Synthesis of isoquinolines and naphthyridines by electrophilic ring closure of iminoalkynes

Substituted isoquinolines and naphthyridines have been prepared in good to excellent yields by the reaction of iminoalkynes with a variety of electrophiles under mild reaction conditions. Reaction: see text.     

Synthesis of isoquinolines and pyridines by the palladium/copper-catalyzed coupling and cyclization of terminal acetylenes and unsaturated imines: the total synthesis of decumbenine B.

Monosubstituted isoquinolines and pyridines have been prepared in good to excellent yields via coupling of terminal acetylenes with the tert-butylimines of o-iodobenzaldehydes and 3-halo-2-alkenals in the presence of a palladium catalyst and subsequent copper-catalyzed cyclization of the intermediate iminoalkynes. In addition, isoquinoline heterocycles have been prepared in excellent yields via copper-catalyzed cyclization of iminoalkynes. The choice of cyclization conditions is dependent upon the nature of the terminal acetylene that is employed, as only aryl and alkenyl acetylenes cyclize under the palladium-catalyzed reaction conditions that have been developed. However, aryl-, vinylic-, and alkyl-substituted acetylenes undergo palladium-catalyzed coupling and subsequent copper-catalyzed cyclization in excellent yields. The total synthesis of the isoquinoline natural product decumbenine B has been accomplished in seven steps and 20% overall yield by employing this palladium-catalyzed coupling and cyclization methodology.     

Efficient Synthesis of Isoquinolines by AgNO3‐Catalyzed Sequential Imination‐Annulation of 2‐Alkynyl Aldehydes with Ammonium Bicarbonate

An operationally simple approach for the tandem synthesis of isoquinolines by the reaction of o‐alkynylaldehydes with ammonium bicarbonate via Ag‐catalyzed 6‐endo‐dig ring closure is described. The reaction conditions and the scope of the reaction are examined, and a variety of substituted isoquinolines are prepared in moderate to excellent yields.     

A tandem approach to isoquinolines from 2-azido-3-arylacrylates and alpha-diazocarbonyl compounds

2-Azido-3-arylacrylates react with alpha-diazocarbonyl compounds and triphenylphosphine to furnish isoquinolines in 60-92% yields. The tandem process involves a Wolff rearrangement, an aza-Wittig reaction, and an electrocyclic ring closure. The procedure is efficient, rapid, and general, and the substrates are readily available.     

Oxidation and hydrogenation of benzo[g]isoquinolines

The oxidation of methyl-substituted (in the pyridine and benzene rings) benzo[g]isoquinolines to substituted 2-azaanthraquinones was realized. It was established that the pyridine ring is partially reduced to give 1,2,3,4-tetrahydrobenzo[g]isoquinolines in the hydrogenation of benzo[g]isoquinolines in the presence of rhenium heptasulfide.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 517–519, April, 1979.     

Synthesis of 3-substituted 4-aroylisoquinolines via Pd-catalyzed carbonylative cyclization of 2-(1-alkynyl)benzaldimines

A number of 3-substituted 4-aroylisoquinolines have been prepared in good yields by treating N-tert-butyl-2-(1-alkynyl)benzaldimines with aryl halides in the presence of CO and a palladium catalyst. Synthetically the methodology provides a simple and convenient route to isoquinolines containing an aryl, alkyl, or vinylic group at C-3 and an aroyl group at C-4 of the isoquinoline ring. The reaction is believed to proceed via cyclization of the alkyne containing a proximate nucleophilic center promoted by an acylpalladium complex.     

Concise preparation of amino-5,6,7,8-tetrahydroquinolines and amino-5,6,7,8-tetrahydroisoquinolines via catalytic hydrogenation of acetamidoquinolines and acetamidoisoquinolines

A method to prepare amino-substituted 5,6,7,8-tetrahydroquinolines and 5,6,7,8-tetrahydroisoquinolines via catalytic hydrogenation of the corresponding acetamido-substituted quinolines and isoquinolines followed by acetamide hydrolysis is described. The yields of the products are good when the acetamido substituent is present on the pyridine ring and moderate with the acetamido substituent on the benzene ring. This method has also been applied to the regioselective reduction of quinoline substrates bearing other substituents (R = OMe, CO(2)Me, Ph).     

Synthesis of 1-hydroxy-substituted pyrazolo[3,4-c]- and pyrazolo[4, 3-c]quinolines and -isoquinolines from 4- and 5-aryl-substituted 1-benzyloxypyrazoles

