Application of the Pictet-Spengler reaction to aryl amine substrates linked to deactivated aromatic heterosystems

Three new substrates with an aryl amine moiety attached to quinoxalines, triazoles and tetrazoles either via C or N have been used for the Pictet-Spengler reaction. The substrates have been designed by applying the concept of ‘aryl amine attached to a deactivated heteroaromatic ring’ in a manner to facilitate endo cyclization. This is in contrast to the substrates used traditionally and reported earlier by us that are based on either aliphatic or aryl amine, respectively, attached to an activated heterocyclic ring. The Pictet-Spengler condensation of the three substrates with aldehydes led to the synthesis of novel N-rich polyheterocyclic system hitherto not reported. Our modified strategy opens up possibilities to design novel substrates with aryl amines linked via C or N to either deactivated or activated heterocyclic privileged structure, which in turn can be used for the synthesis of novel fused polyheterocyclic skeletons.     

Application of the Pictet-Spengler reaction to aryl amine-based substrates having pyrimidine as a π-nucleophile: synthesis of pyrimidoquinolines with structural analogy to benzonaphthyridines present in alkaloids

Synthesis of pyrimidine annulated quinolines, structurally analogous to biologically active benzonaphthyridines present in alkaloids, has been described. Our synthetic strategy is based on the modified Pictet-Spengler reaction involving substrates comprising deactivated pyrimidine ring as the nucleophilic partner whereas aryl amine originating from the C-4 of the pyrimidine ring served as the source for electrophilic partner. The resulting substrates 5-7 with diversity at 2- and 6-position after condensation with a variety of aldehydes underwent 6-endo cyclization to furnish pyrimido[5,4-c]quinolines 14 in good yields. However, attempts to further extend this strategy on new structurally analogous substrate involving the pyridine ring as nucleophilic partner failed, thus limiting the scope of the reaction.     

Asymmetric hydrophosphonylation of aldehydes catalyzed by bifunctional chiral Al(III) complexes

A new bifunctional chiral Al(III) complex of BINOL derivative, which contained tert-amine at 3,3′-position of the BINOL, has been developed for the effective enantioselective hydrophosphonylation of aldehydes. A variety of aromatic, heteroaromatic, condensed-ring, α,β-unsaturated, and aliphatic aldehydes were found to be suitable substrates for the reaction, and the desired α-hydroxy phosphonate were obtained in good to excellent yields (up to 99%) with moderate to good enantioselectivities (up to 87% ee) under mild conditions (at 0 °C). A possible catalytic cycle based on the experimental results was proposed.     

New application of Pictet-Spengler reaction leading to the synthesis of an unusual seven-membered heterocyclic ring system

A novel strategy for the Pictet-Spengler reaction is reported. Our strategy involves reaction of arylamines, linked to the N-1 of disubstituted imidazoles, with aldehydes in the presence of p-TsOH. The iminium ion generated in situ undergoes C-C bond formation with the C-5 of the imidazoles to furnish triazabenzoazulenes as a novel heterosystem. Our strategy differs from conventional Pictet-Spengler reaction since the latter utilizes only aliphatic amines in which the amine functionality is linked to a C instead of N of the activated aromatic moiety.     

A modified strategy for Pictet-Spengler reaction leading to the synthesis of imidazoquinoxalines on solid phase

An alternative strategy for Pictet-Spengler reaction involving an N-1 linked aromatic amine of imidazole and aldehydes is described. This is in contrast to a typical Pictet-Spengler reaction, which involves an aliphatic amine attached to the carbon of an activated aromatic nucleus and an aldehyde. Our strategy commences with the nucleophilic replacement of fluorine in resin-bound o-fluoro-nitrobenzoic acid with mono- or disubstituted imidazole, followed by reduction of the nitro group to give an N1 linked aromatic amine of the resin-bound imidazole. This was subsequently treated with an aldehyde in toluene at 80 degrees C and then oxidized in the presence of DDQ to give resin-bound imidazoquinoxalines. Finally, acidolytic cleavage furnished the desired compounds in high yields and purities.     

