A New Carbanionic One-Carbon Ring Enlargement-Alkylation of Lactams

Michela Valacchi; Walter Cabri; Alessandro Mordini; Arnault De Philippis; Gianna Reginato

doi:10.1055/s-2003-42045

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Synlett 2003(13): 2025-2028
DOI: 10.1055/s-2003-42045

LETTER

A New Carbanionic One-Carbon Ring Enlargement-Alkylation of Lactams

Michela Valacchi*^a, Walter Cabri*^b, Alessandro Mordini^a, Arnault De Philippis^a, Gianna Reginato^a
Istituto di Chimica dei Composti OrganoMetallici, Dipartimento di Chimica Organica ‘U. Schiff’, via della Lastruccia 13, 50019 Sesto Fiorentino, Firenze, Italy
Fax: +39(055)4573580; e-Mail: labormet@unifi.it;
Antibioticos, Research & Development, strada Rivoltana km 6-7, 20090 Rodano, Milano, Italy
Fax: +39(02)95321134; e-Mail: WCabri@antibioticos.it;

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Publication History

Received 3 September 2003
Publication Date:
08 October 2003 (online)

Abstract
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Abstract

The lithium-bromine exchange of bicyclic bromo-substituted γ- and δ-lactams has been investigated finding that the lithium intermediates undergo a ring-enlargement reaction eventually leading to the isomeric six- and seven-membered lactams. Interception of the lithium species with electrophiles allows the synthesis of a series of functionalized quinolinones and benzoazepines.

Key words

lactams - rearrangement - carbanions - ring-expansion - quinolines

References

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7

Typical Rearrangement Procedure: Bromolactam 1 (66.0 mg, 0.25 mmol) was dissolved in the solvent (1 mL) under N₂ and the solution cooled to -45 °C. t-BuLi (0.29 mL of a 1.7 M solution in pentane, 0.5 mmol) was then added drop wise and the resulting clear orange solution stirred at the above temperature for 2 h. After this period, the electrophile was added and the reaction allowed warming to r.t. (about 30 min). The organic layer was washed twice with NaCl sat. solution, the water phase extracted with Et₂O and the combined organic layers dried over Na₂SO₄.
1,4-Dimethyl-3,4-dihydro-2-quinolinone ( 4): [20] The crude mixture was purified by flash chromatography (EtOAc-petroleum ether, 1:1) affording 104 mg (62%) of a colourless oil. ¹H NMR (200 MHz, CDCl₃): δ = 7.26-6.97 (m, 4 H), 3.37 (s, 3 H), 3.05 (m, 1 H), 2.73 (dd, 1 H, J = 15.8, 5.6 Hz), 2.44 (dd, 1 H, J = 15.8, 7.6 Hz), 1.27 (d, 3 H, J = 7.0 Hz). ¹³C NMR (50.3 MHz, CDCl₃): δ = 169.8, 139.8, 131.0, 127.3, 126.15, 123.0, 114.7, 39.1, 30.3, 29.4, 19.2. MS: m/z (%) = 175 (63), 160 (80), 132 (100), 117 (35), 91 (20), 77 (18).

