HETEROCYCLES

Paper | Regular issue | Vol. 81, No. 8, 2010, pp. 1903-1921
Received, 9th June, 2010, Accepted, 23rd June, 2010, Published online, 25th June, 2010.
DOI: 10.3987/COM-10-11992

■ An Efficient and Convenient Synthesis of 4,5,6,7-Tetrahydrothieno[3,2-c]pyridines by a Modified Pictet-Spengler Reaction via a Formyliminium Ion Intermediate

Michikazu Kitabatake, Aki Hashimoto, Toshiaki Saitoh, Takehiro Sano, Kunihiko Mohri, and Yoshie Horiguchi*

Showa College of Pharmaceutical Sciences, 3-3165, Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan

Abstract

A synthesis of N-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridines (5) was achieved in a highly efficient manner via trifluoroacetic acid catalyzed cyclization of formyliminium ion (4), which was produced by imination of 2-(2-thienyl)ethylamine (1) and a carbonyl compound (2) using titanium(IV) tetraisopropoxide followed by formylation with acetic-formic anhydride in a one-pot procedure. This modified Pictet-Spengler reaction provides a convenient method for preparing 4,5,6,7-tetahydrothieno[3,2-c]pyridines (6) possessing various substituents at C-4.

INTRODUCTION
The Pictet-Spengler reaction is a well-known method for constructing 1,2,3,4-tetrahydroisoquinoline and heteroaryl homologs, which constitute important motifs of naturally occurring bioactive compounds.1 The synthesis of these compounds by the Pictet-Spengler reaction consists of two steps: the formation of an imine by condensation of an arylethylamine with a carbonyl compound, and the acid-catalyzed cyclization of the in situ generated imine. We recently modified both the imination and the cyclization steps. We discovered that imination in titanium(IV) tetraisopropoxide2 proceeded in a highly effective manner and that cyclization readily occurred in trifluoroacetic acid (TFA) when the imine was converted into a formyliminium ion.3 This modified method effectively enables the Pictet-Spengler reaction to be applied to ketones, which is known to be difficult,4 providing 1,1-disubstituted 1,2,3,4-tetrahydroisoquinolines3 and 1,1-disubstituted tetrahydro-β-carbolines.5 This modified method also induced the Pictet-Spengler reaction of phenylethylamine with aldehydes, although the benzene ring lacks electron-donating groups, providing 1-substituted 1,2,3,4-tetrahydroisoquinolines in high yields.6 Yokoyama et al. reported that no cyclization of imines proceeded in TFA.7
In this paper we describe the modified Pictet-Spengler reaction of 2-(2-thienyl)ethylamine (1) with aldehydes and ketones, which should provide a convenient method for preparing 4,5,6,7- tetrahydrothieno[3,2-c]pyridines8 with various substituents at the C-4 position. Some 4-substituted derivatives have been reported to have biological activities. For example, 4-methyl-4-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6k) is a known N-methyl-D-aspartate (NMDA) antagonist,9 and 4-aryl-5-aroyl derivatives containing this ring system are glucose-6-phosphatase catalytic enzyme inhibitors.10

RESULTS AND DISCUSSION
The Pictet-Spengler reaction was carried out in a one-pot procedure as follows (Scheme 1). 2-(2-Thienyl)ethylamine (1) (1.2 mol equiv) and a carbonyl compound (2) (1.0 mol equiv) were condensed at 80 °C in titanium(IV) tetraisopropoxide (1.8 mol equiv) for 3 h, and the in situ formed imine (3) was treated with acetic-formic anhydride (100 mol equiv) at 70 °C for 2 h to produce the formyliminium ion (4). To this solution, a large excess (100 mol equiv) of TFA was added at 0 °C and then the solution was heated at 70 °C for an appropriate time, thus producing N-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridines (5). This modified Pictet-Spengler reaction was applied not only to aldehydes (2a-j and 2q) and but also to ketones (2k-o), which produced various derivatives with different substitution patterns at the C-4 position. The structure of the product (5) was assigned by observation of the characteristic C4 carbon signals at δ 52.6 and 58.8 ppm (in the case of 5a) in the 13C NMR spectrum. The results are summarized in Table 1.

Benzaldehyde (2a), cyclopropanecarboxaldehyde (2h), cyclopentanecarboxaldehyde (2i), and cyclohexanecarboxaldehyde (2j) gave the corresponding 4-monosubstituted N-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridines (5a, 5h, 5i, 5j) in yields of 93, 72, 83, and 91%, respectively. The cyclization of imines (3a and 3j), as already reported by Madsen et al., proceeded in TFA at room temperature, but the yields of the products (5a and 5j) were only 24% and 8%, respectively.9 This indicated that our modified method has an advantage over the conventional one.
On the other hand, paraldehyde, a trimer of acetaldehyde (2b) and propionaldehyde (2c) gave the expected products (5b, 5c), although in 24, 12% yields, respectively. This unsatisfactory result of the reaction may be attributed to the high reactivity of these aldehydes for aldol condensation. In fact, the reaction of 2c yielded the N-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (8c) having a pent-2-en-2yl side chain at the C4 as a major product in 31% yield. The formation of 8c is readily explained by assuming the formation of the imine (7c) that is formed from 1 mol eqiv of amine (1) and 2 mol eqiv of propionaldehyde (2c) as shown in Scheme 1. Other alkyl aldehydes, n-butanal (2d), n-pentanal (2e), n-hexanal (2f), and n-heptanal (2g), gave the similar results, thus yielding the corresponding 4,5,6,7-tetrahydrothieno[3,2-c]pyridine derivative (5d, 5e, 5f, 5g) in yields of 49-56% together with the minor one (8d, 8e, 8f, 8g) in yields of 12-14%.

Acyclic ketones such as acetophenone (2k), acetone (2l), and 2-butanone (2m) gave the corresponding, 4,4-disubstituted N-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridines (5k, 5l, and 5m) in high yields (74-84%). Cyclic ketones such as cyclopentanone (2n) and cyclohexanone (2o) also yielded the corresponding 4-spirocycloalkyl N-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridines (5n) and (5o) in yields of 65% and 51%, respectively. The gradually decreased yields observed in the reactions of cyclic ketones suggested that the cyclization was sensitive to steric congestion. In the case of benzophenone

(2p) possessing two bulky phenyl groups, the expected product (5p) was not obtained at all. We previously showed that the reaction of tryptamine with benzophenone (2p) under similar conditions yielded N-formyl-1,1-diphenyl-1,2,3,4-tetrahydro-β-carboline, albeit in low yield (24%),4 indicating that the inhibition of the reaction is attributable to the steric hindrance in the cyclization step, not in the imination one.
Interestingly, paraformaldehyde (2q) afforded N-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5q), the skeletal compound of the ring system, in yield of 69%.
Alkaline or acidic hydrolysis of N-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridines (5 and 8) afforded the corresponding 4,5,6,7-tetrahydrothieno[3,2-c]pyridines (6 and 9) in excellent to good yields as shown in Table 2.
The 4-methyl-4-phenyl derivative (6k) of the NMDA antagonist was prepared previously in a multi-step operation but in low overall yield (27%).9 This method gave 6k in 84% overall yield by these simple manipulations.
