Efficient solventless technique for Boc-protection of hydrazines and amines

A new efficient technique for Boc introduction into hydrazines and amines is reported. The substrate is stirred in molten di-( tert -butyl)dicarbonate without any solvent. The method requires neither DMAP nor other catalyst. The scope of the method is demonstrated using several hydrazines and amines


Introduction
The protecting group strategy has found many applications in preparative organic chemistry.The tert-butoxycarbonyl (Boc) group is one of the most frequently used for protection of NH 2 group in different applications.This is particularly important in peptide and amino acid synthesis.The Boc group is orthogonal to benzyloxycarbonyl (Z), 2,2,2-trichloroethyloxycarbonyl (Troc), ptoluenesulfonyl (Tos) and some other well known and useful protecting groups. 1 Furthermore, two Boc groups at the same nitrogen are also orthogonal. 2 The Boc group is not hydrolyzed under basic conditions, is extremely resistant to many other nucleophiles, and is not susceptible toward catalytic hydrogenolysis.On the other hand, several mild and selective cleavage methods for this group are available.All these factors make the Boc group an excellent tool for many purposes. 1here are several reagents that can be used for the introduction of Boc groups, such as Boc 2 O, BocONH 2 , BocN 3 , 1-(tert-butoxycarbonyl)benzotriazole, and BocON=N(CN)Ph. 3 Among them, di-(tert-butyl) dicarbonate was found to be the best in most applications, owing to its commercial availability, high stability, and low price.This reagent is mainly used in the presence of a basic catalyst (NaOH, K 2 CO 3 , DMAP, NaHMDS, Et 3 N). 4 The Lewis acids 5 and even Brönsted acids 6 have also been used as catalysts for Boc protection.

Results and Discussion
The various monosubstituted hydrazines and amines were protected according to the Scheme:

Scheme 1
Since the reagents are not air-or moisture-sensitive the synthesis can be carried out under very robust conditions.In our experiments, the neat NH 2 -compound in any form (liquid or solid) was directly added to the melted Boc 2 O.In most cases the reaction was fast, and violent liberation of gas was observed.Usually the conversion was complete in a very short time and a simple recrystallization of the reaction mixture gave pure products in very good yield.Whereas the conversion is complete then the products could be just kept under vacuum and used directly for the next steps of the synthetic sequence (Table 1).Sometimes the exothermic solventless reactions are difficult to scale up.Boc-protected hydrazines and amines are thermally stable in the absence of acids.Therefore, the present solventless-, and the non-catalyzed, method could find applications on the industrial scale.
It is obvious that the pKa is a good parameter to evaluate the reactivity of NH compounds under the Boc protection.The pKa values of amines are easy to find in the literature 11 and can be used directly for evaluation since the reaction center is the same for dissociation and protection.The pKa values of monosubstituted hydrazines do not directly describe the reactivity because these are measured at the other nitrogen, and not where the protection is going on.Indeed, the pKa value could be used, but not in the same series with amines.The least acidic hydrazine in the series studied here was the methylhydrazine which reacted very fast even at room temperature.The pKa for this compound is not known, but the acidity could not be much more different than that of hydrazine, having a proposed value of pKa about 37. 12 The methyl group does not have significant electronic and steric effects in order to differentiate the two possible reaction centers.Therefore the protection of this most nucleophilic substrate in our series was not selective, and two products were obtained.The phenyl group in the next weak acid, phenylhydrazine, with the pKa values of 28.8 13 decreased the reactivity of the PhNH center, which resulted in excellent selctivity.Boc-hydrazine is a substantially stronger acid.The pKa is known only for the nearest analog of Boc-hydrazine -the ethoxycarbonyl derivative (pKa 22.2 13 ).The influence of a Boc group on the nucleophilicity of the NH 2 group is relatively weak and excellent results were obtained.There are no pKa data available for Troc-and Z-hydrazines.
Their acidity could be compared with Boc-hydrazine through the influence of the corresponding groups on the acidity of carbamates. 14According to these data the influence of a Troc group is about 1.5 pKa units stronger than that of a Z group, and 1.7 units stronger than the Boc group.It is also known for hydrazines that the ZNH is about 0.2 pKa units stronger as an acid than BocNH. 12Acetylhydrazine has pKa 21.8, 11 and is about 0.4 units stronger as an acid than is ethoxycarbonylhydrazine.There are no pKa data available for 2,4-DNP-hydrazine but it could be indirectly evaluated according to the data for corresponding phenyl derivatives. 13It appeared that the pKa of 2,4-DNPNH is 12.4 units lower than that of corresponding phenyl derivative.Therefore the reactivity of 2,4-DNP-hydrazine should be the lowest in the series and, indeed, this compound demanded strong heating in a microwave oven to react, giving the mixture of compounds.By conventional heating at 75 ºC for several days the reaction was not finished, and also gave a mixture of products.The behavior of the rest of the compounds is in good agreement with the pKa values.Based on the results, it could be proposed that the limit of pKa for monosubstituted hydrazine protected without catalyst could be around 17.According to the increase of acidity, the hydrazines studied could be ordered as follows: Me, Ph, Boc, Z, Troc, Ac, and 2,4-DNP.The reactivity of the corresponding compounds decreased in the same order.The same procedure as described above was also very effective for amines, affording pure products in high yields.Diphenylamine reacted very slowly under the conditions used, and even after 24 hr at room temperature the reaction was not complete.Acetanilide was not reactive, and the protection took place only after the addition of 0.01 equiv of DMAP.Again, this observation is in a good agreement with the pKa values of these substrates. 11Primary as well as secondary aliphatic amines are all very weak acids (pKa higher than 30) and therefore reacted very fast (within minutes).Here, the pKa limit of non-catalyzed protection (within a reasonable time) is between 25.0 (Ph 2 NH) and 21.5 (PhNHAc).

Conclusions
The method for solventless and non-catalyzed Boc-protection of substituted hydrazines and amines was tested experimentally, and the scope and limitations have been demonstrated.The pKa value of the NH acid is a good parameter for evaluation and prediction of the reactivity of the substrates.

Experimental Section
General Procedures. 1 H-NMR (200 MHz) and 13 C-NMR (50 MHz) spectra were recorded on a Bruker Avance II 200 spectrometer, using CDCl 3 as solvent and tetramethylsilane as internal standard.IR spectra were recorded on a Perkin-Elmer PC 16 FTIR spectrometer; all are given in cm -1 ; the material under investigation was mixed in KBr pellets (for solids) or as a liquid film between KBr wafers (for liquids).Thin layer chromatography was performed on "Alugram ® SIL G/ UV 254" silica gel plates provided by Macherey-Nagel.For visualization of the spots, the plates were illuminated under UV-light and treated with phosphomolybdic acid (ca.1% solution in ethanol).All the reactions were carried out in oven-or air-gun-dried round-bottom flasks.