Nucleophilic Substitutions of Nitroarenes and Pyridines

REVIEW

2111

Nucleophilic Substitutions of Nitroarenes and Pyridines: New Insight and New Applications NucleophilcSubstiutionsofNitroaren sandPyridnes Schlosser,*a Renzo Ruzziconi*b Manfred a

Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale (EPFL – BCh), 1015 Lausanne, Switzerland E-mail: [email protected] b Chemistry Department, University of Perugia, Via Elce di Sotto 10, 06100 Perugia, Italy E-mail: [email protected] Received 29 March 2010

Abstract: At the beginning of this article an in-depth comparison of electrophilic and nucleophilic aromatic and heterocyclic substitution processes examines their scopes of applicability in a new light. In the subsequent parts, recent progress in the area of halide and hydride displacement from pyridines is highlighted. Particular attention is paid to the leaving group aptitudes of fluoride and chloride, to the effect of ‘passive’ substituents on the reaction rates, and to the control of the relative reactivity at halogen-bearing 4- versus 2-(or 6-)positions. 1 2 3 4 5 6 7 8 9

Introduction Electrophilic as Opposed to Nucleophilic Substitutions Nitroarenes as Substrates for Nucleophilic Substitutions Nucleophilic Substitution at Resonance-Disabled Positions Nucleofugality Contest between Fluorine and Chlorine Substituent Effects on the Reactivity of 2-Halopyridines ‘Silyl Trick’: Discriminating between Two Potential Exchange Sites Hydride as the Nucleofugal Leaving Group Summing Up

Key words: fluorine, chlorine, lithium, nitroarenes, pyridines

1

Introduction

Physical Organic Chemistry or, in the continental European vocabulary, Reaction Mechanisms, may be conceived as the life science equivalent of the mind-setting current known as Enlightenment (Aufklärung, Illuminismo, Lumières) that shaped the thinking, feeling and literature of the 18th century. Cognition relieves man from his selfimposed minority (I. Kant) and molds an emancipated, responsible and tolerant human being. This became a general belief. In chemistry, the rational approach to cognition has well been triggered by the curiosity of a new generation of experimenters. In 1904, A. Lapworth observed how identical amounts of bromine consecutively added to acetone were decolorized, hence consumed, in progressively shorter intervals.1 Endeavoring to understand this phenomenon, he found the keto–enol equilibrium to be cataSYNTHESIS 2010, No. 13, pp 2111–2123xx. 201 Advanced online publication: 02.06.2010 DOI: 10.1055/s-0029-1218810; Art ID: C02410SS © Georg Thieme Verlag Stuttgart · New York

lyzed by the hydrogen bromide that was evolved. Decades later, other researchers came across the electronic counterpart, namely the base catalysis of the bromination or iodination of acetone.2,3 About that time, mechanistic investigations began to depart in many different directions. They culminated in the systematization of reaction patterns by C. K. Ingold,4 the quantification of substituent effects by L. P. Hammett 5 and H. C. Brown,6 the sophisticated concept of non-classical resonance by S. Winstein7,8 and R. Huisgen’s ground-breaking achievements featuring kinetics and selectivity.9 The manifold contributions by the Huisgen school were unique in the sense that they invariably suggested practical applications and thus played a significant role in the revival experienced by organic synthesis since the 1970s. Some highlights have since become textbook cornerstones, notably the 1,3-dipolar [3+2] cycloadditions (‘Huisgen reactions’), [2+2] cycloadditions, valence tautomerizations, diazonium salt chemistry and 1,2-didehydroarene (‘aryne’) chemistry. The latter subject is closely related to the ‘additive’ nucleophilic (het)aromatic substitution. This highly important topic was covered by J. Sauer and R. Huisgen in their seminal 1960 review.10 The present article takes this previous experience for granted. It intends to focus on more specific features, in particular on the regioselectivity of nucleophilic displacements at the 2- and 4-positions and on leaving group (nucleofuge) effects exerted on the reaction rates.

2

Electrophilic as Opposed to Nucleophilic Substitutions

To bring the existing options into perspective, the electrophilic and nucleophilic classes of aromatic substitutions will be juxtaposed. Both categories of transformations can be accomplished in an addition/elimination or elimination/addition mode (Scheme 1). Unlike carbocations, ‘naked’ carbanions hardly ever exist in the condensed phase. Thus all negatively charged formulas shown below are an idealizing fiction. The real species are carbon–metalbonded compounds as we shall see later. It crucially depends on its identity, whether or not an electrophile can displace an arene-bound hydrogen atom. The

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To a Teacher, Example and Friend

2112

REVIEW

M. Schlosser, R. Ruzziconi X Nu

H El

El – [ El ]

– [H ]

Nu

H

– [ Nu ]

H

El

–[ X ]

Nu

X

X

Bs

El

H-Bs

Nu Nu

Bs H-Bs

– [ Bs ] H-Bs

–[ X ]

