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4.54 (m, 1H), 4.78—4.95 (m, 2H), 6.53—6.66 (m, 2H), 6.75—6.87 (m, 1H),
7.17—7.29 (m, 2H), 7.79 (d, Jꢁ12.2 Hz, 1H), 8.70 (s, 1H), 14.87 (s, 1H); IR
(KBr) 2642, 1724, 1624, 1466 cmꢀ1; FAB-MS Calcd for C22H20F2N3O3 MW
412.1485, Found m/z 412.1473 (MꢅꢅH); Anal. Calcd for C22H19F2N3O3: C,
64.23; H, 4.66; N, 10.21. Found: C, 64.10; H, 4.96; N, 10.12.
4.78—4.92 (m, 2H), 7.15 (d, Jꢁ8.0 Hz, 2H), 7.25 (d, Jꢁ8.0 Hz, 2H), 7.78
(dd, Jꢁ1.6, 12.6 Hz, 1H), 8.70 (s, 1H), 14.84 (s, 1H); IR (KBr) 2681, 1724,
1620, 1462 cmꢀ1; FAB-MS Calcd for C23H21F2N2O3S MW 443.1253, Found
m/z 443.1241 (MꢅꢅH); Anal. Calcd for C23H20F2N2O3S: C, 62.31; H, 4.55;
N, 6.33. Found: C, 62.43; H, 4.56; N, 6.33.
1-Cyclopropyl-6,8-difluoro-7-[3-(4-methoxyanilino)azetidine-1-yl]-4-
oxo-1,4-dihydroquinoline-3-carboxylic Acid (11b): White powder (DMF);
mp 261—262 °C (dec.); 1H-NMR (400 MHz, DMSO) d: 1.09—1.21 (m,
4H), 3.65 (s, 3H), 4.05 (m, 1H), 4.17 (m, 2H), 4.30 (m, 1H), 4.77 (m, 2H),
5.93 (d, Jꢁ6.1 Hz, 1H), 6.51 (d, Jꢁ8.6 Hz, 2H), 6.76 (d, Jꢁ8.6 Hz, 2H),
1-Cyclopropyl-6,8-difluoro-7-(1-methyltetrazol-5-yl)-4-oxo-1,4-dihy-
droquinoline-3-carboxylic Acid (8) To a solution of 1-cyclopropyl-4-
oxo-6,7,8-trifluoro-1,4-dihydroquinoline-3-carboxylic acid (6, 141.6 mg,
0.50 mmol) and 5-mercapto-1-methyltetrazole (58.1 mg, 0.50 mmol) in
MeCN (7 ml) was added DABCO (336.5 mg, 1.50 mmol) at room tempera-
ture. The mixture was refluxed for 20 h and cooled in an ice bath. The pre-
cipitate was collected by filtration and washed with H2O, EtOH, and Et2O.
The crude solid was recrystallized from THF–MeOH–CHCl3 to afford
10 (100.3 mg, 53%) as a white powder. mp 218—218.5 °C; 1H-NMR
(400 MHz, CDCl3) d: 1.23—1.35 (m, 4H), 4.02—4.04 (m, 1H), 4.18 (s,
3H), 8.14 (dd, Jꢁ2.0, 8.1 Hz, 1H), 8.90 (s, 1H), 13.99 (s, 1H); ESI-MS
Calcd for C15H12F2N5O3S MW 380.0629, Found m/z 380.0631 (MꢅꢅH);
Anal. Calcd for C15H11F2N5O3S: C, 47.49; H, 2.92; N, 18.46. Found: C,
47.39; H, 3.21; N, 18.16.
Typical Procedure for the Preparation of 3-Amino Azetidine 10 To a
solution of aniline (0.09 ml, 1.00 mmol) and ABB (3, ca. 0.1 mol/l in THF,
10.3 ml, ca. 1.2 mmol)1) in THF was added a suspension of Mg(ClO4)2
(446.4 mg, 2.00 mmol) in THF (5 ml) at 0 °C. After being stirred at 0 °C for
3 h, 6 N NaOH was added to the reaction mixture and then extracted with
CHCl3. The organic layer was washed with brine and then dried over anhy-
drous MgSO4. Evaporation in vacuo afforded a crude product, which was
purified by column chromatography on basic alumina with CHCl3–MeOH
(10 : 1, v/v) to give 10a (78.6 mg, 53%) as a pale yellow amorphous powder.
