Cycloaddition reactions of acetylenic iminium salts and diazoacetates leading to pyrazole iminium salts

1 Introduction

Pyrazoles are five-membered diaza heterocycles, which have attracted ever growing interest in the past decade under aspects of synthesis, biological activities, and applications [1], [2]. The pyrazole ring system can be found as a structural scaffold in a variety of relevant organics in the pharmaceutical and agrochemical sectors. Biological activities of pyrazoles have been compiled and discussed in several recent reviews [3], [4], [5], [6], [7], [8], [9]. Relatively few pyrazole derivatives occur as natural products; the pharmacological activities of such pyrazoles have been reviewed [10].

For the synthesis of pyrazoles with diverse substitution patterns and functional groups, several different synthetic approaches are available [1], [8], [11], [12]. Besides the frequently used cyclocondensation of 1,3-dicarbonyl compounds (or synthetic equivalents, Knorr pyrazole synthesis [1], [11], [13]) with hydrazines, another straightforward and well established method for the preparation of 3H- and 1H-pyrazoles is provided by the 1,3-dipolar cycloaddition reaction of diazo compounds and alkynes [11], [12], [14], [15]. Since the chemical and thermal stability of some classes of diazo compounds is not high, variations of the cycloaddition method have been developed which allow their in situ preparation. In this manner, they were generated from tosylhydrazones of aldehydes [16], alkyl-aryl-ketones [17] and saturated cyclic ketones [18]. The in situ preparation of 2,2,2-trifluoro-diazoethane by amine diazotization in combination with a silver-mediated cycloaddition at terminal alkynes has been applied to the synthesis of 3-CF₃-substituted pyrazoles including the antiarthritic drug Celecoxib [19].

In this paper, we put a focus on 1,3-dipolar cycloaddition reactions of diazoacetates with acetylenic iminium triflate salts [R–C≡C–C(Ar)=N⁺R₂ TfO⁻], a novel class of electron deficient dipolarophiles. In previous papers we have shown, that these alkynes can undergo [3+2] cycloaddition reactions readily with muenchnones (as masked azomethine ylide dipoles) [20] and organoazides [21] to furnish pyrroles and 1,2,3-triazoles, respectively. The reactivity and regioselectivity of alkyne+diazoacetate cycloaddition reactions can be explained by frontier molecular orbital (FMO) theory [22], [23], according to which reactions under HOMO(diazoacetate)–LUMO(alkyne) control can be classified as “normal electron demand” cycloadditions (for a density functional theory [DFT] study, see ref. [24]). As a consequence, it is expected that alkynes with electron withdrawing substituents lower the LUMO energy level and accelerate the reaction. In line with this, acetylenic iminium salts are expected to be powerful dipolarophiles, even better than acetylenic carbonyl compounds. In contrast to the long known 1,3-dipolar cycloadditions with diazoalkanes as dipoles, the synthesis of pyrazolecarboxylates from diazocarbonyl compounds – such as diazoacetates, diazoacetamides and α-diazoketones – and acetylenic carbonyl compounds (mostly propiolic acid and acetylenedicarboxylic acid esters) has been reported in several recent papers. Typically, these reactions proceed rather slowly at room temperature [25], [26], while sufficiently fast reactions are achieved by thermal activation (e.g. in hot toluene [23], [27]) or under solvent-free conditions [25]. Catalysis by InCl₃ in water also allows the cycloaddition of diazoacetates or α-diazoketones and methyl propiolate to occur at room temperature within 24 h [28].

[3+2] Cycloadditions of acetylenic iminium salts with diazoacetates are not only interesting because of the anticipated high dipolarophilic reactivity of the former, but also because they give access to barely known iminium-functionalized 1H-pyrazoles. These ionic pyrazole compounds could be converted into neutral pyrazoles by addition of nucleophiles at the iminium group.

2 Results and discussion

For the present study, we have chosen the terminal acetylenic iminium (propyne iminium) triflate salt 1 and internal acetylenic iminium triflates 2a–d as electron deficient dipolarophiles (Fig. 1). Although these iminium salts may be considered as synthetic equivalents of acetylenic ketones, they are not prepared from such ketones. Salts 1 [29] and 2a–d [30] were obtained by N-methylation of the corresponding propyne imines, which in turn were prepared by C,C coupling of the appropriate terminal acetylenes and imidoyl chlorides.

Fig. 1:

Terminal and internal acetylenic iminium triflates 1 and 2; TfO⁻=CF₃SO₃⁻.

