Synthesis of New Guanidium-Meldrum Acid Zwitterionic Salts and Dynamic NMR Study of Rotational Energy Barrier Around C-NH bond of Guanidine Moiety

Synthesis of the Guanidium-Meldrum acid zwitterionic salts was developed through a three component reaction of 2, 2-dimethyl-1, 3-dioxane-4, 6-dione (Meldrum acid), aromatic aldehydes and N, N, N’, N’-Tetramethyl-guanidine in benzen at room temperature. These reaction conditions allow the preparation of stable zwitterionic salts in good yields. A dynamic NMR effect is observed as a result of restricted rotation around the C-NH bond in the 1H NMR spectra of these compounds. The free-energy of activation (G#) for this process is 66 ± 2 kJmol-1 for 4b.


INTRODUCTION
The Knoevenagel condensation of Meldrum acid with aromatic aldehydes with the aim of forming a carbon-carbon double bond is a welldocumented reaction 1 that carried out using various conditions. 2Arylidene Meldrum acids are useful reactive intermediates, being susceptible to 1, 4addition, 3 in Diels-Alder reactions acting as activated dienophiles 4 and preparation of heterocyclic molecules such as coumarins, 5 indoles and benzofurans 6 and other useful compounds. 4,7ecently we prepared an unusual chargeseparated Guanidium-meldrum acid zwitterionic salts using three component reaction.][10] we now describe the synthesis zwitterionic salts by means of a reaction of N, N, N', N'-Tetramethyl-guanidine with conjugated electrophilic heterodienes.Dynamic NMR provides important kinetic data and affords good information in this matter on a dynamic process, when discussing the barrier separating two states that are observable by NMR spectroscopy. 11Thus, herein the free-energy of activation ("G # ) for restricted rotation around the C-NH bond of zwitterionic salt 4b is described.

General procedure for preparation of Guanidiummeldrum acid zwitterionic salts (exemplified by 4b)
To a magnetically stirred of 0.158 g of meldrum acid (1.1 mmol) and 0.120 g of 4methylbenzaldehyde (1.0 mmol) in 10 cm 3 of dry benzen (distilled from Na/benzophenone, 5.0 mL, 0.2 M) was added 200 µL of a 0.5 mM solution of pyrrolidinium acetate in benzene (prepared by dropwise addition of AcOH to piperidine in benzene, 0.1 mmol, 10 mol%) and stirred about 20 hour.Then the reaction mixture was washed with saturated NaHCO 3 solution (2 × 10 mL).Then 0.115 g of N, N, N', N'-Tetramethyl-guanidine (1.0 mmol) in 3 cm 3 of benzen was added to organic layer over one minute at room temperature.After less four hours stirring at room temperature, the solvent was removed and the crude product washed by acetone (2 × 3 mL), and residue powder filtered.

RESULTS AND DISCUSSION
The three component condensation reactions of Meldrum acid 1, benzaldehyde derivatives 2, and N, N, N', N'-Tetramethyl-guanidine 3 proceeded with piperidinium acetate at room temperature in benzene and were complete within about a day.Analysis of the IR, 1 H and 13 C NMR spectroscopy, and mass spectrometry spectra as well as elemental analysis confirm the formation and isolation of the desired zwitterion salts as shown in scheme 1.The IR spectrum of 4b exhibits a NH stretching band at 3236 cm -1 , signals for carbonyl groups at 1601 cm -1 and for C=N at 1682 cm -1 .The 1 H NMR spectrum of 4b exhibited four single sharp lines readily recognized as CMe 2 ( = 1.55 ppm), Ar-Me ( = 2.28 ppm), two NMe 2 groups ( = 2.92, 2.98 ppm), along with two characteristic doublets ( = 5.67 and 8.97 ppm, 3

Scheme 1: Synthesis of Guanidium-Meldrum acid zwitterionic salts
The 1 H-decoupled 13 C NMR spectrum of 4b showed six distinct signals below 100 ppm, which were readily recognized as arising from Ar-Me ( = 21.42 ppm), CMe 2 groups ( = 26.34ppm), two NMe 2 groups ( = 40.06,40.73 ppm), methine ( = 57.22,77.05 ppm) carbon atoms.The meldrum acid residue showed only one signal for the carbonyl ( = 166.65)group, which is consistent with the presence of a local C s symmetry, which exhibited characteristic signals with appropriate chemical shifts.The 1 H and 13 C NMR spectra of the other compounds are similar to those of 4b except for the aryl groups, which exhibit characteristic signals with appropriate chemical shifts.The mass and elemental analyses data were in agreement with the proposed structures.The formation of zwitterionic salts 4 can be rationalized by initial formation of a conjugated electron-deficient heterodyne 5 through Knoevenagel condensation 8 of the 1 and benzaldehydes 2 using piperidinium acetate followed by a Michael-type 9, 11 addition reaction with N, N, N', N'-Tetramethyl-guanidine 3 to afford compound 4 as shown in scheme 2. We didn't detect any cyclization of synthetic compounds at room temperature, 12 refluxing for 5h and microwave irradiation.  .Application of the absolute rate theory with a transmission coefficient of 4b gave free-energy activation (G # ) of 66 ± 2 k Jmol -1 , where all known sources of errors were estimated and included. 14nly two 1:1 singlets are observed for the four diastereotopic methyl groups of the guanidino moiety in the 1 H and 13   observed above 308 K. two observed signals for these groups' shows one of the processes should be fast on the NMR timescale.We conceder the contribution of the valence-bond structures A and B to the resonance hybrid of 4 is in fact more important than that of C for the simple reason that they correspond to a more highly substituted carbonnitrogen double bond. 14Therefore the faster process can be the C-NH rotation (process i).In summary, we have reported the synthesis of guanidinium zwitterionic salts by an efficient and simple approach along with three component condensation in benzene in presence of piperidinium acetate at room temperature within one day.A dynamic NMR effect is observed in the 1 H NMR spectra of these compounds as a result of restricted rotation around C-NH bond for two NMe 2 groups.

Scheme 2 :
Scheme 2: Proposed mechanism for the formation of Guanidium-Meldrum acid zwitterionic salts