Manganese-catalysed benzylic C(sp3)-H amination for late-stage functionalization

Abstract

Reactions that directly install nitrogen into C-H bonds of complex molecules are significant because of their potential to change the chemical and biological properties of a given compound. Although selective intramolecular C-H amination reactions are known, achieving high levels of reactivity while maintaining excellent site selectivity and functional-group tolerance remains a challenge for intermolecular C-H amination. Here, we report a manganese perchlorophthalocyanine catalyst [MnIII(ClPc)] for intermolecular benzylic C-H amination of bioactive molecules and natural products that proceeds with unprecedented levels of reactivity and site selectivity. In the presence of a Brønsted or Lewis acid, the [MnIII(ClPc)]-catalysed C-H amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies suggest that C-H amination likely proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where C-H cleavage is the rate-determining step of the reaction. Collectively, these mechanistic features contrast with previous base-metal-catalysed C-H aminations and provide new opportunities for tunable selectivities.

Figure 1.. Converting C–H bonds to C–N bonds.

a. Ampicillin, a broad spectrum antibacterial drug differs from penicillin by an atomistic change of a benzylic C–H to C–N. b. Comparison of site-selectivities for benzylic versus tertiary C–H amination of Mn versus Rh catalyzed C–H aminations. Tces = 2,2,2-trichloroethoxysulfonamide. c. Chemoselectivity in a tertiary amine containing natural product of Mn versus Rh catalyzed C–H aminations. d. Comparison of reactivity of Mn versus Co catalyzed benzylic C–H aminations. *Yield based on equivalents of substrate used. ^†Yield based on equivalents of oxidant used. Troc = 2,2,2-trichloroethoxycarbonyl. e. Observed site-selectivity of Mn versus Co catalyzed C–H aminations. f. Comparison of site-selectivities among sterically differentiated benzylic C–H bonds on estrone/estradiol derivatives of a Mn-catalyzed reaction proceeding via a metallonitrene with previously reported Fe-catalyzed C–H azidation proceeding via a free radical intermediate.

Figure 2.. Intermolecular benzylic C–H amination substrate scope.

a. One-step, gram-scale synthesis of [Mn^III(ClPc)]Cl from commercial materials. b. General reaction conditions and evaluation of aryl and alkyl electronic effects. Reaction conditions: substrate (0.2 mmol, 1 equiv), [Mn^III(ClPc)]Cl 3 (10 mol%), AgSbF₆ (10 mol%), PhI=NTces (2 equiv), C₆H₆ (0.5M), 5Å molecular sieves (40 mg), 40 ˚C, 8–16 h. Isolated yields are average of three runs. Diastereomeric ratios are 1:1 unless otherwise noted c. Evaluation of site-selectivity: benzylic versus tertiary and sterically and electronically differentiated benzylic C–H bonds. d. Nitrogen-containing heterocyclic substrates with electron-withdrawing groups on nitrogen. e. Brønsted and Lewis acid protection strategy for basic tertiary amine and pyridine-containing substrates. *No tertiary product detected by HPLC (detection limit 0.0002 mg/mL using authentic product). ^†No tertiary product detected in ¹H NMR crude or after purification. ^‡No monoamination product detected at C₄ by HPLC (detection limit 0.00015 mg/mL using an authentic product); trace diamination detected using authentic product by HPLC, not seen by ¹H NMR. An imine product at C₁ was isolated in 12% yield. ^§Overall three step yield (1,2-DCE (0.5M): acid complexation, amination and decomplexation. ^||3 equivalents of PhI=NTces. ^¶15 mol% catalyst used. ^#3Å molecular sieves.

Figure 3.. Late-stage benzylic C–H amination of bioactive molecules.

a. [Mn^III(ClPc)] 4 catalyzed benzylic C–H amination (reaction conditions in Figure 2, isolated yields are average of three runs, diastereomeric ratios are 1:1 unless otherwise noted) selectively installs Tces-protected amines into bioactive molecules that can be converted to primary amines (32→33) b. Bioactive molecules with multiple reactive benzylic C–H bonds are selectively aminated at the most sterically accessible site. c. Bioactive molecules are selectively aminated at the most electron rich site. *Tces deprotection performed using Zn/Cu couple (10 equiv), MeOH:AcOH (1:1). After filtration through celite plug the concentrated white solid was stirred in methanolic HCl at 40 ˚C for 12 h to yield the corresponding amine. ^†3Å molecular sieves (40 mg) used. Substrate protonated with HBF₄•OEt₂ (1.1 equiv) in CH₂Cl₂ prior to amination then deprotonated with 1M NaOH in CH₂Cl₂ after amination. ^‡3 equiv of iminoiodinane used. ^§Only the cis-isomer used for alkylation, deprotection. ^||3Å molecular sieves (40 mg) used. Substrate complexed with BF₃•OEt₂ (1.1 equiv) in CH₂Cl₂ prior to amination and decomplexed with tetramethylethylenediamine (TMEDA) in CH₂Cl₂.

Figure 4.. Late-stage benzylic C–H amination of natural products.

The late-stage functionalization of six natural product analogs is demonstrated with [Mn^III(ClPc)] 4 catalysis (reaction conditions in Figure 2, isolated yields are average of three runs, diastereomeric ratios are 1:1 unless otherwise noted) to give preparative yields and excellent levels of site-selectivity. *Tces deprotection: Zn/Cu couple protocol (Figure 3). ^†3Å molecular sieves (40 mg) used. HBF₄•OEt₂ (1.1 equiv, CH₂Cl₂) amine protection followed by 1M NaOH (CH₂Cl₂) deprotection after amination. ^‡3Å molecular sieves (40 mg) used. BF₃•OEt₂ (1.1 equiv, CH₂Cl₂) pyridine protection prior to amination, then deprotection with tetramethylethylenediamine in CH₂Cl₂ after amination. ^§3 equiv of iminoiodinane used.

Figure 5.. Mechanism of [Mn^III(ClPc)] catalyzed benzylic C–H amination.

a. Proposed stepwise mechanism for the [Mn^III(ClPc)] catalyzed benzylic C–H amination. b. C–H cleavage step is rate-determining step. Intermolecular kinetic isotope effect (KIE), evaluating the effect of C–H cleavage on overall reaction rates, closely matches the intramolecular KIE that directly probes the C–H cleavage step. c. The intermolecular rebound of the Mn-imido with a stabilized benzylic radical proceeds with racemization of stereogenic centers. Intramolecular rebound with an aliphatic carbon-centered radical proceeds with complete retention of stereochemistry. d. Site-selectivity of [Mn^III(ClPc)] catalyzed C–H amination is probed in a substrate containing two 2˚ benzylic C(sp³)–H sites that differ electronically and in bond dissociation energies (BDE). The high site-selectivity for the most electron rich site having a higher BDE suggests that the reaction proceeds via an electrophilic metallonitrene intermediate. The 17:1 ratio of 57:58 was measured by HPLC.