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A new approach for the synthesis of 2-substituted indole derivatives via Michael type adducts
Tetrahedron 61 (2005) 2401–2405
A new approach for the synthesis of 2-substituted indole derivatives via Michael type adducts Hu¨seyin C¸avdar and Nurullah Sarac¸og˘lu* Department of Chemistry, Faculty of Art and Sciences, Atatu¨rk University, Erzurum 25240, Turkey Received 5 October 2004; revised 4 December 2004; accepted 7 January 2005 Available online 27 January 2005
Abstract—4,7-Dihydroindole undergoes regioselective alkylation at the 2-position of the indole nucleus through conjugate addition with a,b-unsaturated carbonyl compounds. The oxidation of the Michael adducts affords the corresponding 2-substituted indole derivatives which were characterized by spectroscopic methods. q 2005 Elsevier Ltd. All rights reserved.
1. Introduction The chemistry of indole is one of the most active areas of heterocyclic chemistry. The indole moiety remains at the forefront of biological and medicinal chemistry. The most ubiquitous of the bioactive alkaloids known are based on the indole nucleus.1 Since the 3-position of indole is the preferred site for electrophilic substitution reaction, 3-alkyl or acyl indoles are versatile intermediates for the synthesis of a wide range of indole derivatives.2 The simple and direct method for the synthesis of 3-alkylated indoles involve the conjugate addition of indoles to a,b-unsaturated compounds. 2-Substituted indoles are also potential intermediates for many alkaloids and pharmacologically important substances. 3 While the methods for the preparation of 3-substituted indoles are well established, there is a need for yet easier access to 2-substituted indoles. Generally restricted methods have been reported for the preparation of 2-substituted indoles. a-Lithioindoles have been used to prepare 2-haloindoles and to introduce a variety of substituents by the reaction with appropriate electrophiles such as aldehydes, ketones and chloformates.4 Another method for the synthesis of 2-substituted indoles involves a-palladation at moderate temperature if C-3 is occupied. The metallated products are allowed to react with acrylates, other alkenes (Heck reaction) or carbon monoxide in situ.5 Additionally, 2-methylindoles have been elaborated into many 2-substituted indole derivatives using an allylic bromination reaction.6 However, most of these methods involve protection of the indole 3-position with an ester or Keywords: Indole; Natural product; Michael reaction; Electrophilic substitution; Bismuth nitrate; a,b-Unsaturated compound. * Corresponding author. Tel.: C90 442 2314425; fax: C90 442 2360948; e-mail: [email protected] 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.01.017
benzoyl group and masking the indole nitrogen as a phenyl sulfonyl or acyl.
Indole (1) undergoes electrophilic substitution preferentially at b(C3)-position whereas pyrrole (2) gives reaction at a(C2)-position.7 The positional selectivity in these fivemembered systems is well explained by the stability of the Wheland intermediates for electrophilic substitution. The intermediate cations from b- for indole (1) and a- for pyrrole (2) are the more stabilized. Michael reactions are one of the most important carbon–carbon bond-forming reactions in organic synthesis.8,9 We would like to disclose herein our approach for synthesis of 2-substituted indole derivatives with Michael type adducts. Our synthetic strategy is based on a dipole change by transforming the indole ring into a pyrrole derivative.
2. Results and discussion Firstly, we carried out Birch reduction reaction of indole with Li in liquid ammonia, which is a very powerful reducing system, and which reduces the benzene ring but not the pyrrole ring to form 4,7-dihydroindole (3) and 4,5,6,7-tetrahydroindole (4) (Scheme 1).10 We obtained a mixture consisting of 3 and 4 in a 4:1 ratio, which could be best separated by recrystallization, respectively. Since the
H. C ¸ avdar, N. Sarac¸og˘lu / Tetrahedron 61 (2005) 2401–2405
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Scheme 1.
reduction products are now pyrrole derivatives, we investigated the Michael reaction of 4,7-dihydroindole (3) with a,b-unsaturated carbonyl compounds (Table 1). The
reaction of 3 with maleic anhydride (5) in CHCl3 gave 3-(4,7-dihydro-1H-indol-2-yl)-dihydro-furan-2,5-dione (6) in a 73.5% (Scheme 2). For the next step, we attempted the aromatization of the cyclohexadiene ring in 6 to obtain the indole derivative 7. Whereas, the oxidation of 6 with 1 equiv of 1,2-dicyano-4,5-dichloroquinone (DDQ) gave a complex reaction mixture, the indole derivative 8 was obtained by reaction of 6 with 2 equiv of DDQ in a 90%. Similarly, various a,b-unsaturated carbonyl compounds such as diethyl azodicarboxylate (9), 1,3-diphenyl-propenone (10),11 2-cyclohexenone (11)11 and 2-cyclopentenone (12)11 were reacted with 4,7-dihydroindole (3) in order to
Table 1. Michael addition of 4,7-dihydroindole (3) with some a,b-unsaturated compounds Entry
Nucleophile
Electrophile
3
1
2b
5
3
3
4
–
9
Oxidant
Yield (%)a
Product
8
15
Bi(NO3)3
11 Bi(NO3)3
90
13
Bi(NO3)3
10
3
3
Catalyst
16
45
30
49
12 3
5
a b
Isolated yield. EtO2C–NH–NH–CO2Et (14)12 forms at entry 2.
Scheme 2.
