通过苄醇与炔烃的环化反应快速高效构建茚及螺环茚

引用本文: 余佳佳, 杨珊, 吴镇, 朱晨. 通过苄醇与炔烃的环化反应快速高效构建茚及螺环茚[J]. 有机化学, 2019, 39(1): 223-231. doi: 10.6023/cjoc201808009 shu

Citation: Yu Jiajia, Yang Shan, Wu Zhen, Zhu Chen. Annulation of Benzylic Alcohols with Alkynes for Rapid and Efficient Synthesis of Indenes and Spiroindenes[J]. Chinese Journal of Organic Chemistry, 2019, 39(1): 223-231. doi: 10.6023/cjoc201808009 shu

通过苄醇与炔烃的环化反应快速高效构建茚及螺环茚

余佳佳 ^a, ,
杨珊 ^a, ,
吴镇 ^a, ,
朱晨 ^{a,b,
,}

a.
苏州大学材料与化学化工学部苏州 215123
b.
中国科学院上海有机化学研究所天然产物有机合成重点实验室上海 200032

通讯作者: 朱晨, chzhu@suda.edu.cn

基金项目:

国家自然科学基金（No.21722205）资助项目

摘要: 作为一类重要的碳环化合物，茚、螺环茚及其衍生物常见于各种天然产物骨架结构中，并作为合成中间体广泛地应用于材料、医药、有机不对称合成等领域.在路易斯酸TiCl₄或AlCl₃作用下，二苯甲醇或芳基取代环醇等苄醇通过生成碳正离子中间体，与炔烃进行环化反应高效合成多种茚及螺环茚.该反应仅需30 min，反应过程中完成了2个新C—C键的构建，对具有各种取代基的炔烃均有较好的适用性.芳基取代的环丁醇、环己醇、环庚醇、环辛醇以及环十二醇都可以适用于该方法，多样性地构建多种有合成价值的螺环骨架.该方法具有操作简便、反应时间短、条件温和等优点.

关键词:

路易斯酸
/ 环化反应
/ 茚
/ 螺环茚

English

Annulation of Benzylic Alcohols with Alkynes for Rapid and Efficient Synthesis of Indenes and Spiroindenes

Yu Jiajia ^a, ,
Yang Shan ^a, ,
Wu Zhen ^a, ,
Zhu Chen ^{a,b,
,}

a.
College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123
b.
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Shanghai 200032

Corresponding author: Zhu, Chen, E-mail: chzhu@suda.edu.cn

Received Date: 10 August 2018
Revised Date: 10 September 2018
Available Online: 25 January 2019
Fund Project:

Project supported by the National Natural Science Foundation of China (No. 21722205)

Abstract: As a type of important carbocyclic compounds, indenes and spiroindenes are not only widely found in natural products but extensively employed as synthetic building blocks in materials, pharmaceuticals, and asymmetric synthesis. An efficient and rapid synthesis of indenes and spiroindenes via the annulation of benzylic alcohols (or aryl-substituted cycloalkanols) with alkynes in the presence of TiCl₄ or AlCl₃ was desclosed. This reaction is normally completed within 30 min at room temperature and compatible with a variety of substituted alkynes. Two new C—C bonds are constructed during the reaction. Cycloalkanols such as cyclobutanol, cyclohexanol, cycloheptanol, cyclooctanol, and cyclododecanol are suitable substrates to afford a set of valuable spiroindenes. This method is featured with simple operation, short reaction time, and mild reaction conditions.

Key words:

Lewis acid
/ cyclization
/ indene
/ spiroindene

茚和螺环茚是天然产物中常见的碳环骨架^{[1, 2]}, 并因其特有结构及性质被广泛应用于生物^[3]、医药^[4]、材料^[5]等领域.茚作为配体骨架常用于有机金属化合物的合成中^[6], 螺环茚由于存在螺手性常被用于合成各种手性配体, 并在不对称合成领域发挥着重要作用^[7].因此, 发展一类通用的方法, 以简单易得的原料高效构建这类结构, 具有重要的研究意义.

对于茚的合成方法有很多报道, 大致可以分为过渡金属催化^[8]和路易斯酸催化^[9]两种方式.其中, 路易斯酸以其价格便宜、反应效果好而受到广泛关注.利用路易斯酸攫取醇羟基产生的碳正离子, 既能在分子内与芳环进行Friedel-Crafts环化反应^[9d~9f], 也可与炔烃发生分子间加成^[10].而将这两种途径相结合, 利用苄位碳正离子与炔烃进行环化, 便可构建多种茚类衍生物.例如:田仕凯课题组^[11]利用FeCl₃断裂苄位磺酰胺的C—N键产生苄位碳正离子, 与炔烃发生分子间环化构建了茚类化合物.然而该反应时间较长, 且需加热到80 ℃进行(图 1A).周锡庚课题组^[12]利用FeCl₃攫取二苯甲醇的羟基形成苄位碳正离子, 与炔烃环化得到茚类化合物.但是反应在此条件下容易过度进行, 产生的碳正离子会再次与产物茚发生Friedel-Crafts反应(图 1B).

图 1

图 1. 路易斯酸促进的碳正离子与炔烃的环化反应

Figure 1. Lewis acid-promoted cyclization of carbocation with alkynes

下载: 全尺寸图片幻灯片

由上可见, 目前报道的路易斯酸催化合成茚环的方法仍有一些不足, 且利用其合成螺环茚更是鲜有报道^[13].我们课题组^{[14, 15]}以芳基取代的环醇为原料, 开展了系统性的有机开环反应的研究.基于前期工作的启发, 在本工作中我们利用芳基取代的环醇在路易斯酸TiCl₄或AlCl₃的促进下生产的碳正离子中间体, 与炔烃发生环化反应, 从而快速高效地合成了一系列螺环化合物.该方法反应时间短、条件温和、操作简单, 反应中完成了2个新C—C键的构建, 对具有各种取代基的炔烃均有较好的适用性.通过改变环醇的碳环大小或者结构, 反应能灵活地在产物中引入不同的碳环, 构建了多种含中环以及大环复杂骨架结构的螺环化合物(图 1C).

