α-Chiral Amines via Thermally Promoted Deaminative Addition of Alkylpyridinium Salts to Sulfinimines

Abstract

A deaminative reaction of Katritzky alkylpyridinium salts and sulfinimines has been developed to deliver enantiopure α-chiral amines. The success of this method relied on the discovery of a thermally promoted deamination via single-electron transfer of an anion–π complex of the alkylpyridinium cation with potassium carbonate. This method boasts excellent diastereoselectivity over the α-stereocenter, as well as broad functional group and heterocycle tolerance.

Graphical Abstract

α–Chiral amines are a ubiquitous functional group in a variety of pharmaceuticals and natural products, making them important targets in organic synthesis. In particular, enantiopure α-branched benzylic amines are found in a multitude of biologically active compounds and are of high value in medicinal chemistry.¹ Chiral auxiliary-directed addition to enantiopure sulfinimines has been shown to be a useful strategy to form these desirable products.² Traditionally, these additions have utilized organometallic nucleophiles, inherently limiting the functional group tolerance.³ Recently, addition of an alkyl radical has been demonstrated as an alternative method that offers wider functional group tolerance (Scheme 1A). Tin-mediated activation of alkyl iodides has demonstrated these to be competent alkyl radical precursors.⁴ Redox-active esters have also been used with both photoredox and nickel catalysis.^5,6

Scheme 1.

Radical Additions to Sulfinimines

Because the discovery of new α–chiral amines (and their derivatives) for specific pharmaceutical applications relies on gaining access to a wide array of these structures, we sought to develop a method to these important products that would use an abundant feedstock class and deliver complimentary diversity to that possible from alkyl iodides and carboxylic acids. As such, alkyl amines amply fulfill these criteria, ranging from simple building blocks to complex pharmaceutical intermediates.⁷ Furthermore, their conversion to Katritzky pyridinium salts (1) makes them competent precursors to alkyl radical intermediates.⁸ Since our 2017 report,⁹ these Katritzky pyridinium salts have been activated via single-electron transfer (SET) using nickel catalysts or stoichiometric reductants (e.g., Mn),^{7, 10} photoredox catalysis,¹¹ and photochemically promoted electron transfer of electron donor-acceptor (EDA) complexes.^12,13 Rare examples of thermally promoted SET of EDA complexes of alkylpyridinium salts with amine bases have also been reported.¹⁴ In developing this reaction, we have discovered the ability of potassium carbonate to form a complex with the alkylpyridinium salt, which undergoes SET under thermal conditions. These mild, transition metal-free conditions enable synthesis of α–chiral sulfinamides with broad tolerance for functional groups and heteroaryls, ultimately providing efficient access to valuable enantiopure amines upon cleavage of the sulfinamide (Scheme 1B).

We selected alkylpyridinium salt 1a and sulfinimine 2a for our initial studies. Based on precedent with both redox-active esters and pyridinium salts, we tried both stoichiometric reductants and photoredox-catalyzed methods.^{7, 10–11} Although Zn seemed promising as a reductant (both with and without nickel), these results proved to be irreproducible.¹⁵ In contrast, we observed a reproducible 23% yield of desired product using Ir((dtbbpy)ppy)₂PF₆ as a photoredox catalyst in the presence of K₂CO₃ (Table 1, entry 1).¹⁶ However, a control experiment demonstrated that this reaction proceeds in increased yield without photocatalyst (48%, entry 2). We hypothesized this reaction to be occurring via activation of the alkylpyridinium salt within an electron donor-acceptor (EDA) complex.^{12, 17} Surprisingly, the yield was not impacted when this reaction was performed in the dark at 50 °C (entry 3). We also observed a strong effect of the equivalents and solubility of the carbonate base (entries 3–5) and on the identity of the base (entries 6–8). Ultimately, we found 3 equivalents of K₂CO₃ provided the optimal yield (entry 4). In addition, supersilanol, (TMS)₃SiOH, uniquely provided reactivity. Other common reagents for hydrogen atom transfer (HAT), including other silanols, silanes, and Hantzsch ester, failed (entry 8).¹³ At this point, we considered that activation of the pyridinium may involve either an EDA complex with sulfinimine or an anion–π complex with carbonate. Light-promoted SET of alkylpyridinium salt EDA complexes has been previously reported. Notably, the thermal activation of alkylpyridinium salts via this type of strategy has only been rarely reported.^14,17

Table 1.

