Synthesis of New Crown Ethers Containing Appended Pyridine, 10-hydroxybenzoquinoline, 8-hydroxyquinoline and 2-amino-1-hydroxybiphenyl Sidearms

Twelve crown ethers containing one or two arms were synthesized. Two methods were used to attach arms to the azacrown ethers. Ligands 4 - 12 were prepared by a nucleophilic substitution of secondary macrocyclic amine functions on RX ( X=bromide or tosylate groups). Ligands 13 - 15 were obtained via a Mannich reaction of secondary macrocyclic amines with 5-chloro-8-hydroxyquinoline or a substituted-phenol. Diaza-18-crown-6 was treated with 2-bromomethyl-9-methyl-1,10-phenanthroline at the same conditions in which 4 - 8 and 10 - 12 were prepared. In this case, the main product was the diazacrown ether containing one arm. Twelve new aza-crown ethers bearing aromatic and aliphatic side arms were prepared by nucleophilic substitution by secondary macrocyclic amine functions on halide or tosylates or via a Mannich reaction of the macrocyclic secondary amines with phenolic compounds. R=derivatives of pyridine, 8-hydroxyquiniline, and 1-hydroxybiphenyl. Crown ether include aza-15-crown-5 diaza-18-crown-6 diazatrithia-15 (and 16)-crown-6 and diaza-21-crown-7     

Nucleophilic substitution at the imidoyl carbon atom: intermediate mechanistic and reactivity behavior between carbonyl and vinyl carbon substitution.

Gas-phase nucleophilic substitution reactions at the imidoyl carbon have been investigated using chloride exchanges, Cl- + RY=CHCl right harpoon over left harpoon RY=CHCl + Cl- with Y = N and R = F, H or CH3, at the MP2, B3LYP and G2(+) levels using the MP2/6-311+G geometries. The results are compared with those for the vinyl (Y = CH) and carbonyl (Y = O) carbon substitution. The mechanism and reactivity of substitution at the imidoyl carbon are intermediate between those of carbonyl (SNpi) and vinyl carbon (SNsigma) substitution, which is directly related to the electronegativity of Y, CH < N < O. The prediction of competitive SNsigma with SNpi path for the imidoyl chloride is consistent with the S(N)1-like mechanism proposed for reactions in solution. The important factors in favor of an in-plane concerted SN2 (SNsigma) over an out-of-plane pi-attack (SNpi) path are (i) lower proximate sigma-sigma* charge-transfer energies (DeltaECT), (ii) stronger electrostatic stabilization (DeltaENCT), and (iii) larger lobe size on C(alpha) for the sigma*- than pi*-LUMO despite the higher sigma* than pi* level. The electron correlation energy effects at the MP2 level are overestimated for the relatively delocalized structure (S(N)pi TS) but are underestimated for the localized structure (SNsigma TS) so that the MP2 energies lead to a wrong prediction of preferred reaction path for the vinyl chloride. The DFT at the B3LYP level predicts correct reaction pathways but overestimates the electron correlation effects.     

Scope and mechanism of formal S(N)2' substitution reactions of a monomeric imidozirconium complex with allylic electrophiles

The zirconium imido complex Cp2(THF)Zr=NSi(t-Bu)Me2 (1) reacts with allylic ethers, chlorides, and bromides to give exclusively the products of the SN2' reaction; i.e., attack at the allylic position remote from the leaving group with migration of the double bond. The primary amine products can be isolated in excellent yields, after in situ Cbz protection, in the presence of variety of functional groups. Good diastereoselectivity and complete stereoselectivity allowed the formation of enantioenriched allylic amines from enantioenriched allylic ethers. Regiospecific substitution with 1 has also been achieved with allylic fluorides, which are notoriously poor substrates in other substitution reactions. On the basis of rate and kinetic isotope effect studies, we propose a general mechanism for the allylic substitution reactions with 1 which involves dissociation of THF and binding of the substrate, followed by the substitution step. In a DFT study of the substitution reaction, we identified a six-membered closed transition state for the substitution step and other relevant stationary points along the reaction coordinate. This study shows that the substitution reaction can be described as a concerted asynchronous [3,3]-sigmatropic rearrangement. This detailed knowledge of the reaction mechanism provides a rationale for the origins of the observed regio-, diastereo-, and stereoselectivity and of the unusual reactivity profile observed in the reaction.     

