English

• 1.   Introduction

  Indole derivatives are widely found in numerous natural products and bioactive compounds.^[1] Among them, bisindolylmethanes are privileged structures, which display great potential in pharmaceutical developments (Figure 1). For instance, 2, 2'-bisindolylmethanes Ⅰ and Ⅱ exhibit anti- tumor metastasis and anti-inflammatory activities, ^[2] 2, 2'- bisindolylmethanes Ⅲ and Ⅳ have been used as antitu- mor agents.^[3] Moreover, 3, 2'-bisindolylmethane Ⅴ can inhibit extracellular signal-regulated kinase activation and induce apoptosis in acute myelogenous leukemia, ^[4] and 3, 3'-bisindolylmethane Ⅵ is an orphan nuclear receptor.^[5] Therefore, the efficient construction of bisindolylmethane frameworks has attracted intensive attention from organic chemists.

  Figure 1

  

  Figure 1.  Selected bioactive molecules containing bisindolylmethane frameworks

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  Recently, indolylmethanols have emerged as versatile synthetic building blocks in organic synthesis for the synthesis of indole derivatives including bisindolylmethanes.^[6-7] Particularly, 2-indolylmethanols as a class of active reactants have been widely employed in the synthesis of indole derivatives based on their property of being easily converted into the corresponding cation intermediates via dehydration in the presence of Brønsted acid (B-H), which have a high tendency to be attacked by nucleophiles and thus perform substitution reactions (Scheme 1, a).^[6c] When R=H, the substitution reactions of this class of C(3)-unsubstitued 2-indolylmethanols have been well developed and utilized for the synthesis of indole derivatives.^[8] However, the investigations on the substitution reactions of C(3)-substituted 2-indolymethannols (R≠H) have not received enough attention from the chemists for the synthesis of indole derivatives.^[9] There are only one example on the substitution reactions, and the nucleophiles are limited to azlactones.^[9a] Therefore, developing the substitution reactions of C(3)-substituted-2-indolymethannols for the construction of bisindolylmethane frameworks is highly desired.

  Scheme 1

  

  Scheme 1.  Profile of 2-indolylmethanol and tryptophol-involved reactions

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  Tryptophols belong to a class of promising reactants and competent nucleophiles with multiple reactive sites for the synthesis of indole derivatives, which have been widely employed in cyclization or substitution reactions (Scheme 1, b).^[10-12] So, tryptophols are considered as suitable nucleophiles to participate in the reactions for constructing bisindolylmethane frameworks. However, there is an issue of chemoselectivity in the reactions of tryptophols because both the C(2)-position, C(3)-position and the OH group of tryptophols have nucleophilicity. Commonly, tryptophols often utilize their strong C(3)-nucleophilicity to attack electrophiles (E) to perform cascade dearomatization- cyclization reactions.^[10-11] In addition, tryptophols can utilize the O-nucleophilicity of the OH group to undergo substitution reactions.^[12] On the other hand, the C(2)-position of tryptophols exhibits weak nucleophilicity and can also undergo substitution reactions in some cases.^[13] So, it is challenging to control the chemoselectivity of tryptophol- involved reactions and utilize their C(2)-nucleophilicity for the synthesis of bisindolylmethanes.

  To construct biologically important bisindolylmethane frameworks and to tackle the challenges in controlling the chemoselectivity of tryptophol-involved reactions, based on our long-lasting efforts for the synthesis of indole derivative, ^[14] we designed a Brønsted acid-catalyzed substitution reaction of C(3)-substituted-2-indolymethannols with tryptophols, which accomplished the synthesis of 2, 2'-bisindolylmethanes in high yields by utilizing the C(2)-nucleophilicity of tryptophols (Scheme 1, c). Herein, the details of our investigation are reported.

  2.   Results and discussion

  Our investigation started with the reaction of C(3)- substituted 2-indolylmethanol 1a and tryptophol 2a in the presence of Brønsted acid (B-H) 4a in different solvents at 30 ℃ (Table 1, Entries 1~8). It was discovered that the desired 2, 2'-bisindolylmethane product 3aa could be obtained under the mild conditions (Entries 1~2 and 4~8). Obviously, the reaction could be performed in various solvents except acetone (Entry 3), and 1, 2-dichloroethane (DCE) was the best solvent for this reaction in terms of the yield (82%, Entry 6). Inspired by this preliminary result, a series of Brønsted acids 4 were screened (Entries 9~12). It was found that the reaction could be performed only in the presence of 4a or 4e (Entries 6 and 12), and Brønsted acid 4a remained to be the best catalyst for this reaction with regard to the yield (Entry 6). Thus, B-H 4a and DCE were selected as the optimal catalyst and solvent for this reaction. Then, the effect of the temperature on the reaction was investigated (Entries 13~16). It was revealed that lowering the temperature to -10 ℃ could not improve the yield (Entries 13~16 vs Entry 6), and the reaction failed to occur at the low temperature of -30 ℃ (Entry 16). So, 30 ℃ was still the most suitable temperature for this reaction.

  Table 1

  

  Table 1.  Optimization of reaction conditions^a

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  Entry	B-H (4)	Solvent	T/℃	Yieldb/%
  1	TsOH•H2O (4a)	CH3CN	30	71
  2	TsOH•H2O (4a)	Tetrahydrofuran (THF)	30	75
  3	TsOH•H2O (4a)	Acetone	30	Trace
  4	TsOH•H2O (4a)	PhCH3	30	62
  5	TsOH•H2O (4a)	EtOAc	30	77
  6	TsOH•H2O (4a)	DCE	30	82
  7	TsOH•H2O (4a)	Dichloromethane (DCM)	30	66
  8	TsOH•H2O (4a)	CHCl3	30	62
  9	PhCOOH (4b)	DCE	30	Trace
  10	CF3SO3H(4c)	DCE	30	Trace
  11	CF3COOH (4d)	DCE	30	Trace
  12		DCE	30	70
  13	TsOH•H2O (4a)	DCE	20	70
  14	TsOH•H2O (4a)	DCE	0	73
  15	TsOH•H2O (4a)	DCE	-10	71
  16	TsOH•H2O (4a)	DCE	-30	Trace
  a Unless otherwise indicated, the reaction was carried out at the 0.1 mmol scale in a solvent (1 mL) for 12 h, and the molar ratio of 1a/2a was 1:1.2. b Isolated yield.

  To further improve the yield, additives such as molecular sieves (MS) and anhydrous sulfates were screened (Table 2, Entries 2~6). It was found that the addition of these additives could not bring evident improvement on the yield (Entries 2~6 vs. Entry 1). Then, the reagent ratio was carefully tuned by varying the amount of 1a and 2a (Entries 7~11). Remarkably, when the molar ratio of 1a:2a was adjusted to 1:3, the yield of target product 3aa was raised to 98% (Entry 8). On the contrary, when using excess amount of 1a, nearly no product 3aa could be generated (Entries 9~11). Finally, we investigated the effect of the concentration on the reaction (Entries 12~15). However, either increasing the concentration or lowering the concentration had no evident influence on the yield. Therefore, the optimal reaction conditions were selected as those shown in Entry 8, which afforded product 3aa in an excellent yield of 98%.

  Table 2

  

  Table 2.  Further optimization of reaction conditions^a

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  Entry	x	Additive	1a:2a	Yieldb/%
  1	1	—	1:1.2	82
  2	1	3 Å MS	1:1.2	64
  3	1	4 Å MS	1:1.2	67
  4	1	5 Å MS	1:1.2	63
  5	1	Na2SO4	1:1.2	72
  6	1	MgSO4	1:1.2	80
  7	1	—	1:2	85
  8	1	—	1:3	98
  9	1	—	1.2:1	Trace
  10	1	—	2:1	Trace
  11	1	—	3:1	Trace
  12	0.25	—	1:3	93
  13	0.5	—	1:3	93
  14	1.5	—	1:3	95
  15	2	—	1:3	95
  a Unless otherwise indicated, the reaction was carried out at the 0.1 mmol scale in DCE at 30 ℃ in the presence of 10 mol% 4a for 12 h. b Isolated yield.