10

1,4-Dimethyl-3-d-3,4-dihydro-2-quinolinone ( 11a): The crude mixture was purified by flash chromatography (Et₂O:petroleum ether, 2:3) affording 28 mg (58%) of compound 11a. ¹H NMR (200 MHz, CDCl₃): δ = 7.30-6.99 (m, 4 H), 3.37 (s, 3 H), 3.09-3.00 (m, 1 H), 2.43 (dq, 1 H, J = 7.2, 3.9 Hz), 1.19 (d, 3 H, J = 7.2 Hz). MS: m/z (%) = 176 (60), 161 (85), 133 (100), 91 (25), 77 (20).
1,3,4-Trimethyl-3,4-dihydro-2-quinolinone ( 11b): [21]
The crude mixture was purified by flash chromatography (EtOAc-petroleum ether, 1:3) affording 46 mg (70%) of compound 11b. ¹H NMR (200 MHz, CDCl₃): δ = 7.28-6.82 (m, 4 H), 3.36 (s, 3 H), 2.71 (dq, 1 H, J = 7.4, 4.0 Hz), 2.54 (dq, 1 H, J = 7.2, 4.0 Hz), 1.22 (d, 3 H, J = 7.0 Hz), 1.11 (d, 3 H, J = 7.0 Hz). ¹³C NMR (50.3 MHz, CDCl₃): δ = 172.9, 138.7, 129.8, 127.8, 127.3, 123.1, 114.5, 42.8, 37.8, 29.5, 20.0, 16.0. MS: m/z (%) = 189 (59), 174 (77), 160 (80), 146 (100), 130 (60), 117 (48), 91 (36), 77 (50).
1,4-Dimethyl-3(1-propen-2yl)-3,4-dihydro-2-quinolinone ( 11c): The crude mixture was purified by flash chromatography (Et₂O-petroleum ether, 2:3) affording 36 mg (67%) of compound 11c. ¹H NMR (200 MHz, CDCl₃):
δ = 7.28-6.99 (m, 4 H), 5.80-5.64 (m, 1 H), 5.00 (bd, 1 H, J = 10.2 Hz), 4.92 (bd, 1 H, J = 16.8 Hz), 3.37 (s, 3 H), 2.91-2.81 (m, 1 H), 2.60-2.53 (m, 1 H), 2.30-2.18 (m, 1 H), 2.09-1.96 (m, 1 H), 1.18 (d, 3 H, J = 7.4 Hz). ¹³C NMR (50.3 MHz, CDCl₃): δ = 171.6, 138.6, 135.1, 129.2, 128.0, 127.6, 123.2, 117.3, 114.6, 48.1, 34.9, 34.5, 29.4, 20.6. MS: m/z (%) = 215 (65), 200 (68), 173 (82), 159 (53), 130 (73), 117 (37), 91 (41), 77 (50), 41 (100).
1,4-Dimethyl-(1-phenylmethanol)-3,4-dihydro-2-quinolinone ( 11d): The crude mixture was purified by flash chromatography (EtOAc-petroleum ether, 1:1) affording 54 mg (60%) of compound 11d. ¹H NMR (200 MHz, CDCl₃): δ = 7.40-7.18 (m, 5 H), 7.16-7.03 (m, 4 H), 4.38 (dd, 1 H, J = 10.2 Hz, J = 2.6 Hz), 3.46 (s, 3 H), 2.95 (d, 1 H, J = 2.6 Hz), 2.77 (dd, 1 H, J = 10.2 Hz, J = 1.4 Hz), 2.46-2.42 (m, 1 H), 1.08 (d, 3 H, J = 7.0 Hz). ¹³C NMR (50.3 MHz, CDCl₃): δ = 170.4, 141.9, 138.3, 128.9, 128.6, 128.5, 128.3, 128.0, 127.7, 126.6, 123.6, 115.0, 73.3, 56.6, 33.4, 29.7, 21.2. MS: m/z (%) = 281 (1.5), 175 (5), 160 (100), 146 (4), 132 (6), 117 (6), 91 (7), 77 (17).

12

2,5-Dimethyl-1,2,4,5-tetrahydro-benzo[ c ]azepin-3-one ( 20): The crude mixture was purified by flash chromatography (EtOAc-petroleum ether, 10:1) affording 72 mg (60%) of compound 20. ¹H NMR (200 MHz, CDCl₃): δ = 7.38-7.05 (m, 4 H), 4.47 (AB system, 2 H), 3.39-3.25 (m, 1 H), 3.11 (m, 1 H), 3.05 (s, 3H), 2.72 (m, 1 H), 1.37 (d, 3 H, J = 7 Hz). ¹³C NMR (50.3 MHz, CDCl₃): δ = 172.4, 142.8, 133.6, 130.3, 130.2, 128.6, 128.1, 125.8, 54.6, 41.0, 33.5, 29.7, 24.5. MS: m/z (%) = 243 (2.5), 189 (100), 174 (87), 159 (74), 129 (100).

