Montmorillonite impregnated with bismuth nitrate: a versatile reagent for the synthesis of nitro compounds of biological significance

Montmorillonite impregnated with bismuth nitrate has been found to be an excellent reagent for the synthesis of several nitro compounds of biological significance in high yield.


Introduction
Surface-mediated organic reactions are undergoing extensive investigation especially because they are ecologically friendly. 1The usefulness of clay mediated organic synthesis has been documented in a large number of recent publications. 2For example, montmorillonite which is commercially available has shown considerable promise as a solid support in carrying out different chemical reactions. 2Based on our own work on bismuth 3 salts, we became interested in exploring trivalent bismuth nitrate as the nitrating agent under solid support.These experiments culminated in a facile synthetic method of aromatic nitration of several aromatic hydrocarbons by bismuth nitrate supported on montmorillonite which takes taking only a few minutes. 4In continuation of bismuth nitrate mediated aromatic nitration, we report here the synthesis and characterization of several biologically active aromatic nitro compounds not only with polyaromatic hydrocarbons, but also with steroids and β-lactams.

Polyaromatic Nitro Compounds
Polyaromatic nitro compounds are widespread in the environment.We have been engaged in the development of aromatic compounds as anti-tumor agents and have shown structure-activity relationships with several diamides and diamines to which a polycyclic aromatic ring was bound. 5The nitro compounds required for the synthesis of these types of derivatives were prepared by the conventional nitric acid-sulfuric acid or nitroniun tetrafluoborate methods.We became concerned about the disposal of the large amount of acid-waste that resulted.To avoid this complication and the associated hazards, we set out to test the nitrating abilities of nitratesalts under solid phase conditions in a projected route to develop a simple synthesis of the aromatic nitro compound in a relatively short period of time.
Montmorillonite clay impregnated with anhydrous cupric nitrate termed as "claycop" was used for aromatic nitration reaction. 6A large excess of acetic anhydride was required when claycop was used as the nitrating agent.The actual nitrating species was believed to be acetyl nitrate.Similarly, a clay with ferric nitrate termed as "clayfen" was used as the reagent for the nitration of estrone, though yields were poor. 7In addition, extreme precautions were necessary for the preparation of this reagent. 8Sulfuric acid supported on silica gel that catalyzed nonselective nitration of simple aromatic compounds has also been reported. 9ixing the starting materials with bismuth nitrate and montmorillonite with tetrahydrofuran and evaporation of the solvent under rotavapor comprise the reaction conditions for successful, regiospecific nitration with several aromatic compounds including multicyclic ring systems.The nitration of aromatic compounds by our method is shown in Scheme 1.A comparison with other solid supports, such as silica gel, acidic alumina, and ground molecular sieves was also carried out.Anisole 1, naphthalene 2, fluorene 3, chrysene 4, and dibenzofluorene 5 were regiospecifically converted to the corresponding nitro compounds 6 through 10 by bismuth nitrate-montmorillonite in excellent yield.Interestingly, the site of the electrophilic attack by this reagent was found to be identical to the conventional nitric acid or acetyl nitrate mediated nitration reaction (Scheme 1).
The reaction of naphthalene 2 using silica gel as support under identical conditions as described with montmorillonite failed to produce the nitro derivative although the same mixture upon microwave irradiation 10 afforded the 1−nitronaphthalene 7 in 70% yield.Acidic alumina and molecular sieves alone failed to give any product with or without acid.The results indicated that montmorillonite is the solid support of choice for aromatic nitration.Steroids: At the beginning of the nitration study on steroid, a model reaction was investigated.Phenol 11 produced a mixture of 2− and 4−nitrophenol 12 and 13 in a ratio of 1:3.The formation of the mixture of nitro derivatives 12 and 13 with phenolic substrates indicated lesser selectivity under this condition (Scheme 2).
In order to confirm the reactivity of phenolic substrates, we carried out nitration of estrone 14 with bismuth nitrate−montmorillonite with the goal of synthesizing the biologically active 2− or 4−nitro estrones 15 and 16.In conformity with our results with phenolic substrates, the reaction produced a mixture of 2−nitro and 4−nitro estrones 15 and 16 in a ratio of 1:1 in 94% yield.The nitration of estrone by freshly prepared clayfen using bentonite K−10 demonstrated the production of 2−nitroestrone 15 in 55% yield by stirring the reaction mixture in toluene for overnight. 7However, when we followed this procedure, we isolated a mixture of 2−nitro 15 and 2,4−dinitro estrones in 90% yield (12 h).β−Lactams: The bismuth nitrate mediated nitration was then extended for a facile synthesis of nitro substituted β−lactams.Suitably substituted hydroxy β−lactams on a coupling reaction with commercially available baccatin can produce Taxol and Taxotere. 11Structure-activity study of Taxol and Taxotere with a nitro group at the C−13 side chain has not been investigated.Synthesis of nitro−substituted β−lactams by acid chloride-imine cyclization reaction (Staudinger reaction) 12 provides β−lactam in low yield. 13Considering the potentiality of nitro substituted β−lactam and the mild conditions associated with our present investigation, we undertook nitration study by bismuth nitrate.By following an identical procedure as described above, the cis-acetoxy β−lactam 17 produced a mixture of two nitro β−lactams 18 and 19 within minutes in low yield (60%) and no side reaction, i.e., cleavage of the ring, oxidation of the aromatic system or the deprotection of the ester group was observed (Scheme 3).However, a considerable amount of starting material remained intact.A brief exposure of microwave irradiation to the solid mass helped to increase the yields of the products (94%).The structure of the products 18 and 19 were deduced from the nmr spectra.Only the aromatic group that has the methoxy group was attacked. 14Reaction with trans-β−lactam 20 also afforded two compounds 21 and 22 (1:2) in excellent yield (Scheme 4).Our results indicate that the nitration reaction depends strongly on the nature of the solid support.Further, two solid adsorbents of identical structure with different surface area (particle size) can give different product distribution.Based on a recent publication, 15 we believe that the binding of bismuth nitrate to the free hydroxyl group of the multi-metallic montmorillonite is important and that this complex produces the nitronium ion.Clearly, the failure of bismuth nitrate to produce any product with alumina and only 70% with silica gel (under microwave irradiation), despite the presence of surface hydroxyl groups, strengthens the importance of the composition of the solid support.

