Iodane-guided ortho C-H allylation

: A metal-free C-H allylation strategy is described to access diverse functionalized ortho -allyl-iodoarenes. The method employs hypervalent (diacetoxy)iodoarenes and proceeds through the iodane-guided “iodonio-Claisen” allyl transfer. The use of allylsilanes bearing electron-withdrawing functional groups unlocks the functionalization of a broad range of substrates, including electron-neutral and electron-poor rings. The resulting ortho -allylated iodoarenes are versatile building blocks, with examples of downstream transformation including a concise synthesis of the experimental antimitotic core of Dosabulin. DFT calculations shed additional light on the reaction mechanism, with notable aspects including the virtually barrierless Si-to-I allyl transfer and the aromatic character of the transition state structure for the [3,3] sigmatropic rearrangement.

[12] Importantly, a 2012 study by J. Zhu and coworkers showed that while the C-H coupling of the allyl(trimethyl)silane, 1, was feasible, this reaction was only applicable to certain very electron-rich λ 3 -iodoarene cores, [13][14][15] largely failing even for the "neutral" iodoarene core of the parent ArI(OAc)2 (Scheme 1, B).In this context, our group reported a surprisingly efficient ortho-C-H coupling of the benzothiophene-S-dioxide reagent containing an imbedded allylsilane unit (prod.2a, Scheme 1, C); efficient reactivity was also observed for a tosyl-substituted allyltrimethylsilane (prod.2b). [11,16] his suggested that perhaps equipping an allylsilane reagent with an electron-withdrawing group (EWG) could be the key to a broad-scope iodane-directed C-H allylation process.Prompted by this possibility, a method is now presented to produce a diverse range of ortho-iodo-allylarenes via a C-H allylation process in which the allyl-bound EWG can not only act as a reaction booster, but will subsequently engage in a downstream functionalization, including those leading to potentially bioactive cores (Scheme 1, D).

Initial C-H allylation assays.
As an initial test system, the coupling of the phosphoryl-substituted allylsilane 3, obtained by olefin cross-metathesis between 1 and the diethyl vinylphosphonate, [17] was tested with the para-Cl-λ 3 -iodane 4. When conducted in a CH2Cl2/CH3CN solvent mixture, which has been found optimal in prior works, [13a,8,11] no intended orthoallylarene 5 was detected in the absence of an acid activator (Table 1, entry 1).Gratifyngly, the addition of 1.2 equiv of BF3•Et2O allowed for the formation of phosphorylated allylarene 5 in 57% yield (NMR), with further improvements to 85% (74% isolated) achieved by raising the additive loading to 2.0 equiv.(see entries 2-4). [18]HOTf and TMSOTf could also be employed as acid activators (entries 5, 6).Incidentally, only trace amounts of the C-H coupling product were achieved using the unsubstituted allylsilane 1. [19] Table 1.Additive effect in the reaction between 3 and 4. [a] [a] Using 0.2 mmol ArI(OAc)2 and 0.24 mmol allylsilane 3 in 1.4 mL of solvent; [b] % 1 H-NMR yield using naphthalene as internal standard; [c] isolated yield.
