Investigating the stereochemical outcome of a tandem cyclization - coupling reaction leading to a 3-arylmethylideneisobenzofuran-1-one

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Introduction
2][3] In addition, tandem reactions offer a number of ancillary environmental benefits over the corresponding stepwise processes including fewer synthetic transformations, work-ups, purification steps, and less waste. 2 The cyclization of heteroatom nucleophiles onto pendant alkynes mediated by Pd(II)-arene species represents an important type of tandem reaction that has been utilized to prepare a wide variety of heterocycles. 4,5For the tandem cyclization-coupling reaction of 2-ethynylbenzoic acid derivatives A, there are three possible regiochemical and stereochemical outcomes (Scheme 1): (1) product type B via a 5-exocyclization with anti arrangement of the nucleophilic and Pd(II) moieties; (2) product type C via a 5-exocyclization with syn arrangement of the nucleophilic and Pd(II) moieties; and (3) product type D via a 6-endocyclization.A possible mechanism for the transformations leading to the type B products is as follows: 4,5 (i) oxidative addition of haloarenes generating a Pd(II)-arene species; (ii) coordination of the Pd(II)-arene species with the alkyne; (iii) cyclization onto the Pd(II)-coordinated alkyne by a proximate heteroatom nucleophile; and (iv) reductive elimination giving C.

Scheme 1. Stereochemical and regiochemical outcomes of tandem cyclization-coupling reaction of A.
This transformation has been studied in a few systems previously, by others with differing results.Rossi and co-workers reported that the cyclization-coupling of 2-ethynylbenzoic acid A (Y = O; R 1 = propyl) with iodoarenes led to a mixture of isobenzofuran-1-ones B and isochromen-1-ones D where structures B were the major products. 6Balme and co-workers reported an intramolecular cyclization-coupling variation which also led primarily to 5-exo products B. [7][8][9] Also of note are tandem cyclization-coupling reactions involving antiadditions of acyclic substrates (β-alkynylcarboxylic acids) that have been reported to give monocyclic 5-exo products structurally related to B. [10][11][12][13][14][15][16][17] On the other hand, there are fewer reports of this type of tandem cyclization-coupling reaction involving syn-additions of acyclic substrates.In a palladium-catalyzed cyclizationcoupling reaction involving β-alkynylcarboxamides, Hiemstra and co-workers obtained 5-exo products structurally related to C (Y = N-alkyl; R 1 = SiMe3) that resulted from syn-additions across the alkynes. 18e set out to explore a palladium-mediated tandem cyclization-coupling strategy that could contribute to a novel strategy aimed at the total syntheses of the aristolactam alkaloids 1. Aristolactam alkaloids are highly oxygenated phenanthrene lactam natural products 19,20 that display modest biological activity including anticancer activity (Figure 1). 21Some previously reported synthetic approaches to the aristolactam alkaloids include: (1) photocyclization of isoindolinones; 22 (2) iodocyclization of alkynylbenzamide; 23 (3) Horner olefination-radical cyclization; 24,25 (4) intramolecular aryne cycloaddition; 26,27 (5) carbonylation of aminophenanthrenes; 28 and ( 6) tandem Suzuki coupling-aldol condensation. 29In our retrosynthetic analysis aimed at the construction of the aristolactam alkaloids (Scheme 2), the fused lactam ring can be derived from an amidation of the corresponding fused lactone ring. 30Next, by taking advantage of the electron-donating groups present in all of the aristolactam congeners, formation of the Cring might be possible via an oxidative cyclization [31][32][33] of (E)-arylmethylideneisobenzofuran-1-ones 2 (phthalides).Kita 34,35 and others 36.38 have demonstrated the use of the hypervalent iodine reagent phenyliodine(III) bis(trifluoroacetate) (PIFA) in oxidative cyclizations leading to electron-rich phenanthrenes.Inspired by the precedent discussed at the outset, phthalides 2 would arise from the tandem cyclizationcoupling reaction between 2-ethynylbenzoic acids and iodoarenes.Scheme 2. Proposed approach to aristolactam alkaloids.

