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Main group organometallic reagents in organic synthesis, SPT

References

• Clayden, J. M. (2002). Organolithiums: Selectivity for Synthesis. Pergamon. ISBN 978-0080432625. {{cite book}}: Unknown parameter |city= ignored (|location= suggested) (help)
• Yamamoto, H.; Oshima, K., eds. (2004). Main Group Metals in Organic Synthesis. Wiley. ISBN 978-3527305087. {{cite book}}: Unknown parameter |city= ignored (|location= suggested) (help)
• Knochel, P.; Jones, P., eds. (1999). Organozinc Reagents: A Practical Approach. Oxford University Press. ISBN 978-0198501213.
• Taylor, R. J. K., ed. (1994). Organocopper Reagents: A Practical Approach. Oxford University Press. ISBN 978-0198557586.
• Krause, N., ed. (2002). Modern Organocopper Chemistry. Wiley. ISBN 978-3527297733. {{cite book}}: Unknown parameter |city= ignored (|location= suggested) (help)
• Carey, F. A.; Sundberg, R. J., eds. (2007). Advanced Organic Chemistry Part B: Reactions and Synthesis. Springer. ISBN 978-0387683546. {{cite book}}: Unknown parameter |city= ignored (|location= suggested) (help)

Stereospecific and stereoselective reactions

General reminder:

• Stereospecific Reaction: A reaction in which the stereochemistry of the reactant completely determines the stereochemistry of the product without any other option.
• Stereoselective Reaction: A reaction in which there is a choice of pathway, but the product stereoisomer is formed due to its reaction pathway being more favourable than the others available.

Concise explanation from http://www.chem.ox.ac.uk/vrchemistry/nor/notes/stereo.htm

Preparation

Insertion

In the insertion (reduction) method of preparing a main group organometallic reagent, a metallic main group element M reacts with an organohalide RX. The term reduction refers to the fact that the oxidation state of carbon in the organohalide decreases by two units. For example, MeCl → MeLi can be thought of as carbon(+1) → carbon(−1), or [H₃C⁺ Cl⁻] → [H₃C⁻ Li⁺]. In reality, MeCl and MeLi are much more covalent than this ionic formulation, but it highlights the change in formal oxidation state.

• Halogen remains in the −1 oxidation state throughout
• Oxidation state of carbon decreases by two units
• Oxidation state of metal increases by two units (or two metals atoms are both oxidised by one unit): M → M²⁺ + 2e⁻ or two lots of M → M⁺ + e⁻
• For a Group 1 metal: RX + 2M⁰ → RM^I + M^IX
• For a Group 2 metal: RX + M⁰ → RM^IIX

The insertion reaction can be conducted on a large scale and is best for organobromides and organoiodides. Organochlorides usually require activation with zinc.

Metal-halogen exchange

• RX + R′M → RM + R′X
• Extremely fast - fast than deprotonation
• The reaction works if RM is less basic than R′M, i.e. the organometallic with the lowest pK_aH is formed
• For example, BuLi + PhBr → PhLi + BuBr
  • This works because the pK_aH of PhLi (40) is less than that of BuLi (50)
  • In other words, the pK_a of PhH (40) is less than that of BuH (50), i.e. benzene is more acidic than butane
• Consider PhI + tBuLi in Et₂O and MeOH
  • If deprotonation were faster than metal-halogen exchange, would observe route 1: tBuLi + MeOH → tBuH + LiOMe
  • If metal-halogen exchange were faster than deprotonation, would observe route 2: tBuLi + PhI → tBuI + PhLi, then PhLi + MeOH → PhH + LiOMe
  • PhH is the observed product, implying route 2 takes places, and metal-halogen exchange is faster than deprotonation

Transmetallation

In transmetallation, an organic group from an organometallic species is transferred to a different metal.

