A simple,efficient, regioselective and one-pot preparation of N-hydroxy- and N–O-protected hydroxyindoles via cycloaddition of nitrosoarenes with alkynes. Synthetic scope,applications and novel by-products

The thermal reaction between nitrosoarenes and alkynes under alkylating conditions produces N-alkoxyindoles as the major products in moderate to good yields and excellent regioselectivity. Various electrophiles are used affording different N–O-protected hydroxyindoles in a multi-component fashion. Privileged acetylenic substrates used in reactions with substituted nitrosoarenes are arylalkynes or propiolates. Potentially bioactive compounds and other classes of highly functionalizable indole products were prepared. Reactions between o-carbomethoxy-nitrosoarenes and arylacetylenes provided tricyclic compounds containing an acylaziridine indoline skeleton.     

A convenient CeCl3·7H2O/NaI-promoted synthesis of structurally novel and strained tricyclic β-lactams from hydrazines

A convenient synthetic protocol for structurally novel and strained highly derivatized tricyclic β-lactams has been developed. The synthesis involves CeCl₃·7H₂O/NaI catalyzed addition-condensation of mercaptoacetic acid and N-aroyl-N′-arylidenehydrazines followed by intramolecular cyclodehydration to afford bicyclic 5H-thiazolo[4,3-b][1,3,4]-oxadiazoles, which on treatment with acid chlorides in the presence of triethylamine furnish highly derivatized tricyclic 3H-azetidino[2,1-b]-thiazolo[3,4-d][1,3,4]-oxadiazol-6-ones in 80-93% yields. The process presents an excellent illustration of Ce(III)-catalyzed C-C, C-N and C-S bond formation in a one-pot procedure.     

Chiral N-phosphonyl imine chemistry: asymmetric 1,2-additions of allylmagnesium bromides

Chiral N-phosphonyl homoallylic amines were synthesized by the reaction of allylmagnesium bromide with chiral N-phosphonyl imines. The C₂-symmetric chiral N-phosphonyl group was optimized for this reaction. Excellent yields and good diastereoselectivities were obtained for eight examples.     

[3+2] Cycloaddition of metal-containing azomethine ylides for highly efficient synthesis of mitosene skeleton

Efficient synthesis of tricyclic indole derivatives bearing a substituent at the 3-position of the indole nucleus was achieved by the [3+2] cycloaddition reaction of transition metal-containing azomethine ylides derived from N-(o-alkynylphenyl)imines with vinyl ethers. Third-row transition metal complexes, especially PtCl₂, turned out to be highly efficient for the reaction of internal alkynes and imidate substrates with wide generality. Moreover, as strong support for the reaction mechanism, the intermediate Pt-carbene complex was found to undergo intramolecular C-H bond insertion reaction to give tetracyclic indoline derivatives when benzyl vinyl ether was employed as a dipolarophile. This protocol provided a facile synthesis of highly functionalized tricyclic indole derivatives found as the basic skeleton of the mitosene family, such as mitomycin C.     

The use of N-sulfenylimines in the β-lactam synthon method: Staudinger reaction, oxidation of the cycloadducts and ring opening of β-lactams

Selected N-sulfenylimines act as good nucleophilic partners in the Staudinger reaction with methoxy- and benzyloxy-ketenes. The choice of diisopropylethylamine as a non-nucleophilic Lewis base for the generation of ketenes from acid chlorides is a determining factor for the success of the reaction. N-Sulfenyl-β-lactams are obtained in good to excellent yields and with moderate cis/trans diastereoselectivity. Then, they are quantitatively and selectively transformed to N-sulfinyl- or N-sulfonyl-β-lactams, by adjusting the oxidation state of the sulfur atom. The oxidation process induces an inversion of polarity of the nitrogen atom's substituent and allows a subsequent smooth ring opening by reaction of N-thiolated-β-lactams with various nucleophiles. The overall sequence provides straightforward and efficient route to highly functionalized-β-amino acid derivatives.     

Visible light photoredox catalysis with N-hydroxyphthalimide for [4+2] cyclization between N-methylanilines and maleimides

An efficient [4+2] cyclization of N-methylanilines with maleimides to afford tetrahydroquinolines using N-hydroxyphthalimide as a metal-free and cheap organophotoredox catalyst is reported. The protocol involves C(sp³)H activation of N-methylanilines for the formation of α-amino radical without an oxidant at room temperature. The present method describes an easy preparation of tricyclic heterocycles in good to excellent yields under mild reaction conditions.     

Convergent multicomponent assembly of 2-acyloxymethyl thiazoles

Diverse substituted 2-acyloxymethyl thiazoles can be assembled by a new multicomponent reaction (MCR) of methyl 3-(N,N-dimethylamino)-2-isocyanoacrylate, aldehydes and thiocarboxylic acid under Lewis acid catalysis. The reaction is performed under mild conditions and is compatible with a wide range of functionalized starting materials. 13 examples are given.     

