Mild Dirhodium(II)-Catalyzed Chemo- and Regioselective Azidation of

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

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Mild Dirhodium(II)-Catalyzed Chemo- and Regioselective Azidation of Arenes Yi Wang, Zaixiang Fang, Xiaochuan Chen,* and Yuanhua Wang* Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, P. R. China

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S Supporting Information *

ABSTRACT: A mild chemo- and regioselective aromatic azidation reaction catalyzed by a dirhodium(II) catalyst with Zhdankin’s reagent as the azide source is described. A variety of functional groups were well tolerated under the reaction conditions. Mechanistic studies suggested that the Rh2(II,II)-bound azide intermediate, rather than the free azide radical, is the key active species in the reaction.

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Rh2(II,II).9 Inspired by the base metal catalyzed azide functionalization,10 which is dominated by one-electron processes and involves azide radicals, we assumed that Rh2(II,II) could generate the azide radical with azide reagents. On the basis of this idea, we selected mesitylene 1a as a substrate to study the azidation of arenes. To our delight, the aryl azide product 2a was obtained in 54% yield when the reaction was catalyzed by 1 mol % of Du Bois’ Rh2(esp)211 in dichloromethane (DCM) at room temperature with 2 equiv of IBA-N3 (Table 1, entry 1). The more reactive benzylic C−H bonds in 1a were not affected since no benzyl azide products were detected in this transformation. In addition, the control reaction indicated that Rh2(II,II) was necessary (Table 1, entry 2). Previous studies showed that the empty axial sites of Rh2(II,II) would be occupied by solvents that may slow or inhibit the reactions catalyzed by Rh2(II,II).9,12 Thus, several commonly used solvents, such as ethyl acetate (Ea), methanol, tetrahydrofuran (THF), and acetonitrile (CH3CN), were evaluated (Table 1, entries 3−6). The reactions carried out in noncoordinating solvents such as DCM and dichloroethane (DCE) resulted in better yields than the reactions carried out in coordinating solvents. For instance, compared with the yield with DCE, the yield of 2a decreased to 24% when the reaction proceeded in THF (Table 1, entry 5). Further temperature screening revealed that an optimal temperature of 50 °C resulted in a yield of 2a of 68% when DCE was used as the solvent (Table 1, entries 7−9). The amount of IBA-N3 used affected the yield of 2a. The yield of 2a dropped to 40% and 58% when 1.2 and 1.5 equiv of IBA-N3 were applied,

rganic azides are a class of versatile intermediates extensively used in organic chemistry for the synthesis of various nitrogen-containing compounds.1 Due to their unique reactivity and relatively high stability, aryl azides have found broad applications in synthetic chemistry, materials chemistry, biochemistry, and medicinal chemistry.2 Because the conventional methods for the synthesis of aromatic azides suffer from harsh conditions and require prefunctionalized starting materials, the mild direct intermolecular C−H azidation of arenes is a highly sought-after transformation in organic chemistry.3 In the past few years, substantial progress has been made in research on the direct C−H bond azidation of aromatic rings to obtain aryl azides. Kita et al. described a metal-free oxidative C−H azidation of arenes using stoichiometric hypervalent iodine as an oxidant to obtain the cation radical followed by nucleophilic attack by an azide source (Scheme 1a). 4 Guided approaches, which have been extensively used in C−H activation, have been demonstrated by Jiao, Hao, Zhu, and Li et al. (Scheme 1b,c).5 Thus, there is still ample room to improve synthetic routes to aryl azides. Paddlewheel dirhodium(II) complexes (Rh2(II,II)) as catalysts for metal carbenoid and metal nitrenoid reactions are well known.6 Recently, Driver et al. reported that the Rh2(II,II)catalyzed decomposition of aryl azides generated metal nitrenes to realize the amination reactions.7 Herein, we report that Rh2(II,II) catalyzes the direct azidation of arenes under mild conditions. The Zhdankin reagent, 1-azido-1λ3-benzo[d][1,2]iodaoxol-3(1H)-one (IBA-N3),8 is used as the azide source in this azidation, and directing groups (DGs) are not required. In recent years, our group has been active in the development of the one-electron oxidative process of © XXXX American Chemical Society

Received: August 1, 2018

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DOI: 10.1021/acs.orglett.8b02446 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

respectively, but more than 2 equiv of IBA-N3 did not improve the yield (Table 1, entries 10 and 11). Subsequent experimentation indicated that dioxygen did not play a role in the reaction system (Table 1, entry 12). With low catalyst loadings (0.5 mol %), the reaction still gave 2a in 60% yield (Table 1, entry 13). Next, after testing representative Rh2(II,II) catalysts, Rh2(esp)2 was determined to be a more efficient catalyst than the others (Table 1, entries 14−17). Commercially available Rh2(OAc)4 gave only a 20% yield of 2a (Table 1, entry 14). Doyle’s amide-type catalyst Rh2(cap)4 was inapplicable in this azidation reaction (Table 1, entry 15).13 With Rh2(Opiv)4, 2a was obtained in 46% yield (Table 1, entry 16). Rh2(h-esp)2,9d which possesses the structural characteristics of Rh2(esp)2, was found to be less efficient than Rh2(esp)2 (Table 1, entry 17). As we have discussed in previous reports, we reason that the chelating ligand of Rh2(esp)2 is related to the stability and robustness of this catalyst, preventing Rh2(esp)2 deactivation and resulting in high product yields.9 Using the optimal conditions, we probed the generality of the reaction for aromatic substrates. The results in Scheme 2

