Harnessing Sulfur(VI) Fluoride Exchange Click Chemistry and Photocatalysis for Deaminative Benzylic Arylation

While being among the most common functional handles present in organic molecules, amines are a widely underutilized linchpin for C–C bond formation. To facilitate C–N bond cleavage, large activating groups are typically used but result in the generation of stoichiometric amounts of organic waste. Herein, we report an atom-economical activation of benzylic primary amines relying on the sulfur(VI) fluoride exchange (SuFEx) click chemistry and the aza-Ramberg–Bäcklund reaction. This two-step sequence allows the high-yielding generation of 1,2-dialkyldiazenes from primary amines via loss of SO2. Excitation of the diazenes with blue light and an Ir photocatalyst afford radical pairs upon expulsion of N2, which can be coaxed into the formation of C(sp3)–C(sp2) bonds upon diffusion and capture by a Ni catalyst. This arylative strategy relying on a traceless click approach was harnessed in a variety of examples, and its mechanism was investigated.

P rimary amines are one of the most ubiquitous functional groups found across families of natural products�from proteins and peptides to alkaloids and amino sugars�and in synthetic pharmaceuticals. 1 Despite their undisputed prevalence, aliphatic amines are not nearly as popular as functional handles for scaffold diversification as other functional groups such as alkyl halides, carboxylic acids, and alcohols.−5 Heterolytic displacement of amines is disfavored by the poor leaving group ability of this basic functional group, 6 and synthetically useful homolytic cleavages remain elusive.Various strategies have therefore been explored to favor C−N activation via prefunctionalization (Scheme 1A).Early examples include diazonium salts, 7,8 but these highly reactive intermediates prone to elimination typically lead to undesired side reactions and poor functional group tolerance.An interrupted diazotization strategy was recently leveraged to functionalize α-primary benzylamines with boronic acids. 9Benzylic ammonium salts have been coupled with boronic acids; 10 however, the need for strongly alkylating agents potentially limits the scope of suitable substrates.Katritzky-type pyridinium salts have been employed in several photocatalytic and metal-catalyzed cross-coupling reactions, affording a powerful platform to activate primary amines bearing moderate steric hindrance. 11−23 Electron-rich trimethoxyphenyl imine provided an alternative approach, complementary in scope (αtertiary primary amines) to the pyridylation activation. 24,25inally, a nitrogen-deletion strategy promoted by anomeric amides in the presence of secondary amines has been reported 26 and subsequently expanded to deaminative functionalizations of primary amines, 27,28 albeit not in C−C cross-couplings.A common trade-off for these elegant strategies is the use of large activating groups, which lowers the activation barrier for C−N bond cleavage but creates large amounts of waste.
We describe herein a mild and atom-economical deaminative arylation relying on the formation of N,N′-disubstituted sulfamides using sulfur(VI) fluoride exchange (SuFEx) click chemistry, followed by oxidative formation of a 1,2-diazene concomitant with loss of SO 2 and Ni-catalyzed arylation (Scheme 1B).We hypothesized that fragmentation of the diazene induced by energy transfer would offer a manifold for sp 3 −sp 2 coupling via radical capture of a Ni catalyst if radical recombination can be discouraged.The loss of small, gaseous byproducts would minimize waste and facilitate purification in contrast to the large activating groups traditionally used.While literature precedent on SuFEx 29−31 and diazene chemistry 32 suggests that this sequence would provide a general platform for C−N activation, the desired path is unprecedented and hinges upon optimization of elementary steps in the process to ensure that (1) cage escape outcompetes radical recombination, (2) conditions for the radical generation and Ni catalysis are orthogonal, and (3) the rate of fragmentation closely matches the rate of arylation to avoid accumulation of radicals.Overall, the development of this process is expected to provide both a traceless click method for skeleton diversification and fundamental insights into the reactivity of diazene intermediates.
Our investigation began with the search for efficient conditions to produce diazenes from primary amines and optimize the generation of the radical pair (Scheme 2).(S)-1a was selected as a test substrate because of the relative stability of benzylic radicals.Using an enantiopure amine helped streamline the optimization of the first two steps by preventing the formation of diastereomeric mixtures.SuFEx offers milder reaction conditions leading to high functional group tolerance compared to oxidative reagents such as SO 2 Cl 2 .Our previously developed two-step synthesis of sulfamides 33 was telescoped to offer a one-pot synthesis of symmetrical compounds.Treatment of (S)-1a with imidazolium reagent 2 34 followed by addition of DBU and heating to 50 °C delivered N,N′disubstituted sulfamide (S,S)-3a in 90% yield.−40 Pleasingly, a combination of inexpensive TCCA and DBU delivered diazenes in high yields without epimerization (90% for (S,S)-4a).
Fragmentation of diazenes induced with high-energy UV light proceeds through the singlet excited state on a subpicosecond time scale, which favors fast recombination of the geminate radical pairs within the solvent cage. 41,42Aiming to divert reactivity in the presence of a Ni catalyst and favor capture of the carbon-centered radical instead, we decided to explore a triplet sensitization process using a photocatalyst and visible light.Indirect excitation was hypothesized to provide several advantages.First, generation of a geminate triplet pair  Ratio of Alk• to 6 is 1:1.5.b Abbreviation: DMAc, dimethylacetamide.c Yields were determined by 1 H NMR using phenyltrimethylsilane as standard and calculated based on (S,S)-4a = 2 equiv of Alk•.that must undergo intersystem crossing prior to recombination would potentially increase the likelihood of cage escape. 32,41econd, visible light provides a safer alternative to UV irradiation that also minimizes undesired side reactions.Because of their known compatibility in tandem catalysis involving Ni, and their high triplet excited state energy, 43,44 Ir photocatalysts Ir-1−Ir-4 were screened for the fragmentation

