Assessment of amination reactions via nucleophilic aromatic substitution using conventional and eco-friendly energies

The efficiency of conventional heating energy source compared with Infrared (IR), Ultrasound (US), Microwave and the simultaneous combination US–IR eco-friendly approaches for preparation of new N-(5-R¹ _-amino-2-nitrophenyl)acetamides and 5-R¹-amino-2-nitroaniline by Nucleophilic Aromatic Substitution (S_NAr) via addition–elimination reactions on the halogens F, Cl, Br, I, employing amines as nucleophiles were explored. Moreover, phenyldiazenyl derivatives in good yields by an oxidative one-pot S_NAr-based amination reaction from an unusual oxidation of 2-phenylhydrazinyl derivatives in DMSO was prepared.     

Enantioselective amination of silylketene acetals with (N-arylsulfonylimino)phenyliodinanes catalyzed by chiral dirhodium(II) carboxylates: asymmetric synthesis of phenylglycine derivatives

The first catalytic enantioselective amination of silylketene acetals with (N-arylsulfonylimino)phenyliodinanes is described. The reaction of silylketene acetals derived from methyl phenylacetates with [N-(2-nitrophenylsulfonyl)imino]phenyliodinane (NsN = IPh) under the catalysis of dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], Rh₂(S-TCPTTL)₄, proceeds in benzene at room temperature to give N-(2-nitrophenylsulfonyl)phenylglycine derivatives in high yields and with enantioselectivities of up to 99% ee.     

A simple and efficient approach for the synthesis of a novel class aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives via intramolecular nucleophilic substitution reaction

In this study, we synthesized a new series of substituted aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives (6-24) in yields ranging from 42 to 70% with an interesting mechanism that involves internal nucleophilic substitution followed by an S_N2-type nucleophilic substitution. First, 1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanone (3) was synthesized from the reaction of 5-methyl-1,3,4-thiadiazole-2-thiol (1) with 2-bromo-1-(4-chlorophenyl)ethanone (2) in the presence of potassium hydroxide. Then, 1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanol (4) was synthesized by a reduction reaction of this compound using NaBH₄. Finally, 5-methyl-3-alkyl-1,3,4-thiadiazol-2(3H)-one derivatives (6-24), which are the target compounds, were synthesized from the reaction of this compound (4), which is a secondary alcohol with various alkyl halides (5a-n) in the presence of sodium hydride (NaH). This study presents an interesting reaction mechanism related to the synthesis of aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives that is not recorded in the literature.     

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.     

N- And S-Alkylation of 3-(1-Aadamantyl)-4-methyl-1,2,4-triazole-5-thiol and 2-(1-Adamantyl)-1,3,4-oxadiazole-5-thiol

ABSTRACT

-The reaction of 3-(1-adamantyl)-4-methyl-1,2,4-triazole-5-thiol 1 with certain 2-aminoethyl chlorides in alkaline medium yielded a separable mixture of the S-(2-aminoethyl) derivatives 2 and the N-(2-aminoethyl) derivatives 3. Meanwhile, alkylation of 2-(1-adamantyl)-1,3,4-oxadiazole-5-thiol 4 with 2-aminoethyl chlorides under the same conditions yielded only the S-alkyl derivatives 5. Interaction of 4 with primary or secondary amines and formaldehyde solution yielded the corresponding N-aminomethyl derivatives in high yields.     

Improved synthesis of 4-amino-7-nitrobenz-2,1,3-oxadiazoles using NBD fluoride (NBD-F)

The 7-nitrobenz-2,1,3-oxadiazole (NBD) unit is a highly useful fluorescent tag with wide application in biology. Installation of the NBD group typically proceeds via the S_NAr reaction between an amine and an NBD halide. Herein, we demonstrate that NBD-F 1 results in significantly higher yields than NBD-Cl 2, and that triethylamine in dimethylformamide at 23 °C overnight is a broadly applicable set of conditions for this reaction. In particular, the highly useful fluorescent carbohydrate 2-NBD-glucosamine (2-NBDG, 3) can now be prepared in 75% yield with NBD-F as compared to 12% with NBD-Cl.     

KF/Al2O3 as an Efficient,Green, and Reusable Catalytic System for the Solvent-Free Synthesis of N-Alkyl Derivatives of Sulfonamides via Michael Reactions

KF/Al ₂ O ₃ efficiently catalyzes the microwave-assisted Michael addition of sulfonamides to α,β-unsaturated esters under solvent-free conditions to afford N-alkyl derivatives of sulfonamides as biologically interesting compounds in high yields and in short reaction times. In this reaction, N,N-dialkylsulfonamides are also produced, but in very low yields.     