Scheme 1 The principal modes available for executing electrophilic (left) and nucleophilic (right) aromatic substitutions: ‘electrophile or nucleophile addition first’ (in the upper lanes) versus ‘deprotonation first’ (in the lower lanes) [EI+ = electrophile; Nu– = nucleophile; Bs– = base]

If the (het)aromatic substrate is electron-poor it is advisable to invert the sequence of the two individual steps. Any electron-withdrawing substituent will acidify the ad-

NMe2

NMe2

NMe2

Br2

– [HBr] Br3 H Br

Br 1

Br2 N

NH2

Br H

Br3 N

NH2

– [HBr]

Br N

NH2 2

Scheme 2 Reaction of an electron-rich arene and an electron-rich hetarene with bromine, a moderately strong electrophile

Biographical Sketches Manfred Schlosser, born in Ludwigshafen on Rhine, was awarded a Ph.D. degree (Dr. rer. nat.) under the supervision of Georg Wittig at the University of Heidelberg in 1960. After one year of freelance research with the European Research Associates in Brussels, he

completed his Habilitation in 1966 before moving to the newly founded German Cancer Research Center (also in Heidelberg). In 1971 he was appointed to a chair for organic chemistry at the University of Lausanne. Emeritus since 2004, he continues to be active as a

researcher (e.g., probing metal effects in structure– reactivity correlations), lecturer (e.g., at the University of Kyoto in 2009), author and editor (e.g., Organometallics in Synthesis, 2nd Manual, 2004, 3rd Manual in preparation).

Born in Sassoferrato (Ancona, Italy), Renzo Ruzziconi studied chemistry at the University of Perugia where he accomplished his thesis work under the guidance of Professor Enrico Baciocchi. After the ‘Laurea’ diploma (1973), he was a research fellow of the ‘Accademia Nazionale dei Lincei’ (1975) at the Faculty of

Pharmacy and later at the Chemistry Department of the University of Perugia. From 1980 until 1982 he stayed at the University of Lausanne as a postdoctoral fellow with Professor Manfred Schlosser. Associate Professor at the Perugia Chemistry Department since 1987, he was appointed as full professor to the

Basilicata University in 1994. Since 1998 he holds a chair in Perugia. His research interests cover polar organometallic reagents, metal-oxidant-promoted radical reactions, fluoroorganic compounds and transition metal-catalyzed stereoselective reactions.

Synthesis 2010, No. 13, 2111–2123

© Thieme Stuttgart · New York


nitronium ion being a very powerful Lewis acid, it combines with virtually all (het)aromatic substrates, be that benzene, toluene, nitrobenzene or pyridine. Immediately ensuing proton loss leads to the products, for example nitrobenzene, a mixture of 2- and 4-nitrotoluene, 1,3-dinitrobenzene or 3-nitropyridine. Weaker electrophiles such as the bromonium ion require electron-rich substrates for fast reaction. N,N-Dimethylaniline11–13 (1) or 2aminopyridine14 (2) meet this condition. They form the corresponding ‘para isomers’ as the main, if not exclusive, products (Scheme 2).

REVIEW

2113

Nucleophilic Substitutions of Nitroarenes and Pyridines

jacent ortho site15–17 and in that way facilitate its deprotonation by strong bases such as butyllithium, phenyllithium, lithium diisopropylamide or lithium 2,2,6,6-tetramethylpiperidide. The resulting organometallic intermediate 3 readily combines with virtually any electrophile El-X and thus secures utmost product flexibility (Scheme 3). Li X

El X

Li-R

Numerous aromatic and heterocyclic substrates have been successfully subjected to regiochemically exhaustive functionalizations. For example, 3-fluorophenol,19 3fluoropyridine19 and 2-fluoropyridine20 (Scheme 5, acids 7–9) were ornamented with a carboxy group at each vacant position. In addition, 2-, 3- and 4-(trifluoromethyl)pyridines gave the corresponding ten carboxylic acids21 and several chloro- and bromo(trifluoromethyl)pyridines were converted into a variety of new derivatives.22–24

X

El-X

Cl

SiMe3 Cl

Cl

Cl

3 X = e.g., F, Cl, Br; OMe, OCH2OMe, SPh; NMe2 R = alkyl or aryl El-X = e.g., FClO3, FN(SO2Ph)2; ClCF2CFCl2, Cl2; BrCH2CH2Br, Br2; I2;

