SNAr reactions of β-substituted porphyrins and the synthesis of meso substituted tetrabenzoporphyrins

Reaction of 2,3,7,8,12,13,17,18-octaethylporphyrin with LiR reagents containing functional groups readily yields meso substituted derivatives suitable for further transformations with residues such as -p-C₆H₅Br, -p-C₆H₅-CCH, -p-C₆H₅-NH₂ or -(CH₂)₃-CHCH₂. Similar reactions of tetrabenzoporphyrin with alkyllithium reagents afforded the first entry into meso mono- and dialkylsubstituted tetrabenzoporphyrins while reaction of bicyclo[2.2.2]oct-type masked isoindole precursors with LiR followed by in situ retro-Diels-Alder reaction also afforded the 5-phenyl and 5,10-diphenyltetrabenzoporphyrins in high purity.     

Practical synthesis of aromatic ethers by SNAr of fluorobenzenes with alkoxides

Aromatic fluorines have been substituted by alkoxides in a variety of activated and unactivated aromatic systems.     

Preparation of 4-heteroaryl-4-cyanopiperidines via SNAr substitution reactions

The scope and limitations of S_NAr substitution reactions of metalated 4-cyanopiperidines with heterocyclic halides were explored. These facile reactions provide rapid access to a wide range of 4-heteroaryl-4-cyanopiperidines and have resulted in improved yields, faster reaction times, and lower temperatures than previously published synthetic methods.     

Isomerisation of ω-alkenyl substituted cyclohexane-1,3-dione enol derivatives using rhodium catalysis. A practical synthesis of substituted resorcinols

Treatment of the ω-alkenyl substituted cyclohexane-1,3-dione enol derivatives (1), (11), and (13) with rhodium trichloride trihydrate leads to the corresponding resorcinol derivatives (2), (12), and (15) respectively. By contrast, the RhCl₃.3H₂O catalysed isomerisations of the related enol ethers (5) and (9) instead produce the dienones (6) and (10) respectively.     

Reactions of dibromotetrafluorobenzene derivatives with sodium phenoxide salts. Competing hydrodebromination and SNAr processes

1,2- and 1,3-dibromotetrafluorobenzene react with sodium phenoxide derivatives at sites para to ring bromine because these positions are activated by fluorine atoms ortho and meta to the site of nucleophilic substitution. Fluorine para to the site of nucleophilic attack is usually deactivating in nucleophilic aromatic substitution processes and this is reflected in the significantly reduced reactivity of 1,4-dibromotetrafluorobenzene which undergoes competing hydrodebromination processes to afford, primarily, 3-bromo-1,2,4,5-tetrafluorobenzene.     

Regioselective synthesis of novel substituted indazole-5,6-diamine derivatives

The synthesis of a series of novel indazole-5,6-diamine derivatives is described. This indazole ring system was incorporated in an octahydropyrrolo[3,4-b]phenazine scaffold and was diversely and regioselectively substituted on the nitrogen atoms at the 5- and 10-positions. Thus, the nitrogen atom at the 5-position was found to be more reactive toward electrophiles than the one at the 10-position. This difference of reactivity could be attributed to the electronic effect of the pyrazole moiety. Moreover, an unexpected tetrahydropyran protecting group migration was observed from the N-1 atom to the C-11 position of the octahydropyrrolo[3,4-b]phenazine scaffold.     

Observation of differential reactivity of cyclic amines in SN2 and SNAr displacement reactions in the course of synthesizing C-6, C-7 substituted quinolinecarbonitrile MEK1 kinase inhibitors

We have previously reported on a series of 4-anilino-6,7-dialkoxy-3-quinolinecarbonitriles as potent inhibitors of MEK1 kinase. Herein, we describe our synthetic efforts toward a series of 4-anilino-6-alkoxy-7-amino-3-quinolinecarbonitriles. In the course of this work, we were able to rapidly construct a library of 4-anilino-6-alkoxy-7-amino-3-quinolinecarbonitriles by simultaneous or sequential S_N2 (displacement) reactions on the C-6 chloroalkoxy moiety and S_NAr (addition/elimination) reactions at C-7 with nucleophilic amines.     

Solid support synthesis of 14- and 17-membered macrocycles via the SNAr methodology

Efficient assembly of 14-membered macrocycles utilizing the S_NAr of fluorine in 3-fluoro-4-nitrobenzoic acid with the OH of 3-hydroxytyrosine on solid support is reported. The flexibility of this synthesis, as well as the excellent purity (>90%) of the final products are the distinctive characteristic of the resultant library.     

Ruthenium mediated SNAr reactions in synthetic approaches to ristocetin A aglycon: preparation of an ABCD ring intermediate

A synthesis of an intermediate representing the ABCD ring system of ristocetin A aglycon is described, in which ruthenium-mediated intramolecular etherification is used as a key bond-forming step.     

A novel method to enable SNAr reaction of aminopyrrolopyrazoles

Here we report mild, environmentally-friendly reaction conditions which enable the addition-elimination S_NAr reaction between weakly reactive substrates--an aminopyrrolopyrazole template and several substituted pyrimidines. The method was developed during our efforts to synthesize a series of novel P21-activated kinase (PAK) inhibitors.     

Synthesis of bastadin analogs through an SNAr coupling strategy

The synthesis of a bastadin-5 analog was achieved in 16% overall yield (16 steps, longest linear sequence) using a strategy of intermolecular S_NAr coupling to create diphenyl ether bonds and sequential amide couplings to close the ring. Noteworthy elements include assembly of all four substituted aryl rings from two simple benzaldehydes, strict regiocontrol of meta- versus para-aryl ether bonds and management of the reductively-sensitive aryl bromine substituents.     

