Skip to main content
NCBI home page
JACS Au logoLink to JACS Au
. 2024 Aug 5;4(8):2832–2837. doi: 10.1021/jacsau.4c00500

Transition-Metal-Free C-Diarylations to Reach All-Carbon Quaternary Centers

Shobhan Mondal 1, Benjamin Gunschera 1, Berit Olofsson 1,*
PMCID: PMC11350576  PMID: 39211612

Abstract

graphic file with name au4c00500_0006.jpg

Herein, we disclose a convenient protocol for the α-diarylation of carbon nucleophiles to yield heavily functionalized quaternary products. Diaryliodonium salts are utilized to transfer both aryl groups under transition-metal-free conditions, which enables an atom-efficient and high-yielding method with broad functional group tolerance. The methodology is amenable to a wide variety of carbon nucleophiles and can be utilized in late-stage functionalization of complex arenes. Furthermore, it is compatible with a new class of zwitterionic iodonium reagents, which gives access to phenols with an ortho-quaternary center. The diarylated products bear an ortho-iodo substituent that can be utilized in further transformations, including the formation of novel, functionalized six-membered cyclic iodonium salts.

Keywords: iodonium salts, carbon nucleophiles, difunctionalization, quaternary center, zwitterionic iodonium compounds

The α-arylated carboxylic acid derivatives are a ubiquitous class of compounds that constitutes the backbone for various nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen.1−3 Organic structures with an all-carbon quaternary center pose unique importance because of their bioactivities and constraint arrangements.4,5 α-Arylation of carbon nucleophiles to generate quaternary carbon centers and enrich molecular complexity has attracted significant attention, furnishing a vast range of arylated organic molecules with medicinal importance, such as methadone, isopropamide, and diphenoxylate (Scheme 1 A).6−11

Scheme 1. Diarylation of Carbon Nucleophiles.

Scheme 1

Open in a new tab

The primary challenges for the synthesis of quaternary carbon centers are steric congestion and conformational restrictions.12 Quaternary α-monoarylated centers can be obtained from β-dicarbonyl compounds and nitroalkanes via transition metal catalysis,13−16 and metal-free strategies include SNAr, aryne chemistry, and sulfoxide-mediated arylation.12,17−19 Diaryliodonium salts, which are mild electrophilic arylating reagents,20−23 have also proved efficient in metal-free α-arylation of β-keto esters, malonates, and nitroalkanes.24−31

While α-monoarylation of carbonyl compounds is well investigated, methods to synthesize α-diarylated quaternary centers are more scarce and generally require stepwise, metal-catalyzed monofunctionalization methods (Scheme 1B).32−34 Symmetric diarylation has only been achieved through the Pd-catalyzed diarylation of ethylcyanoacetate,35 through aryne reactions with β-dicarbonyl compounds36,37 (Scheme 1C), and through α-diarylation of enol ethers or pyrazolinones with diaryliodonium salts.38,39 Unsymmetric α-diarylation of carbon nucleophiles has only been reported to yield fluorenes with cyclic diaryliodonium salts under Pd-catalyzed conditions (Scheme 1C).40,41

Our group previously reported a novel strategy to enable one-pot, atom-efficient diarylation of heteroatom nucleophiles under transition-metal-free conditions.42−44 The method employs a special type of diaryliodonium salt to unlock SNAr reactivity, and the approach proved successful in the synthesis of a wide variety of unsymmetric diaryl amines, ethers, and sulfides with the ortho-iodo substituent retained in the products. Herein, we describe the extension of this strategy to carbon nucleophiles to allow for straightforward synthesis of targets bearing an all-carbon quaternary center decorated with two different aryl groups (Scheme 1D). The retained ortho-iodo substituent can be used for further transformations, including one-pot synthesis of six-membered cyclic diaryliodonium salts, which form valuable doubly functionalized diaryl motifs upon reaction with various nucleophiles.45−47 The current methodology for synthesis of six-membered cyclic salts requires multistep routes or functionalized starting materials, which limits the availability of such reagents.45,46

The investigations were focused on the use of stabilized carbon nucleophiles because too basic nucleophiles can result in byproducts via aryne formation.48 The reaction of diaryliodonium salt 1a and diethyl malonate (2a) was first evaluated with various bases and solvents at 100 °C, which resulted in the formation of desired product 3a in low yield, along with a diaryl ether byproduct 3a′.49 To our delight, the diaryl ether formation was completely suppressed when the enolate was preformed from 2a and added dropwise to a solution of 1a at room temperature (Table 1, entry 1). A base screen showed that sodium hydride enabled almost quantitative yield of 3a (entries 2–4), whereas other solvents proved to be less efficient (entries 5 and 6). In the interest of atom efficiency, the equivalents of 2a were reduced but this resulted in decreased yield (entry 7).49 Interestingly, the reactivity was improved when pentane-washed sodium hydride was used (entries 8 and 9), and product 3a could be isolated in 87% yield using only a slight excess of 2a when the reaction was performed at 0 °C to rt (entry 10). For sustainability reasons, these conditions were generally employed in the scope studies, while the results using the conditions in entry 4 are reported for selected products.

