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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Bioorg Med Chem. Author manuscript; available in PMC 2011 January 1.
Published in final edited form as:
PMCID: PMC2818504
NIHMSID: NIHMS159859

Probes for narcotic receptor mediated phenomena. 40.1 N-Substituted cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols

Abstract

A series of N-substituted rac-cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols have been prepared using a simple synthetic route previously designed for synthesis of related cis-2-methyl-4a-alkyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols. The new phenolic compounds, where the aromatic hydroxy moiety is situated ortho to the oxygen atom in the oxide-bridged ring, do not interact as well as the pyridin-6-ols with opioid receptors. The N-para-fluorophenethyl derivative had the highest μ-opioid receptor affinity of the examined compounds (Ki = 0.35 μM).

Keywords: Synthesis, opioid receptor binding, N-substituted cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols, oxide-bridged phenylmorphans, geometry optimization, superposition

1. Introduction

Hexahydrobenzofuro[2,3-c]pyridin-8-ols (1a–f, Fig. 1) and hexahydrobenzofuro[2,3-c]pyridin-6-ols1, 2 (2, Fig. 1) are partial structures of the oxide-bridged phenylmorphan class of opioids (Fig. 1)314 and although they appear to be structurally similar to the d-series of the oxide-bridged phenylmorphans (3a, Fig. 1)1 we have found that they can assume a conformation that is closer to morphine than to the oxide-bridged phenylmorphans and that their μ-opioid affinity and activity is likely to be due to their ability to attain that conformation.1 Hutchinson et al.,2 found that N-phenethyl- and N-cyclopropylmethyl-substituted 1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols, had high affinity for μ-opioid receptors (Ki = 0.9 and 4 nM, respectively) and were potent antinociceptives. We have determined that the high affinity of the N-phenethyl analogue was ascribable to the 4aS,9aR enantiomer (Ki = 0.7 nM).1 In most of the well-known epoxymorphinans, morphinans, 6,7-benzomorphans, and 5-phenylmorphans,15 the phenolic hydroxyl moiety is situated meta to the piperidine ring. The phenolic hydroxy group is also oriented in a meta-position with respect to the piperidine ring in the hexahydrobenzofuro[2,3-c]pyridin-6-ols (2, Figure 1), and para to the oxygen atom in the dihydrofuran ring of the epoxymorphinans. In the hexahydrobenzofuro[2,3-c]pyridin-8-ols (1a–f, Fig. 1), as in the hexahydrobenzofuro[2,3-c]pyridin-6-ols, the phenolic hydroxyl moiety is meta-oriented to the piperidine ring and, unlike the pyridin-6-ols, oriented ortho to the oxygen atom in the dihydrofuran ring. Both the pyridin-6-ols and the pyridin-8-ols might also be expected to show similar affinity for opioid receptors if the meta-orientation to the piperidine ring is essential for interaction with opioid receptors. Also, a 7,8-dimethoxy compound in a hexahydrobenzofuro[2,3-c]pyridine structure (2a, Fig. 1), where the methoxy groups are meta- and para-oriented to the piperidine ring and ortho- and meta-oriented to the oxygen in the dihydrofuran ring, was noted, in a patent by Koelsch in 1957,16, 17 to have “analgesic” action. Some ostensibly similar C-6 and C-8 hydroxy substituted oxide-bridged phenylmorphans (3) have been found to be μ-agonists (N-phenethyl substituted para-e and para-f oxide-bridged phenylmorphans, Fig. 1) and κ-antagonists (N-phenethyl substituted ortho-b and ortho-f oxide-bridged phenylmorphans, Fig. 1).13, 14 Based on the data in the Koelsch patent16 and on our work with oxide-bridged phenylmorphans, we thought that it would be of interest to examine N-substituted hexahydrobenzofuro[2,3-c]pyridin-8-ols (1a–f, Fig. 1) to see if they interacted with opioid receptors. These compounds were prepared both by the well-known route and by an improved, relatively simple, synthetic procedure that was devised for related compounds.18 This procedure also enables the synthesis of compounds with new alkyl, or aralkyl moieties at C-4a. In addition to the C4a ethyl group, we prepared one new compound with a phenethyl moiety at that position, as a proof of concept. The phenethyl moiety was chosen because aromatic rings in an aralkyl moiety are known to influence opioid receptor binding and pharmacological activity when present in a morphinan-like structure (e.g., aralkyl amides19 at C-6, cinnamoyl esters20 or phenylpropyl ethers21 at C-14, or various other substituents on the nitrogen atom).2224

Figure 1
General Structures

2. Results and Discussion

2.1. Chemistry

The basic route for assembling the cis-benzofuropyridin-8-ol system (1a–f, Fig. 1) was initially based on the method developed by Hutchison et al.2 Starting from the known hydroxypropiophenone 4 (Scheme1),25 alkylation with ethyl bromoacetate in DMF with K2CO3 afforded the ester 5 in 91% yield. This material was subjected to the Horner-Emmons reaction with diethyl(cyanomethy1)phosphonate and NaH in THF to give the alkenic cyano ester 6 in 90% yield as a mixture of alkene stereoisomers (Scheme 1). The isomeric mixture was carried through without separation and treated with fresh sodium ethoxide to yield the benzofuronitrile 7 via an intramolecular Michael addition as a 1:l mixture of diastereomers in 82% yield. These diastereomers were subjected to hydrogenation under pressure with platinum oxide in acetic acid to afford a separable mixture of cis-lactam 10 in 38% yield and trans-amine ester 9 in 15% yield. As reported by the Hutchison group,2 the cis-amine 8 cyclizes in situ under the acidic reaction conditions to give the cis-lactam 10 whereas trans-amine 9 fails to undergo a similar cyclization to form the presumably strained trans-lactam under the same conditions. Upon subjecting the trans-amine 9 to epimerizing conditions (sodium ethoxide in refluxing ethanol), cis-lactam 10 could be isolated in 82% yield, and the trans-lactam was not observed. Though an appreciable amount of the cis-lactam was obtained for the synthesis, the inconsistent yields from the hydrogenation step pointed to the need for some modification of the synthetic route. The stereochemistry of the ring junction for benzofurolactam 10 as well as for all subsequent intermediates was assigned on the basis of the 1H NMR spectra of 10 in which the proton on C-9a showed JAX = JBX = 5.0–6.0 Hz, a result consistent with a cis ring junction. Additionally, 2D NOESY experiments provided further proof for the cis stereochemistry. Lactam 10 was reduced under refluxing LAH conditions to the amine 11, which represents the common intermediate from which the new racemic compounds 1a–1f are derived.

Scheme 1
Synthesis of rac-4a-ethyl-8-methoxy-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridine. Reagents and conditions: (a) K2CO3, BrCH2CO2Et, DMF, reflux, 91%; (b) NaH, (OEt)2OPCH2CN, 90%; (c) NaOEt, EtOH, reflux, 82%; (d) Pt/C, AcOH, H2, 50 psi; (e) NaOEt/EtOH, ...

