Harnessing triaryloxonium ions for aryne generation

9 Arynes are highly reactive and versatile intermediates for the functionalization of aromatic rings that are often 10 generated using strong bases or fluoride sources, which in some cases can limit functional group tolerance. Here we

These investigations demonstrate that the oxonium ion is a powerful electron-withdrawing group and a particularly effective leaving group.We anticipate this study will stimulate further investigations into the synthetic utility of aryl oxonium ions.
Benzyne 1 was first proposed as a reactive (diradical) intermediate by Bachman and Clarke during an investigation of the Wurtz-Fittig reaction 2 .Wittig later examined the phenyllithium-mediated elimination of fluorobenzenes and rationalized their observed reactivity in terms of a dipolar form of benzyne 3 .Roberts' classic 14 C labelling experiment subsequently confirmed the existence of a neutral and symmetrical intermediate, most consistent with the bent acetylene-type benzyne structure now regarded as correct 4 .Early experiments in the field of aryne chemistry were almost entirely focussed on mechanistic investigations until accessible and stable aryne precursors were formulated (Figure 1a) 5 .Thermal decomposition of aryl ortho-diazonium carboxylates provides reliable access to arynes, but their shock sensitivity limits their broader application.The hexahydro Diels-Alder reaction of tethered triynes [6][7][8] provides reagent-free (thermal) access to complex polycyclic systems, and transition metal-mediated functionalizations can be exploited as a mild and chemoselective approach to metal-bound arynes 9,10 .Amongst contemporary precursors, Kobayashi's ortho-silyl triflate 11,12 , is largely responsible for the rehabilitation of arynes as viable intermediates in synthetic chemistry as a consequence of its ability to generate a low steady state concentration of aryne upon treatment with a sparingly soluble fluoride source 13 .This has also led to a resurgence in fluoride-free 14 methods for aryne generation, often from monosubstituted precursors [15][16][17] .Many of these methods use activated leaving groups such as l 3 -iodanes to enable milder conditions for aryne generation 18 , but these often necessitate the use of strong bases such as LiHMDS or t-BuOK.There are relatively few reports of benzyne formation with weaker bases although notable progress has been made in the elimination of tricyclic l 3 -chloranes and bromanes 19,20 .
We reasoned that a monosubstituted arene bearing a particularly good leaving group (which could also function as a powerful electron-withdrawing group) could enable the formation of arynes using mild and functional groupcompatible conditions.The leaving group ability of onium salts from nitrogen, oxygen, phosphorus, and sulfur has been calculated to be the greatest for oxygen; 21 hence, we decided to examine whether oxonium salts could function as aryne precursors.Alkyl oxonium salts are exemplified by Meerwein's salt, which although kinetically stable, is a powerful alkylating agent that reacts with many nucleophiles, including water 22,23 .More complex oxonium ions have been proposed as intermediates in natural product biosynthesis 24 , and aside from Mascal's oxatriquinane oxonium ions 25 , are considered to be highly reactive.In contrast, triaryloxonium ions are resistant to the action of many nucleophiles and are kinetically stable isolable solids.An early report from Hellwinkel 26 showed that the addition of phenyllithium to phenyl dibenzofuranium ion led to products consistent with the generation of an aryne.Tolstaya later showed that treatment of a symmetrical triaryloxonium ion with potassium acetate in refluxing benzene led to an arene that could be trapped in situ with tetraphenylcyclopentadienone 27 .
Figure 1.Existing methods for the synthesis of arynes, and a strategy for benzyne generation via the elimination of triaryloxonium salts.a Previous strategies and methods for the synthesis of benzynes include the organometallic elimination of haloarenes, decomposition of diazo-anthranilic acid derivatives, the hexahydro Diels-Alder reaction of tethered trienes, the oxidative insertion-mediated elimination of orthosubstituted leaving groups, the fluoride mediated elimination of ortho-silyl triflates, the base mediated elimination of l 3 -iodanes, and the basemediated elimination of tricyclic l 3 -chloranes and bromanes.b.This work: a diverse range of triaryl oxonium ions can be synthesized through an intramolecular O-arylation process.These oxonium ions can be used in mild and functional group tolerant synthesis of arynes through a base-mediated elimination reaction; a range of arynophiles are effective trapping agents in this process.