Scheme 1. Direct C−H Azidation of Aromatic Rings

Scheme 2. Screening Results for Azidation Reactions To Form Aryl Azidesa

Table 1. Optimization of Reaction Conditionsa

entry

solvent

temp (°C)

catalyst

yieldb (%)

1 2 3 4 5 6 7 8 9 10c 11d 12e 13f 14 15 16 17

DCM DCM Ea CH3OH THF CH3CN DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE

rt 40 40 40 40 40 40 50 60 50 50 50 50 50 50 50 50

Rh2(esp)2 None Rh2(esp)2 Rh2(esp)2 Rh2(esp)2 Rh2(esp)2 Rh2(esp)2 Rh2(esp)2 Rh2(esp)2 Rh2(esp)2 Rh2(esp)2 Rh2(esp)2 Rh2(esp)2 Rh2(OAc)4 Rh2(cap)4 Rh2(Opiv)4 Rh2(h-esp)4

54 NR 34 43 24 28 60 68 69 40 58 67 60 20 trace 46 53

a Reactions were performed by using 1 (0.5 mmol), IBA-N3 (1 mmol), DCE (4 mL), and Rh2(esp)2 (1.0 mol %). bCH3OH was used as solvent. cDCE/CH3OH = 1/1 was used as the solvent. Yield after column chromatography. Ratio of ortho and para products determined by crude 1H nuclear magnetic resonance (NMR) spectroscopy.

indicate that these azidation reactions were sensitive to the substituents on the aromatic substrates and that the electronrich aromatic substrates were more appropriate for azidation than electron-poor ones. For electron-rich aromatic substrates, the observed selectivity was similar to that of electrophilic aromatic substitution reactions since the positions of the installed azide groups on the aromatic ring were ortho or para

a

Reactions were performed by using 1a (0.5 mmol), IBA-N3 (1 mmol), solvent (4 mL), and catalyst (1.0 mol %). bYield after column chromatography. c1.2 equiv of IBA-N3 was used. d1.5 equiv of IBA-N3 was used. eN2 was used instead. f0.5 mol % of Rh2(esp)2 was used.

B

DOI: 10.1021/acs.orglett.8b02446 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters directing. Unlike nucleophilic aromatic azidation,3a,b no ipsosubstituted azide products were found when halogensubstituted substrates were used (2b−c, 2g−m). The tolerance for functional groups such as esters and halogens enabled subsequent transformation. Interestingly, we developed the azidation of electron-rich aromatic aldehydes through this protocol. By simply changing the solvent from DCE to weakly coordinating MeOH, azide-substituted aromatic aldehydes (2q−s) were obtained conveniently in moderate yields. After analysis of the reaction, aldehyde groups were found to transform into acetal groups in situ with MeOH, avoiding the formation of acyl azides. After the reactions were completed, the aldehyde group could be released after acid workup. Next, the direct azidation of the steroid O-methylestrone was carried out. The results show that the azide group was successfully installed on the desired phenyl ring with 40% yield (2t), which indicated this azidation protocol has great potential applications. To expand the scope of azidation reactions, a series of aniline derivatives were applied (Scheme 3). This investigation

applied for further investigation. The results in Scheme 3 show that the selectivity of the reactions was consistent with the directing rules of electrophilic aromatic substitution. Regarding biaryl substrates, the azide group will install on the more electron-rich aromatic ring, which confirmed that the high electron density of the aromatic ring favors this azidation (4k). Of particular interest were the reaction results for Narylacrylamides substrates (3n−r). As a new class of versatile reagents, N-arylacrylamides have recently been applied for the synthesis of azide oxindoles by tandem radical cyclization (Scheme 1d).15−18 In our research, the azidation reactions of N-arylacrylamides displayed different chemoselectivities, favoring aromatic C(sp2)−H azidation over alkeneic C(sp2)−H azidation (4n−r). The above results indicate that an active reaction intermediate exists in this reaction system, and this intermediate may not be the free azide radical. To investigate the plausible mechanism, preliminary mechanistic experiments were conducted. Mass spectrometry (MS) analysis confirmed the generation of (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO)-N3 after the addition of the TEMPO to the reaction mixture to capture the azide radical (Scheme 4).

