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• Betti碱由20世纪初意大利化学家Betti首次合成^[1]. Betti碱及其衍生物具有1, 3-氨基酚的结构(图 1), 是构成具有生物活性的天然产物和药物分子的关键组分, 比如抗菌剂^[2]、杀真菌剂^{[3, 4]}、抗肿瘤^{[5, 6]}以及抗结核^[7]等.除此之外, Betti碱及其衍生物的1, 3-氨基酚配体结构能与许多金属离子生成稳定的六元环配位结构.作为手性配体, Betti碱具有的手性碳原子分别与萘环和苯环相连接, 从而使底物在与配体中心接近时具有更好的立体选择性.因此Betti碱及其衍生物在催化不对称合成和手性辅助合成中显示出优良的催化活性^[8~10].

  图 1

  

  图 1.  贝蒂碱结构通式

  Figure 1.  General structure of a Betti base

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  目前Betti碱的制备方法主要是使用Betti反应将醛、胺和酚三组分制备得到Betti碱, 该反应体系主要通过酸性催化剂来促进反应的进行, 比如SnCl₄·5H₂O^[11]、聚合物负载的磺酸^[12]、离子液体^[13]等, 这些合成方法有一个或多个限制, 如长反应时间长、收率低、反应条件苛刻、使用腐蚀性或有毒试剂、价格昂贵、操作困难等.因此亟需发展一种高效环保构建Betti碱的合成方法.

  邻亚甲基苯醌化合物是一类非常活泼和重要的中间体, 被广泛应用于天然产物和药物化学中^[14~17].因为邻亚甲基苯醌化合物应用广泛, 其制备方法研究一直是有机合成专家关注的热点.现在已经有很多方法来制备这类化合物, 例如热解、光化学反应、酸性和碱性条件等^{[18, 19]}, 但反应条件较为苛刻.关于邻亚甲基苯醌的反应类型主要分为三类:亲核加成反应、环加成反应和6π电环化反应(Scheme 1)^[20~32].邻亚甲基苯醌的反应研究已经有较长的历史, 而基于P、S和N杂原子的迈克尔加成反应较为成熟^[33~35], 其中, 邻亚甲基苯醌的氮杂迈克尔加成反应是构建含氮有机化合物的高效合成方法, 近年来有机化学家对该类反应进行了深入的研究^[36~45], 同时, 药物化学家和生物化学家们使用该类反应发现了较多具有生物活性的药物分子^{[46, 47]}.但是大部分的反应方法仍然需要使用酸碱性催化剂.这样的反应方法不适用于制备含有对酸碱敏感官能团的化合物, 且在反应结束后体系需要中和至中性, 后处理操作繁琐.

  图式 1

  

  图式 1.  邻亚甲基苯醌的反应类型

  Scheme 1.  Reaction type of o-quinone

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  基于以上的研究背景和本课题组^[48]在邻亚甲基苯醌迈克尔加成领域的研究, 我们希望发展绿色环保简单高效的胺对邻亚甲基苯醌的氮杂迈克尔加成反应的方法.本工作以2-(羟基(苯基)甲基)苯酚类化合物和胺为原料, 1, 2-二氯乙烷为溶剂, 在Sc(Ⅲ)促进下原位生成邻亚甲基苯醌, 并发生氮杂迈克尔加成反应合成贝蒂碱衍生物(Eq. 1).反应在封管条件下90 ℃搅拌4 h完成, 以76%~96%的产率得到目标产物.产物的结构经¹H NMR、¹³C NMR和高分辨质谱确证.

  (1)

  1.   结果与讨论

  1.1   反应条件的优化

  首先以2-(羟基(苯基)甲基)苯酚(1a)和硫代吗啉(2a)为原料, 当以1, 2-二氯乙烷烷(DCE)为溶剂时, 分别以Ga(OTf)₃, In(OTf)₃, Y(OTf)₃, Yb(OTf)₃, AlCl₃和CuI为催化剂, 在80 ℃下反应6 h后均没有获得目标产物(Entries 1~6, 表 1).当催化剂为Sc(OTf)₃时, 可获得75%收率的产物(Entry 7, 表 1).然而, 当以Sc(OTf)₃为催化剂, 分别以甲苯(Toluene)、N, N-二甲基甲酰胺(DMF)和1, 4-二氧六环(1, 4-Dioxane)为溶剂时, 在同样的反应条件下, 产物收率都有所降低(Entries 8~10, 表 1).之后, 对反应温度进行了考察, 使用封管反应, 当升高反应温度至90 ℃, 收率上升至92% (Entry 11, 表 1).但是当温度再次升高到100 ℃时, 收率下降到82%(Entry 12, 表 1).然后, 考察了反应时间, 在90 ℃反应时, 将反应时间缩短到4 h, 产物的收率没有变化(92%, Entry 13, 表 1), 但是当反应时间缩短至3 h, 产物的收率下降至78% (Entry 14, 表 1).接着, 对催化剂用量进行了考察.当催化剂用量降至5 mol%时, 产率只有80% (Entry 15, 表 1).当提升催化剂用量至20 mol%时, 产率变化不大(93%, Entry 16, 表 1).因此, 该反应的最佳反应条件是以10 mol% Sc(OTf)₃为催化剂、1, 2-二氯乙烷(DCE)为溶剂、90 ℃下反应4 h.

  表 1

  

  表 1  反应条件优化^a

  Table 1.  Optimization of reaction conditions

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  Entry	Catalyst	Solvent	Temperature/℃	Time/h	Yieldb/%
  1	Ga(OTf)3	DCE	80	8	0
  2	In(OTf)3	DCE	80	8	0
  3	Y(OTf)3	DCE	80	8	0
  4	Yb(OTf)3	DCE	80	8	0
  5	AlCl3	DCE	80	8	0
  6	CuI	DCE	80	8	0
  7	Sc(OTf)3	DCE	80	8	75
  8	Sc(OTf)3	Toluene	80	8	65
  9	Sc(OTf)3	DMF	80	8	21
  10	Sc(OTf)3	1, 4-Dioxane	80	8	62
  11	Sc(OTf)3	DCE	90	8	92
  12	Sc(OTf)3	DCE	100	8	82
  13	Sc(OTf)3	DCE	90	4	92
  14	Sc(OTf)3	DCE	90	3	78
  15c	Sc(OTf)3	DCE	90	2	80
  16d	Sc(OTf)3	DCE	90	2	93
  a Reaction conditions: 2-(hydroxy(phenyl)methyl)phenol (1a, 2.0 mmol), thio- morpholin (2a, 2.4 mmol), solvent (1 mL), run with 10 mol% Sc(OTf)3; b isolated yield; c run with 5 mol% Sc(OTf)3; d run with 20 mol% Sc(OTf)3.

  1.2   底物的扩展

  在获得最佳反应条件后, 本工作将该催化体系应用到2-(羟基(苯基)甲基)苯酚类化合物1与仲胺2的反应中, 来考察该催化体系的底物适用性(表 2).从表 2可以看出, 对于2-(羟基(苯基)甲基)苯酚类化合物, 取代基为给电子的烷基、烷氧基或者为吸电子的卤素等都可以顺利地发生氮杂迈克尔加成反应得到相应的产物, 该反应对不同取代基的兼容性较好.芳环上不同位置的取代基电子效应对反应的产率有一定的影响:当苯环上的不同位置含甲基、叔丁基、甲氧基和乙氧基等供电子取代基时, 可获得优秀收率的产物(90%~96%, 表 2).当取代基是吸电子氯时, 收率下降, 可以得到中等收率的产物(84%~88%), 而当取代基为吸电子效应更强的氟时, 产物的收率进一步的下降但仍能以中等的收率得到相应的产物(78%~84%).对于不同的仲胺, 比如硫代吗啉、吗啉、3-(4-甲氧基苯基)吗啉、4-(4-哌啶基)吗啉、N-甲基-1-苯基甲胺、N-甲基-1-丁胺, 都可以很好地与原位生成的邻亚甲基苯醌发生氮杂迈克尔加成反应, 收率从中等到优秀不等(78%~92%, 表 2).

