Consecutive Three-Component Synthesis of 3-(Hetero)Aryl-1H-pyrazoles with Propynal Diethylacetal as a Three-Carbon Building Block

A novel consecutive three-component synthesis of 3-(hetero)aryl-1H-pyrazoles via room temperature Sonogashira arylation of propynal diethylacetal used as a propargyl aldehyde synthetic equivalent has been disclosed. The final acetal cleavage-cyclocondensation with hydrazine hydrochloride at 80 °C rapidly furnishes the title compounds in a one-pot fashion.

In the past years, we have developed and elaborated the concept of MCR syntheses of multiple classes of heterocycles via Sonogashira coupling of alkynes and (hetero)aroyl chlorides with alkynyl ketones, followed by Michael addition-cyclocondensation, eventually in a one-pot fashion [42][43][44][45]. Alkynyl ketones and aldehydes are ideal three-carbon building blocks as synthetic equivalents of  -dicarbonyl compounds. However, their electrophilicity is enhanced and the inherent regioselectivity is imposed in the Michael-type nucleophilic additions. Within this conceptual framework we have devised regioselective three-component [46] and four-component syntheses [47] of highly luminescent tri-and tetrasubstituted pyrazoles. Here, we communicate a straightforward consecutive threecomponent synthesis of 3-(hetero)aryl-1H-pyrazoles, i.e., monosubstituted pyrazole derivatives, via the concatenation of a Sonogashira alkynylation of (hetero)aryl iodides with the commercially available propynal diethylacetal, an in situ acetal cleavage, and a final cyclocondensation with hydrazine hydrochloride.

Scheme 1.
Retrosynthetic conception of three-component pyrazole syntheses by virtue of alkynyl carbonyl condensation.
Both disconnection approaches proceed via a retro alkynyl carbonyl condensation, thus leading to hydrazine and either to an alkynyl ketone [46][47][48] or a propargyl aldehyde [49][50][51][52][53][54]. While the former disconnection establishes the three-carbon skeleton by virtue of Sonogashira acylation [46,55,56], the latter analysis takes advantage of the ligation of the aryl substituent to a propargyl aldehyde synthon via Sonogashira arylation. Since the direct alkynylation of propargyl aldehyde has not been reported, presumably due to its pronounced electrophilicity, propynal diethylacetal apparently represents a suitable synthetic equivalent [57][58][59]. Although the most recent report on the coupling of aryl halides with propynal diethylacetal taking advantage of a tetradentate phosphane ligand based upon the cyclopentane scaffold affords high yields and requires low catalyst loadings, the requisite high reaction temperatures are less favorable for thermally sensitive functionalities [57].
Therefore, we first set out to optimize the reaction conditions for the Sonogashira coupling step. The transformation of p-iodoanisole (1a) and propynal diethylacetal (2) into 1-(p-anisyl)-3,3diethoxyprop-1-yne (3a) under standard Sonogashira conditions at room temperature was chosen as a model reaction (Scheme 2). The amount of triethylamine, the solvent, and the reaction time were modified (Table 1).
The optimal temperature of the sequential acetal cleavage-cyclocondensation is 80 °C ( Table 2, entries 1-4), as preliminary experiments showed that lower temperatures yield poorer results and higher temperatures lead to no further improvement. Conductive heating ( Table 2, entries 2-4) turns out to be superior to dielectric heating in the microwave oven ( Table 2, entry 1).

Scheme 3.
Optimization of the acetal cleavage-cyclocondensation of 1-(p-anisyl)-3,3diethoxyprop-1-yne (3a) to furnish 3-(p-anisyl)-1H-pyrazole (4a). While the complete conversion is already achieved within 15 min (Table 2, entries 2 and 3), the amount of hydrazine hydrochloride is crucial for the success of the sequence ( Table 2, entries 2 and 4). Strongly Brønsted acidic conditions ( Table 2, entry 5) are not required and the combination of water and hydrazine hydrochloride is sufficient to trigger the acetal cleavage and the Michael addition followed by cyclocondensation. Thereafter, the combination of Sonogashira coupling and sequential acetal cleavage-cyclocondensation was performed with the established model system (Scheme 4, Table 3).
With these optimized conditions for the whole sequence in hand, the stage was set for testing the range of applicable (hetero)aryl iodides 1 in this novel consecutive three-component synthesis of 3-(hetero)aryl-1H-pyrazoles 4. After coupling of (hetero)aryl iodides 1 with propynal diethylacetal (2) at room temperature for two hours the subsequent addition of PTSA·H 2 O, hydrazine hydrochloride, and water, heating to 80 °C for 15 min gave rise to the isolation of 3-(hetero)aryl-1H-pyrazoles 4 in moderate to good yields (Scheme 5). This first study on the methodological scope of this novel three-component pyrazole synthesis shows that electron-rich as well as electron-poor aryl substituents can be readily introduced. Also, chloro and fluoro substituents and even unprotected phenol derivatives, which are incompatible with the coupling of acid chlorides, are well tolerated. Although a thienyl substituent can be carried through the sequence, all attempts to react other heteroaryl iodides such as 3-and 4-pyridyl iodides under the standard conditions met with failure.

General
All cross coupling reactions were carried out in oven dried Schlenk or microwave tubes using septa and syringes under a nitrogen or argon atmosphere. Dry tetrahydrofuran and 1,4-dioxane were supplied by a MBraun system MB-SPS-800 solvent purification system. Chemicals were either commercially obtained from ABCR GmbH & Co KG, Acros Organics, Alfa Aesar GmbH & Co KG, Fluka, Merck KGaA, Riedel-de Haën, Sigma-Aldrich Co., and used as supplied or were already available in the research group.
All products were purified via column chromatography on silica gel 60 M (0.04-0.063 mm) from Macherey-Nagel using the flash technique under a pressure of 2 bar. The crude mixtures were absorbed on Celite ® 545 (0.02-0.10 mm) from Merck KGaA, Darmstadt before chromatographic purification. The reaction progress was observed qualitatively using TLC Silica gel 60 F 254 aluminium sheets. The spots were detected with UV light at 254 nm and with aqueous potassium permanganate solution.

Conclusions
In summary, we have disclosed a novel consecutive three-component synthesis of 3-(hetero)aryl-1H-pyrazoles 4 in moderate to good yields starting with the Sonogashira coupling of (hetero)aryl iodides 1 and the commercially available propynal diethylacetal (2) as a propargyl aldehyde synthetic equivalent, followed by a rapid sequential acetal cleavage-cyclocondensation with hydrazine hydrochloride. Further studies directed to the synthesis of luminescent pyrazole derivatives as ligands for metal organic frameworks (MOFs) are currently underway.