6,7‐Benzotropolone Syntheses Based on Ring‐Closing Metatheses and Four‐Electron Oxidations

Abstract

Four homoallyl ortho-vinylaryl ketones (10a-d) -1,8dienes of sorts -were prepared by several approaches. In the presence of 1-2 mol-% Grubbs-II catalyst, they ring-closed to give 6,7-dihydrobenzocyclohepten-5-ones (11a-d) in 90-96 % yield. With SeO 2 the parent compound (11a) delivered benzocyclohepten-5-one (13a) and/or selenium-containing compounds (18)(19)(20)(21)(22) but no more than traces of 6,7-benzotropolone (5a). However, 5a was accessible from compound 11a via the sodium enolate and allowing it to react with a stream of oxygen [a] Scheme 1. Top: our previously established ring-closing olefin metathesis ("RCM")/ketal hydrolysis route to type-5 6,7-benzotropolones. [9] Underneath: regiocomplementary processings of a type-4 RCM product via the dibromide 7 and the bromoolefins 7 or iso-7 by cross-couplings and hydrolyses giving type-8 or type-iso-8 6,7-benzotropolones, respectively. [10] The Arican routes of Scheme 1 have a major drawback, though, namely the harsh conditions required for hydrolyzing a type-4 ketal in the last step: Liberating the enol required refluxing with 10 equiv. of tosic acid and 100 equiv. of water in acetonitrile for 1 h -2 d. [9,10] These conditions were applicable to certain type-9 or type-iso-9-ketals, as well ( Figure 2). When their substituent R was Et, Ph, CO 2 Me or CO 2 Et, such hydrolyses also proceeded well. [9] However, when their substituent R was CH=CH-CO 2 iPr (in 9a or iso-9a), HC=CH 2 (in 9c or iso-9c) or C≡C-SiMe 3 (in iso-9c) the substrate vanished under hydrolysis conditions without delivering any benzotropolone. [9,10] The C≡C-SiMe 3 -containing ketal 9b was an in-between-case: Its hydrolysis released a benzotropolone as expected but the sidechain R had been converted into C(=O)-CH 3 . [10] Eur.2930 Scheme 2. Can 6,7-benzotropolones 5 be reached via an RCM/oxidation route rather than via the RCM/hydrolysis route of Scheme 1? A 4-e 2 oxidation 11 → 5 would be required overall, but two 2-e 2 oxidations 11 → 12 and 12 → 5 might be used as an alternative. 5.We wondered whether step 2 might be disadvantaged vs. a dehydration delivering the benzotropone 13. While 13 looks like a dead-end at first, it might be re-routable towards 5. This is because unsubstituted benzotropone (13, all R = H) gave unsubstituted benzotropolone (5, all R = H) by endoperoxide formation and an ensuing reduction with thiourea. [11] Consequently, benzotropones 13 appeared as conceivable intermediates of our Scheme-2 strategy towards benzotropolones. A Modified Synthesis of 6,7-BenzotropoloneOur proof-of-principle benzotropolone synthesis by the approach of Scheme 1 delivered the parent compound 5a and is shown in Scheme 3 and Scheme 5. Scheme 3 advances to the RCM product and Scheme 5 supplements its oxidation. Scheme 3. Reaching the RCM product 11a, our synthetic precursor of unsubstituted benzotropolone (5a).Our synthesis began by a salt-free Wittig methylidenation of ortho-bromobenzaldehyde (14, Scheme 3). [12] The resulting ortho-bromostyrene (15) was treated sucessively with nBuLi and the...

Syntheses of 6,7‐Benzotropolone by Using Ring‐Closing Metathesis Variants Obviating a Strongly Acidic Hydrolysis Thereafter

“…We have engaged in uplifting this limitation by developing benzotropolone syntheses employing a ring-closing olefin metathesis ("RCM") as the key step. [13,14,15] In each instance, the substrate of this step is a 5-(ortho-vinylphenyl)pent-4-en-1-one (1 [13,14] and 4 [15] in Scheme 1, 7 a,b and 9 a-c in Scheme 2) and the resulting product a benzocycloheptadienone (2 [13,14] and 5 [15] in Scheme 1, 8 a,b and 10 a-c in Scheme 2). The RCM substrates differ from one another by containing two substituents α to the carbonyl group (1, [13,14] 7 a,b), one substituent (9 a-c), or none (5 [15] ).…”

“…Depending on the number and nature of substituents at C-α, our benzotropolone syntheses access the RCM substrate and process the RCM product in an individually adjusted manner. The α-substituents shown in Scheme 1 were studied previously [13,14,15] whereas the α-substituents summarized in Scheme 2 were newly introduced.…”

“…of NaHMDS and oxidized by a stream of oxygen. [15] Five new routes to unsubstituted 6,7-benzotropolone (6 a) are reported in the following. Their focal points are RCMs of the benzene-fused octa-1,8-dienones-or benzo-1,3,8-trienones or 5-(ortho-vinylphenyl)pent-4-en-1-ones-7 a-b and 9 a-c shown in Scheme 2.…”

N-Heterocyclic Carbene (NHC)/Ag(I) Co-catalyzed Synthesis of 2-Oxo-2-arylethyl Aryl Formates

“…近年来, 化学家们开发了一 些合成 2-氧代-2-芳乙基芳甲酸酯及其类似物的方法 [9] . 其中利用卤代芳基乙酮和芳基甲酸反应是合成 2-氧代-2-芳乙基芳甲酸酯传统方法之一 [10] , 此外还有铵盐催化 的芳基乙烯和苯乙酮的反应 [11] , 铵盐催化苯乙烯的直接 转化 [12] , 金配合物催化的芳基乙炔和芳酸的反应 [13] , 金 属催化的羰基化合物分别与硫叶立德 [14] 、烯胺酮 [15] 、端 炔 [16] 的反应, 单质碘与过氧叔丁醇复合催化体系介导 的碘代苯乙酮和甲苯分子间氧化偶联 [17] 、苯乙酮分子间 的自氧化偶联等 [18] . 但上述合成方法在产物生成效率、 使用过量氧化剂和产物多样性等方面仍然存在一些不 足, 继续寻找更加有效合成 2-氧代-2-芳乙基芳甲酸酯 的方法是有机合成研究领域的重要内容之一.…”

Continuous‐Flow Preparation of Benzotropolones: Combined Batch and Flow Synthesis of Epigenetic Modulators of the (JmjC)‐Containing Domain

“…[15] In order to develop an efficient methodology that eventually allows, not only the isolation of larger quantities of compound 7, [15] but also the preparation of other derivatives in a reproducible manner, we started to study the adequacy of the benzotropolone core ring formation reaction under continuous flow. Besides the different methodologies described in literature for the preparation of benzotropolones, [36][37][38][39] peroxidase-mediated condensation reaction of catechol and pyrogallol derivatives stands out as the most frequently used methodology for the formation of benzotropolone ring, [6,14,15,40] so these reaction conditions were chosen as starting point.…”