Visible light mediated synthesis of 6H-benzo[c]chromenes: transition-metal-free intramolecular direct C-H arylation.

A synthetic approach towards the 6H-benzo[c]chromene ring under visible light and transition-metal-free conditions has been developed. Benzochromenes are synthesized from the corresponding (2-halobenzyl) phenyl ethers or (2-halophenyl) benzyl ethers using KOtBu in dimethyl sulfoxide (DMSO) at room temperature (rt) and blue light-emitting diodes (LEDs) as the light source. This methodology replaces the use of ligands or additives, high temperatures and toxic solvents. The photostimulated reaction exhibits very good tolerance to different functional groups and 5H-dibenzo[c,f]chromenes are also effectively obtained. An electron donor-acceptor complex formed by the dimsyl anion and (2-halobenzyl) phenyl ethers was found and it induces the ET as the initial step in the photocyclization reaction. Furthermore, in order to explain the regiochemical outcome of this reaction, a theoretical analysis was performed using DFT methods.

Design, Synthesis, and in†vitro Evaluation of Tubulin-Targeting Dibenzothiazines with Antiproliferative Activity as a Novel Heterocycle Building Block.

We prepared a series of free NH and N-substituted dibenzonthiazines with potential anti-tumor activity from N-aryl-benzenesulfonamides. A biological test of synthesized compounds (59 samples) was performed in vitro measuring their antiproliferative activity against a panel of six human solid tumor cell lines and its tubulin inhibitory activity. We identified 6-(phenylsulfonyl)-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide and 6-tosyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide as the best compounds with promising values of activity (overall range of 2-5.4 µM). Herein, we report the dibenzothiazine core as a novel building block with antiproliferative activity, targeting tubulin dynamics.

Transition-Metal-Free and Visible-Light-Mediated Desulfonylation and Dehalogenation Reactions: Hantzsch Ester Anion as Electron and Hydrogen Atom Donor.

Novel approaches for N- and O-desulfonylation under room temperature (rt) and transition-metal-free conditions have been developed. The first methodology involves the transformation of a variety of N-sulfonyl heterocycles and phenyl benzenesulfonates to the corresponding desulfonylated products in good to excellent yields using only KOtBu in dimethyl sulfoxide (DMSO) at rt. Alternately, a visible light method has been used for deprotection of N-methyl-N-arylsulfonamides with Hantzsch ester (HE) anion serving as the visible-light-absorbing reagent and electron and hydrogen atom donor to promote the desulfonylation reaction. The HE anion can be easily prepared in situ by reaction of the corresponding HE with KOtBu in DMSO at rt. Both protocols were further explored in terms of synthetic scope as well as mechanistic aspects to rationalize key features of desulfonylation processes. Furthermore, the HE anion induces reductive dehalogenation reaction of aryl halides under visible light irradiation.

Room-Temperature and Transition-Metal-Free Intramolecular α-Arylation of Ketones: A Mild Access to Tetracyclic Indoles and 7-Azaindoles.

A novel approach for the synthesis of tetracyclic indoles and 7-azaindoles is reported. The strategy involves four steps, with a fast rt intramolecular α-arylation of ketones as key step. The reaction was inspected synthetically to achieve the synthesis of 11 novel tetracyclic structures with moderate to very good yields (39-85%). Theoretical combined with experimental studies led us to propose a probable polar mechanism (concerted SNAr).

Photoinduced nucleophilic substitution of iodocubanes with arylthiolate and diphenylphosphanide ions. Experimental and computational approaches.

A new synthetic route to modify the cubane nucleus is reported here. Methyl-4-iodocubane-1-carboxylate (1) and 1,4-diiodocubane (2) were employed as reagents to react with arylthiolate and diphenylphosphanide ions under irradiation in liquid ammonia and dimethylsulphoxide. The reactions proceed to afford thioaryl- and diphenylphosphoryl- cubane derivatives in moderate to good yields. It is also found that the monosubstituted product with retention of the second iodine is an intermediate compound. Mechanistic aspects are supported by DFT calculations.

Initiation in Photoredox C-H Functionalization Reactions. Is Dimsyl Anion a Key Ingredient?

Previous studies have reported the arylation of unactivated arenes with ArX, base (KOtBu or NaOtBu), and an organic additive at high temperatures. Recently, we showed that this reaction proceeds in the absence of additives at rt but employs UV-vis light. However, details of mechanisms that can use a photoinduced base-promoted homolytic aromatic substitution reaction (photo-BHAS) have remained elusive until now. This work examines different mechanistic routes of the essential electron-transfer step (ET) of this reaction in order to identify a possible path for the formation of 1-adamantyl radicals from 1-haloadamantanes (initiation step). On the basis of photochemical and photophysical experiments and computational studies, we propose an unprecedented initiation step that could also be applied to other ET reactions performed in DMSO. For the first time, it is reported that dimsyl anion, formed from a strong base and DMSO (solvent), is responsible for inducing the initiation by a photo-BHAS process on alkyl halides.

