A facile synthesis, dynamic H NMR, and theoretical study of novel stable heterocyclic phosphorus ylides containing a tetrazole ring

A general and practical route has been considered for the synthesis of stable heterocyclic phosphorus ylides by a one-pot condensation reaction between dialkyl acetylenedicarboxylates and triphenylphosphine in the presence of -SH or -NH heterocyclic compounds such as 5mercapto-1-methyltetrazole or 5-aminotetrazole. The stable ylides involving 4d-e exist in solution as a mixture of two isomers, while 4a-c indicate only one isomer. Dynamic parameters including ∆Η≠, ∆S≠ and ∆G≠ were determined on the basis of dynamic H NMR data. In addition, the assignments of more stable Zor Eisomers were investigated using the theoretical calculations.


Introduction
2][3] In recent years a three-component method has been developed [25][26][27][28] for the synthesis of organophosphorus compounds using a novel approach employing vinylphosphonium salts.0][31][32][33] The tetrazole moiety and its derivatives are important in medicinal chemical research. 33Herein we describe an efficient synthetic route to stable phosphorus ylides in excellent yields from 5-mercapto-1-methyltetrazole or 5aminotetrazole.An "atoms in molecules" (AIM) analysis 35 at the HF/6-31G level of theory has been performed in order to gain a better understanding of most geometrical parameters of both the E-4(a, d) and Z-4 (a, d) phosphorus ylides (Scheme 1).

Results and Discussion
The reaction between triphenylphosphine and dialkyl acetylenedicarboxylates 1 led to the zwitterion 2, which was followed by attack by the nitrogen anion of the 5-aminotetrazole, or sulfur anion of the 5-mercapto-1-methyltetrazole, to generate the phosphorus ylides E-4 and Z-4.
These reactions were carried out in diethyl ether at ambient temperature and were complete after 5 hours.The 1 H, 13 C and 31 P NMR spectra of the crude products clearly indicated the formation of the phosphorus ylides 4. No product other than 4 could be detected by NMR spectroscopy.The structures of compounds 4a-e were deduced from the elemental analyses, mass, IR, 1 H, 13 C, and 31 P NMR spectra.The 1 H NMR spectrum of 4a showed two singlets at δ=3.16 and 3.77 ppm for methoxy protons, a doublet at δ=5.40 ppm (J=16.0)arising from methine proton (CH-C-P group), and a significant signal at δ=6.01 for the NH 2 group.The aromatic protons appeared as a multiplet at δ=7.48-7.73ppm.As can be seen in the Experimental Section, the 13 C NMR spectrum of 4a displayed eleven distinct resonances which is in accord with only one isomer.This observation is attributed to the plausible intramolecular hydrogen bond in stable ylides 4a-c containing 5-aminotetrazole (Scheme 2).Scheme 2. Plausible intramolecular hydrogen bond in stable ylides 4a-c containing 5aminotetrazole.
Although the presence of the 31 P nucleus has complicated both the 1 H and 13 C NMR spectra of 4a, it helps in assignment of signals by long-range spin-spin couplings with 1 H and 13 C nuclei.The 1 H and 13 C NMR spectra of compounds 4b and 4c are similar to those of 4a, except for the signals from the ester group, which appear as characteristic resonance lines with the corresponding chemical shifts.The 1 H, 13 C, and 31 P NMR spectra of compounds 4d-e showed the mixture of two isomers [Scheme 1, (j)].5][36][37][38] The 1 H NMR spectrum of 4d exhibited two singlets (δ 3.17 and 3.73 ppm) arising from the methoxy group in the Zisomer, and two singlets at 3.59 and 3.70 ppm for that in the Eisomer.The methyl group at 3.17 in the Zisomer is shielded due to the anisotropic effect of a phenyl group of triphenylphosphine.This effect confirms why the Z-4d and E-4d isomers could appear as the major and minor forms, respectively, with the percentage of both isomers as reported in the Experimental Section.The signals for methine protons appeared as two doublets at δ=5.37 (J=16.7)and δ=5.40 (J=16.2),respectively for the Zand Eisomers.The 13 C NMR spectrum of 4d displayed 24 distinct resonances in agreement with the presence of two isomers.The 1 H and 13 C NMR spectra of compound 4e are similar to that of 4d except for the signals from the ester group.In addition, products 4d and 4e displayed 13 C NMR resonances at δ 163.77 ppm and δ 163.99 ppm, respectively for the N=C-S unit. 16,34For the 13 C NMR spectroscopy the anisotropic effect could not be reported for the methoxy group in the Zisomer because of the small different of their chemical shifts.The carbonyl region of these compounds 4a-e exhibited absorption bands for each compound.The ester absorption is at 1747-1616cm -1 , the conjugation of negative charge of the ylide moiety with the adjacent carbonyl group accounting for the reduction in frequency of the carbonyl bands, and allows determination of the ratio between the Eand Zisomers.The ylide moiety of these compounds is strongly conjugated with the adjacent carbonyl group, and rotation around the partial double bond in E-4 (d, e) and Z-4 (d, e) isomers is slow on the NMR time scale at ambient temperature [Scheme 1 (j)].
Dynamic 1 H NMR 39,40 were also observed for compound 4d.The C-2 methine of the 1 H NMR spectrum of 4d in CDCl 3 at ambient temperature exhibits two sharp doublets at δ= 5.41, 5.38 ppm for the H ( 3 J PH ) group of the (E-) and (Z-) isomers and two singlets at δ= 3.77, 3.16 for the OCH 3 groups, in CDCl 3 at ambient temperature.Increasing the temperature results in coalescence of the H ( 3 J PH ) and the OCH 3 resonances at approximately 63 o C and 65 o C, respectively.The variable coalescence temperature in the 1 H NMR spectrum and calculation of kinetic constant by k C = π∆υ/√2 allowed us to calculate ∆G ≠ , ∆H ≠ and ∆S ≠ for the interconversion of Eand Zisomers (Table 1).

