Reactions of Tetrahydroisoquinolines

As for the reaction mechanism, the actual catalytic species remain unclear, but the Cu complex is likely to play a role in activating hoth substrates. 

Li proposed that copper acetylide is generated and undergoes nucleophilic addition to the iminium ion, which is generated hy Cu-catalyzed oxidation of THIQ. 

To expand the scope of C-based nucleophiles in asymmetric CDC reactions, organocatalysis was examined. Klussmann and co-workers reported a catalytic system consisting of VO(acac)2/TBHP and L-proline for cross-coupling between simple ketones and N-aryl THIQs. These two catalysts are considered to play independent roles. Although the proposed mechanism involves nucleophilic addition of chiral enamines to iminium ions formed oxidatively from THIQs. The level of asymmetric induction was low ( 17% ee). 

The authors noted that reversibility of the aza-Breslow intermediate resulting from the reaetion of NHC with iminium ion is also an important faetor for high chemical yield. 

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Reaction of tetrahydroisoquinoline-3-carboxylic acid 434 with primary amines and isonitriles provided 1,2,3,4, 1,11 -hexahydro-6H-pyrazino [l,2-b]isoquinolin-l-ones 435 (06HEC107). 

Kawase, M. Unusual ring expansion observed during the Dakin-West reaction of tetrahydroisoquinoline-1-carboxylic acids using trifluoroacetic anhydride an expedient synthesis of 3-benzazepine derivatives bearing a trifluoromethyl group. J. Chem. Soc., Chem. Commun. 1992,1076-1077. 

More recently, an ingenious one-pot procedure for the activation, alkylation and deactivation sequence was reported by Katritzky. Reaction of tetrahydroisoquinoline with n-butyllithium followed by carbon dioxide affords the lithium carbamate (8), which can be further metalated with r-butyllithium and alkylated, as shown in Scheme 14. 

Dialkyl malonates are another type of sp3 C-H bond nucleophile often used in synthesis and Li and co-workers examined its use in the oxidative coupling reactions. The reaction of tetrahydroisoquinolines 6 with a variety of dialkyl malonates 7 in the presence of 5.0 mol% of CuBr and THBP (1—1.2 equiv.) at room temperature provided the desired (1-diester amines 8 in high yields (Scheme 5) [21]. 

Secondary products are obtained when adjacent active sites or groups are present, such as the tricyclic compound 212, which is formed when the Vilsmeier reagent from dimethylthioformamide reacts with a dithiolium salt (Eq. 171). Reaction at the pyrimidinyl methyl group in compound 213 results in formation of a pyrrolopyrimidinecarboxaldehyde (Eq. 172), and a similar reaction is seen with pyrazine 214 (Eq. 173). Vilsmeier reaction of tetrahydroisoquinoline 215 gives a mixture of three products, two arising from cyclization (Eq. 174). Cy-... 

Intramolecular base-promoted cyclization of suitable diesters (Scheme 52) is one of the earliest routes to benzo[a]quinolizidines, which was exploited in the synthesis of racemic emetine developed by Oppenshaw <53JCS2463>. Reaction of tetrahydroisoquinoline (255) with ethyl a-formylbutyrate followed by hydrogenation afforded (256), which was cyclized by base to yield (257), the benzo[a]-quinolizidine portion of the alkaloid. On this occasion only one of the two possible Dieckmann condensation products was observed, although this has not always been the case with related cyclizations <73BSF3476>. 

TABLE 4.3. REACTIONS OF TETRAHYDROISOQUINOLINE-l-CARBOXYLIC ACIDS WITH TRIFLUOROACETIC ANHYDRIDE... 

Table 2.59 Asymmetric Coupling Reaction of Tetrahydroisoquinolines With...

Scheme 2.2 Asymmetric CDC reaction of tetrahydroisoquinolines with terminal alkynes reported by Li.