Thus, the modified Pictet-Spengler reaction of 2-(2-thienyl)ethylamine (1) with carbonyl compounds provides a convenient and effective method for synthesizing 4,5,6,7-tetrahydrothieno[3,2-c]pyridines (6) with various substituents at the C-4 position. Particularly, this modified method is of great value in preparing the sterically congested 4,4-disubstituted derivatives by simple one-pot manipulation.

EXPERIMENTAL
Unless otherwise noted, the following procedures were adopted. Melting points were taken on a Yanagimoto SP-M1 hot-stage melting point apparatus and are uncorrected. IR spectra were measured as KBr disks with a HORIBA FT-710 spectrophotometer or Nicolet iS10 spectrophotometer and the values are given in cm-1. NMR spectra were measured on a JEOL JNM-AL 300 (1H-NMR, 300 MHz; 13C-NMR, 75 MHz) NMR spectrometer in CDCl3 or DMSO-d6 with tetramethylsilane as an internal standard and the chemical shifts are given in δ values. LR-MS were taken on JMS-AM20, and high resolution MS (HR-MS) on a JEOL JMS-D300 spectrometer at 70 eV (EI-MS) using direct inlet systems. HRFAB-MS spectra were recorded with JEOL-MS700 spectrometer using glycerol as a matrix. Elemental analyses were recorded on a ThermoFisherScientific model EA1112 IRMS NC-plus CHNS. TLC was performed on Merck precoated Silica gel 60 F254 plates (Merck). Column chromatography was carried out with silica gel (Wakogel C-200). The organic extract from each reaction mixture was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to dryness.
The Pictet-Spengler reaction of 2-(2-thienyl)ethylamine (1) with carbonyl compound (2) : General procedure.
Method A: A mixture of 1 (1.00 g, 7.86 mmol), carbonyl compound (2) (6.4 mmol) and Ti(O-iPr)4 (3.2 g, 11.3 mmol) was heated at 80 °C for 3 h under an argon atmosphere. To the reaction mixture, a solution of acetic-formic anhydride [prepared from HCO2H (29.46 g, 0.64 mol) and Ac2O (65.34 g, 0.64 mol)] was added at 0 °C, then the mixture was heated at 70 °C for 2 h. To this reaction mixture CF3CO2H (72.97 g, 0.64 mol) was added and heated at 70 °C for 3-16 h (Table 1). The reaction mixture was diluted with MeOH (100 mL) and passed through a short SiO2 column (CHCl3-MeOH) to remove TiO2. The eluent was concentrated in vacuo to ca. 50 mL and the residue was extracted with CHCl3. After removal of the solvent of extract in vacuo, the residue was purified by chromatography over SiO2 eluted with AcOEt-hexane (1:1-1:3) to give 5.
Method B: A mixture of 1 (1.00 g, 7.86 mmol), carbonyl compound (2) (7.86 mmol) and Ti(O-iPr)4 (2.68 g, 9.43 mmol) was heated at 80 °C for 2 h under an argon atmosphere. To the reaction mixture, a solution of acetic-formic anhydride [prepared from HCO2H (9.05 g, 196.5 mmol) and Ac2O (20.1 g, 196.5 mmol)] was added at 0 °C, then the mixture was heated at 70 °C for 0.5 h. To this reaction mixture CF3CO2H (22.41 g, 196.5 mmol) was added and heated at 70 °C for 1.5 h. The reaction mixture was diluted with MeOH (100 mL) and passed through a short SiO2 column (CHCl3-MeOH) to remove TiO2. The eluent was concentrated in vacuo to ca. 50 mL and the residue was extracted with CHCl3. After removal of the solvent of extract in vacuo, the residue was purified by chromatography over SiO2 (AcOEt-hexane (2:1-1:3)) to give 5 and 8.
5-Formyl-4-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5a) : Method A
Pale yellow prisms recrystallized from hexane-Et2O. mp 80-83 °C IR:1662. 1H-NMR: 2.87-3.00, 3.42-3.52, 3.65-3.71, 4.48-4.52 (total 4H, each m, H-6 and H-7), 5.74, 6.63 (total 1H, each s, H-4), 6.70, 6.71 (total 1H, each d, J=5 Hz, H-3), 7.14-7.19 (2H, m, H-2 and Ph-H), 7.26-7.38 (4H, m, Ph-H), 8.18, 8.51 (total 1H, each s, -CHO). 13C-NMR: 24.5, 26.1 (C7), 34.4, 40.2 (C6), 52.6, 58.8 (C4), 123.6 (C3), 125.9, 126.3 (C2), 127.7, 127.9 (Ph-CH), 128.3, 128.4 (2 x Ph-CH), 128.5, 128.7 (2 x Ph-CH), 132.6, 132.9 (Ph-C), 133.6, 135.2 (C3a), 139.9, 140.5 (C7a), 161.1, 161.2 (-CHO). LR-EIMS: m/z 243 (M+), 243 (base peak). HR-EIMS m/z (M+): Calcd for C14H13NOS: 243.0718. Found: 243.0669.
5-Formyl-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5b) : Method B (Using paraldehyde 1.04 g, 7.86 mmol) instead of acetaldehyde as a carbonyl compound)
Yellow oil. IR: 1664. 1H-NMR: 1.43, 1.50 (total 3H , each d, J=7 Hz, -CH3), 2.77-3.14, 3.49-3.58, 3.74-3.81, 4.60-4.67 (total 4H, each m, H-6, H-7), 4.77, 5.42 (total 1H, each q, J=7 Hz, H-4), 6.79, 6.80 (total 1H, each d, J=5 Hz, H-3), 7.14 (1H, d, J=5 Hz, H-2), 8.16, 8.29 (total 1H, each s, -CHO). 13C-NMR: 20.1, 22.9 (CH3), 24.7, 26.1 (C7), 34.2, 40.5 (C6), 46.2. 51.6 (C4), 123.6 (C3),124.7, 125.2 (C2), 131.7, 133.4 (C3a), 136.0, 136.5 (C7a), 161.30, 161.33 (-CHO). LR-EIMS: m/z 243 (M+), 243(base peak). HR-EIMS m/z (M+): Calcd for C9H11NOS:181.0561. Found: 181.0555.
4-Ethyl-5-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5c) : Method B
Yellow oil. IR: 1672. 1H-NMR: 1.00 (3H , t, J=7 Hz, -CH2CH3), 1.65-1.95 (2H, m, -CH2CH3), 2.82-3.04, 3.50-3.60, 3.76-3.83, 4.64-4.74, (total 4H, each m, H-6, H-7), [4.41 (dd, J=4, 10 Hz), 5.42 (dd, J=5, 9 Hz) total 1H, H-4], 6.80, 6.81 (total 1H, each d, J=5 Hz, H-3), 7.13, 7.14 (total 1H, each d, J=5 Hz, H-2), 8.22, 8.24 (total 1H, each s, -CHO). HR-EIMS m/z (M+): Calcd for C10H13NOS: 195.0718. Found: 195.0710.
