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DOI: 10.1055/s-0029-1218599
A Two-Step Synthesis of 3,4-Disubstituted Piperidines from Acyclic Precursors through Tetrahydropyridine Intermediates
Publication History
Publication Date:
11 December 2009 (online)
Abstract
Cyclocondensation between acyclic 5-aminopent-2-enoate esters and aliphatic aldehydes containing an unsubstituted α-methylene unit affords 1,2,3,4-tetrahydropyridine derivatives in good yields. The reaction has been applied to a range of aldehydes, showing good functional group tolerance. Chemoselective hydride reduction of the enamine double bond provides 3,4-disubstituted tertiary piperidine derivatives with acceptable to good diastereoselectivities, whereas catalytic hydrogenation of N-benzyl derivatives leads directly to the corresponding secondary piperidines.
Key words
condensation - cyclizations - reductions - piperidines - stereoselective synthesis
The 1,2,3,4-tetrahydropyridine substructure 5 (Scheme [¹] ) is interesting because of its presence in alkaloids such as cathenamine (1) and vallesiachotamine (2) and also as a key functionality in synthetic schemes leading to several natural products (Figure [¹] ). [¹]
Figure 1
We have recently described the synthesis of 2-azabicyclo[3.3.1]nonanes 6 [²] and 3-hydroxypiperidine derivatives 7 [³] using tetrahydropyridine precursors 5 (where R¹, R² = alkyl). These applications took advantage of the ability of the enamine functionality to generate iminium ions or undergo double bond hydrogenation, respectively. Cyclic enamines 5 were readily accessed by condensation of the appropriate amine 3 and aldehyde 4 precursors through presumed acyclic enamine intermediates. [²-4] The preparation of bicyclic piperidines 7 was studied in some detail and found to be compatible with different substitution patterns at R², as well as with the presence at R¹ of functionality, which proved useful for further transformations. [³] [4] Furthermore, in these rigid bicyclic systems good control of the relative stereochemistry over three contiguous stereogenic centers of 7 was easily attained. [³]
Scheme 1
On the other hand, the application of this method to the preparation of monocyclic enamines of type 9 (Scheme [²] ) has been limited to N-benzyl-substituted examples (where additionally R³ = H) derived from simple aliphatic unfunctionalized aldehydes 4, [²] whereas studies devoted to evaluate the generality and stereoselectivity of piperidine synthesis using the strategy depicted in Scheme [²] are lacking. [5] In this paper we disclose the details of a study directed at determining the practicality of the preparation of substituted monocyclic piperidines 10 and 11 (Scheme [²] ) from selected acyclic amines 8 and aldehydes 4 through tetrahydropyridines 9.
Scheme 2
Specific target areas of study have included: 1. the scope in the carbonyl component; 2. the determination of the stereoselectivity of the cyclization and reduction steps in these flexible systems (i.e., in the absence of the geometrical constraints imposed by the rigidity of the bicyclic systems 7 [³] ); and 3. the possibility of extending this strategy to the preparation of secondary piperidines 11 (R² = H) by using appropriate R² substituents in the secondary amine cyclization precursors 8.
Amines 8 were prepared by one of the two routes indicated in Scheme [³] that involved either zinc dienolate addition to an imine [6] or Wittig-type homologation of appropriate aldehydes. Amines 8a,b were selected to exemplify the preparation of both tertiary (using 8b) and secondary piperidines (using 8a [7] with a subsequent debenzylation step), whereas the use of the α-substituted amine 8c [6a] would provide a test of diastereoselectivity in the formation of 9.
Scheme 3
The previously unknown 8b was prepared starting from 3,4-dimethoxyphenethylamine according to Scheme [4] . Thus, initial conjugate addition to ethyl acrylate was followed by amine protection and carbonyl reduction to afford aldehyde 14. Wittig reaction and acidic removal of the Boc-protecting group provided the desired 8b.
Scheme 4 Reagents and conditions: (a) ethyl acrylate, EtOH, r.t.; (b) (Boc)2O, EtOAc, 0 ˚C to r.t.; (c) DIBAL-H, toluene, -78 ˚C; (d) Ph3P=CHCO2Et, CH2Cl2, r.t.; (e) TFA, CH2Cl2, 0 ˚C.
Tetrahydropyridines 9 were then obtained by stirring under reflux equimolar amounts of amine 8 and aldehyde 4 in the appropriate solvent. Results are collected in Table [¹] , which also includes previously reported data (entries 3, 6, and 8) to enable appropriate comparisons. Acetonitrile and ethanol proved to be adequate solvents in this condensation, but benzene failed to give the desired products even with Dean-Stark removal of water. The use of molecular sieves was beneficial in terms of yield when acetonitrile was used as the solvent (cf. entries 1 and 2), but was not required in the case of ethanol (entries 13 and 14), a solvent that provided shorter reactions times. Both linear and branched aldehydes worked well. One exception was phenylacetaldehyde, which reacted rapidly with formation of a presumed acyclic enamine intermediate, [³] [8] but this material failed to cyclize to the desired tetrahydropyridine. Likewise, ketones were found not to participate in this reaction, in this case the starting materials were recovered after prolonged heating when 8a was treated with cyclohexanone, acetophenone, or diethyl ketone. As shown by entries 9-11 and 13-17, useful functionality, both at the amine and aldehyde components, was allowed in the preparation of 9. However, branching at the amine α-position resulted in lower reactivity (entry 18) and, additionally, this cyclization was only moderately diastereoselective.
Reduction of the enamine double bond afforded the corresponding saturated piperidines in good yields with moderate diastereoselectivity, the trans-isomer being formed predominantly (Table [²] ). Hydride-based and catalytic hydrogenation methods were both found to be effective. Conditions based on sodium cyanoborohydride/zinc chloride (Method A, entries 1, 2, 4, and 5) followed those previously described for 10a (entry 1), [²] while initial protonation of the enamine, followed by sodium borohydride reduction, proved also effective in the single case tried (Method B, entry 3). Standard catalytic hydrogenation conditions provided yields and diastereoselectivities in line with those obtained in the hydride reductions (Method C, entries 6 and 7; see also Scheme [5] ). However, in comparison with the similar double bond reductions previously described leading to the more rigid bicyclic piperidines 7, [³] the greater conformational flexibility of tetrahydropyridines 9 resulted in lower diastereoselectivities. Nevertheless, useful isolated overall yields for the major isomers were realized in all cases. The cis/trans relative configurations of piperidines 10 and 11 were assigned by analogy with the known product 10a. [9] In support of these assignments, the expected γ-gauche effects were observed in the ¹³C NMR resonances of the piperidine ring C3 and C4, which were deshielded in the trans-isomers relative to the more congested cis counterparts. [7] [¹0-¹³]
Scheme 5
Synthetic advantage can be also taken from the choice between two alternative reducing methods for the enamine double bond. For example, the hydride method allowed chemoselective enamine reduction in the presence of a second C=C bond (entry 5), whereas hydrogenation conditions applied to benzyl-protected enamines 9 (R² = Bn) resulted in both double bond reduction and debenzylation leading to formation of secondary piperidines 11 (Scheme [5] ). Interestingly, under these conditions reduction of the enamine double bond was observed to take place rapidly, as evidenced by TLC monitoring of the reaction, and was then followed by slower removal of the benzyl group. In any case, two-step preparation of secondary piperidines 11 from amines 8 and aldehydes 4 is readily available.
