Facile synthesis of 2,2′-dinitrosubstituted biaryls through Cu-catalyzed ligand-free decarboxylative homocoupling of ortho-nitrobenzoic acids

Abstract

A novel waste-free Cu-catalyzed decarboxylative homocoupling of ortho-nitrobenzoic acids has been developed, and diverse substituents on the phenyl core of ortho-nitrobenzoic acid are compatible with the transformation. This method provides a practical alternative to synthesize valuable 2,2′-dinitrosubstituted biaryls from cheap and readily available ortho-nitrobenzoic acids.

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It is well known that biaryls not only constitute important structural motifs in many functional materials, natural products and pharmaceuticals,¹ but also are often employed as useful building blocks in organic catalysts and ligands in organic synthesis to construct complex molecules,² therefore, the synthesis of the biaryl scaffold has been a matter of great interest in the organic synthesis community.³ In this regard, considerable studies have been devoted to developing a large number of transformations to create various biaryl compounds, and transition metal-catalyzed coupling procedures have been a preferred choice to synthesize biaryls because they provide straightforward and concise routes. Traditionally, great progress has been achieved through transition metal-catalyzed coupling of haloarenes or arylmetallic reagents, including the well-known Ullmann coupling reaction.^3a,b Nevertheless, the drawbacks including the prefunctionalization of arenes and generation of unwanted byproducts, to some extent, limit the widespread application of the protocols in organic synthesis and industrial production. To address these issues, reactions involving transition metal-promoted oxidative coupling of arene C–H bond activation have emerged as atom- and step-economic alternatives to synthesize biaryls. Thus, transition metal-promoted oxidative coupling of arene C–H bond activation is one of the most widely accepted green transformations to form biaryls.⁴ In spite of the effectiveness of direct functionalization of arene C–H bonds, the challenges associated with these transformations are the difficulty to control the regio- and chemoselectivity of arene C–H bond activation processes, as well as tedious procedures to remove or modify the directing groups in many cases. Consequently, these dilemmas have impeded the widespread preparation of biaryls via the above protocols, and have continued to stimulate the development of facile methods for the synthesis of biaryls with easily available substrates as well as good regio- and chemoselectivities.

Pioneered by Myers who reported a Pd-catalyzed decarboxylative Heck coupling of arene carboxylic acids with olefins,⁵ carboxylic acids and transition metal-catalyzed decarboxylative reactions have been hot research topics in the field of catalysis and organic synthesis in the last decade,^6–10 because of the ready availability and low cost of carboxylic acids as well as the extrusion of nontoxic carbon dioxide as a by-product in the decarboxylative reactions. Therefore, transition metal-catalyzed decarboxylative coupling reactions of aryl carboxylic acids have recently emerged as an attractive and alternative approach to the synthesis of biaryl compounds.¹¹ In this context, it is possible to take advantage of an aromatic carboxylic acid as an arylating partner to couple with aryl (pseudo)halides, arylboron reagents and even unfunctionalized (hetero)arenes to deliver biaryl compounds. Under transition-metal catalysis, the in situ generated aryl–metal intermediate from decarboxylation of an aryl carboxylic acid can serve as either nucleophile or electrophile depending on the nature of the employed transition-metal catalyst, which demonstrates the potential of aromatic carboxylic acids as versatile coupling partners. In spite of the advantages of these decarboxylative coupling methods, and although biaryl compounds can be achieved from the above elegant studies, there is still significant room for improvement in the unwelcome waste and/or reaction selectivity. Most notably, it would be an ideal and much greener route to synthesize biaryls from the decarboxylative coupling reaction between aryl carboxylic acids, since the reaction only takes place at the original aryl position of the carboxylic acid group with high selectivity, and only innocuous carbon dioxide is extruded as by-product from the reaction. In the year of 2011, the group of Larrosa developed the first Pd/Ag-catalyzed decarboxylative homocoupling of substituted aromatic and heteroaromatic carboxylic acids to prepare symmetrical biaryls in good yields.¹² Tan, and Deng et al. further reported a Pd/Ag-mediated decarboxylative homo- and heterocoupling of substituted benzoic acids to deliver symmetrical and unsymmetrical biaryl compounds.¹³ Remarkably, Su disclosed Pd/Ag-promoted decarboxylative cross coupling between various substituted arene carboxylic acids to synthesize asymmetrical biaryls exclusively in synthetically useful yields together with only a trace amount of homocoupling by-products.¹⁴ In view of the high loading and expensiveness of silver salts in their protocols, Djakovitch developed copper as a replacement for silver salt in the above mentioned protocol for decarboxylative heterocoupling of substituted benzoic acids, although it was narrow in substrate scope and low in reaction yield.¹⁵ Therefore, an efficient method for the formation of biaryls via a decarboxylative coupling reaction between aryl carboxylic acids in the absence of a noble metal catalyst is still highly desirable. Inspired by these works, aiming at pursuing our efforts to develop sustainable methods for the synthesis of biaryl compounds¹⁶ and exploit new catalytic methods for environmentally friendly decarboxylative coupling,¹⁷ herein, we describe the first reliable synthesis of valuable 2,2′-dinitrosubstituted biaryls through decarboxylative homocoupling of 2-nitrobenzoic acids with cheap CuI as the sole catalyst under Pd- or Ag-free conditions.

