Efficient monoacylation of symmetrical secondary alkanediamines and synthesis of unsymmetrical diacylated alkanediamines. A new L-proline-based organocatalyst

A simple procedure was developed for the monoacylation of several unprotected alkanediamines with carboxylic acids by using PyBOP-HOBt as coupling agent in the presence of DIEA at room temperature. Yields were moderate with primary alkanediamines and good to excellent with linear or cyclic secondary ones. To illustrate the utility of these monoacylated products, six unsymmetrical diacylated alkanediamines were synthesized. In addition, one of these compounds was evaluated as organocatalyst in an asymmetric aldol reaction

Monoacylated symmetrical alkanediamines (B) are valuable scaffolds that appear in the chemical structure of several biologically active compounds in medicinal chemistry.Figure 2 provides representative examples including the cardiotonic agent vesnarinone 19 (1) and the antihypertensive agents doxazosin (2), prazosin (3) and terazosin (4)  However, monoacylation of symmetrical diamines remains difficult. 21Thus, treating a symmetrical alkanediamine with one equivalent of an acylating agent is expected to yield a statistical distribution of products comprising unreacted starting alkanediamine and the mono-and diacylated products (Fig. 3).Consequently, the maximum theoretical yield of the monoacylated product reach 50% with the yield of the diacylated material not exceeding 25%.Unfortunately, the diacylated products are often formed predominantly or exclusively, even though the alkanediamine is present in large excess over the acylating agent.Such finding was attributed by Sayre and co-workers 22 to a mixing problem due to the rapidity of the acylation reaction.Thus, the initial monoacylated product formed at the interface between the drop of the acylated agent and the alkanediamine solutions is acylated a second time at this interface before being dispersed in the reaction medium.In light of this, monoacylation of symmetrical diamines has attracted considerable interest from the synthetic community and several methodologies have already been published.4] By increasing reactant dilution and decreasing reactivity of the acylating agent, Sayre reached a statistical yield for the mono-acylation of 1,2-ethanediamine and 1,4-butanediamine. 22Furthermore, Chou's group obtained monoacylated products in excellent yields by one-pot neat reaction of aliphatic or aromatic carboxylic esters and alkanediamines. 25Wang's strategy focused on the reaction of one equivalent of an acylating agent with the previously prepared alkanediamine Li di-anion. 26The same group also reached monoacylation by using 9-BBN to protect one of the two amino groups. 27By using ionic immobilization of piperazine and homopiperazine to sulfonic acid-functionalized silica gel, monoacylation was also realized. 28Lai reported a convenient method for preparing aryl monoacylated piperazine derivatives by using trimethylacetic arylcarboxylic anhydrides. 29Fang developed a protocol leading to monoacylated alkanediamines by reacting phenyl esters with a phenyl carbonate as acylation agents in the presence of water. 30Finally, most recently, Bandgar obtained a series of monoacylated piperazine derivatives by the reaction of carboxylic acids with 2chloro-4,6-dimethoxy-1,3,5-triazine. 31Most of the synthetic methods described above suffer from drawbacks, notably the use of drastic reaction conditions or aggressive reagents or are limited to aryl acylations.Therefore, there still exists a need to develop simply and general procedures more efficient than those currently in existence.

Results and Discussion
In this context, our interest in acylated alkanediamines arose from a desire to access a convenient monoacylation procedure for the preparation of secondary and tertiary amides by reaction of carboxylic acids with linear or cyclic alkylenediamines.Thus, we accomplished the synthesis of monoacylated derivatives starting from commercially available carboxylic acids, which were coupled to the corresponding inexpensive alkanediamine in excess utilizing PyBOP-HOBt [32][33][34] as coupling agent in the presence of DIEA and DMF as a solvent.The desired monoacylated alkanediamines could be obtained after purification by column chromatography on silica gel in moderated yields for primary amines to excellent yields for secondary ones.

