Synthesis and conformational analysis of novel tertiary amides derived from N-[( S )-α-phenylethyl]-1,3-Imidazolidine

The synthesis of three chiral tertiary amides by ring opening of the symmetric 1,3-imidazolidine 2 under mild conditions is described. 1 H NMR dynamics studies were performed to identify three rotamers present in solution, which were also examined by DFT calculations.


Introduction
Amide bond formation is one of the most often used transformations in organic synthesis, and amides are frequently employed as building blocks for the synthesis of biologically active compounds [1][2][3] such as antiinflammatory and analgesic agents, 4,5 fungicides antibiotics, parasiticides and antivirals. 6,7The synthetic route used most frequently for amide formation involves the combination of an amine (including ammonia) with an activated carboxylic acid derivatives 8 or directly with the carboxylic acid in a reaction mediated by a coupling reagent. 9The existing methods have several drawbacks in common, such as poor atom-efficiency, the use of hazardous reagents, and the generation of waste that not only reduce the process efficiency but also impose environmental problems.To address these challenging problems in amide synthesis, a plethora of novel amide formation reactions have been developed, 10 i.e. catalytic acylation of amines with carboxylic acids, 11 dehydrogenative amidation of alcohols, [12][13][14] amino carbonylation of aryl chlorides, 15,16 hydroamination of alkynes, 17,18 transamidation of primary amides, 19,20 and oxidative amidation of aldehydes. 21,22ife and Perillo have reported a ring-opening reaction starting from 1,3-imidazolidines via acid catalysis and a mechanism has been proposed. 23][26] As part of an ongoing project involving chiral diamines as chiral ligand adjuvants, 27,28 herein we have also examined the E/Z equilibrium of tertiary amides 3a-3c, which were prepared by a ring-opening reaction of 1,3imidazolidine 2 with n-BuLi and different acyl chlorides.

Results and Discussion
A series of convenient procedures for the preparation of N,N'-ethylene-bis[(S)-1-phenylethyl]amine 1 are available in the literature. 29Accordingly, 1,3-imidazolidine 2 was prepared in excellent yield (98%) by condensation of diamine 1 with aqueous formaldehyde following the general procedure reported by Coldham et al. 30,31 (Scheme 1).An important observation for this reaction is that the use of formaldehyde (37% aq.v/v) instead of paraformaldehyde resulted in higher yields (98% versus 80%).Scheme 1. Reaction sequence for the synthesis of 3a-3c.
For the ring-opening reaction of 1,3-imidazolidine 2, with a series of different bases were tested, including sec-BuLi (1.2 equiv), NaHMDS (1.2 equiv), DBU (1.2 equiv), DMPA (1.2 equiv), DMPA-Et3N (0.05:1.3), and Py (1.2 equiv).The optimal conditions for the preparation of 3a-3c were observed in the presence of n-BuLi (2.5 equiv, 1.0 M solution in hexane). 32After the addition of n-BuLi at 0 o C the reaction mixture was stirred for 0.5 h, whereupon 2.5 equivalents of the corresponding acyl chloride (propionyl, hydrocinamoyl and benzoyl chloride) were added at -78 o C.After chromatographic purification, the tertiary amides 3a-3c were afforded in yields ranging from 89 to 98% (Scheme 1).Compounds 3a-3c are the result of a diacylation reaction of the nitrogen atoms leading to the ring-opening of the imidazolidine ring.This observation indicates that the C-N bonds are activated by coordination of the Lewis acid to the nitrogen. 33hen smaller amounts of acyl chloride were employed, e.g.1.2 equivalents, the imidazolidine ring opens forming 3a-3c rotamers, but there were still traces of the starting material (2).
Even though, compounds 3a-3c seem to be simple molecules, the 1 H and 13 C NMR spectra in CDCl3 at room temperature show the presence of a dynamic equilibrium, giving a total of three sets of signals, which based on HSQC experiment are attributed to rotamers (Z-syn, E-syn, and E-anti, with population ratios of 1.4:1.5:0.3)(Figure 1).Interestingly the Z-anti rotamer was not observed, which was attributed to steric repulsion between the carbonyl group and the phenyl group.Variable temperature 1 H NMR spectra were also measured in DMSO-d6 in a temperature range from 20 to 175 o C. In order to assign all signals unequivocally, COSY and HETCOR experiments were realized also at 175 o C (see Table 1).
In order to examine with more detail of the different rotamers present in solution, we explored the potential energy surface of 3a by quantum mechanical DFT calculations, using the B3LYP/6-31G(d,p) method to optimize the geometries and to calculate the relative energies of all minima (see Figure 2).Of the four possible rotamers three (3a-1, 3a-2 and 3a-3) had similar energy values, (Figure 2), which is in agreement with the NMR data.Rotamer 3a-4 has a significantly higher energy (4.79 kcal/mol) when compared to the most stable conformer 3a-1.
ARKAT USA, Inc  The most stable structures 3a-1 and 3a-3, exhibit two type of hydrogen bonds, the first one is between the carbonyl of the amide group and a hydrogen atom attached to the neighboring methine group with HO distances of 2.16 and 2.20 Å, respectively, and the second one is in between the carbonyl groups and hydrogen atoms from methyl and phenyl groups, with HO distances of 2.51 and 2.61 Å, respectively.On the contrary, 3a-2 showed two C-HO interactions with hydrogen atoms from phenyl and methyl groups with HO distances of 2.52 and 2.59 Å, which are significantly smaller than the sum of the van der Waals radii (2.80 Å).The importance of the C-HO interactions for the molecular conformation of amides has been previously established also by other research group. 34he free energy of activation for the interconversion of compounds 3a-1 to 3a-4 has been investigated by means of dynamic NMR spectroscopy. 35,36To measure the free energy of activation (ΔG  ) by variable temperature 1 H NMR spectroscopy, the coalescence temperature method can be used.The coalescence temperature (Tc, K) is the lowest temperature at which the rotamers merge in the 1 H NMR spectrum (Table 2).The free energy of activation (ΔG  , kcal mol -1 ) and the rate constant (kc, s -1 ) can be derived from the Eyring equation (Eqs.1 and 3). 36