Reactions of Chlorosulfanyl Derivatives of Cyclobutanones with Different Nucleophiles

The reactions of 3‐chloro‐3‐(chlorosulfanyl)‐2,2,4,4‐tetramethylcyclobutan‐1‐one ( 2 ) with N, O, S, and P nucleophiles occur by substitution of Cl at the S‐atom. Whereas, in the cases of secondary amines, alkanols, phenols, thiols, thiophenols, and di‐ and trialkyl phosphates, the initially formed substitution products were obtained, the corresponding products with allyl and propargyl alcohols undergo a [2,3]‐sigmatropic rearrangement to give allyl and allenyl sulfoxides, respectively. Analogous substitution reactions were observed when 3‐chloro‐3‐(chlorodisulfanyl)‐2,2,4,4‐tetramethylcyclobutan‐1‐one ( 3 ) was treated with N, O, and S nucleophiles. The reaction of 3 with Et₃P led to an unexpected product via cleavage of the S? S bond (cf. Scheme 13). In the reactions of 2 with primary amines and H₂O, the substitution products react further via elimination of HCl to yield the corresponding thiocarbonyl S‐imides and the thiocarbonyl S‐oxide, respectively. Whereas the latter could be isolated, the former were not stable but could be intercepted by MeOH (Scheme 4) or adamantanethione (Scheme 5). The structures of some of the substitution products were established by X‐ray crystallography.     

Regio- and enantioselective control in the reactions of alpha-(N-carbamoyl)alkylcuprates with allylic phosphates

Alpha-(N-carbamoyl)alkylcuprates (RCuCNLi or R2CuLi) react with allylic phosphates to afford homoallylic amines in good chemical yields. Regioselectivity is governed by steric factors in both the cuprate reagent and phosphate substrate and systems can be designed to give either the S(N)2' or S(N)2 substitution product cleanly. Excellent enantioselectivities can be achieved with either a scalemic alpha-di[(N-carbamoyl)alkyl]cuprate and an achiral phosphate or with a scalemic allylic phosphate and an achiral cuprate reagent. [reaction: see text]     

Reactions of sulphuryl fluoride,sulphuryl chlorofluoride and sulphuryl chloride with amines

The reactions of sulphuryl fluoride, sulphuryl chlorofluoride and sulphuryl chloride with the amines tert-butylamine, benzylamine, piperidine, pyridine and quinoline have been investigated. The primary and secondary amines react with the elimination of hydrogen halides and formation of SN bonds whereas tertiary amines form 1:2 adducts.     

Toward the development of a structurally novel class of chiral auxiliaries: diastereoselective aldol reactions of a (1R,2S)-ephedrine-based 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one

[reaction: see text] Asymmetric aldol addition reactions have been conducted with (1R,2S)-ephedrine-derived 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one (2). Diastereoselectivities range from 75:25 to 99:1 for the formation of the crude non-Evans syn adducts 8a-h. The facial selectivity of the enolate is directed by the stereogenic N(4)-methyl substituent. Aldol adduct 8a is readily cleaved by acid hydrolysis to afford (2S,3S)-3-hydroxy-2-methyl-3-phenylpropionic acid (9) in >95% ee.     

Intramolecular cyclization of N,N-di(oligooxyethylene)amines: A new synthesis of monoaza crown ethers

The reaction of N,N-di(oligooxyethylene)amines with arenesulfonyl chloride in the presence of alkali metal hydroxide was investigate. It was found that the monoarenesulfonates of N,N-di(oligooxyethylene)amines were first formed as intermediates, and their subsequent intramolecular cyclization gave N-unsubstituted monoaza crown ethers rather selectively.     

Azolyl Derivatives of Nitrohalobutadienes: V. A New Route to Functionally Substituted Benzazetines

Heating of 1-azolyl-1-(4-R-phenylamino)-2-nitro-3,4,4-trichloro-1,3-butadienes and 1-azolyl-1-(4-R-phenylamino)-2-nitro-3,4-dichloro-4-bromo-1,3-butadienes (R = BuO, EtO, MeO, Me; azolyl = 1-benzotriazolyl, 3,5-dimethyl-1-pyrazolyl, and 1,2,4-triazol-1-yl) in methanol or acetic acid gave the corresponding 2-(1-nitrotrihalopropenylidene)-4-R-benzazetines. The latter reacted with amines, sodium alkoxides, and sodium thiolates, affording salts of the aci-nitro form. The reactions with benzoyl chloride and chloroacetyl chloride in the presence of pyridine led to formation of mixed anhydrides.     

