Late-Stage Intermolecular Allylic C–H Amination

Abstract

Allylic amination enables late-stage functionalization of natural products where allylic C–H bonds are abundant, and introduction of nitrogen may alter biological profiles. Despite advances, intermolecular allylic amination remains a challenging problem due to reactivity and selectivity issues that often mandate excess substrate, furnish product mixtures, and render important classes of olefins (for example functionalized cyclic) not viable substrates. Here we report that a sustainable manganese perchlorophthalocyanine catalyst [Mn^III(ClPc)] 2 achieves selective, preparative intermolecular allylic C–H amination of 32 cyclic and linear compounds, including ones housing basic amines and competing sites for allylic, ethereal, and benzylic amination. Mechanistic studies support that the high selectivity of 2 may be attributed to its electrophilic, bulky nature and stepwise amination mechanism. Late-stage amination is demonstrated on five distinct classes of natural products generally with >20:1 site-, regio- and diastereoselectivity.

Alkenes are the second most frequent functional group in natural products, present in approximately 40% of molecules.¹ Their pervasiveness presents the opportunity to introduce functionality in a targeted fashion at allylic C—H bonds, with nitrogen holding special significance as it can alter small molecules’ biological profile.² Traditional methods to introduce amine functionality proceed via alcohol derivatives or carbonyls that are among the most challenging functional groups to react selectively in natural product environments.^3,4 Despite advances, challenges that persist for intermolecular allylic aminations in such settings are the paucity of methods with reactivity and/or selectivity in topologically and functionally complex olefin environments.

Metal-catalyzed C(sp³)–H activation via π-allyl metal (Pd, Ir, Rh) intermediates as well as photocatalytic methods are powerful approaches for allylic C—H amination of terminal olefins and emerging ones for linear internal olefins (Scheme 1a).^5–10 However such methods often have limited applications in natural product settings, likely due to a narrow scope with cyclic olefins.^9,11 The other major approach involves group transfer reactions via metal-nitrenes. Rhodium catalysis is demonstrated for benzylic and aliphatic C(sp³)–H amination in complex substrates;¹² however, for allylic aminations in both intra- and intermolecular settings, olefin aziridination is generally favored.^13–15 Elaborate, chiral rhodium and iridium catalysts, sometimes paired with chiral and/or bulky nitrogen reagents, have been most successful in achieving chemoselectivity in allylic aminations.^16–23 However, these reactions show limited scope and high synthetic overhead without catalyst controlled asymmetric induction in chiral molecule settings.¹⁹ Iron, manganese, cobalt, and ruthenium catalysts promote intramolecular allylic C–H aminations;^24–27 however, face selectivity and reactivity challenges in intermolecular catalysis generally limiting scope to unfunctionalized, symmetrical olefins used in large excess.^28–31

Scheme 1.

Approaches for Allylic C—H Amination

Commercial manganese-perchlorophthlocyanine [Mn^III(ClPc)] 1 was recently demonstrated in its cationic form 2 as a catalyst for preparative, site-selective, late–stage intermolecular benzylic amination.^32,33 Although allylic and benzylic C–H bonds have comparable bond strengths (BDE ca. 82–85 kcal/mol), allylic C–H amination presents a formidable chemoselectivity challenge of competing olefin aziridination.³⁴ In porphyrin, salen and even phthalocyanine ligand frameworks, manganese nitrene-based systems operating under excess olefin effect mixtures of allylic amination products and aziridines(Scheme 1a).^{31, 35–38} We questioned if [Mn^III(ClPc)] 2 aminations proceeding via a bulky, electrophilic metallonitrene may favor reactivity with an electron rich C–H bond over a more electron deficient and sterically demanding π-system. Additionally, aminations likely proceed via a step-wise pathway that should disfavor formation of an unstabilized secondary radical leading to aziridination. Herein we report the discovery that [Mn^III(ClPc)] 2 catalysis effects a highly chemo-, site-, and regioselective allylic C–H amination of linear internal and cyclic olefins including ones housing dense functionality, heterocycles, basic amines, styrenyl olefins, and competing allylic, benzylic, and ethereal sites (Scheme 1b). Late-stage allyic amination is demonstrated in olefin containing natural products that include amino alcohol lipids, glycosides, terpenes, and macrolides.

