Boc-protected allylamine

Figure 1.10 Heck-Mizoroki reactions on N-Boc protected allylamines with aryl bromides by Xiao and coworkers [58].

The secondary allylic methylamine 324 can be prepared by the allylation of A -methylhydroxylamine (323), followed by hydrogenolysis[201], Monoallylation of hydroxylamine, which leads to primary allylamines, is achieved using the jV,0-bis-Boc-protected hydroxylatnine 326. N -... 

Methylenation of ol-(N-Boc-amino) aldehydes. Methylenation of these chiral aldehydes with the Wittig reagent or with CH2Ir-Zn-TiCl4 (13, 114) is accompanied by extensive racemization. However, the neutral reagent 1 obtained from CH2I2, Zn, and A1(CH3), converts these aldehydes to the protected allylamines in 40-75% yield and in >99% ee. 

A related cyclization was recently reported by Jia et al. [14] with allylamine 20 immobilized on poly styrene-Wang resin. The reaction was monitored by acetylation and cleavage to yield 21, as a mixture of free and Boc-protected amines. This solid-phase synthesis of. seco-CBI (21, R = H), related to the pharmacophore of the CC-1065 and duocarmycin class of cyclopropylindole antitumor antibiotics, has potential for the preparation of analogue libraries, and an example of further transformation of resin-bound 21 to a polyamide was presented. 

Farwick and Helmchen [28] prolonged the alkyl chain of chiral allylamines by a hydroformylation-(Wittig olefination) sequence (Scheme 5.139). Particular attention was paid to the choice of the JV-protective group. As expected in the Wittig olefination step, mainly the Z-configured olefins were formed. After selective removal of only one Af-protective group, the obtained Af-Boc protected methyl esters were converted via a diastereoselective aza-Michael reaction into the corresponding fi-proline derivatives. 

The diene precursor 26 is readily prepared from allylamine by carbalkoxyethylation with acrylate, N-Boc protection, and Li(Tms)2-induced a-alkylation with allyliodide. 

Additive in Miscellaneous Reactions. Concurrent addition of TMSCl and an enol triflate into a preformed Boc-protected -aminoalkyl cuprate results in formation of Boc-protected secondary allylamine in good yield (eq 89). 

A different approach to baikiain (175) was also reported two years later by Riera et al. [64]. Their synthesis commenced with a Sharpless epoxidation of 2,5-hexadienol to give the enantiopure epoxide 176. Subsequent epoxide ring opening with allylamine and N-Boc protection afforded the RCM precursor 177, which was readily ring closed ([Ru]-1, CH2CI2) in 72% to the tetrahydropyridine derivative. Finally, oxidative cleavage of the diol, followed by Pinnick oxidation, led to the N-Boc-protected natural product 178 (Scheme 2.40). 

A-allylamine 23 (obtained by standard transformations of 6-iodogluco-side 22) underwent cyclization into the monocycle 24. However, when the amine was in situ protected as a Boc derivative it could be subjected to the RCM process. The products were further converted into the bicyclic aza sugar 26.19 A similar approach to eight-membered ring aza sugars was recently reported (Fig. 9).20... 

Allylic substitution. Di-Boc-allylamines are readily obtained from allyl acetates. The products are converted into protected glycine esters on ozonolysis. 

Stannylcupration of propargylamines. Boc- or Si(CH3)3-protected propargyl-jmines (1) react with Bu3Sn(Bu)Cu(CN)Li2 and then with an electrophile to form 2-substituted 3-(tributylstannyl)allylamines (2). These products can be converted into, 2-disubstituted allylamines (3). 

An iV-phenyl-allylamine has been arylated terminally using phosphine-free conditions and a heteroaryl iodide in the synthesis of an H+/K+-ATPase inhibitor (Figure 3.31) [91]. This class of inhibitors has attracted the interest of many medicinal chemistry groups due to the large sales of the blockbuster Losec/Prilosec (Omeprazole). In the cited case, the allylic amine moiety was added at a late stage of the synthesis and the primary amine was protected by Boc to prevent formation of 7r-allyl palladium complexes. The deprotection was then performed with trifluoroacetic acid. 

Amides, carbamates, imides, and their metal salts also serve as reactive nucleophiles (Scheme 3). Sodium p-toluenesulfonamide attacks l-acetoxy -chloro-cyclohex-2-ene to give an allylic amide in a highly chemoselective manner with retention of conflgura-tion.t Sodium salt of methylcarbamate is also alkylated in DMSO or HMPAJ ° (A, 0)-Bis-fer-Boc hydroxylamine reacts with an aUylic carbonate chemo- and regioselectively to provide a protected A-allylhydroxylamine, in which an ethoxy anion, a counterion of Pd in a 7r-allylpalladium complex, serves to generate an anion of (A, 0)-bis-ter-Boc hydroxylamine.f Preparation of primary allylamines by a selective monoallylation of ammonia is not possible and they are prepared by indirect methods. The monoallylation... 

This intermediate was transformed into allylamine 15 via the 3-iodo derivative, which was reacted with allylamine. Then N-Boc was protected by di-tert-butyl dicarbonate, and finally OTBS protection removed by the aqueous work-up to obtain 15. The detailed protocol for the final steps iv-vi is reported in the patent, which does not state the yields [30]. The final steps of the synthesis of 1 are given in Scheme 16.5 [27]. 

Two years later, Ftirstner et al. developed a synthesis of azepine 277 based on a selective Sharpless asymmetric epoxidation of divinylcarbinol (Scheme 2.60) [89]. The resulting epoxide 272 was then regioselectively opened with allylamine to give the corresponding diene. Protection of the secondary amine with an N-Boc group provided the precursor 275 for RCM. CycUzation proceeded in 94% yield using [Mo]-I catalyst (CH2CI2, 30 min, reflux, 94%). Subsequent conversion of the... 

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