Selective oxymetalation of terminal alkynes via 6-endo cyclization: mechanistic investigation and application to the efficient synthesis of 4-substituted isocoumarins

The oxymetalation of terminal alkynes proceeded in a 6-endo cyclization manner with the use of indium or gallium trihalide.


Introduction
Heterocyclic compounds have attracted much attention in pharmaceutical chemistry as well as in photochemistry and also play a pivotal role as building blocks in organic synthetic transformation. 1 Therefore, a novel efficient synthetic method for heterocyclic frameworks is highly desired in various elds of chemistry. Many well-established methods are available in the literature. 2 The heterocyclization of u-heteroatom-substituted alkynes using p acidic metal salts is undoubtedly a powerful strategy for the preparation of heterocycles (Scheme 1). 3 This addition reaction uses readily available alkynes as a starting material. Furthermore, metal salt-mediated cyclization spontaneously forms a carbon-metal bond and a heterocyclic framework and produces organometallic intermediates leading to target heterocycles via appropriate synthetic reactions such as cross coupling. These features allowed us to directly access various substituted heterocycles from simple organic substrates.
Various heteroatom-containing alkynes have been investigated for use in the synthesis of heterocyclic compounds using p acidic metal salts. Alkyne A includes a carbonyl moiety and is a feasible and benecial substrate to obtain 5-or 6-membered oxacyclic alkenylmetals (Scheme 2A). When A is treated with a metal salt (MX), oxymetalation proceeds to afford heterocyclic compounds through either 5-exo or 6-endo cyclization (Type exo or endo). Considering that the structure of A bears either an internal (R ¼ alkyl, aryl, etc.) or a terminal alkyne (R ¼ H), oxymetalation can be distinguished by four types of reaction courses: Type exo-i, Type exo-t, Type endo-i, and Type endo-t. In Types exo-i and exo-t, the furan frameworks B and C have a metal carbenoid moiety and are obtained via the isomerization of zwitterion intermediates. 4,5 On the other hand, Types endo-i and endo-t lead to 1H-isochromen derivatives D and E via the elimination of R 0 X from zwitterion intermediates. 6,7 Among these four types, only Type endo-t is kinetically unfavorable due to an unstable cationic transition state via an anti-Markovnikov addition manner (Scheme 2B). Furthermore, recent theoretical research about the regioselectivity of cyclization revealed that the nucleophilic cyclization of alkynes displays exo selectivity intrinsically. 8 On the other hand, Lewis acidic metals can promote endo cyclization by decrease of the stereoelectronic penalty, but the exo cyclization was not disturbed, and, thus, the cyclization showed low selectivity. 7,9 For the above reasons, there is no report of a preparation method for species E via Type endo-t in contrast to the cases of Types exo-i, exo-t, and endo-i, for which target organometallic compounds (B-D) are well established. 4b,5a,6c,6e If the reaction course of oxymetalation is realized from A to E in Type endo-t, 10 various 6-membered heterocycles based on E, which have been difficult to obtain and remain unknown, should be synthesized. Therefore, the establishment of a strategy for Type endo-t is an important challenge in heterocyclic chemistry.
Isocoumarins are an important class of oxygen-containing heterocycles that exhibit a wide range of pharmacological properties. 11 Thus, the development of their general synthetic method has attracted much attention. The reaction of Type endo would be a powerful tool for the synthesis of isocoumarins (Scheme 3A). In fact, reports have described the oxymetalation of 2-alkynylbenzoate 1 (R ¼ alkyl, alkenyl, aryl) for Type endo-i and application to the synthesis of isocoumarins. 6a,6b,6e Recently, Blum reported an excellent method for the construction of 4-borylated isocoumarins by the oxyboration of the internal alkynes 1 in the Type endo-i reaction course (Scheme 3B). 6e However, terminal alkyne 1 (R ¼ H) gave only a 5-exo cyclization product according to the Markovnikov rule (blue path in Scheme 3C). 6e This result prompted us to explore the oxymetalation of the terminal alkynes 1 for Type endo-t. The oxymetalation of Type endo-t provides 3-unsubstituted and 4substituted isocoumarins that are seldom investigated due to the lack of synthetic methods, 12 and limited substituents have been introduced at the 4-position despite the well-known benecial signicant bioactivity characteristics such as antitumor, 13 antiangiogenic, 14 antifungal, 15 and antibiotic. 16 Our group developed the indium or gallium salt-mediated carbometalation of simple terminal alkynes with silyl ketene acetals by utilizing their high p electron affinity and moderate Lewis acidity. 17 In this context, we investigated the Type endo-t reaction of 2-ethynylbenzoate using indium or gallium trihalides for the synthesis of corresponding metalated isocoumarins. In this report, we successfully achieved a 6-endo selective oxymetalation of terminal alkynes and fully characterized the target organometallic species E1 via an NMR study and X-ray crystallographic analysis. Furthermore, the intermediate F1 was isolated, which revealed that oxymetalation proceeds via the zwitterion intermediate F1, and the elimination of the alkyl halide gives the target product E1 (Scheme 4). While benzopyrylium species such as F are known as highly reactive intermediates in the proposed catalytic oxymetalation cycle, 10a,18 the isolation of species F is a challenging issue. 10e,10f, 19 To the best of our knowledge, F1 is the rst example of a fully characterized benzopyrylium intermediate F. In addition, we fully disclosed the mechanism by combining experimental data and theoretical calculation. These mechanistic investigations were consistent with the achievement of isolation of the zwitterion intermediate and demonstrated that its stability is a crucial point in this remarkable cyclization regioselectivity.

