A Synthetic Route to Sodium α-Aminoalkanesulfinates and Their

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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A Synthetic Route to Sodium α‑Aminoalkanesulfinates and Their Application in the Generation of α‑Aminoalkyl Radicals for Radical Addition Reactions Ryu Sakamoto,† Tomomi Yoshii,† Hiroyuki Takada,† and Keiji Maruoka*,†,‡ †

Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan School of Chemical Engineering and Light Industry, Guangdong University of Technology, No. 100 West Waihuan Road, HEMC, 4 Panyu District, Guangzhou 510006, China

‡

S Supporting Information *

ABSTRACT: The synthesis of sodium α-aminoalkanesulfinates and their synthetic utility as α-aminoalkyl radical precursors are reported. A variety of α-aminoalkanesulfinates were readily obtained from the reaction between the anions of N-Boc-protected alkylamines and 1,4-diazabicyclo[2.2.2]octanebis(sulfur dioxide). Treatment of sodium α-aminoalkanesulfinates with (diacetoxyiodo)benzene easily generated the corresponding αaminoalkyl radicals under mild conditions, which were then applied in radical 1,2-addition to imines, radical 1,4-addition to electron-deficient olefins, and radical addition/cyclization to 2isocyanobiphenyls. Scheme 1. Nonphotolytic Methods for the Generation of αAminoalkyl Radicals

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n synthetic organic chemistry, considerable research efforts have been devoted to the development of novel methods for the generation of organic radicals, since radical reactions enable transformations of organic molecules that are not observed in ionic reactions.1,2 In particular, the generation of organic radicals that contain a functional group is a very promising means for the introduction of functional groups into other compounds. Among such radicals, α-aminoalkyl radicals have attracted great attention because of the synthetic importance of nitrogen-containing scaffolds.3 Recently, visible-light-induced photoredox catalysis has emerged as a powerful tool for the generation of α-aminoalkyl radicals and has successfully been applied in a variety of radical reactions.4 Meanwhile, nonphotolytic methods for the generation of α-aminoalkyl radicals remain underdeveloped, mainly on account of the limited availability of precursors of α-aminoalkyl radicals. The generation of α-aminoalkyl radicals from alkylamines by direct abstraction of a hydrogen atom adjacent to the nitrogen atom of the alkylamine has recently been realized, employing several radical initiators (Scheme 1, eq 1).5 However, this method often suffers from limited substrate scope and site selectivity and/or overreactions. Alternatively, succinimidomethyl or phthalimidomethyl xanthates or iodides are attractive precursors of α-imidoalkyl radicals, although they also suffer from synthetic limitations such as the need for imido structures (Scheme 1, eq 2).6 Therefore, the development of alternative precursors that are able to generate different α-aminoalkyl radicals under mild conditions is highly desirable. In this context, we report herein an efficient strategy for the generation of a variety of α-aminoalkyl radicals using sodium αaminoalkanesulfinates as novel radical precursors (Scheme 1, eq 3). © XXXX American Chemical Society

As precursors for α-aminoalkyl radicals, we initially focused on the generation of alkyl radicals from sodium alkanesulfinates using a suitable oxidant,7 as we envisioned that sodium αaminoalkanesulfinates could potentially offer great structural diversity. However, the attempted synthesis of sodium αaminoalkanesulfinates by a previous synthetic approach involving sodium alkanesulfinates, i.e., chlorination of sulfonic acids followed by reduction of the sulfonyl chlorides with Received: February 21, 2018

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DOI: 10.1021/acs.orglett.8b00621 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Scheme 3. Addition Reactions of 1a or 2 to α-Imino Ester 3a

sodium sulfite and sodium bicarbonate, was unsuccessful (Scheme 2, eqs 1 and 2).8 Thus, we turned our attention to Scheme 2. Synthesis of Sodium α-Aminoalkanesulfinates 1

Scheme 4 presents the scope of the addition reaction of αaminoalkyl radicals to imines 3. The use of primary sulfinates Scheme 4. Substrate Scope for the 1,2-Addition of Sodium α-Aminoalkanesulfinates 1 to Imines 3