  With the optimal conditions in hand, the substrate scope of C(3)-substituted 2-indolylmethanols 1 in the reaction was investigated. As shown in Table 3, this protocol was applicable to a wide range of C(3)-substituted 2-indolyl- methanols 1 bearing different R¹/R groups, delivering 2, 2'-bisindolylmethane products 3 with structural diversity in moderate to excellent yields (49%~98%). Firstly, C(3)-substituted 2-indolylmethanols 1 with different R1 groups were examined (Entries 1~10). Either meta-, ortho- or para-substituted phenyl groups could serve as suitable R¹ groups, and these substrates 1a~1j smoothly take part in the reaction to deliver 2, 2'-bisindolylmethane products 3aa~3ja in good to excellent yields (63%~98%). It seemed that the position of the substituents on the R¹ group had some effect on the yield since substrate 1e bearing an ortho-methyl substituted phenyl group delivered higher yield than its meta-substituted and para-substituted counterparts 1b and 1f (Entry 5 vs. Entries 2 and 6). Subsequently, we studied the effect of R substituents at different positions of the indole ring on the reaction, and it was disclosed that C(5), C(6) and C(7)-substituted 2-indolyl- methanols 1k~1n could serve as suitable reaction partners (Entries 11~14), which afforded products 3ka~3na in moderate to excellent yields (49%~96%). Among them, C(7)-bromo-substituted 2-indolylmethanol 1n delivered the product in the highest yield of 96% (Entry 14). So, the flexible variation of the R¹/R groups in the skeleton of C(3)-substituted 2-indolylmethanols provided a good opportunity for obtaining structurally diverse bisindolylmethanes.

  Table 3

  

  Table 3.  Substrate scope of C(3)-substituted 2-indolylmethanols 1^a

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  Entry	3	R1/R (1)	Yieldb/%
  1	3aa	m-MeOC6H4/H (1a)	98
  2	3ba	m-MeC6H4/H (1b)	85
  3	3ca	m-FC6H4/H (1c)	68
  4	3da	m-ClC6H4/H (1d)	72
  5	3ea	o-MeC6H4/H (1e)	92
  6	3fa	p-MeC6H4/H (1f)	72
  7	3ga	p-MeOC6H4/H (1g)	76
  8	3ha	p-FC6H4/H (1h)	63
  9	3ia	p-ClC6H4/H (1i)	64
  10	3ja	Ph/H (1j)	80
  11	3ka	m-MeOC6H4/5-Me (1k)	94
  12	3la	m-MeOC6H4/5-Cl (1l)	54
  13	3ma	m-MeOC6H4/6-OMe (1m)	49
  14	3na	m-MeOC6H4/7-Br (1n)	96
  a Unless indicated otherwise, the reaction was carried out in 0.1 mmol scale in the presence of 10 mol% 4a in DCE (1 mL) at 30 ℃ for 12 h, and the molar ratio of 1:2a was 1:3. b Isolated yield.

  Next, the generality of tryptophols 2 in this reaction was investigated by reacting with C(3)-substituted 2-indolyl- methanol 1a (Table 4). Obviously, this reaction could be amenable to a wide range of tryptophols 2 bearing electronically distinct substituents at different positions [C(4)~C(7)] of the indole ring, which generated 2, 2'-bis- indolylmethane products 3 in moderate to excellent yields (53%~98%). Notably, C(4)-methyl-substituted tryptophol 2b could successfully participate in the reaction to give product 3ab in a high yield of 84% (Entry 2). For methyl-substituted tryptophols, it seemed that the position of the methyl group imposed an effect on the yield. In detail, C(4) and C(5)-methyl-substituted tryptophols 2b~2c delivered the products in much higher yields than C(6) and C(7)-methyl-substituted tryptophols 2g and 2j (Entries 2~3 vs. Entries 7 and 10). Nevertheless, the applicability of various tryptophols 2 in this reaction offered 2, 2'-bisin- dolyl-methane products 3 with structural diversity.

  Table 4

  

  Table 4.  Substrate scope of tryptophols 2^a

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  Entry	3	R (2)	Yieldb/%
  1	3aa	H (2a)	98
  2	3ab	4-Me (2b)	84
  3	3ac	5-Me (2c)	90
  4	3ad	5-F (2d)	71
  5	3ae	5-Cl (2e)	75
  6	3af	5-Br (2f)	87
  7	3ag	6-Me (2g)	53
  8	3ah	6-F (2h)	73
  9	3ai	6-Cl (2i)	72
  10	3aj	7-Me (2j)	71
  11	3ak	7-MeO (2k)	75
  12	3al	7-F (2l)	54
  13	3am	7-Cl (2m)	68
  a Unless indicated otherwise, the reaction was carried out in 0.1 mmol scale in the presence of 10 mol% 4a in DCE (1 mL) at 30 ℃ for 12 h, and the molar ratio of 1a:2 was 1:3. b Isolated yield.

  The structures of all 2, 2'-bisindolylmethane products 3 were unambiguously assigned by ¹H NMR and ¹³C NMR, IR and HRMS. Furthermore, the structure of 2, 2'-bisindolylmethane 3aa was confirmed by X-ray single-crystal analysis (Figure 2).^[15]

  Figure 2

  

  Figure 2.  X-ray single-crystal structure of 3aa

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  In order to gain some insights into the activation mode of the catalyst to the substrates, we performed some control experiments. First, N-methyl-protected 2-indolyl- methanol (1o) was employed as a substrate to react with tryptophol (2a) under the standard reaction conditions (Eq. 1). This reaction could still occur to afford product 3oa in a yield of 66%, which was lower than the reaction of 2a with N-unprotected 2-indolylmethanol 1a (98% yield). This result demonstrated that the N—H group in the structure of C(3)-substituted-2-indolylmethanols was important for controlling the reactivity, but the existence of the N—H group was not a decisive factor for this reaction. Secondly, N-methyl-protected tryptophol 2n was utilized to react with C(3)-substituted 2-indolylmethanol 1a, and the reaction could take place to give product 3an in a moderate yield of 60% (Eq. 2), which was still lower than the reaction of N-unprotected tryptophol 2a with 1a (98% yield). This result implied that the N—H group of tryptophol was helpful for increasing the reactivity, but it was not a necessity for performing the reaction. Finally, to investigate the possible role of the OH group in tryptophols 2, O-benzoyl- protected tryptophol derivative 2o was employed to the reaction with 2-indolylmethanol 1a under the standard reaction conditions (Eq. 3). In this case, product 3ao could be generated in a yield of 71%, but it was still much lower than that of tryptophol 2a involved reaction (98% yield). So, this outcome indicated that the OH group of tryptophols might have some interactions with the catalyst 4a to increase the reactivity.

  Based on the experimental results, we suggested a possible reaction pathway. As shown in Scheme 2, carbocation A and vinyl iminium B were generated from C(3)- substituted 2-indolylmethanols 1 via dehydration under the action of Brønsted acid 4a (TsOH) as a catalyst. Then, the anion of TsOH simultaneously activated both vinyl iminium B and tryptophols 2 via hydrogen-bonding and ion-pairing interactions, which facilitated a nucleophilic addition between them by utilizing the C(2)-nucleophili- city of tryptophols 2. Then, again under the activation of the anion of TsOH, the generated intermediates C underwent an isomerization to give products 3 and release the catalyst 4a (TsOH).

  Scheme 2

  

  Scheme 2.  Proposed reaction pathway

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  (1)

  (2)

  (3)

  In addition, to examine the utility of this substitution reaction for the synthesis of 2, 2'-bisindolylmethanes, a one- mmol-scale reaction of C(3)-substituted 2-indolylmethanol 1a with tryptophol 2a was carried out (Eq. 4). In this case, product 3aa was obtained in an excellent yield of 95%, which indicated that this protocol could be used for large-scale synthesis of 2, 2'-bisindolylmethanes.

