Gold(I)-catalyzed rearrangement of 3-silyloxy-1,5-enynes: an efficient synthesis of benzo[b]thiophenes, dibenzothiophenes, dibenzofurans, and indole derivatives

With the IPr ligand (IPr=1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene) on gold(I) excellent yields in the benzanellation of 2-substituted thiophenes, benzothiophenes, pyrroles, benzofurans, and indoles were achieved. The 1-siloxybut-3-ynyl side chains, incorporated in the anellation, are easily accessible by the addition of a propargyl metal reagent to a formyl group and silylation of the alcohol. This conveniently allows an anellation at the position of the formyl group under mild conditions. All reactions involve a 2,3-shift of the side chain in the anellation step and thus, provide an easy access to specific substitution patterns. Only in the case of 2-substituted indoles with their highly nucleophilic 3-position a direct hydroarylation without shift is observed. On the other hand, 3-substituted indoles give the same products as 2-substituted indoles. Then, a 3,2-shift in the indole ring system has to be involved.     

Synthesis of Novel 4‐((Substituted bis‐indolyl)methyl)‐benzo‐15‐crown‐5 for the Colorimetric Detection of Hg2+ Ions in an Aqueous Medium

A practical, two‐step synthesis of novel 4‐(substituted bis‐indolyl)methyl)benzo‐15‐crown‐5 has been reported. The strategy employed for the synthesis of the desired molecules involved Duff formylation of benzo‐15‐crown‐5 to get 4‐formyl benzo‐15‐crown‐5 followed by subsequent reactions with substituted indoles in trifluoroacetic acid to yield novel 4‐(substituted bis‐indolyl)methyl)benzo‐15‐crown‐5 in moderate to good yield. One of the reported novel molecule tested for the complexation behavior with various metal cations, such as Li⁺, Na⁺, K⁺, Mg²⁺ Ca²⁺, Al³⁺, Fe²⁺, Co²⁺, Ni²⁺, Cu²⁺, Zn²⁺, Cd²⁺, Sn²⁺, Ba²⁺, Hg²⁺, and Pb²⁺, showed a visual colorimetric probe for the detection of mercury cations (Hg²⁺) in an aqueous medium.     

Facile access to 6‐substituted 1,4,5,7‐tetrahydropyrrolo[3,4‐b]‐pyridines via hantzsch type dimethyl 4‐aryl‐2‐formyl‐6‐methyl‐1,4‐dihydropyridine‐3,5‐dicarboxylates

Efficient assembly of 6‐substituted 4‐aryl‐5‐oxo‐1,4,5,7‐tetrahydropyrrolo[3,4‐b]pyridines (7a‐f) is described according to a Hantzsch type reaction from formyl‐ester 4 by imination, borohydride reduction and intramolecular thermal amino‐ester cyclization. The starting compound 4 was prepared in three steps from the readily available formyl derivative 1, methyl 4,4‐dimethoxy‐3‐oxobutanoate and methyl 3‐aminocrotonate.     

Synthesis of tetracyclic system of 2,4‐di(tert‐butyl)‐6,7‐dihydrofuro[2′,3′:3,4]cyclohepta[1,2‐b]indole

For the first time, tetracyclic compounds, namely, furo[2′,3′:3,4]cyclohepta[1,2‐b]indoles were synthesized by recyclization of ortho‐substituted aryldifurylmethanes containing tert‐butyl groups at C5 positions of the furan rings. It was shown that [2‐(benzoylamino)phenyl]bis(5‐tert‐butyl‐2‐furyl)methanes 12 are transformed into tetracycles 15 at room temperature under treatment with POCl₃ in benzene solution containing some drops of water. The reaction proceeds via the intermediate formation of 1‐benzoylamino‐3‐(5‐tert‐butyl‐2‐furyl)‐2‐(4,4‐dimethyl‐3‐oxopentyl)indoles 14 which can be isolated from the reaction mixture. The method is very simple but its application is restricted due to side reactions if electron‐releasing groups are present in 12 . On the other hand, the decrease of electron density on furan ring in the starting compounds (for example, the use of [2‐X‐phenyl]difurylmethanes (where X = tosylamino or hydroxy group) prevents cyclization under the studied reaction conditions. As a result, corresponding ketones are formed as products of recyclization. J. Heterocyclic Chem., (2011).     

