A versatile total synthesis of benzo[c]phenanthridine and protoberberine alkaloids using lithiated toluamide-benzonitrile cycloaddition

A new versatile synthesis of benzo[c]phenanthridine and protoberberine alkaloids using lithiated toluamide-benzonitrile cycloaddition was carried out. The coupling reaction between benzonitrile 6 with o-toluamides (8a-c) afforded 3-arylisoquinolines (9a-c) that were transformed to the protoberberines (11a-c) or benzo[c]phenanthridines (14a-c). These compounds were synthesized by ring closure of the two-carbon chain on either position 2 or 4 of the 3-arylisoquinolinone (9a-c). Several kinds of substituted benzo[c]phenanthridine alkaloids such as oxysanguinarine, oxyavicine, and oxynitidine as well as protoberberines such as 8-oxocoptisine, 8-oxopseudoberberine, and 8-oxopseudocoptisine were synthesized.     

A facile synthesis of benzo[c]phenanthridine alkaloids: oxynitidine and oxysanguinarine using lithiated toluamide-benzonitrile cycloaddition

Benzo[c]phenanthridine alkaloids oxynitidine and oxysanguinarine were synthesized from easily available starting benzonitrile 5 and toluamide 6 using toluamide-benzonitrile cycloaddition reaction in six steps. This method is so highly efficient that it could be a more useful way for preparing fully aromatized benzo[c]phenanthridine compounds.     

Selenofluorenone: Synthesis and cycloaddition chemistry

Selenofluorenone, prepared from fluorenyl selenocyanate by base-induced elimination, participates efficiently in Diels-Alder cycloaddition and 1,3-dipolar cycloaddition reactions.     

1,2-Homoheptafulvene: Synthesis and cycloaddition

1,2-Hemoheptafulvene ($\text{2}$) was synthesized and reacted with 4-phenyl-1,2,4-triazoline-3,5-dione to yield [4π + 2π] and [6π + 2σ + 2π] cycloadducts.     

Synthesis of celecoxib via 1,3-dipolar cycloaddition

A regioselective 1,3-dipolar cycloaddition reaction between a nitrile imine and an enamine is described for the preparation of celecoxib. Nitrile imines are generated in situ from the corresponding hydrazonoyl benzenesulfonates.     

Synthesis of novel pyrazoles via [2+3]-dipolar cycloaddition using alkyne surrogates

The syntheses of an important class of hitherto unreported novel pyrazoles are described. The regioselective synthesis of 1,3,4,5-tetrasubstituted pyrazoles was achieved by the Huisgen cyclization of nitrile imines with a trisubstituted bromoalkene. The substituted bromoalkene functions as an alkyne synthon which was used to construct 5,5-disubstituted bromopyrazoline intermediates that undergo aromatization to the analogous pyrazoles through the loss of HBr. The cycloaddition regioselectivity was confirmed through single X-ray crystal data of one of the pyrazoles.     

Synthesis of densely functionalised arenes using [2 + 2 + 2] cycloaddition reactions

Rh(I)-catalysed [2 + 2 + 2] cycloaddition allows the synthesis of aryl ethers and diaryl methanes containing a high degree of steric hindrance from relatively simple diyne and alkyne precursors. The diarylmethanes made in this way show no evidence in their NMR spectra, however, of rotational restriction.     

Deprotonation of lithiated benzenes

The deprotonation energies of all possible lithiobenzenes (C(6)Li(n)H(6-n), n = 0-5) were computed at B3LYP/6-311+G(d,p). Based on natural population analysis, the conjugate bases can be thought of as salts between a polyanionic phenyl core and associated lithium cations. The most stable structures maximize the electrostatic attraction between these two species, typically by positioning the lithium cations to bridge in the ring plane across two adjacent carbanion centers. Favorable deprotonation occurs when the formal carbanion centers are adjacent to each other and then the proton is removed from an adjacent carbon. The deprotonation free energies range from 365.0 to 397.2 kcal mol(-1), with most of them less than the deprotonation free energy of benzene (391.8 kcal mol(-1)).     

Synthesis and cycloaddition reactions of sulfur-substituted quinolizidine dienes

Synthesis of sulfur-substituted quinolizidine dienes via ring-closing enyne metathesis (RCEYM) of the corresponding enynes has been achieved. The cycloaddition reactions of these dienes with electron-deficient dienophiles give tricyclic and tetracyclic nitrogen-containing products.     

Synthesis of spirooxindoles via asymmetric 1,3-dipolar cycloaddition

An efficient method was developed for the asymmetric synthesis of 2′-alkyl-4′aryl-1H-spiro[indole-3,3′-pyrrolidin]-2-ones, which are potential inhibitors of the p53-MDM2 interaction. Our X-ray crystallographic analysis revealed that this 1,3-dipolar cycloaddition proceeds with high stereoselectivity but differently from previously published results.     