N

F

N

F

N

F

N

F

B(OMe)3/H2O2; LiNHOMe, R1OOC-N=N-COOR1, R1-N3; R1-CH=O, R1R2C=O, CO2

The intermediacy of organometallic species in the electrophilic substitution process offers several major advantages. The almost unrestricted choice of the electrophile has been mentioned above. Another trump is the regiochemical reliability. Whereas the classic direct substitution generally gives rise to inseparable ortho/para mixtures, the organometallic route takes us just to the ortho product. More distant positions can nevertheless be selectively metalated and subsequently derivatized (‘regiochemically exhaustive functionalization’) if protective groups such as chloro or trialkylsilyl substituents are deployed.18 For example, it requires little effort to convert 1-fluoronaphthalene into 1- or 4-fluoro-2-naphthoic acid or even 4-fluoro1-naphthoic acid (Scheme 4, compounds 4, 5 or 6, respectively).18 F

F

F Li

s-BuLi

COOH

(1) CO2 (2) aq HCl

4

lF 2

-CC CF Cl 2

F

F Cl

Cl

LITMP

Li

lF -CC CF Cl 2

(1) CO2 (2) aq HCl

Cl

5

(3) H2 {Pd}

COOH

2

F

F

F

F Cl

LIDA

Cl

Cl Li

(1) CO2 (2) aq HCl

6

(3) H2 {Pd} COOH

Scheme 4 Metalation of unprotected or protected 1-fluoronaphthalenes and subsequent carboxylation to afford the naphthoic acids 4–6 alternatively [LITMP = lithium 2,2,6,6-tetramethylpiperidide; LIDA = lithium diisopropylamide]

SiMe3

N

F

N

F

N

7

F

N

F

8

Cl

Cl

Li

COOH HOOC

Cl

Li Cl

N

F

N

F

N

F

HOOC

9

Scheme 5 Regiochemically exhaustive functionalization of 2-fluoropyridine

A final bonus associated with the organometallic approach to electrophilic (het)aromatic substitution is the optional site-selectivity of metalation. The mechanismguided matching of the reagent with a substrate bearing two or three different activating substituents offers the opportunity to direct the permutational hydrogen/metal interconversion process, the ‘metalation’, exclusively to one of two or three potentially competing sites.18 Thus, 2and 4-fluoroanisole undergo lithiation only at the oxygenadjacent position when n-butyllithium is employed, but only at the halogen-adjacent position when sec-butyllithium in the presence of PMDTA (N,N,N¢,N¢¢,N¢¢-pentamethyldiethylenetriamine) or n-butyllithium in the presence of potassium tert-butoxide (the superbasic LIC-KOR mixture) serves as the base.25 n-Butyllithium in diethyl ether and in the presence of 1,8-diazabicyclo[2.2.2]octane (DABCO) deprotonates 3-fluoropyridine (10) at the nitrogen-assisted 2-position26 whereas n-butyllithium in the presence of N,N,N¢,N¢-tetramethylethylenediamine (TMEDA) or lithium diisopropylamide in tetrahydrofuran accomplishes the metalation at the more acidic 4position27–29 (Scheme 6). Both 2- and 4-(trifluoromethyl)pyridine (11 and 12) react with alkyllithiums at the most acidic 3-position,30 but with Caubère’s base, n-butyllithium in the presence of lithium 2-dimethylaminoethoxide (LIDMAE), at the chelation-benefitting 2position30 (Scheme 6).

Synthesis 2010, No. 13, 2111–2123



Scheme 3 Structural elaboration of heterosubstituted arenes applying the ortho-metalation/electrophilic substitution sequence

2114

REVIEW

M. Schlosser, R. Ruzziconi Li F N

Li

F

n-BuLi, DABCO Et2O

THF

N

F

n-BuLi or LIDA N

when sodium methoxide is added to a solution of 2,4,6trinitrophenetole (ethyl picryl ether)42 (Scheme 7, lower line). X

10

7p

n-BuLi, LIDMAE N

CF3

N

CF3

THF

Nu

X N

X Nu

CF3

11

n-BuLi, LIDMAE N

Li

N

13

CF3 Li

LITMP

Et2O

THF

Nu

X X Nu N

R

Nu

12

R

]

Nu

O2 N

NO2

Nitroarenes as Substrates for Nucleophilic Substitutions

In the following part we shall focus entirely on this addition/elimination sequence. There are three variables to be examined in detail: the nucleofugal leaving group X, the entering nucleophile Nu and the electron-withdrawing activating substituent R. How critical is the latter? According to literature reports, even fluorobenzene itself (with sodium methoxide, at 0 °C),32 1- or 2-bromonaphthalene (with piperidine, at 230 °C)33 and, at least partly, 1-fluoronaphthalene (with lithium piperidide, at approximately 40 °C)34 undergo direct substitution according to the addition/elimination mechanism. However, the mechanism of such unactivated reactions remains obscure. In most cases, single-electron-transfer (SET) initiated radical-chain processes35–38 (Scheme 7, upper line) have never been definitively ruled out. In general, nucleophilic (het)aromatic substitutions proceed smoothly only if aided by one or two activating groups (Scheme 7). The nitro group is the most common auxiliary for that purpose (Table 1).39–41 Three nitro groups may delocalize the negative charge so effectively that the intermediate no longer collapses by expulsion of the nucleofuge but rather stays intact as a stable ‘Meisenheimer complex’. This happens, for example,


