Reaction of polyamines with diethyloxalate: a convenient route for the synthesis of tetraazacycloalkanes

The reactivity of various polyamines with diethyloxalate has been investigated. It appears that, in similar experimental conditions, primary diamines give predominantly [2+2] adducts while the use of secondary benzylated polyamines results in [1+1] condensation. Although the intermediate tetraamides formed in the first case are extremely poorly soluble and show very slow reactivity towards reducing agents, cyclam has been obtained by using ultrasounds during the reaction of the corresponding tetraoxomacrocycle with BH 3 /THF. The [1+1] cyclization reaction of diversely N -benzylated linear tetraamines, whose selective syntheses have been devised herein, gives access to various N -benzylated cyclens and cyclams. New macrocyclic ligands containing both amine and amide type nitrogen atoms have been formed as intermediates in these syntheses. Two compounds containing an aminal function exhibit an unexpected reactivity, leading to the formation of new bisaminal products whose structures have been established by X-ray diffraction.


Introduction
The chemistry of tetraazacycloalkanes, especially cyclen and cyclam, has undergone a considerable development in the last thirty years, owing to their coordination properties.Indeed, these macrocyclic polyamines are able to form stable complexes with transition metals as well as lanthanides, actinides, and other heavy metals. 1The affinity and selectivity towards the metal ion can be tuned by varying the size of the macrocyclic core as well as the nature and the number of pendant coordinating arms on the nitrogen atoms.Since the first syntheses of cyclen and cyclam 2) HCl 6M reflux (3h)

Scheme 2
In order to overcome the formation of a hydrogen bonds network, we have decided to use N-benzylated diamines as starting material.Indeed, the presence of benzyl groups on nitrogen atoms should increase the lipophilic character and consequently the solubility in organic solvents.Moreover, the use of secondary amines should prevent the formation of hydrogen bonds and benzyl groups can be easily removed by catalytic hydrogenolysis.The N,N'dibenzylated 1,3-propanediamine 4 was prepared in 80 % yield by reduction of the corresponding diimine intermediate 3 obtained quantitatively by reacting 1,3-propanediamine with benzaldehyde (Scheme 3).The condensation of compound 4 with diethyloxalate, in either THF or ethanol, results in the formation of the [1+1] adduct 5, with no trace of [2+2] derivative, even in relatively high concentration conditions (0.08 mol L -1 ), as shown by mass spectrometry.This diamide was easily reduced by BH 3 /THF to yield the dibenzylated seven-membered heterocycle 6.This experiment shows that, as expected, the reduction of benzylated polyamides is facilitated, but unfortunately secondary diamines behave differently from primary diamines when treated with diethyloxalate.The main formation of the [1+1] cyclization product also indicates that the hydrogen bonds network could be a driving force in the formation of the [2+2] adduct.This result, which has been previously described, 12 prompted us to investigate the cyclization of benzylated tetraamines with diethyloxalate.

Scheme 3
Firstly, we have developed a convenient procedure for the synthesis of selectively benzylated tetraamines (Scheme 4).Some of these compounds have been reported previously. 13n the first step, the reaction of three equivalents of benzaldehyde with triethylenetetraamine and N,N'-bis- (3-aminopropyl)-ethylenediamine in refluxing ethanol gives the corresponding diimine intermediates containing one aminal function 7a and 7b in very good yields (Figures 1 and 2).Depending on the subsequent treatment, these intermediates may yield the N 1 ,N 4 -or the N 2 ,N 3 dibenzylated tetraamines, or the fully benzylated compounds.