In conclusion, secondary N-alkyl- and N-benzyl-substituted acyclic amines, containing a suitably positioned electron-deficient double bond, condense effectively with a range of aldehydes to afford substituted tetrahydropyridines, which undergo chemoselective enamine reduction to yield tertiary piperidine derivatives with acceptable to good diastereoselectivities. In the case of N-benzyl-substituted tetrahydropyridines, under catalytic hydrogenation conditions enamine double bond reduction is followed by debenzylation and this gives alternative access to the corresponding secondary piperidines.
All reactions involving air- and moisture-sensitive materials were performed under an atmosphere of dry argon. CH2Cl2, toluene, and MeCN were freshly distilled from CaH2. Et2O was freshly distilled from Na/benzophenone. EtOH and MeOH were dried with Mg/I2. Flash column chromatography was performed on silica gel (230-400 mesh). NMR spectra were obtained at 250 MHz for ¹H and 62.9 MHz for ¹³C with CDCl3 as solvent and internal reference [δ = 7.26 (¹H), δ = 77.0 (¹³C)]. The DEPT sequence was routinely used for ¹³C multiplicity assignment. IR data include only characteristic absorptions. Mass spectra were obtained at 70 eV. The following compounds have been previously reported: 8a, [7] 8c, [6a] 9a, [²] 9c, [²] 9d, [²] [7] 9e, [7] and 10a. [9]
Ethyl 3-{[2-(3,4-Dimethoxyphenyl)ethyl]amino}propanoate (12)
Ethyl acrylate (19.3 mL, 0.178 mol) was added to a soln of 2-(3,4-dimethoxyphenyl)ethylamine (30.7 mL, 0.178 mol) in anhyd EtOH (135 mL) at r.t. The resulting mixture was stirred for 25 h and evaporated under reduced pressure to afford 12 (50.1 g, quantitative) as an orange oil.
IR (neat): 3320 (N-H), 1735 cm-¹ (C=O).
¹H NMR: δ = 1.07 (t, J = 7.1 Hz, 3 H), 1.19 (br s, 1 H), 2.33 (t, J = 6.5 Hz, 2 H), 2.55-2.61 (m, 2 H), 2.68-2.77 (m, 4 H), 3.68 (s, 3 H), 3.71 (s, 3 H), 3.95 (q, J = 7.1 Hz, 2 H), 6.57-6.66 (m, 3 H).
¹³C NMR: δ = 13.7, 34.3, 35.4, 44.5, 50.7, 55.2, 55.3, 59.8, 110.7, 111.4, 120.0, 132.0, 146.8, 148.3, 172.1.
HRMS: m/z [M]+ calcd for C15H23NO4: 281.1627; found: 281.1637.
Ethyl 3-{( tert -Butoxycarbonyl)[2-(3,4-dimethoxyphenyl)ethyl]amino}propanoate (13)
(Boc)2O (0.34 mL, 1.47 mmol) was added to a soln of 12 (412 mg, 1.47 mmol) in EtOAc (1 mL) at 0 ˚C. The resulting mixture was allowed to warm to r.t. and stirred for 20 h. After dilution with EtOAc (9 mL) the soln was washed successively with 1 M HCl (5 mL), sat. NaHCO3 (5 mL), and brine (5 mL) and dried (Na2SO4). After evaporation, the crude product was purified by flash chromatography (hexanes-EtOAc, 80:20) to yield 13 (510 mg, 91%) as a pale yellow oil as a rotamer mixture.
IR (neat): 1740 (C=O), 1700 cm-¹ (NCO).
¹H NMR: δ = 1.24 (t, J = 7.1 Hz, 3 H), 1.44 (s, 9 H), 2.52-2.54 (br, 2 H), 2.74-2.76 (br, 2 H), 3.38-3.40 (br, 4 H), 3.85 (s, 3 H), 3.86 (s, 3 H), 4.12 (q, J = 7.1 Hz, 2 H), 6.67-6.81 (m, 3 H).
¹³C NMR: δ = 14.0, 28.2, 33.3, 33.9, 34.7, 43.5, 43.7, 49.7, 49.9, 55.5, 55.6, 60.3, 79.3, 79.4, 111.0, 111.8, 120.5, 131.5, 147.3, 148.6, 154.9, 171.7, 171.9.
Anal. Calcd for C20H31NO6: C, 62.96; H, 8.20; N, 3.67. Found: C, 62.80; H, 8.26; N, 3.51.
tert -Butyl [2-(3,4-Dimethoxyphenyl)ethyl](3-oxopropyl)carbamate (14)
A 1 M soln of DIBAL-H in hexanes (3.3 mL, 3.3 mmol) was added dropwise to a soln of 13 (1.0 g, 2.6 mmol) in toluene (8 mL) at -78 ˚C under argon. The resulting mixture was stirred for 10 min and anhyd EtOH (0.13 mL) was added dropwise, followed by Na2SO4˙10 H2O (200 mg). The mixture was then allowed to warm to r.t. and it was filtered over Celite. The solid was washed with EtOAc (150 mL) and the combined filtrate and washings were evaporated to dryness. The crude product was purified by flash chromatography (hexanes-EtOAc, 72:28) to yield 14 (0.55 g, 61%) as a colorless oil as a rotamer mixture.
IR (neat): 1725 (CHO), 1695 cm-¹ (NCO).
¹H NMR: δ = 1.40 (br s, 9 H), 2.61-2.71 (br, 4 H), 3.38 (br, 4 H), 3.82 (s, 3 H), 3.83 (s, 3 H), 6.65-6.78 (m, 3 H), 9.73 (s, 1 H).
