Lithiated tetrahydroisoquinolines

Lithiated tetrahydroisoquinoline pivalamides add to aldehydes with poor diastereoselectivity. However, Seebach and coworkers found that transmetalation to a Grignard... 

Unlike lithiated tetrahydroisoquinolines, a-lithio derivatives of saturated heterocycles are configurationally stable [202-204] (review [163]), and they have a considerably higher kinetic barrier to deprotonation. Nevertheless, there have been a number of activating groups developed for the alkylation of a-lithio amines. In 1991, Beak showed that the complex of sparteine and sec-butyllithium enantioselectively deprotonates BOC-pyrrolidine, and that the derived organolithium is a good nucleophile for the reaction with several electrophiles, as shown in... 

Additions of stabilized carbanions to imines and hydrazones, respectively, have been used to initiate domino 1,2-addition/cyclization reactions. Thus, as described by Benetti and coworkers, 2-subshtuted 3-nitropyrrolidines are accessible via a nitro-Mannich (aza-Henry)/SN-type process [165]. Enders research group established a 1,2-addition/lactamization sequence using their well-known SAMP/ RAMP-hydrazones 2-308 and lithiated o-toluamides 2-307 as substrates to afford the lactams 2-309 in excellent diastereoselectivity (Scheme 2.72) [166]. These compounds can be further transformed into valuable, almost enantiopure, dihydro-2H-isoquinolin-l-ones, as well as dihydro- and tetrahydroisoquinolines. 

Examples of the direct 5-metalation of nonfused compounds containing heterocyclic sp3-nitrogen are quite limited, often because of competing side-reactions such as benzylic deprotonation. However, with the appropriate substitution pattern 8-metalation can occur even in those cases where benzylic deprotonation is a possibility. Examples of successful 8-lithiation include the imidazolidine 172 and 2-methyloxazolidine 173 (91G249), as well as the tetrahydroisoquinoline derivative 174 [69CI(L)621], although in this latter case subsequent steps resulted in only a 10% yield of the desired product 175. 

Derdau, V. Snieckus, V. Condensation of laterally lithiated o-methyl and o-ethyl benzamides with imines mediated by (-)-sparteine. Enantioselective synthesis of tetrahydroisoquinolin- 236 1-ones./. Org. Chem. 2001, 66, 1992-1998. 

Although lithiated 1,2,3,4-tetrahydroisoquinoline reacts with aldehydes with little diastereoselectivity, the presence of MgBr2 dramatically enhances the selectivity. /-Isomers are obtained from 2-pivaloyl-1,2,3,4-tetrahydroisoquinoline in > % de, and a u-isomer predominantly from a formamidine. In Ae latter case, an organomagnesium reagent (3) formed by transmetalation was shown to be the reactive intermediate (Scheme 15). ... 

A one-pot procedure for the activation and metalation of tetrahydroisoquinoline involves the carbona-tion of tie li ium amide anion and then further metalation. As is illustrated in Scheme 45, the dipole-stabilized anion species may be added to carbonyl compounds in good yield.For the activation of tetrahydroisoquinoline Grignards, Seebach examined benzamides, pivalamides and phosphoramides, and found that the benzamides would not metalate, and that although the phosphoramides were most easily removed, the pivalamides were the most nucleoj ilic species. As is shown in Scheme 46, the lithiated pi-valoylisoquinoline adds to cyclohexanone in good yield. 

In 1981, several papers appeared detailing the alkylation of the 1-position of tetrahydroisoquinolines through the intermediacy of lithiated amides ° phosphoramides, and formamidines.- TTiese systems are discussed thoroughly in Beak s 1984 review, and so we will only provide one illustration of each in Scheme 13. 

The yield of the lithiation, in case of benzylamine, is again good only when the amine is tertiary. This then leads to the quaternary salt in the cyclisation reaction. The dehydrogenation of quaternary salt does not proceed in synthetically useful yield. For this reason the method is not suitable for the synthesis of isoquinolines themselves. However, when the desired product is a tetrahydroisoquinoline the method can be of some value as in a synthesis of tetrahydropalmatine (vide infra). 

The reduction of imines such as 3,4-dihydroisoquinolines with chiral sodium triacyloxyborohydrides [NaB(0acyl)3H] has been effected in optical yields of up to 1 % Two new methods for the preparation of 1-substituted tetrahydroisoquinolines have been reported. These both involve directed 1-lithiation and subsequent reaction with electrophiles. The directing groups on nitrogen are CH=N-R and P(0)(NMe2)2 (see above) respectively, both of which are readily removable. 

Methoxy-1,2,3,4-tetrahydroisoquinoline has been obtained through lithiation with butyllithium between the methoxyl group and the side-chain in N-pivaloyl 2-(3-methoxyphenyl)ethylamine (X = H), formylation with dimethylformamide to give the formyl compound (X = CHO), followed by cyclisation with 10% hydrochloric acid and finally reduction with sodium borohydride (ref. 150). 

Quirion has reported the first application of chiral carboxylic acids as activating agents and chiral inducers for a-lithiation of tetrahydroisoquinolines [67]. The diastereoselective lithiation and alkylation of acid-derived amides 78 provided 79 in 41-57% yields with moderate drs of up to 92 8 (Scheme 22). The chiral auxiliary can be removed under refluxing basic conditions (KOH/MeOH) in 60-70% yields. 

Lateral Lithiation. An enantioselective synthesis of tetrahydroisoquinolin-l-ones via a BuLi/(—)-sparteine-mediated lateral metalation-imine addition sequence proceeds with highest yields and induction in toluene/ether mixtures (eq 46). ... 

With respect to lithiated aziridines, their chemical and synthetic utility has been reviewed during the past year (13SL1061). Additionally, synthesis of a series of 1,2,3,4-tetrahydroisoquinolines was reported via microreactor-mediated thermal isomerization of laterally lithiated arylaziridines (13MI1872). Furthermore, chiral aziridines continue to be employed as... 

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