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

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%).

domino cyclizations - iminium salts - hexahydrobenzo[b]phenanthroline

References and Notes

1a Grieco P. Bahsas A. Tetrahedron Lett.  1988,  29:  5855 

1b Kiselyov AS. Armstrong RW. Tetrahedron Lett.  1997,  38:  6163 

2a Campos PJ. Lamaza I. Rodriguez MA. Canal G. Tetrahedron Lett.  1997,  38:  6741 

2b Clerici A. Porta O. Tetrahedron Lett.  1990,  31:  2069 

2c Mellor JM. Merriman GD. Tetrahedron  1995,  51:  6115 

2d Povarov LS. Russ. Chem. Rev.  1967,  36:  656 

2e Lucchini V. Prato M. Scorrano G. Tecilla P. J. Org. Chem.  1988,  53:  2251 

2f Nomura Y. Kimura M. Takeuchi S. Tomoda S. Chem. Lett.  1978,  267 

2g Annunziata R. Cinquini M. Cozzi F. Molteni V. Schupp O. Tetrahedron  1997,  53:  9715 

For the general reviews on hetero Diels-Alder reactions, see:

3a Weinreb SM. Staib RR. Tetrahedron  1982,  38:  3087 

3b Boger DL. Tetrahedron  1983,  39:  2869 

See also:

3c Babu G. Perumal PT. Tetrahedron  1998,  54:  1627 

3d Waldmann H. Angew. Chem., Int. Ed. Engl.  1988,  27:  274 

3e Kappe CO. Murphree SS. Padwa A. Tetrahedron  1997,  53:  14179 

3f Carruthers W. Cycloaddition Reactions in Organic Synthesis   Pergamon Press; Oxford: 1990. 

3g Oppolzer W. In Comprehensive Organic Synthesis   Vol. 5:  Paquette LA. Pergamon; Oxford: 1991.  p.315 

3h Pindur U. Lutz G. Otto C. Chem. Rev.  1993,  93:  741 

3i Waldmann H. Synthesis  1994,  535 

3j Lipshutz BH. Chem. Rev.  1986,  86:  795 

4a Kobayashi S. Nagayama S. J. Org. Chem.  1996,  61:  2256 

4b Kobayashi S. Nagayama S. J. Am. Chem. Soc.  1996,  118:  8977 

4c Kobayashi S. Ishitani H. Nagayama S. Synthesis  1995,  1095 

4d Kobayashi S. Araki M. Ishitani H. Nagayama S. Hachiya I. Synlett  1995,  233 

4e Kobayashi S. Ishitani H. Nagayama S. Chem. Lett.  1995,  423 

5 For synthesis of tetrahydroquinolines and their biological activity see for example: Katritzky AR. Rachwal S. Rachwal B. Tetrahedron  1996,  52:  15031 ; and references cited therein

6a Kiselyov AS. Smith L. Armstrong RW. Tetrahedron  1998,  54:  5089 

6b Kiselyov AS. Smith LS. Virgilio A. Armstrong RW. Tetrahedron  1998,  54:  7987 

7a Schulte JL. Laschat S. Kotila S. Hecht J. Fröhlich R. Wibbeling B. Heterocycles  1996,  43:  2713 

7b Laschat S. Lauterwein J. J. Org. Chem.  1993,  58:  2856 

7c Twin H. Batey RA. Org. Lett.  2004,  6:  4913 

7d Powell DA. Batey RA. Tetrahedron Lett.  2003,  44:  7569 

7e Powell DA. Batey RA. Org. Lett.  2002,  4:  2913 

8a Yadav JS. Reddy BVS. Narsimhaswamy D. Lakshmi PN. Narsimulu K. Srinivasulu G. Kunwar AC. Tetrahedron Lett.  2004,  45:  3493 

8b Gowravaram S. Venkata RE. Narjis F. Yadav JS. Rama Krishna KVS. Kunwar AC. Synthesis  2004,  1150 

8c Gowravaram S. Reddy EV. Yadav JS. Rama Krishna KVS. Sankar AR. Tetrahedron Lett.  2002,  43:  4029 

9 Zhang D. Kiselyov AS. Synlett  2001,  1173 

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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.

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:

12a Wu H.-J. Lin S.-H. Lin C.-C. Heterocycles  1994,  38:  1507 

12b Cattal M. Cossu S. Fabris F. DeLucci O. Synth. Commun.  1996,  26:  637 

12c Burrell SJ. Derome AE. Edenborough MS. Harwood LM. Leeming SA. Isaacs NS. Tetrahedron Lett.  1985,  26:  2229 

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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).