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Synthesis of Ciprofloxacin

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Reaction Information
Reaction

Stages
1.1

R:K2CO3, S:NMP, 12 h, 80C; 80C rt

1.2

R:O2, C:Methylene blue, S:ClCH2CH2Cl, 48 h, rt

Notes

Yield

photochem., regioselective, 354

nm UV lamp used, Reactants: 2,
Reagents: 2, Catalysts: 1,
Solvents: 2, Steps: 1, Stages: 2

14% /
14%

Transformation:
1. Substitution of Aromatic
Halides with Nitrogen
Nucleophiles
References
Direct transformation of Baylis-Hillman acetates into N-substituted quinolones through an SN2' SNAr
(3,4-2,3 shift) oxidation sequence
By Napoleon, John Victor and Manheri, Muraleedharan Kannoth
From Synthesis, (20), 3379-3388; 2011
Experimental Procedure
General/Typical Procedure: Quinolones; General Procedure The appropriate amine 2 (1.52.0 mmol) and dry K2CO3 (1.5-2.0 mmol) were added to a stirred solution of the BaylisHillman acetate 1 (1 mmol) in NMP (6 mL) under N2. The mixture was heated at 70-80C
until starting materials were completely consumed then cooled to r.t., diluted with DCE (40
mL), and washed with H2O (3 30 mL) and brine (30 mL). The organic portion was dried
(Na2SO4) and filtered. Methylene blue (0.7 mmol) was added and the soln was irradiated
with a 200-W tungsten lamp under O2 for 48 h, with the light source 2-3 cm from the
reaction vessel. Once all the dihydroquinoline was consumed, the solvents were removed
under reduced pressure and the residue was purified by chromatography (silica gel, EtOAchexane gradient). Methyl 1-Benzyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (6.1) and
Methyl 1-Benzyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (7.1) Baylis-Hillman acetate 1a
(0.1 g, 0.319 mmol) was treated with BnNH2 (51 mg, 0.05 mL, 0.478 mmol) in the presence
of K2CO3 (66 mg, 0.478 mmol) in NMP (2 mL) at 80C for 12 h, and the resulting
dihydroquinoline was exposed to a 200-W bulb for 48 h according to the general procedure.
Compound 6.1 Crystalline solid; yield: 30 mg (32%). Compound 7.1 Methyl 1-Cyclopropyl6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (6.12) and Methyl 6,7Difluoroquinoline-3- carboxylate (8c) Baylis-Hillman acetate 1c (200 mg, 0.694 mmol) was
