Photoredox-Mediated Generation of gem-Difunctionalized Ketones

12 hours ago - (1) Their synthesis generally involves two steps, including the use of electrophilic nitrogen sources like azadicarboxylates and organo...
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX

Photoredox-Mediated Generation of gem-Difunctionalized Ketones: Synthesis of α,α-Aminothioketones Neha Chalotra,† Masood Ahmad Rizvi,‡ and Bhahwal Ali Shah*,† †

AcSIR and Natural Product Microbes, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India Department of Chemistry, University of Kashmir, Srinagar 190006, India

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S Supporting Information *

ABSTRACT: A photoredox-mediated gem-difunctionalization of alkynes leading to the synthesis of α,α-aminothio-substituted carbonyl compounds is reported. The work presents concomitant introduction of α-C−N and C−S bonds as a key enabling advance. Furthermore, the low bond dissociation energy of the C−S bond compared to that of C−N or C−C bonds has been exploited for selective functionalization using different nucleophiles to build diverse α,αdisubstituted carbonyl scaffolds. Mild reaction conditions, broad substrate scope, and good yields are some of the added advantages of this reaction. arbonyl compounds containing an α-amino moiety have a pervasive presence in natural products and pharmaceutics such as plavix, bupropion, pyrovalerone, and effient.1 Their synthesis generally involves two steps, including the use of electrophilic nitrogen sources like azadicarboxylates and organonitroso compounds followed by subsequent derivatization to obtain desired amine functionality.2 Though the most logical and straightforward approach to access these molecules would be direct α-amination,3,1d it is not allowed as both centers are inherently nucleophilic, which makes them electronically mismatched. Nevertheless, in recent years, some catalytic approaches using aziridine or an α-substituted intermediate to facilitate intermolecular umpolung reactions have been developed for direct installation of an α-amino substituent.4 Furthermore, this becomes even more challenging in cases where we may wish to introduce two functional groups adjacent to carbonyl. To the best of our knowledge, concomitant introduction of two different groups at the geminal position leading to the synthesis of α,α-disubstituted carbonyl compounds is hitherto not reported. A possible reason can be competing reactions of two different nucleophiles, which may result in generation of a mixture of compounds arising out of bisadditions. In this regard, photoredox-catalyzed reaction of a thiyl radical on terminal alkynes to generate vinyl radicals5 renders them amenable to a wide variety of organic transformations. As such, we were interested to find out if vinyl radicals consequently generated can be used for the synthesis of α-aminoketones (Figure 1). Thus, in continuation of our interests,6 herein, we report a thiol-mediated photoredox-catalyzed reaction leading to the synthesis of α,α-aminothio-substituted carbonyl compounds. Notably, previous reports employed lithiated benzimidazoles, benzotriazoles, and oxazolidinone derivatives for synthesis of α,α-aminothioketones.7


© XXXX American Chemical Society

Figure 1. Synthesis of α-aminoketones.

Our method has realized the one-step synthesis of gemdifunctionalized carbonyl derivatives with simultaneous C−N and C−S bond formation via oxidative coupling of alkyne with amine and thiol. The presence of a thio group is surprising as it should conceptually undergo a second nucleophilic substitution reaction with amine to give α,α-diamino-functionalized carbonReceived: May 13, 2019


DOI: 10.1021/acs.orglett.9b01677 Org. Lett. XXXX, XXX, XXX−XXX


Organic Letters

showed Ru(bpy)3Cl2 to be the most suitable photocatalyst. Further, in view of establishing the feasibility of a reaction in different solvents, we carried out reactions in CH3OH, DMF, toluene, and THF, which however returned lower yields and produced the desired product in 39, 15, 11, and 13% yields, respectively. No product formation was observed in the case of DMSO and DCE (Table 1, entries 6−11). Furthermore, control experiments revealed TFA, photocatalyst, and light source to be critical as only a trace amount of α-gem-difunctionalized ketone 4 was isolated in their absence (Table 1, entries 12−14). Having optimized the conditions, we next sought to establish the scope of the reaction. As the present reaction allows us to create diversity at three different centers, that is, amines, alkynes, and thiols, we chose to establish its scope with amines first. As expected, a range of primary aromatic amines participated in the reaction with phenylacetylene and thiophenol under optimized reaction conditions (Scheme 1). The unsubstituted 2-amino-