5-Formyl-4-(pent-2-en-2-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (8c): Method B
Yellow oil. IR: 1672. 1H-NMR: 0.91, 0.94 (total 3H, each t, J=7 Hz, -C=CHCH2CH3), 1.67, 1.70 (total 3H, each s, -CH3) 2.01, 2.06 (total 2H, each q, J=7 Hz, -CH2CH3), 2.77-2.97 (2H, m, H-7), 3.23-3.32, 3.46-3.56, 3.66-3.72, 4.30-4.37 (total 2H, each m, H-6), 4.94, 5.82 (total 1H, each s, H-4), 5.10-5.14, 5.22-5.26 (total 1H, each m, -C=CHCH2CH3), 6.70 , 6.71 (total 1H, each d, J=3 Hz, H-3), 7.11, 7.13 (total 1H, each d, J=3 Hz, H-2), 8.23, 8.30 (total 1H, each s, -CHO). HR-FABMS m/z (MH+): Calcd for C12H18NOS: 208.1160. Found: 208.1158.
5-Formyl-4-propyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5d) : Method B
Yellow oil. IR: 1672. 1H-NMR: 0.91, 1.00 (total 3H , each t, J=7 Hz, - CH2CH2CH3), 1.38-1.50, 1.68-1.79 (total 4H, each m, -CH2CH2CH3), 2.81-3.00 (2H, m, H-7), 3.02-3.10, 3.50-3.58, 3.57-3.76, 4.65-4.69 (total 2H, each m, H-6), 4.50, 5.40 (total 1H, each dd, J=5, 9 Hz, H-4), 6.79, 6.81 (total 1H, each, d, J=5 Hz, H-3), 7.13, 7.16 (total 1H, each , d, J=5 Hz, H-2), 8.20, 8.21 (total 1H, each s, -CHO). HR-FABMS m/z (MH+): Calcd for C11H16NOS: 210.0953. Found: 210.0953.
5-Formyl-4-(hept-3-en-3-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (8d): Method B
Yellow oil. IR: 1675. 1H-NMR: 0.82, 0.85, 1.00, 1.07 (total 6H, each t, J=7Hz, -CH2CH3, -C=CH(CH2)2CH3), 1.23-1.36 (2H, m, -CH2CH3), 1.96-2.05, 2.10-2.26 (total 4H, each m, -C=CH(CH2)2CH3), 2.77-2.92 (2H, m, H-7), 3.07-3.15, 3.45-3.56, 3.62-3.67, 4.40-4.46 (total 2H, each m, H-6), 4.93, 5.03 (total 1H, each t, J=7 Hz, -C=CH(CH2)2CH3), 5.01, 5.96 (total 1H, each s, H-4), 6.65-6.68 (1H, m, H-3), 7.10-7.12 (1H, m, H-2), 8.22, 8.30 (total 1H, each s, -CHO). HR-FABMS m/z (MH+): Calcd for C15H22NOS: 264.1423. Found: 264.1440.
4-Butyl-5-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5e) : Method B
Yellow oil. IR: 1672. 1H-NMR: 0.95, 0.97 (total 3H , each t, J=7 Hz, -(CH2)3CH3), 1.26-1.54, 1.63-1.83 (total 6H, each m, (CH2)3CH3), 2.87-2.97 (2H, m, H-7), 2.97-3.16, 3.50-3.57, 3.74-3.77, 4.65-4.71 (total 2H, each m, H-6), 4.51, 5.40 (total 1H, each dd, J=5, 9 Hz, H-4), 6.79, 7.14 (total 1H, each, d, J=5 Hz, H-3), 7.12, 7.17 (total 1H, each , d, J=5 Hz, H-2), 8.20, 8.21 (total 1H, each s, -CHO). HR-FABMS m/z (MH+): Calcd for C12H18NOS: 224.1110. Found: 224.1103.
5-Formyl-4-(non-4-en-4-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (8e): Method B
Yellow oil. IR: 1675. 1H-NMR: 0.86, 0.89, 0.93, 0.94 (total 6H, each t, J=7 Hz, -(CH2)2CH3, -C=CH(CH2)3CH3), 1.25-1.27, 1.34-1.48 (total 6H, each m, -(CH2)2CH3, -C=CH(CH2)3CH3), 1.90-2.10, 2.10-2.21 (total 4H, each m, -(CH2)2CH3, -C=CH(CH2)3CH3), 2.77-2.96, 3.04-3.14, 3.45-3.52, 3.54-3.66, 4.42-4.47 (total 4H, each m, H-6, H-7), 4.96, 5.06 (total 1H, each t, J=7 Hz, -C=CH(CH2)3CH3), 5.00, 5.94 (total 1H, each s, H-4), 6.64, 6.67 (total 1H, each d, J=5 Hz, H-3), 7.10, 7.11 (total 1H, each d, J=5 Hz, H-2), 8.21, 8.29 (total 1H, each s, -CHO). HR-FABMS m/z (MH+): Calcd for C17H26NOS: 292.1735 Found: 292.1736.
5-Formyl-4-pentyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5f) : Method B
Yellow oil. IR: 1672. 1H-NMR: 0.88, 0.39 (total 3H , each t, J=7 Hz, -(CH2)4CH3), 1.23-1.44 (6H, m, (CH2)4CH3), 1.67-1.77 (2H, m, (CH2)4CH3), 2.75-3.05, 3.48-3.58, 3.73-3.81, 4.45-4.50 (total 4H, each m, H-6, H-7), 4.64-4.69, 5.36-5.39 (total 1H, each m, H-4), 6.79 (1H, d, J=4 Hz, H-3), 7.10, 7.11 (total 1H, each d, J=4 Hz, H-2), 8.188, 8.190 (total 1H, each s, -CHO). HR-FABMS m/z (MH+): Calcd for C13H20NOS: 238.1266. Found: 238.1274.
5-Formyl-4-(undec-5-en-5-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (8f): Method B
Yellow oil. IR: 1675. 1H-NMR: 0.81-0.95 (6H, m, -(CH2)3CH3, -C=CH(CH2)4CH3), 1.24-1.58 (10H, m, -(CH2)3CH3, -C=CH(CH2)4CH3), 1.92-2.24 (4H, m, -(CH2)3CH3, -C=CH(CH2)4CH3), 2.76-4.47 (4H, m, H-6, H-7), 4.93-5.07 (1H, m, -C=CH(CH2)3CH3), 5.95 (1H, s, H-4), 6.64, 6.65 (total 1H, each d, J=5 Hz, H-3), 7.08, 7.10 (total 1H, each d, J=5 Hz, H-2), 8.21, 8.29 (total 1H, each s, -CHO). HR-FABMS m/z (MH+): Calcd for C19H30NOS: 320.2048. Found: 320.2062
5-Formyl-4-hexyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5g) : Method B
Yellow oil. IR: 1672. 1H-NMR: 0.85-0.89 (3H, m, -(CH2)5CH3), 1.23-1.46 (8H, m, (CH2)5CH3), 1.71-1.81 (2H, m, (CH2)5CH3), 2.80-3.07, 3.49-3.59, 3.74-3.81, 4.47-4.51 (total 4H, each m, H-6, H-7), 5.36-5.40, 4.64-4.70 (total 1H, each m, H-4), 6.81, 6.79 (total 1H, each d, J=3 Hz, H-3), 7.11, 7.13（total 1H, each d, J=3 Hz, H-2), 8.20, 8.21 (total 1H, each s, -CHO). HR-FABMS m/z (MH+): Calcd for C14H22NOS: 252.1422. Found: 252.1432.
