N-Boc-piperidine

More recently, Coldham and O Brien have extended this methodology to the arylation of N-Boc piperidine [28],... 

The full potential of this C-H activation process, as a surrogate Mannich reaction, was realized in the direct asymmetric synthesis of threo-methylphenidate (Ritalin) 217 (Eq. 28) [140]. C-H insertion of N-Boc-piperidine 216 using second-generation Rh2-(S-biDOSP)2 and methyl phenyldiazoacetate resulted in a 71 29 diastereomeric mixture, where the desired threo-diastereomer was obtained in 52% yield with 86% enantiomeric excess. Winkler and co-workers screened several dirhodium tetracarboxami-dates and found Rh2(R-MEPY)4 to be the catalyst that gives the highest diastereoselec-tivity for this reaction [142]. 

The reaction of methyl phenyldiazoacetate with N-Boc-piperidine (36) is a good illustration of the potential of this chemistry because it leads to the direct synthesis of f/ireo-methylphenidate (37) [27]. The most efficient rhodium car-boxylate catalyst for carrying out this transformation is Rh2(S-biDOSP)2 (2), which results in the formation of a 71 29 mixture of the readily separable threo and erythro diastereomers. The threo diastereomer 37 is produced in 52% isolated yield and 86% ee [Eq. (19)]. Other catalysts have also been explored for this reaction. Rh2(R-DOSP)4 gives only moderate stereoselectivity while Rh2(R-MEPY)4 gave the best diastereoselectivity in this reaction (94% de) [29]. 

The intermolecular C-H insertion on N-Boc-piperidine leads to the rapid access of the pharmaceutical agent threo-methylphenidate (30) [26], As this reaction is of commercial interest, a range of chiral catalysts have been examined [26], The best enantioselectivity was obtained with Rh2(S-biDOSP)2, which is a bridged second generation analog of Rh2(S-DOSP)4 [26a, b]. 

Winkler et al. reportedt " an enantioselective synthesis of (27 ,2 7 )-(+)-f/ireo-methylphenidate hydrochloride (1) based on the rhodium-mediated C-H insertion of methyl phenyldiazoacetate (40) with N-BOC-piperidine (41). Thus, reaction of methyl phenyldiazoacetate (40) with V-BOC-piperidine (41 ... 

Iodo-N-BOC-piperidine 42 was obtained by iodination of 4-hydroxy-Af-BOC-piperidine 41 with iodine/triphenylphosphine/imidazole in THE. An extractive workup removed the triphenylphos-phine oxide, allowing a direct crystallization of the pure iodide from ethanol/water that typically contained <1 mol% of triphenylphosphine oxide and other by-products. DMAC was later identified as a better solvent to avoid the formation of THF-polymer or dimer impurities resulting from the interaction of I2/THF. 

Efforts to extend the direct asymmetric lithiation and substitution from N-Boc-pyrrolidine to AT-Boc-piperidine have not been successful. Although a low yield of an enantioenriched product can be obtained from N-Boc-piperidine, competing reactions intervene, a result which is consistent with calculations [41]. 

A general one-pot procedure for the synthesis of alkynes from aldehydes (Corey-Fuchs reaction) that involves the synthesis of the triphenylphosphonium dibromomethane reagent has been explored by Michel and coworkers. In general, the base of choice is f-BuOK, but in case of the N-Boc piperidine, use of BuLi in order to avoid unwanted side reactions between the carbamate and the acetylide function provides a cleaner reaction at low temperature (eq 64). 

Also discussed in Volume 55 were syntheses of clavepictines A (2517) and B (2518) by Cha and coworkers, who subsequendy pubftshed a full paper containing additional details and relevant model studies.This later pubHcation included a more convergent second-generation synthesis in which N-Boc piperidine 2525 was metalated at C-6 before reaction with the enantiopure aUene 2526 (made in 13 steps from ethyl ( )-dec-2-enoate) followed by acylation of the resulting alcohol eventually gave the readily separable cyclization precursors 2527 and 2528 in an approximate ratio of... 

Beak and Lee showed that N-Boc-piperidine can undergo a-lithiation with sec-BuLi and TMEDA and react with various electrophiles. Their attempts at the asymmetric deprotonation of N-Boc-piperidine using s-BuLi/ (—)-sparteine, a method that provided excellent enantioselectivily in the case of N-Boc-pyrrolidine, led to less efficient results (Scheme 11.32). The major side product was a mixture of the isomeric enamines (43%) arising from the competitive addition of sec-BuLi to the carbamate group of N-Boc piperidine due to the very slow rate of lithiation observed under these conditions. ... 

As mentioned earlier, one of the most significant applications of a-lithiation chemistry has been its utility in a-arylations. Dieter and Li have extended the a-arylation method to racemic 2-lithio-N-Boc piperidines using the combination of copper cyanide and palladium(O), albeit with the same substrate scope as noted for pyrrolidines vide supra). Coldham and Leonori applied the Negishi protocol to AT-Boc piperidine which gave access to a wider range of racemic 2-arylpiperidines (Scheme 11.33). ... 

