Synthesis and stereochemistry of benzamidines and acetamidines 1

Phosphoric anhydride reacts with benzanilides and acetanilides in a novel self-condensation reaction to give N -substituted aroyl and acyl amidines (2a-g) and (4a-d) respectively. In contrast, an N -alkylbenzamide (5) gave dibenzamide (6). X-ray crystallographic studies of (2b), (2d), (4f) and (6) are reported. NMR spectroscopy of N -benzoyl- N,N ′-bis(2,6-diethylphenyl)-benzamidine (2e), N -benzoyl- N,N ′-bis(2,6-diisopropylphenyl)benzamidine


Introduction
The original aim of this study was the direct preparation of acyclic phosphorylated amides which previously had been prepared by indirect methods only. 2 Due to the ambident nucleophilic character of carboxylic amides there is the possibility of forming N-phosphorylated amides and expected the steric hindrance was greater for the isopropyl analogues than for the methyl analogues.The benzanilide bearing the strong electron-donating dimethylamino group in the para position of the aniline ring reacted readily as indicated by the rapid dissolution of the phosphoric anhydride in the chloroform.However characterisation of the product was inhibited by the extreme insolubility of the isolated product.
Reaction of acetanilides with phosphoric anhydride.Acetanilide and its homologues (3a-f) with different substituents in the aniline ring reacted under similar conditions with phosphoric anhydride to give the products of self-condensation, i. e. substituted acyl acetamidines (4a-f) (Equation 2, Ar as in Equation 1).
Whilst the ortho diethyl and diisopropyl substituted acetanilides were the most reactive -slightly exothermic reactions occurring-the o-methylacetanilide and non-substituted acetanilide required reflux conditions.Although acyl acetamidines were obtained from the latter acetanilide on one occasion, the reaction could not be reproduced.An isolation procedure, similar to benzamidines, was applied.Recrystallisation from ethanol gave pure products in 2-74 % yield.