Iridium‐Catalyzed Enantioselective Intermolecular Indole C2‐Allylation

The enantioselective intermolecular C2‐allylation of 3‐substituted indoles is reported for the first time. This directing group‐free approach relies on a chiral Ir‐(P, olefin) complex and Mg(ClO₄)₂ Lewis acid catalyst system to promote allylic substitution, providing the C2‐allylated products in typically high yields (40–99 %) and enantioselectivities (83–99 % ee) with excellent regiocontrol. Experimental studies and DFT calculations suggest that the reaction proceeds via direct C2‐allylation, rather than C3‐allylation followed by in situ migration. Steric congestion at the indole‐C3 position and improved π–π stacking interactions have been identified as major contributors to the C2‐selectivity.     

Platinum‐Catalyzed Multi‐Step Reaction of Propargyl Alcohols with N‐Heteroaromatics

N‐Methyl indole reacts with but‐2‐yn‐1‐ol in the presence of PtCl₂ in MeOH giving indole derivatives having a substituted 3‐oxobutyl group at the 3‐position in good yield. Under the reaction conditions, various substituted indoles and substituted propargyl alcohols are successfully involved in the reaction giving the corresponding addition products in good to moderate yields. The catalytic reaction can be further extended to N‐phenyl pyrrole. In the present multi‐step reaction, PtCl₂ likely plays dual roles: as the catalyst for the rearrangement of propargyl alcohols to the corresponding alkenyl ketones and as the catalyst for the addition of indoles to the alkenyl ketones. Experimental evidence is provided to support the proposed mechanism.     

Palladium‐Catalyzed Direct C2‐Arylation of an N‐Heterocyclic Carbene: An Atom‐Economic Route to Mesoionic Carbene Ligands

Blocking the C2 position of an imidazole‐derived classical N‐heterocyclic carbene (NHC) with an aryl group is an essential strategy to establish a route to mesoionic carbenes (MICs), which coordinate to the metal via the C4 (or C5) carbon atom. An efficient catalytic route to MIC precursors by direct arylation of an NHC is reported. Treatment of 1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene (IPr) with an aryl iodide (RC₆H₄I) in the presence of 0.5 mol % of [Pd₂(dba)₃] (dba=dibenzylideneacetone) precatalyst affords the C2‐arylated imidazolium salts {IPr(C₆H₄R)}I (R=H, 4‐Me, 2‐Me, 4‐OMe, 4‐COOMe) in excellent (up to 92 %) yields. Treatment of {IPr(C₆H₅)}I with CuI and KN(SiMe₃)₂ exclusively affords the MIC–copper complex [(IPrPh)CuI].     

Microreview: Pyrrol‐3‐yl squaraines (including indol‐3‐yl squaraines)

Pyrrol‐3‐yl squaraine dyes are prepared by the condensation of 3,4‐dihydroxycyclobut‐3‐ene‐1,2‐dione with two‐molar equivalence of a 2,5‐disubstituted pyrrole possessing a free β‐position, or substituted indoles with a similarly free β‐position. From the first reported syntheses of two indol‐3‐yl squaraines in 1966, numerous pyrrol‐3‐yl squaraines (including indol‐3‐yl squaraines) have been reported in both the scientific and patent literatures. This microreview highlights the synthesis, history, spectroscopy, and applications of pyrrol‐3‐yl squaraines from their first preparation to the present date.     

A facile synthesis of 4‐, 6‐ and 7‐formyl‐1H‐indole‐2‐carboxylates: The CH2SO3H functionality as a masked formyl group

The valuable new synthetic intermediates, ethyl 4‐, 6‐ and 7‐formyl‐1H‐indole‐2‐carboxylates ( 10, 11, 12 ) were prepared from 2‐ethoxycarbonyl‐1H‐indole‐4‐, 6‐ and 7‐methanesulfonic acids ( 1, 2, 3 ), respectively. The transformation of sulfomethyl group to formyl function was accomplished through elimination of SO₂ to yield ethyl 4‐, 6‐ and 7‐chloromethyl‐1H‐indole‐2‐carboxylates ( 4, 5, 6 ), hydrolysed to ethyl 4‐, 6‐ and 7‐hydroxymethyl‐1H‐indole‐2‐carboxylates ( 7, 8, 9 ), then oxidized to aldehydes ( 10, 11, 12 ). Protection at N1 of indole was not necessary. A marked increase in the rate of hydrolysis of 7‐chloromethyl‐indoles compared to that of 4‐ and 6‐(chloromethyl)indoles was observed.     

