Short and Simple Method of
Synthesis of Some Pyrrolo[3,2-b]quinoline Derivatives
from Easily Available Nitrobenzene Derivatives

Zbigniew Wróbel; Krzysztof Wojciechowski; Andrzej Kwast; Norbert Gajda

doi:10.1055/s-0030-1258555

Subscribe to RSS

Please copy the URL and add it into your RSS Feed Reader.

https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000083.xml

Share / Bookmark

Facebook X Linkedin Weibo

Download PDF

Synlett 2010(16): 2435-2438
DOI: 10.1055/s-0030-1258555

LETTER

Short and Simple Method of Synthesis of Some Pyrrolo[3,2-b]quinoline Derivatives from Easily Available Nitrobenzene Derivatives

Zbigniew Wróbel*, Krzysztof Wojciechowski, Andrzej Kwast, Norbert Gajda
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44, POB 58, 01-224 Warszawa 42, Poland
Fax: +48(22)6326681; e-Mail: wrobel@icho.edu.pl;

Further Information

Publication History

Received 2 July 2010
Publication Date:
03 September 2010 (online)

Abstract
Full Text
References

Permissions and Reprints All articles of this category

Abstract

The Vilsmeier-Hack condensation of ortho-cyanomethylated nitroarenes with N-methylpyrrolidone, followed by cyclization promoted by O,N-bistrimethylsilylacetamide and DBU in DMF led directly to pyrrolo[3,2-b]quinoline derivatives.

Key words

indoles - cyclization - fused-ring systems - heterocycles - annulation

References and Notes

1a Wróbel Z. Tetrahedron Lett. 1997, 38: 4913

Google Scholar
1b Wróbel Z. Tetrahedron 1998, 54: 2607

Google Scholar
1c Bujok R. Kwast A. Cmoch P. Wróbel Z. Tetrahedron 2010, 66: 698

Google Scholar
2 Wróbel Z. Eur. J. Org. Chem. 2000, 521

Crossref Google Scholar
3 Korda A. Wróbel Z. Synlett 2003, 1465

Article in Thieme Connect Google Scholar
4 Bobin M. Kwast A. Wróbel Z. Tetrahedron 2007, 63: 11048

Crossref Google Scholar
5 Wróbel Z. Synlett 2004, 1929

Article in Thieme Connect Google Scholar
6 Wróbel Z. Kwast A. Mąkosza M. Synthesis 1993, 31

Article in Thieme Connect Google Scholar
7 Wróbel Z. Mąkosza M. Tetrahedron 1993, 49: 5315

Crossref Google Scholar
8a Mąkosza M. Winiarski J. Acc. Chem. Res. 1987, 20: 282

Google Scholar
8b Mąkosza M. Wojciechowski K. Liebigs Ann./Recl. 1997, 1805

Google Scholar
8c Mąkosza M. Kwast A. J. Phys. Org. Chem. 1998, 11: 341

Google Scholar
9a Mardenborough L. Zhu X. Fan P. Jacob M. Khan S. Walkerb L. Ablordeppey S. Bioorg. Med. Chem. 2005, 13: 3955 ; and references cited therein

Google Scholar
9b Lavrado J. Paulo A. Gut J. Rosenthal PJ. Moreira R. Bioorg. Med. Chem. Lett. 2008, 18: 1378

Google Scholar
10a Parrick J. Wilcox RJ. Chem. Soc., Perkin Trans. 1 1976, 2121

Google Scholar
10b Clark BAJ. Parrick J. West PJ. Kelly AH. J. Chem. Soc. 1970, 498

Google Scholar
10c Khan H. Rocha J. Heterocycles 1977, 6: 1927

Google Scholar
10d Davydova NK. Solov’eva NP. Chistyakov VV. Marchenko NB. Glushkov RG. Khim. Geterotsikl. Soedin. 1989, 5: 633

Google Scholar
11a Zalkow L. Nabors J. French K. Bisarya S. J. Chem. Soc. C 1971, 3552

Google Scholar
11b Akue-Gedu R. Gautret P. Lelieur J.-P. Rigo B. Synthesis 2007, 3319 ; and references cited therein

Google Scholar
12 Boisse T. Gautret P. Rigo B. Goossens L. Henichart J.-P. Gavara L. Tetrahedron 2008, 64: 7266

Crossref Google Scholar
13a Sharma S. Kundu B. Tetrahedron Lett. 2008, 49: 7062

Google Scholar
13b Jones G. McKinley WH. J. Chem. Soc., Perkin Trans. 1 1979, 599

