HETEROCYCLES

Paper | Special issue | Vol. 79, No. 1, 2009, pp. 1061-1072
Received, 24th January, 2009, Accepted, 19th February, 2009, Published online, 19th February, 2009.
DOI: 10.3987/COM-09-S(D)84

■ Probes for Narcotic Receptor Mediated Phenomena. 38. An Expeditious Synthesis of rac-cis-4a-Ethyl-2-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol and rac-cis-2-Methyl-4a-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol

Malliga R. Iyer, Jeffrey R. Deschamps, Arthur E. Jacobson, and Kenner C. Rice*

Laboratory of Medicinal Chemistry,
National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bldg 8, Rm B122, Bethesda, Maryland 20892-0815, U.S.A.

Abstract

A high-yielding five-step synthesis of cis-benzofuropyridin-6-ols provided an improved route to compounds with low to subnanomolar affinity at opioid receptors and high antinociceptive potency. This synthesis provided the known rac-cis-4a-ethyl-2-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (1a) in high yield, and the novel rac-cis-2-methyl-4a-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (1b). It was achieved using NBS to prepare the key intermediate 7. Di-demethylation followed by subsequent displacement of the bromine by the phenolic ion in hot Et3N gave the desired 1a. The structure of 1a was confirmed by X-ray crystallography.

INTRODUCTION
As part of our continuing study of the relationship between the three-dimensional structure of ligands that interact with opioid receptors and their pharmacological effects, we have pursued the synthesis of a number of hexahydrobenzofuropyridinols2 (e.g., 1a and 1b) that are structurally related to members of the class of oxide-bridged 5-phenylmorphans 2a through 2f.1,3 The oxide-bridged 5-phenylmorphans compounds are structurally rigid and were based on the 5-phenylmorphan opioids originated by May et al.,4 some of which have been found to interact with high affinity at μ or δ opioid receptors as agonists or antagonists.5

Hexahydrobenzofuropyridinols can be considered as congeners of the 5-phenylmorphans and are in fact partial structures of oxide-bridged phenylmorphans 2a-f. N-substituted rac-cis-benzofuro[2,3-c]pyridin-6-ols (e.g., 4a-ethyl-2-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol, 1a) have been shown by Hutchison et al.,2 to have high affinity for opioid-receptors and possess significant antinociceptive activity. Because of our interest in structurally rigid compounds that interact with opioid receptors, we have developed a concise and efficient synthesis for 4a-ethyl (1a) and 4a-phenethyl (1b) analogues of rac-cis-N-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol. This short simple synthesis enables the preparation of a variety of analogues of N-substituted 4a-alkyl or aralkyl analogues of hexahydrobenzofuro[2,3-c]pyridin-6-ols.


RESULTS AND DISCUSSION
The synthetic approach to 1, shown in Scheme 1 contains two important steps: introduction of the desired R-group to give the intermediate 5 and subsequent formation of the oxide bridge to form the final product. A useful feature of this route is the well precedented synthesis of enamine moiety 5 based on the method of Evans6 and utilized in our oxide-bridged phenylmorphan syntheses.3c-f, 3j With the necessary enamine in hand, additional functionalization needed to close the oxide-bridge can be achieved with relative ease.

A large amount of the known tetrahydropyridine3d 4 was prepared (caution - a related tetrahydropyridine was noted to have neurotoxic effects),7a-b and metalation of 4 was achieved using n-butyllithium at -40 °C. Quenching of the anion with bromoethane gave the enamine 5a in excellent yields. In a departure from previous reports,3d,3j NBS instead of NBA was used to introduce bromine at C-3. Bromination followed by an immediate reduction of the intermediate with NaCNBH3 gave 7a as a pure solid. The structural assignment of the reduction product rests on a single crystal X-ray determination of the HBr salt of 7a that showed that the ethyl and the bromo group bear a trans relationship (Figure 2).

Prior to oxide bridge formation, it was important to remove both of the methyl protecting groups on the aromatic oxygen atoms. Initial attempts at deprotection using BBr3 in refluxing chloroform was marred by the loss of only one of the methyl groups, and solubility issues. Switching to 48% HBr under reflux conditions gave the desired deprotected diol 8a as an HBr salt. X-Ray crystallography on 8a indicated that the ethyl and bromo group still maintained a trans relationship (Figure 3).