1. 结果与讨论

1.1 反应条件优化

室温下, 以二苯甲醇(1a)和二苯乙炔(2b)作为底物, 20 mol% AlCl₃为路易斯酸, 干燥的二氯甲烷(DCM)为溶剂, 进行反应条件探究.考虑到溶剂中的残留水分容易使路易斯酸发生分解, 首先筛选了不同的干燥剂(表 1, Entries 1~3).相比于常规干燥剂硫酸钠和硫酸镁, 反应中加入100 mg 4Å分子筛可使产率达到52%.接着, 当将4Å分子筛的用量逐步增加到400 mg时, 产率达到了68%(表 1, Entries 4, 5).而当考察其他路易斯酸的反应情况时(表 1, Entries 6~12), 惊喜地发现在TiCl₄条件下, 反应仅需30 min, 产率达到了87%.接下来, 考察溶剂对反应的影响(表 1, Entries 13~18), 结果显示CHCl₃和C₆H₅F也能以较优的产率得到目标产物.最后, 分别以1.1 equiv.的TiCl₄和AlCl₃尝试反应, 均得到很高的产率(表 1, Entries 19, 20).考虑到反应的绿色和经济性, 最终我们确定表 1中的Entry 12为最优条件.

表 1

表 1 茚的反应条件优化^a

Table 1. Optimization of reaction conditions for indene^a

下载: 导出CSV


Entry	Lewis acid	Dehydrating agent	Solvent	Yield^b/%
1	AlCl₃	Na₂SO₄ (2.0 equiv.)	DCM	23
2	AlCl₃	MgSO₄ (2.0 equiv.)	DCM	29
3^c	AlCl₃	4Å MS	DCM	52
4^d	AlCl₃	4Å MS	DCM	63
5	AlCl₃	4Å MS	DCM	68
6	AgOTf	4Å MS	DCM	< 5
7	Sc(OTf)₃	4Å MS	DCM	55
8	Gd(OTf)₃	4Å MS	DCM	< 5
9	BF₃•Et₂O	4Å MS	DCM	65
10	FeCl₃	4Å MS	DCM	85
11	ZnCl₂	4Å MS	DCM	0
12^e	TiCl₄	4Å MS	DCM	87
13^e	TiCl₄	4Å MS	CH₃CN	0
14^e	TiCl₄	4Å MS	CHCl₃	84
15^e	TiCl₄	4Å MS	C₆H₅F	83
16^e	TiCl₄	4Å MS	DMF	0
17^e	TiCl₄	4Å MS	THF	0
18^e	TiCl₄	4Å MS	DCE	0
19^{e, f}	TiCl₄	4Å MS	DCM	88
20^{e, g}	AlCl₃	4Å MS	DCM	90
^aReaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), 4Å MS (400 mg), and Lewis acid (20 mol%) in 2 mL of DCM at r.t., 5 h. ^b Yields of isolated products. ^c 100 mg of 4Å MS was used. ^d 300 mg of 4Å MS was used. ^e Reaction time: 30 min. ^f 0.22 mmol of TiCl_4. ^g 0.22 mmol of AlCl₃.

1.2 茚的合成

在得到最优反应条件后, 对反应适用性进行考察.首先, 改变炔烃两侧苯环的取代基.从表 2中可以看出, 取代基为给电子基例如对甲氧基和对叔丁基时, 反应均有较好的兼容性(表 2, 3b, 3c).当取代基为卤素时, 氟代和氯代产物在增加TiCl₄用量的情况下可以得到不错的产率(表 2, 3d, 3e), 溴代产物也能获得中等收率(表 2, 3f).另外, 苯环间位被氟取代时, 反应也能顺利进行(表 2, 3g).该方法还可兼容脂肪炔烃, 并以良好的收率得到产物(表 2, 3h).最后, 我们尝试了单取代炔烃的反应, 但未能得到对应的产物.

表 2

表 2 二苯甲醇与炔烃合成茚^{a, b}

Table 2. Synthesis of indenes from benzhydrol and alkynes

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^a Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol, 1.0 equiv.), TiCl₄ (0.04 mmol, 20 mol%), and 4Å MS (400 mg) in dry DCM (2.0 mL) at r.t.. ^b Yield of isolated products. ^c1.1 equiv. of TiCl₄.

1.3 螺环茚的合成

接着我们将研究重点转向螺环茚的合成.以1-苯基环丁醇作为底物, 在1.1 equiv. TiCl₄的作用下, 尝试与炔烃发生环化反应.值得一提的是, 环丁醇是具有较大环张力的碳环结构^[16], 而在该反应条件下碳环未发生开环, 被成功地引入到底物中.反应仅用30 min, 就以89%的产率得到了对应的螺环茚(表 3, 5a).之后, 对反应底物的普适性进行了研究.考虑到芳基溴化物可以进行交叉偶联反应而显现出重要的应用价值, 我们首先考察了对溴苯基环丁醇的反应情况.反应能以较好的收率得到相应的产物(表 3, 5b), 而芳基溴的保留可以为后期的产物修饰提供平台.在炔烃的苯环对位安装上甲氧基时, 反应可以中等收率得到产物(表 3, 5c).然而, 当苯环的对位和间位分别连接卤素时, 需用1.1 equiv.的AlCl₃替换TiCl₄才能得到较好的产率(表 3, 5d~5g).该反应底物并不局限于芳基炔烃, 脂肪链取代的3-己炔也同样适用于该反应, 以较高产率得到相应的产物(表 3, 5h).但该方法并不适用于端基炔的底物.延长反应时间至1 h, 该方法也能适用于杂芳基环丁醇(表 3, 5i).我们继续考察了1-芳基环己醇的反应情况.从表 3中看到, 改变底物中脂肪环或者芳基的结构能得到多种对应的螺环产物, 甚至对于大位置的金刚烷也有很好的兼容性(表 3, 5j~5o).更令人欣喜的是, 环庚醇、环辛醇以及环十二醇通过该反应均能以很好的产率构建含中环及大环结构的螺环茚(表 3, 5p~5r).但是1-芳基环戊醇在该反应中不能兼容, 主要生成了分子内脱水的副产物.