Encouraged, we synthesized a family of additional transallylsilanes by cross-metathesis.This new substrate family includes the sulphones 6 and 7-Me, as well as the acryloyl ester 8 and amides 9 and 10 (Table 2).In this survey, both the chlorosubstituted iodane 4 and the parent PhI(OAc)2 were used for performance comparison.Gratifyingly, not only 3, but also 6, 7, and 8 afforded the target ortho-allylated products (11-17) in synthetically attractive yields, with no significant efficiency differences within the p-H vs p-Cl substrate pairs (Table 2).All products were obtained as trans-olefins, with only the ester 16 showing small amounts of the cis isomer.Electronic differentiation between iodoarene cores did manifest itself for the N,Ndimethylacrylamide 9, for which the EWG = CONR2 has a Hammett σp <0.36, making it the least withdrawing substituent in the series at hand. [20]This lower Hammett parameter appears to correlate with a less efficient coupling between 9 and the p-Cl substrate 4 (<20% yield, prod.18).Nevertheless, for this substrate switching from 4 to PhI(OAc)2 as coupling partner gave the C-H allylated species 19 in 77% yields.Hence, while the reactivity of 9 could be considered as "borderline", its ability to couple with an electron-neutral aryliodane reflects a performance still far superior to that of the non-substituted allylsilane 1 (e.g see Scheme 1B).Finally, despite the poor performance of the acrylamide 10 (possibly due to the concomitant oxidation of the -NH2 group (e.g. in a Hoffmann-type rearrangement [21] ), its use with PhI(OAc)2 at this stage did afford a 23% yield (NMR) of the ortho-allylated target.
a] C-H allylation: a deeper look at the scope.Next, the study was amplified to a wider range of iodoarenes (Table 3).We were particularly satisfied with the efficient reactions of the electronically neutral and deactivated p-, o-, and m-halogenated substrates (Table 3, prod.20-25), as well as those bearing the para--CO2Me, -CF3, -OCF3 and -Ph groups (prod.26-30).The protocol was also applicable to iodonaphthalenes, including the 2-iodo-4-bromo derivative (prod.31-37), and to the λ 3 -iodanes derived from the 1-and 2-iodothiophenes (prod.38, 39).Despite the presence of two differentiated ortho sites in the 2iodonapthalene and 3-iodothiophene precursors, the allylarenes 36, 37, and 39 each formed as a single regioisomer.In addition, as has been observed in related processes (e.g.ref. 8), the use of the p-OMe iodoarene substrate led to a partial formation of the des-iodo ipso-allylated product.The use of the 1,4'-bis-(λ 3diacetoxyiodo)biphenyl resulted in a 45% yield of the doubly C-Hfunctionalized derivative 40.As a more advanced substrate, the λ 3 -form of the Boc-protected 4-iodophenylalanine, 41, was transformed into the N-deprotected 42 (91%) in the presence of TMSOTf.Finally, the in situ formation of an estrone-derived λ 3iodane gave the formation of 43 as a ~1:1 regioisomeric mixture.The target scope was further amplified through a divergent strategy based on the acyl chloride 44, obtained from acryloyl chloride by olefin metathesis. [22]In an initial test, 44 was converted to the amide 45 (Table 3, lower half), paving the way for the formation of the morpholine-containing C-H allylarene 46.Importantly, the modularity of this approach allowed for a rapid generation of additional amide-based allylarenes 47, 48 or the proline-substituted 49 (Table 3, lower part).At this stage, the coupling of these amide-substituted allylsilanes with electronically deactivated iodoarene cores proved inefficient (see 47´, 7%), but this will be revisited in the final section (vide infra).The acyl chloride 44 was also converted to allylsilanes terminated by the -CO2H and -CON3 groups, both of which show reactivity profiles that are broader than those of their amide analogues, as reflected in the C-H coupling with both activated and deactivated aryliodanes (see products 50-53).Finally, an allylsilane obtained by quenching 44 with NHMe(OMe) allowed for the synthesis of a small family of the Weinreb amides 54-56.a] Mechanistic aspects.To gain better understanding of the underlying mechanistic