy(aryl)methyl) furan-2(5H)-one phosphonates 3 in high yields with good to excellent diastereoselectivities (d.r. up to >99?:?1). 5-(Hydroxy(alkyl)methyl)furan-2(5H)-one phosphonates could also be obtained with good diastereoselectivities.     

Synthesis and Phosphorylation of 2-, 3-, and 4-Halomethyl-5-tert-butylfurans

Synthetic methods for preparing of 2-, 3-, 4-halomethyl-5-tert-butylfurans are developed. Itwas established that the bromination of 3- and 4-methyl-2-tert-butylfurans with N-bromosuccinimide proceedsmainly at the free -position of the furan ring, and not at the methyl group. Therefore, the target halomethyl- furans were prepared through the corresponding 3- and 4-methoxymethyl derivatives. The obtained five products were phosphorylated with sodium diethyl phosphite under the conditions of the Michaelis-Becker reaction to give the corresponding phosphonates.