Regioselective lipase-catalysed γ-monoamidation of d-glutamic acid diesters: effect of the N-protecting group

N-Blocked-d-glutamic acid diethylesters are γ-regioselectively amidated in a reaction catalysed by Candida antarctica lipase B, carried out in an anhydrous organic solvent. The ratio of γ:α-monoamides, as a measure of regioselectivity, depends on the N-protecting group present in the substrate. In the examples reported in this work, we have found that γ:α ranges from about four (N-group=Cbz) to 35 (N-group=isobutyryl). No diamides were detected.     

Proline-mediated formation of novel chroman-4-one tetrahydropyrimidines

Novel tricyclic N-benzylated chroman-4-one tetrahydropyrimidine derivatives have been prepared through a multi-component reaction between various 2-substituted chroman-4-one derivatives, N-methylenebenzylamine and a catalytic amount of proline under mild reaction conditions. The tricyclic structure of 1a was determined by NMR spectroscopy and confirmed by X-ray crystallography. An additional product, 2a, was isolated from the reaction mixture and its structure and conformation were determined by a combination of theoretical (Monte Carlo conformational search) and NMR-based (NOE and ³J_HH couplings) conformational analysis. The NMR analysis revealed one preferred geometry for 1a and 2a in CHCl₃ solution.     

Isocyanide based multicomponent reactions of oxazolidines and related systems

N-Alkyloxazolidines react in a multicomponent reaction with carboxylic acids and isocyanides to give N-acyloxyethylamino acid amides. The previously reported reaction conditions were improved using a design of experiments approach (DoE). Under the optimised conditions, good yields of the N-acyloxyethylamino acid amide products are obtained both via a three- or four-component approach from N-alkylethanolamines, aldehydes/ketones, isocyanides and carboxylic acids. The reaction of oxazolidines without a nitrogen substituent was found to give either the expected Ugi products or the N-acyloxyethylamino acid amides depending on the choice of reaction conditions. Optimised reaction conditions were also developed for the ring-expansion of oxazolidines to morpholin-2-ones via reaction with an isocyanide followed by hydrolysis. The mechanistic pathway of the multicomponent reaction was briefly investigated using an ¹⁸O labelling experiment. The carboxylic acid component can be replaced by a range of other acidic nucleophiles including thiobenzoic acid, thiophenol or 5-phenyltetrazole, which are incorporated via an alternative pathway. These latter reactions can also be applied to 2-aminotetrahydrofurans, 2-aminotetrahydropyrans or 4-hydroxybut-2-one, further extending the structural diversity of the multicomponent reaction products.     

Synthesis of a 1,3,4,5-tetrahydrobenzindole β-ketoester

Pd(OAc)₂-catalyzed decomposition of ethyl 2-diazo-4-(4-indolyl)-3-oxobutanoate leads to a tricyclic tetrahydrobenzindole compound formed by a formal C-H insertion reaction. This tricyclic indole rearranges to a novel and thermodynamically more stable naphthalene derivative. Treatment of N-tosyl-protected ethyl 2-diazo-4-(4-indolyl)-3-oxobutanoate with a base induces facile pyrazole formation.     

Palladium-catalyzed highly regioselective and stereoselective arylation of electron-rich allylamines with aryl bromides

A palladium-catalyzed, highly efficient Heck arylation of electron-rich N,N-diprotected allylamine derivatives with a wide range of aryl bromides under ligand-free conditions has been developed. In the presence of Pd(OAc)₂ and an appropriate additive, the reaction proceeds with excellent regioselectivity and stereoselectivity, leading exclusively to the γ-arylated (E)-allylamine products in good to excellent yields. It was found that the choice of solvent, olefin, additive and temperature has an important influence on the reaction. Worthy of note is that good results were observed only when using N,N-diprotected allylamines containing carbamate moiety, and the steric properties of allylamines also have important impacts on the regiocontrol. The use of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) or HQ (hydroquinone) as the additive is also crucial for securing a faster reaction rate. This method provides a straightforward approach for the efficient synthesis of various γ-arylated, linear (E)-allylamines.     

Nitration of 2,3-dihydroimidazo[1,2-a]benzimidazole and its N 9-substituted derivatives

7-Nitro-2,3-dihydroimidazo[1,2-a]benzimidazole and its N9-substituted derivatives can be conveniently synthesized by nitration of the corresponding tricyclic precursors with a nitrating mixture or with the HNO3 /CF3COOH system. This reaction occurs fairly smoothly and with good regioselectivity.     

Sequential Baylis-Hillman reaction and radical cyclization of furanose derivatives: expeditious approach to enantiopure benzo-fused nine-membered oxacycles

A regioselective 9-endo-trig aryl radical cyclization of d-glucose derived diastereomeric Baylis-Hillman reaction products with Bu₃SnH led to highly functionalized tricyclic benzannulated ethers incorporating cis- and trans-9,5 bicyclic systems in good yields. Degradation of one of the products afforded an enantiopure multifunctionalized benzoxonine derivative.     