Compound 8a was now ready for the final step, oxide bridge formation to give 1a. This was first attempted by treating the HBr salt of 8a with cold methanolic NaOH. Although this transformation gave 1a as the major product, additional products, possibly the trans compound (ca 5%) and other unidentified materials along with decomposition products resulted in a low (~ 40%) yield. That the reaction failed to deliver better and more consistent yields was disconcerting. After unsuccessfully trying reagents such as t-BuOK, NaOEt and NaH to bring about the oxide ring closure, attention was turned to Et3N to facilitate ring closure. It was indeed gratifying to observe the formation of the desired ring closure product upon treatment of 8a•HBr in refluxing Et3N (59% yield). Though some unreacted starting material and Et3N•HBr were found, the reaction behaved consistently in refluxing Et3N. It was interesting to note that 8a proceeded to give 1a with retention of the relative stereochemistry. That the transformation gave the cis-isomer of product 1a was confirmed by single crystal X-ray determination (Figure 4) and NOESY analysis. This seems to rule out a simple SN2 type mechanism for the ring formation.

The yield of 1a was further improved by using compound 8a as a base, not as the HBr salt. Heating 8a and dry Et3N in a sealed tube at 100 °C gave 1a in 85% yield after purification by column chromatography. Using methanol as a co-solvent resulted in oxide-bridge formation with a lower (56%) yield.

A brief effort to demonstrate the utility of this route was undertaken by focusing on the synthesis of rac-cis-2-methyl-4a-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (1b, Scheme 1). Addition of 2-bromoethylbenzene to the metalated 4 gave compound 5b in reasonable yield. The two-step addition/reduction protocol using NBS/NaCNBH3 gave 7b in modest yield over two steps. The relative stereochemistry of this bromo compound was assigned by correlation of spectral data with 7a and NOESY studies. Di-demethylation in refluxing HBr followed by heating the free base of 8b with Et3N in a sealed tube uneventfully gave compound 1b as a single compound with cis-stereochemistry as determined by 2-dimensional NMR spectral data. A small amount of methanol (1 mL) was used with the Et3N (15 mL) to solubilize 8b. That amount of methanol did not appear to effect the yield of 1b.

CONCLUSION
The simple concise synthesis of 1a and 1b represents a facile approach to the preparation of a variety of partial structures of oxide-bridged phenylmorphans. The new compounds will be pharmacologically evaluated and the data used to examine the spatial relationship of hexahydrobenzofuro[2,3-c]pyridin-6-ols to the oxide-bridged phenylmorphans and to other classes of structurally related opioids. The findings from the pharmacological and the quantum chemical topological studies will be reported in due course.

