[2.2]Paracyclophane ([2.2]PCP), in which the para-positions of two benzene rings are connected by two ethylene linkers, has attracted broad interest owing to its prochiral, rigid, three-dimensional, and strained structure.^{1, 2, 3, 4} [2.2]PCP is widely applied as a substructure of functional molecules, including bioactive compounds,² chiral catalysts/ligands,³ and organic materials.⁴ Many methods for the synthesis of functionalized [2.2]PCP have been reported.¹ Derivatization via 4,5-dehydro[2.2]PCP (A), the aryne intermediate of [2.2]PCP, is among the most attractive approaches because it can easily lead to diverse multisubstituted [2.2]PCPs that are difficult to synthesize using other methods.⁵ However, the generation of aryne species of [2.2]PCP is rarely reported. A pioneering work on the generation of A was reported by Longone and Chipman in 1969 (Scheme 1A).⁶ They treated 4-bromo[2.2]PCP with potassium tert-butoxide in the presence of anthracene at 150–170 °C for 27 h, affording a triptycene derivative in ca. 15% yield. There are also some reports mentioning that side products were obtained in low yields via the intermediacy of aryne A.⁷ However, whether these low yields are caused by the inherent properties of aryne A or their harsh reaction conditions has not been clarified. Reports on the efficient generation and transformation of [2.2]PCP-based aryne species have been limited to 4,5,12,13-tetradehydro[2.2]PCP generated from 4,5,12,13-tetrabromo[2.2]PCP,⁸ 4,5-dehydrooctafluoro-[2.2]PCP generated from 4-iodooctafluoro[2.2]PCP, and 4,5,12,13-tetradehydrooctafluoro[2.2]PCP generated from 4,12- or 4,13-diiodooctafluoro[2.2]PCP, respectively.⁹ Herein, we report novel generation methods for 4,5-dehydro[2.2]PCP (A) using two modern versatile aryne precursors, namely, o-iodoaryl triflate-type precursor 1¹⁰ and o-silylaryl triflate-type precursor 2,¹¹ largely enhancing the scope of synthesizable 4,5-disubstituted [2.2]PCPs (Scheme 1B).¹²

Our investigation began with the preparation of aryne precursors 1 and 2. We expected that the known 4-hydroxy-5-iodo[2.2]PCP (4)¹³ would serve as a common intermediate of both precursors (Scheme 2). The synthesis of 4 was achieved in 33% overall yield from commercially available [2.2]PCP (3) with modifications of the reported procedures.^{13, 14} Triflylation of 4 afforded o-iodoaryl triflate 1 in high yield. o-Silylaryl triflate 2 was also prepared from the same intermediate 4 via a method based on the retro-Brook reaction previously reported for the synthesis of p-xylyne precursor.¹⁵ Specifically, O-silyl protection of 4 with 1,1,1,3,3,3-hexamethyldisilazane (HMDS) was followed by the treatment with n-butyllithium to afford o-silylphenol 5.¹⁶ As 5 was found unstable in silica-gel column chromatography, the desired o-silylaryl triflate 2 was prepared via a one-pot procedure in which the reaction mixture containing the phenoxide salt of 5 was directly treated with Tf₂O, affording 2 in 68% overall yield from 4. These methods were reproducible, enabling multigram-scale synthesis of both 1 and 2.

