HETEROCYCLES

Paper | Special issue | Vol. 79, No. 1, 2009, pp. 635-645
Received, 25th September, 2008, Accepted, 5th November, 2008, Published online, 10th November, 2008.
DOI: 10.3987/COM-08-S(D)29

■ Synthesis of Nb-Acyltryptamines and Their 1-Hydroxy-tryptamine Derivatives as New α2-Blockers

Koji Yamada, Yoshio Tanaka, and Masanori Somei*

Faculty of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan

Abstract

Nb-Acyl- and Nb-acyl-1-hydroxytryptamines are found to be novel and structurally simple α2-blocker for the treatment of erectile dysfunction.

Nowadays, a lot of people need a drug for the treatment of erectile dysfunction (ED). Sildenafil citrate (1, Figure 1) has been used as a promising drug, but it has some side-effects2 to be improved. Although yohimbine3 (2) is a folk medicine and widely used among people as a α2-blocker to treat ED, it is a powerful medicine and dangerous unless we are careful about quantity to take. Therefore, when the safer drug is found, it would not only bring happiness to a human being, but also be applied for raising the breeding rate of animals.4,5 Cows and pigs could lay a lot of calves and child pigs, respectively and offer meat to us solving the significant problem of food shortage in the world.

In our project for developing a novel and potent α2-blocker, structurally simpler than 1 and 2, we discovered that Nb-acetyl- (3a) and Nb-methoxycarbonyltryptamines (3b) have weak but reliable activity as a α2-blocker.4 On the other hand, we succeeded in the establishment of 1-hydroxyindole chemistry.5 As a result, we found that 1-hydroxy-Nb-methoxycarbonyltryptamine (3c: IC50 0.32 μM) is one of the best leads and ten times more potent than cilostazol (4: IC50 3.10 μM) in the inhibition test on arachidonic acid induced platelet aggregation in rabbit PRP.6 It is expected to be a possible lead for cerebral and myocardial infarction.7
We attempted therefore to pursue the study of structure-activity relationship of Nb-acyltryptamines and their 1-hydroxytryptamine derivatives hoping to develop a potent lead for ED and cerebral infarction.
For the preparation of Nb-acyltryptamines, a conventional mixed anhydride method was applied. Appropriate carboxylic acids (5, Table 1) were treated with methyl chloroformate. The resultant anhydrides were then reacted with tryptamine (6) to afford the desired compounds (7) and the results are summarized in Table 1. Employing propanoic (5a), pentanoic (5b), heptanoic (5c), and nonanoic acids (5d), the corresponding Nb-propanoyl- (7a), Nb-pentanoyl- (7b), Nb-heptanoyl- (7c), and Nb-nonanoyltryptamines (7d) were produced in 94, 91, 95, and 93% yields, respectively. Cyclopropane- (5e), cyclohexane- (5f), and 2-furancarboxylic acids (5g) provided Nb-cyclopropanecarbonyl- (7e), Nb-cyclohexanecarbonyl- (7f), and Nb-2-furancarbonyltryptamine (7g) in the respective yields of 85, 61, and 62%.

According to the first step of our 1-hydroxyindole synthetic method,5 Nb-acyltryptamines (7) were converted to Nb-acyl-2,3-dihydrotryptamines (8) by the reduction with Et3SiH in trifluoroacetic acid at rt for 30 min. Thus, 7a, 7b, 7c, and 7d afforded 2,3-dihydro-Nb-propanoyl- (8a), -Nb-pentanoyl- (8b), -Nb-heptanoyl- (8c), and -Nb-nonanoyltryptamines (8d) in 98, 86, 87, and 78% yields, respectively. Similarly, 7e and 7f provided 2,3-dihydro-Nb-cyclopropanecarbonyl- (8e) and -Nb-cyclohexanecarbonyltryptamine (8f) in the respective yields of 84 and 73%. In the case of 7g, the reduction was slow and heating at around 60 °C for 1 h was necessary to produce 2,3-dihydro-Nb-2-furancarbonyltryptamine (8g) in 97% yield.
In the second step, 2,3-dihydro-Nb-acyltryptamines (8) were led to the desired new Nb-acyl-1-hydroxytryptamines (9) by the oxidation with Na2WO4·2H2O and 30% aqueous H2O2 in MeOH–H2O. For example, 8a, 8b, 8c, and 8d produced 1-hydroxy-Nb-propanoyl- (9a), -Nb-pentanoyl- (9b), Nb-heptanoyl-1-hydroxy- (9c), and 1-hydroxy-Nb-nonanoyltryptamines (9d) in 67, 61, 68, and 61% yields, respectively. In the cases of 8e, 8f, and 8g, Nb-cyclopropanecarbonyl- (9e), Nb-cyclohexanecarbonyl- (9f), and Nb-2-furancarbonyl-1-hydroxytryptamines (9g) were obtained in 69, 62, and 64% yields, respectively.

