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Reductive radical-initiated 1,2-C migration assisted by an azidyl group

Authors:	Xueying Zhang Zhansong Zhang Jin-Na Song Zikun Wang

Institution:	Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry, Northeast Normal University, Changchun 130024 China.; School of Life Science, Jilin University, Changchun 130012 China,

Abstract:	We report here a novel reductive radical-polar crossover reaction that is a reductive radical-initiated 1,2-C migration of 2-azido allyl alcohols enabled by an azidyl group. The reaction tolerates diverse migrating groups, such as alkyl, alkenyl, and aryl groups, allowing access to n+1 ring expansion of small to large rings. The possibility of directly using propargyl alcohols in one-pot is also described. Mechanistic studies indicated that an azidyl group is a good leaving group and provides a driving force for the 1,2-C migration. We report here a novel reductive radical-polar crossover reaction that is a reductive radical-initiated 1,2-C migration of 2-azido allyl alcohols enabled by an azidyl group. Since the groups of Ryu and Sonoda described the reductive radical-polar crossover (RRPCO) concept in the 1990s,¹ it has attracted considerable attention in modern organic synthesis.² By using this concept, a variety of complex molecules could be assembled in a fast step-economic fashion which is not possible using either radical or polar chemistry alone. However, only two RRPCO reaction modes are known to date: nucleophilic addition and nucleophilic substitution (Fig. 1A). The first RRPCO reaction is the nucleophilic addition of organometallic species, which is generated in situ from the reduction of a strong reducing metal with a carbon-centered radical intermediate and cations (E⁺ = H⁺, I⁺, Br⁺, path 1).³ However, the necessity for a large amount of harmful and strong reducing metals has greatly limited the scope and functional group tolerance of the reaction. Recently, photoredox catalysis has not only successfully overcome the shortcomings of using toxic strong reducing metals in the RRPCO reaction,⁴ but also enabled the development of several new RRPCO reaction types, including the nucleophilic addition with carbonyl compounds or carbon dioxide (path 2),⁵ the cyclization of alkyl halides/tosylates (path 3),⁶ and β-fluorine elimination (path 4).⁷ Although the RRPCO reaction has been greatly advanced by photoredox catalysis, it is still in its infancy, and the development of a novel RRPCO reaction is of great importance.Open in a separate window Fig. 1(A) Reductive radical-polar crossover reactions; (B) this work: reductive radical-initiated 1,2-C migration assisted by an azidyl group.Herein, we wish to report a new type of reductive radical-polar crossover cascade reaction that is the reductive radical-initiated 1,2-C migration under metal-free conditions (Fig. 1B). The development of this approach is not only to further expand the application of the RRPCO reaction, but also to solve the problems associated with the oxidative radical-initiated 1,2-C migration, such as the necessity for an oxidant and/or transition metal for the oxidative termination of the radicals, and also required sufficient ring strain to avoid the generation of epoxy byproducts.⁸ To realize this reaction, a driving force is needed to drive the 1,2-C migration after reductive termination, to avoid the otherwise inevitable protonation of the generated anion.⁹ Inspired by the leaving group-induced semipinacol rearrangement,¹⁰ we envisaged that 2-azidoallyl alcohols¹¹ might be the ideal substrates for the reductive radical-initiated 1,2-C migration because these compounds contain both an allylic alcohol motif, which is vital for the radical-initiated 1,2-C migration, and an azidyl group, a good leaving group,¹² which may facilitate the 1,2-C migration after the reductive termination of the radicals.With the optimal conditions established (ESI, Table S1^†), we then explored the scope of this radical-initiated 1,2-migration. As shown in

Open in a separate window^aStandard reaction conditions: 1 (0.5 mmol), TMSN₃ (2.0 mmol), 2a (3.0 mmol) in H₂O (0.7 mL) and DMSO (1.4 mL) at 50 °C in air for 48 h.^bIsolated yields.Next, we extend the reaction scope to a range of aryl allylic alcohols. In comparison with alkyl allylic alcohols, aryl allylic alcohols gave the migration products in higher yields. The structure of 3ba was unambiguously confirmed by X-ray single crystal diffraction (CCDC 1897779).^† As demonstrated by the arene scope (13 The most common method for synthesising phenols is the hydroxylation of aryl halides.¹⁴ However, the method usually requires transition metals and harsh reaction conditions. Interestingly, by using the current strategy, inexpensive and abundant cyclopentadiene moieties can also be easily converted into phenols (