NaOMe

O2 N

X OMe NO2

if X = Cl

O2 N

NO2

if X = OEt 15

If we turn now to nucleophilic (het)aromatic substitutions we encounter the exact electronic counterpart of the electrophilic substitution formalism. Deprotonation generates an ortho-haloarylmetal (in Scheme 1 oversimplified as an o-haloaryl anion) and, by ensuing halide ejection, a 1,2didehydroarene (‘aryne’) that subsequently undergoes addition of the nucleophile and reprotonation to give the final product. Alternatively to this elimination/addition sequence,31 the nucleophile may get attached first, thus giving rise to a cyclohexadienyl anion intermediate, before the departure of the nucleofuge restores aromaticity10 (Scheme 1).

NO2

NO2

14 X

Synthesis 2010, No. 13, 2111–2123

–[ X

R

– [ Nu ] NO2

Scheme 6 Optionally site-selective lithiations of 3-fluoropyridine and 2- or 4-(trifluoromethyl)pyridine

3

]

?

CF3

CF3

–[X

Nu

NO2

NO2

NO2

R = H or O2N; X = nucleofuge; Nu = nucleophile

Scheme 7 Facile nucleophilic substitution of substrates activated by one or two nitro groups, yet ambiguities in the absence of any or in the presence of three such substituents

The nitrogen atom incorporated into a pyridine ring confers approximately the same activating effect as a nitro group attached to an arene ring does. Both 2- and 4-halopyridines are indeed very prone to nucleophilic substitution processes (see below). Halogenated diazines such as 2,4-dibromopyrimidine43 and triazines prove to be even more reactive. 2,4,6-Trichloro-1,3,5-triazine (cyanuric chloride)44,45 is manufactured in bulk and used to assemble, for example, a colorant and an optical brightener at the heterocycle before linking this ‘reactive dye’, again by nucleophilic hetaromatic substitution, to the surface of a cellulose fiber. The original synthesis of the gyrase inhibitor ofloxacin, a remarkably potent broad-spectrum antibacterial, sets off a firework of nucleophilic aromatic substitutions46–48 (Scheme 8). Starting from the industrially available 1,2dichloro-3-nitrobenzene the more mobile halogen at the 2-position is replaced by fluorine. Subsequent chlorodenitration and reintroduction of the nitro function affords 1,3-dichloro-2-fluoro-4-nitrobenzene that enables one to carry out a double halogen/halogen exchange. Two of the three fluorine atoms in the resulting 1,2,3-trifluoro-4-nitrobenzene are sacrificed in the ensuing final stages of the sequence. Consecutive treatment with potassium hydroxide and chloroacetone followed by Raney nickel catalyzed hydrogenation gives 7,8-difluoro-3,4-dihydro-3-methyl2H-1,4-benzoxazine. Condensation with diethyl (ethoxymethylene)malonate, acid-promoted cyclization


Li

Li

LITMP

Et2O

?

Table 1 Rates of Nucleophilic Aromatic Substitutions as a Function of the Activating (or Deactivating) Substituent R R

R

Cl

R

+ NaOMe

Cl

(ref. 41)

NO2

+

HN (ref. 39)

NO2

N≡N+

3.8 × 10+8 a

–

O=N

+6 a

5.2 × 10

–

O2N

6.7 × 10+5 a

–

MeSO2

7.2 × 10

+4 a

–

N≡C

3.8 × 10+8 a

–

Me3N+

2.2 × 10+4 a

–

O=CH

2.0 × 10+4 a

–

MeCO

8.1 × 10+3 a

–

PhN=N

1.1 × 10+3 a

–

Br

–

7.8 × 100 aa

Cl

5.0 × 10+1 a

5.6 × 100 aa

I

–

5.4 × 100 aa

H

1.0 × 100 aa

1.0 × 100 aa

F

–

2.6 × 10–1 a

Me

–

1.7 × 10–1 b

MeO

–

1.8 × 10–2 a

Me2N

–

1.2 × 10–3 a

HO

–

5.8 × 10–4 a

H2N

–

1.2 × 10–4 a

a b

accompanied by ester hydrolysis and ultimate displacement of the fluorine atom at the 7-position by N-methylpiperazine eventually affords the antibiotic ofloxacin (Scheme 8). If (R)-propane-1,2-diol is used to attach the C3-side chain, no racemate resolution is required to obtain the therapeutically superior S-enantiomer (Levofloxacin).47

