SPECIAL TOPIC
Solid/Solution Phase Synthesis of the Quinolone Antibacterial, Ciprofloxacin
1983
1H NMR (CDCl3): δ = 2.76 (1H, s, OH); 7.31 (1H, s, CHOH); 7.50–
7.80 (12H, m, Harom); 8.10–8.13 (2H, m, Harom); 8.67–8.79 (4H, m,
HRMS (FAB): m/z C48H46O3 (M+)calcd 670.3447; found 670.3447.
H
arom).
4-[10-(17’-Tetrabenzo[a,c,g,i]fluorenyl)decyloxy]benzyl Alco-
hol (8)
13C NMR (CDCl3): δ = 69.6 (CHOH); 122.3, 123.1, 124.3, 126.0,
126.4, 126.6, 126.8, 126.9, 129.0 (aromatic CH); 130.0, 130.3,
130.8, 131.2, 136.3 (q aromatic).
To 7 (2.03 g, 3.03 mmol), in THF (40 mL) was added diisobutyl
aluminium hydride (1.0 M in THF, 12.0 mL, 12.0 mmol) via sy-
ringe and the resulting mixture stirred at r.t. for 2 h. The reaction
was quenched at 0 °C with the careful addition of HCl (2 M, 40 mL)
and the organic products were extracted with EtAc (3 × 50 mL),
washed with sat. Na2CO3 (40 mL) and H2O (40 mL) and dried
(MgSO4). Solvent was removed under reduced pressure to yield 8
as a yellow solid; yield: 1.77g (2.82 mmol, 94%); mp 64–66 °C; Rf
= 0.35 in CH2Cl2).
HRMS (FAB): m/z C29H20O (M+) calcd 384.1514; found 384.1498.
8bH-Tetrabenzo[a,c,g,i]fluorene (5)
To 4 (24.5 g, 63 mmol), in CH2Cl2 (100 mL), was added TFA
(40 mL), dropwise, over a period of 10 min. The yellow suspension
formed was stirred at r.t. for 20 min after which time solvent was re-
moved under reduced pressure. The resulting yellow solid was re-
concentrated from CH2Cl2 (5 x 100 mL), and the residue was then
washed with Et2O, yielding 5 as a bright yellow solid; yield: 16.4g
(45mmol, 70%); mp 276–278 °C; Rf = 0.84 in CHCl3/MeOH, 9:1.
FT–IR (CHBr3): νmax = 3460 (OH); 3016 (aromatic CH); 2920,
2853 (CH); 1609, 1583, 1510 (C=C); 1142 (C-O) cm-1.
UV (CH2Cl2): λmax (ε) = 381 (18400), 365 (18800), 301 (41400),
254 (70700) nm.
FT–IR (CHBr3): νmax = 3019 (aromatic CH); 1608, 1495 (C=C) cm-
.
1H NMR (CDCl3): δ= 0.30–0.42 (2H, m, CH2); 0.72–1.30 (12H, m,
6 × CH2); 1.58–1.64 (2H, m, CH2); 1.87 (1H, s, OH); 2.56–2.61
(2H, m, OCH2CH2); 3.81 (2H, t, 3JHH = 6.5Hz, OCH2); 4.59 (1H, s,
CH2OH); 4.93 (1H, t, 3JHH = 4.3Hz, fluorenyl CH); 6.83–6.86 (2H,
m, Harom); 7.24–7.27 (2H, m, Harom); 7.60–7.72 (8H, m, Tbf Harom);
8.20–8.24 (2H, m, Tbf Harom); 8.69–8.77 (2H, m, Tbf Harom); 8.77–
8.82 (4H, m, Tbf Harom).
13C NMR (CDCl3): δ = 22.0, 25.6, 28.6, 29.0, 29.2, 33.3 (CH2) 47.0
(fluorenyl C); 64.8 (CH2OH); 67.7 (OCH2); 114.2, 128.4 (aromatic
CH); 123.3, 123.3, 124.3, 125.4, 125.7, 126.6, 127.3 (aromatic CH);
127.8, 128.6, 130.2, 131.0, 136.6, 144.2 (q aromatic); 132.6, 158.5
(q Ar C).
1
UV (CH2Cl2): λmax (ε) = 374 (11700), 358 (9880), 301 (31800), 254
(62200) nm.
1H NMR (CDCl3): δ = 5.39 (1H, s, CH); 7.08-8.28 (15H, m, Harom);
8.76–8.81 (2H, m, Harom).
13C NMR (CDCl3): δ = 53.1 (CH); 121.2, 123.2, 123.5, 123.6,
124.6, 124.9, 125.1, 125.8, 126.2, 126.3, 126.5, 126.6, 126.9, 126.9,
127.1, 128.2, 128.3 (aromatic CH); 127.5, 129.3, 130.3, 130.7,
133.2, 134.0, 135.2, 137.2, 141.3, 148.3 (q aromatic C).
HRMS (FAB): m/z C29H18 (M+) calcd 366.1409; found 366.1396.
HRMS (FAB): m/z C46H44O2 (M+)calcd 628.3341; found 628.3339.
