Ritter Reaction Research Articles

Synthesis and Analgesic Activity of 3,3-Dialkyl-Substituted Drotaverine Analogs

Ritter reactions of 3,4-(R1)2-benzylcyanides with 1,1-(R2)2-2-[3,4-(R3)2-phenyl]ethanols synthesized 1-[3,4-(R1)2-benzyl]-3,3-(R2)2-6,7-(R3)2-3,4-dihydroisoquinolines (R1 = H, MeO, EtO; R2 = Alk; R3 = MeO, EtO). The obtained isoquinolines can be considered 3,3-dialkyl-substituted analogs of drotaverine. Aseries of benzo[f]isoquinolines were similarly prepared. Hydrochlorides of all isoquinolines were tested for analgesic activity. Ten of thirteen compounds were active in the hot-plate test. Four of them exhibited an analgesic effect in the acetic-acid-induced writhing test. The most active isoquinoline had R1 = MeO, R2 = Et, and R3 = EtO and inhibited acetic-acid-induced cramps by 71.01%. An analysis of the structure—activity relationship study showed that the analgesic effect was not related to variation of the R1 radical but was typical of structures with an ethoxy group on the isoquinoline ring. The effect increased upon substitution of ethyl for methyl groups (R2 radical) in the isoquinoline 3-position.

Highly Efficient Synthesis and Acaricidal and Insecticidal Activities of Novel Oxazolines with N-Heterocyclic Substituents.

Nitrogen heterocycles are found in numerous natural products, pharmaceuticals, and pesticides. Herein, we report the design and synthesis of a series of novel 2,4-diphenyl-1,3-oxazolines bearing various N-heterocyclic substituents via a 4-(4-(chloromethyl)phenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxazole intermediate generated by a modified Ritter reaction. Evaluation of the activities of the oxazolines against carmine spider mites (Tetranychus cinnabarinus) by means of a leaf-dipping method showed that most of the compounds exhibited good to excellent larvicidal and ovicidal activities. In particular, five compounds (one with a phthalimidyl group and four with a substituted indolyl group) have lower LC50 values than the commercial acaricide etoxazole (0.088 mg/L against larvae and 0.128 mg/L against eggs). This work lays a foundation for the development of novel acaricides.

Tropylium-promoted Ritter reactions.

The Ritter reaction used to be one of the most powerful synthetic tools to functionalize alcohols and nitriles, providing valuable N-alkyl amide products. However, this reaction has not been frequently used in modern organic synthesis due to its employment of strongly acidic and harsh reaction conditions, which often lead to complicated side reactions. Herein, we report the development of a new method using salts of the tropylium ion to promote the Ritter reaction. This method works well on a range of alcohol and nitrile substrates, giving the corresponding products in good to excellent yields. This reaction protocol is amenable to microwave and continuous flow reactors, offering an attractive opportunity for further applications in organic synthesis.

Ultrasonic Synthesis and Characterization of Organic–Inorganic Nafion/Layered Double Hydroxide Nanohybrids and the Application in Ritter Reaction

It is desired to develop a catalytic system for Ritter reaction with the green and fast method, this work designed and synthesized intercalated nafion in layered double hydroxide (LDH) by the ultrasonic method and applied for Ritter reaction of benzyl alcohols with nitriles in water as a green solvent under ultrasonic condition.

Synthesis of Cage Acylamino Derivatives in Nitric Acid Medium

An efficient procedure has been developed for the synthesis of secondary amides by the Ritter reaction of cage substrates with a wide series of nitriles in fuming nitric acid and its mixtures.

Organo-redox-catalysis for the difunctionalization of alkenes and oxidative Ritter reactions by C–H functionalization

Roll over transition metals-triarylamines are redox-catalysts, enabling olefin difunctionalization and C–H functionalization reactions by activating benzoyl peroxide.

Recent advances of Ritter reaction and its synthetic applications

This review provides a comprehensive survey of Ritter reactions from 2014 to 2020.

Recent Applications of Ritter Reactions in Organic Syntheses

AbstractThe Ritter reactions are an important Classes of organic reactions in the synthesis of heterocycles and linear amides. Ritter reaction products are pyridine, quinazolinone, and other heterocyclic structures, which have different biological activities such as antibacterial and antivirous application from 2017 to 2020. Furthermore, the Ritter reaction in the synthesis of linear amides is evaluated from 2015 to 2020 in this review. Linear amides are essential components in drug molecules which are difficult to synthesize by conventional methods but can be synthesized through the Ritter reaction.