5-Formyl-4-(tridec-6-en-6-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (8g): Method B
Yellow oil. IR: 1675. 1H-NMR: 0.80-0.90 (6H, m, -(CH2)4CH3, -C=CH(CH2)5CH3), 1.23-1.33 (14H, m, -(CH2)4CH3, -C=CH(CH2)5CH3), 1.89-2.02, (4H, m, -(CH2)4CH3, -C=CH(CH2)5CH3), 2.74-4.46 (4H, m, H-6, H-7), 4.92-5.07 (1H, m, -C=CH(CH2)3CH3), 5.94 (1H, s, H-4), 6.64, 6.66 (total 1H, each d, J=5 Hz, H-3), 7.09, 7.10 (total 1H, each d, J=5 Hz, H-2), 8.21, 8.29 (total 1H, each s, -CHO). HR-FABMS m/z (MH+): Calcd for C21H34NOS: 348.236. Found: 348.2357.
4-Cyclopropyl-5-Formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5h) : Method A
Colorless prisms recrystallized from hexane-Et2O. mp 88-90 °C IR: 1672. 1H-NMR: 0.36-0.81(4H, m, cyclopropyl-CH2), 1.75 (1H, m, cyclopropyl-CH), 2.81-2.99 (2H, m, H-7), 3.20-3.30, 4.62-4.69 (total 2H, each m, H-6), 3.68-3.86 (1H, m, H-4), 6.92, 6.93 (total 1H, each d, J=5 Hz, H-3), 7.14, 7.15 (total 1H, each , J=5 Hz, H-2), 8.20 (1H, d, J=4 Hz, -CHO). 13C-NMR: 2.85, 3.68, 4.91(2 x cyclopropyl-CH2), 16.6, 17.2 (cyclopropyl-CH), 24.7, 26.2 (C7), 35.3, 41.3 (C6), 54.1, 60.7 (C4), 123.2, 123.3 (C3), 125.1, 125.7 (C2), 132.1, 133.8 (C3a), 134.6, 135.0 (C7a), 161.1, 161.6 (CHO). LR-EIMS: m/z 207 (M+), 166 (base peak). HR-EIMS m/z (M+): Calcd for C11H13NOS: 207.0718. Found: 207.0735.
4-Cyclopentyl-5-Formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5i) : Method A
Yellow oil. IR: 1670. 1H-NMR: 1.25-1.79 (8H, m, cyclopentyl-CH2), 2.80-3.01 (2H, m, H-7), 3.05-3.15, 3.59-3.69 (total 2H, each m, H-6), 3.75-3.79, 4.66-4.72 (total 1H, each m, cyclopentyl-CH), 4.23, 5.24 (total 1H, each d, J=10 Hz, H-4), 6.85 (1H, d, J=5 Hz, H-3), 7.10, 7.11 (total 1H, each d, J=5 Hz, H-2), 8.17, 8.22 (total 1H, each s, -CHO). 13C-NMR: 24.1, 25.2 (cyclopentyl-CH2), 24.3, 25.4 (cyclopentyl-CH2), 24.6, 26.3 (cyclopentyl-CH2), 30.0, 30.6 (cyclopentyl-CH2), 31.0, 34.7 (C7), 40.8 (C6), 45.5 (cyclopentyl-CH), 53.9, 60.7 (C4), 122.8 (C3), 125.7, 126.2 (C2), 132.1, 133.8 (C3a), 135.2, 135.6 (C7a), 161.3, 161.5 (-CHO). LR-EIMS: m/z 235 (M+), 166 (base peak). HR-EIMS m/z (M+): Calcd for C13H17NOS: 235.1031. Found: 235.1010.
4-Cyclohexyl-5-Formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5j) : Method A
Yellow oil. IR: 1670. 1H-NMR: 0.95-2.05 (10H, m, cyclohexyl-CH2), 2.79-3.11, 3.57-3.67 (total 4H, each m, H-6 and H-7), 3.75-3.82, 4.69-4.75 (total 1H, each m, cyclohexyl-CH), 4.21, 5.17 (total 1H, each d, J=7 Hz, H-4), 6.82, 6.83 (total 1H, each d, J=5 Hz, H-3), 7.11, 7.13 (total 1H, each d, J=5 Hz, H-2), 8.16, 8.21 (total 1H, each s, -CHO). LR-EIMS: m/z 249 (M+), 166 (base peak). HR-EIMS m/z (M+): Calcd for C14H19NOS: 249.1187. Found: 249.1175.
5-Formyl-4-methyl-4-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5k) : Method A
Colorless plate recrystallized from AcOEt. mp 139-141 °C. IR: 1666. 1H-NMR: 2.02 (3H, s, -CH3), 2.89-3.05 (2H, m, H-7), 3.75-3.83 (1H, m, H-6), 3.96-4.04 (1H, m, H-6), 6.58 (1H, d, J=5 Hz, H-3), 7.08 (1H, d, J=5 Hz, H-2), 7.21-7.36 (5H, m, Ph-H), 8.25 (1H, s, -CHO). 13C-NMR: 24.6 (C7), 27.7 (CH3 ), 35.8 (C6), 62.6 (C4), 123.2 (C3), 125.6 (C2), 126.7 (2 x Ph-CH), 127.7 (Ph-CH), 128.6 (2 x Ph-CH), 133.5 (C3a), 139.7 (C7a), 144.2 (Ph-C), 162.1 (-CHO). LR-EIMS: m/z 257 (M+), 242 (base peak). HR-EIMS m/z (M+): Calcd for C15H15NOS: 257.0874. Found: 257.0862.
5-Formyl-4,4-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5l) : Method A
Colorless plates recrystallized from hexane-Et2O. mp 88-90 °C. IR: 1641. 1H-NMR: 1.69 (6H, s, 2 x - CH3), 2.83 (2H, t, J=5 Hz, H-7), 3.92 (2H, t, J=5 Hz, H-6), 6.85 (1H, d, J=5 Hz, H-3), 7.12 (1H, d, J=5 Hz, H-2), 8.57 (1H, s, -CHO). 13C-NMR: 24.8 (C7), 29.9 (2x- CH3 ), 35.4 (C6), 57.4 (C4), 123.3 (C3), 124.2 (C2), 133.1 (C3a), 140.7 (C7a), 160.6 (-CHO). LR-EIMS: m/z 195 (M+), 180 (base peak). HR-EIMS m/z (M+): Calcd for C10H13NOS: 195.0718. Found: 195.0708. Anal. Calcd for C10H13NOS: C, 61.50; H, 6.71; N, 7.17 Found: C, 61.59; H, 6.79; N, 7.33.