With the desired compounds in hand, we next evaluated the relaxant potencies of 7b-e and 9b-e as a preliminary test. The extent of the vascular relaxation produced in the muscle contracted with clonidine is summarized in Figure 1, making the activity of yohimbine as a standard for 100. It is interesting to note that the activity increases depending on the length of Nb-acyl side chain.5e,8 In addition, differences in activities are small between N(1)-H (7b-e) and N(1)-OH compounds (9b-e). These results strongly suggest that these simple tryptamine derivatives possess at least the antagonistic effect on vascular smooth muscle α2-AR.8 The potencies of 7d and 9d reached to about 80% of that of yohimbine. Furthermore, LD50 of 7d was determined to be more than 80 mg/kg on ddy male mouse, showing its safety. The details will be reported elsewhere in due course.
In conclusion, we have succeeded in finding new leads for the treatment of ED. We named them SST-VED-I type compounds. In order to discover more potent α2-blocker, we are preparing tryptamines having various Nb-side chain. The biological evaluation concerning cerebral infarction is now in progress.

EXPERIMENTAL
Melting points were determined on a Yanagimoto micro melting point apparatus and are uncorrected. Infrared (IR) spectra were recorded with a Shimadzu IR-420 and proton nuclear magnetic resonance (1H-NMR) spectra with a JEOL GSX-500 or JEOL JMS-AX5 spectrometer with tetramethylsilane as an internal standard. Mass spectra (MS) were recorded on a JEOL JMS-SX102A instruments. Column chromatography was performed on silica gel (SiO2, 100-200 mesh, from Kanto Chemical Co., Inc.) throughout the present study.
Nb-Propanoyltryptamine (7a) from Tryptamine (6) - General Procedure: Et3N (1.89 mL, 13.6 mmol) and ClCO2Me (1.05 mL, 1.36 mmol) were added to a solution of propanoic acid (912.7 mg, 12.3 mmol) in anhydrous CHCl3 (30 mL), and the mixture was stirred at 0 °C for 30 min. To the resulting mixture, 7 (2.17 g, 13.6 mmol) was added and the mixture was stirred at rt for 30 min. After addition of H2O the whole was extracted with CHCl3–MeOH (95:5, v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave a residue, which was column-chromatographed on SiO2 with EtOAc–hexane (1:1, v/v) to give 7a (2.51 g, 94%). 7a: mp 88-89 °C (colorless fine needles, recrystallized from Et2O). IR (KBr): 3377, 1635, 1563, 1453, 1368, 1250 cm-1. 1H-NMR (CDCl3) δ: 1.11 (3H, t, J=7.6 Hz), 2.14 (2H, q, J=7.6 Hz), 2.98 (2H, dt, J=6.6, 0.7 Hz), 3.61 (2H, q, J=6.6 Hz), 5.50 (1H, br s), 7.04 (1H, d, J=2.2Hz), 7.13 (1H, ddd, J=7.8, 7.1, 1.0 Hz), 7.21 (1H, ddd, J=7.8, 7.1, 1.2 Hz), 7.37 (1H, dt, J=7.8, 1.0Hz), 7.61 (1H, ddd, J=7.8, 1.2, 0.7 Hz), 8.09 (1H, br s). Anal. Calcd for C13H16N2O·1/8H2O: C, 71.45; H, 7.50; N, 12.82. Found: C, 71.77; H, 7.34; N, 12.52.
Nb-Pentanoyltryptamine (7b) from 6 - In the general procedure for the synthesis of 7a, Et3N (1.57 mL, 11.3 mmol), ClCO2Me (0.87 mL, 11.3 mmol), pentanoic acid (1.05 g, 10.3 mmol), anhydrous CHCl3 (30 mL), and 6 (1.81 g, 11.3 mmol) were used. After the work-up and column-chromatography with EtOAc–hexane (2:3, v/v), 7b (2.29 g, 91%) was obtained. 7b: mp 93-94 °C (colorless powder, recrystallized from EtOAc–hexane). IR (KBr): 3377, 3237, 2927, 1630, 1561, 1450 cm-1. 1H-NMR (CDCl3) δ: 0.88 (3H, t, J=7.3 Hz), 1.26-1.34 (2H, m), 1.53-1.60 (2H, m), 2.11 (2H, t, J=7.5 Hz), 2.98 (2H, t, J=6.6 Hz), 3.61 (2H, q, J=6.6 Hz), 5.56 (1H, br s), 7.04 (1H, s), 7.13 (1H, ddd, J=7.9, 7.0, 0.9 Hz), 7.22 (1H, ddd, J=7.9, 7.0, 0.9 Hz), 7.38 (1H, dt, J=7.9, 0.9 Hz), 7.61 (1H, d, J=7.9 Hz), 8.09 (1H, br s). Anal. Calcd for C15H20N2O: C, 73.73; H, 8.25; N, 11.47. Found: C, 73.48; H, 8.23; N, 11.42.
