Switchable chemoselective aryne reactions between nucleophiles and pericyclic reaction partners using either 3-methoxybenzyne or 3-silylbenzyne

Arynes are known to serve as highly reactive benzene-based synthons, which have gained numerous successes in preparing functionalized arenes. Due to the superb electrophilic nature of these fleeting species, however, it is challenging to modulate the designated aryne transformation chemoselectively, when substrates possess multiple competing reaction sites. Here, we showcase our effort to manipulate chemoselective control between two major types of aryne transformations using either 3-methoxybenzyne or 3-silylbenzyne, where nucleophilic addition-triggered reactions and non-polar pericyclic reactions could be differentiated. This orthogonal chemoselective protocol is found to be applicable between various nucleophiles, i.e., imidazole, N-tosylated/N-alkyl aniline, phenol, and alcohol, and an array of pericyclic reaction partners, i.e., furan, cyclopentadiene, pyrrole, cycloheptatrienone, and cyclohexene. Beyond arylation reactions, C–N bond insertion, Truce–Smiles rearrangement, and nucleophilic annulation are appropriate reaction modes as well. Moreover, this chemoselective protocol can find potential synthetic application.

both the high electrophilicity 30 and fleeting property of an aryne species, unfortunately, to govern aryne reactions chemoselectively on polyfunctionalized substrates has been traditionally seen as an almost impossible task.Although aryne intermediate can occasionally distinguish a reacting site from the others on a complex molecule, this approach heavily relies on the inherent reactivity difference among those arynophiles and frequently encounters with unavoidable side products from competing reactions whenever this difference is not decisive (Fig. 1B).For instance, a distinct work was reported by Hoye and Ross, in which hexadehydro-Diels-Alder (HDDA) reaction-derived arynes could undergo site-selective transformations on several structurally complex natural products bearing multiple potential reaction sites 31 .Recently, McCormick et al. developed an arynophilicity parameter to describe the relative reactivity of various arynophiles with respect to 3-chlorobenzyne 32 .Besides, there are some other competitive aryne reaction examples 33,34 .It has been commented by Hergenrother that "Can robust predictive models for site-and chemoselectivity of this and other (aryne) methodologies be developed?and eventually enable the ultimate goal of orthogonal functionalization of any site of a complex natural product?" 35 .Unfortunately, there is no doubt that it would be very challenging to govern chemoselectivity at will by using highly reactive and fleeting aryne species.This fundamental topic becomes even emerging in view of the rapid recent discovery of benzyne transformations as well as the potential application of these useful synthetic tools.Here, chemoselective control between two major classes of aryne reactions, namely nucleophilic-type reactions and pericyclic reactions, was developed by using 3-substituted arynes, which employs both electronic effect and steric repulsion to differentiate the reaction rates of a collection of arynophiles.Arynes containing 3-electron-withdrawing groups (3-EWGs) were found to preferentially react with nucleophiles on its C1-position in the presence of non-polar pericyclic reaction partners, the position of which is more electrophilic and less sterically encumbered.Alternatively, an inverse chemoselectivity in favor of pericyclic reactions was unraveled when 3-(tertbutyldimethylsilyl)benzyne (3-(TBS)benzyne) was utilized, whereas nucleophilic addition reactions were prohibited due to the counteracted electronic and steric effect on both the C1-and C2-positions of 3-silylbenzyne.Particularly notable is the power of this protocol to inversely differentiate two types of arynophiles that possess similar reactivity toward simple benzyne.

Results
Along with our study on benzyne chemistry 12 , we were curious about the possibility to discriminate arynophiles of different types, i.e., polar and non-polar ones, by unraveling some seemingly trivial reactivity discrepancy among those highly reactive aryne species.In order to see whether different aryne species behave consistently or not in the presence of various types of arynophiles, we decided to assess the competing reaction of imidazole (2a) and furan (3a) with them.As shown in Fig. 1C, it was found that the trapping reaction of simple benzyne precursor 1a with excess amounts of imidazole (2a) (3.0 equiv) and furan (3a) (3.0 equiv) afforded the N-arylation product 4a in 36% yield and the [4 + 2]-cycloadduct 5a in 47% yield with a ratio of 1:1.3 (entry 1).This ratio could change to 2.1:1 when 18-c-6 was used, suggesting that the reaction conditions could slightly alter the product ratio (entry 2).When 3-methoxybenzyne precursor 1b was employed, 4b was obtained in 74% yield along with only 4% of cycloadduct 5b with a ratio of 19:1 (entry 3).By contrast, other aryne precursors containing 3-F or 3-Br substituent could not provide satisfied product ratio (for details, please see Supplementary Table 1).Next, we turned our attention to arynes bearing 3electron-donating groups (3-EDGs).Among an array of 3-silylbenzyne precursors (Supplementary Table 1), 3-(TBS)benzyne precursor 1c was found to be the most favorable one, featuring cycloadduct 5c as the major product in 72% yield and 4c in 7% yield with a ratio of 10:1 (entry 4).Note that precursors of both 3-chlorobenzyne 1d (entry 5), which was used by McCormick and Stuart in their arynophilicity study 32 , and 3-(trimethylsilyl)benzyne 1e (entry 6) could not gave satisfied product ratio in comparison to the corresponding 1b and 1c, respectively.In addition, 3-tert-butylbenzyne precursor 1f was tested and its reaction furnished both 4f and 5f in a low product ratio (1.3:1), indicating that steric repulsion itself cannot serve as the decisive factor to differentiate these two types of aryne reactions (entry 7).