Gas-phase identity nucleophilic substitution reactions of cyclopropenyl halides

The gas-phase identity nucleophilic substitution reactions of halide anions (X = F, Cl, and Br) with cyclopropenyl halides, X(-) + (CH)(3)X <= => X(CH)(3) + X(-), are investigated theoretically at four levels of theory, B3LYP/6-311+G**, MP2/6-311+G**, G2(+)MP2//MP2/6-311+G**, and G2(+)//MP2/6-311+G**. Four types of reaction paths, the sigma-attack S(N)2, pi-attack S(N)2'-syn, and S(N)2'-anti and sigmatropic 1,2-shift, are possible for all the halides. In the fluoride anion reactions, two types of stable adducts, syn- and anti-1,2-difluorocyclopropyl anions, can exist on the triple-well-type potential energy surface of the identity substitution reactions with rearrangement of double bond (C=C), S(N)2'-syn, and S(N)2'-anti processes. The TSs for the sigma-attack S(N)2 paths have "open" (loose) structures so that the ring positive charges are high rendering strong aromatic cyclopropenyl (delocalized) cation-like character. In contrast, in the pi-attack S(N)2' paths, a lone pair is formed at the unsubstituted carbon (C3), which stabilizes the 1,2-dihalocyclopropyl (delocalized) anion-like TS by two strong n(C)-sigma*(C-F) vicinal charge-transfer delocalization interactions. The barrier height increases in the order S(N)2'-anti < sigma-attack S(N)2 < S(N)2'-syn for X = Cl and Br, whereas for X = F the order is changed to S(N)2'-anti < S(N)2'-syn < sigma-attack S(N)2 due to the stable difluoro adduct formation. The sigmatropic 1,2-shift (circumambulatory) reactions have high activation barriers and cannot interfere with the substitution reactions.     

(R)-N-(β-三氯锗取代丙酰基)TTCA酯的合成及其倍半氧化物

β-三氯锗取代丙酰氯1a～1c与(R)TTCA酯反应, 得到光学活性的(R)-N-(β-三氯锗取代丙酰基)TTCA酯3a～3d([α]D^2^0-86.00～-94.35ⅲ)及光学活性的β-三氯锗取代丙酰氯2a～2d。化合物3a～3d经水解得到(R)-N-(β-取代丙酰基)TTCA酯基锗倍半氧化物4a～4d, [α]D^2^0-44.48～-77.00ⅲ。用半经验量子化学MNDO方法研究了反应物和产物最优构型的电子结构及反应的焓变。     

Radical Ions in Photochemistry. 44. The Photo-NOCAS Reaction with Acetonitrile as the Nucleophile

Studies on the photoinduced electron transfer (PET) reactions of isobutylene (2-methylpropene, 1) in the absence of methanol have identified a new photochemical nucleophile-olefin combination, aromatic substitution (photo-NOCAS) reaction. Under these conditions acetonitrile was found to act as the nucleophile and to combine with the alkene radical cation. The resulting distonic radical cation then adds to the radical anion of 1,4-dicyanobenzene (2(-*)). The final product (6) results from cyclization into the ortho postion of the phenyl group. This product formation is rationalized on the basis of the relatively high oxidation potential of the alkene (i.e., one-electron oxidation yields a reactive radical cation), the fact that addition of the nucleophile (acetonitrile) to the radical cation is relatively unhindered, and the relatively low acidity of the radical cation due to the low radical stability of the allylic radical formed upon deprotonation. High-level ab initio molecular orbital calculations were used to determine the structures and relative energies of the possible intermediate distonic and bridged radical cations. The scope and mechanism of this type of photo-NOCAS reaction are discussed.     