We reasoned that with an appropriately designed oxonium precursor we could generate arynes using weak inorganic bases without any special precautions to exclude moisture or oxygen.An appropriate oxonium precursor should possess ortho-blocking groups to prevent uncontrolled elimination (Figure 1b); this structure could be assembled via cross-coupling between two suitably activated precursors.We have demonstrated that helically chiral triaryloxonium ions can be generated by intramolecular O-arylation of a diphenylether derivative 28 with a diazonium salt, and we rationalized that this strategy offered a viable route to suitable oxonium ions for aryne generation 29 .

Results
2-Bromo biaryl ethers (such as 1a-1v) can be synthesized by a base-mediated SNAr reaction between an electrondeficient fluoroarene and a phenol derivative; this reaction is relatively tolerant of different functional groups and can be performed where the bromine atom is part of either the nucleophilic or electrophilic species.These compounds can also be manipulated to introduce other functional groups (see supplementary information for full details of oxonium ion synthesis).Aniline-containing pinacol borane 2 can be efficiently cross-coupled with aryl bromides in the presence of a catalytic quantity of 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) to yield anilines 3a-3v.Treatment with tert-butylnitrite in the presence of tetrafluoroboric acid led to an intermediate diazonium salt which upon gentle warming underwent intramolecular O-arylation to yield oxonium tetrafluoroborates 4a-4v (Figure 2).Aldehyde and ketone functional groups were incompatible with the crosscoupling strategy due to the presence of an aniline, and hence an alternative procedure was utilized to generate oxonium ions 4d and 4e (route not shown; see supplementary information).Using these methods, we were able to synthesize a wide range of triaryloxonium tetrafluoroborates.These are generally crystalline materials that can be stored indefinitely at ambient temperature without special precautions.The structure of compounds 4a, 4j and 4l was confirmed by single crystal X-ray diffraction, which in all cases shows that these compounds are pyramidal around the trivalent oxygen, with the exocyclic O-aryl substituent oriented almost perpendicular to the plane of the dibenzofuran ring system.These structural features are consistent with previous solid-state investigations of related materials 30 .(1:1, v/v), 95˚C, 24 h; (ii) HBF4 (48% aq., 5 eq.), t-BuONO (5 eq.), CH2Cl2/IPA (1:1), 0 °C, 1 h then 30 °C, 48 h.Yields are reported for isolated and purified materials for each of the two steps pictured.For oxonium ions in which R 1 = NHAc, yields are reported from a precursor R 1 = NO2 and include a reduction and N-acylation step (not pictured, see supplementary information for full details).b.Crystal and molecular structure of dibenzofuran-derived oxonium salts from single crystal X-ray diffraction studies.Tetrafluoroborate counterion is omitted for clarity.Yields for salts 4d and 4e reflect a different synthetic method; see supplementary information for details.