the development of an alternative efficient synthetic method for sodium α-aminoalkanesulfinates and became interested in the use of 1,4-diazabicyclo[2.2.2]octanebis(sulfur dioxide) (DABSO) as a SO2 equivalent.9 Treatment of N-Boc-protected dimethylamine with sec-butyllithium generated an α-lithiated alkylamine, which was subsequently trapped with DABSO to successfully provide the desired α-aminoalkanesulfinate 1a in 81% yield (Scheme 2, eq 3).10 With this simple synthetic procedure, we prepared a range of sodium α-aminoalkanesulfinates (1b−g) from their corresponding alkylamine derivatives.11 With these sulfinates in hand, we examined the alkyl radical addition of sulfinates 1 to α-imino esters to furnish α,β-diamino acid derivatives, which are often encountered in natural products and biologically active compounds.12 The addition of carbon nucleophiles to α-imino esters is a useful method for the preparation of α-amino acid derivatives. However, the use of organometallic reagents, such as Grignard or lithium reagents, in reactions with α-imino esters is often problematic with respect to the regioselectivity of the nucleophilic addition, which may occur on the imino carbon, imino nitrogen, or carbonyl carbon atom.13 In fact, the reaction of in situgenerated α-lithiated alkylamine 2 with α-imino ester 3a afforded a complex mixture (Scheme 3, eq 1). We thus examined the radical addition of sulfinate 1a to α-imino ester 3a (Scheme 3, eq 2). While the use of the oxidant [bis(trifluoroacetoxy)iodo]benzene (PIFA) is effective for the generation of perfluoroalkyl radicals from sodium perfluoroalkanesulfinates,7l it did not generate the desired product 4a. However, the use of (diacetoxyiodo)benzene (DIB) furnished 4a in high yield. The addition of the radical scavenger 2,2,6,6tetramethylpiperidin-1-oxyl (TEMPO) inhibited the reaction, and the radical adduct 5 was successfully detected by mass spectrometry (Scheme 3, eq 3) (for further details, see the Supporting Information (SI)). This result confirmed that the present reaction proceeds via a radical mechanism involving the generation of α-aminoalkyl radicals.

1b and 1c afforded the respective α,β-diamino ester derivatives 4b and 4c in high yield. In the case of secondary sulfinate 1d, a diastereomeric mixture of 4d was obtained. Cyclic sulfinates 1e and 1f derived from piperidine and piperazine afforded 4e and 4f, respectively, while pyrrolidine-derived 1g did not furnish 4g. Subsequently, we examined the scope of imines 3 for this reaction. The reaction of 3b (R″ = C(O)N(CH2CH2)2) with 1a afforded 4h in 66% yield. α-Keto imines 3c−g bearing alkyl, alkenyl, or aryl groups were also well-tolerated, generating α,βdiamino ketone derivatives 4i−m in moderate to good yields. It should be mentioned that DIB could be successfully used as a catalyst for the reaction between 1c and α-imino ester 3a to give 4c in slightly lower yield (Scheme 5a).14 This result B

DOI: 10.1021/acs.orglett.8b00621 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 5. Reaction between 1c and 3a Using a Catalytic Amount of (Diacetoxyiodo)benzene (DIB) and the Proposed Reaction Mechanism

Scheme 7. Radical Addition/Cyclization of 1a or 1e and 2Isocyanobiphenyls

suggests that the present reaction should proceed via a radical chain process (Scheme 5b). Namely, DIB should serve as an initiator for the oxidation of 1 to provide RSO2· (a). Then the elimination of sulfur dioxide from a should afford an αaminoalkyl radical (b). Addition of b to an imine should then furnish an aminyl radical (c), which could oxidize sulfinate 1 to generate a with concomitant formation of 4. The synthetic utility of 1 was demonstrated by performing a 1,4-addition reaction on electron-deficient olefins (6) (Scheme 6).15,16 The reactions between 1a and ethylidenemalonate 6a

In summary, we have developed a new synthetic route to sodium α-aminoalkanesulfinates and demonstrated their synthetic utility as sources of α-aminoalkyl radicals. Our approach allows the synthesis of a wide variety of nitrogencontaining molecules, such as α,β-diamino carbonyl, γ-amino carbonyl, and phenanthridin-6-ylmethanamine compounds. Further investigations of the synthetic applicability of αaminoalkanesulfinate-derived α-aminoalkyl radicals to other systems are currently in progress in our laboratory.

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Scheme 6. Radical 1,4-Addition of 1a to Electron-Deficient Olefins 6

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00621. Experimental procedures and characterization data for all compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Ryu Sakamoto: 0000-0001-8350-2636 Keiji Maruoka: 0000-0002-0044-6411 Notes

and benzylidenemalonate 6b smoothly provided the respective γ-amino ester derivatives 7a and 7b in good yields. Benzylidene acetylacetone (6c) also reacted with 1a in the presence of DIB to afford γ-amino ketone derivative 7c in 91% yield. Additionally, the reactions with α,β-unsaturated keto esters 6d and 6e proceeded satisfactorily to furnish the corresponding products 7d and 7e in acceptable yields. Furthermore, the present system was successfully used in the synthesis of phenanthridines (Scheme 7).16,17 The radical addition/cyclization to 2-isocyanobiphenyls with 1a afforded phenanthridin-6-ylmethanamines 8a−d, which are key fragments for luminescent probes.18 Cyclic sulfinate 1e also furnished the corresponding product 8e in moderate yield.

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by JSPS KAKENHI Grant JP26220803. REFERENCES

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DOI: 10.1021/acs.orglett.8b00621 Org. Lett. XXXX, XXX, XXX−XXX