IUBMB LIFE
(400 MHz, CDCl3) 6.76 (1 H, s, CH), 4.34 (2 H, 2 q, J 5 7 Hz, solvent removal under high vacuum afforded the title
compound.
3,4-Dichloro-5-octyloxy-5H-furan-2-one 19—Yield 99%
OCH2), 1.38 (3 H, t, J 5 7 Hz, OCH2CH3); dC (100 MHz, CDCl3)
163.0, 152.5, 141.4, 119.2, 96.3, 66.0, 14.0.
(100% diethyl ether), colorless oil. dH (400 MHz, CDCl3) 5.77
(1 H, s, CH), 3.78–3.84 (1 H, m, OCH2), 3.66–3.72 (1 H, m,
OCH2), 1.61–1.68 (2 H, m, OCH2CH2), 1.22–1.32 (10 H, m, 5 3
CH2), 0.86 (3 H, t, J 5 6 Hz, CH3); dC (100 MHz, CDCl3) 163.2,
147.5, 124.3, 100.98, 70.4, 31.7, 29.2, 29.2, 29.1, 25.7, 22.6,
14.0.
General Procedure for the Etherification of Carbonates 9-12.
Carbonate 3-8 (7.16 mmol) was combined with the desired phe-
nol (1.1 equiv) and cesium fluoride (0.3 equiv, 1 equiv for
biphenyl) in dichloromethane (65 mL) and stirred at room tem-
perature overnight. The reaction was quenched with saturated
aqueous ammonium chloride (50 mL) and partitioned between
water (50 mL) and dichloromethane (70 mL). The organic
extract was concentrated under reduced pressure and the result-
ing residue was purified by silica gel column chromatography.
5-(Biphenyl-4-yloxy)23,4-dibromo-5H-furan-2-one 10—Yield
72% (5% ethyl acetate: hexane) white crystals, mp 94–96 8C. dH
(400 MHz, CDCl3) 7.61–7.54 (2 H, m, phenyl), 7.50–7.42 (3 H, m,
phenyl), 7.26-7.22 (2 H, m, phenyl), 7.07–7.04 (2 H, m, phenyl),
6.18 (1 H, s, CH); dC (100 MHz, CDCl3) 163.3, 155.3, 154.8,
142.2, 140.1, 138.0, 132.9, 128.8, 128.6, 127.4, 127.0, 119.6,
119.4, 118.0, 117.6, 101.2.
General Procedure for the Amination of 3,4-Dichloro-5-aryl-
or alkyl-oxy-2(5H)-Furanones 20-22. To a solution of 3,4-
dichloro-5-aryloxy-5H-furan-2-one 19 (1 equiv, 1.78 mmol) in
N,N-dimethylformamide (10 mL) was added N1-(7-chloro-
quinolin-4-yl)-ethane-1,2-diamine (1 equiv) and diisopropyle-
thylamine (1 equiv), the stirred reaction mixture was heated at
80 8C for 24 h under a nitrogen atmosphere. The reaction mix-
ture was allowed to cool down to room temperature, poured
into a separating flask containing water (100 mL) and ethyl
acetate (100 mL) and the layers separated. The organic layer
was washed with water (4 3 100 mL), dried over magnesium
sulfate, filtered through a Celite plug and the filtrate concen-
trated on a rotary evaporator. The desired product was
obtained pure after column chromatography.
5-(Octyloxy)23-chloro-4-[2-(7-chloroquinolin-4ylamino)-
ethylamino]-5H-furan-2-one 22—Yield 45% (50% ethyl ace-
tate: hexane), cream white solid, mp 140 8C. dH (400 MHz, d6-
DMSO) 8.42 (1 H, d, J 5 6 Hz, CQ), 8.22 (1 H, d, J 5 9 Hz, CQ),
7.85 (1 H, t, J 5 6 Hz, and J 5 12 Hz, CQ), 7.80 (1 H, d, J 5 2
Hz, CQ), 7.48 (1 H, dd, J 5 2 Hz, and J 5 9 Hz, CQ), 7.37 (1 H,
br s, NH), 6.57 (1 H, d, J 5 6 Hz, CH), 3.49-3.58 (6 H, m, OCH2,
2 3 NCH2), 3.34 (1 H, br s, NH), 1.46 (2 H, quintet, J 5 7 Hz,
OCH2CH2), 1.14–1.18 (10 H, m, 5 3 CH2), 0.81 (3 H, t, J 5 6 Hz
and J 5 14 Hz, CH3); dC (100 MHz, d6-DMSO) 151.8 (2C), 149.9,
149.0, 133.5, 127.5 (2 C), 124.2 (2 C), 123.9, 117.4, 98.7, 88.7,
68.2, 42.7, 31.1, 28.8, 28.6, 28.5, 25.3, 22.0, 13.8. The fura-
none carbonyl does not appear on the 13C NMR spectrum, this
can be rationalized due to the slow relaxation basis.
