Development of highly regioselective amidyl radical cyclization based on lone pair-lone pair repulsion

The substituent effect on the reactivity and regioselectivity of N-(4-pentenyl)amidyl radical cyclization was investigated. Exclusive 6- endo cyclization was observed for N-(4-pentenyl)amidyl radicals with internal vinylic heteroatom substitution (Cl, Br, I, OMe, SEt). The substituent on the carbonyl group also showed a significant influence on the reactivity of amidyl radicals, which increases in the order of Ph < Me < OEt. As a result, the photostimulated reactions of N-(4-halopent-4-enyl)amides and carbamates (X = Cl, Br, I) with DIB/I 2 or Pb(OAc) 4/I 2 led to the efficient and exclusive formation of the corresponding piperidines while those of N-(5-halopent-4-enyl)amides afforded the pyrrolidine products only. The halogen-substitution effect also allowed the 6- exo and 7- endo amidyl radical cyclization to proceed in a highly regioselective manner. The above experimental results, in combination with theoretical analyses, revealed that the lone pair-lone pair repulsion between the nitrogen radical and the vinylic heteroatom played an important role in controlling the regioselectivity of cyclization.     

8-endo versus 7-exo cyclization of alpha-carbamoyl radicals. A combination of experimental and theoretical studies

Atom transfer radical cyclization reactions of N-(4-pentenyl)iodoacetamides were investigated. The reactions were efficiently promoted by BF3.OEt2. For N-alkenyl-substituted iodoamides, excellent regioselectivity in favor of 8-endo cyclization was observed, while both 7-exo and 8-endo cyclization products were formed with the 8-endo cyclization preferred in the cases of N-(2-allylphenyl)-substituted iodoamides. Density functional theory calculations at the B3LYP/6-31G level revealed that both the s-trans and the s-cis conformational transition structures were feasible for the 8-endo cyclization of N-alkenyl-substituted alpha-carbamoyl radicals while 7-exo transition structures were much less stable. For the cyclization of N-(2-allylphenyl)-substituted alpha-carbamoyl radicals, the transition structures for 8-endo and 7-exo cyclizations were of comparable energy. These results were in excellent agreement with the experimental observations.     

Palladium-catalyzed cyclization/carboalkoxylation of alkenyl indoles

Reaction of 1-methyl-2-(4-pentenyl)indole with a catalytic amount of PdCl2(CH3CN)2 (5 mol %) and a stoichiometric amount of CuCl2 (3 equiv) in methanol under CO (1 atm) at room temperature for 30 min led to cyclization/carboalkoxylation to form the corresponding tetrahydrocarbazole in 83% isolated yield as a single regioisomer. Palladium-catalyzed cyclization/carboalkoxylation of 2-(4-pentenyl)indoles tolerated substitution along the alkenyl chain and at the internal and cis-terminal olefinic positions. Palladium-catalyzed cyclization/carboalkoxylation tolerated a range of alcohols and was effective for the cyclization of 2-(3-butenyl)indoles, 3-(3-butenyl)indoles, 3-(4-pentenyl)indoles, and 2-(5-hexenyl)indoles.     

Investigation of bis(tributyltin)-initiated free radical cyclization reactions of 4-pentenyl iodoacetates

Bis(tributyltin)-initiated atom transfer cyclization reactions of 4-pentenyl iodoacetates (1) at 80 degrees C led to the formations of 5-(3-iodopropyl)-substituted dihydro-2(3H)-furanones (3) in high yield. With BF3*Et2O as the catalyst, the reactions were run at room temperature to afford the corresponding gamma-iodoheptanolactones (2), which could be further transformed into 3-(tetrahydro-2-furyl)propanoic acids (6) upon treatment with aqueous NaHCO3. The reaction mechanism was postulated to be the 8-endo free radical cyclization to generate gamma-iodoheptanolactones which easily underwent intramolecular nucleophilic substitution to form bicyclic acylium species (7) as the key intermediate. Subsequent attack by iodide ion furnished gamma-lactones while attack by hydroxide ion gave the tetrahydrofuran derivatives.     

