Metal- and Additive-Free Synthesis of α-Hydroxyamino Ketones Enabled by Organophotocatalyst

Dedicated to Professor Masahiro Murakami on the occasion of his retirement from Kyoto University

Abstract

We report herein a straightforward method for the synthesis of α-hydroxyamino ketones, which involves the benzoylation reaction of nitrones with 2-benzoyl-2-phenylbenzothiazoline under organophotocatalysis. This method offers access to a variety α-hydroxyamino ketones without the use of any transition-metal catalyst or base. Control experiments suggested that the reaction proceeded through a benzoyl radical addition to nitrone. Benzothiazoline was found to be a more suitable radical precursor than Hantzsch ester.

Nitrogen-containing compounds are prevalent in organic compounds, and a range of novel catalytic approaches have been extensively explored. N,N-Dialkylhydroxylamine and its derivatives are valuable and versatile scaffolds of interest in medicinal[1] [2] and materials chemistry, as well as for synthetic purposes.[3,4] For instance, FR900482 and its derivatives were found to possess strong antitumor activity in clinical trials.[1] Crich and co-workers have used N,N,O-trisubstituted hydroxylamine as a bioisostere in medicinal chemistry.[2] Furthermore, hydroxylamine is regarded as a useful amine source. For example, Buchwald has reported a Cu-catalyzed hydroamination reaction of simple alkenes using hydroxylamine as an electrophilic amine source,[3] and Leonori and co-workers have employed O-arylhydroxylamines as a source of aminyl radicals under photoredox conditions.[4]

α-Amino carbonyl compounds have attracted much attention in various fields, and a range of synthetic methods have been developed. In contrast, the synthesis of α-hydroxyamino carbonyl compounds has been sparsely investigated (Scheme [1]). One of the synthetic routes to α-hydroxyamino ketone is based on the nitroso aldol reaction, which is the reaction of enolate equivalent and nitrosobenzene[5] (route A). Another route is the addition reaction of acyl anion equivalent with nitrone, although a strong base is required[6] (route B). Recently, a radical bond-formation reaction by means of photoredox catalysis has emerged as a powerful tool in organic synthesis, and the construction of molecules with functional group tolerance under mild conditions has been demonstrated. We hypothesized that the radical addition[7] of an acyl radical to nitrone[8] would provide novel access to α-hydroxyamino carbonyl compounds.[9]

We reported that benzothiazoline functions as hydrogen donor for the transfer hydrogenation of ketimines in combination with chiral phosphoric acid.[10] Furthermore, we have developed various radical bond-forming reactions using 2-acylbenzothiazoline derivatives under thermal and redox conditions and showed the ready availability of benzothiazoline as a radical precursor.[11] [12] We wish to report herein our synthetic approach toward α-hydroxyamino ketones, which involves the radical acylation of nitrone with 2-acylbenzothiazolene under organophotoredox catalysis (route C).

At the outset, we selected N-benzyl nitrone (1a) as a substrate for the acylation reaction using 2-benzo-2-phenylthiazoline (2a) as a radical precursor. The challenges of this strategy are as follows: 1) nitrone is sensitive to photoirradiation conditions and prone to decomposition to give imine, oxaziridine, and other amines;[13] and 2) hydroxylamine 3a is susceptible to oxidation, and overoxidation and/or oxidative decomposition would occur. Hence, we conducted the initial screening carefully. Irradiation of a mixture of 1a and 2a with white LED (7 W) in the presence of 1 mol% of 4CzIPN in acetonitrile for 14 h afforded the desired hydroxylamine 3a in 73% yield (Table [1], entry 1).[14] Use of other LEDs such as Kessil 370 nm, 427 nm, or 456 nm did not give 3a, although a high conversion of 1a was observed (entries 2–4). We noted that the choice of the solvent was also crucial for obtaining 3a with high efficiency and found that acetonitrile was the solvent of choice (entries 5–8). Although 1,4-dihydropyridine derivatives have been used as a radical donor in radical bond-forming reactions.[7] [15] Compound 4 gave the corresponding adduct 3a in moderate yield in our system (entry 9). Use of a transition-metal photocatalyst instead of 4CzIPN decreased both yields and selectivity (entries 10 and 11). Side reactions were suppressed under the optimized reaction conditions (entry 1). On the other hand, imine and other byproducts were observed under other conditions, which resulted in the low chemoselectivity.

