1-Alkyl-1,2,3,4-tetrahydroisoquinolines

The 1-alkyl-1,2,3,4-tetrahydroisoquinolines are converted to their hydrochloride salts to avoid oxidation. The chiral auxiliary can be recovered from radial chromatography. 

Metallation-alkylation of chiral formamidine derivatives of 1,2,3,4-tetrahydroisoquin-oline provides optically active 1-alkyl-1.2,3,4-tetrahydroisoquinolines. The formam-idines of 10 optically active amino alcohols have been examined as the chiral auxiliaries and of these, the bistrimethylsilyl ether 2 (S.S-BISPAD) of 1 proved to be the mc>st efficient as well as consistent (equation II). The configuration (S) was established by synthesis of the benzoquinolizine (S)-5, a degradation product of an alkaloid. 

The asymmetric hydrogenation of 1-alkyl 3,4-dihydroisoquinolines catalyzed by Ir/(5, i ,i )-17b was developed, providing chiral 1 -alkyl tetrahydroisoquinolines with high yields (88-96%) and good to excellent enantioselectivities (85-99% ee) (Scheme 26) [84]. 

Tetrahydroisoquinoline Oxidation. Papaveraldine could be produced by Fremy s salt oxidation over 7 days in 30% yield (eq 12). The corresponding A( alkyl tetrahydroisoquinolines give cleavage products (eq 13). ... 

The methylene group adjacent to the nitrogen can be metallated with strong base to give an a-amino anion in which the lithium cation is chelated by th two heteroatoms of the chiral auxiliary. It is interesting to compare the alternative route to chiral 2-alkylated tetrahydroisoquinolines described in section 6.4.1. 

Isoquinoline can be reduced quantitatively over platinum in acidic media to a mixture of i j -decahydroisoquinoline [2744-08-3] and /n j -decahydroisoquinoline [2744-09-4] (32). Hydrogenation with platinum oxide in strong acid, but under mild conditions, selectively reduces the benzene ring and leads to a 90% yield of 5,6,7,8-tetrahydroisoquinoline [36556-06-6] (32,33). Sodium hydride, in dipolar aprotic solvents like hexamethylphosphoric triamide, reduces isoquinoline in quantitative yield to the sodium adduct [81045-34-3] (25) (152). The adduct reacts with acid chlorides or anhydrides to give N-acyl derivatives which are converted to 4-substituted 1,2-dihydroisoquinolines. Sodium borohydride and carboxylic acids combine to provide a one-step reduction—alkylation (35). Sodium cyanoborohydride reduces isoquinoline under similar conditions without N-alkylation to give... 

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). 

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. 

Phosphinous amides, based on proline and tetrahydroisoquinoline carboxylic acid, bearing a second donor center (50, Ar=Ph R =H, CH3,Tr, Ph R =H, CH3,Tr, Ph and 51, R =H,Tr R =H,Tr) (Scheme 40) have been developed for use in allylic alkylation and amination of substituted propenyl acetates, yielding the corresponding products in 87-98% (5-94% ee) and 29-97% (14-93% ee) respectively [55, 167]. With bidentate ligands of type 38 where R=(S)-PhMeCH, and with the bis(aminophosphanes) 52 (R=Ph) similar allylic alkylations have been also tested [168,169]. 

The antibacterial agent flumequine 280 was synthetized in optically active form by starting with resolution of the two enantiomers of a suitably substituted racemic tetrahydroquinoline through formation of the (lf )-3-bromocamphor-8-sulfonates. After N-alkylation of the (2K)-tetrahydroisoquinoline enantiomer 277 with diethyl ethoxymethylene-malonate to give 278, the quinolizidine system 279 was formed by acylation onto the peri-position. This compound was finally hydrolyzed to afford 280 (Scheme 60) <1999TA1079>. 

Gawley and coworkers showed that oxazolines can be used in place of formamidines for asymmetric alkylations of tetrahydroisoquinolines. A number of substituted oxazolines were evaluated as chiral auxiliaries, and one derived from valinol was found to be optimal. Interestingly, the same enantiomer of valinol affords the opposite enantiomers of the substituted tetrahydroisoquinoline when incorporated into formamidine or oxazoline auxiliaries. An example is shown in Scheme 58, as applied to a synthesis of laudanosine and the morphinan 9-7 -0-methylflavinantine. ° ... 