Bi(NO3)3
17
45
H. C ¸ avdar, N. Sarac¸og˘lu / Tetrahedron 61 (2005) 2401–2405
synthesize the corresponding indole derivatives. The Michael acceptors 9–12 failed to react with dihydroindole 3 under the present reaction conditions. Compound 3 was treated with 1 mol of diethyl azodicarboxylate (9) in the presence of a catalytic amount of Bi(NO3)39 as mild reagent in CH2Cl2 to give a mixture of the corresponding Michael adduct, indole derivative 13, reduction product 1412 of diethyl azodicarboxylate (9) and the unreacted 3. Therefore, the dihydroindole 3 reacted with 2 equiv of diethyl azodicarboxylate (9) in the presence of Bi(NO3)3 to furnish 13 and 14 in moderate yield. While 1 equiv of the diethyl azodicarboxylate (9) is used as the Michael acceptor, the rest serves as oxidation reagent. Next, the indole derivatives 15–17 were synthesized from the reaction of 3 with the enones 10–12 in the presence of Bi(NO3)3 followed by the oxidation of these formed Michael adducts with p-benzoquinone (18) as the oxidation agent. The structures of the products were determined by 1H NMR, C NMR, IR and elemental analysis. The Michael addition product 6 was characterized by the presence of NH signals at d 8.38 ppm, olefinic protons and C3-H in pyrrole ring at 5.88–5.32 ppm (3H), allylic proton at 4.39 ppm (dd, JZ9.4, 7.7 Hz). Furthermore CH2 protons in the anhydride ring gave rise to a resolved the AB system. While the A part (low field) of the AB system showed at 3.43 ppm (dd, JZ18.7, 9.4 Hz), the B part of the system and the CH2 protons in the cyclohexadiene ring coincided at 3.33–3.15 ppm. Notably, NOE experiments for C3-H in all indole derivatives (8, 13, 15, 16, 17) showed that a NOE between the aromatic C4-H and C3-H in the five-membered ring but not observed NOE between the C3-H and the NH protons. Thus, the reaction of the dihydroindole 3 with the Michael acceptors results in 2-substitution of the indole nucleus. This observed regioselectivity shows that the attack of the dihydroindole 3 to the unsaturated compound occurs at the C-2 position. The reaction of the dihydroindole 3 with the a,b-unsaturated compounds probably proceeds through an intermediate 20 as depicted in Scheme 3. In the last step, the oxidation of the Michael addition products gives the corresponding indole derivatives. 13
Scheme 3.
In summary, we have developed an efficient strategy to access 2-substituted indole derivatives starting from indole. Further applications of this chemistry are currently in progress.
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3. Experimental 3.1. General methods Solvents were concentrated at reduced pressure. Melting points were determined on Buchi 539 capillary melting apparatus and uncorrected. Infrared spectra were obtained from KBr pellets or film on a Mattson 1000 FT-IR spectrophotometer. 1H NMR and 13C NMR spectra were recorded on 200 (50) and 400 (100)-MHz Varian spectrometer and are reported in d units with SiMe4 as internal standard. Elemental analyses were carried out on a Carlo Erba 1108 model CHNS-O analyser. 3.1.1. Birch reduction reaction of the indole (1). Liquid ammonia (500 mL) was distilled under N2 into a predried, three-necked flask. Then, the solution of the indole (1) (25 g, 0.21 mol) in dry methanole (128 g, 4 mol) was added, and the resulting solution was cooled to K35G5 8C and stirred as mechanical. The resulting solution was treated with Lithium metal (6 g, 0.84 mol) added in small pieces for 5–10 min, which reacted very rapidly. The resulting deep blue solution was stirred at the same temperature for 60 min and then the resulting mixture was allowed to warm to rt. After the excess ammonia had evaporated, Et2O (200 mL), NH4Cl (5 g) and H2O (300 mL) were carefully added to the reaction mixture. The layers were separated, the aqueous layer was extracted with Et2O (2!200 mL), and the combined organic layers were washed with NaHCO3 (2! 