Beyond imidazole and furan, the same type of switchable chemoselectivity was observed between an array of nucleophiles, i.e., Ntosylated aniline (2b), N-benzyl aniline (2c), phenol 2d, benzyl alcohol (2e), and benzoic acid (2 f), and pericyclic reaction partners, i.e., cyclopentadiene (3b), N-tosyl pyrrole (3c), and 1-phenylcyclohexene (3d) (Fig. 1D and please also see Supplementary Table 2).These examples illustrate that the designated chemoselectivity could be accomplished between appropriate nucleophile and pericyclic reaction partner.The key tuning factor is by simply switching the 3-substituent, either a methoxy group or a TBS group, on the parent benzyne ring.Notably, the closer the reactivity toward simple benzyne between two types of arynophiles, the more effective tuning ability on both reaction directions with respect to 3-methoxybenzyne and 3-(TBS)benzyne could be reached (Fig. 1D).
Our next goal is to apply this chemoselective control protocol to molecules containing both nucleophilic and pericyclic components, which possesses more practical potential than those intermolecular cases in Fig. 1D.As shown in Fig. 1E, substrate-1 (sub-1) was chosen.Comparing with intermolecular reaction conditions, the conditions for compound sub-1 are apparently different.For instance, stoichiometric or excess amount of aryne precursor is necessary, which in turn markedly raises the risk of aryne to interact with unwanted reaction sites.When 1.5 equiv of 3-methoxybenzyne precursor 1b was used to react with sub-1, compound 6a could be obtained solely in 66% yield.Inversely, the reaction between 1c and sub-1 by using tetrabutylammonium difluorotriphenylsilicate (TBAT) in toluene afforded the cycloadduct 6b in 70% yield with almost no detectable amount of the N-arylation product.In contrast, the reaction of sub-1 with simple benzyne precursor 1a gave rise to a mixture of N-phenylation product (58%), cycloadduct (8%), and a compound resulted from both N-phenylation and [4 + 2]-cycloaddition (23%) (Fig. 1E).Notably, reverse chemoselectivity could be realized on a molecule by employing properly chosen 3-substitued arynes.
Alike compound sub-1, both the N-arylation product 7a (Fig. 2A) and the cycloadduct 7b (Fig. 2B) were obtained from compound sub-2 (Fig. 2C) when treating with either 1b or 1c, respectively.Moreover, Nalkyl anilines as more prevailing functional groups appeared to be appropriate nucleophilic partners with furan.Accordingly, the N-arylation products 8a, 9a, and 10a were obtained from substrates sub-3, sub-4, and sub-5, respectively, in good to high yields, giving an alternative approach for arene amination (Fig. 2A) [36][37][38][39] .Alternatively, when the same substrates were treated with aryne precursor 1c, the corresponding cycloadducts 8b, 9b, and 10b were isolated in high overall yields as mixtures of diastereoisomers (Fig. 2B).By enhancing the steric congestion around the N-nucleophile of anilines, improved product ratio could be achieved, suggesting that steric effect plays an essential role in tuning the product ratio as well.Next, Fuberidazole, a compound used in fungicides, containing a furan and a benzimidazole subunit was investigated.Its reaction with 1b produced only the N-arylation product 11a in high yield; while chemoselective [4 + 2]cycloaddition reaction was achieved when 1c was utilized, furnishing 11b and 11b′ in 86% overall yield as a mixture of 1:1 regioisomers (Fig. 2B).Pyrrole was then considered in our study.Both tosylamide and phenol were found to serve as appropriate reaction partners of pyrrole group.To this end, 12a and 13a were obtained from sub-6 and sub-7 in good yields after arylation with 1b in the presence of carbonate salts (Fig. 2A); while the treatment of 1c delivered the corresponding [4 + 2]-cycloadducts 12b and 13b exclusively (Fig. 2B).Next, the reaction of compound sub-8 bearing a cyclopentadiene and two phenol moieties with excess amount of 1b produced the double O-arylation product 14a in 60% yield.Alternatively, when 1c was employed, the [4 + 2]-cycloadduct 14b could be achieved solely in 70% yield.In addition, substrate sub-9 bearing an alcohol and a cyclohexenyl group was tested, in which both reaction sites were found to possess comparable reaction rate toward benzyne (Fig. 1D).The corresponding O-arylation product 15a and the ene reaction product 15b were obtained by treating sub-9 with 1b and 1c, respectively, in excellent chemoselectivity.In order to demonstrate the merit of both 1b and 1c as distinctive aryne precursors, all the substrates in Fig. 2D were examined with simple benzyne precursor 1a.In sharp contrast to Fig. 2A, B, mixtures of products attributed from single N/O-arylation, single pericyclic reaction, and/or arylation-pericyclic dual reactions were usually isolated (Fig. 2C).
