Dihydroisoquinolines, alkylation

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... 

By acylation of 2-methyl-l,2-dihydroisoquinoline (127) with 3,4-dimeth-oxyphenacylchloride a C-4 alkylated product 128 is formed (208). 

Alkyl-3-ethoxy-4-[(mesyloxy)methyl]-l,4-dihydroisoquinolines 27 on treatment with potassium /Vrt-butoxide in dimethyl sulfoxide undergo ring expansion to 1/7-2-benzazepines.24 0 (For related ring expansions of acridines, see Section 3.2.1.4.1.5.) The 4-methyl and 4-methyl-l-phenyl derivatives 27a and 27b, respectively, yield mixtures of the 3-ethoxy-5-methyl- 28 and 3-ethoxy-4-methyl- 29 l//-2-benzazcpines cyclopropaquinolines are thought to be involved as intermediates (see Section 3.2.1.4.1.6.). In contrast, the 4-[l-(mesyloxy)ethyl] derivatives 27e and 27d yield only the 4,5-dimethyl-li/-2-benzazepines 29c and 29d. 

Alkylation of the lactam 92 via its enolate has been studied and shown to be highly stereoselective. The 4-substituted l,4-dihydroisoquinoline-3-one 93 was obtained in high yield with greater than 97% de <96T(A)(7)417>. 

In this route a dihydroisoquinoline (58) is N alkylated with a highly functionalized o -bromoacetophenone (59) to give a quaternary salt (60), which is treated with base and cyclizes to a pyrroloisoquinoline (60). The pyrrole nucleus is then formylated under Vilsmeier-Haack conditions at position 5 and a proximate mesylated phenolic group is deprotected with base to yield a pen-tasubstituted pyrrole (61). Subsequent oxidative cyclization of this formylpyr-role produces the 5-lactone portion of lamellarin G trimethyl ether (36). This sequence allows for rapid and efficient analog synthesis as well as the synthesis of the natural product. 

Stereochemical control of a reaction can also be achieved using non-chiral catalysts, when a chiral centre already exists in the reactant, as for example in the reaction of cyano- or methoxycarbonylmethyl phosphonates with 3-hydroxy-2-(S)-alkylated products are obtained with ca. 40% de of the 2(S)-3(R)-diastereoisomers [11]. Similarly, when ethyl glycine is Ar-protected with (S)-menthone, C-alkylation under soliddiquid conditions using a non-chiral catalyst (6.4.5) provides a route to chiral a-substituted amino acids with optimum enantiomeric excesses of up to 47% [12],... 

Several 1-benzylisoquinoline alkaloids have been synthesized utilizing the above reaction sequence. For example, takatonine (34) has been obtained from Reissert compound 27 via alkylation with p-methoxybenzyl chloride and subsequent hydrolysis and quatemarization with methyl iodide 17). Similarly, es-cholamine (37) has been prepared from A-benzoyl-l-cyano-6,7-meth-ylenedioxy-1,2-dihydroisoquinoline (28) and 3,4-methylenedioxybenzyl chloride (77) as shown in Scheme 6. 

A Once the 1,2-dihydroisoquinoline is formed by a Potneranz-Friisch synthesis between the reduced imine, from 4-methoxybenzaldehyde and ami noacetaldehyde diethyl acetal, it is combined directly with the l-(2-bromoethyl)-3-meihoxybenzene in a tandem two-steps-in-one procedure (Scheme 3.21), First the compound acts as an enamine and combines with the alkyl bromide at C-4, and then the methoxylated phenyl ring of the intermediate reacts with the iminium unit at C-3 to form the letracycle. 

Another common process involves reaction with C=C or C=N species having adjacent CH2 or CH, groups. Initial attack of the isocyanate is on the electron-rich center of the double bond with subsequent migration and insertion of the CONR group into the CH bond. Suitable reagents include N-alkylated acetamidines, 1-methyl dihydroisoquinoline, and 2-methyl-2-oxazoline [1120-64-5] (35). 

Rozwadowska and coworkers carried out the asymmetric alkylation of isoquino-line Reissert compounds under phase-transfer conditions using cinchonine-derived quaternary ammonium salts as catalysts. The best enantioselectivity was achieved in the benzylation and allylation of 1 -cyano-2-phenoxy carbonyl-1,2-dihydroisoquinoline (17) catalyzed by 2a (Scheme 2.14) [34]. 

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]. 