Scheme 5
In summary, we have shown a simple, rapid and convenient method for the aromatic nitration with bismuth nitrate in the presence of montmorillonite at room temperature.The superiority of this method over others includes a very rapid reaction (approximate 30 minutes instead of 24 hour) with readily available reagents.Further, our method requires no strong acid, 16 no acetic anhydride and it can be applied to a wide range of substrates and results in high overall yield.

Experimental Section
General Procedures.All reactions described in this paper were carried out under a wellventilated hood.IR spectra were recorded on a Perkin-Elmer Spectrum 2000 instrument.NMR spectra were recorded on Bruker 300 MHz spectrometer.Chemical shifts were reported as δvalues in parts per million downfield from t e t r a m e t h yl silane as the internal standard in CDCl 3 .Elemental analysis was performed by Schwarzkopf Microanalytical Laboratory, Inc., New York.Melting points were taken in open capillary tube and are not corrected.Column chromatography was carried out with Aldrich silica gel (230 mesh).TLC was run with precoated silica gel plate.
The compound to be nitrated (1 mmol) and Montmorillonite KSF (500 mg, Aldrich) were added to a suspension of bismuth nitrate (1 mmol) in THF (10 mL).The solvent was then evaporated under reduced pressure and dried in the vacuum pump for 5 min (in some cases the mixture needed microwave irradiation for 2 min to complete the reaction).The mixture was then repeatedly washed with dichloromethane (ca 25 mL) and it was concentrated to afford the crude product.The pure product was isolated after column chromatography and by crystallization.
Compounds 6 to9, 12 and 13 are known (Aldrich Chemical Company) and these gave identical physico-chemical data with respect to authentic compounds.
The procedure for the nitration of β-lactams is different than the method described above.Analytical data of 10, 15 and 16 are reported in earlier publications.5b,7