Synthesis and characterization of new 2-(alkylamino)acetamides

Seven new 2-(alkylamino)acetamides have been synthesized and characterized by 1 H, 13 C NMR, NOESY experiments, infrared and mass spectrometry. The structure of 2-(diphenylmethylamino)acetamide 3b was further established by a single crystal x-ray diffraction study. The NMR study of the transformation of several 2-(alkylamino)acetamides to their corresponding morpholin-2-ones shows that these species are thermodynamically favored through preferred conformations as determined by theoretical calculations of 3h .


Introduction
A number of 2-(alkylamino)acetamides have been shown to possess antiarrhythmic, 1 anticonvulsive, 2 anti-inflammatory 3 and hypotensive 4 activity.They have also been used as precursors in the synthesis of vicinal diamides, morpholin-2-ones, 5 and as ligands in the synthesis of organometallic compounds with potential anti-tumor activity. 6-(Alkylamino)acetamides have been prepared by reaction of 2-chloro-N,N-dimethylacetamide or 2-(alkylamino)methylacetate with amines and β-aminoalcohols, in the presence of sodium bicarbonate or triethylamine.5,[7][8] It is noteworthy that the reaction of 2-chloro-N,Ndimethylacetamide with ephedrines, in the presence of sodium bicarbonate, under reflux of benzene for 20 hours provides both 2-(alkylamino)acetamides and morpholin-2-ones, while the use of triethylamine as base yields exclusively the corresponding 2-(alkylamino)-acetamides. In contrast, when this reaction is carried out under reflux of xylene, the morpholin-2-one is formed exclusively.5 Our current interest in 2-(alkylamino)acetamides prompted us to develop better reaction condition to synthesize these compounds in good yields.Thus, we describe herein the synthesis and characterization of seven new 2-(alkylamino)acetamides 3a-j (Scheme 1).The structure of compound 3b was further established by a single-crystal X-ray diffraction study.

Scheme 1
As confirmed by 1 H NMR the reaction of bromoacetamide 1 and β-aminoalcohols 2f, 2h and 2j leads to 2-(aminoalkyl)acetamides 3f, 3h and 3j which are transformed into the corresponding morpholin-2-ones 5,12 in aproximatly 30%, after 12 hours under reflux except for 3j.Moreover, 2-(aminoalkyl)acetamides 3f, 3h, 3i and 3j were allowed to stand for one month in chloroform solution which resulted in 40% conversion to the morpholine-2-ones, except for 3j (Scheme 2).These data suggests that the transformation of 3f, 3h, and 3i into the corresponding morpholin-2-ones is thermodynamically favored and proceeds through a prefered conformation which was calculated for 3h using a theoretical (AMI, Ab initio STO-3G and 3-21G) approach. 13Figure 1 depicts the particular conformation where there is an intramolecular interaction between the OH group and the carbonyl group, that increases nucleophilicity of the carbonyl group and favors formation of the corresponding morpholin-2-one. R'

NMR spectroscopy
The 1 H NMR spectra of compounds 3a-j exhibit an AB system for the amidic protons (NH 2 ) due to partial C=N double bond character (Table 1).Unambiguous assignment of these protons was attained by NOESY experiments which revealed an interaction of the proton shifted to lower field with H-2, evidencing that it is anti to the carbonyl group, in agreement with analogous systems reported in the literature. 9The spectra of compounds 3a-c, 3h and 3i exhibit a single signal for the methylene protons at position 2, while compounds 3d-g and 3j give an AB system.Since the pyrrolidyl and H-7 protons in compound 3j show a complex pattern, unambiguous identification of H-7 was established using selective decoupling experiments.Thus irradiation of H-3 simplified the ABX system for H-7 to an AB system.The 13 C NMR chemical shift for C-2 in compounds 3a-j is in the range between 46.76 to 59.92 ppm, which is shifted to higher frequency compared with bromoacetamide (δ = 29.05ppm).Assignment of the signals for C-2, C-4 and C-5 in 3h, C-2, C-3, C-8 and C-9 in 3i and C-2, C-3, C-8 and C-9 in 3j, were obtained by 13 C-1 H HETCOR techniques.Unambiguous assignment of C-3 and C-5 in 3a was attained from a 13 C-1 H COLOC spectra.Table 2 summarizes the 13 C NMR data for compounds 3a-j.Table 2. 13 C NMR data of 3a-3j: Scheme 3

Infrared spectroscopy
The IR spectra of compounds 3a-j show the absorption band characteristic of the amide I and II in the range between 1676-1638 and 1672-1588 cm -1 , respectively, as well as absorption bands for the NH and OH groups in the range between 3432-3178 cm -1 .

X-Ray diffraction
Suitable crystals of 3b for X-ray analysis were obtained from chloroform/hexane, the molecular structure and crystallographic numbering is shown in figure 2. In general the bond distances are within the values characteristic of amides. 10Selected bond lengths are:

Conclusions
Optimization of the reaction conditions allowed us to obtain the new 2-(alkylamino)acetamides in good yields.These derivatives were characterized by spectroscopic methods and the structure of compound 3b was confirmed by X-ray analysis.The transformation of 2-(alkylamino)acetamides 3f, 3h and 3i into to the corresponding morpholine-2-ones was observed by 1  with a = 6.225 (10), b = 21.987(4),c = 9.552(2) Å, V = 1307.3(4) Å 3 .Lattice constants were determined from least squares refinement on diffractometer angles for 24 automatically centered reflections; ρ 1.221 Mg/m 3 , Z = 4, µ = 0.078 mm -1 , F (000) = 512.Data collection: monitoring of check reflexion showed no signs of decay.A total of 2447 reflections were measured (2>θ>26º), 2304 were independent and of these 1737 were considered observed [Fo>4.0σ(Fo)].Absorption correction was not necessary.Solution and refinement: direct methods, all non-hydrogen atoms were refined anisotropically, all hydrogen were located by difference Fourier maps and refined with an overall isotropic thermal parameter, R = 0.0365, Rw = 0.0954, w = 1/ σ 2 , GOOF = 1.057, parameter to data ratio 1:7.7, largest residual electron density peak/hole in the final difference map: 0.149/-0.153e Å -3 .Atomic scattering factors were taken from the International Tables for X-ray Crystallography. 14Data reduction was performed by Jana 98. 15 All calculations were carried out on a VAX 4000 computer using the SHELX 93 (sheldrick G. M.) program package. 16