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Stereoretentive cross-coupling of chiral amino acid chlorides and hydrocarbons by way of mechanistically managed Ni/Ir photoredox catalysis


Response optimization

N-Phthaloyl-L-phenylalanine (1a) and cyclohexane have been chosen as mannequin substrates to research the response circumstances (Desk 1). Compound 1a was handled with an in situ generated Vilsmeier reagent47,48 to furnish amino acid chloride 2a. After the straightforward evaporation of volatiles, 2a was used for the response with out additional purification. The response circumstances have been optimized to acquire goal product 3a in 81% NMR yield (74% remoted yield) utilizing 3 equiv of cyclohexane and a couple of equiv of two,6-lutidine (entry 1). Notably, no lack of stereochemical integrity occurred because the product was obtained in 99% ee (an identical to that of 1a, Supplementary Desk 1). A superb yield was additionally obtained with just one equiv of cyclohexane (entry 2) and the yield turned practically quantitative with 5 equiv of cyclohexane (entry 3), indicating that the proportion of a C–H substrate may be flexibly tuned relying on its availability and price. Lowering the quantity of two,6-lutidine led to a slight lower within the response effectivity (entry 4). To evaluate the reactivities of various pyridine derivatives, structurally numerous pyridines have been examined. With pyridine itself, the response effectivity tremendously decreased, doubtless attributable to undesired radical addition to pyridine (entry 5)49. When 2,4,6-collidine was launched as a substitute of two,6-lutidine, an analogous but barely diminished reactivity was noticed (entry 6). Using 2,6-di-tert-butylpyridine led to an enormous lack of response effectivity, demonstrating {that a} sterically extra hindered pyridine spinoff lowers the reactivity (entry 7)50. 2,4,6-Triphenylpyridine, which can kind an acyl analog of the Katritzky salt51,52, generated the focused product in a average yield (entry 8). When 2,6-lutidine was changed with widespread inorganic bases corresponding to cesium carbonate, sodium bicarbonate, or potassium phosphate, the response effectivity decreased considerably (entries 9–11). As well as, underneath base-free circumstances, solely a low yield of the specified product was noticed (entry 12), indicating the important function of two,6-lutidine. Management experiments with out mild, the nickel catalyst, or the photocatalyst failed to provide the specified product, implying that these parts are essential for the response to proceed (entry 13).

Desk 1 Optimization of response circumstancesa

Substrate scope

With the optimized circumstances in hand, the amino acid scope of the developed methodology was investigated (Fig. 2). The response was efficient with a variety of amino acids, demonstrating glorious useful group compatibility. Initially, a number of phenylalanine derivatives have been examined (3a3g). To our delight, even fluorine- or chlorine-substituted derivatives (3b3e) have been nicely tolerated, offering alternatives for additional functionalization. Electron-withdrawing trifluoromethyl and cyano teams on the phenyl ring of the phenylalanine didn’t have an effect on the response effectivity (3f, 3g). Different amino acids additionally efficiently delivered the corresponding chiral amino ketones. The best amino acid, glycine, exhibited an excellent yield (72%, 3h). Alkyl-chain-bearing amino acids corresponding to alanine, homoalanine, norvaline, leucine, and cyclohexylalanine, which possess excessive steric hindrance and hydrophobicity53, reacted easily underneath the usual response circumstances (3i3m). Homophenylalanine, an vital bioactive non-natural chiral amino acid54, successfully produced 3n in average yield (51%). Notably, amino acids bearing polar facet chains is also employed after applicable safety. OMethylated tyrosine reacted easily (43%, 3o). Moreover, benzyl-protected serine gave the specified ketone in average yield (50%, 3p). Aspartic acid and glutamic acid methyl esters furnished chiral amino ketones bearing ester facet chains, albeit in decrease yields (54%, 3q; 27%, 3r). The reactions of cyclic amino acids with totally different defending teams additionally furnished the goal merchandise (40%, 3s; 78%, 3t). Attributable to their innate instability and excessive tendency to endure racemization, peptidyl acid chlorides bearing greater than two amino acid residues couldn’t be employed47,48. As well as, α-amino acid homologues have been examined, as they’re identified to exhibit considerably totally different biochemical properties55. Two β-amino acids (β-alanine and β-phenylalanine) delivered the goal merchandise in superb yields (77%, 3u; 82%, 3v). Furthermore, γ-amino acids, corresponding to γ-aminobutyric acid (GABA), baclofen, and gabapentin, all successfully gave the corresponding merchandise in good yields (67–74%, 3w3y).