Isoquinolinium salts are reduced to 2-alkyl-1,2-dihydroisoquinoline derivatives by sodium dithionite,6 lithium aluminum hydride7,8 (LAH), or dialkyl aluminum hydrides.9 LAH is preferred7 to dithionite since it leads to purer products, and will reduce those salts that are inert to dithionite (e.g., papaverine methiodide). Isoquinoline itself10,11 and 3-methyl-6,7-methylenedioxyisoquinolinelz (5) can be reduced to the 1,2-dihydroisoquinoline with LAH, as can isoquinoline... 

A closely related reaction with berberines has been known80 for some time. Palmatine [(41) R = OMe] condenses with acetone to yield the 1,2-dihydroisoquinoline derivative [(55) R = OMe] which, with methyl iodide, followed by acid-catalyzed removal of the acetone residue, yields 56. Reduction then gives corydaline [(57) R = OMe]. Dihydroberberine (34) is alkylated by methanol in a similar reaction... 

The copper(I) iodide promoted cyclization of 7V-(2-haloaryl)-substituted enaminones is a good method to yield indoles and carbazoles. This type of intramolecular arylation is a reasonable alternative to the route via benzyne (see Section A.l.f) (equation 106). The method could be extended to 7V-(2-haloaryl)alkyl-substituted enaminones which give the expected dihydroisoquinolines whereas a nucleophilic attack of the nitrogen instead of the /1-carbon give the undesired indoles159 (equation 107). 

Sequential reaction of azines with alkyl hthium compounds and chloroformates usually affords the expected Reissert-type products 136, together with minor amounts of doubly acylated compounds 135 (Scheme 18b). Isoquinoline is likely to react directly with the alkyl-lithium compound to generate the alkylated lithio-enamine intermediate E, and this species may account for the formation of dihydroisoquinolines 135 and 136, through interaction with the electrophihc partner. Mamane recently expanded this concept by replacing the acylating agent with different electrophiles. These combinations lead exclusively to isomers 134 (Scheme 18) [118-120]. 

Thiazoles are deactivated towards electrophilic substitution, and thus direct reaction with hydride re-ductants to give thiazolines should be facilitated. There are indeed some examples of this type of reaction, but it is more common to reduce N-alkylated thiazolium salts (209). These compounds are converted first by reaction with sodium borohydride into 4-thiazolines (210), which in protic solvents become protonated and undergo further reduction to yield thiazolidines (211). Similarly the isoquinoli-nium salt (213), formed by the acid-promoted cyclization of the isoquinoline (212), is converted into the tetrahydroisoquinoline (214) (presumably via an intermediate 1,2-dihydroisoquinoline) by reaction with sodium borohydride. ... 

Imines. Secondary amines such as 3,4-dihydroisoquinoline are dehydrogenated on reaction with 1. A similar reaction on A-alkyl-A-methylanilines converts the methyl substituent to a f-butylperoxymethyl group. 

P-Lactams 28 were obtained from reaction of acylhydrazones with chloroacetyl chloride . A -Alkylation of acridine derivatives with 1,3-propane sultone gave 29. P-Phenethylamides gave 3,4-dihydroisoquinolines and N-sulfonyl gave isoquinolines 30. Nucleophilic substitution of 4-bromoisoquinoline gave the corresponding 4-substituted isoquinolines. o-Bromobenzaldehyde was reacted with allylamine and then homophthalic anhydride to afford 31. ... 

Treatment of the compounds 78 with various alkyl halides in the presence of sodium hydride results in 1-alkylation as with normal Reissert com-pounds. ° Acylation has also been reported under these conditions. Under a variety of conditions, however, 78 does not react with benzaldehyde. Acid hydrolysis of 80 gave tetrahydroquinaldic acid, while acid hydrolysis of the alkylated dihydroisoquinoline-Reissert compounds gave the amino acids 81. By first complexing the alkylated dihydroisoquinoline-Reissert compound with zinc chloride in ether and then hydrolyzing the complex, the nitrile was hydrolyzed to an acid, but the amide group was left intact. The perchlorate salts of dihydroisoquinoline-Reissert compounds have also been prepared, and sodium borohydride reduction proceeds in the same manner as reduction of the Reissert salt to... 

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]. 

This method may be used in the case of aliphatic methyl ketones which give, under acidic conditions, the products of aldol condensation, while higher homologues require a very long tirne . N-Methylation of dihydroisoquinolines [32, R = H, Ph, R = R = Me R = H,R = Me,R = Et R R = (CH2)s] with methyl iodide gave enamines JJ186 bicyclic enamine 34 has been prepared by alkylation of the imine 35 followed by treatment of the iminium salt with base . ... 

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