Synthesis of functionalized pyrrole and indole derivatives through carbometallation of lithiated double bonds

Bis(2-lithioallyl)amines derived from bis(2-bromoallyl)amines undergo intramolecular carbometallation of a lithiated double bond, giving dilithiated dihydropyrroles. The cyclizations are promoted by N,N,N',N'-tetramethylethylenediamine (TMEDA). Reaction of these intermediates with electrophiles allows the preparation of some new fused and nonfused five-membered functionalized heterocycles. Although 2-lithioallylamines do not suffer intermolecular carbometallation, dimerization products are obtained with their copper or zirconium derivatives. Finally, the application of this new reaction to 2-lithio-N-(2-lithioallyl)anilines leads to 3-lithiomethylindole derivatives, which are transformed to functionalized indole derivatives by reaction with electrophiles.     

Synthesis of bis-spirofused thiapyrrolizidinooxindoles by 1,3-dipolar cycloaddition

The 1,3-dipolar cycloaddition of unstabilized azomethine ylide, which is generated in situ from isatin and thiaproline, to arylidene derivatives of rhodanine affords bis-spirofused thiapyrrolizidinooxindoles. The 1,3-dipolar addition reactions under consideration are fully regio- and diastereoselective.     

Synthesis of functionalised cyclohexadienes through addition of lithiated phosphine borane complexes to benzonitriles

Functionalised 1,3- and 1,4-cyclohexadienes have been prepared through dearomatisation of benzonitriles by sequential conjugate addition of -lithium alkyl(diphenyl)phosphine borane in the presence of HMPA and capture of the intermediate anion with protonating and alkylating reagents.     

Synthesis of n-alkyl-n-(1-hydroxyperoxyalkyl)nitrosamines by oxygenation of lithiated dialkylnitrosamines

N-Alkyl-N(1-hydroperoxyalkyl)nitrosamines were synthesized from N,N-dialkylnitrosamines by lithiation with lithium diisopropylamide, followed by oxygenation with oxygen in good yields.     

Synthesis of spiropyrazolines via 1,3-dipolar cycloaddition of nitrilimines

The regio- and stereoselective synthesis of spiropyrazolines 7 and 8 via 1,3-dipolar cycloaddition of C-2-(5-nitrofuryl)-N-methylnitrilimine, C-2-(5-nitrofuryl)-N-phenylnitrilimine and C-4-nitrophenyl-N-methyl-nitrilimine to (E)-3-benzylidenechromanone (1), -1-thiochromanone 2, -1-tetralone 3 and (E)-3-benzylidene-flavanone (4) is reported. The relative configuration and conformations of the spiropyrazolines were elucidated by various nmr methods.     

Synthesis of aromatic phosphates via cycloaddition of phosphate dienes

Cycloadditions of phosphate dienes and quinones can be used to generate aromatic phosphates. Diethyl 3-methoxy-1-methylene-2-propenyl phosphate shows reactivity, stability, and regioselectivity comparable to the corresponding silyloxy diene. Because the phosphate ester in the product originates in the diene, cycloadditions with quinones will place this ester regiospecifically in the B-ring and allow facile distinction between the B- and A-ring oxygens of the cycloadduct.     

Charge-remote fragmentation of lithiated fatty acids on a TOF-TOF instrument using matrix-ionization

In numerous studies charge remote fragmentation (CRF) has been shown to be a powerful technique for determination of primary structure by allowing location of double bonds, various functional groups, and branching in a variety of compound types directly by mass spectrometry. Instrumentation and ionization methods traditionally used for CRF, however, are becoming rare, in large part because ESI and MALDI have to a significant extent replaced them. Here we demonstrate that by selecting a matrix that promotes rather than suppresses ionization of fatty acids (FA) by lithium ion adduction, and using a TOF-TOF mass spectrometer for high-energy collisional activation, CRF ions are produced that allow location of double-bond and branching positions. Further, we show that by using solvent-free MALDI sample preparation methods, thus eliminating the inherent segregation of the hydrophobic fatty acid from the hydrophilic LiCl that can occur during the evaporation of solvent, the desired [FA-H+2Li](+) ions are greatly enhanced. Because FAs can be vaporized using laser desorption, matrix assistance in desorption of the fatty acid may occur, but is not necessary. However, the matrix plays a crucial role in enhancing or suppressing ionization. For example, matrix materials with acid (e.g., 2,5-dihydroxybenzoic acid) or hydroxy groups (e.g., dithranol) compete with the FA for Li(+) and because of the high ratio of matrix to analyte, FA lithium adduction is minimized. However, highly electron-deficient matrix materials (e.g., TCNQ) readily donate Li(+) to FAs because of the instability associated with being positively charged.