Table 1. Optimization of the Reaction Conditionsa.

graphic file with name au4c00500_0005.jpg

entry 2a (equiv) base (equiv)b solvent T (°C) yield 3a (%)c
1 2.0 NaOtBu (2) DMF rt 89
2 2.0 KOtBu (2) DMF rt 67
3 2.0 NaOTMS (2) DMF rt 89
4 2.0 NaH (2) DMF rt 99
5 2.0 NaH (2) THF rt 27
6 2.0 NaH (2) Et2O rt 29
7 1.1 NaH (2) DMF rt 71
8 1.0 NaHw (2) DMF rt 78
9 1.0 NaHw (2) DMA rt 79
10d 1.3 NaHw (2.4) DMA 0 °C to rt 93 (87)
Open in a new tab
a

Reaction conditions: 2a and base were prestirred before adding to 1a (0.025 mmol) in solvent (0.03–0.06 M) for 12–14 h reaction time.

b

NaH = sodium hydride 60% in mineral oil; NaHw = sodium hydride washed with pentane.

c

1H NMR yield using 1,3,5-trimethoxybenzene (TMB) as internal standard (isolated yield in parentheses).

d

Reaction scale at 0.2 mmol. DMF = N,N-dimethylformamide; DMA = N,N-dimethylacetamide.

The generality of the methodology was evaluated by variation of diaryliodonium salts 1 (Scheme 2A). To our delight, 3a was isolated in 90% yield when the reaction was performed at gram scale. Alkyl-substituted 1 furnished diaryl malonates 3b–3d in high yields and iodonium salts with halide substituents exhibited excellent reactivity to provide diaryl malonates 3e–3g in excellent yields. This feature makes the methodology complementary to metal-catalyzed cross couplings, which have scope limitations in the synthesis of halide-substituted products15 or require the use of super-stoichiometric Cu salts33,50,51 or unstable diazo esters.52

Scheme 2. Diarylation Scope.

Scheme 2

Open in a new tab

Reaction conditions: 1 (0.20 mmol), 2a (0.26 mmol), NaH (washed, 0.48 mmol), and DMA (0.06–0.07 M) under N2 atmosphere at 0 °C were stirred for 2–4 h at 0 °C and 12–14 h at rt.

Gram-scale synthesis.

Conditions from entry 4 used: 1 (0.20 mmol), 2a (0.40 mmol), NaH (unwashed, 0.40 mmol), DMF (0.6–0.07 M).

OTs– salt was used.

BF4– salt was used.

Compound 2a (0.40 mmol) was used.

Reaction scale of 1.5 mmol.

Reaction conditions as above followed by acidic workup with HCl (1 M).

Electronic effects in 1 were next evaluated, and the electron-donating groups (EDG) OMe, OPh, NHAc, and Ph were well tolerated to produce 3h–3k. The use of electron-withdrawing groups (EWG), like CF3, OCF3, COMe, CN, and NO2, also led to the desired malonates 3l–3p in high to excellent yields, and the combination of EDG and EWG gave decorated malonate derivative 3q. To our delight, ortho-substituted salt 1 was productive in the diarylation and provided malonate 3r with little influence on the yield compared to the corresponding para-substituted salt (see 3b vs 3r). Additionally, an ortho-ester substituent was tolerated and gave the product 3s.

The scope of possible substituents in the electron-deficient aryl ring was investigated by adding further functional groups. Insertion of a CF3 group resulted in a smooth reaction to provide malonate derivative 3t in excellent yield. Likewise, the NO2 group could be placed ortho to the fluoride with CF3 in the para-position (3u). Reactions with salts 1 decorated with two fluorides were employed to evaluate the regioselectivity of the SNAr step (3v–3x). Importantly, complete regioselectivity was observed in the formation of products 3v and 3w. A highly electron-deficient, symmetrical iodonium salt could be used to provide malonate derivative 3x, thereby illustrating that the internal aryl transfer is preferred over a second SNAr reaction and that another SNAr on the product does not take place under the reaction conditions. The SNAr reactivity was also enabled by other strong EWG groups, as demonstrated by products 3y and 3z.