1-Hydroxypyrazolo[3,4-c]quinoline (22), 1-hydroxypyrazolo[4, 3-c]quinoline (21), 1-hydroxypyrazolo[3,4-c]isoquinoline (20), and 1-hydroxypyrazolo[4,3-c]isoquinoline (19) were prepared from 1-benzyloxypyrazole (6), establishing the pyridine B-ring in the terminal step. The pyridine ring of pyrazoloquinolines 14 and 18 was formed via cyclization of a formyl group at C-4 or C-5 and an amino group of a 2-aminophenyl substituent at C-5 or C-4 in 1-benzyloxypyrazole. The pyridine ring of pyrazoloisoquinolines 5 and 9 was created via cyclization of a formyl group in a 2-formylphenyl substituent at C-4 or C-5 with an iminophosphorane group installed at C-5 or C-4 of 1-benzyloxypyrazole by lithiation followed by reaction with tosyl azide and then with tributylphoshine utilizing the Staudinger/aza-Wittig protocol. The 2-aminophenyl and the 2-formylphenyl substituent were introduced at C-5 or C-4 by regioselective metalation followed by transmetalation to the pyrazolylzinc halide and subsequent palladium-catalyzed cross-coupling with 2-iodoaniline or 2-bromobenzaldehyde. The order of reactions and use of protecting groups in the individual sequences have been optimized. The 1-benzyloxy-substituted pyrazoloquinolines and isoquinolines thus obtained were debenzylated by strong acid to the corresponding 1-hydroxy-substituted pyrazoloquinolines and isoquinolines 19-22.     

若干D环带硝基的小檗因衍生物的光环化合成

通过酰烯胺的光环化反应, 合成了六个D环带硝基的小檗因类化合物。在酰烯胺的制备中, 还得到了几个非预期的副产物, 阐明了它们的结构。     

Synthesis of 3,4-Dihydrobenzo[h]isoquinoline Derivatives

1-Substituted 3,3,4-trimethyl-3,4-dihydrobenzo[h]isoquinolines have been obtained by the reaction of 1,2-dimethyl-1-(2-naphthyl)-1-propanol with nitriles in conc. H₂SO₄. It was shown that the presence of a benzene ring annelated at positions 7 and 8 of the isoquinoline does not influence reaction of the 1-methyl derivative with isocyanate, however reactions of the 1-methylthio derivative with C and N nucleophiles are affected significantly.     

Novel synthesis of isoquinolines using isobenzofuran-nitrile Diels-Alder reactions

[reaction: see text] The synthesis of isoquinolines through coupling of 2-alkynylbenzaldehyde derivatives with beta-cyanocarbene complexes has been examined. The reaction involves formation of an isobenzofuran followed by intramolecular Diels-Alder reaction with the nitrile, a process with limited precedent. The unique success of this process in this system has been attributed to deoxygenation of the initial adduct to form the isoquinoline ring system.     

Amino substituted bisketenes: generation, structure, and reactivity

Hitherto unknown diamino-substituted bisketenes with both free (14) and tethered (16) amino substituents have been generated by using laser flash photolysis for ring opening of the corresponding cyclobutenediones. The time-resolved kinetics of ring closure of the amino bisketenes back to the cyclobutenediones were measured by IR or UV spectroscopy, and give first-order rate constants which vary by a factor of 7.5x10(4), and the bis(Me2N) bisketene 14 is the most reactive in ring closure that has been reported. Rate constants for ring closure of these and previously observed bisketenes vary by a factor of 10(13). The dialkylamino bisketenes 16 (R=Me, n-Bu) with tethered substituents and restricted geometries are less reactive than the bis(Me2N) bisketene 14 by factors of 1700 and 540, respectively. Computational results obtained with DFT methods suggest angle strain in the tethered cyclobutenediones 15 inhibits facile cyclization of bisketenes 16.     

The cyclization reaction of ortho-ethynylbenzaldehyde derivatives into isoquinoline derivatives

In order to elucidate the reaction mechanism of the cyclization between an ethynyl group and an imino group at the ortho-position on an aromatic ring to afford isoquinolines, reaction of 2-ethynylbenzaldehydes under various conditions was examined. It is concluded that reaction proceeds via an ionic process and the isoquinoline 4-hydrogen atom derives from the solvent. In addition, it was found that 2-ethynylbenzaldehyde O-methyloximes underwent cyclization in the presence of primary and secondary alcohols to give 3-substituted isoquinolines.     

Mass spectra of tetrahydroisoquinoline-fused 1,3,2-O,N,P- and 1,2,3-O,S,N-heterocycles: influence of ring size and fusion, of present heteroatoms, substituent effects and of the stereochemistry on fragmentation

The electron ionization (EI) mass spectra of a variety of stereoisomeric tricyclic 1,3,2-oxazaphosphino[4,3-a]isoquinolines (1-4), 1,2,3-oxathiazino[4,3-a]isoquinoline-4-oxides (5-7) and the -4,4-dioxides (8-10) of oxazaphospholo- and oxathiazolo[4,3-a]- (11, 12, 15 and 16) and -[3,4-b]isoquinolines (13, 14 and 17) were recorded. Ring size and fusion, the different heteroatoms (P and S) and substituents on the ring systems strongly influence the mass spectra. In addition, mass spectra of the stereoisomers of compounds 1, 2 and 13, 14 revealed stereochemically relevant differences which are not observed for the other pairs of isomers.     