Nb-Heptanoyltryptamine (7c) from 6 - In the general procedure for the synthesis of 7a, Et3N (1.19 mL, 8.58 mmol), ClCO2Me (0.66 mL, 8.58 mmol), heptanoic acid (1.01 g, 7.80 mmol), anhydrous CHCl3 (30 mL), and 6 (1.37 g, 8.58 mmol) were used. After the work-up and column-chromatography with CHCl3 7c (2.02 g, 95%) was obtained. 7c: mp 97-98 °C (colorless powder, recrystallized from EtOAc–hexane). IR (KBr): 3410, 1632, 1565, 1457, 1425 cm-1. 1H-NMR (CDCl3) δ: 0.87 (3H, t, J=7.3 Hz), 1.21-1.31 (6H, m), 1.57 (2H, quint, J=7.5 Hz), 2.10 (2H, t, J=7.5 Hz), 2.98 (2H, t, J=6.6 Hz), 3.61 (2H, q, J=6.6 Hz), 5.52 (1H, br s), 7.04 (1H, d, J=2.2 Hz), 7.13 (1H, ddd, J=8.1, 7.0, 1.0 Hz), 7.22 (1H, ddd, J=8.1, 7.0, 1.0 Hz), 7.38 (1H, dt, J=8.1, 1.0 Hz), 7.61 (1H, d, J=8.1 Hz), 8.08 (1H, br s). Anal. Calcd for C17H24N2O: C, 74.96; H, 8.88; N, 10.29. Found: C, 74.80; H, 8.92; N, 10.26.
Nb-Nonanoyltryptamine (7d) from 6 - In the general procedure for the synthesis of 7a, Et3N (0.99 mL, 7.09 mmol), ClCO2Me (0.55 mL, 7.09 mmol), nonanoic acid (1.02 g, 6.45 mmol), anhydrous CHCl3 (30 mL), and 6 (1.14 g, 7.09 mmol) were used. After the work-up and column-chromatography with EtOAc–hexane (1:2, v/v), 7d (1.78 g, 93%) was obtained. 7d: mp 101-102 °C (colorless fine needles, recrystallized from CHCl3–hexane). IR (CHCl3): 2950, 1652, 1506, 1165 cm-1. 1H-NMR (CDCl3) δ: 0.87 (3H, t, J=7.0 Hz), 1.22-1.31 (10H, m), 1.57 (2H, br quint, J=7.0 Hz), 2.10 (2H, t, J=7.6 Hz), 2.98 (2H, t, J=6.7 Hz), 3.61 (2H, q, J=6.7 Hz, collapsed to t, J=6.7 Hz, on addition of D2O), 5.52 (1H, br s, disappeared on addition of D2O), 7.04 (1H, s), 7.13 (1H, ddd, J=8.1, 7.1, 1.0 Hz), 7.21 (1H, ddd, J=8.1, 7.1, 1.0 Hz), 7.38 (1H, d, J=8.1 Hz), 7.61 (1H, d, J=8.1 Hz), 8.09 (1H, br s, disappeared on addition of D2O). Anal. Calcd for C19H28N2O: C, 75.96; H, 9.39; N, 9.33. Found: C, 75.66; H, 9.49; N, 9.24.
Nb-Cyclopropanecarbonyltryptamine (7e) from 6 - In the general procedure for the synthesis of 7a, Et3N (1.81 mL, 13.0 mmol), ClCO2Me (1.00 mL, 13.0 mmol), cyclopropanecarboxylic acid (1.12 g, 13.0 mmol), anhydrous CHCl3 (30 mL), and 6 (1.89 g, 11.8 mmol) were used. After the work-up and column-chromatography with EtOAc–hexane (1:2, v/v), 7e (2.29 g, 85%) was obtained. 7e: mp 105.5-107 °C (colorless prisms, recrystallized from CHCl3). IR (KBr): 3280, 1611, 1566, 1251, 1235, 1197, 754 cm-1. 1H-NMR (CDCl3) δ: 0.69 (2H, td, J=7.9, 4.6 Hz), 0.97 (2H, dt, J=7.9, 4.6 Hz), 1.23 (1H, tt, J=7.9, 4.6 Hz), 2.99 (2H, t, J=6.8 Hz), 3.63 (2H, q, J=6.7 Hz, collapsed to t, J=6.7 Hz, on addition of D2O), 5.69 (1H, br s, disappeared on addition of D2O), 7.05 (1H, s), 7.13 (1H, ddd, J=8.1, 7.1, 1.1 Hz), 7.21 (1H, ddd, J=8.1, 7.1, 1.1 Hz), 7.38 (1H, dt, J=8.1, 1.1Hz), 7.61 (1H, br d, J=8.1 Hz), 8.12 (1H, br s, disappeared on addition of D2O). Anal. Calcd for C14H16N2O: C, 73.65; H, 7.06; N, 12.27. Found: C, 73.64; H, 7.09; N, 12.29.
