Fluorine-Containing Synthons - American Chemical Society

Chapter 11

Regioexhaustive Functionalizations: To Miss an Isomer Means to Miss a Chance Manfred Schlosser

Downloaded by UNIV OF LEEDS on August 20, 2014 | http://pubs.acs.org Publication Date: July 21, 2005 | doi: 10.1021/bk-2005-0911.ch011

Institute for Chemical Sciences and Engineering, Ecole Polytechnique Fédérale,CH-1015Lausanne, Switzerland

To exploit the chemical potential inherent in a simple, aromatic or heterocyclic, precursor compound optimally one should be able to introduce any kind of substituents, in particular functional groups, into any vacant position. To achieve the latter objective, a specific kit ("toolbox") of advanced organometallic methods and reaction sequences has been elaborated and tested. The concept is illustrated by typical applications in the benzene, naphthalene and pyridine areas.

Only a few commercial organofluorine compounds are endowed with structural complexity whereas most others exhibit deceptively monotonous substituent patterns. To make a maximum out of the opportunities offered by such bulk chemicals has motivated the present investigation. The procedures developed proved most valuable in order to achieve the structural proliferation of fluorinated key compounds but were also applied, with equal success, to substrates carrying other heteroelements such as chlorine, bromine, oxygen or nitrogen (J). There are good reasons for insisting on regioexhaustiveness if the unrestricted chemical modification of a readily available starting material rather than the target-oriented synthesis is the aim. First of all, it is dictated by economical considerations to get a maximum of derivatives out of the same precursor compound. Moreover, one needs the complete selection of isomers to extract valid structure/activity relationships and to find out whether the individual contributions of substituents are additive or depend on their environment. When performing regiochemically exhaustive substitutions, our research is entirely tributary to the organometallic approach (2). This, of course, has to do 218

© 2005 American Chemical Society

In Fluorine-Containing Synthons; Soloshonok, V.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005.

219


with its versatility. Most importantly, we can access all kinds of derivatives by merely choosing the appropriate electrophile to be combined with the organometallic intermediate (5). Although it is most common to quench such reactions with dry ice and to isolate subsequently the corresponding carboxylic acid, there are dozens if not hundreds of other, similarly attractive reagents that open the entry to virtually all types of functionalities. Thus the problem of deciding what derivative to make exactly can be deferred to the very end of the reaction sequence. This unique productflexibilityis a most precious hallmark of organometallic chemistry.

The Toolbox Methods The "oriAo-directed metalation" of substituted benzenes (a somewhat vague translation of Wittig's "gezielter orrAo-Metallierung") has become a common place. To live up to our quest for regioselectivity we have to find ways to selectively introduce substituents, including functional groups, also in meta and para positions. The practical realization of this goal relies on the " 2 x 3 toolbox methods". As already outlined elsewhere (/), they comprise three subcategories of permutational hydrogen/metal interconversions ("metalations") and three subcategories of permutational halogen/metal interconversions ("exchanges"). These methods have been applied to the regioexhaustive substitution of fluorinated or otherwise halogenated benzenes, biphenyls, naphthalenes, un protected phenols, JV-protected anilines and a series of heterocyclic substrates such as indoles, quinolines, pyridines, pyrazoles and pyrroles (/, 4). In the following, each of the existing options will be illustrated by typical examples.

Isomerization by Transmetalation The first subcategory in the metalation sector takes advantage of a trans metalation mechanism to convert a kinetically favored, more basic species into a less basic isomer by equilibration (the "second-chance approach"). When treated with lithium diisopropylamide (LIDA) in tetrahydrofiiran (THF) at -75 °C, 4chloro-3-fluoropyridine undergoes deprotonation mainly at the coordinatively activated 2-position but to a minor extent also at the more acidic 5-position as evidenced by the carboxylic acids l a and l b obtained after the reaction with dry ice. However, in the course of 20 h, the 4~chloro-3-fluoro-2pyridyllithium progressively attacks unconsumed substrate at the 5-position until it has been completely converted into 4-chloro-5-fluoro-3-pyridyllithium (5). In diethyl ether (DEE) the hydrogen/metal permutation process requires the neighboring group assistance of the lone pair of the nitrogen atom at which the


220 lithium can dock. Therefore, with lithium 2,2,6,6-tetramethylpiperidide (LITMP) as the base, metalation occurs quantitatively at the 2-position in this solvent (5).

