Intramolecular Ritter Reaction Research Articles

Dearomative electrophilic spirocyclization via the intramolecular Ritter reaction: Diastereoselective access to hydrogenated spiroindolenines

Dearomative electrophilic spirocyclization via the intramolecular Ritter reaction: Diastereoselective access to hydrogenated spiroindolenines

Convenient Access to Ferrocene Fused aza-Heterocycles via the Intramolecular Ritter Reaction: Synthesis of Novel Racemic Planar-Chiral 3,4-Dihydroferroceno[c]pyridines and 1H-Ferroceno[c]pyrroles

An efficient and easy approach to the synthesis of novel racemic planar-chiral 3,4-dihydroferroceno[c]pyridines and 1H-ferroceno[c]pyrroles via the intramolecular Ritter reaction of 2-ferrocenyl-3,3-dimethylbutan-2-ol with nitriles and thiocyanates in the presence of MeSO3H was developed. Aromatic and aliphatic nitriles, phenylacetonitriles, and β-oxonitriles produced exclusively 3,4-dihydroferroceno[c]pyridines. The condensation of 2-ferrocenyl-3,3-dimethylbutan-2-ol with various thiocyanates, including alkyl thiocyanates, benzyl thiocyanate, and ethyl 2-thiocyanatoacetate, yielded not only 3,4-dihydroferroceno[c]pyridines but also 1H-ferroceno[c]pyrroles. The selectivity of these reactions depended on the temperature and the order of addition. The size of substituents at the α-position to the sulfur atom of thiocyanates also had a significant effect on the distribution of products.

Ritter-based glycoconjugation of amino acids and peptides—access to novel glycoconjugates displaying a β-amide linkage between amino acid and sugar moiety

β-Peptidic- d- gluco-, d- galacto-, and l- fuco-configured glycosyl amino acids can be prepared from the corresponding 2-deoxy-oct-3-ulopyranosonic acids via a one-pot intramolecular Ritter reaction. Initially, a ketopyranoside-based acid condenses under Lewis acid promoted conditions with nitriles (PhCN, MeCN) and a partially protected diamino ester (Boc-DAB- O- t-Bu, Boc-Orn- O- t-Bu) to form a β-peptidic glycosyl amino t-butylesters. The glycosyl amino t-butylesters can be converted into Fmoc-protected glycosyl amino acids that are suitably protected for solid-phase glycopeptide synthesis. Furthermore, replacement of the protected diamino ester by immobilized peptide amines permits post-synthetic N-terminal- and N(ε)-glycoconjugation of peptides on the solid phase.

Access to Unnatural Glycosyl Amino Acid Building Blocks via a One-Pot Ritter Reaction

α-d-Galacto-2-deoxy-oct-3-ulopyranosonic acids, α-d-gluco-2-deoxy-oct-3-ulopyranosonic acids and α-l-galacto-2,8-dideoxy-oct-3-ulopyranosonic acids can be converted into unnatural glycosyl amino acids via a one-pot intramolecular Ritter reaction. Initially, a ketopyranoside-based acid condenses under Lewis acid-promoted conditions with a nitrile (benzonitrile or acetonitrile) and a partially protected diamino ester (Boc-DAB-Ot-Bu, Boc-Orn-Ot-Bu) to form unnatural glycosyl amino esters. The resulting glycosyl amino esters are useful building blocks for solid-phase glycopeptide synthesis. For example, the glycosyl amino acid derived by condensation of α-d-galacto-2-deoxy-oct-3-ulopyranosonic acid with benzonitrile and DAB was used to replace serine in the potent opioid peptide sequence H2N-Tyr-d-Thr-Gly-Phe-Leu-Ser-CONH2.

An Unexpected Result in an Intramolecular Ritter Reaction Induced by Triflic Anhydride.

AbstractFor Abstract see ChemInform Abstract in Full Text.