• Tin-lithium exchange is a common example
• R¹SnBu₃ + R²Li → Li⁺ [R¹R²SnBu₃]⁻ → R¹Li + R²SnBu₃
• The best leaving group, R¹, departs from [R¹R²SnBu₃]⁻ as "R¹⁻"
• RSnBu₃ are bench-stable. Addition of BuLi generates Li[RSnBu₄], which then decomposes to RLi + SnBu₄. These products are easily separated by chromatography, so RSnBu₃ are bench-stable stores of RLi.
• Example: PhSnBu₃ + BuLi →→ SnBu₄ + PhLi

Deprotonation

R-H + R′-M → R-M + R′-H

• Deprotonation of terminal alkynes by BuLi is common: R−C≡C-H + BuLi → R−C≡C-Li + BuH
• Requires the basicity of R′-M to be greater than that of R-M, i.e. R-H must be more acidic than R′-H
• pK_aH BuLi, RMgX ~ 50
• pK_aH R₂N-M ~ 35

Lithium

Organolithiums are common organic reagents. They are a source of "R⁻" and are very reactive towards electrophiles E⁺. They are often used to make other organometallic species by transmetallation.

Aggregation

Tetrahedron and cubane representations of tetrameric organolithium clusters

• Organolithiums are oligomeric in solution - they form unreactive aggregates
  • BuLi is a tetramer in solution: (BuLi)₄
  • tBuLi exists as a dimer in solution, (tBuLi)₂ — this makes it easier to break up and thus more reactive

• Organolithium aggregates can be made more reactive by breaking them up with additives

Additives for disaggregating organolithium clusters

• 
  Hexamethylphosphoramide (HMPA, most reactive but very toxic)
• 
  Pentamethyldiethylenetriamine (PMDTA)
• 
  Dimethylpropyleneurea (DMPU, a safer alternative to HMPA)
• 
  Dimethoxyethane (DME)
• 
  Tetramethylethylenediamine (TMEDA)
• 
  Tetrahydrofuran (THF)
• 
  Diethyl ether (Et₂O, very slow to break aggregates)

• The additives are ligands that complete lithium's coordination sphere

Preparation

Insertion/Reduction

• R/Ar-Cl --[Li⁰]→ R/Ar-Li
• Works best with chlorides rather than bromides or iodides
  • Rate of reaction is proportional to the stability of the radical R^•
  • The mechanism of reduction is single-electron transfer

Alkyl chlorides

• The rate-determining step (RDS) is the first step and involves a single electron from metallic lithium entering the C-Cl σ* orbital of tBuCl, breaking the C-Cl bond as a Cl-Li bond forms. The driving force for the reaction is the precipitation of insoluble LiCl.
• In the much faster second step, a tert-butyl radical tBu^• combines with a neutral lithium atom Li^• to form tBuLi

Aryl chlorides

• With aryl chlorides, the first step is reversible as the electron is entering a π* orbital
• Instead of concerted electron transfer and C-Cl bond fission as shown above, a radical anion intermediate is formed
• The radical anion slowly decomposes (RDS) to an aryl radical Ar^• and LiCl
• Ar^• and another Li^• then combine to form the aryllithium ArLi

Arene-mediated reductive lithiation

• R/Ar-Cl + Li reactions don't work very well in practice, so an arene such as naphthalene is added as an electron shuttle

Naphthalene

• A lithium atom donates its valence electron to naphthalene, generating a radical anion
• The radical anion rapidly reduces the R/Ar-Cl to R/Ar^•
• R/Ar^• reacts with another lithium atom to form R/Ar-Li
• Problems: (i) R/Ar^• can attack naphthalene, forming by-products and lowering yield, and (ii) naphthalene and its by-products can be difficult to separate from the desired product

DBB

• 4,4′-di-tert-butylbiphenyl (DBB) gives higher yields and is more recoverable than naphthalene
  • Electron transfer can occur between species up to 7–9 Å, whereas bond formation requires less than 2 Å separation
  • The bulky tert-butyl groups of DBB separate it enough from other molecules to avoid forming bonds (and thus by-products), but allow sufficiently close approach for electron transfer