¹³C NMR: δ = 28.2, 34.0, 34.7, 41.4, 43.2, 43.6, 49.7, 50.0, 55.7, 55.7, 79.6, 79.9, 111.1, 111.8, 120.6, 131.5, 147.4, 148.7, 154.9, 155.2, 200.7, 201.1.
HRMS: m/z [M]+ calcd for C18H27NO5: 337.1889; found: 337.1890.
Ethyl 5-{( tert -Butoxycarbonyl)[2-(3,4-dimethoxyphenyl)ethyl]amino}pent-2-enoate (15)
A soln of Ph3P=CHCO2Et (661 mg, 1.8 mmol) and 14 (552 mg, 1.6 mmol) in CH2Cl2 (6 mL) was stirred at r.t. for 11 h and then it was evaporated under reduced pressure. The residue was purified by flash chromatography (hexanes-EtOAc, 80:20) to yield (Z)-15 (21 mg, 3%) and (E)-15 (548 mg, 83%) as rotamer mixtures; ratio Z/E 4:96.
E -Isomer ( E )-15
Colorless oil.
IR (neat): 1720 (C=O), 1695 (NCO), 1655 cm-¹ (C=C).
¹H NMR: δ = 1.27 (t, J = 7.1 Hz, 3 H), 1.45 (br s, 9 H), 2.36 (br, 2 H), 2.75 (br, 2 H), 3.22-3.33 (br, 4 H), 3.85 (s, 3 H), 3.86 (s, 3 H), 4.17 (q, J = 7.1 Hz, 2 H), 5.81 (d, J = 15.5 Hz, 1 H), 6.66-6.94 (m, 4 H).
¹³C NMR: δ = 14.1, 28.2, 31.2, 31.8, 34.0, 34.7, 46.1, 46.4, 49.3, 49.7, 55.7, 55.7, 60.1, 79.5, 111.1, 111.8, 120.6, 122.8, 131.5, 145.5, 147.3, 148.7, 155.1, 166.1.
Anal. Calcd for C22H33NO6: C, 64.83; H, 8.17; N, 3.44. Found: C, 64.54; H, 8.33; N, 3.75.
Z -Isomer ( Z )-15
Colorless oil.
IR (neat): 1720 (C=O), 1695 (NCO), 1645 cm-¹ (C=C).
¹H NMR: δ = 1.26 (t, J = 7.1 Hz, 3 H), 1.43 (br s, 9 H), 2.74-2.88 (br, 4 H), 3.25-3.35 (br, 4 H), 3.84 (s, 3 H), 3.86 (s, 3 H), 4.14 (q, J = 7.1 Hz, 2 H), 5.81 (d, J = 11.5 Hz, 1 H), 6.20 (br, 1 H), 6.70-6.80 (br, 3 H).
¹³C NMR: δ = 14.1, 27.9, 28.2, 33.9, 34.6, 45.8, 46.5, 48.9, 55.6, 55.7, 59.7, 79.2, 111.0, 111.8, 120.6, 121.1, 131.7, 146.2, 146.5, 147.2, 148.6, 155.3, 166.0.
Anal. Calcd for C22H33NO6: C, 64.83; H, 8.17; N, 3.44. Found: C, 64.75; H, 8.31; N, 3.30.
Ethyl ( E )-5-[2-(3,4-Dimethoxyphenyl)ethylamino]pent-2-enoate (8b)
TFA (1.5 mL) was added dropwise to a soln of (E)-15 (458 mg, 1.10 mmol) in anhyd CH2Cl2 (8.4 mL) at 0 ˚C under argon. The mixture was allowed to warm to r.t. and then stirred for 3 h. After evaporation, the residue was dissolved in EtOAc (20 mL) and the soln was washed with sat. NaHCO3 (20 mL) and dried (Na2SO4). Solvent evaporation afforded 8b (346 mg, quantitative yield) as a pale yellow oil, which was used without further purification.
IR (neat): 3310 (N-H), 1720 (C=O), 1660 cm-¹ (C=C).
¹H NMR: δ = 1.28 (t, J = 7.1 Hz, 3 H), 1.72 (br s, 1 H), 2.35-2.42 (m, 2 H), 2.72-2.89 (m, 6 H), 3.85 (s, 3 H), 3.86 (s, 3 H), 4.17 (q, J = 7.1 Hz, 2 H), 5.84 (d, J = 15.7 Hz, 1 H), 6.72-6.96 (m, 4 H).
¹³C NMR: δ = 13.9, 32.4, 35.5, 47.6, 50.8, 55.4, 55.5, 59.9, 110.9, 111.5, 120.2, 122.4, 132.0, 146.2, 147.1, 148.5, 166.0.
HRMS: m/z [M]+ calcd for C17H25NO4: 307.1784; found: 307.1790.
Tetrahydropyridines 9; General Procedure
A mixture of amine 8 (1.9 mmol) and aldehyde 4 (1.9 mmol) in anhyd solvent (26 mL) was refluxed for the time indicated in Table [¹] . Where appropriate (Table [¹] ), 4 Å MS (4.8 g) was also used. After cooling, the mixture was filtered over Celite and the solvents were evaporated under reduced pressure. The crude product was purified by flash chromatography (silica gel saturated with Et3N). Purification details and characterization data are provided below for the individual cases.
Ethyl (1-Benzyl-5-butyl-1,2,3,4-tetrahydropyridin-4-yl)acetate (9b)
Chromatography: hexanes-Et3N, 98:2; yellowish oil.
IR (neat): 1740 (C=O), 1680 cm-¹ (C=C).
¹H NMR: δ = 0.89 (t, J = 6.9 Hz, 3 H), 1.22-1.45 (m, 7 H), 1.59-1.69 (m, 1 H), 1.78-2.00 (m, 3 H), 2.06 (dd, J = 15.7, 11.3 Hz, 1 H), 2.52-2.81 (m, 4 H), 3.91 (s, 2 H), 4.12 (q, J = 7.1 Hz, 2 H), 5.81 (s, 1 H), 7.22-7.35 (m, 5 H).
¹³C NMR: δ = 14.0, 14.2, 22.4, 27.4, 30.3, 30.8, 32.4, 39.7, 43.3, 59.6, 60.2, 111.1, 127.0, 128.2, 128.3, 132.4, 138.5, 173.2.
HRMS: m/z [M]+ calcd for C20H29NO2: 315.2198; found: 315.2198.
