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Synlett 2006(3): 0391-0394  
DOI: 10.1055/s-2006-926236
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Domino Cyclization Reaction of Iminium Salts: A Convenient Route to Hexahydrobenzo[b]phenanthrolines

Alexander S. Kiselyov*
Small Molecule Drug Discovery, Chemical Diversity, Inc., 11558 Sorrento Valley Rd., Suite 5, San Diego, CA 92121, USA
Fax: +1(858)7944931; e-Mail: ask@chemdiv.com;
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Publication History

Received 27 September 2005
Publication Date:
06 February 2006 (online)

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Abstract

An efficient synthesis of hexahydrobenzo[b]phenan­throlines is described. These compounds are prepared by the reaction of anilines with the prenylated derivatives of 2-, 3- and 4-pyridine carboxaldehydes. This reaction is catalyzed by both 5% TFA and 1% Yb(OTf)3 in MeCN to furnish the targeted products as a 1:1 mixture of diastereomers in a high yields (63-89%).

Key words

domino cyclizations - iminium salts - hexahydrobenzo[b]phenanthroline

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Prepared in a 31% overall yield by a three-step procedure, as shown in Scheme [3] . The same protocol was used for the synthesis of the respective derivatives of 3- and 4-pyridyl aldehydes (18% and 26% overall yields for the three step sequence, respectively).

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For preparative chromatography we used a Phenomenex Prodigy 5µ ODS(3) 100A 21.2 mm × 250 mm column on Waters DeltaPrep4000 HPLC instrument. The solvent system was MeCN-H2O (start: 20:80; finish 60:40 ratio; 15 min run; 0.05% of formic acid added) with a flow rate of 20 mL/min.

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Experimental Procedure. A solution of aldehyde (1.1 mmol) in MeCN (5 mL) was added to a solution of aniline 1 (1 mmol) in the same solvent (5 mL) followed by 5 mL of TFA. The resulting mixture was stirred for 4 h until LCMS analysis indicated complete conversion of the starting materials to the condensation product(s) 2 or 3. The mixture was concentrated in vacuo to ca. 1 mL, diluted with 25 mL of EtOAc. The organic phase was washed with concentrated NaHCO3 (2 × 20 mL), dried over Na2SO4 and concentrated. For the products 2c/2c′, the precipitate was collected, washed with cold MeCN (1 mL) and Et2O (5 mL) do afford a mixture of diastereomers, 1:1 ratio. The residues were further purified by prep-HPLC to yield analytically pure materials. Isolated ratio of diastereomers 2/2′ or 3/3′ was similar to that observed in the reaction mixtures by 1H NMR and LC MS analyses (ca. 1:1).
Analytical Data for Representative Examples.
rac -(6a S ,12a S )-9-Fluoro-7,7-dimethyl-5,6,6a,7,12,12a-hexahydrobenzo[ b ][1,10]phenanthroline ( 2a): 40% isolated yield, mp 213-215 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 1.35 (s, 6 H), 1.42 (m, 1 H), 1.73 (m, 1 H), 2.46 (m, 1 H), 2.52 (t, J = 7.6 Hz, 1 H), 2.58 (t, J = 7.6 Hz, 1 H), 3.91 (d, J = 7.2 Hz, 1 H), 4.15 (br s, 1 H, exch. D2O), 6.35 (d, J = 8.0 Hz, 1 H), 6.48 (d, J = 8.0 Hz, 1 H), 6.81 (s, 1 H), 7.20 (dd, J 1 = 7.6 Hz, J 2 = 4.0 Hz, 1 H), 7.79 (d, J = 7.6 Hz, 1 H), 8.68 (d, J = 4.0 Hz, 1 H). ESI-MS: m/z = 283 [M + 1], 281 [M - 1]. HRMS: m/z calcd for C18H19FN2: 282.1532; found: 282.1525. Anal. Calcd for C18H19FN2: C, 76.57; H, 6.78; N, 9.92. Found: C, 76.31; H, 6.94; N, 9.75.
rac -(6a S ,12a R )-9-Fluoro-7,7-dimethyl-5,6,6a,7,12,12a-hexahydrobenzo[ b ][1,10]phenanthroline (2a′): 47% isolated yield, mp 198-200 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 1.37 (s, 6 H), 1.45 (m, 1 H), 1.72 (m, 1 H), 2.49 (m, 1 H), 2.53 (t, J = 7.6 Hz, 1 H), 2.60 (t, J = 7.6 Hz, 1 H), 3.90 (d, J = 3.6 Hz, 1 H), 4.20 (br s, 1 H, exch. D2O), 6.37 (d, J = 8.0 Hz, 1 H), 6.47 (d, J = 8.0 Hz, 1 H), 6.83 (s, 1 H), 7.22 (dd, J 1 = 7.6 Hz, J 2 = 4.0 Hz, 1 H), 7.82 (d, J = 7.6 Hz, 1 H), 8.66 (d, J = 4.0 Hz, 1 H). ESI-MS: m/z = 283 [M + 1], 281 [M - 1]. Anal. Calcd for C18H19FN2: C, 76.57; H, 6.78; N, 9.92. Found: C, 76.33; H, 6.91; N, 9.71.
rac -(6 S ,12a S )-9-Fluoro-7,7-dimethyl-5,6,6a,7,12,12a-hexahydrobenzo[ b ][1,9]phenanthroline ( 3a): 36% isolated yield, mp 176-177 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 1.38 (s, 6 H), 1.43 (m, 1 H), 1.72 (m, 1 H), 2.44 (m, 1 H), 2.51 (t, J = 7.6 Hz, 1 H), 2.60 (t, J = 7.6 Hz, 1 H), 3.93 (d, J = 7.2 Hz, 1 H), 4.19 (br s, 1 H, exch. D2O), 6.39 (d, J = 8.0 Hz, 1 H), 6.54 (d, J = 8.0 Hz, 1 H), 6.75 (s, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 8.54 (d, J = 8.0 Hz, 1 H), 8.81 (s, 1 H). ESI-MS: m/z = 304 [M + 1], 302 [M - 1]. HRMS: m/z calcd for C18H26FN3: 303.2111; found: 303.2105. ESI-MS: m/z = 283 [M + 1], 281 [M - 1]. HRMS: m/z calcd for C18H19FN2: 282.1532; found: 282.1527. Anal. Calcd for C18H19FN2: C, 76.57; H, 6.78; N, 9.92. Found: C, 76.42; H, 6.86; N, 9.76.
rac -(6a S ,12a R )-9-Fluoro-7,7-dimethyl-5,6,6a,7,12,12a-hexahydrobenzo[ b ][1,9]phenanthroline (3a′): 32% isolated yield, mp 164-165 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 1.39 (s, 6 H), 1.41 (m, 1 H), 1.70 (m, 1 H), 2.47 (m, 1 H), 2.51 (t, J = 7.6 Hz, 1 H), 2.64 (t, J = 7.6 Hz, 1 H), 3.86 (d, J = 3.6 Hz, 1 H), 4.18 (br s, 1 H, exch. D2O), 6.32 (d, J = 8.0 Hz, 1 H), 6.54 (d, J = 8.0 Hz, 1 H), 6.81 (s, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 8.58 (d, J = 8.0 Hz, 1 H), 8.73 (s, 1 H). ESI-MS: m/z = 283 [M + 1], 281 [M - 1]. Anal. Calcd for C18H19FN2: C, 76.57; H, 6.78; N, 9.92. Found: C, 76.36; H, 6.63; N, 9.77.

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Observed relevant NOE (Figure [1] ; shifts of the bridge protons are indicated in ppm).