Fig. 2: Amino acid scope.
figure 2

Response circumstances: 1a–1y (0.20 mmol), oxalyl chloride (1.8 equiv), DMF (cat., 0.2 μL), and CH2Cl2 (2.0 mL). After evaporation of the remaining solvent, NiCl2·glyme (5 mol %), dtbbpy (10 mol %), 2,6-lutidine (2.0 equiv), cyclohexane (3.0 equiv), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol %), and benzene (8.0 mL) have been added, and the answer was irradiated for 12 h with a Penn PhD M2 photoreactor. All yields are remoted yields.

Subsequent, the scope of C(sp3)–H substrates was examined (Fig. 3). The reactions with easy cyclic alkanes, from cyclopentane to cyclododecane, proceeded easily (4a7a). An acyclic alkane, pentane, additionally easily produce the specified aminoketone as a mix of regioisomers (8a, α:β:γ = 1.0:6.0:3.3, 5% terminal selectivity after statistical correction). Bicyclic compounds corresponding to norbornane and 7-oxanorbornane additionally effectively furnished the goal merchandise (78%, 9a; 67%, 10a). Adamantane was acylated solely on the secondary place (32%, 11a), per a earlier report33. Cyclic ethers together with tetrahydrofuran, tetrahydropyran, and 1,4-dioxane gave superb to glorious yields (12a14a), exhibiting unique selectivity for the extra reactive ethereal C–H bonds. Acyclic ethereal substrates corresponding to diethyl ether and methyl tert-butyl ether additionally reacted easily (89%, 15a; 78%, 16a). Varied anisole derivatives reacted nicely underneath the optimized circumstances (17a19a), exhibiting tolerance for halogen functionalities on the fragrant ring. To our delight, an amino acid fragment was immediately launched into the well-known ionophore 12-crown-4 in a synthetically relevant yield (68%, 20a), thus realizing one-pot manufacturing of a crown ether with a chiral α-amino ketone moiety. When pyranone was used because the coupling associate, the 1,4-dicarbonyl 21a was obtained in 67% yield. Acetals have been additionally efficiently functionalized to supply α-ketoacetal merchandise (80%, 22a; 68%, 23a)56,57.

Fig. 3: C–H substrate scope.
figure 3

Response circumstances: 1a (0.20 mmol), oxalyl chloride (1.8 equiv), DMF (cat., 0.2 μL), and CH2Cl2 (2.0 mL). After evaporation of the remaining solvent, NiCl2·glyme (5 mol %), dtbbpy (10 mol %), 2,6-lutidine (2.0 equiv), C–H substrate (3.0 equiv), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol %), and benzene (8.0 mL) have been added, and the answer was irradiated for 12 h with a Penn PhD M2 photoreactor. All yields are remoted yields. ad.r. = 1:1. bd.r. = 2:1. cr.r. = 4:1; d.r. for the minor regioisomer = 1:1. d10 equiv of C–H substrate. ed.r. = 3:1.