treated with cyclopropylamine (59 mg, 0.07 mL, 1.04 mmol) in the presence of K2CO3 (144
mg, 1.04 mmol) in NMP (4 mL) at 70C for 24 h, and the resulting dihydroquinoline was
exposed to a 354-nm UV lamp for 48 h according to the general procedure. Compound 6.12
Crystalline solid; yield: 27 mg (14%). Compound 8c Crystalline solid; yield: 22 mg (14%).
6.12: mp 224-226C; Rf (EtOAc) = 0.51. IR (neat): 1728, 1614, 1479, 1286, 1232, 1205,
1188, 1166, 1077, 905, 803 cm-1. 1H NMR (400 MHz, CDCl3): = 8.61 (s, 1 H, C2-H), 8.27
(dd, J = 10.4, 8.8 Hz, 1 H, Ar-H), 7.73 (dd, J = 11.2, 6.4 Hz, 1 H, Ar- H), 3.92 (s, 3 H, OCH3), 3.47-3.41 [m, 1 H, NCH(CH2)2], 1.40- 1.33 (m, 2 H, cyclopropyl CHaCHb), 1.18-1.13
(m, 2 H, cyclopropyl CHaCHb). 13C NMR (100 MHz, CDCl3): = 172.8, 166.0, 153.5 (dd, J =
254.0, 16.0 Hz, 1 C), 149.3, 148.8 (dd, J = 251.0, 13.0 Hz, 1 C), 137.7 (d, J = 8.5 Hz, 1 C),
125.8, 115.5 (dd, J = 18.5, 7.3 Hz, 1 C), 110.6 (d, J = 10.8 Hz, 1 C), 105.7 (dd, J = 22.4, 6.8
Hz, 1 C), 52.3, 35.0, 8.4 (2C). HRMS (ESI): m/z [M + H]+ calcd for C14H12F2NO3: 280.0785;
found: 280.0751. 8c: mp 153-155C; Rf (20% EtOAc-hexanes) = 0.55. IR (neat): 1710,
1509, 1464, 1434, 1337, 1281, 1249, 1227, 1214, 1127, 1106, 992, 936, 873, 856, 772 cm1. 1H NMR (400 MHz, CDCl ): = 9.40 (d, J = 1.2 Hz, 1 H, Ar-H), 8.77 (d, J = 2.0 Hz, 1 H,
3
Ar-H), 7.90 (dd, J = 10.8, 7.6 Hz, 1 H, Ar- H), 7.66 (dd, J = 9.6, 8.8 Hz, 1 H, Ar-H), 4.01 (s, 3
H, -OCH3). 13C NMR (100 MHz, CDCl3): = 165.5, 153.9 (dd, J = 257.2, 16.0 Hz, 1 C),
150.8 (dd, J = 253.9, 16.0 Hz, 1 C), 150.5, 147.4 (d, J = 10.8 Hz, 1 C), 138.0 (d, J = 4.9 Hz,
1 C), 124.0 (d, J = 8.0 Hz, 1 C), 123.4, 116.1 (d, J = 16.7 Hz, 1 C), 114.3 (d, J = 17.5 Hz, 1
C), 52.8. HRMS (ESI): m/z [M + H]+ calcd for C11H8F2NO2: 224.0523; found: 224.0526.
CASREACT : Copyright 2014 American Chemical Society. All Rights Reserved. CASREACT contains reactions from CAS and from: ZIC/VINITI
database (1974-1999) provided by InfoChem; INPI data prior to 1986; Biotransformations database compiled under the direction of Professor Dr. Klaus
Kieslich; organic reactions, portions copyright 1996-2006 John Wiley & Sons, Ltd., John Wiley and Sons, Inc., Organic Reactions Inc., and Organic
Syntheses Inc. Reproduced under license. All Rights Reserved.