表 3

表 3 芳基取代环醇与炔烃合成螺环茚^a^, ^b

Table 3. Synthesis of spiroindenes from 1-aryl cycloalkanols and alkynes

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^a Conditions: 4 (0.2 mmol), 2 (0.2 mmol, 1.0 equiv.), TiCl₄ (0.22 mmol, 1.1 equiv.), and 4Å MS (400 mg) in dry DCM (2.0 mL) at r.t. ^b Yield of isolated products. ^c1.1 equiv. of AlCl₃ instead of TiCl₄. ^dReaction time is 1 h.

根据已有的实验结果, 我们提出可能的反应机理(图 2).首先, 1-芳基环丁醇4的羟基被路易斯酸TiCl₄攫取, 形成苄位碳正离子Ⅰ.中间体Ⅰ与炔烃加成产生烯基正离子Ⅱ.中间体Ⅱ与芳环发生分子内亲电环化反应得到芳基正离子Ⅲ.最后, 中间体Ⅲ脱氢芳构化得到螺环产物5.

图 2

图 2. 反应机理

Figure 2. Proposed reaction mechanism

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2. 结论

在路易斯酸TiCl₄或AlCl₃作用下, 二苯甲醇或芳基取代环醇等苄醇通过生成碳正离子中间体, 与炔烃发生环化反应高效合成多种茚及螺环茚.实验结果表明, 具有较大张力的环丁醇未在该反应条件下发生开环断裂, 其碳环结构被成功地引入到产物中.通过这种策略, 仅需改变底物的碳环结构, 就可以灵活地构建多种含中环以及大环骨架结构的螺环产物.反应在室温下仅需30 min即可完成.反应过程中完成了2个新C—C键的构建, 对具有各种取代基的炔烃均有较好的适用性.

3. 实验部分

3.1 仪器与试剂

Bruker公司400 MHz AVANCE III HD核磁共振仪, 溶剂CDCl₃, 内标TMS; BRUKER公司VERTEX 70傅里叶变换红外光谱仪; Waters Micromass公司GCT Premier高分辨质谱仪; INESA WRR显微熔点仪测定.

实验用的所有试剂均为市售试剂, 没有经过进一步纯化.二氯甲烷(DCM)以氢化钙(CaH₂)除水, 经蒸馏收集使用. 4Å MS分子筛经研磨及300 ℃高温烘焙处理.所有已知产物都经核磁氢谱、碳谱和液质联用表征并与文献数据对比确认结构.所有未知产物都经核磁氢谱、碳谱、红外和高分辨质谱表征确定结构.

3.2 实验方法

3.2.1 茚类化合物3的合成

在5 mL的反应瓶中, 依次加入0.2 mmol二苯甲醇(1a), 0.2 mmol二芳基乙炔(2), 400 mg 4Å MS和2.0 mL DCM, 然后加入0.04 mmol(或0.22 mmol) TiCl₄.室温下搅拌30 min.反应结束后, 加水猝灭, DCM萃取, 有机层用无水硫酸钠干燥, 减压旋干溶剂, 经柱层析分离得到目标产物3.

1, 2, 3-三苯基-1H-茚(3a):白色固体, 产率87%. m.p. 132~134 ℃(文献值^[11] m.p. 133~135 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 7.44~7.37 (m, 4H), 7.36~7.32 (m, 1H), 7.30~7.21 (m, 3H), 7.21~7.16 (m, 2H), 7.16~7.13 (m, 3H), 7.13~7.08 (m, 3H), 7.07~6.98 (m, 3H), 5.10 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.8, 145.2, 144.6, 140.4, 139.4, 135.2, 135.1, 129.1, 128.9, 128.3, 128.3, 127.8, 127.4, 127.1, 126.5, 126.3, 126.2, 125.3, 123.5, 120.1, 57.6; FT-IR (film) ν: 3079, 3019, 2925, 2857, 1492, 1027 cm^－1; HRMS [APCI] calcd for C₂₇H₂₁ [M+H]⁺ 345.1638, found 345.1633.

2, 3-二(4-甲氧基苯基)-1-苯基-1H-茚(3b):白色固体, 产率64%. m.p. 127~129 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.43~7.39 (m, 2H), 7.31~7.27 (m, 3H), 7.26~7.22 (m, 2H), 7.21~7.15 (m, 4H), 7.14~7.09 (m, 2H), 7.04~7.00 (m, 2H), 6.69~6.64 (m, 2H), 5.09 (s, 1H), 3.91 (s, 3H), 3.73 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 158.4, 157.7, 147.6, 144.9, 144.2, 139.8, 138.6, 130.3, 123.0, 128.2, 128.1, 127.7, 127.6, 126.4, 126.1, 124.9, 123.3, 119.7, 113.8, 112.9, 57.4, 54.8, 54.5; FT-IR (film) ν: 3060, 2956, 1513, 1244, 1176, 1029 cm^－1; HRMS [APCI] calcd for C₂₉H₂₅O₂ [M+H]⁺ 405.1849, found 405.1859.