Ethyl {1-Benzyl-5-[3-(ethoxycarbonyl)propyl]-1,2,3,4-tetrahydropyridin-4-yl}acetate (9f)
Chromatography: hexanes-Et3N, 98:2; yellowish oil.
IR (neat): 1730 (C=O), 1660 cm-¹ (C=C).
¹H NMR: δ = 1.23 (t, J = 7.1 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.60-1.94 (m, 5 H), 2.00-2.10 (m, 2 H), 2.17-2.34 (m, 2 H), 2.49-2.57 (m, 2 H), 2.64-2.80 (m, 2 H), 3.91 (s, 2 H), 4.10 (q, J = 7.1 Hz, 2 H), 4.11 (q, J = 7.1 Hz, 2 H), 5.81 (s, 1 H), 7.20-7.34 (m, 5 H).
¹³C NMR: δ = 14.2, 23.8, 27.3, 29.9, 32.0, 33.6, 39.6, 43.1, 59.5, 60.1, 60.1, 109.1, 127.0, 128.0, 128.2, 133.2, 138.3, 172.9, 173.8.
HRMS: m/z [M]+ calcd for C22H31NO4: 373.2253; found: 373.2245.
Ethyl {( E )-1-Benzyl-5-[4-(ethoxycarbonyl)but-3-enyl]-1,2,3,4-tetrahydropyridin-4-yl}acetate (9g)
Chromatography: hexanes-Et3N, 98:2; yellowish oil.
IR (neat): 1730 (C=O), 1660 cm-¹ (C=C).
¹H NMR: δ = 1.24 (t, J = 7.1 Hz, 3 H), 1.28 (t, J = 7.1 Hz, 3 H), 1.60-1.70 (m, 1 H), 1.81-2.44 (m, 6 H), 2.47-2.58 (m, 2 H), 2.58-2.82 (m, 2 H), 3.92 (s, 2 H), 4.11 (q, J = 7.1 Hz, 2 H), 4.18 (q, J = 7.1 Hz, 2 H), 5.81 (dt, J = 15.7, 1.4 Hz, 1 H), 5.82 (s, 1 H), 6.96 (dt, J = 15.6, 6.6 Hz, 1 H), 7.01-7.35 (m, 5 H).
¹³C NMR: δ = 14.3, 27.4, 30.2, 31.3, 31.6, 39.7, 43.1, 59.5, 60.1, 60.3, 108.6, 121.3, 127.1, 128.1, 128.3, 133.3, 138.4, 149.0, 166.7, 172.9.
HRMS: m/z [M]+ calcd for C23H31NO4: 385.2253; found: 373.2258.
Ethyl {1-[2-(3,4-Dimethoxyphenyl)ethyl]-5-ethyl-1,2,3,4-tetrahydropyridin-4-yl}acetate (9h)
Chromatography: hexanes-EtOAc-Et3N, 90:8:2; pale yellow oil.
IR (neat): 1735 (C=O), 1660 cm-¹ (C=C).
¹H NMR: δ = 0.97 (t, J = 7.4 Hz, 3 H), 1.27 (t, J = 7.1 Hz, 3 H), 1.64-1.74 (m, 1 H), 1.84-1.97 (m, 3 H), 2.09 (dd, J = 15.6, 11.2 Hz, 1 H), 2.53-2.60 (m, 2 H), 2.65-2.78 (m, 2 H), 2.81-2.93 (m, 2 H), 2.97-3.03 (m, 2 H), 3.86 (s, 3 H), 3.87 (s, 3 H), 4.14 (q, J = 7.1 Hz, 2 H), 5.67 (s, 1 H), 6.70-6.81 (m, 3 H).
¹³C NMR: δ = 13.3, 14.1, 25.4, 27.5, 30.2, 33.6, 39.6, 43.2, 55.6, 55.7, 57.3, 60.0, 111.0, 111.8, 111.9, 120.4, 130.9, 132.4, 147.1, 148.6, 173.0.
HRMS: m/z [M]+ calcd for C21H31NO4: 361.2253; found: 361.2272.
Ethyl {1-[2-(3,4-Dimethoxyphenyl)ethyl]-5-nonyl-1,2,3,4-tetrahydropyridin-4-yl}acetate (9i)
Chromatography: hexanes-EtOAc-Et3N, 90:8:2; yellowish oil.
IR (neat): 1735 (C=O), 1660 cm-¹ (C=C).
¹H NMR: δ = 0.87 (t, J = 6.3 Hz, 3 H), 1.26-1.30 (m, 17 H), 1.65-1.95 (m, 4 H), 2.08 (dd, J = 15.8, 11.5 Hz, 1 H), 2.54-2.60 (m, 2 H), 2.67-2.75 (m, 2 H), 2.86-2.90 (m, 2 H), 2.99 (t, J = 7.7 Hz, 2 H), 3.86 (2 s, 6 H), 4.14 (q, J = 7.1 Hz, 2 H), 5.68 (s, 1 H), 6.70-6.81 (m, 3 H).
¹³C NMR: δ = 14.1, 14.2, 22.6, 27.6, 28.7, 29.3, 29.6, 30.2, 31.9, 32.7, 33.6, 39.7, 43.3, 55.7, 55.8, 57.4, 60.2, 110.7, 111.0, 111.9, 120.5, 131.8, 132.5, 147.2, 148.6, 173.1.
HRMS: m/z [M]+ calcd for C28H45NO4: 459.3349; found: 459.3338.
Ethyl {1-[2-(3,4-Dimethoxyphenyl)ethyl]-5-benzyl-1,2,3,4-tetrahydropyridin-4-yl}acetate (9j)
Chromatography: hexanes-EtOAc-Et3N, 86:12:2; orange oil.
IR (neat): 1730 (C=O), 1660 cm-¹ (C=C).
¹H NMR: δ = 1.23 (t, J = 7.1 Hz, 3 H), 1.63-1.73 (m, 1 H), 1.77-1.90 (m, 1 H), 2.10 (dd, J = 14.5, 10.1 Hz, 1 H), 2.38-2.47 (m, 1 H), 2.53 (dd, J = 14.5, 3.5 Hz, 1 H), 2.63-2.81 (m, 2 H), 2.93 (dd, J = 7.5, 3.9 Hz, 2 H), 3.05 (t, J = 7.6 Hz, 2 H), 3.20 and 3.24 (AB q, J = 15.3 Hz, 2 H), 3.87 (s, 3 H), 3.87 (s, 3 H), 4.09 (q, J = 7.1 Hz, 2 H), 5.74 (s, 1 H), 6.70-6.82 (m, 3 H), 7.14-7.30 (m, 5 H).
