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Letters in Organic Chemistry, 2010, 7, 666-670
Efficient and Metal-Free Friedel-Crafts Alkylation of Indoles with Allyl Acetate Mediated by TFE Zhe Liua,b, Li Liu*,a, Yan-Chao Wua,b and Dong Wanga a
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, P. R. China b
Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100080, P. R. of China Received June 12, 2010: Revised August 30, 2010: Accepted September 06, 2010
Abstract: An efficient, metal-free and chemo-selective Friedel-Crafts allylation of indoles in 2,2,2-trifluoroethanol (TFE) is developed. A possible mechanism has also been discussed to explain the observed competitive pathways in this reaction system.
Keywords: 2,2,2-trifluoroethanol, indole, Friedel-Crafts alkylation. Friedel-Crafts reaction is a conventional and attractive synthetic approach to achieve new C-C bond formation in aromatic rings which has great importance in modern organic chemistry [1]. Among the aromatic compounds, indole derivatives have a broad spectrum of bioactivities and applications in pharmaceutical, material, industrial and agrochemical sectors [2].
our efforts on allylation/propargylation of aromatic compounds under the catalysis of metal/non-metal Lewis acids [9]. On the continuation of developing a novel strategy for the allylation under metal-free and alcoholic conditions, herein we like to describe a simple and efficient TFEmediated allylation of indoles with excellent chemoselectivity at room temperature.
Recently, Friedel-Crafts allylation [3, 4] of indoles with allylic alcohols or esters usually employed precious transition-metals (Tsuji-Trost reaction) such as Pd or Mo as catalysts, but most cases suffered from low regioselectivities due to the competition of N- and C-alkylation, as well as dialkylation [5, 4a, b]. In order to obtain C-3 alkylation, excess base or borane was needed. On the other hand, Friedel-Crafts alkylation reaction of aromatic compounds with allylic or benzyl alcohols could be promoted by some Lewis acids [6], such as Sc(OTf)3 [6c, d], Hf(OTf)4 or Cl2Si(OTf)2 [6e], Ce(SO4)3 [6f], etc. Nevertheless, stoichiometric amount of Lewis acid and harsh conditions (usually heating) were often required. Thus, it is a challenging task for chemists to develop a greener, operationally simple and efficient method of regioselective allylation of indoles for both academic and industrial applications.
Initially, the reaction of indole (1a, R1,R2,R3 = H) with 1,3-diphenylprop-2-enyl acetate (2) was carried out at room temperature without the use of any catalyst and additive (Scheme 1). Several protic solvents were used, respectively, for screening of reaction media (Table 1). It was found that in 2,2,2-trifluoroethanol (TFE) the allylation alkylation reaction could give the best result: short reaction time and high yield (90%) (Entry 4). The other solvents or even common acids, such as AcOH and HCl, could not efficiently promote this transformation (Entries 5 and 6).
Trifluoroethanol (TFE) as a new medium has been used in many reactions due to its unique properties such as high hydrogen bonding donor ability, low nucleophilicity and high ionizing power [7]. Mayr and co-workers [8] reported the TFE-mediated alkylation of SN1-active substrates, benzyl and allyl halides with arenes and enol ethers under mild conditions. The allylation of indoles with allylic halides [4d] was also investigated in which TFE could be used as a reaction media, but with a less satisfactory choice than neutral aqueous media. In our laboratory, we have focused *Address correspondence to this author at the Beijing National Laboratory for Molecular Sciences (BNLMS), Laboratory for Chemical Biology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, P. R. China; Fax +86(10)62554449; E-mail:
[email protected]
1570-1786/10 $55.00+.00
Under the optimal condition, various indoles bearing electron-withdrawing or electron-donating substituents were selected to react with 2 (Scheme 1) and the data were summarized in Table 2. It was encouraging to find that simple indole (1a), 1- and 2-methyl indoles (1b and 1c), as well as dimethylindole (1d) could be transformed within a short time to afford the regioselectively C-3 allylated products (3a-d) in excellent yields (Entry 1-4). When a strong electron-withdrawing substituent (COOEt) (1d) or a relatively steric hindering group (Ph) (1e) existed at 2position, the moderate yields were obtained (Entry 5-6). For the indoles with electron-withdrawing or electrondonating groups (1g-i) the excellent yields of the alkylation products (3g-i) were gained either (Entries 7-9). However, in some cases solvolysis occurred as the side reaction to generate 4 (Entries 5-6, 11-12). In the case of 5benzyloxyindole (1m), the reaction afforded a complex mixture instead of clear allylated product and only minor byproduct 4 was isolated (Entry 13). In addition to electronic and steric considerations, namely the nucleophilic reactivities of indole substrates, the
© 2010 Bentham Science Publishers Ltd.