2, 3-二(4-(叔丁基)苯基)-1-苯基-1H-茚(3c):白色固体, 产率98%. m.p. 114~115 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.47 (d, J＝8.0 Hz, 2H), 7.39 (d, J＝8.0 Hz, 2H), 7.25~7.19 (m, 7H), 7.18~7.13 (m, 2H), 7.12~7.05 (m, 4H), 4.98 (s, 1H), 1.30 (s, 9H), 1.11 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ: 149.8, 148.9, 147.7, 145.1, 143.9, 140.1, 140.0, 132.4, 132.0, 128.6, 128.2, 128.2, 127.6, 126.3, 126.0, 125.1, 125.0, 124.3, 123.2, 120.1, 57.4, 34.2, 33.9, 31.0, 30.7; FT-IR (film) ν: 2961, 2864, 1684, 1508, 1363, 1268 cm^－1; HRMS [APCI] calcd for C₃₅H₃₇ [M+H]⁺457.2890, found 457.2889.

2, 3-二(4-氟苯基)-1-苯基-1H-茚(3d):白色固体, 产率53%. m.p. 144~145 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.43~7.35 (m, 2H), 7.30~7.25 (m, 3H), 7.24~7.18 (m, 3H), 7.18~7.09 (m, 5H), 7.09~7.02 (m, 2H), 6.84~6.75 (m, 2H), 5.06 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 162.7 (d, J＝62.5 Hz), 160.2 (d, J＝62.9 Hz), 147.5, 144.5, 144.2, 139.2, 138.9, 130.9 (d, J＝3.4 Hz), 130.8 (d, J＝3.1 Hz), 130.7 (d, J＝7.9 Hz), 130.4 (d, J＝7.9 Hz), 128.3, 127.7, 126.6, 126.4, 125.5, 123.6, 119.8, 115.4 (d, J＝21.4 Hz), 114.6 (d, J＝21.4 Hz), 57.7; ¹⁹F NMR (376 MHz, CDCl₃) δ: －114.0 (s), －114.7 (s); FT-IR (film) ν: 3077, 3020, 1598, 1499, 1349, 1221 cm^－1; HRMS [APCI] calcd for C₂₇H₁₉F₂ [M+H]⁺ 381.1455, found 381.1460.

2, 3-二(4-氯苯基)-1-苯基-1H-茚(3e):白色固体, 产率61%. m.p. 145~148 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.46~7.40 (m, 2H), 7.38~7.29 (m, 3H), 7.28~7.27 (m, 1H), 7.26~7.24 (m, 1H), 7.24~7.14 (m, 4H), 7.14~7.06 (m, 3H), 7.06~6.99 (m, 3H), 5.05 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 148.0, 144.9, 144.2, 140.1, 139.1, 133.7, 133.6, 133.6, 132.8, 130.8, 130.4, 129.2, 128.8, 128.3, 128.1, 127.1, 126.9, 126.1, 124.1, 120.4, 58.0; FT-IR (film) ν: 3080, 2988, 1456, 1397, 1089, 1012 cm^－1; HRMS [APCI] calcd for C₂₇H₁₉Cl₂ [M+H]⁺ 413.0864, found 413.0876.

2, 3-二(4-溴苯基)-1-苯基-1H-茚(3f):白色固体, 产率45%. m.p. 158~159 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.66~7.53 (m, 2H), 7.35~7.28 (m, 5H), 7.27~7.21 (m, 5H), 7.20~7.15 (m, 1H), 7.15~7.09 (m, 2H), 7.04~6.92 (m, 2H), 5.08 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 148.1, 145.0, 144.2, 140.2, 139.1, 134.1, 134.1, 132.1, 131.3, 131.1, 130.8, 128.8, 128.1, 127.1, 126.9, 126.2, 124.1, 121.8, 121.1, 120.4, 58.0; FT-IR (film) ν: 3061, 3024, 1585 1493, 1183, 1029 cm^－1; HRMS [APCI] calcd for C₂₇H₁₉Br₂ [M+H]⁺ 500.9853, found 500.9865.

2, 3-二(3-氟苯基)-1-苯基-1H-茚(3g):白色固体, 产率34%. m.p. 110~111 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.45~7.37 (m, 1H), 7.30~7.27 (m, 2H), 7.27~7.26 (m, 1H), 7.24~7.11 (m, 8H), 7.10~7.02 (m, 2H), 6.89~6.85 (m, 1H), 6.81~6.73 (m, 2H), 5.07 (s, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 163.5 (d, J＝113.1 Hz), 161.9 (d, J＝111.5 Hz), 148.0, 145.0 (d, J＝2.1 Hz), 144.1, 140.5 (d. J＝1.2 Hz), 139.0, 137.4 (d, J＝8.3 Hz), 137.3 (d, J＝8.3 Hz), 130.4 (d, J＝8.4 Hz), 129.4 (d, J＝8.4 Hz), 128.8, 128.1, 127.1, 126.9, 126.2, 125.2 (d, J＝2.7 Hz), 125.0 (d, J＝2.6 Hz), 124.0, 120.5, 116.3 (d, J＝21.5 Hz), 115.9 (d, J＝21.9 Hz), 114.8 (d, J＝21.0 Hz), 113.9 (d, J＝21.0 Hz), 58.1; ¹⁹F NMR (376 MHz, CDCl₃) δ: －112.5 (s), －113.4 (s); FT-IR (film) ν: 3065, 3026, 1947 1597, 1480, 1263 cm^－1. HRMS [APCI] calcd for C₂₇H₁₉F₂ [M+H]⁺ 381.1455, found 381.1460.

2, 3-二乙基-1-苯基-1H-茚(3h):无色液体.产率63%. ¹H NMR (400 MHz, CDCl₃) δ: 7.33~7.26 (m, 2H), 7.25~7.21 (m, 2H), 7.21~7.17 (m, 1H), 7.14~7.10 (m, 1H), 7.05 (ddd, J＝7.2, 7.2, 1.2 Hz, 1H), 7.03~6.97 (m, 2H), 4.43 (s, 1H), 2.59 (q, J＝7.6 Hz, 2H), 2.50~2.40 (m, 1H), 2.06~1.96 (m, 1H), 1.22 (t, J＝7.6 Hz, 3H), 1.01 (t, J＝7.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.9, 147.4, 145.0, 134.0, 138.3, 128.1, 127.8, 126.1, 126.1, 123.8, 123.2, 118.0, 56.1, 19.3, 18.0, 14.3, 13.5; FT-IR (film) ν: 3061, 3029, 1716, 1599, 1448, 1064 cm^－1; HRMS [APCI] calcd for C₁₉H₂₁ [M+H]⁺ 249.1638, found 249.1639.

