Fluorinated Heterocycles - American Chemical Society

Chapter 2

Site Selective Functionalization of Fluorinated Nitrogen Heterocycles

Downloaded by NORTH CAROLINA STATE UNIV on April 10, 2013 | http://pubs.acs.org Publication Date: January 1, 2009 | doi: 10.1021/bk-2009-1003.ch002

Manfred Schlosser, Alain Borel, and Luc Patiny Institute for Chemical Sciences and Engineering, Ecole Polytechnique Fédérale, CH-1015 Lausanne, Switzerland

Functional groups are prerequisites for the assembly of building blocks to more elaborate structures for research work in the life sciences field. Functionalization can be most conveniently and efficaciously accomplished by generating an organometallic derivative of the aromatic or heterocyclic starting material and subsequently treating it with the electrophile of choice. The presence of heterosubstituents facilitates immensely the introduction of the metal (by permutational halogen/metal or hydrogen/metal interconversion) and at the same time enables a perfect control of the desired regioselectivity as will be illustrated by typical examples selected from the indole, pyrazoles, pyridine and quinoline fields.

2009 American Chemical Society

In Fluorinated Heterocycles; Gakh, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2009.


24 Manoeuverable functional groups are indispensable in order to integrate a substructure into a larger target compound having pharmaceutical or agricultural potential. The desired functionality can be very easily fitted into a heterocyclic core compound if the latter, yet "naked", is converted into an organolithium or other organometallic intermediate which eventually is allowed to react with an appropriate electrophile, for example with carbon dioxide if one wants to create a carboxy substituent. This approach is not only extremely simple but also unparalleled in flexibility (/). It can be employed for the attachment of any kind of functional group at any vacant position. Regiochemical selectivity and exhaustiveness can be readily achieved by recurring to the "toolbox methods", (2), a self-consistent set of new or modified organometallic techniques. Fluorine or trifluoromethyl bearing heterocycles, in particular nitrogencontaining ones, play a privileged role in medicinal chemistry (J). As the lightest halogen is exceptionally effective in stabilizing C-lithiated derivatives thereof, the latter open a versatile entry to a great variety of attractive novel building blocks. The present summary focuses on two five-membered and two sixmembered AMieterocycles.

Indoles Simple indoles are preferentially metalated at the 2-position of the fivemembered ring (4). However, electron-withdrawing substituents may sufficiently increase the kinetic acidity of the six-membered ring to deflect the metalation there. In this way all twelve fluoroindolecarboxylic acids (Scheme 1, 1 - 12) harboring both the halogen and the functional group in the benzo part can be prepared (5). Thus, NH-protection of 7-fluoroindole with triisopropylsilyl (TIPS) followed by metalation with sec-butyllithium, carboxylation and protodesilylation affords the 7-fluoroindole-6-carboxylic acid (9). 7-FluoroindoIe is obtained from the readily accessible 4- or 5-bromo-7-fluoroindole by reductive denomination. The same intermediates serve also as precursors to the acids 3 and 6 which can be made by consecutive bromine/lithium permutation (using two equiv. of butyllithium), reaction with carbon dioxide and neutralization (Scheme 2) (5). Even if the Bartoli cyclization (6) tends to give only moderate if not poor yields, it represents the most convenient route leading to indoles provided that the nitroarene to be treated with vinylmagnesium bromide is readily available. This happens to be the case with 4-bromo-3-nitrobenzotrifluoride. Treatment of the resulting 7-bromo-4-(trifluoromethyl)indole (13) with butyllithium (two equivalents) followed by carboxylation and neutralization affords 4-trifluoromethyl)indole-7-carboxylic acid (14; Scheme 3) (7).



25

ζ!

V)

ë

•S •S δ ο

I

I

Ο

-Ο


26

1 •S δ

λ*


ο

s:

q CD •S δ o ι

O o 5k. ι

s:

o

s:

es

δ

"£> •S to

•g "ë su CD

-s:



Scheme 3. A straightforward access to 4-(trifluoromethyl)indole-7-carboxylic

acid (14).


28


Pyrazoles Depending on the work-up conditions, the condensation of 4-ethoxy-1,1,1trifluoro-3-buten-2-one with methylhydrazine produces either one of two regioisomers (8). One of them, l-methyl-3-(trifluoromethyl)pyrazoles (15) undergoes clean metalation with sec-butyllithium at the 5-position to provide the corresponding acid 16 after carboxylation. Heating with elemental bromine in the presence of iron powder gives 4-bromo-1 -methyl-3-(trifluoromethyl)pyrazole (17) which, when treated either with butyllithium or lithium diisopropylamide ( L D A ) before being poured on dry ice and neutralized with hydrochloric acid, affords l-methyl-3-(trifluoromethyl)pyrazoles-4-carboxylic acid (18) and 4-bromo-1 -methyl-3-(trifluoromethyl)pyrazoles-5-carboxylic acid (19), respectively. Acid 19 can be readily reduced to l-methyl-3(trifluoromethyl)pyrazoles-5-carboxylic acid (16) which, as mentioned above, can also be directly prepared from pyrazole 17 (Scheme 4) (8). Metalated species derived from fluorinated pyrroles or imidazoles have not yet been reported. Therefore we turn now to six-membered heterocycles, in particular pyridines and quinolines.

