Isoquinolines ring synthesis

The [4 + 2] cycloaddition of benzo-l-azadienes with electrophilic carbon—carbon double bonds has been implemented by de Meijere and coworkers (90CC574) in this case, the authors used N-unsubstituted benzo-phenone imine and cyclopropylideneacetates, and the reaction represents a new isoquinoline ring synthesis. 

Improved cyclohydrations could be performed with cyclic acetals in place of the previously used imino derivatives of 0x0 compounds such as oximes or semicarbazones A facile ring closure of suitably o-subst. benzonitriles to anthracene rings has been published. Gyclization of dinitriles with hydrogen halides affords an efficient isoquinoline ring synthesis... 

The one report of a true [3-1-3] cyclization occurs in the only reported synthesis of the pyrazino[2,3-c]isoquinoline ring system. The isoquinolino fused derivative (451) was isolated from dimerization of an intermediate iminoquinone formed by air oxidation of the unstable 4-amino-2-methyltetrahydroisoquinolin-l-one (450) 75JOC1760). 

The Bischler-Napieralski reaction involves the cyclization of phenethyl amides 1 in the presence of dehydrating agents such as P2O5 or POCI3 to afford 3,4-dihydroisoquinoline products 2. This reaction is one of the most commonly employed and versatile methods for the synthesis of the isoquinoline ring system, which is found in a large number of alkaloid natural products. The Bischler-Napieralski reaction is also frequently used for the conversion of N-acyl tryptamine derivatives 3 into p-carbolines 4 (eq 2). 

This approach to the isoquinoline ring, albeit a reduced isoquinoline, is mechanistically similar to the Bischler-Napieralski synthesis, in that it involves electrophilic attack of an iminium cation on to an aromatic ring. In this case, the imine intermediate is formed by reacting a phenylethylamine with an aldehyde. 

A one-pot synthesis of isoquinolines through coupling of 2-alkynylbenzaldehyde derivatives with chromium cyanocarbene complexes was reported. The reaction involved formation of an isobenzofuran first, which then underwent intramolecular Diels-Alder cycloaddition with the nitrile. One important feature of this process was the deoxygenation of the initial adduct to give the isoquinoline ring <03OL4261>. 

This ring synthesis has been extended for the synthesis of azetidinone-containing products 86 <2005BML937>, and to products 87 derived from an isoquinoline <1999HAC598> and 88 from a quinoline <2003PS(178)583>. 

An alternate approach to the fused heterocyclic compounds is the intramolecular cyclisation at an aromatic position. The Bischler-Napieralski reaction for the synthesis of the isoquinoline ring system illustrates this approach. 

The synthesis of the parent ring-system of the protopine alkaloids using Perkin s method has been described.224 The preparation of examples of the indeno[l,2-c]isoquinoline ring system (219), exhibited by a rearrangement product of cryptopine, has been described.225 The transformation of protopine to benzophenanthridine alkaloids will be described in Section 3 J. 

Most work has been in the isoquinoline area, principally because of the usefulness of isoquinoline Reissert compounds in the synthesis of isoquinoline alkaloids.2 Aside from 5-chloro-7 and 3-acetylaminomethylquinoline9 and a few halo,5-16-18 methyl,16,19 and carbomethoxyisoquinolines,20 all the substituted quinoline or isoquinoline Reissert compounds have involved oxygen-type functions in one or more of positions 4-, 5-, 6-, 7-, and 8- of the isoquinoline ring.6,8,15,20-38... 

As mentioned, naphthylisoquinoline alkaloids are structurally unusual on account of the methyl group at the 3-position and oxygenation at the 8- and/or 6-position of the isoquinoline ring which points to a polyketide origin. This postulate has been supported by extensive studies conducted by Btingmann on the in vitro biomimetic synthesis of the naphthalene and isoquinoline portions of these compounds (ref. 13,14) and this work is worth briefly mentioning in a discussion on the total synthesis of these compounds. 

The isoquinoline ring, although common in natural products, is not as important among pharmaceuticals as is the quinoline ring. Several synthetic methods are available, but we will discuss only the most commonly used one, the Bischler-Napieralski synthesis that was reported in 1893. With some modifications, it is stiU of great value today for the synthesis of isoquinolines. The process is simple and involves the reaction of an acyl derivative (an amide) of a 2-arylethylamine with phosphorus oxychloride or phosphorus pentoxide (Scheme 9.54). The... 

