Electronically Mismatched Cycloaddition Reactions via First-Row

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Electronically Mismatched Cycloaddition Reactions via First-Row Transition Metal, Iron(III)−Polypyridyl Complex Jung Ha Shin,† Eun Young Seong,† Hyeon Jin Mun, Yu Jeong Jang, and Eun Joo Kang* Department of Applied Chemistry, Kyung Hee University, Yongin 17104, Korea

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ABSTRACT: The iron(III)−polypyridyl complex and its derivatives showed sufficient oxidizing potential to act as a oneelectron oxidant, producing radical cations from olefins and promoting the efficient radical cation [2 + 2] and [2 + 4] cycloaddition reactions. Subsequent chain propagation afforded trisubstituted cyclobutane or cyclohexene derivatives, and this facile route enables the replacement of rare metals with sustainable, green, and inexpensive iron in radical cation cycloadditions. ycloaddition, forming a cyclic adduct from two πelectron systems, is the most commonly utilized class of pericyclic reactions. Under general pericyclic cycloaddition reactions, most C−C bond formations take place between the electron-rich component and the electron-deficient reaction partner, among the inherently different electronic nature of the π-systems. Electronically mismatched cycloaddition reactions between two electron-rich or two electron-deficient components are considered to be challenging and require high pressure, high energy, or electrochemical modification of the reactants. As a solution to this problem, intermediary radical cationic or anionic approaches have been proposed employing single-electron oxidation or reduction systems. While studies on the radical anion cycloadditions have been relatively limited to enone substrates due to their nature of generating stable anions,1 radical cation cycloadditions may allow for a broader scope and more general application. The first radical cation cyclodimerization of N-vinylcarbazole (NVC) was reported by Ledwith in 1969, via an enamine radical cation using an Fe(III) or Ce(IV) salt as a single-electron oxidant.2 Bauld developed various radical cation catalyzed [2 + 4] and [2 + 2] cycloaddition reactions using triaryl aminium (amine radical cation) antimonate to oxidize 1,3-cyclohexadiene or anethole.3 More recently, hypervalent iodine reagents (PhI(OAc)2 and DMP) were used for styrene dimerization by Donohoe in 2016,4 and since then, research on photocatalysis has expanded rapidly. While photocatalytic systems utilizing the triaryloxopyrylium salt, p-OMePTP,5 have been developed, the most commonly

C

© XXXX American Chemical Society

utilized photocatalysts are Ru(II) and Ir(I) polypyridyl complexes.6 The redox potentials of Ru(II) complexes can be tuned to initiate alkene oxidation and, at the same time, prevent cycloreversion by utilizing diverse polypyridyl ligands. The Ir(I) polypyridyl catalyst can promote the energy transfer from the excited state of the Ir(I) complex that has a higher lowest-lying triplet state energy level than that of the organic substrates, and this triplet sensitization was unrestricted by the redox property of the interactive alkene substrate and promoted the single-electron transfer. Efforts to explore other transition metals as photocatalysts have been established, and Cr(III) polypyridyl complexes were successfully employed in radical cation mediated Diels−Alder reactions between two electron-rich components as well as two electron-deficient components. It is worth noting that chromium, like iron, is an earth abundant, first-row transition metal and that chromium complexes show higher excited state reduction potentials (from +1.40 V to +1.84 V vs SCE) which enabled the oxidation of stilbene.7 Iron(III) perchlorate has been employed as a chemical oxidant in the homodimerization of N-vinylcarbazole2 or trans-anethole. Itoh discovered alumina-supported iron catalysis in the early days, and Zhong recently expanded this methodology in crossed intermolecular [2 + 2] and [2 + 4] cycloadditions.8 Arguably, the most straightforward method for the preparation of cyclobutane rings is the [2 + Received: August 8, 2018

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DOI: 10.1021/acs.orglett.8b02541 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Table 1. [2 + 2] Cycloaddition Condition Screeninga