Platinum-catalyzed intramolecular alkylation of indoles with unactivated olefins

Reaction of 1-methy-2-(4-pentenyl)indole (1) with a catalytic amount of PtCl2 (2 mol %) in dioxane that contained a trace of HCl (5 mol %) at 60 degrees C for 24 h led to the isolation of 4,9-dimethyl-2,3,4,9-tetrahydro-1H-carbazole (2) in 92% yield. Platinum-catalyzed cyclization of 2-(4-pentenyl)indoles tolerated substitution at each position of the 4-pentenyl chain. Furthermore, the protocol was applicable to the synthesis of tetrahydro-beta-carbolinones and was effective for cyclization of unprotected indoles. 2-(3-Butenyl)indoles underwent platinum-catalyzed cyclization with exclusive 6-endo-trig regioselectivity. Mechanistic studies established a mechanism for the platinum-catalyzed cyclization of 2-alkenyl indoles involving nucleophilic attack of the indole on a platinum-complexed olefin.     

水相中可见光下苯甲醇氧化合成喹唑啉酮衍生物的研究

通过在水相中可见光下2-氨基苯甲酰胺与苄醇氧化制备喹唑啉酮的环化反应,应用廉价易得、操作简单的单质碘作为光催化剂,在室温下反应获得较好收率的产物.目标产物的最高产率可达92%,为喹唑啉酮类化合物的合成提供了一种绿色经济的方法.运用此策略合成的N-(2-氟-5-甲基苯基)-6-(2,2,2-三氟乙氧基)蝶啶-4-胺对肿瘤细胞具有明显的抑制活性.     

An Efficient Synthesis of 4-Halo-5-hydroxyfuran-2(5H)-ones via the Sequential Halolactonization and γ-Hydroxylation of 4-Aryl-2,3-alkadienoic Acids

5-Hydroxyfuran-2(5H)ones are an important class of compounds because they often occur in natural products and exhibit a broad range of biological activities. Recently, much attention has been focused on the efficient and di verse synthesis of these compounds, particularly 4-halo-5-hydroxy-2(5H)-furanones. The typical synthetic strategies include acid catalyzed cyclization of ketonic acids, auto oxidation of corresponding lactone in air, rearrangement reactions of α-phenylsulphinylacrylates, oxidation with chromium trioxide in acetic acid, and bromination-hydrolysis of α ,β-butanolides. Herein, we wish to report that 4-halo-5-hydroxyfuran-2(5H)-ones were synthesized via the efficient sequential halolactonization-hydroxylation reaction of 4-aryl-2,3-allenoic acids with I2 or CuX2 (X = Br or Cl) inmoderate to good yields.     

Catalytic reduction and intramolecular cyclization of haloalkynes in the presence of nickel(I) salen electrogenerated at carbon cathodes in dimethylformamide

[reaction: see text] Pentylidenecyclopentane can be conveniently prepared in up to 86% yield via the catalytic reduction of 1-iodo- or 1-bromo-5-decyne by [[2,2'-[1,2-ethanediylbis(nitrilomethylidyne)]bis[phenolato]]-N,N',O,O']nickelate(I) electrogenerated at a carbon cathode in dimethylformamide containing tetramethylammonium tetrafluoroborate. This electrosynthesis can be accomplished at potentials for which the haloalkynes are electroinactive, and it can be completed within 30 min at room temperature. Attempts to synthesize pentylidenecyclobutane and pentylidenecyclohexane from 1-halo-4-nonynes and 11-halo-5-undecynes, respectively, under similar conditions afford the carbocycles in very low yields (2% and 6%, respectively). Other products derived from the various haloalkynes are dimers, alkynes, and 1-alkenynes. Dimers (alkadiynes) arising from 1-halo-4-nonynes and 11-halo-5-undecynes are formed in yields ranging from 80% to 89%, whereas icosa-5,15-diyne (the dimer obtained from a 1-halo-5-decyne) is found in significantly lower yield (相似文献   