The 1,3-dipolar cycloaddition of equimolar amounts of methyl diazoacetate and acetylene iminium salt 1 in dichloromethane was instantaneous at room temperature and furnished the 1H-pyrazole-3(5)-carboxylate 3 almost quantitatively (Scheme 1). It is obvious that the initially formed 3H-pyrazole has undergone a fast sigmatropic [1,5]-H shift to form the aromatic 1H-pyrazole. As in all other cases in this study, the position of the NH proton, i.e. the prevailance of one or the other tautomeric form, was not established (vide infra).

Scheme 1:

Reactions of propyne iminium salt 1 with methyl diazoacetate.

According to the NMR spectra of the crude product mixture, only one regioisomer was formed. Arguments for the assignment of the constitution of 3 will be discussed together with its derivative 6 (vide infra). This regioselectivity meets the general expectations based on FMO theory [31] and DFT calculations [24] as well as steric considerations. The excellent dipolarophilic reactivity of acetylenic iminium salt 1 is highlighted by a comparison with the [3+2] cycloaddition of methyl diazoacetate and methyl propiolate, which required 3 days at room temperature to furnish the pyrazole-3,5-dicarboxylate in 88% yield [32]. For the analogous reaction of the corresponding ethyl esters under solvent-free conditions, quantitative conversion after 8 h at T=20°C has been reported [25].

When the cycloaddition reaction was carried out with a 2:1 excess of alkyne 1, a very hygroscopic, bis(iminium)-substituted pyrazole 4 was obtained in high yield after 4 h (Scheme 1). Again, it is not clear, whether the propene iminium group is located at the nitrogen atom adjacent to the ester group or at the other N atom. For steric reasons, the first mentioned isomer should be favored. The formation of pyrazole 4 can be explained by a slow conjugate addition of monocationic pyrazole 3 at the C≡C bond of alkyne 1, i.e. the overall reaction is a consecutive [3+2] cycloaddition – sigmatropic H shift – Michael addition process. Salt 4 is reminescent of the reaction of methyl diazoacetate with a terminal acetylene iodonium salt, HC≡C–I⁺Ph TfO⁻. In that case, the 1:2 adduct 5 was obtained even when equimolar amounts of both reactants were applied, and its structure was confirmed by a crystal structure determination [33].

When pyrazole 3 was treated with three equivalents of LiAlH₄, both the iminium function and the ester group were reduced. Purification of the neutral 3,5-disubstituted 1H-pyrazole was facilitated by conversion into its hydrobromide 6. The configurational assignment of pyrazole iminium salt 3 and its derivative 6 is based on the consideration of NMR chemical shifts. The signal of the pyrazole carbon atom C(H)-4 is observed at δ=118.31 ppm for 3 and 104.29 ppm for 6. For the opposite regioisomer, this carbon atom would be bonded to a nitrogen atom and a significant deshielding effect by this N atom would be expected.

Methyl diazo(phenyl)acetate also reacted smoothly with alkyne 1, but according to ¹H NMR monitoring at a lower rate than methyl diazoacetate (Scheme 2). Pyrazole iminium salt 8 was obtained in good yield; a 2:1 adduct analogous to Scheme 1 could not be detected. For both electronic and steric factors, the regiochemistry of the cycloaddition step is expected to be the same as with methyl diazoacetate. It is confirmed by an HMBC NMR spectrum, which shows ⁴J(C,H) correlations of the two NCH₃ proton signals with the carbon signal at δ=145.6 ppm, which can be assigned without doubt to one of the C(–N) atoms in the pyrazole ring.

Scheme 2:

Reaction of terminal acetylene iminium salt 1 with methyl diazo(phenyl)acetate.

The formation of 8 is explained by a [1,5] sigmatropic migration of the phenyl group in the initial [3+2] cycloaddition product, 3H-pyrazole 7 (van Alphen-Hüttel rearrangement), followed by a C→N hydrogen migration that could result from two subsequent sigmatropic [1,5]-H shifts. This mechanistic sequence has been proposed earlier for the InCl₃-catalyzed reaction of the same diazoester and methyl propiolate [28]. In contrast to that study, however, a minor amount of an isomeric pyrazole could not be observed by ¹H NMR in our case.

By treatment with an excess of LiAlH₄, both the iminium function and the ester group of salt 8 were reduced and the neutral 3,4,5-trisubstituted 1H-pyrazole 9 was obtained. Pyrazoles with this combination of substituents appear not to be known yet.

