N -Arylhexahydropyrimidines. Electron impact mass spectrometry

The behavior of a series of 1,3-di-and 1,2,3-trisubstituted N -arylhexahydropyrimidines under electron impact (20eV) is analyzed. The compounds under study were divided into four groups according to their substitution patterns, which in turn determine the dominant fragmentations. In general, [M +. ] ions are intense, as well as fragments originating from cleavage of the C-2 substituent, which give rise to highly stabilized amidinium ions ([M-H] + or [M-R 2 ] + ). Their dominant secondary fragmentation involves loss of imines or azetidines. Additional fragmentations are also proposed, resulting from initial homolytic fragmentation of C2–N bonds in [M +. ] ions.


Introduction
Hexahydropyrimidines are of current interest owing to their pharmacological activity, as some members are prodrugs of biologically active di-, 1 and poly-amines. 1,2Also, some suitably substituted derivatives form stable complexes with metal ions, acting as anti-amoebic agents. 3he hexahydropyrimidine nucleus is present in some natural compounds such as tetraponerines, 4 verbamethine and verbametrine. 5n connection with previous research of our group on the characterization of nitrogencontaining heterocycles by mass spectrometry, [6][7][8][9] we have focused our attention on mass spectral analysis of six membered cyclic aminals (hexahydropyrimidines 1, Table 1).In spite of their considerable practical interest, there are only scattered reports concerning the mass spectrometric analysis of hexahydropyrimidines.In 1967, Evans reported the mass spectra of unsubstituted hexahydropyrimidine and its 2-methyl and 2,2-dimethyl derivatives. 10Braekman et al. discussed the fragmentation of some tricyclic hexahydropyrimidines (tetraponerines) isolated from natural sources. 4To our knowledge, however, no systematic study on hexahydropyrimidines is available in the literature.In the present work, the fragmentation patterns of a series of N-arylhexahydropyrimidines 1 (Table 1) are discussed.The behavior of these heterocycles under electron impact depends on the nature of both N-substituents and on the presence or absence of a 2-substituent.The results are correlated with data reported for the corresponding five membered homologues (imidazolidines). 9New fragmentation pathways are proposed to account for some important peaks in the spectra of the compounds under study.

Results and Discussion
On the basis of previously reported work on the mass spectrometry of N-arylimidazolidines, 9  ARKAT + and [M-R 3 ] + through Routes A and B with loss of an imine or an azetidine moiety, respectively, (Schemes 2 and 3) may also be expected.

Scheme 3
The fragmentations depicted in Schemes 1-3, however, do not account for some significant peaks observed in the spectra of hexahydropyrimidines 1.For the compounds under study, we propose additional fragmentation pathways of ions I and II (Scheme 1).Such mechanisms are depicted in Scheme 4 and involve: (a) homolytic α cleavage with loss of an imine, followed by elimination of ethylene, to produce ions g,h respectively (Route 5); (b) homolytic βfission leading to ions i (Route 6); (c) heterolytic cleavage with hydrogen migration producing protonated imines j (Route 7); (d) heterolytic cleavage followed by loss of ethylene, leading to fragments k and l, respectively (Route 8).When R 3 =alkyl, subsequent homolytic αcleavage of ions l 2 may produce ions m; (e) heterolytic C4-C5 fission with hydrogen migration leading to ions n (Route 9).Additionally, R 1 + and R 3 + fragments which may arise from heterolytic C-N cleavage of different ions bearing positively charged nitrogen are also observed in some cases.
For a better understanding of their fragmentation, the compounds under study were divided into four groups according to their substitution patterns.

1,3-Diarylhexahydropyrimidines 1a,b (Table 2)
The molecular ions M +• are intense, as are the [M-1] + fragments, the base peak for both compounds.Loss of H • from M +• could, in principle, take place from C2-H or from the trimethylene chain.However, the higher stabilization of the resulting tetrahydropyrimidinium ions resulting from C2-H homolytic fission and the absence of the [M-H] + fragment in 2,2dimethylhexahydropyrimidine support the proposed fragmentation. 10or derivatives 1a,b, ions a=c and b=d, which can alternatively originate from [M-1] + , [M-R 1 ] + and/or [M-R 3 ] + (Schemes 2 and 3) are important for 1,3-diarylhexahydropyrimidines.However, ions [M-R 1 ] + and [M-R 3 ] + as well as peaks e and f resulting exclusively from their secondary fragmentation are not observed.This suggests that the most probable fragmentation pathway leading to fragments a,b involves [M-1] + ions.

Scheme 4
Fragmentation of ions I and II takes place mainly by heterolytic N-C cleavage followed by loss of ethylene (Scheme 4, Route 8) leading to ions l, and by heterolytic N-C and C4-C5 fission with hydrogen migration, producing ions j and n respectively (Scheme 4, Routes 7 and 9).Instead, peaks corresponding to homolytic αor βcleavage appear with low relative abundance in these derivatives.