Synthesis of Functionalized Indoles with a Trifluoromethyl‐Substituted Stereogenic Tertiary Carbon Atom Through an Enantioselective Friedel–Crafts Alkylation with β‐Trifluoromethyl‐α,β‐enones

Chiral complexes of BINOL‐based ligands with zirconium tert‐butoxide catalyze the Friedel–Crafts alkylation reaction of indoles with β‐trifluoromethyl‐α,β‐unsaturated ketones to give functionalized indoles with an asymmetric tertiary carbon center attached to a trifluoromethyl group. The reaction can be applied to a large number of substituted α‐trifluoromethyl enones and substituted indoles. The expected products were obtained with good yields and ees of up to 99 %.     

Synthesis of 2‐Hydroxy‐1,4‐oxazin‐3‐ones through Ring Transformation of 3‐Hydroxy‐4‐(1,2‐dihydroxyethyl)‐β‐lactams and a Study of Their Reactivity

The reactivity of 3‐hydroxy‐4‐(1,2‐dihydroxyethyl)‐β‐lactams with regard to the oxidant sodium periodate was evaluated, unexpectedly resulting in the exclusive formation of new 2‐hydroxy‐1,4‐oxazin‐3‐ones through a C3? C4 bond cleavage of the intermediate 4‐formyl‐3‐hydroxy‐β‐lactams followed by a ring expansion. This peculiar transformation stands in sharp contrast with the known NaIO₄‐mediated oxidation of 3‐alkoxy‐ and 3‐phenoxy‐4‐(1,2‐dihydroxyethyl)‐β‐lactams, which exclusively leads to the corresponding 4‐formyl‐β‐lactams without a subsequent ring enlargement. In addition, this new class of functionalized oxazin‐3‐ones was further evaluated for its potential use as building blocks in the synthesis of a variety of differently substituted oxazin‐3‐ones, morpholin‐3‐ones and pyrazinones. Furthermore, additional insights into the mechanism and the factors governing this new ring‐expansion reaction were provided by means of density functional theory calculations.     

Reactions of 1‐(3‐aryl‐3‐oxopropenyl)azulenes and 1‐cinnamoylazulenes with malononitrile: Synthesis of 1‐(2‐aryl‐4‐pyridyl)azulenes and 1‐(4‐aryl‐2‐pyridyl)azulenes

The reactions of 1‐formyl‐3‐methoxycarbonylazulene ( 1 ) with acetophenones 3a‐e gave 1‐(3‐aryl‐3‐oxopropenyl)‐3‐methoxycarbonylazulenes 4a‐e which reacted with malononitrile in the presence of sodium methoxide to afford 1‐(2‐aryl‐4‐pyridyl)‐3‐methoxycarbonylazulenes 9a‐d , except for 4′‐nitro‐substituted compounds. Heating of the compounds 9a‐d in 100% phosphoric acid yielded 1‐(2‐aryl‐4‐pyridyl)azulenes 10a‐d . In a similar manner, 1‐(4‐aryl‐2‐pyridyl)azulenes 12a‐1 and 1‐[4‐(2‐furyl)‐ and 4‐(2‐thienyl)‐2‐pyridyl)]azulenes 14a,b were obtained.     

Synthesis and Antimicrobial Activities of Novel 2‐[substituted‐1H‐pyrazol‐4‐yl] Benzothiazoles,Benzoxazoles, and Benzimidazoles

In an endeavor to find a new class of antimicrobial agents, a series of novel substituted benzimidazole, benzoxazole, and benzothiazole derivatives 6 containing pyrazole moiety have been synthesized by reaction of 3‐aryl‐4‐formyl pyrazole 4 with substituted phenylenediamine or o‐aminophenol or o‐aminothiophenol 5 . Reaction of phenyl hydrazine or 2‐hydrazinopyridine 1 with substituted acetophenones 2 gave the corresponding hydrazones 3 , which on Vilsmeier–Haack reaction with POCl₃–DMF gave substituted 3‐aryl‐4‐formyl pyrazoles 4 . All final compounds 6a , 6b , 6c , 6d , 6e , 6f , 6g , 6h , 6i , 6j , 6k were evaluated for in vitro antibacterial activities against Escherichia coli and Staphylococcus aureus strains and in vitro antifungal activity against Candida albicans and Aspergillus niger strains by using serial dilution method. The antimicrobial activities were expressed as the minimum inhibitory concentration in µg/mL. The compound containing benzimidazole and benzoxazole moiety gave better antibacterial and antifungal activities than benzothiazole compounds.     