An unexpected result in an intramolecular Ritter reaction induced by triflic anhydride

The treatment of the methyl 2-(cyanoethyl)-1-hydroxy-2-indane-carboxylate 1b in dichloromethane solution with triflic anhydride at 20°C afforded the tricyclic enone 3 in 65% yield, instead of the expected lactam 2b produced under the ‘classic’ conditions of the Ritter reaction.

Synthesis of cis‐Fused Hexahydro‐4aH‐indeno[1,2‐b]pyridines via Intramolecular Ritter Reaction and Their Conversion into Tricyclic Analogues of NK‐1 and Dopamine Receptor Ligands.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of a 56 component library of sugar beta-peptides.

Many biological processes of vital importance are triggered by the molecular recognition of small carbohydrate units by proteins and receptors thus leading to the belief that carbohydrates could act as candidates for the design of new drugs. We have developed a new useful synthetic approach, which can be applied in a combinatorial manner, giving access to 1,1-di-substituted pyrans projecting amide side chains in both the alpha- and beta-directions. Thus, treatment of the readily accessible hemiketal (1) with TFA followed by trimethylsilyl trifluoromethanesulfonate (TMSOTf) in the presence of a nitrile gives dihydrooxazinones (2) via a new type of modified intramolecular Ritter reaction. The dihydrooxazinones (2) can either be isolated or used directly in reactions with a broad variety of amines. Final deprotection furnishes the 1,1-di-substituted sugar beta-peptides having the general structure (4).

Synthesis of cis-fused hexahydro-4a H-indeno[1,2- b]pyridines via intramolecular Ritter reaction and their conversion into tricyclic analogues of NK-1 and dopamine receptor ligands

Indanol intermediates prepared via Michael addition of 1-indanone β-ketoester and acrylonitrile, followed by Grignard reaction of the ketone group, were submitted to an intramolecular Ritter reaction to produce cis-fused methyl 2-oxo-9b-phenyl-1,2,3,4,5,9b-hexahydro-4a H-indeno[1,2- b]pyridine-4a-carboxylates with 4a,9b-diangular substitution pattern. Further transformation of the bridgehead ester group and the lactam function afforded constrained tricyclic analogues of some monocyclic piperidine NK-1 antagonists and of a bicyclic dopamine receptor ligand.

Insights into regioselective oxy (-O-) and imino (-NH-) group insertions of 3-nortricyclanone.

Lactam 4-azatricyclo[3.2.1.0(2,7)]octan-3-one (16a) was proven to be formed in a previously reported reaction that claimed production of lactam 3-azatricyclo[3.2.1.0(2,7)]octan-4-one (17a). In a related reaction, bicyclo[3.1.0]hex-2-ene-endo-6-carbonitrile (15), lactam (16a), and novel hydroxycarbonitriles 19-21 were selectively formed when 3-nortricyclanone (1) was treated with aqueous hydroxylamine-O-sulfonic acid (HOSA). Since nitrile 15 neither hydrolyzed nor underwent intramolecular Ritter reaction under these conditions, mechanisms involving Beckmann rearrangement of 3 to nitrilium ion 9 (normal) and Beckmann fragmentation of 3 to cation 8 (abnormal) were investigated using semiempirical calculations. When alkaline HOSA was employed, lactams 16a and 17a were formed in a 1:2 ratio, perhaps via oxaziridine 6a. A similar selectivity was observed using an NH(3)/NaOCl reagent solution, which afforded lactone 4-oxatricyclo[3.2.1.0(2,7)]octan-3-one (16b) in addition to both lactams. Consequently, the Baeyer-Villiger oxidation of 1 with NaOCl gave 16b exclusively. Finally, the Schmidt reaction of ketone 1 gave only the lactam 17a, via cyclopropyl migration, and the same fragmentation products obtained from the acidic HOSA reaction. Migration selectivities are rationalized in terms of nucleofugacity, electronic effects, cyclopropyl regulation, and MO theory.

