γ C-H Functionalization of Amines via Triple H-Atom Transfer of a Vinyl Sulfonyl Radical Chaperone

Abstract

A selective, remote desaturation has been developed to rapidly access homoallyl amines from their aliphatic precursors. The strategy employs a triple H-atom transfer (HAT) cascade, entailing (i) cobalt-catalyzed metal-HAT (MHAT), (ii) carbon-to-carbon 1,6-HAT, and (iii) Co-H regeneration via MHAT. A new class of sulfonyl radical chaperone – to rapidly access and direct remote, radical reactivity – enables remote desaturation of diverse amines, amino acids, and peptides with excellent site-, chemo-, and regio- selectivity. The key, enabling C-to-C HAT step in this cascade was computationally designed to satisfy thermodynamic (bond strength) and kinetic (polarity) requirements, and it has been probed via regioselectivity, isomerization, and competition experiments. We have also interrupted this radical transfer dehydrogenation to achieve a family of γ-selective C-Cl, C-CN, and C-N bond formations.

Graphical Abstract

Introduction

Alkenes are highly versatile motifs in synthetic chemistry.^1–6 Ideally, double C-H oxidation would install this valuable linchpin group with chemo- and regio- selectivity at positions distal to common functional groups.⁷ However, in addition to such selectivity targets, oxidative desaturation is difficult to achieve due to a tendency for over-oxidation of the alkene product. To overcome these challenges, we proposed a mild, redox-neutral desaturation of amines – enabled by a new radical chaperone that facilitates selective alkene transfer. We were inspired by metal H-atom transfer (MHAT) as a robust method to generate C-centered radicals via alkenes, silanes, and first-row metals (Figure 1a).^8,9 Such MHAT-mediated strategies enable valuable chemo-, regio-, and stereo- selective alkene hydrofunctionalizations^10–16 and isomerizations¹⁷ within complex molecules.^18–21 Yet, this mechanism has not been coupled with intramolecular HAT to effect remote C-H functionalization.

Figure 1.

Remote C-H functionalization via triple HAT.

Toward this goal, we sought to develop a new class of radical chaperone to complement our β C-H aminations of alcohols via transient imidate radicals.^22–24 In our new design, we envisioned temporary conversion of an amine to alkene A could enable remote, transfer dehydrogenation via a triple HAT cascade (Figure 1b). In this scheme, we sought to leverage our dual expertise in intramolecular HAT²⁵ and Co catalysis²⁶ to promote distal, site-selective desaturation. Our general mechanistic design entails sequential (1) MHAT of A to B, (2) C-to-C HAT of B to C, and (3) MHAT of C to D to generate, translocate, and terminate the respective radical intermediates. Moreover, we recognized an opportunity to interrupt the terminal MHAT and intercept the remote radical C to yield various γ C-H functionalizations E.

Given the high value, yet ongoing limitations, of double C-H desaturation technologies,^27–33 we set out to probe the utility of a new chaperone in addressing this synthetic challenge. Radical desaturations typically require adjacent functional groups (e.g. arene, heteroatom, carbonyl)^34–38 as well as stoichiometric oxidants.^39,40 Among the rare examples of catalytic or regioselective desaturation, it is instructive to note how oxidized precursors are used to access radicals centered on O (via O-O),⁴¹ N (via N-F, N-O),^42,43 or C (via Ar-N₃R, Ar-I, SiCH₂I)^44–46 (Figure 2a). Collectively, these pioneering strategies overcome the thermodynamic challenge of C-H abstraction by generating a strong O-H, N-H, primary or aryl C-H bond. However, weak benzylic or tertiary C-H bonds are still often required for efficient reactivity, likely due to kinetic effects arising from the requisite catalysts (e.g. Pd, Cu) or cationic intermediates.

Figure 2.

Design of a radical chaperone for γ C-H functionalization. (a) State-of-art, (b) Challenges, (c) Evaluation by computational predictions and experimental validation.