¹³C NMR: δ = 14.2, 27.3, 30.1, 33.8, 39.4, 39.6, 42.8, 55.7, 55.8, 57.2, 60.1, 108.8, 111.1, 111.9, 120.5, 125.7, 128.1, 128.5, 132.4, 133.7, 141.2, 147.2, 148.7, 172.8.
HRMS: m/z [M]+ calcd for C26H33NO4: 423.2410; found: 423.2405.
Ethyl {1-[2-(3,4-Dimethoxyphenyl)ethyl]-5-[3-(ethoxycarbonyl)propyl]-1,2,3,4-tetrahydropyridin-4-yl}acetate (9k)
Chromatography: hexanes-EtOAc-Et3N, 84:14:2; yellow oil.
IR (neat): 1735 (C=O), 1655 cm-¹ (C=C).
¹H NMR: δ = 1.21-1.28 (m, 6 H), 1.55-1.90 (m, 5 H), 1.92-2.13 (m, 2 H), 2.22-2.32 (m, 2 H), 2.50-2.58 (m, 2 H), 2.63-2.75 (m, 2 H), 2.86-2.90 (m, 2 H), 2.99 (t, J = 7.7 Hz, 2 H), 3.84, 3.85, 3.86 (3 s, 6 H), 4.06-4.17 (m, 4 H), 5.68 (s, 1 H), 6.69-6.80 (m, 3 H).
¹³C NMR: δ = 14.2, 23.8, 27.5, 29.9, 32.0, 33.6, 33.7, 39.6, 43.1, 55.7, 55.8, 57.3, 60.1, 60.2, 108.6, 111.1, 111.9, 120.5, 132.4, 132.6, 147.2, 148.7, 173.0, 173.8.
HRMS: m/z [M]+ calcd for C25H37NO6: 447.2621; found: 447.2681.
Ethyl (1,5-Dibenzyl-2-phenyl-1,2,3,4-tetrahydropyridin-4-yl)acetate (9l)
Chromatography: hexanes-Et3N, 98:2; orange oil; dr 63:37.
IR (neat): 1730 (C=O), 1660 cm-¹ (C=C).
¹H NMR: δ = 1.14 and 1.18 (2 t, J = 7.1 Hz, 3 H), 1.77-2.15 (m, 3 H), 2.40-2.57 and 2.69-2.72 (2 m, 2 H), 3.21-3.35 (m, 2 H), 3.63 and 3.66 (2 d, J = 14.6 Hz, 1 H), 3.84 (td, J = 10.7, 3.1 Hz, 1 H), 3.91-4.08 (m, 3 H), 5.99 (s, 1 H), 7.04-7.39 (m, 15 H).
¹³C NMR: δ = 14.1, 14.2, 30.6, 31.5, 37.4, 37.9, 38.5, 39.5, 39.7, 39.9, 55.6, 55.7, 60.1, 60.2, 110.3, 110.5, 125.8, 125.9, 127.1, 127.2, 127.2, 127.3, 128.2, 128.2, 128.2, 128.4, 128.5, 128.5, 128.6, 128.6, 128.7, 134.2, 135.1, 137.7, 137.8, 140.6, 141.1, 142.9, 143.0, 172.6, 172.8.
HRMS: m/z [M]+ calcd for C29H31NO2: 425.2355; found: 425.2353.
Piperidines 10; General Procedures
Method A: 0.5 M ZnCl2 in THF (4.1 mL, 2.05 mmol) was added to a suspension of NaBH3CN (0.268 g, 4.20 mmol) in MeOH (2.9 mL) under argon, and the mixture was stirred at r.t. for 1 h and then added to a soln of 9 (2.02 mmol) in MeOH (4.4 mL). The soln was stirred further 2 h and poured over 1 M NaOH (50 mL). The mixture was extracted with EtOAc (3 × 50 mL) and the combined organic layers were dried (Na2SO4). After evaporation, the residue was purified by flash chromatography (silica gel saturated with Et3N).
Method B: TFA (2.57 mmol) was added dropwise to a soln of 9 (1.85 mmol) in Et2O (28 mL) at 0 ˚C. The resulting mixture was stirred at 0 ˚C for 30 min, allowed to warm to r.t. and evaporated under reduced pressure. The residue was dissolved in anhyd EtOH (7 mL) and to the cool soln (0 ˚C) NaBH4 (3.80 mmol) was added. The resulting mixture was allowed to warm to r.t. and evaporated under reduced pressure. After addition of 1 M KOH (25 mL), the soln was extracted with CH2Cl2 (3 × 25 mL), and the combined organic extracts were dried (Na2SO4). After evaporation, the crude product was purified by flash chromatography (silica gel saturated with Et3N).
Method C: A deoxygenated mixture of 9 (1.0 mmol), 10% Pd/C (14 mg), and abs EtOH (12 mL) was treated with H2 (1 atm) for 2 h. The resulting mixture was filtered over Celite, and the solid was washed with EtOAc (50 mL). The combined filtrate and washings were evaporated under reduced pressure and the residue after evaporation was purified by flash chromatography (silica gel saturated with Et3N). Purification details and characterization data are provided below for the individual cases.
Ethyl (1-Benzyl-3-isopropylpiperidin-4-yl)acetate (10c)
Chromatography: hexanes-Et3N, 99:1; colorless oil; ratio cis/trans 19:81.
IR (neat): 1740 cm-¹ (C=O).
¹H NMR: δ = 0.79 (d, J = 7.0 Hz, 3 H, trans), 0.87 (d, J = 6.3 Hz, 6 H, cis), 0.90 (d, J = 7.0 Hz, 3 H, trans), 1.24 (t, J = 7.1 Hz, 3 H), 1.22-1.60 (m, 2 H), 1.67-2.39 (m, 6 H), 2.54 (dd, J = 14.7, 4.1 Hz, 1 H), 2.61-2.84 (m, 2 H), 3.40 and 3.56 (AB q, J = 13.1 Hz, 2 H, trans), 3.43 and 3.57 (AB q, J = 13.1 Hz, 2 H, cis), 4.12 (q, J = 7.1 Hz, 2 H), 7.20-7.34 (m, 5 H).
¹³C NMR: δ = 14.0, 16.1, 20.3 (cis), 21.0, 26.1, 27.2 (cis), 29.2 (cis), 30.1 (cis), 30.6 (cis), 31.4, 34.6, 38.0, 45.4 (trans), 45.7 (cis), 47.6 (cis), 52.8, 52.9, 59.8, 59.9 (cis), 63.3, 126.6, 127.8, 128.7, 138.2, 172.9 (trans), 173.2 (cis).