  表 2

  

  表 2  底物扩展^a

  Table 2.  Exploration of substrate scope

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  a Reaction conditions: o-hydroxybenzyl alcohols 1 (2.0 mmol), secondary amines 2 (2.4 mmol), DCE (1 mL), performed in a sealed tube at 90 ℃, 4 h. Isolated yield.

  为了进一步考察Sc(OTf)₃催化发生氮杂迈克尔加成反应的底物适用性, 将该催化体系应用到各种苄胺4的合成中(表 3).对于2-[羟基(苯基)甲基]苯酚类化合物, 当苯环上的不同位置含甲基、叔丁基、甲氧基和乙氧基等供电子取代基时, 可获得优秀收率的产物(90%~95%, 表 3).当取代基是吸电子氯时, 收率下降, 可以得到中等收率的产物(82%~88%); 而当取代基为吸电子效应更强的氟时, 产物的收率进一步的下降, 但仍能以中等的收率得到相应的产物(76%~82%).对于不同的苄胺, 比如2, 6-二氯苄胺、邻甲基苄胺、间氯苄胺、间甲基苄胺、对溴苄胺、对氟苄胺、对碘苄胺、对甲基苄胺和2-噻吩甲胺, 都可以很好地发生氮杂迈克尔加成反应(表 3), 当苄胺带有给电子基团, 比如甲基, 与带有吸电子取代基(F、Cl、Br和I)的苄胺相比, 收率较高(表 3).实验表明, 不同的苄胺都可以很好地与原位生成的邻亚甲基苯醌发生氮杂迈克尔加成反应.

  表 3

  

  表 3  1与各种苄胺的反应^a

  Table 3.  Reaction of 1 with various benzylamine

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  a Reaction conditions: o-hydroxybenzyl alcohols 1 (2.0 mmol), benzylamines 2 (2.4 mmol), DCE (1 mL), performed in a sealed tube at 90 ℃, 4 h. Isolated yield.

  1.3   反应机理研究

  基于以上的实验结果, 我们提出了一个可能的反应机理(Scheme 2):首先由Sc(OTf)₃催化2-(羟基(苯基)甲基)苯酚类化合物1生成邻亚甲基苯醌中间体, 而后仲胺或者苄胺对邻亚甲基苯醌中间体进行氮杂迈克尔加成反应即得到了最终产物3或5.

  图式 2

  

  图式 2.  可能的反应机理

  Scheme 2.  Proposed reaction mechanism

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  2.   结论

  报道了以2-(羟基(苯基)甲基)苯酚类化合物和胺为原料, 1, 2-二氯乙烷为溶剂, 在Sc(Ⅲ)促进下原位生成邻亚甲基苯醌, 并发生氮杂迈克尔加成反应合成贝蒂碱衍生物.在该催化体系下, 不同的2-(羟基(苯基)甲基)苯酚类化合物与各种仲胺和苄胺都可顺利反应, 收率最高可达96%.该体系具有催化剂廉价易得、反应条件较为温和、底物适应性良好等优点.

  3.   实验部分

  3.1   仪器与试剂

  Bruker AV400型核磁共振仪, CDCl₃或DMSO-d₆为溶剂, TMS为内标; Agilent Q-TOF 6510型高分辨质谱仪, 电喷雾离子化技术(ESI), 直接进样法进样.柱层析使用200~300目硅胶.

  3.2   实验方法

  在38 mL厚壁耐压瓶中加入2-[羟基(苯基)甲基]苯酚类化合物1 (0.2 mmol)、胺类化合物(0.24 mmol)、1, 2-二氯乙烷(2.0 mL)和Sc(OTf)₃ (9.8 mg, 10 mol%), 然后在90 ℃温度下封管搅拌反应4 h.反应停止后, 自然降温至室温, 而后向反应液中加入6 mL水, 再用二氯甲烷(6 mL×3)萃取, 有机相用无水Na₂SO₄干燥, 过滤后, 所得滤液旋蒸除去溶剂得到粗产品.粗产品经柱层析提纯得到目标化合物.洗脱剂为石油醚和乙酸乙酯(V: V＝40:1).薄层色谱(TLC)检测洗脱进程, 合并收集液并旋蒸除去洗脱剂得到相应的纯品, 计算收率.所有目标化合物的结构经核磁共振氢谱、碳谱以及高分辨质谱表征.

  2-[苯基(硫代吗啉)甲基]苯酚(3a):白色固体, 产率92%. m.p. 85.2~87.4 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 11.72 (s, 1H), 7.36 (d, J＝7.1 Hz, 2H), 7.33~7.22 (m, 3H), 7.12~7.08 (m, 1H), 6.86 (dd, J＝10.9, 4.2 Hz, 2H), 6.68 (td, J＝7.5, 0.9 Hz, 1H), 4.56 (s, 1H), 2.82~2.73 (m, 2H), 2.70~2.64 (m, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ: 156.69, 138.37, 129.49, 128.95, 128.93, 128.75, 128.21, 124.72, 119.45, 117.05, 76.34, 53.23, 28.13; HRMS (ESI) calcd for C₁₇H₂₀NOS [M+H]⁺ 286.1260, found 286.1261.

  2-[硫代吗啉(间甲苯基)甲基]苯酚(3b):白色固体, 产率94%. m.p. 65.5~68.2 ℃¹H NMR (400 MHz, CDCl₃) δ: 11.75 (s, 1H), 7.24~7.16 (m, 3H), 7.13~7.07 (m, 2H), 6.89~6.84 (m, 2H), 6.71~6.67 (m, 1H), 4.52 (s, 1H), 2.83~2.67 (m, 8H), 2.32 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 156.67, 138.57, 138.30, 129.48, 129.43, 128.96, 128.80, 128.64, 125.94, 124.78, 119.39, 116.99, 76.40, 53.24, 28.13, 21.58; HRMS (ESI) calcd for C₁₈H₂₂NOS [M+H]⁺ 300.1417, found 300.1417.

  2-[硫代吗啉(邻甲苯基)甲基]苯酚(3c):白色固体, 产率92%. m.p. 70.3~71.4℃; ¹H NMR (400 MHz, CDCl₃) δ: 11.84 (s, 1H), 7.51 (dd, J＝5.6, 3.2 Hz, 1H), 7.23~7.08 (m, 4H), 6.86~6.82 (m, 2H), 6.68 (td, J＝7.5, 1.0 Hz, 1H), 4.98 (s, 1H), 2.90~2.70 (m, 8H), 2.47 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 156.76, 137.43, 135.89, 130.94, 129.16, 128.57, 128.53, 127.75, 127.10, 125.37, 119.47, 117.17, 70.08, 52.95, 28.33, 20.84; HRMS (ESI) calcd for C₁₈H₂₂NOS [M+H]⁺ 300.1417, found 300.1415.