13

2,5,5-Trimethyl-1,2,4,5-tetrahydro-benzo[ c ]azepin-3-one ( 23a): The crude mixture was purified by flash column chromatography (CH₂Cl₂-MeOH, 98:2) affording 72 mg (74%) of compound 23a. ¹H NMR (200 MHz, CDCl₃): δ = 7.45-7.41 (m, 1 H), 7.33-7.24 (m, 1 H), 7.15-6.99 (m, 2 H), 4.47 (s, 2 H), 3.03 (s, 3 H), 2.87 (s, 2 H), 1.40 (s, 6 H). ¹³C NMR (50.3 MHz, CDCl₃): δ = 172.5, 146.6, 133.3, 129.6, 129.5, 128.6, 126.1, 55.9, 48.4, 34.8, 33.3, 28.5, 28.4. MS: m/z (%) = 203 (44), 188 (14), 174 (8), 145 (87).
2,5-Dimethyl-5(prop-3-enyl)-1,2,4,5-tetrahydro-benzo[ c ]azepin-3-one ( 23b): The crude mixture was purified by flash chromatography (CH₂Cl₂-MeOH, 98:2) affording 54 mg (50%) of compound 23b. ¹H NMR (200 MHz, CDCl₃): δ = 7.44-7.30 (m, 2 H), 7.16-7.00 (m, 2 H), 5.62-5.44 (m, 1 H), 5.02 (bd, 1 H, J = 17.2 Hz), 5.00 (bd, 1 H, J = 10.6 Hz), 4.86 (d, 1 H, J = 16.2 Hz), 3.98 (d, 1 H, J = 16.2 Hz), 3.34 (d, 1 H, J = 13.6 Hz), 3.01 (s, 3 H), 2.68 (ddt, 1 H, J = 14.0, 5.8, 1.4 Hz), 2.37 (d, 1 H, J = 13.6 Hz), 2.26 (dd, 1 H, J = 14.0, 8.8 Hz), 1.40 (s, 3 H). ¹³C NMR (50.3 MHz, CDCl₃): δ = 172.6, 144.9, 138.1, 134.4, 134.3, 129.5, 128.7, 126.1, 118.6, 55.8, 50.2, 45.2, 40.0, 34.6, 31.5. MS: m/z (%) = 229 (1), 201 (3), 188 (7), 146 (100).
2,5-Dimethyl-5(hydroxyphenylmethyl)-1,2,4,5-tetrahydro-benzo[ c ]azepin-3-one ( 23c): The crude mixture was purified by flash chromatography (CH₂Cl₂-MeOH, 98:2) affording 88 mg (64%) of compound 23c. ¹H NMR (200 MHz, CDCl₃): δ = 7.47 (dd, 1 H, J = 8.0, 1.2 Hz), 7.36-7.24 (m, 6 H), 7.21-7.05 (m, 2 H), 4.91 (d, 1 H, J = 16.2 Hz), 4.90 (bs, 1 H), 3.96 (d, 1 H, J = 16.2 Hz), 3.59 (d, 1 H, J = 13.6 Hz), 2.98 (s, 3 H), 2.37 (bs, 1 H), 2.22 (d, 1 H, J = 13.6 Hz), 1.34 (d, 3 H, J = 7 Hz). ¹³C NMR (50.3 MHz, CDCl₃): δ = 172.8, 143.2, 139.7, 135.9, 130.0, 129.9, 129.7, 128.8, 128.5, 128.1, 128.0, 126.7, 126.6 83.0, 56.0, 45.8, 40.9, 34.5, 27.8. MS: m/z (%) = 189 (80), 174 (100), 160 (17), 146 (48), 115 (41).