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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Synthesis of 2‑Aryloxy-1,3-dienes from Phenols and Propargyl Carbonates Naoki Ishida, Yusaku Hori, Shintaro Okumura, and Masahiro Murakami* Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510, Japan
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carried out the following experiments to track the relocation of the constituent atoms. A reaction of 2-naphthyl propargyl ether 3 in tBuOD gave the deuterium-incorporated diene 4-d3 with a high D/H ratio (92%) on the 3-carbon (Scheme 2),5
ABSTRACT: A convenient method for the synthesis of 1,3-dienes from readily available compounds is reported. 2-Aryoxy-1,3-dienes are produced stereoselectively by a nickel-catalyzed reaction of propargyl carbonates with phenols. Functional group tolerance is broad to allow iodo, formyl, and boryl groups. The resulting 1,3-dienes are of much synthetic value because they can participate in a wide variety of reactions, including the Diels−Alder reaction.
Scheme 2. Deuterium Labelling Experiments
1,3-Dienes serve as versatile building blocks to rapidly increase molecular complexity.1 Electronic perturbation by oxysubstituents amplifies their reactivities and also dictates the regioselectivities. Although a number of synthetic methods of 1,3-dienes are currently available,2 those for 2-aryloxy-1,3dienes remain only a few with a significantly limited substrate scope.3 We now report a convenient method to synthesize 2aryloxy-1,3-dienes from propargylic carbonates and phenols. A broad range of phenol derivatives including tyrosine and βestradiol afforded the corresponding 2-aryloxy-1,3-dienes. The present study began with a finding of a nickel-catalyzed skeletal isomerization reaction of aryl propargyl ether 1 (Scheme 1). When 1 was treated with Ni(cod)2 (5 mol %)
indicating that the hydrogen comes from the tBuOD solvent rather than the terminal methyl group of 3. Next, the CD3substituted propargyl naphthyl ether 3-d3 was subjected to the isomerization reaction. Two deuterium atoms stayed at the 4position, indicating that the aryloxy group undergoes 1,2migration. Thus a pathway through 1,3-aryloxy migration forming an allenyl aryl ether, followed by transposition of the double bond, seemed unlikely. The experimental results mentioned above are explained by assuming a reaction pathway involving the formation of the nickellacyclobutene intermediate6 (Scheme 3), which is analogous to that proposed for palladium-catalyzed reactions of propargyl carbonates with nucleophiles.7 Initially, 1 undergoes oxidative addition onto nickel(0).8 The propargylic carbon−oxygen bond is cleaved to afford the cationic πallenylnickel(II) complex A9 and an aryloxide anion. The aryloxide attacks the central carbon of the π-allenyl ligand10 to give rise to nickellacyclobutene B. This site-selective nucleophilic attack on the central carbon accounts for the 1,2-aryloxy migration. Subsequent protonolysis of the C(sp2)− Ni bond with tBuOH gives the π-allylnickel intermediate C.11 This site-selective protonolysis explains the deuterium incorporation at the 3-position in Scheme 2a. The tertiary butoxide picks up the hydrogen of the terminal methyl group
Scheme 1. Isomerization of Propargylic Ester 1 to 2Aryloxy-1,3-diene 2
and DPPF (8 mol %) in tBuOH at 40 °C for 24 h, 2-aryloxy1,3-diene 2 was formed quantitatively (1H NMR). The subsequent bulb-to-bulb distillation afforded 2 in 85% isolated yield. The yield of 2 varied depending on the phosphine ligand.4 Whereas DPPB also gave 2 quantitatively, lower yields were observed with other diphosphine ligands such as DPPE and DPPPent. Cyclotrimerization of the alkyne moiety was the major pathway when monodentate ligands such as PCy3, IPr, and ItBu were used. In a formal sense, the phenolic oxygen migrates from the propargylic carbon to its adjacent carbon, and a hydrogen migrates from the terminal methyl carbon to its adjacent carbon through the skeletal isomerization reaction. We next © XXXX American Chemical Society
Received: October 16, 2018 Published: December 19, 2018 A
DOI: 10.1021/jacs.8b11159 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Communication
Journal of the American Chemical Society
intermediate B would be protonated by p-methoxyphenol (8), which is more acidic than tBuOH.14 The resulting phenoxide anion subsequently acts as the base to deprotonate the hydrogen of the terminal methyl group to produce the 1,3diene 2.15 A variety of substituted propargyl carbonates were subjected to the reaction with p-methoxyphenol (8) (Table 1). Carbonate 10, which was an isomer of 9 having a terminal alkynyl group, afforded 2, the identical product to that
Scheme 3. Proposed Mechanism
Table 1. Scope of Propargyl Carbonatesa
to furnish the 1,3-diene 2 and tBuOH along with the regeneration of the Ni(0) species.12 A crossover experiment using 3 and 5 gave a mixture of the 2-aryloxy-1,3-dienes including the crossover products 6 and 2 (Scheme 4), proving that the propargyl (1,3-diene) moiety and Scheme 4. Crossover Experiment
a phenoxy group were combined intermolecularly. This result prompted us to examine an intermolecular reaction of pmethoxyphenol (8) with a tertiary butyl carbonate of propargyl alcohol 9 (Scheme 5).13 The phenol and the propargyl Scheme 5. Addition of p-Methoxyphenol (8) to Propargyl Carbonate 9
moieties were intermolecularly coupled to furnish the 2aryoxy-1,3-diene 2 in 82% yield. Mechanistically, the initial oxidative addition generates the cationic π-allenylnickel complex together with the carbonate anion. The carbonate anion undergoes decarboxylation, and the resulting tertiary butoxide acts as the base to form a phenoxide anion from 8. The cationic π-allenylnickel intermediate A thus generated follows the pathway analogous to the one shown in Scheme 3 incorporating the phenoxide anion. The nickellacyclobutene
a Reaction conditions: p-methoxyphenol (8) (1.65 mmol, 1.1 equiv), propargyl carbonates (1.5 mmol, 1.0 equiv), Ni(cod)2 (0.075 mmol, 5 mol %), DPPF (0.012 mmol, 8 mol %), tBuOH (7.5 mL), 80 °C, 24 h. Isolated by bulb-to-bulb distillation. b40 °C.
