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DOI: 10.1055/s-2008-1078567
Synthesis of New Pyrrolobenzazepines via Pictet-Spengler Cyclization
Publication History
Publication Date:
02 July 2008 (online)
Abstract
A new six-step divergent strategy was developed allowing access to pyrrolobenzazepine structures from pyrrole. This strategy was based on a regioselective Friedel-Crafts acylation followed by a Pictet-Spengler cyclization.
Key words
azepine - pyrrole - fused-ring systems - Pictet-Spengler reaction
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References and Notes
The X-ray crystal structure has been filed with the Cambridge Crystallographic Centre with deposition number CCDC 640594.
19
General Procedure
for Preparation of Compounds 10-13
To a stirred
1 M solution of amine 6, 7, 8, or 9 in anhyd toluene
was added the para-substituted benzaldehyde derivative
(1.1 equiv), under argon atmosphere (in the case of amines 8 and 9, 4 equiv
of MgSO4 were added). The mixture was heated at reflux
until total conversion of the amine into the intermediary imine
(followed by ¹H NMR). Then, the mixture was
cooled to r.t. to add TFA (5 or 10 equiv). The resulting mixture
was left at specified temperature (r.t. or 70 ˚C)
until completion of the reaction. Residual TFA was neutralized at
0 ˚C with an aq sat. NaHCO3 solution.
The reaction mixture was extracted with CH2Cl2.
The combined organic layers were successively washed with H2O
and brine, dried over MgSO4, filtered, and solvents removed
under reduced pressure. The crude product was purified by flash
chromatography.
Analytical Data of
Compound 11a
Pale yellow solid obtained in 98% yield
after flash chromatography (cyclohexane-EtOAc, 9:1). ¹H
NMR (300 MHz, CDCl3): δ = 2.33
(s, 3 H), 3.63 (d, J = 16.2
Hz, 1 H), 3.73 (br s, 1 H), 4.14 (d, 16.2 Hz, 1 H), 6.06 (m, 1 H),
6.08 (dd, J = 1.3,
7.3 Hz, 1 H), 6.28 (d, J = 3.4
Hz, 1 H), 6.73 (d, J = 8.3
Hz, 2 H), 6.85 (m, 2 H), 6.97 (d, J = 8.3
Hz, 2 H), 7.04 (d, J = 8.3
Hz, 2 H), 7.11 (dd, J = 1.3,
7.1 Hz, 1 H), 7.15 (d, J = 8.3
Hz, 2 H), 7.30 (d, J = 3.4
Hz, 1 H). HRMS: m/z = 439.5326.
General Procedure
for Preparation of Compounds 14-17
A mixture
of the azepine 10a-e, 11a-e, 12a-e,
or 13a-e (1 equiv)
and TBAF 1 M solution in THF (10 equiv) was heated at 70 ˚C
for 10 h. The mixture was washed with H2O. The aqueous
phase was extracted with CH2Cl2. The combined organic
layers were dried over MgSO4, filtered, and solvents removed
under reduced pressure. The crude product was purified by flash
chromatography.
Analytical Data of
Compound 15a
Yellow solid obtained in 88% yield
after flash chromatography (heptane-EtOAc, 8:2). ¹H
NMR (300 MHz, CDCl3): δ = 3.75
(s, 2 H), 6.21 (t, J = 2.6
Hz, 1 H), 6.93 (t, J = 2.6
Hz, 1 H), 7.2 (dd, J = 1.7,
6.6 Hz, 1 H), 7.22 (td, J = 1.7,
6.6 Hz, 1 H), 7.29 (td, J = 1.7,
6.6 Hz, 1 H), 7.48 (dd, J = 1.7,
7.2 Hz, 1 H), 7.76 (d, J = 8.3
Hz, 2 H), 8.0 (d, J = 8.3
Hz, 2 H), 8.24 (br s, 1 H). ¹³C NMR
(300 MHz, CDCl3): δ = 32.6,
108.7, 114.1, 118.9, 123.3, 123.5, 126.9, 127.8, 128.2, 128.7, 130.5,
132.0, 132.8, 133.4, 144.2, 147.0, 155.0. HRMS: m/z = 437.5148.