AgSbF6-catalyzed C3 aza-Friedel-Crafts alkylation of N,O-acetals with indoles for the synthesis of N-α indole substituted pyrrolidine and piperidine derivatives.

An efficient approach to access chiral N-α indole substituted pyrrolidine and piperidine skeletons has been developed through a AgSbF6-catalyzed N-α aza-Friedel-Crafts alkylation of N,O-acetals 6a, 6b, 9, and 11a-11d with indoles. As a result, a series of 2,3-trans N-α indole substituted pyrrolidines 8a-8x and piperidines 10a-10j were prepared in moderate to excellent yields and with excellent diastereoselectivities (dr up to 99 : 1). Moreover, several 2,5-cis-N-α indole substituted pyrrolidine derivatives 12a-12k were synthesized according to this strategy with moderate to good yields and diastereoselectivities (dr up to 99 : 1).

SmI2-mediated intermolecular addition-elimination of piperidine and pyrrolidine N-α-radicals with arylacetylene sulfones.

An efficient approach to access α-arylacetylene-substituted pyrrolidine and piperidine derivatives has been developed through a samarium diiodide-mediated addition-elimination process of pyrrolidine and piperidine N-α-radicals with arylacetylene sulfones.

Palladium-Catalyzed Sequential Heck Reactions of Olefin-Tethered Aryl Iodides with Alkenes.

An efficient approach to functionalized (E)-3-cinnamyl-3-methyl-2,3-dihydrobenzofurans and (E)-(3-methyl-2,3-dihydrobenzofuran-3-yl)but-2-enones has been developed through a Pd-catalyzed one-pot cascade process involving two sequential Heck reactions, that is, an intramolecular Heck reaction of olefin-tethered aryl iodides and an intermolecular Heck reaction with substituted styrenes and α,ß-unsaturated ketones. As a result, a series of desired products were obtained in moderate to good yields and with exclusive E-form selectivities.

In(OTf)3-catalyzed N-α phosphonylation of N,O-acetals with triethyl phosphite.

A practical approach to α-aminophosphonates has been developed through an In(OTf)3-catalyzed N-α phosphonylation of N,O-acetals with triethyl phosphite 7. Indoline and isoindoline N,O-acetals 6a-6j and 9a-9j and chain N,O-acetals 11a-11p were subjected to a Lewis acid catalyzed N-α phosphonylation process. As a result, the desired α-aminophosphonates 8a-8j, 10a-10j and 12a-12p were obtained in moderate to good yields.

AgNTf2 catalyzed cycloaddition of N-acyliminium ions with alkynes for the synthesis of the 3,4-dihydro-1,3-oxazin-2-one skeleton.

A catalyzed process for the synthesis of the 4,6-substituted 3,4-dihydro-1,3-oxazin-2-one skeleton has been developed through cycloaddition of in situ generated acyliminium intermediates with alkynes. A range of chain N,O-acetals and terminal alkynes were amenable for this mild transformation. As a result, a series of desired cycloaddition products were obtained in moderate to good yields.

Cu(OTf)2-catalyzed C3 aza-Friedel-Crafts alkylation of indoles with N,O-acetals.

An efficient approach to access functionalized indole derivatives has been developed through Cu(OTf)2-catalyzed C3 aza-Friedel-Crafts alkylation of substituted indoles 5a-5m, N-methyl-pyrrole with linear N,O-acetals 4a-4l. As a result, a series of C3 amide aza-alkylated indole derivatives 6a-6ag and 7 were synthesized in moderate to excellent yields.

AgNTf2-Catalyzed Regioselective C-H Alkenylation of N,N-Dialkylanilines with Ynamides.

Regioselective C-H alkenylation of N,N-dialkylanilines with ynamides was developed using AgNTf2 as a catalyst. This approach represents a facile hydroarylation of ynamides, allowing for the introduction of an alkenyl group exclusively at the para position of aniline derivatives. As a result, a series of 4-alkenyl N,N-dialkylanilines were synthesized with excellent regioselectivities.