In the first case, phosphazenes react with aldehydes or even ketenes to produce aza-diene, which under heating conditions, undergoes electrocyclization to afford the isoquinoline ring. This methodology has been used for the synthesis of marine alkaloid renierol. ... 

This reaction was first and concurrently reported by Pomeranz and Fritsch in 1893. It is the synthesis of isoquinolines via an acid-promoted electrophilic cyclization of benza-laminoacetals prepared from aromatic aldehydes and aminoacetals. Therefore, this reaction is known as the Pomeranz-Fritsch cycUzation, Pomeranz-Fritsch isoquinoline synthesis, Pomeranz-Fritsch reaction," Pomeranz-Fritsch ring closure, Pomeranz-Fritsch ring synthesis, or Pomeranz-Fritsch synthesis. ... 

An important variation of the Jones-Schmid indole synthesis is the base-mediated cyclization onto esters, which affords 3-hydroxyindoles (indoxyl tautomers) under mild conditions. Three case studies are shown in Scheme 2 (equations 1-3) [18-20]. This chemistry, like that in Table 1 (Entries 4-11), represents a powerful route to C-3 functionalized indoles. Kraus and coworkers use the steri-cally hindered phosphazine base, P -t-Bu, to prepare the 5,6-dihydroindolo[2,l-a]isoquinoline ring system (equation 4) [21]. Several derivatives display immunosuppressive activity. 

As shown in Scheme 1.46, a simple synthesis of complex fused 1,4-benzoxaz-epin-2-one derivatives 86 and 87 was aehieved via a three-component leaction of quinoline or isoquinoline, acetylene dicaiboxylic esters and l-(6-hydioxy-2-isopio-penyl-l-benzofman-yl)-l-ethanone in water, in the absence of aiy catalyst [68]. Presumably, this transformation proceeds via the initial formation of a 1 1 zwitter-ionic intermediate 88 from the Michael addition of isoquinohne (or quinolone) to the activated ester. A proton transfer reaction takes then place in which this species is protonatedby the phenol group in the l-(6-hydroxy-2-isopropenyl-l-benzofuran-yl)-l-ethanone substrate, and this is followed by a second Michael addition of the resulting phenoxide anion to the isoquinohnium ion to afford intermediate 88, containing benzofuryl and isoquinoline ring systems. This intermediate then undergoes... 

An alternative approach to the synthesis of l-fluoroisoquinoUnes was accomplished by the nucleophilic aromatic substimtion (SnAt) [12], The chlorine-fluorine exchange reaction (Halex reaction) [13, 14] was effected in 1-chloroisoquinoIines with potassium fluoride to provide l-fluoroisoquinoUnes in high yield (Schane 2). In the case of 1,3-dichloroisoquinoline used as a substrate, 3-chloro-l-fluoroisoquinoline was selectively obtained despite the use of an excess of potassium fluoride. The chemoseleclivity was attributed to the lability of the carbon-halogen bond at the 1-position of the isoquinoline ring. 

Benzylideneaminoacetoaldehyde acetals prepared from benzaldehydes have been key intermediates of a well-established method for isoquinoline synthesis known as the Pomeranz-Fritsch reaction (Scheme 16, route a) [49,50], Intramolecular cycliza-tion of this type of imines under acidic conditions provided isoquinolines, where the two-carbon substituent on the nitrogen atom was transformed into a part of the isoquinoline ring. For the synthesis of 8-fluoroisoquinohne, the application of the standard procedure gave a low yield of the desired product (3 % in two steps from 2-fluorobenzaldehyde) [51]. However, in the modified procedure using ethyl chloro-formate, trimethyl phosphite, and titanium tetrachloride for the cyclization step [52] provided 6-fluoroisoquinoline from 4-fluorobenzaldehyde in 34 % overall yield (Scheme 17) [25],... 

Hydroisoquinolines. In addition to the ring-closure reactions previously cited, a variety of reduction methods are available for the synthesis of these important ring systems. Lithium aluminum hydride or sodium in Hquid ammonia convert isoquinoline to 1,2-dihydroisoquinoline (175). Further reduction of this intermediate or reduction of isoquinoline with tin and hydrochloric acid, sodium and alcohol, or catalyticaHy using platinum produces... 

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