Origin of diastereoselectivity in the organolanthanide-mediated intramolecular hydroamination/cyclisation of aminodienes: a computational exploration of constrained geometry CGC-Ln catalysts

The regulation of ring-substituent diastereoselectivity in the intramolecular hydroamination/cyclisation (IHC) of alpha-substituted aminodienes by constrained geometry CGC-lanthanide catalysts (CGC=[Me(2)Si(eta(5)-Me(4)C(5))(tBuN)](2-)) has been elucidated by means of a reliable DFT method. The first survey of relevant elementary steps for the 1-methyl-(4E,6)-heptadienylamine substrate (1) and the [{Me(2)Si(eta(5)-Me(4)C(5))(tBuN)}Sm{N(TMS)(2)}] starting material (2) identified the following general mechanistic aspects of Ln-catalysed aminodiene IHC. The substrate-adduct 3-S of the active CGC-Ln-amidodiene compound represents the catalyst's resting state, but the substrate-free form 3' with a chelating amidodiene functionality is the direct precursor for cyclisation. This step proceeds with almost complete regioselectivity through exocyclic ring closure by means of a frontal trajectory, giving rise to the CGC-Ln-azacycle intermediate 4. Subsequent protonolysis of 4 is turnover limiting, whilst the ring-substituent diastereoselectivity is dictated by exocyclic ring closure. Unfavourable close interatomic contacts between the substrate's alpha-substituent and the catalyst backbone have been shown to largely govern the trans/cis selectivity. Substituents of sufficient bulk in the alpha-position of the substrate have been identified as being vital for stereochemical induction. The present study has indicated that the diastereoselectivity of ring closure can be considerably modulated. The variation of the lanthanide's ionic radius and introduction of extra steric pressure at the substrate's alpha-position and/or the CGC N centre have been identified as effective handles for tuning the selectivity. The quantification of these factors reported herein represents the first step toward the rational design of improved CGC-Ln catalyst architectures and will thus aid this process.     

Template effects in the formation of [2]pseudo-rotaxanes containing diazapyrenium units

The template effects exerted by guests 14 and 15 in the ring closure reaction of 3 have been quantitatively evaluated. The rate largely increases in the presence of the two templates. The results are compared with those relative to the ring closure reaction of 1 yielding cyclobis(paraquat-p-phenylene), 2. The comparison indicates that the formation of tetracationic aromatic cycles templated by aromatic donors benefits from the use of extended pi surfaces both in the acceptor and in the donor components.     

11H-Pyrido[3',2':4,5]pyrrolo[2,3-g]isoquinoléines (aza-7 ellipticines) substituées sur leur position 6

6-Dialkylaminoalkylamino substituted 11H-pyrido[3',2':4,5]pyrrolo[2,3-g]isoquinolines (7-aza ellipti-cines) were obtained by a six step synthesis starting from 2-chloro-3-nitro pyridine and 6-amino-5-methyl (and 5,8-dimethyl) isoquinoline-1-2H-ones already described. A brief survey of biological results shows that derivatives of this new heterocyclic ring system are less interesting than their 5H-pyrido(3',4':4,5]pyrrolo[2,3-g]isoquinolines (9-aza ellipticines) and pyrido[4,3-b]carbazoles (ellipticines) analogues.     

Synthesis of polysubstituted isoquinolines through cross-coupling reactions with α-alkoxytosylhydrazones

A Pd-catalyzed cross-coupling reaction of α-alkoxytosylhydrazones with sulfonates derived from salicyl aldehydes gives rise to protected 1,5-dicarbonyl compounds. Treatment with ammonium hydroxide readily transforms these alkenes into isoquinolines with diverse substitution patterns at positions 3 and 4. In a similar way, the employment of o-cyanononaflates in the coupling reaction, followed by treatment with an organometallic, provides isoquinolines that incorporate substitution also at position 1. The combination of both approaches represents a versatile method for the preparation of isoquinolines substituted at any position of the heterocyclic ring.     

Dearomatization of naphthalene: novel stereoselective cyclization reactions promoted by Osmium(II)

A series of Michael acceptors has been combined with the Os(II) eta(2)-naphthalene complex (1) to form stable 1H-naphthalenium species. Under acidic conditions, these complexes undergo ring closure at C2 to form the phenanthrenone core. In contrast, the corresponding 1-methylnaphthalene complex (15) upon addition of MVK at C8 undergoes ring closure at C5 to form a bridged tricyclic complex (18). Michael addition of MVK to the naphthalene complex (1) followed by deprotonation, an inter-ring linkage isomerization, and ring closure forms a 9-methylphenalene complex (21). In all cases, the organic cyclization products may be decomplexed by heating with silver triflate and isolated in moderate yield.     

Synthesis of 3,4-dihydrobenzo[g]isoquinoline-1(2H)-ones and 3,4-dihydroisoquinoline-1(2H)-ones skeleton via intramolecular electrophilic cyclization

An original alternative approach to isoquinolines based on the installation of a benzene nucleus on a performed heterocyclic ring. Synthesis of 3,4-dihydrobenzo[g]isoquinoline-1(2H)-ones and 3,4-dihydroisoquinoline-1(2H)-ones via intramolecular electrophilic cyclization of 3,4-disubstituted lactams is reported.