ACS Catalysis pubs.acs.org/acscatalysis
Letter of (S,S)-4a (Scheme 2).MeCN was selected for its low viscosity (0.37 mPa s at 25 °C), 45 a parameter favoring diffusion of radical pairs apart to form free radicals. 46ratifyingly, all four Ir catalysts provided homocoupled product 5a in 61−84% yield under blue light (450 nm).In all cases, racemization was observed and a mixture of meso and non-meso compounds 5a was isolated in ∼1:1 dr.This loss of stereochemistry is similar to that previously observed in the thermal degradation of (S,S)-4a and is consistent with radical diffusion. 47ith the conditions in hand to effect diazene fragmentation with visible light, we turned our attention to the optimization of the Ni-catalyzed arylation process using (S,S)-4a and aryl bromide 6. Extensive screening of the reaction conditions (Tables S1−S6) revealed that NiBr 2 •(L1), Ir-3, and Zn powder in a 95:5 mixture of MeCN and DMAc led to the formation of 7a in 60% yield, along with 27% of homodimer 5a (Table 1, entry 1).Importantly, the yield was calculated based on two carbon-centered radicals generated for each equivalent of diazene (S,S)-4a.Therefore, only a slight effective excess of aryl bromides to the radical species (1.5:1) is necessary for efficient arylation.Replacement of NiBr 2 •(L1) by Ni(acac) 2 or Ni(TMHD) 2 resulted in a small decrease of the yield of 7a (entries 2 and 3).Switching to bisoxazoline ligand L2 was accompanied by a stark decrease in the yield of 7a (entry 4).Interestingly, Ir-2 and Ir-4 also provided reduced efficiency for radical capture concomitant with a marked prevalence for radical recombination in the case of Ir-4 (16% vs 61%, entries 5 and 6).A small amount of DMAc (5%) was found to be crucial to ensure efficient arylation (entry 7).Other reducing agents such as Mn did not perform as well as Zn (entry 8).Addition of KH 2 PO 4 delivered 7a the highest yield (65%, entry 9).Finally, control reactions showed that only a trace amount of 5a was formed without photocatalyst and neither 5a nor 7a were isolated without light (entries 10 and 11).
Exploration of the scope of this transformation revealed that electron-deficient aryl bromides provided arylated products in high yields (Table 2).−50 Pinacol boronate 7j and fluorinated derivative 7k were isolated in good yields, which suggests that this method could be elaborated further with Suzuki coupling and S N Ar, two of the most popular reactions in the arsenal of medicinal chemists for the construction of therapeutic candidates. 51Sulfur(VI)containing functional groups including sulfonamide (7l) and sulfone (7m) that are prevalent in pharmacophores 52 and agrochemicals 53 were also compatible with this catalysis.Consistent with other related transformations, aryl bromides with strongly electron-donating substituents gave poor yields (Table S7) but, interestingly, 1,1′-biphenyl compound 7o was isolated in 42% yield.Finally, heteroaryl bromides are suitable as well, as shown by the synthesis of pyridine-containing product 7p.
