Heteroatom-promoted lateral lithiation

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Heteroatom-promoted lateral lithiation is the site-selective replacement of a benzylic hydrogen atom for lithium for the purpose of further functionalization. Heteroatom-containing substituents may direct metalation to the benzylic site closest to the heteroatom or increase the acidity of the ring carbons via an inductive effect. [1]

Contents

Introduction

Toluene derivatives with heteroatom-containing substituents in the ortho position undergo site-selective benzylic lithiation in the presence of organolithium compounds (either alkyllithiums or lithium dialkylamides). Coordination of the Lewis acidic lithium atom to the Lewis basic heteroatom, as well as inductive effects derived from the electronegativity of the heteroatom, encourage selective deprotonation at the benzylic position. [2] Competitive ring metalation (directed ortho-metalation) is an important side reaction, but a judicious choice of base often allows for selective benzylic metalation. Useful heteroatom-containing directing groups include dialkylamines, [3] amides (secondary or tertiary), ketone enolates, [4] carbamates, and sulfonates. Lateral lithiation of alkyl-substituted heterocycles incorporating heteroatom-containing substituents is also possible, although ring lithiation α to the ring heteroatom may compete with lateral lithiation. [2] The products of lateral lithiation react with a variety of electrophiles, including reactive alkyl halides (allylic, benzylic, and primary), carbonyl compounds, silyl and stannyl chlorides, disulfides and diselenides, and others. A general, highly selective method for benzylic metalation using a mixed lithium and potassium metal amide (LiNK chemistry) has been developed which permits metalation regardless of the relative position (ortho, meta or para) of the methyl group to the heteroatom containing substituent [5]

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Mechanism and stereochemistry

Prevailing mechanism

Two limiting mechanisms, one operating under kinetic and the other thermodynamic control, have been identified for lateral lithiation reactions. The mechanisms of most lateral lithiations fall somewhere between these two limiting mechanisms, and the precise mechanism of a particular lithiation depends on two factors:

When both the Lewis acidity of the organolithium compound and the Lewis basicity of the substituent are high, as in lithiations of ortho-(dialkylamino)methyl toluenes with n-butyllithium in a non-coordinating solvent, coordination of the base to the heteroatom substituent takes place. Lithiation then occurs at the most kinetically accessible ortho benzylic position; ortho lithiation is slower in this case. [2]

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As either the Lewis acidity of the base or the coordinating ability of the substituent decrease, a mechanism involving purely inductive effects becomes more important. For instance, the lithiation of 1 with lithium di(isopropyl)amide (LDA) affords only the product of benzylic metalation 2; none of the ortho-lithiated product 3 is observed. This result is explained by a mechanism in which the amide substituent affects the acidity of the para benzylic position solely through inductive effects and coordination of the base is not operative. Deprotonation occurs to afford the most thermodynamically stable product. [6]

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In most cases, both mechanisms will lead to the same product, as the sites of kinetic and thermodynamic deprotonation will coincide.

Scope and limitations

A variety of heteroatom-containing substituents promote lateral lithiation of an ortho methyl group. Generally, better results are obtained when the heteroatom is in the β position rather than the α position, as the latter tends to promote ortho lithiation. Lithation of primary benzylic positions is slower than lithiation of methyl groups due to inductive electron donation from the additional alkyl group (rather than steric effects). [7] Electrophiles that react with the benzylic anions formed by these methods include aldehydes and ketones, activated (primary, allylic, or benzylic) halides, [8] molecular oxygen, [9] and silyl chlorides. [10] This section describes the scope of directing groups that may be used to effect site-selective lithiation in substituted benzenes and heterocycles.

