: petroleum ether) indicated a new product had formed. The
reaction mixture was filtered and the filtrate concentrated to
dryness under reduced pressure. The resulting brown oil was
crystallised from DCM, to yield cream crystals which were
collected using a Hirsch Funnel (1.253 g, 44%); mp 178.7–
column chromatography (75 : 25 EtOAc : petroleum ether, silica).
The desired fractions were combined and the solvent removed
under reduced p◦ressure, to afford a yellow solid (0.369 g, 46%);
mp 182.1–184.5 C; dH(270 MHz; DMSO-d6, TMS) 3.54 (1H, s,
H1ꢀ), 3.72 (1H, s, H2ꢀ), 7.05 (1H, t, J = 4.8, H5), 7.14 (1H, s, H3),
7.18 (1H, t, J = 4.9, H6), 7.42 (1H, d, J = 5.5, H4), 7.62 (2H, d, J =
2.6, H2ꢀꢀ and 6ꢀꢀ), 7.64 (1H, d, J = 3.4, H7), 7.71 (2H, d, J = 5.7, H3ꢀꢀ
and 5ꢀꢀ), 8.20 (1H, s, C(O)NHCH2), 8.63 (1H, s, amide NH), 9.97
(1H, s, C(O)NHAr), 11.60 (1H, s, H1); dC(270 MHz; DMSO-d6,
TMS) 38.66, 44.01, 103.13, 112.86, 120.27, 122.02, 122.55, 123.60,
123.84, 126.29, 127.63, 132.20, 136.98, 143.75, 162.03, 181.15;);
dF (270 MHz; DMSO-d6, TMS) −59.96, m/z (HRMS) 407.11305
([M + H]+. C19H18N4OF3S requires 407.11479).
◦
180.3 C; dH(270 MHz; DMSO-d6, TMS) 1.38 (9H, s, C(CH3)3),
3.13 (2H, s, H2ꢀ), 3.35 (2H, s, H1ꢀ), 6.94 (1H, s, H3), 7.05 (1H, t,
J = 5.2, H5), 7.09 (1H, s, OC(O)NH), 7.15 (1H, t, J = 5.4, H6),
7.41 (1H, d, J = 5.7, H7), 7.61 (1H, d, J = 5.4, H4), 8.50 (1H, s,
C(O)NH), 11.58 (1H, s, H1); dC(270 MHz; DMSO-d6, TMS) 28.79,
39.62, 40.37, 78.27, 102.97, 112.83, 120.21, 121.98, 123.75, 127.62,
132.28, 136.94, 156.27, 161.83; m/z (HRMS) 607.32259 ([M2 +
H]+. C32H43N6O6 requires 607.32386)
2-[(2ꢀ-Amino)ethylamido]indole 7
2-[6ꢀ-(tert-Butoxycarbonylamino)hexylamido]indole 6
To a solution of protected indole 5 (1.253 g, 4.14 mmol) in
chloroform (60 mL), trifluoroacetic acid (15 mL) was added slowly.
The reaction was stirred under an atmosphere of nitrogen for
4 hours. The reaction was monitored by TLC (75 : 25 EtOAc :
petroleum ether) until no starting material remained. The solvent
was removed under reduced pressure, the resulting crude solid
taken up in chloroform and solvent removed again to leave a
pink-brown solid that was used without further purification in the
following two reactions.
To a solution of indole-2-carboxylic acid (0.545 g, 3.39 mmol)
in dry DMF (20 mL), monoboc diaminohexane7 (1.094 g,
5.06 mmol), EDCI (0.751 g, 3.92 mmol), triethylamine (0.350 g,
3.47 mmol) and hydroxybenzotriazole (8.2 mg, 6.1 × 10−5 mmol)
were added. The reaction was stirred overnight, at room temper-
ature, under an atmosphere of nitrogen whereupon TLC (75 :
25 EtOAc : petroleum ether) indicated the disappearance of the
starting material. The reaction mixture was filtered, and the filtrate
was concentrated to dryness. The resulting crude brown oil was
purified by column chromatography (75 : 25 EtOAc : petroleum
ether, silica gel 60 mesh). The desired fractions were combined
and the solvent removed under reduced pressure, yielding a yellow
solid (1.080 g, 89%); mp 113.1–115.4 ◦C; dH(270 MHz; DMSO-d6,
TMS) 1.3* (4H, H3ꢀ and 4ꢀ), 1.5* (4H, H2ꢀ and 5ꢀ), 1.99 (9H, s,
C(CH3)3), 2.89 (2H, brq, J = 6.4, H6ꢀ), 3.26 (2H, brq, J = 6.4,
H1ꢀ), 6.79 (1H, s, amide NH), 7.02 (1H, t, J = 7.4, H5) 7.09 (1H, s,
H3), 7.16 (1H, t, J = 7.2, H6), 7.43 (1H, d, J = 8.2, H7), 7.61 (1H,
d, J = 7.9, H4), 8.43 (1H, brt, J = 5.7, OC(O)NH), 11.53 (1H, s,
H1); dC(270 MHz; DMSO-d6, TMS) 26.53, 26.76, 28.82, 29.81,
39.24, 40*, 77.82, 102.70, 112.80, 120.16, 121.93, 123.64, 127.65,
132.48, 136.88, 156.11, 161.51. [* obscured by DMSO peak.]