EXPERIMENTAL
General
Mass spectra (CIMS) were obtained using a Finnigan 4600 mass spectrometer unless otherwise noted. 1H NMR (500 MHz) were 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 using 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-(2,5-Dimethoxyphenyl)-4-ethyl-1-methyl-1,2,3,4-tetrahydropyridine (5a)
A solution of 4 (20.0 g, 85.8 mmol)7 (Caution – a structurally related compound was reported to have neurotoxic activity)7 in dry THF (200 mL) was stirred under argon at -40 °C. A solution of n-butyllithium, 2.5 M in hexane (69.0 mL, 172 mmol), was added, producing a deep red color. The mixture was stirred at -40 °C for 2 h. Bromoethane (12.8 mL, 172 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 a saturated aqueous NH4Cl solution (20 mL). The reaction mixture was partitioned between Et2O (2 X 200 mL) and H2O (200 mL). The organic layer was dried over anhydrous Na2SO4 and the organic solvent was removed in vacuo to give an orange oil. Column chromatography of the crude material using 10% hexanes in ether gave 18.0 g (80%) of 5a as a pure yellow oil. IR (CHCl3) 2935 cm-1; 1H NMR (CDCl3, 500 MHz) δ 7.01 (d, 1H, J = 3.0 Hz), 6.77 (d, 1H, J = 8.5 Hz), 6.67 (dd, 1H, J = 3.0 and 8.5 Hz), 5.92 (d, 1H, J = 8.0 Hz), 4.65 (d, 1H, J = 8.0 Hz), 3.77 (s, 3H), 3.75 (s, 3H), 2.73 (m, 1H), 2.54 (s, 3H), 2.47 (m, 2H), 2.19 (m, 1H), 1.86 (dt, 1H, J = 2.0 and 12.0 Hz), 1.65 (m, 1H), 0.63 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 152.79, 151.89, 137.72, 136.22, 119.88, 111.87, 109.88, 104.41, 55.50 (2C), 47.11, 42.41, 41.27, 33.36, 32.31, 9.02; HRMS (TOF MS ES+) calcd for C16H24NO2 (M + H)+ 262.1807, found: 262.1813. Anal. Calcd for C16H23NO2: C, 73.53; H, 8.87; N, 5.36. Found: C, 73.42; H, 8.89; N, 5.08.
3-Bromo-4-(2,5-dimethoxyphenyl)-4-ethyl-1-methylpiperidine (7a)
To a solution of 5a (7.0 g, 27.0 mmol) in dry THF (50 mL) at -78 °C was added N-bromosuccinimide (4.7 g, 27.0 mmol) in dry THF (20 mL). The mixture was stirred at 20 °C for 1 h and the solvent removed to give an orange oil. The crude product was dissolved in MeOH (50 mL) and 37% HCl (1 mL) was added to the suspension. To this suspension was added solid NaBH3CN (1.7 g, 27.0 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 (30 mL) and extracted into CH2Cl2 (100 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 yellow solid (6.0 g, 65% over two steps). A small batch of the yellow solid was dissolved in MeOH and treated with 48% HBr to give white crystals of 7a•HBr, mp 220-223 °C. IR (CHCl3) 2938 cm-1; 1H NMR (CDCl3, 500 MHz) δ 6.78 (d, 1H, J = 8.5 Hz), 6.71 (dd, 1H, J = 2.5 and 8.5 Hz), 6.69 (d, 1H, J = 2.0 Hz), 5.44 (s, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 3.03 (d, 1H, J = 13.5 Hz), 2.89 (d, 1H, J = 11.0 Hz), 2.81 (d, 1H, J = 12.8 Hz), 2.41 (dt, 1H, J = 2.5 and 12.5 Hz), 2.33 (s, 3H), 2.28 (t, 1H, J = 11.5 Hz), 2.06 (m, 1H), 1.93 (m, 1H), 1.86 (d, 1H, J = 12.5 Hz), 0.50 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 153.03, 152.51, 135.66, 115.83, 111.79, 110.04, 58.52 (2C), 55.89, 55.48, 51.11, 46.16, 44.79, 26.77, 23.87, 9.55; HRMS (TOF MS ES+) calcd for C16H25 Br79NO2 (M + H)+ 342.1069, found: 342.1055. Anal. Calcd for C16H24BrNO2•HBr: C, 45.41; H, 5.95; N, 3.31. Found: C, 44.95; H, 5.99; N, 3.26.
