Nucleophilic reactivities of indoles

The kinetics of the coupling of indole (1a), N-methylindole (1b), 5-methoxyindole (1c), and 5-cyanoindole (1d) with a set of reference benzhydryl cations have been investigated in acetonitrile and/or dichloromethane. The second-order rate constants for the reactions correlate linearly with the electrophilicity parameter E of the benzhydryl cations. This allows the determination of the reactivity parameters, N and s, characterizing the nucleophilicity of 1a-d according to the linear free enthalpy relationship log k(20 degrees C) = s(N + E) (Acc. Chem. Res. 2003, 36, 66). The nucleophilicity parameters thus defined describe nicely the reactions of 1a-d with 4,6-dinitrobenzofuroxan (2), a neutral superelectrophilic heteroaromatic whose electrophilicity (E) has been recently determined. On this ground, the kinetics of the coupling of 2 with a large variety of indole structures have been studied in acetonitrile, leading to a ranking of this family of pi-excessive carbon nucleophiles over a large domain of the nucleophilicity scale N. Importantly, two linear and parallel correlations are obtained on plotting the measured N values versus the pK(a)(H(2)O) values for protonation at C-3 of 5-X-substituted indoles and 5-X-substituted 2-methylindoles, respectively. This splitting reveals that the presence of the 2-methyl group causes steric hindrance to the approach of 2 from the adjacent C-3 position of an indole structure. The N vs pK(a)(H(2)O) correlation for 5-X-substituted indoles is used for a rapid determination of the C-3 basicity of indoles whose acidity constants cannot be measured through equilibrium studies in strongly acidic aqueous media.     

Conical intersection control of heterocyclic photochemical bond scission

The photochemistry of the heterocycle 5,6-dihydro-1-methyl-5,5-diphenylpyridin-2(1H)-one (compound 1 in the text) leads to two competitive reactions (the reactions are depicted in the Introduction to the article). These arise from fission of bond a, between the nitrogen (N-6) and C-1, and bond b, between C-4, with the two phenyl substituents, and C-5, adjacent to the nitrogen. Scission of bond a alone leads to a zwitterionic intermediate which can be trapped by nucleophiles, while cleavage of bonds a and b together affords two fragments--a ketene and an imine. The ketene could be intercepted with nucleophiles and the imine trimerized. Computation reveals little weakening of bonds a and b. But as stretching begins, conical intersections are encountered, leading to ground-state products.     

Utility of N‐[4‐(N‐Substituted Sulfamoyl)Phenyl] Cyanothioformamides in the Synthesis of Heterocyclic Compounds

The novel cyanothioformamides 2a‐d were prepared by treatment of isothiocyanatosulfonamides 1a‐d with potassium cyanide at room temperature. Cyclocondensation of compounds 2b,c with phenyl isocyanate as electrophile furnished the corresponding imidazolidines 3a,b . The reactivity of compound 3a towards some nitrogen nucleophiles was investigated. Thus, the thiosemicarbazone 4 and imidazo[4,5‐b]quinoxaline 6 were synthesized by condensation of compound 3a with thiosemicarbazide and o‐phenylenediamine, respectively. Treatment of 3a with hydrochloric acid afforded compound 7 . Our investigation was extended to include the reactivity of cyanothioformamide 2 towards o‐aminophenol, anthranilic acid, and o‐phenylenediamine and yielded the corresponding heterocycles 9 , 11 and 13 derivatives, respectively. Structures of the synthesized compounds were established by their elemental analysis and spectral data.     

Origins of regioselectivity in the reactions of alpha-lactams with nucleophiles. Two distinct acid-catalyzed pathways involving O- and N-protonation

Sterically stabilized alpha-lactams react by two distinct acid-catalyzed pathways. Protonation on oxygen results in nucleophilic attack at the acyl carbon and gives C-2 products. Protonation on nitrogen leads to nucleophilic attack at the C-3 carbon and yields C-3 products. The mechanism thus developed is very useful for understanding the changes in rates and product distributions in the reactions of sterically stabilized alpha-lactams with nucleophiles. It can also be extrapolated to other alpha-lactams so that a more coherent picture of alpha-lactam reactivity can be developed.     