Google Scholar
14 Szmuszkovicz J. Baczynskyj L. Chidester C. Duchamp D. J. Org. Chem. 1976, 41: 1743

Crossref Google Scholar
15 Popowycz F. Mérour J.-Y. Joseph B. Tetrahedron 2007, 63: 8689

Crossref Google Scholar
16 Mąkosza M. Wróbel Z. Rev. Roum. Chim. 1991, 36: 563 ; Chem. Abstr. 1992, 117, 26036

Google Scholar

17

General Procedure for the Synthesis of 5 from 2: The cyanomethylated nitroarene 2 (2 mmol) dissolved in anhyd N-methylpyrrolidone (10 mL) was cooled to 0 ˚C and Et₃N (3 mL) was added followed by slow addition of POCl₃ (0.5 mL). The cooling bath was then removed, and the reaction mixture was stirred for 30 min at r.t. The mixture was treated with diluted, cold, aq NaCl (200 mL) and extracted with EtOAc (3 × 50 mL). The combined extracts were washed with brine and dried with Na₂SO₄. The solvent was evaporated and the residue was chromatographed on SiO₂ using hexane-EtOAc mixture as an eluent. The obtained 3 (0.5 mmol) was dissolved in anhyd DMF (3 mL). BSA (2.5 mmol, 0.6 mL) and DBU (2.5 mmol, 0.38 mL) were added subsequently. The reaction mixture was stirred for the time, and at the temperature specified in Table [¹] , then it was poured into diluted aq NaCl solution (50 mL), and extracted with EtOAc (3 × 30 mL). The extracts were combined, washed with brine, dried over Na₂SO₄, and the solvent was evaporated. The residue was chromatographed on SiO₂ using hexane-EtOAc mixture as an eluent.