We commenced our investigation by taking the decarboxylative homocoupling of 4-chloro-2-nitrobenzoic acid (1a) as the model reaction for the optimization studies. Table 1 presents some selected results from these optimization studies, and shows the effects of the catalyst, reaction temperature and other reaction parameters on the reaction outcome. Initially, in the presence of 2 equivalents of CuI as a mediator, the decarboxylative homocoupling of 4-chloro-2-nitrobenzoic acid (1a) was carried out in DMSO at 160 °C under nitrogen atmosphere and furnished the desired product 4,4′-dichloro-2,2′-dinitrobiphenyl (2a) in 24% isolated yield (entry 1, Table 1). Remarkably, the influence of reaction temperature showed that lowering the reaction temperature to 140 °C led to a much higher efficiency (82%), however, essentially only a trace of the target product was provided when the reaction was performed at 120 °C (entries 2 and 3). The results indicate that the reaction temperature was an important factor to influence the overall yield. Then, the effect of different loadings of CuI was elaborately evaluated. It was found that the reaction offered a moderate yield (45%) in the presence of a catalytic amount of 0.4 equiv. of CuI. Pleasingly, the yield increased to 75% when 4 Å molecular sieves (MS) were introduced into the reaction system (entries 4 and 5). In this regard, MS presumably functioned as a water scavenger to avoid protonation of the decarboxylative aryl–copper intermediate.^11a,b Under otherwise identical conditions, decreasing the loading of CuI to 0.3 equivalents gave a comparable yield (72%), nevertheless, further reducing CuI loading led to a slightly lower yield (61%) (entries 6 and 7). Subsequently, the influence of the counterion of the Cu catalyst on the reaction was examined, and CuI was proved to be the best choice for this decarboxylative homocoupling transformation (entries 8–10). A brief survey of different solvent systems under otherwise equal conditions showed that the combination of CuI and DMSO was clearly the optimized selection for this catalytic system, because either an inferior yield (11%) was obtained when the reaction carried out in DMF or no product was detected when employing NMP as the solvent (entries 11 and 12). Finally, studies indicated that additional nitrogen ligands did not display any beneficial effect on the reaction (entries 13 and 14). On the basis of these results, we decided to perform decarboxylative homocoupling of 4-chloro-2-nitrobenzoic acid (1a) in the presence of 0.3 equiv. of CuI in DMSO at 140 °C with 4 Å MS as additive under nitrogen atmosphere and use these conditions as our standard conditions.

Table 1 Selected results for decarboxylative homocoupling of 4-chloro-2-nitrobenzoic acid 1a under nitrogen atmosphere^a

Entry	Cu (equiv.)	Additive	Solvent	Isolated yield^b (%)
a Conditions: 1a (0.2 mmol), solvent (2 mL), nitrogen atmosphere, 140 °C, 20 h.b Average of two runs.c Reaction conducted at 160 °C.d Reaction conducted at 120 °C.e 0.15 equiv. of 1,10-phenanthroline was added into the reaction.f 0.15 equiv. of 2,2′-bipyridine was added into the reaction.
1^c	CuI (2)		DMSO	24
2	CuI (2)		DMSO	82
3^d	CuI (2)		DMSO	<5
4	CuI (0.4)		DMSO	45
5	CuI (0.4)	4 Å MS	DMSO	75
6	CuI (0.3)	4 Å MS	DMSO	72
7	CuI (0.2)	4 Å MS	DMSO	61
8	Cu2O (0.15)	4 Å MS	DMSO	32
9	CuBr (0.3)	4 Å MS	DMSO	37
10	CuOAc (0.3)	4 Å MS	DMSO	13
11	CuI (0.3)	4 Å MS	DMF	11
12	CuI (0.3)	4 Å MS	NMP	0
13^e	CuI (0.3)	4 Å MS	DMSO	56
14^f	CuI (0.3)	4 Å MS	DMSO	69

