Direct nitration of five membered heterocycles

Direct nitration of a variety of furans, pyrroles, thiophenes, pyrazoles, imidazoles, isoxazoles and thiazoles (17 compounds) with nitric acid/trifluoroacetic anhydride affords mononitro derivatives in average yield of 60 %.


Introduction
Nitro derivatives of five-membered heterocycles are of considerable interest: some are biologically active 1 with anti-inflammatory or vasodilator activity 2 others are useful synthetic intermediates for many biologically active compounds; for instance, nitroimidazoles form the basis of nitro-heterocycles analogous to megazol, an antiparasitic agent 3 .
Nitration of five membered ring heterocycles like furans 4 , pyrroles 5 , thiophenes 6 , pyrazoles 7 , imidazoles 8 , isoxazoles 9 and thiazoles 10 has usually been carried out using either a mixture of concentrated (or fuming) nitric acid and concentrated sulfuric acid, or in some cases with concentrated nitric acid and acetic anhydride (followed by pyridine in case of furans only).The nitration of some of these heterocycles, for example pyrazoles and imidazoles 11 , isoxazoles 12,13 and isothiazoles 12 has been studied kinetically.Previous efforts to find milder nitration conditions for direct nitration have included use of cerium (IV) ammonium nitrate 14 , montmorillonite impregnated with bismuth nitrate 15 and nitrations with dinitrogen pentoxide 16,17 .
In light of our success in the direct nitration of pyridines and pyridine analogs with concentrated nitric acid in trifluoroacetic anhydride, which we believe involves N 2 O 5 18 led us to apply this method to nitration of five-membered heterocycles and we discuss our results here.
While the present work was in progress, Shackelford and coworkers reported 19 the use of tetramethylammonium nitrate in triflic anhydride and included results of nitration of aromatics like furans, thiophenes and isoxazoles.Our work complements and significantly extends that of Shackelford group.

Furans
Typically furans have been nitrated using acetyl nitrate to give addition products, which are subsequently converted on treatment with pyridine into 2-nitrofurans 20,21,22,23 .We have now achieved the direct nitration of furan itself and a series of its derivatives with nitric acid in trifluoroacetic anhydride (method A as described in the experimental section) (Scheme 1) (Table 1).Compounds 2a-d were characterized spectroscopically (see Experimental).Method A is described in the Experimental section; a using method A but replacing TFAA by Ac 2 O; b overall yield is the final yield after multistep conversion to nitrofurans starting with furan; c cross reference of the compound without reported yield; d overall yield is 34% following the reaction sequence 2-furfuraldehyde -[80%]-2-furfuryl alcohol -[76%]-2-iodomethyl-5nitrofuran -[56%]-2-methyl-5-nitrofuran; e general method of synthesis of nitrofurans from furans in two steps using acetyl nitrate via an addition product which is subsequently converted by pyridine into 2-nitrofurans; f indirect method starting from 2-iodomethyl-5-nitrofuran using thiophenolate anion as the reagent.
Inspection of Table 1 clearly shows the advantage of our new method.In most published nitration procedures for furan, nitroacetate intermediates had to be isolated.Our one step nitration procedure produces much higher yields without isolation of any intermediate.

Pyrroles
Again acetyl nitrate has been used for the nitration of pyrrole 33 , to give mainly the 2-nitro derivatives (55%).Our nitration method B, gave novel compounds 4a-b from 3a-b respectively (Scheme 2), structures were confirmed spectroscopically (see Experimental).

Thiophenes
Thiophenes are easy to nitrate compared to other five membered heterocycles.They react with mild nitrating agents such as copper nitrate 34 , usually in the 2-position.Thiophene (5), on nitration with our reagent gave a 78% yield of 2-nitroderivative (6) by method B (Scheme 3) (Table 2).Shackelford reported the nitration of methyl 2-thiophenecarboxylate to give a mixture of 2-and 4-nitro derivatives (1.6:1) in 91% yield 19 .Method: B as described in the Experimental section; a yield from thiophene; b yield from thiophene 2-boronic acid; c yield from 3-bromothiophene.
We found that the nitration of 3-bromo-thiophene ( 7) gave a complicated mixture with the main product (8) (58%).The other component were found to be 9, 10a-b, and 11.The structure of 10a was not unambigiously diffretiated from the structure 10b (Scheme 4).

Pyrazoles
Acetyl nitrate has been employed to nitrate pyrazoles at one of the nitrogen atoms and subsequent rearrangement at 140 ºC has been observed to give 3-or 5-nitropyrazoles, sometimes as a mixture. 40Pyrazole (12) on treatment with our nitrating system following method B gave a 41% yield of the 3,4-dinitrated derivative (13) while N-methylpyrazole under the same reaction condition gave a 65% yield of the 3-nitro product (13).This orientation was confirmed by nOe experiments (Scheme 5) (Table 3).

Imidazoles
Imidazoles unsubstituted at nitrogen are easily nitrated by mixed acid nitration 46,47 .The direct nitration of N-substituted imidazoles is more difficult and most nitro-N-methylimidazoles have been prepared by the N-methylation of the corresponding nitroimidazoles.

Thiazoles
Nitration of thiazoles had not previously been studied extensively. 602,5-Dimethylthiazole (22), gave 2,5-dimethyl-4-nitrothiazole (23) in 67% yield (Scheme 10), which was characterized spectroscopically (see Experimental).We did not study the nitration of thiazole because it was insoluble in our nitration system.Experimental Section General Procedures.Melting points are uncorrected. 1H NMR (300 MHz) and 13 C NMR (75 MHz) spectra were recorded in CDCl 3 (with TMS for 1 H and chloroform-d for 13 C as the internal reference) unless specified otherwise.

General method of preparation of nitro derivatives of five membered heterocycles Method A.
A mixture of trifluoroacetic anhydride (10 mL) and fuming nitric acid (2.4 mL) was chilled at -15ºC and after 1 h a solution of (10 mmol) in trifluoroacetic anhydride (2 mL) was slowly added to the reaction mixture keeping the temperature at -15ºC.The reaction mixture was stirred at -15ºC for 2 h and then the solvents were removed and pyridine (2 mL) was added to the reaction mixture, stirred for 15 min.And then the solvent was again removed and the oily residue was poured in ice and extracted with diethyl ether.The crude product was then purified over a silica gel column to give pure nitro derivatives.Method B. Trifluoroacetic anhydride [10 mL] was chilled in an ice bath and the substrate heterocycle [17 mmol] was slowly added.After 1 h, concentrated nitric acid [3.0 mL] was added dropwise with cooling.After stirring for 12 h at room temperature, the excess trifluoroacetic acid and nitric acid were removed under vacuum to get the nitro derivatives, which were purified by column chromatography.