Nb-Cyclohexanecarbonyltryptamine (7f) from 6 - In the general procedure for the synthesis of 7a, Et3N (1.16 mL, 8.34 mmol), ClCO2Me (0.65 mL, 8.35 mmol), cyclohexanecarboxylic acid (1.07 g, 8.33 mmol), anhydrous CHCl3 (25 mL), and 6 (1.21 g, 7.57 mmol) were used. After the work-up and column-chromatography with EtOAc–hexane (1:2, v/v), 7f (1.25 g, 61%) was obtained. 7f: mp 108.5-109 °C (colorless prisms, recrystallized from CHCl3). IR (KBr): 3270, 2940, 1618, 1561, 1449, 1220, 748 cm-1. 1H-NMR (CDCl3) δ: 1.15-1.26 (3H, m), 1.34-1.41 (2H, m), 1.65-1.81 (5H, m), 1.99 (1H, tt, J=11.7, 3.5 Hz), 2.97 (2H, t, J=6.8 Hz), 3.60 (2H, q, J=6.8 Hz, collapsed to t, J=6.8 Hz, on addition of D2O), 5.52 (1H, br s, disappeared on addition of D2O), 7.03 (1H, s), 7.13 (1H, ddd, J=8.1, 7.1, 1.0 Hz), 7.21 (1H, ddd, J=8.1, 7.1, 1.0 Hz), 7.38 (1H, dt, J=8.1, 1.0Hz), 7.61 (1H, br d, J=8.1 Hz), 8.10 (1H, br s, disappeared on addition of D2O). Anal. Calcd for C17H22N2O: C, 75.52; H, 8.20; N, 10.36. Found: C, 75.33; H, 8.26; N, 10.29.
Nb-2-Furancarbonyltryptamine (7g) from 6 - In the general procedure for the synthesis of 7a, Et3N (1.30 mL, 9.34 mmol), ClCO2Me (0.72 mL, 9.32 mmol), 2-furancarboxylic acid (1.04 g, 9.31 mmol), anhydrous CHCl3 (30 mL), and 6 (1.21 g, 7.57 mmol) were used. After the work-up and column-chromatography with EtOAc–hexane (1:1, v/v), 7g (1.33 g, 62%) was obtained. 7g: mp 158-160 °C (colorless needles recrystallized from EtOAc). IR (KBr): 3255, 1613, 1592, 1533, 1315, 1303, 1192 cm-1. 1H-NMR (CDCl3) δ: 3.28 (2H, t, J=6.8 Hz), 3.78 (2H, q, J=6.8 Hz, collapsed to t, J=6.8 Hz, on addition of D2O), 6.47 (1H, br s, disappeared on addition of D2O), 6.47 (1H, dd, J=3.5, 1.8 Hz), 7.08 (1H, s), 7.09 (1H, dd, J=3.5, 0.7 Hz), 7.13 (1H, ddd, J=8.1, 7.1, 1.0 Hz), 7.21 (1H, ddd, J=8.1, 7.1, 1.0 Hz), 7.36 (1H, dd, J=1.8, 0.7 Hz), 7.38 (1H, dt, J=8.1, 1.0Hz), 7.64 (1H, br d, J=8.1 Hz), 8.10 (1H, br s, disappeared on addition of D2O). Anal. Calcd for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02. Found: C, 70.94; H, 5.62; N, 11.01.
2,3-Dihydro-Nb-propanoyltryptamine (8a) from 7a - General Procedure: A mixture of 7a (1.02 g, 4.74 mmol) and Et3SiH (1.89 mL, 11.9 mmol) in TFA (20 mL) was stirred at rt for 30 min. After evaporation of the solvent, the residue was made alkaline with 8% aqueous NaOH and extracted with CHCl3–MeOH (95:5, v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO2 with CHCl3–MeOH–28% aqueous NH3 (46:1:0.1, v/v) to give 8a (1.01 g, 98%). 8a: yellow viscous oil. IR (film): 3315, 2970, 1635, 1606, 1547, 1486, 1461 cm-1. 1H-NMR (CDCl3) δ: 1.13 (3H, t, J=7.5 Hz), 1.78 (1H, dtd, J=13.6, 7.9, 6.0 Hz), 2.00 (1H, dddd, J=13.6, 7.9, 7.0, 5.0 Hz), 2.16 (2H, q, J=7.5 Hz), 2.82 (1H, br s, disappeared on addition of D2O), 3.26-3.42 (4H, m), 3.72 (1H, t, J=8.8 Hz), 5.62 (1H, br s, disappeared on addition of D2O), 6.67 (1H, d, J=7.3 Hz), 6.75 (1H, td, J=7.3, 0.9 Hz), 7.05 (1H, br t, J=7.3 Hz), 7.10 (1H, d, J=7.3 Hz). HR-MS m/z: Calcd for C13H18N2O: 218.1419. Found: 218.1431.
2,3-Dihydro-Nb-pentanoyltryptamine (8b) from 7b - In the general procedure for the synthesis of 8a, 7b (102.1 mg, 0.42 mmol), Et3SiH (0.17 mL, 1.05 mmol), and TFA (3 mL) were used. After the work-up and column chromatography with the same eluent, 8b (88.1 mg, 86%) was obtained. 8b: yellow viscous oil. IR (film): 3290, 2930, 1640, 1605, 1552, 1484, 1461 cm-1. 1H-NMR (CDCl3) δ: 0.91 (3H, t, J=7.5 Hz), 1.33 (2H, sex, J=7.5 Hz), 1.59 (2H, quint, J=7.5 Hz), 1.73 (1H, dtd, J=13.6, 8.0, 6.1 Hz), 1.99 (1H, dddd, J=13.6, 8.0, 7.0, 5.0 Hz), 2.13 (2H, t, J=7.5 Hz), 2.75 (1H, br s, disappeared on addition of D2O), 3.27-3.42 (4H, m), 3.72 (1H, t, J=8.6 Hz), 5.60 (1H, br s, disappeared on addition of D2O), 6.68 (1H, d, J=7.3 Hz), 6.75 (1H, td, J=7.3, 0.9 Hz), 7.05 (1H, br t, J=7.3 Hz), 7.11 (1H, d, J=7.3 Hz). HR-MS m/z: Calcd for C15H22N2O: 246.1732. Found: 246.1743.