Ionic liquid catalyzed Ritter reaction/Pd-catalyzed directed Ortho-arylation; facile access to diverse libraries of biaryl-amides from Aryl-nitriles

Diverse libraries of biaryl-amides bearing N-t-butyl and N-adamantyl groups were synthesized in two steps by the Ritter reaction of aryl-nitriles, using tBuOH and AdaOH as carbocation precursors, and employing [BMIM(SO3H)][OTf] (neat or with [BMIM][PF6] as co-solvent) or tetramethyl guanidinium-ILs [TMG][X] (X = CF3COO, EtOSO3) as dual catalyst/solvent, followed by a Pd-catalyzed directed regioselective orthoCH arylation of the Ritter amides with Ar-X (X = I, Cl). The feasibility to perform the two-steps in sequence is also demonstrated, and potential for recycling/reuse of the ILs is also shown. Preference for [Pd] coordination to the amide carbonyl versus amide nitrogen is borne out by DFT computations.

Synthesis of 1,3-Oxazine Derivatives Based on (–)-Isopulegol using the Ritter Reaction and Study of their Analgesic Activity

The Ritter reaction between monoterpenoid (–)-isopulegol and nitriles in the presence of concentrated sulfuric acid or trifluoromethanesulfonic acid yielded a series of chiral 1,3-oxazine derivatives. When studying the analgesic activity of the synthesized compounds in vivo, it was found that 1,3-oxazine synthesized by the reaction of (–)-isopulegol with benzyl cyanide increases the time of latency of the animal in the hot plate test of thermal pain irritation, not inferior in effectiveness to the comparison drug diclofenac sodium.

Synthesis of N-benzylidene- and N-alkylidene(3,3-dialkyl-3,4-dihydroisoquinolin-1(2H)-ylidene)acetohydrazides via the Ritter reaction

The Ritter cyclocondensation of 2-methyl-1-phenylpropan-2-ols with cyanoacetohydrazide hydrazones in PhMe–H2SO4 medium at 60–70°С for 20 min resulted in the formation of N-benzylidene- and N-alkylidene(3,3-dialkyl-3,4-dihydroisoquinolin-1(2H)-ylidene)-acetohydrazides. The product of β-C-carbamoylation of the enamine moiety was also obtained.

A convenient synthesis of N-tert-butyl amides by the reaction of di-tert-butyl dicarbonate and nitriles catalyzed by Cu(OTf)2

The utility of Cu(OTf)2 as the catalyst for the synthesis of a series of N- tert-butyl amides in excellent isolated yields via the reaction of nitriles (alkyl, aryl, benzyl, and furyl nitriles) with di- tert-butyl dicarbonate is described. Cu(OTf)2 is a highly stable and efficient catalyst for the present Ritter reaction under solvent-free conditions at room temperature.

Route Evaluation and Ritter Reaction Based Synthesis of Oxazoline Acaricide Candidates FET-II-L and NK-12

Clean synthetic processes are essential for industrial production of bioactive molecules. In this study, we explored several routes for the synthesis of acaricide candidates FET-II-L and NK-12 with...

Effective approach to a synthesis of fluorine-containing 4-acylamino-4,5,6,7-tetrahydrobenzisoxazoles

On the example of synthesis of 4-acetylamino-3-fluoroalkyl(aryl)-4,5,6,7-tetrahydro-1,2-benzisoxazoles, the effective approach to a synthesis of novel 4-acylamino-4,5,6,7-tetrahydro-1,2-benzisoxazoles is proposed. 3-Fluoroalkyl(aryl)- 6,7-dihydro-1,2-benzisoxazol-4-ones were reduced by a sodium borohydride in isopropanol to obtain 3-fluoroalkyl(aryl)- 4,5,6,7-tetrahydro-1,2-benzisoxazol-4-ols that in the conditions of the Ritter reaction (acetonitrile, acetic acid, sulfuric acid) gave target 4-acylamino derivatives with 80–94 % yields.

Antiproliferative activities of tricyclic amides derived from β-caryophyllene via the Ritter reaction against MDA-MB-231 breast cancer cells.

A library of novel tricyclic amides has been synthesised via the Ritter reaction from β-caryophyllene 1 and its monoepoxy derivative 4. The compounds were assessed for antiproliferative activities against the aggressive MDA-MB-231 breast cancer cell line. Of the synthesised compounds, eight were active. 3c and 6b were the most potent and inhibited proliferation with IC50 of 9.7 and 8.2 μM, respectively. Mechanistic studies revealed differences in their antiproliferative actions. 6b inhibited cell cycle progression and induced predominantly apoptotic cell death. In contrast, 3c did not affect cell cycle kinetics and favoured necrotic over apoptotic pathways. Screening against mammalian cells (VERO cells) indicates that 3c and 6b were more active towards MDA-MB-231 cells than noncancerous cells. Facile synthesis and biological results suggest that these caryophyllene derived amides are viable lead compounds for further development.

