Intramolecular oxidative amination

Interesting examples of intramolecular oxidative amination have recently been reported. Permanganate oxidation of the arylhydra-zones of 3-formyl-1-methylquinoxalinium salts leads to pyrazoloquinox-alinium salts (Scheme 24) (02MC68). The reactive a-position in the quinoxalium ring makes the addition of the hydrazone nitrogen easily possible. Oxidation of a DMSO solution of the condensation product of 2-formylquinoxaline with ortho-phenylene diamine... 

Similar cyclic imines can be synthesized by intramolecular oxidative amination of aminoalkenes, which are less expensive than aminoalkynes. In the presence of catalytic amounts of [RuCl2(CO)3]2/l,3-bis(diphenylphosphino)propane and excess K2C03/allyl acetate, various aminoalkenes 19 possessing substituent(s) f3 to the amino group afforded five- and six-membered cyclic imines 20 in mod-erate-to-excellent yields (Eq. 8) [14]. 

Mitsudo et al. reported that the ruthenium-catalyzed intramolecular oxidative amination of the aminoalkenes 195 gave the cyclic imines 196 in high yields (Scheme 66).137 This reaction is categorized into type b in Scheme 56. 

SCHEME 3 Inter- and intramolecular oxidative amination of indoles. 

Acyclic dialkylamines are not very reactive as nucleophiles in the oxidative alkylamination, however they are very prone to oxidation and, therefore, they are capable for unexpected behavior. Presumably, transformation 33 41 starts from oxidation of dialkylamme into imine 42, that is in equilibrium with enamine 43 (Scheme 28). The latter, as bifunctional C,W-nucleophile, attacks C-4 atom of the pyridazine ring to form cr -adduct 44, which then undergoes oxidative aromatiza-tion. Subsequent intramolecular oxidative amination of the intermediate 45 yields pyrrole derivative 41. The participation of imines in this process has been confirmed experimentally. In the presence of AgPy2Mn04, pyrimidopyridazine 33 reacts with authentic aldimines and ketimines 42 to give pyrroles 41. Transformation 33 41 represents not only a rare example of the tandem processes but... 

Intramolecular oxidative aminations of olefins have alsobeen studied, and many of these intramolecular processes were observed prior to the analogous intermolecular variants. The oxidative aminations of alkenes with arylamines and arylamine derivatives catalyzed by palladium complexes were shown by Hegedus to form indoles (Equation 16.120). These reactions were conducted with orf/io-allylaniline and ort/zo-allylaniline derivatives as substrate, Pd(NCMe)jCl2 as catalyst, and benzoquinone as oxidant. Intramolecular reactions of N-tosylated aliphatic amines were reported by Larock. ° For example, the tosylamide in Equation 16.121 imdergoes cyclization in high yield in the presence of dioxygen with Pd(OAc)j as catalyst in DMSO. A related reaction (Equation 16.122) was reported recently in toluene solvent with added pyridine. ... 

In 2009, Stahl and coworkers described the synthesis of the enantiomeri-cally resolved seven-membered ring NHC-Pd dimer 87 [75]. This complex was examined as a chiral catalyst under aerobic conditions in the intramolecular oxidative amination reaction of alkene 88 (Scheme 3.49). In the best case, an enantioselectivity of 63% ee was obtained with low yield (35%), while the other substrates underwent cyclization to afford essentially racemic products. 

Unlike the intermolecular reaction, the intramolecular aminopalladation proceeds more easily[13,14,166], Methylindole (164) is obtained by the intramolecular exo amination of 2-allylaniline (163). If there is another olefinic bond in the same molecule, the aminopalladation product 165 undergoes intramolecular alkene insertion to give the tricyclic compound 166[178]. 2,2-Dimethyl-l,2-dihydroquinoline (168) is obtained by endo cyclization of 2-(3,3-dimethyiallyl)aniline (167). The oxidative amination proceeds smoothly... 

Piperidines bearing a masked aldehyde function in the e-position are easily transformed into quinolizidine compounds through intramolecular reductive amination after deprotection (acetal precursors) or oxidative cleavage (tv e-diols). Some examples are given below. 

Katritzky developed a facile synthesis of l,2-diaryl(heteroaryl)pyrroles in a two-step procedure from A-allylbenzotriazoles via intramolecular oxidative cyclization in the presence of a Pd(II) catalyst <00JOC8074>. Thus, treating A-allylbenzotriazole (21) with n-butyllithium followed by addition of a diarylimine yielded the (2-benzotriazolyl-l-arylbut-3-en)anilines 22 which were subsequently heated in the presence of the system Pd(OAc)2-PPh3-CUCI2-K2CO3 to undergo intermolecular amination with simultaneous oxidation of the intermediate 3-pyrroline to the pyrroles 23. 

Preliminary efforts to examine the mechanism of C-H amination proved inconclusive with respect to the intermediacy of carbamoyl iminoiodinane 12. Control experiments in which carbamate 11 and PhI(OAc)2 were heated in CD2CI2 at 40°C with and without MgO gave no indication of a reaction between substrate and oxidant by NMR. In Hne with these observations, synthesis of a carbamate-derived iodinane has remained elusive. The inability to prepare iminoiodinane reagents from carbamate esters precluded their evaluation in catalytic nitrene transfer chemistry. By employing the PhI(OAc)2/MgO conditions, however, 1° carbamates can now serve as effective N-atom sources. The synthetic scope of metal-catalyzed C-H amination processes is thus expanded considerably as a result of this invention. Details of the reaction mechanism for this rhodium-mediated intramolecular oxidation are presented in Section 17.8. 

