Amination/intramolecular

Intramolecular amination with allylic acetates is used for the synthesis of cyclic alkaloids 175]. Cyclization of 293 affords the six-membered ring compound 294 rather than a four-membered ring. The reaction is particularly... 

If there is no phenyl substituent in the 3-position the amination ability decreases. The acyloxaziridine (104) yields only 11% of a semicarbazide derivative with piperidine. In the presence of strong bases an intramolecular amination competes. Compound (104) reacts with methoxide within a couple of seconds to give phenylhydrazine carboxylic ester (106), and with cyclohexylamine to give the substituted semicarbazide (107). A diaziridinone (105) is assumed to be the common intermediate, formed by an intramolecular reaction from deprotonated (104) (67CB2600). 

Inter- and intramolecular amine coupling was prevented by the use of hydrogen chloride in a synthesis of pyridoxine 33)... 

Buchwald has developed a route to indolines by the Pd-catalyzed intramolecular amination of aryl halides <96T7525> and applied this method to the synthesis of natural products. Thus, cyclization of tetrahydroquinoline 70 provided 71 which was elaborated to a key intermediate in syntheses of damirones A and B and makuluvamine <96JA1028>. 

With the exception of intramolecular amination reactions, all of the early aryl halide aminations were catalyzed by palladium complexes containing the sterically hindered P(o-tol)3. In papers published back-to-back in 1996, amination chemistry catalyzed by palladium complexes of DPPF and BINAP was reported.36,37 These catalysts allowed for the coupling of aryl bromides and iodides with primary alkyl amines, cyclic secondary amines, and anilines. 

Intramolecular amine addition to benzene has been reported in the phenyl-alkylamines 368 to give the meta adducts 369 in low yield,306 whereas the [co-(anilino)alkoxy]nitrobenzenes 370 undergo photocyclization in acetonitrile to give heterocycles 371.307... 

Following the pioneering work by Alterman, several microwave-assisted palladium-catalyzed aminations have been reported for a number of different substrates, using different types of palladium sources and ligands. The examples shown in Scheme 6.59 include bromoquinolines [124], aryl triflates [125], and intramolecular aminations in the synthesis of benzimidazoles [126]. In all cases, the use of micro-wave irradiation dramatically reduced the required reaction times and in many cases also improved the yields. Several authors have also found that the microwave-driven reaction required significantly less catalyst than its conventionally heated counterpart [126]. 

Palladium-catalyzed cyclization reactions with aryl halides have been used to synthesize pyrazole derivatives. V-Aryl-lV-(c>-bromobenzyl)hydrazines 26 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2W-indazoles 27 . Palladium-catalyzed cascade intermolecular queuing-cyclocondensation reaction of o-iodophenol (28) with dimethylallene and aryl hydrazines provided pyrazolyl chromanones 29 <00TL7129>. A novel one-pot synthesis of 3,5-disubstituted-2-pyrazolines 32 has been achieved with an unexpected coupling-isomerization sequence of haloarene 30, propargyl alcohol 31, and methylhydrazine <00ACIE1253>. 

A very elegant expansion of the synthetic utility of this intramolecular amination was the insertion reactions into ethereal G-H bonds. Du Bois and co-workers have exploited this reactivity to prepare cyclic sulfamates that are then used as iminium ion equivalents. Upon treatment with a suitable Lewis acid, nucleophilic addition reactions... 

Hegedus proposed the probable course of the cyclization reaction, which follows a Wacker-type reaction mechanism. Coordination of the olefin to Pd(II) results in precipitate 110, which upon treatment with Et3N undergoes intramolecular amination to afford intermediate 111. As expected, the nitrogen atom attack occurs in a 5-exo-trig fashion to afford 112. Hydride... 

Boger and co-workers were the first to report the intramolecular amination of aryl halides in their synthesis of lavendamycin [436-438], Thus, biaryl 366 is smoothly cyclized under the action of 1.5 equivalents of Pd(PhjP)4 to P-carboline 367, which comprises the CDE rings of lavendamycin. 

Buchwald parlayed the powerful Buchwald-Hartwig aryl amination technology [439-447] into a simple and versatile indoline synthesis [448-452], For example, indole 368, which has been employed in total syntheses of the marine alkaloids makaluvamine C and damirones A and B, was readily forged via the Pd-mediated cyclization shown below [448], This intramolecular amination is applicable to the synthesis of -substituted optically active indolines [450], and o-bromobenzylic bromides can be utilized in this methodology, as illustrated for the preparation of 369 [451]. Furthermore, this Pd-catalyzed amination reaction has been applied to the synthesis of arylhydrazones, which are substrates for the Fischer indole synthesis [453,454],... 

The reaction of 2-aminobenzimidazoles 600 with 2,3-allenenitriles led to pyrimi-dobenzimidazoles 604 via initial attack of the unsaturated nitrogen atom in the imidazole ring followed by a 1,3-H shift to form 602. Intramolecular amination of the nitrile group in 602 and a subsequent 1,3-H shift afforded the final product 604... 

Allylic acetates in conjunction with phosphinooxazolines (PHOX) as chiral ligands were used for the first asymmetric Ir-catalyzed allylic substitution (Scheme 9.7) [5]. The reaction was slow, compared to that catalyzed by the [lr(COD)Cl]2/P(OPh)3 system or the parent complex [lr(COD)Cl]2, although both regioselectivity and enantioselectivity were very high. The aminations were generally slow, yet quite interesting results were achieved in intramolecular aminations nevertheless [17, 18] in particular, a very strong influence of halide salts was found. 