Furthermore, N-deacetyl N-tosyl Colchicine sub-10 was prepared, which contains a tosylamide and a cycloheptatrienone subunit (Fig. 3A).The reaction of sub-10 with 1b produced the N-arylation product 16a only in 66% yield, while the employment of aryne precursor 1c furnished the [4 + 2]-cycloadduct 16b in 78% yield with distinct regio and facial selective control.Beside 3-methoxybenzyne as preferential arylating reagent, several other aryne species were found to serve as the same role to react with compound sub-5, giving rise to 17a-17d in good yields (Fig. 3B).Following Han's protocol 40 , the TBS group on 10b could be selectively removed in the presence of t-BuOK in DMSO, furnishing 18 in excellent yield (Fig. 3C).Alternatively, both cycloadducts 11b and 11b′ could be converted to naphthalene 19 by treating them with chlorotrimethylsilane (TMSCl) and sodium iodide (NaI) in acetonitrile 41 , the transformation of which experiences a deoxygenative aromatization and a desilylation process.Both cases in Fig. 3C demonstrate that the TBS group on the [4 + 2]-cycloadduct could be readily removed, making 3-(TBS)benzyne an equivalent of simple benzyne with the ability to differentiate cycloaddition reactions from nucleophilic addition reactions.
In order to expand the scope of our protocol from arylation reactions to other types of transformations, compound sub-11 containing a trifluoroacetamide and a furanyl group was prepared, the trifluoroacetamide site of which is known to undergo a C-N bond insertion reaction with benzyne 42 .While the reaction of sub-11 with 1b could feature the C-N bond insertion product 20a in 67% yield, the employment of 1c produced the cycloadduct 20b in 81% yield accompanied with 10% of its regioisomer (Fig. 4A).We then prepared compound sub-12 to see whether a Truce-Smiles rearrangement could serve as an appropriate partner of furan cycloaddition reaction 43 .Treating sub-12 with 1b in refluxing THF gave rise to the desired Truce-Smiles rearrangement product 21a in 73% yield, while the furanyl group kept inert even under elevated temperature (Fig. 4A).Alternatively, the reaction between sub-12 and 1c in DCM afforded the cycloadduct 21b in 57% yield along with 14% of its regioisomer.Another example is compound sub-13, which contains a Diels-Alder partner pyrrole and a methyl salicylate component that could undergo nucleophilic annulation reaction (Fig. 4A).The reaction of sub-13 with 1b in refluxing THF delivered the nucleophilic annulation product 22a in 72% yield, while cycloadduct 22b could be obtained in 80% yield as a 1.7:1 mixture of conformational isomers in the reaction with 1c.The examples in Fig. 4A demonstrate that not only typical arylation reactions, but also a range of nucleophilic addition-triggered transformations can be applicable to our chemoselective control protocol.Moreover, we wanted to see whether this strategy can be applied in more sophisticated molecular systems, such as those bearing more than two reaction sites.Furosemide, a loop diuretic medication used to treat fluid build-up due to heart failure, liver scarring, or kidney disease, was chosen, which contains four potential reaction sites, a pericyclic partner furan and three nucleophiles.Due to the low solubility of the zwitterionic structure of Furosemide, its ester derivative sub-14 was prepared for our study (Fig. 4B).It was found that the reaction of Furosemide methyl ester sub-14 with 1b delivered the double nucleophilic addition product 23a exclusively on the sulfonamide.The absence of nucleophilic addition on the secondary amine of sub-14 should be attributed to the steric effect of its ortho-ester group.Alternatively, selective Diels-Alder reaction on the furanyl group of sub-14 occurred with 1c, featuring compound 23b in 78% yield along with 12% of its regioisomer.Next, compound sub-15 bearing two types of N-nucleophiles and a furfuryl group was prepared, where a different reactivity sequence from sub-14 was disclosed (Fig. 4B).In this case, the aniline nitrogen on sub-15 was found to be more reactive than both benzimidazole nitrogen and furan.To this end, simple benzyne precursor 1a was employed to capture it, producing compound 24 in 78% yield.At this stage, the diaryl tertiary amine subunit on 24 turned out to be less nucleophilic than benzimidazole.Consequently, both selective N-arylation on the benzimidazole with 1b and [4 + 2]cycloaddition on the furan with 1c could then be realized on compound 24, affording the corresponding products 25a and 25b, respectively.Compound sub-16 containing a cyclopentadiene, a primary alcohol, and a tertiary alcohol was then prepared.The reaction of sub-16 with 1b featured the O-arylation product 26a in 74% yield, while its reaction with 1c produced the cycloadduct 26b in 78% yield.
