Tianmin
Niu
,
Lehao
Huang
,
Tianxing
Wu
and
Yuhong
Zhang
*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P.R. China. E-mail: yhzhang@zju.edu.cn; Fax: 0086-571-87953244; Tel: 0086-571-87952723
First published on 17th November 2010
An efficient iron-promoted alkylation of indoles with enamides has been accomplished under mild reaction conditions. The reaction proceeded with remarkable regioselectivity leading exclusively to substitution by indoles at α-position of enamides.
Recently, iron has been increasingly explored in organic transformations as an inexpensive and environmentally benign catalyst.13 There have been a series of reports concerning novel iron-catalyzed reactions, which lead to efficient C(sp2)–C(sp3),14 C(sp2)–C(sp2),15 C(sp2)–C(sp),16 and C–N17 bond formations. Herein, we report a highly efficient method for the addition of indoles to enamides in the presence of an iron catalyst under mild reaction conditions (Scheme 1). This facile catalytic system was also applicable to indolizines.
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Scheme 1 Iron-catalyzed alkylation of indoles and indolizines with enamides. |
Entry | Catalyst | Solvent | T/°C | Yield (%)b |
---|---|---|---|---|
a Reaction conditions: indole (0.5 mmol), 1-vinyl-2-pyrrolidinone (0.6 mmol), catalyst (0.05 mmol), solvent (5 ml), 40 °C, 30 min. b Isolated yields based on indole. c The isolated yield in anhydrous CH2Cl2 under nitrogen atmosphere is given in parentheses. d Concentrated hydrochloric acid (wt%: 36.5%) was used. | ||||
1 | none | CH2Cl2 | 40 | n.r |
2 | ZnCl2 | CH2Cl2 | 40 | n.r |
3 | RuCl3 | CH2Cl2 | 40 | trace |
4 | InBr3 | CH2Cl2 | 40 | n.r |
5 | NiCl2·6H2O | CH2Cl2 | 40 | 42 |
6 | SnCl4 | CH2Cl2 | 40 | 41 |
7 | CuCl2 | CH2Cl2 | 40 | 90 |
8 | BF3·Et2O | CH2Cl2 | 40 | 89 |
9 | FeCl3 | CH2Cl2 | 40 | 99 (98)c |
10 | FeCl3·6H2O | CH2Cl2 | 40 | 97 |
11 | Fe2O3 | CH2Cl2 | 40 | 32 |
12 | FeCl2 | CH2Cl2 | 40 | trace |
13 | Fe(acac)3 | CH2Cl2 | 40 | n.r |
14d | HCl | CH2Cl2 | 40 | 77 |
15 | TMSCl | CH2Cl2 | 40 | 74 |
16 | HOAc | CH2Cl2 | 40 | n.r |
17 | FeCl3 | CH2Cl2 | r.t. | 53 |
18 | FeCl3 | DMF | 40 | n.r |
19 | FeCl3 | CH3CN | 40 | 86 |
20 | FeCl3 | THF | 40 | 78 |
21 | FeCl3 | toluene | 40 | 70 |
22 | FeCl3 | acetone | 40 | 80 |
23 | FeCl3 | H2O | 40 | 78 |
Under the optimized reaction conditions, we examined the reactivity of various indoles as summarized in Table 2. In general, indoles with both electron-rich and electron-deficient substituents are active to give the adducts in high yields. Indoles with an electron-donating group were highly active to afford the alkylated indoles in excellent yields at 40 °C within 30 min (Table 2, entries 1–6). The indoles with C2 substituents delivered the corresponding alkylated indoles in high yields (Table 2, entries 7–8), illustrating that steric hindrance played a poor role to the reaction. Indole with moderate electron-withdrawing bromide group was active also to afford the corresponding alkylated indole in 98% yield (Table 2, entry 9). However, the strong electron-withdrawing substituents in indoles led to the decrease of the reaction rate, and the prolongation of the reaction time was needed to access the high yields (Table 2, entries 10–12). N-Substituted indoles presented equally high efficiency in respect to that of free indoles to give the adducts in high yields (Table 2, entries 13–15). Furthermore, this facile catalytic system was also applicable to various indolizines (Table 2, entries 16–18).
Entry | Indole/indolizine | Product | Yield (%)b |
---|---|---|---|
a Reaction conditions: indoles (0.5 mmol), 1-vinyl-2-pyrrolidinone (0.6 mmol), FeCl3 (8 mg, 0.05 mmol), in CH2Cl2 (5 ml), 40 °C, 30 min. b Isolated yields based on indole. c 6-Methyl-1H-indole (0.75 mmol), 1-vinyl-2-pyrrolidinone (0.5 mmol), isolated yields based on N-vinylformamide, 3 h was used. d The reaction time was 6 h. | |||
1 |
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![]() |
99 |
2 |
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82 |
3 |
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78 |
4 |
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96c |
5 |
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95 |
6 |
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88 |
7 |
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96 |
8 |
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90 |
9 |
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98 |
10 |
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99d |
11 |
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83d |
12 |
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86 |
13 |
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![]() |
98 |
14 |
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97 |
15 |
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88 |
16 |
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95 |
17 |
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99 |
18 |
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92 |
The reactivity of various enamindes was examined and the results are summarized in Table 3. Satisfying results were obtained when 1-vinylpyrrolidin-2-one 2a was replaced with 1-vinylazepan-2-one 2b (Table 3, entries 1–3). However, N-vinylformamide 2c gave the corresponding products in low yields under the reaction conditions. To our delight, when the ratio of the substrates was modified from indole:
enamide = 1
:
1.2 to enamide
:
indole = 1
:
1.5, the reaction was dramatically improved to afford the products in excellent yields (Table 3, entries 4–6). N-Methyl-N-vinylacetamide 2d afforded low yield in the reaction with N-free indole 1a possibly due to the decomposition of the product, and a 79% yield was obtained when the reaction was performed at room temperature (Table 3, entry 7). On the contrary, N-methyl indole 1m participated in the reaction smoothly to afford 6b in 81% yield at 40 °C within 30 min (Table 3, entry 8). In the case of indolizine 1q, longer reaction time and higher temperature were required (Table 3, entries 3 and 9).