Water as an efficient medium for the synthesis of tetrahydro-β-carbolines via Pictet-Spengler reactions

A mild and efficient protocol for the Pictet-Spengler reaction in water using an acid catalyst has been described. The condensation of tryptophan, tryptamine, and N_b-benzyl tryptophan with different aldehydes having both electron-withdrawing and -donating substituents in the presence of a catalytic amount of TFA in water furnished tetrahydro-β-carbolines in good isolated yields. A salient feature of the water mediated Pictet-Spengler reaction was the general trend observed during the condensation of Trp-OMe and aryl/aliphatic aldehydes furnishing diastereomeric mixtures with a preference for the cis-isomer.     

An expeditious synthesis of hexahydrobenzo[f]isochromenes and of hexahydrobenzo[f]isoquinoline via iodine-catalyzed Prins and aza-Prins cyclization

Homoallylic alcohols (primary, secondary, or tertiary containing an endocyclic or an exocyclic double bond) react with equimolar amounts of aldehydes (aliphatic or aromatic) and ketones (aliphatic) in the presence of 5 mol % of iodine. This Prins cyclization was used in the preparation of hexahydrobenzo[f]isochromenes and of a 4-hydroxy-tetrahydropyran, in 54-81% yield. The procedure is also efficient for an aza-Prins cyclization of a homoallylic sulfonamide and benzaldehyde, producing a hexahydrobenzo[f]isoquinoline.     

Novel synthesis of tetrahydro-β-carbolines and tetrahydroisoquinolines via three-component reaction using hexagonally ordered mesoporous AlSBA-15 catalysts

Tryptamine, aryl aldehyde, and benzyl chloride undergo smooth coupling using well-ordered mesoporous AlSBA-15 catalyst with hexagonal porous structure in acetonitrile at 80 °C to furnish tetrahydrocarbolines in good yields with a high selectivity. This reaction also proceeds with homoveratrylamine to give the corresponding tetrahydroisoquinolines. A variety of aryl and heteroaryl aldehydes have also been used for producing tetrahydrocarbolines in high yields. This AlSBA-15-promoted Pictet-Spengler reaction provides a mild alternative to the traditional Brönsted or Lewis acids typically employed for the preparation of tetrahydrocarbolines and tetrahydroisoquinolines.     

Preparation of hexahydrobenzo[f]isoquinolines using a vinylogous pictet-spengler cyclization

A vinylogous Pictet-Spengler cyclization has been carried out using activated aldehydes, ketones, and alkynes to prepare a variety of substituted hexahydrobenzo[f]isoquinolines. A unique set of conditions was utilized to effect efficient cyclization with acid-sensitive electrophiles.     

Enantioselective BINOL-phosphoric acid catalyzed Pictet-Spengler reactions of N-benzyltryptamine

Optically active tetrahydro-beta-carbolines were synthesized via an ( R)-BINOL-phosphoric acid-catalyzed asymmetric Pictet-Spengler reaction of N-benzyltryptamine with a series of aromatic and aliphatic aldehydes. The tetrahydro-beta-carbolines were obtained in yields ranging from 77% to 97% and with ee values up to 87%. The triphenylsilyl-substituted BINOL-phosphoric acid proved to be the catalyst of choice for the reaction with aromatic aldehydes. For the aliphatic aldehydes, 3,5-bistrifluoromethylphenyl-substituted BINOL-phosphoric acid was identified as the best catalyst.     

A modular, one-pot, four-component synthesis of polysubstituted 1,3-oxazolidines

A modular, one-pot, two-step, four-component synthesis of polysubstituted 1,3-oxzolidines is described. The method comprises two linked domino processes: an organocatalyzed domino reaction of alkyl propiolate and an aliphatic aldehydes and a microwave-assisted amine addition cyclization domino process. An alternative modular, one-pot, three-step, four-component synthesis has also been developed by linking the organocatalyzed domino process to a sequential amine addition/Yb(OTf)(3)-catalyzed enamine cyclization reaction.     