N-alkylation of 2,3-dihydroimidazo[2,1-b]quinazolin-1(10)H-5-one. On the cryptoanionic mechanism of N-substitution

Quantum chemical methods involving studies of transition states of the reaction showed that the main products of N-alkylation of prototropic 2,3-dihydroimidazo[2,1-b]quinazolin-1(10)H-5-one (1) in the gas phase and under neutral conditions in solution occurring via the S_N2 mechanism should be N(10)-alkyl-substituted derivatives formed from the 1H-tautomer. Minor N(1)-substituted derivatives in solution can be produced from both tautomers. For the alkylation of the free N-anion of compound 1, position 1 is attacked first. Validity of conclusions concerning the overall regioselectivity of the reaction was confirmed experimentally. In the absence of solvent, the alkylation proceeds abnormally with a sharp increase in the content of the 1-substituted isomers up to inversion of the regioselectivity of the reaction, which is explained by the participation in the process of the H-bonded dimer of the substrate (1a)₂, which undergoes alkylation via the cryptoanionic mechanism. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 876–887, May, 2006.     

SiO2/g-C3N4 nanocomposite-catalyzed green synthesis of di-indolyloxindols under mild conditions

In this study, a facile and benign protocol was introduced for the immobilization of SiO₂ nanoparticles onto g-C₃N₄ nanosheets. The corresponding nanocomposite (SiO₂/g-C₃N₄) was characterized by various techniques, including X-ray diffraction, transmission electron microscopy, thermo-gravimetric analysis, and Fourier transform infrared spectra. The activity of a SiO₂/g-C₃N₄ nanocomposite was investigated in C–C bond formation reaction. The Friedel–Crafts 3-indolylation reaction of isatin with indole derivatives was investigated in the presence of a catalytic amount of SiO₂/g-C₃N₄ nanocomposite at ambient temperature in water as a green medium. The results showed that the corresponding products were obtained in good to excellent yields. In addition, the electron-releasing groups in the R¹ position of the indole ring or electron-withdrawing groups on the R⁴ position of isatin gave excellent yields (91–95%). Some advantages of this method include short reaction time, excellent yields, easy work-up, and the use of water as a green solvent.

     

Enantioselective Amination of β-Keto Esters Catalyzed by Chiral Calcium Phosphates

A catalytic enantioselective amination of β-keto esters using (S)-BINOL chiral calcium phosphate has been developed. The reaction produces chiral α-amino-β-keto ester derivatives in most cases with moderate to excellent enantioselectivities (up to 99 %) and good yields (up to 99 %). This mild synthetic method highlights a low catalyst loading and high catalytic efficiency. When the substrate backbone was changed to 1-tetralone-derived β-keto esters, unexpectedly high yields of selective redox products were obtained. The practicality of the reaction was realized by a scale-up without any significant loss in the enantioselectivity and yield. Chiral calcium phosphate was successfully recovered and reused for four runs, indicating its stability and high catalytic activity.     

Selected Reaction of (Z)-Dimethyl α-(Bromomethyl) Fumarate with Secondary Amines

Regioselective reaction of (Z)-dimethyl α-(bromomethyl) fumarate 2 with bulky secondary amines in ether as solvent at room temperature, leads exclusively to the rearranged substitution α-(functional alkyl amino) acrylic esters 4a-i in high yields. The less and more bulky amine gives rise respectively to the two successive (S_N2′) and (S_N2) substitution derivatives 5j,k and 51.     

Metal-free and highly regioselective synthesis of N-heteroaryl substituted pyrazoles from α,β-unsaturated N-tosylhydrazones and heteroaryl chlorides

A cascade cyclization/nucleophilic aromatic substitution (S_NAr) reaction of α,β-unsaturated N-tosylhydrazones with N-heteroaryl chlorides was developed for the synthesis of N-heteroaryl pyrazole derivatives. This one-pot reaction provided bi(heteroaryl) derivatives in good to excellent yields and with excellent regioselectivity. The procedure is operationally simple and applicable to large-scale synthesis.     

Steric and Electronic Requirements in the Synthesis of 2,3‐Dihydro‐4(1H)‐quinolinones by the Tandem Michael‐SNAr Reaction

The steric and electronic requirements have been investigated for the synthesis of 2,3‐dihydro‐4(1H)‐quinolinones by the tandem Michael‐S_NAr reaction. Substrates bearing a single methyl group at the β‐enone carbon gave excellent yields of the title compounds from both the E and Z isomers with X═H or NO₂. Substrates with β,β‐dimethyl substitution at the Michael terminus gave low yields of heterocyclic products in molecules having monoactivated S_NAr aromatic acceptor rings (X═H) and very good yields for diactivated systems (X═NO₂). For these hindered substrates, success in the final cyclization hinges on the ability of the aromatic acceptor to capture the pendant nitrogen nucleophile of the initial Michael adduct before this intermediate can revert to starting materials.     