Design

To address these ongoing challenges, we proposed three principal design elements: (i) an alkene-based radical chaperone must be easily installed and removed, (ii) redox-neutral, intramolecular transfer dehydrogenation can prevent over-oxidation, and (iii) a triple HAT cascade could permit robust desaturation of vicinal, secondary C-H bonds. We anticipated this triple HAT cascade to be critical, yet also most challenging. The requisite radical translocation by C-to-C HAT is difficult,⁴⁷ since it lacks a thermodynamic driving force given the similarity in bond strength of the broken and formed C-H bonds (2° C-H: 98 kcal/mol) (Figure 2b). Moreover, a kinetic barrier exists due to the similar polarities of the two alkyl radicals involved in HAT (2° radical polarity: 0.7 eV).^48,49 Electrophilic radicals are typically employed in HAT (c.f. O > 2.1 eV; N > 1.4 eV)²⁵ to avoid competing side-reactions (e.g. reduction, dimerization, polymerization).

Results and Discussion

To facilitate a rapid evaluation of radical chaperone candidates, we computationally evaluated both of these kinetic (radical electrophilicity, ω)⁴⁹ and thermodynamic (bond dissociation energy, BDE)⁵⁰ parameters (Figure 2c; B3LYP-D3/6-311++G(d,p)). Among five representative examples (see more in SI), we observed the radical polarity (ω) is mismatched for effective secondary C-H HAT kinetics by several linkers, including methylene I (CH₂), silyl II (SiMe₂), and difluoro III (CF₂). All three are significantly less electrophilic than iminyl radicals (ω < 1.4), which are among the least electrophilic radicals to efficiently promote HAT.^51–53 Conversely, only α- carbonyl IV (CO) or sulfonyl V (SO₂) radicals are computed to be electrophilic enough (ω ≥ 1.4) to effect rapid C-to-C HAT of 2°C-H bonds.

To further enrich this kinetic analysis, thermodynamic favorability (ΔG_HAT) was approximated by computing the difference in BDE of the abstracted C-H versus the C-H formed on the chaperone via HAT. Here, α- methylene I (CH₂), silyl II (SiMe₂), and carbonyl IV (CO) were found to be significantly endergonic – forming insufficiently strong C-H bonds (91-95 kcal/mol). Only difluoro III (CF₂) and sulfonyl V (SO₂) chaperones afford a strong enough C-H bond (97 kcal/mol) to render 2° C-H HAT nearly thermoneutral.

Notably, physical experiments validated these computational predictions, wherein the only successful candidate to afford any remote desaturation was vinyl sulfonamide V, which is also the only linker calculated to have an HAT that is both polarity-matched and thermodynamically allowed at room temperature. In contrast, no desaturation was observed among the other candidates tested (I, II, IV; III is not easily synthesized). Notably, while an α-sulfone radical has been employed in 1,5-HAT,⁵⁴ this is the first example of intramolecular HAT mediated by an α-sulfonamide radical. We suspect the divergent γ selectivity observed herein occurs via 1,6-HAT – due to elongated C-S-N bonds that strain a 1,5-HAT transition state, as Roizen observed for N-S-N bonds within N-centered sulfamate radicals.^55–58

The development of this γ C-H desaturation is shown in Figure 3. Crucially, the radical initiator is easily installed onto primary or secondary amines in a single step by combination with commercially available 2-chloroethanesulfonyl chloride (1 equiv) and Et₃N (3.5 equiv). Following transfer hydrogenation, the resulting EtSO₂- (Es) is easily removed with Red-Al (NaAlH₂•C₆H₁₄O₄) or by the phosphonium-based method developed at Merck.⁵⁹ These deprotection strategies are amenable to either secondary or tertiary sulfonamides. Thus, this facile addition and removal renders this vinyl sulfonamide an excellent radical chaperone.

Figure 3.

Development of γ C-H desaturation of amines via vinyl sulfonamide.

