Orthoamides by selective borohydride reduction of N,N′,N″-triacyl- and N,N′,N″-tri(alkoxycarbonyl)-guanidines

N,N′,N″-Triacylguanidines and N,N′,N″-tri(alkoxycarbonyl)guanidines were prepared and reduced with borohydride salts in a mixture of tetrahydrofuran and acetic acid to give triacyl and tri(alkoxycarbonyl) orthoamides in yields of 40–85%. However, similar reduction of N,N′,N″-tri(t-butoxycarbonyl)guanidine did not give orthoamide but the aminal di(t-butyl) methylenedicarbamate.     

Synthesis of 2-(N-arylimino-κN-methyl)pyrrolide-κN complexes of nickel

2-(N-aryliminomethyl)pyrrole precursors (2,6-R₂-C₆H₃-NCH-2-C₄H₃NH) (R = Me, IH; R = ⁱPr, IIH) were prepared and transformed into their corresponding sodium salts (Na⁺I⁻ and Na⁺II⁻) by treatment with NaH. Both salts readily react with [NiBr₂(DME)] (DME = 1,2-dimethoxyethane) to give the respective bis{2-(N-arylimino-κN-methyl)pyrrolide-κN}nickel(II) complexes (1, 2) in almost quantitative yields. The oxidative addition of IH to [Ni(COD)₂] (COD = 1,5-cyclooctadiene) results in the formation of 3, which is a mono(iminomethylpyrrolide)-η³-(cyclic-allyl)-type organonickel(II) complex. The crystal structure of compound 1 has been established by X-ray diffraction studies.     

Efficient synthesis of N-Me, N-Boc-protected α-hydrazinoacids: access to 1:1:1 [N-Me α-hydrazino/α/N-Me α-hydrazino]trimers

The preparation of optically pure N^α-Me, N^β-Boc-protected α-hydrazinoacids in large scale is described via a S_N2 protocol. These compounds were used as starting materials for the synthesis of 1:1:1 [N^α-Me α-hydrazino/α/N^α-Me α-hydrazino]trimers.     

Selective C-N bond oxidation: demethylation of N-methyl group in N-arylmethyl-N-methyl-α-amino esters utilizing N-iodosuccinimide (NIS)

Demethylation of N-methyl group in N-methyl-N-arylmethyl-α-amino esters was accomplished by the oxidation of the amino group using the N-iodosuccinimide (NIS)/acetonitrile system followed by treatment with O-methylhydroxylamine hydrochloride. This combination of reagents could provide a complementary method to catalytic hydrogenolysis, which certainly cleaves N-arylmethyl groups, in organic synthesis.     

N-[1-(Benzotriazol-1-yl)alkyl]amides from N-acyl-α-amino acids or N-alkylamides

A variety of N-(1-methoxyalkyl)amides react with benzotriazole in the presence of PPh₃·HBF₄ and organic bases (Hünig's base, DBU or DABCO) or solid-state-supported bases (SiO₂-Pip or IRA-67) in CHCl₃ to give N-[1-(benzotriazol-1-yl)alkyl]amides in good yields. The most convenient and efficient procedure for obtaining N-[1-(benzotriazol-1-yl)alkyl]amides consists, however, of the addition of benzotriazole sodium salt to a solution of crude 1-(N-acylamino)alkyltriphenylphosphonium salt, obtained in situ from N-(1-methoxyalkyl)amides and PPh₃·HBF₄. A combination of these reactions with the recently described electrochemical decarboxylative α-methoxylation of N-acyl-α-amino acids in the presence of SiO₂-Pip enables an effective two-pot transformation of N-acyl-α-amino acids to N-[1-(benzotriazol-1-yl)alkyl]amides.     

Syntheses and lipophilicity measurement of N/N-terminus-1,1-dihydroperfluoroalkylated α-amino acids and small peptides

(1,1-Dihydroperfluoroalkyl)phenyliodonium N,N-bis(trifluoromethylsulfonyl)imides (4, n = 0-2) were synthesized and used to transfer the corresponding 1,1-dihydroperfluoroalkyl groups to the α-amino group of (l)tyrosine. The obtained N^α-2,2,2-trifluoroethylated (l)tyrosine (6, n = 0) was further used as the N-terminus in the solid phase peptide synthesis of leucine enkephalin analogue. The lipophilicity of the N^α-1,1-dihydroperfluoroalkylated (l)tyrosines (6, n = 0-2) and N-terminus-2,2,2-trifluoroethylated leucine enkephalin analogue (7), as well as the corresponding parent compounds, was measured.     