Synthesis of Dibenzosultams by "Transition-Metal-Free" Photoinduced Intramolecular Arylation of N-Aryl-2-halobenzenesulfonamides.

A new and general synthetic route to prepare dibenzosultams is here reported. This approach involves the synthesis of N-aryl-2-halobenzenesulfonamides (3), followed by intramolecular C-C photoinduced arylation under soft conditions without the use of "Transition Metal". The photostimulated reactions exhibit very good tolerance to different substituent groups with good to excellent isolated yields (42-98%) of products. Moreover, it is shown that LED (λ = 395 nm) is an efficient light energy source to initiate efficiently the reactions. Theoretical inspection of the mechanism was made to probe the involvement of the radical-anion SRN1 process.

"Transition-metal-free" synthesis of carbazoles by photostimulated reactions of 2'-halo[1,1'-biphenyl]-2-amines.

An efficient and simple protocol for the preparation of a series of 9H-carbazoles by photostimulated SRN1 substitution reactions is presented. Substituted 9H-carbazoles were synthesized in low to excellent yields (up to 96%) through an intramolecular C­N bond formation of 2'-halo[1,1'-biphenyl]-2-amines by the photoinitiated SRN1 mechanism under mild and "transition-metal-free" conditions. The biphenylamines used as substrates were obtained with isolated yields ranging from 21% to 84% by two approaches: (A) the cross-coupling Suzuki­Miyaura reaction and (B) the radical arylation of anilines. Some key aspects of the proposed mechanism were evaluated at the B3LYP/6-311+G* level.

Room-temperature and transition-metal-free Mizoroki-Heck-type reaction. Synthesis of E-stilbenes by photoinduced C-H functionalization.

We report a conceptually different approach toward E-stilbene syntheses by photoinduced direct C-H arylation of alkenes at rt without the addition of transition metals, with a broad range of aryl halides, including ArI, ArBr, and even ArCl. This is the first time that this reaction has been produced without extra solvent but with 18-crown-6 ether and t-BuOK in only 15 min of reaction.

Room-temperature photoinduced direct C-H-arylation via base-promoted homolytic aromatic substitution.

Conceptually different approach toward biaryl syntheses by photoinduced direct C-H arylation of benzene and thiophene in the presence of t-BuOK is reported. The reaction proceeds through photo- and base-promoted homolytic aromatic substitution. The o-, m- and p- substituted ArI, as well as the electron-donating and electron-withdrawing nature of the substituents were found be good to excellent substrates. Heteroaryl, ArBr, ArCl and double C-H arylation were successfully achieved.

Photochemical and photophysical behavior of indolyl anions in photostimulated intramolecular arylation reactions.

O-Arylation reaction is obtained when N-(2-halophenyl) indolo carboxamides are irradiated in a basic medium. On the basis of photochemical and photophysical experiments, we propose that 2-indolylbenzoxazole is formed by intramolecular electron transfer followed by fast dehalogenation of the halophenyl radical anion pendant moiety, finally a radical-radical collapse renders the observed product.

Synthesis of 6-substituted 2-pyrrolyl and indolyl benzoxazoles by intramolecular O-arylation in photostimulated reactions.

The synthesis of a series of 6-substituted 2-pyrrolyl and 2-indolyl benzoxazoles by photostimulated C-O cyclization of anions from 2-pyrrole carboxamides, 2-indole carboxamides, or 3-indole carboxamides has been found to proceed in good to excellent yields (41-100%) in DMSO and liquid ammonia. The pyrrole and indole carboxamides are obtained in good to very good isolated yields by an amidation reaction of different 2-haloanilines with 2-carboxylic acid of pyrrole and 2- or 3-carboxylic acid of indole. To explain the regiochemical outcome of these reactions (C-O arylation vs C-N or C-C arylation), a theoretical analysis was performed using DFT methods and the B3LYP functional.

Synthesis of benzo-fused heterocycles by intramolecular α-arylation of ketone enolate anions.

A two-step synthesis of six-, seven-, eight-, and nine-member benzo-fused heterocycles in good to excellent yields is reported. The synthetic strategy involves the generation of a new intramolecular α-aryl ketone bond by the photostimulated S(RN)1 reaction of ketone enolate anions linked to a pendant haloarene as the key step. On the other hand, an intramolecular C(Ar)-C(Ar) coupling led to the formation of five- and six-member benzo-fused heterocycles (9H-carbazole and phenanthridine) when an aromatic amide anion is competitively formed.

Synthesis of carbolines by photostimulated cyclization of anilinohalopyridines.

A general synthetic route to prepare all four carboline regioisomers by photostimulated cyclization of anilinohalopyridines is described. The methodology affords various substituted carbolines in good to excellent yields. In the case of α-carbolines, the S(RN)1 methodology complements previously reported palladium-catalyzed cyclization approaches.

Synthesis of pyrrole and indole quinoxalinone and oxazinone derivatives by intramolecular copper-catalyzed reactions.