We began our investigation by exposing 3 to iminoiodinane oxidant (PhI=NTces) in benzene at 40 °C in the presence of [Mn^III(ClPc)] 2 (Table 1a, b). Using molecular sieves and standard Schlenk benchtop techniques C–H aminated product 4 could be isolated in 63% yield (limiting olefin) with high site-selectivity (>20:1 s.s., dictated by C–H cleavage) and regio-selectivity (6:1 r.r., dictated by rebound) at the site most remote from the electron withdrawing group (EWG). In contrast, Rh catalysis using a commercial Rh₂(esp)₂ furnishes aziridine product 4a in 55% yield.¹³ When allylic amination with 2 was run without precautions to exclude O₂ or water, lower yields and mass balance are observed. Benzylic amination under these conditions furnish ketone bi-products, suggesting pathways involving other manganese oxidants may diminish mass balance (see supporting information).³⁹ Significantly, the reaction can be run with commercial catalyst 1 to afford a useful yield of allylic amine 4 (46%).

Table 1.

[Mn^III(ClPc)] Allylic C—H Amination of Linear and Cyclic Olefins^a

Additional linear olefins with EWGs, like para-toluenesulfonyl (OTs) and esters, are aminated with 2 in high site- and regioselectivity to favor remote allylic amination (5 and 6) whereas rhodium catalysis furnishes aziridine (Table 1c). Chemoselectivity issues may arise with styrenyl olefins due to aromatic stabilization of benzylic radicals in aziridination.⁴⁰ With electronically deactivated styrenyl derivatives, [Mn^III(ClPc)] 2 amination affords regioisomerically pure allylic amination products 7 and 8 with trace aziridine (6–8%), whereas rhodium catalysis again affords primarily aziridine. Styrenyl substrate with chloro groups at the ortho-positions, which may force the olefin and aryl π-systems out of conjugation, affords only allylic amine 9. A coumarin derivative prone to electrophilic epoxidation,⁴¹ also proceeds chemoselectively to afford allylic amine 10. In substrates housing allylic and benzylic sites, selectivity can be achieved via electronic or steric effects. Consistent with an electrophilic metallonitrene, tetralone and electron deficient tetralins containing exocyclic olefins underwent selective allylic C–H amination (11, 12a-b). Analogous electron rich tetralins afford selective benzylic amination (12c, 70% yield, >20:1 B:A, see SI). An ibuprofen analogue with two hindered benzylic sites was aminated by 2 at the more accessible allylic site (13).

Despite their prevalence in natural products and some pharmaceuticals, C–H amination is not well demonstrated for functionalized cyclic olefins (>50% of cyclic olefins reported are simple cycloalkenes n = 5–8).^{9,11,15,17–23,28,30,31,35,37,38} [Mn^III(ClPc)] 2 was successful in aminating an electronically biased cyclohexene derivative to produce 14 as one regio-isomer (Table 1d). Dihydrovalencene, a sterically biased terpene, is selectively aminated to afford allylic amine 15. The Tces group is removed under mild hydrolysis to a free amine for further derivatization (4-bromobenzoyl 16). Prenylated motifs are abundant in terpene natural products. Consistent with a step-wise mechanism, 2-catalyzed amination of α-cedrene affords a mixture of 1° and 2° allylic amine products 17a and 17b (1.5:1). [Mn^III(ClPc)] 2, an effective catalyst for ethereal aminations (see ambroxide SI, 72% yield, 18a), prefers allylic amination when competing ethereal sites are electronically (18) or sterically deactivated (19). For example, a cyclopentene substrate is aminated at the most sterically accessible 2° allylic site to furnish 19 despite the presence of two doubly activated allylic ethereal sites. Notably, all of these cyclic olefin aminations, only one regioisomer was observed.