4

Nucleophilic Substitution at ResonanceDisabled Positions

When a nucleophile binds to the ipso-carbon atom of a haloarene, electron excess builds up at the 2-, 4- and 6-positions. Only when a pyridine nitrogen is located at one of these three centers can it attenuate the negative charge by its electronegativity and only a nitro group that occupies one such site can ‘swallow’ electron density by delocalizing it to its oxygen atoms. Consequently, solely 2-, 4- and 6-halogenated pyridines and nitroarenes are really fit to undergo facile nucleophilic (het)aromatic substitutions. On the whole this is correct, and highest reactivity is indeed associated with such substituent patterns.49,50 Remarkably enough, however, azine nitrogens or nitro groups at 3- and 5-positions, in other words at the electronic nodal points, still exert an activating effect. Thus, 1fluoro-3-nitrobenzene,51 3-fluorobenzotrifluoride,52 3chlorobenzotrifluoride,53 1,3-dinitrobenzene54–56 and 3bromopyridine57 are known to react with sodium alkoxides or piperidine, whereas chlorobenzene58 proves to be fairly inert towards all nucleophiles. 2,3,5-Trichloropyridine (17) can be converted quite smoothly with potassium fluoride into 5-chloro-2,3-difluoropyridine.59,60 The halogen at the 3-position is displaced considerably faster than that at the 5-position although, of course, much more slowly than its neighbor at the 2-position (Scheme 9).

Estimated from the relative rate at +25 °C.40 If t-Bu instead of Me: krel 1.2 × 10–4.

Cl Cl

KF NO2

F F

NO2

Cl

Cl

F

(1) KOH (2) HOCH2CMe O =

F

2115


N F O

HNO3

F

N

F

KF slow

Cl

F N

F

F

F N

F

Scheme 9 5-Chloro-2,3-difluoropyridine made from 2,3,5-trichloropyridine

H2 {Pd}

F

Cl

17 O

F

fast

Cl

NO2

F

Cl

Cl

KF

5 NH

Cl

Nucleofugality Contest between Fluorine and Chlorine

O (MeOOC)2C

=

(2) aq HCl (3) Me N

KCl

NH (1)

MeO-CH

O Cl

Cl KF

F NO2

F Me

Cl NO2

COOH

N N

N O

16

Scheme 8 Synthesis of (S)-ofloxacin featuring six nucleophilic aromatic substitutions

1-Fluoro-2,4-dinitrobenzene belongs to the most popular fluorine-containing compounds. Owing to its ready coupling with the N-terminal amino acid of peptides (Scheme 10) it became the key to a first reliable sequencing method.61,62 Curiously enough, this so-called ‘Sanger reagent’ was found to be far more reactive toward ‘free’ (i.e., non-amidic) amino functions than is 1-chloro-2,4dinitrobenzene, the precursor from which it is made by halogen/halogen displacement.

Synthesis 2010, No. 13, 2111–2123



REVIEW

2116

REVIEW

M. Schlosser, R. Ruzziconi NO2 slow

O2 N

Cl

NO2 O

O

O

O

H2N-CH-C-NH-CH-C-NH-CH-CR1

O2 N

R3

R2

O

O

NH-CH-C-NH-CH-C-NH-CH-CR1

R2

R3

NO2 18 O2 N

F fast

Scheme 10 Condensation of 1-fluoro-2,4-dinitrobenzene with the basic N-terminus of a peptide (to give derivative 18) thus enabling the identification of the correspondingly modified (and colored) a-amino acid after hydrolysis X 19

19

NO2

NO2

HNR2

X NR2

M-OR

X NR2 H

H H

The latter inversion of the halogen effect on the overall reactivity should remind us of the mechanistic complexity of nucleophilic aromatic substitutions employing amines as the nucleophiles. Activated haloarenes such as 1-fluoro- and 1-chloro-4-nitrobenzene (19, X = F or Cl) add ammonia and primary or secondary amines (HNR2, R = H, alkyl, aryl) to form an inner salt, a 6-ammonio-6-halocyclohexa-2,4-dien-1-ide. This intermediate may revert to its constituents or lose a proton to a base or transfer the proton intramolecularly thus giving rise to a 5-amino-5halo-1,3-cyclohexadiene that can undergo amine-promoted b-elimination of H-X to afford the final substitution product (Scheme 11). Compared to the reaction of a metal alkoxide (Scheme 11) or a metal amide, this means several possible additional steps.

Table 2

X

X NR2

X OR

NO2

NO2

HNR2

intramolec. neutralization

NO2

NO2 HNR2 –[ X

– [ HX ]

]

–[ X

NR2

OR

NO2

NO2

X = e.g., F, Cl; R = H, alkyl, aryl; M = Li, Na, K

Scheme 11 The mechanistic pathways of amines (HNR2, on the left) in nucleophilic aromatic substitutions are less unequivocal than those of metal amides (M-NR2) and metal alkoxides (M-OR, on the right)

Comparison between Nucleofuges in Nucleophilic Substitution Reactions; Rates Relative to the Chloro Compounds (X = Cl) NO2