Next, we attempted to generate aryne A from aryne precursors 1 and 2. Treatment of a THF solution of o-iodoaryl triflate 1 and furan (6, 5.0 equiv.) with n-butyllithium^{10a, 10b} (2.4 equiv.) at −78 °C afforded a stereoisomeric mixture of cycloadducts 7 and 7′ in 59% yield (7:7′=80:20) with a small amount of side products (Table 1, Entry 1). This result confirmed the successful generation of aryne A from 1. After changing the activator to moderately basic, and moderately nucleophilic (trimethylsilyl)methylmagnesium chloride (1.5 equiv.),¹⁷ 7/7′ was obtained in 27% yield with 60% recovery of 1 (Entry 2). After conducting the reaction at room temperature, 1 was fully converted and the yield of 7/7′ was markedly improved to 90% (Entry 3). The scalability of this reaction was confirmed by performing the reaction with 1.0 mmol of 1. We also examined the generation of aryne A from o-silylaryl triflate 2. Treatment of a mixture of 2 and furan (6, 5.0 equiv.) in acetonitrile with cesium fluoride (2.1 equiv.) at room temperature afforded 7/7′ in 50% yield (7:7′=80:20) (Entry 4). Increasing the amount of cesium fluoride to 5.2 equiv. and elevating the reaction temperature to 40 °C improved the yield of 7/7′ to 78% (Entry 6). Conducting the reaction in THF at 60 °C was equally effective (Entry 7). Considering that less substituted arynes generated from both types of precursors could be generated to react with furan (6) at lower temperature, 4,5-dehdro[2.2]PCP (A) appears to require higher energy for its generation and is less reactive due to the large steric hindrance. However, these results clearly indicated that 4,5-dehdro[2.2]PCP (A) is practically available as a synthetic intermediate when generated under appropriate conditions.

Table 1. Optimization of the reaction conditions.

Entry	Aryne precursor	Activator (x equiv.)	Sol- vent[a]	Temp. (°C)	Yield (%)[b]
1	1	nBuLi (2.4)	THF	−78	59
2	1	Me3SiCH2MgCl (1.5)	THF	−78	27
3	1	Me3SiCH2MgCl (1.5)	THF	0 to rt	90 (99)[c]
4	2	CsF (2.1)	MeCN	rt	50
5	2	CsF (5.0)	MeCN	rt	76
6	2	CsF (5.2)	MeCN	40	78
7	2	CsF (5.3)	THF	60	76

• ^[a] The reaction concentrations with precursor 1 and 2 were 0.17 M and 0.20 M, respectively. ^[b] Combined isolated yield of major isomer 7 and minor isomer 7′. The ratios were determined by ¹H NMR analyses of crude reaction mixtures. The structures of 7 and 7’ were determined by NMR analysis based on the NOE method. ^[c] Yield for the reaction using 1.0 mmol of 1 is shown in the parentheses.

The optimal reaction conditions for generating aryne A from precursors 1 (Table 1, Entry 3) and 2 (Table 1, Entry 6) were widely applicable to the reactions with various arynophiles (Table 2). Reactions with the diene arynophiles, such as 2,5-dimethylfuran (8), N-phenylpyrrole (9), and anthracene (10), afforded the cycloadducts 17/17′, 18/18′, and 19, respectively, in good yields (Entries 1–3). The reaction with anthracene afforded 19 in a higher yield than the reported method generating the aryne from 4-bromo[2.2]PCP,⁶ demonstrating the effectiveness of our method. [2+3]-Cycloadditions with the 1,3-dipoles, such as nitrone 11 and azide 12, efficiently afforded the desired products 20/20′ and 21, respectively (Entries 4 and 5). [2+2]-Cycloaddition with ketene silyl acetal 13 successfully yielded the cycloadduct 22/22′ when the aryne was generated from 1 (Entry 6), but no 22/22′ was produced through the reaction using 2, probably because silyl group is unstable in the presence of fluoride anions. In contrast, successful reactions with nucleophiles were achieved using 2; reactions with morpholine (14) and m-cresol (15) afforded 4-amino[2.2]PCP 23 and 4-(m-tolyloxy)[2.2]PCP (24), respectively, but the reactions using 1 did not afford these adducts under the general conditions (Entries 7 and 8). Similarly, reaction using precursor 2 and phosphinite 16 afforded phosphine oxide 25 in 68% yield, but the reaction using 1 afforded 25 in only 17% yield (Entry 9).¹⁸ These results clearly demonstrate the value of establishing two complementary aryne-generating systems.

Table 2. Scope of arynophiles.

• ^[a] Isolated yield. ^[b] Ratios based on the isolated yields of each isomer are shown in parentheses. ^[c] Entries not examined. ^[d] Yield for the reaction using 0.20 mmol of 2 is shown in the parentheses. N.D.=not detected.

