Efficient and selective cleavage of the tert -butoxycarbonyl (Boc) group under basic condition

A simple, efficient and mild method for the selective cleavage of tert -butoxycarbonyl (Boc) from dicarbamates and a carbonyl or aromatic ring in conjugation with the nitrogen atom bearing the Boc-group is described under basic condition


Introduction
The natural and unnatural α-amino acids play a central role in chemistry and biology. 1 In addition, to their key biological roles as components of peptides, proteins, and other natural products, α-amino acids are utilized in the pharmaceutical, agrochemical, and related industries.The use of α-amino acids and their derivatives solely depend on the protecting group attached to the amine and acid functionality. 2 Among the various protecting groups for amine functionality, the t-butoxycarbonyl (Boc) group is one of the most frequently used in organic synthesis due to its chemical stability to basic and mildly acidic conditions and its ease of removal under specific conditions. 3However, selective cleavage of the di-t-butylimidodicarbonate, oftenly found as valuable intermediates in Mitsunobu 4 and Gabriel type 5 processes towards the synthesis of several bio-active molecules, protected α-amino acids to mono-Boc compounds still lacks efficient and milder methods.Numerous methods are available for the removal of the Bocgroup, 7 including trifluoroacetic acid, 8 trimethylsilyl iodide, 9 hydrochloric acid in ethyl acetate, 10 ceric ammonium nitrate, 11 tin tetrachloride, 12 tetrabutylammonium fluoride, 13 zinc bromide, 14 boron trifluoride, 15 thermolytic removal 16 etc.However, there are very few methods for the selective cleavage 17a-f of the di-Boc protected α-amino acids to mono-Boc compounds.Still organic community seeks simple, efficient and milder methods for selective deprotection of the well known protecting groups by preserving the other functionalities.
During our investigation towards the synthesis of celogenitins, 18 we tried to perform Suzuki coupling reaction at C-2 position of tryptophan derivative 1a with imidazole in the presence of Cs 2 CO 3 and catalytic amount of palladium reagent in acetonitrile at 70 o C. It is worthy to mention that, under various conditions of employing different palladium reagent, we could able to isolate only the Boc-deprotected product 1b (Scheme 1).

Scheme 1
We report herein a new and mild method for the deprotection of Boc-group from amino compounds under basic conditions, using Cs 2 CO 3 and imidazole system, from di-tbutyldiimidodicarbonate as well as nitrogen atom conjugated to a carbonyl or aromatic system.

Results and Discussion
To explore the scope and limitations, we investigated a series of Boc-protected amino compounds with different protecting groups and functionalities, which are shown in Table 1.Although it is known that cleavage of the protecting groups in methyl N-Boc-α-amino esters gave the corresponding N-Boc-amino acids without racemization 19 under basic condition, in our case, we were worried about such a possibility in the presence of an additional Boc group.To investigate this, we submitted compound 2, 3, and 4 to above basic conditions to cleave the Boc group.We found that the optical rotation of the product obtained changed with time, showing clearly that epimerization has occurred.Furthermore, chiral HPLC analysis of 2b showed two peaks confirming the epimerization during the reaction. 20In light of this result, we decided to convert the acid into its benzyl esters.To ensure the enantiomeric purity of such a product (8b), we again submitted for the chiral HPLC which showed single peak at the corresponding retention time and in addition, the rotation clearly confirmed no detectable racemization.With the retention of optical purity on amino acids, we applied the above method to other Boc-protected compounds.Boc-group attached to nitrogen atoms part of an aromatic system or in conjugation with a carbonyl group was removed in high yields.Simple aliphatic mono-Boc compounds were unaffected under above reaction conditions.In entry 12a, where the nitrogen functionality is protected by Boc as well as Cbz group, we found that only Boc group was selectively cleaved from the nitrogen and Cbz group was untouched affording the product 12b in 82% yield.ii Isolated yield.

Table 1. Selective removal of Boc-group under basic condition
When the nitrogen functionality was doubly protected with an additional protecting group besides Boc (entry 13a), such as p-methoxybenzyl (PMB) group, the deprotection of the Bocgroup was not observed.Interestingly in case of 7a, the t-butoxycarbonyl group attached to the ring nitrogen was cleaved selectively compare to the BOC group present on the aliphatic nitrogen atom to afford compound 7b which is difficult to make directly from histidine in 91% yield.Next various organic solvents were tried and we found that in particular acetonitrile and THF were the solvents where better results were obtained.Another important point is that both the reagents are required in stoichiometric amount for the completion of the reaction.The mechanism proposed by Stafford et al. 16b and Martin et al. 16f for the cleavage of N-Boc amines based on the formation of a six-membered chelate seems to be applicable to our method.We proposed that the initial chelation between the metal ion and two oxygen of the carbonyl group followed by abstraction of proton from the methyl group led to the loss of isobutene, CO 2 and formation of Boc-deprotected product.Our observation supports the structure A, in which both carbonyls are chelated with the cation.

Conclusions
In conclusion, we have described a simple, mild, and efficient protocol for the deprotection of the Boc group from Boc-protected carbamates, amides and nitrogen atom present in the aromatic ring under basic condition at 70 o C.

Experimental Section
General Procedures.Solvents were purified and dried by standard procedures before use.
Column chromatography was carried out with silica gel (60-120 mesh

i
All reactions were carried out in acetonitrile at 70 o C and the products characterized by NMR, IR, elemental analysis.