Formal Enone α-Arylation via I(III)-Mediated Aryl Migration/Elimination

Abstract

A formal enone α-arylation is described. This metal-free transformation relies on the I(III)-mediated skeletal reorganization of silyl enol ethers and features mild conditions, good yields, and high stereoselectivities for β-substituted enones.

The development of novel approaches for the synthesis of α-arylated carbonyl compounds remains a topic of interest in synthetic chemistry. Whereas classical approaches rely on transition-metal-catalyzed couplings of carbonyl-derived enolates with aryl halides or pseudohalides (Scheme 1A),¹ complementary transition-metal-free methods based on electrophilic aromatic derivatives such as sulfur(IV),² bismuth(V),³ iodine(III),⁴ and arynes⁵ have emerged in the last years. Alternative methodologies employing N-alkoxyenamines,⁶ enolonium equivalents,⁷ oxy-allyl cations,⁸ and radical-mediated arylations⁹ have also been developed.

Scheme 1. (A) Transition-Metal-Catalyzed Approach for α-Arylation of Carbonyl Compounds, (B) Enone Arylation via β-Pyridinium Enolonium Species, and (C) This Work: Enone α-Arylation via Iodine(III)-Mediated Aryl Migration/Elimination.

Despite the great progress achieved with transition-metal-free approaches, limitations in achievable substitution patterns and low atom economy still remain as drawbacks. In a recently disclosed elegant contribution by Wengryniuk and coworkers on the transition-metal-free α-arylation of enones, the direct C–H α-arylation occurs via the reductive iodonium Claisen rearrangement of in-situ-generated β-pyridinium silyl enol ethers (4) and ArI(O₂CCF₃)₂ reagents (Scheme 1B).¹⁰ Although this method features high atom economy, comparably expedient substrate synthesis, and a broad arene scope, its modularity is limited by the inevitable presence of an ortho-iodo substituent and accompanying restrictions in the substitution pattern of the aromatic in addition to the need to prepare the iodoarenes.

As part of our long-standing interest in the rearrangements of high-energy intermediates, we have established methodologies for the iodine(III)-mediated α-arylation¹¹ and α-cyclopropanation¹² of carbonyl compounds through oxidative C–C bond activation and carbocationic rearrangements, respectively. Inspired by the outstanding ability of iodine(III)¹³ in promoting oxidative rearrangements,¹⁴ we wondered whether this class of reagents could evoke an intramolecular α-arylation of enones. Herein we report a practical transition-metal-free protocol for the formal α-arylation of enones via iodine(III)-mediated aryl migration/elimination.

Encouraged by our previous work on I(III)-mediated rearrangements,^11,12 we envisioned a process in which intermediate 9 (Scheme 1C), the product of aryl migration on enolonium species 8, would undergo elimination to form 7. We therefore started our investigations with the silyl enol ether 6a as a model substrate and TMSOTf (trimethylsilyl trifluoromethanesulfonate) as the activator for a range of I(III) reagents (Table 1). The commercially available I(III) reagent PIDA (diacetoxyiodo)benzene, PhI(OAc)₂) gave a promising 50% yield of the desired α-arylated enone (entry 1). Increasing the amount of Et₃N (required for elimination) from 2 to 4 equiv led to the formation of 7a in 74% yield (entry 2), and a screening of I(III) reagents revealed PIDA as the optimum oxidant for this transformation (entries 3–5).

Table 1. Optimization of the Reaction Conditions^a.

entry	I(III) reagentb	TMSOTf (equiv)	base	yield (%)g
1	PhI(OAc)2	1.2	Et3Nc	50
2	PhI(OAc)2	1.2	Et3Nd	74
3	PhIO	1.2	Et3Nd	70
4	PhI(OPiv)2	1.2	Et3Nd	56
5	PhI(OCOCF3)2	1.2	Et3Nd	24
6	PhI(OAc)2	1.2	DIPEAd,e	38
7	PhI(OAc)2	1.2	NaOHf	12
8	PhI(OAc)2	1.4	Et3Nd	82h

^aAll screening was performed on 0.2 mmol of 6a (1 equiv) in 2 mL of DCM (0.1 M).

^b1.2 equiv.

^c2 equiv.

^d4 equiv.

^eAlongside 35% β-trifate.

^f1 M, 4 equiv.

^gNMR yields.

^hIsolated yield. TMSOTf = trimethylsilyl trifluoromethanesulfonate. DIPEA = N,N-diisopropylethylamine. DCM = dichloromethane.