  Finally, a preliminary investigation on the catalytic asymmetric version of this reaction was carried out (Table 5). In the presence of BINOL-derived chiral phosphoric acids^[16] (CPAs) 5a~5f, the reaction between C(3)-substituted 2-indolylmethanol 1a with tryptophol 2a smoothly occurred in moderate to high yields albeit with low enantioselectivities (Entries 1~6). Among them, CPA 5f bearing two 2, 4, 6-triisopropylphenyl groups exhibited higher capability in controlling the enantioselectivity than other CPAs 5a~5e (Entry 6 vs. Entries 1~5). To further improve the enantioselectivity, the backbone of CPA 5f was changed to H₈-BINOL (Entry 7). However, H₈-BINOL- derived CPA 6a was not better than CPA 5f in terms of controlling the enantioselectivity and the yield (Entry 7 vs. Entry 6). Then, in the presence of CPA 5f, several representative solvents were evaluated (Entries 8~11), which discovered that toluene, as an arene-type solvent, was still superior to these solvents with regard to the enantioselectivity (Entry 6 vs. Entries 8~11). To find more suitable solvent, a series of arene-type solvents were examined (Entries 12~17), and it was found that o-xylene could slightly improve the enantioselectivity to 22% ee (Entry 15). So, o-xylene was selected as a suitable solvent for further condition optimization. Gratifyingly, the addition of additives such as molecular sieves (MS) and anhydrous sulfates could greatly enhance the enantioselectivity (Entries 18~22). Among them, the addition of 4 Å MS could deliver the reaction in a best enantioselectivity of 40% ee (Entry 19). Finally, in the presence of 4 Å MS, the reaction temperature was modulated (Entries 23~28). It was revealed that elevating the reaction temperature led to a decrease of the enantioselectivity although the yield was increased (Entries 23, 24 vs. Entry 19). In contrast, lowering the reaction temperature resulted in an enhancement of the enantioselectivity (Entries 25~28 vs. Entry 19), but the yield was decreased sharply under the lower temperature (Entries 27, 28). Thus, the best reaction temperature is 10 ℃ (Entry 26), which enabled the reaction to occur in the highest enantioselectivity of 48% ee with a moderate yield of 50%. This preliminary investigation on the catalytic asymmetric transformation implied that there should be a room for further improve the enantioselectivity to a higher level, but the structural modifications on chiral catalysts and the substrates might be needed.

  Table 5

  

  Table 5.  Preliminary investigation on the catalytic asymmetric transformation^a

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  Entry	Cat.	Solvent	T/℃	Additive	Yieldb/%	erc
  1	5a	Toluene	30	—	87	8
  2	5b	Toluene	30	—	46	4
  3	5c	Toluene	30	—	85	2
  4	5d	Toluene	30	—	89	10
  5	5e	Toluene	30	—	77	0
  6	5f	Toluene	30	—	61	20
  7	6a	Toluene	30	—	52	-20
  8	5f	EtOAc	30	—	N.R.	—
  9	5f	THF	30	—	N.R.	—
  10	5f	CH3CN	30	—	51	0
  11	5f	DCE	30	—	54	8
  12	5f	FC6H5	30	—	62	8
  13	5f	ClC6H5	30	—	56	10
  14	5f	BrC6H5	30	—	58	8
  15	5f	o-Xylene	30	—	60	22
  16	5f	m-Xylene	30	—	56	18
  17	5f	p-Xylene	30	—	46	20
  18	5f	o-Xylene	30	3 Å MS	59	38
  19	5f	o-Xylene	30	4 Å MS	52	40
  20	5f	o-Xylene	30	5 Å MS	62	38
  21	5f	o-Xylene	30	Na2SO4	58	38
  22	5f	o-Xylene	30	MgSO4	48	30
  23	5f	o-Xylene	40	4 Å MS	66	38
  24	5f	o-Xylene	50	4 Å MS	71	32
  25	5f	o-Xylene	20	4 Å MS	54	44
  26	5f	o-Xylene	10	4 Å MS	50	48
  27	5f	o-Xylene	0	4 Å MS	38	48
  28	5f	o-Xylene	-10	4 Å MS	Trace	—
  a Unless otherwise indicated, the reaction was carried out at the 0.1 mmol scale in a solvent (1 mL) for 12 h, and the molar ratio of 1a/2a was 1:1.2. b Isolated yield. c The ee value was determined by HPLC. N.R.=No reaction. DCE=1, 2-dichloroethane.

  (4)

  3.   Conclusions

  In summary, a Brønsted acid-catalyzed chemoselective substitution reaction of 2-indolylmethanols with tryptophols was established, which constructed 2, 2'-bisindolyl- methane frameworks in generally high yields (up to 98% yield). This reaction has a wide substrate scope and can be scaled up, which provides an efficient method for constructing biologically important 2, 2'-bisindolylmethane frameworks. In addition, this reaction has advanced the development of 2-indolylmethanol involved substitution reactions, which will enrich the chemistry of 2-indolyl- methanols. Moreover, this approach has utilized the C(2)-nucleophilicity of tryptophols, which provided a good example for controlling the chemoselectivity in tryptophol-involved reactions.

  4.   Experimental section

  4.1   General information

  ¹H NMR and ¹³C NMR spectra were measured respectively at 400 and 100 MHz, respectively. The solvent used for NMR spectroscopy was CDCl₃, using tetramethylsilane as the internal reference. HRMS (ESI) was determined by a HRMS/MS instrument. The X-ray source used for the single crystal X-ray diffraction analysis of compound 3aa was Mo Kα (λ=0.71073 nm), and the thermal ellipsoid was drawn at the 30% probability level. Analytical grade solvents for the column chromatography were distilled before use. All starting materials commercially available were used directly.

  4.2   General procedure for the synthesis of products 3

  To the mixture of C(3)-substituted 2-indolylmethanols 1 (0.1 mmol), tryptophols 2 (0.3 mmol) and catalyst 4a (0.01 mmol) were added DCE (1 mL). The mixture was stirred at 30 ℃ for 12 h. After the completion of the reaction, which was monitored by thin-layer chromatography (TLC), the reaction mixture was directly purified through thin layer chromatography on silica gel to afford pure products 3.

  2-(2-((3-Methoxyphenyl)(3-methyl-1H-indol-2-yl)- methyl)-1H-indol-3-yl)ethan-1-ol (3aa): Yield 98% (40.1 mg), white solid. m.p. 80.0~81.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.98 (s, 1H), 7.95 (s, 1H), 7.65~7.58 (m, 2H), 7.31~7.25 (m, 2H), 7.25~7.15 (m, 5H), 6.90~6.86 (m, 1H), 6.85~6.80 (m, 2H), 6.08 (s, 1H), 3.84~3.71 (m, 5H), 2.96 (t, J=6.4 Hz, 2H), 2.24 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.3, 142.0, 135.6, 135.5, 135.3, 133.2, 130.2, 129.6, 128.9, 122.0, 121.9, 120.8, 119.9, 119.6, 118.8, 118.7, 114.6, 112.5, 111.2, 111.0, 109.3, 108.9, 62.6, 55.4, 41.0, 27.8, 8.7; IR (KBr) ν: 3430, 2986, 1623, 1413, 1266, 1045, 744 cm^-1; ESI FTMS calcd for C₂₇H₂₅N₂O₂ (M-H)^- 409.1921, found 409.1911. The enantiomeric excess: 48%, determined by HPLC (Daicel Chiralpak AD-H, V(hexane):V(isopropanol)=70:30, flow rate 1 mL/min, T=30 ℃, 254 nm): t_R=5.713 (major), t_R=9.123 (minor).

  2-(2-((3-Methyl-1H-indol-2-yl)(m-tolyl)methyl)-1H- indol-3-yl)ethan-1-ol (3ba): Yield 85% (33.5 mg), white solid. m.p. 70.4~72.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.83~7.76 (m, 2H), 7.65~7.53 (m, 2H), 7.30~7.26 (m, 1H), 7.26~7.22 (m, 2H), 7.21~7.15 (m, 4H), 7.14~7.11 (m, 1H), 7.04 (s, 1H), 6.99 (d, J=7.6 Hz, 1H), 6.05 (s, 1H), 3.77 (t, J=6.4 Hz, 2H), 2.94 (t, J=6.4 Hz, 2H), 2.32 (s, 3H), 2.18 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 140.2, 138.9, 135.5, 135.4, 133.5, 129.6, 129.1, 129.0, 128.9, 128.3, 125.4, 121.9, 121.8, 119.8, 119.5, 118.7, 118.6, 111.2, 110.9, 109.2, 108.8, 62.6, 40.8, 27.8, 21.6, 8.6; IR (KBr) ν: 3416, 3131, 1620, 1401, 1384, 1168, 741 cm^-1; ESI FTMS calcd for C₂₇H₂₅N₂O (M-H)^- 393.1972, found 393.1981.