 
On the other hand, the rotational barrier for compounds 3a and 3b has been calculated both experimentally (Table 2) and theoretically (Table 3).The theoretical values were calculated in the gas phase with and without solvent (see Table 3).No significant changes were observed when comparing the experimental data with the theoretical values.Additionally, for 3a crystals suitable for single-crystal X-ray diffraction, analysis could be grown, which allowed to establish that the solid state structure contains only one of the three rotamers found in solutions (Z-syn) (Figure 3).Finally, the molecular structure of 3c was optimized using the same computational method as described before, giving only one low-ebergy rotamer.In this derivative, the phenyl group attached to the diamide group restricts the rotation of the 1-phenylethyl substituents (Figure 4).

Conclusions
We reported on the synthesis of chiral symmetrically N,N'-trisubsituted-1,3-diamides 3a-3c which have been prepared from the corresponding 1,2-diamines in excellent yields (89 -98%).Diacylation of the nitrogen atoms induced ring-opening of 1,3-imidazolidine 2 even in the presence of mild bases.The conformational equilibria have been evaluated by VT NMR techniques and DFT calculations, showing that the rate of interconversion between rotamers is almost completely dependent on the nature of the substituent at the amide group.

Experimental Section
General.All experiments were carried out under an inert N2 atmosphere.THF was distilled from sodium benzophenone.CH2Cl2 was dried from sodium hydride.Melting points were determined on a Fischer Jones apparatus and are uncorrected.Infrared spectra were recorded on a Perkin Elmer 881 spectrophotometer, using polystyrene as reference (1602 cm -1 ).NMR spectra were obtained on Varian Mercury 200 or 400 equipments. 1 H NMR spectra were referenced to tetramethylsilane; 13 C{ 1 H} NMR spectra were referenced to residual non-deuterated solvent.
Computational details.The geometries of all structures were fully optimized by using density functional theory (DFT) with the hybrid-functional B3LYP 41,42 in combination with the 6-31G(dp) 43 basis set implemented in the Gaussian 09 software package. 44order to characterize all structures as minima, their vibrational frequencies were calculated at the same level of theory.The Polarizable Continuum Model (PCM) 45 was used to compute energies in chloroform and DMSO with electrostatic dielectric constants,  4.9 and  46.7, respectively.This calculation was performed in the presence of a solvent by placing the solute in a cavity within the solvent reaction field via a set of overlapping spheres.Results were visualized with the Chemcraft program v1.6.The utility of the B3LYP functional for the theoretical characterization of organic systems has been widely explored in previous publications, showing good results. 46

Table 1 .
VT NMR experiments for the analysis of rotamers 3a-3c in CDCl3 and DMSO-d6

Table 2 .
Relative energies (in kcal/mol) of the barriers of interconversion between the diastereomeric conformations of 3a and 3b, as established by VT-NMR experiments in CDCl3 and DMSO-d6