Nucleofuge

O2 N

NO2

NO2

X

X

O2 N

O2 N

X

X

NO2

X

HN(CH2)5 HN(CH2)5 EtOH52 DMSO58

NaOMe MeOH51,a

F

430

310

410

H2NPh EtOH57 44

NO2

HN(CH2)5 MeOH54

H2NPh EtOH49

770

62

HN(Me)Ph NaOMe EtOH53 MeOH50 0.73

1300

NaSPh MeOH55

H2NPh EtOH56

27

190

Clb

1.0

1.0

1.0

1.0

1.0

1.0

1.0

1.0

1.0

1.0

Br

1.3

1.2

0.85

1.8

1.0

1.5

2.2

0.62

1.7

1.4

I

0.39

0.26

0.36

0.42

0.23

0.43

–

0.24

1.3

0.26

OMe

–

0.002

–

–

–

–

–

–

–

–

NO2

–

8.7

–

210

–

–

–

–

a b

1600

With NaOEt in EtOH at 91 °C: ref. 49. The chloro compound has been chosen as the kinetic reference for each set of substrate/reagent combinations.

Synthesis 2010, No. 13, 2111–2123


]

1900


The superior performance of fluoroarenes as opposed to chloroarenes in nucleophilic substitutions is a general phenomenon. It is encountered with mono-, di- and trinitrosubstituted substrates (Table 2).63–73 The kF/kCl ratios fall in the ranges of 300–1300 and 40–770 with, respectively, sodium alkoxides and aliphatic or aromatic amines as the nucleophiles (Table 2). In a single case (Table 2, eighth column), the chloro compound reacts with N-methylaniline even faster than the fluoro analogue (kF/kCl 0.73).68

REVIEW

Data like those compiled of nitroarenes (Table 2) have been widely lacking in the pyridine field. We have now, for the first time, quantified the effect of the nucleofugal leaving group on the substitution rates of halopyridines. To this end, 2-halopyridines and a few 4-halopyridines were treated with sodium ethoxide in a 1:2 mixture of ethanol and diethyl ether at +25 °C. The relative reactivities were assessed by competition experiments.74 In all cases examined, fluorine turned out to be a better leaving group than the heavier halogens. In particular, 2-fluoropyridine produced 2-ethoxypyridine 300 times faster than did 2chloropyridine (Scheme 12).74

stitution process, whereas it retards it if at the 5-position (Table 4).74 All other halogens, no matter where accommodated, increase the rate by one or up to almost two powers of ten (Table 4).74 Particularly noteworthy is the effect exhibited by a trimethylsilyl group. As a moderate electron acceptor75 it slightly enhances the nucleophilic attack as long as it stays remote from the combat zone. In contrast, it effectively obstructs the nucleofuge/nucleophile exchange in its immediate vicinity (Table 4).74 Table 4 4-Substituted (middle) and 3-Substituted 2,6-Difluoropyridines (left and right, depending on which site is undergoing substitution) Reacting with Sodium Ethoxide

NaOEt

R 3

EtOH–Et2O

X

N

F 2 N 6 F > X = Br krel : X = F >> X = Cl ~

Scheme 12 Substitution of 2-halopyridines by sodium ethoxide: effect of the nucleofuge X on the reaction rates

Substituent Effects on the Reactivity of 2-Halopyridines

The next question to be addressed was to what extent typical substituents R would accelerate or retard the nucleophilic substitution of 2-halopyridines. Competition kinetics again provided the answer. Not surprisingly, electron-donor groups such as ethoxy were found to slow the reaction down and electron-withdrawing entities such as trifluoromethyl to speed it up (Table 3).74 The ambivalent fluorine substituent inductively assists the addition if located at the 3-, 4- or 6-positions, but impedes it by its mesomeric electron-supplying effect (lone pair–lone pair repulsion) if at the 5-position (Table 3). Table 3 Relative Ratesa of Nucleophilic Hetaromatic Substitutions of Substituted 2-Fluoropyridines by Sodium Ethoxide R

R

3

R

R

OEt

20

6

R 4

F 6 N

2 F

F 6 N 2 F

F

5 × 10–1

4 × 10+1 b

5 × 10+1

Cl

8 × 100

–

7 × 10+1

Br

2 × 10+1

–

1 × 10+2

I

3 × 10+1

8 × 10+1 a

5 × 10+1

Si(Me)3

3 × 100

–

8 × 10–2

a Rates relative to the parent compound 2,6-difluoropyridine (R = H), statistically corrected in the case of 4-substituted substrates. b Not considering the substitution at the 4-position competing with that at the 2(6)-position in a ratio of 1:4.