Optimization of reaction conditions
First, we examined the effect of Lewis acids on oxymetalation using methyl 2-ethynylbenzoate 1a ( Table 1). The reaction of 1a with metal halides was carried out in toluene at 50 C, and the reaction mixture was quenched with acetic acid. The reaction using InCl 3 afforded the target isocoumarin 2 via 6-endo cyclization, albeit in a low yield (entry 1). Gratifyingly, InBr 3 and InI 3 mediated oxymetalation smoothly proceeded in a 6-endo cyclization fashion to give 2 in high yields (entries 2 and 3). In these cases, the reaction mixture was quenched with deuterated acetic acid to afford 2 bearing deuterium at the 4-position. We did not observe an isocoumarin bearing deuterium at the 3position which could be produced through the generation of indium acetylide 20 followed by Lewis acid mediated cycloaddition. The reaction using InI 3 showed a higher ratio of D/H than the case of InBr 3 . This result suggested the more efficient generation of the alkenylmetal intermediate X in the case of InI 3 . Gallium salts were also suitable for the 6-endo cyclization of 1a, and GaI 3 gave a high yield (entries 4 and 5). On the other hand, typical Lewis acids such as AlCl 3 , AlI 3 , BBr 3 and TiCl 4 were Scheme 3 (A) Oxymetalation of 2-alkynylbenzoate 1 followed by transformation for the construction of isocoumarins. (B) Previously reported oxyboration of internal alkynes to generate 4-borylated isocoumarins. (C) Oxymetalation of terminal alkynes, reported oxyboration for 5-membered compounds (blue path), and our developed oxymetalation for 6-membered compounds (red path).
Scheme 4 Oxyindation of alkynes for the synthesis of an isocoumarin framework via a zwitterion intermediate. ineffective (entries 6-9). Transition metal salts such as PdCl 2 , CuBr 2 and FeBr 3 provided no target product and resulted in a decomposition of 1a (entries 10-12). Alkynophilic p-acids such as gold and silver salts were subjected to the present cyclization. It was found that AuCl 3 , AuCl, AgOTf and AuCl/ AgOTf resulted in low yields (entries [13][14][15][16]. A decrease in yield was observed at lower temperature (entry 17). The solvent effect was examined on oxyindation using InI 3 . Dichloroethane as a solvent provided a good yield while chlorobenzene and hexane afforded only moderate yields (entries [18][19][20]. The yields were appreciably decreased in CH 3 CN and THF (entries 21 and 22) probably because the coordination of these solvents to InI 3 decreased the Lewis acidity. Finally, InI 3 was the most effective Lewis acid, and, therefore, we chose entry 3 to represent the optimal conditions.

