A One-Step, Versatile Synthesis of Dibenzo [n.2.2] Macrobicyclic Compounds via a Conformation-Directed Macrocyclization Reaction

Abstract

A series of dibenzo [n.2.2] bicyclic compounds (n = 2-20) were prepared in one step and good yields starting from dimethyl anthracene-9,10-dicarboxylate. Reduction of the aromatic diester using lithium/naphthalene led to a bis-enolate that was cyclized with a variety of bis-electrophiles. The ease of the cyclization is probably due to the puckered conformation of the intermediate formed after the first alkylation step, in which the newly introduced chain that will become the bridge portion occupies a pseudoaxial position, positioning the leaving group close to the enolate nucleophile in the macrocyclization step.

Macrocyclization Reactions: The Importance of Conformational, Configurational, and Template-Induced Preorganization

“…The excellent macrocyclization yields observed can be attributed to the puckered conformation of the reaction intermediate 269b formed after the first alkylation step that provides an appropriate geometry for the macrocyclization step ( Figure 80). 280 Interestingly, in the case of using flexible subunits in the electrophile, yields were higher for the generation of smaller and larger rings, being smaller for medium-sized rings (0% for 268f with n = 5, i.e., Br(CH 2 ) 5 Br). Davis and co-workers have described the synthesis of the [2 + 2] macrocyclic tetraamides 273a and 276 and also the [3 + 3] macrocycle 273b, under pseudo-high-dilution conditions using diamines 272 and 275 and activated diacids 271 and 274 as the building blocks ( Figure 81).…”

C–C Bond-Forming and Bond-Breaking Processes from the Reaction of Diesters with Me3SnLi. Synthesis of Complex Bridged Polycycles and Dialkyl Aromatic Compounds

“…The flask was capped with a second septum and cooled to −78 °C. A solution of anthracene diester 38 (200 mg, 0.68 mmol) in THF (1.8 mL) was added, the reaction mixture was stirred for 3 h at −78 °C, and then the corresponding electrophile (220 mol %) was added. The reaction mixture was stirred for 24 h while slowly warming to room temperature.…”

“…Mp 129.4−131.0 °C (CH 2 Cl 2 -hexane); 1 H NMR (500 MHz, CD 2 Cl 2 ) δ 7.20 (m, 3H), 7.08 (m, 1H), 6.50 (d, J = 9.5 Hz, 1H), 5.99 (d, J = 9.6 Hz, 1H), 5.77 (dddt, J = 10.3, 4.1, 3.3, 2.1 Hz, 1H), 5.65 (dtt, J = 9.5, 3.8, 2.0 Hz, 1H), 3.67 (s, 3H), 3.53 (s, 3H), 2.94 (ddq, J = 18.3, 4.0, 2.1 Hz, 1H), 2.70 (dddd, J = 18.3, 5.4, 3.0, 2.2 Hz, 1H), 2.63 (dddd, J = 18.7, 5.3, 3.2, 2.2 Hz, 1H), 2.25 (ddq, J = 18.7, 4.3, 2.2 Hz, 1H); 13 C{ 1 H} NMR (75 MHz, CDCl 3 ) δ 174. 3, 173.6, 137.3, 133.3, 132.4, 128.9, 128.3, 127.3, 127.1, 126.5, 125.0, 124.4, 52.5, 52.5, 52.2, 48.0, 33.3, 33.2 Dimethyl cis-7,12-dihydrotetraphene-6a,12a-dicarboxylate (11). Following general procedure A and using 1,2-bis(chloromethyl)benzene (75 mg, 0.43 mmol) as the electrophile, compound 11 was isolated as a white solid after column chromatography (71 mg, 50%).…”

“…By using this last type of methodology, we have studied the synthesis of fused bicyclic compounds from aromatic diesters in a one-pot dearomatization-bisalkylation reaction. This transformation can be realized in two ways: (a) through a nucleophilic-stanna-Brook rearrangement pathway, by using of (trialkylstannyl)­lithium reagents, , or (b) by reductive means using alkaline metals. , In both cases, a bis -enolate intermediate is formed, which is trapped with a suitable bis -electrophile. For heteroaromatic diesters (pyridine, furane, or benzofurane) better results are obtained with trialkyltinlithium reagents, but for all-carbon aromatic diesters both routes lead to similar yields of the desired bicyclic products, and the later is preferable as hazardous tin reagents are avoided.…”

Bis-enolates with Extended π-Conjugation Are Powerful Nucleophiles: A Study of Their Alkylation Reactions with Very Hindered C-Electrophiles

“…2 These alkylations occur regioselectively, with the C−C bond formation taking place at both the α positions of the enolate moieties, resulting in two adjacent quaternary centers being formed in the process. Reductive alkylation with different primary bis-electrophiles was achieved starting from anthracene 4 and naphthalene 5 diesters as well to give a variety of fused and bridged polycycles. Although two possible nucleophilic sites are available in these dianionic species, αor γto each enolate group, exclusive α-alkylation was always observed when primary halides or tosylates were used as electrophiles (Scheme 1).…”