Direct Amination of \xce\xb1-Hydroxy Amides
A TiCl4-mediated reaction for the direct amination of \xce\xb1-hydroxy amides has been developed. This simple, general, additive/base/ligand-free reaction is mediated by economical TiCl4. The reaction runs under mild conditions. This highly efficient C\xe2\x80\x93N bond formation protocol is valid for diverse amines, including primary, secondary and heterocyclic amines, and even a primary amide and indole.
<p>α-Amino amides are very important molecules that are widely used in organic and medicinal chemistry. They are present in many drugs, such as Leukotriene D4, Safinamide, Lidoderm, Altace, Indinavir, Vyvanse, and in all aminopenicillins. They are also present in many natural products, such as canthiumine, coelichelin,[1] zorbamycin,[2] guadinomine B,[3] myrianthine B,[4] abyssenine,[5] paliurine E,[5] and mucronine J.[6] Moreover, α-amino amides are used as building blocks for the synthesis of different molecules and scaffolds like hydantoins.[7] Recently, the use of α-amino amides as organocatalysts for various asymmetric reactions has proven to be an extremely valuable approach owing to their facile structural modification and accessibility.[8]</p><p>Tremendous progress has been made in the use of C–N bond formation for direct amination reactions.[9] Recently, more efforts have been focused on the direct amination of alcohols by using transition metals or Lewis acids (Scheme 1, method A).[9–10] These protocols improved the waste balance and are a powerful tool for the C–N bond formation. This approach is also strongly preferred in industry, and more research in this field is desirable.[11]</p><p>Despite good progress in this field, the scope of alcohols and amines is largely restricted. Moreover, these approaches are not valid for more complex structure like α-hydroxy amides, and also for inactivated amines, where reaction typically proceeds with poor yield. Direct amination of the α-hydroxy amide is more challenging than the alcohol, as the amide group could hinder the coordination sites on the catalyst to resist direct amination. Therefore, finding a new method for the direct amination of α-hydroxy amide to gain access to highly important α-amino amides remains an important challenge.</p><p>Conversely, to the best of our knowledge, there is only one report by Beller and co-workers for the direct amination of α-hydroxy amides (Scheme 1 method B).[12] They used a ruthenium-catalyzed "borrowing-hydrogen" process for the direct amination. This protocol is simple and green, but it involves the use of a costly catalyst and ligands. Moreover, high reaction temperatures and a limited substrate scope were major disadvantages.</p><p>Here, we are reporting a TiCl4-assisted, general, economical, base/ligand-free mild method for the direct amination of α-hydroxy amides. The method is distinguishable by its wide scope, which includes primary, secondary and heterocyclic amines, and even indole and a primary amide.</p><p>We started our optimization by screening different Lewis acids, as Lewis-acid-activated reactions are well-developed for the direct amination of alcohols, when used in catalytic and stoichiometric amounts.[9–10] We sought to examine the possibility of these economical and non-toxic Lewis acids for the direct amination of α-hydroxy amides. We evaluated different Lewis acids, such as InCl3, ZnCl2, ZrCl4, GdCl2, Sc(OTf)3, TiCl4, and FeCl3, in a catalytic amount at room temperature in 1,2-dichloroethane (DCE); however, a trace of the target product was only observed when using TiCl4. Next, we increased the temperature and catalyst amount of TiCl4. Ultimately, we found that increasing the temperature to 100 °C, and a stoichiometric amount of TiCl4, product formation slightly improved. Then, we screened different solvents with 1 equivalent of TiCl4 at 100 °C (Table 1). In DCE, a low amount of the desired amination product 3a was observed together with a significant amount of starting material (Table 1, entry 1). The reaction did not reach completion even after three days. With further solvent screening, the coupling product yield improved remarkably up to 62% in solvents, such as 1,4-dioxane, toluene, and THF (Table 1, entries 2–4). The reaction in methanol did not proceed at all. In CH2Cl2, a lower product yield (53%) was observed. Further improvement was observed when acetonitrile was used as a solvent, affording the product in excellent yield (85%, Table 1, entry 7). The reaction did not reach completion with xylenes or DMF even after three days.</p><p>Aiming to get a higher yield, we turned our attention toward the use of different additives,[9–10] such as bases (KOH and triethylamine) or drying agents (molecular sieves and MgSO4). With these additives, the reaction became slow and did not finish even with longer reaction times, with starting materials remaining unreacted in substantial amounts ≈50–60%. Next, we performed equivalence studies of the amine morpholine and we found that 1 and 2 equivalents of morpholine formed only 23 and 42% product, respectively. When the TiCl4 equivalents were reduced to 20 mol%, no product was formed. However, when using 50 mol% TiCl4, some product was formed (39%), but the reaction remained incomplete even after three days at 130 °C. In conclusion, the optimal conditions for this reaction were 100 °C with 1 equivalent of TiCl4 in MeCN.</p><p>With these optimized conditions in hand, we examined the scope and limitations of this TiCl4-mediated amination reaction (Scheme 2). Alkylamines like allylamine, cyclohexylamine, and benzylamine effectively worked, forming the corresponding products in good yields (68, 76, and 83%, respectively).</p><p>Arylamines worked well (3e and 3f). Electron-donating and electron-withdrawing substituents on the arylamines were compatible with the reaction, leading to the desired products in good to moderate yield (3g and 3h). Moreover, we expanded the scope of the reaction to heterocyclic amines. Heteroaryl molecules are very important in drugs, as these molecules are present in almost half of the top 200 drugs.[13] Heterocyclic amines like pyrimidine, benzothiazole and benzimidazoles are known to be inactivated amines; however, they can be used in this protocol, providing good yields of 58, 84 and 69%, respectively (3i–3k).</p><p>Next, we screened different secondary amines, including cyclic amines like piperidine and thiomorpholine 1,1-dioxide, which also proved to be good substrates. The reaction with indole also provided the product in 36% isolated yield. The low yield owed to incomplete conversion, although the reaction was carried out for three days at 130 °C and up to 3 equivalents of TiCl4. The method also worked for a primary amide, butyramide, to form bis-amide product 3p, in low 15% yield, while recovering mostly starting material (>50%).</p><p>Finally, we extended the scope of the reaction to differentially substituted α-hydroxy amides. As expected, other α-hydroxy amides derivatives also showed similar results. Aliphatic and aromatic amides, and the heterocycle thiophene also worked well. The product of thiophene-substituted α-hydroxy amide with morpholine 3q was produced in 70% yield. Aliphatic derivatives 3r and 3s formed their corresponding products in moderate yields of 62 and 59%, respectively, as the reaction remained incomplete.</p><p>Previously, TiCl4-assisted substitution reactions were reported to proceed through a carbocation mechanism.[14] Other groups described TiCl4-catalyzed nucleophilic substitutions of alcohol that proceeded via carbocation formation followed by nucleophilic attack.[14a,15] Studies on the detailed mechanism of this direct amination of α-hydroxy amides are now underway.</p><p>In summary, we developed a TiCl4-facilitated, ligand/additive-free relatively mild reaction for the direct amination of α-hydroxy amides. Under the optimized reaction conditions, a broad range of amines including primary, secondary and heterocyclic amines, and even primary amides and indoles were found to participate in this transformation, providing the products in moderate to high yields. Different α-hydroxy amides containing aliphatic, aromatic or heterocyclic substituents such as thiophene also worked well.</p>