Pyridines While the medium- and large-scale metalation of pyridine itself still causes trouble, lithium can be conveniently attached to the ring of. fluoropyridines (9,10) and (trifluoromethyl)pyridines (//) using alkyllithiums or lithium dialkylamides such as lithium diisopropylamide (LDA) or lithium 2,2,6,6tetramethylpiperidide (LTMP) as reagents. In several cases one even benefits from the so-called "optional site selectivity" (12), that is either one of two or three vacant positions may be attacked selectively and alternatively at will (Scheme 5). There is one exception, however. Contrary to literature claims (13), 3(trifluoromethyl)pyridine provides only trace amounts (0.5 - 1.5 %) of 3(trifluoromethyl)pyridine-2-carboxylic acid when consecutively exposed to butyllithium (at -75 °C), dry ice and hydrochloric acid. Nucleophilic addition of the organometallic reagent followed by nucleofugal fluoride elimination occurs as a major reaction pathway instead. This is evidenced by the formation of 2butyl-5-(difluoromethyl)pyridine (20) as the main product (Scheme 6) (lib).

Quinolines The site selective metalation of 2-, 3-, 5- and 7-fluoroquinoline has been briefly reported (Scheme 7) (14). 6-Fluoroquinoline was found to react



rfr~\ 0

N

I

CH 3

16

CH 3

*/ \V'COOH

F3C

F3C

X

-—

0CiH

F

15

F 3

I

CH 3

Br

Br

19

CH

3

N '^ ^ C \ OOH

C

3

FC

'

F3C

17

H — H

A

Br

3

H

Li

N

I

18

CH

3

COOH

c ,

Ν.^ \

FC

3

FC

X

Scheme 4. Three l-methyl-3-(trifluoromethyl)pyrazolecarboxylic acids through organometallic intermediates generated by deprotonation or halo-gen/lithium permutation.

3

FC


SO

30 F F

Ν

Ν

F


CF

^

V

N ^ C F

3

3

Scheme 5. Sues in fluor opyridines and (trifluoromethyl)pyridines where selective deprotonation and lithiation can he brought about.

concomitantly at the 5- and 7-position (14). 2-, 3- and 4-(Trifluoromethyl)quinoline offer the bonus of optional deprotonation at either of two competing sites (Scheme 7) (lib). The extension of such systematic investigations to substrates containing an additional heterosubstituent, in particular a bromine atom, is both challenging and rewarding from a practical point of view. The heavy halogen is susceptible to be replaced with hydrogen by a reductive process or with any nucleophile by nucleophilic hetaromatic substitution or with lithium by permutational halogen/metal interconversion (15). The latter possibility can be exploited to introduce sequentially two different functional groups as exemplified with the readily accessible 2-bromo-4-fluoroquinolines (21) (16). Immediate treatment with butyllithium produces a 2-lithio species which, upon trapping with dry ice, provides the corresponding 2-carboxylic acids (22) (Scheme 8). In contrast, when L D A is used as the reagent, the 4-position is deprotonated and thus becomes amenable to a first electrophilic substitution (Scheme 8) providing, for example, a 2-bromo-3~ fluoro-quinoline-4-carboxylic acid (23). The second functionalization can take place when the latter product is exposed to the action of two equivalents of butyllithium thus generating a 2-lithio carboxylate which, when intercepted for example with dimethylformamide, furnishes the corresponding 3-fluoro-2formylquinoline-4-carboxylic acid (24; Scheme 8) (16).

Summary and Outlook As outlined above, it is very easy to introduce functional groups into heterocyclic core structures by passing through organometallic derivatives of the latter. For simplicity carbon dioxide was used as the standard electrophile in almost all of the described reactions. However, it has to be emphasized once



Η

Λ

"N" ^COOH

Scheme 6. Reactions between 3-(trifluoromethyl)pyridine and butyllithium.

N



7. Regioselective metalation (and subsequent electrophilic substitution) of 2-, and 7-fluorοquinoline and 2-, 3- and 4-(trifluoromethyl)quinoline.



Scheme 8. Simple and double functionalization of 2-bromo-3-fluoro-quinolines featuring halogen/metal and hydrogen/metal permutation processes.


34


more that the choice of trapping reagents is virtually unrestricted. Thus, the key intermediate can be transformed not only into carboxylic acids. Aldehydes, alcohols, phenols, thiols, amines, phosphorus compounds and countless other valuable derivatives are equally accessible easily and efficaciously (17). The organometallic approach to the site selective substitution has been applied to five- and six-membered heterocycles other than those specified above, for example also to pyrimidines (18). Without doubt further applications will appear in the future.