S(N)/S(N)' competition: selective access to new 10-fluoro artemisinins

In this paper, we report a simple route to accede to a new family of C-10 fluorinated derivatives of artemisinin 7. We demonstrated that nucleophilic substitution of the allylic bromide 6 with alcohols can occur at carbon 10 (compounds 7) under solvolytic conditions (S(N)'/S(N) ratio, 87:13). Furthermore, using the particular properties of hexafluoroisopropanol (HFIP), we are able to increase the selectivity of the substitution. Primary alcohols are completely selective for allylic substitution. With amines as nucleophiles, selectivity of substitution is dependent on their nucleophilicity, but attack at carbon 16 was always favored. However, the S(N)'/S(N) ratio could be slightly increased by adding HFIP, which is able to modulate their nucleophilicity through hydrogen bonding. In preliminary in vitro assessments, these new compounds, 7, exhibited a satisfying activity against malaria.     

An extremely highly electrophilic heteroaromatic structure: 4,6-dinitrotetrazolo[1,5-a]pyridine

A detailed thermodynamic and kinetic investigation of the reactions of 4,6-dinitrotetrazolo[1 ,5-a]pyridine (DNTP) with water and methanol has been made in the corresponding solvents. In aqueous solution, covalent addition of water to DNTP occurs with the exclusive formation of an anionic hydroxy sigma-complex C-4a which is half-formed in a 0.4 M HCl solution (pKa(sigma) = 0.4). This corresponds to a 3 pK-units jump in thermodynamic stability from the most stable hydroxy sigma-complex known so far, i.e. the hydroxy adduct C-3a of 4,6-dinitrobenzofuroxan (DNBF). DNTP forms similarly a very stable methoxy sigma-complex C-4b in methanol (pKa(sigma) = 2.64). Interestingly, the addition of methanol to DNTP also results in the partial formation of a neutral carbinolamine-type adduct (C-5b) at low pH. Rate and equilibrium constants pertaining to most of the reaction pathways involved in the interactions have been determined. In particular, the following rate constants k1(H2O) and k1(MeOH) for formation of C-4a and C-4b have been measured: k1(H2O) = 1.93 s(-1); k1(MeOH) = 3.50 s(-1), to be compared with k1(H20) = 0.035 s(-1); k1(MeOH) = 0.030 s(-1) for sigma-complexation of DNBF under similar experimental conditions. Altogether, the results obtained reveal that DNTP is a considerably more powerful electrophile than DNBF, the common reference as to whether an electron-deficient aromatic or heteroaromatic substrate may be accorded superelectrophilic properties in addition or substitution processes.     

Synthesis of acyclic nucleosides and other C-1 substituted alditols from carbohydrates using a tandem alkoxyl radical β-fragmentation–nucleophilic addition

The oxidative β-fragmentation of alkoxyl radicals generated from easily available carbohydrates is an efficient methodology to obtain acyclic nucleosides and other C-1 substituted alditols. In the reaction conditions an oxycarbenium ion is generated, which can be trapped by a variety of oxygen, carbon and nitrogen nucleophiles, in good yields and stereoselectivities.     

Nucleophilicity and solvent effects on the kinetics of 4-(pyren-1-yl)thiazol-2-amine interaction with 4,6-dinitrobenzofuroxan

A multistep synthesis of novel pyrene-based thiazole moiety been has been realized following some synthetic challenges and complications. The chemical structure of the synthesized compound has been established on the basis of both spectroscopic and analytical tools. Its nucleophilic reactivity with 4,6-dinitrobenzofuroxan (DNBF) has been successfully studied in solution. A kinetic study of the covalent electrophile/nucleophile combination of dinitrobenzofuroxan (DNBF, electrophile) and 4-(pyren-1-yl)thiazol-2-amine (nucleophile) resulting in the formation of the corresponding σ-adduct in solution is reported. The rate constant (k₁) of the second-order relating to the CC bond forming step of this complexation process has been found to fit into the linear correlation log k = s_N (N + E), thereby permitting the evaluation of the nucleophilicity parameter (N) of the 4-(pyren-1-yl)thiazol-2-amine. 4-(Pyren-1-yl)thiazol-2-amine has been subsequently ranked according to its reactivity profile on the general nucleophilicity scale developed recently by Mayr et al., leading to an interesting and direct comparison over a large domain of π-, σ-, and n-nucleophiles.     