Reaction

Stages

Notes

Copyright 2014 American Chemical Society (ACS). All Rights Reserved.

Yield

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2

1.1

R:Et3N, S:DMF, 2 h, 140C; 140C rt

1.2

R:NaOH, S:H2O, S:MeOH, rt; 1 h, 70C; cooled

1.3

R:HCl, S:H2O, 0-5C, pH 6

Page 3
regioselective, Reactants: 2,
Reagents: 3, Solvents: 3, Steps:
1, Stages: 3

70%

Transformations:
1. Hydrolysis or Hydrogenolysis
of Carboxylic Esters or
Thioesters
2. Substitution of Aromatic
Halides with Nitrogen
Nucleophiles

References
Direct transformation of Baylis-Hillman acetates into N-substituted quinolones through an SN2' SNAr
(3,4-2,3 shift) oxidation sequence
By Napoleon, John Victor and Manheri, Muraleedharan Kannoth
From Synthesis, (20), 3379-3388; 2011
Experimental Procedure
Synthesis of Ciprofloxacin: To a solution of 6.12 (18mg, 0.064 mmol) in DMF (1.3 mL), was
added piperazine (11mg, 0.127 mmol) followed by triethylamine (0.02 mL, 0.14 mmol) and
the mixture was heated at 140C for 2 h. It was allowed to cool to room temperature, diluted
with dichloromethane (10 mL), washed with water (3 x 5 mL) and brine (10 mL). The organic
portion was dried (Na2SO4), filtered and the solvents evaporated to get a residue which was
dissolved in methanol (2 mL), and 10% NaOH solution (2 mL) was added to it. This mixture
was then heated at 70C for 1 h, acidified with 10% HCl (to pH 6) and cooled to 0-5C to get
a precipitate which was filtered, washed with water and dried. Ciprofloxacin (15 mg, 70%)
as a crystalline solid. mp 254-256C; 1H NMR (400 MHz, CD3OD) 8.98 (s, 1H, -C2 H),
8.13 (d, 1H, ArH, J= 13.0 Hz), 7.81 (s, 1H, ArH), 3.99 (brs, 1H, CH(CH2)2), 3.64-3.57 (m,
4H, piperazine N-CHs), 3.38- 3.30 (m, 4H, piperazine N-CHs), 2.83 (s, 1H, NH), 1.65-1.58
(m, 2H, 2 x cyclopropyl CH a Hb), 1.46-1.40 (m, 2H, 2 x cyclopropyl CHa Hb ); IR (neat) cm1: 3369, 3162, 1614, 1575, 1479, 1378, 1292, 1255, 1178, 1144, 1024, 941, 891, 823;
HRMS (ESI) exact mass calcd. for C17H19N3O3F [M+H]+ 332.1410, found [M+H]+ 332.1409.
CASREACT : Copyright 2014 American Chemical Society. All Rights Reserved. CASREACT contains reactions from CAS and from: ZIC/VINITI
database (1974-1999) provided by InfoChem; INPI data prior to 1986; Biotransformations database compiled under the direction of Professor Dr. Klaus
Kieslich; organic reactions, portions copyright 1996-2006 John Wiley & Sons, Ltd., John Wiley and Sons, Inc., Organic Reactions Inc., and Organic
Syntheses Inc. Reproduced under license. All Rights Reserved.

Copyright 2014 American Chemical Society (ACS). All Rights Reserved.

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Substance Information
110-85-0

C4 H10 N2
Piperazine
Related Info:
~ 14948 References
Reactions
~ 127 Commercial Sources
Regulatory Information

127371-54-4

C14 H11 F2 N O3
3-Quinolinecarboxylic acid, 1-cyclopropyl-6,7difluoro-1,4-dihydro-4-oxo-, methyl ester
Related Info:
~ 6 References
Reactions

765-30-0

85721-33-1

C3 H7 N
Cyclopropanamine

C17 H18 F N3 O3
3-Quinolinecarboxylic acid, 1-cyclopropyl-6fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-

Related Info:
~ 5865 References
Reactions
~ 112 Commercial Sources
Regulatory Information

Related Info:
~ 29349 References
Reactions
~ 137 Commercial Sources
Regulatory Information

1353669-51-8

C11 H7 F2 N O2
3-Quinolinecarboxylic acid, 6,7-difluoro-, methyl
ester
Related Info:
~ 1 References
Reactions

952741-81-0

C13 H11 F3 O4
Benzenepropanoic acid, -(acetyloxy)-2,4,5trifluoro--methylene-, methyl ester
Related Info:
~ 4 References
Reactions

Copyright 2014 American Chemical Society (ACS). All Rights Reserved.

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References
Direct transformation of Baylis-Hillman acetates into N-substituted quinolones through an SN2' SNAr (3,4-2,3
shift) oxidation sequence
By Napoleon, John Victor; Manheri, Muraleedharan Kannoth
From Synthesis (2011), (20), 3379-3388. Language: English, Database: CAPLUS, DOI:10.1055/s-0030-1260189
When subjected to tandem SN2'-SNAr cyclization in the presence of alkyl- or aralkylamines, Baylis-Hillman acetates gave
the corresponding 1,2-dihydroquinolines, which on simple exposure to light and oxygen afforded the corresponding 4and 2-quinolones through sensitized oxidn. or a 3,4-2,3 shift oxidn. cascade. The mechanism of the oxidn. step, the
stabilities of the 1,2- and 1,4-dihydroquinolines in soln. and in the solid state, and the synthetic elaboration of the key
intermediates to known therapeutic agents are discussed.
~3 Citings
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Copyright 2014 American Chemical Society (ACS). All Rights Reserved.

Copyright 2014 American Chemical Society (ACS). All Rights Reserved.