Advanced organic chemistry II course Aa 2014-2015 Prof ... · • Distillation (solvent recovery) • Drying (final treatment of solids). • Equipments (lab hoods, centrifuges, pumps

Advanced organic chemistry II course

Aa 2014-2015 Prof. Maurizio Taddei [email protected] 00577234275 Organic chemistry production, fine chemistry. Green chemistry, the 12 principles; green chemistry metrics. Catalysis. Organic chemistry catalytic processes. Homogeneous/ heterogeneous processes

pro and con. Metal-catalysis, organo-catalysis and bio-catalysis, general points. Catalytic couplings C-C bond formation. Kumada, Neghishi, Stille, Suzuki and Sonoghashira couplings C-N bond formation. Buckwald-Hartwig reaction The Heck reaction The metathesis process. Reduction. Hydrogenation of olefins: homogeneous and heterogeneous catalyst.

Hydrogenation of functional groups. Oxidation. Wacker-process and related olefins oxidations. Epoxidation. Cross-coupling. Amide formation, Buckwald-Hartwig reaction. Hydrogen borrowing and related red-ox catalytic processes. Hydroformylation Domino reactions, some applications. Special synthetic techniques: Microwave dielectric heating, continuous flow and

microreactors. Laboratory experiments: preparation of a relevant intermediate using a cross coupling

reaction and a comparison between traditional and modern synthetic technologies.

Maurizio Taddei

Maurizio Taddei

Maurizio Taddei

Organic Chemistry Production

Levothyrosine Lisinopril Rosuvastatin

Mesotrione

Muscone Indigo Quinacridone

Types of Chemical Production

1.##Preven)on.!!It!is!be(er!to!prevent!waste!than!to!treat!or!clean!up!waste!a4er!it!is!formed.!2.#Atom#Economy.!Synthe;c!methods!should!be!designed!to!maximize!the!incorpora;on!of!all!materials!

used!in!the!process!into!the!final!product.!3.#Less#Hazardous#Chemical#Synthesis.!Whenever!prac;cable,!synthe;c!methodologies!should!be!designed!

to!use!and!generate!substances!that!possess!li(le!or!no!toxicity!to!human!health!and!the!environment.!!

4.#Designing#Safer#Chemicals.##Chemical!products!should!be!designed!to!preserve!efficacy!of!the!func;on!while!reducing!toxicity.!

5.#Safer#Solvents#and#Auxiliaries.#The!use!of!auxiliary!substances!(solvents,!separa;on!agents,!etc.)!should!be!made!unnecessary!whenever!possible!and,!when!used,!innocuous.!

6.#Design#for#Energy#Efficiency.##Energy!requirements!should!be!recognized!for!their!environmental!and!economic!impacts!and!should!be!minimized.!!Synthe;c!methods!should!be!conducted!at!ambient!temperature!and!pressure.!

7.#Use#of#Renewable#Feedstocks.##A!raw!material!or!feedstock!should!be!renewable!rather!than!deple;ng!whenever!technically!and!economically!prac;cal.!!

8.#Reduce#Deriva)ves.#Unnecessary!deriva;za;on!(blocking!group,!protec;on/deprotec;on,!temporary!modifica;on!of!physical/chemical!processes)!should!be!avoided!whenever!possible!.#

9.#Catalysis.#Cataly;c!reagents!(as!selec;ve!as!possible)!are!superior!to!stoichiometric!reagents.!#10.#Design#for#Degrada)on.#Chemical!products!should!be!designed!so!that!at!the!end!of!their!func;on!they!

do!not!persist!in!the!environment!and!instead!break!down!into!innocuous!degrada;on!products.!#11.#RealQ)me#Analysis#for#Pollu)on#Preven)on.#Analy;cal!methodologies!need!to!be!further!developed!to!

allow!for!realM;me!inMprocess!monitoring!and!control!prior!to!the!forma;on!of!hazardous!substances.!

12.#Inherently#Safer#Chemistry#for#Accident#Preven)on.#Substance!and!the!form!of!a!substance!used!in!a!chemical!process!should!be!chosen!so!as!to!minimize!the!poten;al!for!chemical!accidents,!including!releases,!explosions,!and!fires.!!