Lithiations of substituted benzenes

Aldehyde substituents suffer nucleophilic addition in the presence of organolithium compounds; however, adducts of aldehydes with lithium diamines can serve as effective directing groups for lateral lithiation. Subsequent treatment with an electrophilic primary alkyl halide and elimination of the diamine provides functionalized aryl aldehydes. [11]

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Tertiary amides are highly effective directing groups. After treatment of the resulting benzylic anion with an aldehyde, cyclization leads to lactones. [12] Carboxamides, in which the amide is attached to the aromatic ring through nitrogen rather than carbon, are also effective directing groups. [13]

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Related O-aryl carbamates are good directing groups; upon warming, the resulting organolithiums undergo rearrangement to benzylic amides (the Snieckus-Fries rearrangement) via migration of the carbonyl carbon from oxygen to carbon. [14]

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Secondary N-aryl carbamates (along with secondary amides, ketones, and other directing groups containing acidic hydrogens) must be treated with two equivalents of organolithium reagent for lateral lithiation to occur. In the case below, sec-butyllithium is used to avoid competitive addition to the Boc group. [15]

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Sulfonamides require two equivalents of an organolithium reagent for lateral lithiation, but represent a useful class of directing groups. Treatment with ketones leads to tertiary alcohols in high yield. [16]

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Lithiations of substituted heterocycles

Convenient generation of a directing group on the nitrogen of indoles is possible through treatment with an organolithium reagent and carbon dioxide. [17] A similar method can be applied for lateral lithiations of ortho-tolyl anilines. [18]

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Oxazoles containing two methyl groups exhibit interesting selectivity patterns. In the absence of a directing substituent, the methyl group closer to the more electronegative oxygen atom is selectively metalated. However, in the presence of a directing substituent, the director fully controls the site of lithiation. [19]

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Synthetic applications

Ortho lithiation followed by methylation with methyl iodide is a convenient method for the synthesis of starting materials for lateral lithiations. Elaboration of the benzylic carbon through lateral lithiation and treatment with an electrophile provides a powerful synthetic alternative to direct electrophilic aromatic substitution (EAS). Although yields over the entire sequence are moderate, site selectivity is generally higher than analogous EAS reactions. [20]

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Comparison to other methods

Ortho lithiation can be used to generate many of the same structures as lateral lithiation; however, reactivity differences between aryl- and benzyllithium species may suggest the use of one method over the other. [15] A useful alternative method for stereoselective functionalization of the benzylic position involves the use of chromium arene complexes. Substitution at the benzylic position is much better tolerated in methods that employ benzylic lithiation of chromium arene complexes than lateral lithiations; however, the chromium byproducts of these reactions pose waste disposal difficulties. [21] The use of mixed zinc/copper organometallic reagents generated from benzyl bromides represents a second alternative to lateral lithiation. The functional group compatibility of this method is greater than lateral lithiation, but more steps are required to generate the reactive organometallic species from an unfunctionalized benzylic position. [22]

Experimental conditions and procedure

Typical conditions

Organolithium reagents are sensitive to moisture and thus should be handled under inert atmosphere in anhydrous conditions. Tetrahydrofuran is the most common solvent employed for lateral lithiation reactions. Measurement of the concentration of commercial or prepared alkyllithium solutions may be accomplished using well-established titration methods. [23]

A useful indicator for the progress of lateral lithiations is the color of the reaction mixture. Benzyllithium compounds range in color from red to deep purple, and in many cases the lack of a color change upon addition of an organolithium reagent to the substrate may indicate the presence of an undesired proton source in solution.

Example procedure [24]

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n-Butyllithium (14.0 mL of a 2.5 M solution in hexane, 35 mmol) was added dropwise to a solution of 2,6-dimethylanisole (4.95 mL, 35 mmol) in 60 mL of tetrahydrofuran at 0°, and the resulting solution was stirred at 0° for 1 hour and then at ambient temperature for 4 hours. The reaction mixture was cooled to 0°, treated with cyclohexanecarboxaldehyde (4.2 mL, 35 mmol), allowed to warm to ambient temperature again, and poured into saturated aqueous ammonium chloride solution. The mixture was extracted with ether and the ether extract was washed with water and brine and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane-ether, 5:1 v/v) to give 4.2 g (48%) of the product as a colorless oil; 1H NMR (CDCl3) δ 1.05–1.50 (m, 6H), 1.64–1.82 (m, 4H), 1.92 (m, 1H), 2.28 (d, 1H, J = 3 Hz), 2.31 (s, 3H), 2.68 (dd, 1H, J = 10, 13 Hz), 2.85 (dd, 1H, J = 3, 13 Hz), 3.57 (m, 1H), 3.75 (s, 3H), 6.95–7.10 (m, 3H).

