Nitrogen protecting groups

HCl, Et20, 6 h, 83-88% yield.Acidic deprotection of the BOC group could not be achieved with complete selectivity in the presence of an MTM ester. The trityl and NFS (2-nitrophenylsulfenyl) groups were the preferred nitrogen protective groups. 

The BOC group can be cleaved with TBDMSOTf and the intermediate silyl carbamate converted to other nitrogen protective groups. 

Allylamines have been used as nitrogen protective groups. They can be removed by isomerization to the enamine (t-BuOK, DMSO) or by rhodium-catalyzed isomerization. ... 

Sulfonamides (R2NSO2R ) are prepared from an amine and sulfonyl chloride in the presence of pyridine or aqueous base. The sulfonamide is one of the most stable nitrogen protective groups. Arylsulfonamides are stable to alkaline hydrolysis, and to catalytic reduction they are cleaved by Na/NH3, Na/butanol, sodium naphthalenide, or sodium anthracenide, and by refluxing in acid (48% HBr/cat. phenol). Sulfonamides of less basic amines such as pyrroles and indoles are much easier to cleave than are those of the more basic alkyl amines. In fact, sulfonamides of the less basic amines (pyrroles, indoles, and imidazoles) can be cleaved by basic hydrolysis, which is almost impossible for the alkyl amines. Because of the inherent differences between the aromatic — NH group and simple aliphatic amines, the protection of these compounds (pyrroles, indoles, and imidazoles) will be described in a separate section. One appealing proj>erty of sulfonamides is that the derivatives are more crystalline than amides or carbamates. 

The nature of the nitrogen protecting group also played a significant role in the chemoenzymatic total synthesis ofepibatidine, which shall be outlined as an example for the synthetic elaboration of the regioselective biooxidation product of a nonnatural precursor. B. bassiana mediated hydroxylation of the aza-norbornane system enabled functionalization for the subsequent introduction of the pyridine system (Scheme 9.10) [82,83]. 

At the beginning of the project, we had studied the introduction of the pMB group to 4 as a nitrogen protecting group, as used in the Medicinal Chemistry route. There was a classical regioselectivity problem, O- versus N-alkylation. Under the Medicinal Chemistry conditions, the desired N-alkylated product 5 was mainly formed, but around 10-12% of the corresponding O-alkylated product 16 was also... 

Taking Tomioka s pioneering work [8] as a precedent, we have screened 13-amino alcohols as chiral modifiers [9] in the nucleophilic addition of lithium 2-pyridinylacetylide 6 to the pMB protected ketimine 5. We were pleased to discover that when 5 was treated with a mixture prepared from 1.07 equiv each of quinine and 2-ethynylpyridine by addition of 2.13 equiv of n-BuLi in THF at -40 to -20 °C, the desired adduct 19 was obtained in 84% yield with maximum 64% ee. Soon after, we found selection of the nitrogen protective group had great influence on the outcome of the asymmetric addition and the ANM (9-anthranylmethyl)... 

The ANM group was selected as the nitrogen protecting group for the novel asymmetric nucleophilic substitution providing the optimum enantioselectivity. 

The effect of the nitrogen protective group in 37 was briefly studied and the results are summarized in Table 1.7. The pMB group provided a good selectivity. It is also noted that the reaction was sluggish and provided a lower enantiomeric excess (72%) if the nitrogen atom was not protected. 

If one employs o-iodoaniline derivatives in this double insertion chemistry, 2-quinolones are generated in good yield after a basic work-up to remove the nitrogen protecting group (Scheme 14).15... 

Scheme 4.48 Comparative study of nitrogen protecting groups.

The iodocyclizations of 2-alkoxycarbonylamino-3-alken-l-ols proved to be highly stereoselective processes resulting in either l,3-oxazin-2-one or THF derivatives, depending on the substituents at the double bond and the nitrogen protecting group <2000TA3769>. 

N-Acylation and 3-alkoxycarbonylation reactions may be achieved by conventional acylation procedures. A variety of 3-acyl derivatives 157 can be prepared most conveniently by the treatment of DPPOx 266 with carboxylic acids in the presence of a tertiary amine. tert-Butoxycarbonyl (Boc-Ox, 236) and benzyloxy carbonyl (Cbz-Ox, 267) (Cbz = benzyloxycarbonyl) compounds are of practical use for introduction of nitrogen protecting groups. ... 

A related approach exploited a A-cyanomethyl group to serve in the dual role of a nitrogen protecting group and a latent precursor of the formaldehyde im-inium ion (e.g., 478), and this innovative modification in tactics resulted in a simplified route to the c/.v-3a-aryloctahydroindole 474 (203a,c). To this end, the amino ketone 482 was readily prepared in one step by the reaction of 1,2-bis(trimethylsilyloxy)cyclopentene with A -benzyl-A -cyanomethyl amine. When 482 was exposed to [l-(3,4-methylenedioxyphenyl)ethenyl]lithium, a mixture (1 14) of 483 and 484 was obtained. It is noteworthy that the stereochemical sense... 

Besides activating the ring for substitution reactions, the A-oxide moiety can serve as an effective nitrogen-protecting group. For example, in order to suppress the product of N-N bond formation (Equation 11) in favor of the desired C l reaction product 32, azide 31 was prepared from A-oxide 29 in two steps (Scheme 4) <2002TL6035>. 

Application of the halogenation of y-aminoolefins preceding intramolecular cyclization has been applied to the synthesis of fused piperidines (Equation 33) <2003CC1918>. The presence of chiral substituents (e.g., via the nitrogen protecting group) generates a diastereoselective reaction (Equation 34). 

Also, in order to obtain a nitrogen protecting group that would be easier to remove than thep-toluenesulfonyl group (Ts), the ferf-butoxycarbamate (BocNR2) derivative 71 (Scheme 5.31) was also engaged in the same reaction to efficiently yield the desired dienyl product 72. 

Note that the first-formed product from the cycloaddition is actually the sodium tetrazolate salt 8.32. Protonation affords the neutral tetrazole 8.31. Prolonged acidic hydrolysis accomplishes several transformations hydrolytic removal of both the phthalimide and acetyl nitrogen protecting groups, and... 

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