An efficient one-pot synthesis of N,N′-disubstituted phenylureas and N-aryl carbamates using hydroxylamine-O-sulfonic acid

We have developed an efficient one-pot method for the microwave-assisted synthesis of ureas and carbamates via a proposed Lossen rearrangement. Herein we report the first examples of the direct conversion of benzoyl chlorides into N,N′-disubstituted ureas and N-aryl carbamates using hydroxylamine-O-sulfonic acid as reagent. Using our general method, we have produced 11 examples of N,N′-disubstituted phenylureas in yields up to 95% using various substituted anilines, and primary and secondary amines. Additionally, we were able to generate a series of N-aryl carbamates in moderate yields using primary, secondary and tertiary alcohols.     

Regioselective halogenation of pyridinium N-(benzoazynyl) aminides as a way to produce N-benzyl-α-aminobenzoazines

The halogenation of pyridinium N-(benzoazynyl) aminides with N-halosuccinimides provides a mild and regioselective method to functionalize the negatively charged diazine moiety in most cases. In some examples, however, formation of other products is explained. Finally, alkylation of the exocyclic nitrogen and reduction of the N–N bond provides a simple and straightforward strategy to obtain functionalized N-benzyl-benzoazynyl-α-amines.     

Facile rearrangement of N-(α-aminoacyl)cytidines to N-(4-cytidinyl)amino acid amides

Under near neutral and mildly basic conditions, primary N⁴-(α-aminoacyl)cytidines (4a-g) undergo a facile rearrangement to form N-(4-cytidinyl)amino acid amides (5a-g). Secondary aminoacyl derivatives rearrange with other competing pathways. Tertiary aminoacyl derivatives do not rearrange.     

Visible-light photo-catalytic C–C bond cleavages: preparations of N,N-dialkylformamides from 1,2-vicinal diamines

A range of 1,2-vicinal diamines were smoothly converted into N,N-dialkylformamides under the synergistic actions of Ru(bpy)₃Cl₂ photo-catalyst, 45 W household lighting bulb, and Cs₂CO₃ basic additive under very mild reaction conditions. The process involves visible light-enabled photo-catalytic cleavage of C–C bond as the strategic event.     

Diastereoselective electrophilic α-amination of camphor N-acyl N-phenylpyrazolidinones: the metal enolate-dependent synthesis of two possible hydrazide diastereomers

Complementary approaches under enolate amination reactions for the synthesis of both α-hydrazidoacyl diastereomers have been achieved. Both isomers are obtained with high to excellent chemical yields and high stereoselectivities (up to >95:5 dr) when aryl-substituted camphor N¹-acyl N²-phenylpyrazolidinone was treated with potassium hexamethyldisilylamide (KHMDS) and lithium hexamethyldisilylamide (LHMDS), respectively, followed by the addition of di-tert-butyl azodicarboxylate. The nondestructive removal of the chiral auxiliary, which can be carried out under mild condition, afforded the hydrazido alcohol with high enantiomeric ratio. The facial stereoselectivity and stereochemical course of the reactions are discussed.     

N-Carbamate α-aminoalkyl-p-tolylsulfones—convenient substrates in the nitro-Mannich synthesis of secondary N-carbamate protected syn-2-amino-1-nitroalkanephosphonates

An efficient one-pot synthesis of secondary N-carbamate protected syn-β-amino-α-nitroalkanephosphonates using diethyl nitromethanephosphonate and N-Boc or N-Cbz imines, generated in situ from stable N-Boc or N-Cbz α-aminoalkyl-p-tolylsulfones has been developed under PTC conditions. A model enantioselective version of this reaction is also described. Enantioselectivity up to 67% ee is achieved using a chiral thiourea catalyst derived from a cinchona alkaloid. Completely stereoselective conversion of the title compounds into partially N-carbamate protected syn-1,2-diaminoalkanephosphonates has also been elaborated.     

1-(N-Acylamino)alkyltriphenylphosphonium salts as synthetic equivalents of N-acylimines and new effective α-amidoalkylating agents

1-(N-Acylaminoalkyl)triphenylphosphonium salts 2a-f on reaction with DBU in MeCN are transformed into 1-(N-acylaminoalkyl)amidinium salts 3a-f. Amidinium salts 3d-f with a proton at the β-position undergo slow tautomerization into the corresponding enamides 6d-f. The same 1-(N-acylamino)alkyltriphenylphosphonium salts 2d-f in the presence of Hünig’s base are transformed directly into the corresponding enamides. Phosphonium salts 2, amidinium salts 3, and enamides 6 react with dialkyl malonates in the presence of DBU to give the corresponding amidoalkylation products. α-Amidoalkylation of dialkyl malonates is not observed in the presence of (i-Pr)₂EtN, yet proceeds well under these conditions with more acidic nucleophiles, for example, phthalimide or benzyl mercaptan.     