Room temperature hydroamination of N-alkenyl ureas catalyzed by a gold(i) N-heterocyclic carbene complex

[Structure: see text] Treatment of an N-4-pentenyl or N-5-hexenyl urea with a catalytic 1:1 mixture of a gold(I) N,N-diaryl imidazol-2-ylidine complex and AgOTf at or near room temperature leads to intramolecular exo-hydroamination to form the corresponding nitrogen heterocycle in excellent yield.     

Cobalt-mediated cross-coupling reactions of primary and secondary alkyl halides with 1-(trimethylsilyl)ethenyl- and 2-trimethylsilylethynylmagnesium reagents

[reaction: see text] This paper describes cobalt-mediated cross-coupling reactions of alkyl halides with 1-(trimethylsilyl)ethenylmagnesium bromide and 2-(trimethylsilyl)ethynylmagnesium bromide, respectively. The cobalt system allows for employing secondary as well as primary alkyl halides as the substrates. The reactions offer facile formations of alkyl-alkenyl and alkyl-alkynyl bonds. The reaction mechanism would include single-electron transfer from a cobalt complex to alkyl halide to generate the corresponding alkyl radical. The cobalt system thus enables sequential radical cyclization/alkenylation and cyclization/alkynylation reactions of 6-halo-1-hexene derivatives.     

Regioselective unusual formation of spirocyclic 4-{2'-benzo(2',3'-dihydro)furo}- 9-methyl-2,3,9-trihydrothiopyrano[2,3-b]indole by 4-exo-trig aryl radical cyclization and rearrangement

4-(2'-Bromoaryloxymethylene)-9-methyl-2,3,9-trihydrothiopyrano[2,3-b]indoles under tri-n-butyltin hydride mediated aryl radical cyclization furnished exclusively the 4-{2'-benzo(2',3'-dihydro)furo}-9-methyl-2,3,9-trihydrothiopyrano[2,3-b]indoles in excellent yield (75-80%) via 4-exo-trig cyclization, opening of the oxetene ring, and 5-endo-trig cyclization.     

Cobalt-catalyzed trimethylsilylmethylmagnesium-promoted radical alkenylation of alkyl halides: a complement to the Heck reaction

A cobalt complex, [CoCl2(dpph)] (DPPH = [1,6-bis(diphenylphosphino)hexane]), catalyzes an intermolecular styrylation reaction of alkyl halides in the presence of Me3SiCH2MgCl in ether to yield beta-alkylstyrenes. A variety of alkyl halides including alkyl chlorides can participate in the styrylation. A radical mechanism is strongly suggested for the styrylation reaction. The sequential isomerization/styrylation reactions of cyclopropylmethyl bromide and 6-bromo-1-hexene provide evidence of the radical mechanism. Crystallographic and spectroscopic investigations on cobalt complexes reveal that the reaction would begin with single electron transfer from an electron-rich (diphosphine)bis(trimethylsilylmethyl)cobalt(II) complex followed by reductive elimination to yield 1,2-bis(trimethylsilyl)ethane and a (diphosphine)cobalt(I) complex. The combination of [CoCl2(dppb)] (DPPB = [1,4-bis(diphenylphosphino)butane]) catalyst and Me3SiCH2MgCl induces intramolecular Heck-type cyclization reactions of 6-halo-1-hexenes via a radical process. On the other hand, the intramolecular cyclization of the prenyl ether of 2-iodophenol would proceed in a fashion similar to the conventional palladium-catalyzed transformation. The nonradical oxidative addition of carbon(sp2)-halogen bonds to cobalt is separately verified by a cobalt-catalyzed cross-coupling reaction of alkenyl halides with Me3SiCH2MgCl with retention of configuration of the starting vinyl halides. The cobalt-catalyzed intermolecular radical styrylation reaction of alkyl halides is applied to stereoselective variants. Styrylations of 1-alkoxy-2-bromocyclopentane derivatives provide trans-1-alkoxy-2-styrylcyclopentane skeletons, one of which is optically pure.     