Bifuctional amino-squaramides catalyzed asymmetric spiroannulation cascades with aliphatic β,γ-unsaturated α-keto esters: controlling an aldehyde enolate

A quinidine-derived squaramide Ib catalyzed cyclization reaction of β-oxo aldehydes 1 and aliphatic or aromatic β,γ-unsaturated α-keto ester 2 is described. Using cyclic aldehyde substrates, this procedure provided a promising approach to a variety of spiro-3,4-dihydropyrans bearing three continuous quaternary and tertiary stereocenters in moderate to good yield with high stereoselectivities. Substituents on the nitrogen atoms of the squaramide moiety of the catalyst proved crucial to the reaction outcome. The stereochemistry of the three newly formed chiral centers (trans-selective) of the major product indicates a Micheal addition/hemiacetalization domino sequence for the present annulations.     

Lithium diisobutyl-t-butoxyaluminum hydride, a new and efficient reducing agent for the conversion of esters to aldehydes

Lithium diisobutyl-t-butoxyaluminum hydride (LDBBA), easily prepared by reaction of lithium t-butoxide with DIBALH, readily reacts with common aromatic and aliphatic esters to give the corresponding aldehydes in 74-88% yield at 0 °C. Especially, this reagent proved to be the most effective partial reducing agent for conversion of isopropyl esters to aldehydes, in most cases, with >90% yield under the same reaction temperature.     

Direct reductive amination of aldehydes using lithium-arene(cat.) as reducing system. A simple one-pot procedure for the synthesis of secondary amines

A simple one-pot procedure for the direct reductive amination of aldehydes using lithium powder and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB) or a polymer supported naphthalene as reducing system is described. The direct reductive amination of a variety of aldehydes with primary amines was achieved simply by adding a mixture of the corresponding carbonyl compound and the amine, over a solution of the lithium arenide in THF at room temperature. For most of the substrates tested the main reaction products were the secondary amines along with variable amounts of the corresponding alcohol and/or imine products. Theoretical DFT calculations have been applied in order to explain the differences in reactivity observed for aromatic substrates.     

Synthetic investigations of (1,3′)-bistetrahydroisoquinolines: towards pentacyclic analogues of piperazine core alkaloids

Synthetic investigations of (1,3′)-bistetrahydroisoquinolines are reported as the key intermediates for the synthesis of ecteinascidin and phthalascidin pentacyclic structure analogues through successive Pictet-Spengler cyclization and intramolecular peptide coupling. The direct Pictet-Spengler reaction between a derivative of l-DOPA and N-protected-α-aminoaldehyde was first extended to the synthesis of cis-(1,3′)-bistetrahydroisoquinoline. After introduction of the required amino acid moiety, an efficient six-membered ring intramolecular peptide coupling gave rise to piperazine derivative structures. Complete structural assignments were corroborated by NMR and X-ray spectroscopic methods. Nevertheless, the optical integrity of the N-protected-α-aminoaldehyde seems to be sensitive to the reaction conditions. Pentacylic structures, having an anti C3-C11 backbone stereochemistry, were obtained from cyclization para- and ortho- to the 3-OH group of the l-DOPA derivative.     

Synthesis of novel substituted naphthoquino[b]-benzo[e][1,4]diazepines via Pictet-Spengler cyclization

Synthesis of novel 4,5-dihydro-1H-1,4-naphthoquino[b]-benzo[e][1,4]diazepine derivatives via Pictet-Spengler cyclization is reported. Reaction of 2,3-diamino-naphthoquinones with aldehydes in the presence of BF₃·Et₂O gives benzodiazepine-naphthoquinones in good yields.     