Results and Discussion
We commenced our study with the synthesis of o-ethynylbenzoic acid substrates 3.After some experimentation, we settled on 2-ethynylbenzoic acid 3a, which was prepared following a five-step sequence (Scheme 3): (i) iodination 39 of piperonyl alcohol giving the known 6-iodopiperonyl alcohol; 40 (ii) PCC oxidation giving the known 6-iodopiperonal; 41 (iii) oxidative conversion 42,43 to the corresponding ester with iodine in the presence of methanol to give the known methyl 6-iodopiperonylate; 44 (iv) Sonogashira cross-coupling 45 to the triisopropyl-substituted alkyne; and (v) hydrolysis of the methyl ester with hydroxide giving 3a.We found it necessary to cap the alkyne moiety with a triisopropylsilyl group; structurally related substrates 3b or 3c were not stable and readily produced the corresponding 3-methylidenephthalide 46 or keto hydrolysis product 47 under mildly acidic or basic conditions (see Experimental Section); this same problem was also observed by Boger and Wolkenberg. 47heme 3. Synthesis of o-ethynylbenzoic acid substrate 3a.
With 3a in hand, we next explored tandem cyclization-coupling reactions (Scheme 4).Using a modification of the conditions previously reported by Rossi and co-workers for the tandem cyclization of 2-(1'butynyl)benzoic acid, treatment of 3a and p-iodoanisole with Pd(PPh3)4 in the presence of potassium carbonate in MeCN/DMSO gave a ~5:1 mixture of two isolable products (note: omission of DMSO significantly diminished the yield).We presumed the major product to be the expected anti-addition product 2a by analogy and the minor product to be the syn-addition product 4a.Purification by column chromatography gave the major product in 57% yield (average yield of six runs).Spectroscopic ( 1 H and 13 C NMR) and analytical data (CHN and HRMS) for the major product were consistent with the presumed structure 2a.Scheme 4. Tandem cyclization-coupling reaction of 3a.
We next attempted an oxidative ring closure of the C-ring.In the event, treatment of the major product (2a or 4a) of the tandem cyclization-coupling reaction with PIFA and boron trifluoride-etherate at -70 °C did not give the expected oxidative cyclization product, phenanthrene 5 (Scheme 5).Instead, the reaction led to an isomerization of the major tandem product (at this point, presumably 2a) to the minor tandem product (at this point, presumably 4a).Harsher reaction conditions (rt) led to decomposition of the starting material and no identifiable products.Scheme 5. Attempted oxidative cyclization.
The independent synthesis of 2b utilized the iodocyclization method developed by Larock and co-workers (Scheme 7). 45Substrate 6 was prepared by Sonogashira alkynylation of methyl 6-iodopiperonylate (available from our synthesis of 3).Treatment of 6 with iodine led to 3-methylideneisobenzofuran-1-one 7 via an iodocyclization.Suzuki-Miyaura cross-coupling of 7 with p-methoxyphenylboronic acid gave the expected isobenzofuran-1-one 2c.Desilylation of 2c then gave 2b.Unexpectedly, 2b was not identical to the material derived from the desilylation of the major product of the tandem cyclization-coupling reaction.Thus, our tandem reaction did not give the anti-addition product observed in the closely related system by Rossi and co-workers. 6Scheme 7. Independent synthesis of (E) product 2b.
We next turned our attention to the independent synthesis of stereoisomer 4b.The synthesis of 4b utilized the method developed by Terada and Kanazawa (Scheme 8) for the synthesis of (E)-arylmethylideneisobenzofuran-1-ones by 5-exo-cyclization of the corresponding o-alkynylbenzoates. 48,49Sonogashira crosscoupling of methyl 6-iodopiperonylate (8) with 4-ethynylanisole produced alkyne 9a.Mild hydrolysis of 9a with lithium hydroxide gave benzoic acid 9b.Treatment of 9b with DBU led to the formation of known isobenzofuran-1-one 4b. 50Compound 4b turned out to be identical to the desilylated material derived from the major tandem cyclization-coupling product.Overall, these independent syntheses provide excellent support that our original tandem cyclization-coupling reaction of 3 led to a mixture of 4a and 2a where the syn-addition product 4a was the major product.Scheme 8. Independent synthesis of (Z) product 4b.
Although we observed the syn-addition product 4a as the major product from our palladium-mediated tandem reaction, we were still able to achieve a synthesis of the desired (E)-arylmethylideneisobenzofuran-1one 2b (Scheme 9).Treatment of 4a with PIFA led to the formation of 2a via an alkene isomerization (presumably via a radical intermediate).The spectral data obtained for isomerization product 2a matched spectral data obtained for the minor product of the original tandem cyclization-coupling reaction involving 3a.Finally, desilylation of 2a by treatment with TBAF gave 2b.As discussed above, 2b matched the material prepared utilizing the Larock iodocyclization methodology (Scheme 7).Scheme 9. Overall results.Scheme 10.Mechanism to major product 4a.