Scheme 1.64). The Ag(I)-mediated cyclization afforded dipole 306 for 1,3-dipolar cycloaddition with methyl vinyl ketone to yield adducts 307 and the C(2) epimer as a 1 1 mixture (48%). Hydrogenolytic N—O cleavage and simultaneous intramolecular reductive amination of the pendant ketone of the former dipolarophile afforded a mixture of alcohol 308 and the C(6) epimer. Oxidation to a single ketone was followed by carbonyl removal by conversion to the dithiolane and desulfurization with Raney nickel to afford the target compound 305 (299). By this methodology, a seven-membered nitrone (309) was prepared for a dipolar cycloaddition reaction with Al-methyl maleimide or styrene (301). 

Ab Initio MO calculations of a model complex Rh(PH3)2(NH3)(CH2=CHCH2NH2) were earned out to shed light to the detailed mechanism of Rh(l)-catalyzed isomerization of allylic amines to enamines.5 This study suggests that the square-planar [RhiPHjyNHjXCf CHCHjNHj) complex is transformed to [Rh(PH3)2(NH3)(( )-CH3CH=CHNH2)]+ via intramolecular oxidative addition of the C(l)-H bond to the Rh(I) center, giving a distorted-octahedral Rh(lll) hydride intermediate, followed by reductive elimination accompanied by allylic transposition. 

A facile intramolecular hydroamination of unactivated alkenes (58), catalysed by the palladium complex (60), has been reported to take place at room temperature. The formation of hydroamination products (59) rather than oxidative amination products is believed to be due to the use of a tridentate ligand, which effectively inhibits -hydride elimination.78... 

The alkaloid (+)-pinidine81 (4) is obtained as a single a s-stereoisomer in a one-pot transformation of the chiral methyl sulfide 3 via oxidative amination, rearrangement, intramolecular imine formation and stereoselective reduction. 

Williams and co-workers form the C(7)-C(8) bond first through the addition of benzyl anion to an aziridino aldehyde 317 <20020L3711, 2004JOC2825>. The resulting hydroxyl group is protected and the -methoxybenzyl (PMB) group is removed and the hydroxyl-oxidized to aldehyde 319 (Scheme 62). An intramolecular reductive amination was used to form the final bond of the tricycle. 

Biomimetic syntheses of benzylisoquinoline alkaloids have been performed by intramolecular oxidative phenol-coupling reactions using a variety of oxidants. Of them, K3Fe(CN)e has long been used for alkaloid syntheses The amine 732 bearing... 

Several other biomimetic approaches to the synthesis of cephalotaxine have also been reported. In 1977, Kupchan etal. (72,73) prepared tetrahy-droisoquinoline 214, which underwent intramolecular oxidative coupling to 215 by means of vanadium(V) oxytrifluoride and trifluoroacetic acid/ trifluoroacetic anhydride (Scheme 38). Treatment of 215 with 1 N sodium hydroxide in methanol yielded the ring-expanded product, imine 216, which was converted in five steps to amine 217. Transannular cyclization of 217... 

Scheme 10 Pd-catalyzed intramolecular allylic oxidative amination...

In 1923 the bacterium Acinetobacter suboxydans was isolated and, starting in 1930, was used for the industrial oxidation of L-sorbitol to L-sorbose in the Reichstein-Griissner synthesis of vitamin C[39]. Bayer uses the same type of reaction, but instead of Acinetobacter the bacterium Gluconobacter suboxydans is used in the oxidation of N-protected 6-amino-L-sorbitol to the corresponding 6-amino-L-sorbose, which is an intermediate in miglitol production (Fig. 19-7). 1-Desoxynojirimydn is produced by chemical intramolecular reductive amination of 6-amino-L-sorbose. In contrast, the... 

Alternatively, compound 14 was oxidized with sodium periodate, followed by reduction with sodium borohydride in ethanol to afford 18 (Scheme 3). Hydrolysis of the isopropy-lidene group in 18 with 50% aqueous trifluoroacetic acid followed by hydrogenation of the azide group and then intramolecular reductive amination and protection of the imine group afforded 19. Selective mesylation of the primary hydroxyl group in 19 followed by silylation and subsequent removal of the benzyloxycarbonyl group and then cyclization with sodium acetate afforded 20. Deprotection of 20 led to me50-quinuclidine-3,5-diol (3). 

Protection of t-amines. Recent examples of use of amine borane complexes include the intramolecular oxidative phenol coupling of 1 to 2, a reaction that fails with the free amine. Several spirodienone precursors to aporphine and... 

In the homoerythrina series, full details of work described earlier (Volume 8 of these Reports) have now appeared, and it was shown that intramolecular oxidative coupling of the phenolic 1-phenylacetamidoquinoline (17a) afforded a c-homo-erythrinandienone (18) in 67% yield, whereas the corresponding amine... 

After realizing that our hypotheses about oxidative cross-coupling reactions were not as unique as assumed, we quickly turned our attentirai to intermolecular oxidative amination reactions. In the carbazole example, regioselectivity was coti-trolled by the presence of a Lewis base that was attached near the C—H bmid that would be cleaved, resulting in a metallacyle intermediate. For die development of an intramolecular reaction, we chose to take advantage of the selectivity that is often observed in the selective metalation of electron-rich heteroarenes. At the time, the palladation of indoles was presumed to operate by an electrophilic aromatic substitution mechanism. (This has since been demonstrated to be incorrect, vide infra.) We hypothesized that regioselective palladation of an indole substrate could be followed by a subsequent C—N bond reductive elimination. At the time, the exact mechanism by which the intermediate containing Pd—C and Pd—N bonds could be formed was not clear, nor was the order of the two metalation steps, but the overall process seemed plausible. 

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