18

Analytical data for the products: (2 E , Z )-(5-Chloro-2-nitrophenyl)(1-methylpyrrolidin-2-ylidene)acetonitrile (3a): red crystals; mp 112-115 ˚C. Two isomers, M (major)/N (minor) = 1.4. ^¹H NMR (500 MHz, CDCl₃): δ = 1.85-1.92 (m, 2 H, N), 2.00-2.10 (m, 2 H, M), 2.37 (t, J = 7.7 Hz, 2 H, N), 2.47 (s, 3 H, M), 3.06 (t, J = 7.7 Hz, 2 H, M), 3.38 (s, 3 H, N), 3.50-3.58 (m, 2 H, M + 2 H, N), 7.34-7.38 (m, 1 H, M + 1 H, N), 7.44 (d, J = 2.0 Hz, 1 H, M), 7.46 (d, J = 2.0 Hz, 1 H, N), 7.82 (d, J = 8.7 Hz, 1 H, N), 7.88 (d, J = 8.7 Hz, 1 H, M). MS (EI, 70 eV): m/z (%) = 277 (21), 137 (100). HRMS (EI): m/z calcd for C₁₃H₁₂N₃O₂ ^³5Cl: 277.0618; found: 277.0615. (2 E , Z )-(5-Bromo-2-nitrophenyl)(1-methyl-pyrrolidin-2-ylidene)acetonitrile (3b): red crystals; mp 105-107 ˚C (EtOH). Two isomers, M (major)/N (minor) = 1.3. ^¹H NMR (500 MHz, CDCl₃): δ = 1.85-1.92 (m, 2 H, N), 2.00-2.10 (m, 2 H, M), 2.37 (t, J = 7.6 Hz, 2 H, N), 2.47 (s, 3 H, M), 3.06 (t, J = 7.8 Hz, 2 H, M), 3.38 (s, 3 H, N), 3.50-3.58 (m, 2 H, M + 2 H, N), 7.34-7.38 (m, 1 H, M + 1 H, N), 7.44 (d, J = 2.0 Hz, 1 H, M), 7.46 (d, J = 2.0 Hz, 1 H, N), 7.82 (d, J = 8.7 Hz, 1 H, N), 7.88 (d, J = 8.7 Hz, 1 H, M). MS (EI, 70 eV): m/z (%) = 323 (10), 321 (10), 137 (100). HRMS (EI): m/z calcd for C₁₃H₁₂N₃O₂ ⁷⁹Br: 321.0113; found: 321.0118. (2 E , Z )-(5-Fluoro-2-nitrophenyl)(1-methylpyrrolidin-2-ylidene)acetonitrile (3c): orange crystals; mp 120-121 ˚C (hexane-EtOAc). Two isomers, M (major)/N (minor) = 1.4. ^¹H NMR (500 MHz, CDCl₃): δ = 1.84-1.92 (m, 2 H, N), 2.00-2.11 (m, 2 H, M), 2.38 (t, J = 7.7 Hz, 2 H, N), 2.47 (s, 3 H, M), 3.06 (t, J = 7.8 Hz, 2 H, M), 3.39 (s, 3 H, N), 3.50-3.58 (m, 2 H, M + 2 H, N), 7.05-7.10 (m, 1 H, M + 1 H, N), 7.12-7.17 (m, 1 H, M + 1 H, N), 7.92 (dd, J = 8.8, 5.3 Hz, 1 H, N), 7.99 (dd, J = 8.9, 5.3 Hz, 1 H, M). MS (EI, 70 eV): m/z (%) = 261 (11), 137 (100). HRMS (EI): m/z calcd for C₁₃H₁₂N₃O₂F: 261.0914; found: 261.0925. (2 E , Z )-(5-Methoxy-2-nitrophenyl)(1-methylpyrrolidin-2-ylidene)acetonitrile (3d):^¹6 red crystals; mp 89-92 ˚C. Two isomers, M (major)/N (minor) = 2. ^¹H NMR (500 MHz, CDCl₃): δ = 1.82-1.88 (m, 2 H, N), 2.00-2.09 (m, 2 H, M), 2.34 (t, J = 7.7 Hz, 2 H, N), 2.44 (s, 3 H, M), 3.06 (t, J = 7.7 Hz, 2 H, M), 3.44-3.65 (m, 2 H, M + 2 H, N), 3.88 (s, 3 H, N), 3.89 (s, 3 H, M), 3.99 (s, 3 H, N), 6.86-6.90 (m, 2 H, M + 2 H, N), 7.97 (d, J = 9.0 Hz, 1 H, N), 8.02 (d, J = 9.0 Hz, 1 H, M). MS (EI, 70 eV): m/z (%) = 274 (14), 137 (100). Anal. Calcd for C₁₄H₁₅N₃O₃: C, 61.53; H, 5.53; N, 15.38. Found: C, 61.59; H, 5.46; N, 15.22.
