Scalable Process for 4‐(2‐Hydroxy‐2‐methyl)‐ethyl‐benzylamine

Bromoacetic Acid-Promoted Nonheme Manganese-Catalyzed Alkane Hydroxylation Inspired by α-Ketoglutarate-Dependent Oxygenases

“…This result is significant and contrasts with the previous reports, 16b,c in which a mixture of cumyl alcohol, acetophenone, 1-phenylethyl acetate, and α-methylstyrene were yielded. Additionally, phthalimide-protected 4-isopropylbenzylamine was hydroxy-lated with a high regioselectivity at the tertiary C−H position to afford protected 4-(2-hydroxy-2-methyl)-ethyl-benzylamine (52%; 34b in Figure 1D), which is a key intermediate for a drug candidate; 18 however, reported synthesis of this important compound, entailing a stepwise synthesis of 4-(2hydroxypropan-2-yl)benzonitrile first, followed by cyanoreduction by lithium aluminum hydride, was not as straightforward as the present reaction. 18 To examine the stereoselectivity in C−H hydroxylation by the current catalytic system, selective oxidation of substrates having a specific configuration was performed (Figure 1D).…”

“…Additionally, phthalimide-protected 4-isopropylbenzylamine was hydroxy-lated with a high regioselectivity at the tertiary C−H position to afford protected 4-(2-hydroxy-2-methyl)-ethyl-benzylamine (52%; 34b in Figure 1D), which is a key intermediate for a drug candidate; 18 however, reported synthesis of this important compound, entailing a stepwise synthesis of 4-(2hydroxypropan-2-yl)benzonitrile first, followed by cyanoreduction by lithium aluminum hydride, was not as straightforward as the present reaction. 18 To examine the stereoselectivity in C−H hydroxylation by the current catalytic system, selective oxidation of substrates having a specific configuration was performed (Figure 1D). cisand trans-4-Methylcyclohexyl benzoates housing competing methine and methylene sites were preferentially hydroxylated at the methine site to deliver the corresponding cis-and transtertiary alcohols, respectively (35b and 36b in Figure 1D).…”

“…Isotopically labeled water (H 2 18O) experiments have been extensively used as a mechanistic tool to verify the intermediacy of high-valent metal−oxo intermediates in the catalytic cycles of enzymatic and biomimetic oxidation reactions (Scheme 5). 23−26 Hence, 18 O-labeled water experiments were performed to investigate whether a high-valent manganese−oxo intermediate is involved in the catalytic oxidation reactions by analyzing the extent of 18 O-incorporation from H 2 18 O into the oxygenation product(s) (see the SI for details). Interestingly, we observed that significant amounts S5, and Figure S3; Scheme 5C).…”

“…The relatively low catalyst loading, readily available BPMCN ligand, environmentally friendly oxidant, ease of operation and scale-up, synthetically useful yields, and site-selectivity make this method practically useful. Mechanistic studies, including the kinetic isotope effect (KIE), the correlation between the logarithm of relative C−H bond oxidation reaction rates and the C−H BDEs of substrates, the Hammett analysis, the stereospecificity, the dissociation mechanism of the O−O bond, the property of the hydroxylating intermediate, and 18 O-labeled water experiments provide strong experimental evidence for the involvement of a manganese(V)−oxo bromoacetate intermediate as a responsible oxidizing species effecting the C−H bond hydroxylation via an oxygen-rebound mechanism (Scheme 1C). Density functional theory (DFT) calculations supported the experimental observations for the effects of bromoacetic acid on the generation of the Mn(V)−oxo intermediate and its high reactivity toward C−H bond activation reactions.…”

Development of a Synthesis of a 2,3-Disubstituted 4,7-Diazaindole Including Large-Scale Application of CH3Li/TiCl4-Mediated Methylation of an Enolizable Ketone

“…Alternative substrates were also considered. An oxidative protocol using p -cuminonitrile was low yielding, and the aldol side reaction was still problematic when ester substrates were employed.…”