With a range of oxonium salts in hand, we examined conditions for elimination of para-nitro oxonium 4a in the presence of furan as an exemplar arynophile.Homogeneous bases such as 2,6-lutidine and diisopropylethylamine were mostly ineffective.However, solid inorganic bases such as potassium carbonate at room temperature led to the formation of bicyclic product 5a, while treatment with sodium hydrogen carbonate led to recovery of oxonium ion (see supplementary information for full details).Potassium phosphate led to complete consumption of oxonium ion and a high yield of the furan trapping product 5a, and hence we focussed on the use of this base to enable aryne generation.Our optimized conditions employ 5 equivalents of solid potassium phosphate in the presence of 5 equivalents of the trapping agent in acetonitrile.This process does not require any special precautions beyond rapid stirring, is not carried out under an inert atmosphere and does not require dry solvents or reagents.Under our optimized conditions, p-nitro oxonium ion 4a led to the formation of tricycle 5a in 97% isolated yield; this increased to 99% when the reaction was carried out on a 1 mmol scale.This aryne generation and trapping process is tolerant of amides (to afford 5b in 91% yield) and esters (yielding 5c in 94% yield).Ketone and aldehyde-containing oxonium salts can also be transformed into arynes and trapped with furan to yield 5d (96% yield) and 5e (93% yield), respectively.Oxonium ions bearing other electron-withdrawing groups such as p-chloro (affording 5f, 94%) and pmethylsulfone 5g (94%) are also effective in this transformation.Free alcohols do not have any deleterious effect on the aryne generation and trapping reaction; oxonium 4h affords p-hydroxymethyl tricycle 5h in 96% yield.Oxonium 4i bearing a para-aryl group is also successfully converted to 5i (86% yield), and simple unsubstituted benzyne can also be generated from 4j, yielding 5j in 81% yield.Ortho-nitro 31,32 oxonium ions smoothly generate the corresponding aryne, which upon trapping generates 5k in 91% yield; this reactivity is complementary to that of the corresponding Kobayashi silyl triflate aryne precursor, which preferentially undergoes the thia-Fries rearrangement 33 .
Para-alkenes bearing electron-withdrawing groups are tolerated without incident (5s, 86% yield) as are more functionalized alkyl groups (to afford 5t), albeit in reduced yield.We can also apply these conditions to the synthesis of modified natural products and drugs.A capsaicin-derived oxonium ion was generated, which yielded tricycle 5u in 31% yield upon trapping with furan.This approach was also successful in the generation of an aryne derived from a diflusinal derivative, which yielded tricycle 5v in 88% yield.There are relatively few substituents that are unsuccessful in this process: these include oxonium ions bearing nucleophilic groups such as p-SMe, and groups such as p-CH2CO2Et that may be preferentially deprotonated in the benzylic rather than the ortho-position (see supplementary information).
We also considered whether we could use this strategy to access hetarynes.4,5-Pyrimidynes are a class of aryne that are significantly more challenging to generate than modified benzynes 34,35 and there are few reports of their generation and reactivity [36][37][38][39] .Pyrimidine oxonium 6 was assembled via a Suzuki coupling route similar to that employed for other oxonium ions (see supplementary information).We reasoned that the electron-donating methoxy group adjacent to the oxonium oxygen could lead to enhanced trapping reactivity, as demonstrated in 2,3-pyridynes 40 .
Treatment of this oxonium ion with solid potassium phosphate at room temperature in the presence of furan as trapping agent led to tricyclic product 7 in 39% yield.Trapping with ethanol is also effective, leading to 8 in 38% yield; in both of these reactions a high concentration of trapping agent led to substantially increased yields.
Employing pyrazole as the trapping agent led to formal insertion of the aryne into the N-H bond affording 9 as a single regioisomer in 55% yield.This regioselectivity is consistent with nucleophilic attack distal to the electronwithdrawing oxygen substituent 41 .We observed similar reactivity in the addition of N-methyl aniline to give 10, albeit in a moderate 24% yield.These results indicated that trapping reactions beyond cycloadditions with furan could be viable and we explored the compatibility of a range of different trapping agents under our base-mediated conditions for aryne generation (table 2).and 18 (74% yield), respectively in the presence of oxonium 4k.This oxonium ion also engages in an ene reaction with cyclohexene in the presence of potassium phosphate to yield 19.More complex structures are accessible: reaction of in situ generated benzyne with tethered bisbiaryl furan led to exo, exo-polycycle 20 in 47% yield 43 .
Tryptycene 21 was formed in 83% yield from cycloaddition between anthracene and the aryne generated from precursor 4a.