3.2.2 螺环化合物5的合成

在5 mL的反应瓶中, 依次加入0.2 mmol芳基环醇(4a), 0.2 mmol二芳基乙炔(2), 400 mg 4Å MS和2.0 mL DCM, 然后加入0.22 mmol TiCl₄或AlCl₃.室温下搅拌30 min.反应结束后, 加水猝灭, 加DCM萃取, 有机层用无水硫酸钠干燥, 减压旋干溶剂, 经柱层析分离得到目标产物5.

2', 3'-二苯基螺[环丁烷-1, 1'-茚](5a):白色固体, 产率89%. m.p. 131~133 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.88~7.82 (m, 1H), 7.41~7.35 (m, 4H), 7.35~7.30 (m, 6H), 7.29~7.22 (m, 3H), 2.74~2.63 (m, 2H), 2.63~2.52 (m, 2H), 2.31~2.15 (m, 1H), 1.90~1.77 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 152.3, 149.5, 142.8, 138.1, 137.2, 135.1, 129.9, 129.5, 128.1, 128.1, 127.0, 126.9, 126.6, 125.8, 121.5, 120.2, 56.6, 29.1, 16.8; FT-IR (film) ν: 3050, 3023, 1592, 1454, 1238, 1027 cm^－1; HRMS [APCI] calcd for C₂₄H₂₁ [M+H]⁺ 309.1638, found 309.1640.

5'-溴-2', 3'-二苯基螺[环丁烷-1, 1'-茚](5b):白色固体, 产率67%. m.p. 140~141 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.72~7.67 (m, 1H), 7.57~7.44 (m, 2H), 7.44~7.35 (m, 3H), 7.34~7.22 (m, 7H), 2.73~2.61 (m, 2H), 2.61~2.46 (m, 2H), 2.30~2.16 (m, 1H), 1.91~1.77 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 150.5, 150.4, 144.5, 136.9, 136.1, 133.9, 129.2, 128.8, 127.8, 127.7, 127.7, 126.8, 126.7, 122.8, 122.4, 120.0, 55.9, 28.3, 16.2; FT-IR (film) ν: 3054, 2979, 1591, 1454, 1239, 1072 cm^－1; HRMS [APCI] calcd for C₂₄H₂₀Br [M+H]⁺ 387.0748, found 387.0752.

2', 3'-二(4-甲氧基苯基)螺[环丁烷-1, 1'-茚](5c):白色固体, 产率43%. m.p. 137~139 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.83~7.76 (m, 1H), 7.35~7.31 (m, 2H), 7.30~7.27 (m, 1H), 7.24~7.18 (m, 4H), 6.92~6.86 (m, 2H), 6.84~6.80 (m, 2H), 3.83 (s, 3H), 3.79 (s, 3H), 2.67~2.58 (m, 2H), 2.57~2.48 (m, 2H), 2.26~2.15 (m, 1H), 1.91~1.79 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 158.5, 158.3, 152.4, 148.5, 143.0, 137.4, 131.0, 130.6, 129.5, 127.6, 126.4, 125.5, 121.3, 120.1, 113.6, 113.5, 56.4, 55.2, 55.1, 29.1, 16.7; FT-IR (film) ν: 3002, 2935, 1574, 1503, 1458, 1239 cm^－1; HRMS [APCI] calcd for C₂₆H₂₅O₂ [M+H]⁺ 369.1855, found 369.1861.

2', 3'-二(4-氟苯基)螺[环丁烷-1, 1'-茚](5d):白色固体, 产率52%. m.p. 164~165 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.82~7.77 (m, 1H), 7.38~7.33 (m, 1H), 7.31~7.27 (m, 2H), 7.25~7.19 (m, 4H), 7.08~7.02 (m, 2H), 7.00~6.93 (m, 2H), 2.62~2.50 (m, 4H), 2.26~2.14 (m, 1H), 1.86~1.74 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 162.7 (d, J＝30.7 Hz), 160.2 (d, J＝30.8 Hz), 151.5, 148.1, 141.9, 137.1, 132.3 (d, J＝3.5 Hz), 130.9 (d, J＝7.9 Hz), 130.5 (d, J＝7.8 Hz), 130.3 (d, J＝3.3 Hz), 126.2, 125.5, 121.0, 119.6, 114.9 (d, J＝15.6 Hz), 114.7 (d, J＝15.7 Hz), 56.0, 28.5, 16.2; ¹⁹F NMR (376 MHz, CDCl₃) δ: －114.8 (s), －115.0 (s); FT-IR (film) ν: 3066, 2991, 1596, 1508, 1353, 1273 cm^－1; HRMS [APCI] calcd for C₂₄H₁₉F₂ [M+H]⁺ 345.1455, found 345.1461.

2', 3'-二(4-氯苯基)螺[环丁烷-1, 1'-茚](5e):白色固体, 产率51%. m.p. 169~170 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.85~7.79 (m, 1H), 7.41~7.32 (m, 3H), 7.31~7.26 (m, 4H), 7.25~7.14 (m, 4H), 2.72~2.45 (m, 4H), 2.29~2.16 (m, 1H), 1.90~1.77 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 151.6, 148.1, 141.6, 137.2, 134.8, 132.8, 132.7, 132.4, 130.6, 130.2, 128.1, 128.0, 126.2, 125.7, 121.1, 119.6, 56.1, 28.5, 16.2; FT-IR (film) ν: 3019, 2935, 1491, 1239, 1089, 1014 cm^－1; HRMS [APCI] calcd for C₂₄H₁₉Cl₂ [M+H]⁺ 377.0864, found 377.0865.

