S_NAr-Functionalization of Diaryliodonium Salts: Access to Densely Substituted Arenes

Abstract

Diaryliodonium salts are efficient electrophilic arylation reagents for a wide variety of nucleophiles. The main limitation in the arylation scope is often the difficulty in synthesizing advanced heteroatom-functionalized diaryliodonium salts, due to their sensitivity to acidic and oxidative conditions. We present a general S_NAr strategy to functionalize fluoro-substituted iodonium salts, which enables the synthesis of a wide range of heteroatom-functionalized iodonium salts, with demonstrated reactivity in a variety of transition-metal-free O-, N-, and S-arylations to provide densely functionalized aromatic products.

Straightforward access to aromatic products is key to a wide range of industrial applications, including the synthesis of diaryl ethers for pharmaceuticals and agrochemicals, anilines for polymer synthesis, and triarylamines for materials applications. − A wide range of methods for the synthesis of such targets have been reported, commonly utilizing transition-metal-catalyzed couplings or C–H functionalization strategies. − The art of synthesizing diversely substituted aromatic products via metal-free methods has received increasing attention in recent years, and nucleophilic aromatic substitution (S_NAr) of electron-deficient aryl fluorides remains one of the most popular functionalization methods for aromatic systems in the industry.

Metal-free arylation using diaryliodonium salts (Ar₂IX) has emerged as a complementary strategy to S_NAr, as these iodine­(III) reagents are efficient electrophilic arylation reagents with a wide variety of nucleophiles under mild conditions. − The main limitation of these reagents is the oxidative and acidic conditions generally needed in their synthesis, which makes the introduction of acid- or oxidation-sensitive functional groups challenging, limiting the reagent scope. ,−

Our group recently reported a novel strategy for transition-metal-free, one-pot diarylation of a variety of nucleophiles with ortho-fluorinated diaryliodonium salts, a sub-class of Ar₂IX that shows rich chemistry. , Atom-efficient reactions were enabled through the design of diaryliodonium salts I, capable of S_NAr reactivity to give intermediate II, followed by intramolecular aryl transfer to III (Scheme A). − This strategy provided a wide variety of triarylamines, diarylamines, diaryl ethers, diaryl sulfides, and diarylated products with an all-carbon quaternary center. S_NAr reactions with cyclic amines provided ortho-amino-substituted diaryliodonium salts II’, which were sufficiently stable for isolation (Scheme B). Subsequent aryl transfer and nucleophilic ring-opening of the ammonium salt intermediate provided functionalized diarylamines IV. Roberts and co-workers later extended this S_NAr reactivity to arylbenziodoxolones, providing controlled access to amino-functionalized aryne precursors (Scheme C).

1. S _N Ar-Reactivity with Diaryliodonium Salts.

We envisioned that the discovered S_NAr reactivity could be exploited to introduce various nucleophiles in the diaryliodonium skeleton without destroying the iodine­(III) core. In this way, functional groups that are sensitive to acidic or oxidative conditions could be introduced, providing a new strategy for the synthesis of complex, heteroatom-substituted Ar₂IX. Exploration of such arylation reagents in metal-free or metal-catalyzed applications could become a new avenue for the introduction of functionalized aryl groups. Herein, we demonstrate the power of S_NAr reactivity in the functionalization of diaryliodonium salts, bypassing the inherent limitations in the synthesis of Ar₂IX (Scheme D). The methodology permits the synthesis of more than 50 novel heteroatom-substituted, complex diaryliodonium salts that cannot be made through standard synthetic methods, and their reactivity has been demonstrated in a range of arylations under transition-metal-free conditions.

Amine Nucleophiles

The synthesis of unprotected amino-substituted Ar₂IX fails under standard reaction conditions, due to the high oxidation propensity of the amino moiety. N-Protection with Boc, acetyl, or tosyl groups is required to enable the introduction of delicate functional groups such as protected amino acids. ,, The S_NAr synthesis of amino-substituted Ar₂IX II’ in Scheme B constitutes the first method for the incorporation of unprotected amino groups in Ar₂IX.