Reaction of N-alkyl amides with phosphoric anhydride
N-Isobutylbenzamide (5a) reacted slowly with 3 equivalents of phosphoric anhydride to give N-isobutyldibenzamide (6a) as shown in Equation 3. The reaction was carried out in chloroform at room temperature over a period of 41 h .Column chromatography gave a 24 % yield of the imide.While the method cannot be used for the synthesis of N-alkylamidines, the reaction did provide some key information on the reaction mechanism (discussed below).N-Isobutylacetamide (5b) was unreactive under these reaction conditions.
Structure determination of benzamidines.The proton decoupled 13 C NMR spectra of substituted benzamidines contained two low intensity signals, broadened by the nitrogen atom, one in the region of δC 170.4 -173.5 ppm and the other in the region of δC 155.3 -158.3 ppm attributed to the amide C=O and C=N groups, respectively (Table 1).The presence of only one carbonyl signal indicated one geometric isomer about the amide bond.X-ray crystallographic analysis of benzamidines 2b and 2d showed the aryl groups on the amide group to be trans orientated (Figures 1 and 2, Table 2).An appropriate number of signals in the region 135.9-114.0ppm arising from the presence of four aromatic rings, was evident.The remainder of the aliphatic region depended on the aryl substituents, non-equivalence being observed for three compounds.The infra-red spectra of the products contained a strong amide I band in the region ISSN 1551-7004 Page 324  ARKAT USA, Inc 1675 -1648 cm -1 which was generally of higher wave number than the parent anilides, i.e. 1654 -1639 cm -1 (Table 3).The increase is attributed to additional delocalisation of the amide nitrogen lone pair of electrons with the imine group.Also present in the spectra was a band in the region 1646 -1619 cm -1 assigned to the imine stretching mode and a band near 1300 cm -1 assigned tentatively to an amide III band due to overlap with other bands.
ISSN 1551-7004 Page 325  ARKAT USA, Inc     4).Whereas for the bis(2,6-di-isopropylphenyl) benzamidine (2f), the methyl signals (but not the methine signals) of the ortho orientated iso-propyl groups for both rings were split into two equally intense signals in the 1 H and 13 C NMR spectra.Similar spectra were obtained using several solvents.Splitting due to E and Z geometric isomers about the amide or imine group can be eliminated since the non equivalence was absent for the bis(dimethylphenyl) and bis(trimethylphenyl) benzamidines (2c) and (2d) and for the methine carbon of the isopropyl groups of (2f).Restricted rotation about the N-aryl rings would produce chiral molecules in an analogous way to biphenyls, the benzyolated amidine groups providing the necessary non-symmetry.Thus the prochiral nature of the groups and the equal intensity of the split signals provide convincing evidence that the benzamidines are chiral due to restricted rotation about the N-aryl rings and thus the origin of non equivalence of the prochiral groups.
The unsymmetrically substituted bis(2-methylphenyl) benzamidine (2b) also showed additional splitting of the methyl signals in the 1 H and 13 C NMR spectra.In the absence of prochirality this non-equivalence clearly must have a different origin to the above.The possible causes of the additional splitting of the NMR methyl signals of (2b) were investigated by molecular modelling (see conformational analysis section below).X-ray crystallography of the bis(2-methylphenyl) benzamidine (2b) and bis(2,4,6trimethylphenyl) benzamidine (2d) (Figures 1 and 2 and Table 2) showed trans orientated aryl groups on the amide group for both structures.However, the orientation of the aryl groups on the imine group differed being trans for the 2-methylphenylbenzamidine (2b) and cis for the mesityl compound (2d).The mesityl rings were at approximately 80° angles to the amidine group supporting the concept of restricted rotation leading to a chiral molecule.This was reduced for the mono methyl compound (2b) the tolyl groups being about 60° and 50° out of the plane of the amide and imine groups respectively.In this structure the methyl groups have a syn relationship with respect to the bent amidine group, butthe most marked relationship was the juxtapositions of the amide tolylmethyl group and the amide carbonyl group (Figure 1).4).The latter pair of signals were partially resolved two subsets of doublet of quartets ( 2 JHH 14.6 and 3 JHH.7.3 Hz) which coalesced to a singlet at 120°C.Application of the Eyring equation to the nmr data by treating the system as an uncoupled AB case with equal rotamer population gave an approximate barrier of 80 kJ mol -1 .MM Molecular modelling was used to probe the stereochemistry of (2e) on the assumption that the amide group retains the trans aryl rings geometry as shown by the X-ray diffraction studies for amidines (2b) and (2d).While AM1 calculations indicated little difference in stability between the isomer with a cis imine group and that with the trans imine geometry, MM and HF STO-3G favoured the former by 20 kJ mol -1 .MM suggested that the most restricted N-aryl rotation was associated with the imine N-aryl group for both isomers.Molecular modelling of the bis(2,6-di-isopropylphenyl) benzamidine (2f) indicated that the cis imine trans amide isomer is more stable than the trans imine trans amide structure by 10 to 40 kJ.mol -1 (AM1 and MM respectively).These results follow the trend shown by the solid state structures of amidines (2b) and (2d), i.e. the more hindered di-ortho substituted benzamidine favours a cis imine geometry.A variable temperature study of the 270 MHz 1 H NMR spectrum of the benzamidine (2f) inC2D2Cl4 showed the upfield ortho-methyl signal pair of doublets at 0.95 and 0.81 ppm coalescing to a doublet at 90°C the other pair of doublets at 1.3 ppm being unchanged (Table 4).Calculation of the activation barrier from the nmr data, as above, gave a barrier of 76 kJ mol -1 .MM modelling predicted a lower rotational barrier about the amide aniline ring for both the trans(imine)-trans(amide) and cis(imine)-trans(amide) isomers thus indicating that for amidine (2f) the estimated energy barrier refers to restricted rotation about the N-aryl bond of the amide group.Bis(2-methylphenyl) benzamidine (2b) also exhibits splitting of the methyl signals in the 1 H and 13 C NMR spectra.The 1 H and 3 C NMR spectra of a chloroform-d solution both contained three signals with an intensity ratio of 1:1:2 and the spectrum of a solution in 1,1,2,2tetrachloroethane-d2 exhibited four 1 H signals -the highest field signal at 1.35 ppm being broadened.As pointed out above, this non-equivalence must have a different origin to the chirality case.Variable temperature NMR experiments of a tetrachloroethane solution showed coalescence of the split 13 C signal at 65°C and coalescence of the two split 1 H nmr signals at 35°C (upfield pair) and 80°C (downfield pair) respectively, which together with the broadness of one signal, the similar intensity of the signals and the presence of only