Subscribe to RSS
DOI: 10.1055/s-2006-950423
Anionic Ring-Enlarging Reaction of a Hemiaminal System: Stereoselective Approach to Disubstituted Tetrahydroisoquinolone
Publication History
Publication Date:
08 September 2006 (online)
![](https://www.thieme-connect.de/media/synlett/200615/lookinside/thumbnails/10.1055-s-2006-950423-1.jpg)
Abstract
Treatment of N-substituted phthalimide-derived hemiaminal with alkyllithium led to tetrahydroisoquinolones with high diastereoselectivity. Mechanistic studies furnish persuasive evidence that the present ring-enlarging reaction proceeds via tautomerization of the hemiketal moiety and the resulting ketone undergoes an intramolecular nucleophilic addition reaction.
Key words
hemiaminal - α-aminocarbanion - stereoselective synthesis - tetrahydroisoquinolone - axial chirality
-
1a
Chrzanowska M.Rozwadowska MD. Chem. Rev. 2004, 104: 3341 -
1b
Briet N.Brookes MH.Davenport RJ.Galvin FCA.Gilbert PJ.Mack SR.Sabin V. Tetrahedron 2002, 58: 5761 - For recent studies of the asymmetric synthesis of tetrahydro-isoquinolones, see:
-
2a
Vicario JL.Badia D.Carrillo L.Anakabe E. Tetrahedron: Asymmetry 2003, 14: 347 -
2b
Derdau V.Snieckus V. J. Org. Chem. 2001, 66: 1992 -
2c
Davis FA.Mohanty PK.Burns DM.Andemichael YW. Org. Lett. 2000, 2: 3901 -
2d
Davis FA.Andemichael YW. J. Org. Chem. 1999, 64: 8627 -
2e
Clark RD.Souchet M.Kern JR. J. Chem. Soc., Chem. Commun. 1989, 930 -
3a
Tomoyasu T.Tomooka K. Synlett 2004, 1925 -
3b
Tomoyasu T.Tomooka K.Nakai T. Tetrahedron Lett. 2003, 44: 1239 -
3c
Tomoyasu T.Tomooka K.Nakai T. Tetrahedron Lett. 2000, 41: 345 -
3d
Tomoyasu T.Tomooka K.Nakai T. Synlett 1998, 1147 - 4 The ring-enlarging reaction of the phthalimide-derived enolate is well established as the Gabriel-Colman rearrange-ment; see:
Allen CFH. Chem. Rev. 1950, 47: 275 - 7 Bisagni and co-workers reported a similar tetrahydroiso-quinolone synthesis involving the dilithiated intermediate, see:
Delcey MC.Huel C.Bisagni E. Heterocycles 1995, 41: 1721 - Reviews on aza-Wittig rearrangement:
-
11a
Tomooka K. In The Chemistry of Organolithium CompoundsRappoport Z.Marek I. John Wiley & Sons; New York: 2004. p.749 -
11b
Vogel C. Synthesis 1997, 497 - 15 It has been reported that the α-amino benzylic carbanion is stereochemically unstable; see:
Hoffmann RW.Ruhl T.Harbach J. Liebigs Ann. Chem. 1992, 725
References and Notes
All the compounds were characterized by 1H and 13C NMR analyses (recorded in CDCl3 unless specified otherwise). Data for selected products follow.
(1R*,1′R*)-2: 1H NMR (270 MHz): δ = 7.71-7.67 (m, 1 H), 7.52-7.40 (m, 3 H), 7.25-7.09 (m, 5 H), 3.23 (dd, J = 9.2, 5.3 Hz, 1 H), 2.70-1.90 (m, 6 H), 1.61-0.79 (m, 34 H). 13C NMR (67.5 MHz): δ = 166.8, 146.5, 141.9, 131.8, 131.6, 129.6, 128.3, 125.8, 123.0, 121.7, 92.8, 38.7, 35.8, 34.6, 29.3, 29.1, 27.6, 25.9, 22.6, 13.7, 11.4.
(1S*,1′R*)-2: 1H NMR (270 MHz): δ = 7.75-7.72 (m, 1 H), 7.52-7.45 (m, 3 H), 7.30-7.17 (m, 5 H), 3.43-3.35 (m, 1 H), 2.80-2.51 (m, 3 H), 2.18-1.90 (m, 3 H), 1.65-0.74 (m, 34 H). 13C NMR (67.5 MHz): δ = 167.1, 146.2, 141.7, 131.7, 129.6, 128.3, 128.2, 125.9, 122.8, 121.6, 91.9, 39.1, 36.0, 34.7, 29.3, 29.1, 27.5, 26.1, 22.5, 13.6, 11.1.
3: 1H NMR (270 MHz): δ = 8.03-7.99 (m, 1 H), 7.57-7.48 (m, 2 H), 7.42-7.34 (m, 1 H), 7.27-7.11 (m, 6 H), 6.83 (dd, J = 14.3, 4.8 Hz, 1 H), 3.41 (td, J = 7.9, 2.8 Hz, 1 H), 2.84-2.75 (m, 1 H), 2.66-2.55 (m, 1 H), 2.28 (s, 1 H), 2.18-2.07 (m, 1 H), 2.02-1.92 (m, 1 H), 1.87-1.75 (m, 1 H), 1.65-1.52 (m, 1 H), 1.39-1.04 (m, 4 H), 0.81 (t, J = 7.1 Hz, 3 H). 13C NMR (67.5 MHz): δ = 164.8, 143.2, 141.0, 132.5, 128.6, 128.5, 128.3, 127.8, 127.6, 126.6, 126.1, 124.4, 74.1, 58.8, 40.8, 32.2, 31.6, 25.4, 22.8, 13.9.