100 mL), dried (MgSO4), filtered, and concentrated. The 1H NMR of the residue showed that the formation of 3 and 4 in a 4:1 ratio. The residue (23 g) was recrystallized with CH2Cl2/hexane to give the dihydroindole 3 (19 g, 75%) as a colourless crystals, mp: 35–36 8C (lit.10 mp 37–39 8C). Further the recrystalliztion of the residue furnished the tetrahydroindole 4 (4.10 g, 16%) as a pale yellow crystals from hexane; mp 53–54 8C (lit.10 mp 54–55 8C); For 4,7dihydro-1H-indole (3): 1H NMR (200 MHz, CDCl3): d 7.70 (m, NH, 1H), 6.72 (t, JZ2.5 Hz, A part of AB system, ]CH, H-2, 1H), 6.07 (t, JZ2.5 Hz, B part of AB system, ]CH, H-3, 1H), 5.95 (bd, JZ10.1 Hz, A part of AB system, ]CH, H-5 or H-6, 1H), 5.87 (bd, JZ10.1 Hz, B part of AB system, ]CH, H-5 or H-6, 1H), 3.30 (bs, H-4 and H-7, CH2, 4H); 13C NMR (50 MHz, CDCl3): d 128.00, 127.93, 125.98, 118.28, 115.88, 108.77, 27.01, 26.02; IR (CH2Cl2, cmK1): 3364, 3018, 2856, 2825, 1651, 1555, 1362, 1324, 1208, 1150, 1085, 958. For 4,5,6,7-tetrahydro1H-indole (4): 1H NMR (200 MHz, CDCl3): d 7.72 (m, NH, 1H), 6.66 (t, JZ2.6 Hz, A part of AB system, ]CH, H-2, 1H), 6.03 (t, JZ2.6 Hz, B part of AB system, ]CH, H-3, 1H), 2.64–2.55 (m, CH2, 4H), 1.93–1.73 (m, CH2, 4H); 13C NMR (50 MHz, CDCl3): d 128.97, 118.90, 117.73, 109.44, 26.02, 25.61, 25.04, 24.88; IR (CH2Cl2, cmK1): 3370, 3093, 2923, 2846, 1673, 1596, 1542, 1442, 1311, 1203, 1133, 1079, 1056, 910, 833. 3.1.2. 3-(4,7-Dihydro-1H-indol-2-yl)-dihydro-furan-2,5dione (6). A solution of 4,7-dihydroindole (3) (300 mg, 2.50 mmol) and freshly sublimed maleic anhydride (247 mg, 2.50 mmol) in 20 mL CHCl3 was stirred at room temperature for 2 days. After removal of the solvent, the residue was filtered on a short silica gel column (5 g) eluting with CHCl3 (200 mL) to give 400 mg (73.5%) of the title
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compound 6. The crystallization of the residue from CHCl3/ hexane gave dark yellow powder; mp 145–146 8C: 1H NMR (200 MHz, CDCl3): d 8.38 (m, NH, 1H), 5.88–5.82 (m, ]CH, pyrrole and cyclohexadiene ring, 3H), 4.39 (dd, JZ 9.4, 7.7 Hz, CH, 1H), 3.43 (dd, JZ18.7, 9.4 Hz, A part of AB system, CH2, 1H), 3.33–3.15 (m, CH2, 5H); 13C NMR (50 MHz, CDCl3): d 173.51, 170.95, 128.11, 127.55, 124.56, 123.23, 116.57, 107.16, 41.78, 36.29, 26.65, 25.81; IR (CH2Cl2, cmK1): 3401, 3031, 2861, 2831, 1859, 1774, 1604, 1411, 1272, 1234, 1149, 1072, 1002. Anal. calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C, 67.03; H, 5.04; N, 6.39. 3.1.3. 3-(1H-Indol-2-yl)-furan-2,5-dione (8). To a stirred solution of 6 (152 mg, 0.71 mmol) in 10 mL of dry benzene (CAUTION-CARCINOGENIC) was added a solution of DDQ (355 mg, 1.54 mmol). After the addition was complete, stirring was continued for 1 h at room temperature. The solvent was evaporated and residue was filtered on a short silica gel column (5 g) eluting with CH2Cl2 (100 mL). The residue (148 mg, 99%) was recrystallized from ethyl acetate/hexane to give 8 as dark brown powder (135 mg, 90%); mp 223–224 8C: 1H NMR (200 MHz, CD3COCD3): d 11.00 (m, NH, 1H), 7.71 (d, JZ7.7 Hz, A part of AB system, 1H), 7.55 (d, JZ1.5 Hz, H-3, 1H), 7.48 (d, JZ7.7 Hz, A part of AB system, 1H), 7.31 (bt, JZ 7.7 Hz, A part of AB system, 1H), 7.12 (s, 1H), 7.11 (d, JZ 7.7 Hz, B part of AB system, 1H); 13C NMR (50 MHz, CD3COCD3): d 167.61, 167.25, 142.13, 141.26, 131.02, 129.94, 128.94, 125.20, 123.74, 123.45, 121.40, 116.35, 114.76, 114.06; IR (CH2Cl2, cmK1): 3394, 1835, 1766, 1619, 1511, 1411, 1280, 1241, 1141, 910. Anal. calcd for C12H7NO3: C, 67.61; H, 3.31; N, 6.57. Found: C, 67.04; H, 3.26; N, 6.69. 3.1.4. Reaction of 4,7-dihydroindole (3) diethyl azodicarboxylate (9). A solution of 4,7-dihydroindole (3) (179 mg, 1.50 mmol), diethyl azodicarboxylate (9) (502 mg, 3.01 mmol) and Bi(NO3)3 (117 mg, 0.24 mmol) in 2 mL CH2Cl2 was stirred at room temperature for 16 h. The residue was filtered on a silica gel column (60 g) eluting with ethyl acetate/hexane (5%) to give the indole derivative 13, which was crystallized from CH2Cl2/hexane (140 mg, 45%, dark grey powders, mp: 115–116 8C. Further elution with ethyl acetate/hexane (40%) furnished the product 14: (140 mg, 40%) colourless powder from CH2Cl2/hexane; mp 119–120 8C (lit.12 mp 128–130 8C); For 13: 1H NMR (200 MHz, CDCl3): d 9.76 (m, NH, 1H), 7.51 (bd, JZ 6.6 Hz, 1H), 7.31 (bd, JZ7.7 Hz, 1H), 7.26–7.06 (m, 2H), 6.12 (m, ]CH, H-3, 1H), 4.37–4.15 (m, CH2, 4H), 1.36– 1.17 (m, CH3, 6H); 13C NMR (50 MHz, CDCl3): d 157.75, 156.08, 135.26, 129.07, 123.36, 123.22, 122.11, 121.91, 121.83, 112.86, 65.64, 64.70, 16.38 (2C); IR (CH2Cl2, cmK1): 3324, 3062, 2993, 2931, 1720, 1627, 1604, 1558, 1465, 1380, 1319, 1249, 1172, 1072, 1010. Anal. calcd for C14H17N3O4: C, 57.72; H, 5.88; N, 14.42. Found: C, 57.56; H, 5.97; N, 14.30. For 14: 1H NMR (200 MHz, CDCl3): d 6.62 (m, NH, 2H), 4.20 (q, JZ7.1 Hz, OCH2, 4H), 1.27 (t, JZ7.1 Hz, CH3, 6H); 13C NMR (50 MHz, CDCl3): d 158.73, 64.25, 16.39; IR (CH2Cl2, cmK1): 3301, 2993, 1712, 1519, 1380, 1326, 1241, 1072. 3.1.5. 3-(1H-Indol-2-yl)-1,3-diphenyl-propan-1-one (15).