Radical Generation/Addition Reaction Optimization^a

entry	mol % [Ir]	base	conditions	temp (°C)	yield (%)b
1	2.5	K2CO3	Blue LED	38	23
2	0	K2CO3	Blue LED	38	48
3	0	K2CO3	dark	50	52
4c	0	K2CO3	dark	50	65
5	0	Na2CO3	dark	50	16
6	0	K3PO4	dark	50	14
7	0	KHCO3	dark	50	26
8d	0	K2CO3	dark	50	2
9	0	none	dark	50	0

^aConditions: alkylpyridinium salt 1a (0.25 mmol, 2.5 equiv), sulfinimine 2a (0.1 mmol, 1.0 equiv), Ir((dtbbpy)ppy)₂PF₆ (0.025 equiv), K₂CO₃, TMS₃SiOH (0.15 mmol, 1.5 equiv), DMA (0.11 M), 22 h, unless noted otherwise.

^bDetermined by ¹H NMR using 1,3,5-trimethoxybenzene as internal standard.

^c3.0 equiv K₂CO₃.

^dHantzsch ester (1.5 equiv) in place of (TMS)₃SiOH.

These optimized conditions were successful for a range of secondary alkylpyridinium salts. Both cyclic (3–9) and acyclic (10–14) alkyl groups can be incorporated in moderate to high yields, including a variety of alkyl ring sizes. Additionally, this method tolerates a variety of functional groups including ethers (3 and 14), carbamates (4), esters (8, 13, and 14), and ketones (13 and 14). The sulfinimine effectively controls the diastereoselectivity at the α-position, giving single diastereomers (>20:1 dr) when the α-carbon is the only new stereocenter. For stereogenic alkylpyridinium salts, a mixture of diastereomers is observed, consistent with an alkyl radical intermediate (11–14). Alkylpyridinium salt derivatives of isoxepac (13) and ketoprofen (14) were synthesized and successfully functionalized, demonstrating the utility of this method for late-stage derivatization of more complex molecules. Notably, when our model reaction was performed without oven-dried glassware and without precautions against air or moisture, product 3 is still generated in useful yield, which may be advantageous for certain medicinal chemistry applications such as library generation. As is commonly observed for photochemically promoted reactions of alkylpyridinium salts and is consistent with the more difficult generation of a primary alkyl radical,¹⁸ primary alkylpyridinium salts do not form desired product.¹³

With respect to the sulfinimine, we were excited to observe broad functional group tolerance, including multiple phenyl derivatives as well as a range of heteroaryl groups. Substrates with electron-poor aryl groups work best, presumably due to their increased electrophilicity (16–19). Specifically, this method was effective for substrates with aryl chloride (16), fluoride (19), trifluoromethyl (17), and nitrile (18) groups. The incorporation of the aryl chloride and nitrile conveniently allows for further functionalization of these products. In terms of heteroaryl groups, 2- and 3-pyridyl (21 and Scheme 2), pyrimidyl (20), indolyl (23), and quinolyl (24) were well tolerated. Steric hindrance is also allowed; ortho-methylpyridine 22 was formed in 54% yield. As expected, with enantiopure sulfinimines, we observe comparable yields, confirming that this method can provide enantiopure α-branched benzylic amines after cleavage of the sulfinamide auxiliary.^5b

Scheme 2. Scope of Alkylpyridinium Salts^a.

aConditions: alkylpyridinium salt 1 (2.5 mmol, 2.5 equiv), sulfinimine 2a (1.0 mmol, 1.0 equiv), K₂CO₃ (3.0 mmol, 3.0 equiv), (TMS)₃SiOH (1.5 mmol, 1.5 equiv), DMA (0.11 M), 50 °C, 24 h. Single diastereomer observed (>20:1 dr) unless noted otherwise. ^bMinimal precautions to protect from air and moisture. See Supporting Information. ^cTrans and cis unassigned.