!Anastas,#P.#T.;#Warner,#J.C.#Green#Chemistry:#Theory#and#Prac)ce,#Oxford#University#Press,1998.#

Green Chemistry – The Twelve Principles

1 - Prevention

•  Love!Canal!–  in!Niagara!Falls,!NY!Hooker!Chemical!(now!Occidental!Petroleum!Corp.)!had!

used!an!old!canal!bed!as!a!chemical!dump!from!1930s!to!1950s.!The!land!was!then!used!for!a!new!school!and!housing!track.!The!chemicals!leaked!through!a!clay!cap!that!sealed!the!dump.!It!was!contaminated!with!at!least!82!chemicals!(benzene,!chlorinated!hydrocarbons,!dioxin).!Health!effects!of!the!people!living!there!included:!high!birth!defect!incidence!and!siezureMinducing!nervous!disease!among!the!children.!

–  Occidental!Petroleum!Corp.!!was!found!to!be!negligent!by!Federal!Court!and!sued!to!pay!129!million!$!

2- Atom economy

Atom economy (atom efficiency) describes the conversion efficiency of a chemical process in terms of all atoms involved (desired products produced). In an ideal chemical process, the amount of starting materials or reactants equals the amount of all products generated and no atom is wasted. Yield = (mol of product/mol of limiting reagent) % Atom economy = (Molecular mass of product/molecular mass of all reagent) %

37%

71%

3- Less hazard chemical synthesis

Whenever practicable, synthetic methodologies should be designed to use and generate substances that possess little or no toxicity to human health and the environment

LD50 0.4 mg/Kg

LD50 300 mg/Kg

The Bhopal disaster occurred on the night of 2–3 December 1984 at the Union Carbide India Limited (UCIL) pesticide plant in Bhopal, Madhya Pradesh. Over 500,000 people were exposed to methyl isocyanate gas. The toxic substance made its way in and around the shanty towns located near the plant. The official immediate death toll was 2,259. The government of Madhya Pradesh confirmed a total of 3,787 deaths related to the gas release. Others estimate 8,000 died within two weeks and another 8,000 or more have since died from gas-related diseases. A government affidavit in 2006 stated the leak caused 558,125 injuries including 38,478 temporary partial injuries and approximately 3,900 severely and permanently disabling injuries.

Methylisocyanate

4- Designing safer chemicals

Chemical products should be designed to preserve efficacy of the function while reducing toxicity

Antifoulants are generally dispersed in the paint as it is applied to the hull. Organotin compounds have traditionally been used, particularly tributyltin oxide (TBTO). TBTO works by gradually leaching from the hull killing the fouling organisms in the surrounding area

TBTO and other organotin antifoulants have long half-lives in the environment (half-life of TBTO in seawater is > 6 months). They also bioconcentrate in marine organisms (the concentration of TBTO in marine organisms to be 104 times greater than in the surrounding water). Organotin compounds are chronically toxic to marine life and can enter food chain. They are bioaccumulative.

Sea-Nine® 211 works by maintaining a hostile growing environment for marine organisms. When organisms attach to the hull (treated with DCOI), proteins at the point of attachment with the hull react with the DCOI. This reaction with the DCOI prevents the use of these proteins for other metabolic processes. The organism thus detaches itself and searches for a more hospitable surface on which to grow. Only organisms attached to hull of ship are exposed to toxic levels of DCOI. Readily biodegrades once leached from ship (half-life is less than one hour in sea water).

Designing safer chemicals

5- Safer solvents

Preferred Useable Undesirable

Water Cyclohexane Pentane

Acetone Heptane Hexane(s)

Ethanol Toluene Di-isopropyl ether

2-Propanol Methylcyclohexane Diethyl ether

1-Propanol Methyl t-butyl ether Dichloromethane

Ethyl acetate Isooctane Dichloroethane

Isopropyl acetate Acetonitrile Chloroform

Methanol 2-MethylTHF Dimethyl formamide

Methyl ethyl ketone Tetrahydrofuran N-Methylpyrrolidinone

1-Butanol Xylenes Pyridine

t-Butanol Dimethyl sulfoxide Dimethyl acetate

Acetic acid Dioxane

Ethylene glycol Dimethoxyethane

Benzene

Carbon tetrachloride

Green chemistry tools to influence a medicinal chemistry and research chemistry based organization Dunn and Perry, et. al., Green Chem., 2008, 10, 31-36

Solvent Selection

Red#Solvent# Flash#point#(°C)# Reason#

Pentane# M49! Very!low!flash!point,!good!alterna;ve!available.!