To demonstrate the synthetic potential of this chemoselective strategy, an asymmetric preparation of dihydrexidine, an agonist at the dopamine D1 and D5 receptors with antiparkinson effects, was developed (Fig. 5) 44 .Starting from Sesamol, a TBS group was incorporated onto its 2-position in a one-pot process, featuring compound 27 in 85% yield.Next, compound 28 was obtained in 83% yield upon bromination, which was converted to aryne precursor 29 following the standard procedure.Meanwhile, compound 30 was readily prepared via Suzuki-Miyaura coupling reaction and reduction, which could then reactive toward benzyne, it can be trapped by simple benzyne so that subsequent chemoselective control between other arynophiles with matched reactivity could occur.By contrast, a less reactive reaction site will keep inert with respect to any aryne species.
be transformed to compound 31 in two steps.Chemoselective Diels-Alder reaction between 29 and 31 furnished cycloadducts 32a and 32b as a mixture of 1:1.2 regioisomers in 90% overall yield, whereas almost no nucleophilic addition reaction was observed.The TBS group on 32a and 32b could then be easily removed upon treating with t-BuOK in DMSO, affording compound 33 in 90% yield.Notably, this two-step operation could facilely convert compound 31 to 33 in an overall excellent yield.Next, rhodium-catalyzed cycloisomerization on oxabicycle 33 was examined.Inspired by Lautens' previous study 45 , kinetic resolution of racemic oxabicycle 33 in the presence of the (R,S)-PPF-P t Bu 2 Josiphos ligand gave rise to compound 34 in 30% yield and 98% ee (Fig. 5).The absolute configuration of compound 34 was assigned by its x-ray single crystal analysis.With enantiopure 34 in hand, hydrogenation, followed by dehydroxylation reaction by using triethylsilane and boron trifluoride etherate, generated compound 35 in 44% yield, accompanied with 45% of its diastereoisomer.Finally, deprotection of both the acetal and the tosylate groups on 35 delivered dihydrexidine hydrobromide salt in 86% yield.
To elucidate the origin of the above chemoselectivity, we decided to compare the reaction rates of several 3-substituted arynes in the presence of both n-butylamine and t-butylamine.In the study on 3-silylbenzyne carried out by both the groups of Akai 46 and Garg 47 , they disclosed that the size of a nucleophile could significantly influence the preferred site of attack, where a small nucleophile prefers the electronically favored ortho-position of the silyl group and a bulky nucleophile inclines to attack the electronically disfavored metaposition.When 1e was treated with both n-butylamine (3.0 equiv) and t-butylamine (3.0 equiv), 36a, 36b, and 36c were isolated in 68%, 13%, and 7% yields, respectively (Fig. 6A).Moreover, the employment of 1c produced 37a in 44% yield, 37b in 40% yield, and 37c in 3% yield, which is consistent with the fact that TBS group is more sterically congested than TMS group.In comparison, a competing reaction with 3-methoxybenzyne precursor 1b was carried out, furnishing 38a in 60% yield and 38b in 32% yield (Fig. 6A).These experiments demonstrate that although t-butylamine is slightly less efficient than that of nbutylamine in the reaction with 1b, its reactions with 1e and 1c are suppressed by the presence of n-butylamine.In this context, a σ-electron-donating silyl group (in our study the TBS group) on the C3position of a benzyne not only perturbs benzyne distortion to favor ortho-attack with respect to small nucleophiles, but also slows down the rate of nucleophilic addition by bulky nucleophiles when metaselectivity becomes demanding due to steric repulsion on its orthoposition (Fig. 6B).Whenever an arynophile is not heavily influenced by the aryne distortion imposed by the 3-silyl group, chemoselective control should be realized.By contrast, 3-methoxybenzyne would undoubtedly favor nucleophilic-type reactions on its C1-position, because this site is both electronically favored and sterically less congested.Of course, the success of this protocol also depends on the magnitude of nucleophilicity of an arynophile.In this scenario, either a strong nucleophile would by no means to attack 3-silylbenzyne over other arynophiles or a weak nucleophile should keep inert throughout the reaction (Fig. 4B).