2] photocycloaddition reaction, and this prototypical photochemical reaction has been demonstrated in numerous synthetic applications. However, in-depth research is still needed to adapt benign and sustainable iron catalysts for use in these cycloadditions to address the cost, scalability, and environmental impact of first-row transition metal catalysts and to remove the need for high-energy irradiation processes.9 Based on our research interests10 investigating the competency of polypyridine ligands in controlling the oxidation potential of Fe(III) catalysts, herein, we report a radical cation catalyzed electron-mismatched heterocyclodimerization and Diels−Alder reaction to effect a highly stereoconvergent outcome with E/Z mixtures of anethole derivatives. We initially focused our studies on the [2 + 2] heterocyclodimerization of trans-anethole and styrene using the simple iron complex Fe(phen)3(PF6)3. To our delight, the trisubstituted cyclobutane 3aa was produced in 65% yield for the chemoselective crossed cycloaddition without any homodimerization cycloadduct formation, indicating that the Fe(III) complex acts as a single-electron oxidant and can selectively oxidize the trans-anethole to a radical cation species. While increasing the amount of the iron complex up to 25 mol % could induce a full conversion of the transanethole, the cooperative use of trifluoroethanol enabled sufficient reactivity even with a reduced amount (10 mol %) of the iron complex, due to the solvent’s ability to stabilize charged intermediates. Various fluorinated solvents and ratios were utilized to find the optimum solvent ratio (Table 1, entries 3−4, 13).11 Reducing the amount of styrene (5 equiv) decreased the isolated yield of 3aa, but there were no significant differences between using 10 and 3 mol % of the Fe(III) complex (entries 5−6). Changing the anion to bis(trifluoromethylsulfonyl)amide (NTf2) to improve solubility resulted in decomposition even at reduced temperature (entry 7). Furthermore, various polypyridyl ligands were utilized to control the oxidation potential of the Fe(III) complexes (entries 8−12). As we expected, varying the oxidation potential of the Fe(III) complex effected the yield: for catalysts with phenanthroline ligands, the catalyst with the lowest oxidation potential (E1/2 = +0.91 V) afforded the highest yield,12 but the efficiency decreased somewhat when the oxidation potential passed +1.15 V. Also, while the addition of oxygen gas is known to benefit this reaction,6b,7a using additional oxygen was not necessary in the general optimization (Table S3), but was found to be beneficial for cases where the electronic or steric demand decreased the rate of the reaction (vide infra). Ultimately, the [Fe(Me4phen)3] (PF6)3 catalyst with a lower oxidizing capability (+0.91 V) was determined to be the optimal Fe(III) complex to effect this selective and mild oxidation (trans-anethole, E1/2 = +1.11 V). Under the optimized conditions, both electron-rich and electron-poor styrenes reacted smoothly with the generated radical cation of anethole 1a (Scheme 1). Reaction with 5 equiv of the electron-rich 4-methylstyrene proceeded well to afford cyclobutane 3ab. 4-Chlorostyrene and 3- or 2bromostyrene required an additional amount of the Fe(III) complex to complete the heterodimerization reaction, suggesting that the reactivity of the styrene depended on the degree of electron withdrawal and steric hindrance (3ad− 3ag). The reaction with 4-acetoxy styrene did not afford full conversion, and only 43% of the product (3ah) was obtained

entry

Fe(III) complex (x)

solvent

yield (%)b

1 2 3 4 5c 6 7d 8 9 10 11 12 13d

Fe(phen)3(PF6)3 (15) Fe(phen)3(PF6)3 (25) Fe(phen)3(PF6)3 (10) Fe(phen)3(PF6)3 (10) Fe(phen)3(PF6)3 (10) Fe(phen)3(PF6)3 (3) Fe(phen)3(NTf2)3 (3) Fe(Ph2phen)3(PF6)3 (3) Fe(Me2phen)3(PF6)3 (3) Fe(Me4phen)3(PF6)3 (3) Fe(bpy)3(PF6)3 (3) Fe(tBu2bpy)3(PF6)3 (3) Fe(Me4phen)3(PF6)3 (3)

DCE DCE DCE/TFE (9:1) DCE/TFE (4:1) DCE/TFE (4:1) DCE/TFE (4:1) DCE/TFE (4:1) DCE/TFE (4:1) DCE/TFE (4:1) DCE/TFE (4:1) DCE/TFE (4:1) DCE/TFE (4:1) DCE/HFIP (9:1)