Nb-Heptanoyl-2,3-dihydrotryptamine (8c) from 7c- In the general procedure for the synthesis of 8a, 7c (1.04 g, 3.82 mmol), Et3SiH (1.52 mL, 9.54 mmol), and TFA (20 mL) were used. After the work-up and column chromatography with EtOAc–hexane (2:1, v/v), 8c (912.7 mg, 87%) was obtained. 8c: pale brown viscous oil. IR (film): 3310, 2960, 1634, 1606, 1544, 1484, 1461 cm-1. 1H-NMR (CDCl3) δ: 0.88 (3H, t, J=7.5 Hz), 1.25-1.34 (6H, m), 1.60 (2H, quint, J=7.5 Hz), 1.78 (1H, dtd, J=13.6, 7.9, 5.9 Hz), 1.99 (1H, dddd, J=13.6, 7.9, 7.1, 5.1 Hz), 2.12 (2H, t, J=7.7 Hz), 2.68 (1H, br s, disappeared on addition of D2O), 3.27-3.42 (4H, m), 3.72 (1H, t, J=8.6 Hz), 5.60 (1H, br s, disappeared on addition of D2O), 6.68 (1H, d, J=7.5 Hz), 6.75 (1H, td, J=7.5, 1.1 Hz), 7.05 (1H, br t, J=7.5 Hz), 7.10 (1H, d, J=7.5 Hz). HR-MS m/z: Calcd for C17H26N2O: 274.2045. Found: 274.2057.
2,3-Dihydro-Nb-nonanoyltryptamine (8d) from 7d - In the general procedure for the synthesis of 8a, 7d (1.10 g, 3.65 mmol), Et3SiH (1.45 mL, 9.10 mmol), and TFA (20 mL) were used. After the work-up and column chromatography with EtOAc–hexane (1:1, v/v), 8d (862.4 mg, 78%) was obtained. 8d: mp 41-42.5 °C (colorless powder recrystallized from EtOAc–hexane). IR (KBr): 3300, 2935, 2870, 1638, 1546, 1486, 1465cm-1. 1H-NMR (DMSO-d6) δ: 0.84 (3H, t, J=7.0 Hz), 1.20-1.27 (10H, m), 1.45-1.57 (3H, m), 1.83 (1H, dtd, J=13.2, 7.6, 5.6 Hz), 2.04 (2H, t, J=7.5 Hz), 3.05 (1H, ddd, J=9.3, 8.1, 2.2 Hz), 3.09-3.16 (3H, m), 3.54 (1H, td, J=8.6, 1.7 Hz), 5.40 (1H, br s, disappeared on addition of D2O), 6.47 (1H, d, J=7.5 Hz), 6.52 (1H, td, J=7.5, 0.7 Hz), 6.90 (1H, br t, J=7.5 Hz), 7.00 (1H, d, J=7.5 Hz), 7.80 (1H, br t, J=6.1 Hz, disappeared on addition of D2O). Anal. Calcd for C19H30N2O: C, 75.45; H, 10.00; N, 9.26. Found: C, 75.25; H, 10.16; N, 9.24.
Nb-Cyclopropanecarbonyl-2,3-dihydrotryptamine (8e) from 7e - In the general procedure for the synthesis of 8a, 7e (137.3 mg, 0.60 mmol), Et3SiH (0.24 mL, 1.51 mmol), and TFA (3 mL) were used. After the work-up and column chromatography with EtOAc–hexane (2:1, v/v), 8e (116.3 mg, 84%) was obtained. 8e: mp 41-42.5 °C (colorless powder, recrystallized from EtOAc). IR (KBr): 3310, 1621, 1605, 1543, 1490, 1258, 1240 cm-1. 1H-NMR (DMSO-d6) δ: 0.60-0.67 (4H, m), 1.49-1.60 (2H, m), 1.86 (1H, dtd, J=13.4, 7.6, 5.4 Hz), 3.06 (1H, dd, J=8.8, 7.8 Hz), 3.12-3.17 (3H, m), 3.54 (1H, t, J=8.8 Hz), 5.41 (1H, br s, disappeared on addition of D2O), 6.48 (1H, d, J=7.6 Hz), 6.53 (1H, td, J=7.6, 1.0 Hz), 6.90 (1H, br t, J=7.6 Hz), 7.01 (1H, d, J=7.6 Hz), 8.08 (1H, br t, J=6.0 Hz, disappeared on addition of D2O). Anal. Calcd for C14H18N2O: C, 73.01; H, 7.88; N, 12.17. Found: C, 72.81; H, 7.92; N, 11.88.
