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. Author manuscript; available in PMC: 2011 May 5.
Published in final edited form as: Tetrahedron Lett. 2010 May 5;51(18):2536–2538. doi: 10.1016/j.tetlet.2010.03.009

An Alkoxide Anion Triggered tert-Butyloxycarbonyl Group Migration. Mechanism and Application

Fengtian Xue 1,†, Richard B Silverman 1,*
PMCID: PMC2856655  NIHMSID: NIHMS189787  PMID: 20414457

Abstract

We report a fast N→O tert-butyloxycarbonyl (Boc) migration of the imide (3R,4R)-tert-butyl 3-((6-(bis(tert-butoxycarbonyl)amino)-4-methylpyridin-2-yl)methyl)-4-hydroxypyrrolidine-1-carboxylate (2) via a base-generated alkoxide. The mechanism of the migration is intramolecular, involving an unusual nine-membered cyclic transition state.

Keywords: N to O migration, Boc group migration, intramolecular migration, crossover experiment

In the course of research on the development of chiral pyrrolidine-based inhibitors for neuronal nitric oxide synthase (nNOS), we evaluated various methods for the synthesis of compounds 1a and 1b, the key intermediates to prepare drug candidates for different kinds of neurodegenerative diseases.1–3 Given the poor efficiency of benzyl deprotection during the reported synthetic route to 1a,2 we attempted to use bis-Boc protection of the amino group on the pyridine ring (1b); these groups could be removed in one step during the late stage deprotection of the synthesis in excellent yields, providing a much more practical preparation of the final products on a multigram scale.4

graphic file with name nihms189787f7.jpg

To generate 1b, allylation of alcohol 2 was attempted by treating a solution of 2 in DMF with NaH (2 equiv) at room temperature, followed by the addition of allyl bromide (2 equiv). The reaction was quenched with H2O to form the product with 93% isolated yield (Scheme 1). To our surprise, mass spectrum and 1H NMR data for this product did not match the anticipated product (1b). The isolated product has only an (M + H+) peak at 448, which is 100 less than the calculated molecular weight of 1b, implying a possible lost of one Boc group from the desired product. This was further confirmed by the fact that there were two distinctive singlets at 1.46 and 1.52 ppm (each integrating to nine protons) in the 1H NMR spectrum (in CDCl3) of the product. The instability of the Boc protecting group under strong basic conditions has been documented.5–6 Interestingly however, one broad singlet in the 1H NMR spectrum was found from 2.30 to 2.40 ppm, indicating the presence of a hydroxyl group in the product. Further NOSEY NMR data showed that the allyl group was connected through the nitrogen atom of the amino functionality to the pyridine ring.7 On the basis of these results, we assigned the product as (3R,4R)-tert-butyl 3-((6-(allyl(tert-butoxycarbonyl)amino)-4-methylpyridin-2-yl)methyl)-4-hydroxypyrrolidine-1-carboxylate (3).8 It was also noted that: 1) compound 2 showed significant stability in aqueous NaOH even at accelerated temperature,9 and 2) no O-allylation product was detected in the reaction process.

Scheme 1.

Scheme 1

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Formation of 3 from 2

To elucidate the origin of N-allyl alcohol 3, the reaction was repeated and monitored closely by thin layer chromatography (TLC) and LC/MS analysis. Time course studies clearly showed the disappearance of the starting material (2), and the buildup of a new compound with significantly less polarity when 2 was treated with NaH in DMF. After the addition of H2O, the product (3), with similar polarity to that of 2, was formed quickly (Scheme 1). Accordingly, we speculated that the basic environment generated during the quenching step catalyzed a hydrolysis reaction of the initial product, leading to the formation of alcohol 3. To test this hypothesis, the same reaction was repeated and quenched with saturated aqueous NH4Cl, to avoid the potential base-catalyzed hydrolysis step. As a result, compound 4 was isolated in a 96% yield (Scheme 2).10 This result implies that a carbonate derivative was an intermediate involved in the reaction course, which explains why there was no O-allylation product formed from the reaction.

Scheme 2.

Scheme 2

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Formation of 4 from 2

On the basis of this collected evidence, we propose that deprotonation of 2 by treatment with NaH forms 5 at the beginning of the reaction (Scheme 3). Alkoxide 5 initiates the migration of one of the two Boc groups on the aminopyridine through a nine-membered ring transition state to generate amide anion (6), which reacts with allyl bromide to generate 4. Several examples of anion triggered migration reactions have been described in literature.11–15 The carbonate linkage of 4 is unstable to the strong basic environment (e.g., aqueous NaOH, generated during the quench step), and is hydrolyzed quickly to give alcohol 3 as the only product. To prove the presence of 6, the reaction was quenched with saturated aqueous NH4Cl before the addition of allyl bromide. As seen in Scheme 4, compound 7 was isolated in quantitative yields and characterized.16

Scheme 3.

Scheme 3

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Proposed mechanism for the formation of 3

Scheme 4.

Scheme 4

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Formation of 7 from 2

To further investigate the reaction mechanism, we carried out a crossover experiment using a mixture of compounds 2 and 8 as starting material. The mixture was treated with NaH, and after 5 min the reaction mixture was quenched with saturated aqueous NH4Cl. The reaction did not give any crossover product (i.e., O-Boc-8) as shown in Scheme 5: compound 7 was isolated in almost quantitative yield, and 8 was fully recovered from the reaction mixture. These results clearly indicate that the Boc migration reaction takes place by an intramolecular pathway.

Scheme 5.

Scheme 5

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Crossover experiment for Boc migration

The unusual Boc-protecting group migration also provides a facile approach to selectively add an allyl or a benzyl group onto the amide N atom without hydroxyl group protection. The previous method for this reaction suffered from competition of O-allylation or O-benzylation reactions, leading to unsatisfactory yields of products unless the hydroxyl group was protected (Scheme 6).2 Using di-Boc-protected 2 as the starting material, however, the reaction (e.g., allylation or benzylation) produces the desired compound as the only product in excellent yields without interference of side reactions at the hydroxyl group.

Scheme 6.

Scheme 6

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Alkylation of the aminopyridine without hydroxyl protection

In summary, we demonstrated a novel alkoxide anion triggered N→O Boc migration, involving an unusually large nine-membered ring transition state. The Boc migration process provides a new high yield method to perform selective amide allylation/benzylation over hydroxyl allylation/benzylation reactions.

Acknowledgment

The authors are grateful for financial support from the National Institutes of Health (GM049725).

Footnotes

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References

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