4-Ethyl-5-formyl-1-methyl-4,5,6,7-tetrahydtothieno[3,2-c]pyridine (5m) : Method A
Pale yellow prisms recrystallized from AcOEt-hexane. mp 55-57 °C. IR: 1658. 1H-NMR: 0.58, 0.73 (total 3H, each t, J=7 Hz, -CH2CH3), 1.64 (3H, s, -CH3), 2.02 (2H, qd, J=7, 2 Hz, -CH2CH3), 2.76-2.88 (2H, m, H-7), 3.81-3.95 (2H, m, H-6), 6.79 (1H, d, J=5 Hz, H-3), 7.13 (1H, d, J=5 Hz, H-2), 8.47 (1H, s, -CHO). 13C-NMR: 7.72, 8.13 (-CH2CH3), 24.3, 25.5 (-CH2CH3), 25.8, 28.2 (-CH3), 32.1, 34.0 (C7), 35.5, 44.3 (C6), 60.3, 62.4 (C4), 122.9, 123.0 (C3), 124.0, 124.1 (C2), 132.7, 133.7 (C3a), 139.3, 140.6 (C7a), 161.0, 162.2 (-CHO). LR-EIMS: m/z 209 (M+), 180 (base peak). HR-EIMS m/z (M+): Calcd for C11H15NOS: 209.0874. Found: 209.0871. Anal. Calcd for C11H15NOS: C, 63.12; H, 7.22; N, 6.69. Found: C, 63.11; H, 7.31; N, 6.90.
5-Formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-4-spirocyclopentane (5n) : Method A
Colorless plates recrystallized from AcOEt-hexane. mp 108-110 °C. IR: 1643. 1H-NMR: 1.75-2.26 (8H, m, cyclopentyl), 2.84 (2H, t, J=6 Hz, H-7), 3.91 (2H, t, J=6 Hz, H-6), 6.82 (1H, d, J=5 Hz, H-3), 7.12 (1H, d, J=5 Hz, H-2), 8.33 (1H, s, -CHO). 13C-NMR: 23.8 x 2 (2 x cyclopentyl-CH2), 24.9 (C7), 36.3 (C6), 39.6 x 2 (2 x cyclopentyl-CH2), 68.8 (C4), 123.1 (C3), 124.1 (C2), 134.2 (C3a), 139.4 (C7a), 160.4(d, -CHO). LR-EIMS: m/z 221 (M+), 151 (base peak). HR-EIMS m/z (M+): Calcd for C12H15NOS: 221.0874 Found: 221.0856. Anal. Calcd for C12H15NOS: C, 65.12; H, 6.83; N, 6.33. Found: C, 65.04; H, 6.80; N, 6.46.
5-Formyl-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-1-spirocyclohexane (5o) : Method A
Yellow prisms recrystallized from AcOEt-Et2O. mp 156-159 °C. IR: 1643. 1H-NMR: 1.33-1.97 (8H, m, cyclohexyl-CH2), 2.22 (2H, d, J=14 Hz, cyclohexyl-CH2), 2.85 (2H, t, J=6 Hz, H-7), 3.93(2H, t, J=6 Hz, H-6), 6.87 (1H, d, J=5 Hz, H-3), 7.07 (1H, d, J=5 Hz, H-2), 8.58(1H, s, -CHO). 13C-NMR: 21.7 (cyclohexyl-CH2), 22.0 (cyclohexyl-CH2), 24.5 (cyclohexyl-CH2), 25.5 (C7), 34.9 (C6), 35.9 (2 x cyclohexyl-CH2), 60.0 (C4), 122.7 (C3), 124.1 (C2), 134.1 (C3a), 142.3 (C7a), 162.3, 162.4(CHO). LR-EIMS: m/z 235 (M+), 193 (base peak). HR-EIMS m/z (M+): Calcd for C13H17NOS: 235.1031. Found: 235.1046. Anal. Calcd for C13H17NOS: C, 66.34; H, 7.28; N, 5.95. Found: C, 66.47; H, 7.58; N, 5.99.
5-Formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5q) : Method B (Using paraformaldehyde (0.24 g) instead of formaldehyde (7.86 mmol) as a carbonyl compound).
Yellow oil. IR: 1668. 1H-NMR: 2.88, 2.92 (total 2H, each t, J=7 Hz and 6 Hz, H-7), 3.69, 3.86 ( total 2H, each t, J=6 Hz, H-6), 4.47, 4.60 (total 2H, t and s, J=2 Hz, H-4), 6.79, 6.80 (total 1H, each d, J=5 Hz, H-3), 7.15, 7.16 (total 1H, each d, J=5 Hz, H-2), 8.19, 8.23 (total 1H, each s, -CHO). 13C-NMR: 24.3, 25.7 (C7), 37.8, 40.5 (C6), 43.6. 45.6 (C4), 123.7 (C3), 124.2, 124.9 (C2), 130.6, 130.7 (C3a), 132.1, 133.7 (C7a), 161.3, 161.6 (-CHO). HR-EIMS m/z (M+): Calcd for C8H9NOS: 167.0405. Found: 167.0416
Hydrolysis of 5-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.
Typical procedure: NaOH aq hydrolysis. (see Table 2)
A solution of 5 (200 mg) in EtOH (60 mL) and 20% NaOH solution (60 mL) was refluxed for 18 h under an argon atmosphere. The reaction mixture was diluted with water, and extracted with CHCl3. The residue was purified by column chromatography over SiO2 with MeOH-CHCl3 (9:1) to give 6.
Typical procedure: HCl aq hydrolysis. (see Table 2)
A solution of 5 and 8 (200 mg) in EtOH (14 mL) and c-HCl (6 mL or 12 mL) was refluxed for 4-18 h under an argon atmosphere. The reaction mixture was diluted with water, alkalized with 10% NaOH solution and extracted with CHCl3. The residue was purified by column chromatography over SiO2 with MeOH-CHCl3 (9:1) to give 6 and 9.
4-Phenyl-4,5,6,7- tetrahydrothieno[3,2-c]pyridine (6a)
Colorless prisms recrystallized from Et2O-hexane. mp 80-82 °C (lit.,10 mp 79.8-80.7 °C ). IR: 3255, 1655. 1H-NMR : 2.83-3.04 (2H, m, H-7), 3.07~3.35 (2H, m, H-6), 5.02 (1H, s, H-4), 6.47 (1H, d, J=5 Hz, H-3), 7.00 (1H, d, J=5 Hz, H-2), 7.26-7.36 (5H, m, Ph-H). 13C-NMR: 26.0 (C7), 42.5 (C6), 60.0 (C4), 121.7 (C3), 126.3 (C2), 127.5 (PhCH), 128.2 (2 x PhCH), 128.4 (2 x PhCH), 134.9 (PhC) 136.8 (C3a), 143.7 (C7a). LR-EIMS: m/z 215 (M+), 138 (base peak). HR-EIMS m/z (M+): Calcd for C13H13NS:215.0769. Found: 215.0786.
4-Metyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6b)
Pale yellow oil. IR: 2924, 1653. 1H-NMR : 1.39 (3H, d, J=7 Hz，-CH3), 1.66 (1H，brs, -NH)，2.68-2.90 (2H, m, H-7), 3.01 (1H, ddt, J=12, 5, 4 Hz, H-6), 3.32 (1H, ddd, J=13, 5, 4 Hz, H-6), 4.00 (1H, qt, J=7, 2 Hz, H-4), 6.80 (1H, d, J=5 Hz, H-3), 7.05 (1H, d, J=5 Hz, H-2). 13C-NMR: 22.0 (-CH3), 26.1 (C7), 42.7 (C6), 50.6 (C4), 121.7 (C3), 124.8 (C2), 133.8 (C3a), 139.3 (C7a). HR-EIMS m/z (M+): Calcd for C8H11NS:153.0612. Found: 153.0588.