Nb-Cyclohexanecarbonyl-2,3-dihydrotryptamine (8f) from 7f - In the general procedure for the synthesis of 8a, 7f (93.8 mg, 0.35 mmol), Et3SiH (0.14 mL, 0.88 mmol), and TFA (1.5 mL) were used. After the work-up and column chromatography with EtOAc–hexane (1:1, v/v), 8f (68.7 mg, 73%) was obtained. 8f: mp 109-111 °C (colorless plates, recrystallized from CHCl3–hexane). IR (KBr): 3290, 2930, 1622, 1545, 1536, 1464, 1252 cm-1. 1H-NMR (CDCl3) δ: 1.16-1.29 (3H, m), 1.35-1.43 (2H, m), 1.65-1.68 (1H, m), 1.73-1.84 (4H, m), 1.95-2.05 (3H, m), 2.53 (1H, br s, disappeared on addition of D2O), 3.26-3.41 (4H, m), 3.72 (1H, t, J=8.5 Hz), 5.60 (1H, br s, disappeared on addition of D2O), 6.68 (1H, d, J=7.3 Hz), 6.75 (1H, td, J=7.3, 0.9 Hz), 7.05 (1H, br t, J=7.3 Hz), 7.11 (1H, d, J=7.3 Hz). Anal. Calcd for C17H24N2O: C, 74.96; H, 8.88; N, 10.29. Found: C, 74.89; H, 8.96; N, 10.20.
Nb-2-Furanecarbonyl-2,3-dihydrotryptamine (8g) from 7g - In the general procedure for the synthesis of 8a, 7g (814.1 mg, 3.21 mmol), Et3SiH (1.28 mL, 8.03 mmol), and TFA (20 mL) were used. After the work-up and column chromatography with EtOAc–hexane (2:1, v/v), 8g (794.3 mg, 97%) was obtained. 8g: colorless viscous oil. IR (CHCl3): 3275, 1651, 1592, 1515, 1475, 1285 cm-1. 1H-NMR (CDCl3) δ: 1.87 (1H, dtd, J=13.7, 7.9, 6.0 Hz), 2.10 (1H, dtd, J=13.7, 7.9, 5.1 Hz), 3.33 (1H, dd, J=8.8, 6.3 Hz), 3.37-3.43 (1H, m), 3.47 (1H, dtd, J=13.7, 7.9, 6.3 Hz collapsed to dt, J=13.7, 7.9 Hz, on addition of D2O), 3.57 (1H, ddt, J=13.7, 7.9, 6.3 Hz collapsed to ddd, J=13.7, 7.9, 6.3 Hz, on addition of D2O), 3.75 (1H, t, J=8.8 Hz), 6.49 (1H, dd, J=3.5, 1.8 Hz), 6.54 (1H, br s, disappeared on addition of D2O), 6.69 (1H, d, J=7.5 Hz), 6.76 (1H, td, J=7.5, 1.0 Hz), 7.05 (1H, br t, J=7.5 Hz), 7.09 (1H, dd, J=3.5, 0.8 Hz), 7.13 (1H, d, J=7.5 Hz), 7.42 (1H, dd, J=1.8, 0.8 Hz). HR-MS m/z: Calcd for C15H16N2O2: 256.1211. Found: 256.1214.
1-Hydroxy-Nb-propanoyltryptamine (9a) from 8a - General Procedure: A solution of 30% aqueous H2O2 (1.11 g, 9.80 mmol) in MeOH (3 mL) was added with stirring to a solution of 8a (211.8 mg, 0.97 mmol) and Na2WO4·2H2O (64.1 mg, 0.19 mmol) in MeOH (7 mL) and H2O (1 mL) under ice cooling. Stirring was continued at rt for 15 min. After addition of H2O, the whole was extracted with CHCl3–MeOH (95:5, v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO2 with CHCl3–MeOH (99:1, v/v) to give 9a (150.2 mg, 67%). 9a: mp 132-133 °C (colorless fine prisms, recrystallized from CHCl3). IR (KBr): 3290, 3100, 2935, 1598, 1566, 1352 cm-1. 1H-NMR (DMSO-d6) δ: 0.99 (3H, t, J=7.6 Hz), 2.06 (2H, q, J=7.6 Hz), 2.79 (2H, t, J=7.3 Hz), 3.30 (2H, td, J=7.3, 6.1 Hz, collapsed to t, J=7.3 Hz, on addition of D2O), 6.98 (1H, dd, J=8.0, 7.3 Hz), 7.13 (1H, dd, J=8.0, 7.3 Hz), 7.24 (1H, s), 7.32 (1H, d, J=8.0 Hz), 7.53 (1H, d, J=8.0 Hz), 7.84 (1H, br t, J=6.1 Hz, disappeared on addition of D2O), 11.01 (1H, s, disappeared on addition of D2O). Anal. Calcd for C13H16N2O2: C, 67.22; H, 6.94; N, 12.06. Found: C,66.94; H, 6.95; N, 12.02.