Synthesis of tricarbonyl(N-methylisatin)chromium(0) and an unanticipated transformation of a N-MEM to a N-MOM group

The synthesis of tricarbonyl(N-methylisatin)chromium(0) (6) was achieved by protection of the keto functionality of the ligand as an acetal followed by complexation with tricarbonyl(naphthalene)chromium(0) and subsequent deprotection with formic acid. In order to obtain a removable substituent at nitrogen, N-methoxyethoxymethyl (N-MEM) substituted isatin 12 was prepared. Upon acetalization with trimethylformiate in methanol under acidic reaction conditions the corresponding methoxymethyl (N-MOM) derivative was unexpectedly obtained. This substitution was highly accelerated by microwave irradiation. Complexation of the N-MEM and N-MOM substituted isatin afforded only poor yields. The addition of vinylmagnesium bromide at 6 takes place not only at the keto group but also at the lactam carbonyl group. Divinylation at either one of the carbonyl functions was also achieved with the product distribution being highly dependent on the reaction time.     

Lewis acid-catalyzed Friedel-Crafts/Michael cascade reaction of N,N-dialkyl-3-vinylanilines with N-tosylaziridines for the stereoselective synthesis of highly functionalized tetrahydroisoquinolines

A Lewis acid-catalyzed Friedel-Crafts/Michael cascade reaction between N-dialkyl-3-vinylanilines and N-tosylaziridines has been developed for the stereoselective synthesis of tetrahydroisoquinolines (THIQs). The reaction using Gd(OTf)₃ as the Lewis acid catalyst was tolerant to the various N-dialkyl-3-vinylaniline and N-tosylaziridine substrates and provided access to 28 new, highly functionalized THIQs in typically high yields with moderate- to- excellent diastereoselectivities.     

Asymmetric Allylation of Ketones and Subsequent Tandem Reactions Catalyzed by a Novel Polymer‐Supported Titanium–BINOLate Complex

By using a novel, simple, and convenient synthetic route, enantiopure 6‐ethynyl‐BINOL (BINOL=1,1‐binaphthol) was synthesized and anchored to an azidomethylpolystyrene resin through a copper‐catalyzed alkyne–azide cycloaddition (CuAAC) reaction. The polystyrene (PS)‐supported BINOL ligand was converted into its diisopropoxytitanium derivative in situ and used as a heterogeneous catalyst in the asymmetric allylation of ketones. The catalyst showed good activity and excellent enantioselectivity, typically matching the results obtained in the corresponding homogeneous reaction. The allylation reaction mixture could be submitted to epoxidation by simple treatment with tert‐butyl hydroperoxide (TBHP), and the tandem asymmetric allylation epoxidation process led to a highly enantioenriched epoxy alcohol with two adjacent quaternary centers as a single diastereomer. A tandem asymmetric allylation/Pauson–Khand reaction was also performed, involving simple treatment of the allylation reaction mixture with Co₂(CO)₈/N‐methyl morpholine N‐oxide. This cascade process resulted in the formation of two diastereomeric tricyclic enones in high yields and enantioselectivities.     

An unusual Mannich type reaction of tertiary aromatic amines in aqueous micelles

An efficient, unusual Mannich type reaction of tertiary aromatic amines, formaldehyde and 1,3-dicarbonyl compounds is described in aqueous micelles catalyzed by boric acid to afford dialkylaminoarylated 1,3-dicarbonyls. In this unusual Mannich type reaction, tertiary aromatic amines react with formaldehyde to generate an N-alkyl-N-(4-methylenecyclohexa-2,5-dienylidene)alkylaminium intermediate (aza quinone methide), which undergoes nucleophilic addition with 1,3-dicarbonyl compounds. The reaction is highly regioselective, and exclusively para functionalized products are formed in high yields.     

Palladium-catalyzed ortho-olefination of 2-arylpyrrolidines: A tool for increasing structural complexity in nitrogen heterocycles

The dual role of the (2-pyridyl)sulfonyl unit as directing functionality and readily removable N-protecting group has enabled an efficient and practical transformation of 2-arylpyrrolidine derivatives into more complex tricyclic frameworks via palladium-catalyzed ortho-olefination with electron deficient alkenes and subsequent cyclization upon N-deprotection under mild conditions. The key cross coupling step in the presence of N-fluoro-2,4,6-trimethylpyridinium triflate ([F+]) as the terminal oxidant is both highly efficient and tolerant to a variety of steric and electronic changes at both coupling partners. By adequate choice of reductive conditions, the N-sulfonyl deprotection can be directed to the selective formation of benzo-fused pyrrolizidine or fused pyrrolidino-benzazapine frameworks.     

Pd-catalyzed reactions on pyridinium N-heteroarylaminides. Step-by-step synthesis of 3,5-unsymmetrically disubstituted 2-aminopyridines

Suzuki-Miyaura cross-coupling processes on N-pyridinium bromoazinyl aminides allow access to 3,5-disubstituted N-alkyl-2-aminopyridines. The synthetic pathway involves a regioselective bromination of pyridinium N-(pyridin-2-yl)aminide and a subsequent reaction with boronic acids to afford monosubstituted aminides in good yields. An additional bromination in the 5-position of the pyridine ring followed by a coupling reaction gives pyridinium N-(3,5-diarylpyridin-2-yl)aminides. Finally, a regioselective alkylation on the exo-nitrogen and reduction of the N-N bond yields highly substituted 2-aminopyridines.