Mechanistic investigation
To gain insight into the reaction mechanism, we used 1 H NMR spectroscopy to monitor the oxyindation. When 2-alkynylbenzoate 1a was mixed with InI 3 in CDCl 3 at À30 C, no reaction occurred. At À5 C, some amount of a new product was observed (see Fig. S1 and S2 † in the ESI). At room temperature, a large amount of white precipitation was formed. This white solid was also obtained in the reaction of 1a with InI 3 in toluene at room temperature (eqn (1)). X-ray crystallographic analysis revealed that the white solid was a 6-membered oxacyclic zwitterion 3 bearing a carbon-indium bond (Fig. 1). The bond lengths of the two carbon-oxygen bonds (C1-O1 ¼ 1.267Å and C1-O2 ¼ 1.298Å) in the zwitterion 3 existed between a C-O double bond (1.203Å) and the single bond (1.377Å) of a typical isocoumarin derivative, 21 and, thus, the positive charge was delocalized in an ester moiety. The indium atom was coordinated to three iodines and showed a distorted tetrahedral structure with a formal negative charge. The formed zwitterionic alkenyl indium 3 was heated at 50 C in toluene to give a neutral alkenylindium product 4a, quantitatively by the elimination of MeI (eqn (2)). Although a suitable single crystal of 4a for X-ray analysis was not obtained, we successfully conducted X-ray diffraction analysis of nitro-substituted alkenylindium 4b produced from 2-ethynyl-5-nitrobenzoate 1b (eqn (3) and Fig. 2). The bond lengths of C1-O1 (1.211Å) and C1-O2 (1.367Å) were similar to those of a reported isocoumarin framework. 21 The indium complex 4b displayed trigonal bipyramidal coordination with two THF ligands in axial positions. These results indicated a two-step pathway including a fast cyclization and a slow elimination of MeI during the 6-endo oxyindation process from 1 to 4. (1) (2)
(red) is shown in Fig. 3. We selected 1a and In 2 I 6 as the starting materials because InI 3 exists in a dimer fashion. 22 The coordination of two 1a to In 2 I 6 dissociates the aggregation of InI 3 to give complex 7, in which InI 3 is chelated with the alkyne moiety and carbonyl group of 1a ( Fig. S3 † in the ESI shows the detailed mechanism of generating the complex 7 from 1a and In 2 I 6 ). The dissociation of the carbonyl oxygen atom generates complex 5, in which InI 3 directly activates the alkyne moiety. In this pathway, the anti-addition of InI 3 and the ester moiety to the alkyne moiety proceeds in a concerted mechanism to provide a stable 6-membered zwitterion intermediate 3. The elimination of MeI proceeds in an intermolecular fashion, because the intramolecular elimination of MeI requires a very unstable intermediate (Fig. S4 † in the ESI shows the potential energy prole for the intramolecular elimination of MeI). Two zwitterions aggregate in a head-to-tail fashion to give complex 8, and then the elimination step starts from 8. The intermolecular nucleophilic substitution of the methyl group by I À proceeds in an S N 2-mechanism to give complex 10 and MeI, and then a subsequent elimination of MeI affords the target product 4a. 23 A carbonyl group of 4a coordinates to the indium atom of another 4a to give the stable dimeric product 13. The activation energy of the elimination step (8 to TS2-6-endo, 28.7 kcal mol À1 ) Scheme 5 A proposed mechanism for the formation of the isocoumarin 4a. Fig. 3 The energy profiles of 6-endo and 5-exo oxyindations and 3D molecular structures of transition states. DFT calculation was performed using wB97XD/6-31+G (d,p) for C, H, and O and using DGDZVP for In and I. Solvation effect was introduced using the IEFPCM model, and toluene was used as a solvent.
is much higher than that of the cyclization step (7 to TS1-6-endo, 19.7 kcal mol À1 ). 24 Therefore, the elimination of MeI is a ratedetermining step. We also calculated the 5-exo cyclization pathway (blue) to investigate the regioselectivity. This process proceeds via concerted cyclization, wherein the 5-membered zwitterion 6 is much more unstable than the 6-membered version 3. The intermolecular elimination of MeI takes place in an S N 2-manner (9 to 11). The transition state (TS2-5-exo) shows the highest energy level, and it is even higher than the energy prole of the 6-endo cyclization process (red) due to the instability of the 5-membered zwitterion 6.