The conversion of amine 11 to cis-benzofuropyridin-8-ols la and 1b–1f is shown in Scheme 2. Analogue la was prepared by the treatment of amine with HCHO in MeOH under hydrogenating conditions in presence of catalytic Pd/C, followed by subsequent O-demethylation. Analogues 1b–1f were obtained by directly alkylating the amine with an alkyl halide/NaHCO3 in DMF system followed by BBr3 deprotection of the aromatic methoxy group (see General Method for the synthesis of 1b–f in the Experimental section).

Scheme 2
Synthesis of rac-N-substituted 4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols. Reagents and conditions: (a) 1. HCHO/MeOH/PtO2, H2, 1atm; 2. BBr3, 53% over 2 steps; (b) 1. alkyl bromide/NaHCO3; 2. BBr3.

Since the hydrogenation step gave inconsistent yields, we focused on modifying the synthesis of 1a, using a procedure that would enable introduction of alkyl or aralkyl substituents at C-4a, to obtain, for example, compound 12.

An external file that holds a picture, illustration, etc.
Object name is nihms-159859-f0001.jpg

Toward that end the starting alkene substrate 13 (Scheme 3) was assembled via known literature procedures.6 With the alkene 13 in hand, functionalization leading to the enamine 14 bearing the desired ethyl group, or any alkyl or aralkyl group was easily achieved using the method of Evans et al.,26 and earlier reports from our laboratory.6, 7, 911 A simple two-step procedure, originally conceived for the synthesis of the pyridin-6-ols,18 involved bromination of the alkene with NBS followed by NaCNBH3 reduction in acidic medium and gave the late stage intermediate 15. The relative stereochemistry of the bromo compound 15a was determined by single crystal X-ray diffraction analysis of the salt 15a• HCl (Fig. 2).

Figure 2
X-ray crystal structure of 2-methyl-4a-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ol (12, top) and 3-bromo-4-(2,3-dimethoxyphenyl)-4-ethyl-1-methylpiperidine hydrochloride (15a.HCl, bottom). Displacement ellipsoids are shown at the 50% ...
Scheme 3
Simplified synthesis of rac-hexahydrobenzofuro[2,3-c]pyridin-8-ols. Reagents and conditions: (a) n-BuLi −40 °C, alkyl bromide; (b) 1. NBS, THF; 2. NaCNBH3, HCl; (c) 48% HBr, reflux; (d) Et3N, 100 3C, sealed tube.

Hydrobromic acid-assisted deprotection of the two aromatic O-methyl groups gave the diol 16 (Scheme 3) that is the needed template for the base-mediated oxide-ring formation. The base Et3N worked well in this reaction. Refluxing the diol in methanolic Et3N gave 1a (Scheme 3) in excellent yield. The same route was put to use in the synthesis of 12. Following similar manipulations noted in Scheme 3, the analogue 12 was synthesized and its stereochemistry was confirmed by X-ray diffraction analysis (Fig. 2).

2.2. Opioid receptor binding studies

The N-methyl substituted pyridin-8-ol, 1a, had little affinity for opioid receptors (Ki = 795 nM, Table 1). It had 40 times less affinity for μ-receptors than the comparable pyridin-6-ol. Even a greater difference between the pyridin-8- and 6-ols was seen with the N-cyclopropylmethyl and N-phenethyl analogues (Ki = 4670 and 1630 respectively, in Table 1), both of these pyridin-8-ols showing about three orders of magnitude less affinity for μ-receptors than the comparable pyridin-6-ols. Clearly, interaction with the μ-receptor was greatly facilitated by a phenolic hydroxyl at the C-6 position. We formerly observed, in overlay studies with the pyridin-6-ols, that the likely pharmacologically active conformer of 4aS,9aR-(-)-cis-4a-ethyl-2-(2-phenylethyl)-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (17, Table 1) had its aromatic hydroxyl group is in the same general area of three-dimensional space as that of morphine.1 In order to map the spatial region of these phenolic hydroxyl groups with respect to the phenolic hydroxyl group of morphine, geometry optimization on compound 1b and its superposition onto morphine were carried out as previously noted.1 While the backbone of both 1b and 17 has considerable overlap with morphine, it can be seen in Fig. 3 that the overlap between the phenolic hydroxy groups of compound 17 and morphine cannot be attained by compound 1b. The effect of the N-substituent on μ-receptor affinity in the pyridin-8-ols was relatively slight, and the bulky phenethyl moiety at C-4a in 12 (Ki = 740 nM) did not appear to have much influence on affinity, possibly because of the overwhelming detrimental effect of the poorly situated phenolic hydroxyl group. Compared with the ethyl group in 1a (Ki = 795 nM); the phenethyl's aromatic ring in the spatial area around C4a did not appear to influence interaction with the opioid receptor. Of the compounds examined, the N-p-fluorophenethyl substituted pyridin-8-ol (1f) had the highest affinity for the μ-receptor, it had five fold better affinity than the unsubstituted N-phenethyl compound 1b (Ki = 354 nM vs 1630 nM for 1b). The fluorine atom in the phenyethyl moiety at C4a increased receptor affinity in the pyridin-8-ols. That finding is of interest and will be explored in further studies in the pyridin-6-ol series.

Figure 3
Overlay of the piperidine ring of conformers of compounds 1b and 171 onto that of morphine, illustrating the topographical similarity of the high affinity ligand 17 with morphine, and the lack of overlap of the oxygen atoms in 1b, a compound with little ...
Table 1
[3H] Binding Data for rac-cis-Benzofuro[2,3-c]pyridin-8-ols

3. Conclusion

A surprisingly large difference in binding affinity was found between comparably substituted pyridin-6-ol and pyridin-8-ol compounds. Some showed about a thousand-fold difference in their ability to bind to μ-opioid receptors. As we discussed with the pyridin-6-ols,1 compound 17 was able to reach a conformation in which its phenolic hydroxyl group was in the same vicinity as that of morphine, whereas compound 1b could not attain such overlap. Thus, it is apparent that the spatial location of the phenolic hydroxyl in these cis-4a-alkyl or aralkyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6 and -8-ols, not just the meta-orientation to the piperidine ring as in the well-known epoxymorphinans, morphinans, 6,7-benzomorphans, and 5-phenylmorphans, is one of the most important factors in determining their ability to interact with opioid receptors.

4. Experimental

4.1. Chemistry

4.1.1. General

Mass spectra (CIMS) were obtained using a Finnigan 4600 mass spectrometer unless otherwise noted. 1H nuclear magnetic resonance (1H NMR, 500 MHz) was recorded on a Bruker Avance 500 instrument in deuterated solvents (Cambridge Isotope Laboratories, Inc.) as specified. TMS was used as an internal standard. IR spectra were recorded on a Beckman IR 4230 spectrometer. Column chromatography was performed with the use of 230-400-mesh EM silica gel. Melting points were determined on a Buchi B-545 melting point apparatus and are uncorrected. Combustion analyses were determined at Atlantic Microlabs, Atlanta, GA.