1,3,5,7-Tetramethyl-8-aminozide-difluoroboradiaza-s-indacene as a new fluorescent labeling reagent for the determination of aliphatic aldehydes in serum with high performance liquid chromatography

A BODIPY-based fluorescent derivatization reagent with a hydrazine moiety, 1,3,5,7-tetramethyl-8-aminozide-difluoroboradiaza-s-indacene (BODIPY-aminozide), has been designed for aldehyde labeling. An increased fluorescence quantum yield was observed from 0.38 to 0.94 in acetonitrile when it reacted with aldehydes. Twelve aliphatic aldehydes from formaldehyde to lauraldehyde were used to evaluate the analytical potential of this reagent by high performance liquid chromatography (HPLC) on C₁₈ column with fluorescence detection. The derivatization reaction of BODIPY-aminozide with aldehydes proceeded at 60 °C for 30 min to form stable corresponding BODIPY hydrazone derivatives in the presence of phosphoric acid as a catalyst. The maximum excitation (495 nm) and emission (505 nm) wavelengths were almost the same for all the aldehyde derivatives. A baseline separation of all the 12 aliphatic aldehydes (except formaldehyde and acetaldehyde) is achieved in 20 min with acetonitrile–tetrahydrofuran (THF)–water as mobile phase. The detection limits were obtained in the range from 0.43 to 0.69 nM (signal-to-noise = 3), which are better than or comparable with those obtained by the existing methods based on aldehyde labeling. This reagent has been applied to the precolumn derivatization followed with HPLC determination of trace aliphatic aldehydes in human serum samples without complex pretreatment or enrichment method.     

Zirconium-catalyzed asymmetric Kabachnik–Fields reactions of aromatic and aliphatic aldehydes

An effective catalyst has been developed for the three-component reaction of aldehydes, anilines and phosphites in an asymmetric catalytic Kabachnik–Fields reaction to give α-aminophosphonates. A catalyst was sought that would give high asymmetric inductions for aromatic and, and more particularly, for aliphatic aldehydes since there has not previously been an effective catalyst developed for this class of aldehydes. The optimal catalyst is prepared from three equivalents of the 7,7′-di-t-butylVANOL ligand, one equivalent of N-methylimidazole and one equivalent of zirconium tetraisopropoxide. This catalyst was most efficient in the presence of 10 mol% benzoic acid. Optimal conditions for aryl aldehydes required the use of 3,5-diisopropyl-2-hydroxyaniline and gave the aryl α-aminophosphonates in up to 96% yield and 98% ee over 11 different aryl aldehydes. The best aniline for aliphatic aldehydes was found to be 3-t-butyl-2-hydroxyaniline and gave the corresponding phosphonates in up to 83% yield and 97% ee over 18 examples. The asymmetric inductions for aliphatic aldehydes were comparable with those for aromatic aldehydes with a mean induction of 90% ee for the former and 91% ee for the latter. The best method for the liberation of the free amine from the aniline substituted α-aminophosphonates involved oxidation with N-iodosuccinimide.

An effective catalyst has been developed for the three-component reaction of aldehydes, anilines and phosphites in an asymmetric catalytic Kabachnik–Fields reaction to give α-aminophosphonates.     

Iodine-catalyzed Friedel-Crafts alkylation of electron-rich arenes with aldehydes: efficient synthesis of triarylmethanes and diarylalkanes

Iodine is shown to be an efficient catalyst for the Friedel-Crafts alkylation of arenes with a wide variety of aldehydes in toluene under ‘open-flask’ and mild conditions. In the presence of 10 mol % of iodine, the reaction of arenes with aromatic aldehydes gives the corresponding triarylmethane derivatives (TRAMs), regioselectively, in good to excellent yields. On the other hand, a series of diarylalkane derivatives is synthesized smoothly by the reaction with aliphatic aldehydes.     

Nickel-catalyzed selective conversion of two different aldehydes to cross-coupled esters

In the presence of a Ni(0)/NHC catalyst, an equimolar mixture of aliphatic and aryl aldehydes can be employed to selectively yield a single cross-coupled ester. This reaction can be applied to a variety of aliphatic (1°, 2°, cyc-2°, and 3°) and aryl aldehyde combinations. The reaction represents 100% atom efficiency and generates no waste. Mechanistic studies have revealed that the striking feature of the reaction is the simultaneous coordination of two aldehydes to Ni(0).