A solution of 4,7-dihydroindole (3) (300 mg, 2.52 mmol), 1,3-diphenyl-propenone (10) (132 mg, 0.63 mmol) and Bi(NO3)3 (219 mg, 0.45 mmol) in 2 mL CH2Cl2 was stirred at room temperature for 16 h. After the solvent was evaporated, the residue was filtered on a short silica gel column (5 g) eluting with CH2Cl2 (100 mL). The crude product (432 mg, 1.32 mmol) and 147 mg (1.32 mmol) p-benzoquinone were dissolved in CH2Cl2 (20 mL) and stirred at room temperature for 24 h. Reaction mixture was diluted with CH2Cl2 (100 mL), and the organic phase was washed with NaOH (2!50 mL, 10%), washed with water (2!50 mL) and dried over MgSO4. After removal of the solvent, the residue was purified on a silica gel column (50 g) eluting with ethyl acetate/hexane (5%) to give 40 mg of unreacted 1,3-diphenyl-propenone (10) as the first fraction. Further elution with ethyl acetate/hexane (5%) furnished the product 15: (242 mg, 30%) yellow crystals from CH2Cl2/hexane; mp 124–125 8C; 1H NMR (200 MHz, CDCl3): d 8.23 (m, NH, 1H), 8.02–7.97 (m, 2H), 7.63–7.50 (m, 4H), 7.48–7.23 (m, 6H), 7.15–7.00 (m, 2H), 6.20 (m, ]CH, H3, 1H), 4.96 (dd, JZ7.7 Hz, 5.5 Hz, CH, 1H), 3.92 (dd, JZ17.7, 7.7 Hz, A part of AB system, CH2, 1H), 3.70 (dd, JZ17.7, 5.5 Hz, B part of AB system, CH2, 1H); 13C NMR (50 MHz, CDCl3): d 200.56, 144.26, 143.66, 138.80, 138.14, 135.41, 130.81, 130.69, 130.17, 130.12, 129.13, 123.51, 122.07, 121.63, 114.63, 112,62, 101.96, 46.92, 41.76; IR (CH2Cl2, cmK1): 3392, 3046, 2923, 2869, 1684, 1600, 1458, 1346, 1292, 1253, 1223, 992, 753, 700. Anal. calcd for C23H19NO: C, 84.89; H, 5.89; N, 4.30. Found: C, 85.01; H, 5.74; N, 4.41. 3.1.6. 3-(1H-Indol-2-yl)-cyclohexanone (16). A solution of 4,7-dihydroindole (3) (100 mg, 0.84 mmol), 2-cyclohexenone (11) (81 mg, 0.84 mmol) and Bi(NO3)3 (73 mg, 0.30 mmol) in 2 mL CH2Cl2 was stirred at room temperature for 16 h. After the solvent was evaporated, the residue was filtered on a short silica gel column (5 g) eluting with CH2Cl2 (100 mL). The crude product (181 mg, 0.82 mmol) and p-benzoquinone (98 mg, 0.90 mmol) were dissolved in CH2Cl2 (20 mL) and stirred at room temperature for 24 h. Reaction mixture was diluted with CH2Cl2 (100 mL), and the organic phase was washed with NaOH (2!50 mL, 10%), washed with water (2!50 mL) and dried over MgSO4. After removal of the solvent, the residue was filtered on a silica gel column (45 g) eluting with ethyl acetate/hexane (20%) to give 90 mg (49%) as a dark brown powder which was recrystallized from CH2Cl2/hexane; mp 148–149 8C; 1H NMR (200 MHz, CDCl3): d 8.10 (m, NH, 1H), 7.56 (bd, JZ6.5 Hz, 1H), 7.32 (bd, JZ8.0 Hz, 1H), 7.20–7.05 (m, 2H), 6.28 (bs, ]CH, H3, 1H), 3.26 (pentet, JZ4.8 Hz, CH, 1H), 2.85–1.75 (m, CH2, 8H); 13C NMR (50 MHz, CDCl3): d 212.26, 143.32, 137.84, 130.35, 123.66, 122.19, 121.90, 112.57, 100.86, 49.06, 43.28, 39.73, 33.23, 26.67; IR (CH2Cl2, cmK1): 3340, 3054, 2939, 2861, 1704, 1643, 1596, 1550, 1457, 1419, 1349, 1311, 1234, 1172, 1141. Anal. calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found: C, 79.01; H, 6.97; N, 6.71. 3.1.7. 3-(1H-Indol-2-yl)-cyclopentanone (17). A solution of 4,7-dihydroindole (3) (200 mg, 1.68 mmol), 2-cyclopentenone (12) (146 mg, 1.68 mmol) and Bi(NO 3) 3 (146 mg, 0.37 mmol) in 2 mL CH2Cl2 was stirred at room temperature for 16 h. After the solvent was evaporated, the
H. C ¸ avdar, N. Sarac¸og˘lu / Tetrahedron 61 (2005) 2401–2405
residue was filtered on a short silica gel column (5 g) eluting with CH2Cl2 (100 mL). The crude product (350 mg, 1.74 mmol) and p-benzoquinone (206 mg, 1.91 mmol) were dissolved in CH2Cl2 (20 mL) and stirred at room temperature for 24 h. Reaction mixture was diluted with CH2Cl2 (100 mL), and the organic phase was washed with NaOH (2!50 mL, 10%), washed with water (2!50 mL) and dried over MgSO4. After removal of the solvent, the residue was filtered on a silica gel column (45 g) eluting with ethyl acetate/hexane (20%) gave 150 mg (45%) as a dark brown powder which was recrystallized from CH2Cl2/ hexane; mp 100–101 8C; 1H NMR (200 MHz, CDCl3): d 8.21 (bs, NH, 1H), 7.58 (bd, JZ8.2 Hz, 1H), 7.33 (bd, JZ 7.4 Hz, 1H), 7.23–7.08 (m, 2H), 6.30 (bs, ]CH, H3, 1H), 3.59–3.51 (m, CH, 1H), 2.77–2.05 (m, CH2, 6H); 13C NMR (50 MHz, CDCl3): d 219.82, 142.69, 138.18, 130.34, 123.71, 122.19, 121.96, 112.59, 100.78, 46.56, 40.00, 37.58, 31.54; IR (CH2Cl2, cmK1): 3384, 3061, 2961, 2906, 1738, 1630, 1461, 1407, 1300, 1246, 1153, 1015. Anal. calcd for C13H13NO: C, 78.36; H, 6.58; N 7.03. Found: C, 78.48; H, 6.44; 6.90. Acknowledgements The authors are indebted to the Department of Chemistry and Atatu¨rk University for financial support.