4.1.2. Ethyl 2-(2-methoxy-6-propionylphenoxy)acetate (5)

A mixture of 1-(2-hydroxy-3-methoxyphenyl)propan-1-one (4) (50.0 g, 0.28 mol),25 ethyl bromoacetate (37.0 mL, 0.33 mol) and powdered K2CO3 (77.4 g, 0.56 mol) in dry DMF (750 mL) was vigorously stirred at 90 °C for 6 h. The reaction mixture was cooled and then poured onto ice water (200 mL) and the product was extracted with Et2O (2 × 300 mL). After drying over MgSO4, the solvent was removed in vacuo and the residue was distilled under aspirator pressure at 200 °C to give 67.7 g (91%) of 5 as a colorless viscous oil. IR (neat): 1756, 1683 cm−1; 1H NMR (CDCl3, 300 MHz) δ 7.12 (dd, 2H, J = 2.0 and 8.0 Hz), 7.01 (dd, 1H, J = 2.0 and 7.5 Hz), 4.67 (s, 2H), 4.22 (q, 2H, J = 7.0 Hz), 3.85 (s, 3H), 3.05 (q, 2H, J = 7.0 Hz), 1.26 (t, 3H, J = 7.0 Hz), 1.15 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 204.06, 169.21, 152.14, 145.54, 134.67, 124.54, 120.77, 115.26, 69.83, 61.14, 56.07, 36.79, 14.23, 8.31; HRMS (TOF MS ES+) calcd for C14H19O5 (M+H)+: 267.1232; found: 267.1227. Anal. Calcd for C14H18O5: C, 63.15; H, 6.81. Found: C, 63.04; H, 6.88.

4.1.3. Ethyl 2-(2-(1-cyanobut-1-en-2-yl)-6-methoxyphenoxy)acetate (6)

To an ice-cooled suspension of 60% NaH (3.6 g, 90.0 mmol), which had been washed free of oil with hexane in THF (300 mL), was added diethyl(cyanomethy1)phosphonate (13.2 mL, 82.5 mmol) in a dropwise fashion. After 15 min at room temperature, a solution of 5 (20.0 g, 75.0 mmol) in THF (350 mL) was added dropwise at 0 °C. After 2 h at 0 °C, the reaction mixture was poured on ice water and the product was extracted with Et2O. After drying over MgSO4, the solvent was removed in vacuo to give a dark yellow oil. Purification by flash chromatography using 30% EtOAc in hexanes gave 19.5 g (90%) of an isomeric mixture 6 as a yellow oil. IR (neat) 1746, 1460 cm−1; 1H NMR (CDCl3, 300 MHz) δ (mixture of isomers) 7.20 (m, 1H), 7.02 (m, 1H), 6.84 (m, 1H), 5.53 (s, 1H), 4.64 (s, 2H), 4.36 (m, 2H), 3.95 (s, 3H), 3.03 (q, 2H, J = 7.2 Hz), 1.38 (m, 3H), 1.15 (t, 3H); 13C NMR (CDCl3, 75 MHz) δ (mixture of isomers) 168.86, 165.80, 152.13, 144.27, 132.53, 124.648, 124.53, 12 152.133, 204.06, 169.21, 152.14, 145.54, 134.67, 124.64, 124.53, 121.08, 120.88, 116.93, 113.43, 113.25, 98.28, 96.65, 69.79, 61.08, 55.92, 55.83, 31.24, 28.67, 14.23, 12.73, 120.77, 115.26, 69.83, 61.14, 56.07, 36.79, 14.23, 8.31; HRMS (TOF MS ES+) calcd for C16H20NO4 (M+H)+: 290.1392; found: 290.1390. Anal. Calcd for C16H19NO4•0.25H2O: C, 65.40; H, 6.69; N, 4.77. Found: C, 65.36; H, 6.78; N, 4.46.

4.1.4. Ethyl 3-(cyanomethyl)-3-ethyl-7-methoxy-2,3-dihydrobenzofuran-2-carboxylate (7)

Compound 6 (17.0 g, 58.8 mmol) in 20 mL EtOH was carefully added to a solution of freshly cut sodium metal (850 mg, 37.0 mmol) in EtOH (20 mL). The mixture was heated at 80 °C for 90 min. After cooling to room temperature, the reaction mixture was poured onto ice water, and the product was treated with 37% HCl (5 mL) to neutralize the excess base. The organic layer was extracted with Et2O (2 × 200 mL), and after drying over MgSO4 the solvent was removed in vacuo to give a dark oil. Purification by flash chromatography using 50% EtOAc in hexanes gave 14.0 g (82%) of isomeric mixture 7 as a sticky solid. IR (neat) 1755, 1493 cm−1; 1H NMR (CDCl3, 500 MHz) δ (single isomer) 6.96 (t, 1H, J = 7.5 Hz), 6.85 (t, 2H, J = 7.5 Hz), 5.07 (s, 1H), 4.35 (m, 2H), 3.89 (s, 3H), 2.99 (d, 1H, J = 16.5 Hz), 2.89 (d, 1H, J = 16.5 Hz), 1.86 (m, 1H), 1.67 (m, 1H), 1.33 (t, 3H, J = 7.5Hz), 0.80 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ (single isomer) 168.03, 146.54, 145.07, 129.77, 122.84, 116.98, 115.34, 112.86, 87.40, 61.95, 56.07, 51.62, 26.83, 14.36, 14.34; HRMS (TOF MS ES+) calcd for C16H20NO4 (M+H)+: 290.1392; found: 290.1382. Anal. Calcd for C16H19NO4: C, 66.42; H, 6.62; N, 4.84. Found: C, 66.42; H, 6.60; N, 4.84.

4.1.5. General Procedure for the synthesis of ethyl 3-(2-aminoethyl)-3-ethyl-7-methoxy-2,3-dihydrobenzofuran-2-carboxylate (9) and 4a-ethyl-8-methoxy-2,3,4,4a-tetrahydrobenzofuro[2,3-c]pyridin-1(9aH)-one (10)

A mixture of the nitrile 7 (3.4 g, 11.7 mmol) and PtO2 (0.5 g) in acetic acid (50 mL) was hydrogenated at 50 psi at room temperature for 6 h. After filtration, the solvent was removed in vacuo and the reaction mixture was poured on an ice water and NH4OH mixture, the product was extracted with CHCl3 (2 × 100 mL) and washed with a saturated NaHCO3 solution. After drying over Na2SO4, the solvent was removed in vacuo and the residue was subjected to flash chromatography on silica gel with 90:9:1 CH2Cl2:MeOH:NH4OH to give 1.1 g of the cis lactam 10 in 38% yield as a sticky foam. Eluting the above column with 50% MeOH in CH2Cl2 gave 0.5 g (15%) of 9 as a sticky solid.

4.1.5.1. Ethyl 3-(2-aminoethyl)-3-ethyl-7-methoxy-2,3-dihydrobenzofuran-2-carboxylate (9)

IR (neat) 3278, 1746 cm−1; 1H NMR (CDCl3, 300 MHz) δ 6.96 (t, 1H, J = 7.5 Hz), 6.85 (d, 1H, J = 8.1 Hz), 6.76 (d, 1H, J = 7.2 Hz), 5.17 (bs, 2H), 5.08 (s, 1H), 4.38 (m, 2H), 3.96 (s, 3H), 2.88 (m, 2H), 2.19 (m, 2H), 1.83 (m, 1H), 1.58 (m, 1H), 1.41 (t, 1H, J = 7.2 Hz), 0.86 (t, 3H, J = 7.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 170.93, 148.05, 146.06, 133.47, 123.02, 117.13, 113.67, 88.27, 62.46, 56.64, 53.71, 40.33, 38.19, 30.23, 14.51, 8.78; HRMS (TOF MS ES+) calcd for C16H24NO4 (M+H)+: 294.1705; found: 294.1711. Anal. Calcd for C16H23NO4.•0.75 H2O: C, 62.62; H, 8.04; N, 4.56; found: C, 62.95; H, 7.87; N, 4.62.