Weakly basic nitrogen heterocycles, like a 5-alkylated barbituric acid derivative, undergo [Mn^III(ClPc)] 2 allylic C–H amination in good yields and excellent selectivities (20, Table 1e). Basic amines must be deactivated towards oxidation and/or catalyst inhibition with Lewis or Brønsted acid complexation or via covalent modification with EWGs. A fused-ring cyclopentene trifluoroacetamide pyrrole 21 underwent site-, regio-, and diastereoselective allylic amination from the most exposed convex face. Selective removal of the trifluoroacetyl group in the presence of the Tces amine afforded 22. BF₃ complexation of azaspirocyclic system 23 affords a column and bench stable piperidine—BF₃ complex that enables 2-catalyzed remote allylic C–H amination (24) followed by base-mediated hydrolysis to the free amine (25). For Lewis basic N-heterocycles and tertiary amines, a BF₃ or HBF₄ complexation strategy is uniquely effective for enabling C–H amination.^32,42 In tetrahydroquinoline, BF₃ complexation promotes remote allylic over benzylic C–H amination and a mild tetramethymethelenediamine (TMEDA) workup preserves the hydrolytically labile ester to afford 26. In tertiary amines like 27, steric hinderance blocks effective BF₃ complexation and renders HBF₄ protonation more effective in allylic amination to furnish 28. Notably, [Mn^III(ClPc)] 2 C–H aminations have been unique in demonstrating tolerance for basic amines using this strategy.^12,23,32

A central advantage of [Mn^III(ClPc)] 2 allylic C–H amination is that the reactivity and selectivity trends observed for simple substrates are generally enhanced in complex olefin containing natural product settings (Scheme 2a–c). A linear amino alcohol lipid, sphingosine analogue 29, housing a densely functionalized, contiguous amino 1,3-diol adjacent to the olefin was regioselectively aminated at the most electron rich site to afford 30. Pentacyclic triterpenoid α-amyrin 31, with two sterically differentiated 2° and 3° allylic C–H bonds is selectively aminated at the more sterically accessible 2° site to afford 32 as a single isomer. Amination occurs diastereoselectively from the alpha face circumventing beta face 1,3-diaxial interactions with C10/C8 angular methyls. The sulfamate is readily hydrolyzed to primary amine 33. Geniposide is an iridoid glycoside possessing six ethereal sites, including an oxidatively labile glycosidic bond, and a cyclopentene-[C]-pyran skeleton housing two olefins having multiple 2° and 3° allylic sites. Bulky O-silyl groups deter ethereal C—H amination, enabling allylic amination of silylated geniposide 34 at the 2° allylic site from the most sterically accessible convex face of the molecule to afford 35 as a single isomer.

Scheme 2.

Late-Stage Allylic C–H Amination on Five Classes of Olefin-containing Natural Products^a

Rigid, cyclic systems position allylic C–H bonds in well-defined chemical environments and restrict free rotation, enabling remarkably diastereoselective aminations with 2. Zearalenone, an estrogenic mycotoxin, is a resorcyclic acid macrolide housing a styrenyl olefin that is perpendicular to the aryl moiety that defines the plane of the ring (Scheme 2d).⁴³ This conformation disfavors olefin aziridination and affords steric and stereoelectronic differentiation of the allylic C–H bonds where H_a is positioned on the sterically more accessible peripheral face of the π-system capable of stabilizing an incipient allylic radical.⁴⁴ Consistent with this analysis, amination of 36 occurs at H_a to furnish 37 as one isomer with no observed aziridination.