one carbonyl environment, make geometric isomerism most unlikely.In the crystal the two methyl groups are approximately orthogonal and therefore the simpler explanation of syn and anti tolyl groups does not seem to apply and indeed there appears to be little hindrance to cause restricted rotation about the imino tolyl group which was confirmed by modelling studies.AM1 semi-empirical calculations and molecular mechanics (MM) modelling of the trans-trans compound (as established by X-ray crystallography) gave two global minima.As shown in Diagram 1, rotamer (2b-cisoid) (455 kJ mol -1 ) resembled the crystal structure.It possessed a spiral cisoid chromophore* (N=C-N-C(O)) [*cisoid about the central C-N bond] with face-to-face stacking of the benzoyl ring with the imino N-tolyl ring and having the other two facing rings with their planes opened to about 80 o .The second global minimum corresponded to rotamer (2b-transoid) (455 kJ mol -1 ).It possessed a transoid chromophore (N=C-N-C(O)) and had the two N-tolyl groups face to face with the two methyl groups anti and the two C-phenyl rings face-to-face with the two pairs of rings approaching orthogonality.A large part of the stabilisation energy of these rotamers appears to arise from the favourable double set of aryl-aryl face-to-face interactions.The two rotamers are interconverted by rotation about the single C-N bond of the amidine group.Modelling indicated the barrier to be about 70 ±10 kJ mol -1 .The similar rotamer energies and unique environments for the methyl groups in the two rotamers account for the NMR four signals, with similar intensity.Modelling also identified four conformations contributing to the rotamer structures (2b-cisoid) andanother four to (2b-transoid), facile interconvertion of the conformers occurring by rotation about the N-tolyl groups.
Structure and stereochemistry of acetamidines.Key data from the NMR and IR spectra of the acetamidines (4a-f) are given in Tables 5 -7 and were consistent with the acetamidine structures.The appearance of only one carbonyl signal in the 13 C NMR spectra at 172.3 -172.8 ppm, one acetyl signal in the 1 H NMR spectra and one carbonyl band in the IR spectra showed that the amide group had only one geometry in all six acetamidines.The structure and stereochemistry of bis(2,6-diisopropylphenyl) acetamidine (4f) was established by X-ray diffraction analysis (Figure 3, Table 8).The consistency of the positions of the NMR signals and IR bands indicated that they all resemble (4f) having the methyl group cis to the amide N-aryl group which is in contrast to the benzamidines.The 1 H and 13 C NMR spectra of N-acetyl-N,N′-bis(2,6-diisopropylphenyl)-acetamidine (4f) in tetrachloroethane exhibited similar non-equivalence of the isopropyl methyl groups to the corresponding benzamidine (2f).In this case the non-equivalence for both the carbon and proton signals persisted up to 130°C despite the smaller chemical shift differences between the split signals.
Non equivalence of the methylene signals of N-acetyl-N,N′bis(2,6diethylphenyl)acetamidine (4e) was also evident for solutions in chlorinated solvents but not in acetone.In contrast to the corresponding benzamidine the N-acetyl-N,N′-bis(2methylphenyl)acetamidine does not exhibit non equivalence of the methyl signals in the NMR spectra.The absence of the benzoyl group removes the possibility of twin aryl-aryl interactions which lends support to this phenomenon being a stabilising effect on the rotamers for the benzamidine (2b) discussed above.Structure of N-isobutyldibenzamide -The 1 H, 13 C NMR and infra red spectra were consistent with the structure, N-isobutyldibenzamide ( 6) and was confirmed by X-ray diffraction analysis (Figure 4, Table 9).Notable for all the products (2), ( 4) and ( 6) was the typical carbonyl bond lengths Reaction mechanism.Amides are important functional groups in living systems and an improved understanding of their reactivity would be invaluable.Thus, the site of phosphorylation and potential for phosphorotropy, the diverging reaction pathways depending on the nitrogen substituents, together with possible involvement of amide tautomers (imidols) in the condensation process, promised that a study of the reaction pathway might provide useful mechanistic information.NMR spectroscopic monitoring of the phosphorylation of N-benzoyl- While MO calculations give larger partial negative charges on the amide N atoms and give larger coefficients for N compared to O in their HOMO's, 11 it has been established experimentally that amides, which include benzamide, are O-protonated in strong acids, such as trifluoroacetic acid, to give delocalised cations (9; Y = H) 12b and there is strong evidence that alkylation and acylation also occurs initially on oxygen with potential to rearrange to N-alkylated and N-acylated products when they are thermodynamically favoured.12c In addition, phosphorylation of tertiary amides, such as DMF, readily forms O-phosphorylated Vilsmeier reagents. 13M and MO studies indicated that these observed trends may be assigned to the greater stability of the intermediates.Thus semi empirical AM1 calculations on the solvated molecules were consistent with experimental results showing the cation from O protonation of formamide and benzanilide (9; Y = H) to be 40 kJ•mol -1 and 80 kJ•mol -1 , respectively, more stable than the cations such as ( 10 The possibility of amides reacting as nucleophiles via their iminol tautomers (11) has long been recognised 14 despite the extensive predominance of the amide form. 15Phosphorylation of very low concentrations of the iminol tautomer would be a plausible route to the phosphorylated amide (8).Since prototropy is subject to acid catalysis, the phosphorylation of benzanilide was carried out in the presence of additional phosphoric acid.No rate enhancement was observed. 16ollowing the above additional studies we have revised the tentative conclusion made in our preliminary communication 1 and now prefer to assign the O-phosphorylated imidate structure (7)  to the initially formed intermediate rather than the phosphorylated amide structure (8) for the following reasons:-1) the less hindered position of the carbonyl oxygen to attack by phosphoric anhydride, 2) consistency with other studies showing electrophilic attack at amide oxygen in solution, 3) the calculated greater stability of the initial O-phosphorylated cation (9; Y = P(O)X2) and 4) the absence of phosphoric acid catalysed formation of an imidol tautomer.
The next step of the pathway is a condensation reaction involving the formation of a new C-N bond.Thus O-phosphorylated imidate appears to be reacting as an electrophile.If it has sufficient reactivity, presumably attack would again occur at the amide oxygen to give bis imidate (12) and intramolecular rearrangement would then be necessary to generate the amidine as shown in Scheme 1.However this mechanism could only explain the formation of dibenzamide ( 6) from the N-alkylbenzamide if the amide reacted as a nitrogen nucleophile.