Ethyl 4-[10-(17’-Tetrabenzo[a,c,g,i]fluorenyl)decyloxy]ben-
zoate (7)
Ethyl 3-Oxo-3-(2,4,5-trifluorophenyl)propionate (10)9
To 5 (2.08 g, 5.68 mmol), in degassed dioxane (80 mL) heated at re-
flux, was added tetrabutylammonium hydroxide (40% w/w in H2O,
3.50 g, 5.41 mmol) as a solution in degassed dioxane (20 mL), im-
mediately forming a yellow precipitate. This was filtered under N2
and washed with warm dioxane (100 mL) and Et2O (100 mL). The
salt was resuspended in dioxane (100 mL) and to it added ethyl 4-
(10-bromodecyloxy)benzoate, 3 (2.08 g, 5.40 mmol), and the mix-
ture heated to reflux for 2 h. Solvent was removed from the dark-
ened solution, forming a residue which was dissolved in Et2O
(50 mL), and the supernatant removed to leave a yellow slurry
which was washed with Et2O (2 × 30 mL). The combined extracts
Magnesium chloride and potassium ethyl malonate were dried over
silica gel in a vacuum desiccator overnight prior to use. To potassi-
um ethyl malonate (3.66 g, 21.5 mmol) in freshly distilled MeCN
(70 mL) at 10-15 °C was added anhyd MgCl2 (2.44 g, 25.7 mmol)
and Et3N (2.05 g, 20.3 mmol). The mixture was then stirred at r.t.
for 2.5 h, followed by cooling the resultant white slurry to 0 °C, and
subsequent addition of 2,4,5-trifluorobenzoyl chloride (2.00 g,
10.3 mmol) over a period of 15 min, followed by more Et N
3
(0.23 g, 2.3 mmol). The mixture was then stirred at r.t. for 16 h.
MeCN was removed under reduced pressure and toluene (30 mL)
added. The mixture was reconcentrated and further toluene (60 mL)
added HCl (1.5 M, 40 mL) was cautiously added, ensuring that the
temperature did not exceed 25 °C, and the aqueous layer separated.
The organic fraction was washed with 1.5 M HCl (2 × 25 mL) and
H2O (2 × 25 mL), dried (MgSO4) and solvent removed under re-
duced pressure to yield 10 as a pale orange solid: yield: 2.35g
(9.55mmol, 94%); mp 57–59 °C; Rf = 0.55 in CH2Cl2.
were dried (MgSO ), and solvent removed under reduced pressure,
4
forming a residue which was purified by flash chromatography us-
ing (CH2Cl2/hexane, 1:1, Rf = 0.71 in CH2Cl2). The product was iso-
lated as a pale yellow airy solid which was triturated with Et2O, to
yield 7 as a pale yellow powder; yield: 2.46 g (3.67 mmol, 68%);
mp 122–124 °C.
FT–IR (CHBr3): νmax = 3072 (aromatic CH); 2922, 2850 (CH);
1702 (C=O); 1605, 1505 (C=C); 1105 (C-O) cm-1.
FT–IR (CHBr3): νmax = 3018 (aromatic CH); 2990 (CH); 1735 (ester
C=O); 1687 (C=O); 1622, 1514 (C=C) cm-1.
UV (CH2Cl2): λmax (ε) = 381 (20700), 365 (21000), 301(45800),
256 (86900) nm.
UV (CH2Cl2): λmax (ε) = 295 (4781), 281 (3962), 240 (5191) nm.
1H NMR (CDCl3): δ = 0.28–0.32 (2H, m, CH2); 1.42 (3H, t,
3JHH = 7.1Hz, CH3); 0.71–1.23 (12H, m, 6 × CH2); 1.53–1.76 (2H,
m, CH2); 2.52–2.60 (2H, m, OCH2CH2); 3.86 (2H, t, 3JHH = 6.5Hz,
1H NMR (CDCl3, 250MHz): δ = 1.24 and 1.31 (3H, both t,
3JHH = 7.1Hz); 4.17 and 4.24 (2H, both q, 3JHH = 7.1Hz); 6.98 (1H,
m, Harom); 7.74 (1H, m, Harom); [3.92 (d, 3JHH = 3.9Hz), 12.69 (s) and
5.81 (s) (2H, keto-enol tautomers)].
13C NMR (CDCl3, 63MHz): δ = 14.0 (CH3); 49.4 (CH2); 60.6, 61.4
(OCH2); 92.9 (HC=C); 106.6, 118.7 (Ar CH); 120.9, 145.3, 149.0,
151.8, 155.9, 159.8, 163.7 (q aromatic); 166.9 (CO2Et); 173.0
(HC=C); 187.8 (C=O).
3
OCH2); 4.39 (2H, q, JHH = 7.1Hz, OCH2CH3); 4.92 (1H, t,
3JHH = 4.2Hz, fluorenyl CH); 6.82–6.93 (2H, m, Harom); 7.58–7.72
(8H, m, Harom); 7.98–8.06 (2H, m, Harom); 8.18–8.23 (2H, m, Harom);
8.68 and 8.81 (both 3H, m, Harom).
13C NMR (CDCl3): δ = 14.2 (CH3); 33.4, 29.2, 28.9, 28.8, 28.6,
25.5, 22.0 (CH2); 47.0 (fluorenyl C); 67.9, 60.4 (OCH2); 113.8,
131.3 (aromatic CH); 122.4, 162.7 (q aromatic); 123.3, 123.3,
124.3, 124.8, 125.4, 125.7, 126.6, 127.3 (aromatic CH); 127.9,
128.6, 130.2, 131.1, 136.6, 144.2 (q aromatic C); 166.3 (C=O).
HRMS (EI): m/z C11H9F3O3 (M+) calcd 246.0504; found 246.0514.
Anal. calcd for C11H9F3O3 (%): C, 53.67; H, 3.68; found C, 53.97,
H, 3.77.
Synthesis 1999, No. 11, 1979–1985 ISSN 0039-7881 © Thieme Stuttgart · New York