Table 1 Optimized Conditions for the Acylation Reaction of Nitrone^a

Entry	Deviation from the standard conditions	Conv. (%)b	Yield (%)b
1	none	100	73c
2	Kessil 370 nm	94	0
3	Kessil 427 nm	100	0
4	Kessil 456 nm	90	0
5	1,2-dichloroethane	87	46
6	toluene	91	9
7	1,4-dioxane	59	0
8	DMSO	100	15
9	4 was used instead of 2a	67	49c
10	Ru(bpy)3(PF6)2	97	6
11	Ir[dF(CF3)2ppy]2(dtbbpy)PF6	87	47

^a Reactions were performed in 0.05 mmol scale.

^b Yield and conversion were determined by ¹H NMR measurement of the crude reaction mixture.

^c Isolated yield.

With the optimized reaction conditions in hand, we examined the generality of the reaction using nitrone 1 and benzothiazoline 2 (Figure [1]). A range of nitrones bearing cyclohexyl (1b), cyclopropyl (1c), phenethyl (1d), and t-butyl (1e) groups participated in the photoredox reaction with 2a to provide the desired adducts (3b–e) in moderate to good yields. We next investigated the scope of the benzoyl moiety. Electron-rich benzoyl radicals gave the corresponding hydroxylamines in good yields (3g and 3h). α-Hydroxyamino ketones including fluorine (3i) and bromine (3j) were obtained in 74% yield and 46% yield, respectively. The method is synthetically useful, with a good efficiency maintained when running the reaction on a 1 mmol scale (Scheme [2]).

The N–O bond of 3a was reductively cleaved using Zn metal in DCM/2 M HCl aq. without affecting ketone to give α-amino ketone 5 in 58% yield (Equation 1).

In order to elucidate the mechanism, control experiments were undertaken. The addition reaction was completely suppressed by air and TEMPO (Scheme [3]), which supports that an acyl radical generated from benzothiazoline is a crucial intermediate. We suppose that an α-amino alkyl radical would not be generated in situ because 3c was obtained in a good yield without ring opening.

As a result, we wish to propose that the reaction proceeded by radical addition process. An acyl radical was formed through the oxidation of benzothiazoline by photoexcited 4CzIPN* (E_1/2(PC*/PC) = +1.35 V vs SCE). The radical addition reaction with nitrone formed an α-acylated aminoxyl radical. Subsequent one-electron reduction and protonation afforded the desired product and 4CzIPN was recovered (Scheme [4]).

In summary, we have developed a metal- and additive-free radical acylation reaction of nitrones using 2-benzoyl-2-phenylbenzothiazoline 2 as a benzoyl radical precursor under the organophotoredox catalysis, which provided a novel synthetic route to α-hydroxyamino ketones. The results also suggested the compatibility of benzothiazoline derivatives as a radical precursor in the radical addition reaction. An α-hydroxyamino ketone was readily transformed into the corresponding α-amino ketone by the combined use of zinc and 2 M HCl aq. with high chemoselectivity. Further investigation aimed at expanding the utility of the catalytic acylation reaction is underway in our group.

Conflict of Interest

The authors declare no conflict of interest.