ISSN 1551-7004
Page 335  ARKAT USA, Inc Scheme 1 Since the formation of amidine was accelerated by the addition of protic media at the end of the reaction, it is envisaged that the careful work up with a protic solvent could be responsible for converting a proportion of the O-phosphorylated imidate (7) to the imidol tautomer (11).The lifetime of the imidol should be increased by hydrogen bonding of the imidol proton to a phosphoryl group which might also assist the association of thereacting intermediates.The imidol, like enols, would be expected to be more reactive towards electrophiles with much better potential for reacting at its N atom with O-phosphorylated imidate as shown in Scheme 2. This was supported by ab initio calculations which estimated the N-protonated benzimidol cation, [PhNH=COHPh] + , to be over 220 kJ•mol -1 more stable than the O protonated cation [PhN=COH2Ph] + .

Scheme 2
AM1 and PM3 calculations indicated that after proton loss by the cations the phosphorylated amide and imidate have similar stabilities.Thus phosphorotropy leading to an equilibrium mixture of N and O phosphorylated intermediates seems quite feasible and has been previously invoked. 17Indeed, the formation of dibenzamide (6) in the reaction of N-isobutylbenzamide with phosphoric anhydride supports for the formation of N-phosphorylated amide (8) by phosphorotropyof the O-phosphorylated imidate (7).The detection of only one transitory set of NMR signals indicates that the equilibrium strongly favours the imidate in the case of the phosphorylated benzanilides.The lower yield of dibenzamide may be due to a poorer match of the rate of conversion of imidate to imidol to the rate of phosphorotropy.
Thus the proposed reaction mechanism for the phosphorylation of the benzamides is summarised in Scheme 3. The first step is envisaged as involving O-phosphorylation of the amide with phosphorotropy leading to the formation of an equilibrium mixture of Ophosphorylated imidate (7) and N-phosphorylated amide (8), the former predominating.It is postulated that the action of a protic solvent or atmospheric moisture on the O-phosphorylated imidate (7) produces the iminol tautomer (11), which attacks the imino carbon of the Ophosphorylated intermediate to give a reactive intermediate possessing a nitrogen anion stabilised by the N-aryl ring.Elimination of phosphate produces the amidine.When the N-aryl group is replaced by an N-alkyl group the developing nitrogen anion is not delocalised and thus the reactive intermediate is less stable and instead attack by iminol at the carbonyl group of the tautomeric N-phosphorylated amide is faster leading to imide (6) after elimination of phosphate as shown in Scheme 3.
In conclusion, our evidence indicates that both steps in the reaction pathway are controlled by the stabilities of the first transitory intermediate, i.e. that there are late transition states, and thus the reactions do not involve concerted delivery of a proton to the phosphoric anhydride during its electrophilic attack of the substrate.This was also supported by an ab initio calculation of a high barrier to rotation about the amide C-N of benzanilide (~40 kJ•mol -1 ) to convert the trans amide to a cis amide which would be necessary for a six membered concerted mechanism to occur.The barrier was estimated to be ~270 kJ•mol -1 for the imine C=N bond of the corresponding iminol tautomer.

