Stereoselective Intra- and Intermolecular [2+2] Photocycloaddition Reactions of 4-(2′-Aminoethyl)quinolones

Abstract

The 4-(2′-aminoethyl)quinolones 6, 8 and 9 were prepared starting from 4-(2′-bromoethyl)quinolone (4) in two steps and overall yields of 56-93%. They underwent inter- and intramolecular [2+2] photocycloaddition reactions with an alkene to provide the cyclobutanes 1-3 in racemic form (61-89% yield). The photochemical reaction proceeded with very good chemo-, regio- and stereo­selectivity. It was in one case (8b → 2b) also performed enantioselectively (93% ee).

asymmetric synthesis - cycloadditions - cyclobutanes - diastereoselectivity - photochemistry - quinolones

References

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The formation of photodimer was also observed. The simple diastereoselectivity in the [2+2] photocycloaddition of monosubstituted alkenes was low:

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Intramolecular [2+2] photocycloaddition reactions of 4-alkenyloxy-2-quinolones are known:

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7

Representative Procedure for the Intermolecular [2+2] Photocycloaddition:
A solution of quinolone 6 (767 mg, 2.03 mmol, 30.0 mM) and methacrylate (3.67 mL, 3.49 g, 40.5 mmol, 20 equiv, 0.6 M) in toluene (70 mL) was irradiated at 350 nm (RPR-3500 Å) in a merry-go-round apparatus at r.t. for 4 h. After removal of the solvent in vacuo, the crude product was purified by flash chromatography (silica 60: 5 × 20 cm, pentane-EtOAc = 50:50) to give 750 mg (80%) rac-1a as a white foam. ¹H NMR (360 MHz, DMSO-d ₆, 80 °C): δ = 9.91 (s, 1 H, NH), 7.30-7.20 (m, 3 H, H_ar), 7.15-7.05 (m, 4 H, H_ar), 6.99 (virt. t, ³ J = 7.5 Hz, 1 H, H_ar), 6.89 (d, ³ J = 7.9 Hz, 1 H, H_ar), 4.27 (s, 2 H, CH ₂Ph), 3.65 (s, 3 H, COOCH₃), 3.18 (virt. t., ³ J = 10.0 Hz, 1 H, CHCOOMe), 3.01-2.90 (m, 2 H, CHHN, COCH), 2.72-2.58 (m, 2 H, CHCHH, CHHN), 2.38-2.19 (m, 1 H, CHCHH), 2.06-1.93 (m, 1 H, CCHH), 1.86-1.73 (m, 1 H, CCHH), 1.40 [s, 9 H, C(CH₃)₃].
¹³C NMR (90.6 MHz, DMSO-d ₆, 80 °C): δ = 171.4 (COOMe), 168.8 (CONH), 154.3 (COOtBu), 138.1 (s, C_ar), 137.0 (s, C_ar), 127.9 (d, C_arH), 127.6 (d, C_arH), 127.0 (d, C_arH), 126.6 (d, C_arH), 125.7 (d, C_arH), 124.5 (s, C_ar), 122.5 (d, C_arH), 115.3 (d, C_arH), 78.7 [C(CH₃)₃], 50.9 (COOCH₃), 49.7 (CH₂Ph), 48.8 (CHCOOMe), 44.8 (CCH₂), 41.7 (CH₂N), 39.2 (CHCH₂), 33.9 (CCH₂), 27.7 [C(CH₃)₃], 24.4 (CCH₂). Anal. calcd for C₂₇H₃₂N₂O₅ (464.55): C, 69.81; H, 6.94; N, 6.03. Found: C, 69.54; H, 6.79; N, 5.87.

8 Review: Grosch B. Bach T. In CRC Handbook of Photochemistry and Photobiology   2nd ed.:  Horspool WM. Lenci F. CRC Press; Boca Raton: 2004.  p.61-1  

9 Bach T. Bergmann H. Grosch B. Harms K. Herdtweck E. Synthesis  2001,  1395 

For investigations on the binding of lactams to complexing agent 10, see:

10a Bach T. Bergmann H. Grosch B. Harms K. J. Am. Chem. Soc.  2002,  124:  7982 

10b Bach T. Grosch B. Strassner T. Herdtweck E. J. Org. Chem.  2003,  68:  1107 

10c Bergmann H. Grosch B. Sitterberg S. Bach T. J. Org. Chem.  2004,  69:  970 

10d Grosch B. Orlebar CN. Herdtweck E. Kaneda M. Wada T. Inoue Y. Bach T. Chem.-Eur. J.  2004,  10:  2179 

11

Enantioselective Intramolecular [2+2] Photocyclo-addition of Compound 8b:
A solution of 8b (20.0 mg, 5.84·10^-2 mmol) and 10 (47.6 mg, 1.35·10^-1 mmol) in toluene (8 mL) was degassed with argon. After cooling to -60 °C the solution was irradiated with a mercury high pressure arc (Original Hanau TQ 150) using a Duran filter in a merry-go-round apparatus at -60 °C for 8 h. After removal of the solvent in vacuo, the crude product was purified by flash chromatography (silica 60: 2 × 30 cm, CH₂Cl₂-MeOH = 98:2) to give 15.6 mg (78%) 2b as a white solid (93% ee); 41.3 mg of the chiral complexing agent 10 were recovered. ¹H NMR (360 MHz, CDCl₃): δ = 9.73 (s, 1 H, NH), 7.16 (dd, ³ J = 6.6 Hz, ³ J = 7.7 Hz, 1 H, H_ar), 7.08-6.95 (m, 2 H, H_ar), 6.86 (d, ³ J = 7.7 Hz, 1 H, H_ar), 3.72-3.63 (m, 2 H, NCH ₂CH₂), 3.72-3.63 and 3.45 (d, ² J = 14.0 Hz, 1 H, NCHH), 3.30 (dd, ³ J = 6.9 Hz, ³ J = 10.9 Hz, 1 H, CH), 3.22 and 3.08 (d, ² J = 14.0 Hz, 1 H, NCHH), 2.62 and 2.54 (virt. t, ³ J = 12.0 and 11.7 Hz, 1 H, CHCHH), 2.44-2.24 (m, 1 H, NCH₂CHH), 2.05 (dd, ³ J = 6.9 Hz, ³ J = 12.5 Hz, 1 H, CHCHH), 1.90-1.77 (m, 1 H, NCH₂CHH), 1.50 and 1.49 [s, 9 H, C(CH₃)₃], 0.79 and 0.76 (s, 3 H, CH₃). ¹³C NMR (90.6 MHz, CDCl₃): δ = 172.6 and 172.4 (CONH), 155.9 and 155.3 (COOtBu), 136.6 (s, C_ar), 128.0 (d, C_arH), 127.4 and 126.9 (d, C_arH), 124.4 and 124.2 (s, C_ar), 123.3 (d, C_arH), 116.1 (d, C_arH), 79.7 [C(CH₃)₃], 50.5 and 48.6 (NCH₂), 43.5 and 43.0 (s, C_al), 42.0 (s, C_al), 39.8 and 39.4 (NCH₂CH₂), 36.1 and 35.5 (CH), 35.2 (CHCH₂), 32.4 and 31.9 (NCH₂ CH₂), 28.5 [C(CH₃)₃], 23.5 (CH₃). [α]_D ²⁰ -31.7 (c 0.4, CHCl₃). HRMS (EI): m/z calcd for C₂₀H₂₆N₂O₃: 342.1943. Found: 342.1935.