2-(3-Bromo-4-ethyl-1-methylpiperidin-4-yl)benzene-1,4-diol (8a)
To compound 7a (5.7 g, 16.7 mmol) was added 48% HBr (20 mL) and the emulsion was refluxed for 10 h. After completion of the reaction, the excess HBr was removed by distillation to leave 8a•HBr as a white solid (4.6 g, 70%). A small batch was recrystallized from MeOH to give white crystals of 8a•HBr, mp 248-251 °C. IR (CHCl3) 3020 cm-1; 1H NMR (CD3OD, 500 MHz) δ 6.62 (d, 1H, J = 8.5 Hz), 6.57 (dd, 1H, J = 2.5 and 8.5 Hz), 6.46 (d, 1H, J = 2.0 Hz), 5.94 (s, 1H), 4.02 (d, 1H, J = 14.0 Hz), 3.79 (d, 1H, J = 14.0 Hz), 3.55 (d, 1H, J = 12.5 Hz), 3.40 (t, 1H, J = 12.5 Hz), 2.99 (s, 3H), 2.46 (m, 2H), 2.24 (d, 1H, J = 14.0 Hz), 2.03 (m, 1H) 0.60 (t, 3H, J = 7.5 Hz); 13C NMR (CD3OD, 125 MHz) δ 150.72, 149.79, 131.54, 117.55, 115.85, 115.18, 57.95, 55.13, 51.79, 44.13, 44.10, 25.76, 23.78, 10.03; HRMS (TOF MS ES+) calcd for C14H21BrNO2 (M + H)+ 314.0756, found: 314.0755. Anal. Calcd for C14H20BrNO2•HBr: C, 42.56; H, 5.36; N, 3.54. Found: C, 42.26; H, 5.41; N, 3.48.
4a-Ethyl-2-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (1a)
Compound 8a (0.80 g, 2.54 mmol) (free base was obtained after neutralization of the HBr salt of 8a by partitioning between NaHCO3 and CHCl3) was treated with 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 chromatographed on a silica-gel column and the desired product 1a was eluted using 15% MeOH in CH2Cl2 to give an off-white solid (504 mg, 85%), mp 178-180 °C. IR (CHCl3) 3020 cm-1; 1H NMR (CDCl3, 500 MHz) δ 6.65 (d, 1H, J = 8.0 Hz), 6.59 (d, 2H, J = 9.5 Hz), 4.48 (t, 1H, J = 5.5 Hz), 2.85 (dd, 1H, J = 4.0 and 11.5 Hz), 2.54 (dd, 1H, J = 5.0 and 10.0 Hz), 2.37 (dd, 1H, J = 7.0 and 12.0 Hz), 2.30 (s, 3H), 2.18 (t, 1H, J = 10.0 Hz), 2.01 (d, 1H, J = 14.0 Hz), 1.83 (t, 1H, J = 10.5 Hz), 1.68 (m, 1H), 1.55 (m, 1H), 0.81 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 152.53, 150.41, 134.56, 114.63, 111.02, 110.75, 84.14, 56.05, 51.85, 46.15, 46.00, 32.00 (2C), 8.55; HRMS (TOF MS ES+) calcd for C14H20NO2 (M + H)+ 234.1494, found: 234.1498. Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C, 71.85; H, 8.10; N, 6.00.
4-(2,5-Dimethoxyphenyl)-1-methyl-4-phenethyl-1,2,3,4-tetrahydropyridine (5b)
5b was prepared from 4 (10.0 g, 42.9 mmol) (Caution – a structurally related compound was reported to have neurotoxic activity)7, a solution of n-butyllithium, 2.5 M in hexane (34.5 mL, 85.8 mmol) and phenethyl bromide (11.7 mL, 85.8 mmol), as noted with 5a, to give 8.6 g (59%) of 5b as a pure yellow oil. IR (CHCl3) 2937, 1493 cm1; 1H NMR (CDCl3, 500 MHz) δ 7.52 (t, 2H, J = 7.5 Hz), 7.12 (d, 1H, J = 7.0 Hz), 7.09 (m, 3H), 6.80 (d, 1H, J = 8.5 Hz), 6.71 (dd, 1H, J = 3.5 and 9.0 Hz), 5.99 (d, 1H, J = 8.0 Hz), 4.75 (d, 1H, J = 7.5 Hz), 3.80 (s, 3H), 3.78 (s, 3H), 2.75 (dd, 1H, J = 3.0 and 7.0 Hz), 2.57 (s, 3H), 2.44-2.51 (m, 4 H), 2.19 (dt, 1H, J = 4.0 and 12.5 Hz), 1.91 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 152.94, 151.97, 143.83, 137.47, 136.56, 128.47 (2C), 128.26 (2C), 125.40, 120.06, 111.80, 110.55, 104.27, 55.71, 55.52, 47.08, 42.54, 42.28, 41.16, 33.94, 31.47; HRMS (TOF MS ES+) calcd for C22H28NO2 (M + H)+ 338.2120, found: 338.2124.
3-Bromo-4-(2,5-dimethoxyphenyl)-1-methyl-4-phenethylpiperidine (7b)
