Derivatives of N , N '-bis [ 2-hydroxy-1 , 1-bis ( hydroxymethyl ) ethyl ] ethanediamide

O composto [(HOCH2)3CNHC(O)]2 (1), formado a partir da reacao de (HOCH2)3CNH2 com EtOC(O)C(O)OEt, reage com aldeidos aromaticos ArCHO, gerando como produtos bis-alquilideno simetricos, N,N'-bis(2-Ar-5-ROCH2-1,3-dioxan-5-a)etanodiamides 3 (Ar = Ph, p-MeC6H4 or p-MeOC6H4, R = H). Uma reacao similar com Me2CO produziu N'-bis(2,2-dimethil-5-hidroximetil-1,3-dioxan-5-a)etanodiamida (2). Enquanto tres estereoisomeros (Z,Z)-, (Z,E)- e (E,E)-3 (Ar = Ph, R = H) foram formados a partir da reacao de 1 com PhCHO, somente (Z,Z)-3 (Ar = p-MeC6H4 ou p-MeOC6H4, R = H) foi isolado quando 1 reagiu com ArCHO (Ar = p-MeC6H4 ou p-MeOC6H4). As conformacoes Z tem os grupos: aril- equatorial, HOCH2- equatorial e amido-axial, no solido e em solucao, enquanto as conformacoes E tem os grupos aril- equatorial, amido- equatorial e HOCH2-axial. Uma mistura na proporcao 1:1 de (Z,Z)-: (E,E)-3 (Ar = Ph, R = H) co-cristaliza. As energias de conformacao de (Z,Z)- e (E,E)-3 (Ar = Ph, R = H) e 1 foram determinadas por calculos de mecânica molecular. O estereoisomero (Z,Z)-3 (Ar = Ph, R = H) e mais reativo do que o (E,E) em reacoes de alquilacao: somente o estereoisomero (Z,Z)-3 (Ar = Ph, R = Ph3SnCH2) foi isolado da reacao de uma mistura de (Z,Z)- e (E,E)-3 (Ar = Ph, R = H) com Ph3SnCH2I. Quando uma mistura 1:1 de (Z,Z)- e (E,E)-3 (Ar = Ph, R = H) foi reagida com um excesso de brometo alilico, uma mistura na proporcao de 4:3 de (Z,Z)- e (E,E)-3 (Ar = Ph, R = H2C=CHCH2) foi isolada. Reacao de oxomercuracao de (Z,Z)- e (E,E)-3 (Ar = Ph, R = H2C=CHCH2) com Hg(OAc)2 em metanol, seguida por uma troca anionica utilizando NaCl, produziu um unico estereoisomero, {N-(Z)-[[(R2)-5-(3-cloromercuria-2-metoxipropil)oximetil]-2-fenil-1,3-dioxan-5-il]}{ N'-(Z)-[[(S2)-5-(3-cloromercuria-2-metoxipropil)oximetil]-2-fenil-1,3-dioxan-5-il]}etanodiamida (4) que foi caracterizado por cristalografia de raio X.


Introduction
Despite being known for at least half a century, 1 and being readily prepared from common precursors, the symmetric diamido-hexol, N,N'-bis[2-hydroxy-1,1bis(hydroxymethyl)ethyl]ethanediamide, [(HOCH 2 ) 3 CNHC(O)] 2 (1), has attracted only occasional attention.However, its versatility as a precursor has still been well indicated, e.g., its hexa-O-derivatives have been mentioned in patents as potential explosives, 2 as sustained release [nitrogen] fertilizers, 3 in preparations of ink-jets dyes 4 and as antioxidants. 5Unsubstituted 1 has also been used as a precursor of sucrose mimics 6 and as a ligand in lanthanide complexes in a study of the catalysed hydrolysis of phosphate esters. 7he versatility of 1 as a precursor would be greatly enhanced if reactions at the hydroxyl groups were controlled.Such a control effectively requires selective protection of the OH groups.A study of the protection of the OH groups in 1 has been carried out and the findings on the use of alkylidene groups are reported here.

