Isoquinoline derivatives synthesis

The only other synthesis of a benzo fused derivative involves the pyridazino[4,3-cjisoquinoline series, the isoquinoline derivative (377) reacting with hydrazine to give (378) (74YZ607), although an s-triazolo-fused pyrido[2,3-tf Ipyridazine was obtained in the reaction of l-amino-3-iminoisoindolenine with hydrazine and formic acid (56GEP951993). 

Substituted 4-aryl-1 -oxo-1,2-dihydropyrazino[l, 2-i]isoquinolinium salts 402 were obtained when 3-substituted isoquinolines 401 were cleaved from a polymer by treatment 25% TFA (00MIP5). c/i-3,lla-H-3-Phenyl-1,2,3,4,11,11 fl-hexahydropyrazino[l, 2-i]isoquinoline-1,4-dione (404) formed when isoquinoline derivative 403 was cleaved from a resin with 25% TFA during an automated solid-phase synthesis (98BMCL2369). 

The mechanism of palladium-catalyzed intramolecular cyclization of o-bromo(aminoalkyl)benzenes has been discussed earlier (see Scheme 50 in Section IV,A,4). An example illustrating the use of this approach for the synthesis of 2,3,4,5-tetrahydro-l//-2-benzazepin-l-ones is given in Scheme 17386 and examples indicating the synthesis of isoquinoline derivatives are given earlier (see Scheme 146 in Section V,A,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. 

Similarly, ketimines (benzylimines of aromatic ketones) undergo the rhodium-catalyzed ortho-alkenylation with alkynes to give or/ o-alkenylated aromatic ketones after hydrolysis.61 This method is applied to an efficient one-pot synthesis of isoquinoline derivatives by using aromatic ketones, benzylamine, and alkynes under Rh catalysis (Equation (55)). 

Isopulegol, 24 517-519, 526 Isoquinoline. See also Isoquinolines reduction of, 27 201 uses for, 27 206-208 Isoquinoline derivatives. See also Isoquinolines drugs, 27 207—208t synthesis of, 27 201-206 uses for, 27 206-208 Isoquinoline TV-oxide, 27 200-201 Isoquinolines, 27 182, 200-208 alkyl, 27 205... 

The Delft synthesis makes use of an acid-catalyzed ring closure - in fact an intramolecular aromatic alkylation - of a l-(3,5-dihydroxy-4-methoxybenzyl) isoquinoline derivative that is prepared starting from (natural) gallic acid. One of the hydroxyl groups is removed via a Pd/ C hydrogenation of the benzyl ether. Other catalytic steps play an important role some steps were improved recently [27]. The crucial step in the Rice synthesis makes use of a l-(2-bromo-5-hydroxy-4-methoxybenzyl)isoquinoline derivative that is also cyclized in an acid-catalyzed ring closure to the morphinan skeleton, followed by catalytic removal of the bromo substituent (Scheme 5.8). 

Dihydropyridines have also been starting points for stereospecific syntheses of hydro-phenanthridines and isoquinolines. Interest exists in these compounds because of the occurrence of this structural feature in alkaloids. For example, isoquinuclidine (263), derived from JV-alkoxycarbonyl-l,2-dihydropyridine, undergoes a Cope rearrangement to give the isoquinoline derivative (264) (80JA6157). Further chemical transformations of (264) provided a formal total synthesis of reserpine (Scheme 50). 

Makosza118 has also shown that Reissert compounds, A-benzoyl-1,2-dihydroisoquinaldenitrile (67), can be alkylated in the presence of NaOH and TEBA. Alkaline hydrolysis of alkylated 68 will give isoquinoline derivatives, which are starting materials for the synthesis of alkaloids. 

The quinoline derivatives (100) to (103) exemplify two important overall strategies by which the heterocyclic ring may be constructed, indicated by (105) and (106). The isoquinoline derivative (104) has been selected to illustrate the overall strategy shown in (107). It should be pointed out however that a range of other strategies have been employed for the synthesis of quinolines and isoquinolines and the reader s attention is directed to specialist texts.27... 