4.1.5.2 4a-Ethyl-8-methoxy-2,3,4,4a-tetrahydrobenzofuro[2,3-c]pyridin-1(9aH)-one (10)

Compound 10 was alternatively obtained from compound 9. The trans amino ester 9 (500 mg, 1.76 mmol) was carefully added to a solution of freshly cut sodium metal (23 mg, 1.0 mmol) in EtOH (5 mL). The mixture was heated at 80 °C for 90 min. After cooling to room temperature, the reaction mixture was poured onto ice water, and the product was treated with 37% HCl (2 mL) to neutralize the excess base. The organic layer was extracted with CHCl3 (2 × 30 mL), and after drying over Na2SO4 the solvent was removed in vacuo to give a dark oil. Purification by flash chromatography using 90:9:1 CH2Cl2:MeOH:NH4OH gave 345 mg (82%) of 10 as a foam. IR (neat) 3211, 1678 cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.02 (bs, 1H), 6.85 (t, 1H, J = 7.5 Hz), 6.73 (t, 1H, J = 8.0 Hz), 6.62 (d, 1H, J = 7.5 Hz), 4.64 (s, 1H), 3.80 (s, 3H), 3.17 (ddd, 1H, J = 4.5, 9.0 and 17.0 Hz), 3.05 (t, 1H, J = 10.5 Hz), 2.16 (m, 2H), 1.71 (m, 2H), 0.80 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 169.25, 147.86, 144.63, 131.86, 121.97, 114.9, 112.08, 99.34, 85.47, 55.94, 50.00, 38.30, 32.78, 8.26; HRMS (TOF MS ES+) calcd for C14H18NO3 (M+H)+: 248.1287; found: 248.1295. Anal. Calcd for C14H17NO3•0.1 H2O: C, 67.51; H, 6.96; N, 5.62. Found: C, 67.43; H, 6.95; N, 5.43.

4.1.6. 4a-Ethyl-8-methoxy-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridine (11)

To a solution of LAH (1.8 g, 4.25 mmol) in THF (30 mL) was added cis-lactam 10 (3.0 g, 1.21 mmol) in THF (20 mL) and the reaction mixture was refluxed for 2 h. After cooling to room temperature, the reaction was quenched with EtOAc and treated with 50% NaOH, the organic layer was then extracted with CHCl3 (2 × 50 ml), dried over Na2SO4 and the solvent was removed in vacuo to afford a brown oil. Purification on a silica gel column using 90:10 CH2Cl2:MeOH gave 2.6 g (92%) of compound 11 as a pale yellow oil. IR (neat) 2938, 1489 cm−1; 1H NMR (CDCl3, 500 MHz) δ 6.97 (t, 1H, J = 7.5 Hz), 6.86 (dd, 1H, J = 1.2 and 8.1 Hz), 6.79 (dd, 1H, J = 1.5 and 7.5 Hz), 4.47 (t, 1H, J = 4.5 Hz), 3.99 (s, 3H), 3.21 (d, 1H, J = 4.5 Hz), 2.88 (m, 1), 2.80 (m, 1H), 1.75–1.93 (m, 4H), 0.96 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 147.23, 144.98, 135.70, 121.28, 115.17, 111.08, 84.37, 59.97, 55.85, 46.68, 46.11, 41.63, 33.96, 30.79, 29.74, 8.69; HRMS (TOF MS ES+) calcd for C14H20NO2 (M+H)+: 234.1494; found: 234.1491. Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00; found: C, 72.00; H, 7.90; N, 5.70.

4.1.7. 4a-Ethyl-2-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ol (1a)

A deoxygenated solution of compound 11 (600 mg, 2.57 mmol), HCHO (2 mL) and 10% Pd on carbon (20 mg) in MeOH (10 mL) was stirred at room temperature under H2 at 1 atm for 2 h. The resultant mixture was filtered through Celite and concentrated in vacuo to give a yellow oil. The oil was taken up in CHCl3 and treated with neat BBr3 (0.97 mL, 10.3 mmol) and refluxed for 2 h. The reaction mixture was cooled and treated with MeOH to quench the excess BBr3, poured in to a mixture of water and NH4OH and extracted with CH2Cl2. After evaporation of the solvent in vacuo the crude compound was subjected to flash chromatography on silica gel using 5% MeOH in CH2Cl2 as the eluent to give 1a (320 mg, 53% over two steps) as a pale yellow solid, mp 158–160 °C. IR (neat) 2983, 1732 cm−1; 1H NMR (CDCl3, 500 MHz) δ 6.82 (t, 1H, J = 7.5 Hz), 6.76 (d, 1H, J = 8.0 Hz), 6.62 (d, 1H, J = 7.0 Hz), 4.65 (t, 1H, J = 6.0 Hz), 2.97 (dd, 1H, J = 5.5 and 11.5 Hz), 2.57 (dd, 1H, J = 6.0 and 11.5 Hz), 2.26 (m, 1H), 2.21 (s, 3H), 2.11 (m, 2H), 1.89 (ddd, 1H, J = 3.5, 11.0 and 15.0 Hz), 1.70 (m, 1H), 1.56 (m, 1H), 0.83 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 145.66, 141.99, 134.27, 121.67, 115.90, 114.61, 85.08, 56.65, 52.04, 46.52, 46.15, 32.70, 31.80, 8.54; HRMS (TOF MS ES+) calcd for C14H20NO2 (M+H)+: 234.1494; found: 234.1505. Anal. Calcd for C14H19NO2•0.2H2O: C, 70.97; H, 8.25; N, 5.91; found: C, 71.17; H, 8.12; N, 5.91.

4.1.8. General method for the synthesis of 1b through 1f

A mixture of the amine 11, alkyl bromide (1.2 equiv) and NaHCO3 (2 equiv) in DMF (20 mL) was heated at 100 °C for 3 h. After cooling to room temperature, the reaction mixture was poured on ice water, and the product was extracted with Et2O. The ethereal extracts were washed with a saturated NH4Cl solution. After drying over Na2SO4, the solvent was removed in vacuo to afford an oil. This oil was taken up in CHCl3 and treated with neat BBr3 (4 equiv) and refluxed for 2 h. The reaction mixture was cooled and treated with MeOH to quench the excess BBr3, poured in to a mixture of H2O and NH4OH and extracted with CH2Cl2. After evaporation of the solvent in vacuo the crude compound was subjected to flash chromatography on silica gel using 5% MeOH in CH2Cl2 as the eluent to give the compounds 1b–f as a solid.