In 2010, Stepehenson and coworkers developed aza-Henry reactions of tetrahydroisoquinolines 14 on the assumption that electron-rich tertiary alkylamines serve as electron donors to be converted into iminium ion through SET photoredox processes [50]. They showed that the Ir photocatalyst is more efficient than the Ru photocatalyst, [Ru(bpy)3]Cl2. Proposed reaction mechanism based on the reductive quenching cycle is illustrated in Scheme 10. The photoex-cited Ir species undergoes SET from tetrahydroisoquinoline 14 to give the... 

The IBX-mediated oxidative Ugi-type multicomponent reaction of tetrahydroisoquinoline with isocyanides and carboxyHc acids affords the nitrogen- and carbon-functionalized tetrahydroisoquinoHnes 305 in good-to-exceUent yields (2006ACE3495). Likewise, the three-component Passer-ini reaction of an alcohol, carboxyUc acid, and an isonitrile in the presence of IBX affords the corresponding a-acyloxy carboxamides 306 in generally high yields (Scheme 81 2007ACE5775). 

Reactions of 3- and 4-piperidone-derived enamines with a dienester gave intermediates which could be dehydrogenated to tetrahydroquinolines and tetrahydroisoquinolines (678). The methyl vinyl ketone annelation of pyrrolines was extended to an erythrinan synthesis (679). Perhydrophenan-threnones were obtained from 1-acetylcyclohexene and pyrrolidinocyclo-hexene (680) or alternatively from Birch reduction and cyclization of a 2-pyridyl ethyl ketone intermediate, which was formed by alkylation of an enamine with a 2-vinylpyridine (681). 

In 1911, Ame Pictet and Theodor Spengler reported that P-arylethyl amines condensed with aldehydes in the presence of acid to give tetrahydroisoquinolines. Phenethylamine 6 was combined with dimethoxymethane 7 and HCl at elevated temperatures to give tetrahydroisoquinoline 8. Soon after, the Pictet-Spengler reaction became the standard method for the formation of tetrahydroisoquinolines. 

Stereoselectivity in the condensation reaction of 2-arylethylamines with carbonyl compounds to give 1,2,3,4-tetrahydroisoquinoline derivatives was somewhat dependent on whether acid catalysis or superacid catalysis was invoked. Particularly in the cases of 2-alkyl-N-benzylidene-2-phenethylamines, an enhanced stereoselectivity was observed with trifluorosulfonic acid (TFSA) as compared with the weaker acid, trifluoroacetic acid (TFA). Compound 43 was cyclized in the presence of TFA to give modest to good transicis product ratios. The analogous compound 44 was cyclized in the presence of TFSA to give slightly improved transicis product ratios. 

The rhodium(II) acetate catalyzed reaction of 2-(3-oxo-2-diazobutyryl)-1,2,3,4-tetrahydroisoquinoline in boiling toluene yielded 2-methyl-4,6,7,l 16-tetra-hydro[l, 3]oxazino[2,3-n]-isoquinoline-4-one in 72% yield (99TL8269). 

Reactions of 3-methyl-1,2,3,4-tetrahydroisoquinoline-1-acetamides 202 (R = H) with 36% aqueous CH2O at 60 °C gave 1,3,4,6,7,1 Ih-hexahydro-2//-pyrimido[6,l-a]isoquinolin-2-ones 152 and their 3-methyl derivatives (97LA1165). When the reaction was carried out in the presence of 37% aqueous NaOH 3-hydroxymethyl derivatives 151 were obtained. Reactions with PhCHO were stereospecific to afford only diastereomers 203. 

Treatment of (11 aS)-3-isopropyl-11 a-methyl-4-phenyl-1,6,11,11 a-tetrahy-dro[l,4]oxazino[4,3-6]isoquinolin-l-one (243) with 6N HCl in a pressure tube, then the reaction of the work-up residue with propylene oxide gave (3S)-3-methyl-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (244) (99S704). 

Cyclocondensation of 2-(2-chloroacetyl)-l, 2,3,4-tetrahydroisoquinoline-3-carboxylate 418 (R =N02, R = Me) with liquid NH3 in MeOH in a stainless steel pressure vessel at room temperature overnight gave 8-nitro-2,3,4,6,1 1,1 la-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-dione (419, R=H, R =N02) (97MIP4). (1 la/i)-2-Cycloalkyl-8-hydroxy-2,3,4,6,ll, 1 la-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-diones 419 (R = cycloalkyl, R = OH) were prepared in the reactions of (3/i)-2-chloroace-tyl-l,2,3,4-tetrahydroisoquinoline-3-carboxylate (418, R = OH, R = Et) with cycloalkylamines (98MIP7). 