Intramolecular chiral relay at stereogenic nitrogen. Synthesis and application of a new chiral auxiliary derived from (1R,2S)-norephedrine and acetone

(1R,2S)-Norephedrine has been employed in the synthesis of a novel 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one via reductive alkylation with acetone, N-nitrosation, reduction, and cyclization. The oxadiazinone was treated with either propionyl chloride or 3-thiophenylpropionyl chloride to afford the corresponding N(3)-acylated oxadiazinones 9a and 9b, respectively. X-ray crystallographic analysis of the N(3)-thiophenylpropionyl oxadiazinone 9b revealed that the C(2)-urethane carbonyl and the N(3)-carbonyl are arranged in an anti-periplanar conformation. The oxadiazinones were subsequently applied in the titanium-mediated asymmetric aldol addition reaction by treatment with titanium tetrachloride, triethylamine, and a variety of aldehydes at 0 degrees C. The aldol adducts 10a-i and 11a,b were found to have diastereoselectivities ranging from 8:1 to >99:1 favoring the formation of the non-Evans syn configuration. The absolute stereochemistry of the adduct 10a was determined by acid hydrolysis. This process afforded the N(4)-isopropyloxadiazinone 8 and (2S,3S)-3-hydroxy-2-methyl-3-phenylpropanoic acid 14 in >/=95% enantiomeric excess.     

Quantum yields of the initiation step and chain propagation turnovers in S(RN)1 reactions: photostimulated reaction of 1-iodo-2-methyl-2-phenyl propane with carbanions in DMSO

Neophyl radicals were generated by photoinduced electron transfer (PET) from a suitable donor to the neophyl iodide (1, 1-iodo-2-methyl-2-phenylpropane). The PET reaction of 1 with the enolate anion of cyclohexenone (2) afforded mainly the reduction products tert-butylbenzene (5) and the rearranged isobutylbenzene (6), arising from hydrogen abstraction of the neophyl radical (15) and the rearranged radical 16 intermediates, respectively. The photostimulated reaction of 1 with 2 in the presence of di-tert-butylnitroxide, as a radical trap, afforded adduct 10 in 57% yield. The photoinduced reaction of the enolate anion of acetophenone (3) with 1 gave the substitution products 11 (50%) and 12 (16%), which arise from the coupling of 3 with radicals 15 and 16, respectively. The rate constant obtained for the addition of anion 3 to radical 15 was 1.2 x 10(5) M(-)(1) s(-)(1), by the use of the rearrangement of this radical as a clock reaction. The anion of nitromethane (4) was almost unreactive at the initiation step, but in the presence of 2 under irradiation, it gave high yields (67%) of the substitution product 13 and only 2% of the rearranged product 14. When the ratio of 4 to 1 was diminished, it was possible to observe both substitution products 13 and 14 in 16% and 6.4% yields, respectively. These last results allowed us to estimate the coupling rate constant of neophyl radicals 15 with anion 4 to be at least of the order of 10(6) M(-)(1) s(-)(1). Although the overall quantum yield determined (lambda = 350 nm) for the studied reactions is below 1, the chain lengths (Phi(propagation)) for the reaction of 1 with anions 3 and 4 are 127 and 2, respectively.     

Synthesis of luminescent homo-dinuclear cationic lanthanide cyclen complexes bearing amide pendant arms through the use of copper catalysed (1,3-Huisgen, CuAAC) click chemistry

The design and synthesis of dinuclear-lanthanide complexes possessing triazole-based bridges, formed by using copper catalysed 1,3-cycloaddition reactions between heptadentate alkyne functionalised cyclen europium or terbium complexes and di-azides (CuAAC reactions), are described. While this click reaction worked well for the formation of the homo-Eu(III) and Tb(III) bis-tri-arm cyclen N,N-dimethyl acetamide complexes, 2Eu and 2Tb, and for the homo-Eu(III) chiral N-methylnaphthalene based complexes 3Eu (S,S,S) and 4Eu (R,R,R), the formation of the Eu(III) complex of the primary amide analogue of 2, namely 1Eu, was not successful, clearly demonstrating the effect that the nature of the pendant arms has on this reaction. Furthermore, the click reactions between the free alkyne cyclen bis-derivatives (5-8) and the di-azide were unsuccessful, most likely due to the high affinity of the cyclen macrocycles for Cu(II). The Eu(III) complexes of 2-4 and 2Tb all gave rise to sensitised metal ion centred emission upon excitation of the triazole or the naphthalene antennae in methanol solution, and their hydration states were determined, which showed that while the Eu(III) mono-nuclear complexes had q ～ 2, the click products all had q ～ 1. In the case of 3Eu (S,S,S) and 4Eu (R,R,R), the circular polarised emission (CPL) was also observed for both, demonstrating the chiral environment of the lanthanide centres.     

