Novel Effect of Thiourea/Urea Additives on the Nucleophilic Aromatic Substitution of 2,4‐Dimethoxynitrobenzene

(Thio)ureas could suppress the reduction of the aromatic notro compound to aniline in the presence of alkoxide. The nucleophilic aromatic substitution (SNAr) reaction is a convenient method to synthesize polysubstituted aromatics without the use of any transition metal catalyst.1-3 The conditions for the regioselective SNAr reaction in 2,4-dihaloaromatics have been reported.4-10 Recently, we reported that the SNAr reaction of 2,4-dimethoxynitrobenzene (1) with a bulky nucleophile, sodium tert-butoxide afforded the desired product 2 (2-t-butoxy-4-methoxy nitrobenzene) in an excellent yield with exclusive ortho-selectivity under the optimized condition and the formation of the detectable byproduct 3 (2,4-dimethoxy-N-(5-methoxy-2-nitrophenyl) aniline) was elucidated using X-ray crystallography.11 In our previous report, under the optimized condition without any additives, the formation of product 2 was limited, and an increase in the reaction time resulted in the decomposition of 2 and increased formation of the byproduct 3 (Table 1, entry 1). The use of 10% dimethoxyethane (DME) increased the formation of the desired product 2 and reduced that of 3 (Table 1, entry 2), compared to the condition without DME (Table 1, entry 1). DME may impede the reduction of the nitrobenzene to aniline through interaction with the nitro group, assuming its role based on the reports that nitrobenzenes could be reduced to anilines or azobenzenes in the presence of alkoxide.12, 13 Our interest has been concentrated on additives as alternatives of DME that affect the SNAr reaction. Herein, we describe the additives affecting the SNAr reaction of 2,4-dimethoxynitrobenzene with sodium tert-butoxide. A well-known organocatalyst, thiourea/urea, and its analogues14-18 were explored to study their effect on the reaction. All reactions were carried out under microwave irradiation, according to our previous report.11 As shown in Table 1, the use of additives gave varied results, depending on the species and amount; e.g., 0.1 equiv of thiourea afforded 2 in 53% and 78% yields for 20 and 30 min reaction times, respectively (Table 1, entry 3). Interestingly, 30 min of the reaction resulted in a higher yield of 2 without the formation of the byproduct 3. However, further addition of thiourea (0.2 and 1.1 equiv.) resulted in a reduced yield, with increased formation of 3 (Table 1, entries 4 and 5). Increasing the reaction time (to 30 min) declined the yield of 2. The use of 0.1 or 0.2 equiv of urea (Table 1, entries 6–8) afforded approximately 53–60% yields of the product 2, but could not prevent the formation of 3. However, the addition of 1.1 equiv of urea afforded 71% yield after 30 min. Unlike thiourea, the higher the amount of urea added, the more 2 was formed after 30 min of the reaction. N-methylthiourea (Table 1, entry 9) and N,N′-dimethylthiourea (Table 1, entry 10) did not produce better results than thiourea. The presence of N,N′-dimethylurea (Table 1, entry 12) seemed to inhibit the reaction, because the substrate 1 and product 2 were not detected at all. Noticeably, 0.1 equiv of N,N,N′,N′-tetramethyl thiourea afforded an excellent yield (82%) after 30 min, with little formation of 3 (Table 1, entry 11). N,N,N′,N′-tetramethyl thiourea afforded 2 in as high a yield as thiourea. This study indicates that thiourea and N,N,N′,N′-tetramethyl thiourea may act similarly to DME, which may stabilize nitrobenzene under strongly basic and high-temperature conditions and suppress the reduction of the nitro group to aniline. The exact role of the additives should be further investigated. In summary, we have demonstrated that some additives including thioureas are effective for the SNAr reaction of 2,4-dimethoxynitrobenzene with sodium t-butoxide. They played a role in improving the yield as well as in reducing the formation of byproducts like DME in the SNAr reaction condition. Although their role has been observed under a limited reaction, our finding provides a novel role of urea derivatives in organic reaction. This research was supported by Advanced Research Center Program (2015R1A5A1008958) funded by the Korean government.