HRMS: m/z [M]+ calcd for C19H29NO2: 303.2198; found: 303.2195.
Ethyl (1,3-Dibenzylpiperidin-4-yl)acetate (10d)
Chromatography: hexanes-Et3N, 98:2; pale yellow oils.
trans -Isomer
IR (neat): 1730 cm-¹ (C=O).
¹H NMR: δ = 1.27 (t, J = 7.1 Hz, 3 H), 1.38-1.47 (m, 1 H), 1.66-1.85 (m, 4 H), 1.95 (td, J = 11.3, 2.5 Hz, 1 H), 2.21 (dd, J = 14.9, 7.9 Hz, 1 H), 2.34 (dd, J = 13.6, 8.2 Hz, 1 H), 2.65-2.76 (m, 3 H), 2.94 (dd, J = 13.6, 2.1 Hz, 1 H), 3.28 and 3.53 (AB q, J = 13.1 Hz, 2 H), 4.15 (q, J = 7.1 Hz, 2 H), 7.12-7.30 (m, 10 H).
¹³C NMR: δ = 14.2, 31.2, 37.5, 38.0, 38.7, 42.0, 52.4, 58.5, 60.2, 63.1, 125.8, 126.8, 128.0, 128.2, 129.0, 129.0, 138.2, 140.2, 173.0.
Anal. Calcd for C23H29NO2: C, 78.58; H, 8.32; N, 3.99. Found: C, 78.26; H, 8.42; N, 3.86.
cis -Isomer
IR (neat): 1740 cm-¹ (C=O).
¹H NMR: δ = 1.30 (t, J = 7.1 Hz, 3 H), 1.53-1.72 (m, 2 H), 1.89-2.25 (m, 4 H), 2.33-2.62 (m, 4 H), 2.80-2.92 (m, 2 H), 3.38 and 3.46 (AB q, J = 13.0 Hz, 2 H), 4.19 (q, J = 7.1 Hz, 2 H), 7.05-7.37 (m, 10 H).
¹³C NMR: δ = 14.3, 28.2, 32.4 (br), 36.0 (br), 37.5 (br), 40.4, 53.2 (br), 55.5, 60.2, 63.2, 125.5, 126.8, 128.1, 129.2, 138.9, 141.4, 172.9.
Anal. Calcd for C23H29NO2: C, 78.58; H, 8.32; N, 3.99. Found: C, 78.25; H, 8.47; N, 3.86.
Ethyl [1-Benzyl-3-(3,4-dimethoxybenzyl)piperidin-4-yl]acetate (10e)
Chromatography: hexanes-EtOAc-Et3N, 86:12:2; light yellow oils.
trans -Isomer
IR (neat): 1730 cm-¹ (C=O).
¹H NMR: δ = 1.24 (t, J = 7.1 Hz, 3 H), 1.35-1.45 (m, 1 H), 1.64-1.79 (m, 4 H), 1.93 (td, J = 11.3, 2.5 Hz, 1 H), 2.17 (dd, J = 14.9, 7.9 Hz, 1 H), 2.26 (dd, J = 13.8, 8.1 Hz, 1 H), 2.62-2.75 (m, 3 H), 2.86 (dd, J = 13.7, 2.0 Hz, 1 H), 3.30 and 3.50 (AB q, J = 13.1 Hz, 2 H), 3.84 (s, 6 H), 4.12 (q, J = 7.1 Hz, 2 H), 6.62-6.66 (m, 2 H), 6.74 (d, J = 8.7 Hz, 1 H), 7.19-7.25 (m, 5 H).
¹³C NMR: δ = 14.2, 31.3, 37.5, 37.6, 38.7, 42.0, 52.5, 55.7, 55.8, 58.5, 60.2, 63.2, 111.0, 112.0, 120.9, 126.8, 128.0, 129.0, 132.7, 138.1, 147.1, 148.6, 173.0.
Anal. Calcd for C25H33NO4: C, 72.95; H, 8.09; N, 3.41. Found: C, 73.07; H, 8.17; N, 3.30.
cis -Isomer
IR (neat): 1740 cm-¹ (C=O).
¹H NMR: δ = 1.26 (t, J = 7.1 Hz, 3 H), 1.52-1.68 (m, 2 H), 1.87-1.93 (m, 1 H), 2.02-2.22 (m, 3 H), 2.30-2.48 (m, 2 H), 2.53 (dd, J = 13.0, 3.9 Hz, 2 H), 2.74-2.84 (m, 2 H), 3.40 (s, 2 H), 3.77 (s, 3 H), 3.82 (s, 3 H), 4.15 (q, J = 7.1 Hz, 2 H), 6.58 (dd, J = 8.1, 1.9 Hz, 1 H), 6.66 (d, J = 1.9 Hz, 1 H), 6.68 (d, J = 8.1 Hz, 1 H), 7.19-7.34 (m, 5 H).
¹³C NMR: δ = 14.2, 28.1, 32.1 (br), 35.6 (br), 37.2 (br), 40.3, 52.8 (br), 55.6, 55.6, 55.7, 60.1, 63.0, 110.9, 112.2, 121.0, 126.7, 128.0, 128.9, 133.8, 138.8, 146.8, 148.5, 172.8.
HRMS: m/z [M]+ calcd for C25H33NO4: 411.2410; found: 411.2409.
Ethyl {1-Benzyl-3-[3-(ethoxycarbonyl)but-3-enyl]piperidin-4-yl}acetate (10g)
Chromatography: hexanes-EtOAc-Et3N, 96:2:2; pale yellow oils.
trans -Isomer
IR (neat): 1730 (C=O), 1660 cm-¹ (C=C).
¹H NMR: δ = 1.24 (t, J = 7.1 Hz, 3 H), 1.28 (t, J = 7.1 Hz, 3 H), 1.32-1.45 (m, 3 H), 1.46-1.77 (m, 4 H), 1.98-2.25 (m, 4 H), 2.52 (dd, J = 15.0, 4.3 Hz, 1 H), 2.76-2.81 (m, 1 H), 2.83-2.88 (m, 1 H), 3.45 and 3.51 (AB q, J = 13.2 Hz, 2 H), 4.07-4.21 (m, 4 H), 5.75 (dt, J = 15.6, 1.4 Hz, 1 H), 6.89 (dt, J = 15.6, 6.9 Hz, 1 H), 7.20-7.37 (m, 5 H).
