Direct Preparation of N-Substituted Pyrazoles from Primary Aliphatic or Aromatic Amines

Despite a large number of synthesis procedures for pyrazoles known today, those directly employing primary amines as substrates are rare. Herein, we report an original method for the preparation of N-alkyl and N-aryl pyrazoles from primary aliphatic or aromatic amines as a limiting reagent of the reaction. The protocol utilizes no inorganic reagents and requires a short reaction time, mild conditions, and the use of structurally simple and commercially available starting reagents. During this study, pyrazoles containing a wide variety of N-substituents were obtained using the same procedure for both aliphatic and aromatic amines.


■ INTRODUCTION
Pyrazoles can be obtained by numerous synthetic methods, 1−5 but their versatile applicability as pharmaceuticals, 6,7 crop protection chemicals, 8,9 building blocks for organic and inorganic chemistry 10,11 still propels research to develop new synthetic methodologies. Over the past decade, a new specific application has appeared for N-substituted pyrazoles, i.e., as a metal-coordinating directing group for transition-metal-catalyzed reactions. 12−18 A large number of such chemical transformations significantly increase interest in pyrazolefunctionalized molecules. Preparation of N-substituted pyrazoles from primary amines as a limiting reagent and source of N-substituent gives a wide variety of potential products that might be further functionalized. 15 In contrast to N-alkyl indazoles for which synthetic methodology starting from primary aliphatic amines is wellknown and broadly used, 19−21 N-alkyl pyrazoles are usually synthesized from difficult to handle hydrazines or hydrazine derivatives. 2−4,22−24 With a great variety of synthetic methods for N-alkyl pyrazoles, there are just two reports describing primary aliphatic amine as a limiting reagent that introduces an N-linked substituent into a product's structure (Scheme 1). 25,26 The known methods are limited because of multistep functionalizations of diketone (A) or amination reagent preparation (B). The drawback of the methodologically elegant reaction B is, moreover, a complicated and timeconsuming procedure (Scheme 1).
Electrophilic amination of primary aliphatic amines is a wellknown strategy for the preparation of hydrazines. 27−29 However, in all cases, a large excess of the amine is required due to hydrazine's enhanced nucleophilicity relative to the corresponding origin amine. 30 This problem might be solved by utilizing N-protected electrophilic amination reagents that form hydrazines that are stable under reaction conditions, but this requires a further deprotection step. 25,31,32 Transformation with commercially available amination reagents that form unprotected hydrazine has practical advantages. Here we report a fast and straightforward method for the preparation of pyrazoles from primary aliphatic and aromatic amines as limiting reagents using bench-stable, commercially available amination reagent.