The direct cross-coupling of amino acids and amino alkyl substrates produced unsymmetrical α,α′-diaminoketones in superb yields (79–89%, 24a26a). Though some 1,3-diaminoketone compounds have been reported to exhibit bioactive properties2, artificial entry to this substrate class has been restricted13. To the very best of our information, the developed response is exclusive in offering direct artificial entry to α′-oxy- or α′-amino-substituted chiral amino ketones. As a result of α-heteroatom-substituted organometallic reagents can’t be readily ready, transition-metal-catalyzed cross-coupling reactions (Fig. 1a) usually are not readily relevant for synthesizing such compounds14,15. Toluene, o-xylene, and p-xylene delivered the specified merchandise in average yields (52–70%, 27a29a); nonetheless, benzylic functionalization required extra equivalents (10 equiv) of the C–H substrate. Aryl chlorides have been additionally tolerated because the C–H substrate, as within the case of amino acids (30a32a). Complicated bioactive C–H substrates have been additionally tolerated producing the corresponding amino-acid-coupled complexes. Ambroxide (61%, 33a) and gemfibrozil (70%, 34a) reacted easily to supply the coupled merchandise in a regioselective trend, which demonstrates the streamlined late-stage introduction of a chiral amino acid moiety, benefiting from the wonderful useful group compatibility of the developed protocol. Having noticed that our response disfavors tertiary C–H bonds when adamantane was used, we tried an intermolecular competitors experiment utilizing an equal quantity of cyclohexane and a couple of,3-dimethylbutane (Supplementary Fig. 40). The response solely furnished the secondary C–H functionalized product 3a, albeit in a lowered yield (63%, 99% ee). We presume this uncommon secondary selectivity arises from steric hindrance decreasing the reactivity on the tertiary place. Lastly, the stereochemical integrity of chosen merchandise (3a, 3k, 3l, 3n, 3o, 3s, 16a, 17a, 26a, and 27a as chosen based mostly on the restricted availability of racemic compounds) was investigated. The stereochemistry was totally maintained through the response, besides with benzylic substrates, which led to a small lower in enantiopurity (from 99% to 98% ee, Supplementary Desk 1).

Mechanistic investigations

After demonstrating the vast applicability of the developed response circumstances, the underlying response mechanism was investigated by way of complete computational and experimental research. First, management experiments have been carried out to check the developed response circumstances with the 2 beforehand reported protocols, which featured oxidative addition first16,30,31,32 or C–H activation first33 (Desk 2). The optimized response circumstances (entry 1) afforded the specified product in excessive yields with none enantiomeric loss, whereas the beforehand reported response circumstances exhibited low yields accompanied by a big lower in enantioselectivity (entries 231 and three33). Even when N-acylsuccinimide 35a was employed underneath the reported circumstances33 for the C–H-activation-initiated pathway, no product was generated (entry 4). It has been reported that such acyclic secondary-alkyloyl-derived N-acylsuccinimide substrates are incompatible, presumably attributable to their sensitivity to sterics33. Notably, a dimerization byproduct (2a-dimer) was detected in each entries 2 and three, however no such product was generated underneath the developed response circumstances, implying that undesirable decarbonylation or transmetalation processes have been efficiently suppressed by the proposed technique.

Desk 2 Management experiments underneath reported circumstances for Ni/Ir-catalyzed C(sp3)–H acylationa

It’s nicely documented that N-acylpyridiniums may be generated from acyl chlorides and pyridines58. Some stabilized N-acylpyridiniums, corresponding to N-acylpyridinium and N,N-dimethylaminopyridinium salts, have been remoted and totally characterised44,59. Nonetheless, makes an attempt to isolate the N-acyllutidinium intermediate 2z-lut have been unsuccessful, presumably as a result of its stability was decreased by the steric hindrance of the pyridine ring.

As a substitute, in situ NMR research have been carried out to research the formation of 2a-lut. The 1H NMR spectrum of a 1:2 combination of 2a and a couple of,6-lutidine is proven in Fig. 4a. Right here, an upfield shift of the 2a resonances and a downfield shift of the two,6-lutidine methyl peak was witnessed. This commentary is in good settlement with the analogous lutidinium salt generated from ethyl chlorooxoacetate and a couple of,6-lutidine, reported by the Wu group46. As well as, pronounced peak broadening and even separation of the α-carbonyl proton resonance have been detected, doubtless as a result of steric bulkiness of the two,6-lutidine moiety resulting in the formation of rotameric species. An NOE research of this combination indicated NOE indicators between the carbonyl α-proton, benzylic proton and the lutidine methyl group, indicating their presence in the identical molecule. Additional research have been carried out by monitoring the IR carbonyl stretch of cyclohexane carbonyl chloride (2aa) with and with out the addition of two,6-lutidine (Fig. 4b). Right here, 2aa was chosen because the phthalimide group current in 2a led to complicated carbonyl absorptions. The attribute carbonyl stretch of 2aa was noticed at 1789 cm−1. When 1 equiv of two,6-lutidine was launched, the IR spectrum clearly confirmed a brand new absorption band within the carbonyl area at 1741 cm−1. That is indicative of the formation of a brand new carbonyl species, just like the postulated N-acyllutidinium intermediate.