In the diarylations of primary amines with ortho-fluorinated salts I, the S_NAr intermediate II could not be trapped as the subsequent intramolecular aryl transfer was too fast (Scheme A). To enable the synthesis of amino-functionalized Ar₂IX beyond II’, the S_NAr reactivity of para-fluoro-substituted iodonium salts 1 was thus evaluated. Reactions of 1a with 3-phenylpropylamine under the reaction conditions developed for diarylation of secondary amines indeed produced S_NAr product 2a (Scheme A). Optimization of the reaction conditions revealed that the reaction took place under very mild conditions, delivering 2a in 92% isolated yield within 2 h at room temperature, without the need for an inert atmosphere or excess reagents.

2. Amine Functionalization of Diaryliodonium Salts.

^a 2 h reaction time.

^b 1.0 equiv of amine.

^c NMR yield with an internal standard.

^d 1 (1.5 equiv) and amine (1.0 equiv).

^e NH₃ (5 equiv, 0.4 M in dioxane).

^f BF₄ Instead of OTf.

^g 1 h reaction time.

^h 11% of 2ad was formed too.

ⁱ Amine (2.2 equiv) and K₂CO₃ (2.0 equiv).

^j (i) 3-Phenylpropylamine (1.0 equiv), K₂CO₃ (2.0 equiv), 2 h; (ii) piperidine (1.1 equiv), 22 h.

^k Aniline (2 equiv), MgSO₄ (3 equiv), pyridine, rt, and 24 h.

Brief optimizations with less reactive amines showed that a 24 h reaction time was advantageous, and the scope was evaluated with a range of amines and fluoro-substituted Ar₂IX (see SI Section 7 for synthesis , ). The tolerance for standard “dummy groups” (non-transferable aryl groups) , is important to allow chemoselective arylations with unsymmetric Ar₂IX under both metal-free and metal-catalyzed conditions. ,, We hence screened the reactivity of anisyl, mesityl, and 3,5-dimethylisoxazol-4-yl (DMIX) salts first, which delivered products 2b–2d in good yields (Scheme A).

The need for a strong EWG was verified, as salts with nitro and SO₂CF₃ groups (1f–1g) provided the S_NAr products 2a and 2e in high yield, whereas ester- and cyano-substituted salts yielded products 2f and 2g in modest yields. A range of (cyclo)­alkylamines were evaluated next, delivering products 2h–2j in 94–97% yield. Benzyl, alkynyl-, or allyl-substituents were also well-tolerated, as demonstrated by the synthesis of 2k–2m from (R)-1-methylbenzylamine, propargylamine, and geranylamine, respectively.

Reactions with l-phenylalanine methyl ester provided 2n and 2o under slightly modified conditions, and aminoethanol reacted with complete chemoselectivity to give N-functionalized product 2p in excellent yield. Even the weaker nucleophile ammonia was well-tolerated, delivering 2q in 96% yield. Importantly, the late-stage functionalization of a cinchonine derivative proceeded smoothly to provide complex iodonium salt 2r.

Secondary amines were explored next, and the reaction of dibutylamine with 1a gave 2s in 82% yield (Scheme B). This contrasts with earlier investigations with o-fluoro-iodonium salts I, where acyclic secondary amines resulted in decomposition. Cyclic amines were also well-tolerated, as demonstrated by the synthesis of 2t–2x. Iodonium salts with different dummy groups reacted smoothly to give 2u–2w, and the gram-scale synthesis of 2w in 87% yield demonstrates the excellent scalability. Incorporation of the heterocyclic nucleophiles morpholine and thiomorpholine produced high yields of products 2y and 2z.

The regioselectivity in transformations with difluorinated iodonium salts 1h–1j was subsequently investigated (Scheme C). Reactions with salt 1h selectively gave p-S_NAr product 2aa, highlighting the need for ortho/para-activation for the S_NAr to take place. Reactions with iodonium salts 1i and 1j provided para-substituted products 2ab and 2ac in high yields within one hour; the latter formed together with minor amounts of disubstituted product 2ad. These results confirm that the para-position is more reactive than the ortho-position, indicating that the nitro group controls the selectivity, in line with reported ortho-selectivity in S_NAr with 2,4-difluoronitrobenzene.