Intramolecular N-arylation of pyrrole and indole carboxamides and carboxylates linked with a pendant haloarene by Cu-catalyzed reactions to synthesize pyrrole and indole quinoxalinone and oxazinone derivatives is reported. The ring closure reactions were carried out by conventional heating and MW irradiation. The use of conventional heating affords moderate to good yields of the quinoxalinone and oxazinone derivatives (34-72%), while by using MW heating the best results are obtained (41-99%).

Short access to 6-substituted pyrimidine derivatives by the S(RN)1 mechanism. Synthesis of 6-substituted uracils through a one-pot procedure.

The synthesis of 6-substituted 2,4-dimethoxypyrimidines with different nucleophiles was accomplished with good to excellent yields (50-95%) through S(RN)1 reactions, starting from commercially available 6-chloro-2,4-dimethoxypyrimidine (1). Hydrolysis of these derivatives gave access to 6-substituted uracils with good yields and short times by the use of microwave irradiation. The preparation of uracils from 1 without the isolation of 2,4-dimethoxypyrimidine derivatives affords a rapid access to these compounds in good yields and excellent purity by avoiding an unnecessary step of purification.

Electron-transfer-mediated synthesis of phenanthridines by intramolecular arylation of anions from N-(ortho-halobenzyl)arylamines: regiochemical and mechanistic analysis.

The synthesis of a series of substituted phenanthridines by photostimulated C-C cyclization of anions from N-(ortho-halobenzyl)arylamines has been found to proceed in very good to excellent yields (79-95%) in liquid ammonia and in DMSO. The N-(ortho-halobenzyl)arylamines are obtained in good to very good isolated yields (44-85%) by nucleophilic substitution of ortho-halobenzylchlorides with different arylamines. The reaction of the anions of a diverse set of N-(ortho-halobenzyl)arylamines was studied, and the methodology was extended to the synthesis of trispheridine, a natural product, in very good yield. In order to explain the regiochemical outcome of these reactions, a theoretical analysis was performed with DFT methods and the B3LYP functional.

Synthesis of carbazoles by intramolecular arylation of diarylamide anions.

The synthesis of a series of substituted 9H-carbazoles by the photostimulated S(RN)1 substitution reaction with diarylamines as starting substrate was performed. The diarylamines were obtained by two approaches, the Pd-catalyzed reactions (Buchwald-Hartwig) or Cu-catalyzed reactions of 2-haloanilines with aryl halides, or 2-bromoiodobenzene with anilines, with moderate to very good isolated yields (45-89%). Through an intramolecular C-C bond formation of diarylamines by the S(RN)1 mechanism, carbazoles were achieved. These reactions proceeded synthetically in very good to excellent yields (81-99%) in liquid ammonia and DMSO. The reaction of N-(2-bromophenyl)-2-phenylbenzenamine gave 1-phenyl-9H-carbazole (38%) and the isomer 9H-tribenz[b,d,f]azepine (58%). By using this methodology, 9H-carbazoles, substituted 9H-carbazoles, benzocarbazoles, and even 3,3'-bi(9H-carbazole) were obtained by a double S(RN)1 reaction with benzidine.

A novel approach to the synthesis of 6-substituted uracils in three-step, one-pot reactions.

From the commercial 6-chloro-2,4-dimethoxypyrimidine (1) and by a photostimulated reaction with Me(3)Sn(-) ions, 2,4-dimethoxy-6-(trimethylstannyl)pyrimidine (2) was obtained in 95% yield. By the cross-coupling reaction of 2 with 1-iodonaphthalene as electrophile catalyzed by Pd (Stille reaction), 2,4-dimethoxy-6-(naphthalen-1-yl)pyrimidine (9) was obtained in 76% yield. By hydrolysis of 9, 6-(1-naphthyl)uracil was obtained in 98% of isolated yield. When the three steps (S(RN)1 reaction-cross coupling reaction-hydrolysis) were performed in a one-pot reaction, 6-substituted uracils (1-naphthyl, 4-chlorophenyl, 3-chlorophenyl, 2,3,4,5,6-pentafluorophenyl) were obtained (43-57%) of isolated pure products. When the electrophile was a benzoyl chloride, 6-benzoyl uracil (54%) and 6-(2-chlorobenzoyl) uracil (49%) were obtained in isolated pure products.

Syntheses of aporphine and homoaporphine alkaloids by intramolecular ortho-arylation of phenols with aryl halides via SRN1 reactions in liquid ammonia.

The photostimulated intramolecular ortho-arylation reactions of bromoarenes linked with pendant phenoxy containing N-substituted tetrahydroisoquinolines in liquid ammonia afforded aporphine (54-82% yield) alkaloid derivatives via SRN1 reactions. This strategy was extended for the first time to the synthesis of a homoaporphine derivative (40% yield). Tetrahydroisoquinoline precursors that contained electron-withdrawing groups on nitrogen (i.e., amides, sulfonamides, and carbamates) gave cyclized products, whereas precursors with basic nitrogens (i.e., NH or NMe) either failed to yield cyclized products or gave aporphines in only low yield.