(2 E , Z )-(1-Methylpyrrolidin-2-ylidene)[2-nitro-5-(phenylthio)phenyl]acetonitrile (3e): red crystals; mp 147-151 ˚C (hexane-EtOAc). Two isomers, M (major)/N (minor) = 1.5. ^¹H NMR (500 MHz, CDCl₃): δ = 1.80-1.88 (m, 2 H, N), 1.95-2.10 (m, 2 H, M), 2.30 (t, J = 7.6 Hz, 2 H, N), 2.42 (s, 3 H, M), 3.00-3.05 (m, 2 H, M), 3.36 (s, 3 H, N), 3.46-3.56 (m, 2 H, M + 2 H, N), 6.99-7.06 (m, 1 H, M + 1 H, N), 7.15 (d, J = 2.0 Hz, 1 H, M), 7.17 (d, J = 1.9 Hz, 1 H, N), 7.42-7.47 (m, 3 H, M + 3 H, N), 7.50-7.55 (m, 2 H, M + 2 H, N), 7.76 (d, J = 8.6 Hz, 1 H, N), 7.82 (d, J = 8.6 Hz, 1 H, M). MS (EI, 70 eV): m/z (%) = 351 (38), 252 (76), 223 (54), 137 (100). HRMS (EI): m/z calcd for C₁₉H₁₇N₃SO₂: 351.1041; found: 351.1050. (2 E , Z )-(3,5-Dichloro-2-nitrophenyl)(1-methylpyrrolidin-2-ylidene)acetonitrile (3f): pale yellow crystals; mp 163-167 ˚C (hexane-EtOAc). Two isomers, M/N = 1. ^¹H NMR (500 MHz, CDCl₃): δ = 1.85-1.92 (m, 2 H, N), 1.98-2.06 (m, 2 H, M), 2.43 (t, J = 7.8 Hz, 2 H, M or N), 2.56 (s, 3 H, M or N), 2.96-3.02 (m, 2 H, M or N), 3.33 (s, 3 H, M or N), 3.48-3.55 (m, 2 H, M + 2 H, N), 7.33 (d, J = 2.1 Hz, 1 H, M or N), 7.33 (d, J = 2.0 Hz, 1 H, M or N), 7.45 (d, J = 2.0 Hz, 1 H, M or N), 7.46 (d, J = 2.1 Hz, 1 H, M or N). MS (EI, 70 eV): m/z (%) = 311 (9), 137 (100). HRMS (EI): m/z calcd for C₁₃H₁₁N₃O₂ ^³5Cl₂: 311.0228; found: 311.0222. (2 E , Z )-(5-Chloro-3-methoxy-2-nitrophenyl)(1-methylpyrrolidin-2-ylidene)- acetonitrile (3g): yellow crystals; mp 146-149 ˚C (EtOH). Two isomers, M (major)/ N (minor) = 1.2. ^¹H NMR (500 MHz, CDCl₃): δ = 1.82-1.90 (m, 2 H, N), 1.96-2.04 (m, 2 H, M), 2.44 (t, J = 7.8 Hz, 2 H, N), 2.57 (s, 3 H, M), 2.95-3.01 (m, 2 H, M), 3.32 (s, 3 H, N), 3.46-3.54 (m, 2 H, M + 2 H, N), 6.96-7.00 (m, 2 H, M + 2 H, N). MS (EI, 70 eV): m/z (%) = 307 (24), 137 (100). 7-Chloro-1-methyl-1 H -pyrrolo[3,2- b ]quinoline-9-carbonitrile (5a): yellow crystals; mp 198-201 ˚C. ^¹H NMR (500 MHz, THF-d ₈): δ = 4.19 (s, 3 H), 6.79 (d, J = 3.5 Hz, 1 H), 7.65 (dd, J = 9.1, 2.3 Hz, 1 H), 7.86 (d, J = 3.5 Hz, 1 H), 8.14 (d, J = 9.1 Hz, 1 H), 8.19 (d, J = 2.3 Hz, 1 H). ^¹³C NMR (125 MHz, THF-d ₈): δ = 34.8, 94.5, 103.4, 115.5, 123.4, 124.8, 128.8, 129.7, 132.8, 133.2, 142.4, 143.3, 152.6. MS (EI, 70 eV): m/z (%) = 241 (100), 240 (31), 179 (5). HRMS (EI): m/z calcd for C₁₃H₈N₃ ^³5Cl: 241.0407; found: 241.0410. 7-Bromo-1-methyl-1 H -pyrrolo[3,2- b ]quinoline-9-carbonitrile (5b): yellow crystals; mp 209-211 ˚C. ^¹H NMR (500 MHz, THF-d ₈): δ = 4.20 (s, 3 H), 6.80 (d, J = 3.5 Hz, 1 H), 7.78 (dd, J = 8.9, 2.2 Hz, 1 H), 7.88 (d, J = 3.5 Hz, 1 H), 8.07 (d, J = 8.9 Hz, 1 H), 8.36 (d, J = 2.2 Hz, 1 H). ^¹³C NMR (125 MHz, THF-d ₈): δ = 33.8, 93.4, 102.4, 114.5, 120.4, 124.3, 125.7, 128.6, 130.4, 131.8, 141.6, 142.4, 151.6. MS (EI, 70 eV):
