Bai-Jing
Peng
ab,
Wen-Ting
Hsueh
a,
Ferenc
Fülöp
b and
Shyh-Chyun
Yang
*acd
aSchool of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
bInstitute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary
cDepartment of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
dDepartment of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. E-mail: scyang@kmu.edu.tw; Tel: +886-918-665-770
First published on 9th November 2018
Due to their biological activity, indoles and substituted indoles have attracted considerable attention from both synthetic and medicinal scientists. Much effort has been directed toward the development of methods for the functionalization of the indole nucleus. The protocol uses a catalytic amount of catalyzed platinum as a promoting agent, producing N-allylated indoles in considerable yields. Moreover, water, with its large heat capacity, is one of the most abundant molecules on earth. The use of water as a solvent may bring about many environmental benefits. Herein, we have demonstrated that the platinum-catalyzed selective N-allylation of 2,3-disubstituted indoles proceeds in water. This method provides a simple, convenient, and efficient way to afford a high yield of N-allylated indoles.
Transition metal catalysis has been and continues to be a predominant tool to form carbon–carbon, carbon–nitrogen, carbon–oxygen, and carbon–heteroatom bonds in organic synthesis.5 In particular, palladium-catalyzed Suzuki–Miyaura, Heck, and Negishi couplings are essential, as recorded by the 2010 Nobel Prize.6 The palladium-catalyzed allylation of nucleophiles has been proven to be an efficient, established, and highly chemo- and stereo-selective method.7 The catalytic cycles have been shown to proceed via the attack of nucleophiles on cationic η3-allylpalladium(II) complexes, an intermediate generated by the oxidative addition of allylic compounds, including carbamates, carbonates, esters, halides, phosphates, and related derivatives, to a Pd(0) complex.7c,8 Ruthenium, as well as palladium, have been used in the allylation reaction of 2,3-disubstituted indoles, but according to our knowledge, the use of platinum is rare.9 Platinum is a good transition metal, which is not often discussed.10 During our previous research on allylation with platinum as a catalyst agent, we established the application of processed platinum catalysis with desirable data.11
In recent years, our team has reported the Pt(II)-catalyzed allylation of 2,3-disubstituted indoles in benzene.12 However, benzene is a highly flammable and toxic liquid with a sweet smell, and increases the risk of cancer and other illnesses.13 In this scenario, considering both green chemistry and safety, it is crucial to find an alternative, environmentally-friendly solvent.14 Organic reactions in water have attracted much attention, because water is inexpensive, nonflammable, nontoxic, and has a large heat capacity.15 Water in its pure form is completely benign, so it would appear to be an attractive solvent.16 Therefore, the development of atom-economic reactions in water is one of the most important objectives of synthetic chemistry.11a,17 In this paper, we intend to disclose our study of the N-allylation of indoles with allylic acetates in the presence of a catalytic amount of platinum/phosphine complexes. The protocol allowed the N-selectivity of the reaction in water to be effectively controlled. This reaction system created a simple, convenient, and efficient way to afford a high yield of N-allylated indoles in water.