A variety of α-secondary benzylic amines were carried through the C−N activation sequence.Notably, inconsequential mixtures of diastereomers were used for the cross-coupling step.Electron-donating substituents including alkyl (7q) and methoxy (7r,s) provided yields up to 81% compared to that of neutral 7a (65%), while catechol derivative 7t was produced in 47% yield.Interestingly, fluorinated product 7u was isolated in 45% yield.Increasing the steric hindrance around the amine resulted in moderate yields (7v−x).Finally, naphthalene derivative 7y was isolated in 47% yield.
The photoluminescence of Ir-1−Ir-4 with different concentrations of diazene (S,S)-4a was measured to gain a better understanding of the reaction mechanism.With all catalysts, the photoluminescence quenching by (S,S)-4a followed the Stern−Volmer equation (1), which, combined with literature precedent, 32 supports the postulated photosensitization step (Figure 1). 54 Importantly, the best catalyst for the arylation (Ir-3) corresponds to the lowest slope coefficient (K SV = 26 M −1 ), which is in line with our hypothesis that a low concentration of radical species would increase the yield of arylation.The generation of carbon-centered radical species was supported by the isolation of adduct 8 in the presence of TEMPO (2 equiv, Scheme 3A) and of unsaturated product 7z′ following cyclopropane ring opening during the coupling of diazene 4c and aryl bromide 6 (Scheme 3B).Finally, the stoichiometric reaction between Ni(II) complex Ni ox •(L1) and diazene 4b without Zn powder delivered 7n in a yield almost identical with that under catalytic conditions (Scheme 3C).A postulated mechanism based on these results is depicted in Scheme 3D.Putatively, photosensitized fragmentation of the diazene with Ir-3 leads to a carbon-centered radical pair, which, upon diffusion, is captured by the Ni(II) complex 55 arising from oxidative addition of the aryl bromide and Ni(0). 56Reductive elimination then delivers the cross-coupled product and single-electron reduction from Zn turns over the catalyst.−66 In summary, we have developed a mild and atomeconomical C−N activation strategy relying on SuFEx click chemistry combined with the aza-Ramberg−Backlund reaction.This sequence affords an efficient access to diazene molecules, which can be fragmented under blue light with a photocatalyst to form a radical pair.In the presence of a catalytic amount of NiBr 2 •(L1), an aryl bromide, and Zn, the carbon-centered radical can be directed toward the formation of the nondimeric C(sp 3 )−C(sp 2 ) bond-forming pathway rather than undergo recombination.In contrast to known deaminative arylations employing a photocatalyst in tandem with a Ni catalyst, this reaction is postulated to follow a neutral redox cycle.Substrate activation via sensitization 67 rather than single-electron transfer remains uncommon in light-mediated dual catalysis. 68This method therefore offers a unique manifold for reaction development, as well as a practical approach for the diversification of complex scaffolds that makes use of an underemployed type of functional handle.

* sı Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acscatal.3c01981.Detailed experimental procedures, spectroscopic characterization, and additional supporting data (PDF)

Table 2 .
Scope of the Deaminative Ni-catalyzed Arylation b a Ni(acac) 2 was used in lieu of NiBr 2 •(L1).b All reactions were run on a 0.13 mmol scale.Yields based on diazenes = 2 equiv of Alk•.

Table 1 .
Arylation Optimization and Control Reactions b