New bis-oxalamides from trans -1,2-diaminocyclohexane

The synthesis of six new bis-oxalamides 2-7 derived from trans -1,2-diaminocyclohexane and aliphatic amines is reported. These compounds were characterized by IR, MS and 1 H and 13 C NMR spectroscopy.


Introduction
Oxalamides are molecules that possess in their structure acidic protons and O-lone pairs which form inter-and intramolecular hydrogen bonds.2][3] Due to these interactions, oxalamides are applied in diverse areas such as artificial receptors for biological recognition, 4 in engineering and crystal design 5 and in organogels formation. 6Recently, oxalamide derivatives were identified as HIV-1 inhibitors. 7Another important application of these compounds is in coordination chemistry as ligands. 8n this paper we report the synthesis and structural characterization by IR, MS and 1 H and 13 C NMR of six new oxalamides 2-7 derived from trans-1,2-diaminocyclohexane (Scheme 1).

Synthesis
Synthesis of bis-oxalamides 2-7 started with the preparation of the oxalamate 1 from condensation reaction of trans-1,2-diaminocyclohexane and ethyl chlorooxoacetate in the presence of Et 3 N as catalyst, according to a procedure reported in the literature. 9Oxalamate 1 was first prepared by Albano and co-workers from enantiopure (R,R)-and (S,S)-trans-1,2diaminocyclohexane. 10 Spectroscopic data for oxalamate 1 determined in this study are similar to those reported by Albano, however we observed a melting point of 180-182°C which is 15 ºC higher than that reported.Condensation reaction of 1 and two equivalents of the corresponding alkylamines gave oxalamides 2-6.Under the same conditions 1 and trans-1,4diaminocyclohexane produced the macrocycle 7. Formation of 7 requires an excess of the diamine, no product formation was observed when the reaction was performed in an equimolar ratio.2][13] Compounds 2-7 were analyzed in solution by 1 H and 13 C NMR spectroscopy using [ 2 H]TFA as solvent, because they were isolated as very insoluble solids.

Infrared spectra
The IR spectrum of 1 shows characteristic absorption bands at 3248 (νN-H), 1745 (νO=C ester) and 1665 cm -1 (νO=C amide), in agreement with reported values 10 .For compounds 2-7 the IR spectra show one absorption band in the region of 3282-3276 cm -1 for the νN-H and only one strong band with an average value of 1644 cm -1 for νO=C due to a similar connectivity in the oxalyl moiety.IR absorptions of 2-7 show a high frequency shift for νN-H and a low frequency ARKAT USA, Inc.
shift for νC=O with respect to 1, this behavior indicates that the electronic density of nitrogen is more engaged with carbonyl group in 2-7 than in 1.These values agree with reported data for similar compounds. 9,10,14

Mass spectra
The analysis by mass spectrometry of compounds 4 and 5 showed the molecular ion, whereas 2, 3 and 6 showed the [M+1] + peak.Additionally 2 and 3 present the [M-OH] + characteristic peak for a hydroxyl group.The molecular ion for compound 7 was not observed.

NMR analysis
The 1 H and 13 C NMR chemical shifts of compounds 1-7 are listed in Tables 1 and 2 respectively.The 1 H and 13 C NMR data determined for oxalamate 1 in this study are similar to those reported by Albano and co-workers. 10Intramolecular hydrogen bonding between N-H acidic protons and carbonyl oxygen atoms is known to favor the planar conformation and trans configuration of the oxalyl moiety. 1 Because 2-7 were only soluble in [ 2 H]TFA, which is a solvent that favors deuterium interchange, it was not possible to observe N-H chemical shifts and to conclude about hydrogen bonding in solution.The 1 H and 13 C NMR spectra of compounds 2-6 showed one half of the total expected signals because of the C 2 symmetry axis.H1 was observed as a broad signal between 3.91 -4.00 ppm and it is in the expected range. 9H3 and H4 appeared as broad signals.
The rigid conformation of 1,2-diaminocyclohexane ring for 1-6 in solution, allowed to distinguish equatorial H3 and H4 from axial H3 and H4 at room temperature.We were able to observe that the pendant arm of oxalamate 1 displayed a triplet for methyl protons and a highly symmetric 14 lines multiplet for the methylene protons, in contrast to the quartet triplet multiplicity reported by Albano and co-workers 10 and for the analog oxalamate derived from trans-1,4-diaminocyclohexane. 9 In our case, the multiplicity of methylene protons indicates that they have a different chemical environment, probably as a result of slow or no rotation of the pendant arm.The same behavior was observed for compound 2 and is equally expected for 3-6 because they gave broad signals.On the other hand, 13 C chemical shifts for 2-6 are in the characteristic range for this kind of compounds. 9,10,15 macrocyclic structure was proposed for compound 7 because its 13 C NMR spectrum showed only seven signals, instead of the nine expected if only one NH 2 of trans-1,4diaminecyclohexane had reacted to give an open structure like that showed by 2-6.In the 1 H spectrum, compound 7 displayed only six broad signals, which fully correlated with 13 C NMR signals in the HETCOR spectrum. 1H and 13 C NMR chemical shifts of 7 are similar to those determined for 2-6.
In future work, we will use the bis-oxalamides reported here as ligands in coordination chemistry.

General synthesis of compounds 2-7
Compounds 3-7 were synthesized according to the procedure described for 2.

Table 2 .
13lting points were determined on a Melt Temp II apparatus in an open capillary tube and were not corrected.IR spectra were recorded in a Varian 3100 FT-IR Excalibur Series spectrometer equipped with an ATR device in the range of 400-4000 cm -1 . 1 H and13C NMR spectra were recorded in a Varian Mercury 300 ( 1 H, 300.08; 13 C, 75.46 MHz) spectrometer in CDCl 3 and [ 2 H]TFA solution following standard techniques, chemical shifts are given in ppm and referred to SiMe 4 as internal reference.Assignments of 1 H and13C signals were made on the basis of HETCOR experiments and by comparison to the reported values for similar compounds when possible.13Cpeak multiplicities were determined by APT experiments.The mass spectra were recorded on a Hewlett-Packard HP 5989A, EI MS, 70 eV.Elemental analyses were carried out in a Flash 1112 Thermo Finnigan analyzer.