Preparation of isoquinolines

Chen et al. reported a more environmentally friendly version of the Pictet-Spengler reaction 06H1651 . In this report, a series of 2-phenylsulfonyl-l,2,3,4- 

Kobayashi and co-workers have described a new synthesis of a range of 1,4-disubstituted isoquinoline derivatives 117 06S2934 . Initially, a lithium halogen exchange of 118 was performed to form 119, followed by treatment with a variety of nitriles 120 resulting in 1,4-disubstituted isoquinolines 117. 

Kobayashi and co-workers have also reported an alternate synthesis of 1,4-disubstituted isoquinolines and a new synthesis of 1,3,4-dihydroisoquinoline derivatives 06BCJ 1126 06S2934 . The 1,4-disubstituted isoquinolines 121 are synthesized in good yields by reacting a variety of organolithiums 122 with different benzonitriles 123. In addition, a variety of lithium dialkylamides 124 were also reacted with different benzonitriles 123 to form 1 -amino-4-substituted isoquinolines 121 in moderate yields. 

Additionally, Kobayashi and co-workers demonstrated the reaction of 125 with phenyl lithium, followed by treatment with different electrophiles results in 1,3,4-trisubstituted dihydroisoquinolines 126, as shown below 06BCJ1126 . 

Bravo et al. synthesized a series of 1-alkyl- and l-aryl-3-aminoisoquinolines 127 06JHC235 . Treatment of 2-acylphenyl-acetonitriles 128 with amines 129 and a catalytic amount of trifluoroacetic acid results in the formation of 1-alkyl or l-aryl-3-aminoisoquinolines 127 in a single reaction step and in good yields. 

Rutjes and co-workers developed an efficient method to construct a-vinyltetrahydroisoquinolines through a palladium-catalyzed ally he A(0-acetal 

Variations and improvements of the Pictet-Spengler reaction continued to be a popular area of research for the synthesis of isoquinolines. Ruchirawat et al. reported a new version of the Pictet-Spengler reaction where V-acylcarbamatcs 122 were partially reduced with DIBAL-H followed by the sequential addition of BF3-OEt2 to provide 1,2-disubstituted tetrahydroisoquinoline derivatives 123 07TL8182 . 

In two reports Hanzawa and co-workers described a mild and facile Pictet-Spengler reaction catalyzed by perfluorooctane sulfonic acid (PFOSA) in water 07T4039 07TL835 . Many of their examples outline the reaction of 3,4-dimethoxyphenethylamines 124 with a variety of aldehydes catalyzed by PFOSA in water using l,l,l,3,3,3-hexafluoro-2-propanol (HFIP) as an additive resulted in the formation of 1,2-disubstituted tetrahydroisoquinoline derivatives 125 in high yield. 

Multi-component reactions were also utilized for the synthesis of isoquinolines. Yadav et al. reported the reaction of homophthalic anhydride 125, benzaldehyde 126, and anilines 127, under neutral conditions, in the presence of iodine in dichloromethane at room temperature to afford the desired cfs-oxoisoquinolinecarboxylic acid derivatives 128 in high yields 07S3191 . 

Wu and co-workers described a novel one-pot multi-component reaction between 2-alkynylbenzaldehydes 129, amines 130 and ketones 131 catalyzed by AgOTf and proline to give 1,2-dihydroisoquinolines 132 07OL4959 . 

R = 4-CIC6H4, 95% yield R = 4-MeC6H4, 91% yield R = 4-FC6H4, 77% yield R = 4-CIC6H4, 95% yield 

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The Pomeranz-Fritsch reaction involves the preparation of isoquinolines 4 via the acid-mediated cyclisation of the appropriate aminoacetal intermediate 3. The best yields are usually obtained when the benzaldehyde portion 1 has electron-donating substituents in the 3- or 3,4- positions relative to the aldehyde. 

Toward the end of the 19 century both Pomeranz and Fritsch independently reported the preparation of isoquinolines by the reaction of aminoacetaldehyde dimethyl acetal 2 (R = Me) with aromatic aldehydes 1 followed by cyclisation in acidic media. " Unfortunately yields were often poor and not always reproducible. This has prompted the search for various improvements and modifications on the original theme, including the use of reagents other than strong mineral acid which tends to destroy the intermediate imine. ... 

A Diels-Alder reaction of arynes with 1,2,4-triazines 102 allows the preparation of isoquinolines substituted with electron-withdrawing groups in the nitrogen-containing ring. The isoquinoline-1-carboxylic esters bearing additional substituents are of particular interest because they are not readily available by the usual routes [100,101] (Scheme 2.42). 

Scheme 42. Preparation of isoquinoline derivative 126 and its subsequent heterocyclization [7m, 60a]...