The broad application possibilities and wide functional group tolerance of the methodology was illustrated by the use of more complex arenes. Heterocycles, bioactive compounds and drug molecules were first converted with complete regioselectivity to the corresponding diaryliodonium salts using established one-pot methods.53−56 Subsequent diarylation yielded complex heterodiarylated products with an all-carbon quaternary center (Scheme 2B). In this fashion, a coumarin-derived iodonium salt underwent diarylation to give target product 3aa in a good yield. An electron-rich pyridine moiety and a phthalimide derivative were also tolerated to furnish 3ab and 3ac. Furthermore, late-stage functionalization of the drug molecules clofibrate and gemfibrozil provided the corresponding diaryl malonates 3ad and 3ae. To the best of our knowledge, these applications are the first examples where complex heterodiarylated products are formed by a regioselective insertion of an active methylene onto arene scaffolds with further functionalization opportunities (vide infra).

The scope of activated methylene compounds was subsequently explored (Scheme 2C). Common symmetric malonates, such as dimethyl, diisopropyl, and dibenzyl reacted smoothly to give the desired products 4a–4c in excellent yields. Similar reactivities were observed with unsymmetric malonates, which furnished their diarylated derivatives 4d and 4e. α-Cyano esters were found to be compatible carbon nucleophiles under the same reaction conditions, which provided their derivatives 4f and 4g in excellent yields. Additionally, the synthesis of 4f was scaled up to 1.5 mmol, which resulted in a slightly elevated yield. Because of the strong precedence of phosphonate esters as nucleophiles,57,58 a cyano-substituted phosphonate ester was tested and delivered diarylated species 4h in moderate yield. While monoarylation of nitro-alkanes is well investigated,59,60 α-diarylation methods have not been explored. Hence, the successful diarylation of nitroalkanes to provide quaternary nitroalkanes 4i and 4j constitutes a new route to such targets.

Aryliodonium ylides are special types of iodine(III) reagents that are generally formed from dicarbonyl compounds. Such reagents have been used in C-functionalizations via, e.g., fluorination, trifluoromethylation, cycloaddition reactions, and as carbene precursors in metal-catalyzed reactions.61−64 Zwitterionic iodonium compounds with a phenoxy moiety are a related compound class that can undergo intramolecular aryl transfer to form diaryl ethers.65−67 The utility of such reagents in diarylations to transfer both aryls of the reagent remains unexplored. To our delight, reactions with zwitterionic reagent 5 smoothly delivered the corresponding diarylated malonates 6a–6c decorated with two different handles for further functionalization (Scheme 2D).

We have previously studied the mechanism in diarylation of heteroatom nucleophiles and supported the proposed SNAr pathway by isolation of the diaryliodonium intermediate, as well as through DFT studies.42−44 Moreover, β-dicarbonyls are well known nucleophiles for SNAr reactions under basic reaction conditions.17,68 Based on those results and NMR studies of the current system,49 we propose that the reaction proceeds by facile deprotonation of the malonate to give enolate I, which might coordinate to the iodine or directly undergo SNAr reaction to give α-arylated malonate species II (Scheme 3). This is quickly deprotonated by the remaining base to give intermediate III, which was observed during low-temperature NMR studies and could also be trapped by HCl in diethyl ether to give II.49 Finally, intramolecular transfer of the phenyl group to the enolate carbon with concomitant breaking of the C–I bond leads to product 3a.

Scheme 3. Proposed Mechanism.

Scheme 3

Open in a new tab

To evaluate the ease of postsynthetic transformations, products 3a and 4a were derivatized through a range of reactions (Scheme 4). Transition-metal-free reduction of 3a gave the corresponding amine derivative 7a in excellent yield. Decarboxylation proceeded smoothly to provide diarylated ester 7b, thereby highlighting the ease of obtaining α-diarylated products from enolates that were unsuitable nucleophiles in the diarylation.49

Scheme 4. Postsynthetic Applications of Malonate 3a.

Scheme 4

Open in a new tab

Reaction conditions: (i) B2(OH)4, 2,2′-bipyridine, DMF, 40 °C, 4 h; (ii) LiCN, KCN, H2O, DMSO, 100 °C, 3 h; (iii) Pd(OAc)2, PCy3, K2CO3, PivOH, 120 °C, 12 h; (iv) Pd(PPh3)4, CuI, NEt3, 100 °C, 3 h; (v) mCPBA (meta-chloroperoxybenzoic acid), TfOH or TsOH, CH2Cl2, rt, 12 h; (vi) BnNHCS2NHEt3, CuSO4, 2,2-bipyridine, MeCN, 50 °C, 3 h (from 8b); (vii) NaN3, DMA, 120 °C, 30 min (from 8b); (viii) mCPBA, TfOH, CH2Cl2, rt, 2 h.