A new and versatile Ugi/SNAr synthesis of fused 4,5-dihydrotetrazolo[1,5-a]quinoxalines

A combinatorial synthetic route yielding fused tetrazolo[1,5-a]quinoxalines is described. The use of 2-fluorophenylisocyanide in the Ugi-tetrazole reaction (tetrazole-U-4CR) followed by a nucleophilic aromatic substitution (S_NAr) affords the tricylic tetrazolo[1,5-a]quinoxaline moiety in good yields and with high diversity.     

Michael addition/pericyclization/rearrangement--a multicomponent strategy for the synthesis of substituted resorcinols

The combination of methyl 3,7-dioxo-2-diazo-4-octenoate from the zinc triflate catalyzed Mukaiyama-Michael reaction of methyl 3-tert-butylsilyloxy-2-diazobutenoate and 4-methoxy-3-buten-2-one with Michael acceptors (methyl vinyl ketone, N-phenylmaleimide, β-nitrovinylarenes) in the presence of a catalytic amount of base provides convenient access to highly substituted resorcinol derivatives. This transformation is achieved in an efficient one-pot multi-component transformation by the sequential addition of the reagents.     

卤素离子与卤代苯气相SNAr反应理论研究

采用B3LYP/6-311+G**和MP2/6-311+G**方法,研究了卤素离子与卤代苯气相SNAr反应(Ar Y+X-=Ar X+Y-,X,Y=F,Cl,Br和I)。结果显示,气相里除了X=Y=F反应为分步路径外,其余反应通道都是协同SNAr机理;F离子进攻卤苯SNAr反应无论从动力学(总能垒ΔGb=9.0~17.3 k J/mol)还是热力学上来说都很容易进行,然而Cl、Br和I离子进攻的反应,其MP2吉布斯自由能垒(ΔGb)高达91.3~202.5 k J/mol,因此在气相里很难发生;另外,标题反应的反应性可以通过卤素离子质子亲和能(PA)、最高占据轨道能(EHOMO)、Mulliken电负性(χ)以及Wiberg键级(BO)与NPA电荷(Q)来分析,其中,过渡态里C─Y键的断裂是引起反应能垒升高的主要因素,亲核试剂的亲核能力主要由EHOMO控制,而卤素离子的离去能力由其PA或χ决定。     

Facile preparation of alkoxybenzoxazoles via direct SNAr on the benzoxazole ring

The synthesis of alkoxybenzoxazoles is in general quite challenging. During our investigation, we discovered that C-4 and C-7 fluoro precursors undergo S_NAr with alkoxides affording moderate to excellent yields of substituted product.     

One-pot derivatization of medicinally important 9-aminoacridines by reductive amination and SNAr reaction

A new highly efficient one-pot derivatization of medicinally important 9-aminoacridines (9-AA) at the amine position is described. Simple reductive amination and S_NAr reaction using easily accessible starting materials give a fast entry to novel 9-AA derivatives for biological screening.     

Versatile acenaphtho[1,2-b]pyrrol-carbonitriles as a new family of heterocycles: diverse SNAr reactions, cytotoxicity and spectral behavior

The diverse reactivity of highly electron-deficient 8-oxo-8H-acenaphtho[1,2-b]pyrrol-9-carbonitrile 1 is attractive for the preparation of derivatives bearing different substituents via S_NAr^H reaction with N, O, S nucleophiles. These derivatives were versatile, possessing potential antitumor activities and displaying tunable fluorescence spectral behavior.     

Regioselective and diastereoselective synthesis of highly substituted cyclopentanes

Highly substituted cyclopentane rings are present in a wide range of targets, and the efficient synthesis of such compounds constitutes a continuing challenge to organic synthesis. We present two complementary approaches to the regio- and diastereoselective synthesis of highly substituted cyclopentane structures. In both cases, a non-symmetrically disposed norbornene is employed as a common intermediate. One strategy relies on the Lewis acid-catalyzed ring opening of an anhydride, while the other employs production of a bicyclic lactone followed by its selective functionalization.     

Regioselective synthesis of two types of highly substituted 2-pyridones through similar multicomponent reactions

The refluxing of a mixture of ethylcyanoacetate, aromatic aldehydes, and primary monoamines in ethanol produces highly substituted 2-amino-6-pyridones such as 2-amino-1-(alkyl)-5-cyano-6-oxo-4-(aryl)-1,6-dihydropyridine-3-ethylcarboxylates in one-pot. On the other hand the refluxing of a mixture of ethylcyanoacetate, aromatic aldehydes, and primary diamines (1,2-ethylenediamine/1,3-propylenediamine) in ethanol furnishes symmetrical zwitterionic 2-pyridones such as 1-(2-amino-ethyl/3-amino-propyl)-6-hydroxy-2-oxo-4-(aryl)-1,2-dihydropyridine-3,5-dicarbonitriles. The result shows that primary diamines and monoamines react differently in the reactions, which provides new mechanistic insight into the regioselective synthesis of these biologically important compounds.     

Regioselective synthesis of fluoroalkyl pyridine derivatives from 3-fluoroalkyl substituted 2-aza-1,3-butadienes

A method for the preparation of 3-fluoroalkyl substituted 2-aza-butadienes by aza-Wittig reaction of N-vinylic phosphazenes and aldehydes is reported. [4+2] Cycloaddition reaction with enamines affords fluoralkyl substituted pyridine derivatives in a regioselective fashion.