■ RESULTS AND DISCUSSION
Initially, we tested reagents R1, R2, and R4, and we found that only R1 gives the desired product under initial conditions. Solvent, temperature, time, and proportion of reagents optimization with R1 allowed obtaining the desired N-alkyl pyrazole 1a with 44% isolated yield (Table 1, for the full table,   see Table S1). Adding all three reagents simultaneously at 0°C followed by their heating is critical to obtain the desired product with a reproducible yield. Minor changes in the reaction temperature or equivalents of reagents R1 and 1 slightly reduce the yield (Table 1, entries 3−7). The addition of a stoichiometric amount of water, acetic acid, or weak basic salts has a minor effect on yield, showing that the reaction is not promoted by this species, and it is not sensitive to them ( Table 1, entries 8−12). The presence of diisopropylethylamine (DIPEA) decreases the yield of 1a, which is probably an effect of an R1 consumption for a side formation of 1,1diisopropyl-1-ethylhydrazonium salt (entry 12). Alternative amination reagents R2−R6 were tried under optimized conditions (Table 1, entries 13−17). The product was obtained in 23%, 41%, and 53% yields for R2, R3, and R6, respectively, and was not observed ( 1 H NMR and GC−MS) for reactions conducted with R4 and R5.
A series of primary aliphatic and aromatic amines were reacted under optimal conditions yielding corresponding pyrazoles (Scheme 2). Reactions were typically carried out on a 1 mmol scale. It was found that aliphatic amines with quaternary carbon or sterically hindered tertiary carbon adjacent to the amine group gave around 40% yields (1a, 1b, 1d, 1h, and 1i), whereas amines with neighboring secondary or less hindered tertiary carbon gave yields close to 30% (1c, 1e, 1g, 1j, and 1k). Aromatic amines reacted under the same condition and gave pyrazoles 1l−p generally with higher yields (47−70%) than aliphatic amines. Compounds with electrondonating and withdrawing substituent at phenyl ring (1m and 1n) and substituent in ortho position to an amine group (1p) were successfully obtained. Besides ester, methoxy, and haloarene functionalities, the reaction tolerates unprotected N−H of indole and aliphatic O−H group. However, the target product was not observed in the presence of unprotected phenol (1q), probably due to competitive O-amination. Syntheses of 1a and 1g were conducted on a 3.0 and 5.0 mmol scale, respectively, to underline the method's synthetic applicability. The structure of 1o was confirmed by X-ray single-crystal analysis (Scheme 4).
Reactivity of a series of diketones was tested in reaction with tert-octylamine, and it was found that it strongly depends on the electronic and steric properties of diketone's substituents (Scheme 3). 3,5-Dialkyl and 3,4,5-trialkyl pyrazoles (2b, 3b, and 6b) were obtained in 37−43% yields, whereas 4b in only 24% even with 5.0 equiv of b. Reaction conducted with diketone containing aryl substituent 5 under standard  conditions gave a 20% yield. However, the use of 5.0 equiv of 5 instead of standard 1.1 allowed for 5b with a 46% yield. Sterically hindered 7 and electron-deficient 8 did not react under the standard conditions and when they were used in 5.0 equiv excess (7b and 8b). Interestingly, for reactions with diketones 5 and 6, only one isomer of pyrazoles 5b or 6b was obtained. The other was observed in the crude reaction mixture by GC−MS in a very small amount, but they were not isolated in both cases. The structure of the obtained isomer 5b was confirmed by X-ray single-crystal analysis (Scheme 4). Additional experiments conducted for 9 and 10 showed that both compounds are not intermediates in the reaction (Scheme 4). This and selectivity of formed products from unsymmetrical diketones (Scheme 3, 5b and 6b) that indicate a nucleophilic attack of prior formed hydrazine on less hindered carbonyl gave reason to believe that the reaction starts from a nucleophilic attack of amine on II (Scheme 5). Delivered during this step, hydrazine III is trapped by diketone V before the next competitive attack on II. It is also consistent with the fact that the addition of diketone 1 with a few minutes delay caused a significantly lower yield (17%, Table 1, entry 2). Relatively strong p-nitrobenzoic acid that forms in the first step from R1 catalyzes the formation of hydrazone followed by heterocyclization to give pyrazole in Knorr condensation reaction. The observed moderate yield of the reaction explains the formation of side products VI, VII, and IX (Scheme 5). GC−MS of a crude mixture of 1a indicated corresponding imine VI, and the product of hydrazine decomposition VII was observed by the same method running reaction without diketone (see Supporting Information). The product of amination of pyrazole IX was not detected in reaction mixtures. However, deprotonated pyrazole efficiently reacts with R1, 33 and the addition of the next portion of amination reagent II decreases the yield of VIII, pointing to the formation of IX (see Table S1, entries 5 and 9).
In contrast to the multistep method of pyrazole synthesis from amines, which in showed examples gave comparable overall yields (Scheme 1, B), 25 the presented method is characterized by a short time and a simple procedure that delivers products with less effort. In this context, the availability of R1 amination reagent from commercial sources offers an extra advantage over the requiring five-step synthesis of oxaziridine (15% overall yield). Alternatively, a known twostep large-scale synthesis allows to obtain R1 from basic reagents (81% overall yield). 33

■ CONCLUSIONS
In conclusion, we have developed a new method for the preparation of N-alkyl and N-aryl substituted pyrazoles directly from primary aliphatic or aromatic amines and diketones, applying readily accessible from commercial sources electrophilic amination reagent R1. Despite the modest yields in some cases, the use of an amine as the limiting reagent, the absence of metals, short reaction times, and a simple procedure makes this method practical for functionalizing amines, giving pyrazoles containing a wide variety of N-substituents.
■ EXPERIMENTAL SECTION General Information. All reactions were carried out and purified using standard, commercially available glassware. Chemicals for reactions, workup, and chromatography were reagent grade or ACS grade and were used as received. Silica gel 60 Å 0.04−0.06 mm