5a: dr = 85:15. 1H NMR (300 MHz): δ = 8.10 (d, J = 7.5 Hz, 1 H), 7.65-7.35 (m, 3.90 H), 7.20-7.15 (m, 2.58 H), 7.07-7.04 (m, 1.71 H), 6.64 (br s, 0.85 H), 6.36 (br s, 0.15 H), 4.86 (s, 0.15 H), 4.64 (d, J = 4.5 Hz, 0.85 H), 2.31 (br s, 0.15 H), 2.05-1.97 (m, 1.85 H), 1.90 (br s, 0.85 H), 1.57-1.40 (m, 0.85 H), 1.57-1.07 (m, 3.15 H), 1.06-0.95 (m, 0.15 H), 0.86 (t, J = 7.5 Hz, 2.55 H), 0.68 (t, J = 7.5 Hz, 0.45 H). 13C NMR (75 MHz): δ = 166.43, 165.10, 143.89, 142.89, 136.73, 135.56, 132.72, 132.25, 128.74, 128.58, 128.51, 128.46, 128.00, 127.86, 127.70, 126.63, 125.40, 125.13, 74.54, 73.61, 65.78, 63.74, 41.66, 34.72, 29.70, 25.82, 24.88, 22.89, 14.06, 13.96.
5b: dr = >95:<5. 1H NMR (300 MHz): δ = 8.10 (d, J = 7.5 Hz, 1 H), 7.57-7.50 (m, 2 H), 7.45-7.40 (m, 1 H), 7.30-7.26 (m, 3 H), 7.22-7.19 (m, 2 H), 6.40 (br s, 1 H), 4.61 (d, J = 3.3 Hz, 1 H), 2.08 (s, 1 H), 1.67 (s, 3 H). 13C NMR (75 MHz): δ = 65.17, 143.70, 136.58, 133.36, 128.83, 128.75, 128.70, 128.30, 128.11, 126.67, 124.14, 71.21, 65.50, 28.33.
5c: dr = >95:<5. 1H NMR (270 MHz, DMSO-d
6): δ = 8.22 (d, J = 3.1 Hz, 1 H), 7.98 (dd, J = 7.3, 1.8 Hz, 1 H), 7.54-7.46 (m, 2 H), 7.26 (s, 5 H), 7.16-7.04 (m, 6 H), 6.14 (s, 1 H), 4.98 (d, J = 3.1 Hz, 1 H).
5d: dr = 58:42. 1H NMR (300 MHz): δ = 7.97 (d, J = 7.2 Hz, 0.42 H), 7.69 (d, J = 7.2 Hz, 0.58 H), 7.53-7.30 (m, 5 H), 7.25-7.14 (m, 3 H), 6.51 (br s, 0.58 H), 6.25 (br s, 0.42 H), 4.88-4.74 (m, 2 H), 2.71 (br s, 0.58 H), 2.18 (br s, 0.42 H). 13C NMR (75 MHz): δ = 166.02, 165.96, 139.24, 138.90, 138.51, 136.61, 132.99, 132.81, 128.98, 128.80, 128.58, 128.19, 128.04, 127.83, 127.41, 127.17, 127.07, 71.68, 69.24, 62.48, 60.33.
The diastereomeric ratio was determined by 1H NMR analysis.
8The exact origin of the observed high reactivity of MeLi compared with that of n-BuLi is not clear at present, though it might be considered as the result of a difference of their aggregation states.
9Ring-Enlarging Reaction; Typical Procedure: To a solution of hemiaminal 6b (61 mg, 0.24 mmol) in anhyd THF (10 mL) was added MeLi (1.04 M solution in Et2O; 1.15 mL, 1.20 mmol) dropwise at -78 °C under an argon atmosphere. The resulting mixture was stirred at -78 °C for 30 min and then the temperature was allowed to rise to 0 °C over a period of 30 min. The reaction was quenched with a sat. aq solution of NH4Cl. The aqueous layer was extracted with EtOAc. Then, the combined organic layer was washed with a sat. aq solution of NaCl, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Puri-fication by silica gel chromatography (hexane-EtOAc, 3:1) gave 56 mg (91%; dr 93%) of tetrahydroisoquinolone 5b.
10The relative stereochemistry of 5c was determined as syn by X-ray crystallography of its dimethylated derivative 13 (Scheme [10] ). The stereochemistry of tetrahydroiso-quinolones 5a, 5b, and 5d was speculated as syn based on its similarity with 5c. Crystallographic data for 13 have been deposited with the Cambridge Crystallographic Data Center as supplementary publication no. CCDC 610566. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (deposit @ccdc.cam.ac.uk).
Scheme 10
Generation of the benzylic anion was confirmed by a trapping experiment using TMSCl.
13DFT calculations were performed at the B3LYP/6-31+G(d) level with Gaussian 03 on TSUBAME system at Tokyo Institute of Technology. To simplify the calculation the possibility of the aggregation was not considered. The sum of electronic and zero-point energies was used as the energy values in Figure 2 and Scheme [7] .
14The enantiopurity of 3 was determined by HPLC analysis using a Sumichiral OA-3200 column.
16Stereochemistry of the major epimer of 2 (dr = 69:31) was assigned as (1R,1′R)-isomer based on a correlation with the vinyl analogue. The reaction of (R)-1 with H2C=CHMgBr provides (1R,′R)-isomer as the major epimer (dr = 83:17) and its stereochemistry was unambiguously determined by X-ray crystallography. The detailed result as well as a ring-enlarging reaction of a vinyl analogue will be reported elsewhere.
17The absolute stereochemistry of 3 was speculated based on the reaction mechanism.