Arenediazonium-generated aryl radical and nitrile coupling cascade under neat and catalyst-free conditions: green synthesis of anilides

Abstract

In addition to their use as building blocks in organic synthesis, anilides are widely applied in a variety of industries, such as pharmaceutical, materials science, and agrochemical. The previously reported methods generally require transition-metal catalysts, co-catalysts, bases, solvents, and additives. Herein, we report a neat, catalyst-, and additive-free sustainable method for generating aryl radicals from arenediazonium salts and their subsequent reactions with nitriles to afford anilides under mild conditions (80 °C). The reaction features promising green chemistry metrics, including a low E-factor, a low PMI, and high mass productivity. The developed method is operationally simple and can be used for the synthesis of desired anilides in low-to-moderate and excellent yields (32–90%) with a broad substrate scope. In addition, the reaction exhibits excellent chemoselectivity, proceeding with the evolution of a nitrogen molecule to yield C–N coupling products exclusively. Furthermore, in the case of cinnamyl nitriles, the reaction was found to be 100% stereoselective, delivering only E-configured cinnamides. Mechanistic studies revealed the generation of an aryl radical via a self-sustained autoredox-active mechanism. This method of producing aryl radicals from arenediazonium ions under neat and/or catalyst-free conditions has been previously unexplored.

The simple and green! An eco-benign approach to generate aryl radicals from arenediazonium salts and their subsequent in situ reactions with nitriles to access anilides has been developed under neat, catalyst-, and additive-free conditions.

Introduction

Arenediazonium salts represent a main class of precursors for the generation of aryl radicals because of their high reactivity under mild conditions and easy availability from anilines.¹ They have been employed to generate aryl radicals in various elegant transformations² such as Sandmeyer reactions, photoredox difunctionalization of alkenes, Gomberg–Bachmann biaryl formation, and Meerwein arylation of alkenes for accessing valuable products.

Anilides (also known as N-arylamides) are important building blocks in organic synthesis.^3,4 Apart from this, their derivatives are used in various therapies as active pharmaceutical ingredients (Fig. 1a).^5–10 In the field of agrochemicals, amides are used as herbicides¹¹ and antimicrobials.¹² Furthermore, amides have applications in the polymer industry, ranging from the production of nylons and adhesives¹³ to drug delivery.^14,15 Owing to its importance in diverse fields and the neat and robust nature of amide bond formation, amide synthesis¹³ has been selected as a Key Green Chemistry Research Area by the ACS Green Chemistry Institute Pharmaceutical Roundtable (GCIPR).^16,17

Fig. 1. (a) Some bioactive anilides, (b) previous synthetic routes to anilides (A, B, C, D, and E) vs. our contribution, TM is a transition-metal.

Green chemistry has gained wide recognition as an eco-benign approach and discipline for ensuring sustainable development across the chemical sciences over the past decades.¹⁸ The principles of green chemistry include the development of transformations that can be sustained under metal-free, additive-free conditions, as well as minimizing or completely avoiding the use of hazardous solvents, among others. This approach not only helps in the minimization of environmental pollution during the production and the utilization of useful chemical products, but also improves the economic efficiency of the involved transformations.^18c–h In this context, multiple approaches have been employed to synthesize anilides (Fig. 1b).^19–29 Classical preparation of anilides, which have widespread uses,¹⁹ includes the reaction of anilines with acyl chlorides or anhydrides in the presence of bases. Recently, there has been a growing tendency to prepare anilides directly from carboxylic acids instead of using their derivatives.²⁰ Using this concept, Antonella Leggio et al. synthesized amides from carboxylic acids and amines using thionyl chloride as a coupling reagent in the presence of triethylamine and dichloromethane.²¹ A number of transition-metal-catalyzed methods are also available.²² For instance, a preformed Au/DNA catalytic system was used to access anilides.²³ Wang and Xiang synthesized anilides by copper-catalyzed amidation of aryl boronic acids with nitriles.²⁴ Kazemi developed a titanium dioxide-catalyzed synthetic approach to the synthesis of anilides.²⁵ Xile Hu et al. developed a method for the synthesis of anilides from substituted nitrobenzene and aryl iodides, using an Ni(glyme)Cl₂-based catalyst and Co₂(CO)₈ as a source of carbonyl.²⁶ In 2023, Schaub unveiled the manganese-catalyzed synthesis of anilides by aminolysis of unactivated esters.²⁷ Anilides have also been prepared with organocatalyst²⁸ and catalyst-free conditions.²⁹