Because numerous derivatization methods using o-silylaryl triflates as aryne precursors are reported in the literature,^{5d, 5j, 5m} we applied some of these methods using 2 to synthesize diverse [2.2]PCP derivatives with slight modifications to the reaction conditions when necessary. The reaction with sulfilimine 26 afforded 4-amino-5-thio[2.2]PCP derivative 31 through migrative thioamination (Table 3, Entry 1).¹⁹ The reactions with phenols bearing a neighboring electrophilic moiety, namely, ester 27 and thiosulfonate 28, afforded xanthone 32 and phenoxathiine 33, respectively, through cyclization subsequent to the reaction with aryne A (Entries 2 and 3).^20-22 The reaction with thioalkyne 29 yielded thiophene-fused derivative 34 (Entry 4).²³ Moreover, aryne A was applicable to the Pd-catalyzed [2+2+2] cycloaddition reaction;²⁴ specifically, the reaction of 2 with dimethyl acetylenedicarboxylate (30) in the presence of Pd₂(dba)₃ afforded benzo[2.2]PCP derivative 35 (Entry 5).

Table 3. Synthesis of various difunctionalized [2.2]PCP derivatives using aryne precursor 2.

• ^[a] See Supporting Information for details on reaction conditions. ^[b] Isolated yield.

Transformation through aryne A also enabled facile construction of [2.2]PCP-fused π-extended polyaromatics (Scheme 3). The Diels–Alder reaction using precursor 1 and 1,3-diphenylisobenzofuran (36) followed by aromatization in the presence of sodium iodide and trimethylsilyl chloride afforded the [2.2]PCP-fused naphthalene derivative 37 in 84% yield (Scheme 3A). Aryne A generated from precursor 2 reacted with phencyclone (38) to afford a mixture of cycloadduct 39 and the [2.2]PCP-fused triphenylene derivative 40 (Scheme 3B). Subsequent thermal decarbonylation of 39 yielded 40 (72% overall yield). Other [2.2]PCP-fused naphthalene derivatives were easily synthesized through sequential reactions of oxadiazinone 41 (Scheme 3C). The reaction of aryne A generated from precursor 2 with 41 afforded the [2.2]PCP-fused α-pyrone derivative 42 in 71% yield (Scheme 3D). This is in stark contrast with the reaction between sterically less hindered benzyne and 41, which was reported to give a homo-dimerized product.²⁵ α-Pyrone 42 reacted with another aryne generated from 43 to afford doubly assembled 44 in 75% yield. Compound 42 also reacted with dimethyl acetylenedicarboxylate (30) under heating conditions, furnishing functionalized benzo[2.2]PCP 45.

Finally, the reaction using optically enriched precursor (S_p)-1 was examined (Scheme 4). The treatment of (S_p)-1 with the Grignard reagent in the presence of benzyl azide (12) afforded triazole 21, which was found racemic by HPLC analysis using a chiral stationary phase column (see Supporting Information for details). This result confirmed the generation of achiral aryne A in this reaction.

In summary, we have succeeded in generating 4,5-dehydro[2.2]PCP from o-iodoaryl triflate- and o-silylaryl triflate-type precursors. The scopes of the arynophiles compatible with the two precursors were complementary, expanding the number of available [2.2]PCP derivatives. We demonstrated the utility of the methods for synthesizing various [2.2]PCP derivatives, including [2.2]PCP-fused π-extended polyaromatics. Further studies on the synthesis of more complex [2.2]PCP derivatives are currently in progress.

Experimental Section

Typical Procedure Using o-Iodoaryl Triflate 1

To a solution of 4-iodo-5-triflyloxy[2.2]paracyclophane (1) (47.9 mg, 99.3 μmmol) and furan (6) (36.2 μL, 0.500 mmol, 5.0 equiv.) dissolved in THF (0.59 mL) was slowly added (trimethylsilyl)methylmagnesium chloride (0.780 M, THF solution, 0.190 mL, 0.148 mmol, 1.5 equiv.) at 0 °C. The mixture was allowed to warm to room temperature and after stirring for 3 h at the same temperature, to the solution was added an aqueous phosphate buffer solution (pH 7, 4 mL). The mixture was extracted with EtOAc (10 mL×3), and the combined organic extract was washed with brine (10 mL), dried (Na₂SO₄), and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (n-hexane/EtOAc=85/15) to give cycloadduct 7 (18.3 mg, 66.7 μmol, 67.2%) as a colorless solid and its stereoisomer 7′ (6.1 mg, 22 μmol, 22%) as a colorless solid.