Au‐Catalyzed Stereoselective Ritter Reaction of Haloalkynes with Nitriles for (Z)‐β‐Halogenated Enamides

An efficient and stereoselective protocol has been developed for the synthesis of (Z)‐β‐halogenated enamide through gold catalyzed Ritter reaction. In the presence of 2 mol% BrettPhosAuCl and 2 mol% AgNTf2, a broad range of nitriles smoothly underwent Ritter reaction with aromatic, vinylic or aliphatic haloalkynes to give structurally diverse (Z)‐β‐halogenated enamides in excellent to good yields.

Studies of radical homopolymerization of N-(4-iodo-1,3-diphenylbutyl) acrylamide

N-(4-iodo-1,3-diphenylbutyl) acrylamide (NIAM) is a potential hydrophobic monomer for preparation of hydrophobically modified polyacrylamide largely used for enhanced oil recovery. Moreover, it has an iodine group as substitute allowing further modification reactions. This monomer was synthesized via Ritter reaction as described in the literature and characterized by nuclear magnetic resonance (NMR), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). DSC analysis of monomer showed two endothermic peaks referring to the melting points of a mixture of diastereoisomers. Conventional radical homopolymerization of NIAM was investigated, and the polymer was characterized by NMR, TGA, DSC and size-exclusion chromatography. The polymerization was successfully performed only in the presence of large amounts of radical initiator 2,2′-azobis(2-methylpropionitrile) (AIBN) suggesting an iodine transfer polymerization mechanism. The polymer showed low degree of polymerization, dispersity lower than 1.1 and glass transition temperature of 19.5 °C.

Nitration reactions of conjugated compounds employing lithium nitrate and trifluoroacetic anhydride

Tandem nitration and Ritter reaction of three conjugated dienes using trifluoroacetyl nitrate in acetonitrile led predominantly to 1,4-addition products and concomitant N-nitration. The major products, N-nitro-N-(4-nitrobut-2-enyl)acetamide derivatives, were obtained in 57%–70% yield. Tandem nitration and Ritter reaction of 4-methylpent-3-en-2-one led to the 1,2-addition product, a base-sensitive α-nitroketone. Nitration of N-methylacetamide and pyrrolidine by trifluoroacetyl nitrate occurs on the N-atom, whereas nitration of N-phenylacetamide occurs on the aromatic ring.

Approaches to primary tert-alkyl amines as building blocks

Primary tert-alkyl amines include analogues of amantadine, a fragment commonly linked to pharmacophoric groups to enhance biological activity. The preparation of primary tert-alkyl amines is considered to be a difficult problem. Four synthetic procedures, some of which have been previously reported for the synthesis of amines with primary (RCH2NH2) or secondary (RR'CHNH2) alkyl and/or aryl groups, were tested for the synthesis of primary tert-alkyl amines (RR′R″CNH2) in aliphatic series including adamantane adducts. These procedures included the formation and reduction of tert-alkyl azides, the Ritter reaction in standard and modified conditions, the addition of organometallic reagents to N-tert-butyl sulfinyl ketimines and one-pot reactions between nitriles and organometallic reagents in the presence of a Lewis acid, Τi(iPrO)4 or CeCl3. These synthetic routes are unexplored for primary tert-alkyl amines. Studies on the synthetic routes for primary tert-alkyl amines are currently lacking. The reaction conditions and substrate limitations were studied for each procedure, with the first procedure being the most general and applicable also for compounds bearing bulky adducts.

Synthesis of Arylamides via Ritter-Type Cleavage of Solid-Supported Aryltriazenes.

A novel route for the synthesis of N-arylamides via the cleavage of aryltriazenes with alkyl or aryl nitriles is presented. We developed a variation of the Ritter reaction that allows the use of acetonitrile as solvent and reagent in reactions with solid-supported precursors. The reaction was optimized for the generation of N-aryl acetamides using a diverse range of immobilized building blocks including o-, m-, and p-substituted aryltriazenes. The cleavage via the Ritter-type conversion was combined with an on-bead cross-coupling reaction of halogen-substituted aryltriazenes with pyrazoles. Additionally, the synthesis of on-bead generated arylboronic ester-substituted triazenes was shown. The developed procedure was further expanded to use other commercially available nitriles, such as acrylonitrile, benzonitrile, and chlorinated alkyl nitriles as suitable reagents for a Ritter-type cleavage of the prepared triazene linkers.