To probe the mechanism of the formation of arynes from oxonium ions, we synthesized ortho-deuterated fluoroarene 22 (80% deuterium), which was transformed into oxonium 23 in three steps without any loss of deuterium.We reasoned that this monodeuterated intermediate could allow us to perform an intramolecular competition experiment by measuring the selectivity of proton vs. deuteron removal 44 .Subjecting 23 to our standard aryne-generating conditions in the presence of furan as trapping agent afforded tricycle 24 in 98% isolated yield in which 50% of the deuterium label was retained.This allows us to calculate the kinetic isotope effect kH/kD = 1.67.We used quantum chemical calculations to investigate the mechanism of benzyne formation from an oxonium ion with inorganic phosphate at the ωB97X-D/6-31+G(d,p) level of theory with SMD solvation (CH3CN) [45][46][47][48] .The computed potential energy surface (PES) reveals a formally stepwise E1cB elimination mechanism with respect to C-H abstraction and C-O bond cleavage steps (Figure 4).Deprotonation at the ortho-position by K3PO4 takes place via transition structure (TS) TS1 (DG ‡ = 9.9 kcal mol -1 ) and leads to the formation of a stable but shallow intermediate on the PES, IM2.Relatively little lengthening of the exocyclic C-O bond is observed in this 1,3zwitterionic intermediate compared to the parent oxonium ion (0.01 Å) 49,50 .Subsequently, C-O bond cleavage proceeds via TS2 with a low barrier (DG ‡ = 2.3 kcal mol -1 ) relative to intermediate IM2, resulting in the exergonic and irreversible formation of benzyne and dibenzofuran products IM3.We also computed the Diels-Alder cycloaddition of this benzyne intermediate with furan, which occurs via TS3 (DG ‡ = 7.1 kcal mol -1 ) in a highly exergonic fashion.These data are consistent with the rapid and irreversible consumption of benzyne once formed.
The stepwise formation of benzyne from an oxonium ion (Figure 4) stands in contrast to the mechanism of benzyne formation from a diaryliodonium ion.We computationally investigated base-mediated aryne generation from an exemplar diphenyl iodonium ion at the same level of theory; this demonstrated that C-H abstraction and C-I cleavage occur in a concerted asynchronous single step without an intervening intermediate (see supporting information for further details) 18,51 .This is partly due to the greater strength of the (exocyclic) C-O bond in an oxonium ion versus the C-I bond in an iodonium ion; however, electronic effects are also apparent.While the formal positive charge in the Lewis structures of both -onium ions is placed at the heteroatom, polarization in the oxonium ion differs profoundly from the halonium ion.For example, computed natural charges illustrate that the oxygen atom retains substantial negative charge in oxonium ion IM1 (-0.36, cf.-0.48 in neutral 2,4,6,8-tetramethyldibenzofuran), while the neighbouring carbon atom (C1) has a partial positive charge of 0.28.This dipole provides electrostatic stabilization to the adjacent developing negative charge during ortho-C-H abstraction, which reaches -0.40 in IM2.
In contrast, for the iodonium ion a large positive charge is coincident with the position of the formal charge at the iodine atom (1.11).Natural Bond Orbital (NBO) analysis shows that IM2 is further stabilized through delocalization of the in-plane C6 sp 2 lone pair into the exocyclic C-O s* orbital (by 26.4 kcal mol -1 ).Finally, we compared the computationally predicted kH/kD isotope effect based on our Gibbs energy profile against experiment.While the TS for C-O bond cleavage is formally rate-limiting, it is only 0.7 kcal mol -1 higher in energy than the C-H abstraction TS, such that the kinetic isotope effect (KIE) value is influenced by both TS1 and TS2.Quantitatively, the computed value of 1.93 (Figure 4b) is in close agreement with the observed KIE of 1.67 52 .

Conclusion
Triaryl oxonium ions are stable and accessible compounds that can be transformed into arynes via a practically simple and mild base-mediated elimination.The functional group tolerance of this process enables efficient trapping of a wide range of functionalized arynes including those bearing alcohols, amides and ortho-electron withdrawing groups.
Extension to the synthesis and trapping of 2,3-pyrimidynes is also successful.We anticipate that triaryloxonium salts may find application in the generation and reactions of other functionalized arynes.