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A new approach for the synthesis of 2-substituted indole derivatives via Michael type adducts Hu¨seyin C¸avdar and Nurullah Sarac¸og˘lu* Department of Chemistry, Faculty of Art and Sciences, Atatu¨rk University, Erzurum 25240, Turkey Received 5 October 2004; revised 4 December 2004; accepted 7 January 2005 Available online 27 January 2005
Abstract—4,7-Dihydroindole undergoes regioselective alkylation at the 2-position of the indole nucleus through conjugate addition with a,b-unsaturated carbonyl compounds. The oxidation of the Michael adducts affords the corresponding 2-substituted indole derivatives which were characterized by spectroscopic methods. q 2005 Elsevier Ltd. All rights reserved.
1. Introduction The chemistry of indole is one of the most active areas of heterocyclic chemistry. The indole moiety remains at the forefront of biological and medicinal chemistry. The most ubiquitous of the bioactive alkaloids known are based on the indole nucleus.1 Since the 3-position of indole is the preferred site for electrophilic substitution reaction, 3-alkyl or acyl indoles are versatile intermediates for the synthesis of a wide range of indole derivatives.2 The simple and direct method for the synthesis of 3-alkylated indoles involve the conjugate addition of indoles to a,b-unsaturated compounds. 2-Substituted indoles are also potential intermediates for many alkaloids and pharmacologically important substances. 3 While the methods for the preparation of 3-substituted indoles are well established, there is a need for yet easier access to 2-substituted indoles. Generally restricted methods have been reported for the preparation of 2-substituted indoles. a-Lithioindoles have been used to prepare 2-haloindoles and to introduce a variety of substituents by the reaction with appropriate electrophiles such as aldehydes, ketones and chloformates.4 Another method for the synthesis of 2-substituted indoles involves a-palladation at moderate temperature if C-3 is occupied. The metallated products are allowed to react with acrylates, other alkenes (Heck reaction) or carbon monoxide in situ.5 Additionally, 2-methylindoles have been elaborated into many 2-substituted indole derivatives using an allylic bromination reaction.6 However, most of these methods involve protection of the indole 3-position with an ester or Keywords: Indole; Natural product; Michael reaction; Electrophilic substitution; Bismuth nitrate; a,b-Unsaturated compound. * Corresponding author. Tel.: C90 442 2314425; fax: C90 442 2360948; e-mail: [email protected] 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.01.017
benzoyl group and masking the indole nitrogen as a phenyl sulfonyl or acyl.
Indole (1) undergoes electrophilic substitution preferentially at b(C3)-position whereas pyrrole (2) gives reaction at a(C2)-position.7 The positional selectivity in these fivemembered systems is well explained by the stability of the Wheland intermediates for electrophilic substitution. The intermediate cations from b- for indole (1) and a- for pyrrole (2) are the more stabilized. Michael reactions are one of the most important carbon–carbon bond-forming reactions in organic synthesis.8,9 We would like to disclose herein our approach for synthesis of 2-substituted indole derivatives with Michael type adducts. Our synthetic strategy is based on a dipole change by transforming the indole ring into a pyrrole derivative.
2. Results and discussion Firstly, we carried out Birch reduction reaction of indole with Li in liquid ammonia, which is a very powerful reducing system, and which reduces the benzene ring but not the pyrrole ring to form 4,7-dihydroindole (3) and 4,5,6,7-tetrahydroindole (4) (Scheme 1).10 We obtained a mixture consisting of 3 and 4 in a 4:1 ratio, which could be best separated by recrystallization, respectively. Since the
H. C ¸ avdar, N. Sarac¸og˘lu / Tetrahedron 61 (2005) 2401–2405
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Scheme 1.
reduction products are now pyrrole derivatives, we investigated the Michael reaction of 4,7-dihydroindole (3) with a,b-unsaturated carbonyl compounds (Table 1). The
reaction of 3 with maleic anhydride (5) in CHCl3 gave 3-(4,7-dihydro-1H-indol-2-yl)-dihydro-furan-2,5-dione (6) in a 73.5% (Scheme 2). For the next step, we attempted the aromatization of the cyclohexadiene ring in 6 to obtain the indole derivative 7. Whereas, the oxidation of 6 with 1 equiv of 1,2-dicyano-4,5-dichloroquinone (DDQ) gave a complex reaction mixture, the indole derivative 8 was obtained by reaction of 6 with 2 equiv of DDQ in a 90%. Similarly, various a,b-unsaturated carbonyl compounds such as diethyl azodicarboxylate (9), 1,3-diphenyl-propenone (10),11 2-cyclohexenone (11)11 and 2-cyclopentenone (12)11 were reacted with 4,7-dihydroindole (3) in order to
Table 1. Michael addition of 4,7-dihydroindole (3) with some a,b-unsaturated compounds Entry
Nucleophile
Electrophile
3
1
2b
5
3
3
4
–
9
Oxidant
Yield (%)a
Product
8
15
Bi(NO3)3
11 Bi(NO3)3
90
13
Bi(NO3)3
10
3
3
Catalyst
16
45
30
49
12 3
5
a b
Isolated yield. EtO2C–NH–NH–CO2Et (14)12 forms at entry 2.
Scheme 2.
