Encyclopedia of Reagents for Organic Synthesis || 3-Fluoropyridine
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3-FLUOROPYRIDINE 1 3-Fluoropyridine N F [372-47-4] C 5 H 4 FN (MW 97.09) InChI = 1/C5H4FN/c6-5-2-1-3-7-4-5/h1-4H InChIKey = CELKOWQJPVJKIL-UHFFFAOYAH (reagent employed in the preparation of substituted pyridines) Physical Data: bp 107–108 ◦ C/760 mmHg; d 1.13 g cm −3 ; fp 13 ◦ C. Form Supplied in: colorless liquid. Handling, Storage, and Precautions: avoid prolonged or repeated exposure. Store in cool and dry place. Keep away from sources of ignition. In case of contact with eyes, rinse immediately with plenty of water and seek medical attention. C-2/C-4 Metallation of 3-Fluoropyridine. 3-Fluoropyri- dine can be regioselectively lithiated at either C-2 or C-4 depending on the reaction conditions. 1 Quenching of these metal- lated intermediates with electrophiles leads to the corresponding substituted pyridines. The optimized conditions for C-2 substi- tution involves treatment of 3-fluoropyridine with precomplexed n-BuLi (1.1 equiv) and DABCO (1.2 equiv) in methyl tertiary butyl ether (MTBE) at −45 ◦ C followed by quenching with the electrophile. Alternatively, the C-4 substitutions of 3-fluoropyri- dine can be achieved by deprotonation with n-BuLi (1.0 equiv) in THF at −45 ◦ C and subsequent quenching with the electrophile (eq 1). N F O OLi N F N F OLi O 1. n-BuLi/DABCO MTBE 2. CO 2 , −45 °C 1. n-BuLi,THF 2. CO 2 ,−45 °C (1) It has been proposed that lithiation of 3-fluoropyridine in ether at low temperatures is kinetically controlled. 2 The n-BuLi/ TMEDA preferentially coordinates with the pyridine nitrogen and abstracts the nearest acidic proton leading to the 2-lithio derivative via an intramolecular deprotonation. In THF, the n-BuLi/TMEDA/3-fluoropyridine chelate is dissociated and thus the metallation occurs at C-4, the most acidic site of 3-fluoropyri- dine. Applications of the reactions involving deprotonation followed by trapping of the anion by various electrophiles have been widely reported (eq 2). 2−4 N F N F R base R = -SiMe 3 , -I, -CHO, -CEt 2 OH, -CMe 2 OH, -CHMeOH (2) 3-Fluoropyridine-4-boronic acids and esters are prepared by directed ortho-metallation employing LDA (eq 3). 5 Subsequent quenching with triisopropylborate followed by work up, leads to the desired boronic acid. In situ transesterification with the pinacol provides the corresponding ester. The 3-fluoropyridine-4-boronic acid is not stable, whereas, the boronic ester is more stable and easier to handle. Cross-coupling Reactions. C-4 deprotonation of 3-fluoro- pyridine via hydrogen-magnesium exchange to form the inter- mediate (3-fluoro-4-pyridyl)magnesate has been reported. 6 This intermediate was subjected to reaction with 2-bromopyridine to afford the bipyridine (eq 4). N F Li N F B OiPr OiPr iPrO Li N F N F B OH HO N F B O O + LDA/ether B(OiPr) 3 1. NaOH 1. pinacol AcOH (3) 2. NaOH 3. HCl 2. HCl − N F 1/3 equiv Bu 3 MgLi THF, −10 °C, 2 h N F Mg* + N Br 1. PdCl 2 (dppf) 1 mol %, reflux 18 h 2. hydrolysis N F N (4) Cross-coupling of 3-fluoropyridine with phenylmagnesium chloride employing [NiCl 2 (dppe)] as catalyst is also known (eq 5). 7 N F N 1. PhMgCl [NiCl 2 (dppe)] THF, rt, 18 h 2. H 2 O (5) Avoid Skin Contact with All Reagents
Transcript of Encyclopedia of Reagents for Organic Synthesis || 3-Fluoropyridine
3-FLUOROPYRIDINE 1
3-Fluoropyridine
N
F
[372-47-4] C5H4FN (MW 97.09)InChI = 1/C5H4FN/c6-5-2-1-3-7-4-5/h1-4HInChIKey = CELKOWQJPVJKIL-UHFFFAOYAH
(reagent employed in the preparation of substituted pyridines)
Physical Data: bp 107–108 ◦C/760 mmHg; d 1.13 g cm−3;fp 13 ◦C.
Form Supplied in: colorless liquid.Handling, Storage, and Precautions: avoid prolonged or repeated
exposure. Store in cool and dry place. Keep away from sourcesof ignition. In case of contact with eyes, rinse immediately withplenty of water and seek medical attention.