Given the stereochemical outcome that we observed with the tandem cyclization-coupling reaction of 3a, we propose the following mechanism for the formation of 4a (Scheme 10).This type of mechanism was suggested by Hiemstra and co-workers in a similar system. 18The mechanism consists of four steps: (i) oxidative addition of haloarenes generating a Pd(II)-arene species; (ii) nucleophilic substitution of the Pd(II)arene species with the carboxylic acid; (iii) syn-oxypalladation across the alkyne; and (iv) reductive elimination giving 4a.

Conclusions
In summary, we have developed new methodology that can be utilized to prepare both (Z)-and (E)arylmethylideneisobenzofuran-1-ones.The tandem cyclization-coupling reaction of 3a with p-iodoanisole gave a ~5:1 mixture of the syn-addition product 4a and the anti-addition product 2a, respectively.A novel PIFA-mediated E/Z isomerization was discovered that converted 4a into 2a.We plan to further investigate the use of the isobenzofuran-1-ones prepared for the synthesis of complex heterocycles including the aristolactam alkaloids.

Experimental Section
General. 38All reactions were performed under a positive atmosphere of argon with magnetic stirring unless otherwise noted.Tetrahydrofuran (THF) and dichloromethane (CH2Cl2) were purified by passage through a column of alumina utilizing a PureSolv 400 solvent purification system.Unless otherwise indicated, all other reagents and solvents were purchased from commercial sources and were used without further purification. 1H NMR and 13 C NMR chemical shifts are reported in parts per million (ppm δ) using the residual proton or carbon signal of the solvent (CDCl3: δ 7.26 ppm, C δ 77.3 ppm; d6-DMSO: H δ 2.50 ppm, C δ 39.5 ppm) as an internal reference.Flash chromatography was performed with silica gel (230-400 mesh), and thin-layer chromatography (TLC) was performed with glass-backed silica gel plates and visualized with UV (254 nm).IR spectra were measured utilizing an infrared spectrometer fitted with an ATR (attenuated total reflectance) sampler.High resolution mass spectra (HRMS) were obtained using a Fourier transfer ion cyclotron resonance (FTICR) mass spectrometer and electrospray ionization (ESI). 40A modification of a literature procedure was followed. 39To a 0 °C stirred solution of piperonyl alcohol (5.00 g, 32.9 mmol) and silver trifluoroacetate (8.71 g, 39.4 mmol) in CHCl3 (80 mL) in the dark (aluminum foil wrapped flask) was added a solution of I2 (10.01 g, 39.44 mmol) in MeOH (90 mL) dropwise via an addition funnel.The reaction mixture was stirred at 0 C for 2 h and then at rt for an additional 22 h.The reaction mixture was filtered through Celite and the Celite layer was washed with CHCl3 (2 x 50 mL).The solvent was removed in vacuo and the crude material obtained was taken up in CH2Cl2 (100 mL).The organic layer was washed with a saturated aqueous solution of Na2S2O3 (3 x 100 mL) and then dried over Na2SO4.Removal of the solvent in vacuo gave the title compound ii (8.27 g, 29.7 mmol, 91% yield), which was used without further purification.Off-white amorphous solid.mp 110-111 °C (lit. 39110-111 mp °C).1 A modification of a literature procedure was followed. 41To a stirred solution of 6-iodo-1,3-benzodioxole-5-methanol (ii) (3.10 g, 11.2 mmol) in CH 2 Cl 2 (100 mL) at 0 °C was added pyridinium chlorochromate (PCC) (4.81 g, 22.3 mmol).The reaction mixture was stirred at 0 °C for 2 h and then for an additional 16 h at rt by which time TLC showed complete conversion.The reaction mixture was filtered through a short plug of silica gel.The silica gel was washed with additional CH2Cl2 (100 mL).The combined organic layers were dried over Na2SO4 and removal of the solvent in vacuo gave the title compound iii (2.67 g, 9.67 mmol, 87% yield), which was used without further purification.Off-white amorphous solid.mp 108-109 °C (lit. 41 Methyl 6-iodo-1,3-benzodioxole-5-carboxylate (8). 41,44A modification of a literature procedure was followed. 