Results and Discussion.
Compound 1 was readily obtained by a published route 6 from (HOCH 2 ) 3 CNH 2 and EtO 2 CCO 2 Et.
Three solid stereoisomeric benzylidene products, (Z,Z)-, (Z,E)-and (E,E)-3 (Ar = Ph, R = H), were isolated from the reaction of 1 with excess PhCHO, see Figure 1.The mole ratios of the initial products, (Z,Z)-, (Z,E)-and (E,E)-3 (Ar = Ph, R = H), as determined by 1 H NMR spectroscopy, were 1.8: 1.3: 1, i.e., an overall (Z): (E) ratio of ca.3:2.Recrystallisation of the initial reaction products from aqueous acetone gave as the first crop of crystals, a 1:1 mixture of (Z,Z)-and (E,E)-3 (Ar = Ph, R = H), as indicated by NMR spectroscopy and confirmed by X-ray crystallography. 8Of interest, while co-crystallisation of enantiomers is often reported, reports of the co-crystallisations of other types of isomers, such as the stereoisomers here, are seldom made.This co-crystallized stereoisomeric mixture possessed a wide melting range, 185-224 o C. Successive recrystallisations, from ethyl acetate, of the material left in the mother liquor, led to the isolation of crystalline (Z, Z)-3 (Ar = Ph, R = H), m.p. 238-241 o C, and subsequently (Z,E)-3 (Ar = Ph, R = H), m.p. 194-197 o C. As well as the crystal structure of the 1:1 stereoisomeric mixture, that of the (Z,Z)-stereoisomer has also been reported. 8Suitable crystals of the (Z,E)-3 (Ar = Ph, R = H) isomer could not be grown for crystallography but its stereochemistry was readily resolved from the 1 H and 13 C NMR spectra.The (Z,Z)-3 (Ar = Ph, R = H) molecules in the solid state are Zshaped, whereas the (E,E)-isomers are maximally extended, as shown in Figure 1.A "L"-shape is proposed for the (Z,E)stereoisomer.The (Z,Z)-3 (Ar = Ph, R = H) molecular shapes are essentially identical in the 1:1 stereoisomeric mixture and in the pure single stereoisomer sample.The 1,3dioxanyl rings adopt chair conformations in all molecules, with the phenyl substituents, at C-2, always in equatorial sites.In (E)-and (Z)-5-hydroxymethyl-2-phenyl-1,3dioxane rings, the hydroxymethyl groups at C-5 are in axial and equatorial sites, respectively.There are inversion symmetry related pairs of intramolecular N-H-O hydrogen bonds between amide N-H and adjacent carbonyl Scheme 1. Table 2. 13  a J( 119,117 Sn-13 C) = 54Hz; b J( 119,117 Sn- 13 C) = 470, 452Hz; c J( 119,117 Sn- 13 C-p) = 17Hz; d J( 119,117 Sn- 13 C-m) = 44Hz; e J( 119,117 Sn- 13 C-o) = 33Hz; f J( 119,117 Sn- 13 C) = 486, 470Hz oxygen centres: intermolecular O-H-O hydrogen bonding between hydroxymethyl group and carbonyl atoms link molecules. 8rom reaction of 1 with p-methoxybenzaldehyde or pmethylbenzaldehyde, only the (Z,Z)-isomer of 3 (Ar = p-R'C 6 H 4 , R' = MeO or Me, R = H) was isolated.NMR spectra clearly indicated their stereochemistries to be (Z,Z), with no other isomer present in the isolated and toluene-washed compounds.Both the (Z,Z)-isomers were essentially insoluble in most common organic solvents, and only sparingly so in DMSO.They were obtained from the reaction mixtures as pure compounds merely by extensive extractions with toluene, to remove the excess aldehyde.Small quantities of the other stereoisomers could have been lost with the washings: as there was no indications in the NMR spectra for other stereoisomers in the original crude product mixtures, the maximum amounts of these would have to be less than 5%.

