Nitrogen protection

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 section on sulfonamides should be consulted for a related approach to nitrogen protection. Some of the derivatives presented there may also be applicable to amides. 

CH2CI2, Pyr, 71-88% yield) and is cleaved with thiourea to release the alcohol that closes to the phthalide, releasing the carbohydrate.Its use for nitrogen protection was unsuccessful. 

Pyridinethiol, Et3N, CH2CI2, 95% yield. The methylthioamide group is stable to 2.5 N NaOH, THF, H2O and to 10% H2SO4, MeOH, H20. The section on sulfenamides should be consulted for a related approach to nitrogen protection. Some of the derivatives presented there may also be applicable to amides. 

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... 

A nitrogen-protective benzyl group was hydrogenolytically removed and replaced by a tert-butyloxycarbonyl moiety in a single operation. The protected compound and (Boc)20 in MeOH and 10% Pd/C were treated for 48 hours under 3 atm H2 (Scheme 4.79).325,326... 

Scheme 4.48 Comparative study of nitrogen protecting groups.

Use of histidine derivatives substituted at the x-nitrogen. -protection prevents isomerization during coupling (see Section 4.3), but -protection may not suppress it completely (see Section 6.10). 

Finally, the intramolecular coupling reaction between an olefin and a pyrrole ring has been examined (Scheme 40). In this example, a 66% isolated yield of the six-membered ring product was obtained. A vinyl sulfide moiety was used as the olefin participant and the nitrogen protected as the pivaloyl amide in order to minimize the competition between substrate and product oxidation. Unlike the furan cyclizations, the anodic oxidation of the pyrrole-based substrate led mainly to the desired aromatic product without the need for subsequent treatment with acid. 

The lithiation of 2,3-pyrrolines has received only moderate attention, but two different nitrogen protection systems have been found acceptable. Thus the terf-butylformamidine derivative metalates readily with either n-or t-butyllithium, and after reaction with a variety of electrophiles the formamidine group can be removed with hydrazine to give 2-substituted... 

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. ... 

Polyethylene glycol should be weighed into clean, dry, light-resistant containers and sealed under nitrogen protection. Bulk container should be flushed with nitrogen and resealed. 

Filter solution through 8-micron membrane filter (or similar) into a suitable container, under nitrogen protection. 

Bubble C02 or nitrogen gas into clear filtrate for 5 minutes. Then seal tank and hold product under C02 or nitrogen protection. 

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