4-Ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6c)
Pale yellow oil. IR: 2860, 2927, 1652. 1H-NMR: 1.00 (3H , each t, J=7 Hz, -CH2CH3), 1.54-1.70 (2H, m, -CH2CH3), 1.92 (1H, dddd, J=15, 11, 8, 4 Hz, H-7), 270-2.91 (1H, m, H-7), 3.00 (1H, ddd, J= 12, 8, 5 Hz, H-6), 3.32 (1H, ddd, J=12, 5, 4, Hz, H-6), 3.83 (1H, ddd, J=8, 4, 2 Hz, H-4). 6.81 (1H, d, J=5 Hz, H-3), 7.05 (1H, d, J=5 Hz, H-2). 13C-NMR: 10.3 (CH3), 26.2 (C7), 28.6 (-CH2CH3), 38.2, 42.5 (C6), 56.2 (C4), 121.6 (C3), 124.9 (C2), 134.3 (C3a), 138.3 (C7a). HR-FABMS m/z (MH+): Calcd for C9H14NS: 168.0847. Found: 168.0858.
4-Propyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6d)
Yellow oil. IR: 2958, 2925, 1666. 1H-NMR: 0.97 (3H, t, J=7 Hz, -(CH2) 2CH3), 1.36-1.65, (2H, m, -(CH2)2CH3), 2.78-1.89 (2H, m, -(CH2)2CH3), 2.72-2.89 (2H, m, H-7), 2.95-3.04 (1H, m, H-6), 3.28-3.35 (1H, m, H-6), 3.88-3.91 (1H, m, H-4), 6.81 (1H, d, J=5 Hz, H-3), 7.05 (1H, d, J=5 Hz, H-2). 13C-NMR: 14.1 (CH3), 19.1 (-(CH2) 2CH3), 26.1 (C7), 38.2 (-(CH2) 2CH3), 42.4 (C6), 54.6 (C4), 121.6 (C3), 124.8 (C2), 134.0 (C3a), 138.4 (C7a). HR-FABMS m/z (MH+): Calcd for C10H16NS: 182.1003. Found: 182.1004.
4-Butyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6e)
Yellow oil. IR: 2960, 2930, 1668. 1H-NMR: 0.92 (3H, t, J=7 Hz, -(CH2)3CH3), 1.26-1.54, 1.49-1.62, 1.76-1.89 (total 6H, each m, (CH2)3CH3), 2.71-2.87 (2H, m, H-7), 2.96-3.03 (1H, m, H-6), 3.27-3.35 (1H, m, H-6), 3.89 (1H, dd, J=2, 7 Hz, H-4), 6.81 (1H, d, J=5 Hz, H-3), 7.05 (1H, d, J=5 Hz, H-2). 13C-NMR: 13.9 (CH3), 22.7 (-(CH2) 3CH3), 25.9 (C7), 28.0 (-(CH2) 3CH3), 35.5 (-(CH2) 3CH3), 42.2 (C6), 54.8 (C4), 121.7 (C3), 124.8 (C2), 133.9 (C3a), 138.7 (C7a). HR-FABMS (MH+): Calcd for C11H18NS: 196.1160. Found: 196.1151.
4-Pentyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6f)
Yellow oil. IR: 2956, 2929, 1662. 1H-NMR: 0.90 (3H, t, J=7 Hz, -(CH2)4CH3), 1.26-1.63 6H, m, (CH2)4CH3), 1.79-1.88 (2H, m, (CH2)4CH3), 2.71-2.88 (2H, m, H-7), 2.95-3.03 (1H, m, H-6), 3.28-3.35 (1H, m, H-6), 3.87-3.89 (1H, m, H-4), 6.81 (1H, each, d, J=5 Hz, H-3), 7.04-7.08 (1H, m, H-2). 13C-NMR: 13.4 (CH3), 22.5 (-(CH2) 4CH3), 25.5 (C7), 26.1 (-(CH2) 4CH3), 31.9 (-(CH2)4CH3), 35.9 (-(CH2) 4CH3), 42.3 (C6), 54.8 (C4), 121.5 (C3), 124.7 (C2), 133.9 (C3a), 138.4 (C7a). HR-FABMS (MH+): Calcd for C12H20NS: 210.1316. Found: 210.1319.
4-Hexyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6g)
Yellow oil. IR: 2954, 2929, 1662. 1H-NMR: 0.88 (3H, t, J=7 Hz, -(CH2)5CH3), 1.21-1.60 (8H, m, (CH2)5CH3), 1.73-1.84 (2H, m, (CH2)5CH3), 2.71-3.35 (4H, m, H-6, H-7), 3.86-3.89 (1H, m, H-4), 6.81 (1H, d, J=5 Hz, H-3), 7.05 (1H, d, J=5 Hz, H-2). 13C-NMR: 14.0 (CH3), 22.6 (-(CH2)5CH3), 25.9 (C7), 26.1 (-(CH2)5CH3), 29.4 (-(CH2)5CH3), 31.7 (-(CH2) 4CH3), 35.9 (-(CH2) 4CH3), 42.3 (C6), 54.9 (C4), 121.7 (C3), 124.9 (C2), 134.0 (C3a), 138.3 (C7a). HR-FABMS (MH+): Calcd for C13H22NS: 224.1473. Found: 224.1474.
4-Cyclopropyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6h)
Pale yellow oil. IR: 2920, 1647. 1H-NMR: 0.31-0.76 (4H, m, cyclopropyl-CH2), 0.95-1.07 (1H, m, cyclopropyl-CH), 2.72-3.03 (4H, m, H-6 and H-7), 3.30-3.39 (1H, m, H-4), 7.06 (1H, d, J=5 Hz, H-3), 7.08 (1H, d, J=5Hz, H-2). 13C-NMR: 2.46 (cyclopropyl-CH2), 3.84 (cyclopropyl-CH2), 17.0 (cyclopropyl-CH), 26.0 (C7), 42.9 (C6), 60.9 (C4), 121.7 (C3), 125.1 (C2), 134.0 (C3a), 138.0 (C7a).LR-EIMS: m/z 179 (M+), 138 (base peak). HR-EIMS m/z (M+): Calcd for C10H13NS:179.0769. Found: 179.0793.
1-Cyclopentyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6i)
Yellow oil. IR: 2949, 2866, 1670. 1H-NMR: 1.20-1.40 (1H, m, cyclopentyl-CH2), 1.45-1.80 (7H, m, cyclopentyl-CH2), 2.27-2.32 (1H, m, cyclopentyl-CH), 2.79-2.81 (2H, m, H-7), 2.94-3.03 (1H, m, H-6), 3.29~3.36 (1H, m, H-6), 3.84 (1H, d, J=6 Hz, H-4), 6.87 (1H, d, J=5 Hz, H-3), 7.04 (1H, d, J=5 Hz, H-2). 13C-NMR: 25.3 (cyclopentyl-CH2), 26.0 (cyclopentyl-CH2), 26.3 (cyclopentyl-CH2), 28.5 (cyclopentyl-CH2), 30.0 (C7), 42.1 (C6), 44.9 (cyclopentyl-CH), 58.6 (C4), 22.3 (C3), 125.7 (C2), 134.5 (C3a), 138.1 (C7a). LR-EIMS: m/z 207 (M+), 166 (base peak). HR-EIMS m/z (M+): Calcd for C12H17NS:207.1082. Found: 207.1095.