In order to clarify the unique 6-endo cyclization selectivity of oxyindation, the energy proles of the two cyclization manners were compared. The activation energy of 5-exo cyclization is lower 15.5 kcal mol À1 ) than that of 6-endo cyclization (7 to TS1-6-endo, 19.7 kcal mol À1 ). However, 5-exo cyclization is reversible because the activation energy for the elimination of MeI (9 to TS2-5-exo, 21.9 kcal mol À1 ) is much higher than that of retro-cyclization (6 to TS1-5-exo, 9.3 kcal mol À1 ) due to the instability of the zwitterion 6. On the other hand, during 6-endo cyclization, both activation energies of elimination (8 to TS2-6-endo, 28.7 kcal mol À1 ) and retro-cyclization (3 to TS1-6-endo, 23.0 kcal mol À1 ) are high because the 6membered zwitterion intermediate 3 is thermodynamically stable. This result indicates that 6-endo cyclization is irreversible and the most thermodynamically stable form of intermediate 8 is exclusively generated to provide the target product 4a, which is consistent with the successful isolation of the zwitterion intermediate 3 (Fig. 1). Therefore, oxyindation proceeds under thermodynamic control to afford the stable 6-membered product 4a. We also calculated an energy prole of InCl 3mediated oxyindation and found the same pathway with the case of InI 3 (see Fig. S5 † in the ESI). The activation energy of the elimination step in the case of InCl 3 is higher than that of InI 3 because of the low nucleophilicity of Cl À , and it caused much less reactivity of InCl 3 (entry 1, Table 1).  (1) values of 6-membered zwitterion 3 and 5-membered zwitterion 6. The aromaticity was calculated using B3LYP/6-31G (d,p) for C, H, and O and using DGDZVP for In and I for their optimized structures.
Scheme 6 A proposed mechanism for oxyboration. The remarkable regioselectivity of oxyindation is ascribed to the differences in stability between the 6-membered zwitterion 3 and the 5-membered 6. Zwitterion 3 is much more stable than 6, and this difference in stability originates from the aromaticity of these compounds, although ring strain is also a consideration. To verify this possibility, the aromaticity of zwitterions was evaluated via NICS(1) 25 (Fig. 4), and the 6-membered compound 3 showed a higher level of aromaticity than 6.

Theoretical calculation for oxyboration
Blum and co-workers reported that the oxyboration of 1a using B-chlorocatecholborane (ClBcat) gave a 5-membered product 6e rather than the 6-membered version (Scheme 6). ClBcat is coordinated to the carbonyl moiety of 1a. Then, oxyboration proceeds via 5-exo cyclization to give the zwitterion intermediate 16, and the elimination of MeCl gives the target product 18. We also performed DFT calculation of oxyboration to investigate the striking change in the regioselectivity between oxyboration and oxyindation. First, the calculation of oxyboration was performed for a similar oxyindation mechanism via concerted cyclization and S N 2-type elimination of MeCl from aggregated zwitterion intermediates (see Fig. S6 † in the ESI). We considered another possibility for the elimination step, because the recent theoretical investigation of ClBcat-mediated heterocyclization has shown other mechanisms, 26 whereby the Me group is attacked either by dissociated chloride 26a or by [Cl 2 -Bcat] À . 26b Thus, we considered these additional two plausible elimination steps assisted by either free Cl À or [Cl 2 Bcat] À (see Fig. S7 † in the ESI and Fig. 5 and 6). The result of comparison between these three pathways showed that the most probable path was the use of [Cl 2 Bcat] À (details of the comparison are shown in the ESI †).
The total reaction prole of oxyboration is described in Fig. 5  and 6. In that prole, 5-exo cyclization from 1a and 2ClBcat to 16 has an activation energy (27.9 kcal mol À1 ) that is lower than that of 6-endo cyclization (1a and 2ClBcat to 15, 34.4 kcal mol À1 ). The chloride moiety of zwitterion 16 coordinates to another ClBcat to provide complex 19. The chloride transfer process (19 to 20) has a low energy barrier (5.8 kcal mol À1 ), and [Cl 2 Bcat] À is generated rapidly. Cl in [Cl 2 Bcat] À approaches the methyl group in the ester moiety (20 / 21 / 22), and an elimination of MeCl (22 to 23) in the S N 2-mechanism occurs to give 5-membered product 18. The activation energy of the elimination of MeCl (22 to TS3-5-exo) is 20.7 kcal mol À1 , which allows the elimination of MeCl to proceed smoothly to give the nal product 18. The fast elimination step allows oxyboration to proceed under kinetic control to accomplish the 5-exo selective cyclization.
Comparing the transition state of the cyclization step in oxyindation with that in oxyboration based on an electrostatic potential map.