Molecular mechanics calculations on 1 and 3 (Ar = Ph, R = H)
Molecular mechanics calculations on 1 and 3 (Ar = Ph, R = H) were obtained 9 using the program Macromodel v6.5.Molecules in the gas phase were investigated using a 5000 step Monte Carlo search for conformers, followed by energy minimisation of the conformers generated.All energy minimisations were performed with the Macromodel MM2 * force field: solvent effects were assessed by the GB/AS continuum solvent model. 10alculations on 1 and 3 (Ar = Ph, R = H) were limited to symmetric structures, e.g., only the (Z,Z)-and (E,E)-and not (Z,E)-forms of 3 were included in the calculations.Two favoured conformations, 1a and 1b, were calculated for 1, the more stable form in the three phases considered being invariably 1a, see Figure 2 and Table 3.In both conformations, one of the CH 2 OH groups in each C(CH 2 OH) 3 unit is H-bonded to the carbonyl oxygen of the adjacent amide.The distinction between 1a and 1b resides in the orientations of the other two CH 2 OH units, see Figure 2: these two OH groups are considered to be those used in the formation of the 1,3-dioxanyl rings in 3 (Ar = Ph, R = H).Calculations were carried out on four conformers of 3 (Ar = Ph, R = H) -two (Z,Z)-and two (E,E)forms in three different phases, see Figure 3. Differences in the relative energies are found between the three phases, indicating the importance of solvation and H-bonding.The relative energies calculated for the organic solvent, CHCl 3 , are most relevant to the reactions carried out in the aryl aldehyde.
Reaction of PhCHO with the more stable 1a conformer provides either the (E,E)-conformer [(E,E)-3a] (Ph axial/ CH 2 OH equatorial) or the (Z,Z)-conformer [(Z,Z)-3a] (Ph equatorial/ CH 2 OH equatorial): calculations show that [(Z,Z)-3a] is the more stable in CHCl 3 .Reaction of PhCHO with the other conformer 1b will provide either the (E,E) conformer [(E,E)-3b] (Ph equatorial/ CH 2 OH axial) or the (Z,Z)-conformer [(Z,Z)-3b] (Ph axial/ CH 2 OH axial).Calculations indicated that of these two, [(E,E)-3b] is favoured.Thus the molecular mechanics calculations point to the favoured formations of [(Z,Z)-3a] and [(E,E)-3b] with the former dominating, from the two symmetrical forms of  1.The calculated preference for the Z-conformations of the 1,3-dioxanyl rings [i.e. with axial amido groups] and the indications that the phenyl groups are generally in equatorial sites are in agreement with the NMR and crystallographic findings.
The preference for the amido group over the CH 2 OH group to occupy axial sites in 3 is similar to the situation reported for cyclohexane derivatives.In cyclohexanes, substituents, X, invariably favour equatorial sites.For example, the preferences [conformational energies] 11 for NHC(O)OPh, CH 2 OH and Ph to be in equatorial sites in cyclohexanes are 6.7, 7.36 and 11.7 kJ mol -1 , respectively, the NHC(O)Ph group being the nearest to the NHCOCONH group for which data could be found. 11However, this equatorial preference need not apply to X-substituted 1,3dioxanes, where polar O-X interactions have to be considered.As also pointed out by Eliel and Wilen, 11 steric compression of axial groups by lone pairs on oxygen atoms in 1,3-dioxanes is very small compared to the compression by syn-axial H-atoms in cyclohexanes.These effects can, in fact, result in a preference for axial positions, as shown, for example, by the CH 2 OH group in 5-hydroxymethyl-2isopropyl-1,3-dioxane in CCl 4 solution. 11
A bis-stannylated derivative was, however, obtained from 3 (Ar = Ph, R = H): the compound, (Z,Z)-3 (Ar = Ph, R = Ph 3 SnCH 2 ), d 119 Sn = -139.8ppm,was isolated from the reaction of the 1:1 mixture of (Z,Z)-:(E,E)-3 (Ar = Ph, R = H), with Ph 3 SnCH 2 I [1:2.05mole ratio], in DMF in the presence of NaH, after chromatography, see Figure 6.The 119 Sn NMR spectrum of the crude reaction product, prior to chromatographic separation, exhibited several peaks: the most intense peak being at -139.8ppm, i.e. the precise value of the isolated product.Other peaks were also in the region expected for Ph 3 SnCH 2 OR* compounds [-145 to -135ppm], 23 but all these were minor peaks.It is possible  that the stannylated derivative of (E,E)-3 (Ar = Ph, R = H) would also have a d 119 Sn value of -139.8ppm, and that it was also present among the reaction products, but it somehow escaped isolation by chromatography.However, the latter is considered unlikely, and it is assumed that (E,E)-3 (Ar = Ph, R = Ph 3 SnCH 2 ) could not be a significant product, if formed at all.The crystal structure determination of (Z,Z)-3 (Ar = Ph, R = Ph 3 SnCH 2 ), already reported, 24 indicated the tin centres to be 4-coordinate, with slightly distorted tetrahedral geometries, as have been found for other Ph 3 SnOR* compounds. 23As also in these other Ph 3 SnCH 2 OR* compounds, the intramolecular Sn-O(C-5) separation is short [2.91(1)Å] and within the limits accepted for coordination [the sum of the van der Waals radii for Sn and O is ca.4.1Å]. 20However, no Sn-O bonding is assumed since the C-Sn-C angles are close to those expected for a 4-coordinate and near tetrahedral arrangement.Any Sn-O interaction would create, in any case, highly strained three membered rings.
As shown by the structures listed in the Cambridge Crystallographic Data Base, 25 tetraorganotin compounds generally have 4-coordinate tin centres with near tetrahedral geometries.This is a consequence of the poor acceptor strength of the tin centre: however, in a limited number of rigid tetraorganotin compounds with suitably sited donor groups, intramolecular complexation can occur with the formation of 5-and even 6-coordinate tin centres. 26