Scheme 3
Experimental Section General Procedures. 1 H and 13 C NMR spectra were recorded using a Jeol JNM-FX270 spectrometer.Chloroform-d, 1,1,2,2-tetrachloroethane-d2, methanol-d or methanol-d4, acetone-d6 and dimethylsulfoxide-d6 were used as solvents and TMS was used as internal reference standard. 31P NMR spectra were obtained on a Jeol FX90Q spectrometer operating at 90 MHz with 85% phosphoric acid as the external reference standard.IR spectra (KBr discs) were recorded on a ATI Mattson Genesis Series FTIR TM spectrometer.Melting points were measured using a Gallenkamp manual operation apparatus and are uncorrected.
Benzanilides (1a-h) were prepared by the Schotten-Baumann reaction from the appropriate anilines and benzoyl chloride, purified by recrystallisation from hot ethanol and dried in vacuo at 60 o C for 12 h before use.Acetanilides (3a-h) were synthesised from the corresponding anilines and acetic anhydride, purified by recrystallisation from hot ethanol and dried in vacuo at 60 o C for 12 h prior to use.N-Isobutylbenzamide (5a) was prepared under the conditions of the Schotten-Baumann reaction from N-isobutylamine and benzoyl chloride followed by recrystallisation from ethanol and drying in vacuo at 45 o C for 12 h before use.N-Isobutylacetamide (5b) was prepared by reacting N-isobutyl amine with acetic anhydride.The liquid compound was purified by extraction with dichloromethane and dried by sodium sulphate.

General procedure for preparation of N-substituted aroyl benzamidines (2a-h)
The reactions involved the addition of dry powdered benzanilide to phosphoric anhydride suspended in chloroform (freshly distilled over P4O10) in the amide to anhydride ratio of 3:1.The reaction mixture was stirred at room temperature until the anhydride was consumed.The removal of the solvent gave a viscous residue which was taken up in a minimum of ethanol.Slow addition of water precipitated a mixture of the product and starting benzanilide.After filtration the crude benzamidine was extracted by carbon tetrachloride and purified by recrystallisation from ethanol.The 1 H and 13 C NMR data of the products are summarised in Tables 1 and 4.The IR data are listed in Table 3. N-Benzoyl-N,N′-diphenyl-benzamidine (2a).was prepared as outlined above from benzanilide (4.1 g, 0.021 mol) and phosphoric anhydride (1.99 g, 0.007 mol) in dry chloroform (15 mL)

N-Benzoyl-N,N′-bis(2-methylphenyl)-benzamidine (2b)
. N-Benzoyl-2-methylaniline (2.7 g, 0.013 mol) and phosphoric anhydride (1.22 g, 0.004 mol) were reacted in dry chloroform (15 mL) using the method described above, yielding the yellow crystalline product (2.15 g, 83 %), m. p. 144-146 o C.The reaction in chloroform-d (15 mL) was monitored using 1 H, 13 C and 31 P NMR spectroscopy.Anal.Calc.for C28H24N2O: C, 83.14; H, 5.98; N, 6.93.Found: C, 83.12; H, 5.98; N, 6.95.General procedure for preparation of N-substituted acetamidines (4a-f) Dry and powdered acetanilide was added to a heterogeneous chloroform solution of phosphoric anhydride (chloroform was freshly distilled over P4O10) and was stirred at room temperature until the mixture became homogeneous.Evaporation of the solvent under reduced pressure gave viscous residue which was dissolved in a minimum of ethanol.The mixture of acyl acetamidine and a parent acetanilide was precipitated then by addition of water.After filtration the crude acetamidine was extracted from the mixture by diethyl ether (unless otherwise stated) and purified by recrystallisation from ethanol.The 1 H and 13 C NMR data of N-substituted acetamidines studied are given in Tables 2 and 3 respectively.The IR characteristic data are listed in Table 4.