• References and Notes

• 1a Judd TC, Williams RM. Angew. Chem. Int. Ed. 2002; 41: 4683
  CrossrefPubMedSearch in Google Scholar
• 1b Bugg T. ChemBioChem 2014; 15: 2467
  CrossrefSearch in Google Scholar
• 1c Lambert KM, Cox JB, Liu L, Jackson AC, Yruegas S, Wiberg KB, Wood JL. Angew. Chem. Int. Ed. 2002; 41: 4686
  CrossrefPubMedSearch in Google Scholar
• 2a Hill J, Hettikankanamalage AA, Crich D. J. Am. Chem. Soc. 2020; 142: 14820
  CrossrefPubMedSearch in Google Scholar
• 2b Hill J, Crich D. ACS Med. Chem. Lett. 2022; 13: 799
  CrossrefPubMedSearch in Google Scholar

For selected exaples, see:
• 3a Niu D, Buchwald SL. J. Am. Chem. Soc. 2015; 137: 9716
  CrossrefPubMedSearch in Google Scholar
• 3b Zhu S, Niljianskul N, Buchwald SL. J. Am. Chem. Soc. 2013; 135: 15746
  CrossrefPubMedSearch in Google Scholar
• 4a Svejstrup TD, Ruffoni A, Julia F, Aubert VM, Leonori D. Angew. Chem. Int. Ed. 2017; 56: 14948
  CrossrefPubMedSearch in Google Scholar
• 4b Chen J, Xu Y, Shao W, Ji J, Wang B, Yang M, Mao G, Xiao F, Deng GJ. Org. Lett. 2022; 24: 8271
  CrossrefPubMedSearch in Google Scholar
• 5a Yamamoto H, Momiyama N. Chem. Commun. 2005; 28: 3514
  CrossrefPubMedSearch in Google Scholar
• 5b Momiyama N, Yamamoto H. J. Am. Chem. Soc. 2005; 127: 1080
  CrossrefPubMedSearch in Google Scholar
• 5c Yanagisawa A, Kasahara S, Takeishi A, Marui T. Synlett 2022; 33: 2019
  Thieme ConnectSearch in Google Scholar

Umpolung approach using strong base:
• 6a Reeves JT, Lorenc C, Camara K, Li Z, Lee H, Busacca CA, Senanayake CH. J. Org. Chem. 2014; 79: 5895
  CrossrefPubMedSearch in Google Scholar
• 6b Garrett MR, Tarr JC, Johnson JS. J. Am. Chem. Soc. 2007; 129: 12944
  CrossrefPubMedSearch in Google Scholar

For selected example of radical addition reaction of nitrone under photoredox catalysis, see:
• 7a Supranovich VI, Levin VV, Struchkova MI, Dilman AD. Org. Lett. 2018; 20: 840
  CrossrefPubMedSearch in Google Scholar
• 7b Li HH, Li JQ, Zheng X, Huang PQ. Org. Lett. 2021; 23: 876
  CrossrefPubMedSearch in Google Scholar
• 8 For a review on nitrone, see: Murahashi S.-I, Imada Y. Chem. Rev. 2019; 119: 4684
  CrossrefPubMedSearch in Google Scholar
• 9 During preparation of the manuscript, Paxaio and co-workers recently reported carbamoylation of nitrone under photoredox catalysis. See: Oliveira P. H. R., Tordato E. A., Vélez J. A. C., Carneiro P. S., Paixão M. W.; J. Org. Chem.; 2022, in press; DOI: 10.1021/acs.joc.2c02266
• 10a Zhu C, Akiyama T. Org. Lett. 2009; 11: 4180
  CrossrefPubMedSearch in Google Scholar
• 10b Zhu C, Saito K, Yamanaka M, Akiyama T. Acc. Chem. Res. 2015; 48: 388
  CrossrefPubMedSearch in Google Scholar
• 11a Uchikura T, Toda M, Mouri T, Fujii T, Moriyama K, Ibanez I, Akiyama T. J. Org. Chem. 2020; 85: 12715
  CrossrefPubMedSearch in Google Scholar
• 11b Uchikura T, Kamiyama N, Mouri T, Akiyama T. ACS Catal. 2022; 12: 5209
  CrossrefSearch in Google Scholar
• 11c Uchikura T, Moriyama K, Toda M, Mouri T, Ibanez I, Akiyama T. Chem. Commun. 2019; 55: 11171
  CrossrefPubMedSearch in Google Scholar