Switching from Et₃N to either DIPEA (N,N-diisopropylethylamine) or NaOH did not lead to any improvement (entries 6 and 7); rather, through the presence of 35% β-triflated, α-arylated ketone, we were able to determine that the observed process likely proceeds via the capture of 9 by a triflate anion rather than direct elimination. It is additionally worth mentioning that during the examination of the conditions employing PIDA as the I(III) reagent, we observed the formation of distinct side products (α- and β-acetates), generated by competitive reactions with intermediates 8 and 9.^11,12,15 Attempting to avoid the formation of these byproducts, we increased the amount of the activator TMSOTf, which led to an improved isolated yield (82%) of the α-arylated enone 7a (entry 8).

With the optimized conditions in hand, we investigated the impact of electronics and sterics on the employed silyl enol ethers (Scheme 2). We first evaluated different substituents on the benzoyl moiety (Scheme 2a). Electron-donating, -withdrawing, and -neutral groups were all well tolerated, and the products 7a–j were obtained in good yields regardless of the position of the substituent. Furthermore, a silyl enol ether bearing a disubstituted aromatic ring was also susceptible to rearrangement in high yield (7i). Substrates bearing more elaborate aromatic rings such as 2-naphthyl (7k) and 1,3-benzodioxol-5-yl (7l) were also successfully transformed, as was 2-thienoyl-derived substrate (7m). In addition, an alkyl α-arylated enone 7n and an enal 7o were formed in 86 and 60% yield, respectively.¹⁶

Scheme 2. Scope of I(III)-Mediated α-Arylation of Enones.

All yields refer to pure, isolated products, unless otherwise stated.

NMR yields were determined using mesitylene as an internal standard.

Next, we evaluated the migration of substituted aryl groups. The rearrangement of an o-tolyl moiety afforded the product 7p in 57% yield, whereas the migration of a m-fluoro derivative provided the enone 7q in 51% yield. Additionally, the migration of a disubstituted aromatic group was accomplished effectively, yielding enone 7r in 65%. Unfortunately, the shift of an electron-poor aryl group such as p-CF₃C₆H₄ proved fruitless as a consequence of its diminished migratory ability. Instead, we obtained the corresponding β-arylated, α,β-unsaturated ketone as a major product under standard conditions.

Interestingly, we found that substrates with fused rings underwent I(III)-mediated aryl migration/ring expansion/elimination, leading to α-arylated enones 7t and 7u in high yields (Scheme 2b). Gratifyingly, the formal α-arylation of β-substituted enones proceeded readily, giving the desired products 7v and 7w in excellent yields and with excellent stereoselectivities. (See the Supporting Information for a rationalization of this selectivity.) It is worth highlighting that the product 7w proved more reactive to aryl migration/elimination than to a competitive intramolecular Friedel–Crafts reaction. In the case of an iso-propyl-substituted silyl enol ether (6x), we found that 2,3-dihydrofuran 7x was formed in 62% yield (Scheme 3a). We presume that this heterocycle was generated through a phenyl migration/Wagner–Meerwein rearrangement/cyclization sequence.

Scheme 3. Occurrence of a Cyclization Product and Functionalizations of α-Arylated Enone 7a.

To explore the synthetic utility of the new method, we chose product 7a for further derivatization (Scheme 3b). Scale up (5 mmol) of its preparation could be achieved without a significant decrease in yield. The enone 7a subsequently readily underwent Nazarov cyclization or a (3 + 2)-cycloaddition reaction. The synthesis of 2-phenyl-1-indanone (10) was accomplished in 59% yield, whereas the cycloaddition of 7a with N-phenyl-C-phenyl nitrone furnished the desired isoxazolidine 11 in an excellent yield of 97%.

In summary, we have developed a skeletal rearrangement-based methodology for the α-arylation of enones. The use of I(III) to mediate the aryl migration/elimination enabled the formation of a series of α-arylated enones in good yields under mild conditions. Furthermore, we demonstrated that our method is suitable for substrates bearing fused rings, promoting aryl migration/ring expansion/elimination, as well as for β-substituted silyl enol ethers, giving high yields and excellent stereoselectivities.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.1c00251.

• Experimental procedures, ¹H and ¹³C NMR spectra, and characterization data of compounds (PDF)

Author Contributions

^† B.S.M. and D.K. contributed equally.

The authors declare no competing financial interest.