  2-(2-((3-Fluorophenyl)(3-methyl-1H-indol-2-yl)- methyl)-1H-indol-3-yl)ethan-1-ol (3ca): Yield 68% (27.1 mg), white solid. m.p. 78.2~80.3 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.88 (s, 1H), 7.78 (s, 1H), 7.65~7.53 (m, 2H), 7.36~7.26 (m, 2H), 7.26~7.11 (m, 5H), 7.05~6.96 (m, 2H), 6.95~6.89 (m, 1H), 6.08 (s, 1H), 3.81 (t, J=6.4 Hz, 2H), 2.93 (t, J=6.4 Hz, 2H), 2.18 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.4 (J=246.2 Hz), 143.0 (J=6.5 Hz), 135.6 (J=12.9 Hz), 134.7, 132.7, 130.7 (J=8.3 Hz), 129.5, 128.8, 124.1, 122.3, 122.1, 120.0, 119.7, 118.8, 118.7, 115.5 (J=22.0 Hz), 114.6 (J=21.0 Hz), 111.3, 111.0, 109.7, 109.1, 62.6, 40.7, 27.7, 8.7; IR (KBr) ν: 3564, 3440, 1613, 1455, 1265, 1009, 744 cm^-1; ESI FTMS calcd for C₂₆H₂₂FN₂O (M-H)^- 397.1721, found 397.1695.

  2-(2-((3-Chlorophenyl)(3-methyl-1H-indol-2-yl)- methyl)-1H-indol-3-yl)ethan-1-ol (3da): Yield 72% (29.7 mg), white solid. m.p. 86.0~88.3 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.87 (s, 1H), 7.77 (s, 1H), 7.64~7.53 (m, 2H), 7.31~7.26 (m, 3H), 7.26~7.23 (m, 1H), 7.23~7.19 (m, 2H), 7.19~7.12 (m, 3H), 7.10~7.06 (m, 1H), 6.07 (s, 1H), 3.81 (t, J=6.0 Hz, 2H), 2.92 (t, J=6.4 Hz, 2H), 2.18 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 142.5, 135.7, 135.5, 135.1, 134.6, 132.5, 130.3, 129.5, 128.8, 128.4, 127.8, 126.6, 122.2, 122.1, 120.0, 119.7, 118.8, 118.7, 111.2, 111.0, 109.7, 109.1, 62.5, 40.6, 27.7, 8.7; IR (KBr) ν: 3415, 3128, 1638, 1400, 1384, 1080, 741 cm^-1; ESI FTMS calcd for C₂₆H₂₂ClN₂O (M-H)^- 413.1426, found 413.1433.

  2-(2-((3-Methyl-1H-indol-2-yl)(o-tolyl)methyl)-1H- indol-3-yl)ethan-1-ol (3ea): Yield 92% (36.3 mg), white solid. m.p. 85.2~87.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.75 (s, 1H), 7.71 (s, 1H), 7.65~7.54 (m, 2H), 7.28~7.21 (m, 4H), 7.20~7.12 (m, 5H), 6.97 (d, J=7.6 Hz, 1H), 6.14 (s, 1H), 3.74 (t, J=6.4 Hz, 2H), 2.89 (t, J=6.4 Hz, 2H), 2.28 (s, 3H), 2.17 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 138.8, 136.6, 135.4, 135.2, 133.0, 131.1, 129.7, 129.1, 128.1, 127.8, 126.8, 121.9, 121.8, 119.9, 119.6, 118.7, 111.2, 111.0, 109.1, 108.9, 62.6, 38.3, 27.9, 19.5, 8.6; IR (KBr) ν: 3415, 3130, 1619, 1400, 1384, 1169, 740 cm^-1; ESI FTMS calcd for C₂₇H₂₅N₂O (M-H)^- 393.1972, found 393.1971.

  2-(2-((3-Methyl-1H-indol-2-yl)(p-tolyl)methyl)-1H- indol-3-yl)ethan-1-ol (3fa): Yield 72% (28.5 mg), white solid. m.p. 71.8~73.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.79 (s, 2H), 7.64~7.53 (m, 2H), 7.29~7.25 (m, 1H), 7.25~7.21 (m, 1H), 7.21~7.11 (m, 6H), 7.11~7.07 (m, 2H), 6.05 (s, 1H), 3.77 (t, J=6.4 Hz, 2H), 2.94 (t, J=6.4 Hz, 2H), 2.37 (s, 3H), 2.18 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 137.2, 135.7, 135.5, 135.4, 133.5, 129.8, 129.6, 128.9, 128.3, 121.9, 121.8, 119.8, 119.5, 118.7, 118.6, 111.1, 111.0, 109.1, 108.7, 62.6, 40.5, 27.8, 21.1, 8.6; IR (KBr) ν: 3414, 3137, 1618, 1400, 1384, 1184, 741 cm^-1; ESI FTMS calcd for C₂₇H₂₅N₂O (M-H)^- 393.1972, found 393.1976.

  2-(2-((4-Methoxyphenyl)(3-methyl-1H-indol-2-yl)- methyl)-1H-indol-3-yl)ethan-1-ol (3ga): Yield 76% (31.1 mg), white solid. m.p. 90.7~91.8 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.83~7.76 (m, 2H), 7.64~7.53 (m, 2H), 7.29~7.24 (m, 1H), 7.24~7.21 (m, 1H), 7.21~7.13 (m, 4H), 7.13~7.09 (m, 2H), 6.90~6.84 (m, 2H), 6.03 (s, 1H), 3.81 (s, 3H), 3.77 (t, J=6.8 Hz, 2H), 2.94 (t, J=6.8 Hz, 2H), 2.17 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 158.9, 135.8, 135.5, 135.4, 133.7, 132.2, 129.7, 129.5, 129.0, 122.0, 121.8, 119.9, 119.6, 118.7, 118.6, 114.5, 111.2, 111.0, 109.1, 108.7, 62.7, 55.4, 40.1, 27.8, 8.7; IR (KBr) ν: 3412, 3135, 1610, 1400, 1384, 1177, 742 cm^-1; ESI FTMS calcd for C₂₇H₂₅N₂O₂ (M-H)^- 409.1921, found 409.1932.

  2-(2-((4-Fluorophenyl)(3-methyl-1H-indol-2-yl)- methyl)-1H-indol-3-yl)ethan-1-ol (3ha): Yield 63% (24.9 mg), white solid. m.p. 78.9~82.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.84 (s, 1H), 7.75 (s, 1H), 7.63~7.53 (m, 2H), 7.30~7.26 (m, 1H), 7.26~7.10 (m, 7H), 7.06~6.97 (m, 2H), 6.07 (s, 1H), 3.80 (t, J=6.4 Hz, 2H), 2.92 (t, J=6.4 Hz, 2H), 2.17 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 162.1 (J=245.4 Hz), 136.1, 135.6 (J=13.1 Hz), 135.2, 133.1, 130.0 (J=7.9 Hz), 129.6, 128.9, 122.2, 122.0, 120.0, 119.7, 118.8, 118.7, 116.0 (J=21.2 Hz), 111.2, 111.0, 109.5, 108.9, 62.6, 40.2, 27.7, 8.7; IR (KBr) ν: 3572, 3439, 1603, 1504, 1265, 1157, 743 cm^-1; ESI FTMS calcd for C₂₆H₂₂FN₂O (M-H)^- 397.1721, found 397.1699.

  2-(2-((4-Chlorophenyl)(3-methyl-1H-indol-2-yl)- methyl)-1H-indol-3-yl)ethan-1-ol (3ia): Yield 64% (26.4 mg), white solid. m.p. 94.2~96.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.86 (s, 1H), 7.75 (s, 1H), 7.63~7.54 (m, 2H), 7.33~7.31 (m, 1H), 7.31~7.27 (m, 2H), 7.25~7.19 (m, 2H), 7.18~7.13 (m, 4H), 7.13~7.11 (m, 1H), 6.06 (s, 1H), 3.80 (t, J=6.4 Hz, 2H), 2.91 (t, J=6.4 Hz, 2H), 2.17 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 138.8, 135.6, 135.5, 134.8, 133.4, 132.8, 129.8, 129.5, 129.2, 128.8, 122.2, 122.0, 120.0, 119.7, 118.8, 118.7, 111.2, 111.0, 109.6, 109.0, 62.5, 40.3, 27.7, 8.7; IR (KBr) ν: 3418, 3130, 1487, 1401, 1384, 1171, 743 cm^-1; ESI FTMS calcd for C₂₆H₂₂ClN₂O (M-H)^- 413.1426, found 413.1447.