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Interestingly, as we carried out the monoacylation of cyclic alkanediamines (piperazine and homopiperazine, Table 2) using the same conditions described before (vide supra), the reaction crudes were proved by LC-MS to contain only traces of the contaminant diacylated alkane diamines.The use of an excess of alkane diamine was necessary to avoid the formation of significant amounts of the corresponding diacylated alkanediamines.Consequently, the corresponding monoacylated piperazine and homopiperazine derivatives were obtained, after purification by column chromatography on silica gel, in good to high yields (67-96%).As shown in Table 2, monoacylated homopiperazine compounds were obtained in somewhat lower yields than piperazine analogues (compare entries 1,3 and 5 with entries 2,4 and 6. (S)-Naproxen was reacted with a linear secondary amine (entry 7) yielding the corresponding tertiary amide 25 in 96% yield and confirming that the nucleophilic power of cyclic diamines and not their constrained form was responsible for their better reactivity compared to primary amines.In order to demonstrate the general scope of this procedure, we also prepared in good yields N-acylpiperazines 26-28 (entries 8-10) as precursors of vesnarinone (1) and the antihypertensive agents doxazosin (2) and a prazosin 2-thienyl analogue respectively in addition to compound 29 bearing a linear chain. 35  The synthetic potential of this methodology was further exemplified by using the monoacylated alkanediamines in hand as intermediates for the construction of unsymmetrical diacylated alkanediamines.7] For this meaning, as detailed in Scheme 1, in compounds 8, 9 and 10, the remaining free amine was coupled to commercially available Boctryp-OH by using the PyBOP/HOBt methodology [32][33][34] in the presence DIEA obtaining the pseudopeptidic models 30, 31 and 33 in good yields.Analogously, we carried out the coupling of compounds 10 and 22 with Boc-tyr-OH providing models 32 and 34.Finally, the N-monoacylated compound 10 was reacted with Z-Pro-OH giving, after cleavage of the proline amine protecting group, the unsymmetrical diacylated piperazine 35.
9][40][41] In this context, we decided to evaluate the catalytic properties of the proline-based compound 35.
As a benchmark reaction, we examined the aldol reaction between p-nitrobenzaldehyde and acetone.The results of this study are reported in Table 3.
In our initial experiments, we screened various solvent systems by using 30 mol % catalyst 35 to promote the reaction (entries 1-4).Thus, in a 1:4 acetone/DMSO mixture, 42 after stirring the homogenous reaction mixture for 8 days at room temperature, chiral-phase HPLC analysis revealed that the expected aldol product 36 was formed in 19% ee.When using DMF instead of DMSO as a co-solvent, the reaction took place in 5 days improving slightly the enantioselectivity.With the system acetone/AcCN (1:4), after 3 days, the ee was enhanced to 36% with a 92% of conversion rate.The use of chloroform as a co-solvent induced lower enantioselectivity and gave a shorter reaction time.We decided then to conduct the reaction with acetone serving as an only solvent.Thus, aldol 36 was formed in 46% ee (entry 5).By decreasing the catalyst loading to 10%, the reaction rate increased and the ee dropped dramatically (entry 6).By further reduction of the amount of the catalyst (5%) only 54% of conversion was achieved after 3 days with a comparable enantiomeric excess (entry 7).The increase of the quantity of catalyst (50%) considerably accelerated the reaction (4h) but resulted in a lower enantioselectivity (entry 8).Finally, we studied the influence of the reaction temperature in the enantioselectivity (entries 9-11).Thus, when the reaction was carried out at 0°C, the ee increased to 52%.The best result was obtained when the reaction proceeded at -20°C giving the hydroxyketone 36 in 69% yield and 72% ee.Further decrease of the reaction temperature to -30°C reduced somewhat the ee value (66%).Interestingly, when the reaction was conducted by using L-proline as a catalyst with acetone serving as a solvent, no reaction occurred after 3 days stirring of the heterogeneous mixture (entry 12).We attributed this lack of reactivity to the low solubility of proline in acetone.In order to get the completion of the reaction promoted by proline, a 1:4 acetone/DMSO solvent system is necessary (entries 13 and 14). 42,43Compared to the described conditions using proline as catalyst at room temperature or at -20°C (entries 13 and 14), we observed similar yield and enantioselectivity by using our proline-based organocatalyst 35 at -20°C.However, it is worth mentioning that in our case the use of DMSO, which is not easy to remove, as a co-solvent was not necessary.

Conclusions
In conclusion, a convenient protocol to obtain monoacylated acyclic and cyclic alkanediamines has been developed.We have demonstrated that this is a general procedure leading to secondary, and more efficiently to tertiary amides, and illustrated its utility by preparing in good yields three monoacylated piperazine derivatives as key intermediates in the synthesis of bioactive compounds.This simple procedure provides a practical and timely method for the synthesis of unsymmetrical diacylated alkanediamines, avoiding the employment of any pre-protected alkanediamine as we have demonstrated by the synthesis of six pseudopeptidic derivatives.This protocol is particularly useful for the acylation of inexpensive alkanediamines with precious carboxylic acids.We strongly believe that this methodology will find broad application in synthetic organic chemistry.In addition, one of these compounds was tested as organocatalyst in an asymmetric aldol reaction showing similar results to that described in the literature employing proline.Further studies focusing on new applications of this promising proline-based catalyst and analogues are now under investigation.

Experimental Section
General.All reagents and solvents were purchased from commercial sources.Reactions were conducted in flame-dried glassware under an argon atmosphere. 1 H NMR and 13 C NMR spectra were recorded at 300 or 400 MHz and at 75 or 101 MHz in CD3OD or DMSO-d6.Chemical shifts are given in ppm and reported to the residual solvent peak (CD3OD 3.31 ppm and 49.00 ppm; DMSO-d6 2.50 ppm and 39.52 ppm).Data are reported as follows: chemical shift (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants, and integration.Analytical TLC were performed on silica gel 60 F254 plates.
Column chromatographies were carried out on silica gel 60 (63-200 μm).High-resolution mass spectra (HRMS) were measured using electrospray ionization (ESI) and Q-Tof detection.Melting points were measured with a Büchi apparatus and are reported uncorrected.
General procedure for the synthesis of monoacylated diamines.In a typical procedure, alkanediamine (0.014 mol) was suspended in 20 ml DMF.Diisopropylethylamine (DIEA, 0.48 ml, 2.78 mmol) was added, followed by the appropriate carboxylic acid (1.39 mmol), 1-Hydroxybenzotriazole (HOBt, 380 mg, 2.78 mmol) and PyBOP (720 mg, 1.39 mmol).The reaction was allowed to proceed at room temperature 24-30 hours.DMF was then removed by evaporation under reduced pressure and the resultant residue was suspended in ethyl acetate and treated with an aqueous saturated solution of NaHCO3.Phases were separated and the aqueous one extracted with ethyl acetate.The organic layers were dried over magnesium sulfate and rotary evaporated to produce a crude yellow oil, which was purified by column chromatography (silica, CH2Cl2/MeOH 4:1).

Figure 1 .
Figure 1.Strategy for the classical synthesis of unsymetrical diacylated alkanediamines A.

Table 3 .
Aldol Reaction between p-Nitrobenzaldehyde and Acetone Catalyzed by proline derivative 35 a Conversion and enantioselectivity of the aldol product were determined by analytical chiral HPLC analysis on a chiralpak AS-H column, detection at 270 nm.bNo secondary products were observed by analytical chiral HPLC analysis.cTheabsolute configuration of the major enantiomer was assigned by comparison with literature data.d Compound 36 was isolated with 69 % yield.