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We next evaluated the substrate scope of this novel Cu-catalyzed decarboxylative homocoupling protocol with respect to aromatic carboxylic acids. As depicted in Table 2, ortho-nitrobenzoic acid 1h was an effective substrate and afforded 53% isolated yield under the standard conditions, and all of the ortho-nitrobenzoic acid substrates bearing an electron-deficient (1a–g) or -rich group (1i, 1k–l) directly provided the corresponding symmetrical biaryl compounds in moderate or satisfactory yields. Generally speaking, this protocol worked for a variety of ortho-nitrobenzoic acids with electron-withdrawing (chloro, fluoro, bromo, trifluoromethyl, and sulfonyl) and electron-donating groups (methoxy and methyl). 4-Chloro-2-nitrobenzoic acid (1a) and its isomer 5-chloro-2-nitrobenzoic acid (1b) smoothly formed the hoped-for products (2a and 2b) with the halogen moiety surviving from this catalytic system. Interestingly, the halogen moiety could be used for late-stage modification via the transformation of the C–Hal bond. Unlike its isomer 4-methyl-2-nitrobenzoic acid 1i, 6-methyl-2-nitrobenzoic acid 1j was an inert substrate toward this process in the presence of CuI catalyst, indicative of the sensitivity of this transformation to steric hindrance. Unfortunately, the attempt to employ a broad range of other benzoic acids in this transformation failed, regardless of the presence of other groups (chloro, methoxy, fluoro, etc.) or the absence of a nitro group at the ortho-position of benzoic acid substrate, this result is consistent with our recent observation on the requirements for the Pd/Cu-catalyzed decarboxylative methylthiolation reaction: namely, a nitro group at the ortho-position of benzoic acid substrate is crucial for the decarboxylative process to stabilize the transition structure of the decarboxylation procedure and enhance the formation rate of the aryl–copper intermediate in the transformation.¹⁷ It is worth noting that the desired nitro-containing biaryl products formed in this protocol can be converted into bioactive amino-substituted biaryls via selective reduction¹⁸ and can be used as building blocks in various fields such as dyes, plastics, perfumes, explosives as well as pharmaceuticals.¹⁹ Thus, these transformations highlight the further potential application of this methodology in the research laboratory and industrial production.

Table 2 Synthesis of symmetrical biaryls via Cu-catalyzed decarboxylative homocoupling of ortho-nitrobenzoic acids^a

a Conditions: 1 (0.2 mmol), CuI (30 mol%), 4 Å MS, DMSO (2 mL), nitrogen atmosphere, 140 °C, 20 h.

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Conclusions

In conclusion, we have developed a novel waste-free protocol for Cu-catalyzed decarboxylative homocoupling of ortho-nitrobenzoic acids under noble metal-free conditions. The method exhibited good functional group tolerance with respect to both electron-donating and -withdrawing groups and furnished the desired nitro-containing biaryl compounds in moderate or satisfactory yields with high selectivity. Thus, the procedure is complementary to the previously established methods for the preparation of symmetrical 2,2′-dinitrosubstituted biaryls. Investigation on Cu-catalyzed decarboxylative heterocoupling of different aromatic carboxylic acids under palladium or silver-free conditions is currently in progress and will be reported in due course.

Acknowledgements

Financial support from the National Key Basic Research Program of MOST of China (2012CBA01204), National Natural Science Foundation of China (NSFC) (21301088 and 21162015), Natural Science Foundation of Jiangxi Province (20142BAB213001) and Science Foundation of State Key Laboratory of Structural Chemistry (20150022) is greatly appreciated.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copy the ¹H, ¹³C and ¹⁹F spectra for all compounds. See DOI: 10.1039/c5ra07771k

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