Cu(OTf)2 catalyzed Ugi-type reaction of N,O-acetals with isocyanides for the synthesis of pyrrolidinyl and piperidinyl 2-carboxamides.

The Cu(OTf)2 catalyzed Ugi-type reactions of N,O-acetals with isocyanides have been described for the synthesis of pyrrolidinyl and piperidinyl 2-carboxamides. 4-Hydroxy-5-substituted-prolinamides can be obtained in high diastereoselectivities (2,4-cis/trans > 19 : 1) and a stereoselective model was proposed for 2,4-cis selectivity. Moreover, 4-F-VH 032, a novel analog of the VHL ligand, was conveniently obtained by utilizing the present method.

TMSOTf-mediated synthesis of skipped dienes through the addition of olefins to imines and semicyclic N,O-acetals.

A novel approach to skipped dienes has been developed through the TMSOTf-mediated one-pot addition-substitution of olefins 2a, 2f and 2g with imines 1a-1g, and a series of aryl substituted skipped dienes 3aa-3gf were accordingly obtained in 62%-94% yields. Moreover, semicyclic N,O-acetals 5 and 7 could also undergo this transformation to produce the corresponding skipped dienes 6aa and 6af-6al and 8ba and 8bf-8bk in moderate to good yields.

A One-Pot Approach to 2-Substituted-2-(Dimethoxyphosphoryl)-Pyrrolidines from Substituted tert-Butyl 4-Oxobutylcarbamates and Trimethyl Phosphite.

A novel approach to 2-substituted-2-(dimethoxyphosphoryl)-pyrrolidines 7a-7o and 9a-9r has been developed, which features a TMSOTf-mediated one-pot intramolecular cyclization and phosphonylation of substituted tert-butyl 4-oxobutylcarbamates. The major advantages of this method include simple operation under mild reaction conditions, the use of cheap Lewis acid, and good to excellent yields with high diastereoselectivities (dr up to 99:1).

Zn(OTf)2-catalyzed hydroamination of ynamides with aromatic amines.

The Zn(OTf)2-catalyzed hydroamination of ynamides 2a-2l with aromatic amines 1a-1r was developed. This protocol features broad substrate scope of aromatic amines, good functional group tolerance for ynamides, and excellent regioselectivities. As a result, a variety of substituted amidine compounds 3aa-3oa, 3ab-3al and 3pa-3rk were prepared in moderate to excellent yields and with high regioselectivities.

Synthesis of Functionalized Bicyclo[2.2.2]octan-2-ones Skeleton via Tandem Process of Amino Acid Involved Formal [4 + 2] and Decarboxylative-Mannich Sequence.

An efficient approach to a functionalized bicyclo[2.2.2]octan-2-one scaffold has been developed through a one-pot cascade process including amino acid involved successive Michael addition and decarboxylative-Mannich sequence. Starting from α,ß-unsaturated ketones and amino acids, a series of desired products 7a-7m and 8a-8o were obtained with moderate yields. In addition, the tandem process was reasonably explained by the results of DFT calculations.

Nickel-Catalyzed Regioselective Hydroamination of Ynamides with Secondary Amines.

The first Ni(OTf)2-catalyzed hydroamination of ynamides 2 was developed by reacting with secondary amines (1 and 4). This protocol features excellent regioselectivity, a broad substrate scope of secondary aryl amines, and good functional group tolerance for ynamides. Using this method, a variety of substituted ethene-1,1-diamine compounds were prepared in moderate to excellent yields with high regioselectivities.

Sc(OTf)3-catalyzed [3 + 2]-cycloaddition of nitrones with ynones.

An efficient approach to access functionalized (2,3-dihydroisoxazol-4-yl) ketones has been developed by reacting nitrones 4 with ynones 7 or terminal ynones 10 in a one-pot fashion. The reaction went through a formal Sc(OTf)3-catalyzed [3 + 2]-cycloaddition process to generate a number of functionalized (2,3-dihydroisoxazol-4-yl) ketones 11aa-11aw, 11ba-11la and 12aa-12ae in moderate to good yields.