Other groups also reported acylation reactions using 2-acylthiazoline as a radical precursor, see:
• 12a Li L, Guo S, Wang Q, Zhu J. Org. Lett. 2019; 21: 5462
  CrossrefPubMedSearch in Google Scholar
• 12b He X.-K, Lu J, Ye H.-B, Li L, Xuan J. Molecules 2021; 26: 6843
  CrossrefPubMedSearch in Google Scholar

Photorearrangement reaction of nitrone:
• 13a Zhang Y, Blackman ML, Leduc AB, Jamison TF. Angew. Chem. Int. Ed. 2013; 52: 4251
  CrossrefPubMedSearch in Google Scholar
• 13b Lipczynska-Kochany E, Kochany J. J. Photochem. Photobiol., A 1988; 45: 65
  CrossrefSearch in Google Scholar
• 13c Koyano K, Suzuki H, Mori Y, Tanaka I. Bull. Chem. Soc. Jpn. 1970; 43: 3582
  CrossrefSearch in Google Scholar
• 13d Splitter JS, Su T.-M, Ono H, Calvin M. J. Am. Chem. Soc. 1971; 93: 4075
  CrossrefSearch in Google Scholar
• 14 Example Synthetic ProcedureSequentially, nitrone 1a (0.050 mmol), benzothiazoline 2a (0.10 mmol), 4CzIPN (1 mol%), and acetonitrile (1 mL, 0.05 M) were added to a dried 20 mL test tube containing a stirrer bar. The mixture was subjected to freeze-pump-thaw process (3 cycles) and back-filled with N₂. The reaction was irradiated with white LED at rt for 14 h. After being exposed to air, the reaction mixture was concentrated and purified by preparative thin-layer chromatography on silica gel (hexane/ethyl acetate, 5:1 v/v) to give the corresponding α-hydroxyamino ketone 3a in 73% yield as a white solid. Spectral Information for Compound 3a ¹H NMR (400 MHz, CDCl₃): δ = 8.87 (dd, J = 1.3, 8.5 Hz, 2 H), 7.60 (tt, J = 0.9, 7.6 Hz, 1 H), 7.46 (dd, J = 7.7, 8.1 Hz, 2 H), 7.33–7.22 (m, 5 H), 6.08 (br s, 1 H), 4.21 (d, J = 9.0 Hz, 1 H), 4.13 (d, J = 13.4 Hz, 1 H), 3.85 (d, J = 13.4 Hz, 1 H), 2.48–2.33 (m, 1 H), 1.17 (d, J = 6.6 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 205.7, 138.4, 137.5, 133.6, 129.0, 128.7, 128.4, 128.3, 127.3, 71.6, 61.2, 29.4, 20.3, 19.8 ppm. HRMS (ESI): m/z calcd for C₁₈H₂₁NO₂Na: 306.1470; found: 306.1470.

For selected examples of an acylation reaction using 1,4-dihydropyridine derivatives as a radical precursor, see:
• 15a Goti G, Bieszczad B, Vega-Penaloza A, Melchiorre P. Angew. Chem. Int. Ed. 2019; 58: 1213
  CrossrefPubMedSearch in Google Scholar
• 15b Zhao X, Li B, Xia W. Org. Lett. 2020; 22: 1056
  CrossrefPubMedSearch in Google Scholar

Corresponding Author

Publication History

Received: 09 February 2023

Accepted after revision: 21 March 2023

Accepted Manuscript online:
21 March 2023

Article published online:
14 April 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References and Notes