2', 3'-二(4-溴苯基)螺[环丁烷-1, 1'-茚](5f):白色固体, 产率73%. m.p. 146~147 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.80 (d, J＝7.6 Hz, 1H), 7.51~7.46 (m, 2H), 7.44~7.39 (m, 2H), 7.38~7.33 (m, 1H), 7.30~7.27 (m, 2H), 7.16~7.10 (m, 4H), 2.61~2.50 (m, 4H), 2.25~2.16 (m, 1H), 1.88~1.76 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 152.1, 148.5, 142.0, 137.6, 135.7, 133.7, 131.6, 131.5, 131.4, 131.0, 126.7, 126.2, 121.6, 121.5, 121.2, 120.1, 56.6, 29.0, 16.7; FT-IR (film) ν: 3061, 2929, 1480, 1463, 1069, 1009 cm^－1; HRMS [APCI] calcd for C₂₄H₁₉Br₂ [M+H]⁺ 464.9853, found 464.9868.

2', 3'-二(3-氟苯基)螺[环丁烷-1, 1'-茚](5g):白色固体, 产率42%. m.p. 151~152 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.82~7.77 (m, 1H), 7.39~7.27 (m, 4H), 7.24~7.20 (m, 1H), 7.05~6.88 (m, 6H), 2.63~2.49 (m, 4H), 2.25~2.14 (m, 1H), 1.87~1.75 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 163.4 (d, J＝4.2 Hz), 161.8 (d, J＝3.6 Hz), 151.9, 148.6, 141.9, 138.9 (d, J＝7.8 Hz), 137.6 (d, J＝1.2 Hz), 136.9 (d, J＝8.0 Hz), 129.7 (d, J＝8.6 Hz), 129.6 (d, J＝8.4 Hz), 126.7, 126.1, 125.6 (d, J＝2.6 Hz), 125.1 (d, J＝2.6 Hz), 121.5, 120.2, 116.6 (d, J＝21.2 Hz), 116.1 (d, J＝21.6 Hz), 114.2 (d, J＝20.9 Hz), 114.1 (d, J＝20.9 Hz), 56.6, 29.0, 16.7; ¹⁹F NMR (376 MHz, CDCl₃) δ: －113.1 (s), －113.3 (s); FT-IR (film) ν: 3063, 2952, 1579, 1428, 1263, 1181 cm^－1; HRMS [APCI] calcd for C₂₄H₁₉F₂ [M+H]⁺ 345.1455, found 345.1462.

2', 3'-二乙基螺[环丁烷-1, 1'-茚](5h):无色液体, 产率64%. ¹H NMR (400 MHz, CDCl₃) δ: 7.43~7.39 (m, 1H), 7.37~7.29 (m, 2H), 7.23~7.18 (m, 1H), 2.65~2.53 (m, 2H), 2.51~2.42 (m, 2H), 2.28 (q, J＝7.2 Hz, 2H), 2.23 (q, J＝7.2 Hz, 2H), 1.98~1.87 (m, 1H), 1.85~1.78 (m, 1H), 1.02 (t, J＝7.2 Hz, 3H), 1.00 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.2, 143.6, 133.5, 128.3, 126.0, 125.9, 52.0, 35.5, 29.8, 26.1, 16.2, 13.4, 12.3; FT-IR (film) ν: 2965, 2936, 1708, 1458, 1375, 1157 cm^－1; HRMS [APCI] calcd for C₁₆H₂₁ [M+H]⁺ 213.1643, found 213.1649.

4', 5'-二苯基螺[环丁烷-1, 6'-环戊烯并[b]噻吩](5i):白色固体, 产率35%. m.p. 134~135 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.43~7.32 (m, 6H), 7.32~7.26 (m, 3H), 7.25~7.16 (m, 3H), 2.68~2.57 (m, 2H), 2.40~2.25 (m, 3H), 1.84~1.74 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 155.3, 148.2, 142.6, 137.4, 134.7, 134.0, 130.0, 128.5, 128.3, 128.2, 127.2, 127.2, 125.3, 120.6, 55.4, 28.4, 17.4; FT-IR (film) ν: 2992, 2923, 1497, 1338, 1129, 1184 cm^－1; HRMS [APCI] calcd for C₂₂H₁₉S [M+H]⁺ 315.1207, found 315.1208.

2', 3'-二苯基螺[环己烷-1, 1'-茚](5j):白色固体, 产率80%. m.p. 172~173 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.95 (d, J＝7.2 Hz, 1H), 7.44~7.38 (m, 1H), 7.36~7.19 (m, 10H), 7.16~7.12 (m, 2H), 2.15~2.00 (m, 2H), 1.95~1.87 (m, 3H), 1.80~1.70 (m, 2H), 1.60~1.50 (m, 2H), 1.33~1.22 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 153.9, 151.3, 143.3, 138.0, 136.4, 134.7, 130.2, 129.0, 127.4, 127.3, 126.4, 126.3, 126.0, 124.4, 124.0, 120.2, 54.2, 31.1, 24.7, 21.9; FT-IR (film) ν: 3053, 3029, 1600, 1461, 1075, 1029 cm^－1; HRMS [APCI] calcd for C₂₆H₂₅ [M+ H]⁺ 337.1956, found 337.1957.