  2-(2-((3-Methyl-1H-indol-2-yl)(phenyl)methyl)-1H- indol-3-yl)ethan-1-ol (3ja): Yield 80% (30.5 mg), white solid. m.p. 60.2~61.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.86~7.78 (m, 2H), 7.67~7.54 (m, 2H), 7.39~7.30 (m, 3H), 7.29~7.25 (m, 1H), 7.25~7.18 (m, 4H), 7.18~7.10 (m, 3H), 6.09 (s, 1H), 3.77 (t, J=6.4 Hz, 2H), 2.94 (t, J=6.8 Hz, 2H), 2.18 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 140.4, 135.6, 135.5, 135.4, 133.4, 129.6, 129.2, 129.0, 128.5, 127.6, 122.1, 121.9, 119.9, 119.6, 118.8, 118.7, 111.2, 111.0, 109.4, 108.9, 62.6, 40.9, 27.8, 8.7; IR (KBr) ν: 3435, 2917, 1619, 1459, 1263, 1038, 744 cm^-1; ESI FTMS calcd for C₂₆H₂₃N₂O (M-H)^- 379.1816, found 379.1818.

  2-(2-((3, 5-Dimethyl-1H-indol-2-yl)(3-methoxyphenyl)- methyl)-1H-indol-3-yl)ethan-1-ol (3ka): Yield 94% (39.9 mg), white solid. m.p. 75.7~77.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.85 (s, 1H), 7.74 (s, 1H), 7.63~7.58 (m, 1H), 7.37 (s, 1H), 7.29~7.26 (m, 1H), 7.25~7.23 (m, 1H), 7.21~7.11 (m, 3H), 7.03~6.98 (m, 1H), 6.87~6.82 (m, 1H), 6.81~6.76 (m, 2H), 6.04 (s, 1H), 3.83~3.59 (m, 5H), 2.95 (t, J=6.4 Hz, 2H), 2.49 (s, 3H), 2.17 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.3, 142.1, 135.6, 135.4, 133.8, 133.5, 130.2, 129.9, 129.0, 128.9, 123.4, 122.0, 120.8, 119.9, 118.7, 118.4, 114.6, 112.5, 111.2, 110.7, 109.2, 108.5, 62.7, 55.4, 41.0, 27.9, 21.6, 8.7; IR (KBr) ν: 3435, 2916, 1598, 1461, 1262, 1042, 747 cm^-1; ESI FTMS calcd for C₂₈H₂₇N₂O₂ (M-H)^- 423.2078, found 423.2082.

  2-(2-((5-Chloro-3-methyl-1H-indol-2-yl)(3-methoxy- phenyl)methyl)-1H-indol-3-yl)ethan-1-ol (3la): Yield 54% (24.0 mg), white solid. m.p. 90.5~92.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.96 (s, 1H), 7.78 (s, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.52~7.49 (m, 1H), 7.30~7.23 (m, 2H), 7.21~7.04 (m, 4H), 6.87~6.81 (m, 1H), 6.79~6.71 (m, 2H), 6.01 (s, 1H), 3.86~3.70 (m, 5H), 2.98~2.86 (m, 2H), 2.12 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.3, 141.6, 135.6, 134.9, 133.7, 130.7, 130.3, 128.9, 125.3, 122.2, 122.0, 120.7, 120.0, 118.8, 118.2, 114.6, 112.5, 111.9, 111.2, 109.6, 108.5, 62.6, 55.4, 41.0, 27.7, 8.6; IR (KBr) ν: 3434, 2917, 1598, 1461, 1264, 1045, 743 cm^-1; ESI FTMS calcd for C₂₇H₂₄ClN₂O₂ (M-H)^- 443.1532, found 443.1547.

  2-(2-((6-Methoxy-3-methyl-1H-indol-2-yl)(3-methoxy- phenyl)methyl)-1H-indol-3-yl)ethan-1-ol (3ma): Yield 49% (21.6 mg), white solid. m.p. 77.4~79.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.82 (s, 1H), 7.69 (s, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.30~7.22 (m, 2H), 7.19~7.09 (m, 2H), 6.88~6.76 (m, 4H), 6.75~6.72 (m, 1H), 5.99 (s, 1H), 3.84~3.69 (m, 8H), 2.93 (t, J=6.4 Hz, 2H), 2.14 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.3, 156.4, 142.2, 136.2, 135.5, 131.8, 130.2, 129.0, 124.0, 122.0, 120.8, 119.9, 119.2, 118.7, 114.6, 112.4, 111.2, 109.4, 109.2, 108.7, 94.8, 62.6, 55.8, 55.4, 40.9, 27.8, 8.7; IR (KBr) ν: 3424, 2920, 1629, 1459, 1328, 1157, 745 cm^-1; ESI FTMS calcd for C₂₈H₂₇N₂O₃ (M-H)^- 439.2027, found 439.2024.

  2-(2-((7-Bromo-3-methyl-1H-indol-2-yl)(3-methoxy- phenyl)methyl)-1H-indol-3-yl)ethan-1-ol (3na): Yield 96% (46.8 mg), white solid. m.p. 73.7~74.8 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.19 (s, 1H), 7.90 (s, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.34~7.23 (m, 3H), 7.21~7.11 (m, 2H), 7.05~6.98 (m, 1H), 6.88~6.82 (m, 1H), 6.81~6.77 (m, 2H), 6.07 (s, 1H), 3.87~3.77 (m, 2H), 3.76 (s, 3H), 3.00~2.92 (m, 2H), 2.15 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.3, 141.6, 135.8, 134.8, 134.3, 134.2, 130.8, 130.2, 128.8, 124.3, 122.2, 120.7, 119.9, 118.8, 117.9, 114.6, 112.5, 111.2, 110.1, 109.7, 104.5, 62.7, 55.4, 41.0, 27.7, 9.0; IR (KBr) ν: 3439, 2917, 1651, 1486, 1453, 1043, 747 cm^-1; ESI FTMS calcd for C₂₇H₂₄BrN₂O₂ (M-H)^- 487.1026, found 487.1044.

  2-(2-((3-Methoxyphenyl)(3-methyl-1H-indol-2-yl)- methyl)-4-methyl-1H-indol-3-yl)ethan-1-ol (3ab): Yield 84% (35.7 mg), white solid. m.p. 186.5~188.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.81 (s, 1H), 7.69 (s, 1H), 7.60~7.53 (m, 1H), 7.29~7.27 (m, 1H), 7.25~7.21 (m, 1H), 7.19~7.13 (m, 2H), 7.13~7.10 (m, 1H), 7.08~7.02 (m, 1H), 6.91~6.83 (m, 2H), 6.81~6.76 (m, 2H), 6.08 (s, 1H), 3.82~3.66 (m, 5H), 3.11 (t, J=6.8 Hz, 2H), 2.72 (s, 3H), 2.18 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.2, 142.0, 135.8, 135.4, 135.3, 133.3, 130.5, 130.2, 129.6, 127.1, 121.9, 121.8, 120.8, 119.6, 118.6, 114.6, 112.4, 110.9, 109.6, 109.2, 108.8, 63.9, 55.3, 40.7, 28.8, 20.4, 8.6; IR (KBr) ν: 3748, 3413, 1617, 1400, 1263, 1044, 744 cm^-1; ESI FTMS calcd for C₂₈H₂₇N₂O₂ (M-H)^- 423.2078, found 423.2076.

  2-(2-((3-Methoxyphenyl)(3-methyl-1H-indol-2-yl)- methyl)-5-methyl-1H-indol-3-yl)ethan-1-ol (3ac): Yield 90% (38.2 mg), white solid. m.p. 108.5~110.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.98 (s, 1H), 7.84 (s, 1H), 7.59~7.49 (m, 1H), 7.28~7.19 (m, 3H), 7.18~7.10 (m, 2H), 7.10~7.03 (m, 1H), 6.86~6.81 (m, 1H), 6.80~6.74 (m, 2H), 6.64 (d, J=7.6 Hz, 1H), 6.03 (s, 1H), 3.89 (s, 3H), 3.82~3.67 (m, 5H), 2.93 (t, J=6.4 Hz, 2H), 2.18 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.2, 142.0, 135.4, 133.8, 133.3, 130.1, 129.6, 129.2, 129.1, 123.5, 121.8, 120.7, 119.5, 118.6, 118.4, 114.6, 112.4, 110.9, 108.8, 62.6, 55.3, 40.9, 27.8, 21.6, 8.6; IR (KBr) ν: 3413, 3131, 1615, 1400, 1385, 1044, 741 cm^-1; ESI FTMS calcd for C₂₈H₂₇N₂O₂ (M-H)^- 423.2078, found 423.2078.