Next, derivatizations using the iodine handle were evaluated, and a Pd-catalyzed cyclization delivered fluorene derivative 7c, whereas a Sonogaschira coupling produced 7d in excellent yield. The ortho-iodo motif was also utilized in the synthesis of novel six-membered cyclic iodonium salts 8a–8c under our standard reaction conditions for iodonium salt synthesis.42 Preliminary evaluation of the reactivity of 8b revealed that Cu-catalyzed insertion of a sulfur bridge to give 7e and metal-free azidation to give ortho-difunctionalized product 7f were feasible. Furthermore, cyclic iodonium triflate 8d was easily synthesized from monoester product 7b.

In conclusion, we have developed an efficient protocol for the C-diarylation of carbon nucleophiles under mild, transition metal-free conditions. Using this procedure, unsymmetrically diarylated malonates, nitroalkanes, cyano-substituted esters, and phosphonate esters were attainable. Both diaryliodonium salts and novel zwitterionic iodonium compounds were utilized in the transformation. Furthermore, a variety of functional groups were well tolerated on both the iodonium salts and the carbon nucleophiles. The various functionalities present on the diaryated products allow diverse downfield diversification and even the formation of a novel class of six-membered iodonium salts, which will be further explored. We anticipate that this efficient C-diarylation methodology will become a versatile tool for mild and metal-free synthesis of complex molecules containing quaternary centers.

Acknowledgments

Financial support for this study was provided through Olle Engkvist Foundation (207-0615) and Stockholm University.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.4c00500.

  • Experimental procedures, mechanistic studies, and spectral data (PDF)

Author Contributions

CRediT: Shobhan Mondal investigation, methodology, writing-original draft; Benjamin Gunschera investigation, methodology; Berit Olofsson conceptualization, project administration, resources, supervision, validation, writing-review & editing.

The authors declare no competing financial interest.

Supplementary Material

au4c00500_si_001.pdf (20.7MB, pdf)