1-Cyclohexyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6j)
Pale yellow oil. IR: 2925, 1670. 1H-NMR: 0.99-1.45 (5H, m, cyclohexyl-CH2), 1.65-1.88 (6H, m, cyclohexyl-CH2, cyclohexyl-CH), 2.65-2.85 (2H, m, H-7), 2.96 (1H, ddd, J=12, 9, 5 Hz, H-6), 3.33 (1H, dd, J=12, 5, 3 Hz, H-6), 3.82-3.83 (1H, m, H-4), 6.81 (1H, d, J=5 Hz, H-3), 7.06 (1H, d, J=5 Hz, H-6). 13C-NMR: 26.3 (cyclohexyl-CH2), 26.60 (cyclohexyl-CH2), 26.64 (cyclohexyl-CH2), 26.8 (cyclohexyl-CH2), 26.9 (cyclohexyl-CH2), 30.5 (C7), 42.7 (cyclohexyl-CH), 43.0 (C6), 59.9 (C4), 121.4 (C3), 125.0 (C2), 134. 8 (C3a), 137.2 (C7a). LR-EIMS: m/z 221(M+), 138 (base peak). HR-EIMS m/z (M+): Calcd for C13H19NS: 221.1238. Found: 221.1193.
4-Methyl-4-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6k)
Pale yellow oil. HCl-salt, colorless prisms recrystallized from MeOH-Et2O, mp 268-270 °C (sublimed). 1H-NMR (DMSO-d6): 2.06 (3H, s, -CH3), 3.04-3.23 (4H, m, H-7 and H-6), 6.95 (1H, d, J=5 Hz, H-3), 7.33-7.46 (5H, m Ph-H), 7.54 (1H, d, J=5 Hz, H-2). The 1H-NMR was identical with the reported one.9 13C-NMR (DMSO-d6): 21.6 (C7), 26.0 (-CH3), 37.4 (C6), 61.3 (C4), 125.0 (C3), 125.7 (C2), 127.7 (2 x Ph-CH), 128.6 (2 x Ph-CH), 128.9 (Ph-CH), 132.9 (Ph-C), 135.6 (C3a), 139.8 (C7a).
4,4-Dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6l)
Pale yellow oil. HCl salt mp 277-280 °C (sublimed), recrystallized from MeOH-Et2O. IR: 2971, 2937, 2892, 1641. 1H-NMR: 1.32 (6H, s, 2 x -CH3), 2.68 (2H, t, J=5 Hz, H-7), 3.10 (2H, t, J=5 Hz, H-6), 6.76 (1H, d, J=5 Hz, H-3), 6.96 (1H, d, J=5 Hz, H-2). 13C-NMR: 26.4 (C7), 30.2 (2 x -CH3), 40.0 (C6), 52.6 (C4), 121.6 (C3), 124.9 (C2), 133.0 (C3a), 142.9 (C7a). LR-EIMS: m/z 167 (M+), 152 (base peak). HR-EIMS m/z (M+): Calcd for C9H13NS:167.0769. Found: 167.0768.
4-Ethyl-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6m)
Yellow oil. HCl salt mp 242-243 °C, recrystallized from MeOH-Et2O. IR: 2962. 1H-NMR: 0.83 (3H, t, J=7 Hz, -CH2CH3), 1.33 (3H, s, - CH3), 1.62-1.84 (2H, m, -CH2CH3), 2.74 (2H, t, J=6 Hz, H-7), 3.14 (2H, m, H-6), 6.77 (1H, d, J=5 Hz, H-3), 7.03 (1H, d, J=5 Hz, H-2). 13C-NMR: 8.26 (CH2CH3), 26.4 (- CH2CH3), 27.7 (-CH3), 34.6 (C7), 39.5 (C6), 55.2 (C4), 121.3 (C3), 125.0 (C2), 133.6 (C3a), 142.1 (C7a). LR-EIMS: m/z 181 (M+), 58 (base peak). HR-EIMS m/z (M+): Calcd for C10H15NS: 181.0925. Found: 181.0925. HCl salt: Anal. Calcd for C10H16ClNOS: C, 55.16; H, 7.41; N, 6.43. Found: C, 55.27; H, 7.48; N, 6.63.
4,5,6,7-Tetrahydrothieno[3,2-c]pyridine-4-spirocyclopentane (6n)
Yellow oil. HCl salt mp 264-266 °C, recrystallized from MeOH-Et2O. IR: 2949. 1H-NMR: 1.80-1.89 (8H, m, cyclopentyl-CH2), 2.75 (2H, t, J=5 Hz, H-7), 3.12 (2H, t, J=5 Hz, H-6), 6.81 (1H, d, J=5 Hz, H-3), 7.03 (1H, d, J=5 Hz, H-2). 13C-NMR: 24.7 (2 x cyclopentyl-CH2), 26.3 (C7), 40.5 (C6), 41.6 (2x cyclopentyl-CH2), 63.9 (C4), 121.5 (C3), 124.7 (C2), 133.5 (C3a), 142.2 (C7a). LR-EIMS: m/z 193 (M+), 164 (base peak). HR-EIMS m/z (M+): Calcd for C11H15NS:193.0925. Found: 193.0899. HCl salt: Anal. Calcd for C11H16ClNOS: C, 57.50; H, 7.02; N, 6.10 Found: C, 57.47; H, 7.11; N, 6.28.
4,5,6,7-Tetrahydrothieno[3,2-c]pyridine-4-spirocyclohexane (6o)
Yellow oil. IR:2852, 2927. 1H-NMR: 1.25-1.29 (1H, m, cyclohexyl-CH2), 1.57-1.76 (9H, m, cyclohexyl-CH2), 2.75 (2H, t, J=6 Hz, H-7), 3.11 (2H, t, J=6 Hz, H-6), 6.85 (1H, d, J=5 Hz, H-3), 7.03 (1H, d, J=5 Hz, H-2). 13C-NMR: 21.6 (2 x cyclopentyl-CH2), 25.7 (cyclopentyl-CH2), 26.5 (C7), 37.3 21.6 (2 x cyclopentyl-CH2), 39.0 (C6), 54.4 (C4), 121.4 (C3), 124.9 (C2), 133.6 (C3a), 143.7 (C7a)LR-EIMS: m/z 207 (M+), 58 (base peak). HR-EIMS m/z (M+): Calcd for C12H17NS: 207.1082. Found: 207.1100.
4,5,6,7-Tetrahydrothieno[3,2-c]pyridine (6q)
Yellow oil. IR: 2925. 1H-NMR: 1.74 (1H, brs, NH), 2.80 (2H, t, J=6 Hz, H-7), 3.15 (2H, t, J=6 Hz, H-6), 3.92 (2H, t, J=2 Hz, H-4), 6.74 (1H, d, J=5 Hz, H-3), 7.07 (1H, d, J=5 Hz, H-2). 13C-NMR: 25.9 (C7), 43.8 (C6), 45.7 (C4), 121.9 (C3), 125.0 (C2), 133.7 (C3a), 134.4 (C7a). HR-EIMS m/z (M+): Calcd for C7H9NS:139.0453. Found: 139.0430.