Gawley and Beng have shown that asymmetric a-arylation and vinylations of N-Boc-piperidines can be achieved through the expansion of their catalytic dynamic resolution of 2-lithio-N-Boc-piperidine followed by trans-metallation of lithium to zinc and a subsequent Negishi coupling (Scheme 11.34). ... 

In their quest for CCR3 antagonists such as 8 (Scheme 11.38) for the treatment of asthma, Wacker and Duncia et al. utilised an a-lithiation and functionalisation of an N-Boc-piperidine to access the racemic Beak allq l-ated benzylpiperidines. In the synthesis of the 4-fluoro-benzyl analogue, a silyl protection was necessary to avoid competing metalation ortho to the fluorine in the a-lithiation step. " ... 

Baudoin demonstrated that the choice of ligand ean have a directing effect on the reductive elimination of Pd-complexes from N-Boc-piperidine, as outlined above. Transmetallation of the 2-piperidyl zinc forms a palla-dium(ii) complex that undergoes palladium hydride elimination followed by rotation of the 7i-complex and reductive elimination to the p-arylated... 

In the majority of cases, the deprotonation of carbamates occurs in the presence of diamines (TMEDA, sparteine or like-sparteine diamine). Complex s-BuLi with the chiral (-)-sparteine efficiendy and enantioselectively deprotonates N-Boc-pyrrolidine (127), but the same base complex is less effective with N-Boc-piperidine. So, lithiation of N-t-Boc-piperidine with sec-BuLi-(-)/sparteine requires 16 h for completion of the deprotonation and after subsequent addition of trimethylchlorosilane, the yield of (S)-195 is detected to be only 8% (133). However, the replacement of sparteine by other diamine results in the increased yield of (S)-195 (135). 

This approach may find application in peptide bond formation that would eliminate the use of irritating and corrosive chemicals such as trifluoroacetic acid and piperidine as has been demonstrated recently for the deprotection of N-boc groups (Scheme 6.7) a solvent-free deprotection of N-tert-butoxycarbonyl group occurs upon exposure to microwave irradiation in the presence of neutral alumina doped with aluminum chloride (Scheme 6.7) [41]. 

The alcohol 10 introduced at step j was prepared following a literature procedure from ethyl-2-(piperidin- 4-yl)acetate after N-Boc protection and selective reduction of the ester group using lithium aluminum hydride (Villalobos et al., 1994) (reaction scheme b). 

Deprotection of the N-Boc group of piperidine 305 by TFA to afforded a TFA salt, followed by basic aqueous workup with aqueous NaHC03 solution gave a single racemate of perhydropyrido[2,l-c][l,4]oxazin-3-one 306, while that of the O-TBS protected piperidine 307 by TFA or TBAF yielded diastereomeric mixtures of 308 (09OBC655). 

Golebiowski et al. reported the solid-phase [92] and the solution-phase [93] syntheses of bycyclic diketopiperazines which were of great interest because their conformation was similar to the type-1 /i-turn motif. A Merrifield hydroxymethyl resin was esterified with a-N-Boc-fi-N-Fmoc-L-diaminopropionic acid and then mono-deprotected at the />-N with piperidine. Ugi-4CR of the resulting resin-bound amine gave the resin-bound adducts 168. Subsequent N-Boc deprotection and intramolecular N-alkylation afforded the ketopiperazines 169. The diketopiperazines 170 were formed via N-Boc amino acid coupling followed by N-Boc deprotection... 

Whilst carbamate derivatives of indoles and pyrroles are easily prepared, they have limited synthetic utility because they are easily attacked by nucleophiles. For example, A -Aloc525 and A -Cbz526 derivatives of tryptophan are known, but they are destroyed by piperidine. Boc derivatives of indoles, pyrroles and imidazoles are sufficiently hindered to be synthetically useful For example, N-Boc indole is stable towards piperidine and it can be metallated in the 2-position with ferf-butyllithium.527 Nevertheless, they are still more easily cleaved by nucleophiles than Boc-derivatives of secondary amines as illustrated by the fact that Boc-derivatives of pyrrole are cleaved with sodium methoxide, ammonia or hydrazine in methanol527 In tryptophan derivatives, the Ar>w-Boc group is less susceptible to aridolysis than an Na-Boc group with trifluoroacetic acid. However, the M"-Boc group can be cleaved selectively by thermolysis as illustrated by a step in a synthesis of Asperazine [Scheme 8,271 ].52 ... 

PPh3, TFIF, rt, 24 h. (b) Fmoc deprotections with 25% piperidine In DMF followed by couplings using DMTMM In NMP with N-Fmoc-Phe-OFI N-Fmoc-Ala-OFI, and N-Boc-Val-OFI. (c) Sml2 0.1 M In TFIF, rt, 4 h. 

Scheme 2.12. Synthesis of bulk recoded resin. Reagents and conditions (i) N-Boc-e-iV-Fmoc-Lys-OH, DIG, HOBt, DCM (ii) piperidine, DCM (iii) F-tags-COOH, DIG, HOBt, DCM.

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