  2-(5-Fluoro-2-((3-methoxyphenyl)(3-methyl-1H-indol- 2-yl)methyl)-1H-indol-3-yl)ethan-1-ol (3ad): Yield 71% (30.3 mg), white solid. m.p. 90.0~92.3 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.82~7.75 (m, 2H), 7.62~7.50 (m, 1H), 7.30~7.26 (m, 1H), 7.25~7.19 (m, 2H), 7.19~7.10 (m, 3H), 6.94~6.81 (m, 2H), 6.79~6.72 (m, 2H), 6.02 (s, 1H), 3.82~3.71 (m, 5H), 2.87 (t, J=6.4 Hz, 2H), 2.17 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.3, 158.0 (J=233.8 Hz), 141.7, 137.2, 135.5, 133.0, 131.9, 130.2, 129.5, 129.3 (J=9.5 Hz), 121.9, 120.7, 119.6, 118.6, 114.6, 112.4, 111.7 (J=9.6 Hz), 111.0, 110.2 (J=26.0 Hz), 109.5 (J=4.5 Hz), 109.0, 103.7 (J=23.3 Hz), 62.4, 55.3, 41.0, 27.7, 8.6; IR (KBr) ν: 3418, 3131, 1634, 1400, 1385, 1170, 740 cm^-1; ESI FTMS calcd for C₂₇H₂₄FN₂O₂ (M-H)^- 427.1827, found 427.1832.

  2-(5-Chloro-2-((3-methoxyphenyl)(3-methyl-1H-indol- 2-yl)methyl)-1H-indol-3-yl)ethan-1-ol (3ae): Yield 75% (33.2 mg), white solid. m.p. 96.0~98.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.86 (s, 1H), 7.82 (s, 1H), 7.60~7.52 (m, 2H), 7.29~7.21 (m, 2H), 7.19~7.16 (m, 1H), 7.16~7.12 (m, 2H), 7.12~7.08 (m, 1H), 6.87~6.82 (m, 1H), 6.79~6.73 (m, 2H), 6.02 (s, 1H), 3.79~3.68 (m, 5H), 2.92~2.84 (m, 2H), 2.16 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.3, 141.7, 136.9, 135.5, 133.8, 132.9, 130.3, 130.0, 129.6, 125.6, 122.2, 122.0, 120.7, 119.7, 118.7, 118.2, 114.6, 112.5, 112.2, 111.0, 109.2, 109.1, 62.5, 55.4, 41.0, 27.7, 8.7; IR (KBr) ν: 3417, 3131, 1606, 1400, 1385, 1150, 742 cm^-1; ESI FTMS calcd for C₂₇H₂₄ClN₂O₂ (M-H)^- 443.1532, found 443.1554.

  2-(5-Bromo-2-((3-methoxyphenyl)(3-methyl-1H-indol- 2-yl)methyl)-1H-indol-3-yl)ethan-1-ol (3af): Yield 87% (42.6 mg), white solid. m.p. 94.5~96.3 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.87 (s, 1H), 7.82 (s, 1H), 7.72~7.68 (m, 1H), 7.58~7.52 (m, 1H), 7.30~7.24 (m, 2H), 7.23~7.21 (m, 1H), 7.19~7.13 (m, 2H), 7.12~7.08 (m, 1H), 6.88~6.82 (m, 1H), 6.78~6.72 (m, 2H), 6.02 (s, 1H), 3.78~3.70 (m, 5H), 2.86 (t, J=6.4 Hz, 2H), 2.16 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.3, 141.6, 136.6, 135.5, 134.0, 132.8, 130.7, 130.3, 129.5, 124.7, 122.0, 121.3, 120.7, 119.7, 118.7, 114.6, 113.1, 112.5, 111.0, 109.1, 109.0, 62.4, 55.3, 40.9, 27.6, 8.6; IR (KBr) ν: 3417, 3130, 1615, 1401, 1384, 1163, 740 cm^-1; ESI FTMS calcd for C₂₇H₂₄BrN₂O₂ (M-H)^- 487.1026, found 487.1049.

  2-(2-((3-Methoxyphenyl)(3-methyl-1H-indol-2-yl)- methyl)-6-methyl-1H-indol-3-yl)ethan-1-ol (3ag): Yield 53% (22.4 mg), white solid. m.p. 93.0~94.9 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.79 (s, 1H), 7.66 (s, 1H), 7.58~7.52 (m, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.29~7.24 (m, 1H), 7.24~7.20 (m, 1H), 7.18~7.10 (m, 2H), 7.06 (s, 1H), 7.02~6.94 (m, 1H), 6.86~6.81 (m, 1H), 6.79~6.74 (m, 2H), 6.01 (s, 1H), 3.83~3.71 (m, 5H), 2.92 (t, J=6.4 Hz, 2H), 2.45 (s, 3H), 2.16 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.2, 142.1, 136.0, 135.4, 134.5, 133.3, 131.9, 130.1, 129.6, 126.7, 121.8, 121.5, 120.7, 119.5, 118.6, 118.4, 114.6, 112.4, 111.2, 111.0, 109.1, 108.7, 62.6, 55.3, 40.9, 27.8, 21.7, 8.7; IR (KBr) ν: 3415, 3131, 1619, 1400, 1385, 1152, 742 cm^-1; ESI FTMS calcd for C₂₈H₂₇N₂O₂ (M-H)^- 423.2078, found 423.2070.

  2-(6-Fluoro-2-((3-methoxyphenyl)(3-methyl-1H-indol- 2-yl)methyl)-1H-indol-3-yl)ethan-1-ol (3ah): Yield 73% (31.4 mg), white solid. m.p. 85.4~87.6 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.88~7.82 (m, 2H), 7.58~7.52 (m, 1H), 7.51~7.44 (m, 1H), 7.29~7.21 (m, 2H), 7.19~7.10 (m, 2H), 6.95~6.81 (m, 3H), 6.80~6.73 (m, 2H), 6.00 (s, 1H), 3.82~3.63 (m, 5H), 2.90 (t, J=6.4 Hz, 2H), 2.17 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.3, 159.9 (J=236.4 Hz), 141.9, 135.5, 135.4 (J=6.0 Hz), 133.1, 130.3, 129.6, 125.5, 121.9, 120.7, 119.6, 119.4 (J=10.1 Hz), 118.7, 114.7, 112.4, 111.0, 109.4, 109.0, 108.5 (J=24.2 Hz), 97.6 (J=26.0 Hz), 62.6, 55.4, 40.9, 27.8, 8.7; IR (KBr) ν: 3418, 3131, 1621, 1400, 1385, 1043, 742 cm^-1; ESI FTMS calcd for C₂₇H₂₄FN₂O₂ (M-H)^- 427.1827, found 427.1841.

  2-(6-Chloro-2-((3-methoxyphenyl)(3-methyl-1H-indol- 2-yl)methyl)-1H-indol-3-yl)ethan-1-ol (3ai): Yield 72% (32.0 mg), white solid. m.p. 91.1~93.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.83 (s, 2H), 7.58~7.53 (m, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.29~7.25 (m, 1H), 7.25~7.19 (m, 2H), 7.18~7.11 (m, 2H), 7.10~7.06 (m, 1H), 6.87~6.82 (m, 1H), 6.79~6.72 (m, 2H), 6.01 (s, 1H), 3.81~3.67 (m, 5H), 2.88 (t, J=6.4 Hz, 2H), 2.17 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.3, 141.7, 135.9, 135.8, 135.5, 132.9, 130.2, 129.5, 127.8, 127.5, 121.9, 120.7, 120.5, 119.6, 119.5, 118.6, 114.6, 112.5, 111.1, 111.0, 109.5, 109.0, 62.5, 55.3, 40.9, 27.6, 8.6; IR (KBr) ν: 3415, 3134, 1617, 1400, 1385, 1149, 742 cm^-1; ESI FTMS calcd for C₂₇H₂₄ClN₂O₂ (M-H)^- 443.1532, found 443.1554.

  2-(2-((3-Methoxyphenyl)(3-methyl-1H-indol-2-yl)- methyl)-7-methyl-1H-indol-3-yl)ethan-1-ol (3aj): Yield 71% (30.2 mg), white solid. m.p. 170.2~171.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.91 (s, 1H), 7.68 (s, 1H), 7.59~7.53 (m, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.30~7.22 (m, 2H), 7.18~7.11 (m, 2H), 7.11~7.0 (m, 1H), 7.03~6.98 (m, 1H), 6.88~6.82 (m, 1H), 6.81~6.77 (m, 2H), 6.05 (s, 1H), 3.84~3.70 (m, 5H), 2.97~2.89 (m, 2H), 2.39 (s, 3H), 2.19 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.2, 142.0, 135.4, 135.2, 134.9, 133.2, 130.1, 129.6, 128.4, 122.7, 121.8, 120.7, 120.4, 120.1, 119.5, 118.6, 116.4, 114.6, 112.4, 111.0, 110.1, 108.8, 62.6, 55.3, 41.0, 27.9, 16.7, 8.7; IR (KBr) ν: 3416, 3131, 1615, 1400, 1385, 1150, 743 cm^-1; ESI FTMS calcd for C₂₈H₂₇N₂O₂ (M- H)^- 423.2078, found 423.2076.