Fig. 4: Mechanistic research.
figure 4

a NMR research. b IR research. c Radical scavenger experiment. Yields have been decided utilizing 1H NMR spectroscopy with 1,1,2,2-tetrachloroethane as an inner commonplace. d Cyclic voltammetry research. e Stern–Volmer quenching experiment.

After confirming the technology of an N-acyllutidinium compound, the single-electron discount of the N-acyllutidinium intermediate was investigated. When 2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO, 1 equiv) was launched, acyl-TEMPO (2a-TEMPO) was shaped in 51% yield, not directly confirming the technology of acyl radicals through the response (Fig. 4c). Subsequent, cyclic voltammetry experiments have been carried out with 2aa because the mannequin substrate (Fig. 4d). The measured discount potential of 2aa was –2.45 V vs SCE, which signifies that the direct discount of 2aa just isn’t possible with the iridium photocatalyst (Ir[dF(CF3)ppy]2(dtbbpy)PF6, Eopink = −1.37 V vs SCE)60,61. After the addition of two,6-lutidine, the discount wave of 2aa was diminished, accompanied by the formation of a brand new irreversible discount wave at Ep = −0.95 V vs SCE. This new discount doubtless originated from the lutidinium intermediate 2aa-lut. The noticed worth, which falls inside the vary appropriate for discount by Ir[dF(CF3)ppy]2(dtbbpy)PF6, is in good settlement with the computed discount potential of 2aa-lut (−1.05 V vs SCE). This variation within the discount potential means that the technology of acyl radicals is facilitated by the formation of an N-acyllutidinium intermediate, as initially postulated. Moreover, the discount potential of the lutidinium species when coordinated to nickel catalyst (3IV-2aa) was computed to be much less destructive (–0.85 V vs SCE), indicating that the nickel catalyst might facilitate the discount course of. As well as, Stern–Volmer quenching experiments have been carried out with 2a and a couple of,6-lutidine. 2a or 2,6-lutidine alone couldn’t successfully quench the iridium photocatalyst. Nonetheless, a 1:2 combination of 2a and a couple of,6-lutidine confirmed extremely environment friendly quenching of the excited photocatalyst (Fig. 4e). General, these mechanistic research verify that the proposed N-acyllutidinium intermediate is certainly generated and may be successfully diminished to furnish the postulated acylnickel species.

Moreover, to acquire an improved understanding of the response mechanism, computational research have been carried out utilizing density useful principle (DFT) on the B3LYP-D3/6-311++G**/SDD62,63 degree of principle (Supplementary Information 1). First, the redox limitations (ΔG) of preliminary catalytic species (dtbbpy)NiIICl2 3I have been investigated utilizing Marcus principle64,65 to make clear its conduct (Fig. 5). The barrier for discount of 3I to Ni(I) species 2II, a key course of within the oxidative-addition-initiated pathway, was computed to be 21.7 kcal/mol. Equally, the barrier for the oxidation of 3I to high-valent Ni(III) species 2III within the C–H-activation-initiated pathway was decided to be 25.4 kcal/mol. In distinction, the proposed single-electron discount of 2z-lut after binding to nickel species 3IV was discovered to be virtually barrierless, immediately delivering acylnickel(III) intermediate 2V. These outcomes clearly point out that the discount of 2z-lut is favored over the redox processes of the related nickel species, and this serves as a thermodynamic sink to drive the response.

Fig. 5: Computed redox properties of Ni(II) and N-acyllutidinium species.
figure 5

The discount of Ni-coordinated N-acyllutidinium species 3IV was computed to be virtually barrierless (0.7 kcal/mol), outcompeting different redox pathways involving the nickel precatatlyst 3I.