The signicant difference between oxyindation and oxyboration was investigated because each showed a characteristic energy prole, particularly for the cyclization step. The energy barrier of cyclization in oxyindation (6-endo: 19.7 kcal mol À1 , 5-exo: 15.5 kcal mol À1 ) is much lower than that of oxyboration (6-endo: 34.4 kcal mol À1 , 5-exo: 27.9 kcal mol À1 ). Therefore, the electrostatic potential maps for the transition states of cyclization (TS1-6endo and TS1-5-exo) were calculated (Fig. 7). The value of V min , which represents the most negative surface electrostatic potential, was investigated to evaluate the degree of localization for a negative charge. 27 The V min of the organoindium species (le, in Fig. 7) was less negative than that of boron (right, in Fig. 7), which showed that the negative charge was delocalized in the transition state of oxyindation compared with oxyboration. The value of V max , which is the most positive surface electrostatic potential, was also calculated and was less affected by the differences in the metals (see Table S2 † in the ESI). The polarizability of the indium, boron and heteroatoms binding to  Electrostatic potential maps were calculated on the 0.001 au isosurface of electron density for optimized structures of the transition states of oxyindation (left) and oxyboration (right). The potential is depicted by a color gradient from the most negative (red) to the most positive (blue) value (kcal mol À1 ). V min represents the most negative surface electrostatic potential. a metal explained these results. Indium and iodine atoms have large polarizability (a In ¼ 69 a.u. and a I ¼ 35.1 a.u.), 28 and the increasing negative charge in the TS1 of oxyindation was efficiently delocalized to stabilize the zwitterionic TS1-6-endo. 29 On the other hand, boron, chlorine and oxygen atoms have smaller polarizability (a B ¼ 20.5 a.u., a Cl ¼ 14.7 a.u., and a O ¼ 6.04 a.u.) 28 than indium and iodine atoms, so that TS1-5-exo becomes unstable due to the localization of a negative charge. The difference in the fundamental features between indium and boron atoms imparts a signicant amount of inuence on the regioselectivity of oxymetalation.

Summary of DFT calculation
In oxyindation (Fig. 8A), the activation energy of 5-exo cyclization is much lower than that required for the elimination of MeI to lead to reversible 5-exo cyclization. Therefore, the thermodynamically stable 6-membered zwitterion 3 was selectively produced to accomplish the remarkable 6-endo selectivity. The elimination step from 3 is a rate-determining step that provides the target metalated isocoumarin 4a. On the other hand, the energy barrier for cyclization in oxyboration (Fig. 8B) is higher than that for the elimination of MeCl and the cyclization step is a rate-determining step, which leads to irreversible 5-exo cyclization to afford the 5-membered product 18 under kinetic control. Therefore, the activation energies of cyclization as well as elimination are important factors to determine the regioselectivity in cyclization.

Application to the synthesis of isocoumarin derivatives
Our developed oxyindation was applied to the synthesis of isocoumarin derivatives. First, the gram-scale synthesis of an organoindium species was carried out. Methyl ester 1a (10 mmol) reacted with InI 3 to give organoindium 4a, and 1.14 g of isocoumarin was isolated by the addition of H 2 O (Scheme 7).
Next, the oxidation of the produced alkenylindium compounds was performed (Table 2). An oxyindation of 1a using InI 3 was carried out, and the organoindium 4a was oxidized with PhI(OAc) 2 in a one-pot procedure to give 4iodoisocoumarin 24a (entry 1). Subjecting InBr 3 to the oxidation reaction provided 4-bromoisocoumarin 25a in a high yield (entry 2). Therefore, various types of 2-alkynylbenzoates were surveyed in the sequential oxyindation/halogenation process to give 4-halogenated isocoumarins. Substrates with electron withdrawing groups such as nitro and carbonyl groups gave the target products 24b and 24c in high yields (entries 3 and 4). The structure of 24b was characterized by X-ray crystallographic analysis (see Fig. S11 † in the ESI). Substrates with methyl or aryl groups efficiently afforded the target isocoumarins 24d and 24e (entries 5 and 6). Also, 2-alkynylbenzoates, including halogen moieties (Br, Cl and F), were suitable for this reaction system to give the isocoumarins 25f-24h in moderate yields (entries 7-9). The synthesis of isocoumarins from internal alkynes was also investigated. The optimization of the reaction conditions showed that gallium salts were more suitable than indium salts for the oxymetalation of an internal alkyne (see Table S3 † in the ESI). Therefore, gallium salts were employed in the reactions of internal alkynes 1i-1k to provide the 3,4-disubstituted isocoumarins 24i, 24j and 25k (entries 10-12).