  2-(7-Methoxy-2-((3-methoxyphenyl)(3-methyl-1H- indol-2-yl)methyl)-1H-indol-3-yl)ethan-1-ol (3ak): Yield 75% (32.8 mg), white solid. m.p. 92.4~94.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.83 (s, 1H), 7.74 (s, 1H), 7.60~7.53 (m, 1H), 7.40 (s, 1H), 7.30~7.20 (m, 2H), 7.19~7.11 (m, 3H), 7.05~6.99 (m, 1H), 6.87~6.82 (m, 1H), 6.81~6.76 (m, 2H), 6.03 (s, 1H), 3.85~3.56 (m, 5H), 2.93 (t, J=6.4 Hz, 2H), 2.48 (s, 3H), 2.18 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.2, 146.0, 142.0, 135.4, 134.9, 133.2, 130.1, 129.6, 125.9, 121.7, 120.7, 120.3, 119.4, 118.6, 114.5, 112.4, 111.4, 110.9, 109.8, 108.7, 102.0, 62.6, 55.3, 55.2, 40.8, 28.0, 8.7; IR (KBr) ν: 3418, 3130, 1651, 1401, 1384, 1150, 739 cm^-1; ESI FTMS calcd for C₂₈H₂₇N₂O₃ (M-H)^- 439.2027, found 439.2059.

  2-(7-Fluoro-2-((3-methoxyphenyl)(3-methyl-1H-indol- 2-yl)methyl)-1H-indol-3-yl)ethan-1-ol (3al): Yield 54% (23.2 mg), white solid. m.p. 182.6~184.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.96 (s, 1H), 7.84 (s, 1H), 7.58~7.51 (m, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.28~7.26 (m, 1H), 7.26~7.22 (m, 1H), 7.19~7.10 (m, 2H), 7.07~7.00 (m, 1H), 6.93~6.82 (m, 2H), 6.81~6.73 (m, 2H), 6.04 (s, 1H), 3.83~3.70 (m, 5H), 2.92 (t, J=6.8 Hz, 2H), 2.19 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.3, 149.4 (J=242.7 Hz), 141.6, 136.2, 135.6, 132.8, 132.6 (J=5.0 Hz), 130.3, 129.6, 123.8 (J=12.9 Hz), 122.0, 120.7, 120.2 (J=6.0 Hz), 119.6, 118.7, 114.6 (J=12.4 Hz), 112.5, 111.0, 110.4, 109.0, 107.1 (J=16.2 Hz), 62.5, 55.4, 40.9, 27.9, 8.7; IR (KBr) ν: 3414, 3131, 1618, 1400, 1385, 1163, 743 cm^-1; ESI FTMS calcd for C₂₇H₂₄FN₂O₂ (M-H)^- 427.1827, found 427.1834.

  2-(7-Chloro-2-((3-methoxyphenyl)(3-methyl-1H-indol- 2-yl)methyl)-1H-indol-3-yl)ethan-1-ol (3am): Yield 68% (30.2 mg), white solid. m.p. 186.7~187.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.98 (s, 1H), 7.93 (s, 1H), 7.59~7.53 (m, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.30~7.22 (m, 2H), 7.19~7.10 (m, 3H), 7.10~7.04 (m, 1H), 6.88~6.82 (m, 1H), 6.80~6.73 (m, 2H), 6.04 (s, 1H), 3.82~3.65 (m, 5H), 2.99~2.81 (m, 2H), 2.20 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.2, 141.5, 136.1, 135.5, 132.8, 132.7, 130.3, 130.2, 129.5, 121.9, 121.5, 120.7, 120.6, 119.5, 118.7, 117.3, 116.6, 114.6, 112.5, 111.0, 110.7, 109.0, 62.5, 55.3, 40.9, 27.8, 8.7; IR (KBr) ν: 3417, 3131, 1620, 1400, 1385, 1160, 743 cm^-1; ESI FTMS calcd for C₂₇H₂₄ClN₂O₂ (M-H)^- 443.1532, found 443.1541.

  2-(2-((1, 3-Dimethyl-1H-indol-2-yl)(3-methoxyphenyl)- methyl)-1H-indol-3-yl)ethan-1-ol (3oa): Yield 66% (28.1 mg), white solid. m.p. 104.0~106.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.71 (s, 1H), 7.64~7.59 (m, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.32~7.21 (m, 4H), 7.20~7.09 (m, 3H), 6.89~6.81 (m, 1H), 6.78~6.72 (m, 2H), 6.14 (s, 1H), 3.79 (t, J=6.6 Hz, 2H), 3.75 (s, 3H), 3.57 (s, 3H), 2.96 (t, J=6.6 Hz, 2H), 1.82 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.2, 141.6, 136.8, 135.2, 134.4, 134.0, 130.0, 129.0, 128.7, 121.8, 121.1, 119.7, 119.0, 118.6, 114.7, 112.4, 111.2, 109.3, 109.2, 109.0, 62.6, 55.3, 40.8, 30.2, 28.0, 8.7; IR (KBr) ν: 3523, 3446, 1697, 1436, 1374, 1044, 740 cm^-1; ESI FTMS calcd for C₂₈H₂₇N₂O₂ (M-H)^- 423.2078, found 423.2076.

  2-(2-((3-Methoxyphenyl)(3-methyl-1H-indol-2-yl)- methyl)-1-methyl-1H-indol-3-yl)ethan-1-ol (3an): Yield 60% (25.4 mg), white solid. m.p. 148.6~149.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.19 (s, 1H), 7.61~7.54 (m, 2H), 7.33~7.28 (m, 1H), 7.27~7.24 (m, 1H), 7.23~7.17 (m, 2H), 7.16~7.08 (m, 3H), 6.88~6.80 (m, 1H), 6.77~6.70 (m, 2H), 6.10 (s, 1H), 3.97~3.82 (m, 1H), 3.80~3.68 (m, 4H), 3.61 (s, 3H), 2.76~2.63 (m, 1H), 2.51~2.40 (m, 1H), 2.29 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.0, 142.0, 137.0, 135.6, 132.1, 129.6, 129.1, 127.9, 121.8, 121.4, 120.9, 119.2, 119.0, 118.7, 118.4, 114.5, 112.1, 111.0, 109.7, 109.2, 108.1, 62.6, 55.3, 40.4, 30.1, 27.4, 8.7; IR (KBr) ν: 3446, 2923, 1653, 1457, 1362, 1047, 740 cm^-1; ESI FTMS calcd for C₂₈H₂₇N₂O₂ (M-H)^- 423.2078, found 423.2083.

  2-(2-((3-Methoxyphenyl)(3-methyl-1H-indol-2-yl)- methyl)-1H-indol-3-yl)ethyl benzoate (3ao): Yield 71% (36.4 mg), white solid. m.p. 80.1~82.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.98 (s, 1H), 7.96 (s, 1H), 7.77 (s, 1H), 7.73~7.65 (m, 2H), 7.59~7.50 (m, 2H), 7.43~7.35 (m, 2H), 7.28~7.21 (m, 3H), 7.20~7.10 (m, 4H), 6.87~6.81 (m, 1H), 6.81~6.75 (m, 2H), 6.06 (s, 1H), 4.43 (t, J=7.2 Hz, 2H), 3.73 (s, 3H), 3.15 (t, J=7.2 Hz, 2H), 2.16 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 166.7, 160.2, 141.7, 135.4, 134.8, 133.0, 132.9, 130.3, 130.2, 129.6, 128.9, 128.3, 122.0, 121.8, 120.8, 119.9, 119.5, 118.8, 118.6, 114.5, 112.6, 111.1, 111.0, 109.0, 108.8, 64.7, 55.3, 40.9, 24.1, 8.6; IR (KBr) ν: 3502, 3446, 1683, 1435, 1386, 1048, 743 cm^-1; ESI FTMS calcd for C₃₄H₂₉N₂O₃ (M-H)^- 513.2183, found 513.2173.

  Supporting Information  ¹H NMR and ¹³C NMR spectra of products 3, HPLC spectra of compound 3aa, X-ray single crystal data for compound 3aa. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

  
  Dedicated to the 40th anniversary of Chinese Journal of Organic Chemistry.
  