4.1.9. 4a-Ethyl-2-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ol (1b)

Using the general method of 4.1.9, the amine 11 (1.1 g, 4.85 mmol), 2-bromoethylbenzene (0.78 mL, 5.82 mmol) and subsequent treatment with BBr3 (1.84 mL, 19.4 mmol) gave 0.76 g of 1b (49% over two steps) as a white solid, mp 195–198 °C. IR (neat) 3019, 1264 cm−1; 1H NMR (CD3OD, 500 MHz) δ 7.24 (t, 2H, J = 7.5 Hz), 7.15 (m, 3H), 6.72 (t, 1H, J = 8.0 Hz), 6.63 (d, 1H, J = 7.0 Hz), 6.59 (d, 1H, J = 7.5 Hz), 4.61 (bs, 1H), 4.48 (t, 1H, J = 6.0 Hz), 2.94 (dd, 1H, J = 5.5 and 12.5 Hz), 2.77 (m, 2H), 2.63 (m, 1H), 2.56 (d, 1H, J = 8.0 Hz), 2.42 (dd, 1H, J = 7.0 and 12.0 Hz), 2.22 (ddd, 1H, J = 2.5, 10.0 and 12.0 Hz), 2.05 (ddd, 1H, J = 3.0, 5.5 and 14.0 Hz), 1.78 (ddd, 1H, J = 4.0, 9.5 and 14.0 Hz), 1.70 (m, 1H), 1.59 (m, 1H), 0.80 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 145.02, 141.56, 136.30, 132.71, 128.80 (2C), 128.76 (2C), 126.99 122.65, 116.78, 114.46, 81.719, 59.06, 50.03, 48.62, 46.31, 30.66, 30.33, 30.31, 29.65, 8.42; HRMS (TOF MS ES+) calcd for C21H26NO2 (M+H)+: 324.1964; found: 324.1972. Anal. Calcd for C21H25NO2•0.25H2O: C, 76.91; H, 7.83; N, 4.27. Found: C, 77.02; H, 7.84; N, 4.22.

4.2. 4a-Ethyl-2-(4-nitrophenethyl)-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ol (1c)

Using the general method of 4.1.9, amine 11 (600 mg, 2.57 mmol) 1-(2-bromoethyl)-4-nitrobenzene (651 mg, 2.83 mmol) and subsequent treatment with BBr3 (977 μL, 10.3 mmol) gave 270 mg (28% over two steps) of 1c as a pale yellow crystalline solid, mp 144–146 °C. IR (neat) 3020, 1214 cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.10 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J = 8.0 Hz), 6.82 (t, 1H, J = 7.5 Hz), 6.79 (d, 1H, J = 8.0 Hz), 6.64 (d, 1H, J = 7.0 Hz), 4.56 (t, 1H, J = 5.5 Hz), 2.94 (d, 1H, J = 7.5 Hz), 2.89 (t, 1H, J = 7.5 Hz), 2.63 (d, 1H, J = 6.5 Hz), 2.48 (dd, 1H, J = 6.5 and 11.0 Hz), 2.27 (t, 1H, J = 9.5 Hz), 2.08 (dt, 1H, J = 4.5 and 10.5 Hz), 1.83 (t, 1H, J = 9.5 Hz), 1.70 (m, 1H), 1.60 (m, 1H), 0.83 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 148.12, 146.69, 145.63, 141.26, 134.36, 129.62 (2C), 123.81 (2C), 121.75, 115.53, 115.12, 85.47, 59.49, 54.57, 49.74, 47.12, 33.35, 32.30, 32.12, 8.54 145.66, 141.99, 134.27, 121.67, 115.90, 114.61, 85.08, 56.65, 52.04, 46.52, 46.15, 32.70, 31.80, 8.54; HRMS (TOF MS ES+) calcd for C21H25N2O4 (M+H)+: 369.1814; found: 369.1816. Anal. Calcd for C21H24N2O4: C, 68.46; H, 6.57; N, 7.60. Found: C, 68.24; H, 6.70; N, 7.51.

4.2.1. 2-(Cyclopropylmethyl)-4a-Ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ol (1d)

Using the general method of 4.1.9, amine 11 (320 mg, 1.37 mmol) (bromomethyl)cyclopropane (147 μL, 1.51 mmol) and subsequent treatment with BBr3 (520 μL, 5.48 mmol) gave 200 mg of 1d (53 % over two steps) as a pale yellow solid, mp 139−141 °C. IR (neat) 3019 cm−1; 1H NMR (CDCl3, 500 MHz) δ 6.80 (t, 1H, J = 7.5 Hz), 6.77 (d, 1H, J = 8.0 Hz), 6.61 (d, 1H, J = 7.0 Hz), 4.83 (t, 1H, J = 7.0 Hz), 3.35 (dd, 1H, J = 6.0 and 10.5 Hz), 2.89 (d, 1H, J = 10.0 Hz), 2.32 (dd, 1H, J = 6.5 and 12.5 Hz), 2.23 (dd, 1H, J = 6.5 and 12.5 Hz), 2.16 (m, 3H), 2.00 (ddd, 1H, J = 4.0, 11.0 and 15.0 Hz), 1.64 (m, 1H), 1.54 (m, 1H), 0.84 (m, 1H), 0.79 (t, 3H, J = 7.5 Hz) 0.45 (t, 2H, J = 3.5 Hz), 0.03 (d, 2H, J = 3.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 145.88, 142.30, 133.81, 121.66, 116.41, 114.52, 84.83, 63.56, 54.65, 50.03, 47.28, 33.83, 30.52, 8.38, 7.59, 4.29, 4.27; HRMS (TOF MS ES+) calcd for C17H24NO2 (M+H)+: 274.1807; found: 274.1814. Anal. Calcd for (C17H23NO2•0.25 H2O: C, 73.48; H, 8.52; N, 5.04. Found: C, 73.11; H, 8.50; N, 4.93.

4.2.2. 4a-Ethyl-2-(4-fluorobenzyl)-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ol (1e)

Using the general method of 4.1.9, amine 11 (233 mg, 1 mmol), 1-(bromomethyl)-4-fluorobenzene (147 μL, 1.2 mmol) and subsequent treatment with BBr3 (379 μL, 4 mmol) gave 60 mg of 1e (31% over two steps) as light white crystals, mp 138–140 °C. IR (neat) 3019, 1214 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.24 (m, 2H), 6.97 (t, 2H, J = 8.5 Hz), 6.79 (t, 1H, J = 7.5 Hz), 6.76 (d, 1H, J = 7.0 Hz), 6.63 (d, 1H, J = 7.0 Hz), 5.51 (bs, 1H), 4.52 (t, 1H, J = 6.0 Hz), 3.44 (m, 2H), 2.88 (dd, 1H, J = 5.0 and 11.5 Hz), 2.53 (dd, 1H, J = 5.5 and 11.0 Hz), 2.26 (dd, 1H, J = 7.5 and 12.0 Hz), 2.04–2.13 (m, 2H), 1.80 (ddd, 1H, J = 3.5, 10.0 and 13.5 Hz), 1.68 (m, 1H), 1.55 (m, 1H), 0.81 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 163.16, 161.21, 145.70, 141.25, 134.43, 133.63, 130.80, 130.73, 121.56, 115.363, 115.27, 115.18, 115.10, 85.76, 62.12, 54.75, 49.73, 47.25, 32.77, 31.94, 8.48; HRMS (TOF MS ES+) calcd for C20H23FNO2 (M+H)+: 328.2713; found: 328.1706. Anal. Calcd for C20H22FNO2: C, 73.37; H, 6.77; N, 4.28. Found: C, 73.34; H, 6.78; N, 4.30.