Scheme 4
The reduction of the Schiff bases 7a-b with NaBH 4 in ethanol at room temperature gives the dibenzylated monoaminal compounds 8a-b.The compound 8a was not isolated because a rearrangment was observed during the work-up (vide infra).The acidic hydrolysis of 8a-b allows ARKAT the removal of the aminal group to release the N 1 ,N 4 -dibenzylated tetraamines 9a-b in good overall yields (54.5 and 90 % respectively).The reaction of intermediates 7a-b with two equivalents of benzyl bromide in refluxing acetonitrile results in the quantitative formation of the N 2 ,N 3 -dibenzylated diimines 10a-b.It is noteworthy that lower yields are observed when using only one equivalent of benzyl bromide.The reaction should proceed through the nucleophilic attack of one aminal type nitrogen on one equivalent of benzyl bromide, followed by the loss of one equivalent of benzaldehyde, which can be easily detected, and finally the reaction of the resulting secondary amine with the second equivalent of benzyl bromide.The presence of water in the solvent can explain the formation of benzaldehyde.The two imine functions in 10a-b can be either hydrolysed with hydrobromic acid solution to give after neutralization and extraction the corresponding N 2 ,N 3 -dibenzylated tetraamines 11a-b in 48 and 95 % overall yields respectively, or reduced with NaBH 4 in refluxing ethanol to yield the tetrabenzylated tetraamines 12a-b.
This methodology can be applied to different aromatic aldehydes, allowing the Nfunctionalization with other groups than the protecting benzyl groups.For instance, we have used 3-bromobenzaldehyde and 2-pyridinecarboxaldehyde to prepare difunctionalized tetraamines 15a-b (Scheme 5).The aminal group linked to a pyridine appears to be more reluctant towards hydrolysis.Indeed, the action of a 4M HBr solution in ethanol at 0°C, i.e. conditions used to remove the aminal group obtained with benzaldehyde and 3bromobenzaldehyde, gives a 50/50 mixture of di-and tribenzylated tetraamines 15a and 16a.However, 15a can be obtained as the sole product by refluxing the solution.

Scheme 5
The next step was to investigate the cyclization reaction of the different benzylated tetraamines with diethyloxalate.The reaction of N 1 ,N 4 -dibenzylated tetraamines 9a-b with the diester in refluxing ethanol gives the aimed dioxodibenzylcyclen 18a and dioxodibenzylcyclam 18b in 20 % and 30 % yields respectively, after optimisation of the reaction conditions, i.e. solvent, concentration, temperature (Scheme 6, Method 1).The formation of stable six-ARKAT membered rings is predominant and the major products are the dioxopiperazine derivatives 17ab.The ratio 17b/18b can be increased up to 91/9 by lowering the temperature (-10 °C).It has to be noted that 17a was not isolated as a pure compound since for such a series the formation of a six-membered ring can lead to another isomer.The reduction of dioxomacrocycles 18a-b with borane in THF allows the synthesis of 1,4-dibenzyltetraazacycloalkanes 19a-b.The benzyl groups can be removed to give respectively cyclen 2a and cyclam 2b.More interestingly, intermediates 19a and 19b are valuable precursors of macrocyclic polyamines functionalized on two adjacent nitrogen atoms when the N-functionalization is performed before the deprotection step.Such 1,4-difunctionalized cyclens and cyclams are difficult to prepare using known methodologies. 14he cyclization reaction of tetrabenzylated tetraamines 12a-b with diethyloxalate gives the expected dioxomacrocycles 20a and 20b in 50 % and 75 % yields respectively (Scheme 6, Method 2).In this case, the formation of six-membered rings does not occur due to the presence of the two tertiary amines.However, six days in refluxing ethanol were necessary to perform the cyclization reaction in good yields, thus illustrating the deactivating effect of the benzyl groups on the reactivity of the secondary amines.The reduction of compounds 20a-b with BH 3 /THF leads to the tetrabenzylated cyclen and cyclam 21a-b, which can be deprotected to yield finally cyclen and cyclam.