One-pot syntheses of 4-substituted isocoumarins were performed via oxyindation followed by a palladium-catalyzed crosscoupling reaction (Table 3). 30 Aer the oxymetalation of 1a using InBr 3 , the addition of a palladium catalyst, lithium chloride, organic halides 27, and an additional solvent to the resultant toluene solution afforded the coupling product 28. Iodobenzene 27a and aryl iodides bearing an electron donating group 27b or an electron withdrawing group 27c were applicable to give the 4-arylisocoumarins 28aa-28ac in high yields (entry 1). Palladium-catalyzed cross coupling with acid chlorides also proceeded efficiently. Reactions using the benzoyl chloride derivatives 27d and 27e, as well as the alkanoyl chloride 27f, afforded the isocoumarins 28ad-28af with ketone moieties in good yields (entries 2 and 3). The structure of 28ae was characterized by X-ray crystallographic analysis (see Fig. S12 † in the Scheme 7 Gram-scale synthesis of isocoumarin including a carbonindium bond. Fig. 8 The summarized results of DFT calculation. ESI). In this reaction system, alkyl halides such as benzyl bromide 27g and allyl bromide 27h were also suitable to give 4alkylisocoumarins 28ag and 28ah, respectively (entries 4 and 5). Various types of 4-substituted isocoumarins were obtained from an isocoumarin that included a carbon-indium bond by utilizing palladium-catalyzed cross coupling.

Formal total synthesis of oosponol
Finally, a formal total synthesis of oosponol, which exhibits strong antifungal activity, 15 was conducted (Scheme 8). Firstly, the iodination of commercially available compound 29 proceeded via a method found in the literature. 31 During the initial investigation, 30 was transformed into methyl 2-ethynyl-6methoxybenzoate, and then we attempted the synthesis of the precursor of oosponol via oxyindation and cross-coupling, but the reaction returned a complicated mixture (see Scheme S1 † in the ESI). Therefore, in another synthetic route, the OMe group  of 29 was converted to an OAc group with less ability to donate electrons. The OMe moiety of 30 was completely deprotected with BBr 3 . The acid-catalyzed esterication and acetylation of the phenol moiety gave methyl 6-iodoacetylsalicylate 33 in a high yield. Sonogashira coupling followed by the removal of a silyl moiety afforded the desired 2-alkynylbenzoate derivative 35. The oxymetalation of 35 using InBr 3 and sequential palladium-catalyzed cross coupling with acid chloride 27i produced the key intermediate 36, and the hydrolyzation of 36 yielded oosponol. 16b Our method used a readily available starting material and gave a higher yield than previous studies. 16b,32

Conclusions
We achieved the synthesis of isocoumarins bearing a metalcarbon bond at the 4-position via 6-endo selective oxymetalation of 2-alkynylbenzoate 1 (Type endo-t). Indium and gallium salts showed high activity for the oxymetalation of 2-ethynylbenzoate 1a. Both the metalated isocoumarin 4b and the zwitterion intermediate 3 were identied by X-ray crystallographic analysis. This is the rst example of the isolation of the product E and the benzopyrylium intermediate F proposed in the mechanism of oxymetalation (Scheme 2A). The elimination of MeI from zwitterion 3 occurred under heating conditions to give the target product 4a, which means that the rate-determining step was the elimination step. DFT calculation suggested that thermodynamic control led to 6-endo selective oxyindation, while kinetic control led to 5-exo selective oxyboration. The 6membered product proved much more stable than the 5membered product due to a difference in the degree of aromatic stability. The investigation of the electrostatic potential of the transition state in the cyclization pathway suggested that a delocalization of negative charge by the large atomic radii of In and I atoms stabilizes the zwitterionic transition state. In contrast, the small atomic radii of B, Cl, and O atoms cause a localization of negative charge to destabilize the corresponding transition state. The difference in stability between the 6and 5-membered zwitterions and the elemental character of InI 3 both played important roles in the unique regioselectivity of oxymetalation and in the facile preparation of the E species. These isocoumarins bearing a carbon-metal bond at the 4position were applied to organic synthesis. Oxymetalation provided isocoumarins on a gram scale. The oxidation of organoindium or gallium species yielded various types of 4halogenated isocoumarins. Palladium-catalyzed cross coupling with aryl iodide, acid chloride, and alkyl bromide gave a wide range of 4-substituted isocoumarins in a one-pot reaction. Therefore, the unprecedented regioselectivity of the present oxymetalation contributed to the synthesis of new types of isocoumarins. We accomplished a formal total synthesis of oosponol to demonstrate the utility of our reaction system.

Conflicts of interest
There are no conicts to declare.