4.2.3. 4a-Ethyl-2-(4-fluorophenethyl)-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ol (1f)

Using the general method of 4.1.9, amine 11 (288 mg, 1.23 mmol), 1-(2-bromoethyl)-4-fluorobenzene (208 μL, 1.48 mmol) and subsequent treatment with BBr3 (467 μL, 4.92 mmol) gave 100 mg of 1f (24 % over two steps) as a light yellow crystalline compound, mp 156–158 °C. IR (neat) 3019, 1214 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.10 (t, 2H, J = 8.0 Hz), 7.10 (d, 2H, J = 8.5 Hz), 6.80 (t, 1H, J = 7.5 Hz), 6.77 (d, 1H, J = 7.5 Hz), 6.65 (d, 1H, J = 7.0 Hz), 5.15 (bs, 1H), 4.55 (t, 1H, J = 6.0 Hz), 2.92 (dd, 1H, J = 5.0 and 12.0 Hz), 2.75 (t, 2H, J = 8.0 Hz), 2.54 (m, 3H), 2.46 (dd, 1H, J = 7.0 and 12.0 Hz), 2.25 (dd, 1H, J = 3.0 and 12.0 Hz), 2.08 (ddd, 1H, J = 3.5, 5.5 and 14.0 Hz), 1.81 (ddd, 1H, J = 3.5, 9.0 and 13.5 Hz), 1.73 (m, 1H), 1.61 (m, 1H), 0.82 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 162.51, 160.57, 145.63, 141.23, 135.89, 134.65, 130.18, 130.11, 121. 65 , 115.38, 115.32, 115.22, 115.16, 85.72, 60.57, 54.61, 49.88, 47.11, 32.78, 32.50, 32.08, 8.60; HRMS (TOF MS ES+) calcd for C21H25NFO2 (M+H)+: 342.1869; found: 342.1857. Anal. Calcd for C21H24NFO2: C, 73.88; H, 7.09; N, 4.10. Found: C, 73.99; H, 7.08; N, 4.29.

4.2.4. 4-(2,3-Dimethoxyphenyl)-4-ethyl-1-methyl-1,2,3,4-tetrahydropyridine (14a)

A solution of 13 (33.0 g, 141 mmol) in dry THF (350 mL) was stirred under argon at −40 °C. A solution of n-butyllithium, 2.5 M in hexane (113 mL, 283 mmol), was added to the reaction, producing a deep red color. The mixture was stirred at −40 °C for 3 h. Bromoethane (21.1 mL, 283 mmol) was added, producing a yellow solution, which was then stirred and brought to 20 °C over 1 h. The reaction mixture was then treated with saturated aqueous NH4Cl solution (40 mL). The reaction mixture was partitioned between Et2O (2 × 300 mL) and H2O (300 mL). The organic layer was dried over anhydrous Na2SO4 and removal of the solvent in vacuo gave an orange oil. Column chromatography of the crude material using 10% hexanes in Et2O gave 31.0 g (84%) of 14a as a pure yellow oil. IR (neat) 2932, 1637 cm−1; 1H NMR (CDCl3, 300 MHz) δ 7.09 (m, 2H), 6.90 (d, 1H, J = 7.8 Hz), 6.02 (d, 1H, J = 7.8 Hz), 4.82 (d, 1H, J = 7.8 Hz), 4.00 (s, 6H), 2.89 (d, 1H, J = 10.5 Hz), 2.65 (s, 3H), 2.59 (m, 2H), 2.24 (m, 1H), 2.02 (t, 1H, J = 12.0 Hz), 1.84 (m, 1H), 0.79 (t, 3H, J = 7.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 153.12, 147.53, 141.32, 135.89, 124.09, 122.36, 110.54, 105.07, 60.07, 55.73, 47.20, 42.47, 41.37, 34.49, 33.56, 9.13; HRMS (TOF MS ES+) calcd for C16H24NO2 (M+H)+: 262.1807; found: 262.1820. Anal. Calcd for C16H24NO2: C, 73.53; H, 8.87; N, 5.08. Found: C, 73.42; H, 8.89; N, 5.36.

4.2.5. 3-Bromo-4-(2,3-dimethoxyphenyl)-4-ethyl-1-methylpiperidine (15a)

To a solution of compound 14a (10.0 g, 38.0 mmol) in dry THF (75 mL) at −78 °C was added N-bromosuccinimide (6.8 g, 38.0 mmol) in dry THF (40 mL). The mixture was stirred at 20 °C for 1 h and then evaporated to an orange oil. The crude product was taken in MeOH (75 mL) and 37% HCl (2 mL) was added to the suspension. To this suspension was added solid NaBH3CN (2.4 g, 38.0 mmol), and the reaction mixture was stirred at room temperature for 45 min. The reaction mixture was then diluted with aqueous saturated NaHCO3 and the organic layer was washed with H2O (50 mL) and extracted into CH2Cl2 (150 mL). Removal of the solvent in vacuo gave a brown oil. Purification of the crude product by column chromatography using 30% hexanes in Et2O gave a pale yellow solid (9.0 g, 69% over two steps). A small batch of the yellow solid was dissolved in MeOH and treated with 37% HCl to give white crystals of 15a.HCl that were used for X-ray crystallography (Figure 2). Mp 220–223 °C; IR (neat) 2937 cm−1; 1H NMR (CDCl3, 500 MHz) δ 6.99 (t, 1H, J = 8.0 Hz), 6.88 (d, 1H, J = 8.0 Hz), 6.69 (d, 1H, J = 7.5 Hz), 5.29 (s, 1H), 3.97 (s, 3H), 3.86 (s, 3H), 3.15 (d, 1H, J = 13.0 Hz), 3.00 (m, 2H), 2.50 (t, 1H, J = 14.0 Hz), 2.47 (s, 3H), 2.43 (m, 1H), 2.05 (m, 2H), 1.92 (d, 1H, J = 12.5 Hz), 0.51 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 152.67, 147.92, 138.72, 122.79, 120.01, 111.48, 60.33, 58.46, 55.78 (2C), 51.14, 46.13, 45.13, 26.77, 24.86, 9.65; HRMS (TOF MS ES+) calcd for C16H25NBr79O2 (M+H)+: 342.1069; found: 342.1055. Anal. Calcd for C16H24NBrO2.HCl: C, 50.74; H, 6.65; N, 3.70. Found: C, 50.74; H, 6.71; N, 3.74.

