An amine protecting group deprotectable under nearly neutral oxidative conditions

The 1,3-dithiane-based dM-Dmoc group was studied for the protection of amino groups. Protection was achieved under mild conditions for aliphatic amines, and under highly reactive conditions for the less reactive arylamines. Moderate to excellent yields were obtained. Deprotection was performed by oxidation followed by treating with a weak base. The yields were good to excellent. The new amino protecting group offers a different dimension of orthogonality in reference to the commonly used amino protecting groups in terms of deprotection conditions. It is expected to allow a collection of transformations to be carried out on the protected substrates that are unattainable using any known protecting groups.


Introduction
In multistep organic synthesis, amino groups usually have to be protected [1]. Protecting groups for the purpose mainly include those deprotectable by acid (e.g., tert-butyloxycarbonyl (Boc) group) [2][3][4], base (e.g.,  group and trifluoroacetyl group) [5][6][7], catalytic hydrogenation (e.g., benzyl group) [8], photoirradiation (e.g., 2-nitrophenylethyl carbamate and 6-nitroveratryl carbamate) [9,10] and fluoride (e.g., trimethylsilylethyloxycarbonyl (Teoc) group) [11,12]. The 1,3-dithian-2-ylmethoxycarbonyl (Dmoc) group first reported by Kunz and co-workers provides a different dimension of orthogonality of amine protection in terms of deprotection conditions [13][14][15][16][17]. This group was deprotected under oxidative conditions under which the commonly used Boc, Fmoc, benzyl and Teoc groups could potentially survive. Oxidation was achieved by hydrogen peroxide in the presence of an ammonium molybdate catalyst. Recently, we reported the use of the Dmoc group for amine protection in automated solidphase oligodeoxynucleotide (ODN) synthesis [18]. For deprotection, we found that sodium periodate could effectively oxidize multiple Dmoc functions in the ODNs to achieve com-Scheme 1: Dmoc and dM-Dmoc protection and deprotection of amines. plete deprotection. Under these oxidative conditions, oxidation of the ODN was not observed. The mild deprotection conditions allowed us to introduce sensitive functionalities into ODNs, which are otherwise impossible or highly difficult to achieve [18]. In addition, we also investigated the potential of the dimethyl-1,3-dithian-2-ylmethyl (dM-Dim) group for orthogonal carboxylic acid protection [19]. To further explore the use of the 1,3-dithiane function as protecting group in organic synthesis, here we report the results of our studies on the use of the dimethyl-1,3-dithian-2-ylmethoxycarbonyl (dM-Dmoc) group for amine protection (Scheme 1). Compared with the Dmoc group, the dM-Dmoc group is expected to be more stable under nucleophilic conditions, which will allow many transformations including base hydrolysis of esters and amides, hydride reduction of carbonyl compounds, and a wide range of nucleophilic substitution reactions to be carried out without losing the protection. With Dmoc protection, such transformations would be unattainable or require fine tuning of reaction conditions to keep the protection. In addition, the side product 2 from deprotection of dM-Dmoc is less likely to act as a Michael acceptor to react with the amine product than 1 from deprotection of Dmoc due to its higher steric hindrance. Such side reactions could be a serious issue in some situations [18].