Entry | Ligand | Platinum catalyst | Solvent | Yield (%) (3a + 4a) | Yieldb (%) of 3a | Yieldb (%) of 4a |
---|---|---|---|---|---|---|
a Reaction conditions: 1a (1 mmol), 2a (2 mmol), Pt catalyst (0.025 mmol), and ligand (0.1 mmol) in solvent (5 mL) were refluxed for 2 h. b Isolated yield. c (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene. d 1,1-Bis(diphenylphosphino)ferrocene. e 1,4-Bis(diphenylphosphino)butane. f 1,1-Bis(diphenylphosphino)methane. g 1,2-Bis(diphenylphosphino)ethane. h Stirred at 80 °C. i Refluxed for 1 h. j (4-ClC6H4)3P (0.05 mmol). k 2a (1.2 mmol). | ||||||
1 | PPh3 | Pt(acac)2 | H2O | 28 | 28 | 0 |
2 | (2-Furyl)3P | Pt(acac)2 | H2O | 2 | 2 | 0 |
3 | (2-CH3C6H4)3P | Pt(acac)2 | H2O | 3 | 3 | 0 |
4 | (3-CH3C6H4)3P | Pt(acac)2 | H2O | 17 | 17 | 0 |
5 | (4-CH3C6H4)3P | Pt(acac)2 | H2O | 9 | 0 | 9 |
6 | (4-FC6H4)3P | Pt(acac)2 | H2O | 18 | 14 | 4 |
7 | (4-ClC6H4)3P | Pt(acac)2 | H2O | 95 | 95 | 0 |
8 | (4-CH3OC6H4)3P | Pt(acac)2 | H2O | 8 | 0 | 8 |
9 | (n-Butyl)3P | Pt(acac)2 | H2O | 12 | 12 | 0 |
10 | [2,4,6-(CH3O)3C6H2]3P | Pt(acac)2 | H2O | 8 | 0 | 8 |
11 | (2-Pyridyl)Ph2P | Pt(acac)2 | H2O | 4 | 4 | 0 |
12 | [2,6-(CH3O)2C6H3]3P | Pt(acac)2 | H2O | 5 | 5 | 0 |
13c | BINAP | Pt(acac)2 | H2O | 19 | 19 | 0 |
14d | dppf | Pt(acac)2 | H2O | 7 | 7 | 0 |
15e | dppb | Pt(acac)2 | H2O | 5 | 5 | 0 |
16f | dppm | Pt(acac)2 | H2O | 12 | 6 | 7 |
17g | dppe | Pt(acac)2 | H2O | 29 | 29 | 0 |
18 | — | Pt(acac)2 | H2O | 0 | 0 | 0 |
19h | (4-ClC6H4)3P | Pt(acac)2 | H2O | 67 | 67 | 0 |
20i | (4-ClC6H4)3P | Pt(acac)2 | H2O | 70 | 70 | 0 |
21 | (4-ClC6H4)3P | — | H2O | 0 | 0 | 0 |
22 | (4-ClC6H4)3P | cis-PtCl2(PhCN)2 | H2O | 93 | 86 | 7 |
23 | (4-ClC6H4)3P | cis-PtCl2(PPh3)2 | H2O | 82 | 72 | 10 |
24 | (4-ClC6H4)3P | Pt(COD)Cl2 | H2O | 12 | 12 | 0 |
25 | (4-ClC6H4)3P | O[Si(CH3)2C![]() |
H2O | 89 | 68 | 21 |
26 | (4-ClC6H4)3P | PtCl2 | H2O | 13 | 13 | 0 |
27 | (4-ClC6H4)3P | PtI2 | H2O | 12 | 9 | 3 |
28 | (4-ClC6H4)3P | Pt(CN)2 | H2O | 9 | 0 | 9 |
29 | — | Pt(CH2![]() |
H2O | 11 | 8 | 3 |
30 | (4-ClC6H4)3P | Pt(CH2![]() |
H2O | 34 | 23 | 11 |
31 | — | Pt(PPh3)4 | H2O | 3 | 3 | 0 |
32 | (4-ClC6H4)3P | Pt(PPh3)4 | H2O | 11 | 11 | 0 |
33j | (4-ClC6H4)3P | Pt(acac)2 | H2O | 50 | 50 | 0 |
34k | (4-ClC6H4)3P | Pt(acac)2 | H2O | 60 | 60 | 0 |
35 | (4-ClC6H4)3P | Pt(acac)2 | Benzene | 34 | 10 | 24 |
36 | (4-ClC6H4)3P | Pt(acac)2 | Toluene | 28 | 9 | 19 |
37 | (4-ClC6H4)3P | Pt(acac)2 | CH2Cl2 | 34 | 2 | 31 |
38 | (4-ClC6H4)3P | Pt(acac)2 | CH3OH | 17 | 17 | 0 |
39 | (4-ClC6H4)3P | Pt(acac)2 | C2H5OH | 26 | 26 | 0 |
The outcomes of the reaction conditions examined above were found to be applicable to a wide variety of allylic compounds. The results for the allylation of a number of allylic compounds (2b–g) with 1,2,3,4-tetrahydrocarbazole (1a) using Pt(acac)2 and (4-ClC6H4)3P are compiled in Table 2. The allylation of 3-buten-2-yl acetate (2b) gave N-allylated tetrahydrocarbazole 3b in a yield of 86% (entry 1). The N-allylated tetrahydrocarbazole E/Z ratio of 3b was determined by GC. Obviously, the E alkene product was generated from the more thermodynamically-stable syn complex. It was in a 73% overall yield that the corresponding reaction with crotyl acetate (2c) afforded N-allylated and C-allylated tetrahydrocarbazole (entry 2). These N-allylated products might all originate from the same π-allylic intermediate, which could be attacked at the C-1 position. The formation of the regioisomeric product was not observed. It is probable that the C-3 position products, which were involved in the internal N-allylation, were not generated in this scenario. Moreover, the reaction was considered to proceed via π-allylplatinum intermediates. The loss of stereochemistry in the starting acetate 2b was