  2-[硫代吗啉(对甲苯基)甲基]苯酚(3d):白色固体, 产率95%. m.p. 72.6~74.5 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 11.76 (s, 1H), 7.24 (d, J＝7.9 Hz, 2H), 7.12~7.07 (m, 3H), 6.85 (dd, J＝11.0, 4.4 Hz, 2H), 6.67 (td, J＝7.5, 1.0 Hz, 1H), 4.53 (s, 1H), 2.81~2.63 (m, 8H), 2.29 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 156.75, 137.94, 135.29, 129.62, 129.46, 128.88, 128.66, 124.90, 119.42, 117.00, 76.01, 53.17, 28.15, 21.16; HRMS (ESI) calcd for C₁₈H₂₂NOS [M+H]⁺ 300.1417, found 300.1416.

  4-甲基-2-[苯基(硫代吗啉)甲基]苯酚(3e):白色固体, 产率94%. m.p. 54.3~56.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 11.43 (s, 1H), 7.37 (d, J＝7.2 Hz, 2H), 7.26 (ddd, J＝10.8, 9.7, 5.4 Hz, 3H), 6.90 (dd, J＝8.2, 1.6 Hz, 1H), 6.75 (d, J＝8.2 Hz, 1H), 6.69 (s, 1H), 4.46 (s, 1H), 2.82~2.63 (m, 8H), 2.12 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 154.11, 138.92, 129.91, 129.26, 128.99, 128.83, 128.49, 128.15, 124.53, 116.86, 76.54, 53.40, 28.14, 20.56; HRMS (ESI) calcd for C₁₈H₂₂NOS [M+H]⁺ 300.1417, found 300.1417.

  2-叔丁基-6-[苯基(硫代吗啉)甲基]苯酚(3f):无色油状液体, 产率93%. ¹H NMR (400 MHz, CDCl₃) δ: 12.14 (s, 1H), 7.39 (d, J＝6.9 Hz, 2H), 7.34~7.25 (m, 3H), 7.15 (dd, J＝7.7, 1.4 Hz, 1H), 6.75 (d, J＝7.1 Hz, 1H), 6.64 (t, J＝7.6 Hz, 1H), 4.59 (s, 1H), 2.80 (d, J＝53.0 Hz, 8H), 1.44 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz) δ: 155.86, 138.39, 137.27, 129.00, 128.85, 128.07, 127.50, 125.84, 124.56, 118.44, 76.72, 52.95, 34.84, 29.47, 27.97; HRMS (ESI) calcd for C₂₁H₂₈NOS [M+H]⁺ 342.1886, found 342.1885.

  4-甲氧基-2-[苯基(硫代吗啉)甲基]苯酚(3g):白色固体, 产率96%. m.p. 113.2~115.5 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 11.21 (s, 1H), 7.38 (d, J＝7.1 Hz, 2H), 7.32~7.24 (m, 3H), 6.79 (d, J＝8.8 Hz, 1H), 6.68 (dd, J＝8.8, 3.0 Hz, 1H), 6.47 (d, J＝2.9 Hz, 1H), 4.49 (s, 1H), 3.63 (s, 3H), 2.83~2.65 (m, 8H); ¹³C NMR (CDCl₃, 100 MHz) δ: 152.60, 150.28, 138.41, 128.96, 128.86, 128.22, 125.39, 117.42, 115.23, 113.65, 76.43, 55.64, 53.30, 28.10; HRMS (ESI) calcd for C₁₈H₂₂NO₂S [M+H]⁺ 316.1366, found 316.1366.

  2-乙氧基-6-[苯基(硫代吗啉)甲基]苯酚(3h):白色固体, 产率95%. m.p. 117.1~119.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 11.75 (s, 1H), 7.39 (d, J＝7.1 Hz, 2H), 7.28 (dt, J＝6.9, 4.5 Hz, 3H), 6.75 (dd, J＝8.0, 1.0 Hz, 1H), 6.64 (t, J＝7.9 Hz, 1H), 6.53 (d, J＝7.6 Hz, 1H), 4.57 (s, 1H), 4.08 (q, J＝7.0 Hz, 2H), 2.86~2.68 (m, 8H), 1.49 (t, J＝7.0 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 147.64, 146.17, 138.64, 128.86, 128.84, 128.08, 125.17, 121.21, 118.94, 111.96, 75.99, 64.28, 53.33, 28.10, 15.00; HRMS (ESI) calcd for C₁₉H₂₄NO₂S [M+H]⁺ 330.1522, found 330.1520.

  2-([1, 1'-二苯基]-4-基(硫代吗啉)甲基)苯酚(3i):白色固体, 产率90%. m.p. 112.5~114.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 11.74 (s, 1H), 7.54 (dd, J＝8.1, 2.3 Hz, 4H), 7.52~7.40 (m, 4H), 7.33 (t, J＝7.3 Hz, 1H), 7.16~7.11 (m, 1H), 6.93~6.92 (m, 1H), 6.88 (d, J＝8.1 Hz, 1H), 6.74~6.70 (m, 1H), 4.61 (s, 1H), 2.88~2.69 (m, 8H); ¹³C NMR (CDCl₃, 100 MHz) δ: 156.67, 141.07, 140.43, 137.35, 129.45, 129.29, 128.84, 128.80, 127.62, 127.50, 127.04, 124.67, 119.51, 117.10, 76.04, 53.27, 28.14; HRMS (ESI) calcd for C₂₃H₂₄NOS [M+H]⁺ 362.1573, found 362.1575.

  4-氯-2-[苯基(硫代吗啉)甲基]苯酚(3j):白色固体, 产率88%. 95.3~96.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 11.84 (s, 1H), 7.36~7.29 (m, 5H), 7.06 (dd, J＝8.7, 2.5 Hz, 1H), 6.86 (d, J＝2.5 Hz, 1H), 6.79 (d, J＝8.7 Hz, 1H), 4.52 (s, 1H), 3.05~2.55 (m, 8H); ¹³C NMR (CDCl₃, 100 MHz) δ: 155.41, 137.56, 129.09, 128.84, 128.60, 128.52, 126.19, 123.87, 118.43, 118.40, 75.94, 53.18, 28.04; HRMS (ESI) calcd for C₁₇H₁₉ClNOS [M+H]⁺ 320.0870, found 320.0872.

  2-(4-氯苯基)(硫代吗啉)苯酚(3k):白色固体, 产率84%. m.p. 102.5~104.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 11.57 (s, 1H), 7.30 (q, J＝8.7 Hz, 4H), 7.14~7.10 (m, 1H), 6.85 (d, J＝8.1 Hz, 2H), 6.70 (td, J＝7.6, 1.0 Hz, 1H), 4.54 (s, 1H), 2.82~2.69 (m, 8H); ¹³C NMR (CDCl₃, 100 MHz) δ: 156.47, 137.02, 134.05, 130.17, 129.29, 129.16, 128.96, 124.28, 119.61, 117.21, 75.61, 53.24, 28.07; HRMS (ESI) calcd for C₁₇H₁₉ClNOS [M+H]⁺ 320.0870, found 320.0870.