Intramolecular Diels-Alder reaction of substituted fiirans has been investigated as a route to the synthesis of isoquinoline alkaloids. Tetrahydroisoquinoline 81 was prepared from furan 80 in 40% yield <95JCS(P1)2393>. 

The vinylogous Pummerer reaction of an amido-substituted sulfoxide has been used for the preparation of tetrahydroisoquinoline 83 <95JOC(60)7082>. 

The reaction of electron deficient iV-benzenesulfonyl- 3-phenethylainines 84 with ethyl chloro(methylthio)acetate gives tetrahydroisoquinoline-1-carboxylates 85 in high yields <96H(42)141>. 

Nucleophilic addition reactions of allylic tin reagents to chiral 3-substituted 3,4-dihydroisoquinolines 89 activated by acyl chlorides afford trans 1,3-disubstituted 1,2,3,4-tetrahydroisoquinolines 90 stereoselectively <95CL1003>. 

Friedel-Crafts reaction remains unexplored, possibly due to the difficulty of the cycloalkyne formation. A mild, versatile, and efficient method for the one-step synthesis of substituted dihydro- and tetrahydroisoquinolines has been developed by the FeCl3-6H20-catalyzed intramolecular allenylation/cyclization reaction of benzylamino-substituted propargylic alcohols, representing the first example of the intramolecular Friedel-Crafts reaction of propargylic alcohols (Scheme 8) [24, 25]. FeCls, InCls, and Yb(OTf)3 also exhibit good catalytic activity for the reaction. 

Depending on the reaction temperature and reaction time, tetrahydroisoquinoline 357 afforded different mixtures of 1,2,3,4,11,11 a-hcxahydro-6//-pyrazino[ 1,2-3]isoquinolines 358-361 and tetracyclic compound 362 (Scheme 30) <2005JA16796>. Each of the individual diastereoisomers 358-361 could be transformed into the compound 362. z7r-3//,4a//-3-Phcnylpcrhydropyra/ino[ 1,2-7]isoquinoline-l,4-dione was prepared via automated parallel solid-phase synthesis on Kaiser oxime resin <1998BML2369>. l,2,3,5,6,7-Hexahydropyrido[l,2,3-r/f ]quinoxaline-2,5-dionc was obtained by catalytic hydrogenation of ethyl 3-(2-oxo-l,2,3,4-tetrahydro-5-quinoxalinyl)acrylate in the presence of TsOH over 5% Pd/C catalyst under 40 psi of hydrogen <1996JME4654>. 

Ugi five-center three-component reaction of pipecolinic acid and glycol aldehyde dimer with isocyanides gave a 1 1.7-2.1 diastereomeric mixture of l-oxoperhydropyrido[2,Tc][l,4]oxazine-9-carboxamides 397 (Scheme 35) <20010L4149>. Using CF3CH2OH as solvent is critical for the reaction. When 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid was employed, 1,3,4,6,11,11 a-hexahydro-[ l,4]oxazino[4,3+]isoquinoline-4-carboxarnide was formed. 

The /V -hydroxylamino compounds (404) and (405), obtained from the reaction of tert-butyl acetate with 3,4-dihydroisoquinoline-A-oxide or 5,5-dimethyl-pyrroline-/V-oxide, when boiled in methylene chloride in the presence of triphenylphosphine, carbon tetrachloride and triethylamine, are transformed to (1,2,3,4- tetrahydroisoquinolin-l-ilidene) acetate (406) or (pyrrolidin-2-ilidene) acetate (407) (Scheme 2.181) (645). 

The subject of metabolism of tetrahydroisoquinolines and related alkaloids in mammalian metabolic systems has recently been reviewed (205, 206). The formation of biogenic amine-derived alkaloids in mammals and their transformation by O-methylation reactions have been described. 

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