2-[2ꢀ-(Phenylureido)ethylamido]indole 1
To a solution of crude indole amine 7 (0.250 g, 1.23 mmol) in
1,4-dioxane (40 mL), phenylisocyanate (2.0 mL of 10% in 1,4-
dioxane, 1.85 mmol) and sodium hydroxide (3 drops of 10%) were
added dropwise. The reaction was stirred under an atmosphere of
nitrogen for 2 hours whereupon the solvent was removed under
reduced pressure. The resulting crude product was purified by
column chromatography (50 : 50 EtOAc : petroleum ether, silica),
the desired fractions combined and the solvent removed under
reduced pressure to afford a cream solid (0.248 g, 83%); mp 202.7–
◦
204.2 C; dH(270 MHz; DMSO-d6, TMS) 3.5* (2H, s, H2ꢀ), 3.7*
(2H, s, H1ꢀ), 6.30 (1H, brt, J = 3.9, C(O)NHCH2), 6.89 (1H, t,
J = 4.9, H4ꢀꢀ), 7.03 (1H, t, J = 5.2, H5), 7.12 (1H, s, H3), 7.17
(1H, t, J = 5.4, H6), 7.23 (2H, d, J = 5.2, H2ꢀꢀ and 5ꢀꢀ), 7.39 (2H,
d, J = 5.1, H12ꢀꢀ and 6ꢀꢀ), 7.44 (1H, d, J = 6.1, H7), 7.61 (1H, d,
J = 5.3, H3), 8.56 (1H, s, C(O)NHAr), 8.58 (1H, s, amide NH),
11.58 (1H, s, H1); dC(270 MHz; DMSO-d6, TMS) 38.5*, 44.1*,
102.96, 112.85, 118.23, 120.24, 121.59, 122.00, 123.77, 127.64,
129.18, 132.30, 136.95, 141.04, 155.96, 161.88; m/z(ES): 357.3
(M + Cl−. C18H18N4O2 + Cl requires 357.1), (HRMS) 645.29246
2-[(6-Amino)hexylamido]indole 8
To a solution protected indole 6 (549 mg, 1.53 mmol) in chloroform
(30 mL), trifluoroacetic acid (7.5 mL) was added slowly. The
reaction was stirred under an atmosphere of nitrogen for 4 hours.
The reaction was monitored by TLC (75 : 25 EtOAc : petroleum
ether) until no starting material remained. The solvent was
removed under reduced pressure, the resulting crude solid washed
in chloroform and solvent removed again to leave a pink-brown
solid (crude 437 mg) that was used directly in the following step.
1
([M2 + H]+. C36H37N8O4 requires 645.29322). [* H NMR peaks
3.5 and 3.7 and 13C NMR peaks 38.5 and 44.1 were obscured by
DMSO, and assigned by analogy to other molecules in the series.]
2-[2ꢀ-(p-nitrophenylthioureido)hexylamido]indole 3
To a solution of crude indole amine 8 (0.594 g, 1.53 mmol) in dry
DMF (20 mL) p-nitrophenylisothiocyanate (0.463 g, 2.56 mmol)
and DIPEA (0.826 g, 6.39 mmol) were added. The reaction
was stirred overnight, at room temperature under a nitrogen
atmosphere, whereupon TLC (75 : 25 EtOAc : petroleum ether)
analysis indicated a new product had formed. The solvent was
removed under reduced pressure and the resulting crude orange
oil was purified by column chromatography (3 : 1 EtOAc : EtOH,
Al2O3). The desired fractions were combined and the solvent
2-[2ꢀ-(p-Trifluoromethylphenylthioureido)ethylamido]indole 2
To a solution of crude indole amine 7 (0.600 g, 2.96 mmol) in dry
DMF (20 mL), p-trifluoromethylphenylisothiocyanate (0.750 g,
3.69 mmol) and DIPEA (0.805 g, 6.22 mmol) were added. The
reaction was stirred overnight, at room temperature under a
nitrogen atmosphere, whereupon TLC (75 : 25 EtOAc : petroleum
ether) indicated the formation of a new product. The solvent was
removed under reduced pressure, and the crude product purified by
1798 | Org. Biomol. Chem., 2007, 5, 1795–1799
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The Royal Society of Chemistry 2007
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