2', 3', 4-三苯基螺[环己烷-1, 1'-茚](5k):白色固体, 产率82%. m.p. 181~182 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.12~8.05 (m, 1H), 7.50~7.45 (m, 1H), 7.44~7.28 (m, 15H), 7.24~7.21 (m, 2H), 2.67~2.58 (m, 1H), 2.43~2.32 (m, 2H), 2.20~2.10 (m, 2H), 2.08~2.00 (m, 2H), 1.76~1.68 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 153.9, 151.4, 147.4, 144.0, 138.9, 136.6, 135.1, 130.8, 129.5, 128.6, 128.0, 128.0, 127.0, 126.9, 126.9, 126.7, 126.2, 124.9, 124.7, 120.9, 54.1, 43.2, 31.9, 30.1; FT-IR (film) ν: 3054, 2930, 1598, 1440, 1358, 1068 cm^－1; HRMS [APCI] calcd for C₃₂H₂₉ [M+H]⁺ 413.2269, found 413.2276.

4, 4-二甲基-2', 3'-二苯基螺[环己烷-1, 1'-茚](5l):白色固体, 产率87%. m.p. 169~170 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.90 (d, J＝7.6 Hz, 1H), 7.46~7.41 (m, 1H), 7.39~7.27 (m, 9H), 7.26~7.23 (m, 1H), 7.22~7.19 (m, 2H), 2.17 (ddd, J＝13.6, 13.6, 4.0 Hz, 2H), 2.04 (ddd, J＝13.6, 13.6, 3.6 Hz, 2H), 1.52~1.40 (m, 4H), 1.16 (s, 3H), 0.85 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 153.7, 151.4, 143.2, 138.1, 136.4, 134.7, 130.1, 129.0, 127.5, 127.3, 126.4, 126.3, 126.0, 124.0, 124.0, 120.2, 53.9, 34.9, 32.2, 28.8, 27.0, 24.3; FT-IR (film) ν: 3081, 2942, 1494, 1440, 1344, 1200 cm^－1; HRMS [APCI] calcd for C₂₈H₂₉ [M+ H]⁺ 365.2269, found 365.2273.

3, 3, 5, 5-四甲基-2', 3'-二苯基螺[环己烷-1, 1'-茚](5m):白色固体, 产率46%. m.p. 122~123 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.69~7.62 (m, 1H), 7.32~7.21 (m, 10H), 7.20~7.16 (m, 3H), 2.20 (d, J＝14.4 Hz, 2H), 1.67 (d, J＝14.0 Hz, 1H), 1.48 (d, J＝15.2 Hz, 2H), 1.40 (d, J＝14.0 Hz, 1H), 1.07 (s, 6H), 0.77 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 156.0, 154.6, 143.3, 138.1, 136.9, 135.2, 131.1, 129.4, 127.9, 127.7, 126.9, 126.7, 125.9, 124.9, 124.7, 120.5, 56.3, 50.1, 39.9, 34.1, 32.5, 30.5; FT-IR (film) ν: 2989, 2897, 1470, 1438, 1364, 1028 cm^－1; HRMS [APCI] calcd for C₃₀H₃₃ [M+H]⁺ 393.2582, found 393.2582.

(1R, 3S, 5r, 7r)-2', 3'-二苯基螺[金刚烷-2, 1'-茚](5n):白色固体, 产率93%. m.p. 135~136 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.29~7.27 (m, 1H), 7.23~7.15 (m, 6H), 7.15~7.12 (m, 1H), 7.11~7.05 (m, 1H), 7.03~6.96 (m, 3H), 6.80~6.73 (m, 2H), 3.20 (t, J＝4.4 Hz, 1H), 2.92 (d, J＝2.4 Hz, 1H), 2.68~2.62 (m, 1H), 2.40~2.31 (m, 1H), 2.08~1.96 (m, 3H), 1.96~1.86 (m, 3H), 1.86~1.80 (m, 1H), 1.79~1.69 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 146.0, 142.4, 141.8, 137.5, 136.4, 128.1, 127.8, 127.5, 127.3, 127.2, 127.2, 126.0, 125.5, 125.0, 59.5, 50.5, 48.2, 35.4, 34.8, 32.1, 31.3, 29.2, 25.9, 25.9; FT-IR (film) ν: 3075, 2911, 1573, 1442, 1185, 1078 cm^－1; HRMS [APCI] calcd for C₃₀H₂₉ [M+H]⁺ 389.2269, found 389.2270.

1', 2'-二苯基螺[环己烷-1, 3'-环戊烯并[a]萘](5o):白色固体, 产率60%. m.p. 201~202 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.11 (d, J＝8.4 Hz, 1H), 7.88 (d, J＝8.4 Hz, 1H), 7.77 (d, J＝8.4 Hz, 1H), 7.41 (d, J＝8.8 Hz, 1H), 7.34 (ddd, J＝8.0. 6.8, 0.8 Hz, 1H), 7.28~7.22 (m, 7H), 7.21~7.16 (m, 1H), 7.15~7.10 (m, 1H), 7.10~7.06 (m, 2H), 2.18~2.03 (m, 2H), 2.00~1.90 (m, 2H), 1.91~1.84 (m, 1H), 1.82~1.70 (m, 2H), 1.66~1.60 (m, 2H) 1.40~1.32 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 156.6, 150.3, 140.1, 138.2, 138.1, 136.9, 133.3, 130.7, 129.9, 128.5, 128.4, 127.9, 127.5, 126.7, 126.6, 125.0, 125.0, 124.6, 123.1, 54.3, 31.6, 25.2, 22.5; FT-IR (film) ν: 3052, 2916, 1514, 1460, 1234, 1071 cm^－1; HRMS [APCI] calcd for C₃₀H₂₇ [M+H]⁺ 387.2113, found 387.2122.

