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DOI: 10.1055/s-0030-1258555
Short and Simple Method of Synthesis of Some Pyrrolo[3,2-b]quinoline Derivatives from Easily Available Nitrobenzene Derivatives
Publication History
Publication Date:
03 September 2010 (online)
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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
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References and Notes
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.
18Analytical 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 C14H10N3O³5Cl:
271.0512; found: 271.0519.