Facile, high-yield, regioselective synthesis of ortho-nitrophenols using cerium (IV) ammonium nitrate

Certain phenols possessing at least one unsubstituted ortho position have been found to undergo rapid, regioselective ortho nitration with CAN (cerium (IV) ammonium nitrate) in the presence of NaHCO 3 at room temperature to yield o -nitrophenols in high yields. Substituents tolerating these nitration conditions ranged from the activating methoxy and methyl groups to the moderately deactivating Cl, Br, CHO and CO 2 Me groups. In contrast, phenols that contained a strongly deactivating group such as nitro or cyano or 2,6-disubstituted phenols were not nitrated by the CAN/NaHCO 3 reagent. More complex nitrophenols such as 6-hydroxy-5-nitro-1,3-benzoxanthiol-2-one, 7-hydroxy-6-nitro-3,4,8-trimethylcoumarin, 6-hydroxy-5-flavanone, 1-(4-hydroxy-3-nitrophenyl)-1 H -tetrazole-5-thiol, 2-(2-hydroxy-3-nitrophenyl)benzoxazole were also prepared in good yields by the CAN/NaHCO 3 reagent.


Introduction
Nitrations of phenols using the classical method of nitric acid in sulphuric acid generally gives complex mixtures containing oand p-nitrophenols, dinitrated phenols, plus inextractible tars of phenolic oxidation products. 1Consequently, alternative nitration methods have been sought to accomplish clean and regioselective mononitration of phenols.Some of these include the use of: (1) a two-phase system (ether-phenol/water-NaNO 3 -NaNO 2 -H + ), 2 (2) an ionic complex of N 2 O 4 with 18-crown-6, 3 (3) nitrosation-oxidation with metallic HSO 4  -and NaNO 3 4 and (4) nitrocyclohexadienone as the nitrating agent, 5 etc.While these methods give clean mononitration of phenols, both o and p-nitrophenols are obtained.o-Nitrophenols are valuable precursors to a variety of biologically important heterocycles such as 2,3-dihydro-2H-1,4-benzoxoin-3(4H)ones, 6 and benzoxazoles. 7Thus, a convenient method for the regioselective introduction of an ortho nitro group onto phenols is desirable.A survey of the literature shows the lack of 100% ortho nitration, however, there are a few reports of almost regioselective ortho nitration of phenols.Two of these involved passing NO 2 -N 2 O 4 gas into a solution of phenol and pyridinium carboxylic acid 8 or vigorously stirring a suspension of phenol with "claycop" (an acidic montmorillonite clay impregnated with anhydrous cupric nitrate). 9These methods gave mixtures of oand p-nitrophenols with high o/p ratios of 95:5 and 86:6, respectively.

