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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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  • A derivative of 5-pyrazole aldehyde was attempted as a substrate for the cyclization reaction with 1a under the conditions described above (Scheme 4). However, the only product detected in the reaction mixture was the corresponding imine (73% yield). Attempts to cyclize this intermediate under a variety of experimental conditions, including diverse catalysts (BF3·OEt2, TiCl4, and FeCl3) or temperature (boiling in xylenes or chlorobenzene in the presence of p-TsOH or camphorsulphonic acid) were not successful. This result may be attributed to the unfavorable thermodynamics for the formation of this [5,5] fused system. Notably, the attempted reactions of the 2-pyridyl aldehyde derivatives with a single or no Me substituent at the double bond failed as well, presumably due to the insufficient electron density on the olefinic fragment. Similar difficulties in the intramolecular cycloaddition reactions for the formation of fused have been reported, see for example:
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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).