Lithium-halogen exchange

Mechanism of transmetallation

Tin-lithium exchange

Deprotonation

Superbases

Enantioselective deprotonations

Reaction of organolithiums with electrophiles

Carbonyls

Orbital considerations

Lithiated carbamates

Rearrangements

Shapiro reaction

• Shapiro reaction

Bamford–Stevens reaction

• Bamford–Stevens reaction

Brook rearrangement

• Brook rearrangement

Wittig rearrangements

• 1,2-Wittig rearrangement
• 1,4-Wittig rearrangement

Magnesium

Grignard reagents

• Discovered by Victor Grignard in 1900, for which he won the 1912 Nobel Prize in Chemistry
• They have a more covalent metal-carbon bond than organolithiums, and are less pyrophoric
• A wide range of Grignard reagents are commercially available

Schlenk equilibrium

In ether solution, dissociation of Grignard reagents occurs:

2 R–Mg–X ⇌ R–Mg–R + X–Mg–X

Organomagnesium iodides, RMgI, exist primarily as R–Mg–R in THF.

References

• Silverman, G. S.; Rakita, P. E. (1996). Handbook of Grignard Reagents. Marcel Dekker. ISBN 978-0824795450. {{cite book}}: Unknown parameter |city= ignored (|location= suggested) (help)
• Richey, Jr., H. G., ed. (1999). Grignard Reagents: New Developments. Wiley. ISBN 978-0471999089. {{cite book}}: Unknown parameter |city= ignored (|location= suggested) (help)

Preparation of Grignard reagents

Insertion/reduction

R–X + Mg⁰ ⇌ R–Mg–X

Groups that react with Grignard reagents inhibit Grignard formation completely

• At the temperature required for Grignard reagents to form (warm enough for Mg to insert into C–X bond), the newly formed C–Mg group will react with the following functional groups:
  • Aldehydes RCHO and ketones RCOR
  • Nitriles RCN
  • Nitro compounds, RNO₂
  • Esters RCO₂R, carboxylic acids RCO₂H, amides RCONR₂
  • A leaving groups (such as tosylate) beta to MgX will be expelled, forming an alkene

Mechanism of Grignard reagent formation

• Single electron transfer, as for organolithiums (see above)

Transmetallation and magnesium-halogen exchange

• Although standard Grignard formation does not occur well below 0 °C, magnesium-halogen exchange is rapid
• At these low temperatures, Grignard reagents do not react with many functional groups, including esters
• They do still react with aldehydes and ketones, however
• It is therefore possible to prepare Grignards bearing ester groups (which would react with themselves at higher temperatures) by Mg-X exchange
• The usual reagent is iPrMgCl, which has bulky isopropyl groups
• It is added to aryl bromides or chlorides at, say, −20 °C or −35 °C
• The arylmagnesium halide formed by magnesium-halogen exchange
• It can then react with an aldehyde or ketone

Knochel reactions in synthesis

Reactions of Grignards with electrophiles

Carbonyls

Differences in reactivity between RLi and RMgX

Copper

Overview

1,4-Addition of RCu to enones

Reaction of RCu with RX

Carbocupration

1,4-Addition

• Corey, E. J.; Boaz, N. W. (1985). Tet. Lett. 26: 6015–6018. doi:10.1016/S0040-4039(00)95113-X. {{cite journal}}: Missing or empty |title= (help)

• Reaction of R₂CuLi with certain chiral enones leads to 92:8 of one diastereomer (the thermodynamic product)
• Adding Me₃SiCl to the reaction mixture gives > 99:1 of the other diastereomer (the kinetic product)
  • These results suggest the cuprate addition is reversible unless trimethylsilyl chloride is present to trap the enolate intermediate

• The key step is oxidative addition of the C=C bond of the enone to Cu^I, forming Cu^III
  • J. Am. Chem. Soc. 129: 7208–7209. 2008. doi:10.1021/ja067533d. {{cite journal}}: Missing or empty |title= (help)