To a solution of 5b (5.0 g, 14.8 mmol) in dry THF (40 mL) at -78 °C was added N-bromosuccinimide (2.6 g, 14.8 mmol) in dry THF (15 mL). The reaction was carried out as with 7a to give a brown oil. The crude product was dissolved in MeOH (50 mL) and 37% HCl (1 mL) was added. Solid NaBH3CN (0.93 g, 14.8 mmol) was then added and the reaction continued as with 7a. The organic layer was washed with H2O (30 mL) and extracted into CH2Cl2 (100 mL). Evaporation of the solvent gave a brown oil. Purification of the crude product by column chromatography using 30% hexanes in Et2O gave white crystalline solid 7b (3.0 g, 48% over two steps), mp 134-136 °C. IR (CHCl3) 2941 cm-1; 1H NMR (CDCl3, 500 MHz) δ 7.24 (t, 2H, J = 7.5 Hz), 7.17 (t, 1H, J = 7.5 Hz), 7.02 (d, 2H, J = 7.5 Hz), 6.86 (d, 1H, J = 7.5 Hz), 6.78 (m, 2H), 5.46 (s, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.05 (d, 1H, J = 13.5 Hz), 2.99 (d, 1H, J = 11.5 Hz), 2.82 (d, 1H, J = 13.5 Hz), 2.56 (dt, 1H, J = 3.0 and 10.0 Hz), 2.43 (m, 2H), 2.36 (s, 3H), 2.33 (m, 1H), 2.22 (dt, 1H, J = 4.5 and 12.5 Hz), 2.00 (d, 1H, J = 13.0 Hz), 1.93 (dt, 1H, J = 3.5 and 12.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 153.23, 152.53, 142.56, 135.52, 128.34 (2C), 128.24 (2C), 125.74, 115.67, 111.92, 110.42, 58.36, 58.15, 55.90, 55.53, 51.12, 46.10, 44.55, 33.76, 31.97, 27.45; HRMS (TOF MS ES+) calcd for C22H29 Br81NO2 (M + H)+ 420.1316, found: 420.1356. Anal. Calcd for C22H28BrNO2: C, 63.16; H, 6.75; N, 3.35. Found: C, 63.32; H, 6.63; N, 3.31.
2-(3-Bromo-1-methyl-4-phenethylpiperidin-4-yl)benzene-1,4-diol (8b)
To 7b (2.0 g, 4.8 mmol) was added 48% HBr (20 mL) and the emulsion was refluxed for 10 h. After completion of the reaction, the excess HBr was removed by distillation to leave 8b•HBr as a light brown solid. Neutralization of the HBr salt by partitioning between NaHCO3 and CHCl3 gave 1.6 g (86%) of 8b. A small batch of 8b•HBr was recrystallized from MeOH to give white crystals of 8b•HBr, mp 226-228 °C. IR (CHCl3) 3020 cm-1; 1H NMR (CD3OD, 500 MHz) δ 7.21 (t, 2H, J = 7.5 Hz), 7.12 (d, 1H, J = 7.5 Hz), 7.07 (d, 2H, J = 7.0 Hz), 6.69 (d, 1H, J = 8.0 Hz), 6.62 (dd, 1H, J = 2.5 and 8.5 Hz), 6.54 (d, 1H, J = 2.0 Hz), 5.92 (s, 1H), 3.99 (d, 1H, J = 14.5 Hz), 3.76 (d, 1H, J = 14.0 Hz), 3.58 (d, 1H, J = 12.5 Hz), 3.48 (t, 1H, J = 10.5 Hz), 2.98 (s, 3H), 2.70 (dt, 1H, J = 3.0 and 12.0 Hz), 2.55 (dt, 1H, J = 3.00 and 11.0 Hz), 2.41 (dt, 1H, J = 5.5 and 12.5 Hz), 2.30 (m, 2H), 2.05 (dt, 1H, J = 3.5 and 12.5 Hz); 13C NMR (CD3OD, 125 MHz) δ 150.89, 149.82, 143.23, 131.65, 129.44 (2C), 129.32 (2C), 126.85, 117.69, 115.79, 115.46, 57.90, 54.96, 51.85, 44.92, 44.10, 33.47, 33.23, 26.39; HRMS (TOF MS ES+) calcd for C20H25 Br79NO2 (M + H)+ 390.1069, found: 390.1070. Anal. Calcd for C20H24BrNO2•HBr•H2O: C, 49.10; H, 5.56; N, 2.86. Found: C, 48.95; H, 5.92; N, 2.67.
2-Methyl-4a-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (1b)