due to the more rapid σ ↔ η3 ↔ σ interconversion of the intermediates compared to the rate of allylation. trans-2-Hexen-1-yl acetate (2d), which reacted with 1a, gave 3c and 4c in 69% and 3% yields, respectively (entry 3). In the reaction of hex-1-en-3-yl acetate (2e), the corresponding N-allylated products were formed in 81% overall yields (entry 4). Unfortunately, the reaction of allyl chloride (2e), which is not an appropriate reagent for allylation, only produced 3a in a yield of 12% (entry 5). Increasing the amount of the reagents Pt(acac)2 and (4-ClC6H4)3P to twice the original dose could improve yields of 3a up to 57% (entry 6). The catalyst could not affect the yield, but this concept was built on the use of a sufficient amount of catalyst. In our catalyst system, we established N-allylation with trace amounts of platinum. Last but not least, with allyl carbonate (2g), the reaction afforded 3a and 4a in a 97% overall yield (entry 7). 3a was still the dominant product and was obtained in a yield of 92% in the allylation of 2g.
Entry | 2 | Yieldb (%) | |
---|---|---|---|
a Reaction conditions: 1a (1 mmol), 2a (2 mmol), Pt(acac)2 (0.025 mmol), and (4-ClC6H4)3P (0.1 mmol) in solvent (5 mL) were refluxed for 2 h. b Isolated yield. c Pt(acac)2 (0.05 mmol) and (4-ClC6H4)3P (0.2 mmol). d Determined by GC. | |||
1 |
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2 |
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3b 71 (E/Z = 89/11)d | 4b 2 |
3 |
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4 |
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3c 81 (E/Z = 85/15)d | 4c 0 |
5 |
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3a 12 | 4a 0 |
6c | 2f | 3a 57 | 4a 0 |
7 |
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3a 92 | 4a 5 |
The good efficiency of the allylation reactions described above prompted us to extend the reaction to corresponding indole derivatives (Table 3). The results summarized in Table 3 showed that the allylation of allyl acetaete (2a) with indoles, using Pt(acac)2 and (4-ClC6H4)3P, gave generally good yields of a variety of allylic indoles (entries 1–5). First, the allylation of the simpler 3-methylindole 1b was investigated. The overall yield was 73% (entry 1). 2,3-Dimethyl indole (1c) was a desirable substrate and generated N-allylated tetrahydrocarbazole in a 92% yield (entry 2). 1,2-Dimethyl-3H-benzoindole (1d), which consisted of the substituted benzene ring of tetrahydrocarbazole, was well tolerated and gave 96% yields of the corresponding N-allylated products (entry 3). The cyclopentane- and cycloheptane-fused indoles 1e and 1f participated in the reaction and gave high yields of the corresponding N-allylated compounds (entries 4 and 5).
A possible mechanism for the formation of N-allyl-2,3-disubstituted indoles from 1 and 2 is illustrated in Scheme 2, in which the substituent on allylic acetate is omitted. The circulation indicates that a Pt(II)-assisted mechanism is the feasible mechanism for C–N formation and activation. The entire pathway consists of three steps: allyl acetate 2 with Pt(0)Ln, allylation of the 2,3-disubstituted indole, and elimination from the π-allylplatinum intermediate. As detailed, 2 reacts with Pt(0) and the phosphine ligand species, which generate in situ, to produce π-allylplatinum intermediate 5. Subsequently, the reaction of 5 with 2,3-disubstituted indole 1 gives the π-allylplatinum intermediate with indole 6. Finally, the C–N bond formation is followed by the elimination of the π-allylplatinum intermediate with indole 6. Then, the whole system gives N-allyl-2,3-disubstituted indole 3.
Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8nj05051a |
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2019 |