C-2/C-4 Metallation of 3-Fluoropyridine. 3-Fluoropyri-dine can be regioselectively lithiated at either C-2 or C-4depending on the reaction conditions.1 Quenching of these metal-lated intermediates with electrophiles leads to the correspondingsubstituted pyridines. The optimized conditions for C-2 substi-tution involves treatment of 3-fluoropyridine with precomplexedn-BuLi (1.1 equiv) and DABCO (1.2 equiv) in methyl tertiarybutyl ether (MTBE) at −45 ◦C followed by quenching with theelectrophile. Alternatively, the C-4 substitutions of 3-fluoropyri-dine can be achieved by deprotonation with n-BuLi (1.0 equiv) inTHF at −45 ◦C and subsequent quenching with the electrophile(eq 1).
N
F
O OLiN
FN
F
OLi
O
1. n-BuLi/DABCO MTBE
2. CO2, −45 °C
1. n-BuLi,THF
2. CO2 ,−45 °C
(1)
It has been proposed that lithiation of 3-fluoropyridine inether at low temperatures is kinetically controlled.2 The n-BuLi/TMEDA preferentially coordinates with the pyridine nitrogenand abstracts the nearest acidic proton leading to the 2-lithioderivative via an intramolecular deprotonation. In THF, then-BuLi/TMEDA/3-fluoropyridine chelate is dissociated and thusthe metallation occurs at C-4, the most acidic site of 3-fluoropyri-dine.
Applications of the reactions involving deprotonation followedby trapping of the anion by various electrophiles have been widelyreported (eq 2).2−4
N
F
N
F
Rbase
R = -SiMe3, -I, -CHO, -CEt2OH, -CMe2OH, -CHMeOH
(2)
3-Fluoropyridine-4-boronic acids and esters are prepared bydirected ortho-metallation employing LDA (eq 3).5 Subsequentquenching with triisopropylborate followed by work up, leads tothe desired boronic acid. In situ transesterification with the pinacolprovides the corresponding ester. The 3-fluoropyridine-4-boronicacid is not stable, whereas, the boronic ester is more stable andeasier to handle.
Cross-coupling Reactions. C-4 deprotonation of 3-fluoro-pyridine via hydrogen-magnesium exchange to form the inter-mediate (3-fluoro-4-pyridyl)magnesate has been reported.6 Thisintermediate was subjected to reaction with 2-bromopyridine toafford the bipyridine (eq 4).
N
F
Li
N
F
BOiPr
OiPriPrO
Li
N
F
N
F
BOHHO
N
F
B OO+
LDA/ether B(OiPr)3
1. NaOH
1. pinacol AcOH
(3)
2. NaOH
3. HCl
2. HCl
−
N
F 1/3 equiv Bu3MgLiTHF, −10 °C, 2 h
N
F
Mg*
+N Br
1. PdCl2(dppf) 1 mol %, reflux 18 h
2. hydrolysis
N
F
N(4)
Cross-coupling of 3-fluoropyridine with phenylmagnesiumchloride employing [NiCl2(dppe)] as catalyst is also known(eq 5).7
N
F
N
1. PhMgCl [NiCl2(dppe)] THF, rt, 18 h
2. H2O(5)
Avoid Skin Contact with All Reagents
2 3-FLUOROPYRIDINE
Nucleophilic Substitution Reactions. The nucleophilic sub-stitution reactions of halopyridines with sulfur, oxygen, andcarbon nucleophiles under microwave irradiation have beenreported (eq 6).8 These reactions proceed with yields in therange of 50–88%. This is a facile method for the synthesis of3-substituted pyridines which are not readily accessible by con-ventional procedures.
N
F
N
Xnucleophile, solventmicrowave
X = -SPh, -SMe, -OCH2Ph, -CH(CN)Ph
(6)
1. Emerson, K. M.; Wilson, R. D.; Ashwood, M. S.; Kennedy, D. J.; Hands,D.; Brands, K. M. J.; Cottrell, I. F.; Dolling, U., Synth. Commun. 2003,33, 4235.
2. Marsais, F.; Quéguiner, G., Tetrahedron 1983, 39, 2009.
3. Rocca, P.; Marsais, F.; Godard, A.; Quéguiner, G., Tetrahedron 1993, 49,49.
4. Moon, S. C.; Shin, J.-H.; Jeong, B. H.; Kim, H. S.; Yu, B. S.; Lee,J.-S.; Lee, B. S.; Namgoong, S. K., Bioorg. Med. Chem. Lett. 2000, 10,1435.
5. Bouillon, A.; Lancelot, J.-C.; Collot, V.; Bovy, P. R.; Rault, S., Tetrahedron2002, 58, 4369.
6. Awad, H.; Mongin, F.; Trècourt, F.; Quéguiner, G.; Marsais, F.; Blanco,F.; Abarca, B.; Ballesteros, R., Tetrahedron Lett. 2004, 45, 6697.
7. Mongin, F.; Mojovic, L.; Guillamet, B.; Trècourt, F.; Quèguiner, G.,J. Org. Chem. 2002, 67, 8991.
8. Cherng, Y.-J., Tetrahedron 2002, 58, 4931.
Punit Bhardwaj & Pat ForgioneBoehringer Ingelheim (Canada), Laval, Quebec, Canada
A list of General Abbreviations appears on the front Endpapers