Enaminones in heterocyclic synthesis: Synthesis and chemical reactivity of 3‐anilino‐1‐substituted‐2‐propene‐1‐ one

The 3‐anilinoenones 3a,b were prepared from the corresponding 3‐dimemyl‐aminopropenones. The reactivity of 3a,b towards a variety of carbon and nitrogen nucleophiles as well as naphthoquinones is reported.     

Evidence for the intermediacy of Wheland-Meisenheimer complexes in SEAr reactions of aminothiazoles with 4,6-dinitrobenzofuroxan

Reactions of DNBF with a series of 2-aminothiazoles (1 a-f) to afford thermodynamically stable C-bonded sigma-adducts have been investigated in acetonitrile. A most significant finding emerged on recording NMR spectra immediately after mixing of equimolar amounts of DNBF and the unsubstituted 2-aminothiazole (1 a) in Me2SO: namely, that the formation of 9 a is preceded by that of a short-lived intermediate species X. From the 1H NMR parameters characterizing this intermediate, as well as the dependence of its lifetime on the experimental conditions-the presence of excess DNBF over 1 a increases the lifetime of X while an excess of base (1 a) accelerates its conversion into 9 a--it is convincingly demonstrated that the structure of X combines the presence of a positively charged Wheland complex moiety (with regard to the thiazole ring) with that of a negatively charged Meisenheimer complex moiety (with regard to the benzofuroxan system). So far, only one intermediate of this type (noted WM) has been successfully characterized, in the reactions of DNBF with 1,3,5-tris(N,N-dialkylamino)benzenes. Among the key features supporting the intermediacy of X along the reaction coordinate leading to 9 a is the fact that the reactions of DNBF with 1 a in the presence of an alcohol (MeOH, EtOH, nPrOH) produce new adducts arising from the addition of an alcohol molecule to the thiazole moiety of WM-1 a. Reflecting the presence of three chiral centres, these species are formed as mixtures of several diastereomers that could all be characterized in their racemic forms in ethanol. These findings generalize the previous report on the formation of Wheland-Meisenheimer carbon-carbon complexes in homocyclic series.     

Assessing the nucleophilic character of 2-amino-4-arylthiazoles through coupling with 4,6-dinitrobenzofuroxan: Experimental and theoretical approaches based on structure-reactivity relationships

A kinetic study of the reactions of potentially bioactive 2-amino-4-arylthiazoles with highly reactive 4,6-dinitrobenzofuroxan (DNBF) is reported herein in acetonitrile solution. The complexation reaction was followed by recording the UV–vis spectra with time at λ_max = 482 nm. Electronic effects of substituents influencing the rate of reaction have been studied using structure-reactivity relationships. It is shown that the Hammett plot relative to the reaction of DNBF with 2-amino-4-(4-chlorophenyl)thiazole exhibit positive deviation from the log k₁ versus σ correlation, while it showed excellent linear correlation in terms of Yukawa–Tsuno equation. It has be noticed that the nonlinear Hammett plot observed for 2-amino-4-(4-chlorophenyl) thiazole is not attributed to a change in rate-determining step but is due to nature of electronic effect of substituent caused by the resonance of stabilization of substrates. The second-order rate constant (k₁) relating to the bond C–C and C-N forming step of the complexation processes of DNBF with 4-substituted-aminothiazoles and 2-amino-5-methyl-4-phenylthiazole, respectively, is fit into the linear relationship log k = s_N (N + E), thereby permitting the assessment of the nucleophilicity parameter (N) of the 2-amino-4-arylthiazoles of the range (4.90 < N < 6.85). 2-amino-4-arylthiazoles is subsequently ranked by positioning its reactivity on the general nucleophilicity scale developed recently by Mayr and coworkers (2003) leading an interesting and a direct comparison over a large domain of π-, σ -, and n-nucleophiles. The global electrophilicity/nucleophilicity reactivity indexes of the 2-amino-4-arylthiazoles have been investigated by means of a density functional theory (DFT) method. .     

