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