Synthesis of a 3,4-Dihydro-1,3-oxazin-2-ones Skeleton via an Intermolecular [4 + 2] Process of N-Acyliminium Ions with Ynamides/Terminal Alkynes.

An approach to access functionalized 3,4-dihydro-1,3-oxazin-2-ones has been developed by reacting semicyclic N,O-acetals 5 and 6 with ynamides 7 or terminal alkynes 8 in a one-pot fashion. The reaction went through a formal [4 + 2] cycloaddition process to generate a number of functionalized 3,4-dihydro-1,3-oxazin-2-ones 9a-9ak and 10a-10bc in yields of 34-97%. In addition, the utility of this transformation was demonstrated by the synthesis of (±)-sedamine 13.

Synthesis of 1-benzylisoindoline and 1-benzyl-tetrahydroisoquinoline through nucleophilic addition of organozinc reagents to N,O-acetals.

A new approach to access 1-benzylisoindoline and 1-benzyl-tetrahydroisoquinoline has been developed through nucleophilic addition of organozinc reagents to N,O-acetals. A number of substituted organozinc reagents were amenable for this transformation, and the desired products were obtained with excellent yields. Moreover, Sc(OTf)3 proved to be an effective catalyst for the formation of 1-benzylisoindoline and 1-benzyl-tetrahydroisoquinoline using such nucleophilic addition.

Gold-Catalyzed Addition-N-Boc Cleavage-Cyclization of N,O-Acetal with Ynamides for Construction of 6-(tert-Butyldimethylsilyl)oxy-tetrahydropyrrolo[1,2-c][1,3]oxazin-1-ones.

A highly efficient gold-catalyzed approach between N,O-acetals and ynamides for the construction of 6-(tert-butyldimethylsilyl)oxy-tetrahydropyrrolo[1,2-c][1,3]oxazin-1-ones was developed. This reaction tolerated a wide range of substituted N,O-acetals and TsN-substituted ynamides, leading to novel heterocycles in moderate to good yields and with excellent diastereoselectivities (dr > 99:1).

Synthesis of Amide Enol Carbamates and Carbonates through Cu(OTf)2-Catalyzed Reactions of Ynamides with t-Butyl Carbamates/Carbonates.

A highly regioselective approach to access amide enol carbamates and carbonates 5a-5c', 7a-7h, and 9 was developed through Cu(OTf)2-catalyzed reactions of ynamides 4 with t-butyl carbamates 2 and 8 and t-butyl carbonates 6. Moreover, this strategy was successfully applied to generate amide enol carbamates 11a-11s and 14a-14f from imides 10 and 13 with ynamides through an N-Boc cleavage-addition ring-opening process. A range of substituents was amenable to this transformation, and the desired amide enol carbamates and carbonates were obtained in moderate to good yields.

Approach to Tertiary-Type ß-Hydroxyl Carboxamides Through Sc(OTf)3-Catalyzed Addition of Ynamides and Ketones.

An efficient approach to access functionalized tertiary-type ß-hydroxyl carboxamides has been developed through Sc(OTf)3-catalyzed addition of ynamides and substituted ketones. Water was found to be an important reaction substrate, and the solvent was not needed in this process. A broad range of substituted ynamides and ketones was well applicable to the reaction with excellent chemical selectivities. Moreover, several chiral ß-hydroxyl carboxamides 3j-3r were prepared with excellent regioselectivities and outstanding diastereoselectivities.

Divergent synthesis of N-heterocyclic 1,6-enynes through a zinc-catalyzed decarboxylative A3 reaction.

A zinc-catalyzed decarboxylative A3 reaction of cyclic amino acids, α,ß-unsaturated aldehydes and terminal alkynes has been developed. A series of functionalized N-heterocyclic 1,6-enynes have been successfully obtained with excellent regioselectivities through this novel approach. In addition, the utility of this straightforward process is demonstrated by the preparation of a polycyclic nitrogen-containing heterocyclic compound.