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Copper-Catalyzed Addition of Alcohols to Carbodiimides: Oxygen as an Accelerant
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2022-05-31 , DOI: 10.1021/acs.oprd.1c00465 Lucille A. Wells 1 , Michael R. Gau 2 , Michael B. Peddicord 2 , Kirsten F. Bostwick 3 , Marisa C. Kozlowski 1 , Michael J. Zacuto 3
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2022-05-31 , DOI: 10.1021/acs.oprd.1c00465 Lucille A. Wells 1 , Michael R. Gau 2 , Michael B. Peddicord 2 , Kirsten F. Bostwick 3 , Marisa C. Kozlowski 1 , Michael J. Zacuto 3
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The use of N,N′-diisopropylcarbamimidate (1) to prepare a tert-butyl ester of a carboxylic acid was required for the synthesis of a key pharmaceutical intermediate. Commercial sources were not adequate to supply this reagent in the quantity and quality required for our campaigns. While developing a process to prepare this compound, we discovered that an aerobic copper-catalyzed reaction between tert-butyl alcohol and N,N′-diisopropylcarbodiimide (DIC) afforded superior reaction rates and conversion compared with the reported conditions under inert atmospheres. Screening and mechanistic studies concluded that CuICl is oxidized in situ by O2 in the atmosphere to a generate a more active CuII(OH)Cl species. Screening studies designed to uncover key catalyst attributes concluded that both chloride and DIC act as ligands on the metal center. The consumption of O2 over the course of the reaction resulted in the low-level production of impurities (notably N,N′-diisopropylurea, which is the stoichiometric byproduct in the ensuing reaction that utilizes 1), but sufficient reaction rates and conversion of DIC were not attainable in the absence of O2. The production of 1 was safely executed using commercially available atmospheres of 4–5% O2/95–96% N2 while still meeting our high-quality product needs. The benefit of aerobic copper catalysis was found to also be useful with less hindered alcohols to form the analogous isoureas.
中文翻译：
在碳二亚胺中铜催化醇类的加成：氧作为促进剂
使用N , N'-二异丙基氨基甲酸酯( 1 )制备羧酸叔丁酯是合成关键医药中间体的必要条件。商业来源不足以提供我们活动所需的数量和质量的试剂。在开发制备这种化合物的方法时，我们发现与报道的惰性气氛下的条件相比，叔丁醇和N , N'-二异丙基碳二亚胺(DIC) 之间的需氧铜催化反应提供了更高的反应速率和转化率。筛选和机理研究得出结论，Cu I Cl 被氧化大气中的 O 2原位生成更活泼的 Cu II (OH)Cl 物种。旨在揭示关键催化剂属性的筛选研究得出结论，氯化物和 DIC 都充当金属中心的配体。在反应过程中 O 2的消耗导致杂质的低水平产生（特别是N，N'-二异丙基脲，它是随后反应中利用1的化学计量副产物），但足够的反应速率和转化率在没有 O 2的情况下无法获得 DIC 。1的生产是使用 4-5% O的市售气氛安全执行的2 /95–96% N 2同时仍能满足我们的高品质产品需求。发现好氧铜催化的好处也可用于较少受阻的醇以形成类似的异脲。
更新日期：2022-05-31
中文翻译：
在碳二亚胺中铜催化醇类的加成：氧作为促进剂
使用N , N'-二异丙基氨基甲酸酯( 1 )制备羧酸叔丁酯是合成关键医药中间体的必要条件。商业来源不足以提供我们活动所需的数量和质量的试剂。在开发制备这种化合物的方法时，我们发现与报道的惰性气氛下的条件相比，叔丁醇和N , N'-二异丙基碳二亚胺(DIC) 之间的需氧铜催化反应提供了更高的反应速率和转化率。筛选和机理研究得出结论，Cu I Cl 被氧化大气中的 O 2原位生成更活泼的 Cu II (OH)Cl 物种。旨在揭示关键催化剂属性的筛选研究得出结论，氯化物和 DIC 都充当金属中心的配体。在反应过程中 O 2的消耗导致杂质的低水平产生（特别是N，N'-二异丙基脲，它是随后反应中利用1的化学计量副产物），但足够的反应速率和转化率在没有 O 2的情况下无法获得 DIC 。1的生产是使用 4-5% O的市售气氛安全执行的2 /95–96% N 2同时仍能满足我们的高品质产品需求。发现好氧铜催化的好处也可用于较少受阻的醇以形成类似的异脲。
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