Ν

Ν

(1.)C0 |


2

Li

Ν

(2.) HCI

(1.)C0

e

J (2.)HCI

00C

cV N^COOH

2

" tV 1a

Ν

1b

LIDA / THF 20 h -75 C

0%

71%

LITMP / DEE 2 h-75*C

91%

0%

Reagent-Controlled Optional Site Selectivity of Metalations Optional site selectivity in metalation reactions is hardly attained by lucky gambling with the reaction conditions but is better based on mechanistically guided substrate/reagent matching (d). Ordinary alkyllithiums prefer to abstract a proton from a site in the vicinity of an electron donor substituent which can coordinate the metal by virtue of a lone pair and thus lower the energy of the transition state. In contrast, if butyllithium is coordinatively saturated by powerful donor ligands such as potassium ter/-butoxide or N N,N',N",N"pentamethyldiethylenetriamine (PMDTA), it just seeks to travel along the steepest acidity gradient, in other words to generate the least basic of all possible intermediates. This would imply the proton abstraction from a fluorine-adjacent rather than oxygen- or nitrogen-adjacent position if there is a choice. For this reason l-fluoro-4-(methoxymethoxy)benzene (like its ortho isomer too), was exclusively deprotonated at the 3- or the 2-position affording respectively the acids 2a and 2b, depending on whether butyllithium was employed in the absence or presence of additives such as potassiumteri-butoxideor PMDTA (7, 8). f

COOH

The weaker the base, the more it tends to generate the "least expensive", thermodynamically most stable intermediate (P). Thus, proton abstraction from the O-


221


methoxymethyl protected 2-chloro-3,4-difluorophenol occurs exclusively at the 6- or 5-position and gives subsequently rise to the acids 3a or 3b depending on whether butyllithium in diethyl ether or lithium 2,2,6,6-tetramethylpiperidide (LITMP) in tetrahydrofiiran is employed.

Deploying Site Protective Groups The concept of deflecting the metalation from the top reactive site to a neighboring position by using a suitable perturbation has been described in a recent review article (4). "If optional site selectivity and basicity-driven halogen shuffling fail to outwit the thermodynamically most acidic position of the substrate, there is still one last chance left which appears at the same time to be the most obvious one. One merely has to bow to the inevitable, deprotonate the most reactive site and then to block it with an atom or a group electronegative and slim enough to activate its immediate vicinity for further deprotonation. The desired electrophilic substitution once accomplished, all what remains to be done is to remove the temporary substituent (¥)." This description of a would-be helper reads like a warrant of apprehension for chlorine. Actually chlorine perfectly fulfills all the given requirements. It has a considerable activating effect as shown by the comparison between the very facile metalation of 3-chlorobenzotrifluoride with that of benzotrifluoride which reacts quite sluggishly unless superbases are used (//). When the mixture is quenched by reaction with dry ice and neutralized, the carboxylic acid 4a is isolated in high yield. The dechlorination to the 2-(trifluoromethyl)benzoic acid can be readily accomplished by catalytic hydrogénation or treatment with zinc powder in alkaline medium (5). Remarkably, the regioselectivity of the meta lation is completely altered when butyllithium is replaced by the bulkier secbutyllithium. The deprotonation takes now place exclusively at the CF -remote 4position to afford the acid 4b and, after subsequent reduction, 4-(trifluoromethyl)benzoie acid. The 3-isomer can be obtained starting from either 2- or 4chlorobenzotrifluoride and passing through the chlorinated acids 4c and 4d. The three (trifluoromethyl)benzoic acids could of course also be readily prepared from the equally commercial, though more expensive 2-, 3- and 4-bromobenzotrifluorides by submitting them to a consecutive halogen/metal permutation and carboxylation. 3



222

Another, if rarely exploited, option is to replace the "fill-in" chlorine sub stituent by a nucleophile rather than by hydrogen. l,2,3-Trifluoro-4-nitrobenzene (5), a key intermediate on the route to the antibacterial Ofloxacin (12) is technically produced from l,3-dichloro-2-fluoro-4-nitrobenzene which in turn is made from l,3-dichloro-2-fluorobenzene (13). This material is generally prepared in a multi-step sequence. It can be more readily obtained in a one-pot procedure from the inexpensive fluorobenzene by repetitive metalation with secbutyllithium and chlorination with l,l,2-trichloro-l,2,2-trifluoroethane (14).