  2-[(3-氟苯基)(硫代吗啉)甲基]苯酚(3l):白色固体, 产率82%. m.p. 115.3~117.5 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 11.52 (s, 1H), 7.26 (dt, J＝7.8, 4.8 Hz, 1H), 7.13 (ddd, J＝8.0, 7.4, 4.7 Hz, 3H), 6.98~6.94 (m, 1H), 6.87 (dd, J＝9.5, 4.0 Hz, 2H), 6.71 (td, J＝7.6, 0.8 Hz, 1H), 4.54 (s, 1H), 2.83~2.67 (m, 8H); ¹³C NMR (CDCl₃, 100 MHz) δ: 162.98 (d, J＝245.6 Hz), 156.48, 141.08 (d, J＝6.7 Hz), 130.50 (d, J＝8.2 Hz), 129.34, 128.99, 124.46, 124.18, 119.59, 117.22, 115.63 (d, J＝21.6 Hz), 115.19 (d, J＝20.9 Hz), 75.87, 53.28, 28.07; HRMS (ESI) calcd for C₁₇H₁₉FNOS [M+H]⁺ 304.1166, found 304.1166.

  2-[(4-氟苯基)(硫代吗啉)甲基]苯酚(3m):白色固体, 产率78%. m.p. 119.6~121.3 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 11.66 (s, 1H), 7.35 (dd, J＝8.2, 5.5 Hz, 2H), 7.15~7.11 (m, 1H), 7.01 (t, J＝8.7 Hz, 2H), 6.86 (d, J＝8.0 Hz, 2H), 6.71 (dd, J＝11.6, 4.2 Hz, 1H), 4.57 (s, 1H), 2.84~2.73 (m, 8H); ¹³C NMR (CDCl₃, 100 MHz) δ: 162.48 (d, J＝245.9 Hz), 156.48, 134.22 (d, J＝3.2 Hz), 130.54 (d, J＝7.9 Hz), 129.32, 128.87, 124.53, 119.59, 117.15, 115.86, 75.49, 53.19, 28.07; HRMS (ESI) calcd for C₁₇H₁₉FNOS [M+H]⁺ 304.1166, found 304.1167.

  2-[吗啉(苯基)甲基]苯酚(3n):白色固体, 产率88%. m.p. 115.2~116.3 ℃(lit.^[49] m.p. 112~114 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 11.71 (s, 1H), 7.41 (d, J＝7.1 Hz, 2H), 7.30~7.21 (m, 3H), 7.13~7.09 (m, 1H), 6.94~6.92 (m, 1H), 6.86 (d, J＝8.1 Hz, 1H), 6.71 (td, J＝7.5, 0.9 Hz, 1H), 4.39 (s, 1H), 3.77~3.72 (m, 4H), 2.58~2.42 (m, 4H); ¹³C NMR (CDCl₃, 100 MHz) δ: 156.15, 139.33, 129.43, 128.97, 128.73, 128.57, 128.14, 124.84, 119.64, 117.08, 76.87, 66.92, 52.28; HRMS (ESI) calcd for C₁₇H₂₀NO₂ [M+H]⁺ 270.1489, found 270.1490.

  2-[吗啉(对甲苯基)甲基]苯酚(3o):白色固体, 产率90%. m.p. 110.3~111.2 ℃(lit.^[50] m.p. 110~111 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 11.74 (s, 1H), 7.29 (d, J＝7.6 Hz, 2H), 7.11~7.07 (m, 3H), 6.92 (dd, J＝7.6, 1.2 Hz, 1H), 6.85 (dd, J＝8.1, 0.8 Hz, 1H), 6.70 (td, J＝7.5, 1.0 Hz, 1H), 4.36 (s, 1H), 3.76~3.71 (m, 4H), 2.56~2.41 (m, 4H), 2.27 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 156.19, 137.88, 136.31, 129.63, 129.40, 128.64, 128.50, 125.04, 119.62, 117.03, 76.52, 66.95, 52.23, 21.11; HRMS (ESI) calcd for C₁₈H₂₂NO₂ [M+H]⁺ 284.1645, found 284.1647.

  4-甲氧基-2-[吗啉(苯基)甲基]苯酚(3p):白色固体, 产率92%. m.p. 87.4~89.2 ℃(lit.^[51] m.p. 87~89 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 11.21 (s, 1H), 7.42 (d, J＝7.1 Hz, 2H), 7.26 (dtd, J＝10.0, 7.5, 2.8 Hz, 3H), 6.79 (d, J＝8.8 Hz, 1H), 6.68 (dd, J＝8.8, 3.0 Hz, 1H), 6.51 (d, J＝2.9 Hz, 1H), 4.32 (s, 1H), 3.78~3.73 (m, 4H), 3.65 (s, 3H), 2.58~2.41 (m, 4H); ¹³C NMR (CDCl₃, 100 MHz) δ: 152.72, 149.80, 139.27, 128.96, 128.56, 128.17, 125.41, 117.50, 114.95, 113.80, 76.97, 66.91, 55.61, 52.32; HRMS (ESI) calcd for C₁₈H₂₂NO₃ [M+H]⁺ 300.1594, found 300.1595.

  2-[(3-氟苯基)(吗啉)甲基]苯酚(3q):白色固体, 产率87%. m.p. 135.2~137.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 11.52 (s, 1H), 7.29~7.11 (m, 4H), 6.97~6.93 (m, 2H), 6.89~6.86 (m, 1H), 6.74 (td, J＝7.5, 0.9 Hz, 1H), 4.38 (s, 1H), 3.80~3.76 (m, 4H), 2.60~2.43 (m, 4H); ¹³C NMR (CDCl₃, 100 MHz) δ: 163.00 (d, J＝245.5 Hz), 155.97, 141.92 (d, J＝6.4 Hz), 130.50 (d, J＝8.2 Hz), 129.31, 129.00, 124.27, 124.13, 119.76, 117.25, 115.42, 115.13 (d, J＝20.9 Hz); HRMS (ESI) calcd for C₁₇H₁₉FNO₂ [M+H]⁺ 288.1394, found 288.1394.

  2-{[3-(4-甲氧基苯基)吗啉](苯基)甲基}苯酚(3r):白色固体, 产率92%. m.p. 146.3~147.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 12.79 (s, 1H), 7.38~7.30 (m, 5H), 7.12~6.94 (m, 5H), 6.87~6.85 (m, 1H), 6.58 (dd, J＝11.0, 4.0 Hz, 1H), 6.47 (d, J＝7.8 Hz, 1H), 5.47 (s, 1H), 3.81 (s, 3H), 3.59 (dd, J＝9.7, 3.2 Hz, 1H), 3.43 (dd, J＝10.7, 2.2 Hz, 1H), 3.08~3.00 (m, 2H), 2.86~2.83 (m, 1H), 2.58~2.55 (m, 1H), 2.50~2.48 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ: 159.35, 158.65, 133.26, 133.00, 131.46, 129.95, 129.52, 128.75, 128.39, 128.11, 122.71, 118.56, 116.58, 114.61, 67.43, 66.11, 55.35, 49.97, 36.86, 28.05; HRMS (ESI) calcd for C₂₄H₂₆NO₃ [M+H]⁺ 376.1907, found 376.1908.

  2-[吗啉(邻甲苯基)甲基]苯酚(3s):白色固体, 产率90%. m.p. 46.2~48.5 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 11.87 (s, 1H), 7.60~7.58 (m, 1H), 7.14~7.09 (m, 4H), 6.91~6.84 (m, 2H), 6.69 (td, J＝7.5, 1.0 Hz, 1H), 4.87 (s, 1H), 3.76~3.71 (m, 4H), 2.64~2.62 (m, 2H), 2.49 (s, 3H), 2.46~2.45 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz) δ: 156.40, 137.97, 135.61, 130.91, 129.09, 128.60, 128.32, 127.71, 127.18, 125.32, 119.58, 117.25, 70.30, 67.03, 51.87, 20.91; HRMS (ESI) calcd for C₁₈H₂₂NO₂ [M+H]⁺ 284.1645, found 284.1648.