Bi(NO3)3
17
45
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synthesize the corresponding indole derivatives. The Michael acceptors 9–12 failed to react with dihydroindole 3 under the present reaction conditions. Compound 3 was treated with 1 mol of diethyl azodicarboxylate (9) in the presence of a catalytic amount of Bi(NO3)39 as mild reagent in CH2Cl2 to give a mixture of the corresponding Michael adduct, indole derivative 13, reduction product 1412 of diethyl azodicarboxylate (9) and the unreacted 3. Therefore, the dihydroindole 3 reacted with 2 equiv of diethyl azodicarboxylate (9) in the presence of Bi(NO3)3 to furnish 13 and 14 in moderate yield. While 1 equiv of the diethyl azodicarboxylate (9) is used as the Michael acceptor, the rest serves as oxidation reagent. Next, the indole derivatives 15–17 were synthesized from the reaction of 3 with the enones 10–12 in the presence of Bi(NO3)3 followed by the oxidation of these formed Michael adducts with p-benzoquinone (18) as the oxidation agent. The structures of the products were determined by 1H NMR, C NMR, IR and elemental analysis. The Michael addition product 6 was characterized by the presence of NH signals at d 8.38 ppm, olefinic protons and C3-H in pyrrole ring at 5.88–5.32 ppm (3H), allylic proton at 4.39 ppm (dd, JZ9.4, 7.7 Hz). Furthermore CH2 protons in the anhydride ring gave rise to a resolved the AB system. While the A part (low field) of the AB system showed at 3.43 ppm (dd, JZ18.7, 9.4 Hz), the B part of the system and the CH2 protons in the cyclohexadiene ring coincided at 3.33–3.15 ppm. Notably, NOE experiments for C3-H in all indole derivatives (8, 13, 15, 16, 17) showed that a NOE between the aromatic C4-H and C3-H in the five-membered ring but not observed NOE between the C3-H and the NH protons. Thus, the reaction of the dihydroindole 3 with the Michael acceptors results in 2-substitution of the indole nucleus. This observed regioselectivity shows that the attack of the dihydroindole 3 to the unsaturated compound occurs at the C-2 position. The reaction of the dihydroindole 3 with the a,b-unsaturated compounds probably proceeds through an intermediate 20 as depicted in Scheme 3. In the last step, the oxidation of the Michael addition products gives the corresponding indole derivatives. 13
Scheme 3.
In summary, we have developed an efficient strategy to access 2-substituted indole derivatives starting from indole. Further applications of this chemistry are currently in progress.
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3. Experimental 3.1. General methods Solvents were concentrated at reduced pressure. Melting points were determined on Buchi 539 capillary melting apparatus and uncorrected. Infrared spectra were obtained from KBr pellets or film on a Mattson 1000 FT-IR spectrophotometer. 1H NMR and 13C NMR spectra were recorded on 200 (50) and 400 (100)-MHz Varian spectrometer and are reported in d units with SiMe4 as internal standard. Elemental analyses were carried out on a Carlo Erba 1108 model CHNS-O analyser. 3.1.1. Birch reduction reaction of the indole (1). Liquid ammonia (500 mL) was distilled under N2 into a predried, three-necked flask. Then, the solution of the indole (1) (25 g, 0.21 mol) in dry methanole (128 g, 4 mol) was added, and the resulting solution was cooled to K35G5 8C and stirred as mechanical. The resulting solution was treated with Lithium metal (6 g, 0.84 mol) added in small pieces for 5–10 min, which reacted very rapidly. The resulting deep blue solution was stirred at the same temperature for 60 min and then the resulting mixture was allowed to warm to rt. After the excess ammonia had evaporated, Et2O (200 mL), NH4Cl (5 g) and H2O (300 mL) were carefully added to the reaction mixture. The layers were separated, the aqueous layer was extracted with Et2O (2!200 mL), and the combined organic layers were washed with NaHCO3 (2! 