m/z (%) = 287 (88), 285 (100), 205 (10), 179 (9). HRMS (EI): m/z calcd for C₁₃H₈N₃ ⁷⁹Br: 284.9902; found: 284.9911. 7-Fluoro-1-methyl-1 H -pyrrolo[3,2- b ]quinoline-9-carbonitrile (5c): pale green crystals; mp 182-185 ˚C (hexane-EtOAc). ^¹H NMR (500 MHz, THF-d ₈): δ = 4.18 (s, 3 H), 6.79 (d, J = 3.5 Hz, 1 H), 7.53 (ddd, J = 9.3, 8.1, 2.8 Hz, 1 H), 7.83 (d, J = 3.5 Hz, 1 H), 7.84 (ddd, J = 9.7, 2.8, 0.5 Hz, 1 H), 8.19 (ddd, J = 9.3, 5.7, 0.5 Hz, 1 H). ^¹³C NMR (125 MHz, THF-d ₈): δ = 34.8, 94.7 (d, J _C-F = 5.9 Hz), 103.4, 107.8 (d, J _C-F = 24.5 Hz), 115.7, 118.4 (d, J _C-F = 26.4 Hz), 125.1 (d, J _C-F = 10.2 Hz), 129.7, 133.8 (d, J _C-F = 9.3 Hz), 141.6 (d, J _C-F = 1.0 Hz), 142.1, 151.9 (d, J _C-F = 2.4 Hz), 161.8 (d, J _C-F = 247.8 Hz). MS (EI, 70 eV): m/z (%) = 225 (100), 197 (15), 183 (10), 171 (6). HRMS (EI): m/z calcd for C₁₃H₈N₃F: 225.0702; found: 225.0709. 7-Methoxy-1-methyl-1 H -pyrrolo[3,2- b ]quinoline-9-carbonitrile (5d): yellow crystals; mp 217-218 ˚C (EtOAc). ^¹H NMR (400 MHz, THF-d ₈): δ = 3.99 (s, 3 H), 4.16 (s, 3 H), 6.73 (d, J = 3.5 Hz, 1 H), 7.32 (dd, J = 9.3, 2.8 Hz, 1 H), 7.45 (d, J = 2.8 Hz, 1 H), 7.69 (d, J = 3.5 Hz, 1 H), 8.03 (dd, J = 9.3, 0.3 Hz, 1 H). ^¹³C NMR (100 MHz, THF-d ₈): δ = 34.7, 55.9, 93.8, 101.8, 103.3, 116.3, 121.5, 125.9, 129.5, 132.6, 139.8, 141.4, 150.0, 159.6. MS (EI, 70 eV): m/z (%) = 237 (100), 222 (39), 194 (69). HRMS (EI): m/z calcd for C₁₄H₁₁N₃O: 237.0902; found: 237.0896. 1-Methyl-7-(phenylthio)-1 H -pyrrolo[3,2- b ]quinoline-9-carbonitrile (5e): yellow crystals; mp 186-188 ˚C (EtOAc). ^¹H NMR (500 MHz, THF-d ₈): δ = 4.16 (s, 3 H), 6.76 (d, J = 3.5 Hz, 1 H), 7.30-7.40 (m, 3 H), 7.46-7.49 (m, 2 H), 7.50 (dd, J = 9.0, 2.0 Hz, 1 H), 7.81 (J = 3.5 Hz, 1 H), 8.05 (J = 9.0, 0.5 Hz, 1 H), 8.11 (J = 2.0, 0.5 Hz, 1 H). ^¹³C NMR (125 MHz, THF-d ₈): δ = 33.8, 93.5, 102.3, 114.6, 123.6, 123.7, 127.8, 128.6, 128.7, 129.4, 130.8, 132.1, 134.2, 135.7, 140.8, 142.9, 151.1. MS (EI, 70 eV): m/z (%) = 315 (100), 299 (12), 194 (8). HRMS (EI): m/z calcd for C₁₉H₁₃N₃S: 315.0830; found: 315.0837. 5,7-Dichloro-1-methyl-1 H -pyrrolo[3,2- b ]quinoline-9-carbonitrile (5f): pale brown crystals; mp 252 ˚C (dec.). ^¹H NMR (500 MHz, THF-d ₈): δ = 4.22 (s, 3 H), 6.91 (d, J = 3.5 Hz, 1 H), 7.90 (d, J = 2.2 Hz, 1 H), 7.96 (d, J = 3.5 Hz, 1 H), 8.17 (d, J = 2.2 Hz, 1 H). ^¹³C NMR (125 MHz, THF-d ₈): δ = 34.8, 95.3, 103.8, 115.3, 122.8, 125.6, 128.8, 130.0, 132.2, 136.4, 139.4, 143.5, 152.7. MS (EI, 70 eV): m/z (%) = 277 (70), 275 (100). HRMS (EI): m/z calcd for C₁₃H₇N₃ ^³5Cl₂: 275.0017; found: 275.0025. 7-Chloro-5-methoxy-1-methyl-1 H -pyrrolo[3,2- b ]quinoline-9-carbonitrile (5g): pale brown crystals; mp >250 ˚C. ^¹H NMR (500 MHz, THF-d ₈): δ = 4.06 (s, 3 H), 4.19 (s, 3 H), 6.82 (d, J = 3.5 Hz, 1 H), 7.08 (d, J = 2.0 Hz, 1 H), 7.75 (d, J = 2.0 Hz, 1 H), 7.83 (d, J = 3.5 Hz, 1 H). ^¹³C NMR (125 MHz, THF-d ₈): δ = 34.7, 56.6, 94.2, 103.9, 107.8, 114.9, 115.8, 125.7, 129.7, 133.7, 136.0, 141.6, 150.9, 158.4. MS (EI, 70 eV): m/z (%) = 271 (95), 242 (100), 236 (35), 206 (11). HRMS (EI): m/z calcd for C₁₄H₁₀N₃O^³5Cl: 271.0512; found: 271.0519.