Results and Discussion
Recently, 7-hydroxycoumarins have been nitrated with CAN and H 2 O 2 as co-oxidants in water to give a 9:1 mixture of 7-hydroxy-6-nitro-and 7-hydroxy-6,8-dinitrocoumarins. 10 However, nitration of simple phenols with the CAN/H 2 O 2 reagent was found to produce mixtures of nitrophenols as well as hydroxylation and coupling products. 11 , 12When CAN is coated on silica (CAN/SiO 2 ), a milder nitrating reagent is obtained which has been used in the nitration of, polynuclear, 13 heterocyclic 14 and electron-rich aromatic compounds . 15In the latter case, mixtures of oand p-isomers were obtained.
In an unrelated study, CAN in the presence of NaHCO 3 and acetonitrile was found to mediate the oxidative coupling between thiophenols and aromatic nitriles affording benzothiazoles. 16It occurred to us, that the replacement of H 2 O 2 with NaHCO 3 might result in a more selective CAN nitrating reagent with diminished oxidative capability.Thus, we have treated a variety of phenols, having at least one unsubstituted ortho position with CAN/NaHCO 3 and , as shown in   (2a-o), exclusively.In all cases, 1 H NMR and 13 C NMR and GC/MS analysis confirmed the structure and purity of the isolated products.
Table 1 also lists the results for the nitration of 3-substituted phenols, i.e. 3-methoxy-(1e), 3bromo-(1f), 3-methyl-(1g) and 3-chlorophenol (1h) and (1e-h), as well as ethyl 3hydroxybenzoate (1n) and 3-hydroxybenzaldehyde (1o).With the exception of 1e, the 3substituted derivatives were nitrated regioselectively at the unhindered site (C-6, in the case of the 3-substituted phenols and C-4, in the case of the 3-hydroxy derivatives) to give the 5substituted 2-nitrophenols (2f-h), 3-hydroxy-4-nitro benzoate (2n) and 3-hydroxy-4-nitrobenzaldehyde (2o).The yields ranged from 87% to 93%.With the exception of methyl, the aforementioned substituents are -I groups (electron-withdrawing by induction) and thus would be expected to discourage electrophilic addition at the hindered site.Steric factor for these substituents as well as weakly activating methyl should also impede addition at the hindered site.In the exceptional case, 3-methoxyphenol (1e) underwent CAN nitration exclusively at the hindered C-2 site giving 3-methoxy-2-nitrophenol (2e) in 90% yield.This anomalous result indicates that the strong mesomeric effect of methoxy activates the hindered carbon site.Not only are the previous yields of substituted nitrophenols lower that those reported here, but most preparations involve at least two steps.For example, the highest yield of 2e previously reported was 70% using a two-step process of nitrosation of 1e followed by nitric acid oxidation. 19mportantly, 3-hydroxybenzaldehyde (1o) and 3-methoxyphenol (1e) were not oxidized using the CAN/NaHCO 3 reagent.
We subsequently found that anisole, 2,6-dimethoxy phenol, aniline and p-anisidine did not react with CAN/NaHCO 3 , indicating that a hydroxyl group and an unsubstituted carbon ortho to the phenol are required for nitration.Several dihydroxyarenes, aromatic amines, and aminophenols were also not nitrated by CAN/NaHCO 3 reagent, whereas the dihydroxyarenes and aminophenols upon addition of CAN were rapidly oxidized giving mixture of products.Furthermore, phenols possessing strongly deactivating groups (in the electrophilic aromatic sense), i.e. 4-cyanophenol and 2-chloro-4-nitrophenol, resisted nitration even when stirred overnight.Interestingly, 3-pyridol (1v) did undergo nitration with stirring for 6 h in refluxing acetonitrile to give 2-nitro-3-pyridol (2v) in 76% yield.The high ortho regioselectivity observed in the CAN nitration suggest that a Fries type rearrangement may be involved in the nitration.A possible mechanism is shown in Scheme 1.As shown the hydroxy group of the phenol reacts with CAN to give complex 3 from which a nitro group is transferred from the CAN moiety to the 2-position of the phenol.The resulting intermediate 4 then undergoes aromatization of the ring and the elimination of [(ONO 2 ) 5 CeOH] - 2 .In conclusion, a high-yield, regioselective ortho nitration of a wide range of phenols using the inexpensive and easy to use CAN reagent has been demonstrated.It should become an important tool in organic synthesis.

Experimental Section
General Procedures.Melting points were in open capillaries and are uncorrected.All reactions were carried out under an atmosphere of dry nitrogen.Phenols (1a-v), CAN, and acetonitrile were purchased from commercial sources.Reactions were monitored by GC/MS.Concentrations were performed by rotary evaporator using water aspirator system.Low-pressure chromatography was carried out by applying air pressure to Pyrex columns packed with silica gel 60 (0.040-0.063 mm particle size, 230-400 mesh).Routine 1 H NMR were recorded on a FT NMR at 400 MHz and 13 C NMR spectra were recorded at 100 MHz.
Experimental procedure.CAN (3.84 g, 7.0 mmol) was added to a stirred mixture containing 3.5 mmol of appropriate phenol (1a-x), NaHCO 3 (1.0 g) and 40 mL of anhydrous MeCN at rt.The resulting mixture was stirred for 30 min during which time the yellow color of CAN was discharged.The mixture was filtered, washed with water, and extracted with CHCl 3 (3 X 20 mL).The combined CHCl 3 extracts were dried (Na 2 SO 4 ), and the solvent evaporated in vacuo to give the corresponding 2-nitrophenol (2).Prior to purification of 2, an aliquote was subjected to

Table 1 .
, obtained o-nitrophenols in all cases.Best yields of the o-nitrophenols were attained by carrying out the reactions in MeCN at room temperature for 30 min.The absence of p-nitrophenols as well as hydroxylation and coupling products was ascertained by GC/MS analysis of the crude reaction mixtures.Yields a of nitrophenols (2a-v from the CAN/NaHCO 3 nitration of phenols (1a-v)

Table 1 .
Continued a isolated yields.b 20% yield of benzoquinone.c stirring for 6 h.