yl compounds. Notably, sulfur-containing compounds comprised as much as one-fifth of the 200 most-prescribed pharmaceutical products in 2011.8 Also, the introduction of a thio moiety is important from the chemistry perspective as selective activation and functionalization of the C−S bond is easier compared to that of C−N, C−C, or C−O bonds owing to its low bond dissociation energy.9 This has been exemplified in our reactions wherein we were able to selectively cleave a sulfidic C−S bond with different nucleophiles such as indole, thiophene, indazole, pyrazole, and secondary amines to access different α,αdifunctionalized carbonyl compounds. It would be pertinent to mention that, although monofunctionalized α-ketones can be easily accessed via enolization,10 the introduction of a second group requires a sequential deprotonation for further enolization, which is difficult. We could also synthesize disubstituted carbonyl compounds with an aliphatic side chain, which is significant as under conventional conditions an aliphatic keto system would generate a mixture of compounds owing to its equally reactive unsubstituted α-positions. We began our studies using an equimolar mixture of 2-amino4-cyanopyridine 1, phenylacetylene 2, and thiophenol 3 as model substrates to determine the optimal reaction conditions. Irradiation of the reaction mixture under blue LEDs in the presence of TFA with mesitylacridinium tetrafluoroborate (Mes-Acr+BF4−) as photocatalyst led to the formation of αgem-difunctionalized ketone 4 in 64% yield (Table 1, entry 1).

Scheme 1. Substrate Scope with Amines

Table 1. Optimization of Reaction Conditionsa





yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14

as shown as shown as shown as shown as shown as shown as shown as shown as shown as shown as shown no TFA as shown as shown

Mes-Acr+BF4− eosin-Y Ru(bpy)3Cl2 Rose Bengal 9-fluorenone Ru(bpy)3Cl2 Ru(bpy)3Cl2 Ru(bpy)3Cl2 Ru(bpy)3Cl2 Ru(bpy)3Cl2 Ru(bpy)3Cl2 Ru(bpy)3Cl2 no photocatalyst no light


64 46 79 49 40 39 15 ND 11 13 ND traces traces traces


Reaction conditions: 2-amino-4-cyanopyridine (1 mmol), phenylacetylene (1 mmol), thiophenol (1 mmol), TFA (10 mol %), photocatalyst (2 mol %), solvent (2 mL), 20 h.

The reaction exhibited a remarkable addition of amine and thiophenol in tandem, thereby circumventing the possible formation of side products arising out of in situ nucleophilic substitution of thiophenol with amine. We next examined the effect of different photocatalysts on the reaction outcome. The use of eosin-Y, Ru(bpy)3Cl2·6H2O, Rose Bengal, and 9fluorenone produced corresponding product 4 in 46, 79, 49, and 40% yields, respectively (Table 1, entries 2−5). The results

pyridine coupled efficiently with phenylacetylene and thiophenol to generate product 5 in 72% yield. Also, halosubstituted 2-aminopyridines ranging from 5-chloro, 6-chloro, 5-bromo, 4-bromo, and 5-iodo derivatives readily undergo reaction with phenylacetylene and thiophenol to give corresponding ketones (6−10) in 71−78% yields. The reaction was also found to be feasible with 3-amino-5-bromo-2-chloropyrB

DOI: 10.1021/acs.orglett.9b01677 Org. Lett. XXXX, XXX, XXX−XXX


Organic Letters

investigating its ability to generate products with aliphatic alkynes. The reaction with cyclopropylacetylene and 1-octyne with 4-nitroaniline also favored the product formation to give corresponding ketones 29 and 30 in 78 and 75% yields, respectively. We next investigated the scope of reaction with different thiols (Scheme 3). The reaction of 2-amino-4-cyanopyridine and

idine to give corresponding product 11 in 78% yield. The scope of the reaction was also extended to simple homoaromatic anilines such as 3,4-difluoro-, 3-chloro-, 4-bromo-, 3,5-bis(trifluoromethyl)-, and 4-nitroaniline, thereby producing corresponding products (12−17) in 73−82% yields. It would be pertinent to mention that the reaction returned best yields with 4-nitroaniline. Next, we explored the scope of the reaction with different alkynes (Scheme 2). The reaction of 2-amino-4-cyanopyridine

Scheme 3. Substrate Scope with Thiols

Scheme 2. Substrate Scope with Alkynes

phenylacetylene with halo-substituted thiophenols such as 4chloro-, 2-chloro-, and 4-bromothiophenol produced corresponding ketones 31−33 in 74−79% yields. Furthermore, comparable yields were obtained with alkyl-substituted thiophenols such as 3-methyl and 2,5-dimethyl thiophenol to give 34 and 35 in 77 and 73% yields, respectively. Aliphatic thiols including octanethiol and hexanethiol also coupled with 2amino-4-cyanopyridine and phenylacetylene to generate corresponding analogues 36 and 37 in 68 and 65% yields, respectively. Additionally, the electron-rich 4-methyl and 4methoxy thiophenol also reacted with 2-aminopyridine and phenylacetylene to synthesize corresponding products 38 and 39 in 75 and 70% yields. The Stern−Volmer analysis of all the reaction ingredients revealed that, among the possible quenchers present in the reaction system, the photoluminescence of [Ru(bpy)3]Cl2 was effectively quenched by thiophenol in CH3CN, supporting the proposed thiyl radical path as a plausible mechanism (see Supporting Information). Also, the radical nature was confirmed by complete inhibition of the reaction in the presence of the radical quencher TEMPO. Moreover, the reaction failed to give a product in the absence of oxygen under argon atmosphere with a degassed solvent system. On the basis of these results, a plausible reaction mechanism is depicted in Scheme 4. Initially, photoexcited [Ru(bpy)3]2+ undergoes reductive quenching with thiophenol to give thiyl radical cation 40 that subsequently