Scheme 3. Screening Results for Azidation Reactions of Arylamine Substratesa

Scheme 4. Capture of Azide Radical by TEMPO

UV/vis spectroscopy was applied in the mechanistic investigation to monitor the possible oxidation state change of the Rh2(II,II) complex (Figure 1). The characteristic band

a

Figure 1. UV/vis spectroscopy of the Rh2(esp)2 with reactants and solvents.

revealed that anilines were unsuitable for azidation, leading to unidentified mixtures. Additionally, N,N-dimethylaniline and N-methylaniline could not produce the desired products under the reaction conditions. However, after protecting aniline with groups such as tert-butyloxycarbonyl (Boc) and acetyl (Ac), azidation proceeded smoothly at the position para to the amine group in MeOH (4a−d). Considering that Boc can be removed efficiently without affecting the azide group,14 Bocprotected anilines bearing different substituent groups were

at 775 nm was observed in the UV/vis spectrum when Rh2(esp)2 reacted with Zhdankin’s reagent in DCE, which indicated Rh2(esp)2 is one-electron oxidized to Rh2(esp)2+ during the reaction (Figure 1 (3)). The UV/vis spectrum of one-electron-oxidized Rh2(esp)2Cl with an axially ligated chloride group was described in our previous study (Figure 1 (2)).9a,b,d Compared with the UV/vis spectrum of this dualoxidative Rh2(esp)2 species, the spectrum of the one-electronoxidized species shows different spectroscopic characteristics (480 and 846 nm vs 515 and 775 nm, respectively); therefore, they are not the same chemical species. Since the energy of the Rh2 transition in Rh2(II,II) species is strongly affected by the identity of the axial ligands,12 Rh2(esp)2+ in this azidation

Reactions were performed by using 3 (0.5 mmol), IBA-N3 (1 mmol), CH3OH (4 mL), and Rh2(esp)2 (1.0 mol %). Yield after column chromatography. Ratio of ortho and para products determined by crude 1H nuclear magnetic resonance (NMR) spectroscopy.

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DOI: 10.1021/acs.orglett.8b02446 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters system would have different axial ligands. Because the azide radical was captured, the oxidative Rh2(esp)2+ species is suggested to be the axially ligated Rh2(esp)2N3. However, the proposed Rh2(esp)2N3 species was found to be unstable and decomposed rapidly because of the high oxidation potential of Rh2(esp)2. In order to obtain a stable azide intermediate, we replaced Rh2(esp)2 with Rh2(cap)4, which has a very low oxidation potential.13 When Rh2(cap)4 and IBA-N3 were dissolved in methanol, the solution turned red very quickly, indicating that Rh2(cap)4 was easily oxidized. The red color of the obtained solution persisted for a long time, and the UV/vis spectrum revealed that the generated Rh2(cap)4+ was stable (Scheme 5, II). After the workup, the

Scheme 6. Proposed Reaction Mechanism

Scheme 5. Characterization of the Rh2(cap)4N3 Complexa

converted to products via hydrogen abstraction by radical A, resulting in the formation of 2-iodobenzoic acid, which was confirmed by 1H NMR. In conclusion, we have developed a mild method for aromatic azidation with IBA-N3 catalyzed by Rh2(esp)2. The developed procedure is suitable for a variety of electron-rich aromatic substrates and exhibits high chemo- and regioselectivity. On the basis of these preliminary mechanistic studies, we propose that the catalyst-bound intermediate Rh2(esp)2N3 exists in the reaction procedure. Future studies will be directed toward the elucidation of the detailed reaction mechanism.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02446. Experimental details and spectral data for all compounds (PDF)

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a

(I) Electrospray ionization mass spectrum of the Rh2(cap)4N3. (II) Rh2(cap)4 in CH3OH and Rh2(cap)4 + IBA-N3 in CH3OH. (III) 1H NMR spectrum of the Rh2(cap)4N3. (IV) IR spectrum of the Rh2(cap)4N3.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected].

deep red crystalline solids were obtained to be characterized (see the Supporting Information). The absorption band at 2108 cm−1 in the infrared spectrum, demonstrating the existence of an azide group, was monitored (Scheme 5, IV).19 The peak at m/z 654.05 in MS was attributable to Rh 2(cap) 4 + , suggesting that the structure of Rh 2 (cap) 4 remained intact under oxidative conditions (Scheme 5, I). The 1H NMR spectra clearly show that the Rh2(cap)4 signal diminished, which indicated the generation of a paramagnetic one-electron-oxidized Rh2(cap)4+ species (Scheme 5, III). Though we did not obtain crystals of this active species, the above spectral data prove the existence of the stable Rh2(cap)4N3 species. Thus, based on these results, we believe that Rh2-bound azide species are the key catalytic species in this azidation reaction. Based on these results and the literature, we outlined a tentative mechanism for this transformation (Scheme 6). It is suggested that Rh2(esp)2 cleaves the weak I−N3 bond of the IBA-N 3 to generate a 2-iodobenzoxyl radical A and Rh 2 (esp) 2 N 3 . Then C−N bond formation between Rh2(esp)2N3 and aromatic substrates leads to azidated radical B and regenerated Rh2(esp)2. The resulting radical B is readily

ORCID

Xiaochuan Chen: 0000-0003-3901-0524 Yuanhua Wang: 0000-0003-0514-6976 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the National Science Foundation of China (Grant No. 21272162, 21172153). REFERENCES

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DOI: 10.1021/acs.orglett.8b02446 Org. Lett. XXXX, XXX, XXX−XXX