phenomena, a combined computational and experimental study was undertaken.The density functional theory (DFT) computations were performed at the M06-2X/augcc-pVTZ(-PP)//M06-2X/def2-SVP level.The entire reaction profile was elucidated for allylic sulfone precursor 7-Me (Figure 1, G = SO2Me); in addition, individual stages were studied for the systems with EWG = PO(OEt)2, CONMe2, and COOMe.Based on the group's earlier mechanistic studies, [18] the BF3-activated adduct PhI(OAc)(OAc•BF3) was employed as the reacting λ 3iodane species.The reaction begins with an initial iodine(III)-olefin interaction between this species and the allylsilane 7-Me, which weakens the C-Si bond (via the β-Si effect) and culminates with an abstraction of the Me3Si group by one of the fluorides ceded by the F3B-OAc -anion (see Figure 1 and Figure S1 for more details).This results in a new I-C σ-bond (Int0) and the release of Me3SiF, the latter observed by 1 H and 19 F NMR (Figure 1).The leftover acidic F2B-OAc can then strongly bind to the OAc ligand on the allyliodonium intermediate Int0, thus leading to the key Int1 species formulated as [PhI-(allyl)][(OAc)2BF2].As expected, the allyl transfer stage is highly exergonic, especially once the latter O••B acid-base interaction is taken into account, with an overall Gibbs reaction energy of -50 kcal•mol -1 (see Figure S1 for additional substrate profiles).The equilibrium constant for the dissociation of Int1 into the allyliodonium intermediate Int1' and (OAc)2BF2-anion, computed under simulated experimental conditions, showed that although "naked" cationic Int1' constitutes the major component, a non-negligible proportion of the anion-bound λ 3 -iodane Int1 would also be present in solution (see Table S1) .In line with the iodonium-Claisen mechanism, [7] the carboncarbon bond-forming step from both Int1 and Int1' could take place via a readily accessible cyclic transition state.For the cationic Int1', the rearrangement takes place with a ΔG ‡ energy of 11.9 kcal•mol -1 and lead to the Wheland-type intermediate Int2' located some 2.5 kcal•mol -1 lower than Int1' (Figure 2-top, G = SO2Me, blue trace).The process is completed by a rapid proton transfer to the (AcO)2BF2 anion to give the final aromatic target.While a similar activation barrier was obtained for the unsubstituted system (G = H), the rearrangement stage in this case was thermodynamically uphill (Figure 2-top, red trace).It should be noted that although the chair conformation was used as the default geometry for the 6-membered TS2', its boat-shaped counterpart (TS2'-boat) lies just ca. 2 kcal mol -1 higher in energy (see Figure S2 in the ESI), suggesting that both paths are accessible.This study also provides, for the first time, a detailed look at the key cyclic transition state in an iodonio-Claisen process.Thus, analysis of TS2' revealed a significant synchronicity (Sy) value of 0.83, while the diatropic induced ring currents (Figure 2bottom, left), considerable negative NICS(0)zz and NICS(1)zz values, and the electron delocalization (see Fig. S9 for more details) in the iodine-containing six-membered ring (Figure 2bottom, right) that are consistent with non-negligible in-plane aromatic character of the transition state, [23] as would be expected for a thermally allowed pericyclic reaction (see Figure S3).Interestingly, for the non-dissociated Int1 form, a concerted "allin-one" stage was identified in which the rearrangement takes place with a simultaneous intramolecular H-removal by an Oatom of the bound anion, leading directly the aromatized product (see ESI, Figure S5).This process takes place with a higher ΔG ‡ = 14.1 kcal•mol -1 , while the barrier for the corresponding unsubstituted analogue (G = H) has the Gibbs energy barrier of 16.4 kcal•mol -1 .A lower Sy value of 0.49 is observed for this anion-assisted process.A priori, both the equilibrium constant and the activation energies favor the stepwise path taking place via cationic Int1', as depicted in Figure 2. A similar preference was found for the analogues with G = SO2Me and COOMe (see ESI).The lower Gibbs energy barriers associated to substrates with G = EWG (as