Efficient and Metal-Free Friedel-Crafts Alkylation of Indoles
Letters in Organic Chemistry, 2010, Vol. 7, No. 8
R1 R3
N R2
R3 N
OAc + Ph
Ph
OCH2CF3
R2
CF3CH2OH
+
r.t. Ph
R1 1
Ph
Ph
Ph
2
3
4
Scheme 1. Media Screening for Allylation of Indole (1a) with 2a
Table 1.
Entry
Media
Time (min)
Yieldb %
1
H2 O
60
N.R.c
2
MeOH
60
38
3
EtOH
60
29
4
TFE
10
90
5
AcOH
60
O2N N H
MeO
N H
BnO
N H
N H
N H
>>
N H
CO2Et
Ph N H
Fig. (1). The sequece of the solubilities of indole compounds in TFE. OAc Ph
Ph 2
In conclusion, a mild, efficient and metal-free TFEmediated allylation of indoles has been developed which could afford the corresponding C-3 allylated products in good to excellent yields. Both reactivity and solubility of indoles are crucial factors in the distribution of allylation and solvolysis products. Further applications and detailed mechanism of this protocol are studied underway in our laboratories.
OCH2CF3
TFE r. t., 2 h 83%
Ph
Ph 4
Scheme 2.
Considering the bifunctional role of TFE being both solvent and promoter, we could suggest that there should be two competitive reactions: allylation and solvolysis in the reaction system. The chemoselectivity depends on both solubility in TFE and reactivity of indole substrates. A possible mechanism of substitution reaction was triggered by first protonation of allyl acetate or hydrogen bond activation [10] of TFE molecule to general intermediate A, which could be attacked by indoles or TFE (Scheme 3). If the indole compound had great nucleophilic reactivity enough to surpass the attack of TFE anion, the alkylation product 3 would be formed dominantly (path a), whereas insoluble and nonreactive indoles would lose the chance to attack the allylic system and solvolysis product 4 was formed (path b) [8].
GENERAL PROCEDURE [11] To a mixture of 1,3-diphenylprop-2-enyl acetate 2 (92 mg, 0.36 mmol) and 5-bromoindole 1k (72 mg, 0.36 mmol) 2,2,2-triflouroethanol (2 mL) were added. The reaction mixture was stirred for 40 min at room temperature until starting materials were consumed as monitered by TLC. After evaporation of the solvent in vacuo, the residue was purified by flash chromatography on silica gel (eluent: 20:1 petroleum ether/ethyl acetate) to provide 3-[(E)-1,3diphenyl-2-propenyl)-5-bromo-indole (3k) as a brown solid (81% yield) and (E)-1,3-diphenyl-2-propenyl trifluoroethyl ether (4) as a colorless oil (13% yield).
O OH O CF3CH2OH Ph
O
Ph Ph
Ph Nu
HN
R
A
a Nu: a
b
R
OCH2CF3
N H Ph
Scheme 3.
Ph
b. CF3CH2O
Ph
P h
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Letters in Organic Chemistry, 2010, Vol. 7, No. 8
Liu et al.
ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China, the Ministry of Science and Technology of China (No. 2009ZX09501-006) and the Chinese Academy of Sciences (KJCX2.YW.H16) for the financial support. REFERENCES AND NOTES [1] [2] [3]
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