References

  1. Rieu J.-P.; Boucherle A.; Cousse H.; Mouzin G. Tetrahedron report number 205: Methods for the synthesis of antiinflammatory 2-aryl propionic acids. Tetrahedron 1986, 42, 4095–4131. 10.1016/S0040-4020(01)87634-1. [DOI] [Google Scholar]
  2. Lou Y.; Zhu J. Carboxylic Acid Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). Bioactive Carboxylic Compound Classes 2016, 221–236. 10.1002/9783527693931.ch16. [DOI] [Google Scholar]
  3. Cívicos J. F.; Costa P. R. R.; Domingos J. L. O. Palladium-Catalyzed α-Arylation of Dimethyl Malonate and Ethyl Cyanoacetate with o-Alkoxybromobenzenes for the Synthesis of Phenylacetic Acid, Esters and Phenylacetonitriles. SynOpen 2017, 01, 0091–0096. 10.1055/s-0036-1588550. [DOI] [Google Scholar]
  4. Li C.; Ragab S. S.; Liu G.; Tang W. Enantioselective formation of quaternary carbon stereocenters in natural product synthesis: a recent update. Nat. Prod. Rep. 2020, 37, 276–292. 10.1039/C9NP00039A. [DOI] [PubMed] [Google Scholar]
  5. Marek I.; Minko Y.; Pasco M.; Mejuch T.; Gilboa N.; Chechik H.; Das J. P. All-Carbon Quaternary Stereogenic Centers in Acyclic Systems through the Creation of Several C-C Bonds per Chemical Step. J. Am. Chem. Soc. 2014, 136, 2682–2694. 10.1021/ja410424g. [DOI] [PubMed] [Google Scholar]
  6. Sheldrick G. M.; Jones P. G.; Kennard O.; Williams D. H.; Smith G. A. Structure of vancomycin and its complex with acetyl-D-alanyl-D-alanine. Nature 1978, 271, 223–225. 10.1038/271223a0. [DOI] [PubMed] [Google Scholar]
  7. Takeda T.; Gonda R.; Hatano K. Constitution of lucumin and its related glycosides from Calocarpum sapota Merrill. Chem. Pharm. Bull. 1997, 45, 697–699. 10.1248/cpb.45.697. [DOI] [Google Scholar]
  8. Hegde V. R.; Dai P.; Patel M.; Gullo V. P. Complestatin and chloropeptin I, condensed aromatic peptides from two strains of streptomycetes. Tetrahedron Lett. 1998, 39, 5683–5684. 10.1016/S0040-4039(98)01145-9. [DOI] [Google Scholar]
  9. Brown R.; Kraus C.; Fleming M.; Reddy S. Methadone: applied pharmacology and use as adjunctive treatment in chronic pain. Postgrad. Med. J. 2004, 80, 654–659. 10.1136/pgmj.2004.022988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Boss E. G.; Buchanan G. C. Effect of Isopropamide Iodide on Basal Gastric Secretion in the Human. Gastroenterology 1957, 33, 730–736. 10.1016/S0016-5085(19)35625-2. [DOI] [PubMed] [Google Scholar]
  11. Stern J.; Ippoliti C. Management of acute cancer treatment-induced diarrhea. Semin. Oncol. Nurs. 2003, 19, 11–16. 10.1053/j.soncn.2003.09.009. [DOI] [PubMed] [Google Scholar]
  12. Peng P.-K.; Isho A.; May J. A. Regio- and enantioselective synthesis of acyclic quaternary carbons via organocatalytic addition of organoborates to (Z)-Enediketones. Nat. Commun. 2024, 15, 504. 10.1038/s41467-024-44744-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Uno M.; Seto K.; Takahashi S. A new method of synthesis of arylmalononitriles catalysed by a palladium complex. J. Chem. Soc., Chem. Commun. 1984, 932–933. 10.1039/c39840000932. [DOI] [Google Scholar]
  14. Hennessy E. J.; Buchwald S. L. A General and Mild Copper-Catalyzed Arylation of Diethyl Malonate. Org. Lett. 2002, 4, 269–272. 10.1021/ol017038g. [DOI] [PubMed] [Google Scholar]
  15. Culkin D. A.; Hartwig J. F. Palladium-Catalyzed α-Arylation of Carbonyl Compounds and Nitriles. Acc. Chem. Res. 2003, 36, 234–245. 10.1021/ar0201106. [DOI] [PubMed] [Google Scholar]
  16. Yip S. F.; Cheung H. Y.; Zhou Z.; Kwong F. Y. Room-Temperature Copper-Catalyzed α-Arylation of Malonates. Org. Lett. 2007, 9, 3469–3472. 10.1021/ol701473p. [DOI] [PubMed] [Google Scholar]
  17. Kobbelgaard S.; Bella M.; Jørgensen K. A. Improved Asymmetric SNAr Reaction of β-Dicarbonyl Compounds Catalyzed by Quaternary Ammonium Salts Derived from Cinchona Alkaloids. J. Org. Chem. 2006, 71, 4980–4987. 10.1021/jo060627l. [DOI] [PubMed] [Google Scholar]
  18. Huang X.; Maulide N. Sulfoxide-Mediated α-Arylation of Carbonyl Compounds. J. Am. Chem. Soc. 2011, 133, 8510–8513. 10.1021/ja2031882. [DOI] [PubMed] [Google Scholar]