Related Research Articles

An aromatic hydrocarbon or arene is a hydrocarbon with sigma bonds and delocalized pi electrons between carbon atoms forming a circle. In contrast, aliphatic hydrocarbons lack this delocalization. The term "aromatic" was assigned before the physical mechanism determining aromaticity was discovered; the term was coined as such simply because many of the compounds have a sweet or pleasant odour. The configuration of six carbon atoms in aromatic compounds is known as a benzene ring, after the simplest possible such hydrocarbon, benzene. Aromatic hydrocarbons can be monocyclic (MAH) or polycyclic (PAH).

Carboxylic acid oxoacid having the structure RC(=O)OH, used as a suffix in systematic name formation to denote the –C(=O)OH group including its carbon atom

A carboxylic acid is an organic compound that contains a carboxyl group. The general formula of a carboxylic acid is R–COOH, with R referring to the rest of the molecule. Carboxylic acids occur widely. Important examples include the amino acids and acetic acid. Deprotonation of a carboxyl group gives a carboxylate anion. Important carboxylate salts are soaps.

A carbanion is an anion in which carbon is trivalent (forms three bonds) and bears a formal negative charge in at least one significant mesomeric contributor (resonance form). Absent π delocalization, carbanions assume a trigonal pyramidal, bent, or linear geometry when the carbanionic carbon is bound to three (e.g., methyl anion), two (e.g., phenyl anion), or one (e.g., acetylide anion) substituents, respectively. Formally, a carbanion is the conjugate base of a carbon acid:

Organolithium reagent organometallic compound with a direct bond between a carbon and a lithium atom

Organolithium reagents are organometallic compounds that contain carbon – lithium bonds. They are important reagents in organic synthesis, and are frequently used to transfer the organic group or the lithium atom to the substrates in synthetic steps, through nucleophilic addition or simple deprotonation. Organolithium reagents are used in industry as an initiator for anionic polymerization, which leads to the production of various elastomers. They have also been applied in asymmetric synthesis in the pharmaceutical industry. Due to the large difference in electronegativity between the carbon atom and the lithium atom, the C-Li bond is highly ionic. Owing to the polar nature of the C-Li bond, organolithium reagents are good nucleophiles and strong bases. For laboratory organic synthesis, many organolithium reagents are commercially available in solution form. These reagents are highly reactive, and are sometimes pyrophoric.

Allyl group functional group

An allyl group is a substituent with the structural formula H2C=CH−CH2R, where R is the rest of the molecule. It consists of a methylene bridge (−CH2−) attached to a vinyl group (−CH=CH2). The name is derived from the Latin word for garlic, Allium sativum. In 1844, Theodor Wertheim isolated an allyl derivative from garlic oil and named it "Schwefelallyl". The term allyl applies to many compounds related to H2C=CH−CH2, some of which are of practical or of everyday importance, for example, allyl chloride.

The Wittig reaction or Wittig olefination is a chemical reaction of an aldehyde or ketone with a triphenyl phosphonium ylide to give an alkene and triphenylphosphine oxide.

<i>N</i>-Bromosuccinimide chemical compound

N-Bromosuccinimide or NBS is a chemical reagent used in radical substitution, electrophilic addition, and electrophilic substitution reactions in organic chemistry. NBS can be a convenient source of Br•, the bromine radical.

<i>n</i>-Butyllithium chemical compound

n-Butyllithium is an organolithium reagent. It is widely used as a polymerization initiator in the production of elastomers such as polybutadiene or styrene-butadiene-styrene (SBS). Also, it is broadly employed as a strong base (superbase) in the synthesis of organic compounds as in the pharmaceutical industry.