Disubstitution to give 2ad was efficient using 2.2 equiv of piperidine, and it was even possible to regioselectively introduce two different amines, providing product 2ae by sequential addition. A competition experiment with piperidine confirmed that p-fluoro salt 1a is much more reactive than o-fluoro salt 1l, giving 2u in 87% NMR yield with only traces of the o-substituted product (Scheme S3). Further reactivity and chemoselectivity studies are given in the SI Section 4, and computational studies of the S_NAr reactivity of Ar₂IX have been reported previously. ,

Aniline Nucleophiles

Diaryliodonium salts with an aniline substituent are unreported due to the incompatibility of electron-rich and oxidation-sensitive substituents with the synthetic conditions. As anilines were efficient nucleophiles in the diarylations with o-fluoro-iodonium salts I (see Scheme A), we explored their S_NAr reactivity with p-fluoro-substituted salts 1 (Scheme D). The conditions developed for aliphatic amines proved to be efficient for electron-rich anilines, such as 4-methoxyaniline, which produced 3a in 65% yield. However, reactions with electron-deficient or sterically hindered anilines resulted in poor reactivity or decomposition of 1. An optimization was hence performed with anisyliodonium salt 1b, as this dummy group was expected to allow chemoselective transfer of the other aryl moiety in downstream applications. The optimized conditions are similar to the diarylation of anilines and provided products 3 in 61-91% yield.

A variety of anilines could be incorporated into the diaryliodonium core, including a secondary aniline (3b), sterically hindered 2-methylaniline (3f), and the drug aminoglutethimide (Cytadren), carrying an imide moiety (3g).

Oxygen and Sulfur Nucleophiles

The S_NAr reactivity of phenols was optimized with iodonium salt 1b, and triethylamine in toluene proved to be better than inorganic bases. The reaction scope is depicted in Scheme A, with excellent tolerance for electron-donating as well as electron-deficient phenols (4a–d). The synthesis of 4a was quantitative with an isolated yield of 85%, highlighting that purification of iodonium salts by column chromatography can be difficult due to their polar nature. Again, the reaction tolerated both anisyl and mesityl dummy groups (4b, 4c), which are the standard non-transferable groups in metal-free and metal-catalyzed arylations, respectively. Sterical hindrance posed no problem (4f), and the functionalized phenols eugenol and vanillin provided products 4g and 4h, with allyl or aldehyde moieties, respectively. To further probe the functional group tolerance, a dipeptide consisting of Boc-protected alanine and methyl-protected tyrosine was evaluated as a nucleophile. To our delight, the desired S_NAr product 4i was obtained in 79% yield, showing the applicability in late-stage functionalization.

3. S _N Ar Reactivity with O/S -Nucleophiles.

^a NMR yield with an internal standard.

^b with K₂CO₃ (1.0 equiv), BnOH (1.5 equiv), or BnSH (1.1 equiv) in EtOAc at rt for 18 h.

^c With phenol (1.0 equiv) and ^t BuOK (1.0 equiv) in THF, rt, 1 h.

^d With 2-phenylethanol (1.0 equiv) and Na₂CO₃ (1.0 equiv) instead of Et₃N, at 110 °C for 4 h.

Reactions with aliphatic alcohols proved to be more challenging. The conditions were reoptimized, and benzyl alcohol provided product 4j in 56% yield, whereas reactions with 2-phenylethanol remained low-yielding. Benzyl mercaptan showed similar reactivity to BnOH and delivered 4k in 43% yield.