Unlike chlorine, organic bromine is not inert toward organometallic reagents but rather entertains a halogen/metal permutation with them. 2,3,6-Trifluorophenol can be very easily converted into the acid 6a by selective para bromination (using molecular bromine), acetalization and reaction with


223


butyllithium followed by carboxylation and neutralization. On the other hand, the acid 6b is isolated if butyllithium is replaced by LIDA, thus promoting deprotonation, and the bromine protective group is reductively removed after the carboxylation (14).

Deprotonation-Triggered Heavy Halogen Hopping 2-Bromobenzotrifluoride represents the most impressive model case in the arene series. A proton is abstracted from the bromine-adjacent 3-position with LITMP in tetrahydrofuran at -100°C, leading to the acid 7a upon carboxylation. However, when the mixture is brought to -75°C before quenching, bromine and lithium swap places by halogen/metal permutation involving traces of accidentally formed 2,3-dibromobenzotrifluoride as catalytic turntables and ending up, after carboxylation with the acid 7b (//).

S

Li

Br

CF (1-)CQ

2

( 2 ) H C I

3

^ y C O O H

^ S r

7b

The nature of the halogen is critical for such basicity gradient driven isomerizations. Chlorine proves to be immobile in this respect at any temperature below -25°C whereas bromine and iodine migrate even at -125°C. Thus, when consecutively treated with the "Faigl mix" (15), the mixture of LITMP, PMDTA and potassium ieri-butoxide, at -125°C and dry ice, 2-chloro-l,3-difluorobenzene


224


is converted into the acid 8a whereas 2-bromo-l,3-difluorobenzene and 1,3difluoror2-iodobenzene give the acids 8b and 8c (16).

8b: 8c:

X = Br X =

ι

Discrimination Between Bromine and Iodine When the readily accessible l,5-dibromo-2,3,4-trifluorobenzene and 1bromo-2,3,4-trifluoro-5-iodobenzene are subjected to a heavy halogen dislo cation under the action of LID A, the isomers l,2-dibromo-3,4,5-trifluorobenzene and 2-bromo-3,4,5-trifluoro-l-iodobenzene result in high yield. The dibromo compound reacts with butyllithium in tetrahydrofuran at -100°C to generate cleanly an organolithium species which forms the acid 9a upon carboxyiation. However, under the same conditions, the iodobromo precursor affords the acid 9b as the heavier halogen is displaced exclusively (17).

U

i2)HCl

V^COOH

Discrimination Between Seeming Equal Halogens For a long while the only example known was procured by 2,5dibromopyridine as the substrate. With butyllithium in toluene the halogen/metal permutation occurs at the 2-position where the lone pair of the nitrogen atom can


225


coordinate the metal and thus stabilize the transition state (18). Such a neighboring group participation is unnecessary in the more polar solvent tetrahydrofuran and, as a consequence, the exchange process is now oriented to the 5-position in order to produce the less basic intermediate (19). Quite similarly, 2,3,5-tribromopyridine, made in a two-step protocol from 2aminopyridine (20, 21), can be converted in the two isomeric acids 10a and 10b. In toluene the coordination-seeking butyllithium attacks again the 2-position whereas isopropylmagnesium chloride in tetrahydrofuran promotes the permutational exchange at the most acidified 3-position (22).