Mechanisms

Kinetics

• 1,4-addition is first order in (Me₂CuLi)₂ – two equivalents of Me₂CuLi
• Proceeds somewhat like a Grignard reaction
• The rate determining step is reductive elimination of the enolate product from the Cu^III intermediate
• Krauss, S. R.; Smith, S. G. (1981). J. Am. Chem. Soc. 103: 141–148. doi:10.1021/ja00391a026. {{cite journal}}: Missing or empty |title= (help)

R₂CuLi cluster

• Readable account: Carey and Sundberg, Part B, chapter 8
• Hardcore account: Nakamura; et al. (1997). J. Am. Chem. Soc. 119: 4900–4910. doi:10.1021/ja964209h. {{cite journal}}: Explicit use of et al. in: |author= (help); Missing or empty |title= (help)
  • All sorts of complicated equilibria and intermediate structures
  • A nightmare to remember for the exam! Are we really expected to memorise this?

Asymmetric 1,4-addition

Conjugate reduction of enones

Crystal structure of Stryker's reagent

Stryker's reagent

• Need a soft source of H⁻ to favour addition at the 4 position
• Ph₃P + CuCl --[1. tBuONa, 2. H₂]→ [(Ph₃P)CuH]₆ — Stryker's reagent, a red crystalline solid, 50-65 %
• React with enone in benzene at room temperature for 28 h
• Acts as "H-Cu", irreversible addition of hydride, under kinetic control

Asymmetric enone reduction

• Use (S)-p-tol-BINAP instead of Ph₃P as a ligand for Cu, [{(S)-p-tol-BINAP}CuH]
• Use polymethylhydrosiloxane (PMHS), (SiHMeO)_n, as a very stable source of hydride
• React with enone in toluene at room temperature for 22 h
• Can even tolerate aldehydes — selective 1,4-addition, c.f. NaBH₄/LiBH₄

Zinc

Overview

• Organozinc reagents are highly tolerant of functional groups - the least reactive R-M
• Undergo facile transmetallation
• Highly reactive with H₂O and O₂
• Need a Lewis base (LB) to activate organozincs — they're unreactive when linear but reactive when bent by coordination of an LB

Addition to enones

Addition to aldehydes

Asymmetric addition to aldehydes

Simmons-Smith reaction

• The Simmons-Smith reaction is the conversion of an alkene to a cyclopropane by reaction with CH₂I₂ and Zn/Cu
• (Z)-alkenes give cis-cyclopropanes, (E)-alkenes give trans-cyclopropanes

Mechanism

• Syn addition of CH₂ to the alkene
• Zn inserts into a C-I bond, forming I-Zn-CH₂I, which acts like the carbene :CH₂, being both electrophilic and nucleophilic at C
• Five-centred transition state
  • Two C-Zn bonds form, C=C, C-I and C-Zn bonds break

Alcohol-directed Simmons-Smith

• Cyclic allylic and homoallylic alcohols have an OH group fixed above one side of the C=C bond
• This OH group coordinates to Zn in IZnCH₂I, directing addition of CH₂ to the same face of the alkene
• If the OH group is further away than homoallylic, no directing effect is observed and a racemic mixture of products is formed

Asymmetric Simmons-Smith

• Developed by André Charette at the Université de Montréal
• Requires allylic alcohols
• Uses a cyclic boronic ester as a stoichiometric chiral ligand: B-Zn transmetallation?
• Deployed in the synthesis of the natural product V-106305, which contains five trans cyclopropanes in a row

Boron

Hydroboration

Asymmetric hydroboration

• Enantioselective syn addition of R₂B–H across C=C of an alkene
• Diisopinocampheylborane (Ipc₂BH) + Z/cis-alkene → Ipc₂B–alkyl, 87% ee