Studies on highly stereoselective addition-elimination reactions of 3-(methoxycarbonyl)-1,2-allen-4-ols with MX. An efficient synthesis of 3-(methoxycarbonyl)-2-halo-1,3(Z)-dienes

3-(Methoxycarbonyl)-2-halo-1,3(Z)-dienes were prepared highly stereoselectively via SN2'-type addition-elimination reactions of 3-(methoxycarbonyl)-1,2-allen-4-ols with MX. These products may easily undergo Negishi or Sonogashira coupling reactions to yield a series of stereodefined polysubstituted (E)-1,3-dienes.     

Conformationally constrained dipeptide surrogates with aromatic side-chains: synthesis of 4-aryl indolizidin-9-one amino acids by conjugate addition to a common alpha,omega-diaminoazelate enone intermediate

Four methyl 9-oxo-8-(N-(Boc)-amino)-4-phenyl-1-azabicyclo[4.3.0]nonane carboxylates (11, 4-Ph-I(9)aa-OMe) were synthesized from (2S,8S,5E)-di-tert-butyl-4-oxo-5-ene-2,8-bis[N-(PhF)amino]azelate [(5E)-7, PhF = 9-(9-phenylfluorenyl)] via a seven-step process featuring a conjugate addition/reductive amination/lactam cyclization sequence. Various nucleophiles were used in the conjugate addition reactions on enone (5E)-7 as a general route for making alpha,omega-diaminoazelates possessing different substituents in good yield albeit low diastereoselectivity except in the case of aryl Grignard reagents (9/1 to 15/1 drs). 6-Phenylazelates (6S)-8d and (6R)-8d were separated by chromatography and diastereoselective precipitation and independently transformed into 4-Ph-I(9)aa-OMe. From (6S)-8d, (2S,4R,6R,8S)-4-Ph-I(9)aa-OMe 11 was prepared selectively in 51% yield. Reductive amination of (6R)-8d provided the desired pipecolates 9 along with desamino compound 10, which was minimized by performing the hydrogenation in the presence of ammonium acetate. Subsequent ester exchange, lactam cyclization, and amine protection provided three products (2R,4S,6S,8R)-, (2R,4S,6S,8S)-, and (2S,4S,6R,8S)-4-Ph-I(9)aa-OMe 11 in 10, 6, and 6% yields, respectively, from (6R)-8d. Ester hydrolysis of (2S,4R,6R,8S)-11 furnished 4-phenyl indolizidin-9-one N-(Boc)amino acid 3 as a novel constrained Ala-Phe dipeptide surrogate for studying conformation-activity relationships of biologically active peptides.     

Enantioselective total synthesis of (-)-triptolide, (-)-triptonide, (+)-triptophenolide, and (+)-triptoquinonide

The first enantioselective total synthesis of (-)-triptolide (1), (-)-triptonide (2), (+)-triptophenolide (3), and (+)-triptoquinonide (4) was completed. The key step involves lanthanide triflate-catalyzed oxidative radical cyclization of (+)-8-phenylmenthyl ester 30 mediated by Mn(OAc)3, providing intermediate 31 with good chemical yield (77%) and excellent diastereoselectivity (dr 38:1). (+)-Triptophenolide methyl ether (5) was then prepared in > 99% enantiomeric excess (> 99% ee), and readily converted to natural products 1-4. In addition, transition state models were proposed to explain the opposite chiral induction observed in the oxidative radical cyclization reactions of chiral beta-keto esters 17 (without an alpha-substituent) and 17a (with an alpha-chloro substituent).     