4.2.6. 2-(3-Bromo-4-ethyl-1-methylpiperidin-4-yl)benzene-1,2-diol (16a)

To compound 15a (7.5 g, 21.9 mmol) in a clean round-bottom flask was added 48% HBr (30 mL) and the emulsion was refluxed at 105 °C for 10 h. After completion of the reaction, the excess HBr was removed by distillation to leave 16a.HBr as a pale yellow solid (7.0 g, 80%). A small batch was recrystallized from MeOH to give off-white crystals of 16a.HBr, mp 248–251 °C. IR (neat) 3458 cm−1; 1H NMR (CD3OD, 500 MHz) δ 6.76 (d, 1H, J = 7.0 Hz), 6.65 (t, 1H, J = 8.0 Hz), 6.51 (d, 1H, J = 7.0 Hz), 5.95 (s, 1H), 4.04 (d, 1H, J = 14.0 Hz), 3.81 (d, 1H, J = 14.0 Hz), 3.54 (d, 1H, J = 12.0 Hz), 3.41 (t, 1H, J = 16.5 Hz), 3.00 (s, 3H), 2.50 (dt, 1H, J = 3.5 and 14.5 Hz), 2.45 (dd, 1H, J = 7.0 and 13.5 Hz), 2.28 (d, 1H, J = 14.5 Hz), 2.08 (m, 1H) 0.63 (t, 3H, J = 7.0 Hz); 13C NMR (CD3OD, 125 MHz) δ 146.06, 145.10, 130.77, 119.55, 119.47, 114.89, 57.95, 55.19, 51.80, 45.22, 44.14, 25.86, 23.85, 10.04; HRMS (TOF MS ES+) calcd for C14H21NBrO2 (M+H)+: 314.0756; found: 314.0744. Anal. Calcd for C14H20NBrO2•HBr: C, 42.56; H, 5.36; N, 3.54. Found: C, 42.59; H, 5.42; N, 3.55.

4.2.7 4a-Ethyl-2-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ol (1a)

Compound 16a (2.0 g, 6.37 mmol) (free base was obtained after neutralization of the HBr salt of 16a partitioned between NaHCO3 and CHCl3) was treated with excess Et3N (30 mL). The reaction mixture was placed in a sealed tube and heated at 100 °C for 4 h. Cooling of the reaction mixture, followed by evaporation of the excess Et3N gave a brown solid. This solid was subject to silica-gel column chromatography and the desired product 1a was eluted using 15% MeOH in CH2Cl2 to give an off-white solid (1.3 g, 88%), mp 158–160 °C. IR (neat) 2983, 1732 cm−1; 1H NMR (CDCl3, 500 MHz) δ 6.82 (t, 1H, J = 7.5 Hz), 6.76 (d, 1H, J = 8.0 Hz), 6.62 (d, 1H, J = 7.0 Hz), 4.65 (t, 1H, J = 6.0 Hz), 2.97 (dd, 1H, J = 5.5 and 11.5 Hz), 2.57 (dd, 1H, J = 6.0 and 11.5 Hz), 2.26 (m, 1H), 2.21 (s, 3H), 2.11 (m, 2H), 1.89 (ddd, 1H, J = 3.5, 11.0 and 15.0 Hz), 1.70 (m, 1H), 1.56 (m, 1H), 0.83 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 145.66, 141.99, 134.27, 121.67, 115.90, 114.61, 85.08, 56.65, 52.04, 46.52, 46.15, 32.70, 31.80, 8.54; HRMS (TOF MS ES+) calcd for C14H20NO2 (M+H)+: 234.1470; found: 234.1480. Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C, 71.85; H, 8.10; N, 6.00.

4.2.8. 4-(2,3-Dimethoxyphenyl)-1-methyl-4-phenethyl-1,2,3,4-tetrahydropyridine (14b)

A solution of 13 (10.0 g, 42.9 mmol) in dry THF (100 mL) was stirred under argon at −40 °C. A solution of n-butyllithium, 2.5 M in hexane (34.5mL, 85.8 mmol), was added to the reaction, producing a deep red color. The mixture was stirred at −40 °C for 2 h. Phenethyl bromide (11.7 mL, 85.8 mmol) was added, producing a yellow solution, which was then stirred and brought to 20 °C over 1 h. The reaction mixture was then treated with saturated NH4Cl solution (15 mL). The reaction mixture was partitioned twice between Et2O (100 mL) and H2O (100 mL). The organic layer was dried over anhydrous Na2SO4 and removal of the solvent gave an orange oil. Column chromatography of the crude material using 20% hexanes in Et2O gave 8.0 g (55%) of compound 14b as pure yellow oil. IR (neat) 2929, 1496 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.20 (t, 2H, J = 7.5 Hz), 7.12 (d, 3H, J = 7.5 Hz), 7.05 (d, 1H, J = 7.5 Hz), 6.97 (t, 1H, J = 7.5 Hz), 6.83 (d, 1H, J = 8.0 Hz), 5.95 (d, 1H, J = 8.0 Hz), 4.79 (d, 1H, J = 7.5 Hz), 3.87 (s, 3H), 3.86 (s, 3H), 2.78 (dd, 1H, J = 4.0 and 8.0 Hz), 2.56 (s, 3H), 2.43–2.51 (m, 4 H), 2.39–2.43 (m, 2 H), 2.26 (dt, 1H, J = 5.5 and 12.5 Hz), 1.98 (dt, 1H, J = 3.0 and 12.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 153.22, 147.69, 143.46, 141.16, 128.46 (2C), 128.28 (2C); HRMS (TOF MS ES+) calcd for C22H28NO2 (M+H)+: 338.2120; found: 338.2113.

4.2.9. 3-Bromo-4-(2,3-dimethoxyphenyl)-1-methyl-4-phenethylpiperidine (15b)

To a solution of compound 14b (9.5 g, 28.1 mmol) in dry THF (75 mL) at −78 °C was added N-bromosuccinimide (5.0 g, 28.1 mmol) in dry THF (30 mL). The mixture was stirred at 20 °C for 1 h and the solvent was removed to give a brown oil. The crude product was placed in MeOH (75 mL) and 37% HCl (2 mL) was added to the suspension. To this suspension was added solid NaBH3CN (1.76 g, 28.1 mmol), and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then diluted with aqueous saturated NaHCO3 and the organic layer was washed with H2O (50 mL) and extracted into CH2Cl2 (150 mL). Removal of the solvent gave a brown oil. Purification of the crude product by column chromatography using 30% hexanes in Et2O gave 15b (9.0 g, 76% over two steps) as a white crystalline solid, mp 132–135 °C. IR (neat) 2940 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.24 (t, 2H, J = 7.5 Hz), 7.15 (t, 1H, J = 7.5 Hz), 7.04 (d, 3H, J = 7.0 Hz), 6.92 (d, 1H, J = 8.0 Hz), 6.78 (d, 1H, J = 7.5 Hz), 5.29 (s, 1H), 4.00 (s, 3H), 3.89 (s, 3H), 3.09 (d, 1H, J = 13.5 Hz), 2.99 (d, 1H, J = 11.0 Hz), 2.88 (d, 1H, J = 13.0 Hz), 2.60 (dt, 1H, J = 2.5 and 12.5 Hz), 2.47 (t, 1H, J = 11.5 Hz), 2.38 (s, 3H), 2.27 (m, 3H), 2.03 (dt, 1H, J = 13.0 Hz), 1.90 (dt, 1H, J = 3.0 and 11.0 Hz); 13C NMR (CDCl3, 125 MHz) δ 152.69, 148.08, 142.37, 138.82, 128.38 (2C), 128.32 (2C), 125.81, 122.79, 119.77, 111.77, 60.27, 8.95, 58.44, 55.81, 51.13, 46.11, 44.87, 34.56, 31.92, 27.69; HRMS (TOF MS ES+) calcd for C22H29NBr79 O2 (M+H)+: 418.1382; found: 418.1382. Anal. Calcd for C22H28NBrO2: C, 63.16; H, 6.75; N, 3.35. Found: C, 63.22; H, 6.78; N, 3.40.

