Sodium dithionite-mediated reductive N-acetylation/formylation of nitroarenes employing DMAc/DMF as acetyl/formyl surrogates

Abstract

The present invention discloses a unified strategy for N-acetylation/formylation directly from nitroarenes employing solvents DMAc/DMF as the source of acetyl/formyl groups, with sodium dithionite serving as the sole reagent. Unlike the conventional N-acetylation/formylation of anilines, the method uses precursor nitroarenes to form acetanilides/formanilides via in situ reduction to anilines. The regioselectivity, application to drug molecules, tandem process, and dual role of the reagent are the key features of the method.

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Acetylation¹ and formylation² are indispensable organic synthetic tools, largely achieved using classical methods^3,4 to introduce acetyl and formyl groups, respectively.⁵ In addition to their biological implications, these groups serve as platforms for further derivatization and pharmacophore modification, and as protecting groups (Scheme 1).⁶ In stark contrast, reductive N-acetylation/formylation is a non-traditional emerging strategy wherein nitroarenes can be used instead of anilines, avoiding an additional reduction step to form the final corresponding products, acetanilides/formanilides.^7,8 Available reductive acetylation methods, though elegant, often rely on corrosive acetylating agents—such as acetic acid,⁹ acetic anhydride,¹⁰ acetyl chloride,¹¹ or acetic acid ester¹²—combined with either stoichiometric metal reductants (Pt, Pd, or Ti), or catalytic systems (Ni, Ru or Fe) in the presence of a reductant¹³ under acidic or basic conditions, generally requiring harsh conditions. The recently developed methods catalyzed by Fe¹⁴ or Ni,¹⁵ or mediated by B₂(OH)₄ ¹⁶ using an organic compound as the acetyl source, such as N-acetylbenzotriazoles, despite being non-corrosive, are poorly atom- and step-economical. Despite significant advancements in contemporary reductive acetylation, a metal-reductant- or catalyst-free method featuring a green approach remains elusive. Reported reductive formylation uses HCOOH^17a,b as a formyl surrogate and a stoichiometric amount of a transition metal, e.g., Sn or Fe, as the reductant, or CO₂ ^17c as a formyl surrogate coupled with stoichiometric Zn and Pd as the reductant. Several admirable catalytic (including palladium, cobalt, rhodium, and gold) reductive formylation¹⁸ and other distinguished techniques¹⁹ were developed employing various formyl sources, e.g., methanol, oxalic acid, ammonium formate, formic acid, and triethyl orthoformate. Remarkably, Wu et al. developed a transition-metal-free rongalite-mediated reductive N-formylation wherein rongalite serves as both a formyl surrogate and a reductant.²⁰ However, the chemistry is limited to N-formylation only.

Scheme 1 Biologically active compounds, transition-metal-catalyzed and transition-metal-free N-acetylation/formylation.

To the best of our knowledge, a unified strategy for both reductive N-acetylation and N-formylation is yet to be explored. While sodium dithionite (Na₂S₂O₄), an inexpensive ($30 per kg) single-electron reductant,²¹ is largely used in coloring industries, its versatile use in reduction and reductive functionalization has not been fully examined. Our group has been involved in exploring sodium dithionite-mediated intramolecular reductive cyclization/amidation for the synthesis of various heterocycles, including pyrrole-fused N-heterocycles,²² 2-indolinones,²³ dihydro-benzothiadiazine-1,1-dioxides,²⁴ and tetrahydropyrrolo/pyrido [1,2-a] quinoxalinones.²⁵

Now, we report our first success in the intermolecular reductive functionalization of nitroarenes mediated by sodium dithionite. Herein, we describe a general method for reductive N-acetylation/formylation of nitroarenes employing DMAc/DMF as the acetyl/formyl surrogates and synthesis of benzimidazoles from 2-nitroanilines. The method features a solvent as the functional motif, application of regioselective reductive N-acetylation/formylation to the synthesis of drug molecules, and scalability. Unlike the conventional N-acetylation/formylation of anilines, nitroarenes, precursors to anilines, are used as substrates. According to the mechanistic understanding, in situ reduction of nitroarenes mediated by sulfoxylate radical anion occurred to form anilines, which, upon subsequent N-acetylation/formylation by solvents without any external reagent, could form the acetanilides/formanilides.

