Potassium iodide catalysis in the alkylation of protected hydrazines

Potassium iodide catalysis was applied for the synthesis of protected benzylhydrazines and hydrazinoacetic acid esters by the alkylation of protected hydrazines. Benzylic halogenides and halogenoacetic acid esters were employed as alkylating agents. In these syntheses the reactive alkyl iodide molecules were generated in situ from less reactive halogenides, which significantly accelerated the alkylation reaction. The effectiveness of potassium iodide catalysis was proved by experiments performed under the same conditions in the absence of this salt.


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Replacement of natural amino acids with their azaanalogues in peptides yields aza-peptides, a class of peptide-like compounds where the α-C atom of an amino amino acids are included into peptides by using protected alkylhydrazines as precursors of α-aza-amino acids.
The most straightforward way for the synthesis of aza-amino acid precursors is direct alkylation of protected hydrazines with alkylhalogenides [8][9][10][11][12].Compared to the more widely applied reductive alkylation approach, direct alkylation reduces the number of reaction steps and allows omitting the reduction step of hydrazone, formed in the condensation step of a carbonyl compound and hydrazine [8].This reduction step is technically complicated, especially if a Pd/C catalyst is used at elevated hydrogen pressure [1].On the other hand, in the case of a direct alkylation reaction, the formation of polyalkylated products should be considered [13].However, the formation of these side products could be suppressed by using excess of hydrazine and applying an appropriate base and solvent [8,9].
Our previous work [9] about synthesis of azaphenylalanine, aza-tyrosine, and aza-tryptophan precursors, where alkylation of monoprotected hydrazines was used, revealed that application of alkyl chlorides resulted in a very low yield of monoalkylated hydrazine, while higher yields were obtained in the case of alkyl bromides and especially alkyl iodides [9].However, practical application of these reactions is often complicated, as alkyl iodides are not readily available and often tend to decompose during storage and purification.
In this study we report the possibility of hydrazine alkylation by generating alkyl iodides from less reactive alkylhalogenides in situ in the presence of catalytic amounts of inorganic iodides such as NaI and KI.Although the iodide catalysed alkylation reaction is known and effectively applied for the synthesis of different organic compounds [22][23][24], no attention has so far been paid to KI catalysed alkylation of hydrazine and its derivatives.In the reported study we filled this gap.

RESULTS AND DISCUSSION
In this study we observed that a catalytic amount of KI (0.1 eq) promoted the alkylation of different protected hydrazines and provided a possibility of using different alkyl halogenides of rather low reactivity for this reaction.As a result of this catalysis, it was possible to significantly improve the preparation of the precursors for aza-tyrozine, aza-Asp, and aza-phenylalanine.
Firstly, we used the catalytic reaction for the preparation of aza-tyrosine precursor, proceeding from p-cresol, which was O-protected with a Boc protecting group and thereafter brominated at the methyl group by using the radical halogenation reaction (Scheme 1).The obtained bromide was thereafter used for the bromination of various hydrazines.Yields of these reactions were 49-59% after 5-hour long refluxing (Scheme 1).
Encouraged by the described results, we decided to apply the above-mentioned KI catalysis for the preparation of other protected alkylhydrazines.More specifically, we used benzyl bromide, benzyl chloride, 4-methoxybenzyl chloride, tert-butyl bromoacetate, methyl bromoacetate, and ethyl chloroacetate for the alkylation of Fmoc-, Boc-, and Z-protected hydrazines.
In the case of benzylation of hydrazines (Scheme 2) the application of KI catalysis allowed us to react protected hydrazines effectively even with compounds that have a rather low electrophilicity, and nearly equal yields were obtained (Table 1) when Bn bromide and benzyl chloride were used as the alkylating reagents.At the same time the alkylation of protected hydrazines with benzyl chloride in the absence of KI gave only traces of the monoalkylated product during 6-hour refluxing and 21-55% of the desired product after 24 hours (Table 1).
In the reactions with 4-methoxybenzyl chloride (Scheme 2) protected 4-methoxybenzyl hydrazines were obtained in moderate to good yields after 6-hour long reflux, while attempts to use this reaction in the absence of KI gave the products in 13-27% yield after 24-hour long refluxing (Table 1).
We tested alkylation of protected hydrazines with ethyl chloroacetate in the absence of KI and obtained monoalkyl products with 15-20% yield after 24 hours of refluxing.These experiments together with the results of the alkylation reactions with benzyl chloride and 4-methoxybenzyl chloride clearly show the effectiveness of KI catalysis.9-H-Fluorenyl-9-methyl carbazate was prepared according to the literature method [1] with slight modifications.Briefly, the slurry of Fmoc-NHNH 2 was cooled on ice bath before filtration, ice cold water and toluene were used for washing the product, followed by air drying and drying in vacuum.Fmoc [27]).Rf (EA/PE 1 : 7) = 0.77.

N-tert-Butyloxycarbonyl
General procedure for the preparation of compounds (12)-( 18): 1 eq of N-protected hydrazine was dissolved in ACN (0.1 M solution), 1.5 eq of 2,4,6-trimethylpyridine (for the alkylation of Fmoc-NHNH 2 ) or DiPEA (for BocNHNH 2 or Z-NHNH 2 ) and 0.1 eq of KI were added.The reaction mixture was heated to reflux.Solution of 1 eq of alkylbromide in ACN (approximately 0.1 g of bromide in 1 mL of ACN) was added dropwise and the reaction mixture was refluxed overnight.ACN was evaporated under reduced pressure, the residue was dissolved in EA, washed with 1 M NaHCO 3 , 2 × H 2 O, and brine.The water phase was extracted twice with EA, combined organic solutions were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated using a rotatory evaporator.The crude product was purified on silica gel using an EA/PE 1 : 2 or 1 : 1 mixture as the eluent.[33]).Rf (EA/PE 1 : 1) = 0.59.Yield: 60% [11,33].[34].

CONCLUSIONS
Potassium iodide catalysis was applied for the alkylation of protected hydrazines.This allowed incorporating less reactive halogenides and performing the alkylation remarkably faster and more effectively than without KI.By using this approach six new Fmoc-, Boc-, and Z-protected hydrazines of interest as precursors for insertion of aza-Tyr and aza-Asp into aza-peptides were prepared.

EXPERIMENTALGeneral.
All solvents and reagents were purchased from Merck, Sigma-Aldrich, or Lach-Ner.NMR spectra were measured on 200 MHz and 700 MHz instruments (Bruker, Germany) in DMSO-d6 or CDCl 3 as the solvent and using TMS as the internal reference.The LRMS were obtained on an Agilent Series 1100 LC/MSD Trap XCT (Agilent Technologies, Santa Clara, USA) spectrometer using acetonitrile as the solvent.The IR spectra were determined by using the ATR measuring technique on a Perkin-Elmer Spectrum BX spectrometer.The structure of the synthesized compounds was verified by NMR and IR spectroscopy.Purity was checked by means of NMR and TLC.Additional mass spectra analysis was performed.All the yields are given in comparison with the theoretical yield and are calculated proceeding from the mass of the obtained product.All the melting points are uncorrected.