¹³C NMR: δ = 14.2, 29.2, 29.5, 31.3, 37.1, 38.4, 39.8, 53.1, 58.0, 60.1, 60.3, 63.2, 121.4, 126.9, 128.1, 129.0, 138.2, 148.7, 166.5, 173.0.
HRMS: m/z [M]+ calcd for C23H33NO4: 387.2410; found: 387.2406.
cis -Isomer
IR (neat): 1730 (C=O), 1660 cm-¹ (C=C).
¹H NMR: δ = 1.22 (t, J = 7.1 Hz, 3 H), 1.26 (t, J = 7.1 Hz, 3 H), 1.19-1.36 (m, 1 H), 1.51-1.62 (m, 4 H), 1.85-2.27 (m, 5 H), 2.22 (d, J = 7.6 Hz, 2 H), 2.46 (br, 1 H), 2.64 (br, 1 H), 3.30 and 3.51 (AB q, J = 13.1 Hz, 2 H), 4.05-4.19 (m, 4 H), 5.72 (d, J = 15.6 Hz, 1 H), 6.89 (dt, J = 15.4, 7.0 Hz, 1 H), 7.17-7.32 (m, 5 H).
¹³C NMR: δ = 14.1, 24.8 (br), 28.2, 29.7, 35.2 (br), 36.3 (br), 37.1, 52.9 (br), 55.1, 60.0, 60.1, 63.0, 121.2, 126.8, 128.0, 128.7, 138.8, 149.0, 166.5, 172.8.
Anal. Calcd for C23H33NO4: C, 71.27; H, 8.59; N, 3.62. Found: C, 71.43; H, 8.61; N, 3.31.
Ethyl {1-[2-(3,4-Dimethoxyphenyl)ethyl]-3-ethylpiperidin-4-yl}acetate (10h)
Chromatography: hexanes-EtOAc-Et3N, 84:14:2; pale yellow oil; ratio cis/trans 37:63.
IR (neat): 1730 cm-¹ (C=O).
¹H NMR: δ = 0.86-0.94 (m, 3 H), 1.05-1.46 (m, 6 H), 1.26 (t, J = 7.1 Hz, included in m at δ = 1.05-1.46), 1.51-1.81 (m, 3 H), 1.93-2.08 (m, 1 H), 2.17-2.64 (m, 6 H), 2.67-2.79 (m, 2 H), 2.95-3.04 (m, 1 H), 3.85 (s, 3 H), 3.87 (s, 3 H), 4.13 (q, J = 7.1 Hz, 2 H), 6.72-6.81 (m, 3 H).
¹³C NMR: δ = 10.5 (trans), 11.5 (cis), 13.8, 20.0 (br, cis), 23.2, 28.2, 31.3, 32.8, 32.9, 34.0 (br, cis), 34.6 (br, cis), 36.7 (trans), 38.0, 39.4 (cis), 41.4 (trans), 51.5 (br, cis), 53.0, 54.7, 55.1, 55.2, 58.0, 59.6, 60.5, 60.6, 110.6 (cis), 110.6 (trans), 111.4, 119.9, 132.6 (trans), 132.7 (cis), 146.6 (cis), 146.7 (trans), 148.2 (cis), 148.2 (trans), 172.5 (trans), 172.6 (cis).
HRMS: m/z [M]+ calcd for C21H33NO4: 363.2410; found: 363.2408.
Ethyl {3-Benzyl-1-[2-(3,4-dimethoxyphenyl)ethyl]piperidin-4-yl}acetate (10j)
Chromatography: hexanes-EtOAc-Et3N, 78:20:2; colorless oil; ratio cis/trans 22:78.
IR (neat): 1730 cm-¹ (C=O).
¹H NMR: δ = 1.26 (t, J = 7.1 Hz, 3 H), 1.41-1.51 (m, 1 H), 1.63-1.72 (m, 3 H), 1.81-1.87 (m, 1 H), 1.95-2.04 (m, 1 H), 2.15-2.31 (m, 2 H), 2.37-2.78 (m, 6 H), 2.92-2.99 (m, 2 H), 3.81-3.85 (m, 6 H), 4.10-4.19 (m, 2 H), 6.63-6.79 (m, 3 H), 7.07-7.28 (m, 5 H).
¹³C NMR: δ = 14.1, 28.2 (cis), 31.5, 33.1, 35.5 (cis), 36.7 (trans), 37.7 (trans), 37.8, 38.6, 40.1 (cis), 42.0 (trans), 53.0, 55.1 (cis), 55.5, 55.7, 55.7 (cis), 58.5, 60.2, 60.7, 110.9, 111.6 (trans), 111.8 (cis), 120.2 (trans), 120.4 (cis), 125.6 (cis), 125.8 (trans), 128.0 (cis), 128.1 (trans), 128.8 (trans), 129.0 (cis), 132.8 (trans), 133.2 (cis), 139.9 (trans), 141.1 (cis), 147.0, 148.5, 172.8 (cis), 172.8 (trans).
HRMS: m/z [M]+ calcd for C26H35NO4: 425.2566; found: 425.2572.
Debenzylated Piperidines 11; General Procedure
A deoxygenated mixture of 9 (1.5 mmol), 10% Pd/C (22 mg), and EtOH (7 mL) was treated with H2 (3.45 bar) at r.t. for 48 h. The mixture was filtered through Celite, which was washed with CH2Cl2 (100 mL). The combined filtrate and washings were evaporated under reduced pressure and the residue was purified by flash chromatography (silica gel saturated with Et2NH). Purification details and characterization data are provided below for the individual cases.
Ethyl (3-Isopropylpiperidin-4-yl)acetate (11c)
Chromatography: EtOAc-Et2NH, 98:2; colorless oil; ratio cis/trans 26:74.
IR (neat): 3300 (N-H), 1735 cm-¹ (C=O).
¹H NMR: δ = 0.78 (d, J = 7.1 Hz, 3 H, trans), 0.88 (d, J = 6.0 Hz, 6 H, cis), 0.92 (d, J = 7.0 Hz, 3 H, trans), 1.09-1.30 (m, 5 H), 1.23 (t, J = 7.1 Hz, included in m at δ = 1.09-1.30), 1.57-2.05 (m, 4 H), 2.21-3.02 (m, 6 H), 4.10 (q, J = 7.1 Hz, 2 H).