The direct anionic cyclization of 2-alkynylbenzonitriles 45 was applied to the synthesis of isoquinolinones <99T13193> and phenanthridines <990L767>. A bw-alkylation process of an amine with a hii-mesylate afforded the tetrahydroisoquinoline ring system <99SC645>. 

Table 4. l-Alkyl-1,2,3,4-tetrahydroisoquinolines by Alkylation of 2-Iminomethyl-Substituted 1,2,3,4 Tetrahydroisoquinolines... 

Consistently high levels of asymmetric induction have been achieved in the alkylation of tetrahydroisoquinolines using this methodology, as is demonstrated in the synthesis of chiral isoquinolinium alkaloids, e.g., (-)-salsolidine (61% yield, 95% ee)13, ( + )-homolaudanosine (48% yield, 96% op)14, ( —)-norcoralydine (37% yield, 98.5% op)15, some ben-zo[ ]quinolizidines (>99%ee), precursors of natural emetine16, corynantheine alkaloids17 and some azasteroids (93% ee)18. 

Some further examples of stereoselective deprotonation/alkylation reactions of tricarbonyl-chromium complexed (V-methyl tetrahydroisoquinolines have been reported27. Starting with the enantiomerically pure (35)-methyl tetrahydroisoquinoline reaction with hexacarbonyl-chromium led to a mixture of endo- (40%) and exo- (60%) complexes, which were deprotonated with butyllithium and subsequently methylated with iodomethane. In this way methylation occurred firstly at the 4- and secondly at the 1-position. In all cases, the methyl group entered anti to the chromium complexed face. After separation of the alkylated complexes by chromatography and oxidative decomplexation, the enantiomerically pure diastereomers (—)-(l 5,35,47 )-and ( + )-(17 ,35,45)-1,2,3,4-tetrahydro-l,2,3,4-tetramethylisoquinolme were obtained, benzylic amines such as tetrahydroisoquinoline to 2-amino-4,5-dihydrooxazoles. Deprotona... 

Valine-derived (5)-2-ethoxy-4,5-dihydro-4-isopropyloxazole, obtained by alkylation of 4-isopropyl-2-oxazolidinone with Meerwein s reagent, has been used to convert secondary tion and alkylation occurs smoothly to give alkylated derivatives I, which can be deprotected to give tetrahydroisoquinolines 2 with recovery of the chiral auxiliary28. 

Only one example has been reported in which an acyclic amine was alkylated with this method32. Using the oxazoline derivative of Af-methylbenzeneamine, deprotonation, subsequent alkylation with iodomethane at — 78 °C and removal of the oxazoline moiety afforded the 7 -confi-gurated a-methylbenzenamine in high yield (95%) with a selectivity of 64% ee. This value is nearly the same as that obtained on reaction of the tetrahydroisoquinoline derivatives at that temperature. Thus, as in the case of methanimidamides, no conclusions concerning the effectiv-ity of this approach in acyclic stereoselection can be drawn at present. 

Asymmetric alkylation of amines.1 Reaction of 1 with tetrahydroisoquinoline affords the aminooxazoline 2, which is alkylated with high asymmetric induction... 

Seebach, D. Lohmann, J.-J. Syfrig, M. A. Yoshifuji, M. Alkylation of the isoquinoline skeleton in the 1-position. Lifhiated 2-pivaloyl and 2-bis(dimefhylamino)phosphinoyl-l,2,3,4-tetrahydroisoquinolines. Tetrahedron 1983, 39, 1963-1974. 

Palladium chemistry has been used in the synthesis of tetrahydroisoquinolines. Different combinations of iodoaryl-amine-alkene can be used in these multicomponent reactions. For example, the metal-mediated o-alkylated/alkenyl-ation and intramolecular aza-Michael reaction (Scheme 109) give moderate yields of heterocycle <2004TL6903>, whereas the palladium-catalyzed allene insertion-nucleophilic incorporation-Michael addition cascade (Equation 172) produces good yields of tetrahydroisoquinolines in 15 examples <2003TL7445> with further examples producing tetrahydroquinolines (Scheme 110) <2000TL7125>. 

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