  2-[(4-吗啉哌啶-1-基)(苯基)甲基]苯酚(3t):白色固体, 产率82%. m.p. 83.5~85.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 12.11 (s, 1H), 7.39~7.25 (m, 5H), 7.13~7.08 (m, 1H), 6.90~6.84 (m, 2H), 6.69 (td, J＝7.5, 0.9 Hz, 1H), 4.46 (s, 1H), 3.71~3.69 (m, 4H), 3.23 (d, J＝10.5 Hz, 1H), 2.84~2.81 (m, 1H), 2.55~2.50 (m, 4H), 2.20 (tt, J＝11.2, 3.7 Hz, 1H), 2.11~2.10 (m, 1H), 1.97 (t, J＝11.3 Hz, 1H), 1.90~1.81 (m, 2H), 1.66 (ddd, J＝24.4, 12.2, 3.8 Hz, 1H), 1.53 (ddd, J＝15.5, 12.2, 3.7 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ: 156.85, 139.60, 129.26, 129.13, 128.80, 128.59, 128.45, 127.95, 125.43, 119.21, 116.95, 75.98, 67.24, 61.59, 52.37, 49.81, 49.73, 28.38, 28.33; HRMS (ESI) calcd for C₂₂H₂₉N₂O₂ [M+H]⁺ 353.2224, found 353.2224.

  2-[(苄基(甲基)胺)(苯基)甲基]苯酚(3u):白色固体, 产率80%. m.p. 80.2~81.4 ℃(lit.^[49] m.p. 80~81 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 12.34 (s, 1H), 7.47 (d, J＝7.3 Hz, 2H), 7.36~7.24 (m, 8H), 7.15~7.11 (m, 1H), 6.91 (t, J＝7.4 Hz, 2H), 6.71 (dd, J＝11.6, 4.2 Hz, 1H), 4.70 (s, 1H), 3.55 (s, 2H), 2.16 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 156.99, 137.23, 129.34, 129.19, 129.03, 128.86, 128.71, 128.68, 128.65, 128.12, 127.61, 125.42, 119.24, 117.01, 75.55, 59.65, 39.19; HRMS (ESI) calcd for C₂₁H₂₂NO [M+H]⁺ 304.1696, found 304.1695.

  2-[(丁基(甲基)胺)(苯基)甲基]苯酚(3v):无色油状液体, 产率78%. ¹H NMR (400 MHz, CDCl₃) δ: 12.53 (s, 1H), 7.40 (d, J＝7.1 Hz, 2H), 7.34~7.26 (m, 3H), 7.13~7.09 (m, 1H), 6.87~6.84 (m, 2H), 6.70~6.66 (m, 1H), 4.60 (s, 1H), 2.44~2.38 (m, 2H), 2.26 (s, 3H), 1.53~1.52 (m, 2H), 1.29 (dd, J＝14.4, 7.3 Hz, 2H), 0.87 (t, J＝7.3 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 157.33, 139.00, 129.03, 128.96, 128.65, 128.45, 127.89, 125.57, 118.90, 116.84, 75.63, 54.49, 38.94, 29.10, 20.38, 13.92; HRMS (ESI) calcd for C₁₈H₂₄NO [M+H]⁺ 270.1852, found 270.1855.

  2-氟-6-[吗啉(苯基)甲基]苯酚(3w):白色固体, 产率82%. m.p. 135.3~137.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 12.19 (s, 1H), 7.31 (ddd, J＝27.4, 18.3, 7.0 Hz, 5H), 7.05~6.78 (m, 1H), 6.65 (ddd, J＝17.7, 12.6, 6.3 Hz, 2H), 4.47 (s, 1H), 3.76~3.73 (m, 4H), 2.58~2.43 (m, 4H); ¹³C NMR (CDCl₃, 100 MHz) δ: 151.64 (d, J＝241.9 Hz), 144.66 (d, J＝12.6 Hz), 138.63, 129.07, 128.56, 128.41, 127.11 (d, J＝2.3 Hz), 124.34 (d, J＝3.1 Hz), 119.15 (d, J＝7.1 Hz), 115.19 (d, J＝18 Hz), 76.51, 66.82, 52.19; HRMS (ESI) calcd for C₁₇H₁₉FNO₂ [M+H]⁺ 288.1394, found 288.1395.

  2-氟-6-[苯基(硫代吗啉)甲基]苯酚(3x):白色固体, 产率84%. m.p. 121.3~122.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 12.26 (s, 1H), 7.59~7.16 (m, 5H), 6.93 (t, J＝9.1 Hz, 1H), 6.62 (dt, J＝7.6, 6.0 Hz, 2H), 4.63 (s, 1H), 3.26~2.33 (m, 8H); ¹³C NMR (CDCl₃, 100 MHz) δ: 151.63 (d, J＝241.9 Hz), 145.18 (d, J＝12.7 Hz), 137.60, 129.03, 128.94, 128.48, 126.91 (d, J＝2.3 Hz), 124.40 (d, J＝2.9 Hz), 118.83 (d, J＝7.1 Hz), 115.22 (d, J＝18 Hz), 76.09, 53.20, 28.06; HRMS (ESI) calcd for C₁₇H₁₉FNOS [M+H]⁺ 304.1166, found 304.1168.

  4-氟-2-[苯基(硫代吗啉)甲基]苯酚(3y):白色固体, 产率80%. m.p. 140.3~142.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 11.57 (s, 1H), 7.42~7.25 (m, 5H), 6.89~6.72 (m, 2H), 6.60 (dd, J＝9.1, 2.6 Hz, 1H), 4.54 (s, 1H), 3.12~2.48 (m, 8H); ¹³C NMR (CDCl₃, 100 MHz) δ: 156.05 (d, J＝235.3 Hz), 152.66, 137.50, 129.04, 128.91, 128.48, 125.44 (d, J＝6.7 Hz), 117.74 (d, J＝7.7 Hz), 115.74 (d, J＝23.8 Hz), 115.17 (d, J＝22.5 Hz), 75.95, 53.13, 28.07; HRMS (ESI) calcd for C₁₇H₁₉FNOS [M+ H]⁺ 304.1166, found 304.1165.

  2-[(苄胺)(苯基)甲基]苯酚(5a):无色粘稠油状液体, 产率90%. ¹H NMR (400 MHz, DMSO-d₆) δ: 11.19 (s, 1H), 7.42 (d, J＝7.4 Hz, 2H), 7.35~7.30 (m, 6H), 7.27~7.21 (m, 2H), 7.08~7.04 (m, 2H), 6.73 (dd, J＝13.5, 7.4 Hz, 2H), 5.01 (s, 1H), 3.66 (s, 2H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 156.85, 143.24, 140.07, 128.78, 128.71, 128.69, 128.34, 128.23, 127.97, 127.92, 127.41, 127.34, 119.29, 116.28, 62.83, 51.15; HRMS (ESI) calcd for C₂₀H₂₀NO [M+H]⁺ 290.1539, found 290.1540.