1-Hydroxy-Nb-pentanoyltryptamine (9b) from 8b - In the general procedure for the synthesis of 9a, 30% aqueous H2O2 (2.37 g, 20.9 mmol), MeOH (5 mL), 8b (513.3 mg, 2.09 mmol), Na2WO4·2H2O (138.0 mg, 0.42 mmol), MeOH (20 mL), and H2O (2.5 mL) were used. After the work-up and column chromatography with EtOAc–hexane (2:1, v/v), 9b (331.2 mg, 61%) was obtained. 9b: mp 114.5-115 °C (colorless powder, recrystallized from CHCl3). IR (CHCl3): 3125, 2922, 1649, 1513 cm-1. 1H-NMR (DMSO-d6) δ: 0.86 (3H, t, J=7.4 Hz), 1.25 (2H, sex, J=7.4 Hz), 1.47 (2H, quint, J=7.4 Hz), 2.05 (2H, t, J=7.4 Hz), 2.78 (2H, t, J=7.4 Hz), 3.30 (2H, td, J=7.4, 6.1 Hz, collapsed to t, J=7.4 Hz, on addition of D2O), 6.98 (1H, ddd, J=8.1, 7.1, 1.0 Hz), 7.12 (1H, ddd, J=8.1, 7.1, 1.0 Hz), 7.23 (1H, s), 7.32 (1H, d, J=8.1 Hz), 7.53 (1H, d, J=8.1 Hz), 7.86 (1H, br t, J=6.1 Hz, disappeared on addition of D2O), 11.00 (1H, s, disappeared on addition of D2O). Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76. Found: C, 69.17; H, 7.70; N, 10.68.
Nb-Heptanoyl-1-hydroxytryptamine (9c) from 8c - In the general procedure for the synthesis of 9a, 30% aqueous H2O2 (461.4 mg, 4.07 mmol), MeOH (1 mL), 8c (111.3 mg, 0.41 mmol), Na2WO4·2H2O (27.3 mg, 0.08 mmol), MeOH (4 mL), and H2O (0.5 mL) were used. After the work-up and column chromatography with EtOAc–hexane (2:1, v/v), 9c (79.8 mg, 68%) was obtained. 9c: mp 83-83.5 °C (colorless prisms, recrystallized from CHCl3–hexane). IR (KBr): 3280, 2930, 1601, 1555, 1435, 1358, 1241 cm-1. 1H-NMR (DMSO-d6) δ: 0.86 (3H, t, J=7.5 Hz), 1.21-1.29 (6H, m), 1.47 (2H, quint, J=7.5 Hz), 2.04 (2H, t, J=7.5 Hz), 2.78 (2H, t, J=7.5 Hz), 3.29 (2H, td, J=7.5, 6.1 Hz, collapsed to t, J=7.5 Hz, on addition of D2O), 6.98 (1H, ddd, J=8.1, 7.1, 1.0 Hz), 7.12 (1H, ddd, J=8.1, 7.1, 1.0 Hz), 7.24 (1H, s), 7.32 (1H, dt, J=8.1, 1.0 Hz), 7.52 (1H, dt, J=8.1, 1.0 Hz), 7.86 (1H, br t, J=6.1 Hz, disappeared on addition of D2O), 11.00 (1H, s, disappeared on addition of D2O). Anal. Calcd for C17H24N2O2: C, 70.80; H, 8.39; N, 9.71. Found: C, 70.73; H, 8.40; N, 9.64.
1-Hydroxy-Nb-nonanoyltryptamine (9d) from 8d - In the general procedure for the synthesis of 9a, 30% aqueous H2O2 (451.3 mg, 3.98 mmol), MeOH (1 mL), 8d (119.3 mg, 0.40 mmol), Na2WO4·2H2O (26.7 mg, 0.08 mmol), MeOH (4 mL), and H2O (0.5 mL) were used. After the work-up and column chromatography with CHCl3–MeOH (99:1, v/v), 9d (75.8 mg, 61%) was obtained. 9d: mp 82.5-83 °C (colorless powder, recrystallized from CHCl3–hexane). IR (CHCl3): 3155, 2915, 1648, 1510, 1457 cm-1. 1H-NMR (DMSO-d6) δ: 0.86 (3H, t, J=7.4 Hz), 1.15-1.30 (10H, m), 1.47 (2H, quint, J=7.4 Hz), 2.03 (2H, t, J=7.4 Hz), 2.78 (2H, t, J=7.4 Hz), 3.30 (2H, td, J=7.4, 6.1 Hz, collapsed to t, J=7.4 Hz, on addition of D2O), 6.98 (1H, ddd, J=8.1, 7.1, 1.0 Hz), 7.12 (1H, ddd, J=8.1, 7.1, 1.0 Hz), 7.24 (1H, s), 7.32 (1H, d, J=8.1 Hz), 7.52 (1H, d, J=8.1 Hz), 7.86 (1H, br t, J=6.1 Hz, disappeared on addition of D2O), 11.01 (1H, s, disappeared on addition of D2O). Anal. Calcd for C19H28N2O2: C, 72.11; H, 8.92; N, 8.85. Found: C, 72.09; H, 8.96; N, 8.85.