Compound 8b (800 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 chromatographed using a silica-gel column and the desired product was eluted using 15% MeOH in CH2Cl2 to give an off-white solid 1b (389 mg, 61%), mp 203-205 °C. IR (CHCl3) 3055 cm-1; 1H NMR (CD3OD, 500 MHz) δ 7.23 (t, 2H, J = 7.5 Hz), 7.13 (d, 1H, J = 7.5 Hz), 7.10 (d, 2H, J = 7.0 Hz), 6.66 (s, 1H), 6.63 (d, 1H, J = 8.5 Hz), 6.58 (d, 1H, J = 8.5 Hz), 4.48 (t, 1H, J = 5.5 Hz), 2.80 (dd, 1H, J = 5.0 and 12.5 Hz), 2.58 (dt, 1H, J = 5.0 and 13.0 Hz), 2.44-2.55 (m, 2H), 2.36 (dd, 1H, J = 7.0 and 12.5 Hz), 2.25 (s, 3H), 2.15 (dt, 1H, J = 2.5 and 11.0 Hz), 2.09 (m, 1H), 1.94 (dt, 1H, J = 5.0 and 13.5 Hz), 1.77-1.87 (m, 2H); 13C NMR (CD3OD, 125 MHz) δ 153.24, 152.90, 143.62, 135.48, 129.42 (2C), 129.27 (2C), 126.80, 115.42, 111.54, 111.44, 85.20, 57.15, 52.74, 46.93, 46.23, 42.68, 33.82, 31.69; HRMS (TOF MS ES+) calcd for C20H24NO2 (M + H)+ 310.1807, found: 310.1803. Anal. Calcd for C20H23NO2•0.25H2O: C, 76.52; H, 7.54; N, 4.46. Found: C, 76.30; H, 7.47; N, 4.56.
X-Ray crystal structure of 4a-ethyl-2-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (1a), 3-bromo-4-(2,5-dimethoxyphenyl)-4-ethyl-1-methylpiperidine (7a•HBr), and 2-(3-bromo-4-ethyl-1-methylpiperidin-4-yl)benzene-1,4-diol (8a•HBr)
Single-crystal X-ray diffraction data on compounds 1a, 7a•HBr, and 8a•HBr 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 717736, 717737, and 717738 for compounds 1a, 7a•HBr, and 8a•HBr 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 e-mail: deposit@ccdc.cam.ac.uk
4a-Ethyl-2-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (1a)
A 0.816 x 0.546 x 0.439 mm3 crystal of 1a was prepared for data collection coating with high viscosity microscope oil (Paratone-N, Hampton Research). The oil-coated crystal was placed on a MicroMesh mount (MiTeGen, Ithaca, NY) and transferred immediately to the cold stream on the diffractometer. The crystal was triclinic in space group P-1 with unit cell dimensions a = 6.8808(3) Å, b = 8.7656(3) Å, c = 10.9505(5) Å, α= 100.844(2)°, β= 97.239(2)°, and γ = 106.358(2)°. Corrections were applied for Lorentz, polarization, and absorption effects. Data were 91.8% complete to 25.0° θ (approximately 0.83 Å) with an average redundancy of 1.8.
3-Bromo-4-(2,5-dimethoxyphenyl)-4-ethyl-1-methylpiperidine (7a•HBr)
A 0.671 x 0.368 x 0.093 mm3 crystal of 7a•HBr was prepared for data collection coating with high viscosity microscope oil (Paratone-N, Hampton Research). The oil-coated crystal was placed on a MicroMesh mount (MiTeGen, Ithaca, NY) and transferred immediately to the cold stream on the diffractometer. The crystal was monoclininc in space group P21/n with unit cell dimensions a = 13.1119(4) Å, b = 7.4416(3) Å, c = 17.5915(8) Å, and β= 97.8690(10)°. Corrections were applied for Lorentz, polarization, and absorption effects. Data were 99.4% complete to 28.35° θ (approximately 0.75 Å) with an average redundancy of 4.15.
2-(3-Bromo-4-ethyl-1-methylpiperidin-4-yl)benzene-1,4-diol (8a•HBr)
A 0.332 x 0.102 x 0.076 mm3 crystal of 8a•HBr was prepared for data collection coating with high viscosity microscope oil (Paratone-N, Hampton Research). The oil-coated crystal was placed on a MicroMesh mount (MiTeGen, Ithaca, NY) and transferred immediately to the cold stream on the diffractometer. The crystal was monoclininc in space group P 212121 with unit cell dimensions a = 7.3762(6) Å, b = 11.7948(9) Å, and c = 18.6205(13) Å. Corrections were applied for Lorentz, polarization, and absorption effects. Data were 95.7% complete to 25.0° θ (approximately 0.83 Å) with an average redundancy of 2.77.