The catalytic and chiral efficiency of (S,S)-le was also appreciated in the asymmetric synthesis of isoquinoline derivatives, which are important conformationally constrained a-amino acids. Treatment of 2 with a,a -dibromo-o-xylene under liquid-liquid phase-transfer conditions in the presence of (S,S)-le showed complete consumption ofthe starting Schiffbase. Imine hydrolysis and subsequent treatment with an excess amount of NaHCOs facilitated intramolecular ring closure to give 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert-butyl ester 38 in 82% yield with 98% ee. A variety of l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives possessing different aromatic substituents, such as 39 and 40, can be conveniently prepared in a similar manner, with excellent enantioselectivity (Scheme 5.20) [25]. 

This powerful quaternization method enabled the catalytic asymmetric synthesis of quaternary isoquinoline derivatives with 42 (R1 = Me) as a substrate. When 42 (R1 = Me) was treated with a,a -dibromo-o-xylene, CsOHH20 and (S,S)-le (1 mol%) in toluene at 0 °C, the transient monoalkylation product was rapidly produced, and subsequently transformed into the desired 44 (64%, 88% ee) during the work-up procedure. Catalytic asymmetric alkylation of 42 (R1 = Me) with functionalized benzyl bromide 45, followed by the sequential treatment with 1 M HC1 and then excess NaHC03, furnished the corresponding dihydroisoquinoline derivative 46 in 87% with 94% ee (Scheme 5.23) [25]. 

Nickel(O) complexes catalyse [2+2+2] cycloaddition. Catalytic asymmetric synthesis of isoquinoline derivative 134 is possible based on enantiotopic group-selective formation of the nickelacyclopentadiene 133 from 132 using the Ni(0) complex coordinated by a chiral ligand under acetylene atmosphere [56]. 

A 2-pyridone ring can be a building block for the synthesis of isoquinoline derivatives by acting as a dienophile in a Diels-Alder reaction. An electron-withdrawing group at C-4 is necessary for reaction with various substituted 1,3-butadienes (Equation 109) <2000CPB1814>. 

The same reaction has been developed that allows for in situ olefination in the synthesis of isoquinoline derivatives (Equation 11) <2003JOC980>. Although numerous examples were reported, it was found that the aryl methoxy substituent was necessary for the reaction to be successful. 

Similar methodology was used in the synthesis of 3-methyl derivatives of the alkaloids thalactamine, doryanine, and 6,7-dimethoxy-A-methyl-l(2//)-isoquinolone652. The S l reaction between 0rr/20-halogenobenzylamines and enolates derived from a series of ketones and aldehydes affords 1,2-dihydroisoquinolines, from which the isoquinoline derivatives can be obtained by dehydrogenation and the 1,2,3,4-tetrahydroisoquinolines by reduction653. The products of the S l reactions of (2-halo-4,5-dimethoxyphenyl)acetic... 

An efficient method was developed for the synthesis of new 6,1 l-dihydroindolo[l,2- ]isoquinoline derivatives 747 by reaction of easily available A -(2-lithiobenzyl)-2-lithioindole 746 with a wide range of aliphatic or aromatic carboxylic esters as electrophiles (Scheme 148) <2007ARK84>. 

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). 

Photoamination of a variety of aromatic compounds with ammonia and alkyl-amines under photosensitized electron transfer mediated reaction conditions has been extensively investigated by Yasuda and coworkers (Scheme 70) [320-324]. The photoamination reactions of stilbene derivatives with ammonia have been utilized for the synthesis of a variety of isoquinoline derivatives [324]. The photoamination is initiated by photochemical electron transfer from the arenes to the electron acceptor followed by nucleophilic attack of ammonia or primary amines on the aromatic radical cations (Scheme 70). 

Another useful variation is the Pictet-Spengler isoquinoline synthesis, also known as the Pictet-Spengler reaction. The reactive intermediate is an iminium ion 49 rather than an oxygen-stabilized cation, but attack at the electrophilic carbon of the C=N unit (see 16-31) leads to an isoquinoline derivative. When a p-aryla-mine reacts with an aldehyde, the product is an iminium salt, which cyclizes with an aromatic ring to complete the reaction and generate a tetrahydroisoquinoline." ° A variety of aldehydes can be used, and substitution on the aromatic ring leads to many derivatives. When the reaction is done in the presence of a chiral thiourea catalyst, good enantioselectivity was observed." ... 

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