  2-{[(2-甲基苄基)胺](苯基)甲基}苯酚(5b):无色粘稠油状液体, 产率92%. ¹H NMR (400 MHz, DMSO-d₆) δ: 11.13 (s, 1H), 7.46 (d, J＝7.3 Hz, 2H), 7.34~7.31 (m, 3H), 7.23 (t, J＝7.3 Hz, 1H), 7.17~7.12 (m, 3H), 7.07~7.04 (m, 2H), 6.76 (dd, J＝6.3, 2.3 Hz, 1H), 6.71 (t, J＝7.4 Hz, 1H), 5.09 (s, 1H), 3.64 (s, 2H), 2.20 (s, 3H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 156.80, 143.24, 138.11, 136.52, 130.44, 129.09, 128.78, 128.67, 128.61, 128.34, 128.03, 127.43, 127.34, 126.23, 119.25, 116.24, 63.15, 48.85, 19.05; HRMS (ESI) calcd for C₂₁H₂₂NO [M+H]⁺ 304.1696, found 304.1698.

  2-[(苄胺)(间甲基)甲基]苯酚(5c):无色粘稠油状液体, 产率93%. ¹H NMR (400 MHz, DMSO-d₆) δ: 11.26 (s, 1H), 7.33~7.30 (m, 4H), 7.27~7.19 (m, 4H), 7.05 (t, J＝7.5 Hz, 3H), 6.72 (t, J＝8.3 Hz, 2H), 4.96 (s, 1H), 3.65 (s, 2H), 2.27 (s, 3H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 156.84, 143.16, 140.02, 137.78, 129.14, 128.74, 128.69, 128.44, . 128.29, 128.18, 128.07, 127.33, 124.97, 119.26, 116.25, 62.86, 51.12, 21.62; HRMS (ESI) calcd for C₂₁H₂₂NO [M+H]⁺ 304.1696, found 304.1696.

  2-[(苄胺)(邻甲基)甲基]苯酚(5d):无色粘稠油状液体, 产率92%. ¹H NMR (400 MHz, DMSO-d₆) δ:11.28 (s, 1H), 7.42 (d, J＝7.2 Hz, 1H), 7.35~7.24 (m, 5H), 7.21~7.11 (m, 3H), 7.11~7.02 (m, 1H), 6.91~6.82 (m, 1H), 6.77 (d, J＝7.5 Hz, 1H), 6.70 (t, J＝7.4 Hz, 1H), 5.20 (s, 1H), 3.66 (s, 2H), 2.16 (s, 3H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 157.29, 140.63, 140.01, 136.45, 130.67, 128.82, 128.77, 128.67, 128.36, 127.68, 127.61, 127.38, 127.24, 126.51, 119.19, 116.19, 58.07, 51.20, 19.26; HRMS (ESI) calcd for C₂₁H₂₂NO [M+H]⁺ 304.1696, found 304.1698.

  2-{[(4-甲基苄基)胺](苯基)甲基}苯酚(5e):无色粘稠油状液体, 产率94%. ¹H NMR (400 MHz, DMSO-d₆) δ: 11.29 (s, 1H), 7.40 (d, J＝7.3 Hz, 2H), 7.31 (t, J＝7.5 Hz, 2H), 7.21 (dd, J＝16.2, 7.6 Hz, 3H), 7.13 (d, J＝7.9 Hz, 2H), 7.05 (dd, J＝7.0, 5.5 Hz, 2H), 6.72 (dd, J＝13.6, 7.4 Hz, 2H), 4.99 (s, 1H), 3.61 (s, 2H), 2.28 (s, 3H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 156.90, 143.16, 136.87, 136.38, 129.29, 128.78, 128.73, 128.67, 128.33, 128.10, 127.91, 127.42, 119.25, 116.28, 62.78, 50.77, 21.18; HRMS (ESI) calcd for C₂₁H₂₂NO [M+H]⁺ 304.1696, found 304.1696.

  2-{[(4-甲基苄基)胺](苯基)甲基}苯酚(5f):无色粘稠油状液体, 产率90%. ¹H NMR (400 MHz, DMSO-d₆) δ: 11.27 (s, 1H), 7.43 (d, J＝7.4 Hz, 2H), 7.31 (t, J＝7.5 Hz, 2H), 7.21 (dd, J＝14.3, 7.2 Hz, 2H), 7.13~7.04 (m, 5H), 6.77~6.70 (m, 2H), 5.02 (s, 1H), 3.63 (s, 2H), 2.28 (s, 3H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 156.9, 143.22, 139.93, 137.75, 129.35, 128.79, 128.74, 128.62, 128.35, 128.20, 127.98, 127.94, 127.42, 125.77, 119.28, 116.30, 63.01, 51.19, 21.53; HRMS (ESI) calcd for C₂₁H₂₂NO [M+H]⁺ 304.1696, found 304.1695.

  2-[(苄胺)(苯基)甲基]-4-甲基苯酚(5g):无色粘稠油状液体, 产率90%. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.97 (s, 1H), 7.42 (d, J＝7.4 Hz, 2H), 7.31 (dd, J＝8.8, 6.1 Hz, 6H), 7.26~7.21 (m, 2H), 6.90 (s, 1H), 6.90~6.84 (m, 1H), 6.65 (d, J＝8.1 Hz, 1H), 4.98 (s, 1H), 3.66 (s, 2H), 2.13 (s, 3H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 154.47, 143.42, 140.10, 129.13, 128.77, 128.71, 128.68, 128.61, 127.88, 127.81, 127.64, 127.37, 127.32, 116.16, 63.03, 51.22, 20.76; HRMS (ESI) calcd for C₂₁H₂₂NO [M+H]⁺ 304.1696, found 304.1698.

  2-[(苄胺)(对甲苯基)甲基]苯酚(5h):无色粘稠油状液体, 产率95%. ¹H NMR (400 MHz, DMSO-d₆) δ: 11.30 (s, 1H), 7.35~7.25 (m, 7H), 7.12 (d, J＝7.9 Hz, 2H), 7.14~7.12 (m, 2H), 6.73~6.68 (m, 2H), 4.96 (s, 1H), 3.64 (s, 2H), 2.26 (s, 3H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 156.90, 140.07, 140.01, 136.51, 129.35, 128.81, 128.71, 128.64, 128.62, 128.27, 127.84, 127.34, 119.20, 116.24, 62.67, 51.05, 21.12; HRMS (ESI) calcd for C₂₁H₂₂NO [M+H]⁺ 304.1696, found 304.1693.

  2-[(苄胺)(苯基)甲基]-6-(叔丁基)苯酚(5i):无色粘稠油状液体, 产率92%. ¹H NMR (400 MHz, DMSO-d₆) δ: 13.05 (s, 1H), 7.45 (d, J＝7.3 Hz, 2H), 7.37~7.31 (m, 6H), 7.29~7.26 (m, 2H), 7.07 (dd, J＝6.0, 3.4 Hz, 1H), 6.60~6.58 (m, 2H), 4.95 (s, 1H), 4.23 (s, 1H), 3.68 (d, J＝4.3 Hz, 2H), 1.39 (s, 9H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 157.19, 141.86, 139.13, 136.37, 129.00, 128.88, 128.81, 128.18, 127.85, 127.61, 127.35, 126.26, 125.65, 118.30, 66.04, 50.98, 34.88, 29.93; HRMS (ESI) calcd for C₂₄H₂₈NO [M+H]⁺ 346.2165, found 346.2165.