Cis-Fused hexahydro-4a H-indeno[1,2- b]pyridines: transformation of bridgehead ester group and conversion to tricyclic analogues of NK-1 and dopamine receptor ligands

The bridgehead ester group of cis-fused methyl 2-oxo-9b-phenyl-1,2,3,4,5,9b-hexahydro–4a H-indeno[1,2- b]pyridine-4a-carboxylates obtained via an intramolecular Ritter reaction, was transformed into acid, alcohol, aldehyde, and amine groups. Further elaboration afforded conformationally constrained tricyclic analogues of NK-1 antagonists and a bicyclic dopamine receptor ligand.

Diastereoselective intramolecular Ritter reaction: generation of a cis-fused hexahydro-4aH-indeno[1,2-b]pyridine ring system with 4a,9b-diangular substituents.

Indanol intermediates 5, prepared via Michael addition of 1-indanone beta-ketoester and acrylonitrile followed by reduction or Grignard reaction of the ketone group, were submitted to intramolecular Ritter reaction using various acid reaction conditions to produce tricyclic lactams 4. This cis-fused hexahydro-4aH-indeno[1,2-b]pyridine ring system, substituted at both angular positions 4a and 9b, provides access to constrained analogues of non-peptide NK(1)-antagonists with monocyclic piperidine structure.

Zeolite-Catalyzed Isomerization of Aromatic Amines to Methyl-Aza-Aromatics

The scope and mechanism of the isomerization of arylamines to methyl-substituted aromatic heterocycles have been studied. Aniline, toluidines, naphthylamines and m-phenylenediamine all reacted to the corresponding ortho-methyl-substituted aza-aromatics when exposed to high NH3 pressure and elevated temperature in the presence of acid catalysts. Zeolites with a three-dimensional pore structure, especially H-ZSM-5, showed the best performance. Optimum reaction conditions are around 600 K and 10 MPa. Two mechanisms which had been proposed earlier for this apparent N-ortho C exchange reaction proved untenable. Neither incorporation of the N atom into the aromatic ring nor a mechanism based on an intramolecular Ritter reaction could explain the required high NH3 pressure or the product distribution. Two new mechanisms are proposed which can explain all observations. In both mechanisms, reaction starts with addition of NH3 to the arylamine, followed by ring opening. In one mechanism an alkyno-imine intermediate is formed; in the other mechanism an enamino-imine intermediate is formed through a reverse aldol reaction. In both cases ring closure and NH3 elimination lead to the required aromatic heterocycles. The high NH3 pressure is explained by the need to add NH3 to the aromatic ring, and the high temperature by the need to desorb NH3 from the acid sites.

Cycloaromatization ofα-oxoketene dithioacetals with lithioacetonitrile and lithiopropionitrile: a facile route to substituted and annelated pyridines

The enolacetals 2 obtained by 1,2-addition of lithioacetonitrile or lithioprop- ionitrile to α-Oxoketene dithioacetals 1 undergo intramolecular Ritter reaction accompanied with 1,3-MeS shift in the presence of phosphoric acid to afford a variety of substituted and annelated 2,6-bis(methylthio)pyridines 3 and 4 respectively in good yields. Cyclization of 2 in the presence of bromine and acetic acid yielded the corresponding 2-bromo-6- methylthio-4,5-substituted and annelated pyridines 9 in good yields. The bis(methylthio) groups in 3 could either be removed with Raney Nickel or replaced by methyl group in the presence of triphenylphosphine-Nickel chloride complex to afford the corresponding desulphurized (8) or methylated (15) pyridines in good yields. Attempted cyclization of enolacetals 2a, 2p and 2s in the presence of borontrifluoride etherate and methanol yielded only the dienes 14a-b and β-cyanomethyl-α,β -unsaturated ester 14c respectively.

Configurations of Substituted 5-Cyanosorbic Acids. An Intramolecular Ritter Reaction

Configurations of Substituted 5-Cyanosorbic Acids. An Intramolecular Ritter Reaction