Scheme 6
Unexpected products have been obtained from the reaction of aminal diimine derivative 8b with diethyloxalate (Scheme 7).Indeed, this reaction does not lead to the aimed dioxoaminal macrocycle but to the rearranged product 22b (Figure 4) containing two aminal moieties, together with the dioxopiperazine derivative 17b.The formation of this cyclic diamide can be explained by the initial attack of diethyloxalate on one aminal nitrogen atom, implying the loss of one equivalent of benzaldehyde, as observed in the reaction of aminal derivatives 7a-b with benzyl bromide, followed by the cyclization to yield the six-membered aminal ring.The formed benzaldehyde can then react faster than diethyloxalate with starting material 8b, to give the bisaminal compound 22b.Due to this rearrangement, the aminal moiety cannot be used as a protecting group.The compound 8a behaves in a similar manner, since the bisaminal 22a (Figure 3) is obtained directly from 7a, together with the dibenzylated tetraamine 9a in a 1:1 ratio, by reduction with NaBH 4 followed by hydrolysis.In this case, the intermediate 8a was not isolated, thus indicating that the formation of two five-membered rings to give 22a occurs more readily than the formation of two six-membered rings to yield 22b.The compound 22b was also obtained without using diethyloxalate, together with the dibenzylated product 9b in a 1:1 ratio, by refluxing 8b in water.

Scheme 7
It has to be noted that the reaction of one equivalent of benzaldehyde with the dibenzylated tetraamine 9b gives the monoaminal product 8b, which is almost quantitatively converted to the rearranged product 22b by addition of a second equivalent of benzaldehyde.This experiment indicates that the rearrangement is induced by the attack of an electrophilic reagent, for instance diethyloxalate or in the latter case a second equivalent of benzaldehyde, on the tertiary nitrogen atom rather than on the terminal secondary amines.Thus, the reaction should proceed via the formation of the intermediate 23, which after nucleophilic attack of the secondary amines and loss of a water molecule, gives the bisaminal product (Scheme 8).The first step of this reaction, corresponding to the insertion of the double-bond into the C-N aminal bond is in agreement with the mecanism postulated earlier for the reaction of aminals with polarized double bonds. 15oreover, we were able to prove the formation of such an intermediate by reacting formaldehyde with the monoaminal diimine 7b.Indeed, the rearrangement was in this case prevented by the presence of the two imine functions, and the formation of the product resulting ARKAT from the insertion of the carbonyl group into the C-N aminal bond is evidenced by MALDI-TOF mass spectrometry.

Scheme 8
All compounds have been fully characterized by NMR spectroscopy, including 1 H-1 H and 1 H-13 C correlations experiments.It is clear that only one out of the three possible diastereoisomers (EE, ZZ, and EZ regarding the two C=N configurations) is obtained for the monoaminal diimines 7a and 7b.The EZ isomer is not compatible with the symmetry of the molecule in agreement with the number of signals on the NMR spectra.Single crystals were obtained from recrystallization of 7a and 7b in ethanol and THF respectively.In both cases, the most stable EE configuration was undoubtedly confirmed by X-ray diffraction (Figures 1 and 2).
The symmetry observed in solution is not preserved in the solid state, especially in the case of 7b.Indeed, one C-N aminal bond is considerably longer than the other one (1.470Å vs 1.452 Å).The distortion of the five-membered ring can result from interactions between the methylenic protons of the propylene chain and the π electrons of the benzyl groups of an adjacent molecule.The loss of symmetry in the solid state is also evidenced by CP-MAS 13 C NMR. Indeed, the 13 C spectrum of 7b in the solid state exhibits a splitting or broadening of all signals.3 and 4).In both cases, the meso compound is obtained.

Conclusions
Diethyloxalate proved to be a valuable precursor for the synthesis of polyazacycloalkanes.The cyclization reaction can be performed in good yields without using high dilution conditions, probably due to the conformational rigidity of the diester.However, the nature of the starting polyamine is a key parameter since [1+1] or [2+2] adducts can be preferably obtained depending on the presence or not of benzyl groups on the terminal nitrogen atoms.Indeed, the reaction of ethylene diamine or 1,3-propanediamine with diethyloxalate gives tetraamides which appear to be quite reluctants towards reduction, although cyclam can be obtained in 19 % overall yield, in only two steps, providing that ultrasounds are used during the reduction step.Convenient routes for the synthesis of various di-or tetrabenzylated linear tetraamines have been devised, implying the use of aminal intermediates obtained by reaction of the linear tetraamines with aldehydes.The cyclization of these N-benzylated tetraamines with diethyloxalate leads to various 2,3-dioxo N-benzylated tetraazamacrocycles, which after reduction and removal of benzyl groups, can yield cyclen or cyclam.Beside the synthesis of these two tetraazacycloalkanes, the interest of the synthetic routes described herein also lies in the intermediates.Thus, 1,4-dibenzylcyclen and cyclam are valuable cis-diprotected macrocycles for the preparation of new tetraazamacrocyclic ligands.Diamide intermediates also represent a new class of ligands and the coordination properties of these macrocycles incorporating both amine and amide type nitrogen atoms will be studied.Finally, we have shown that the reactivity of five-membered cyclic aminal compounds forbids the use of this moiety as protecting group in the cyclization reaction, but allows the stereoselective synthesis of new bisaminal compounds.