Rhodium-catalysed hydroboration

• The topic of GCLJ's PhD with J. Brown. Hyashi also investigated.
• R–CH=CH₂ + HB(OR)₂ (catecholborane) --[Rh(I)L_n]→ R–CH₂–CH₂–B(OR)₂ (β) or R–CHMe–B(OR)₂ (α)
• Rh^I catalysts tend to give the branched α-product (Markovnikov addition)
• Catalytic cycle involes four major steps:
  • Oxidative addition of H–B to Rh(I)L_n
  • Coordination of the alkene to Rh(III)
  • Hydride transfer to the alkene (hydrorhodation) – becomes alkyl–Rh (selectivity-determining step)
  • Reductive elimination of the boronic ester RB(OR)₂

Oxidation of organoboranes

To alcohols

• H₂O₂ and NaOH convert R₃B to ROH
• Retention of B–C stereochemistry due to orbital requirements of the mechanism
• Mechanism:
  • HOO⁻ and R₃B form an ate-complex [R₃B–OOH]⁻
  • A 1,2-metallate rearrangement (stereospecific, antiperiplanar step) sees an R-group migrate from B to O, expelling OH⁻ in the process
  • A boronic ester R₂B–O–R is the product
  • This is hydrolysed to the alcohol ROH by NaOH/H₂O

To amines

• H₂N–OSO₃H converts R₃B to RNH₂
• Mechanism:
  • H₂N–OSO₃H and R₃B form an ate-complex [R₃B–NH–OSO₃H]⁻
  • An R-group migrates from B to N, expelling OSO₃H⁻, leaving R–NH–BR₂
  • R–NH–BR₂ is hydrolysed to RNH₂ by H₂O

Carbonyl reduction

• RCO₂H is reduced to RCH₂OH by BH₃
• Very selective for carboxylic acids, even in the presence of aldehydes, ketones (which are more reactive), amides and esters
• Mechanism:
  • The OH oxygen of RCO₂H forms an ate complex with BH₃, losing H⁺ to give RC(=O)–O–BH₂
  • H–BH₂ then adds across C=O, forming R–CH(OBH₂)₂
  • Some further (not given in lectures) step(s) occur to give the alcohol

1,2-Metallate rearrangement

• H. Brown, D. Matteson, D. Hoppe. P. Kocienski, VKA
  • Addition of "R⁻" from R–M to (RO)₂B–CR′₂(LG) gives ate-complex [(RO)₂BR–CR′₂(LG)]⁻
  • R migrates from B to C, expelling LG in the process, generating RR′₂C–B(OR)₂ (the actual 1,2-metallate rearrangement step)
  • RR′₂C–B(OR)₂ can be oxidised to RR′₂C–OH
• The 1,2-metallate rearrangement step is stereospecific, requiring antiperiplanar R–B and C-LG bonds and involving inversion at carbon

Matteson

• Add LiCHCl₂ to R′–B(OR)₂, where (OR)₂ is actually a chiral bidentate "ligand" for B
• Initial ate-complex formed is [R′–B(OR)₂–CHCl₂]⁻
• Undergoes 1,2-met to R′–CHCl–B(OR)₂ with loss of Cl⁻
• Add a Grignard R″–MgX to R′–CHCl–B(OR)₂, attack at B is faster than S_N2 at C–Cl σ*, forming [R′–CHCl–B(OR)₂–R″]⁻
• Another 1,2-met: R″ migrates from B to C, expelling the second chloride, undergoing inversion at C, and forming R′R″HC–B(OR)₂
• R′R″HC–B(OR)₂ is then oxidised to R′R″HC–OH or R′R″HC–NH₂
• Two inversions at carbon lead to overall retention at carbon, stereospecific reaction

VKA: lithiation-borylation

• Enantioselective deprotonation (s-BuLi, (−)-sparteine) converts a carbamate to a lithiated carbamate
• The lithiated carbamate forms an ate-complex with a pinacol-boronic ester RBpin
• 1,2-met: R migrates from B to C, expelling OCb, forming a different pinacol-boronic ester