ACS Combinatorial Science
ARTICLE
(3-20) in the unit cell. One (conformation A) is forming an
intramolecular hydrogen bridge between the amide and the pyridine
nitrogen, whereas the morpholinoethyl side chain is stretched. In the
second molecule (conformation B) themorpholinoethyl side chain
is bent back to the amide group to form a bifurcated hydrogen
bond; the NH comprises a bifurcated hydrogen bond donor.
Such intramolecular hydrogen bonds can be actively used in
drug design and have a pronounced effect on key compound
parameters such as membrane permeability, water solubility, and
lipophilicity.35
Not surprisingly the amidine substructure in 3-20 forms an
intermolecular hydrogen bond to the amide carbonyl but also
intermolecular and trifurcated hydrogen bonds to carbonyls of
adjacent molecules.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: asd30@pitt.edu. Fax: þ1 412-383-5298. Tel: þ1 412-
383-5300.
Author Contributions
A.D. conceived and designed the experiments. K.W. performed
the experiments. E.H. performed the X-ray diffraction.
Funding Sources
This research has been partially supported by NIH (1R21GM-
087617-01A1, 1R01GM097082-01 and 1P41GM094055-01) and
the University of Pittsburgh.
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’ CONCLUSION
In summary, we have described a highly efficient one-pot
sequence toward 2-amino indole-type molecules involving an
aromatic substitution and a subsequent reduction/cyclization pro-
cess. Significantly, heteroaromates are substrates for this reaction
sequence. Scope and limitation of the sequence are described.
Further work is being performed in our laboratory to investigate
the extraordinary biological activities of these molecules and will
be reported in due course.
’ EXPERIMENTAL PROCEDURES
General Two-Step, One-Pot Procedure for Preparing 2-
Amino-N-butyl-1H-indole-3-carboxamide (3-1). Cyanoace-
tamide (1a, 2.0 mmol, 1.0 equiv.) in dry DMF (0.5 M) and
NaH (60% dispersion in mineral oil, 2.2 mmol, 2.2 equiv) were
added to a 50 mL flask equipped with stir bar. After 10 min,
2-fluoronitrobenzene (2a, 2.0 mmol, 1.0 equiv) was added, and
the reaction mixture was stirred at room temperature for 1 h. The
reaction mixture became deep purple. Then 1.0 N HCl (4.0 mmol,
2.0 equiv) was added, following FeCl3 (6.0 mmol, 3 equiv.) and
Zn dust (20 mmol, 10 equiv.). The reaction mixture was heated
to 100 °C for 1 h. The reaction mixture was cooled down, and
20 mL of water was added to the crude reaction mixture. The
crude reaction mixture was filtered, washed with 25 mL of ethyl
acetate. The solution was extracted with ethyl acetate (20 mL ꢀ 2).
The combined organic phase was washed by saturated sodium
bicarbonate solution (10 mL) and brine (10 mL). The organic
phase was dried with anhydrous sodium sulfate and the solvent was
removed. The crude product was purified by short silica gel column
chromatography with 5% methanol in ethyl acetate to generate
393 mg (85%) the title compound as a yellow solid. HRMS ESL-
TOF for C13H17N3ONa (M þ Naþ) Found: m/z 254.1288. Calcd
Mass: 254.1269. 1H NMR (DMSO-d6, 600 MHz): δ 10.54 (s, 1H),
7.53 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 6.93 (t, J = 7.8 Hz,
1H), 6.85 (t, J = 7.8 Hz, 1H), 6.70 (s, 2H), 6.67 (t, J = 6.6 Hz, 1H),
3.27 (m, 2H), 1.51 (m, 2H), 1.32 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H)
ppm. 13C NMR (DMSO-d6, 150 MHz): δ 167.2, 152.8, 132.7, 125.7,
120.2, 118.8, 116.8, 110.1, 86.8, 38.5, 32.5, 20.2, 14.3 ppm.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental methods of the
b
products, NMR data of all new compounds, and X-ray data of
compound 3-20. This material is available free of charge via the
(13) Hajduk, P. J.; Boyd, S.; Nettesheim, D.; Nienaber, V.; Severin,
J.; Smith, R.; Davidson, D.; Rockway, T.; Fesik, S. W. Identification of
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dx.doi.org/10.1021/co100040z |ACS Comb. Sci. 2011, 13, 140–146