Prins cyclizations in silyl additives with suppression of epimerization: versatile tool in the synthesis of the tetrahydropyran backbone of natural products

[reactions: see text] A catalytic Prins cyclization reaction has been developed. The involvement of trimethylsilyl halides offers a versatile route to the formation of cis-4-halo-2,6-disubstituted tetrahydropyran rings. The problem of epimerization in Prins cyclization has also been addressed in the total synthesis of (-)-centrolobine using this methodology.     

Aromatic amino-claisen rearrangement in the synthesis of ellipticine

A convenient route is described for the preparation of 1,4-dimethylcarbazole — the key compound in the synthesis of the antitumoral alkaloid ellipticine. The interaction of 2,5-xylidine with 3-chlorocyclohexene led to N-(cyclohex-2-enyl)-2,5-xylidine (I), the two-hour heating of which at 140–150°C gave the product of an amino-Claisen rearrangement, 6-(cyclohex-2-enyl)-2,5-xylidine (II) with a yield of 82%. The intramolecular cyclization of compound (II) in polyphosphoric acid (130–140°C, 5 h) led to 5,6,7,8,12,13-hexahydro-1,4-dimethylcarbazole (III) in a yield of 75%. The dehydrogenation of substance (III) by boiling in trimethylbenzene in the presence of Pd/C gave 1,4-dimethylcarbazole (IV) with a yield of 87%. The conditions for performing the reactions and the physicochemical constants of the compounds obtained are given.     

Cobalt-catalyzed cross-coupling reactions of alkyl halides with aryl Grignard reagents and their application to sequential radical cyclization/cross-coupling reactions

Reactions of alkyl halides with arylmagnesium bromides in the presence of cobalt(II)(diphosphine) complexes are discussed. Treatment of 1-bromooctane with phenylmagnesium bromide with the aid of a catalytic amount of CoCl₂(dppp) [DPPP=1,3-bis(diphenylphosphino)propane] yielded octylbenzene in good yield. The reaction mechanism would include single electron transfer from an electron-rich cobalt complex to alkyl halide to generate the corresponding alkyl radical. The mechanism was justified by CoCl₂(dppe)-catalyzed [DPPE=1,2-bis(diphenylphosphino)ethane] sequential radical cyclization/cross-coupling reactions of 6-halo-1-hexene derivatives that yielded benzyl-substituted cyclopentane skeletons.     

Indium-mediated atom-transfer and reductive radical cyclizations of iodoalkynes: synthesis and biological evaluation of HIV-protease inhibitors

Novel indium-mediated radical cyclization reactions of aliphatic iodoalkynes have been studied. Treatment of iodoalkynes with a catalytic amount of In (0.1 equiv) and I(2) (0.05 equiv) promotes atom-transfer 5-exo cyclization to give five-membered alkenyl iodides. In contrast, reaction with In (2 equiv) and I(2) (1 equiv) yields reductive 5-exo cyclization products via the same 5-exo cyclization. Both processes are most likely initiated by low-valent indium species. To demonstrate versatility of these reactions, optically active HIV protease inhibitors were synthesized by this reductive cyclization method. Among them, several products, which contain a hydroxyethylamine dipeptide isostere as a transition state-mimicking substructure, proved to possess potent activity (IC(50) = 5-39 nM) against a wide spectrum of HIV strains, including multidrug-resistant variants.     

达比加群酯的合成

3-硝基-4-氯苯甲酸(2)经甲胺化得3-硝基-4-甲氨基苯甲酸(3),2-氨基吡啶与丙烯酸乙酯经迈克尔加成得3-[(吡啶-2-基)氨基]丙酸乙酯(5),化合物3与5经缩合、催化氢化得3-{[(3-氨基-4-甲胺基)苯甲酰基](吡啶-2-基)氨基}丙酸乙酯(7),化合物7再与N-(4-氰基苯基)甘氨酸(8)酰化、环合和Pinner反应,最后与氯甲酸正己酯反应得到达比加群酯(1),总收率约40%(以3-硝基-4-氯苯甲酸计),结构经IR、1H NMR和MS测试技术确证。