• 1a Judd TC, Williams RM. Angew. Chem. Int. Ed. 2002; 41: 4683
  CrossrefPubMedSearch in Google Scholar
• 1b Bugg T. ChemBioChem 2014; 15: 2467
  CrossrefSearch in Google Scholar
• 1c Lambert KM, Cox JB, Liu L, Jackson AC, Yruegas S, Wiberg KB, Wood JL. Angew. Chem. Int. Ed. 2002; 41: 4686
  CrossrefPubMedSearch in Google Scholar
• 2a Hill J, Hettikankanamalage AA, Crich D. J. Am. Chem. Soc. 2020; 142: 14820
  CrossrefPubMedSearch in Google Scholar
• 2b Hill J, Crich D. ACS Med. Chem. Lett. 2022; 13: 799
  CrossrefPubMedSearch in Google Scholar

For selected exaples, see:
• 3a Niu D, Buchwald SL. J. Am. Chem. Soc. 2015; 137: 9716
  CrossrefPubMedSearch in Google Scholar
• 3b Zhu S, Niljianskul N, Buchwald SL. J. Am. Chem. Soc. 2013; 135: 15746
  CrossrefPubMedSearch in Google Scholar
• 4a Svejstrup TD, Ruffoni A, Julia F, Aubert VM, Leonori D. Angew. Chem. Int. Ed. 2017; 56: 14948
  CrossrefPubMedSearch in Google Scholar
• 4b Chen J, Xu Y, Shao W, Ji J, Wang B, Yang M, Mao G, Xiao F, Deng GJ. Org. Lett. 2022; 24: 8271
  CrossrefPubMedSearch in Google Scholar
• 5a Yamamoto H, Momiyama N. Chem. Commun. 2005; 28: 3514
  CrossrefPubMedSearch in Google Scholar
• 5b Momiyama N, Yamamoto H. J. Am. Chem. Soc. 2005; 127: 1080
  CrossrefPubMedSearch in Google Scholar
• 5c Yanagisawa A, Kasahara S, Takeishi A, Marui T. Synlett 2022; 33: 2019
  Thieme ConnectSearch in Google Scholar

Umpolung approach using strong base:
• 6a Reeves JT, Lorenc C, Camara K, Li Z, Lee H, Busacca CA, Senanayake CH. J. Org. Chem. 2014; 79: 5895
  CrossrefPubMedSearch in Google Scholar
• 6b Garrett MR, Tarr JC, Johnson JS. J. Am. Chem. Soc. 2007; 129: 12944
  CrossrefPubMedSearch in Google Scholar

For selected example of radical addition reaction of nitrone under photoredox catalysis, see:
• 7a Supranovich VI, Levin VV, Struchkova MI, Dilman AD. Org. Lett. 2018; 20: 840
  CrossrefPubMedSearch in Google Scholar
• 7b Li HH, Li JQ, Zheng X, Huang PQ. Org. Lett. 2021; 23: 876
  CrossrefPubMedSearch in Google Scholar
• 8 For a review on nitrone, see: Murahashi S.-I, Imada Y. Chem. Rev. 2019; 119: 4684
  CrossrefPubMedSearch in Google Scholar
• 9 During preparation of the manuscript, Paxaio and co-workers recently reported carbamoylation of nitrone under photoredox catalysis. See: Oliveira P. H. R., Tordato E. A., Vélez J. A. C., Carneiro P. S., Paixão M. W.; J. Org. Chem.; 2022, in press; DOI: 10.1021/acs.joc.2c02266
• 10a Zhu C, Akiyama T. Org. Lett. 2009; 11: 4180
  CrossrefPubMedSearch in Google Scholar
• 10b Zhu C, Saito K, Yamanaka M, Akiyama T. Acc. Chem. Res. 2015; 48: 388
  CrossrefPubMedSearch in Google Scholar
• 11a Uchikura T, Toda M, Mouri T, Fujii T, Moriyama K, Ibanez I, Akiyama T. J. Org. Chem. 2020; 85: 12715
  CrossrefPubMedSearch in Google Scholar
• 11b Uchikura T, Kamiyama N, Mouri T, Akiyama T. ACS Catal. 2022; 12: 5209
  CrossrefSearch in Google Scholar
• 11c Uchikura T, Moriyama K, Toda M, Mouri T, Ibanez I, Akiyama T. Chem. Commun. 2019; 55: 11171
  CrossrefPubMedSearch in Google Scholar