65 82 76 87 71 85 69 63 80 86 44 57 66

a

Reaction conditions: 1a (0.1 mmol), 2a (1.0 mmol), solvent (0.1 M), rt, 3 h. bIsolated yield. cReaction with 0.5 mmol of 2a. dReaction at 0 °C. Ph2phen = 4,7-diphenyl-1,10-phenanthroline, Me2phen = 2,9dimethyl-1,10-phenanthroline, Me4phen = 3,4,7,8-tetramethyl-1,10phenanthroline, bpy = 2,2′-bipyridine, tBu2bpy = 4,4′-di-tert-butyl2,2′-dipyr-idine, TFE = 2,2,2-trifluoroethanol, HFIP = 1,1,1,3,3,3hexafluoro-2-propanol.

with recovery of trans-anethole (32%). The methoxy substituent on benzene in the anethole radical cation could be replaced with an allyloxy or benzyloxy substituent (3ba− 3ca), implying the necessity of an electron-donating group on benzene, which is similar to other results involving a radical cation intermediate.4−8 The dimethoxy-substituted anetholes, 1d and 1e, showed a slight reduction in reactivity, presumably because the radical cation intermediate formed is more stable and, thus, less reactive. Treatment of reactive styrene 2b with a balloon of oxygen afforded the production of 3db and 3eb in moderate yield.7a,13 Longer carbon chains on the terminus of the anethole olefin were introduced, and these reactants also afforded the product in good yield with a balloon of oxygen. The yields of adducts 3gb−3hb are noteworthy in that both ethers and free hydroxy groups are tolerated in this reaction.14 Additionally, the E/Z ratio of the anethole (1f, 2:1; 1g, 1:1; 1h, 3:1) had no impact on the outcome of the cycloaddition; only trans stereochemical arrangements (antiproducts) were observed exclusively. Aliphatic olefins are not suitable reaction partners, such as ethyl vinyl ketone, dihydropyran, and dihydrofuran, and the observed difference of alkene reactivities (1 vs 2) appears to correlate well with their respective reduction potentials. This radical cation cycloaddition strategy could be expanded to the [2 + 4] Diels−Alder reaction described in B

DOI: 10.1021/acs.orglett.8b02541 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 1. Radical Cation [2 + 2] Cycloadditiona

complex under more hydrophilic conditions to afford 5ca. Additionally, using a mixture of the E and Z isomers of the anethole derivatives (1f, 2:1; 1i, 1:1.5) yielded one diastereomeric product, 5fa or 5ia respectively, and a longer alkyl substituent or an ester functional group had little effect on their reactivity. To better understand the mechanism of these cycloaddition reactions, we first set out to identify the radical cation intermediate and verify the role of the Fe(III) polypyridyl complex. Treatment of 1a with Fe(Me4phen)3(PF6)3 and TEMPO afforded the corresponding TEMPO adduct 7 (Scheme S1), identifying the position of the carbon radical as well as the carbocation center. Next, the stereochemical outcome of the [2 + 2] cycloaddition was examined. In most of the reactions utilizing stereoisomeric mixtures (Scheme 1, 1f−j), the stereochemical E/Z integrity is lost, and only one diastereomer is produced. Further experimentation showed that the E substrate was consumed faster than the Z substrate. Typically, the radical cation cycloaddition reaction can be explained using an ‘asynchronous concerted pathway’ or ‘stepwise pathway.’ However, several previous studies demonstrated that the distonic (longbond) radical cation intermediate formed with the first bond is highly reactive, so any rearrangement including a singlebond rotation is not thought likely to occur.3b,16 Thus, the stereoconvergent phenomenon observed here can arise from two possibilities: C−C rotation of cis- to trans-radical cation anethole intermediate or cycloreversion during the reaction. When 1f and 1i were subjected to the Fe(III) reaction conditions without styrene, the isomerization reaction proceeded, increasing the ratio of the E-isomer (Scheme 3A). At the same time, when cycloadduct 3aa was resubjected to the reaction conditions, the monomeric anethole 1a did not appear in the reaction medium. Attempts to use isoprene to trap the putative radical cation intermediate, which would have been present if cycloreversion was possible under these conditions, did not afford any Diels−Alder cycloadduct (Scheme 3B).6c Thus, the stereoconvergent nature of the radical cation cycloaddition under these reaction conditions arises from C−C rotation to the stable trans intermediate rather than a cycloreversion process. In a competitive cycloaddition experiment, the reactivity of the diene toward the radical cation intermediate was higher than the reactivity with the alkene, forming a 2:1 ratio of the [2 + 4] and [2 + 2] cycloadducts (Scheme 3C). The addition of oxygen was also required for reactivity when sterics and electronics hindered the reaction progress. Though the role of oxygen in facilitating this specific process is not certain, it should not be directly involved in enabling iron(II) catalyst oxidation.17 Instead, oxygen may be stabilizing the radical cation intermediates on the reaction pathway, supported by the oxidative cleavage of the radical cation-oxygen intermediate.18 More studies are necessary to further establish the feasibility of the potential mechanistic pathways and the critical role of oxygen. Our mechanism for this radical cation cycloaddition is proposed in Figure 1. Single-electron transfer from the anethole to the Fe(III) complex generates the radical cation (1a•+). At this point, the Z-configured anethole derivatives can transform to the stable trans-radical cation intermediate that can be stabilized by oxygen via equilibrium with a dioxetane radical cation. Next, the olefin radical cation undergoes asynchronous cycloaddition to the cyclized radical