异戊烯与甲醇成醚反应机理的量子化学研究

对2-甲基-1-丁烯、2-甲基-2-丁烯与甲醇反应生成甲基叔戊基醚的反应历程进行了量子化学研究, 结果表明, 反应过程包括两个基元步骤: 2-甲基-1-丁烯和2-甲基-2-丁烯与氢离子作用生成碳正离子, 活化能分别为E1=2.26 kJ/mol, E2=7.72 kJ/mol; 甲醇与叔碳正离子反应成醚, 活化能为E3=1.29 kJ/mol, 碳正离子的生成是反应的速控步骤. 2-甲基-1-丁烯与2-甲基-2-丁烯相互转化的异构化活化能分别为E'1=4.40 kJ/mol, E'2=63.11 kJ/mol, 高于成醚的活化能, 反应体系不发生烯烃相互转化的异构化反应.     

A photolabile protection strategy for terminal alkynes

We present a strategy for photolabile protection of terminal alkynes. Several photo-caged alcohols were synthesized via mild copper(II)-catalyzed substitution between tertiary propargylic alcohols and 2-nitrobenzyl alcohol to build up robust, base stable o-nitrobenzyl (NB) photo-cleavable compounds. We compare the new photolabile protecting group with the commonly used alkyne protecting group, 2-methyl-3-butyn-2-ol and the results show that NB ethers are stable under the cleaving conditions for the cleavage of methylbutynol protected alkynes. Additionally, we present the synthesis of photo-cleavable NB derivatives containing thiol groups that can serve as agents for photoinduced surface functionalization reactions.     

Trends in alkyl substituent effects on nucleophilic reactions of carbonyl compounds: gas phase reactions between amines and the methoxy methyl cation

The reactions of various amines (RNH(2); R = H, CH(3), C(2)H(5) and i-C(3)H(7)) with the methoxy methyl cation (CH(2)OCH(3)(+)) have been investigated using an FT-ICR mass spectrometer, and the experimental results are supplied with ab initio calculations. The amines show clear trends in their reactivities with variable degree of: 1) nucleophilic substitution, 2) addition-elimination and 3) hydride abstraction. In all cases addition-elimination dominates over nucleophilic substitution, and for R not equal H the observed reactions occur at the collisional limit. The potential energy profiles for all three reaction types correlate with the basicities of the amines; the more basic amine-the more favourable is the reaction; in other words: nucleophilicity follows basicity in the gas phase.     

Gas phase reactions of NH2Cl with anionic nucleophiles: Nucleophilic substitution at neutral nitrogen

Reactions of chloramine, NH2Cl, with HO-, RO- (R = CH3, CH3CH2, CH3CH2CH2, C6H5CH2, CF3CH2), F- , HS- , and Cl- have been studied in the gas phase using the selected ion flow tube technique. Nucleophilic substitution (S(N)2) at nitrogen to form Cl- has been observed for all the nucleophiles. The reactions are faster than the corresponding S(N)2 reactions of methyl chloride; the chloramine reactions take place at nearly every collision when the reaction is exothermic. The thermoneutral identity S(N)2 reaction of NH2Cl with Cl-, which occurs approximately once in every 100 collisions, is more than two orders of magnitude faster than the analogous reaction of CH3Cl. The significantly enhanced S(N)2 reactivity of NH2Cl is consistent with a previous theoretical prediction that the barrier height for the S(N)2 identity reaction at nitrogen is negative relative to the energy of the reactants, whereas this barrier height for reaction at carbon is positive. Competitive proton abstraction to form NHCl- has also been observed with more highly basic anions (HO-, CH3O-, and CH3CH2O-), and this is the major reaction channel for HO- and CH3O-. Acidity bracketing determines the heat of deprotonation of NH2Cl as 374.4 +/- 3.0 kcal mol(-1).     

One-pot two-step microwave-assisted reaction in constructing 4,5-disubstituted pyrazolopyrimidines

[reaction: see text] A microwave-assisted reaction was developed to facilitate the construction of 4,5-disubstituted pyrazolopyrimidines. This one-pot two-step process involves a sequential S(N)Ar displacement of the C4 chloro substituent with various anilines and amines, followed by a Suzuki coupling reaction with different boronic acids. Using microwave irradiation leads to high product conversion, low side product formation, and shorter reactions.