Acknowledgment Financial support was provided by the Schweizerische Nationalfonds zur Fôrderung der wissenschaftlichen Forschung (grant 20-63'584-00), the Bundesamt fur Berufsbildung und Technologie (KTI-Projekt 5474.1 KTS) and the Bundesamt fur Bildung und Wissenschaft (grant 97.0083 linked to the TMR project FMRXCT-970129; grant C02.0060 linked to a COST D24 project).

References 1. Schlosser, M. Organometallics in Synthesis, 3rd Manual, Wiley, Hoboken, 2009 (in preparation). 2. Schlosser, M . Angew. Chem. 2005, 117, 380-398; Angew. Chem. Int. Ed. 2005, 44, 376-393. 3. (a) Schlosser, M . in Enantiocontrolled Synthesis of Fluoro-Organic Compounds : Stereochemical Challenges and Biomedical Targets (Ed.: Soloshonok, V. Α.), Wiley, Chichester, 1999, pp. 613-659; (b) M . Schlosser, in Fluorine-Containing Synthons (Ed.: Soloshonok, V. Α.), Am. Chem. Soc., Washington, 2005, pp. 218-231. 4. Schlosser, M. Organometallics in Synthesis: A Manual, 2nd edition, Wiley, 2002. 5. Schlosser, M.; Ginanneschi, Α.; Leroux, F. Eur. J. Org. Chem. 2006, 29562969. 6. (a) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1989, 30, 2129 -2132; (b) Bosco, M.; Dalpozzo, R.; Bartoli, G.; Palmieri, G.; Petrini, M. J. Chem. Soc, Perkin Trans. 2 1991, 657-663; (c) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Palmieri, G.; Marcantoni, E. J. Chem. Soc, Perkin Trans. 1 1991, 2757-2761. 7. Leroux, F.; Ginanneschi, Α.; Schlosser, M. Unpublished results, 2005. 8. Schlosser, M.; Voile, J.-N.; Leroux, P.; Schenk, K. Eur. J. Org. Chem. 2002, 2913-2920.


35 9. 10.


11.

12.

13. 14.

15.

16. 17. 18.

(a) Gribble, G. W.; Saulnier, M. G. Tetrahedron Lett. 1980, 21, 4137-4140; (b) Gribble, G. W.; Saulnier, M. G. Heterocycles 1993, 35, 151-169. (a) Marsais, F.; Quéguiner, G. Tetrahedron 1983, 39, 2009-2021; (b) Estel, L.; Marsais, F.; Quéguiner, G. J. Org. Chem. 1988, 53, 2740-2744; (c) Marsais, F.; Trécourt, F.; Bréant, P.; Quéguiner, G . J. Heterocycl. Chem. 1988, 25, 81-87. (a) Cottet, F.; Marull, M . ; Lefebvre, O.; Schlosser, M. Eur. J. Org. Chem. 2003, 1559-1568; (b) Schlosser, M.; Marull, M . Eur. J. Org. Chem. 2003, 1569-1575; (c) Schlosser, M.; Mongin, F. Chem. Soc. Rev. 2007, 36, 11611172. (a) Katsoulos, G.; Takagishi, S.; Schlosser, M . Synlett 1991, 731-732; (b) Mongin, F.; Maggi, R.; Schlosser, M . Chimia 1996, 50, 650-652; (c) Schlosser, M. Eur. J. Org. Chem. 2001, 3975-3984. Porwisiak, J.; Dmowski, W. Tetrahedron 1994, 50, 12259-12266. (a) Marsais, F.; Bouley, E.; Quéguiner, G. J. Organomet. Chem. 1979, 171, 273-282; (b) Shi, G.-q.; Takagishi, S.; Schlosser, M . Tetrahedron 1994, 50, 1129-1134. (a) Marull, M.; Schlosser, M. Eur. J. Org. Chem. 2003, 1576-1588; (b) Lefebvre, O.; Marull, M . ; Schlosser, M . Eur. J. Org. Chem. 2003, 21152121. Ondi, L.; Voile, J.-N.; Schlosser, M. Tetrahedron 2005, 61, 717-725. Schlosser, M . ; Gorecka, J.; Castagnetti, E. Eur. J. Org. Chem. 2003, 452462. (a) Plé, N.; Turck, Α.; Heynderickx, Α.; Quéguiner, G. J. Heterocycl. Chem. 1994, 31, 1311-1315; (b) Plé, N.; Turck, Α.; Heynderickx, Α.; Quéguiner, G.; J. Heterocycl. Chem. 1997, 34, 551-556; (c) Schlosser, M . ; Lefebvre, O.; Ondi, L.; Eur. J. Org. Chem. 2006, 1593-1598.


Fluorinated Heterocycles - American Chemical Society

Recommend Documents