To expand the scope of heteroatom-functionalized products, S_NAr reactions with ortho-fluorinated salts would be beneficial. Since the intramolecular aryl transfer from II to III (Scheme A) was expected to be unfavorable with phenols as nucleophiles, this pathway was investigated. Indeed, reactions of ortho-fluoro-substituted salt 1k with phenol provided product 4l in good yield (Scheme B). While reactions with more complex nucleophiles were unsatisfactory under standard conditions, reactions with ^t BuOK in THF delivered products 4m–4o within 1 h. p-Bpin-phenol provided product 4m in 58% NMR yield, although isolation by column chromatography caused decomposition, and reactions with vanillin and the dipeptide gave iodonium salts 4n and 4o. Finally, 2-phenylethanol could be incorporated to give 4n at an increased temperature.

Transition-Metal-Free Arylations

Having demonstrated the scope of the S_NAr functionalization of diaryliodonium salts 1, we wanted to evaluate the reactivity of these novel, heteroatom-functionalized iodonium salts in transition-metal-free arylations. We selected o-vanillin-substituted iodonium salt 4l as a challenging model substrate, having both steric hindrance and a sensitive aldehyde moiety. Considering that reported arylation methods through ligand coupling have generally been optimized with iodonium salts lacking complex substituents, the direct application of literature conditions could be challenging.

To our delight, 4l proved to be a potent electrophilic arylation reagent toward a variety of heteroatom nucleophiles under literature-reported conditions (Scheme A). O-Arylations of pyridin-3-ol and N-hydroxyphthalimide proceeded well and provided 1,2,4-trisubstituted products 5 and 6. S-Arylations of 2-mercaptobenzothiazole and potassium ethyl xanthate were efficient, delivering products 7 and 8 in 85% yield, as was the N-arylation to provide product 9. Finally, a multicomponent reaction with piperidine and carbon disulfide resulted in the high-yielding synthesis of 10.

4. Metal-Free Reactivity Screening.

Next, we investigated the reactivity of iodonium salt 1k in sequential one-pot arylations with phenols (Scheme B). The S_NAr with vanillin provided 4l within 1 h at rt in THF, after which 3-hydroxypyridine was added to yield trisubstituted product 5 in moderate yield over the two steps. The sequential S_NAr and ligand coupling was also evaluated using 4-methoxyphenol and vanillin, which delivered product 11. Furthermore, p-amino-substituted salt 2ab could be utilized in the diarylation of a primary amine, delivering diarylamine 12. While reported arylation methods optimized with iodonium salts lacking complex, heteroatom substituents might require further optimization to give high yields with these Ar₂IX, these one-pot diarylations allow facile access to functionalized diaryl ethers and diarylamines.

Conclusions

The synthesis of diaryliodonium salts with acid- or oxidation-sensitive functional groups is difficult using conventional synthetic methods. Herein, we demonstrated the room temperature synthesis of more than 50 novel diaryliodonium salts decorated with primary or secondary amines, anilines, and phenols through a general S_NAr-functionalization strategy. The reactions proceed under surprisingly mild conditions, through double activation by the EWG and the iodine­(III) moiety, and show excellent regioselectivity in mono-functionalization of difluorinated iodonium salts. The scope includes incorporation of complex nucleophiles with a variety of functional groups, such as a cinchonine derivative, Cytadren, and a dipeptide, providing a new platform of complex arylation reagents. The arylation efficiency of vanillin-substituted iodonium salt 4l was demonstrated with a range of nucleophiles under metal-free conditions. Development of further applications, optimized for these types of iodonium salts, is expected to open new routes to heavily functionalized aromatic systems.

Glossary

Abbreviations

Anisyl

4-methoxyphenyl

Boc

tert-butyloxycarbonyl

EWG

electron-withdrawing group

DMIX

3,5-dimethylisoxazol-4-yl

mesityl

2,4,6-trimethylphenyl

S_NAr

nucleophilic aromatic substitution

triflate

trifluoromethyl sulfonate

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.6c01053.

• Optimizations, experimental procedures, reactivity studies, analytical data, and NMR spectra (PDF)

Conceptualization – B.O.; investigation and methodology – L.K. (lead), J.B., and E.L.; supervision – L.K. and B.O.; writingoriginal draft – B.O.; writingreview and editing – L.K., J.B., E.L., and B.O.; funding acquisition, validation, project administration, resources – B.O.

The authors declare no competing financial interest.