Combining Eosin Y with Selectfluor: A Regioselective Brominating

Letter pubs.acs.org/OrgLett

Combining Eosin Y with Selectfluor: A Regioselective Brominating System for Para-Bromination of Aniline Derivatives Binbin Huang,† Yating Zhao,† Chao Yang,† Yuan Gao,‡ and Wujiong Xia*,† †

State Key Lab of Urban Water Resource and Environment, School of Chemistry and Chemical Engineering, Harbin Institute of Technology (Shenzhen), Shenzhen 518055, China ‡ School of Chemistry and Chemical Engineering, Yantai University, 30 Qingquan Road, Laishan District, Yantai 264005, China S Supporting Information *

ABSTRACT: A mild, metal-free, and absolutely para-selective bromination of aniline derivatives has been developed in excellent yields, wherein the organic dye Eosin Y is employed as the bromine source in company with Selectfluor. Neither air nor moisture sensitive, this facile reaction proceeds smoothly at room temperature and completes within a short time. Mechanistic studies indicate a radical pathway; therefore, the existence of an in situ generated brominating reagent, “Selectbrom”, is postulated, which may reasonably account for the unique regioselectivity for the para-bromination of N-acyl- as well as N-sulfonylanilines.

I

groups has recently emerged as an attractive goal (Scheme 1b).3 On the other hand, the commonly used electrophilic halogenations generally yield the para-halogenated anilines as major products; however, the ortho-position isomers are still difficult to eliminate.4 Hence, we present here a new brominating protocol for certain aniline derivatives with absolute para-selectivity and high efficiency under mild conditions (Scheme 1c). As a kind of classic organic dye, Eosin Y has been well-known and utilized in many fields. With the recent development of visible-light photoredox reactions, it has been more frequently applied as a visible-light photocatalyst owing to its comparable photo and redox properties with the general Ru/Ir complexes.5 Selectfluor is a representative of a new class of electrophilic fluorinating reagents. In addition to introducing fluorine substituents to various substrates, it can also serve as an oxidant or mediate other electrophilic additions in certain transformations.6 Recently, we found that Selectfluor is able to activate the C− Br bond of Eosin Y (in its basic form with two sodium counteranions) and make it possible for Eosin Y to serve as a bromine source, which had never been reported before. After the cleavage of the C−Br bond, an elusive intermediate, “Selectbrom”, is presumed formed in situ via a radical process, which exhibits robust reactivity and unique regioselectivity as a brominating reagent for aniline derivatives (Scheme 2). At the initial stage of investigation, a negligible amount of monobrominated N-acetylaniline was unexpectedly detected by GC−MS in our tentative study of photoinduced fluorination of N-acetylaniline (1a) employing Eosin Y as photocatalyst and Selectfluor as fluorine source. Upon determination that the

n the realm of organic synthesis, halogenated aromatic compounds are widely accepted as significant building blocks, mainly due to their versatile applications as key precursors for a variety of cross-couplings, including the wellestablished Suzuki, Heck, and Ullmann couplings and many other newly developed methods.1 Thus, viable methods to access this class of compounds are highly desirable, especially the ones with high efficiency and excellent regioselectivity. Despite the development of various methods, halogenation of activated aromatic compounds such as aniline derivatives remains challenging. Available classical methods generally suffer from certain drawbacks such as application of hazardous reagents and harsh conditions, poor tolerance of functional groups, production of metal salts as stoichiometric byproducts, and unavoidable overhalogenation. But above all, the most important problem of these protocols is the poor regioselectivity of halogenated products, which limits the synthetic utilities of these procedures (Scheme 1a).2 In this regard, considerable efforts have been made to overcome these limitations. The application of metal or organocatalysts in catalyzing the ortho-halogenation of anilines bearing directing Scheme 1. Aromatic C−H Halogenation of Anilines

Received: June 3, 2017 Published: June 29, 2017 © 2017 American Chemical Society

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DOI: 10.1021/acs.orglett.7b01427 Org. Lett. 2017, 19, 3799−3802

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Organic Letters Table 2. Scope of the Brominationa

Scheme 2. Mechanistic Hypothesis

product was N-acetyl-4-bromoaniline (2a), the appropriate input ratio of the two reagents, 2 equiv of Eosin Y and 4 equiv of Selectfluor, was then settled. Furthermore, the reaction was shown to occur without the need for light irradiation, additives, and inert atmosphere (Table S1).7 To reach an optimal set of reaction conditions, various oxidants and solvents were subsequently examined, and the results are listed in Table 1. When oxidants other than Table 1. Optimization of the Reaction Conditionsa

entry

oxidant

solvent

yield (%) of 2ab

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

(NH4)2S2O8 Oxone CBr4 Ph2IOTf Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor

CH3CN CH3CN CH3CN CH3CN CH3CN DMF THF CH2Cl2 EtOAc CH3OH H2O CH3CN

ND ND 12 ND >99 20 6 23 ND 4 65 >99 (96)

a

Reaction conditions: aniline substrate (0.1 mmol), Eosin Y (0.2 mmol), and Selectfluor (0.4 mmol) in acetonitrile (1.0 mL) stirred at 25 °C for the time listed. Isolated yields are given on the basis of the substrates. bEosin Y (0.15 mmol) and Selectfluor (0.30 mmol) were employed.

yield, along with a 2,4-dibrominated product 2g′ in 35% yield, which was probably due to the electronic effect of the additional methyl group compared to the reaction of 1f. Changing the acetyl to other aliphatic acyl groups of substrates 1h−l showed no influence on the efficacy of these reactions, and the desired products 2h−l were obtained in nearly quantitative yields. A series of anilines with aromatic acyl groups on the nitrogen atoms (1m−q) were also examined. Substituted with electrondonating or -withdrawing groups at the para-position of benzoyl groups, anilines 1n−q exhibited a small variation in reaction rates, but no significant discrepancies of yields were observed. Again, the brominations of 1r and 1s were found to be highly efficient and selective. However, when it came to Nfuroylaniline (1t), byproducts of overbromination on the furan ring were generated due to the high reactivity of the heterocycle, but the yield could be improved by reducing the feed amounts of Eosin Y and Selectfluor and prolonging reaction time. Moreover, in the subsequent attempts of N-Bocaniline (1u), cyclic anilines (1v,w), and N-sulfonylanilines (1x,y), the desired products 1u−y were successfully obtained in good to excellent yields. Furthermore, N-acylanilines with their protons of N−H replaced by alkyl groups (1aa−ac) were also found to be capable of producing the para-brominated products in excellent yields, indicating that the naked N−H is not a prerequisite for this transformation. Interestingly, when substrate 3a with its para-position occupied by a methyl group was subjected to the standard conditions, the bromination proceeded smoothly at the ortho-position instead to furnish product 4a in 98% yield. To gain clearer insights into this transformation, mechanistic studies were started with three sets of control experiments in comparison with literature precedents to determine the

a

Reactions were carried out on a 0.1 mmol scale of N-acetylaniline 1a. GC yield; isolated yield is given in parentheses. cCommercial acetonitrile (AR) was directly used without further treatment. ND: not detected. b

Selectfluor were applied, the formation of 2a was either not detected or extremely sluggish (entries 1−4). Among all of the employed solvents, the originally used acetonitrile gave the best result, with no detectable signal of byproducts based upon GC analysis (entries 5−11). It is worth noting that when water was used as the reaction medium the reaction also proceeded to give the product 2a in 65% yield (entry 11), which suggested the system was not sensitive to water. Next, commercial acetonitrile (AR, Analytical Reagent) was directly applied as solvent, the reaction presented a quantitative GC yield, and subsequent isolation afforded 2a in 96% yield (entry 12). The scope of this para-bromination was then explored under the optimized reaction conditions.8 As shown in Table 2, the bromination occurred specifically at the para-position of Nacyl- and N-sulfonylanilines and tolerated a wide range of functional groups. When the N-acetylanilines bearing fluoride, chloride, or methyl at the ortho- or meta-position (1b−f) were applied, the corresponding brominated products 2b−f were obtained in excellent yields. However, when N-acetyl-3,5dimethylaniline (1g) was subjected to the conditions, the desired para-brominated product 2g was only acquired in 58% 3800