100 mL), dried (MgSO4), filtered, and concentrated. The 1H NMR of the residue showed that the formation of 3 and 4 in a 4:1 ratio. The residue (23 g) was recrystallized with CH2Cl2/hexane to give the dihydroindole 3 (19 g, 75%) as a colourless crystals, mp: 35–36 8C (lit.10 mp 37–39 8C). Further the recrystalliztion of the residue furnished the tetrahydroindole 4 (4.10 g, 16%) as a pale yellow crystals from hexane; mp 53–54 8C (lit.10 mp 54–55 8C); For 4,7dihydro-1H-indole (3): 1H NMR (200 MHz, CDCl3): d 7.70 (m, NH, 1H), 6.72 (t, JZ2.5 Hz, A part of AB system, ]CH, H-2, 1H), 6.07 (t, JZ2.5 Hz, B part of AB system, ]CH, H-3, 1H), 5.95 (bd, JZ10.1 Hz, A part of AB system, ]CH, H-5 or H-6, 1H), 5.87 (bd, JZ10.1 Hz, B part of AB system, ]CH, H-5 or H-6, 1H), 3.30 (bs, H-4 and H-7, CH2, 4H); 13C NMR (50 MHz, CDCl3): d 128.00, 127.93, 125.98, 118.28, 115.88, 108.77, 27.01, 26.02; IR (CH2Cl2, cmK1): 3364, 3018, 2856, 2825, 1651, 1555, 1362, 1324, 1208, 1150, 1085, 958. For 4,5,6,7-tetrahydro1H-indole (4): 1H NMR (200 MHz, CDCl3): d 7.72 (m, NH, 1H), 6.66 (t, JZ2.6 Hz, A part of AB system, ]CH, H-2, 1H), 6.03 (t, JZ2.6 Hz, B part of AB system, ]CH, H-3, 1H), 2.64–2.55 (m, CH2, 4H), 1.93–1.73 (m, CH2, 4H); 13C NMR (50 MHz, CDCl3): d 128.97, 118.90, 117.73, 109.44, 26.02, 25.61, 25.04, 24.88; IR (CH2Cl2, cmK1): 3370, 3093, 2923, 2846, 1673, 1596, 1542, 1442, 1311, 1203, 1133, 1079, 1056, 910, 833. 3.1.2. 3-(4,7-Dihydro-1H-indol-2-yl)-dihydro-furan-2,5dione (6). A solution of 4,7-dihydroindole (3) (300 mg, 2.50 mmol) and freshly sublimed maleic anhydride (247 mg, 2.50 mmol) in 20 mL CHCl3 was stirred at room temperature for 2 days. After removal of the solvent, the residue was filtered on a short silica gel column (5 g) eluting with CHCl3 (200 mL) to give 400 mg (73.5%) of the title
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compound 6. The crystallization of the residue from CHCl3/ hexane gave dark yellow powder; mp 145–146 8C: 1H NMR (200 MHz, CDCl3): d 8.38 (m, NH, 1H), 5.88–5.82 (m, ]CH, pyrrole and cyclohexadiene ring, 3H), 4.39 (dd, JZ 9.4, 7.7 Hz, CH, 1H), 3.43 (dd, JZ18.7, 9.4 Hz, A part of AB system, CH2, 1H), 3.33–3.15 (m, CH2, 5H); 13C NMR (50 MHz, CDCl3): d 173.51, 170.95, 128.11, 127.55, 124.56, 123.23, 116.57, 107.16, 41.78, 36.29, 26.65, 25.81; IR (CH2Cl2, cmK1): 3401, 3031, 2861, 2831, 1859, 1774, 1604, 1411, 1272, 1234, 1149, 1072, 1002. Anal. calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C, 67.03; H, 5.04; N, 6.39. 3.1.3. 3-(1H-Indol-2-yl)-furan-2,5-dione (8). To a stirred solution of 6 (152 mg, 0.71 mmol) in 10 mL of dry benzene (CAUTION-CARCINOGENIC) was added a solution of DDQ (355 mg, 1.54 mmol). After the addition was complete, stirring was continued for 1 h at room temperature. The solvent was evaporated and residue was filtered on a short silica gel column (5 g) eluting with CH2Cl2 (100 mL). The residue (148 mg, 99%) was recrystallized from ethyl acetate/hexane to give 8 as dark brown powder (135 mg, 90%); mp 223–224 8C: 1H NMR (200 MHz, CD3COCD3): d 11.00 (m, NH, 1H), 7.71 (d, JZ7.7 Hz, A part of AB system, 1H), 7.55 (d, JZ1.5 Hz, H-3, 1H), 7.48 (d, JZ7.7 Hz, A part of AB system, 1H), 7.31 (bt, JZ 7.7 Hz, A part of AB system, 1H), 7.12 (s, 1H), 7.11 (d, JZ 7.7 Hz, B part of AB system, 1H); 13C NMR (50 MHz, CD3COCD3): d 167.61, 167.25, 142.13, 141.26, 131.02, 129.94, 128.94, 125.20, 123.74, 123.45, 121.40, 116.35, 114.76, 114.06; IR (CH2Cl2, cmK1): 3394, 1835, 1766, 1619, 1511, 1411, 1280, 1241, 1141, 910. Anal. calcd for C12H7NO3: C, 67.61; H, 3.31; N, 6.57. Found: C, 67.04; H, 3.26; N, 6.69. 3.1.4. Reaction of 4,7-dihydroindole (3) diethyl azodicarboxylate (9). A solution of 4,7-dihydroindole (3) (179 mg, 1.50 mmol), diethyl azodicarboxylate (9) (502 mg, 3.01 mmol) and Bi(NO3)3 (117 mg, 0.24 mmol) in 2 mL CH2Cl2 was stirred at room temperature for 16 h. The residue was filtered on a silica gel column (60 g) eluting with ethyl acetate/hexane (5%) to give the indole derivative 13, which was crystallized from CH2Cl2/hexane (140 mg, 45%, dark grey powders, mp: 115–116 8C. Further elution with ethyl acetate/hexane (40%) furnished the product 14: (140 mg, 40%) colourless powder from CH2Cl2/hexane; mp 119–120 8C (lit.12 mp 128–130 8C); For 13: 1H NMR (200 MHz, CDCl3): d 9.76 (m, NH, 1H), 7.51 (bd, JZ 6.6 Hz, 1H), 7.31 (bd, JZ7.7 Hz, 1H), 7.26–7.06 (m, 2H), 6.12 (m, ]CH, H-3, 1H), 4.37–4.15 (m, CH2, 4H), 1.36– 1.17 (m, CH3, 6H); 13C NMR (50 MHz, CDCl3): d 157.75, 156.08, 135.26, 129.07, 123.36, 123.22, 122.11, 121.91, 121.83, 112.86, 65.64, 64.70, 16.38 (2C); IR (CH2Cl2, cmK1): 3324, 3062, 2993, 2931, 1720, 1627, 1604, 1558, 1465, 1380, 1319, 1249, 1172, 1072, 1010. Anal. calcd for C14H17N3O4: C, 57.72; H, 5.88; N, 14.42. Found: C, 57.56; H, 5.97; N, 14.30. For 14: 1H NMR (200 MHz, CDCl3): d 6.62 (m, NH, 2H), 4.20 (q, JZ7.1 Hz, OCH2, 4H), 1.27 (t, JZ7.1 Hz, CH3, 6H); 13C NMR (50 MHz, CDCl3): d 158.73, 64.25, 16.39; IR (CH2Cl2, cmK1): 3301, 2993, 1712, 1519, 1380, 1326, 1241, 1072. 3.1.5. 3-(1H-Indol-2-yl)-1,3-diphenyl-propan-1-one (15).