B
DOI: 10.1021/jacs.8b11159 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Communication
Journal of the American Chemical Society
reacted at the hydroxy group chemoselectively, and the N−H moiety remained intact (38). The two hydroxy groups of dihydroquinone (39) both reacted with the carbonate 9 (2.2 equiv) to produce bis(1,3diene) 40 (Scheme 6). Analogously, benzophenone-tethered bis(1,3-diene) 42 was synthesized from 4,4′-dihydroxybenzophenone (41).
obtained from the carbonate 9, in 53% yield (entry 1). This result is consistent with the mechanism involving π-allylnickel intermediate C proposed in Scheme 3. The reaction of the carbonate of pent-3-yn-2-ol 11 gave the 1,3-pentadiene 7 in 92% yield with the Z/E ratio of 95/5 (entry 2). The Z selectivity can be ascribed to the predominance of the synisomer over the anti-isomer with the π-allylnickel intermediate D (Chart 1). The carbonate of pent-2-yn-1-ol 12 gave rise to
Scheme 6. Synthesis of Bis(dienyloxy)arenes
Chart 1. π-Allylnickel Intermediates
the 1,3-pentadiene (E)-13 in a stereoselective fashion (entry 3). The carbonate of the hex-3-yn-2-ol 14 furnished 1,3hexadiene 15 in preference to 2,4-hexadiene 16 (15/16 = 94/ 6) (entry 4). An analogous isomeric ratio of 15/16 was observed with the 1,3-dienes resulting from the carbonate of hex-2-yn-3-ol 17 (entry 5). These results are accounted for by assuming that an aryloxide attacks the methyl side in preference to the sterically more congested ethyl side with E (Chart 1). 1,3-Hexadiene 19 was exclusively formed from the carbonate 18 (entry 6), with which the difference in steric congestion between methyl and isopropyl groups was larger with F (Chart 1). The propargyl carbonate 21 having a phenyl substituent was an eligible substrate to stereoselectively furnish diene 22 (71%) (entry 7). A diverse array of phenols successfully participated in the reaction with the carbonate 9 (Table 2). Of particular note is the broad functional group tolerance; even iodo (29), formyl (30), and boryl (35) functionalities survived under the present reaction conditions. Sterically congested ortho-substituted phenols could also be employed (36 and 37). 4-Hydroxyindole
Interestingly, it was possible to derive 2-aryloxy-1,3-dienes from naturally occurring compounds equipped with a phenolic hydroxy group (Scheme 7). Umbelliferone (43), which is a Scheme 7. Dienylation of Natural Products
Table 2. Dienylation of Alcoholsa
coumarin natural product, produced 1,3-diene 44 in 68% yield. Eugenol (45) afforded the corresponding 2-aryloxy-1,3-diene 46 without transposition of the carbon−carbon double bond of the allylbenzene moiety. With 17β-estradiol (47), the phenolic hydroxy group selectively formed an ether linkage to 1,3-diene, and the hydroxy group at the D ring remained untouched. Protected tyrosine 49 successfully reacted with 9 to furnish 1,3-diene 50 with the integrity of the stereochemistry of the αcarbon center.
a
Reaction conditions: phenol (1.65 mmol, 1.1 equiv), propargyl carbonate 9 (1.5 mmol, 1.0 equiv), Ni(cod)2 (5 mol %), DPPF (8 mol %), tBuOH (0.2 M), 80 °C, 24 h. Isolated by bulb-to-bulb distillation. b0.20 mmol scale. Isolated by column chromatography on diol-modified silica gel. C
DOI: 10.1021/jacs.8b11159 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Journal of the American Chemical Society
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In addition to phenol derivatives, other oxygen nucleophiles such as alkanols and a silanol also produced the corresponding dienes 51−54, albeit in moderate yields with the use of 5.0 equiv of the nucleophile, except for the case of 53 (Table 3). When nitrogen nucleophiles like indazole were used, the corresponding dienes were formed in