Access to Vinyl Ethers and Ketones with Hypervalent Iodine Reagents as Oxy-Allyl Cation Synthetic Equivalents

We report an Umpolung strategy of enol ethers to generate oxy-allyl cation equivalents based on the use of hypervalent iodine reagents. Under mild basic conditions, the addition of nucleophiles to aryloxy-substituted vinylbenziodoxolone (VBX) reagents, easily available in two steps from silyl alkynes, resulted in the stereoselective formation of substituted aryl enol ethers. The reaction was most efficient with phenols as nucleophiles, but preliminary results were also achieved for C- and N- nucleophiles. In absence of external nucleophiles, the 2-iodobenzoate group of the reagent was transferred. The obtained aryl enol ethers could then be transformed into α-difunctionalized ketones by oxidation. The described “allyl cation”-like reactivity contrast with the well-established “vinyl-cation” behavior of alkenyl iodonium salts.     

A new general method of α-amino-alkylation

N-(1-p-Toluenesulphonyl-alkyl) amides, which are readily prepared from a aldehyde, an amide and sodium p-toluenesulphinate, are versatile α-amido-alkylating agents for sulphur nitrogen and carbon nucleophiles.     

A novel free C-12 higher carbon sugar: asymmetric synthesis and reactivity with nucleophiles

A novel C-12 higher carbon sugar, (1R)-(1,4:3,6-dianhydro-d-mannitol-2-yl)-1,4:3,6-dianhydro-d-fructose, was firstly synthesized via a convenient aldol reaction of 1,4:3,6-dianhydro-d-fructose without any protection and activation of functional groups. The reactivity of the novel higher sugar with nucleophiles was also studied, through which a series of oxazolidines and other derivatives of the higher sugar were available. The study showed that the higher sugar possesses a highly reactive carbonyl group and a good stereo controlling ability in the reaction.     

Convenient synthesis of novel sulfonamide derivatives as promising anticancer agents

Novel sulfonamide derivatives have been synthesized from the readily accessible N-(4-acetylphenyl)benzenesulfonamide (1) . Condensation of 1 with phenylhydrazine in refluxing ethyl alcohol gave the corresponding phenylhydrazone 2 , which was then added to the Vilsmeier-Haack reagent (POCl₃/DMF) to give the 4-formylpyrazole derivative 3 . Fusion of 1 with thiourea in the presence of iodine at 130°C afforded the 2-aminothiazole derivative 4 . Refluxing 1 with an excess of N, N-dimethylformamide dimethyl acetal furnished the enaminone 5 . The chemical reactivity of enaminone 5 toward some nitrogen and carbon nucleophiles has been studied to obtain polyfunctionalized heteroaromatic systems bearing a sulfonamide moiety. Besides, the enaminone 5 undergoes the Gewald reaction and reacts with ethyl cyanoacetate and elemental sulfur in the presence of morpholine to yield the 2-aminothiophene derivative 18 . Moreover, the utility of 5 for the synthesis of 4-(phenylsulfonamido)benzoic acid (19) was investigated. The synthesized sulfonamides were evaluated for their in vitro cytotoxic activities against two human cell lines, MCF-7 (breast adenocarcinoma cells) and RPE-1 (normal retina pigmented epithelium cells). The results revealed that compounds 1-3 , 6-8 , 10 , 12b , 18 , 19 , and 21 have a potent cytotoxic effect on MCF-7 and less on RPE-1 cells compared to the positive control doxorubicin®.     