Experimental Section
General Procedures. 1 H (200 or 500 MHz) and 13 C NMR (50 or 125 MHz) spectra were recorded on Bruker AC 200 or Bruker DRX-500 spectrometers at the "Centre de Spectroscopie Moléculaire de l'Université de Bourgogne (CSM FR 2604)".Chemical shifts (δ) were measured by reference to the residual protons or carbon signals of the deuterated solvent.IR spectra were recorded on a Bruker IFS 66v spectrometer.MALDI-TOF mass spectra were recorded on a Bruker Daltonics Proflex III device using dithranol as a matrix.The melting points were determined using a Büchi B-545 apparatus and are uncorrected.Elemental analyses were carried out with a Fisons EA 1108 CHNS instrument at the CSM or done at the "Service Central d'Analyses du CNRS" in Vernaison.X-Ray data collection and structure refinement.Colourless single-crystals of 7a, 7b, 22a and 22b, were obtained from ethanol, THF, dichloromethane and acetone/dichloromethane (50/50) respectively.For compounds 7a, 7b and 22b, data collections were carried out at low temperature (T = 110(2) K) on a Nonius KappaCCD diffractometer equipped with a nitrogen jet stream low-temperature system (Oxford Cryosystems), and for compound 22a data were collected at room temperature on a Enraf-Nonius CAD4.In all experiments the X-ray source was graphite monochromatized Mo-Kα radiation (λ= 0.71073 Å) from a sealed tube.Intensity data were recorded as ϕ and ω scans with κ offsets in the former diffractometer, and as a θ/2θ scan mode in the later.No significant intensity decay was observed during data collections.No diffractometer or temperature problems occurred during the experiments.A psi-scan absorption correction 16 was carried out for compound 22a.
In the case of 7b, inspection of the X-ray pattern on the collected images indicated a severe twinning, which did not permit to fit the lattice parameters in an initial stage.Thus, using the data reduction software (DENZO program 17 ) we omitted a subset of the data, permitting us both to fit good unit-cell parameters and to integrate reflections properly.This procedure led to a completeness of only 52 % up to θ max = 25.0°, and therefore to a quite small ratio N reflections / N parameters = 4.5.In spite of that, the structure could be solved (the best phase set in the solving procedure gave all the positions for the non-H atoms) and the refinement was very stable and fast converged to the final model.
All the structures were solved by direct methods using the SIR92 program. 18While for 7a, 7b and 22b the refinements were carried out by full-matrix least squares on F 2 using the SHELXL97 program 19 and the complete set of reflections, in the case of 22a the refinement was done by full-matrix least squares on F using the LSFM OpenMolEN program 20 and the 1220 observed reflections (I > 3σ(I)).Anisotropic thermal parameters were refined for non-hydrogen atoms in the four structure determinations.Then, hydrogen atoms were located by Fourier synthesis and placed at calculated positions by using a riding model.They were refined with a global isotropic thermal factor in each structural model.As far as heavy atoms are not present in the non-centrosymmetric crystal structures of 7a and 7b, their absolute structures were not determined and Friedel pairs were merged in both cases.
For 22b, the first twenty residual peaks observed at the convergence (0.25 < ∆ρ res < 0.39 eÅ -3 ) correspond to the deformation of the electron distribution in the middle of the covalent bonds and in lone pairs regions.