[3+2] Cycloaddition reactions of ethyl diazoacetate and internal acetylenic iminium salts 2a–d were considerably slower than those with the terminal alkyne 1. Even when up to ~5 molar equivalents of the diazoester were applied, complete conversion of alkynes 2 into the expected pyrazole iminium triflates 10 required 3–7 days at room temperature (Scheme 3). After the extractive removal of excess diazoester, iminium salts 10 were obtained as yellow foams, which unfortunately were highly hygroscopic and readily turned into almost untractable resinous materials on contact with solvents and even traces of air. In all cases, the ¹H NMR spectra indicated the formation of unknown impurities in a molar amount of ~15–20%. These impurities gave rise to ¹H NMR signals mainly at δ=3.4–4.0 ppm, but not close to the signals of the cyclopropyl protons and without clearly detectable additional NMe and OMe signals. Therefore, it appears that only one regioisomer of the pyrazole has been formed, but the presence of minor amounts of the opposite regiosomer cannot be excluded for sure. In order to obtain derivatives that were convenient to handle, the iminium salts 10 were subjected to mild hydrolysis, yielding after chromatographic workup the pyrazolyl ketones 11a–d in overall yields of 49–64%. These ketones could be isolated in almost analytically pure form, whereas some minor by-products could neither by isolated nor identified spectroscopically. Thus, any substantial indication of the presence of another regioisomer is absent, which corroborates the assumption of a high, if not complete, regioselectivity of the cycloaddition reaction. The orientation of the cycloaddition can be deduced from NOESY NMR spectra which clearly point to the neighborhood of the ester group and the cyclopropyl substituent (Fig. 2).

Scheme 3:

Preparation of 3(5)-aroyl-5(3)-carboxylates 11; for Ar see Fig. 1. Conditions for 2→10: excess diazoester, 3–7 days, crude product yields 84–94%; isolated yields for 2→10→11 49–64%.

Fig. 2:

NMR chemical shifts (¹H/¹³C, δ [ppm] of pyrazole 11c; the arrows indicate NOE relationships.

It should be mentioned that the synthesis of 1,3-diaryl- 1H-pyrazole-4-carbaldehydes by soda-alkaline hydrolysis of the corresponding 4-iminium salts is known [34]. In that case, however, the pyrazole 4-iminium salts were prepared from arylhydrazones and aryl methyl ketones.

In the IR spectra of 1H-pyrazoles 11a–d, the N–H valence vibration appears as a broad signal between 3300 and 3250 cm⁻¹; the broadened ¹H NMR signal of NH is found in the range 11.3–12.2 ppm. The carbon atoms C-3 and C-5 of the pyrazole ring give rise to strongly broadened, weak ¹³C NMR signals at δ=135.6–135.8 and 147.0–149.2 ppm, respectively. The assignment shown in Fig. 2 is based on the somewhat greater variance of the aroyl- or thienyl-substituted pyrazole-C signal, which reflects the influence of the specific (het)aryl group.

The prototropic tautomerism of NH-pyrazoles has been adressed and studied both experimentally and theoretically in a number of publications [35], [36], [37]. In many cases, equilibria of the two NH tautomers are found in solution. This appears to be the case also for most or all the NH-pyrazoles reported in this study. In the ¹³C NMR spectra, the temperature-dependent line-broadening observed for the C-3 and C-5 carbon signals and the NH proton signal clearly point to a dynamic equilibrium. NMR spectra of pyrazole 8 may serve as typical examples: At 298 K, the ¹³C signals of the pyrazole’s carbon atoms C-3 and C-5 are very weak and broadened and the NH signal (δ~13.0 ppm) is extremely broad; in contrast, at 223 K the two ¹³C signals are sharp and NH appears at δ=13.62 ppm as an only little broadened signal.

3 Conclusion

This study has shown that acetylenic iminium triflate salts are powerful electron deficient reaction partners in 1,3-dipolar cycloaddition reactions with diazoacetates leading to 1H-pyrazole iminium salts. In particular an iminium salt with a terminal C,C triple bond is a superior dipolarophile, which reacts with methyl diazoacetate almost instantly, quantitatively, and with high, if not complete, regioselectivity. An interesting observation was the subsequent Michael addition of the formed pyrazole from which a pyrazole bis(iminium) salt results. These reactivities resemble quite much those of organoazides as 1,3-dipolar components [21]; in both cases, the HOMO(dipole)–LUMO(dipolarophile) interaction dominates the reactivity and regioselectivity. The crude pyrazole iminium salts, which are highly hygroscopic and moisture-sensitive, are difficult to purify, but addition of nucleophiles at the iminium function allows to convert them into neutral 1H-pyrazoles with functional groups in the 3- and 5-positions.

Finally, it should be mentioned that C-cyclopropyl substituted pyrazoles are occasionally claimed in the patent literature, whereas reports on their synthesis by ring formation are rare. Cyclopropyl-substituted 1,3-dicarbonyl compounds [38], [39], [40] and ethyl cyclopropanecarboxylate [41] have been used as substrates to prepare C-cyclopropyl substituted 1H-pyrazoles. Here we show that cyclopropylacetylene, as a precursor to cyclopropyl-substituted acetylenic iminium salts, can also serve as a building block.

4 Experimental section