Intrigued by the rarity of this thermally activated deamination, we undertook a series of mechanistic experiments. We studied the UV-Vis spectra of pyridinium salt 1a with the other reaction components. As shown in Figure 1, the combination of pyridinium 1a with K₂CO₃ resulted in formation of a new complex, with a diagnostic red-shifted absorption consistent with formation of an anion–π complex (Figure 1A and B). Importantly, this same UV-Vis peak is observed under our reaction conditions (Figure 1B). Although this complex was not observed by ¹H NMR spectroscopy, by employing Job’s method of continuous variation, we determined the stoichiometry of this complex to be 1:1 between the alkylpyridinium salt 1a and K₂CO₃. Potassium carbonate has been previously shown to form anion–π complexes with N-aryloxyamides, lending credence to our proposal.¹⁹ In contrast, the addition of sulfinimide or supersilanol to the pyridinium did not result in a new complex by UV-Vis. We also confirmed the likely intermediacy of the proposed alkyl radical. Addition of the radical trapping agent diphenyl disulfide to the reaction resulted in formation of thiol 25 (Figure 1C). Sulfinamide 15 was not formed under these conditions.

Figure 1.

Mechanistic Investigations: (A) Color change upon combination of pyridinium 1a and K₂CO₃. Vial 1: pyridinium 1a (0.28 M), DMA. Vial 2: K₂CO₃, DMA. Vial 3: pyridinium 1a (0.28 M), K₂CO₃, DMA. (B) UV-Vis spectra. ● Pyridinium 1a (3.0 mM), DMA. ■ K₂CO₃ (3.0 mM), DMA. ▲ Pyridinium 1a (3.0 mM), K₂CO₃ (3.0 mM), DMA. ▼ Pyridinium 1a (3.0 mM), K₂CO₃ (3.0 mM), sulfinimine 2a (1.0 mM), (TMS)₃SiOH (1.5 mM), DMA. (C) Radical trapping experiment. Yield determined by ¹H NMR using 1,3,5-trimethoxybenzene as internal standard.

These results are consistent with the mechanism shown in Scheme 4. The complex formed between the alkylpyridinium salt and K₂CO₃ (26) can undergo a thermally promoted SET to generate dihydropyridyl radical 27, which fragments to provide alkyl radical 28. This alkyl radical can then add to the sulfinimine, forming radical 29. Hydrogen-atom transfer (HAT) from supersilanol can then provide our final product 30 and oxygen-centered radical 31. The unique effect of supersilanol to promote this reaction may be due to the ability of radical 30 to undergo a Brook-type rearrangement to give the more stable silicon-centered radical 32.¹⁶ Radical 32 may then trap the carbonate radical anion, ultimately resulting in decarboxylation and providing a thermodynamic sink to drive this reaction forward. Since Katritzky’s 1981 report of the reaction of alkylpyridinium salts with alkyl nitronates,¹⁷ this is one of a few rare examples of a thermally promoted activation of alkylpyridinium salts via an anion–π or EDA complex.¹⁴

Scheme 4.

Proposed Mechanism

In summary, we have developed a deaminative approach for the preparation of highly enantioenriched α-chiral amines via the reaction of alkylpyridinium salts and sulfinimines. This method offers broad functional group and heteroaryl tolerance. The success of this method relied on the realization of an underutilized activation mode for alkylpyridinium salts: a thermally promoted single-electron transfer of an anion–π complex. Our mechanistic studies suggest that this complex is formed with K₂CO₃, and we are excited to understand the generality of this approach for deaminative reactions. These studies are ongoing in our lab.

Scheme 3. Scope of Aryl Sulfinimines^a.

aConditions: alkylpyridinium salt 1 (3 mmol, 3 equiv), sulfinimine 2 (1.0 mmol, 1.0 equiv), K₂CO₃ (3.0 mmol, 3.0 equiv), (TMS)₃SiOH (1.5 mmol, 1.5 equiv), DMA (0.11 M), 50 °C, 24 h. Single diastereomer observed (>20:1 dr). ^b0.5 mmol scale. ^c0.25 mmol scale.