Hydrogen bonding lowers intrinsic nucleophilicity of solvated nucleophiles

The relationship between nucleophilicity and the structure/environment of the nucleophile is of fundamental importance in organic chemistry. In this work, we have measured nucleophilicities of a series of substituted alkoxides in the gas phase. The functional group substitutions affect the nucleophiles through ion-dipole, ion-induced dipole interactions and through hydrogen bonding whenever structurally possible. This set of alkoxides serves as an ideal model system for studying nucleophiles under microsolvation settings. Marcus theory was applied to analyze the results. Using Marcus theory, we separate nucleophilicity into two independent components, an intrinsic nucleophilicity and a thermodynamic driving force determined solely by the overall reaction exothermicity. It is found that the apparent nucleophilicities of the substituted alkoxides are always much lower than those of the unsubstituted ones. However, ion-dipole, ion-induced dipole interactions, by themselves, do not significantly affect the intrinsic nucleophilicity; the decrease in the apparent nucleophilicity results from a weaker thermodynamic driving force. On the other hand, hydrogen bonding not only stabilizes the nucleophile but also increases the intrinsic barrier height by 3 to approximately 4 kcal mol (-1). In this regard, the hydrogen bond is not acting as a perturbation in the sense of an external dipole but more directly affects the electronic structure and reactivity of the nucleophilic alkoxide. This finding offers a deeper insight into the solvation effect on nucleophilicity, such as the remarkably lower reactivities in nucleophilic substitution reactions in protic solvents than in aprotic solvents.     

The half-wave oxidation potential as a criterion for estimating the reactivity of anionic nucleophiles

It was shown that the oxidation E_1/2 can be used as the criterion for estimating the nucleophilicity of different anions. This approach was also suitable for estimating the nucleophilic reactivity of nonanionic nucleophiles. A linear correlation was found between the difference in the halfwave oxidation potentials of the nucleophiles and reduction of electrophiles (δE_1/2) and the kinetics of the S_N2 reaction involving them.     

Regio- and stereoselectivity of the addition of O-, S-, N-, and C-nucleophiles to the beta vinyl oxirane derived from D-glucal

6-O-Trityl- (1a) and 6-(O-benzyl)-substituted epoxide (1b) derived from D-glucal were examined in their addition reactions with O-, C-, N-, and S-nucleophiles. A 1,4-regio- and beta-stereoselective or an anti 1,2-addition pathway is commonly observed depending on the ability of the nucleophile to coordinate with the oxirane oxygen. When TMSN(3) or LiN(3) are used as azide-based nucleophiles, a 1,2-syn-addition pathway is also observed.     

Synthesis and Structural Assignment of 1-O-Acetyl-2,3,5-tri-O-benzoyl-4-(thymin-1-yl)-α-l-lyxofuranose

Abstract

Analogues of nucleosides in which the nucleobase is fixed onto the C-4 of the sugar moiety are generally prepared either from 4,5-unsaturated sugar derivatives or via a formaldehyde condensation.¹ We tested the furanosyl bromide reactivity of 1 ² towards a series of nucleophiles, mostly azides or cyanides, without success. Conversely, the nucleosidation of 1 using 5-methyl-2,4-bis(trimethyl-silyloxy)pyrimidine in the presence of stannic chloride took place at the second anomeric position (C-4) and led to the isolation in acceptable yield (47%) of a unique anomer 2 (Scheme 1).     

Über Reaktionen von Alkylbiguaniden mit Benzoin beimpH der Biguanidbasen

Summary Alkylbiguanides2 a–e react with benzoin (1) at thepH of the base in different ways.1 undergoes in presence of2 a, c oxidation to benzoic acid which reacts with the bases2 a, c to yield 4-phenyl-1,3,5-triazinamines3 c, 4 c; in presence of2 b 1 is transformed to benzil, which reacts with2 b under rearrangement to yield 1-(4-oxo-5,5-diphenyl-2-imidazolin-2-yl)-3,3-dimethylguanidine (5 b). However, the cycloalkylbiguanides2 d, e, react in presence of nitrogen as well as oxygen with1 to yield piperidine-1-[N-(4,5-diphenylimidazol-2-yl)-carboxamidine] (7 d), resp. morpholine-4-[N-(4,5-diphenylimidazol-2-yl)-carboxamidine] (7 e). The structure of7 e was established by means of an X-ray structure analysis. All proton- and carbon resonances were assigned on the basis of 2-dimensional NMR data.