  2-[(苄胺)(苯基)甲基]-6-乙氧基苯酚(5j):无色粘稠油状液体, 产率89%. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.86 (s, 1H), 7.41 (d, J＝7.3 Hz, 2H), 7.31 (dd, J＝10.4, 5.7 Hz, 6H), 7.24 (dd, J＝11.1, 5.8 Hz, 2H), 6.78 (dd, J＝7.4, 1.9 Hz, 1H), 6.70~6.63 (m, 2H), 5.02 (s, 1H), 3.98 (q, J＝6.9 Hz, 2H), 3.66 (d, J＝5.3 Hz, 2H), 3.37 (s, 1H), 1.32 (t, J＝6.9 Hz, 3H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 147.28, 146.44, 143.21, 139.99, 128.75, 128.71, 128.67, 128.36, 127.86, 127.41, 127.34, 120.65, 118.88, 112.48, 64.31, 62.94, 51.11, 15.30; HRMS (ESI) calcd for C₂₂H₂₄NO₂ [M+H]⁺ 334.1802, found 334.1805.

  2-{[1, 1'-二苯基]-4-基(苄胺)甲基}苯酚(5k):无色粘稠油状液体, 产率88%. ¹H NMR (400 MHz, DMSO-d₆) δ: 11.15 (s, 1H), 7.62 (t, J＝8.2 Hz, 4H), 7.50 (d, J＝8.2 Hz, 2H), 7.44 (t, J＝7.6 Hz, 2H), 7.36~7.32 (m, 5H), 7.26 (dd, J＝8.6, 4.2 Hz, 1H), 7.16 (d, J＝6.9 Hz, 1H), 7.19~7.05 (m, 1H), 6.75 (t, J＝8.0 Hz, 2H), 5.07 (s, 1H), 3.69 (s, 2H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 156.72, 142.59, 140.46, 140.13, 139.33, 129.37, 128.72, 128.67, 128.46, 128.35, 128.27, 127.78, 127.33, 127.12, 127.07, 119.36, 116.27, 62.30, 51.15; HRMS (ESI) calcd for C₂₆H₂₄NO [M+H]⁺ 366.1852, found 366.1855.

  2-[(苄胺)(4-氯苯基)甲基]苯酚(5l):无色粘稠油状液体, 产率84%. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.84 (s, 1H), 7.44 (d, J＝8.5 Hz, 2H), 7.37 (d, J＝8.5 Hz, 2H), 7.32 (d, J＝4.3 Hz, 4H), 7.25 (dd, J＝8.8, 4.5 Hz, 1H), 7.14 (d, J＝7.6 Hz, 1H), 7.06 (dd, J＝11.2, 4.1 Hz, 1H), 6.77~6.73 (m, 2H), 5.04 (s, 1H), 3.64 (s, 2H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 156.41, 142.52, 140.19, 131.83, 129.77, 128.69, 128.67, 128.63, 128.44, 128.42, 128.30, 127.30, 119.43, 116.21, 61.42, 51.14; HRMS (ESI) calcd for C₂₀H₁₉ClNO [M+H]⁺ 324.1150, found 324.1152.

  2-[(苄胺)(3-氟苯基)甲基]苯酚(5m):无色粘稠油状液体, 产率82%. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.83 (s, 1H), 7.38~7.30 (m, 5H), 7.28~7.22 (m, 3H), 7.16 (d, J＝7.5 Hz, 1H), 7.06 (dt, J＝12.0, 5.5 Hz, 2H), 6.77 (dd, J＝14.6, 7.6 Hz, 2H), 5.08 (s, 1H), 3.66 (s, 2H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 162.73 (d, J＝241.6 Hz), 156.41, 146.59 (d, J＝6.6 Hz), 140.19, 130.59 (d, J＝8.1 Hz), 128.71 (d, J＝2.4 Hz), 128.66, 128.63, 128.47, 128.29, 127.30, 124.02 (d, J＝2.5 Hz), 119.46, 116.24, 114.42 (d, J＝21.5 Hz), 114.04 (d, J＝20.9 Hz), 61.57, 51.16; HRMS (ESI) calcd for C₂₀H₁₉FNO [M+H]⁺ 308.1445, found 308.1446.

  2-{[(2, 6-二氯苄基)胺](苯基)甲基}苯酚(5n):无色粘稠油状液体, 产率82%. ¹H NMR (400 MHz, DMSO- d₆) δ: 10.50 (s, 1H), 7.47 (d, J＝7.3 Hz, 2H), 7.43 (d, J＝8.1 Hz, 2H), 7.35~7.22 (m, 4H), 7.07~7.01 (m, 2H), 6.78 (d, J＝7.9 Hz, 1H), 6.71 (t, J＝7.4 Hz, 1H), 5.15 (s, 1H), 3.90 (s, 2H), 3.06 (s, 1H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 156.41, 142.85, 135.93, 135.44, 130.33, 128.96, 128.84, 128.68, 128.47, 128.36, 128.15, 127.45, 119.17, 116.05, 62.72, 47.10; HRMS (ESI) calcd for C₂₀H₁₈Cl₂NO [M+H]⁺358.0760, found 358.0762.

  2-{[(4-碘苄基)胺](苯基)甲基}苯酚(5o):无色粘稠油状液体, 产率82%. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.92 (s, 1H), 7.68 (d, J＝8.2 Hz, 2H), 7.41 (d, J＝7.3 Hz, 2H), 7.30 (t, J＝7.5 Hz, 2H), 7.21 (t, J＝7.3 Hz, 1H), 7.14~7.11 (m, 3H), 7.07~7.03 (m, 1H), 6.76~6.71 (m, 2H), 5.00 (s, 1H), 3.60 (s, 2H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 156.56, 143.33, 140.07, 137.43, 131.06, 128.75, 128.61, 128.39, 128.30, 127.88, 127.36, 119.36, 116.21, 93.06, 62.23, 50.52; HRMS (ESI) calcd for C₂₀H₁₉INO [M+H]⁺ 416.0506, found 416.0505.

  2-{[(4-溴苄基)胺](苯基)甲基}苯酚(5p):无色粘稠油状液体, 产率80%. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.94 (s, 1H), 7.50 (d, J＝8.3 Hz, 2H), 7.42 (d, J＝7.3 Hz, 2H), 7.29 (dd, J＝15.3, 7.8 Hz, 4H), 7.21 (t, J＝7.3 Hz, 1H), 7.14~7.12 (m, 1H), 7.18~7.03 (m, 1H), 6.78~6.71 (m, 2H), 5.02 (s, 1H), 3.63 (s, 2H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 156.61, 143.34, 139.68, 131.56, 130.87, 128.76, 128.64, 128.38, 128.33, 127.89, 127.37, 120.38, 119.37, 116.25, 62.33, 50.45; HRMS (ESI) calcd for C₂₀H₁₉INO [M+H]⁺ 416.0506, found 416.0505.

  2-{[(4-氟苄基)胺](苯基)甲基}苯酚(5q):无色粘稠油状液体, 产率76%. ¹H NMR (400 MHz, DMSO-d₆) δ: 11.07 (s, 1H), 7.42 (d, J＝7.3 Hz, 2H), 7.37~7.20 (m, 6H), 7.16~7.04 (m, 5H), 6.74 (dd, J＝15.4, 7.8 Hz, 2H), 5.02 (s, 1H), 3.65 (s, 2H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 161.73 (d, J＝240.8 Hz), 156.70, 143.31, 136.30 (d, J＝2.9 Hz), 130.57 (d, J＝8.0 Hz), 128.763, 128.714, 128.67, 128.31, 127.89, 127.38, 119.33, 116.25, 115.49, 115.28, 62.51, 50.36; HRMS (ESI) calcd for C₂₀H₁₉FNO [M+H]⁺ 308.1445, found 308.1445.

