Anionic Ring-Enlarging Reaction of a Hemiaminal System: Stereoselective Approach to Disubstituted Tetrahydroisoquinolone

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.

hemiaminal - α-aminocarbanion - stereoselective synthesis - tetrahydroisoquinolone - axial chirality

References and Notes

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 

5

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.

6

The diastereomeric ratio was determined by ¹H NMR analysis.

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 

8

The 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.

9

Ring-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.

10

The 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

Reviews on aza-Wittig rearrangement:

11a Tomooka K. In The Chemistry of Organolithium Compounds   Rappoport Z. Marek I. John Wiley & Sons; New York: 2004.  p.749 

11b Vogel C. Synthesis  1997,  497 

12

Generation of the benzylic anion was confirmed by a trapping experiment using TMSCl.

13

DFT 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] .

14

The enantiopurity of 3 was determined by HPLC analysis using a Sumichiral OA-3200 column.

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 

16

Stereochemistry 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.

17

The absolute stereochemistry of 3 was speculated based on the reaction mechanism.