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Joined 2026-09-21 Message
Incoming links: Reductive amination
Methylamine 2026-10-20
Disconnect the amide into 2-propylhexanoic acid and N-methyl-2-(4-hexylphenyl)ethylamine. This keeps the nitrogen substituents distinct: one is Me and the other is the two-carbon aryl side chain. The acid's alpha carbon must bear both n-butyl and n-propyl groups.
For the acid fragment, esterify the supplied hexanoic acid, form its ester enolate with LDA, and alkylate with 1-iodopropane:hydrolysis gives 2-propylhexanoic acid; conversion with gives the acyl chloride for the final coupling. Limit the alkylating reagent and isolate the monoalkylated ester to avoid overalkylation.
For the aryl fragment, use another portion of hexanoic acid to make hexanoyl chloride. A Friedel-Crafts acylation of bromobenzene with this reagent and gives ortho and para products; isolate the para bromoaryl ketone. A Wolff-Kishner reduction converts into without deliberately hydrogenolyzing the aryl bromide. Acylation followed by carbonyl reduction installs an unrearranged n-hexyl group; direct Friedel–Crafts alkylation is a less reliable way to do that.
Convert the retained aryl bromide into its grignard reagent, open ethylene oxide, and work up to obtain . Oxidize the primary alcohol to under conditions that stop at the aldehyde, then perform reductive amination with methylamine and sodium triacetoxyborohydride. Excess methylamine helps favour the desired secondary amine over further alkylation. Finally acylate that secondary amine with the isolated acyl chloride, using a separate base to capture HCl.
The final amide has an N-methyl group, the para n-hexyl phenethyl group, and the required n-butyl/n-propyl acyl branching. The carbon check is in the acyl fragment plus in the amine fragment, giving overall. No absolute stereochemistry is specified at the acid alpha carbon.
Disconnect the N–cyclohexyl bond as a late reductive amination of a primary amine with cyclohexanone. Disconnect the exocyclic methylene as a Wittig methylenation of a substituted cyclohexanone. The useful ring precursor is 3-methyl-5-substituted cyclohex-2-en-1-one, accessible by a Robinson annulation. The pendant substituent throughout ring construction should be .
Start with nucleophilic substitution of the supplied bromo ester by cyanide:Reduce the nitrile selectively to the primary amine while retaining the ester, for example by controlled catalytic hydrogenation with Raney nickel in the presence of ammonia, and trap the amine promptly as its Boc carbamate. Avoid heating or concentrating the free amino ester, which can cyclize to a lactam. lithium aluminium hydride would be unsuitable at this stage because it also reduces the ester.
Partial reduction of the protected ester with DIBAL at low temperature gives . The carbon of the original nitrile is now the methylene nearest nitrogen; the original ester carbonyl is the aldehyde carbon. Condense this aldehyde with acetone and dehydrate to .
Now add the enolate of a second acetone molecule in a Michael addition. With , the resulting chain isIntramolecular aldol condensation gives 3-Me-5-R-cyclohex-2-en-1-one. The beta methyl derives from the carbonyl end attacked in the ring closure; the pendant aminoalkyl chain remains at C5. Hydrogenate the ring C=C selectively, retaining the ketone, then methylenate the ketone with preformed . Do the hydrogenation before installing the exocyclic methylene so that it is not hydrogenated away.
Remove Boc under brief mild conditions, checking for acid-induced exocyclic alkene isomerization. reductive amination of the resulting primary amine with cyclohexanone, followed by selective imine reduction, installs the secondary N-cyclohexyl group. Use controlled stoichiometry to suppress tertiary amine formation. The methyl and four-carbon aminoalkyl substituents occupy the required 1,3-related ring positions, with the exocyclic methylene at the former carbonyl. No ring stereochemistry is specified. The target contains eighteen carbons: six ring carbons, one ring methyl, one methylene, four in the linker, and six in the N-cyclohexyl group.
Disconnect the tertiary amide into cyclohex-3-ene-1-carboxylic acid and the secondary amine . The acid-derived ring is an immediate Diels–Alder disconnection: buta-1,3-diene plus the indicated methyl acrylate gives methyl cyclohex-3-ene-1-carboxylate. Heating, or suitable Lewis-acid activation of the dienophile, forms the two new sigma bonds and leaves the diene's internal double bond as the ring alkene.
Hydrolyse this ester to the acid. Convert it to its acid chloride with oxalyl chloride or thionyl chloride, and react with the secondary amine in the presence of a base to capture HCl. The tertiary amide now contains the complete cyclohexene acyl fragment; direct conjugate addition of the amine to methyl acrylate before ring construction would give the wrong connectivity.
Prepare the amine by reductive amination of 4-phenylbutan-2-one, , with ethylamine, using sodium triacetoxyborohydride or another iminium-selective reducing system. This places nitrogen on , not on a terminal methylene. If a route from simpler carbon compounds is wanted, crossed aldol condensation of acetone with benzaldehyde gives , and selective C=C reduction gives the required ketone before reductive amination.
The acid branch retains the acrylic carbonyl as the amide carbonyl; the amine branch supplies both N-ethyl and N-(4-phenylbutan-2-yl) substituents. The unlabelled stereogenic centres may be racemic mixture. This sequence separates ring formation from amide formation and avoids invoking uncontrolled alkylation of a tertiary amide nitrogen.
Original two-branch synthesis combining a Diels–Alder acid fragment with a reductively aminated secondary amine
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Sodium triacetoxyborohydride 2026-10-20