General Procedure for the Amination of the Phenoxy or
(Biphenyl-4-yloxy)-dihalide-5H-furan-2-ones 13-16. To a stirred
solution of 9-12 (0.307 mmol) in dry tetrahydrofuran or N-
methylpyrrolidinone (2 mL), the corresponding amine (2
equiv) was added at room temperature. After 2 h, the reac-
tion mixture was diluted with water (10 mL) and left over-
night in the fridge. The resulting solid was filtered, washed
with water (10 mL), then heptane (5 mL), and dried. The
product was purified by flash column chromatography.
5-(Biphenyl-4-yloxy)23-bromo-4-[2-(7-chloroquinolin-4-
ylamino)-ethylamino]-5H-furan-2-one 14—Yield 78% (1–5%
methanol: dichloromethane), yellow solid, mp 131–133 8C. dH
(400 MHz, CDCl3) 8.24 (1 H, br s, CQ), 8.04 (1 H, d, J 5 9 Hz,
CQ), 7.80 (1 H, d, J 5 2 Hz, CQ), 7.54 (1 H, dd, J 5 9 Hz and
J 5 2 Hz, CQ), 7.44–7.38 (5 H, m, phenyl), 7.07–7.05 (2 H, m,
phenyl), 6.93–6.91 (2 H, m, phenyl), 6.54 (1 H, br s, CQ), 6.39
(1 H, br s, CH), 3.77 (2 H, br s, N-CH2 or CQ-N-CH2), 3.67 (2 H,
br s, N-CH2 or CQ-N-CH2); dC (100 MHz, CDCl3) 152.3 (2 C),
149.7, 138.2, 136.6, 133.7, 129.9, 129.3, 128.3 (3 C), 127.8
(2 C), 126.4, 124.2 (2 C), 119.8 (2 C), 118.1, 117.3, 97.0, 44.3.
The furanone carbonyl does not appear on the 13C NMR spec-
trum, this can be rationalized due to the slow relaxation basis.
General Procedure for the Preparation of 3,4-Dichloro-5-(phenyl
or 4’-biphenyl)22(5H)-furanones 23-24. A solution was pre-
pared of mucochloric acid (1 equiv, 11.5 mmol) and the
desired phenyl (1 equiv) in dichloromethane (50 mL) and was
cooled to 0 8C. To this cooled solution was added aluminum
trichloride (1.5 equiv) in four portions over 30 min. The reac-
tion mixture was initially stirred for 2 h at 0 8C and then
stirred at room temperature for a further 18 h. The reaction
mixture was poured onto ice-water and extracted with ethyl
acetate (50 mL). The partially separated emulsion was filtered
through celite, the phases were separated and the solvent was
removed from the organic phase. The resulting residue was
purified by silica gel column chromatography.
General Procedure for the Preparation of 3,4-Dichloro-5-
aryloxy-2(5H)-furanones 17-19. To a solution of mucochloric
acid (1 equiv, 11.8 mmol) in tetrahydrofuran (20 mL), stirred
at room temperature, was added the desired alcohol (0.75
equiv) and followed by drop-wise addition of concentrated sul-
furic acid (2.00 mL). The reaction mixture, in a stoppered
flask, was allowed to stir at room temperature for 48 h then
poured into a separating flask containing water (100 mL) and
diethyl ether (100 mL). The layers were separated, the organic
layer washed with water (3 3 100 mL) and dried over magne-
3,4-Dichloro-5-(4’-biphenyl)22(5H)-furanone 24—Yield 22%
(0-20% ethyl acetate: hexane), off-white solid, mp 154–155 8C.
sium sulfate. This was then filtered through a silica gel plug dH (400 MHz, CDCl3) 7.58 (2 H, d, J 5 8 Hz, phenyl), 7.51 (2 H,
and the filtrate concentrated on a rotary evaporator. Residual d, J 5 8 Hz, phenyl), 7.37–7.39 (2 H, m, phenyl), 7.29–7.30 (3 H,
614
In Vitro Anti-TB Activity of Synthetic Furanones