a

Reaction conditions: 1 (0.1 mmol), 2 (1.0 mmol), DCE/TFE (4:1, 0.1 M), rt. bReaction with 1 mmol of 1a. cReaction at 0 °C. dReaction with 5 equiv of 2b. eDCE/TFE (9:1). fReaction under O2 balloon.

Scheme 2. 15 Treatment of trans-anethole with Fe(Me4phen)3(PF6)3 in a DCE/TFE (9:1) solvent system Scheme 2. Radical Cation [2 + 4] Cycloadditiona

a

Reaction conditions: 1 (0.1 mmol), 4 (1.0 mmol), DCE/TFE (9:1, 0.1 M), rt. bReaction at 0 °C. cReaction with 5 equiv of 4d. dDCE/ TFE (4:1). 5Reaction under O2 balloon.

afforded the cycloaddition with isoprene (4a) or 2,3dimethyl-1,3-butadiene (4b) to the corresponding adducts (5aa and 5ab) in excellent yield. Endo stereoselectivity was exclusively achieved with 1-substituted dienes (5ac, 5ad), while 1,4-substituted dienes were unreactive. The allyloxy substituted 1b showed excellent reactivity, while the benzyloxy substituted 1c required 10 mol % of the Fe(III) C

DOI: 10.1021/acs.orglett.8b02541 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 3. Mechanistic Investigation

Figure 1. Plausible mechanism for radical cation cycloaddition in Fe(III)−polypyridyl system.

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cation intermediate. Electron transfer with another equivalent of the anethole affords the product and propagates the following process by generating another equivalent of the radical cation (1a•+). This work represents a detailed report of Fe(III)− polypyridyl complexes applied to radical cation cycloaddition reactions. Not only does this effort demonstrate the viability of designing catalysts utilizing first-row transition metals, but it also validates the notion that sensitive reactivity can be discovered in these redox reaction systems. The current efforts are dedicated toward the development of additional catalyst systems based on earth-abundant Fe metal and further synthetic applications, and these will be reported in due course.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02541. Experimental procedures and characterization data for

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new compounds (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. D

DOI: 10.1021/acs.orglett.8b02541 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters ORCID

(14) In the Cr photocatalysis (ref 7a), the positioning of the pendant oxygen atom is critical, as the ether gave diminished yield and the alcohol afforded no product whatsoever. These observations were explained by a competitive intramolecular donation of the oxygen electrons into the putative radical cation intermediate. (15) See Table S1 for [2 + 4] condition screening experiments. (16) Marquez, C. A.; Wang, H.; Fabbretti, F.; Metzger, J. O. J. Am. Chem. Soc. 2008, 130, 17208. (17) Méndez, M. A.; Partovi-Nia, R.; Hatay, I.; Su, B.; Ge, P. Y.; Olaya, A.; Younan, N.; Hojeij, M.; Girault, H. H. Phys. Chem. Chem. Phys. 2010, 12, 15163. (18) (a) Chen, C.-C.; Fox, M. A. J. Comput. Chem. 1983, 4, 488. (b) Additional experiments on the oxygen effect were described in the Supporting Information (Table S3 and Scheme S2).

Eun Joo Kang: 0000-0002-7600-3609 Author Contributions †

J.H.S. and E.Y.S. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study was supported by the Kyung Hee University Research Fund (KHU-20160603).

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REFERENCES

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DOI: 10.1021/acs.orglett.8b02541 Org. Lett. XXXX, XXX, XXX−XXX