The reaction of biphenyl radical anion and dianion with alkyl fluorides. From ET to SN2 reaction pathways and synthetic applications

The reaction of dilithium biphenyl (Li₂C₁₂H₁₀) with alkyl fluorides has been studied from the point of view of the distribution of products. Two main reaction pathways, the nucleophilic substitution (S_N2) and the electron transfer (ET), can compete to yield the same alkylation products in what is known as the S_N2-ET dichotomy. S_N2 seems to be the main mechanism operating with primary alkyl fluorides (n-RF). Alkylation proceeds in good yields, and the resulting alkylated dihydrobiphenyl anion (n-RC₁₂H₁₀Li) can be trapped with a second conventional electrophile (E⁺) affording synthetically interesting dearomatized biphenyl derivatives (n-RC₁₂H₁₀E). The reaction gives a higher amount of ET products as we move to secondary (s-RF) and to tertiary alkyl fluorides (t-RF), in which case the mechanism seems to be dominated by ET. In this case, alkylation by radical coupling is still feasible, giving access to the synthesis of t-RC₁₂H₁₀E, although in lower yields. A rational interpretation of this S_N2-ET dichotomy is given on the basis of the full distribution of products observed when 5-hexenyl fluoride and 1,1-dimethyl-5-hexenyl fluoride were are used as radical probes in their reaction with Li₂C₁₂H₁₀ and LiC₁₂H₁₀.     

Two Different Green Catalytic Systems for One‐Pot Regioselective and Chemoselective Synthesis of Some Pyrimido[4,5‐d]Pyrimidinone Derivatives in Water

In this work, we have developed green and efficient regioselective and chemoselective syntheses of 5‐aryloyl‐1,3‐dimethyl‐7‐thioxo‐5,6,7,8‐tetrahydropyrimido[4,5‐d ]pyrimidine‐2,4(1H ,3H )‐dione and 5‐aryloyl‐1,3‐dimethyl‐2,7‐dithioxo‐2,3,5,6,7,8‐hexahydropyrimido[4,5‐d ]pyrimidin‐4(1H )‐one derivatives via one‐pot three‐component Biginelli‐like condensation of arylglyoxal monohydrates, N ,N‐dimethylbarbituric acid or N ,N‐dimethyl‐2‐thiobarbituric acid, and thiourea in water at 50°C. The presence of two different green catalytic systems (ZrOCl₂.8H₂O and also DABCO) proceeded efficiently to afford the desired products in good‐to‐excellent yields. An aqueous reaction medium, high regioselectivity and chemoselectivity, simple operation and suitable yields of products are the important features of these green protocols.     

The definition of the toxicologically relevant applicability domain for the SNAr reaction for substituted pyridines and pyrimidines

This study outlines how results from a glutathione reactivity assay (so-called in chemico data) can be used to define the applicability domain for the nucleophilic aromatic substitution (S_NAr) reaction for nitrogen-containing aromatic compounds. S_NAr is one of the six mechanistic domains that have been shown to be important in toxicological endpoints in which the ability to bind covalently to a protein is a key molecular initiating event. This study has analysed experimental data (2 h RC₅₀ values), allowing a clear and interpretable structure–activity relationship to be developed for pyridines and pyrimidines which reside within the S_NAr domain. The in-ring nitrogen(s) act as activating groups in the S_NAr reaction. The position(s) of the in-ring nitrogen(s) as well as other activating groups, especially in relationship to the leaving group, affect reactive potency. The experimentally defined applicability domain has resulted in a series of structural alerts. These results build on early work on the benzene derivatives residing in the S_NAr domain. The definition of the applicability domain for the S_NAr reaction and the resulting structural alerts are likely to be beneficial in the development of computational tools for category formation and read-across in hazard identification, and the development of adverse outcome pathways.     