compared to G = H) appear to stem from unequal destabilization effects caused by these substituents in the positively charged charge-localized Int1' and the more charge-delocalized TS2' (see NPA charges Table S2 of the ESI).An interesting aspect of the reaction is the apparent retention of the trans geometry of the trans-allylsilanes used throughout this work.A detailed look at the Si-to-I allyl transfer, already illustrated for the trans substrate in Figure 1, shows that the analogous transfer from a cis substrate takes place with a Gibbs energy barrier of 9.3 kcal mol -1 .Notably, the cis/trans stereo-information of the precursor would be lost, as both stereoisomers provide the same allyliodonium intermediate Int1'.Indeed, rather than being stereo-retentive, the trans outcome appears arises from the stereo-preference in the rearrangements step.Specifically, two reactive dispositions of Int1' were identified, differing in their orientation of the SO2Me moiety with respect to the ArI unit: the SO2Me-out form (already shown in Figure 2), and the SO2Me-in form for which the SO2Me substituent points towards the aromatic core.As shown in Figure 3-A, while the out-form evolves the trans product, the SO2Me-in form would to the cis isomer.The trans selectivity would then stem from the ΔG ‡ energy for cis path being 1.8 kcal•mol -1 higher than for the trans path.The trans product should, therefore, be favored regardless of the initial allylsilane configuration, which leaves the door open to attractive stereo-convergent applications of cis/trans allylsilane mixtures.This was indeed confirmed via a selective conversion of cis-6 to trans-12 in 86% (Figure 3-B).This trans outcome, however, is only a preference, and so the cyclic allylsilane 57, with a cis-locked CH2Si / EWG pair, coupled readily with PhI(OAc)2 to give 58 in 60% yield (9:1 o/p, Figure 3-C).

Insights into the stereoselectivity of the C-H allylation. A:
Comparison between the computed trans-and cis-forming transition states.[a] Conditions as in Table 2; [b] 9:1 ortho-para regioisomeric ratio.
We also addressed the question of the surprisingly high regiopreference of the 2-iodonapthalene core towards the C1-allylated products (e.g.36 in Table 3).Hence, starting with a common λ 3 -(2-napthyl)allyliodonium intermediate, the activation barrier leading to the C1 product (ΔG ‡ = 6.6 kcal•mol -1 ) was found to be 2.1 kcal•mol -1 lower than for the (unobserved) C3 path (ΔG ‡ = 8.7 kcal•mol -1 , see Fig. S7 of the ESI).In terms of scope, a remarkable aspect of this C-H allylation reaction is the striking efficiency enhancement provided by electron-poor allylsilanes (G = EWG).13a,11] This process can take place either through direct nucleophilic attack (e.g. via SN2'), or via an SN1 mechanisms involving the initial dissociation of the allyliodonium precursor, and would compete with the productive rearrangement path (see Scheme 2-A). [15]Indeed, the reaction between allyltrimethylsilane (1) and the p-Cl λ 3 -iodane 4 showed a nearly quantitative reduction of the hypervalent precursor to ArI, accompanied by a series of allylsilane umpolung byproducts, with the Ritter-derived N-allylacetamide as the major component in CH3CN-containing solvent mixtures (Scheme 2-B; also see ESI).Our DFT calculations show that both the SN1 and SN2' umpolung paths are energetically accessible, albeit with generally lower ΔG ‡ barrier in the SN1 manifold.Further insights can be gained by comparing the overall energetic barriers between the target rearrangement and the umpolung process, e.g.SN1.Despite the difficulty inherent in comparing intra-and intermolecular processes, our data suggest that the sulfonate system (G = SO2Me) favors the rearrangement path, with the ΔG ‡ = 11.9 kcal•mol -1 for rearrangement vs 12.5 kcal•mol - 1 for SN1, while the unsubstituted system (G = H) favors the SN1 umpolung process by a ΔΔG ‡ of 4.7 kcal•mol -1 (see Figure S6 in the ESI).Furthermore, the exergonic nature of the rearrangement step for G = H (red trace, Figure 2) implies an iodonio-Claisen equilibrium favoring the Int1', and, by extension, the likelihood of the competing umpolung reaction.