  2-[(苄胺)(环己基)甲基]苯酚(5r):无色粘稠油状液体, 产率82%. ¹H NMR (400 MHz, DMSO-d₆) δ: 11.73 (s, 1H), 7.34~7.23 (m, 5H), 7.07 (td, J＝8.0, 1.5 Hz, 1H), 6.91~6.89 (m, 1H), 6.74~6.69 (m, 2H), 3.68 (d, J＝13.5 Hz, 1H), 3.50~3.37 (m, 4H), 1.86 (d, J＝12.5 Hz, 1H), 1.6~1.56 (m, 4H), 1.43 (d, J＝12.5 Hz, 1H), 1.11~0.88 (m, 5H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 158.03, 139.74, 130.23, 128.70, 128.66, 128.14, 127.35, 125.01, 118.59, 116.16, 66.42, 51.08, 43.17, 29.87, 29.50, 26.42, 26.33, 26.25; HRMS (ESI) calcd for C₂₀H₂₆FNO [M+H]⁺ 296.2009, found 296.2010.

  2-{苯基[(噻吩-2-基甲基)胺]甲基}苯酚(5s):无色粘稠油状液体, 产率93%. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.65 (s, 1H), 7.40 (t, J＝5.5 Hz, 3H), 7.31 (t, J＝7.5 Hz, 2H), 7.21 (t, J＝7.3 Hz, 1H), 7.14~7.12 (m, 1H), 7.07~7.03 (m, 1H), 6.96 (dd, J＝4.9, 3.5 Hz, 1H), 6.92 (d, J＝3.0 Hz, 1H), 6.75 (dd, J＝14.2, 7.4 Hz, 2H), 5.09 (s, 1H), 3.83 (s, 2H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 156.45, 143.90, 143.26, 128.72, 128.57, 128.50, 128.31, 127.95, 127.33, 127.23, 125.70, 125.26, 119.37, 116.17, 61.66, 45.75; HRMS (ESI) calcd for C₁₈H₁₈NOS [M+H]⁺ 296.1104, found 296.1105.

  2-{[(3-氯苄基)胺](苯基)甲基}苯酚(5t):无色粘稠油状液体, 产率88%. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.85 (s, 1H), 7.43 (d, J＝7.4 Hz, 3H), 7.32 (dt, J＝10.8, 7.6 Hz, 4H), 7.26~7.20 (m, 2H), 7.16~7.14 (m, 1H), 7.08~7.04 (m, 1H), 6.75 (dd, J＝15.5, 7.8 Hz, 2H), 5.04 (s, 1H), 3.66 (s, 2H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 156.50, 143.39, 142.95, 133.47, 130.48, 128.75, 128.58, 128.39, 128.30, 127.87, 127.87, 127.35, 127.28, 127.21, 119.39, 116.21, 62.20, 50.58; HRMS (ESI) calcd for C₂₀H₁₉ClNO [M+H]⁺ 324.1150, found 324.1150.

  2-[(苄胺)(苯基)甲基]-3-氟苯酚(5u):无色粘稠油状液体, 产率81%. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.73 (s, 1H), 7.44 (d, J＝7.4 Hz, 2H), 7.33 (t, J＝6.0 Hz, 6H), 7.29~7.18 (m, 2H), 7.06 (dd, J＝9.8, 3.0 Hz, 1H), 6.98~6.83 (m, 1H), 6.75 (dd, J＝8.8, 4.9 Hz, 1H), 5.05 (s, 1H), 3.66 (s, 2H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 156.00 (d, J＝232.1 Hz), 152.57, 143.07, 140.26, 130.53 (d, J＝6.3 Hz), 128.79, 128.65 (d, J＝5.0 Hz), 127.87, 127.37 (d, J＝17.7 Hz), 116.85, 114.71, 114.45 (d, J＝4.4 Hz), 114.20; HRMS (ESI) calcd for C₂₀H₁₉FNO [M+H]⁺ 308.1445, found 308.1447.

  2-[(苄胺)(苯基)甲基]-6-氟苯酚(5v):无色粘稠油状液体, 产率82%. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.44 (d, J＝7.4 Hz, 2H), 7.41~7.29 (m, 6H), 7.30~7.16 (m, 2H), 7.09~6.93 (m, 1H), 6.84 (d, J＝7.7 Hz, 1H), 6.69 (td, J＝7.9, 5.1 Hz, 1H), 5.09 (s, 1H), 3.69 (d, J＝0.8 Hz, 2H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 151.58 (d, J＝238.5 Hz), 145.19 (d, J＝12.9 Hz), 142.36, 139.52, 130.62 (d, J＝2.3 Hz), 128.97, 128.79, 128.74, 127.96, 127.79, 127.50, 124.07 (d, J＝2.5 Hz), 118.84 (d, J＝7.0 Hz), 114.89 (d, J＝18.0 Hz), 63.42 (d, J＝1.8 Hz), 51.05; HRMS (ESI) calcd for C₂₀H₁₉FNO [M+H]⁺ 308.1445, found 308.1447.

  辅助材料(Supporting Information)化合物3a~3y和5a~5v的¹H NMR和¹³C 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  贝蒂碱结构通式

  Figure 1  General structure of a Betti base

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  图式 1  邻亚甲基苯醌的反应类型

  Scheme 1  Reaction type of o-quinone

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  图式 2  可能的反应机理

  Scheme 2  Proposed reaction mechanism

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  表 1  反应条件优化^a

  Table 1.  Optimization of reaction conditions

  Entry	Catalyst	Solvent	Temperature/℃	Time/h	Yieldb/%
  1	Ga(OTf)3	DCE	80	8	0
  2	In(OTf)3	DCE	80	8	0
  3	Y(OTf)3	DCE	80	8	0
  4	Yb(OTf)3	DCE	80	8	0
  5	AlCl3	DCE	80	8	0
  6	CuI	DCE	80	8	0
  7	Sc(OTf)3	DCE	80	8	75
  8	Sc(OTf)3	Toluene	80	8	65
  9	Sc(OTf)3	DMF	80	8	21
  10	Sc(OTf)3	1, 4-Dioxane	80	8	62
  11	Sc(OTf)3	DCE	90	8	92
  12	Sc(OTf)3	DCE	100	8	82
  13	Sc(OTf)3	DCE	90	4	92
  14	Sc(OTf)3	DCE	90	3	78
  15c	Sc(OTf)3	DCE	90	2	80
  16d	Sc(OTf)3	DCE	90	2	93
  a Reaction conditions: 2-(hydroxy(phenyl)methyl)phenol (1a, 2.0 mmol), thio- morpholin (2a, 2.4 mmol), solvent (1 mL), run with 10 mol% Sc(OTf)3; b isolated yield; c run with 5 mol% Sc(OTf)3; d run with 20 mol% Sc(OTf)3.

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  表 2  底物扩展^a

  Table 2.  Exploration of substrate scope

  a Reaction conditions: o-hydroxybenzyl alcohols 1 (2.0 mmol), secondary amines 2 (2.4 mmol), DCE (1 mL), performed in a sealed tube at 90 ℃, 4 h. Isolated yield.

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  表 3  1与各种苄胺的反应^a

  Table 3.  Reaction of 1 with various benzylamine

  a Reaction conditions: o-hydroxybenzyl alcohols 1 (2.0 mmol), benzylamines 2 (2.4 mmol), DCE (1 mL), performed in a sealed tube at 90 ℃, 4 h. Isolated yield.

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