ACKNOWLEDGEMENT
We would like to thank Dr. Klaus Gawrisch and Dr. Walter Teague of the Laboratory of Membrane Biochemistry and Biophysics, NIAAA, for NMR spectral data. The authors also express their thanks to Noel Whittaker and Wesley White of the Laboratory of Analytical Chemistry, NIDDK, for mass spectral data and 1H NMR spectral data. 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. X-ray crystallographic work was supported by NIDA under contract Y1-DA6002.

References

1. M. Kurimura, H. Liu, A. Sulima, A. K. Przybyl, E. Ohshima, S. Kodato, J. R. Deschamps, C. Dersch, R. B. Rothman, Y. S. Lee, A. E. Jacobson, and K. C. Rice, J. Med. Chem., 2008, 51, 7866. CrossRef
2. A. J. Hutchison, R. de Jesus, M. Williams, J. P. Simke, R. F. Neale, R. H. Jackson, F. Ambrose, B. J. Barbaz, and M. A. Sills, J. Med. Chem., 1989, 32, 2221. CrossRef
3. (a) J. Zezula, L. B. Singer, A. K. Przybyl, A. Hashimoto, C. M. Dersch, R. B. Rothman, J. Deschamps, Y. S. Lee, A. E. Jacobson, and K. C. Rice, Org. & Biomol. Chem., 2008, 6, 2868; CrossRef (b) J. Zezula, A. E. Jacobson, and K. C. Rice, Heterocycles, 2007, 71, 881; CrossRef (c) A. Hashimoto, A. K. Przybyl, J. T. M. Linders, S. Kodato, X. R. Tian, J. R. Deschamps, C. George, J. L. Flippen-Anderson, A. E. Jacobson, and K. C. Rice, J. Org. Chem., 2004, 69, 5322; CrossRef (d) J. T. M. Linders, S. Mirsadeghi, J. L. Flippen-Anderson, C. George, A. E. Jacobson, and K. C. Rice, Helv. Chim. Acta, 2003, 86, 484; CrossRef (e) D. Tadic, J. T. M. Linders, J. L. Flippen-Anderson, A. E. Jacobson, and K. C. Rice, Tetrahedron, 2003, 59, 4603; CrossRef (f) K. Yamada, J. L. Flippen-Anderson, A. E. Jacobson, and K. C. Rice, Synthesis, 2002, 2359; (g) T. R. Burke, Jr., A. E. Jacobson, K. C. Rice, B. A. Weissman, and J. V. Silverton, 'Problems of Drug Dependence, 1983', Vol. 49, ed. by L. S. Harris, National Institute on Drug Abuse Research Monograph 49, DHHS ((ADM) 84-1316): Washington DC, 1984, p. 109; (h) T. R. Burke, Jr., A. E. Jacobson, K. C. Rice, and J. V. Silverton, J. Org. Chem., 1984, 49, 1051; CrossRef (i) T. R. Burke, Jr., A. E. Jacobson, K. C. Rice, and J. V. Silverton, J. Org. Chem., 1984, 49, 2508; CrossRef (j) T. R. Burke, Jr., A. E. Jacobson, K. C. Rice, B. A. Weissman, H. C. Huang, and J. V. Silverton, J. Med. Chem., 1986, 29, 748. CrossRef
4. E. L. May and J. G. Murphy, J. Org. Chem., 1954, 19, 618. CrossRef
5. A. C. Hiebel, Y. S. Lee, E. J. Bilsky, D. Giuvelis, J. R. Deschamps, D. A. Parrish, M. D. Aceto, E. L. May, E. M. Harris, A. Coop, C. M. Dersch, J. S. Partilla, R. B. Rothman, A. E. Jacobson, and K. C. Rice, J. Med. Chem., 2007, 50, 3765. CrossRef
6. D. A. Evans, C. H. Mitch, R. C. Thomas, D. M. Zimmerman, and R. L. Robbey, J. Am. Chem. Soc., 1980, 102, 5955. CrossRef
7. (a) J. W. Langston, P. Ballard, J. W. Tertrud, and I. Irwin, Science, 1983, 219, 979; CrossRef (b) R. S. Burns, C. C. Chiueh, S. P. Markey, M. H. Ebert, D. M. Jacobowitz, and I. J. Kopin, Proc. Natl. Acad. Sci. U.S.A., 1983, 80, 4546. CrossRef