The most frequently used method for the preparation of isoquinoline Reissert compounds is treatment of an isoquinoline with acyl chloride and potassium cyanide in water or in a dichloromethane-water solvent system. Though this method could be successfully applied in a great number of syntheses, it has also some disadvantages. First, the starting isoquinoline and the Reissert compound formed in the reaction are usually insoluble in water. Second, in the case of reactive acyl halides the hydrolysis of this reaction partner may became dominant. Third, the hydroxide ion present could compete with the cyanide ion as a nucleophile to produce a pseudobase instead of Reissert compound. To decrease the pseudobase formation phase-transfer catalysts have been used successfully in the case of the dichloromethane-water solvent system, resulting in considerably increased yields of the Reissert compound. To avoid the hydrolysis of reactive acid halides in some cases nonaqueous media have been applied, e.g., acetonitrile, acetone, dioxane, benzene, while utilizing hydrogen cyanide or trimethylsilyl cyanide as reactants instead of potassium cyanide. 

Although the transition-metal-catalyzed reaction of a-diazocarbonyl compounds with aromatic molecules has received much attention in recent years,104 the metal-catalyzed behavior of these compounds with N-containing heteroaromatics has not been extensively studied. An early example involved the preparation of isoquinoline-carboethoxymethylide... 

PictetGams preparation of isoquinolines from iV-acylated 2-hydroxyphenethylamines, e.g., the synthesis of papaverine 180 (Scheme 107), utilizes similar conditions. 

The methods discussed in this chapter have made possible the facile synthesis of isoquinoline derivatives oxygenated at the 7-position, the 5,8-positions, the 6,7-positions, the 7,8-positions, and the 6,7,8-positions [Eq. (7)] or having carbon substituents at the 6-position [Eq. (6)]. The starting materials are readily available aromatic aldehydes, and the reactions are experimentally simple. These methods are not suitable for the preparation of isoquinolines with oxygen at the 5-position, the 6-position, or the 5,6-positions. These must still be prepared by the Bischler-Napieralski method,61 the Pictet-Spengler method,83 or the Dieckmann route shown in Eq. (22). 

The preparation of isoquinolines by methods of ring closure has been reviewed. ... 

Bischler-Napieralski isoquinoline synthesis Preparation of isoquinolines from acylated phenylethylamines. 62... 

When thebenine is distilled with zinc-dust, in addition to pyrene a phenanthridine-like base, stable to chromic acid, is obtained. This substance, thebenidine, has the structure [xvn] [19] and has recently been synthesized by the action of phosphorus pentoxide on 4-formami-dophenanthrene [20]. During the dehydration of the oxime [xn] a quantity of a basic substance was obtained. It is believed to be [xvm] or the isomeric [xix] [11] (cf. the rearrangement of C and N during the preparation of isoquinoline by the dehydration of cinnamaldoxime [21]). 

Narasimhan and Ranade (57) have incorporated the 2-metalation procedure into the preparation of isoquinoline. Furthermore their obser-... 

The TT-cyclization of A/ -acyliminium ions onto aromatic rings is a useful method for the preparation of isoquinolines fused with heterocycles. Heating azide 102 with one of the compounds methyl (5)-mandelate (103) or methyl (i )-mandelate (63) in toluene provides the carbamates 104 and 105 respectively. DIBAL reduction of 104 or 105 with DIBAL in toluene... 

Tetrahydroisoquinolines were also prepared by an electrophilic aromatic substitution reaction of 2-amidoacroleins. Exposure of IV-aryl-substituted 3-amido-1,3-dioxins 82 to Lewis acids results in retrocycloadditions to afford 2-amidoacroleins 83 and concomitant electrophilic aromatic substitution to afford tetrahydroisoquinolines 84 <01OL3349>. The synthesis of isoquinoline derivatives via cyclization reactions received attention as well. Some examples include the preparation of isoquinolines by a photocyclization of l-methoxy-2-azabuta-l,3-dienes <01TL3575>. The photochemically induced preparation of 1-methyl-1,2,3,4-tetrahydronaphtho[2,l-/ isoquinolines was also reported <01T1981>. 

The ET-sensitized photoamination of 1,1-diarylethylenes with ammonia and most primary amines yields the anti-Markovnikov adducts. Photoamination of unsymmetrically substituted stil-benes yields mixtures of regioisomers 15 and 16. Modest re-gioselectivity is observed for p-methyl or p-chloro substituents however, highly selective formation of adduct 15 is observed for the p-methoxy substituent (Table 5). Selective formation of 15 was attributed to the effect of the methoxy substituent on the charge distribution in the stilbene cation radical. This re-gioselectivity has been exploited in the synthesis of intermediates in the preparation of isoquinolines and other alkaloids." Photoamination of 1-phenyl-3,4-dihydronaphthalene yields a mixture of syn and anti adducts 17 and 18 (Scheme 5)." Use of bulky primary amines favors formation of the syn adduct (Table 5), presumably as a consequence of selective anti protonation of the intermediate carbanion. 

This reaction is useful for the preparation of isoquinoline derivatives. 

The closing chapter also is written by Professor Heravi, in which he describes another classical reaction, by Bischler and Napieralski, for preparation of isoquinolines. 

Cyclodehydrations. The Pictet-Gams modification of the Bischler-Napieralski reaction is an important method for the preparation of isoquinolines. This reaction relies on the dehydration of molecules such as (2) with P2O5 at high temperature... 

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