Reexamination of the Bromination of 2-Nitrobenzaldehyde with NBS or NaBr-NaIO4 in Sulfuric Acid

Abstract Two literature procedures for selective bromination of 2-nitrobenzaldehyde using N-bromosuccinimide (NBS) or NaBr-NaIO4 in sulfuric acid were examined. In contrast to the reports that 4-bromo-2-nitrobenzaldehyde is formed as a single product in good yield, reactions using NBS gave a number of isomeric mono- and dibrominated products identified by spectroscopical methods and by sodium borohydride reduction to the corresponding benzyl alcohol, and reactions using NaBr-NaIO4 did not furnish any product. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.] GRAPHICAL ABSTRACT


INTRODUCTION
A mild and attractive method for the bromination of deactivated aromatic compounds [1] using N-bromosuccinimide (NBS) in sulfuric acid was reported by Rajesh et al. in 2007. [2] Nine different substrates were examined and 60-92% yields of single products were reported. For eight of the starting materials, the directing effect of the functional groups present on the aromatic ring for aromatic electrophilic bromination coincided in the same position. Thus, the regioselectivity of the incoming electrophile was not an issue. The last substrate examined by the authors, 2-nitrobenzaldehyde (1), does not have this luxury, but nevertheless 4-bromo-2nitrobenzaldehyde (2) was reported as the only product in more than 60% yield (Scheme 1). In addition to the reaction of 1 with NBS in sulfuric acid, a related regioselective bromination using sodium bromide-sodium periodate in sulfuric acid-water to afford 2 in 88% isolated yield was reported by Kumar et al. in 2012 (Scheme 1). [3] These two procedures were of interest to us because gram scale amounts of 2 were needed as a starting material for a total synthesis currently pursued in our laboratories.
The experimental procedures, as described in the literature, were repeated a number of times. However, in our hands, we were unable to duplicate the reported results in any of these experiments. Reaction with NBS gave a complex mixture of brominated products and attempted reaction using NaBr-NaIO 4 resulted only in quantitative recovery of starting material. Herein is reported the outcome of the experiments using NBS and a characterization of products from the complex reaction mixtures obtained. It should be noted that each of the products obtained are potentially useful building blocks in organic chemistry, although they are obtained in relatively poor yields.

RESULTS AND DISCUSSION
In an attempt to decipher the composition of the complex reaction mixtures obtained, 2-nitrobenzaldehyde (1) was reacted with NBS in sulfuric acid at the originally reported reaction temperature (25 C) and at 60 C. In addition, experiments employing different amounts of NBS were performed, and the results are summarized in Table 1. Complex mixtures containing the four possible monobrominated compounds (2)(3)(4)(5) and three dibrominated products (6-8) were observed in the crude reaction mixtures of all reactions performed (Scheme 2). The number in parenthesis represents isolated yields of products after chromatography. Yields in parentheses and italics were calculated from 1 H NMR spectra of mixtures. Starting material (1) was detected in all reactions except for the reaction using 5 equivalents of NBS. Chromatographic purification on silica gel was only partially successful in separating the isomers. Pure 3 was isolated using <5 equivalents of NBS, pure 7 could be isolated at any NBS amount, and pure 6 and 8 were isolated at 5 equivalents of NBS. Compounds 2, 4, and 5 were always isolated as inseparable mixtures containing two or three components. The identities of compounds 2-5 and 8 were verified by comparison with literature NMR, infrared (IR), and melting-point data. Compound 6 has not been previously reported and for the dibrominated product 7, only a melting point was found in the literature. 1 H NMR, 13 C NMR, and IR spectra and HRMS (for 6) were obtained, all in agreement with the structure of 6 and 7.
To further corroborate the identity of each isomeric compound, all pure compounds and some of the mixtures were reduced using sodium borohydride to give the corresponding benzylalcohols, and the results are summarized in Scheme 2. Reduction of 3 gave the known benzylalcohol 9 in 81% isolated yield. The aromatic 1 H NMR splitting pattern, consisting of two doublets and a triplet, and a nuclear Overhauser effect (nOe) between the methylene and one of the aromatic doublets confirmed the structure of 9 and thus of isomer 3. This transformation also verified the structure of 5, the other monobrominated product with the same aromatic doublet-doublet-triplet 1 H NMR splitting pattern. We were unable to separate 1, 5, and 8; however reducing the mixture with sodium borohydride gave pure 12, the reduction product of 5.
Compounds 2 and 4 could not be separated but upon treatment with sodium borohydride gave a separable mixture of the known benzyl alcohols 10 and 11. The benzyl alcohols also provided the opportunity to corroborate the structure of 2 and 4 by nOe experiments.
As expected, no nOe was observed between the methylene protons of 15 derived from 8 and either of the two aromatic protons. Compound 7 was the only isomer exhibiting two singlets in the 1 H NMR spectrum. Reductions to give 13 and 14 corroborated the structures of 6 and 7, because the expected nOes were observed between the benzylic CH 2 and one of the aromatic protons.
Monobrominated products dominated at lower amounts of NBS and, not surprisingly, dibrominated products were the major products using a large excess of Scheme 2. NBS bromination followed by NaBH 4 reduction of 2-nitrobenzaldehyde. NBS. A much lower total yield of bromination products was obtained at 60 C using 2.5 equivalents of NBS (compared to entries 2 and 3). Because only a small amount of dibrominated products were formed using 0.75 equivalents of NBS, the ratio of 2-4 is a rough measure of the reactivity of the different positions in 1 toward electrophilic aromatic bromination. The reactivity was normalized to compound 3, the minor monobrominated product, and was calculated to be 6.1:1:3.7:6.7 (in order of 2 to 5). This order of reactivity probably reflects the electron-withdrawing ability of the nitro group, compared to the aldehyde, wherein the former more effectively deactivates the 3 and 5 positions that would lead to formation of 3 and 4. The data for the reactions using 0.75 and 5.0 equivalents of NBS also suggest that compounds 3, 4, and 5 were brominated a second time at a much faster rate compared to 2, because a significant amount of the latter remains even at 5.0 equivalents of NBS. A rough order of reactivity for the second bromination can be calculated by comparing the ratios of monobrominated products at 0.75 and 5.0 equivalents of NBS. The reactivity order was 5 > 3 > 4 > 2.
In summary, we were unable to duplicate the reported selective bromination of 2-nitrobenzaldehyde (1) using NBS in sulfuric acid to give 4-bromo-2-nitrobenzaldehyde (2). Four monobrominated and three dibrominated products were isolated and identified and reduced to the corresponding benzyl alcohol. It should be noted that the methodology works very well for deactivated aromatic substrates wherein the directing effects of substituents do not conflict. Bromination of 2-nitrobenzaldehyde (1) using NaBr-NaIO 4 in sulfuric acid resulted only in the recovery of starting material.

EXPERIMENTAL
All NMR spectra were recorded in CDCl 3 at 600 MHz ( 1 H NMR) and 150 MHz ( 13 C NMR). The chemical shifts are expressed in d values relative to Me 4 Si (0.0 ppm, 1 H and 13 C) or CDCl 3 (77.0 ppm, 13 C) internal standards. The yields and weights of compounds in the mixtures were calculated from 1 H NMR spectra.
N-Bromosuccinimide was recrystallized from water. All other reagents and solvents were obtained from commercial sources and used as received. Solvents were removed from reaction mixtures and products on a rotary evaporator at water aspirator pressure.