Utilizing nitrobenzene (1a) as a model substrate, we primarily concentrated on employing Na₂S₂O₄ as the exclusive reagent for our preliminary study on reductive N-acetylation/formylation. Upon heating 1a and Na₂S₂O₄ (2 equiv.) in the presence of NaOH (2 equiv.) as an additive in DMAc/DMF at 80 °C for 24 h, the reductive N-acetylated/formylated product 2a/3a formed in 26/25% yield (Table 1, entry 1). Following this preliminary observation, we increased the amount of sodium dithionite to 3 equiv., which improved the yield to 36/35% (entry 2). In later attempts, we varied the base and discovered that NaHCO₃ (2 equiv.) worked better than other bases, improving the yield to 43/42% (entries 3–4). The yield further increased to 54/56% in the absence of any base, indicating that the base hinders the reaction (entry 5). A mixture of solvents [DMAc/DMF : H₂O = 3 : 1] improved the yield to 64/62% (entry 6). The yield improved further to 72/71% on increasing the solvent ratio from 3 : 1 to 5 : 1 (entry 7). A positive impact was observed when the temperature was raised up to 100 °C (entries 8–9). However, further increasing the amount of Na₂S₂O₄ did not improve the yield (entry 10). Therefore, the optimized condition of reductive N-acetylation/formylation entails conversion of 1a to products 2a/3a in the presence of Na₂S₂O₄ (3 equiv.) in a mixture of solvents [DMAc : H₂O, DMF : H₂O = 5 : 1, entry 9]. Using a metal-free green reductant and the solvent's ability to serve as an acetyl/formyl surrogate without the need for an external acetylating or formylating agent are the main advantages of this method.

Table 1 Optimization of the reaction conditions^a

Entry	Reductant (equiv.)	Additive (equiv.)	Solvent	Temp (°C)	Yield^b (%) (2a/3a)
a Reaction conditions: 1a (0.5 mmol), Na2S2O4 (x mmol), solvent (2 mL), at specified temperature for up to 24 h. b Isolated yields.
1	2	NaOH (2)	DMAc/DMF	80	26/25
2	3	NaOH (2)	DMAc/DMF	80	36/35
3	3	Na2CO3 (2)	DMAc/DMF	80	39/36
4	3	NaHCO3 (2)	DMAc/DMF	80	43/42
5	3	—	DMAc/DMF	80	54/56
6	3	—	DMAc/DMF : H2O (3 : 1)	80	64/62
7	3	—	DMAc/DMF : H2O (5 : 1)	80	72/71
8	3	—	DMAc/DMF : H2O (5 : 1)	90	77/78
9	3	—	DMAc/DMF : H2O (5 : 1)	100	87/85
10	4	—	DMAc/DMF : H2O (5 : 1)	100	87/84

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Next, we examined the substrate scope of nitroarenes that could participate in this reductive N-acetylation/formylation reaction. Under the optimized reaction conditions (Table 1, entry 9), the reductive N-acetylation of various substituted nitroarenes was investigated, which led to the synthesis of substituted acetanilides (2a–j) in good to excellent yields (Scheme 2). The reaction was investigated with nitroarenes bearing various electron-donating or electron-withdrawing groups at different positions.

Scheme 2 Substrate scope of reductive N-acetylation. Reaction conditions: 1a–j (0.5 mmol), Na₂S₂O₄ (1.5 mmol), DMAc : H₂O (5 : 1; 2 mL), 100 °C, 6–8 h.

A –CH₃ group in the para position on the nitrobenzene yielded the corresponding product 2b in 86% yield. Likewise, 4-nitrophenol under the optimized conditions yielded 2c, a generic drug paracetamol, via reductive N-acetylation with 92% yield. Exclusive regioselective acetylation at the amino group as opposed to the –OH group is especially noteworthy. The presence of halogens, –OEt, and disubstitution on the aryl ring produces the acetanilides with a yield between 71 and 82% (2d–2h). The reaction of (hetero)nitroarenes such as 5-nitrobenzo[d][1,3]dioxole, 2-methyl-6-nitrobenzo[d]thiazole also work well affording the desired products 2i–j in varying yields (81–84%).

After successful evaluation of reductive N-acetylation, we further investigated the scope of nitroarenes (1b–o) with various substitutions on the aryl ring and (hetero)nitroarenes (1p–s) in reductive N-formylation under the optimized reaction conditions (Scheme 3). The presence of a –CH₃ group at the para position of substrate 1b gave the corresponding product 3b in 84% yield. The halogens (–Br, –Cl, –I and –F) at the 4-position resulted in the production of 3c–f in 63–73% yields. 4-Nitrophenol reacted efficiently under the optimized conditions, resulting in the corresponding N-(4-hydroxyphenyl)formamide 3g in 91% yield. As observed earlier, the –OEt group is well tolerated in reductive N-formylation. A slight reduction in yield was observed with ortho substitution, while meta and para substitutions on the aryl ring gave yields similar to those of the others. Our optimized reaction conditions work well when disubstitution is present on the aryl ring (3k–o). The heterocycles benzo[d]thiazole, quinolone, N-methylindole and benzo[d][1,3]dioxole also give the desired N-formylated products in 67–82% yield.