The amide challenge and downstream outlook.Wondering whether the allylsilane EWG requisites might be relaxed by the appropriate choice of conditions, we took a second look at the formation of amide-substituted allylarenes such as 47' (Table 3), which had proven difficult with electron-deficient iodoarenes (also see last entries in Table 2).Interestingly, for such borderline cases, the use of 1,1,1,3,3,3-hexafluoro-isopropanol (HFIP) in combination with BF3•Et2O causes a drastic efficiency improvement, with the yield of 47' going from the previously obtained 7% to 83% under the new conditions (Scheme 3-top).
Importantly, poor results were obtained when omitting the BF3 additive.Even the primary amide 10, inefficient under standard conditions (see Table 1), now provided synthetically meaningful yields with both PhI(OAc)2 and the para-Cl iodane 4 (Scheme 3bottom, 59 and 60).The mechanistic origin and the full synthetic potential of this medium are currently under study.Scheme 3. Alternative conditions for the coupling of amide-substituted allylsilanes.
The newly introduced allyl group could also be further elaborated, with applications including the formation of the alkenyl carbamate 61 (82%) (Scheme 4A), the Horner-Wadsworth-Emmons olefination to give polyenes such as the diene SI-3 (ESI) or the triene 62 (Scheme 4B), or the conversion of the Weinreb amide 56 to the allyl ketone (see ESI).In another experiment, the crude allyliodane 17 was converted to the versatile vinyl diazoacetate 63 (Scheme 4C), [24] which underwent a thermally induced electrocyclization to give the 5-(2-iodophenyl)-1Hpyrazole 64 in 88% yield.Motivated by a recent report on usage the bromo-analogue of 63 as linchpin in a diversity-oriented medicinal chemistry project, the iodoarene 63 was applied to the ready synthesis of the n-Bu ester of (±)-Dosabulin, a potent antimitotic agent, [25] by exploiting a Rh-catalyzed cyclopropanation/ring expansion/reduction sequence to give 66 (Scheme 4C). [25]Thanks to the more reactive ortho-iodide, the yield in the final Suzuki-Miyaura step to give 67 improved from the original 78% to nearly quantitative.In another extension, we envisaged accessing larger polycyclic aromatic hydrocarbons (PAH) via Pd-catalyzed formal [4+2] cycloaddition reaction developed by Worlikar and Larock. [26]ndeed, the Pd/dppm-catalyzed annulation of the iodonaphthalenes 36 or 37 with benzyne delivered the chrysene cores 68 and 69 in 77% and 52% yield, respectively (Scheme 4D).The usefulness of this transformation was highlighted by the ready conversion of the ester 68 to the aminoalcohol 71 (via aldehyde 70), a one-carbon homologue of the intercalator-type experimental anticancer agent Crisnatol. [27]We note that the our aim with sequences C and D (Scheme 4) is not primarily to improve upon the existing routes, but rather to highlight the potential of the iodane-guided C-H allylation as a tool to rapidly scan swaths of chemical space of interest.

Conclusion
In summary, functionalized ortho-allylated iodoarenes can be obtained by iodane-guided C-H functionalization.In this process, the efficiency of the C-H allylation is unlocked through to the introduction of a terminal EWG groups to the allylsilane, including the SO2R, the -PO(Et)2 or a variety of -COX substituents.Such substrates were conveniently accessed through olefin crossmetathesis, including a modular variant involving acryloyl chloride.The method could be applied to a series of activated and deactivated iodoarenes cores.DFT calculations revealed that, after a barrierless Si-to-I allyl transfer, in the case of EWG a [3,3]  sigmatropic rearrangement takes place through an aromatic transition state to yield ortho-allylated iodoarenes, whereas for unsubstituted allylsilane the SN1 umpolung process is preferred.The newly prepared o-iodo allylarenes constitute a valuable family of building blocks, as was illustrated by applications ranging from the double bond migration and HWE olefination, to the synthesis of cores based on the experimental agents Dosabulin and Crisnatol.We feel that these applications are but a tip of the iceberg, and that many more uses for the functionalized iodoarenes produced by this method will be discovered.