Nevertheless, all these reactions require resources such as transition-metal catalysts, toxic and/or expensive reagents, setups for inert conditions (glove box, Schlenk line, etc.), photo setups, organic solvents, and the use of additives, among other challenges.³⁰ At the same time, they add to the environmental hazardous wastes and raise sustainability concerns.³¹ In this study, we report a simple, neat, base- and catalyst-free access to anilides via the coupling of arenediazonium tetrafluoroborates with nitriles.³² The current reaction involves the use of inexpensive and readily available arenediazonium tetrafluoroborates as reactants. These salts are versatile substrates used for a variety of organic transformations³³ and material functionalizations.³⁴ A handful of these salts are available from commercial suppliers, while the others are readily prepared from the corresponding anilines via diazotization with aqueous fluoroboric acid and sodium nitrite at 0–5 °C, mostly in water as solvent (Fig. 1b, bottom right).³⁵ They are purified by filtration, washing with cold ether, dried under vacuum, and can be stored in the dark at low temperatures (4 °C or below).^34a,r,36 The purity of these salts can be confirmed by FTIR and NMR spectroscopies.^34a

Results and discussion

Our investigation of the reaction began with the model reaction of benzenediazonium tetrafluoroborate salt (1a) with acetonitrile (2a). After screening of various reaction parameters, it was found that stirring 1a with 6.0 equiv. of 2a at 80 °C for 24 h under air and neat conditions, afforded an excellent yield (82%) of acetanilide, 3a, by silica gel column chromatography (Table 1, entry 1). The use of solvents, temperature changes, and inert conditions showed no improvement in reaction efficiency (entries 2–11). Finally, with optimized conditions (Table 1, entry 1), 3a was isolated in 85% yield via recrystallization, which further improved the purification process and time. Additionally, it made the method less costly and more eco-friendly. The currently developed method has intriguing green chemistry metrics³⁷ (see SI for calculations of these metrics), such as a low environmental factor (E-factor), a low process mass intensity (PMI), a high mass productivity (MP), and an ideal value of solvent intensity (SI = 0) compared with the previous methods (Table 2). The most promising aspect is that these excellent metrics have been achieved with limited resources, making our method sustainable. Moreover, the method is more effective and robust in terms of operational simplicity (for reaction setup, see Scheme 1 on page S5 in the SI), relatively milder conditions, more economy, and eco-friendliness. The desired anilides can be produced without using any reaction solvent, base, transition-metal catalyst, or other reagents.

Table 1. Optimization of reaction conditions^a.

Entry	Variations from optimized conditions	3a (%)
01	None	82, 85b
02	At 90 °C for 20 h	47, 51b
03	At rt for 20 h	44
04	At 50 °C for 20 h	65
05	At 60 °C for 20 h	66
06	Toluene (0.2 M), 4.0 equiv. 2a, at 50 °C	5
07	1,4-diox. (0.2 M), 4.0 equiv. 2a, at 50 °C	44
08	EtOH (0.2 M), 4.0 equiv. 2a, at 50 °C	Traces
09	With 1.0 equiv. H2O	50
10	80 °C for 20 h	77
11	2 equiv. H2O under N2	63

^aIsolated yield after column chromatography.

^bIsolated yield via recrystallization.

Table 2. A comparison of the reaction conditions, yields, and green metrics of previous methods (Fig. 1b) with those of our work, MI is mass intensity.

Reaction conditions/Green metrics	Previous methods					This work
	A	B	C	D	E
TM catalyst	Au	Cu	Ti	Ni	Mn	✗
Solvent	EtOH/H2O	DCE/H2O	EtOH	DMF	MeCy	✗
Additive	✓	✓	✓	✓	✓	✗
atmosphere	Air	Air	Ar	Air	N2	Air
Temp. (oC)	50	Reflux	rt	120	140	80
Light source	✗	✗	LED	✗	✗	✗
% Yield	47–97	42–87	45–100	41–91	26–92	32–90
% AE	98	87	60	65	87	58
E-factor	111.5	59.5	1183	15	24	2.8
PMI	112.5	60.5	1184	16	25	3.8
MI	88.5	60.2	1184	16	25	3.8
% MP	1.1	1.7	0.084	6.3	4	26
SI	44	51	1178	11	11	0

Scheme 1. Substrate scope of arenediazonium salts. Reaction conditions: 1 (0.2 mmol), 2a (1.2 mmol) at 80 °C under air for 24 h. Isolated yields via (a) column chromatography and (b) recrystallization.