Typical Procedure Using o-Silylaryl Triflate 2

To a solution of 4-triflyloxy-5-trimethylsilyl[2.2]paracyclophane (2) (41.6 mg, 97.1 μmol) and furan (6) (36.2 μL, 0.500 mmol, 5.1 equiv.) dissolved in acetonitrile (0.50 mL) was added cesium fluoride (77.3 mg, 0.509 mmol, 5.2 equiv.) at room temperature. The mixture was stirred with heating at 40 °C (aluminum block temp.) for 24 h. After cooling to room temperature, to the mixture was added water (4 mL). The mixture was extracted with CH₂Cl₂ (10 mL×3), and the combined organic extract was washed with brine (10 mL), dried (Na₂SO₄), and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (n-hexane/EtOAc=85/15) to give cycloadduct 7 (15.0 mg, 54.7 μmol, 56.3%) as a colorless solid and its stereoisomer 7′ (5.9 mg, 22 μmol, 22%) as a colorless solid.

Crystallographic Data

CCDC 2369959 and 2369960 contain the supplementary crystallographic data for compounds 22 and 42, respectively. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.

Acknowledgments

This work was supported by the Japan Agency for Medical Research and Development (AMED) under Grant Number JP24ama121043 (Research Support Project for Life Science and Drug Discovery, BINDS); JSPS KAKENHI Grant Numbers JP23H02091 and JP23 K26784 (Scientific Research (B); T.H., T.N.), JP23 K17911 (Challenging Research (Exploratory); T.H.), JP23 K13853 (Early-Career Scientists; J.T.), JP23H04880 and JP23H04890 (Transformative Research Areas (A) “Latent Chemical Space”; T.N.); and the Cooperative Research Project of Research Center for Biomedical Engineering.

中文翻译：

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重新审视 4,5-脱氢[2.2] 对环烷的合成效用

[2.2]副环烷 （[2.2]PCP） 其中两个苯环的对位由两个乙烯连接剂连接，由于其前手性、刚性、三维和应变结构而引起了广泛关注。^{1， 2， 3， 4} [2.2]PCP 广泛用作功能分子的子结构，包括生物活性化合物^、2 手性催化剂/配体³ 和有机材料。⁴ 已经报道了许多合成功能化 [2.2]PCP 的方法。¹ 通过 4,5-脱氢 [2.2]PCP 衍生化 （A） 是 [2.2]PCP 的芳烃中间体，是最具吸引力的方法之一，因为它很容易导致使用其他方法难以合成的多种多取代 [2.2]PCP。⁵ 然而，[2.2] PCP 的芳烃种类的产生很少报道。Longone 和 Chipman 于 1969 年报道了 A 产生的开创性工作（方案 1A）。⁶ 他们在 150-170 °C 的蒽存在下用叔丁醇钾处理 4-溴[2.2]PCP 27 小时，得到 ca 中的三苯衍生物。收率 15%。还有一些报告提到，副产品是通过 aryne A 的中介以低产量获得的。⁷ 然而，这些低产率是由芳烃 A 的固有特性还是它们恶劣的反应条件引起的，目前尚不清楚。关于基于 [2.2]基于 PCP 的芳烃物质的高效生成和转化的报道仅限于 4,5,12,13-四脱氢[2.2]由 4,5,12,13-四溴[2.2]PCP，8 4,5-脱氢八氟-生成的 PCP[2.2]分别由 4-碘八氟[2.2]PCP 和 4,5,12,13-四脱氢八氟[2.2]PCP 生成。⁹ 在此，我们报道了使用两种现代多功能芳烃前驱体的 4,5-脱氢 [2.2] PCP （A） 的新生成方法，即邻碘芳基三氟磺酸型前驱体 1¹⁰ 和邻硅烷芳基三氟磺酸型前驱体 ^2,11，这在很大程度上增强了可合成的 4,5-二取代 [2.2] PCP 的范围（方案 1B）。¹²