2', 3'-二苯基螺[环庚烷-1, 1'-茚](5p):白色固体, 产率77%. m.p. 161~162 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.69~7.62 (m, 1H), 7.32~7.24 (m, 6H), 7.24~7.20 (m, 4H), 7.20~7.13 (m, 3H), 2.14 (dd, J＝14.8, 9.6 Hz, 2H), 1.89~1.70 (m, 4H), 1.68~1.57 (m, 2H), 1.53~1.36 (m, 4H); ¹³C NMR (150 MHz, CDCl₃) δ: 154.7, 154.3, 142.9, 137.4, 137.4, 135.0, 130.3, 129.4, 127.8, 127.7, 126.7, 126.6, 126.4, 125.1, 122.5, 120.5, 57.8, 35.8, 31.9, 25.2; FT-IR (film) ν: 2925, 2851, 1466, 1439, 1075, 1030 cm^－1; HRMS [APCI] calcd forC₂₇H₂₇ [M+H]⁺ 351.2107, found 351.2113.

2', 3'-二苯基螺[环辛烷-1, 1'-茚](5q):白色固体, 产率62%. m.p. 123~124 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.58~7.53 (m, 1H), 7.38~7.34 (m, 1H), 7.33~7.31 (m, 3H), 7.30~7.23 (m, 6H), 7.23~7.18 (m, 3H), 2.32~2.14 (m, 2H), 1.89~1.71 (m, 6H), 1.57~1.50 (m, 2H), 1.43~1.31 (m, 4H); ¹³C NMR (150 MHz, CDCl₃) δ: 155.9, 151.6, 143.4, 137.8, 137.0, 135.0, 130.1, 129.5, 127.8, 127.6, 126.7, 126.6, 126.4, 124.8, 123.6, 120.6, 58.2, 31.3, 29.2, 26.1, 25.2; FT-IR (film) ν: 3023, 2924, 1572, 1441, 1239, 1028 cm^－1; HRMS [APCI] calcd for C₂₇H₂₇ [M+H]⁺ 365.2269, found 365.2277.

2', 3'-二苯基螺[环十二烷-1, 1'-茚](5r):白色固体, 产率91%. m.p. 135~136 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.56~7.50 (m, 1H), 7.34~7.30 (m, 1H), 7.30~7.27 (m, 2H), 7.26~7.24 (m, 2H), 7.24~7.21 (m, 4H), 7.21~7.19 (m, 3H), 7.18~7.16 (m, 1H), 2.02~1.94 (m, 2H), 1.86~1.77 (m, 2H), 1.50~1.31 (m, 18H); ¹³C NMR (150 MHz, CDCl₃) δ: 154.0, 151.9, 143.1, 138.7, 138.7, 135.2, 130.0, 129.6, 127.8, 127.7, 126.6, 126.5, 126.3, 124.5, 123.5, 120.4, 58.2, 31.9, 27.5, 26.2, 23.4, 23.2, 21.3; FT-IR (film) ν: 3061, 2961, 1490, 1261, 1072, 1028 cm^－1; HRMS [APCI] calcd for C₃₂H₃₇ [M+H]⁺ 421.2895, found 421.2906.

辅助材料(Supporting Information) 化合物3a~3h和5a~5r的¹H NMR、¹³C NMR和¹⁹F NMR谱图.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.

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图 1 路易斯酸促进的碳正离子与炔烃的环化反应

Figure 1 Lewis acid-promoted cyclization of carbocation with alkynes

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图 2 反应机理

Figure 2 Proposed reaction mechanism

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表 1 茚的反应条件优化^a

Table 1. Optimization of reaction conditions for indene^a


Entry	Lewis acid	Dehydrating agent	Solvent	Yield^b/%
1	AlCl₃	Na₂SO₄ (2.0 equiv.)	DCM	23
2	AlCl₃	MgSO₄ (2.0 equiv.)	DCM	29
3^c	AlCl₃	4Å MS	DCM	52
4^d	AlCl₃	4Å MS	DCM	63
5	AlCl₃	4Å MS	DCM	68
6	AgOTf	4Å MS	DCM	< 5
7	Sc(OTf)₃	4Å MS	DCM	55
8	Gd(OTf)₃	4Å MS	DCM	< 5
9	BF₃•Et₂O	4Å MS	DCM	65
10	FeCl₃	4Å MS	DCM	85
11	ZnCl₂	4Å MS	DCM	0
12^e	TiCl₄	4Å MS	DCM	87
13^e	TiCl₄	4Å MS	CH₃CN	0
14^e	TiCl₄	4Å MS	CHCl₃	84
15^e	TiCl₄	4Å MS	C₆H₅F	83
16^e	TiCl₄	4Å MS	DMF	0
17^e	TiCl₄	4Å MS	THF	0
18^e	TiCl₄	4Å MS	DCE	0
19^{e, f}	TiCl₄	4Å MS	DCM	88
20^{e, g}	AlCl₃	4Å MS	DCM	90
^aReaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), 4Å MS (400 mg), and Lewis acid (20 mol%) in 2 mL of DCM at r.t., 5 h. ^b Yields of isolated products. ^c 100 mg of 4Å MS was used. ^d 300 mg of 4Å MS was used. ^e Reaction time: 30 min. ^f 0.22 mmol of TiCl_4. ^g 0.22 mmol of AlCl₃.

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表 2 二苯甲醇与炔烃合成茚^{a, b}

Table 2. Synthesis of indenes from benzhydrol and alkynes




^a Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol, 1.0 equiv.), TiCl₄ (0.04 mmol, 20 mol%), and 4Å MS (400 mg) in dry DCM (2.0 mL) at r.t.. ^b Yield of isolated products. ^c1.1 equiv. of TiCl₄.

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表 3 芳基取代环醇与炔烃合成螺环茚^a^, ^b

Table 3. Synthesis of spiroindenes from 1-aryl cycloalkanols and alkynes




^a Conditions: 4 (0.2 mmol), 2 (0.2 mmol, 1.0 equiv.), TiCl₄ (0.22 mmol, 1.1 equiv.), and 4Å MS (400 mg) in dry DCM (2.0 mL) at r.t. ^b Yield of isolated products. ^c1.1 equiv. of AlCl₃ instead of TiCl₄. ^dReaction time is 1 h.

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