Entry

R¹

R²

Yield^a (%)

3d′

1da

t-Bu

1db

C₆H₅

1dc

4-MeOC₆H₅

1dd

4-CF₃C₆H₅

1de

C₆H₅

4-MeC₆H₅

1df

C₆H₅

4-MeOC₆H₅

1dg

C₆H₅

4-ClC₆H₅

1dh

C₆H₅

4-CF₃C₆H₅

Open in a separate window^aIsolated yields.After the evaluation of the scope of our allylic alcohols, we turned our attention to sulfonyl radical precursors ( Open in a separate window^aIsolated yields.In this work, the 2-azidoallyl alcohols substrates were derived from propargylic alcohols through a silver-catalyzed hydroazidation of alkynes.¹⁵ Consequently, we hypothesized that the radical-initiated 1,2-carbon migration could be directly achieved from propargylic alcohols in a one pot process. With a slight modification of the reaction conditions, we realized the one-pot preparation of the desired products from propargylic alcohols ( Open in a separate window^aStandard reaction conditions: 4 (0.5 mmol), TMSN₃ (2.0 mmol), 2 (3.0 mmol), Ag₂CO₃ (0.05 mmol) in H₂O (0.7 mL) and DMSO (1.4 mL) at 50 °C in air for 48 h.^bIsolated yields.To gain more insight into the mechanism of radical-initiated 1,2-carbon migration, we conducted various experiments to confirm the presence or absence of radical and carbanion intermediates (Scheme 1). When the reaction of 1ba was performed in the presence of TEMPO (6.0 equiv.), the reaction was suppressed under the standard conditions (Scheme 1, eqn (1)), supporting the involvement of a radical intermediate. To prove the formation of a carbanion intermediate, we carried out two deuterium labeling experiments (Scheme 1, eqn (2) and (3)). The resulting products d]-3ba and MA-1 contain the deuterium atom α in the carbonyl group, confirming the formation of a carbanion intermediate. To identify the key intermediate of the 1,2-migration, we prepared a potential intermediate M1 and subjected it to the standard conditions (Scheme 1, eqn (4)). But, the product 3ba was not observed and almost all of the M1 was recovered, which indicates that M1 is not a key intermediate. However, the product 3ba was obtained in a yield of 41% while M2 was subjected to the standard conditions (eqn (5)). If the hydroxyl group in the 2-azidoallyl alcohols was protected (M3), the reaction would not give the corresponding migration product (3ga), but generate product 5 with a yield of 51% (eqn (6)).^11c These results proved that the reaction involved a 1,3-H migration process thereby enabling an oxygen anion intermediate IV (other mechanistic studies are discussed in ESI Fig. S1^†).Open in a separate window Scheme 1Mechanistic investigations.Based on the above experimental results and relevant literature, a possible reaction pathway was proposed as shown in Fig. 2. First, TolSO₂TMS (I) is generated by the anion exchange of TolSO₂Na with TMSN₃. Such intermediates are known to be somewhat unstable,¹⁶ as similar to the analogous compounds, such as TolSO₂I,¹⁷ and TMSTePh¹⁸ and thus undergo homolysis. Therefore, we anticipated that TolSO₂TMS (I) should also yield sulfonyl and trimethylsilyl radicals.¹⁹ Then the 2-azidoallyl alcohol 1ba is readily attacked by the sulfonyl radical, leading to carbon-centered radical II. Subsequently, the carbon-centered radical II undergoes single electron transfer by the oxidation of sulfinate to the sulfonyl radical yielding the carbanion III.²⁰ A 1,3-H shift of carbanion III affords the intermediate IV²¹ which rapidly undergoes 1,2-migration with the assistance of the azidyl leaving group, generating the desired product. It is worth noting that the present work is a novel radical reaction mode for vinyl azides compared to the existing reports that involve N–N bond breaking in the presence of radicals. Moreover, the development of this strategy is of great significance for the application of vinyl azides in the reconstruction of C–C bonds.Open in a separate window Fig. 2Proposed mechanism.On the other hand, the coupling of sulfonyl radicals produces intermediate V.²² The azidyl anion that is generated in the reaction is more prone to attack intermediate V to afford tosyl azide.²³ Subsequently, tosyl azide is reduced to p-toluenesulfonamide by the trimethylsilyl radical.²⁴ The sideproducts tosyl azide and p-toluenesulfonamide were isolated by column chromatography, and the associated TMSOH and TMS₂O have been detected by GC-MS.²⁵ Keywords:

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