1-Aryl-3-alkylhexahydropyrimidines, 1c-g (Table 3)
The fragmentation patterns of hexahydropyrimidines 1c-g show remarkable differences depending on the type of alkyl substituent R 3 .As in 1,3-diaryl derivatives, the molecular ion is generally intense.The primary fragmentation of M + • takes place mainly by loss of H • leading to [M-1] + ions, the base peaks for derivatives 1c-f.Peaks resulting from loss of substituents on either N-1 or N-3 (Scheme 1, Routes 3 and 4) are of low relative intensity in all cases, with the exception of compound 1f where expulsion of a stable tert-butyl radical following Route 4 is favored.Although ions [M-R 1 ] + and [M-R 3 ] + are generally not relevant, peaks e corresponding to their secondary fragmentation are important in derivatives 1e-g, bearing branched N-alkyl substituents.This suggests that the most probable fragmentation pathway leading to e fragments involves [M-R 3 ] + ions.The peak of m/z 209 in compound 1g cannot be explained by any of the primary fragmentation pathways already proposed.Such a fragment would arise from homolytic αcleavage of the molecular ion, with expulsion of an alkyl radical R • leading to ions o (Scheme 5, Route 10).Loss of methyl radical following Route 10 in compounds 1e,f leads to the corresponding o=[M-15] + ions.

Scheme 5
For derivatives 1c-g, ions a=c could, in principle, originate from [M-H] + , [M-R 1 ] + and/or [M-R 3 ] + (Schemes 2 and 3).In this series, fragments a 2 appear with higher relative abundances than ions a 1 , with the exception of compound 1g, where a 1 is the base peak.
Fragmentation of ions I and II by elimination of an imine and ethylene (Scheme 4, Route 8) leads to ions k and l, of variable importance in this series.In compounds 1c, d, g, homolytic α− cleavage of ions l 2 (when R 3 =CR 4 R 5 R 6 ) with loss of an alkyl radical R 6 produces fragments m (m/z = 42, R 4 =R 5 =H), of increasing relative abundances in this series in which R 6 = methyl, ethyl, or tert-butyl.In compounds 1e, f, α−cleavage of ions l 2 with loss of methyl radical yields the corresponding m (R 4 =R 5 =CH 3 ) fragments.As in 1,3-diarylhexahydropyrimidines, fragmentation following Route 9 is important.It can be observed that the fragments n 1 have higher relative abundance for the lower homologues 1c-e, while n 2 ions follow the opposite trend.The R 3 + ions are only important for the hexahydropyrimidine 1f (R 3 =tert-C 4 H 9 ) as a consequence of the stability of the resulting positively charged fragment.

1,2,3-Triarylhexahydropyrimidine, 1h (Table 4)
For this compound the molecular ion is less important than in the corresponding 2-unsubstituted derivative 1a.[M-R 1 ] + =[M-R 3 ] + fragments have low relative intensities, while an [M-H] + ion is absent.Instead, as in other trisubstituted cyclic aminals, 9 the fragment corresponding to loss of R 2 (Scheme 1, Route 2) is the base peak.Peaks b and d corresponding to secondary fragmentation of such ion are also important.Fragmentation of ions I = II takes place mainly by Route 5 (Scheme 4), absent in the corresponding 2-unsubstituted hexahydropyrimidine 1a.It involves homolytic α−cleavage followed by elimination of ethylene, leading to fragments h.Fragments attributable to Routes 6-9 (Scheme 4) are not important.The routes already discussed, however, cannot account for fragment of m/z 140, for which we propose the structure [R 1 NH=CH 2 ] + .Such an ion is present in all trisubstituted derivatives in which R 1 =4-chlorophenyl (1h-j).It is analogous to ion j 2 (Scheme 4), and may arise from an intermediate which has previously lost R 2 .Fragmentation of ions I, II takes place mainly by homolytic β−fission leading to ions i 1 and by heterolytic C4-C5 fission with hydrogen migration leading to ions n 1 (Scheme 4, Routes 6 and 9, respectively).Ions R 1 + , [R 1 NHCH 2 ] + and [R 3 NHCH 2 ] + are also important for these derivatives.
Compounds 1a-j were described in the literature. 11,12They were synthesized by condensation of N,N'-disubstituted 1,3-propanediamines with aldehydes and were characterized by 1 H-NMR and by their elemental analysis.Mass spectra were recorded in a MS Shimadzu QP-1000 spectrometer operating at 20 eV with direct sample introduction.The ion source temperature was 280ºC.The mass range studied was m/z 40-700.

the primary fragmentation pathways expected for hexahydropyrimidines 1
are depicted in Scheme 1 and include: (a) loss of either H or R 2 by homolytic C2-R 2 or C2-H fission of the molecular ion, generating tetrahydropyrimidinium ions [M-H] + and [M-R 2 ] + (Routes 1 and 2, respectively); (b) loss of R 1 or R 3 by homolytic C-N fission of the molecular ion with hydrogen migration, leading to stabilized tetrahydropyrimidinium ions [M-R 1 ] + and [M-R 3 ] + (Routes 3 and 4 respectively); (c) initial ring cleavage of M +. through homolytic C2-N1 or C2-N3 fission leading to ions I and II.

Table 5 )
As in the previous series, [M-R 2 ] + ions appear with high relative abundances, being the base peak for the 3-ethyl derivative 1j, while [M-H] + , [M-R 1 ] + and [M-R 3 ] + fragments (Scheme 1) are not important.Secondary fragmentation of [M-R 2 ] + ions occurs mainly following Route B (Scheme 2), leading to fragments b 2 .Ions e, f, arising probably from [M-R 1 ] + , are also important for these derivatives.