HETEROCYCLES

Communication | Special issue | Vol. 77, No. 2, 2009, pp. 767-772
Received, 28th July, 2008, Accepted, 26th September, 2008, Published online, 29th September, 2008.
DOI: 10.3987/COM-08-S(F)66

■ Friedel-Crafts Reaction of Indole Derivatives Using the Iminium Salt Generated by the Oxidation of Amino Ketene Silyl Acetal

Takuya Iwao and Makoto Shimizu*

Department of Chemistry for Materials, Faculty of Engineering, Mie University, 1577 Tsu, Mie 514-8507, Japan

Abstract

Friedel-Crafts reaction of various indole derivatives proceeded with the iminium salt generated by the oxidation of amino ketene silyl acetal to give the addition products in good yields. Further reaction of the introduced glycine moiety of the adducts with the second nucleophiles provided double nucleophilic addition products.

Intriguing reactivity of the iminim salts generated by the oxidation of aluminum enolate derivatives has enabled the use of α-imino esters as acceptors of two nucleophiles (eq 1).1 Generation of iminium species by the oxidation of the intermediary enolates was extended to the use of amino ketene silyl acetal, readily isolable enolate derivatives as starting materials, and this methodology offers a simple approach to a variety of α-amino esters in a short step (eq 2).2

Indole skeletons are often found in many of biologically active compounds such as tryptophan, indomethacin, and dragmacidin derivatives, and several methodologies have been reported to functionalize indoles.3 When these iminium salts are used as electrophiles, this methodology offers a regio- and chemoselective introduction of a glycine moiety into indoles. Further treatment of this adduct with a second nucleophile in the presence of BF3.Et2O induces displacement of the dibenzylamino moiety to give a double nucleophilic addition product (4).4

The initial examination was carried out to find optimum Friedel–Crafts reaction conditions using 1-methylindole (2b) as nucleophile, and Table 1 summarizes the results.

Regarding the oxidation reagent, use of NCS and NBS gave the adduct (4b) in low yields (Entries 1 and 2), whereas NIS and iodine effected the formation of the 1:2 addition product (5) (Entries 3 and 4). The best yield of the adduct (4b) was obtained, when DDQ was used in EtCN or DMF, where the by-product (5) was not formed (Entries 5 and 8). The use of BF3.Et2O did not noticeably accelerate the addition, but induced the formation of the 1:2 addition product (5) (Entries 9 ~ 11). Under the optimum reaction conditions found for the addition of 1-methylindole a variety of indoles were subjected to the Friedel–Crafts reaction, and the representative results are shown in Scheme 2.

Regarding the substituent at the nitrogen of indole, methyl and triisopropylsilyl (TIPS) groups effected the addition efficiently (4b, d), whereas p-toluenesulfonyl (Ts) inhibited the product formation in the absence of a Lewis acid (4e). 1-TIPS derivatives having a 5- or 6-substituent were next examined, and the bromo and methoxy derivatives gave the adduct in good yields (4g, h), while the 5-nitro derivative suppressed the addition reaction (4f). Except for the case with 6-bromoindole (4i), N-unprotected derivatives did not serve as good nucleophiles in the present system, and the adducts were obtained in low yields (4a, k, l, m). 3-Methylindoles did not participate in the addition reaction with the present iminium salt (4n, o).

As indicated in Table 1, under certain conditions a 1:2 addition product (5) was formed as a by-product, and therefore, we next examined the subsequent nucleophilic displacement of the dibenzylamino moiety of the adduct (6). Table 2 summarizes the results.

After a series of experiments, the best conditions were found for the addition of ketene silyl acetal derived from ethyl isobutyrate, and the adduct (6a) was obtained in 78% yield (Entry 1). Under these conditions, allyltrimethylsilane, and 1,3,5-trimethoxybenzene gave the adducts (6a, b) in moderate yields (Entries 2 and 3). Replacement of the dibenzylamino group with ethanol was effected by pyridinium p-toluenesulfonate to give the ethoxy derivative (6d) in moderate yield (Entry 4). A one-pot transformation was also carried out using five equivalents of the second nucleophile. In this case the adduct (6a) was obtained in 87% yield.

A possible reaction mechanism is depicted in Scheme 3. First, oxidation of the amino ketene silyl acetal (1) with DDQ gives the iminium salt (A), which in turn is attacked by indole to give the Friedel-Crafts adduct (4b). This adduct is further activated with BF3.Et2O to give the second iminium salt (B). This species would be responsible for the attack of the second nucleophile such as ketene silyl acetal to give the double addition product (6).