Brefeldin A is a storied 13-membered macrolide investigated extensively in chemical synthesis and biology.⁴⁵ Structures of brefeldin A show a trans relationship between the vicinal hydrogens at C9 and C10 that places the plane of the isolated olefin perpendicular to the plane of the macrocycle (Scheme 2e).⁴⁶ We again postulated that the macrocyclic conformation of silylated brefeldin A 38 places allylic hydrogens in distinct chemical environments where H_a is more sterically accessible and able to achieve more facile π-system overlap upon abstraction.⁴⁴ [Mn^III(ClPc)] 2 amination of 38 occurred selectively at the isolated trans alkene to afford aminated 39 as one isomer. Despite the well-defined conformations of many macrocyclic structures, selective C–H functionalizations have rarely been reported outside of enzymatic catalysis.^47,48

To distinguish between a radical rebound and a concerted insertion event, we examined [Mn^III(ClPc)] 2-catalyzed amination of symmetrical trans-5-decene 40 (Scheme 3a). Only one allylic aminated product is expected under a concerted C–H insertion pathway; however, nearly equal mixtures of regioisomers 41 (1.7: 1 r.r.) resulted from amination onto an undifferentiated allyl radical intermediate. Such a pathway favors allylic amination over aziridination due to generation of a stabilized allylic radical. Additionally, sequential amination at the metal limits radical engagement in off-cycle pathways to afford preparative yields with limiting substrate.

Scheme 3.

Mechanistic Insights Probing Reaction Pathway (a), and Reactivity Properties (b, c, d)^a

We probed the reactivity properties of the aminating species by examining [Mn^III(ClPc)] 2 catalyzed C–H amination in substrates having two labile sites distinguished electronically, sterically, or stereoelectronically (Scheme 3b, c, d). Substrate 42 has two electronically distinct olefins, and we observed amination only at the most electron rich site (43). Orthogonal site-selectivity is observed in cobalt-catalyzed intermolecular allylic C–H aminations that show reactivity only with electron deficient arylcrotonate esters.⁴⁹

The steric nature of the transition structure for amination was examined by conducting intra- and intermolecular competition studies with substrates housing electronically unbiased benzylic and allylic sites. Previous studies with [Mn^III(ClPc)] 2 benzylic aminations did not examine substrates containing olefins.³² The high energy barriers required to achieve C–H bond cleavage contrast the small energetic differences between the two bond types (ca. 3 kcal/mol). In the absence of steric bias, we expected only minor differences in the allylic-to-benzylic product ratios (A:B).²⁵ Consistent with this, 2 catalyzed intramolecular amination of 44, where the metallonitrene intermediate is formed on the substrate prior to C–H cleavage, afforded only a modest preference for allylic amination 45 (A:B = 3:1, Scheme 3c). In contrast, 2 catalyzed intermolecular amination of 46 afforded high site-selectivity for allylic amination 47 (A:B = 16:1). This is consistent with a bulky metallonitrene sensing the steric difference between a phenyl (A value ~ 2.8 kcal/mol) versus an allyl (A value ~ 1.7 kcal/mol) in an intermolecular C–H cleavage event.⁵⁰

The impact of stereoelectronic stabilization of substrate radical intermediates on selectivity was probed by examining a series of hydroaromatics of varying ring sizes (Scheme 3d). In tetralin 48a, aromatic π-system overlap with an incipient benzylic radical results in minimal ring strain and affords a mixture of allylic and benzylic amination (49a, Scheme 3d). In larger ring sizes 48b and 48c, where torsional strain is introduced during aromatic radical stabilization,⁵¹ only products of allylic C–H amination 49b and 49c are observed. Electronics can override both steric and stereoelectronic effects. Consistent with 2-catalyzed aminations proceeding via an electrophilic metallonitrene, incorporation of a para-aryl methoxy group in 46 and 48b affords predominantly benzylic amination products in 62% and 58% yield, respectively (47S, 49bS see SI). It is notable that among reagents capable of allylic and benzylic C–H functionalization, none have previously been shown to preparatively distinguish between these bond types.⁵²

[Mn^III(ClPc)] 2 catalyzed late-stage allylic amination enables the atomistic change of allylic C–H to C–N in complex natural products and their derivatives. By generating an electrophilic, bulky metallonitrene amination catalyst, 2 distinguishes C–H bonds, even ones of closely matched BDEs, based on subtle differences in their electronic, steric and stereoelectronic environments. We anticipate that the facile access to aminated complex molecules using this method will enable broader interrogation of natural products as new sources of drugs.