Other groups also reported acylation reactions using 2-acylthiazoline as a radical precursor, see:
• 12a Li L, Guo S, Wang Q, Zhu J. Org. Lett. 2019; 21: 5462
  CrossrefPubMedSearch in Google Scholar
• 12b He X.-K, Lu J, Ye H.-B, Li L, Xuan J. Molecules 2021; 26: 6843
  CrossrefPubMedSearch in Google Scholar

Photorearrangement reaction of nitrone:
• 13a Zhang Y, Blackman ML, Leduc AB, Jamison TF. Angew. Chem. Int. Ed. 2013; 52: 4251
  CrossrefPubMedSearch in Google Scholar
• 13b Lipczynska-Kochany E, Kochany J. J. Photochem. Photobiol., A 1988; 45: 65
  CrossrefSearch in Google Scholar
• 13c Koyano K, Suzuki H, Mori Y, Tanaka I. Bull. Chem. Soc. Jpn. 1970; 43: 3582
  CrossrefSearch in Google Scholar
• 13d Splitter JS, Su T.-M, Ono H, Calvin M. J. Am. Chem. Soc. 1971; 93: 4075
  CrossrefSearch in Google Scholar
• 14 Example Synthetic ProcedureSequentially, nitrone 1a (0.050 mmol), benzothiazoline 2a (0.10 mmol), 4CzIPN (1 mol%), and acetonitrile (1 mL, 0.05 M) were added to a dried 20 mL test tube containing a stirrer bar. The mixture was subjected to freeze-pump-thaw process (3 cycles) and back-filled with N₂. The reaction was irradiated with white LED at rt for 14 h. After being exposed to air, the reaction mixture was concentrated and purified by preparative thin-layer chromatography on silica gel (hexane/ethyl acetate, 5:1 v/v) to give the corresponding α-hydroxyamino ketone 3a in 73% yield as a white solid. Spectral Information for Compound 3a ¹H NMR (400 MHz, CDCl₃): δ = 8.87 (dd, J = 1.3, 8.5 Hz, 2 H), 7.60 (tt, J = 0.9, 7.6 Hz, 1 H), 7.46 (dd, J = 7.7, 8.1 Hz, 2 H), 7.33–7.22 (m, 5 H), 6.08 (br s, 1 H), 4.21 (d, J = 9.0 Hz, 1 H), 4.13 (d, J = 13.4 Hz, 1 H), 3.85 (d, J = 13.4 Hz, 1 H), 2.48–2.33 (m, 1 H), 1.17 (d, J = 6.6 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 205.7, 138.4, 137.5, 133.6, 129.0, 128.7, 128.4, 128.3, 127.3, 71.6, 61.2, 29.4, 20.3, 19.8 ppm. HRMS (ESI): m/z calcd for C₁₈H₂₁NO₂Na: 306.1470; found: 306.1470.

For selected examples of an acylation reaction using 1,4-dihydropyridine derivatives as a radical precursor, see:
• 15a Goti G, Bieszczad B, Vega-Penaloza A, Melchiorre P. Angew. Chem. Int. Ed. 2019; 58: 1213
  CrossrefPubMedSearch in Google Scholar
• 15b Zhao X, Li B, Xia W. Org. Lett. 2020; 22: 1056
  CrossrefPubMedSearch in Google Scholar

• Supplementary Material