Experimental Section
General Procedures.Dialkyl acetylenedicarboxylates, triphenylphosphine, 5-mercapto-1methyl tetrazole and 5-aminotetrazole were obtained from Fluka (Buchs, Switzerland) and used without further purification.Melting points and IR spectra were measured on an Electrothermal 9100 apparatus and a Shimadzu IR-460 spectrometer, respectively.The mass spectra were recorded on a Shimadzu QP 1100 EX mass spectrometer operating at an ionization potential of 70ev.Elemental analyses for C, H, and N were performed using a Heraeus CHN-O-Rapid analyzer.The 1 H, 13 C and 31 P NMR spectra were obtained from a Bruker DRX-500 AVANCE instrument with CDCl 3 as solvent, at 500.1, 125.8 and 202.5 MHz, respectively.

Theoretical study
Recently, different reports have been published on the synthesis of stable phosphorus ylides from the reaction between triphenylphosphine and reactive acetylenic esters in the presence of N-H, C-H or S-H heterocyclic compounds.These ylides usually exist as a mixture of two isomers.The determination of the more stable isomer is impossible by the 31 P, 13 C and 1 H NMR techniques.For this reason quantum mechanical calculations have been performed in order to gain a better understanding of most important geometrical parameters and also the relative energies of both isomers.

Structure and stabilities
In order to determine which is the more stable form of both Z-4(a, d) and E-4(a, d) isomers of ylides (4a and 4d are selected as typical ylides from the different categories of 4a-c and 4d-e, respectively), their structures were first optimized at the HF/6-31G level of theory 42 by using the Gaussian 98 program package. 43Also, the relative energies of the two isomers have been calculated at the HF/6-31G and B3LYP/6-311++G (d,p) levels (see Figures 1 and 2).The relative stabilization energies for both Z-4(a, d) or E-4(a, d) isomers are reported in Table 2.As can be seen, Z-4a and E-4d conformers are more stable than the E-4a and Z-4d forms (3.50 and 0.26 kcal/mol, respectively) at the B3LYP level.
Further investigation was undertaken in order to determine more effective factors on the stability of both isomers, on the basis of AIM calculations 44 at the HF/6-31G level of theory by the AIM2000 program package. 45As noted in the literature, 46 the ranges of ρ(r) and ∇ 2 ρ(r) are 0.002-0.035e/a0 3 and 0.024-0.139e/a 0 5 , respectively, if H-bonds exist.The number of hydrogen bonds in both categories (Z-4a and E-4a) and (Z-4d and E-4d) are (9 and 10) and also (8 and 9), respectively.In addition, the ranges of their electron densities are in (0.0022 -0.0184 and 0.0021 -0.0210 au) and also (0.0038 -0.0190 and 0.0390 -0.0190 au), respectively.With respect to the large number of hydrogen bonds in both the Zand Eisomers it is difficult to make a precise decision for determination of the more stable isomer.On the basis of theoretical calculations (Table 2), the difference between the relative stability of the E-4d and Z-4d isomers in the gas phase is small (0.26 kcal/mol), while it is considerably greater in the E-4a and Z-4a isomers (3.50 kcal/mol).Perhaps this noticeable difference is taken more in solution media for 4a, and for this reason it is possible to observe only one isomer of 4a (Z or E).In the Experimental Section both the 1 H NMR and 13 C NMR spectroscopies indicated only one isomer, in accordance with the category of the ylides 4a-c.Nevertheless, the result of our calculations is different for ylide 4d (observed as the two isomers), which may be attributed to the negligible difference in relative stability of Z-4d and E-4d isomers.Perhaps this negligible difference is not taken more considerably in solution media for 4d and for this reason it is possible to see the two isomers of 4d (both Z and E isomers).In recent case, the 1 H, 13 C, 31 P NMR data showed the two isomers for the category of ylides 4d-e which were consistent with the obtained result from the theoretical investigations.

Conclusions
We have prepared the novel tetrazole stable phosphorus ylides using a one-pot reaction between triphenylphosphine and acetylenic compounds in the presence of NH or SH heterocyclic compounds such as 5-mercapto-1-methyltetrazole or 5-aminotetrazole.The present method has the advantage that not only is the reaction performed under neutral conditions, but also the substances can be mixed without any activation or modification.In addition, dynamic 1 H NMR of 4d, and also the assignment of the Zand Eisomers as a major or minor form in both of 4a and 4d ylides were undertaken in the theoretical study.