With the optimized conditions in hand, it was found that a variety of arenediazonium salts (1) reacted smoothly with acetonitrile (2a) to give the corresponding anilides (3) in moderate to excellent yields (Scheme 1). Arenediazonium salts having functional groups like alkyl (3b, 3k–3l), aryl (3c), trifluoromethyl (3d), acyl (3e), ether (3i and 3j), chloro (3f), bromo (3g), and ester (3h), were found compatible with the reaction conditions. Arenediazonium salts derived from 3-methyl and 3,5-dimethyl anilines were converted to the corresponding anilides (3k and 3l) in 62% and 90% isolated yields. Ortho-substituted arenediazonium salt can also be used as a substrate, and the corresponding anilide 3m was isolated in 63% yield. A benzo-fused arenediazonium salt reacted with 2a to afford the corresponding anilide 3n in 55% yield. In addition, no homocoupling, azo-coupling, or photo-dediazoniation side reactions were observed. Only in two examples involving arenediazonium salts 1e and 1h, formation of the corresponding phenols as by-products was observed.

After this, the varying structures of nitriles (2) were reacted with 1. The corresponding anilides were afforded smoothly under the optimized conditions (Scheme 2). It was revealed that nitriles substituted with both aryl (2c–2g) and aliphatic (2h–2l) moieties were good coupling partners in the reaction, and the corresponding anilides were obtained in moderate to good yields (3o–3z, 3aa, and 3ac). Generally, nitriles with electron-rich moieties on the para-position of the aryl ring perform better than those with electron-withdrawing groups. Thus, anilide 3p was isolated in 81% yield from p-methoxybenzonitrile (2c), whereas anilide 3q was isolated in 47% yield from p-triflouromethylbenzonitrile (2d). Aromatic nitriles with ortho-methyl and iodo-substituents (2e and 2f) worked well despite increased steric hindrance, and the corresponding anilides (3r and 3s) were afforded in 62% and 60% yields, respectively. When both the sterically hindered ortho-methoxybenzenediazonium salt (1p) and ortho-methoxybenzonitrile (2g) were used, the anilide 3u was still afforded in 32% yield. Remarkably, cinnamyl nitrile (2h) reacted with 1a and its substituted analogues to give exclusively E-selective products (3u–3y) in each case out of the two possible geometric isomers. The E-configuration of these cinnamides, 3u–3y, was confirmed by the large coupling constant value (J = 15 Hz or above) in their ¹H NMR spectra. Pentanenitrile, 2i, reacted with 1a to provide the corresponding anilide (3z) in 68% yield. Anilide 3aa was isolated from ethyl cyanoacetate (2j) in 47% yield. However, benzoylacetonitrile (2k) gives only a trace reaction. Interestingly, in the case of malononitrile (2l), only one product was detected on TLC, and the corresponding anilide (3ac) with the second nitrile group remaining intact was afforded in 56% yield. Moreover, all the studied reactions were found to proceed with excellent chemoselectivity, leading to C–N coupling products exclusively. Neither N–N coupling nor any other side reaction was observed in any case.

Scheme 2. Substrate scope of nitriles. Reaction conditions: 1 (0.2 mmol), 2 (1.2 mmol), at 80 °C under air for 24 h. Isolated yields via (a) column chromatography and (b) recrystallization (c) reaction temperature was kept at 90 °C.

After this, a gram-scale synthesis of 4-methoxy-N-phenylbenzamide, 3p, was worked out by reacting phenyldiazonium tetrafluoroborate (3a) and 4-methoxybenzonitrile (2c) on a 10 mmol scale under optimized conditions (Scheme 3). After column chromatography on silica gel, 1.75 g (77%) of 3p was obtained along with 97% recovery of the excess 2c, showcasing the large-scale applicability of our method. Alternatively, in another gram-scale reaction, 3p was isolated in pure form by first distilling and recovering the excess 2c, then passing the residue through a short Celite bed, and finally affording 3p by recrystallization in 81% yield.

Scheme 3. Gram-scale synthesis of 4-methoxy-N-phenylbenzamide, 3p.

In this way, the use of acidic silica (making the stationary phase) and organic solvents used as the eluents in column chromatography was excluded, making the process greener and more economical.