A solution of 4,7-dihydroindole (3) (300 mg, 2.52 mmol), 1,3-diphenyl-propenone (10) (132 mg, 0.63 mmol) and Bi(NO3)3 (219 mg, 0.45 mmol) in 2 mL CH2Cl2 was stirred at room temperature for 16 h. After the solvent was evaporated, the residue was filtered on a short silica gel column (5 g) eluting with CH2Cl2 (100 mL). The crude product (432 mg, 1.32 mmol) and 147 mg (1.32 mmol) p-benzoquinone were dissolved in CH2Cl2 (20 mL) and stirred at room temperature for 24 h. Reaction mixture was diluted with CH2Cl2 (100 mL), and the organic phase was washed with NaOH (2!50 mL, 10%), washed with water (2!50 mL) and dried over MgSO4. After removal of the solvent, the residue was purified on a silica gel column (50 g) eluting with ethyl acetate/hexane (5%) to give 40 mg of unreacted 1,3-diphenyl-propenone (10) as the first fraction. Further elution with ethyl acetate/hexane (5%) furnished the product 15: (242 mg, 30%) yellow crystals from CH2Cl2/hexane; mp 124–125 8C; 1H NMR (200 MHz, CDCl3): d 8.23 (m, NH, 1H), 8.02–7.97 (m, 2H), 7.63–7.50 (m, 4H), 7.48–7.23 (m, 6H), 7.15–7.00 (m, 2H), 6.20 (m, ]CH, H3, 1H), 4.96 (dd, JZ7.7 Hz, 5.5 Hz, CH, 1H), 3.92 (dd, JZ17.7, 7.7 Hz, A part of AB system, CH2, 1H), 3.70 (dd, JZ17.7, 5.5 Hz, B part of AB system, CH2, 1H); 13C NMR (50 MHz, CDCl3): d 200.56, 144.26, 143.66, 138.80, 138.14, 135.41, 130.81, 130.69, 130.17, 130.12, 129.13, 123.51, 122.07, 121.63, 114.63, 112,62, 101.96, 46.92, 41.76; IR (CH2Cl2, cmK1): 3392, 3046, 2923, 2869, 1684, 1600, 1458, 1346, 1292, 1253, 1223, 992, 753, 700. Anal. calcd for C23H19NO: C, 84.89; H, 5.89; N, 4.30. Found: C, 85.01; H, 5.74; N, 4.41. 3.1.6. 3-(1H-Indol-2-yl)-cyclohexanone (16). A solution of 4,7-dihydroindole (3) (100 mg, 0.84 mmol), 2-cyclohexenone (11) (81 mg, 0.84 mmol) and Bi(NO3)3 (73 mg, 0.30 mmol) in 2 mL CH2Cl2 was stirred at room temperature for 16 h. After the solvent was evaporated, the residue was filtered on a short silica gel column (5 g) eluting with CH2Cl2 (100 mL). The crude product (181 mg, 0.82 mmol) and p-benzoquinone (98 mg, 0.90 mmol) were dissolved in CH2Cl2 (20 mL) and stirred at room temperature for 24 h. Reaction mixture was diluted with CH2Cl2 (100 mL), and the organic phase was washed with NaOH (2!50 mL, 10%), washed with water (2!50 mL) and dried over MgSO4. After removal of the solvent, the residue was filtered on a silica gel column (45 g) eluting with ethyl acetate/hexane (20%) to give 90 mg (49%) as a dark brown powder which was recrystallized from CH2Cl2/hexane; mp 148–149 8C; 1H NMR (200 MHz, CDCl3): d 8.10 (m, NH, 1H), 7.56 (bd, JZ6.5 Hz, 1H), 7.32 (bd, JZ8.0 Hz, 1H), 7.20–7.05 (m, 2H), 6.28 (bs, ]CH, H3, 1H), 3.26 (pentet, JZ4.8 Hz, CH, 1H), 2.85–1.75 (m, CH2, 8H); 13C NMR (50 MHz, CDCl3): d 212.26, 143.32, 137.84, 130.35, 123.66, 122.19, 121.90, 112.57, 100.86, 49.06, 43.28, 39.73, 33.23, 26.67; IR (CH2Cl2, cmK1): 3340, 3054, 2939, 2861, 1704, 1643, 1596, 1550, 1457, 1419, 1349, 1311, 1234, 1172, 1141. Anal. calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found: C, 79.01; H, 6.97; N, 6.71. 3.1.7. 3-(1H-Indol-2-yl)-cyclopentanone (17). A solution of 4,7-dihydroindole (3) (200 mg, 1.68 mmol), 2-cyclopentenone (12) (146 mg, 1.68 mmol) and Bi(NO 3) 3 (146 mg, 0.37 mmol) in 2 mL CH2Cl2 was stirred at room temperature for 16 h. After the solvent was evaporated, the
H. C ¸ avdar, N. Sarac¸og˘lu / Tetrahedron 61 (2005) 2401–2405
residue was filtered on a short silica gel column (5 g) eluting with CH2Cl2 (100 mL). The crude product (350 mg, 1.74 mmol) and p-benzoquinone (206 mg, 1.91 mmol) were dissolved in CH2Cl2 (20 mL) and stirred at room temperature for 24 h. Reaction mixture was diluted with CH2Cl2 (100 mL), and the organic phase was washed with NaOH (2!50 mL, 10%), washed with water (2!50 mL) and dried over MgSO4. After removal of the solvent, the residue was filtered on a silica gel column (45 g) eluting with ethyl acetate/hexane (20%) gave 150 mg (45%) as a dark brown powder which was recrystallized from CH2Cl2/ hexane; mp 100–101 8C; 1H NMR (200 MHz, CDCl3): d 8.21 (bs, NH, 1H), 7.58 (bd, JZ8.2 Hz, 1H), 7.33 (bd, JZ 7.4 Hz, 1H), 7.23–7.08 (m, 2H), 6.30 (bs, ]CH, H3, 1H), 3.59–3.51 (m, CH, 1H), 2.77–2.05 (m, CH2, 6H); 13C NMR (50 MHz, CDCl3): d 219.82, 142.69, 138.18, 130.34, 123.71, 122.19, 121.96, 112.59, 100.78, 46.56, 40.00, 37.58, 31.54; IR (CH2Cl2, cmK1): 3384, 3061, 2961, 2906, 1738, 1630, 1461, 1407, 1300, 1246, 1153, 1015. Anal. calcd for C13H13NO: C, 78.36; H, 6.58; N 7.03. Found: C, 78.48; H, 6.44; 6.90. Acknowledgements The authors are indebted to the Department of Chemistry and Atatu¨rk University for financial support.
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