SN2’ versus SN2 Reactivity: Control of Regioselectivity in Conversions of Baylis–Hillman Adducts

TiCl₄‐induced Baylis–Hillman reactions of α,β‐unsaturated carbonyl compounds with aldehydes yield the (Z)‐2‐(chloromethyl)vinyl carbonyl compounds 5 , which react with 1,4‐diazabicyclo[2.2.2]octane (DABCO), quinuclidine, and pyridines to give the allylammonium ions 6 . Their combination with less than one equivalent of the potassium salts of stabilized carbanions (e.g. malonate) yields methylene derivatives 8 under kinetically controlled conditions (S_N2’ reactions). When more than one equivalent of the carbanions is used, a second S_N2’ reaction converts 8 into their thermodynamically more stable allyl isomers 9 . The second‐order rate constants for the reactions of 6 with carbanions have been determined photometrically in DMSO. With these rate constants and the previously reported nucleophile‐specific parameters N and s for the stabilized carbanions, the correlation log k (20 °C)=s(N + E) allowed us to calculate the electrophilicity parameters E for the allylammonium ions 6 (?19<E <?18). The kinetic data indicate the S_N2’ reactions to proceed via an addition–elimination mechanism with a rate‐determining addition step.     

Nucleophilic Aromatic Substitution Reactions of meso‐Bromosubporphyrin: Synthesis of a Thiopyrane‐Fused Subporphyrin

meso‐Bromosubporphyrin undergoes nucleophilic aromatic substitution (S_NAr) reactions with arylamines, diarylamines, phenols, ethanol, thiophenols, and n‐butanethiol in the presence of suitable bases to provide the corresponding substitution products. The S_NAr reactions also proceed well with pyrrole, indole, and carbazole to provide substitution products in moderate to good yields. Finally, the S_NAr reaction with 2‐bromothiophenol and subsequent intramolecular peripheral arylation reaction affords a thiopyrane‐fused subporphyrin.     

Enantiomeric separation and detection by high-performance liquid chromatography-mass spectrometry of 2-arylpropionic acids derivatized with benzofurazan fluorescent reagents

The enantiomneric separation and the detection of 2-arylpropionic acids after derivatization with the fluorescent reagents with a benzofurazan structure, ( S )-(+)-4-( N,N -dimethylaminosulphonyl)-7-(3-aminopyrrolidin-1-yl)-2,1,3-benzoxadiazole (( S )-DBD-Apy), (R)-(-)-4-nitro-7-(3-aminopyrrolidin-1-yl)-2,1,3-benzoxadiazole (( R )-NBD-Apy), 4- N,N -dimethylaminosulphonyl-7-piperazino-2,1,3-benzoxadiazole (DBD-PZ) and N -hydrazinoformylmethyl- N -methylamino-4,4- N,N -dimethylaminosulphonyl-2,1,3-benzoxadiazole (DBD-CO-Hz) by high-performance liquid chromatography (HPLC) and electrospray ionization mass spectrometry (ESI-MS) were examined. The diastereomeric derivatization with ( S )-DBD-Apy or ( R )-NBD-Apy and the separation on the reversed phase column afforded the high sensitivity. The separation on chiral stationary phase after non-chiral derivatization with DBD-PZ or DBD-CO-Hz provided less sensitivity. The signal-to-noise ratio of ( S )-DBD-Apy-( S )-ketoprofen of 200:1 was observed for 12.5 picomole (pmol) injection and selected ion monitoring (SIM) of the quasi-molecular ion after splitting 1:7 before entering into the electrospray ion sources. As a result, the usefulness of these reagents for MS detection has been demonstrated. © 1998 John Wiley & Sons, Ltd.     

HPLC enantioseparation of α,α‐diphenyl‐2‐pyrrolidinemethanol and methylphenidate using a chiral fluorescent derivatization reagent and its application to the analysis of rat plasma

Enantioseparation of α,α‐diphenyl‐2‐pyrrolidinemethanol (D2PM) and methylphenidate (MPH; Ritalin^®) using (R)‐(?)‐4‐(N,N‐dimethylaminosulfonyl)‐7‐(3‐isothiocyanatopyrrolidin‐1‐yl)‐2,1,3‐benzoxadiazole as the chiral derivatization reagent has been achieved for the first time, and a simple, reliable detection method using HPLC with fluorescence detection has been developed. D2PM and MPH have been derivatized with (R)‐(?)‐4‐(N,N‐dimethylaminosulfonyl)‐7‐(3‐isothiocyanatopyrrolidin‐1‐yl)‐2,1,3‐benzoxadiazole at 55°C for 15 min. The derivatives of D2PM and MPH have been separated, completely and rapidly, using a reversed‐phase system within 16 min (resolution factor (R_s)=1.60 and 2.53, respectively). The detection limits of (R)‐ and (S)‐D2PM were found to be 6.8 and 13 ng/mL, respectively, and those of D ‐ and L ‐threo‐MPH were 61 and 66 ng/mL, respectively (S/N=3). The proposed method was successfully applied to the analysis of rat plasma, where the rats were separately dosed with D2PM and MPH (Ritalin).