Molecular modelling
Calculations were performed on a Silicon Graphics O2 workstation using a Spartan 5.0 program.MM and semi-empirical MO studies of benzamidine (2b).-Based on the retention of the transtrans geometries for the imine and amide groups, a molecular mechanics conformational search gave eight conformers whose structures were optimised by AM1 calculations.Four conformers had spiral cisoid amidine groups (A-D-cisoid) with close phenyl-tolyl interactions and four had a transoid amidine group (A-D-transoid) with close phenyl-phenyl and tolyl-tolyl interactions as shown in Diagram 1.The energy of the most stable cisoid conformer (A-cisoid) and the energy of the most stable transoid conformer (A-transoid) were the same.Rotational barriers were estimated using MM coordinate driving and AM1 calculations of conformer transition state energies.
Energy barriers between the appropriate pairs of (2b-cisoid) and (2b-transoid) rotamers were calculated by MM and AM1 and found to be approximately 75 to 65 kJ•mol -1 respectively whereas the barriers between the four cisoid and between the four transoid conformers were in the range 2 -20 kJ•mol -1 .
; Y = H) from N-protonation.The difference was even greater for phosphorylation.The cation formed upon phosphorylation at oxygen (9; Y = P(O)(OH)2) was favoured over that from phosphorylation at nitrogen (10;Y = P(O)(OH)2)) by nearly 200 kJ•mol - 1 .The extra stabilisation can be attributed to the formation of a very strong P-O bond.It seems unlikely that solvation by chloroform would reverse these trends.

Table
1.13C NMR chemical shifts of the N-substituted aroyl benzamidines (2a-g) aThe assignment of signals to the amide or imine part of the molecule was tentative.

Table 2 .
Selected bond lengths [Å], bond angles and torsion angles [deg] for the substituted

Table 3 .
Characteristic aThe amide-I band mainly involves C-O stretching, C a -C-N deformation, and CN stretching.

Table 5 .
13C NMR chemical shifts of the N-substituted acyl acetamidines (4c-f) aThe assignment of signals to the amide or imine part of the molecule was tentative.

Table 9 .
Selected bond lengths [Å], bond angles and torsion angles [deg] for the N- 1.22 -1.23 Å but low field position of the C NMR signals for the amide carbonyl groups i.e. 170.4 -174.4 ppm c.f. 165.2 for benzanilide.On the other hand, the imide groups which have slightly shorter bond lengths (1.26 -1.28 Å) than normal (1.29 -1.33 Å), had 13 C NMR signals 156 -158 ppm close to those of the imine groups in Schiff's bases c.f. 158 ppm for PhCH=NPh.
X2).A 13 C NMR chemical shift prediction programme gave very similar parameters for the signals of the carbonyl group and imine group of each of these structures.Thus a larger deshielding effect expected by introducing a directly bound O-phosphate group on an imine carbon, normally at 158 ppm, could bring its chemical shift to a similar position to that caused by a smaller deshielding effect caused by phosphorylation of an amide nitrogen atom normally at 165 ppm.
2-methylaniline showed after 15 minutes the appearance and increase in intensity of transitory NMR signals at δH 1.98 ppm and δC 18.79 and 170.8 ppm corresponding to an ortho methyl group and a sp 2 carbon atom of an intermediate.After 10 days the spectra contained signals corresponding to the presence of starting material, benzamidine (2b) and intermediate in approximate ratio of 2:3:7,respectively.It was anticipated that this intermediate may be either the O-phosphorylated imidate (7; Y = P(O)X2) or the phosphorylated amide (8; Y = P(O)ISSN 1551-7004 Page 334  ARKAT USA, Inc