3-Anilinoazetidine (10a)39): Pale yellow amorphous powder; 1H-NMR
(400 MHz, CDCl3) d: 2.05 (br s, 1H), 3.40—3.60 (m, 2H), 3.82—4.00 (m,
2H), 4.03 (br s, 1H), 4.26—4.59 (m, 1H), 6.47—6.57 (m, 2H), 6.66—6.84
(m, 1H), 7.07—7.24 (m, 2H); 13C-NMR (75 MHz, CDCl3) d: 48.13, 55.0,
112.8, 117.7, 129.1, 146.4; IR (KBr) 2933, 1602, 1498, 1317 cmꢀ1; EI-MS
Calcd for C9H12N2 MW 148.1002, Found m/z 148.1000 (Mꢅ).
7.73 (m, 1H), 8.59 (s, 1H); IR (KBr) 3407, 2360, 1725, 1629, 1517 cmꢀ1
;
FAB-MS Calcd for C23H22F2N3O4 MW 442.1578, Found m/z 442.1549
(MꢅꢅH); Anal. Calcd for C23H21F2N3O4·1/2H2O: C, 61.33; H, 4.92; N,
9.33. Found: C, 61.60; H, 4.86; N, 9.50.
1-Cyclopropyl-6,8-difluoro-4-oxo-7-[3-(p-tolylamino)azetidine-1-yl]-1,4-
dihydroquinoline-3-carboxylic Acid (11c): White powder (DMF); mp 253—
1
255 °C (dec.); H-NMR (400 MHz, CDCl3) d: 1.10—1.28 (m, 4H), 2.27 (s,
3H), 3.91 (m, 1H), 4.05 (m, 1H), 4.26 (m, 2H), 4.43 (m, 1H), 4.84 (m, 2H),
6.51 (d, Jꢁ8.1 Hz, 2H), 7.05 (d, Jꢁ8.1 Hz, 2H), 7.79 (m, 1H), 8.69 (s, 1H),
14.88 (s, 1H); IR (KBr) 3361, 1722, 1629, 1525, 1471 cmꢀ1; FAB-MS Calcd
for C23H22F2N3O3 MW 426.1629, Found m/z 426.1639 (MꢅꢅH).
7-[3-(4-Chloroanilino)azetidine-1-yl]-1-cyclopropyl-6,8-difluoro-4-oxo-
1,4-dihydroquinoline-3-carboxylic Acid (11d): Pale yellow powder (DMF);
mp 286—288 °C (dec.); 1H-NMR (400 MHz, DMSO) d: 1.10—1.20 (m,
4H), 4.06 (m, 1H), 4.20 (m, 2H), 4.34 (m, 1H), 4.79 (m, 2H), 6.56 (m, 3H),
7.15 (d, 2H), 7.74 (m, 1H), 8.60 (s, 1H), 15.01 (s, 1H); IR (KBr) 3409, 3048,
2360, 1722, 1629 cmꢀ1; FAB-MS Calcd for C22H19ClF2N3O3 MW 446.1083,
Found m/z 446.1083 (MꢅꢅH); Anal. Calcd for C22H18ClF2N3O3: C, 59.27;
H, 4.07; N, 9.42. Found: C, 58.98; H, 4.28; N, 9.50.
1-Cyclopropyl-6,8-difluoro-7-[3-(4-ethoxycarbonylanilino)azetidine-1-
yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic Acid (11e): White powder
(DMF); mp 261—263 °C (dec.); 1H-NMR (400 MHz, CDCl3) d: 1.12—1.29
(m, 4H), 1.37 (t, 3H), 3.91 (m, 1H), 4.28—4.38 (m, 4H), 4.52 (m, 1H), 4.73
(m, 1H), 4.88 (m, 2H), 6.56 (d, Jꢁ8.9 Hz, 2H), 7.76 (m, 1H), 7.92 (d,
Jꢁ8.9 Hz, 2H), 8.66 (s, 1H), 14.86 (s, 1H); IR (KBr) 3369, 2979, 2360,
1729, 1698 cmꢀ1; FAB-MS Calcd for C25H24F2N3O5 MW 484.1684, Found
m/z 484.1646 (MꢅꢅH); Anal. Calcd for C25H23F2N3O5: C, 62.11; H, 4.80;
N, 8.69. Found: C, 61.82; H, 4.79; N, 8.72.