4.3. 2-(3-Bromo-1-methyl-4-phenethylpiperidin-4-yl)benzene-1,2-diol (16b)

To compound 15b (2.2 g, 5.26 mmol) in a round-bottom flask was added 48% HBr (25 mL) and the emulsion was refluxed at 105 °C for 10 h. After completion of the reaction, the excess HBr was removed by distillation to leave compound 16b.HBr as a light brown solid. Neutralization of the HBr salt by partitioning between NaHCO3 and CHCl3 gave 1.6 g (78%) of the free base. A small batch of 16b.HBr was recrystallized from MeOH to give white crystals of 16b•HBr, mp 190–193 °C. IR (neat) 3479 cm−1; 1H NMR (CD3OD, 500 MHz) δ 7.20 (t, 2H, J = 7.5 Hz), 7.12 (d, 1H, J = 7.0 Hz), 7.07 (d, 2H, J = 7.5 Hz), 6.82 (d, 1H, J = 7.5 Hz), 6.70 (t, 1H, J = 8.0 Hz), 6.58 (d, 1H, J = 8.0 Hz), 5.92 (s, 1H), 4.02 (d, 1H, J = 14.5 Hz), 3.76 (d, 1H, J = 14.0 Hz), 3.56 (d, 1H, J = 12.0 Hz), 3.44 (t, 1H, J = 13.0 Hz), 2.98 (s, 3H), 2.75 (dt, 1H, J = 3.5 and 12.5 Hz), 2.56 (dt, 1H, J = 2.0 and 13.0 Hz), 2.41 (dt, 1H, J = 7.5 and 13.0 Hz), 2.31 (m, 2H), 2.03 (dt, 1H, J = 3.5 and 12.0 Hz),; 13C NMR (CD3OD, 125 MHz) δ 146.17, 145.17, 143.22, 130.94, 129.47 (2C), 129.30 (2C), 126.81, 119.75, 119.39, 115.13, 57.87, 55.06, 51.84, 45.06, 44.16, 33.54, 33.21, 26.50; HRMS (TOF MS ES+) calcd for C20H25NBr79O2 (M+H)+: 390.1069; found: 390.1070. Anal. Calcd for C20H24NBrO2•HBr•H2O: C, 49.10; H, 5.56; N, 2.86. Found: C, 48.90; H, 5.62; N, 2.77.

4.3.1. 2-Methyl-4a-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ol (12)

Compound 16b (820 mg, 2.1 mmol) was treated with MeOH (1 mL) and excess Et3N (15 mL). The reaction mixture was placed in a sealed tube and heated at 100°C for 3 h. Cooling of the reaction mixture followed by evaporation of the excess Et3N gave a brown solid. This solid was subjected to silica-gel column chromatography and the desired product was eluted using 15% MeOH in CH2Cl2 to give an off-white solid 12 (400 mg, 62%), mp 187–189 °C. IR (neat) 3020 cm−1. The X-ray crystallographic analysis confirmed the molecular structure (Figure 2). 1H NMR (CDCl3, 500 MHz) δ 7.23 (t, 2H, J = 7.0 Hz), 7.15 (t, 1H, J = 7.0 Hz), 7.08 (d, 2H, J = 7.5 Hz), 6.86 (t, 1H, J = 7.5 Hz), 6.80 (d, 1H, J = 8.0 Hz), 6.71 (d, 1H, J = 7.0 Hz), 4.68 (t, 1H, J = 5.5 Hz), 2.90 (dd, 1H, J = 4.0 and 11.5 Hz), 2.55 (m, 3H), 2.42 (dd, 1H, J = 7.0 and 11.5 Hz), 2.28 (s, 3H), 2.23 (t, 1H, J = 11.0 Hz), 2.14 (m, 1H), 1.97 (m, 2H), 1.85 (dt, 1H, J = 5.0 and 13.0 Hz); 13C NMR (CDCl3, 125 MHz) δ 145.62, 142.17, 141.79, 134.34, 128.54 (2C), 128.37 (2C), 125.99, 122.00, 115.92, 114.68, 85.25, 56.37, 51.87, 46.36, 46.20, 41.56, 32.85, 30.68; HRMS (TOF MS ES+) calcd for C20H24NO2 (M+H)+: 310.1807; found: 310.1817. Anal. Calcd for C20H23NO2•0.25 H2O: C, 76.52; H, 7.54; N, 4.46. Found: C, 76.70; H, 7.33; N, 4.52.

4.3.2. X-ray crystal structures (Figure 2) of 2-methyl-4a-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ol (12) and 3-bromo-4-(2,3-dimethoxyphenyl)-4-ethyl-1-methylpiperidine hydrochloride (15a.HCl)

Single-crystal X-ray diffraction data on compounds 12 and 15a.HCl were collected using MoKα radiation and a Bruker APEX 2 CCD area detector. The structures was solved by direct methods and refined by full-matrix least squares on F2 values using the programs found in the SHELXTL suite (Bruker, SHELXTL v6.10, 2000, Bruker AXS Inc., Madison, WI). Parameters refined included atomic coordinates and anisotropic thermal parameters for all non-hydrogen atoms. Hydrogen atoms on carbons were included using a riding model [coordinate shifts of C applied to H atoms] with C–H distance set at 0.96 Å. Atomic coordinates for these compounds have been deposited with the Cambridge Crystallographic Data Centre (deposition numbers 729148 and 729149 for compounds 12 and 15a.HCl respectively). Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44(0)-1223-336033 or ku.ca.mac.cdcc@tisoped

Supplementary Material

01

Acknowledgements

We would like to thank Dr. Klaus Gawrisch and Dr. Walter Teague of the Laboratory of Membrane Biochemistry and Biophysics (LMBB) in NIAAA for NMR spectral data. The authors also express their thanks to Noel Whittaker and Wesley White of the Laboratory of Analytical Chemistry for mass spectral data and 1H NMR spectral data, and we thank NIDA for support of the X-ray crystallographic studies (NIDA contract Y1-DA6002). The work of the Drug Design and Synthesis Section, CBRB, NIDA, & NIAAA, was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA) and the National Institute of Alcohol Abuse and Alcoholism. The quantum chemical study utilized PC/LINUX clusters at the Center for Molecular Modeling of the NIH (http://cit.nih.gov), and this research was supported by the NIH Intramural Research Program through the Center for Information Technology.

Footnotes

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Supplementary data. Atomic coordinates and crystallographic data for compounds 15a.HCl and 12 can be found in the online version.

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