Entry | Enamide | Indole/indolizine | Product | Yield (%)b |
---|---|---|---|---|
a Reaction conditions: indoles (0.5 mmol), enamides (0.6 mmol), FeCl3 (8 mg, 0.05 mmol), in CH2Cl2 (5 ml), 40 °C, 30 min. b Isolated yields based on indole. c 3 h, 60 °C, were used. d Indole (0.75 mmol), N-vinylformamide enamide (0.5 mmol), isolated yields based on N-vinylformamide. e Isolated yield when concentrated HCl (10 mol %) was used as catalyst. f Isolated yield when TMSCl (10 mol%) used as catalyst. g The reaction was at room temperature. | ||||
1 |
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1a |
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90 |
2 | 2b | 1m |
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91 |
3 | 2b | 1q |
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99c |
4d |
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1a |
![]() |
97
67e 81f |
5d | 2c | 1m |
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99 |
6d | 2c | 1q |
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99 |
7 |
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1a |
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79g |
8 | 2d | 1m |
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81 |
9 | 2d | 1q |
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80c |
During the study of the reaction of indoles with N-methyl-N-vinylformamide 2d, we found that the ratio of indoles to enamides influenced the final products. An excess of indole led to the substitution of indoles to 2d to give a mixture of alkylated indole 6a and a second alkylation product of bis-indolylmethane 7a. Since bis-indolylmethane and its derivatives are key structural units in many natural drugs used as cancer growth inhibitors,18 we investigated the reaction conditions for selective formation of bis-indolylmethane products as shown in Table 4. It was found that the amount of indole played a key role for the second alkylation. When 3 equivalents of indole were used, only bis-indolylmethane 7a was obtained in 91% yield (Table 4, entry 1). This transformation was compatible with a broad of functional groups, including –CH3, –Br, –CN, and N–CH3 (Table 4, entries 2–6). Importantly, asymmetric bis-indolylmethanes could be prepared by the use of 6a as initial substrate (Table 4, entry 7–8). The reaction was also applicable to indolizine (Table 4, entry 9). The enamides 2a, 2b, and 2c failed to furnish the bis-indolylmethane under the reaction conditions.
Entry | Indole/indolizine | Product | Yield (%)b |
---|---|---|---|
a Reaction conditions: indoles (1.5 mmol), N-methyl-N-vinylacetamide (0.5 mmol), FeCl3 (8 mg, 0.05 mmol), in CH2Cl2 (5 ml), 40 °C, 1 h. b Isolated yields based on N-methyl-N-vinylacetamide. c The reaction time prolongs to 5 h. d 12 h was used. e The reaction was in 60 °C for 12 h. | |||
1 |
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91 |
2 |
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89 |
3 |
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88c |
4 |
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67d |
5 |
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75 |
6 |
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90 |
7 |
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97 |
8 | 6a |
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96 |
9 |
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88e |
There are two possible pathways for the intermolecular C-3 indole alkylation as shown in Scheme 2. (1) With the aid of Lewis acid FeCl3, enamide 2a transforms to the iminium species I, which reacts with indole 1avia a Friedel–Crafts-type process to afford the alkylation product 3a (Scheme 1, path A).19 (2) The protonation of enamide 2a by the Brønsted acid hydrolyzed from FeCl3 generates the iminium II, which undergoes nucleophilic addition with indoles to give the final product (Scheme 1, path B).12,20 We performed the reaction in anhydrous CH2Cl2 under nitrogen atmosphere, and it was found that a high yield of desired product 1-(1-(1H-indol-3-yl)ethyl)pyrrolidin-2-one 3a was obtained (Table 1, entry 9). Furthermore, typical Lewis acid BF3·Et2O also worked well in this transformation (Table 1, entry 8). On the other hand, the employment of hydrochloric acid (10 mol%) and trimethyl chlorosilane (TMSCl) (10 mol%) as catalysts resulted in the desired products with enamide 2a and 2c in moderate yields (Table 1, entries 14 and 15; Table 4, entry 4), and the reaction with enamides 2b and 2d failed. Thus, we postulate the reaction takes place mainly through path A.
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Scheme 2 Proposed mechanism for alkylation of indoles from enamide. |
The production of bis-indolylmethanes in Table 4 might take place through the elimination of amine moiety of N-(1-(1H-indol-3-yl)ethyl)-N-methylacetamide 6a with the assistance of iron catalyst to form the intermediate III, which undergoes a Friedel–Crafts-type process with indoles or indolizine to deliver the symmetrical or unsymmetrical bis-indolylmethanes (Scheme 3).18a,21
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Scheme 3 Proposed mechanism for bis-indolylmethanes. |
Footnote |
† Electronic supplementary information (ESI) available: Experimental procedures and characterization data for all new compounds along with copies of 1H and 13C NMR spectral data. See DOI: 10.1039/c0ob00709a |
This journal is © The Royal Society of Chemistry 2011 |