Scheme 3 Substrate scope of reductive N-formylation. Reaction conditions: 1a–s (0.5 mmol), Na₂S₂O₄ (1.5 mmol), DMF : H₂O (5 : 1, 2 mL), 100 °C, 6–8 h.

The scope of reductive N-formylation was also demonstrated in the synthesis of heterocycles (Scheme 4). Thus, when 2-nitroaniline was exposed to the optimized conditions, benzimidazole 5a was isolated as the final product. A brief screening of mono- and di-substituted 2-nitroanilines yielded the tandem products, benzimidazoles 5b–g, in varying yields (70–75%). Further investigation is required to establish whether (a) reductive formylation occurs followed by annulation, or (b) formylation, reduction and annulations occur sequentially in the order mentioned.

Scheme 4 Substrate scope of 2-nitroanilines for the synthesis of benzimidazoles. Reaction conditions: 4a–g (0.5 mmol), Na₂S₂O₄ (1.5 mmol), DMF : H₂O (5 : 1), (2 mL), 100 °C, 12–16 h.

After successful evaluation of substrate scopes, gram-scale syntheses of a marketed drug, paracetamol 2c, and other compounds 3a and 3g were demonstrated (Scheme 5). Nevertheless, the yield in gram-scale synthesis of paracetamol is similar to that of small-scale without having any processing technical difficulties. In this way, the current strategy offers a better outcome as compared to the procedure followed in the pharmaceutical industry.

Scheme 5 Large-scale demonstration.

A series of control experiments was then carried out to understand the plausible reaction mechanism (Scheme 6). In order to ascertain whether the reaction proceeds through a radical pathway, the standard reaction was conducted in the presence of TEMPO (4 equiv.) or BHT (4 equiv.). The formation of desired product 2a was not detected in any case, revealing that the radical pathway is indeed involved in the reaction (expt. a). A second control experiment was performed using aniline (1ad) as the substrate rather than nitrobenzene (1a). To our expectation, 85% yield of 2a was obtained, which suggests the formation of aniline as an intermediate in the reaction (expt. b). Indeed, isolation of 2-methylbenzo[d]thiazol-6-amine (6) clearly supports that the reaction proceeds through aniline. To further understand how the acetylated product forms after aniline formation, several control experiments were performed under the optimized conditions using aniline (1ad) as the substrate with varying amounts of TEMPO. All these experiments produced acetanilides, ruling out a radical pathway (expt. c). A control experiment was performed to check whether acid is generated during the reaction, which could facilitate the acetylation of aniline with DMAc. While nitrobenzene under the optimized conditions at pH (ca. 7, maintained by adding NaOH) did not give 2a in 1.5 h, 2a was obtained only in poor yield at pH 5.3 after 10 h, revealing the second role of the reagent in making the medium acidic. Drawing upon prior research^22–25 and these control experiments, a plausible reaction mechanism is suggested. Following homolytic cleavage, Na₂S₂O₄ produces a sulfoxylate anion radical, which transfers electrons to 1a and produces the nitroso intermediate 1ab. Additional electron transfer to 1ab followed by protonation produces hydroxylamine 1ac. The repetition of a similar sequence yields the amine 1ad. Later, a condensation intermediate 1ae is formed from 1ad, which, upon elimination of N,N-dimethylamine leads to the formation of the final N-acetylated product.

Scheme 6 Plausible mechanism.

Conclusions

Unlike the well-known transition-metal-catalyzed reductive N-acetylation/formylation reactions, a transition-metal-free unified strategy for direct N-acetylation/formylation using DMAc/DMF as acetyl/formyl surrogates employing Na₂S₂O₄ as the sole reagent is developed for the first time. The method features certain advantages, including nitroarene as the starting substrate, regioselective acylations that are otherwise difficult to achieve, the use of solvent as the source of a functional group, and an a debatable mechanism. According to the mechanistic understanding, in situ reduction of nitroarenes mediated by sulfoxylate radical anion, followed by N-acetylation/formylation by the acidic medium of the reaction, could form the acetanilides/formanilides. Further research is ongoing to develop reductive acylation/formylation of nitroalkanes.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Characterization data (mp, ¹H NMR, ¹³C NMR, HRMS, IR, etc.) for all new compounds and characterization data (¹H NMR and ¹³C NMR) for known compounds. See DOI: https://doi.org/10.1039/d5qo01199j.

Acknowledgements

The authors strongly acknowledge the generous financial support from the Center of Excellence (CoE), NIPER S.A.S. Nagar.

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