DOI: 10.1021/acs.orglett.7b01427 Org. Lett. 2017, 19, 3799−3802

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Organic Letters

Eosin Y in which Selectfluor acts as the one-electron oxidant to form a dicationic radical A, while Eosin Y serves as the reductant undergoing a C−Br bond cleavage to produce a bromine radical. The subsequent radical cross-coupling of A and the bromine radical generates a putative in situ brominating reagent, Selectbrom (B). When N-acetylaniline (1a) is employed in this system, the bulky reagent B would preferably draw close to the less hindered para-position to deliver C and cationic intermediate D after the cleavage of N−Br bond. Then D aromatizes after removal of the proton with the assistance of C to yield the final brominated product 2a. Despite our efforts using 1H NMR and HRMS methods to in situ detect the putative key intermediate Selectbrom (B), we obtained no indicative evidence for this species. Nevertheless, isolation attempts were also in vain, with compound C as the only acquired product (Scheme S4).7 To add more credence to the putative mechanism, further control experiments were performed employing several selected substrates with their potential reactive sites’ Mulliken charge distributions calculated (Scheme S5).7 The common rules of the well-known EAS (electrophilic aromatic substitution)-type reaction may be found followed by this radical-involved bromination. Representing aniline derivatives bearing sensitive groups, Nmethacrylaniline (1h) was selected as a substrate to undergo bromination under other conditions (Table S2).7 The comparative results demonstrated the unique regio- as well as chemoselectivity of the Selectfluor/Eosin Y combination. A gram-scale reaction of 1a was next carried out to check the synthetic potential of this methodology. The scaled-up reaction with 5 mmol of 1a provided 2a in 98% yield within 1 h under the standard conditions, showing no compromise in efficiency when compared to the 0.1 mmol scale one (Table 2). As a versatile building block, the resulting 2a is able to undergo a variety of further transformations,10 and in a representative Suzuki coupling with phenylboronic acid, the coupling product was acquired in 90% yield (Scheme S6).7 In summary, a highly para-selective bromination of aniline derivatives has been developed using a combination of commercially available and user-friendly organic dye Eosin Y and Selectfluor. This transformation has been proven to be compatible with a wide range of anilines bearing various functional groups. Mechanistic studies indicate a radical pathway, and a reactive intermediate, Selectbrom, is postulated. Owing to its broad substrate scope, mild reaction conditions, high efficiency, and excellent selectivity, this method should be of great synthetic potential.

reaction pattern (Scheme 3). In these works, Selectfluor was employed as an oxidant to achieve regioselective bromination Scheme 3. Comparative Experiments with Previous Works

a Detected by GC−MS. quantitative yield.

b

Starting material 1a was recovered in

with NaBr,6f KBr,6g and HBr (40% aqueous),6h respectively, and either a Br+ or Br2 pathway was suggested. For example, the double bond of styrene (3b) could be attacked by the in situ generated Br+ and a nucleophile such as CH3OH and H2O to afford the corresponding difunctionalized product (Scheme 3a, 3b).6g However, neither of 4b and 4c was detected in its corresponding Selectfluor/Eosin Y system, indicating that Br+ formation is not likely to be included in this process (Scheme 3a, 3b). Moreover, although the addition of radical scavenger TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was proved absolutely ineffective in the Selectfluor/HBr system,6h it completely inhibited the bromination of 1a in our system, suggesting that a radical process should be involved (Scheme 3c). Furthermore, a series of fluorescence quenching experiments were performed (Schemes S1−S3).7,9 The Stern−Volmer plots revealed that Selectfluor was capable of quenching Eosin Y, whereas 1a was not. Such a result suggested that the mechanism should begin with the interaction of Eosin Y with Selectfluor, most likely through a redox pathway with their redox potentials taken into consideration (Ered = −1.11 V vs SCE of Eosin Y5a and Ered = 0.33 V vs SCE of Selectfluor6b). Accordingly, a plausible mechanism is proposed and presented in Scheme 4. The initial step is assumed to be an SET (single-electron transfer) process between Selectfluor and Scheme 4. Proposed 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.7b01427. Experimental procedures and compound characterization data (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yuan Gao: 0000-0002-6442-262X 3801

DOI: 10.1021/acs.orglett.7b01427 Org. Lett. 2017, 19, 3799−3802

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Organic Letters

with EtOAc/petroleum ether = 1:2) to afford the corresponding parabrominated product 2a as a light yellow solid (20.6 mg, 96%). (9) Huo, H.; Harms, K.; Meggers, E. J. Am. Chem. Soc. 2016, 138, 6936. (10) (a) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550. (b) Kotadia, D. A.; Patel, U. H.; Gandhi, S.; Soni, S. S. RSC Adv. 2014, 4, 32826. (c) Zhang, Q.; Wang, D.; Wang, X.; Ding, K. J. Org. Chem. 2009, 74, 7187. (d) Xi, Z.; Liu, F.; Zhou, Y.; Chen, W. Tetrahedron 2008, 64, 4254.

Wujiong Xia: 0000-0001-9396-9520 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the China NSFC (Nos. 21372055, 21472030, and 21672047) and SKLUWRE (No. 2018DX02). We thank Dr. Yuan Yao, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, for theoretical calculations.

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REFERENCES

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DOI: 10.1021/acs.orglett.7b01427 Org. Lett. 2017, 19, 3799−3802