我们的研究从制备芳烃前体 1 和 2 开始。我们预计已知的 4-羟基-5-碘[2.2]PCP （4）¹³ 将作为两种前体的共同中间体（方案 2）。通过修改报告的程序，以 33% 的总产量从市售 [2.2]PCP （3） 合成 4。^13、144 的三飞化得到高产率的邻碘芳基三氟甲磺酸 1。邻水杨酰三氟甲磺酸酯 2 也通过基于先前报道的用于合成对二甲苯前体的 Retro-Brook 反应的方法，从相同的中间体 4 制备。¹⁵ 具体来说，用 1,1,1,3,3,3-六甲基二硅氮烷 （HMDS） 对 4 进行 O-硅烷保护，然后用正丁基锂处理得到邻硅烷基苯酚 5。¹⁶ 由于在硅胶柱色谱中发现 5 不稳定，因此通过一锅法制备所需的邻三氟磺酸乙二烯丙酯 2，其中含有苯氧盐 5 的反应混合物直接用 Tf₂O 处理，得到 4 中 2 的 68% 总产率。这些方法具有可重现性，可实现 1 和 2 的多克级合成。

接下来，我们尝试从芳烃前体 1 和 2 生成芳烃 A。在 -78 °C 下处理邻碘芳基三氟磺酸 1 和呋喃（6,5.0 当量）与正丁基锂^10a、10b（2.4 当量）的 THF 溶液，得到环加合物 7 和 7' 的立体异构混合物，收率为 59% （7：7′=80：20） 和少量副产物（表 1，条目 1）。这一结果证实了从 1 成功生成芳烃 A。将活化剂更改为中等碱性和中等亲核（三甲基硅烷基）甲基氯化镁（1.5 当量）后，以 27% 的产率获得 ¹⁷7/7'，1 的回收率为 60%（条目 2）。在室温下进行反应后，1 完全转化，7/7' 的产率显着提高至 90%（条目 3）。通过用 1.0 mmol 的 1.我们还检查了从邻硅烷芳基三氟甲磺酸 2 生成芳烃 A。在室温下用氟化铯（2.1 当量）在乙腈中处理 2 和呋喃（6,5.0 当量）的混合物，以 7/7' 的收率 （7：7'=80：20） （条目 4）。将氟化铯的量增加到 5.2 当量并将反应温度提高到 40 °C，可将 7/7' 的产率提高到 78%（条目 6）。 在 60 °C 的 THF 中进行反应同样有效（条目 7）。考虑到在较低温度下，两种前驱体产生的取代较少的芳烃都可以产生与呋喃 （6） 反应，4,5-dehdro[2.2]PCP （A） 似乎需要更高的能量来产生，并且由于空间位阻大，反应性较低。然而，这些结果清楚地表明，在适当的条件下生成 4,5-dehdro[2.2]PCP （A） 实际上可以作为合成中间体使用。

Table 1. Optimization of the reaction conditions.

进入	阿里恩  前兆	活化剂  （x 等值。	溶胶-  通风口[a]	温度 （°C）	屈服  (%)[二]
1	1	n布里 （2.4）	THF	−78	59
2	1	Me3SiCH2MgCl （1.5）	THF	−78	27
3	1	Me3SiCH2MgCl （1.5）	THF	0 到 rt	90  (99)[三]
4	2	环氟 （2.1）	乙酮	rt	50
5	2	CsF （5.0）	乙酮	rt	76
6	2	碳化硅 （5.2）	乙酮	40	78
7	2	环孢氟 （5.3）	THF	60	76

• 
  ^[a] 前驱体 1 和 2 的反应浓度分别为 0.17 M 和 0.20 M。^[b] 主要异构体 7 和次要异构体 7' 的组合分离产量。通过粗反应混合物的 ¹H NMR 分析确定比率。7 和 7' 的结构是通过基于 NOE 方法的 NMR 分析确定的。^[c] 使用 1.0 mmol 1 的反应产率如括号所示。