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      (江晓莉, 戴伟, 赵佳佳, 石枫, 有机化学, 2016, 36, 1014.)
      (d) Ma, C.; Jiang, F.; Sheng, F.-T.; Jiao, Y.; Mei, G.-J.; Shi, F. Angew. Chem., Int. Ed. 2019, 58, 3014.
      (e) Wang, C.-S.; Li, T.-Z.; Liu, S.-J.; Zhang, Y.-C.; Deng, S.; Jiao, Y.; Shi, F. Chin. J. Chem. 2020, 38, 543.
      (f) Sheng, F.-T.; Li, Z.-M.; Zhang, Y.-Z.; Sun, L.-X.; Zhang, Y.-C.; Tan, W.; Shi, F. Chin. J. Chem. 2020, 83, 583.

  15. [15]

      CCDC 2010881 for 3aa. See the Supporting Information for details.

  16. [16]

      For some reviews: (a) Akiyama, T. Chem. Rev. 2007, 107, 5744.
      (b) Terada, M. Chem. Commun. 2008, 35, 4097.
      (c) Terada, M. Synthesis 2010, 1929.
      (d) Su, E.-J.; Shi, F.-J. Chin. J. Org. Chem. 2010, 30, 486(in Chinese).
      (苏亚军, 史福强, 有机化学, 2010, 30, 486.)
      (e) Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem. Res. 2011, 44, 1156.
      (f) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047.
      (g) Wu, H.; He, Y.-P.; Shi, F. Synthesis 2015, 47, 1990.
      (h) Xia, Z.-L.; Xu-Xu, Q.-F.; Zheng, C.; You, S.-L. Chem. Soc. Rev. 2020, 49, 286.

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  Figure 1  Selected bioactive molecules containing bisindolylmethane frameworks

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  Scheme 1  Profile of 2-indolylmethanol and tryptophol-involved reactions

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  Figure 2  X-ray single-crystal structure of 3aa

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  Scheme 2  Proposed reaction pathway

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  Table 1.  Optimization of reaction conditions^a

  Entry	B-H (4)	Solvent	T/℃	Yieldb/%
  1	TsOH•H2O (4a)	CH3CN	30	71
  2	TsOH•H2O (4a)	Tetrahydrofuran (THF)	30	75
  3	TsOH•H2O (4a)	Acetone	30	Trace
  4	TsOH•H2O (4a)	PhCH3	30	62
  5	TsOH•H2O (4a)	EtOAc	30	77
  6	TsOH•H2O (4a)	DCE	30	82
  7	TsOH•H2O (4a)	Dichloromethane (DCM)	30	66
  8	TsOH•H2O (4a)	CHCl3	30	62
  9	PhCOOH (4b)	DCE	30	Trace
  10	CF3SO3H(4c)	DCE	30	Trace
  11	CF3COOH (4d)	DCE	30	Trace
  12		DCE	30	70
  13	TsOH•H2O (4a)	DCE	20	70
  14	TsOH•H2O (4a)	DCE	0	73
  15	TsOH•H2O (4a)	DCE	-10	71
  16	TsOH•H2O (4a)	DCE	-30	Trace
  a Unless otherwise indicated, the reaction was carried out at the 0.1 mmol scale in a solvent (1 mL) for 12 h, and the molar ratio of 1a/2a was 1:1.2. b Isolated yield.

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  Table 2.  Further optimization of reaction conditions^a

  Entry	x	Additive	1a:2a	Yieldb/%
  1	1	—	1:1.2	82
  2	1	3 Å MS	1:1.2	64
  3	1	4 Å MS	1:1.2	67
  4	1	5 Å MS	1:1.2	63
  5	1	Na2SO4	1:1.2	72
  6	1	MgSO4	1:1.2	80
  7	1	—	1:2	85
  8	1	—	1:3	98
  9	1	—	1.2:1	Trace
  10	1	—	2:1	Trace
  11	1	—	3:1	Trace
  12	0.25	—	1:3	93
  13	0.5	—	1:3	93
  14	1.5	—	1:3	95
  15	2	—	1:3	95
  a Unless otherwise indicated, the reaction was carried out at the 0.1 mmol scale in DCE at 30 ℃ in the presence of 10 mol% 4a for 12 h. b Isolated yield.

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  Table 3.  Substrate scope of C(3)-substituted 2-indolylmethanols 1^a

  Entry	3	R1/R (1)	Yieldb/%
  1	3aa	m-MeOC6H4/H (1a)	98
  2	3ba	m-MeC6H4/H (1b)	85
  3	3ca	m-FC6H4/H (1c)	68
  4	3da	m-ClC6H4/H (1d)	72
  5	3ea	o-MeC6H4/H (1e)	92
  6	3fa	p-MeC6H4/H (1f)	72
  7	3ga	p-MeOC6H4/H (1g)	76
  8	3ha	p-FC6H4/H (1h)	63
  9	3ia	p-ClC6H4/H (1i)	64
  10	3ja	Ph/H (1j)	80
  11	3ka	m-MeOC6H4/5-Me (1k)	94
  12	3la	m-MeOC6H4/5-Cl (1l)	54
  13	3ma	m-MeOC6H4/6-OMe (1m)	49
  14	3na	m-MeOC6H4/7-Br (1n)	96
  a Unless indicated otherwise, the reaction was carried out in 0.1 mmol scale in the presence of 10 mol% 4a in DCE (1 mL) at 30 ℃ for 12 h, and the molar ratio of 1:2a was 1:3. b Isolated yield.

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  Table 4.  Substrate scope of tryptophols 2^a

  Entry	3	R (2)	Yieldb/%
  1	3aa	H (2a)	98
  2	3ab	4-Me (2b)	84
  3	3ac	5-Me (2c)	90
  4	3ad	5-F (2d)	71
  5	3ae	5-Cl (2e)	75
  6	3af	5-Br (2f)	87
  7	3ag	6-Me (2g)	53
  8	3ah	6-F (2h)	73
  9	3ai	6-Cl (2i)	72
  10	3aj	7-Me (2j)	71
  11	3ak	7-MeO (2k)	75
  12	3al	7-F (2l)	54
  13	3am	7-Cl (2m)	68
  a Unless indicated otherwise, the reaction was carried out in 0.1 mmol scale in the presence of 10 mol% 4a in DCE (1 mL) at 30 ℃ for 12 h, and the molar ratio of 1a:2 was 1:3. b Isolated yield.

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  Table 5.  Preliminary investigation on the catalytic asymmetric transformation^a

  Entry	Cat.	Solvent	T/℃	Additive	Yieldb/%	erc
  1	5a	Toluene	30	—	87	8
  2	5b	Toluene	30	—	46	4
  3	5c	Toluene	30	—	85	2
  4	5d	Toluene	30	—	89	10
  5	5e	Toluene	30	—	77	0
  6	5f	Toluene	30	—	61	20
  7	6a	Toluene	30	—	52	-20
  8	5f	EtOAc	30	—	N.R.	—
  9	5f	THF	30	—	N.R.	—
  10	5f	CH3CN	30	—	51	0
  11	5f	DCE	30	—	54	8
  12	5f	FC6H5	30	—	62	8
  13	5f	ClC6H5	30	—	56	10
  14	5f	BrC6H5	30	—	58	8
  15	5f	o-Xylene	30	—	60	22
  16	5f	m-Xylene	30	—	56	18
  17	5f	p-Xylene	30	—	46	20
  18	5f	o-Xylene	30	3 Å MS	59	38
  19	5f	o-Xylene	30	4 Å MS	52	40
  20	5f	o-Xylene	30	5 Å MS	62	38
  21	5f	o-Xylene	30	Na2SO4	58	38
  22	5f	o-Xylene	30	MgSO4	48	30
  23	5f	o-Xylene	40	4 Å MS	66	38
  24	5f	o-Xylene	50	4 Å MS	71	32
  25	5f	o-Xylene	20	4 Å MS	54	44
  26	5f	o-Xylene	10	4 Å MS	50	48
  27	5f	o-Xylene	0	4 Å MS	38	48
  28	5f	o-Xylene	-10	4 Å MS	Trace	—
  a Unless otherwise indicated, the reaction was carried out at the 0.1 mmol scale in a solvent (1 mL) for 12 h, and the molar ratio of 1a/2a was 1:1.2. b Isolated yield. c The ee value was determined by HPLC. N.R.=No reaction. DCE=1, 2-dichloroethane.

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