Data of 2-chloropyridines have been collected only sporadically. They reveal the same propensities as already recognized with fluoropyridines. 2,6-Dichloropyridine reacts with sodium ethoxide 60 times faster, or, after statistical correction, 30 times faster than does 2-chloropyridine.74 An iodo substituent at the 4-position accelerates by a factor of 20. 2,6-Dichloro-3-(trifluoromethyl)pyridine outperforms 2-chloropyridine 1000-fold if the CF3-proximal and 6000-fold if the CF3-remote chlorine atom is displaced by sodium ethoxide.74

R

R R

N

F

N

F

N

F

N

F

EtO

8 × 10–2 a

–

–

–

F

3 × 10+1 b

7 × 10–1

4 × 10+1 c

5 × 10+1

Cl

–

–

7 × 10+1 a

8 × 10+1

F3C

–

3 × 10+3

–

–

a

Rates relative to unsubstituted 2-fluoropyridine (R = H). Experimental rate divided by two for statistical correction. c Relative rate of reaction at the 2-position (concomitant substitution at the 4-position giving a 1:1 mixture of 2-ethoxy-4-fluoropyridine and 4-ethoxy-2-fluoropyridine). b

An evaluation of the reactivity of substituted 2,6-difluoropyridines toward sodium ethoxide confirms the trends observed. A fluorine substituent at the 3- or 4-position (with respect to the departing nucleofuge) accelerates the sub-

7

‘Silyl Trick’: Discriminating between Two Potential Exchange Sites

If two or three halogens occupy exchange-active sites in a pyridine it is difficult to tell a priori which one is going to act as the leaving group and which one stays on. As seen above, sodium ethoxide attacks the regioisomerically different positions in 2,4-difluoropyridine (Table 3) and 2,4,6-trifluoropyridine (Table 4) concomitantly. Lack of selectivity was observed before. For example, 2,4dichloropyridine76 and 2,4,6-tribromopyridine77 were found to give 2- and 4-amino substitution products in 1:3 and 1:1 ratios, respectively, when treated with aqueous ammonia at 150–175 °C. Regioselectivity in favor of the 4-position can, nevertheless, be achieved with secondary amines (e.g., dimethylamine) and, in particular, with hydrazine hydrate.78 The Synthesis 2010, No. 13, 2111–2123



N

2117


REVIEW

M. Schlosser, R. Ruzziconi

arylhydrazines thus obtained can be converted with mild oxidants (such as cupric sulfate) via the ephemeral aryldiazenes into the corresponding arenes (Scheme 13).79 Alternatively, arylhydrazines may be reductively cleaved to aminopyridines using zinc,80 sodium,81 Raney nickel82 or hydrogen83 (Scheme 13). N=NH

O Su

4

X2

N

X1

X2

N

X1

C

X1

NHNH2 H2NNH2 X1

X2

X1

N 21

H

N

Nu

NH2

2 P{ }d

X2

2,4-Dichloropyridine behaves analogously.78 When treated with dimethylamine or hydrazine, it selectively undergoes substitution at the 4-position. In contrast, 2,4dichloro-5-(triethylsilyl)pyridine reacts exclusively at the 2-position. The same scenario is encountered with 2,4,6-trifluoropyridine and 2,4,6-trichloropyridine (compounds 23, Scheme 15). Direct substitution with dimethylamine, hydrazine and, this time even, sodium ethoxide occurs cleanly at the 4-position. After introduction of a trimethylsilyl or triethylsilyl group into the 3-position the nucleophile is rigorously diverted to the 6-position (Scheme 15).78 Protodesilylation of the thus accessible 2,4-dihalo-6-hydrazino-3-(trialkylsilyl)pyridines (24) gives 2,4-dihalo-6hydrazinopyridines and, upon oxidation/dediazotation, the corresponding 2,4-dihalopyridines (Scheme 15).78 X

X2

N

X2

X1

N

Nu

X1

M-Nu N

X

X

X1 = F, Cl; X2 = H or X1; Nu = e.g., Br, I, OH

X

The regioselectivity in favor of the 4-position can be completely reversed by exploiting the screening effect of trialkylsilyl groups (Table 4). Whereas 2,4-difluoropyridine reacts cleanly with dimethylamine or hydrazine at the 4position (Scheme 14), its 5-trimethylsilyl or 5-triethylsilyl derivatives (22) undergo nucleophilic substitution exclusively at the 2-position (Scheme 14).78 The controlling trialkylsilyl unit can be readily introduced by a sequence consisting of lithiation and iodination at the 3-position, lithium diisopropylamide triggered migration18 of the heavy halogen from the 3- to the 5-position, permutational iodine/lithium interconversion and ultimate condensation with chlorotrimethyl- or chlorotriethylsilane. The trialkylsilyl screen can eventually be removed and replaced by hydrogen, bromine or iodine using tetrabutylammonium fluoride hydrate, molecular bromine or iodine chloride, respectively.78,79 F

R3Si X

4

5

R3Si TBAF

6 N

2 X

M-Nu

X

N

Nu

H2 O

X

N

X = F, Cl; R = Me, Et; M-Nu = NaOEt, HNMe2, H2NNH2

Scheme 15 Selective nucleophilic substitution of 2,4,6-trifluoropyridine and 2,4,6-trichloropyridine at the 4-position or, by virtue of the ‘silyl trick’, at the 2- (or 6-) position