Next, we focused on the possible reaction pathway. A reaction of 1a and 2a was started in the presence of 2.0 equiv. of 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) under optimized conditions (Scheme 4a). No formation of anilide 3a was observed on TLC (see SI for details), giving a clue that the reaction might involve a radical route. A GC-MS analysis of the crude reaction mixture was performed, yielding a peak at 12.014 minutes corresponding to m/z 233, indicating the formation of phenyl-TEMPO adduct (4a) (Scheme 5b). The presence of daughter peaks further confirmed the formation of 4a. Interestingly, when a separation of the reaction mixture was attempted, 4a was isolated in 43% yield. After this, we tried to react 1a with cinnamyl nitrile (2h) under nitrogen and anhydrous conditions; however, no anilide 3u (neither trans nor cis), nor any cyclized product was detected (Scheme 4b). This indicates that intermediate radical D prefers to remain in a stable trans configuration rather than the sterically hindered cis configuration (see proposed mechanism, Scheme 5). An intermolecular competition reaction between electron-rich (1b) and -deficient (1h) arenediazonium salts with 2a showed that 1b reacts 1.6 times faster than 1h (Scheme 4c). In another competition reaction, the electronic density on benzonitriles was varied. It was found that electron-rich nitrile (2c) reacted with 1a 3.8 times more favorably than electron-deficient nitrile (2d) (Scheme 4d), which indicated a developing positive charge in the transition state upon addition of nitrile in the rate-determining step. The subsequent stabilization of the positive charge by electron-rich substituents results in an increased rate of reaction. Based on the yields obtained with electronically varied benzonitriles (Scheme 2, products 3o–3q), a Hammett correlation was plotted (Scheme 4e).

Scheme 4. Mechanistic studies.

Scheme 5. (a) Proposed mechanism (b) GC-MS analysis of the reaction of 1a with 2a in the presence of 2.0 equiv. TEMPO.

Keeping in view the above observations and the literature reports,³⁸ we propose an autoredox-active radical mechanism for the current anilide formation, depicted in Scheme 5. The aryl radical A is initially produced from arenediazonium tetrafluoroborate (1) by anion-induced homolytic dediazoniation¹via accepting an electron from tetrafluoroboarate anion to liberate a N₂ molecule. Alternatively, the electron donation of nitrile to arenediazonium ion can produce a nitrilium diazo intermediate,³⁹ which undergoes homolysis to give Avia the release of a stable nitrogen molecule and oxidized form of nitrile (Scheme 5, on top right). A in turn reacts with nitrile (2) to produce radical B, which transfers an electron to tetrafluoroborate radical or alternatively to oxidized nitrile to give nitrilium ion C. Reaction of C with water produces enol E, which tautomerizes to anilide 3. In the case of cinnamyl nitrile, the radical intermediate B prefers to remain in the sterically stable trans-form and subsequently converts to nitrilium ion C–Evia single-electron transfer. The trans-configured nitrilium ion C–E reacts with water to give exclusively E-selective cinnamyl anilides (3u–3y). Interestingly, unlike the typical Meerwein arylation of alkenes,^2,40 which produces an aryl radical mediated by one-electron metal donor or catalyzed by a photocatalyst, the current method of generating radicals does not require any electron donor or a photocatalyst. Our proposed mechanism also differs from those of Sandmeyer, Gomberg–Bachmann, and Pschorr reactions, which often need copper or other transition-metals as one-electron transfer agents to generate aryl radicals.²

Conclusions

In summary, a neat, catalyst- and additive-free synthesis of anilides with promising green chemistry metrics has been developed from arenediazonium salts⁴¹ and nitriles. This greener approach eliminates toxic, expensive, air- and moisture-sensitive catalysts and/or solvents, requires no specialized equipment or inert atmosphere, and hence can be carried out with limited resources. The simplicity, gram scalability, and green nature of this protocol make it more attractive for synthesizing desired anilides for applications in organic synthesis, pharmaceutical science, and materials studies. Further mechanistic studies of the current radical-producing method, expansion to other coupling partners beyond nitriles, and the development of intramolecular versions are highly expected.

Author contributions

S. A. designed the reaction. Q. U. and R. U., with the help of guidelines from S. A., optimized the reaction conditions. Q. U., R. U., W. U. K., and T. B. synthesized the substrates. The examples generation was done by Q. U., R. U., W. U. K., and M. A. A. Further, Q. U., M. I., A. J., and S. A. A. S. performed structural elucidation and wrote the original draft of the manuscript. A. B. M. and R. H. did mechanistic studies and helped in explaining the results. A. J., S. A. A. S., and S. A. supervised the project, assisted in the writing, reviewing, and editing of the manuscript. All authors have read and agreed to the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting the findings of the article are available within the main article and the supporting information (SI). Supplementary information: the NMR details and general procedures. See DOI: https://doi.org/10.1039/d6ra03684h.