Catalyst activation became a necessity when reactions with bulky aliphatic amines and arylamines (cf Section 9.4.2) as nucleophiles were probed. It was also required for intramolecular aminations [8,18]. Thus, with Ph2CHNH2, an ammonia equivalent, conversion was only 11% upon application of procedure (a) (Table 9.2, entry 11), while the reaction promoted by the activated catalyst proceeded with high selectivity and yield. Catalyst activation is faster with ligand L2 than LI, and accordingly in situ activation occurs more readily for the former (cf entries 10 and 12). Examples presented in entries 16-20 further demonstrate the advantages of catalyst activation [53] (note that excellent results can be achieved with the simpH-fied ligand L5a). 

Trons-divinyl-pyrrolidines and -piperidines were prepared by sequential intermolecular and intramolecular aminations of bis-allylic carbonates (Scheme 9.21) [22aj. Due to double stereoselection, these reactions proceeded with high diastereoselectivity and enantioselectivity. 

Intramolecular reactions of a phenolate were also reported (Scheme 9.33) [22a]. The preparation of a chromane derivative is described below, where the catalyst was activated with the base TBD. As in the case of intramolecular aminations, these cyclizations could be run at concentrations as high as 0.5-1 M. 

Diphenyl- -triazole is aminated by reaction with hydroxylamine-0-sulfonic acid. The I - and 2-aminotriazoles are formed in approximately equal amounts. Intramolecular amination of 1- and 2-aryltriazoles is achieved by generating a nitrene intermediate in the ortho position of the aryl substituent for example, in the thermolysis (Scheme 42) of the azide (17). ... 

Some intramolecular aminations of olefins have been reported for solenopsin A (Id) and its isomer (Ic) (389-392). The dimer (200) of methyl vinyl ketone was converted to the ketone (202) by a standard procedure. Borohydride reduction of 202, followed by acid-catalyzed cyclization, yielded an exo/endo (60/40)... 

Thietes can be prepared by elimination from appropriately substituted thietanes. 2,4-Diarylthiete 1,1-dioxides (146 and 147) were produced in good yields by peracid oxidation and intramolecular amine oxide elimination of 3-dimethylaminothietane 1,1-dioxides (Eq. 23). 

Treatment of N-oxides with imidoyl chlorides or nitrilium salts can lead to intramolecular amination. This is a useful direct method for the introduction of a 2-arylamino group into the pyridine ring (Scheme 99) (74JOC1795). The by-products that are isolated in some of these reactions are believed to be formed as shown. When the a-positions are blocked a... 

A unique acyclic C-nucleoside containing the pyrido[2,3-. ]pyrazine nucleus 675 was prepared by the action of AcOH, whereby rearrangement of 3 -keto-2 -deoxypyrazine C-nucleoside derivatives 673 occurs via the intramolecular aminal intermediate 674, followed by furanose ring opening and subsequent aromatization (Equation 56)... 

The corresponding reaction of 23 with dimethylamine and with cyclic secondary amines (piperidine and morpholine) is less facile and gives the thermodynamically more favored C-3 addition product (Equation 13) <1999RCB1150>. Using ethylenediamine, the cyclization product 29 is obtained in 80% yield (Scheme 12), although with 1,3-propane-diamine, 1,4-butanediamine, and 1,2-cyclohexanediamine the yields are reduced (70%, 25%, and 1%, respectively), consistent with the importance of entropy as a driving force for the second (intramolecular) amination. 

A quinazoline alkaloid skeleton has been synthesized by means of the Rh-catalyzed cyclohydrocarbonylation of diaminoalkenes. The reaction of 2-(A -allylaminomethyl)aniline 55 gave quinazoline 59 in excellent yield through the highly linear-selective hydroformylation of 55 to aldehyde 56, followed by the sequential formations of hemiaminal 57 and iminium ion 58 as intermediates and then the subsequent intramolecular amine addition (Scheme In the same manner, the reaction of A -allyl-2-aminomethylaniline 60 afforded 61 in 96% yield. ... 

One route to the tetrahydro-1,8-naphthyridine (84) employs an intramolecular amination of compound 83 in the presence of sodium.47... 

Azepinones, for example, 97, can also be accessed in high yield from an allene precursor (e.g., 96) by BOC-group removal and then intramolecular amine addition to the allene (Scheme 12) <2005T6309>. 

Pd-catalysed allylation of amines proceeds smoothly. Allylamine (132) and di- and triallylamines are produced commercially by the Pd-catalysed reaction of ammonia with allyl alcohol using DPPB as a suitable ligand [69]. Allylic alcohols are rather unreactive substrates for 7r-allylpalladium complex formation under usual conditions. The intramolecular amination of 133 afforded the azaspiro ring 134 and the reaction was applied to the synthesis of perhydrohistrionicotoxin (135) [70]. Smooth Pd-catalyzed allylation of the purine base 136 gives 137, which is utilized for the synthesis of nucleosides [71]. 

Nucleophilic attack of the electron-rich aromatic ring 124 to the cationic complex 123, and intramolecular amination afforded the intermediate 125 for the synthesis of discorhabdin and prianosin alkaloids [29]. 

---