¹³C NMR: δ = 14.1, 15.9, 20.0, 21.0, 21.1, 26.1, 27.3, 30.7, 32.9, 35.4, 38.5, 40.7, 45.2, 45.5, 46.5, 47.0, 47.2, 60.0, 60.1, 173.1, 173.5.
HRMS: m/z [M]+ calcd for C12H23NO2: 213.1729; found: 213.1723.
Ethyl {3-[3-(Ethoxycarbonyl)propyl]piperidin-4-yl}acetate (11f)
Chromatography: EtOAc-Et2NH, 98:2 EtOAc-Et2NH; pale yellow oil; ratio cis/trans 30:70.
IR (neat): 3340 (N-H), 1740 cm-¹ (C=O).
¹H NMR: δ = 1.07-1.25 (m, 2 H), 1.22 (t, J = 7.1 Hz, 6 H), 1.27-1.76 (m, 7 H), 2.02 (dd, J = 14.8, 8.9 Hz, 1 H, trans), 2.14-2.31 (m, 3 H), 2.49-3.12 (m, 4 H), 4.09 (q, J = 7.1 Hz, 4 H).
¹³C NMR: δ = 14.1, 21.9, 22.7, 26.1, 29.0, 30.4, 32.6, 34.3, 34.4, 35.2, 35.9, 37.8, 38.1, 38.8, 41.3, 44.7, 46.3, 48.4, 51.3, 60.1, 173.0, 173.4, 173.4.
HRMS: m/z [M]+ calcd for C15H27NO4: 285.1940; found: 285.1938.
Acknowledgment
Financial support by Janssen-Cilag is gratefully acknowledged.
- 1
Gracia J.Casamitjana N.Bonjoch J.Bosch J. J. Org. Chem. 1994, 59: 3939 - 2
Aurrecoechea JM.Gorgojo JM.Saornil C. J. Org. Chem. 2005, 70: 9640 - 3
Aurrecoechea JM.Suero R.de Torres E. J. Org. Chem. 2006, 71: 8767 - 4
Aurrecoechea JM.Coy CA.Patino OJ. J. Org. Chem. 2008, 73: 5194 - 5 For reviews on synthetic approaches
to piperidines, see:
Hopper DW.Kutterer KMK.Crombie AL.Clemens JJ. In Progress in Heterocyclic Chemistry Vol. 20:Gribble GW.Joule JA. Elsevier; Oxford: 2009. p.289-332 ; and previous volumes in the series - 6a
Bustos F.Gorgojo JM.Suero R.Aurrecoechea JM. Tetrahedron 2002, 58: 6837 - 6b
Aurrecoechea JM.Fernandez A.Gorgojo JM.Suero R. Synth. Commun. 2003, 33: 693 - 7
Aurrecoechea JM.Fernandez A.Gorgojo JM.Saornil C. Tetrahedron 1999, 55: 7345 - 9
Bonjoch J.Linares A.Guardià M.Bosch J. Heterocycles 1987, 26: 2165 - 10
Whitesell JK.Minton MA. Stereochemical Analysis of Alicyclic Compounds by C-13 NMR Spectroscopy Chapman and Hall; London: 1987. - 11
Yadav V.Fallis AG. Can. J. Chem. 1991, 69: 779
References
This was indicated by the presence in the crude ¹H NMR spectrum of new doublets at ca. δ = 5.3 and 6.8 ppm replacing the characteristic phenylacetaldehyde signals.
12Stereochemical elucidation based on NOE measurements was impractical in this case due to signal overlap. In previous work, we have confirmed the validity of assignments based on the observation of γ-gauche effects using NOE studies on related piperidine derivatives (see ref. 3).
13Also characteristic of the cis-isomers was the room temperature broadening of some of the ¹³C NMR resonances, because of conformational interconversion between two equatorial/axial conformers, whereas the corresponding signals in the diequatorial trans-isomers were sharp.
- 1
Gracia J.Casamitjana N.Bonjoch J.Bosch J. J. Org. Chem. 1994, 59: 3939 - 2
Aurrecoechea JM.Gorgojo JM.Saornil C. J. Org. Chem. 2005, 70: 9640 - 3
Aurrecoechea JM.Suero R.de Torres E. J. Org. Chem. 2006, 71: 8767 - 4
Aurrecoechea JM.Coy CA.Patino OJ. J. Org. Chem. 2008, 73: 5194 - 5 For reviews on synthetic approaches
to piperidines, see:
Hopper DW.Kutterer KMK.Crombie AL.Clemens JJ. In Progress in Heterocyclic Chemistry Vol. 20:Gribble GW.Joule JA. Elsevier; Oxford: 2009. p.289-332 ; and previous volumes in the series - 6a
Bustos F.Gorgojo JM.Suero R.Aurrecoechea JM. Tetrahedron 2002, 58: 6837 - 6b
Aurrecoechea JM.Fernandez A.Gorgojo JM.Suero R. Synth. Commun. 2003, 33: 693 - 7
Aurrecoechea JM.Fernandez A.Gorgojo JM.Saornil C. Tetrahedron 1999, 55: 7345 - 9
Bonjoch J.Linares A.Guardià M.Bosch J. Heterocycles 1987, 26: 2165 - 10
Whitesell JK.Minton MA. Stereochemical Analysis of Alicyclic Compounds by C-13 NMR Spectroscopy Chapman and Hall; London: 1987. - 11
Yadav V.Fallis AG. Can. J. Chem. 1991, 69: 779
References
This was indicated by the presence in the crude ¹H NMR spectrum of new doublets at ca. δ = 5.3 and 6.8 ppm replacing the characteristic phenylacetaldehyde signals.
12Stereochemical elucidation based on NOE measurements was impractical in this case due to signal overlap. In previous work, we have confirmed the validity of assignments based on the observation of γ-gauche effects using NOE studies on related piperidine derivatives (see ref. 3).
13Also characteristic of the cis-isomers was the room temperature broadening of some of the ¹³C NMR resonances, because of conformational interconversion between two equatorial/axial conformers, whereas the corresponding signals in the diequatorial trans-isomers were sharp.
Figure 1
Scheme 1
Scheme 2
Scheme 3
Scheme 4 Reagents and conditions: (a) ethyl acrylate, EtOH, r.t.; (b) (Boc)2O, EtOAc, 0 ˚C to r.t.; (c) DIBAL-H, toluene, -78 ˚C; (d) Ph3P=CHCO2Et, CH2Cl2, r.t.; (e) TFA, CH2Cl2, 0 ˚C.
Scheme 5