In conclusion, we have found that even in the absence of acid promoters, a facile Friedel-Crafts reaction of indoles proceeded with the iminium salt generated by the oxidation of amino ketene silyl acetal. The Friedel–Crafts adduct was further subjected to the second addition reaction to give the double addition products in good yields. Since a variety of bioactive compounds have indole skeletons and this reaction enables a simple introduction of the glycine moiety into indoles, the present methodology offers a useful addition to the existing functionalization of indoles.

* This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

References

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5. A typical procedure for the preparation of ethyl 2-dibenzylamino-2-(1-methylindolyl)acetate (4b) is as follows: Under an argon atmosphere, 1-ethoxy-2-dibenzylamino-1-trimethylsiloxyethylene (1) (0.20 mL, 0.10 mmol, 0.5 M in CH₂Cl₂) and a solution of 1-methylindole (2b) (13.1 mg, 0.10 mmol) in DMF were successively added to a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (25.0 mg, 0.11 mmol) in DMF (1.0 mL) at -78 °C. The reaction mixture was allowed to warm to ambient temperature with stirring for 14 h. The reaction was quenched with sat. aq. NaHCO₃, and the whole mixture was extracted with EtOAc (10 mL x 3). The combined extracts were washed with brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crude product was purified by preparative TLC on silica gel (EtOAc/n-hexane = 1/4) to give ethyl 2-dibenzylamino-2-(1-methylindolyl)acetate (4b) (>99%, 41.2 mg) as a colourless oil. ¹H NMR (500 MHz, CDCl₃) δ : 1.32 (t, J = 7.3 Hz, 3H), 3.67 (d, J = 13.7 Hz, 2H), 3.74 (s, 3H), 3.92 (d, J = 13.7 Hz, 2H), 4.21 (dq, J = 7.2, 10.7 Hz, 1H), 4.34 (dq, J = 7.2, 10.7 Hz, 1H), 4.87 (s, 1H), 7.08-7.12 (m, 3H), 7.20-7.34 (m, 11H), 7.50-7.51 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ : 14.5, 32.8, 54.4, 58.6, 60.3, 109.2, 109.5, 119.3, 121.8, 126.8, 127.6, 128.1, 128.8, 129.1, 137.1, 140.0, 172.4; IR (neat) 3439, 2838, 1727, 1640, 1544, 1452, 1370, 1027, 968, 740, 699, 566, 501 cm-1.
6. A typical procedure for the preparation of diethyl 2,2-dimethyl-3-(1-methylindolyl)succinate (6a) is as follows: Under an argon atmosphere, to a solution of ethyl 2-dibenzylamino-2-(1-methylindolyl)acetate (4b) (30.5 mg, 0.074 mmol) in CH₂Cl₂ (1.0 mL) were added successively a solution of 1-ethoxy-2-methyl-1-trimethylsiloxypropan-1-ene (28.3 mg, 0.148 mmol) in CH₂Cl₂ (1.5 mL) and BF₃·Et₂O (0.148 ml, 0.148 mmol, 1.0 M in CH₂Cl₂) at rt. The reaction mixture was allowed to stand at rt for 5 h. The reaction was quenched with sat. aq. NaHCO₃, and the whole mixture was extracted with EtOAc (10 mL x 3). The combined extracts were washed with brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crude product was purified by preparative TLC on silica gel (developed first with EtOAc/n-hexane = 1/4 and then with CH₂Cl₂/n-hexane = 1/3) to give diethyl 2,2-dimethyl-3-(1-methylindolyl)succinate (6a) (78%, 18.1 mg) as a colourless oil. ¹H NMR (500 MHz, CDCl₃) δ : 1.17-1.26 (m, 9H), 1.36 (s, 3H), 3.78 (s, 3H), 4.03-4.19 (m, 4H), 4.42 (s, 1H), 7.09-7.13 (m, 2H), 7.21-7.30 (m, 2H), 7.59-7.61 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ : 14.1, 14.1, 21.2, 25.1, 32.9, 45.7, 48.7, 60.5, 60.7, 107.9, 109.2, 119.2, 119.3, 121.5, 128.4, 129.1, 136.5, 173.3, 177,3; IR (neat) 2948, 1729, 1446, 1216, 1152, 1025, 883, 770, 697, 522, 417 cm-1