There have been numerous previous attempts to impose regioselectivity on the nucleophilic substitution of 2,4-dihalopyridines. The only approach that has so far been met with success, if only a modest one, was the palladiumcatalyzed condensation of 2,4-dichloropyridine with phenylurea. 4-Chloro-2-(N¢-phenylureido)pyridine and 2chloro-4-(N¢-phenylureido)pyridine are formed in a 93:7 ratio and in a total yield of 86%.84 NR1R2

(1) n-BuLi

HNR1R2

(2) I2

N

F

N

F

(1) LIDA (2) H2O

F

F R33Si (1) n-BuLi

I N

F

(2) R33SiCl

R33Si

El El-X

2

N

F

F

4

5

F

HNR1R2

N

NR1R2

N

NR1R2

22 R3

Scheme 14

= Me, Et;

NR1R2

= e.g., NMe2, NHNH2; El = H, Br, I

Selective nucleophilic substitution of 2,4-difluoropyridine at the 4-position or, by virtue of the ‘silyl trick’, at the 2-position

Synthesis 2010, No. 13, 2111–2123


Nu

24

F

F

X

X

X

N

X

(1) n-BuLi (2) R3SiCl

Scheme 13 Regioselective substitution of 2,4-dihalo- or 2,4,6-trihalopyridines with hydrazine at the 4-position and subsequent transformations

I

N

23


2118

REVIEW

2119

Hydride as the Nucleofugal Leaving Group t-BuLi (2.0 equiv)

Br

The venerable Tchitchibabin reaction85,86 remains one of the most popular textbook examples of nucleophilic hetaromatic substitution. Sodium amide and pyridine are heated in an inert medium (e.g., xylene) to approximately 150 °C. Under such circumstances, smooth addition of the amide and elimination of sodium hydride take place simultaneously. When the reaction is stopped by cautious neutralization, 2-aminopyridine can be isolated in high yield. It is tempting to rationalize the initial addition step by attributing to pyridine, despite it p-sextet aromaticity, the electrophilic character of a cyclic azomethine. However, nucleophilic aminations of heteroatom-free naphthalenes had already been reported by F. Sachs.87 K. Ziegler et al.88,89 were able to separate operationally the addition from the elimination step. As they demonstrated, butyllithium and phenyllithium combine very readily with pyridine, quinoline, isoquinoline or acridine at ambient temperature to afford 2-substituted 1,2-dihydropyrid-1yllithiums (25) or, respectively, benzo derivatives thereof. In the absence of oxidants, heating to approximately 100 °C is required to provoke elimination of lithium hydride and thus to restore the azine aromaticity (Scheme 16). ≤ +25 °C N

Li-R

R H

– [LiH]

N

N –75

–75 °C

26

+100 °C

OMe

OMe

OMe

Q*

Q*

Br

t-BuLi (2.0 equiv)

Li

N –75

–75 °C

N 27

+100 °C

Q* = Si(Me)2(i-Pr)

Scheme 17 Preparation of 2-[2-(methoxymethyl)phenyl]pyridine and 2-o-tolyl-4-(isopropyldimethylsilyl)pyridine by aryl/hydride substitution

R

H H

H Q*

Q*

Q*

H H R

H R

H

H

28 R = MeO, Q* = H or R = H, Q* = Si(Me)2(i-Pr)

Scheme 18 Enantiomerization of 2-arylpyridine rotamers by passing through a coplanar transition state

≥ +90 °C N

Li

N

R

Li 24 R = n-Bu, Ph

Scheme 16 Fast addition of alkyl- or aryllithiums to the 2-position of pyridine followed by slow elimination of lithium hydride

The practical potential of this method has so far been neglected. By taking advantage of the addition/elimination sequence, an entry to new 2-arylpyridines was opened. Thus, 2-[(2-methoxymethyl)phenyl]pyridine (26; 56%) was prepared by reaction of 2-(methoxymethyl)phenyllithium with pyridine itself90 and 2-o-tolyl-4-(isopropyldimethylsilyl)pyridine (27; 67%) by reaction of otolyllithium with 4-(isopropyldimethylsilyl)pyridine,90 the latter made from 4-bromopyridine (Scheme 17). Both pyridines bear a diastereotopicity probe, the oxygenadjacent methylene group in the first case and the siliconbonded geminal methyls in the second. Line shape analysis of variable temperature (‘dynamic’) NMR spectra can therefore provide the torsional barrier that has to be crossed by passing through a coplanar transition state (28) when one enantiomeric conformer switches into its mirror image (Scheme 18). Such B values (B standing for biaryl barriers) are more meaningful measures of steric bulk than other scales.

The rotational barriers of both 2-arylpyridine model compounds were found to be too small (