Our evaluation of this radical alkene transfer revealed the combination of Co(II) precatalyst Co1, Selectfluor oxidant to access Co(III), PhSiH₃ to generate Co-H, and a DCE/^tBuOH solvent mixture was optimal for enabling γ desaturation of vinyl sulfonamide 1. Variations in electronic and steric parameters of the salen ligand on Co show that subtle substituent effects may impact the rate of radical cage collapse or MHAT kinetics (entries 1-3).⁶⁰ Although an oxidized version of precatalyst Co1 – as Co(III)Cl – affords comparable yields in the absence of Selectfluor, the Co(II) precatalyst/oxidant combination affords greater regioselectivity for the γ-δ desaturated amine (12:1 rr vs 4:1). The unique role of Selectfluor in providing high regioselectivity (for MHAT elimination away from the sulfonamide) remains unclear. Use of N-fluoro-collidine•BF₄ as oxidant – to form Co(III)F alternatively – does not resurrect the rr, thus ruling out Cl vs F (or BF₄) counterion effects (entries 4-5). Other hydrides and solvents, which have been employed in MHAT,⁸ were examined and found to be less effective (entries 6-7; see SI for full details). It is likely that the advantageous addition of a polar, protic solvent (^tBuOH) either stabilizes the HAT transition state⁶¹ or generates an alkoxysilane in situ, as Shenvi has shown.⁶² Dilute conditions yield greater efficiency, likely by suppressing side-reactions such as H₂ evolution and dimerization; O₂ is also deleterious to this radical reaction (entries 8-9). Lastly, control experiments demonstrate the importance of each component, including the Co1 catalyst, silane, and oxidant (entries 10-12).

Synthetic Scope

With optimized conditions in hand, we next evaluated the generality of this alkene transfer (Figure 4). In addition to primary amines, we were pleased to see this strategy is also amenable to amides and carbamates (2-4). The higher regioselectivity observed in these cases (up to >20:1 rr (γ-δ vs β-γ) is likely due to increased steric repulsion in the transition state of the terminal MHAT step that disfavors abstraction of the β C-H (vs δ C-H). Other alicycles (cyclo-pentane, -heptane) and heterocycles (tetrahydropyran, piperidine) also cleanly afford γ desaturated analogs (5-8). For piperidine 8, steric control of the MHAT by the opposing NBoc (vs the Es) nearly reverses regioselectivity. The functional group tolerance of free alcohols, pyridines, aryl halides, and α or β substituents also showcase the chemoselectivity of this method (9-11) – including in forming contra-thermodynamic, terminal olefins.^63,64 Notably, efficient desaturation of vicinal, secondary C-H bonds (12-13) is enabled by this C-to-C HAT – illustrating the broad synthetic utility of this triple HAT strategy. Even though there is less driving force for this abstraction of a 2° C-H (vs 3° C-H), subsequent MHAT formation of a disubstituted olefin likely affords the requisite thermodynamic driving force for this net alkene transfer from a vinyl sulfonamide.

Figure 4.

γ-Transfer dehydrogenation: scope and generality. rr denotes regioisomeric ratio (γ-δ:β-γ). See SI for full details.

To further probe the generality and chemoselectivity of this radical chaperone strategy, a range of amines found within drug and natural products were desaturated (14-18). In these examples, multiple substitution patterns (α, β, γ, δ), rings (polycyclics, arenes), and divergent core functionality (anilines, endo-amide 18) are tolerated. Formation of non-conjugated systems (17 vs styrene; 1,4-diene 18 vs enone or 1,3-diene) are illustrative of the orthogonal selectivity of this desaturation method.^43,45 As a solution to the central challenge of accessing medicinally relevant, unnatural amino acids,⁶⁵ we were pleased to find several Cy-alanine (Cha) esters are selectively and efficiently dehydrogenated (19-21; >20:1 rr in all cases; see SI for x-ray structure of 19). Similarly, leucine (Leu) 22 and various di-peptides of Leu (23-25) are selectively desaturated at the γ C-H of the Leu residue, even in the presence of weak C-H bonds (Leu-Val, Leu-Phe) or unprotected indoles (Leu-Trp).

Lastly, an additive robustness⁶⁶ investigation was performed (on the reaction of 1 to 2) to explore tolerance of reactive functionalities and facilitate a comparison with Pd-catalyzed methods.^45,46 Representative examples (see SI for full additive screen) show the desaturation uniquely permits the presence of aryl iodides, carboxylic acids, epoxides, and ketones – with minimal effect on yield or selectivity. The only major limitations observed are those groups that may interact with Co-H, such as aldehydes or alkynes.