  19. Mohanan K.; Coquerel Y.; Rodriguez J. Transition-Metal-Free α-Arylation of β-Keto Amides via an Interrupted Insertion Reaction of Arynes. Org. Lett. 2012, 14, 4686–4689. 10.1021/ol302180v. [DOI] [PubMed] [Google Scholar]
  20. Merritt E. A.; Olofsson B. Diaryliodonium Salts: A Journey from Obscurity to Fame. Angew. Chem., Int. Ed. 2009, 48, 9052–9070. 10.1002/anie.200904689. [DOI] [PubMed] [Google Scholar]
  21. Yoshimura A.; Zhdankin V. V. Advances in Synthetic Applications of Hypervalent Iodine Compounds. Chem. Rev. 2016, 116, 3328–3435. 10.1021/acs.chemrev.5b00547. [DOI] [PubMed] [Google Scholar]
  22. Aradi K.; Tóth B. L.; Tolnai G. L.; Novák Z. Diaryliodonium Salts in Organic Syntheses: A Useful Compound Class for Novel Arylation Strategies. Synlett 2016, 27, 1456–1485. 10.1055/s-0035-1561369. [DOI] [Google Scholar]
  23. Takenaga N.; Kumar R.; Dohi T. Heteroaryliodonium(III) Salts as Highly Reactive Electrophiles. Front. Chem. 2020, 8, 599026. 10.3389/fchem.2020.599026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Oh C. H.; Kim J. S.; Jung H. H. Highly Efficient Arylation of Malonates with Diaryliodonium Salts. J. Org. Chem. 1999, 64, 1338–1340. 10.1021/jo981065b. [DOI] [Google Scholar]
  25. Aggarwal V. K.; Olofsson B. Enantioselective α-Arylation of Cyclohexanones with Diaryl Iodonium Salts: Application to the Synthesis of (−)-Epibatidine. Angew. Chem., Int. Ed. 2005, 44, 5516–5519. 10.1002/anie.200501745. [DOI] [PubMed] [Google Scholar]
  26. Norrby P.-O.; Petersen T. B.; Bielawski M.; Olofsson B. α-Arylation by Rearrangement: On the Reaction of Enolates with Diaryliodonium Salts. Chem.—Eur. J. 2010, 16, 8251–8254. 10.1002/chem.201001110. [DOI] [PubMed] [Google Scholar]
  27. Malmgren J.; Santoro S.; Jalalian N.; Himo F.; Olofsson B. Arylation with unsymmetrical diaryliodonium salts: a chemoselectivity study. Chem.—Eur. J. 2013, 19, 10334–10342. 10.1002/chem.201300860. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Matsuzaki K.; Okuyama K.; Tokunaga E.; Shiro M.; Shibata N. Sterically Demanding Unsymmetrical Diaryl-λ3-iodanes for Electrophilic Pentafluorophenylation and an Approach to α-Pentafluorophenyl Carbonyl Compounds with an All-Carbon Stereocenter. ChemistryOpen 2014, 3, 233–237. 10.1002/open.201402045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Monastyrskyi A.; Namelikonda N. K.; Manetsch R. Metal-Free Arylation of Ethyl Acetoacetate with Hypervalent Diaryliodonium Salts: An Immediate Access to Diverse 3-Aryl-4(1H)-Quinolones. J. Org. Chem. 2015, 80, 2513–2520. 10.1021/jo5023958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Dey C.; Lindstedt E.; Olofsson B. Metal-Free C-Arylation of Nitro Compounds with Diaryliodonium Salts. Org. Lett. 2015, 17, 4554–4557. 10.1021/acs.orglett.5b02270. [DOI] [PubMed] [Google Scholar]
  31. Bugaenko D. I.; Tikhanova O. A.; Andreychev V. V.; Karchava A. V. Arylation of Diethyl Acetamidomalonate with Diaryliodonium Salts En Route to α-Arylglycines. J. Org. Chem. 2024, 89, 9923–9928. 10.1021/acs.joc.4c00768. [DOI] [PubMed] [Google Scholar]
  32. Chan W.-W.; Zhou Z.; Yu W.-Y. Palladium-catalyzed oxidative direct C-H/C-H cross coupling of anilides with β-keto esters. Chem. Commun. 2013, 49, 8214–8216. 10.1039/c3cc44769c. [DOI] [PubMed] [Google Scholar]
  33. Moon P. J.; Halperin H. M.; Lundgren R. J. Oxidative Coupling of Aryl Boron Reagents with sp3-Carbon Nucleophiles: The Enolate Chan-Evans-Lam Reaction. Angew. Chem., Int. Ed. 2016, 55, 1894–1898. 10.1002/anie.201510558. [DOI] [PubMed] [Google Scholar]
  34. For a metal-free stepwise method, see:; Uchikura T.; Sánchez-Sordo I.; Yoshimura T.; Makino Y.; Osakabe H.; Akiyama T. Enantioselective Synthesis of an All-Carbon Quaternary Stereocenter by Chiral Brønsted Acid-Catalyzed Friedel-Crafts-Type Reaction between Pyrroles and 3-Indolylmethanols. J. Org. Chem. 2023, 88, 7774–7783. 10.1021/acs.joc.2c02633. [DOI] [PubMed] [Google Scholar]