Which Tool to Select When ? One of the six "educated methods" featured in the foregoing part is particular dear to the heart of the present author. The reagent-modulated optional site selectivity is, when it works, an extremely effective and straight forward solution to the problem. In fortunate cases it enables the substrate to metamorphose to three different isomeric identities by merely varying the metalating base (7). Moreover, to be successful in this area happens rarely by mere coincidence, but is rather guided by deep mechanistic insight and hence provides a feeling of triumph. However, optional site selectivity depends on electronic differences between competing substituents which may be too subtle or too unbalanced to be exploitable. In other words, it is not an all-round option. The faithful workhorses among the toolbox methods are deprotonationtriggered halogen hopping and the metalation-rerouting by protective groups. Before someone embarks on any of these possibilities, it would be helpful to dispose of some criteria of evaluation that allow one to estimate the performance in advance. Therefore we shall focus in the following two subchapters on some fundamentals and their boundary conditions.


226


Bromine or Iodine for Halogen Dislocations? The key step of deprotonation-triggered heavy halogen migration being a halogen/metal permutation, iodine should outperform bromine by far. Instead, there are cases where an orfAo-lithiated bromoarene proves perfectly stable whereas the iodoarene analog isomerizes instantanously. The 6-fluoroindole family offers an instructive example. Treatment of the unprotected starting material with two equivalents of the superbasic "LIC-KOR" mixture (butyllithium in the presence of potassium ter/-butoxide; 2, 23, 24) and subse quent carboxylation provides the pure 6-fluoroindole-7-carboxylic acid (11a). Conversely, the N-triisopropylsilyl congener undergoes metalation with PMDTA-activated sec-butyllithium at the 5-position. Both the 5-bromo and the 5-iodo derivative, obtained by treatment of the organolithium intermediate with the elemental halogen, are deprotonated by LIDA at the 4-position. However, only the iodinated species isomerizes to afford, after carboxylation and reduction, the acid 11c whereas the acid l i b can be accessed on the bromine route (25).

Iodine as a migrating substituent nevertheless suffers from some short comings which bromine exhibits only to a lesser extent. First of all, it sometimes becomes the prey of a reductive side reaction which simply replaces it by hydrogen (26). Alternatively or simultaneously, the isomerization may stop abruptly leaving some 15 - 25% of the starting material unconsumed. Fortunately, such an accident can easily be repaired by a kinetic purification. Addition of a little more than the stoichiometrically required amount (20 - 30%) of butyllithium to the mixture containing the main product (e.g. 12) along with the undesired precursor 13 selectively eliminates the latter by preferential halogen/metal


227 permutation. After hydrolysis, the deiodinated compound can readily be sepa rated from the iodine-containing main product (27).

t^J^^t

LIDA

F ^ ^ k ^ F

I 13

(partially unconsumed)

LiC H 4

9

12

(main product) L i C H : slower

very fast

4

9

t HQ


2

F.

The Protective Group Contest: Chlorine vs. Trialkylsilyl Chlorine is the first choice as a metalation-rerouting substituent for several good reasons. It reliably blocks the initially most acidic position and activates the neighboring one if vacant. It can be used repetitively as illustrated by the metalation of l-fluoronaphthalene where it deflects the attack of sec-butyllithium from the 2- to the 3- and, after accumulation, to the 4-position as mirrored by the isolation of the acids 14a, 14b and 14c after reductive dechlorination (2). 1,2,3Trichloro-4-fluoronaphtalene does no longer reacts with organometallics by metalation but rather by chlorine/lithium permutation. If one wishes to move the battlefield to the annulated ring, one may introduce at the fluorine-opposite position an easily removable group such as amino (28) or aminosulfonyl (29% both known to promote metalation at the peri position.


228


Chlorine can be used as a metalation-rerouting group also in the heterocyclic area as the following example demonstrates convincingly. The CH-acidity of 1substituted imidazoles is highest at the 2- and lowest at the 4-position (30). Protection of the firstly deprotonated 2-position by a chlorine atom enables one to functionalize subsequently the 5-position selectively in order to obtain the pro duct 15 after appropriate electrophilic substitution and removal of the protective groups (57).

r

r

* ι \

OR JLiC H

OR

OR

4

°

OR H |{Pd)

9

2

/N

< j)

[0R = 0CH C H ] 2

6

5

1

5

Fluorine-Containing Synthons - American Chemical Society

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