Although robust regioselectivity was observed in nearly all cases (accessing homoallyl amines via γ-δ desaturation), certain outlier substrates afford allyl amines via β-γ desaturation (Figure 5). These cases are either biased toward forming a more substituted β-3° olefin (26), or entail small, undifferentiated groups (e.g. isopentyl primary amine 27 or N-butyl secondary amine 28) that would afford terminal alkenes by MHAT of primary C-H bonds (vs longer groups that yield internal olefins 12). Smaller amino acids with β-3° centers similarly afford β-γ desaturated analogs, including of valine (Val) and Cy-glycine (Chg) (29-30). Finally, small amides afford α-β desaturation (31).

Figure 5.

Allyl amines via β-γ desaturation of smaller amines.

Mechanistic Investigations

To understand the origin of regioselectivity in this triple MHAT (and the switch in olefin position of the outliers), we designed several mechanistic experiments and HAT probes (Figure 6). First, isopentylamide 27, which only differs in its lack of α or β substitution compared with amines 9-11, 15-16 or Leu analogs 22-25, is the only of these 10 examples with β (vs γ) selectivity. We proposed this may result from Co-catalyzed isomerization of a transiently generated, typical γ alkene.^17,67 To test this hypothesis, homoallyl amine 32 was prepared and subjected to reaction conditions (Fig 6a). In this case, 4:1 isomerization to trisubstituted olefin 27 recapitulates the 3:1 rr observed in the catalytic reaction (c.f. Fig 5). To explain why this post-reaction isomerization does not occur in most cases, we propose that α or β substituents on amines create steric bias for the MHAT elimination to afford terminal olefin 32 rather than allyl amines 27 (Fig 6b). Thus, while 1,6-HAT selectively affords a γ-radical in all cases, the less sterically hindered δ MHAT (vs β MHAT) affords kinetic selectivity for contra-thermodynamic desaturation. As support for this model (Fig 6c), increasingly larger α-substituents reverse β MHAT selectivity (4:1 β) to afford increasingly greater δ MHAT selectivity (6:1 δ) with α-Me and α-ester (>20:1 δ) amines.

Figure 6.

Mechanistic experiments probing isomerization, as well as MHAT and HAT regioselectivity.

Next, we designed a series of intramolecular competition experiments to interrogate the regioselectivity of the key C_sp3-C_sp3 HAT (Fig 6d). To discern the effect of bond strength on HAT site-selectivity, we compared abstraction of 3° and 2° C-H bonds (33). As expected, tertiary C-H abstraction is significantly favored over secondary (13:1). With this baseline thermodynamic preference for 3° HAT in hand, we probed the kinetic preference of 1,5-, 1,6-, and 1,7-HAT by varying the 3° position. Consequently, we observed a relative reactivity trend of 1,6 > 1,5 > 1,7 HAT. The significant selectivity of 1,6- over 1,5-HAT (34, 7:1) is consistent with our hypothesis that elongated C-S-N bonds preclude 1,5-HAT by straining its transition state.^55,56 The even greater preference for 1,6- over 1,7-HAT (35, >20:1) reflects an entropic barrier to the larger macrocyclic transition state.²⁵ Taken together, these data suggest 1,6-HAT robustly abstracts the γ C-H in all cases and MHAT (dictated by sterics of α or β substituents) affords regioselectivity of the net desaturation – including by forming contra-thermodynamic terminal olefins in many cases.

DFT calculations

To gain further insight on the energetic preference for 1,6-HAT regioselectivity, we modeled the reaction coordinate for six competing HAT pathways within a single competition probe and computed the transition state (TS) energies of each feasible HAT event (Figure 7; ωB97X-D/6-311++G(d,p)/IEFPCM(DCE)). This permitted simultaneous examination of multiple variables at once – quantifying both site-selectivity of radical generation (3° > 2° > 1°) as well as HAT regioselectivity (1,6 > 1,5 > 1,7). As expected, we observed a kinetic preference for HAT of a 3° γ C-H bond (left box) over 2° γ C-H bonds (right box) by 2.3 kcal/mol. Additionally, 1,6-HAT is kinetically favored over both 1,5-HAT (by 4.0 kcal/mol) and 1,7-HAT (by 5.8 kcal/mol) for 3° C-H bonds (left). This preference can be explained by enthalpic (ring strain: 1,6 < 1,5) and entropic (reorganization energy: 1,6 < 1,7) forces, respectively.²⁵

Figure 7.

