Facile, high-yield, regioselective synthesis of ortho -nitro derivatives of hydroxy heterocycles using cerium (IV) ammonium nitrate

A series of hydroxy heterocycles with two different unsubstituted ortho sites undergo exclusive regioselective nitration with the CAN/NaHCO 3 reagent at the less hindered ortho site. Neither dinitro nor oxidized products were observed. The hydroxy heterocycles studied include: some derivatives of 7-hydroxycoumarins, sesamol, 2,3-dihydrobenzo[ b ]furan-3-one, 6-hydroxy-1,3-benzoxathiol, 5-hydroxybenzothiazol, 5-hydroxyindole, 7-benzofuranol, and (5-isoxazolyl)phenols. A mechanism is proposed in which an initial oxidation of the phenol to a radical cation by CAN occurs. Another molecule of CAN subsequently reacts with the phenolic radical cation to give an radical adduct from which an NO 2 radical is transferred to the less hindered carbon via a tight ion-radical pair yielding the Wheland complex that furnishes the nitrophenol after proton loss.


Introduction
We 1 recently reported that certain phenols possessing at least one unsubstituted ortho position underwent 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 ring activating methoxy and methyl groups to the moderately ring-deactivating Cl, Br, CHO and CO 2 Me groups.In contrast, phenols which contained a strongly deactivating group such as nitro, cyano or 2,6-disubstituted phenols were not nitrated by the CAN/NaHCO 3 reagent.We have extended this reaction to include several hydroxy heterocycles (1a-k) and report the results herein.

Results and Discussion
We first studied the hydroxy compounds (1a-h) which, in principle, can give two different ortho nitration products, namely compounds (2a-h), in which substitution of H by NO 2 occurs at the less hindered carbon and compounds, and (3a-h) in which substitution of H by NO 2 occurs at the more hindered carbon.

98-72% not detected
As shown in eq. 1, nitration occurred, in all cases, regioselectively at the less hindered position to give 2a-h in yields ranging from 98-72%.The regiochemistry was confirmed by 1 H NMR spectroscopy (the two para hydrogens appear as two slightly broadened singlets) and, in the case of 2a, by X-ray crystallographic analysis.An ORTEP drawing of 2a is shown below.

ORTEP Compound (2a)
A few of the nitro compounds listed in Table 1 had been prepared previously using other nitrating reagents.However, these were obtained in lower yields and as mixtures of mono-nitro and/or dinitro-compounds.For example, as shown in Table 1, 6-hydroxycoumarin (1a) was nitrated regioselectively using CAN/NaHCO 3 to give 6-hydroxy-7-nitrocoumarin (2a) in 84% yield; no other positional isomers or dinitrated products were detected.On the other hand, the use of CAN in acetic acid gave both 2a and 8-nitro-6-nitrocoumarin in 68% and 18% yields, respectively. 2The nitration of 1a using chromium nitrate gave nearly equal amounts of the aforementioned isomers. 3Recently, Wu et al. 4 found that nitration of 1a with NO/O 2 gave 2a in only 63% yield as well as 7-hydroxy-3-nitro-and 7-hydroxy-8-nitrocourmarin in 20% and 5%, respectively.
Interestingly the 6-nitro-3-cyanocoumarin derivative (2f) in which the cyano group is not on the phenolic ring was obtained by CAN/NaHCO 3 nitration of the corresponding 3cyanocoumarin derivative (1f).We showed previously that phenols possessing a cyano group such as 3-cyanophenol did not undergo nitration with this reagent. 1he generality of the regioselective CAN/NaHCO 3 nitration at the less hindered ortho site of hydroxy heterocycles with two different ortho sites prompted us to reinvestigate our previous finding that nitration of 3-bromophenol occurred at the more hindered site to give 3-bromo-2nitrophenol. 1 The result of our reinvestigation showed that assignment to be incorrect; CAN/NaHCO 3 nitration does indeed occur at the less hindered site affording 3-bromo-4nitrophenol.
The results from this study are consistent with an elegantly conceived oxidative mechanism of nitration proposed by Ganguly et al. 5 for the CAN regioselective ortho nitration of coumarins.Accordingly, an electron-rich phenol react with Ce(NO 2 ) 6 -2 to give a phenolic radical cation species 3 by one-electron transfer.In this process Ce(NO 2 ) 6 -2 is reduced to Ce(NO 2 ) -3 (the ammonium ion have been omitted for simplicity).A second molecule of Ce(NO 2 ) 6 -2 then forms a complex with 3 from which a NO 2 radical is transferred via a tight ion radical pair 5 yielding the Wheland complex (6) that furnishes the nitrophenol after proton loss.It is not clear what the exact nature of complex, but there probably is some type of interaction between the Ce and O atoms to account for the observed ortho regioselectivity.This mechanism is shown in Scheme 1.We next studied the CAN/NaHCO 3 nitration of the hydroxy heterocycles 1i-l.Our nterest in compounds 1i, j and l was to confirm that a single ortho nitrated product is obtained and to see if the oxazole and pyrazol rings in these compounds could tolerate the CAN reagent.Compound 1k was investigated to see if ortho nitration would prevail over para nitration.The data in Table 1 shows that these compounds gave the expected ortho nitrated product and that the two aforementioned rings did indeed tolerate the CAN/NaHCO 3 reagent.

ISSN 1424-6376
Page 93 © ARKAT USA, Inc In conclusion, we have shown that the CAN/NaHCO 3 reagent provides a facile way to introduce a single nitro group regioselectively to the ortho position of a wide range of hydroxy heterocycles.To our knowledge no other nitrating reagent can match this.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.Hydroxy heterocycles (1a-l), CAN, and acetonitrile were purchased from commercial sources.The nitration reactions were monitored by GC/MS.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 spectra were recorded on a FT NMR instrument at 400 MHz and 13 C NMR spectra were recorded at 100 MHz.