Results and Discussion
To protect amines, compound 4 was prepared readily by reacting deprotonated 1,3-dithiane with acetone followed by treating with p-nitrophenylchloroformate (see experimental section). The compound is stable, which allows easy purification and storage. However, we expected that it could react with amines under suitable conditions. Using benzylamine (3a) as the model substrate, we tested a variety of reaction conditions to form the dM-Dmoc protected carbamate 5a (see Table 1 for structures). These include using different solvents such as THF, DCM, acetonitrile and toluene, and different bases such as DIPEA, pyridine and trimethylamine. We found that the condi-tions most suitable for the reaction were to react one equivalent amine with one equivalent of 4 in the solvent THF using five equivalents of DIPEA as the base. At room temperature, the reaction could complete within eight hours.
After suitable conditions for protection of amines with dM-Dmoc were identified, we investigated the substrate scope of the reaction. As shown in Table 1, primary aliphatic amines including 3a-d gave good to excellent isolated yields of carbamates 5a-d ( Table 1, entries [1][2][3][4]. Under these conditions, however, secondary aliphatic amines could not react or could react but gave very low yields. We tried a variety of other conditions such as deprotonating the amine followed by reacting with 4 and heating excess amine with 4 without any solvent but failed to identify one that could afford useful yields. We also tried to use the optimized conditions for the protection of aliphatic primary amines to protect arylamines, but found that arylamines were not reactive enough for the reaction. Therefore, for protecting arylamines, we used conditions for the formation of hindered O-tert-alkyl N-arylcarbamates we reported earlier [20]. Treating one equivalent 3e with two equivalents LDA and one equivalent 4 in THF gave the desired arylamine dM-Dmoc carbamate 5e in synthetically useful yield (Table 1, entry 5).
Three additional arylamines were also tested, which include the two heterocyclic arylamines 3g and 3h, all gave synthetically useful yields of the aryl carbamate products 5f-h (Table 1, entries [6][7][8]. Finally, to investigate the suitability of the dM-Dmoc group for protecting amino acids, phenylalanine (3i) was selected to react with 4 to give 5i (Table 1, entry 9). The general conditions for aliphatic amine protection were used, but due to the low solubility of 3i in THF, DMSO was used as the solvent. Compound 5i was obtained in 80% isolated yield.
For deprotection of dM-Dmoc protected amines, we used the conditions we developed earlier for the deprotection of Dmoc protected ODNs directly without making additional efforts to evaluate other conditions [18]. These conditions could be superior to reported conditions [13,15,17,21] because they do not require transition metal catalysts or any special devices such as an electrochemical cell. Therefore, the dM-Dmoc carbamates were first oxidized with sodium periodate at room temperature. After removing the excess oxidizing agent and other inorganic salts by filtration, β-elimination to give the amine products was initiated with the weak base potassium carbonate at room temperature. The products were then purified with flash column chromatography. As shown in Table 1, the yields of the deprotection ranged from 48% to 88%. Among them, 3a and 3d, which are aliphatic amines, gave better yields ( Table 1, entries 1 and 4). Compounds 3b and 3c are also aliphatic amines, but their yields were lower. This might be caused by evaporation due to their low boiling points during work-up and purification. The arylamines were obtained in lower yields (Table 1, entries 5-8) compared with the aliphatic ones. Among the four arylamine examples, 5g and 5h contained a pyridine ring, which could be sensitive to oxidative conditions. However, it looked like that sodium periodate was benign to pyridine and some other nitrogen containing aromatic heterocycles [18]. The dM-Dmoc protected phenylalanine (5i) was deprotected under slightly different conditions (Table 1, entry 9). In the β-elimination step, when methanol was used as the solvent as in the general deprotection procedure, no reaction occurred even after stirring overnight. This might be caused by the more favoured deprotonation of the carboxylic acid group by potassium carbonate, which made the starting material insoluble and prevented deprotonation of H-2 in the oxidized 1,3-dithiane function. The problem was solved by using a solvent mixture of methanol and water. It is important to note that carrying out the deprotection reaction in one pot by performing the oxidation under basic conditions is not feasible. In theory, using the one pot approach, once the sulfides in dM-Dmoc were oxidized, β-elimination would follow to give the desired amine products directly. We tested the idea, and as expected, complex mixtures were formed. Reasons for the observation include oxidation of amine products by sodium periodate and its reduced products.
In addition, we also found that oxidation of sulfides by sodium periodate was significantly slower under basic conditions than under neutral and acidic conditions.
To demonstrate the feasibility of selective deprotection of dM-Dmoc protected amines in the presence of Boc protected ones, compound 6 [22] was reacted with 4 under the general aliphatic amine protection conditions to give the Boc and dM-Dmoc protected diamine 7 (Scheme 2). Selective removal of dM-Dmoc was simply achieved under the general deprotection conditions without any fine tuning of conditions. The desired Boc protected 6 was obtained in 80% isolated yield. To demonstrate the orthogonality of dM-Dmoc and Fmoc protections, compound 9 was prepared (Scheme 2). Compound 4 was reacted with 1,2-bis(2-aminoethoxy)ethane to give 8, which was reacted with Fmoc-Cl to give the dM-Dmoc and Fmoc protected diamine 9. We found that selective removal of Fmoc from 9 to give 8 could be achieved under typical Fmoc deprotection conditions involving piperidine. Selective removal of dM-Dmoc was also simple; treating 9 under the standard dM-Dmoc deprotection conditions gave the Fmoc protected diamine 10 in 75% isolated yield (Scheme 2). The basic conditions involving potassium carbonate used to induce β-elimination of oxidized dM-Dmoc did not cause any loss of Fmoc protection.

Conclusion
In summary, we have demonstrated that dM-Dmoc could serve as a new protecting group for aliphatic and arylamines. This group could be removed under nearly neutral oxidative conditions, which are orthogonal to the commonly used conditions for deprotection of protected amines including acid, base, and catalytic hydrogenation. Compared to Dmoc, dM-Dmoc has the advantage of being stable under a wide range of basic and nucleophilic conditions. We expect that the new protecting group will find wide applications in multistep organic synthesis.

Supporting Information
Supporting Information File 1 Images of 1 H and 13 C NMR spectra of new compounds including 5a-i and 7-9.