4-(Pent-2-en-2-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (9c)
Pale yellow oil. IR: 2960, 2928. 1H-NMR: 0.98 (3H, t, J=7 Hz, -C=CHCH2CH3), 1.51 (3H, t, J=1 Hz, -CH3), 2.07 (2H, quintet J=7 Hz, -C=CHCH2CH3), 2.39-2.77 (1H, m, H-7), 2.85-2.95 (1H, m, H-7), 3.02 (1H, ddd, J=12, 10, 4 Hz, H-6), 3.26 (1H, ddd, J=12, 5, 3 Hz, H-6), 4.35 (1H, t, J=2 Hz, H-4), 5.43 (1H, td, J=7, 1 Hz, -C=CHCH2CH3), 6.63 (1H, d, J=5 Hz, H-3), 7.00 (1H, d, J=5 Hz, H-2). HR-FABMS m/z (MH+): Calcd for C12H18NS: 208.1160. Found: 208.1158.
4-(Hept-3-en-3-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (9d)
Yellow oil. IR: 2963, 1651. 1H-NMR: 0.84 (3H, t, J=7 Hz, -CH2CH3), 0.90 (3H, t, J=7 Hz, -C=CH(CH2)2CH3), 1.31 (2H, sextet, J=7 Hz, -CH2CH3), 1.84-2.14 (4H, m, -C=CH(CH2)2CH3,), 2.63-2.84 (2H, m, H-7), 2.88-2.96 (1H, m, H-6), 3.16-3.24 (1H, m, H-6), 4.32 (1H, s, H-4), 5.16 (1H, t, J=7 Hz, -C=CH(CH2)2CH3), 6.56 (1H, d, J=5 Hz, H-3), 6.92 (1H, d, J=5 Hz, H-2). 13C-NMR: 13.9 (CH3), 14.5 (CH3), 21.4 (-CH2CH3), 22.9 (-C=CH(CH2)2CH3), 26.0 (C7), 29.7 (-C=CH(CH2)2CH3), 42.2 (C6), 62.4 (C4), 121.0 (C3), 124.8 (C2), 129.3 (-C=CH(CH2)2CH3), 134.6 (C3a), 136.8 (C7a), 142.4 (-C=CH(CH2)2CH3). HR-FABMS m/z (MH+): Calcd for C14H22NS: 264.1422. Found: 264.1421.
4-(Non-4-en-2-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (9e)
Yellow oil. IR: 2962, 1666. 1H-NMR: 0.89 (6H, t, J=7 Hz, -(CH2)2CH3, -C=CH(CH2)3CH3), 1.26-1.49 (6H, m, -(CH2)2CH3, -C=CH(CH2)3CH3), 1.89-1.98 (4H, m, -(CH2)2CH3, -C=CH(CH2)3CH3), 2.71-2.90 (2H, m, H-7), 3.22-3.29 (2H, m, H-6), 4.38 (1H, s, H-4), 5.22 (1H, t, J=7 Hz, -C=CH(CH2)3CH3), 6.62 (1H, t, J=5 Hz, H-3), 6.99 (1H, t, J=5 Hz, H-2). 13C-NMR: 13.9 (CH3), 14.4 (CH3), 22.4 (-(CH2)2CH3), 23.0 (-C=CH(CH2)3CH3), 25.9 (C7), 27.5 (-(CH2)2CH3), 30.9 (-C=CH(CH2)3CH3), 31.9 (-C=CH(CH2)3CH3), 41.8 (C6), 61.8 (C4), 121.0 (C3), 126.4 (C2), 130.1 (-C=CH(CH2)3CH3), 134.6 (C3a), 136.7 (C7a), 140.5 (-C=CH(CH2)3CH3).HR-FABMS (MH+): Calcd for C16H26NS: 264.1786. Found: 264.1774.
4-(Undec-5-en-5-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (9f)
Yellow oil. IR: 2957, 2930, 1652. 1H-NMR: 0.73 (6H, m, -(CH2)3CH3, -C=CH(CH2)4CH3), 1.18-1.40 (10H, m, -(CH2)3CH3, -C=CH(CH2)4CH3), 1.82-2.10 (4H, m, -(CH2)3CH3, -C=CH(CH2)4CH3), 2.61-2.80 (2H, m, H-7), 2.82-2.94 (1H, m, H-6), 3.14-3.21 (1H, m, H-6), 4.30 (1H, s, H-4), 5.13 (1H, t, J= 7 Hz, -C=CH(CH2)3CH3), 6.54 (1H, d, J=5 Hz, H-3), 6.91 (1H, d, J=5 Hz, H-2). 13C-NMR: 13.9 (CH3), 14.0 (CH3), 22.5 (-(CH2)3CH3), 23.1 (-C=CH(CH2)4CH3), 26.1 (C7), 27.7 (-(CH2)3CH3), 28.5(-(CH2)3CH3), 29.4 (-C=CH(CH2)4CH3), 31.6 (-C=CH(CH2)4CH3), 32.0 (-C=CH(CH2)4CH3), 42.0 (C6), 62.0 (C4), 120.9 (C3), 126.4 (C2), 129.7 (-C=CH(CH2)4CH3), 134.7 (C3a), 136.9 (C7a), 140.9 (-C=CH(CH2)4CH3). HR-FABMS (MH+): Calcd for C18H30NS: 292.2099. Found: 292.2092.
4-(Tridec-6-en-6-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (9g)
Yellow oil. IR: 2956, 2928, 1653. 1H-NMR: 0.84-0.90 (6H, m, -(CH2)4CH3, -C=CH(CH2)5CH3), 1.18-1.42 (14H, m, -(CH2)4CH3, -C=CH(CH2)5CH3), 1.89-2.10 (4H, m, -(CH2)4CH3, -C=CH(CH2)5CH3), 2.61-2.99 (3H, m, H-6, H-7), 3.14-3.22 (1H, m, H-6), 4.39 (1H, s, H-4), 5.20 (1H, t, J=7 Hz, -C=CH(CH2)3CH3), 6.61 (1H, d, J=5 Hz, H-3), 6.99 (1H, d, J=5 Hz, H-2). 13C-NMR: 13.97 (CH3), 14.0 0 (CH3), 22.4 (-(CH2)4CH3), 22.5 (-C=CH(CH2)5CH3), 25.4 (C7), 27.8 (-(CH2)4CH3), 28.8 (-(CH2)4CH3), 29.0 (-(CH2)4CH3), 29.3 (-C=CH(CH2)5CH3), 29.6 (-C=CH(CH2)5CH3), 31.7 (-C=CH(CH2)5CH3), 32.1 (-C=CH(CH2)5CH3), 41.4 (C6), 61.3 (C4), 121.4 (C3), 126.3 (C2), 130.9 (-C=CH(CH2)5CH3), 134.4 (C3a), 135.9 (C7a), 139.9 (-C=CH(CH2)5CH3). HR-FABMS (MH+): Calcd for C20H34NS: 320.2412. Found: 320.2412.

References

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