42To a 0 °C stirred solution of KOH (0.800 g, 14.5 mmol) in MeOH (50 mL) was added a solution of 6iodo-1,3-benzodioxole-5-carboxaldehyde (iii) (0.500 g, 1.81 mmol) in MeOH (80 mL) followed by solid I2 (1.84 g, 7.24 mmol).The reaction was mixture was stirred at 0 °C for 2 h and then at rt for an additional 14 h.The reaction mixture was treated with solid Na2S2O3until the brown color dissipated.The bulk of the solvent was removed in vacuo and the residue was taken up in CH2Cl2 (100 mL).The organic layer was washed with a saturated solution of Na2S2O3 (2 x 100 mL), brine (100 mL), and dried over Na2SO4.Removal of the solvent in vacuo gave a crude yellow solid (0.59 g).Purification by flash chromatography (1:20 EtOAc/petroleum ether to 1:10 EtOAc/petroleum ether) gave the title compound 8 (0.510 g, 1.67 mmol, 92% yield).Off-white amorphous solid.mp 83-85 °C (lit. 41 Methyl 6-(trimethylsilylethynyl)-1,3-benzodioxole-5-carboxylate (6).A modification of a literature procedure was followed. 42To a stirred solution of methyl ester (8) (0.500 g, 1.63 mmol) and TMS-acetylene (0.460 mL, 3.26 mmol) in Et3N (15 mL) at rt was added Pd(PPh3)2Cl2 (0.110 g, 0.163 mmol) and CuI (6 mg, 0.03 mmol) with stirring.The reaction mixture was heated to 55 C for 23 h.The resulting solution was filtered through a plug of Celite (washing with excess CH2Cl2) and the filtrate was washed with 1.0 M HCl (2 x 75 mL) and brine (150 mL).Solvent was removed in vacuo giving a crude brown solid (0.57 g).Purification by flash chromatography ( Methyl 6-ethynyl-1,3-benzodioxole-5-carboxylate (iv). 47To a stirred solution of methyl ester (6) (0.500 g, 1.81 mmol) in MeOH (10 mL) at rt was added K2CO3 (0.500 g, 3.62 mmol) and the reaction was monitored by TLC (1:8 EtOAc/petroleum ether).After 0.5 h, TLC showed complete conversion.The solvent was removed in vacuo giving a crude solid (0.97 g).Purification by flash chromatography (1:15 EtOAc/petroleum ether to 1:5 EtOAc/petroleum ether) gave the title compound iv (0.240 g, 1. 18

6-Acetyl-1,3-benzodioxole-5-carboxylic acid (v)
. 47 To a rt stirred solution of ester iv (0.050 g, 0.24 mmol) in THF (5 mL) was added a mixture of LiOH•H2O (0.050 g, 1.2 mmol) in MeOH (5 mL) and H2O (5 mL).The reaction mixture was heated to 40 °C for 19 h and then the solvent was removed in vacuo.The crude orange residue was taken up in H2O (50 mL) and the resulting aqueous solution was washed with Et2O (50 mL).The aqueous layer was then acidified by the addition of an aqueous HCl (1.0 M, 2 mL) and then was extracted with EtOAc (2 x 50 mL).The combined organic layers were ashed with brine (100 mL) and dried over Na2SO4.Removal of the solvent in vacuo gave the title compound v (42
6-((4-Methoxyphenyl)ethynyl)-1,3-benzodioxole-5-carboxylic acid (9b).To a rt stirred solution of ester 9a (0.224 g, 0.722 mmol) in THF (10 mL) was added a solution of LiOH monohydrate (0.151 g, 3.61 mmol) in MeOH (5 mL) and H2O (5 mL).The reaction mixture was heated to 50 °C for 40 min by which time TLC showed incomplete conversion to product along with the formation of two UV-active by-products.At this point, the solvent was removed in vacuo giving a brown residue which was taken up in H2O (30 mL).The aqueous layer was washed with Et2O (2 x 30 mL) and then acidified by the addition of an aqueous solution of HCl (1.0 M, 3 mL).The acidified aqueous layer was extracted with CH2Cl2 (2 x 30 mL).The combined organic layers were washed with brine (60 mL) and dried over Na2SO4.Removal of the solvent in vacuo gave a yellow film (0.201 g).Trituration (CH2Cl2/petroleum ether) of the yellow film gave title compound 9b (note: flash chromatography of a different batch led to decomposition of this material).Light green amorphous solid.mp 170-174 °C.Rf 0.30 (  50 A modification of a literature procedure was followed. 48To a rt stirred solution of carboxylic acid 9b (0.050 g, 0.17 mmol) in MeCN (2 mL) was added DBU (1 drop, catalytic).The reaction mixture was stirred at 80 °C for 2.5 h and then allowed to cool to rt.Removal of the solvent in vacuo gave a crude solid product (0.10 g).Purification by flash chromatography (1:4 EtOAc/petroleum ether) gave the title compound 4b (0.029 g, 0.10 mmol, 58% yield), which gave spectral data that matched the material obtained by desilylation of 4a (vide supra).