User:Benjah-bmm27/degree/4/SPT

=Main group organometallic reagents in organic synthesis, SPT=

Stereospecific and stereoselective reactions
General reminder: Concise explanation from http://www.chem.ox.ac.uk/vrchemistry/nor/notes/stereo.htm
 * 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.

=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 → RMI + MIX
 * For a Group 2 metal: RX + M0 → RMIIX

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 pKaH is formed
 * For example, BuLi + PhBr → PhLi + BuBr
 * This works because the pKaH of PhLi (40) is less than that of BuLi (50)
 * In other words, the pKa 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
 * pKaH BuLi, RMgX ~ 50
 * pKaH 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

 * 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


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



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



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.

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

Differences in reactivity between RLi and RMgX
=Copper=

1,4-Addition



 * 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 CuI, forming CuIII

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 CuIII intermediate

R2CuLi cluster

 * Readable account: Carey and Sundberg, Part B, chapter 8
 * Hardcore account:
 * All sorts of complicated equilibria and intermediate structures
 * A nightmare to remember for the exam! Are we really expected to memorise this?

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

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=

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)Ln]→ R–CH2–CH2–B(OR)2 (β) or R–CHMe–B(OR)2 (α)
 * RhI catalysts tend to give the branched α-product (Markovnikov addition)
 * Catalytic cycle involes four major steps:
 * Oxidative addition of H–B to Rh(I)Ln
 * 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

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 SN2 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