Nb-Cyclopropanecarbonyl-1-hydroxytryptamine (9e) from 8e - In the general procedure for the synthesis of 9a, 30% aqueous H2O2 (498.0 mg, 4.39 mmol), MeOH (1 mL), 8e (101.6 mg, 0.44 mmol), Na2WO4·2H2O (29.2 mg, 0.09 mmol), MeOH (4 mL), and H2O (0.5 mL) were used. After the work-up and column chromatography with CHCl3–MeOH (99:1, v/v), 9e (74.6 mg, 69%) was obtained. 9e: mp 155-158 °C (colorless prisms, recrystallized from EtOAc). IR (KBr): 3290, 3140, 2955, 1580, 1494, 1450, 1412, 1356, 1248, 1240, 1205 cm-1. 1H-NMR (DMSO-d6) δ: 0.60-0.69 (4H, m), 1.49-1.54 (1H, m), 2.80 (2H, t, J=7.4 Hz), 3.32 (2H, td, J=7.4, 6.1 Hz, collapsed to t, J=7.4 Hz, on addition of D2O), 6.98 (1H, ddd, J=8.1, 7.1, 1.0 Hz), 7.13 (1H, ddd, J=8.1, 7.1, 1.0 Hz), 7.25 (1H, s), 7.32 (1H, dt, J=8.1, 1.0 Hz), 7.53 (1H, dt, J=8.1, 1.0 Hz), 8.15 (1H, br t, J=6.1 Hz, disappeared on addition of D2O), 11.03 (1H, br s, disappeared on addition of D2O). Anal. Calcd for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C, 68.84; H, 6.57; N, 11.45.
Nb-Cyclohexanecarbonyl-1-hydroxytryptamine (9f) from 8f - In the general procedure for the synthesis of 9a, 30% aqueous H2O2 (1.91 g, 16.8 mmol), MeOH (5 mL), 8f (457.3 mg, 1.68 mmol), Na2WO4·2H2O (112.7 mg, 0.34 mmol), MeOH (20 mL), and H2O (2.5 mL) were used. After the work-up and column chromatography with EtOAc–hexane (2:3, v/v), 9f (297.9 mg, 62%) was obtained. 9f: mp 138.5-140 °C (colorless fine needles, recrystallized from EtOAc–hexane). IR (KBr): 2940, 1628, 1535, 1448, 1368 cm-1. 1H-NMR (DMSO-d6) δ: 1.09-1.24 (3H, m), 1.28-1.36 (2H, m), 1.59-1.71 (5H, m), 2.06 (1H, tt, J=11.7, 3.4 Hz), 2.77 (2H, t, J=7.3 Hz), 3.28 (2H, br q, J=7.3 Hz, collapsed to t, J=7.3 Hz, on addition of D2O), 6.98 (1H, t, J=8.0 Hz), 7.12 (1H, t, J=8.0 Hz), 7.22 (1H, s), 7.31 (1H, d, J=8.0 Hz), 7.53 (1H, d, J=8.0 Hz), 7.77 (1H, br t, J=6.1 Hz, disappeared on addition of D2O), 11.01 (1H, s, disappeared on addition of D2O). Anal. Calcd for C17H22N2O2: C, 71.30; H, 7.74; N, 9.78. Found: C, 71.33; H, 7.79; N, 9.75.
Nb-2-Furancarbonyl-1-hydroxytryptamine (9g) from 8g - In the general procedure for the synthesis of 9a, 30% aqueous H2O2 (2.94 g, 25.9 mmol), MeOH (5 mL), 8g (696.9 mg, 2.58 mmol), Na2WO4·2H2O (171.0 mg, 0.52 mmol), MeOH (25 mL), and H2O (3 mL) were used. After the work-up and column chromatography with EtOAc–hexane (1:1, v/v), 9g (467.2 mg, 64%) was obtained. 9g: mp 167-168 °C (decomp., colorless fine needles, recrystallized from CHCl3–hexane). IR (KBr): 3680, 3120, 2950, 1628, 1598, 1531, 1317, 1187 cm-1. 1H-NMR (CDCl3) δ: 2.90 (2H, t, J=7.5 Hz), 3.49 (2H, td, J=7.5, 6.1 Hz, collapsed to t, J=7.5 Hz, on addition of D2O), 6.60 (1H, dd, J=3.4, 2.0 Hz), 6.98 (1H, ddd, J=8.0, 7.0, 1.0 Hz), 7.06 (1H, dd, J=3.4, 0.7 Hz), 7.13 (1H, ddd, J=8.0, 7.0, 1.0 Hz), 7.28 (1H, s), 7.32 (1H, d, J=8.0 Hz), 7.57 (1H, d, J=8.0 Hz), 7.80 (1H, dd, J=2.0, 0.7 Hz), 8.45 (1H, br t, J=6.1 Hz, disappeared on addition of D2O), 11.02 (1H, s, disappeared on addition of D2O). Anal. Calcd for C15H14N2O3: C, 66.65; H, 5.22; N, 10.37. Found: C, 66.63; H, 5.21; N, 10.36.

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