从前体 1（表 1，条目 3）和 2（表 1，条目 6）生成芳烃 A 的最佳反应条件广泛适用于与各种嗜芳烃的反应（表 2）。与亲芳异烯化合物，如 2,5-二甲基呋喃 （8）、N-苯基吡咯 （9） 和蒽 （10） 反应，分别以良好的产率获得环加合物 17/17′、18/18′ 和 19（条目 1-3）。与蒽反应得到 19 的产率高于报道的从 4-溴[2.2]PCP 生成芳烃的方法，⁶ 证明了我们方法的有效性。[2+3]-带有 1,3-偶极子的环加成反应，如硝基 11 和叠氮化物 12，分别有效地提供了所需的产物 20/20' 和 21（条目 4 和 5）。当从 1（条目 6）生成芳烃时，用乙烯酮甲硅烷基缩醛 13 进行环加成反应成功地产生了 22/22'，但使用 2 反应没有产生 22/22'，可能是因为甲硅烷基在氟化物阴离子存在下不稳定。相比之下，使用 2 实现与亲核试剂的成功反应;与吗啉 （14） 和间甲酚 （15） 反应得到 4-氨基[2.2]PCP 23 和 4-（间甲苯氧基）[2.2]PCP （24），但在一般条件下，使用 1 的反应不能产生这些加合物（条目 7 和 8）。同样，使用前驱体 2 和亚膦酸盐 16 反应得到氧化膦 25，产率为 68%，但使用 1 反应得到 25，产率仅为 17%（条目 9）。¹⁸ 这些结果清楚地证明了建立两个互补的芳烃生成系统的价值。

表 2. 嗜靵菌的范围。

• 
  ^[a] 孤立产量。^[b] 基于每种异构体分离产量的比率显示在括号中。^[c] 未审查的参赛作品。^[d] 使用 0.20 mmol 2 的反应产率如括号所示。N.D.=未检测到。

由于文献中报道了许多使用邻硅烷基三氟磺酸作为芳烃前体的衍生化方法，^5d、5j、5m，我们使用 2 应用其中一些方法来合成不同的 [2.2]PCP 衍生物，必要时对反应条件进行轻微修改。与硫胺 26 的反应通过迁移硫代胺化生成 4-氨基-5-硫代[2.2]PCP 衍生物 31（表 3，条目 1）。¹⁹ 与带有相邻亲电基团的酚类反应，即酯 27 和硫代磺酸盐 28，通过与芳烃 A 反应后的环化，分别得到氧杂蒽酮 32 和吩噻嘌呤 33（条目 2 和 3）。^20-22 与硫代炔烃 29 反应得到噻吩熔融衍生物 34（条目 4）。²³ 此外，芳烃 A 适用于 Pd 催化的 [2+2+2] 环加成反应;²⁴ 具体来说，2 在 Pd₂（dba）₃ 存在下与乙酰二羧酸二甲酯 （30） 反应得到苯并[2.2]PCP 衍生物 35（条目 5）。

表 3. 使用芳烃前驱体 2 合成各种双功能化 [2.2]PCP 衍生物。

• 
  ^[a] 有关反应条件的详细信息，请参阅支持信息。^[b] 孤立产量。

通过芳烃 A 的转化还能够轻松构建 [2.2] PCP 熔融π延伸的多环芳烃（方案 3）。使用前驱体 1 和 1,3-二苯基异苯并呋喃 （36） 进行 Diels-Alder 反应，然后在碘化钠和三甲基硅烷基氯化物存在下进行芳构化，得到 [2.2] PCP 熔融萘衍生物 37，收率为 84%（方案 3A）。由前体 2 生成的 Aryne A 与 phencyclone （38） 反应，得到环加合物 39 和 [2.2] PCP 熔融三苯衍生物 40 的混合物（方案 3B）。随后对 39 进行热脱羰，得到 40（总收率为 72%）。其他 [2.2] PCP 熔融萘衍生物很容易通过噁二嗪酮 41 的连续反应合成（方案 3C）。由前驱体 2 生成的芳烃 A 与 41 反应得到 [2.2] PCP 熔融的 α-吡喃酮衍生物 42，产率为 71%（方案 3D）。这与空间受阻较少的苄炔与 41 之间的反应形成鲜明对比，据报道，41 会产生同源二聚化产物。²⁵ α-吡喃酮 42 与 43 生成的另一种芳烃反应，得到双组装 44，产率为 75%。化合物 42 还在加热条件下与乙酰二羧酸二甲酯 （30） 反应，形成功能化的苯并[2.2]PCP 45。