Photocatalytic aerobic cross-coupling reaction of N-substituted anilines with N-aryl glycine esters: Synthesis of α-aryl α-amino esters

A novel photocatalytic cross dehydrogenative coupling reaction of N-aryl glycine esters with N-substituted anilines has been developed. The reaction proceeds effectively using methylene blue as a photocatalyst under visible light irradiation without any metal, chemical oxidant or additive. A variety of α-aryl α-amino derivatives were prepared in moderate to excellent yields with a high para-regioselectivity.     

Cyclisation at very high temperature. Thermal transformations of N-alkyl and N, N-dialkyl amides of α,β-unsaturated acids into mono- and bicyclic heterocycles under FVT conditions

Cyclisations of N-alkyl and N,N-dialkyl cinnamic amides to the corresponding pyrrolidin-2-ones under the conditions of flash vacuum thermolysis (FVT), are described. It was found that these reactions proceed at 950-1000 °C affording in various yields the mixtures of isomeric mono and bicyclic γ-lactams, which were separated chromatographically and analysed by means of NMR spectroscopy. Two alternative mechanisms for the title process are proposed.     

Tertiary-butoxycarbonyl (Boc) – A strategic group for N-protection/deprotection in the synthesis of various natural/unnatural N-unprotected aminoacid cyanomethyl esters

A number of cyanomethyl esters of natural/unnatural aminoacids with un-protected amino functionality were synthesized because of their synthetic and medicinal importance. Critical N-Boc deprotection methods in the presence of labile (hydrolytic sensitivity) cyanomethyl functionality were screened thoroughly and it was found that readily available 4M HCl in 1,4-dioxane solution (2–4 equiv); acetonitrile, 0?°C, 2–4?h was a suitable condition. This condition was generalized and successfully applied to a variety of alkyl, alkynyl, aryl, heteroaryl, benzyl, azido, spiro amino acid cyanomethylesters irrespective of the nature of the amine (primary or secondary) and the distance between the amine and ester group to achieve final deprotected amino esters with high yield, and purity compared to other commonly known N-protecting groups (Cbz, Fmoc, Ac, Bn, Bz etc.). It was also demonstrated that N-Boc protected aminoacid cyanomethylesters are stable enough to carry out further functionalization compared to N-unprotected counterparts.     

The acid-mediated ring opening/cyclisation reaction of N-benzyl-α-aryl-azetidinones

N-Benzyl-4-aryl-azetidinones undergo ring opening with triflic acid to form N-benzyl-cinnamamides, which either undergo cyclisation to give 5-aryl-benzazepin-3-ones or N-debenzylation to give cinnamamides.     

Diastereoselective carbonyl phosphonylation using chiral N,N′-bis-[(S)-α-phenylethyl]-bicyclic phosphorous acid diamides

Addition of aldehydes to the P-anion derivatives of chiral phosphorous acid diamides (1S,2S,1′S,1″S)-2 and (1R, 2R,1′S,1″S)-2 in THF gave α-hydroxyphosphonamides in good yield (64-100%) and moderate diastereoselectivities.     

Chiral N-phosphonyl imine chemistry: asymmetric additions of malonate-derived enolates to chiral N-phosphonyl imines for the synthesis of β-aminomalonates

Chiral N-phosphonyl imines attached by 1-naphthyl group were found to react with lithium malonate enolates smoothly to give chiral β-aminomalonates. Good yields and excellent diastereoselectivity were achieved for sixteen examples. The chiral auxiliary can be readily removed by treating with trifluoroacetic acid (TFA) to give free amino malonates. The absolute structure has been unambiguously determined by converting one of the products into an authentic sample.     

CAN mediated decarboxylative hydroxylation/alkoxylation of N-aryl-γ-lactam-carboxylic acids at room temperature: an easy access to N-aryl-α-hydroxy/alkoxy-γ-lactams

An efficient and mild protocol for one-pot decarboxylative hydroxylation/alkoxylation of 1,3-diaryl-5-oxo-pyrrolidine-2-carboxylic acids to trans-5-hydroxy-1,4-diarylpyrrolidin-2-ones and 5-alkoxy-1,4-diaryl-1,5-dihydropyrrol-2-ones at room temperature using CAN in organo-aqueous solvent has been developed.