Conclusions
Protection of 4 of the 6 hydroxyl groups in 2 can be achieved by standard alkylidene procedures: the bis alkylidene derivatives, 3, can be further derivatised by standard means.Transformations of the bis-mercurated, 4, and the bis stannylated, (Z,Z)-3 (Ar = Ph, R = Ph 3 SnCH 2 ), compounds provide further routes to selected derivatives.

Experimental
Melting points were determined using a Kofler hotstage and are uncorrected Solution NMR spectra were obtained on Bruker 250 MHz and Varian 400 MHz instruments.IR spectra were obtained on Philips Analytical PU 9800 FTIR and Nicolet 205 FTIR instruments.
All solvents were removed from the mother liquor under vacuo to leave a solid residue, which was recrystallised from ethyl acetate.The colourless crystalline solid obtained was the single steroisomer, (Z,Z)-3 (Ar = Ph, R = H); m.p. 238-241 o C. The mother liquor from the second crystallisation, on concentration and further recrystallisation gave crystals of stereoisomer, (Z,E)-3 (Ar = Ph, R = H); m.p. 194-197 o C. NMR spectra of the three stereoisomers are displayed in Tables 1 and 2.

X-Ray crystallography
Data were collected on an Enraf-Nonius CAD-4 diffractometer: data collection: CAD-4/PC. 27Cell refinement: SET4 and CELDIM Software. 27.Program used to solve structure: SHELXS-97. 29Program used to refine structure: SHELXL-97. 30Preparation of material for publication: SHELXL-97 30 and WordPerfect macro PRPKAPPA. 31Diagrams were prepared with the aid of PLATON. 32he compound 4 was found to be unstable in the X-ray beam.The compound lies on an inversion centre in the crystal and has an overall Z-shape.H atoms were treated as riding atoms with C-H 0.93 to 0.98Å, N-H 0.86Å.Atoms C(7) to C(12) had anisotropic displacement parameter restraints applied to them.The C(14)-C(14) a distance (symmetry operation: a: -x, 2-y, 1-z) was constrained to be 1.520(5)Å, this was the average distance found for this bond in the 3 molecules reported in 3 (Ar = Ph, R = H). 8he largest peaks in the difference map were adjacent to the Hg atom at distances 1.11 to 1.06Å.
Crystal refinement data for the compound are listed in Table 5.
C NMR and 119Sn NMR data for 2 and 3 in DMSO-d 6

Table 1 .
1 H NMR data for 2 and 3 in DMSO-d 6