Next, Density functional theory (DFT) calculations were carried out at the M062x/6-31 + G(d) level of theory.Our calculation indicates that simple benzyne could not differentiate the reaction with either imidazole (2a) or furan (3a) due to close activation energies between transition states TS1 and TS2 (9.2 kcal/mol vs. 9.4 kcal/mol) (Fig. 6C).Indeed, the reactions with 3-methoxybenzyne prefers N-arylation reaction due to lower activation energy for TS4 than that for TS3; whereas the energy difference between transition states of [4 + 2]cycloaddition TS5 and N-arylation TS6 with respect to 3-(TBS)benzyne is 1.4 kcal/mol in favor of the cycloaddition reaction (Fig. 6C).Overall, three factors ensure the success of this chemoselective aryne reaction strategy: a. the inherent reactivity difference between a nucleophile and a pericyclic reaction partner determines the probability for chemoselective control; b. proper 3-substituent on benzyne could modulate the preferred reaction mode; c. additional factors, such as steric effect and reaction conditions, further enhance the product ratio.
We have been able to demonstrate that chemoselective control between two major types of benzyne transformations, namely nucleophilic addition-triggered reactions and pericyclic reactions, could be accomplished by simply varying the 3-substituent on aryne intermediate.In the presence of appropriate nucleophile and pericyclic reaction partner, arynes containing 3-EWG groups incline to take part in nucleophilic addition reactions.Alternatively, 3-(tert-butyldimethylsilyl)benzyne slows down nucleophilic addition reaction on both its triple bond carbons due to a mismatch between electronic effect and steric repulsion and, hence, results in preferential pericyclic reaction.This protocol is amenable to a broad range of both nucleophilic addition reactions, i.e., transition metal-free arylation reactions, insertion reaction, Truce-Smiles rearrangement, and nucleophilic annulation reaction, and pericyclic reactions, i.e., Diels-Alder reaction and ene reaction, which unravels a great potential of aryne chemistry in manageable chemoselective functionalization of complex molecules.It is expected that more general and effective chemoselective strategies can be unraveled in the future.

Methods
General procedure for the reaction of benzyne precursor 1a A mixture of benzyne precursor 1a (89.5 mg, 0.3 mmol, 1.5 equiv), substrate (0.2 mmol, 1.0 equiv), and CsF (91.1 mg, 0.6 mmol, 3.0 equiv) in MeCN (2.0 ml) under inert atmosphere was stirred at room temperature overnight.The resulting mixture was filtered through a short pad of silica gel (EtOAc eluent, 20 ml).All the volatiles were removed on a rotary evaporator.The crude material was purified by flash column chromatography to afford the corresponding products.

General procedure for the reaction of aryne precursor 1c
A mixture of aryne precursor 1c (123.8 mg, 0.3 mmol, 1.5 equiv), substrate (0.2 mmol, 1.0 equiv), KF (46.5 mg, 0.8 mmol, 4.0 equiv), and 18c-6 (105.7 mg, 0.4 mmol, 2.0 equiv) in anhydrous THF, MeCN, or DCM (2.0 ml) under inert atmosphere was stirred at room temperature overnight.The resulting mixture was filtered through a short pad of silica gel (EtOAc eluent, 20 ml).All the volatiles were removed on a rotary evaporator.The crude material was purified by flash column chromatography to afford the corresponding products.

Fig. 6 |
Fig. 6 | Mechanistic investigation.A Competing reactions of aryne precursors with n-butylamine and t-butylamine.B Rational for selectivity in nucleophilic type reactions on either 3-methoxybenzyne or 3-(TBS)benzyne.C Transition states for the reactions of benzyne, 3-methoxybenzyne, and 3-(TBS)benzyne with either furan and imidazole.The free energy values are calculated at the M06-2X/6-31 + G(d) level of theory in acetonitrile with SMD model using the Gaussian 09 series of programs.Hydrogen, white; Carbon, gray; oxygen, red; silicon, yellow; nitrogen, purple.