A full power profile for the proposed pathway was constructed by way of intensive computational research (Fig. 6). Initially, the N-acyllutidinium intermediate undergoes facile coordination to nickel precatalyst 3I to provide 3IV. Initially, the N-acyllutidinium intermediate undergoes facile coordination to nickel precatalyst 3I to provide 3IV, adopted by an primarily barrierless discount (0.7 kcal/mol) to kind 2V (–28.8 kcal/mol), which serves as a thermodynamic sink, rendering this course of irreversible. The photolysis of 2V might result in its excited state V*, which undergoes chlorine-mediated hydrogen atom switch to provide alkylnickel species 2VI (3.7 kcal/mol). Excited state V* and its C–H abstracting transition state couldn’t be positioned in a simple method utilizing DFT. Nonetheless, it’s nicely documented that such processes are downstream transformations when assisted by mild as an power supply66,67. This course of has served as a elementary step for the event of quite a lot of C(sp3)–H functionalization reactions by way of the implementation of photoirradiated Ni/Ir twin catalysis68. Kinetic isotope impact (KIE) experiments utilizing 2a as a substrate resulted in okH/okD values of 1.08 (parallel reactions) and PH/PD values of 1.83 (intermolecular competitors reactions)69 (Supplementary Fig. 5557). This means that the product-determining C–H activation (2V to 2VI) just isn’t the turnover-limiting step33. Reductive elimination by way of 2VI-TS to provide the specified product was discovered to have an activation barrier of 8.7 kcal/mol70. Lastly, the oxidation of Ni(I) species 2VII to preliminary precatalyst 3I by way of VII-TS (–21.5 kcal/mol) completes the catalytic cycle. On this case, the general response barrier (8.7 kcal/mol) may be very low, which accounts for the kinetic inhibition of facet reactions corresponding to decarbonylation. These outcomes point out that modulation of the redox state of the nickel species is fairly sluggish. Thus, the designed technique, which bypasses the redox processes of the nickel species, is essential for direct C(sp3)–H coupling between chiral α-amino acid chlorides and hydrocarbons.

Fig. 6: Computed free power profile for the general response with substrate 2z.
figure 6

The computed response profile demonstrates facile discount of 3IV adopted by photolytic C–H activation and reductive elimination to ship amino ketone product 3z. Energies are given in kcal/mol values.

Combining the experimental and computational findings, a believable mechanism is proposed, as proven in Fig. 7. The N-acyllutidinium intermediate binds to the nickel(II) precatalyst, producing 3IV. Subsequent single electron discount of 3IV furnishes acyl group-bound 2V together with the liberation of two,6-lutidine. This high-valent nickel species undergoes hydrogen atom switch mediated by a chlorine radical liberated by way of direct photolysis to yield alkyl acyl nickel species 2VI. This species then undergoes reductive elimination to ship the specified ketone product, adopted by reoxidation of the ensuing Ni(I) species 2VII to its preliminary state 3I.

Fig. 7: Proposed response mechanism.
figure 7

The iridium photocatalyst serves to scale back the N-acyllutidnium sure to the Ni(II) species (3IV), furnishing Ni(III) species 2V. 2V undergoes light-assisted C–H activation and discount elimination to ship the ketone product and Ni(I) species 2VII. Lastly, 2VII is oxidized again the the preliminary catalyst 3I.

In conclusion, cross-coupling between chiral amino acid chlorides and unactivated C(sp3)–H substrates was realized utilizing nickel/photoredox twin catalysis underneath delicate response circumstances. By means of strategic modulation of the response mechanism, quite a lot of chiral amino acids have been remodeled into the corresponding amino ketones with out the lack of stereochemical integrity. This methodology overcomes the constraints related to decarbonylative racemization in beforehand reported methodologies for Ni/photoredox catalysis. Complete mechanistic research revealed that the N-acyllutidinium intermediate, generated from the acid chloride and a couple of,6-lutidine, is essential for driving the response to the profitable reduction-initiated pathway. This pathway commences with the single-electron discount of the N-acyllutidinium species, thus immediately furnishing an acylnickel(III) intermediate and stopping undesirable facet reactions. Computational evaluation revealed that modulating the nickel oxidation state is a sluggish course of that will result in acyl radical decarbonylation. Thus, circumventing this course of with the developed reduction-initiated technique is essential for sustaining the optical purity of the product. Varied functionalized chiral amino ketones have been effectively synthesized utilizing the developed response. The current findings exhibit profitable mechanistic management to understand a difficult coupling response in Ni/photoredox catalysis, which may present additional perception into the event of recent artificial strategies.

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