Competitive Gold‐Promoted Meyer–Schuster and oxy‐Cope Rearrangements of 3‐Acyloxy‐1,5‐enynes: Selective Catalysis for the Synthesis of (+)‐(S)‐γ‐Ionone and (−)‐(2S,6 R)‐cis‐γ‐Irone

We report a simple, highly stereoselective synthesis of (+)‐(S)‐γ‐ionone and (‐)‐(2S,6R)‐cis‐γ‐irone, two characteristic and precious odorants; the latter compound is a constituent of the essential oil obtained from iris rhizomes. Of general interest in this approach are the photoisomerization of an endo trisubstituted cyclohexene double bond to an exo vinyl group and the installation of the enone side chain through a [(NHC)Au^I]‐catalyzed Meyer–Schuster‐like rearrangement. This required a careful investigation of the mechanism of the gold‐catalyzed reaction and a judicious selection of reaction conditions. In fact, it was found that the Meyer–Schuster reaction may compete with the oxy‐Cope rearrangement. Gold‐based catalytic systems can promote either reaction selectively. In the present system, the mononuclear gold complex [Au(IPr)Cl], in combination with the silver salt AgSbF₆ in 100:1 butan‐2‐one/H₂O, proved to efficiently promote the Meyer–Schuster rearrangement of propargylic benzoates, whereas the digold catalyst [{Au(IPr)}₂(μ‐OH)][BF₄] in anhydrous dichloromethane selectively promoted the oxy‐Cope rearrangement of propargylic alcohols.     

Palladium‐Catalyzed Direct C2 Arylation of N‐Substituted Indoles with 1‐Aryltriazenes

A novel and efficient palladium‐catalyzed C2 arylation of N‐substituted indoles with 1‐aryltriazenes for the synthesis of 2‐arylindoles was developed. In the presence of BF₃ ? OEt₂ and palladium(II) acetate (Pd(OAc)₂), N‐substituted indoles reacted with 1‐aryltriazenes in N,N‐dimethylacetamide (DMAC) to afford the corresponding aryl–indole‐type products in good to excellent yields.     

Divergent Reactivity in Palladium‐Catalyzed Annulation with Diarylamines and α,β‐Unsaturated Acids: Direct Access to Substituted 2‐Quinolinones and Indoles

A palladium‐catalyzed C?H activation strategy has been successfully employed for exclusive synthesis of a variety of 3‐substituted indoles. A [3+3] annulation for synthesizing substituted 2‐quinolinones was recently developed by reaction of α,β‐unsaturated carboxylic acids with diarylamines under acidic conditions. In the present work, an analogous [3+2] annulation is achieved from the same set of starting materials under basic conditions to generate 1,3‐disubstituted indoles exclusively. Mechanistic studies revealed an ortho‐palladation–π‐coordination–β‐migratory insertion–β‐hydride elimination reaction sequence to be operative under the reaction conditions.     

Thermal Cyclization of Phenylallenes That Contain ortho‐1,3‐Dioxolan‐2‐yl Groups: New Cascade Reactions Initiated by 1,5‐Hydride Shifts of Acetalic H Atoms