最后，检查使用光学富集前体 （S_p）-1 的反应（方案 4）。在叠氮化苄 （12） 存在下，用 Grignard 试剂处理 （S_p）-1 得到三唑 21，使用手性固定相柱进行 HPLC 分析发现三唑 21 为外消旋（有关详细信息，请参阅支持信息）。该结果证实了在该反应中生成非手性芳烃 A。

总之，我们已经成功地从邻碘芳基三氟甲磺酸酯和邻甲硅烷基三氟甲磺酸型前体中生成了 4,5-脱氢[2.2]PCP。与两种前体相容的嗜芳菌的范围是互补的，扩大了可用的 [2.2] PCP 衍生物的数量。我们证明了合成各种 [2.2] PCP 衍生物的方法的实用性，包括 [2.2] PCP 熔融π延伸的聚芳烃。目前正在进一步研究合成更复杂的 [2.2]PCP 衍生物。

 实验部分

使用邻碘芳基三氟甲磺酸 1 的典型程序

向溶解在 THF （0.59 mL） 中的 4-碘-5-三氟氧基[2.2]对环烷 （1） （47.9 mg， 99.3 μmmol） 和呋喃 （6） （36.2 μL， 0.500 mmol， 5.0 当量） 溶液中，在 0 °C 下缓慢加入（三甲基硅烷基）甲基氯化镁（0.780 M，THF 溶液，0.190 mL，0.148 mmol，1.5 当量）。 将混合物加热至室温，在相同温度下搅拌 3 小时后，向溶液中加入磷酸盐缓冲水溶液 （pH 7， 4 mL）。用 EtOAc （10 mL×3） 萃取混合物，用盐水 （10 mL） 洗涤合并的有机提取物，干燥 （Na₂SO₄），过滤后减压浓缩滤液。通过制备型 TLC （正己烷/EtOAc=85/15） 纯化残基，得到环加合物 7 （18.3 mg， 66.7 μmol， 67.2%） 为无色固体，其立体异构体 7' （6.1 mg， 22 μmol， 22%） 为无色固体。

使用 o-水杨酰 Triflate 2 的典型程序

向溶解于乙腈 （0.50 mL） 的 4-三氟氧基-5-三甲基硅烷[2.2]对环烷 （2） （41.6 mg， 97.1 μmol） 和呋喃 （6） （36.2 μL， 0.500 mmol， 5.1 当量） 溶液中加入室温下氟化铯（77.3 mg， 0.509 mmol，5.2 当量）。将混合物在 40 °C（铝块温度）下加热搅拌 24 小时。冷却至室温后，向混合物中加入水 （4 mL）。用 CH₂Cl₂ （10 mL×3） 提取混合物，用盐水 （10 mL） 洗涤合并的有机提取物，干燥 （Na₂SO₄），过滤后减压浓缩滤液。通过制备型 TLC （正己烷/EtOAc=85/15） 纯化残基，得到环加合物 7 （15.0 mg， 54.7 μmol， 56.3%） 为无色固体，其立体异构体 7' （5.9 mg， 22 μmol， 22%） 为无色固体。

 晶体学数据

CCDC 2369959 和 2369960 分别包含化合物 22 和 42 的补充晶体学数据。数据可通过 www.ccdc.cam.ac.uk/structures 从 The Cambridge Crystallographic Data Centre 免费获得。

 确认

这项工作得到了日本医学研究与开发机构 （AMED） 的支持，资助号为 JP24ama121043（生命科学和药物发现研究支持项目，BINDS）;JSPS KAKENHI 资助号 JP23H02091 和 JP23 K26784（科学研究 （B）;T.H.， T.N.）， JP23 K17911 （挑战性研究（探索性）;TH）、JP23 K13853（早期职业科学家;J.T.）、JP23H04880 和 JP23H04890 （变革性研究领域 （A） “潜在化学空间”;T.N.）;生物医学工程研究中心合作研究项目。