3-(4-Methoxyanilino)azetidine (10b): Pale yellow amorphous powder;
1H-NMR (400 MHz, CDCl3) d: 1.91 (br s, 1H), 3.48 (m, 2H), 3.74 (s, 3H),
3.92 (m, 2H), 4.31 (m, 1H), 6.51 (d, Jꢁ9.0 Hz, 2H), 6.78 (d, Jꢁ9.0 Hz, 2H);
13C-NMR (75 MHz, CDCl3) d: 49.3, 55.4, 55.7, 114.4, 115.0, 140.7, 152.5;
IR (KBr) 3255, 2931, 1508, 1251, 1166, 1039, 821 cmꢀ1; EI-MS Calcd for
C10H14N2O MW 178.1106, Found m/z 178.1088 (Mꢅ).
1-Cyclopropyl-7-(3-dibenzylaminoazetidin-1-yl)-6,8-difluoro-4-oxo-1,4-
dihydroquinoline-3-carboxylic Acid (11f): Pale yellow powder (THF–
1
3-(p-Tolylamino)azetidine (10c): Pale yellow amorphous powder; 1H-
NMR (400 MHz, CDCl3) d: 1.79 (br s, 1H), 2.23 (s, 3H), 3.48 (m, 2H), 3.92
(m, 2H), 4.34 (m, 1H), 6.46 (d, Jꢁ8.2 Hz, 2H), 6.99 (d, Jꢁ8.2 Hz, 2H); 13C-
NMR (75 MHz, CD3OD) d: 32.1, 32.1, 41.0, 54.9, 147.6, 151.0; IR (KBr)
3289, 2931, 1878, 1619, 1525, 1261, 985, 808 cmꢀ1; EI-MS Calcd for
C10H14N2 MW 162.1157, Found m/z 162.1166 (Mꢅ).
MeOH); mp 213—215 °C; H-NMR (400 MHz, CDCl3) d: 1.08—1.29 (m,
4H), 3.60 (s, 4H), 3.71—3.82 (m, 1H), 3.83—3.95 (m, 1H), 4.16—4.27 (m,
2H), 4.34—4.45 (m, 2H), 7.19—7.40 (m, 10H), 7.77 (d, Jꢁ12.5 Hz, 1H),
8.69 (s, 1H), 14.90 (s, 1H); FAB-MS Calcd for C30H28F2N3O3 MW
516.2084, Found m/z 516.2099 (MꢅꢅH); Anal. Calcd for C30H27F2N3O3: C,
69.89; H, 5.28; N, 8.15. Found: C, 69.59; H, 5.52; N, 8.08.
3-(4-Chloroanilino)azetidine (10d): Pale yellow amorphous powder; 1H-
NMR (400 MHz, CDCl3) d: 1.79 (br s, 1H), 3.48 (m, 2H), 3.93 (m, 2H),
4.30 (m, 1H), 4.06 (br s, 1H), 6.44 (d, Jꢁ8.6 Hz, 2H), 7.11 (d, Jꢁ8.6 Hz,
2H); 13C-NMR (75 MHz, CDCl3) d: 48.5, 55.1, 114.1, 122.5, 129.2, 145.2;
IR (KBr) 3289, 2946, 1872, 1596, 1490, 1259, 985, 815 cmꢀ1; EI-MS Calcd
for C9H11ClN2 MW 182.0611, Found m/z 182.0597 (Mꢅ).
Synthesis of N-Benzyl-3-bromoazetidine 13 To ABB (3, ca. 0.1 mol/l
in THF, 100 ml, ca. 10 mmol)1) was added dropwise a HBr (48% in H2O,
3.6 ml, 32 mmol) at 0 °C, and the mixture was stirred at room temperature
for 30 min. The reaction mixture was evaporated in vacuo to give a residue,
which was washed with CHCl3 and crystallized from MeOH–AcOEt to give
compound 12 (1.4 g, 61%) as colorless needles.