  35. Beare N. A.; Hartwig J. F. Palladium-catalyzed arylation of malonates and cyanoesters using sterically hindered trialkyl-and ferrocenyldialkylphosphine ligands. J. Org. Chem. 2002, 67, 541–555. 10.1021/jo016226h. [DOI] [PubMed] [Google Scholar]
  36. Yang Y.-Y.; Shou W.-G.; Wang Y.-G. Tandem coupling reactions of benzynes and 1,3-diones: a novel synthesis of 2,2-diphenyl-1,3-diones. Tetrahedron Lett. 2007, 48, 8163–8165. 10.1016/j.tetlet.2007.09.092. [DOI] [Google Scholar]
  37. Dhokale R. A.; Thakare P. R.; Mhaske S. B. Transition-Metal-Free C-Arylation at Room Temperature by Arynes. Org. Lett. 2012, 14, 3994–3997. 10.1021/ol301768r. [DOI] [PubMed] [Google Scholar]
  38. Chen K.; Koser G. F. Direct and regiocontrolled synthesis of α-phenyl ketones from silyl enol ethers and diphenyliodonium flouride. J. Org. Chem. 1991, 56, 5764–5767. 10.1021/jo00020a013. [DOI] [Google Scholar]
  39. Huang T.; Ji X.; Wu W.; Liang F.; Cao S. Metal-free one-pot sequential direct diarylation of pyrazolin-5-ones with diaryliodonium salts. RSC Adv. 2015, 5, 66598–66601. 10.1039/C5RA14368C. [DOI] [Google Scholar]
  40. Peng X.; Luo H.; Wu F.; Zhu D.; Ganesan A.; Huang P.; Wen S. Synthesis of Fluorenes with an All-Carbon Quaternary Center via Palladium-Catalyzed Dual Arylation using Cyclic Diaryliodonium Triflates. Adv. Synth. Catal. 2017, 359, 1152–1156. 10.1002/adsc.201601260. [DOI] [Google Scholar]
  41. For another route to reach alfa-diarylated products, see:; Qiu H.; Li M.; Jiang L.-Q.; Lv F.-P.; Zan L.; Zhai C.-W.; Doyle M. P.; Hu W.-H. Highly enantioselective trapping of zwitterionic intermediates by imines. Nat. Chem. 2012, 4, 733–738. 10.1038/nchem.1406. [DOI] [PubMed] [Google Scholar]
  42. Linde E.; Bulfield D.; Kervefors G.; Purkait N.; Olofsson B. Diarylation of N- and O-nucleophiles through a metal-free cascade reaction. Chem. 2022, 8, 850–865. 10.1016/j.chempr.2022.01.009. [DOI] [Google Scholar]
  43. Mondal S.; Di Tommaso E. M.; Olofsson B. Transition-Metal-Free Difunctionalization of Sulfur Nucleophiles. Angew. Chem., Int. Ed. 2023, 62, e202216296 10.1002/anie.202216296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Linde E.; Olofsson B. Synthesis of Complex Diarylamines through a Ring-Opening Difunctionalization Strategy. Angew. Chem., Int. Ed. 2023, 62, e202310921 10.1002/anie.202310921. [DOI] [PubMed] [Google Scholar]
  45. Peng X.; Rahim A.; Peng W.; Jiang F.; Gu Z.; Wen S. Recent Progress in Cyclic Aryliodonium Chemistry: Syntheses and Applications. Chem. Rev. 2023, 123, 1364–1416. 10.1021/acs.chemrev.2c00591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Caspers L. D.; Spils J.; Damrath M.; Lork E.; Nachtsheim B. J. One-Pot Synthesis and Conformational Analysis of Six-Membered Cyclic Iodonium Salts. J. Org. Chem. 2020, 85, 9161–9178. 10.1021/acs.joc.0c01125. [DOI] [PubMed] [Google Scholar]
  47. Spils J.; Wirth T.; Nachtsheim B. J. Two-step continuous-flow synthesis of 6-membered cyclic iodonium salts via anodic oxidation. Beilstein J. Org. Chem. 2023, 19, 27–32. 10.3762/bjoc.19.2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Sundalam S. K.; Nilova A.; Seidl T. L.; Stuart D. R. A Selective C-H Deprotonation Strategy to Access Functionalized Arynes by Using Hypervalent Iodine. Angew. Chem., Int. Ed. 2016, 55, 8431–8434. 10.1002/anie.201603222. [DOI] [PubMed] [Google Scholar]
  49. See the Supporting Information.
  50. Doyle M. G. J.; Lundgren R. J. Oxidative cross-coupling processes inspired by the Chan-Lam reaction. Chem. Commun. 2021, 57, 2724–2731. 10.1039/D1CC00213A. [DOI] [PubMed] [Google Scholar]
  51. Xie X.; Cai G.; Ma D. CuI/l-Proline-Catalyzed Coupling Reactions of Aryl Halides with Activated Methylene Compounds. Org. Lett. 2005, 7, 4693–4695. 10.1021/ol0518838. [DOI] [PubMed] [Google Scholar]
  52. Ng F.-N.; Chan C.-M.; Li J.; Sun M.; Lu Y.-S.; Zhou Z.; Huang B.; Yu W.-Y. [RhIII(Cp*)]-catalyzed arylfluorination of α-diazoketoesters for facile synthesis of α-aryl-α-fluoroketoesters. Org. Biomol. Chem. 2019, 17, 1191–1201. 10.1039/C8OB02801J. [DOI] [PubMed] [Google Scholar]