HAT regioselectivity: DFT calculations support experimental observations.

For the less differentiated, fully 2° C-H bond system (right), 1,6-HAT is similarly kinetically favored over both 1,5- and 1,7- HAT (by 1.3 kcal/mol). In all cases, the experimental reactivity trend of 1,6 > 1,5 > 1,7 HAT is also reflected in the relative stabilization of the respected distal radical products. This thermodynamic preference is pronounced for the γ 3° position (left) over δ 1° and β 2° (by 5.6 and 3.9 kcal/mol, respectively), and it is also significant (1.6-2.0 kcal/mol) for the fully 2° C-H bond case (right), likely due to radical destabilizing effects of the sulfonamide and terminal methyl groups.

Further Classes of Reactivity

Lastly, to showcase the broader utility of this new sulfonamide radical chaperone, we sought to complement this desaturation by also developing a series of γ C-H functionalizations (Figure 8). We recently interrupted the N-radical-mediated Hofmann-Löffler-Freytag reaction with Cu catalysts to realize δ C-H functionalization of amines.^68,69 With the hopes of accessing complementary γ selectivity, we questioned if this Co-catalyzed C-to-C HAT strategy could also be interrupted. The central challenge to achieving remote functionalization in this manifold is differentiating between the two C-centered radicals. We reasoned that electron-deficient radical traps may preferentially react with the transposed alkyl radical C due to a polarity matched coupling of this nucleophilic intermediate (versus the electrophilic α- sulfonamide radical B). Carreira has shown Co-catalyzed MHAT may be coupled with electrophilic traps to afford alkene hydrofunctionalizations.^11,70,71 To our delight, these new radical chaperones also enable interruption of this cascade by intramolecular HAT to realize γ C-Cl, C-CN, and C-N bond formation – by the addition of stoichiometric PhSiH₃ and various radical traps (e.g. TsCl, TsCN, DBAD).

Figure 8.

Several classes of γ C-H functionalizations enabled by an interrupted radical cascade.

To probe the generality of these new γ C-H functionalizations, we chose three representative substrates, including amines with either a 3° C-H (36-38) or 2° C-H (39-41) at the γ position, as well as the amino acid, Leu (42-44). Notably, C-H chlorination (with TsCl) and C-H cyanation (with TsCN) are as efficient as the desaturation reaction. And although hydrazination with the bulky reagent, DBAD, was less efficient, its viability nonetheless shows that other radical trap classes are also amenable to this γ C-H functionalization. Importantly, γ C-H selectivity was exclusively observed in all cases (>20:1 rr), further demonstrating the robust 1,6-HAT selectivity of the α-sulfonamide radical.

Conclusions

In summary, a new vinyl sulfonamide radical chaperone has been computationally designed and experimentally developed to realize chemoselective, remote desaturation of amines, amino acids, and peptides. This strategy utilizes a triple HAT cascade, consisting of 1,6-HAT sandwiched between two metal-mediated HAT events, to facilitate remote transfer dehydrogenation. The scope of this transformation displays broad functional group tolerance with a range of amines including natural products and drug-like motifs. The selectivity of intramolecular C_sp3-C_sp3 HAT from the α-sulfonamide radical was interrogated by competition experiments that reveal a strong preference for 1,6-HAT. Lastly, this triple HAT cascade was interrupted by addition of radical traps to realize remote C-Cl, C-CN, and C-N bond formation via polarity-matched couplings. We anticipate this new (i) radical chaperone and (ii) MHAT-HAT-MHAT cascade will each serve as platforms for inventing further, versatile tools for remote C-H functionalization.