Method (A): To a solution of 12 (506.7 mg, 2.36 mmol) and potassium
carbonate (678 mg, 4.9 mmol) in DMF (2.3 ml) was added benzyl bromide
(278 ml, 2.36 mmol) at room temperature. After being stirred at room tem-
perature for 3.5 h, the reaction mixture was treated with water and then ex-
tracted with CHCl3. The extract was dried over anhydrous MgSO4. Evapora-
tion in vacuo afforded a crude product, which was purified by column chro-
matography on silica gel with n-hexane–AcOEt (4 : 1, v/v) to yield 13
(205.4 mg, 39%) as a colorless oil.
3-(4-Ethoxycarbonylanilino)azetidine (10e): Pale yellow oil; 1H-NMR
(400 MHz, CDCl3) d: 1.36 (t, 3H), 1.79 (br s, 1H), 3.52 (m, 2H), 3.97 (m,
2H), 4.31 (q, 2H), 4.41 (m, 1H), 6.48 (d, Jꢁ8.7 Hz, 2H), 7.87 (d, Jꢁ8.7 Hz,
2H); IR (neat) 3357, 2950, 1693, 1604, 1527, 1274, 1174, 1105 cmꢀ1; EI-
MS Calcd for C12H16N2O2 MW 220.1212, Found m/z 220.1193 (Mꢅ).
3-Dibenzylaminoazetidine (10f): Pale yellow oil; 1H-NMR (400 MHz,
CDCl3) d: 1.61—2.05 (m, 1H), 3.30—3.42 (m, 2H), 3.42—3.57 (m, 6H),
3.57—3.69 (m, 1H), 7.18—7.42 (m, 10H); 13C-NMR (75 MHz, CDCl3) d:
52.9, 55.1, 57.9, 127.0, 128.1, 129.0, 138.6; IR (neat) 3289, 3060, 2943,
2866, 1603, 1493, 1454, 1367 cmꢀ1; EI-MS Calcd for C17H20N2 MW
253.1705, Found m/z 253.1706 (Mꢅ).
Typical Procedure for the Preparation of New Quinolone 11 To a so-
lution of 1-cyclopropyl-4-oxo-6,7,8-trifluoro-1,4-dihydroquinoline-3-car-
boxylic acid (6, 120.2 mg, 0.42 mmol) and 10a (62.9 mg, 0.42 mmol) in
MeCN (6 ml) was added DABCO (142.8 mg, 1.27 mmol) at room tempera-
ture. The mixture was refluxed for 0.5 h and cooled in an ice bath. The pre-
cipitate was collected by filtration and then washed with H2O, EtOH, and
Et2O to afford 11a (130.9 mg, 76%) as a pale yellow powder.
Method (B): To ABB (3, ca. 0.1 mol/l in THF, 125 ml, ca. 12.5 mmol)1)
was added dropwise benzyl bromide (1.5 ml, 12.5 mmol) at 0 °C, and the
mixture was stirred under reflux for 6 h. The reaction mixture was evapo-
rated in vacuo to give an oily residue, which was purified by column chro-
matography on silica gel with n-hexane–AcOEt (4 : 1, v/v) to yield 13
(1.72 g, 61%) as a colorless oil.
3-Bromoazetidine Hydrobromide (12): Colorless needles, mp 119 °C; 1H-
NMR (400 MHz, CD3OD) d: 4.26 (m, 2H), 4.74 (m, 2H), 4.8—5.0 (m, 1H);
IR (KBr) 3003, 2881, 2630, 1441, 1338, 1269, 1229 cmꢀ1. EI-MS Calcd for
C3H7NBr MW 134.9684, Mꢅ2 136.9663, Found m/z 134.9684 (Mꢅ),
136.9684 (Mꢅꢅ2). Anal. Calcd for C3H7NBr2: C, 16.61; H, 3.25; N, 6.46.
Found: C, 16.60; H, 3.21; N, 6.47.
7-(3-Anilinoazetidin-1-yl)-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydro-
quinoline-3-carboxylic Acid (11a): Pale yellow powder (THF–MeOH–
N-Benzyl-3-bromoazetidine (13): Colorless oil; 1H-NMR (400 MHz,
CDCl3) d: 3.44 (m, 2H), 3.69 (s, 2H), 3.88 (m, 2H), 4.48 (m, 1H), 7.21—
1
CHCl3); mp 278 °C (dec.); H-NMR (400 MHz, CDCl3) d: 1.05—1.33 (m,
4H), 3.84—4.00 (m, 1H), 4.12—4.23 (m, 1H), 4.24—4.36 (m, 2H), 4.41—