  53. Bielawski M.; Zhu M.; Olofsson B. Efficient and general one-pot synthesis of diaryliodonium triflates: optimization, scope and limitations. Adv. Synth. Catal. 2007, 349, 2610–2618. 10.1002/adsc.200700373. [DOI] [Google Scholar]
  54. Bielawski M.; Olofsson B. High-yielding one-pot synthesis of diaryliodonium triflates from arenes and iodine or aryl iodides. Chem. Commun. 2007, 2521–2523. 10.1039/b701864a. [DOI] [PubMed] [Google Scholar]
  55. Dohi T.; Ito M.; Morimoto K.; Minamitsuji Y.; Takenaga N.; Kita Y. Versatile direct dehydrative approach for diaryliodonium (III) salts in fluoroalcohol media. Chem. Commun. 2007, 4152–4154. 10.1039/b708802g. [DOI] [PubMed] [Google Scholar]
  56. Chen Y.; Gu Y.; Meng H.; Shao Q.; Xu Z.; Bao W.; Gu Y.; Xue X.-S.; Zhao Y. Metal-Free C-H Functionalization via Diaryliodonium Salts with a Chemically Robust Dummy Ligand. Angew. Chem., Int. Ed. 2022, 61, e202201240 10.1002/anie.202201240. [DOI] [PubMed] [Google Scholar]
  57. Bilska-Markowska M.; Kaźmierczak M. Horner-Wadsworth-Emmons reaction as an excellent tool in the synthesis of fluoro-containing biologically important compounds. Org. Biomol. Chem. 2023, 21, 1095–1120. 10.1039/D2OB01969H. [DOI] [PubMed] [Google Scholar]
  58. Grün A.; Bálint E.; Keglevich G. Solid-Liquid Phase C-Alkylation of Active Methylene Containing Compounds under Microwave Conditions. Catalysts 2015, 5, 634–652. 10.3390/catal5020634. [DOI] [Google Scholar]
  59. Walvoord R. R.; Berritt S.; Kozlowski M. C. Palladium-Catalyzed Nitromethylation of Aryl Halides: An Orthogonal Formylation Equivalent. Org. Lett. 2012, 14, 4086–4089. 10.1021/ol301713j. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Huang J.; Li T.; Lu X.; Ma D. Copper-Catalyzed α-Arylation of Nitroalkanes with (Hetero)aryl Bromides/Iodides. Angew. Chem., Int. Ed. 2024, 63, e202315994 10.1002/anie.202315994. [DOI] [PubMed] [Google Scholar]
  61. Yusubov M. S.; Yoshimura A.; Zhdankin V. V. Iodonium ylides in organic synthesis. ARKIVOC 2016, 2016, 342–374. 10.3998/ark.5550190.p009.732. [DOI] [Google Scholar]
  62. Mi X.; Pi C.; Feng W.; Cui X. Recent progress in the application of iodonium ylides in organic synthesis. Org. Chem. Front. 2022, 9, 6999–7015. 10.1039/D2QO01332K. [DOI] [Google Scholar]
  63. Rotstein B. H.; Stephenson N. A.; Vasdev N.; Liang S. H. Spirocyclic hypervalent iodine(III)-mediated radiofluorination of non-activated and hindered aromatics. Nat. Commun. 2014, 5, 4365. 10.1038/ncomms5365. [DOI] [PubMed] [Google Scholar]
  64. Zhao Z.; Luo Y.; Liu S.; Zhang L.; Feng L.; Wang Y. Direct Cyclization of Tertiary Aryl Amines with Iodonium Ylides. Angew. Chem., Int. Ed. 2018, 57, 3792–3796. 10.1002/anie.201800389. [DOI] [PubMed] [Google Scholar]
  65. Malamidou-Xenikaki E.; Spyroudis S. Zwitterionic iodonium compounds: useful tools in organic synthesis. Synlett 2008, 2008, 2725–2740. 10.1055/s-2008-1078261. [DOI] [Google Scholar]
  66. Chen H.; Han J.; Wang L. Intramolecular Aryl Migration of Diaryliodonium Salts: Access to ortho-Iodo Diaryl Ethers. Angew. Chem., Int. Ed. 2018, 57, 12313–12317. 10.1002/anie.201806405. [DOI] [PubMed] [Google Scholar]
  67. In special cases, they generate ketenes that can arylate nitrogen nucleophiles; see:; Spagou K.; Malamidou-Xenikaki E.; Spyroudis S. A survey on the reactivity of phenyliodonium ylide of 2-hydroxy-1,4-naphthoquinone with amino compounds. Molecules 2005, 10, 226–237. 10.3390/10010226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Bella M.; Kobbelgaard S.; Jørgensen K. A. Organocatalytic Regio- and Asymmetric C-Selective SNAr ReactionsStereoselective Synthesis of Optically Active Spiro-pyrrolidone-3,3‘-oxoindoles. J. Am. Chem. Soc. 2005, 127, 3670–3671. 10.1021/ja050200g. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

au4c00500_si_001.pdf (20.7MB, pdf)

Articles from JACS Au are provided here courtesy of American Chemical Society

RESOURCES