A series of 2‐(1,3‐dioxolan‐2‐yl)phenylallenes that contained a range of substituents (alkyl, aryl, phosphinyl, alkoxycarbonyl, sulfonyl) at the cumulenic C3 position were prepared by using a diverse range of synthetic strategies and converted into their respective 1‐(2‐hydroxy)‐ethoxy‐2‐substituted naphthalenes by smooth thermal activation in toluene solution. Electron‐withdrawing groups at the C3 position accelerated these tandem processes, which consisted of 1) an initial hydride‐like [1,5]‐H shift of the acetalic H atom onto the central cumulene carbon atom; 2) a subsequent 6π‐electrocyclic ring‐closure of the resulting reactive ortho‐xylylenes; and 3) a final aromatization step with concomitant ring‐opening of the 1,3‐dioxolane fragment. If the 1,3‐dioxolane ring of the starting allenes was replaced by a dimethoxymethyl group, the reactions led to mixtures of two disubstituted naphthalenes, which were formed by the migration of either the acetalic H atom or the methoxy group, with the latter migration occurring to a lesser extent. Two of the final 1,2‐disubstituted naphthalenes were converted into their corresponding naphtho‐fused dioxaphosphepine or dioxepinone through an intramolecular transesterification reaction. A DFT computational study accounted for the beneficial influence of the 1,3‐dioxolane fragment on the carbon atom from which the H‐shift took place and also of the electron‐withdrawing substituents on the allene terminus. Remarkably, in the processes that contained a sulfonyl substituent, the conrotatory 6π‐electrocyclization step was of lower activation energy than the alternative disrotatory mode.     

Gold(III) Chloride Catalyzed Synthesis of Chiral Substituted 3‐Formyl Furans from Carbohydrates: Application in the Synthesis of 1,5‐Dicarbonyl Derivatives and Furo[3,2‐c]pyridine

This report describes a gold(III)‐catalyzed efficient general route to densely substituted chiral 3‐formyl furans under extremely mild conditions from suitably protected 5‐(1‐alkynyl)‐2,3‐dihydropyran‐4‐one using H₂O as a nucleophile. The reaction proceeds through the initial formation of an activated alkyne–gold(III) complex intermediate, followed by either a domino nucleophilic attack/anti‐endo‐dig cyclization, or the formation of a cyclic oxonium ion with subsequent attack by H₂O. To confirm the proposed mechanistic pathway, we employed MeOH as a nucleophile instead of H₂O to result in a substituted furo[3,2‐c]pyran derivative, as anticipated. The similar furo[3,2‐c]pyran skeleton with a hybrid carbohydrate–furan derivative has also been achieved through pyridinium dichromate (PDC) oxidation of a substituted chiral 3‐formyl furan. The corresponding protected 5‐(1‐alkynyl)‐2,3‐dihydropyran‐4‐one can be synthesized from the monosaccharides (both hexoses and pentose) following oxidation, iodination, and Sonogashira coupling sequences. Furthermore, to demonstrate the potentiality of chiral 3‐formyl furan derivatives, a TiBr₄‐catalyzed reaction of these derivatives has been shown to offer efficient access to 1,5‐dicarbonyl compounds, which on treatment with NH₄OAc in slightly acidic conditions afforded substituted furo[3,2‐c]pyridine.     

One‐Pot Sequential Propargylation/Cycloisomerization: A Facile [4+2]‐Benzannulation Approach to Carbazoles

A novel one‐pot [4+2]‐benzannulation approach to substituted carbazoles is accomplished by acid‐catalyzed C3‐propargylation of 2‐alkenyl/aryl indoles with 1‐aryl propargylic alcohols, followed by cycloisomerization. A variety of 2‐alkenylated indoles and 2‐aryl/heteroaryl indoles successfully participated in this tandem reaction with 1‐aryl/heteroaryl propargylic alcohols to provide diversely substituted and annulated carbazoles, as well as an aza[5]helicene.     

Intramolecular CH Activation through Gold(I)‐Catalyzed Reaction of Iodoalkynes

The cycloisomerization reaction of 1‐(iodoethynyl)‐2‐(1‐methoxyalkyl)arenes and related 2‐alkyl‐substituted derivatives gives the corresponding 3‐iodo‐1‐substituted‐1H‐indene under the catalytic influence of IPrAuNTf₂ [IPr=1,3‐bis(2,6‐diisopropyl)phenylimidazol‐2‐ylidene; NTf₂=bis(trifluoromethanesulfonyl)imidate]. The reaction takes place in 1,2‐dichloroethane at 80 °C, and the addition of ttbp (2,4,6‐tri‐tert‐butylpyrimidine) is beneficial to accomplish this new transformation in high yield. The overall reaction implies initial assembly of an intermediate gold vinylidene upon alkyne activation by gold(I) and a 1,2‐iodine‐shift. Deuterium labeling and crossover experiments, the magnitude of the recorded kinetic primary isotopic effect, and the results obtained from the reaction of selected stereochemical probes strongly provide support for concerted insertion of the benzylic C? H bond into gold vinylidene as the step responsible for the formation of the new carbon–carbon bond.