and thiophenol proceeded smoothly with halo-substituted 4fluoro- and 2-chlorophenylacetylenes to give compounds 18 and 19 in 75 and 72% yields, respectively. The reaction was also facile with electron-rich phenylacetylenes such as 4-tert-butyl, 3methoxy-, and 4-phenoxyphenylacetylenes, furnishing the desired products (20−22) in 73−77% yields. Further, we were intrigued to find out if the reaction is expandable to 2amino-4-cyanopyridine by investigating the behavior of varied alkynes with unsubstituted 2-aminopyridine. Phenylacetylenes such as 4-methyl-, 4-ethyl-, 4-n-propyl-, 4-n-pentyl-, and 4methoxyphenylacetylene reacted efficiently with 2-aminopyridine to produce corresponding α,α-difunctionalized ketones 23−27 in 71−77% yields. The reaction of a substituted phenylacetylene, such as 3-fluorophenylacetylene, was also found to be feasible with 4-nitroaniline to afford compound 28 in 80% yield. We were particularly curious to find out if this transformation is not limited to aromatic alkynes by C

DOI: 10.1021/acs.orglett.9b01677 Org. Lett. XXXX, XXX, XXX−XXX


Organic Letters Scheme 4. Plausible Mechanism

Scheme 5. Late-Stage Modifications

deprotonates to form thiyl radical 41.11 The [Ru(bpy)3]2+ is regenerated by molecular oxygen.12 Thiyl radical 41 with further addition to alkyne forms reactive vinyl radical 42.13 Afterward, radical 42 undergoes oxygen insertion to give superoxide radical 43.14,12b Intermediate 43 undergoes intermolecular cycloaddition with simultaneous release of a thiyl radical to produce 44.15 Nucleophilic addition of a primary amine on 44 gives intermediate 45. Successive dehydration of 45 in the presence of TFA affords iminium ion 46, 16 which on consequent nucleophilic attack by thiophenol17 gives the α,α-difunctionalized ketone. With the low bond dissociation energies of the C−S bond in mind, we were intrigued to explore the possibility of its late-stage modification/functionalization (Scheme 5) as it would create further diverse heterogeneous α,α-difunctionalized carbonyl systems. To begin with, we envisaged creation of a RCOCH(C)(N) system by using an indolyl system as a nucleophile. Notably, 3-substituted indoles are valuable synthetic intermediates and core structural components of myriad pharmaceutics, natural products, and functional materials.18 Simple use of TFA favored the selective cleavage of the C−S bond followed by substitution with indole to give indolyl gem-functionalized ketone 47 in 82% yield. Furthermore, to ensure the reaction was not limited to indole, we chose 3-methylthiophene as a relatively different system, which also as expected readily transformed into corresponding difunctionalized ketone 48 in 74% yield. Again, thiophene has frequent occurrence in many natural products and functional materials.19 Next, we sought to create a RCOCHN1N2 system using indazole and pyrazole, which again to our anticipation participated in a facile manner, giving a new class of α-gem-disubstituted ketones 49 and 50 in 79−84% yields. Intriguingly, the use of secondary amines pyrrolidine and piperidine participated efficiently in the reaction to give amidines 51 and 52 in 71 and 68% yields, respectively. Importantly, amidines are well-known structural motifs present in numerous bioactive natural products, pharmacophores, and synthetic intermediates.20 In conclusion, a visible-light-mediated strategy for oxidative α,α-oxidative difunctionalization of alkynes leading to the

synthesis of α,α-aminothio-substituted carbonyl compounds has been developed. The reaction presents a remarkable tandem introduction of α-C−N and C−S bonds as key enabling advances. The significance of the C−S bond in terms of its low bond dissociation energies has been utilized to create a diverse α,α-difunctionalized carbonyl system. Further reactivity and applicability of this reaction system is currently under investigation in our laboratory.


S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01677. Experimental procedures, characterization data, 1H and C NMR spectra of all compounds (PDF)



Corresponding Author

*E-mail: [email protected] ORCID

Bhahwal Ali Shah: 0000-0001-6629-0002 Notes

The authors declare no competing financial interest. D

DOI: 10.1021/acs.orglett.9b01677 Org. Lett. XXXX, XXX, XXX−XXX


Organic Letters

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ACKNOWLEDGMENTS B.A.S. thanks CSIR for a Young Scientist Award Grant (P-81113) and DBT (1151/2016), New Delhi, for financial assistance. IIIM Communication No. 2296/2019.


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DOI: 10.1021/acs.orglett.9b01677 Org. Lett. XXXX, XXX, XXX−XXX