The Madelung synthesis is a chemical reaction that produces indoles by the intramolecular cyclization of N-phenylamides using strong base at high temperature.The Madelung synthesis was reported in 1912 by Walter Madelung, when he observed that 2-phenylindole was synthesized using N-benzoyl-o-toluidine and two equivalents of sodium ethoxide in a heated, airless, reaction. Common reaction conditions include use of sodium or potassium alkoxide as base in hexane or tetrahydrofuran solvents, at temperatures ranging between 200–400 °C. A hydrolysis step is also required in the synthesis. The Madelung synthesis is important because it is one of few known reactions that produce indoles from a base-catalyzed thermal cyclization of N-acyl-o-toluidines. The overall reaction for the Madelung synthesis follows.

Duff reaction

The Duff reaction or hexamine aromatic formylation is a formylation reaction used in organic chemistry for the synthesis of benzaldehydes with hexamine as the formyl carbon source. It is named after James Cooper Duff, who was a chemist at the College of Technology, Birmingham, around 1920–1950.

Directed ortho metalation

Directed ortho metalation (DoM) is an adaptation of electrophilic aromatic substitution in which electrophiles attach themselves exclusively to the ortho- position of a direct metalation group or DMG through the intermediary of an aryllithium compound. The DMG interacts with lithium through a hetero atom. Examples of DMG's are the methoxy group, a tertiary amine group and an amide group.

Asymmetric induction

Asymmetric induction in stereochemistry describes the preferential formation in a chemical reaction of one enantiomer or diastereoisomer over the other as a result of the influence of a chiral feature present in the substrate, reagent, catalyst or environment. Asymmetric induction is a key element in asymmetric synthesis.

Organozinc compound

Organozinc compounds in organic chemistry contain carbon to zinc chemical bonds. Organozinc chemistry is the science of organozinc compounds describing their physical properties, synthesis and reactions.

Vicinal difunctionalization refers to a chemical reaction involving transformations at two adjacent centers. This transformation can be accomplished in α,β-unsaturated carbonyl compounds via the conjugate addition of a nucleophile to the β-position followed by trapping of the resulting enolate with an electrophile at the α-position. When the nucleophile is an enolate and the electrophile a proton, the reaction is called Michael addition.

Electrophilic substitution of unsaturated silanes involves attack of an electrophile on an allyl- or vinylsilane. An allyl or vinyl group is incorporated at the electrophilic center after loss of the silyl group.

Reductions with metal alkoxyaluminium hydrides are chemical reactions that involve either the net hydrogenation of an unsaturated compound or the replacement of a reducible functional group with hydrogen by metal alkoxyaluminium hydride reagents.

Benzylic activation and stereocontrol in tricarbonyl(arene)chromium complexes refers to the enhanced rates and stereoselectivities of reactions at the benzylic position of aromatic rings complexed to chromium(0) relative to uncomplexed arenes. Complexation of an aromatic ring to chromium ++

+stabilizes both anions and cations at the benzylic position and provides a steric blocking element for diastereoselective functionalization of the benzylic position. A large number of stereo selective methods for benzylic and homobenzylic fictionalization have been developed based on this property.

Reactions of organocopper reagents involve species containing copper-carbon bonds acting as nucleophiles in the presence of organic electrophiles. Organocopper reagents are now commonly used in organic synthesis as mild, selective nucleophiles for substitution and conjugate addition reactions.

Metal-catalyzed C–H borylation reactions are transition metal catalyzed organic reactions that produce an organoboron compound through functionalization of aliphatic and aromatic C–H bonds and are therefore useful reactions for carbon–hydrogen bond activation. Metal-catalyzed C–H borylation reactions utilize transition metals to directly convert a C–H bond into a C–B bond. This route can be advantageous compared to traditional borylation reactions by making use of cheap and abundant hydrocarbon starting material, limiting prefunctionalized organic compounds, reducing toxic byproducts, and streamlining the synthesis of biologically important molecules. Boronic acids, and boronic esters are common boryl groups incorporated into organic molecules through borylation reactions. Boronic acids are trivalent boron-containing organic compounds that possess one alkyl substituent and two hydroxyl groups. Similarly, boronic esters possess one alkyl substituent and two ester groups. Boronic acids and esters are classified depending on the type of carbon group (R) directly bonded to boron, for example alkyl-, alkenyl-, alkynyl-, and aryl-boronic esters. The most common type of starting materials that incorporate boronic esters into organic compounds for transition metal catalyzed borylation reactions have the general formula (RO)2B-B(OR)2. For example, Bis(pinacolato)diboron (B2Pin2), and bis(catecholato)diborane (B2Cat2) are common boron sources of this general formula.

In organic chemistry, a directing group (DG) is a substituent on a molecule or ion that facilitates reactions by interacting with a reagent. The term is usually applied to C-H activation of hydrocarbons, where it is defined as a "coordinating moiety, which directs a metal catalyst into the proximity of a certain C–H bond." In a well known example, the ketone group in acetophenone is the DG in the Murai reaction.

References

  1. ↑ Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 1. doi : 10.1002/0471264180.or047.01
  2. 1 2 3 Gschwend, H. W.; Rodriguez, H. R. Org. React.1979, 26, 1.
  3. ↑ Jones, F. N.; Zinn, M. F.; Hauser, C. R. J. Org. Chem.1963, 28, 663.
  4. ↑ Klein, J.; Medlik-Balan, A. J. Org. Chem.1976, 41, 3307.
  5. ↑ Fleming P.; O'Shea D.F. J. Am. Chem. Soc. 2011, 133, 1698.
  6. ↑ Beak, P.; Brown, R. A. J. Org. Chem.1982, 47, 34.
  7. ↑ Broaddus, C. D. J. Org. Chem.1970, 35, 10.
  8. ↑ Flippin, L. A. Tetrahedron Lett.1991, 32, 6857.
  9. ↑ Wasserman, H. H.; Lipshutz, B. H. Tetrahedron Lett.1975, 1731.
  10. ↑ Mills, R. J.; Taylor, N. J.; Snieckus, V. J. Org. Chem.1989, 54, 4372.
  11. ↑ Comins, D. L.; Brown, J. D. J. Org. Chem.1983, 49, 1078.
  12. ↑ Watanabe, M.; Sahara, M.; Kubo, M.; Furukawa, S.; Billedeau, R. J.; Snieckus, V. J. Org. Chem.1984, 49, 742.
  13. ↑ Fuhrer, W.; Gschwend, H. W. J. Org. Chem.1979, 44, 1133.
  14. ↑ Sibi, M. P.; Snieckus, V. J. Org. Chem.1983, 48, 1935.
  15. 1 2 Clark, R. D.; Muchowski, J. M.; Fisher, L. E.; Flippin, L. A.; Repke, D. B.; Souchet, M. Synthesis1991, 871.
  16. ↑ Watanabe, H.; Mao, C.-L.; Barnish, I. T.; Hauser, C. R. J. Org. Chem.1969, 34, 919.
  17. ↑ Katritzky, A. R.; Akutagawa, K. J. Am. Chem. Soc.1986, 108, 6808.
  18. ↑ Katritzky, A. R.; Black, M.; Fan, W.-Q. J. Org. Chem.1991, 56, 5045.
  19. ↑ Cornwall, P.; Dell, C. P.; Knight, D. W. J. Chem. Soc., Perkin Trans. 11991, 2417.
  20. ↑ Tamura, Y.; Sashio, M.; Akai, S.; Wada, A.; Kita, Y. Tetrahedron1984, 40, 4539.
  21. ↑ Uemura, M. Org. React.2006, 67, 217.
  22. ↑ Berk, S. C.; Knochel, P.; Yeh, M. C. P. J. Org. Chem.1988, 53, 5789.
  23. ↑ Kofron, W. G.; Baclawski, L. M. J. Org. Chem.1976, 41, 1879.
  24. ↑ Michaelides, M. R.; Schoenleber, R.; Thomas, S.; Yamamoto, D. M.; Britton, D. R.; MacKenzie, R.; Kebabian, J. W. J. Med. Chem. 1991, 34, 2946.
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