Hexane(s)# M23! More!toxic!than!the!alterna;ve!heptane,!classified!as!a!HAP!in!the!US.!

DiQisopropyl#ether# M12! Very!powerful!peroxide!former,!good!alterna;ve!ethers!available.!

Diethyl#ether# M40! Very!low!flash!point,!good!alterna;ve!ethers!available.!

Dichloromethane# n/a! High!volume!use,!regulated!by!EU!solvent!direc;ve,!classified!as!HAP!in!US.!

Dichloroethane# 15! Carcinogen,!classified!as!a!HAP!in!the!US.!

Chloroform# n/a! Carcinogen,!classified!as!a!HAP!in!the!US.!

Dimethyl#formamide# 57! Toxicity,!strongly!regulated!by!EU!Solvent!Direc;ve,!classified!as!HAP!in!the!US.!

NQMethylpyrrolidinone# 86! Toxicity,!strongly!regulated!by!EU!Solvent!Direc;ve.!

Pyridine# 20! Carcinogenic/mutagenic/reprotoxic!(CMR)!category!3!carcinogen,!toxicity,!very!low!threshold!limit!value!(TLV)!for!worker!exposures.!

Dimethyl#acetate# 70! Toxicity,!strongly!regulated!by!EU!Solvent!Direc;ve.!

Dioxane# 12! CMR!category!3!carcinogen,!classified!as!HAP!in!US.!

Dimethoxyethane# 0! CMR!category!2!carcinogen,!toxicity.!

Benzene# M11! Avoid!use:!CMR!category!1!carcinogen,!toxic!to!humans!and!environment,!very!low!TLV!(0.5!ppm),!strongly!regulated!in!EU!and!the!US!(HAP).!

Carbon#tetrachloride# n/a! Avoid!use:!CMR!category!3!carcinogen,!toxic,!ozone!depletor,!banned!under!the!Montreal!protocol,!not!available!for!largeMscale!use,!strongly!regulated!in!the!EU!and!the!US!(HAP).!

5 Safer solvents

Undesirable Solvent Alternative

Pentane Heptane

Hexane(s) Heptane

Di-isopropyl ether or diethyl ether 2-MeTHF or tert-butyl methyl ether

Dioxane or dimethoxyethane 2-MeTHF or tert-butyl methyl ether

Chloroform, dichloroethane or carbon tetrachloride

Dichloromethane

Dimethyl formamide, dimethyl acetamide or N-methylpyrrolidinone

Acetonitrile

Pyridine Et3N (if pyridine is used as a base)

Dichloromethane (extractions) EtOAc, MTBE, toluene, 2-MeTHF

Dichloromethane (chromatography) EtOAc/heptane

Benzene Toluene

Solvent replacement table

Is water a good solvent for chemical reactions ?

6-Design for energy efficiency

Energy requirements should be recognized for their environmental and economic impacts and should be minimized. Synthetic methods should be conducted at ambient temperature and pressure.

•  Thermal (electric) •  Cooling (water condensers, water circulators) •  Distillation (solvent recovery) •  Drying (final treatment of solids). •  Equipments (lab hoods, centrifuges, pumps etc)

Source of energy: •  Power plant – coal, oil, natural gas

Chemicals and petroleum industries account for 50% of industrial energy usage. ~1/4 of the energy used is consumed in distillation and drying processes

7- Use of renewable feedstocks

A raw material or feedstock should be renewable rather than depleting whenever technically and economically practical.

O

HO

O

Paper mill sludge

Levulinic acid

Municipal solid waste and waste paper

Agricultural residues, Waste wood

O

HO

O

O

H2NOH

O

O

HO

DALA (δ-amino levulinic acid) (non-toxic, biodegradable herbicide)

O

HO

O

OH

C

CH3

CH2

CH2

C

O

OHHO

Diphenolic acid

Acrylic acid Succinic acid

O

THF

O

MTHF (fuel additive)

HOOH

butanediol

OO

gamma butyrolactone

A chemical platform

8 - Reduce derivatives

The best protecting group is no protection. Catalytic process are better then stoichiometric processes

9 - Catalysis

More efficient syntheses are more sustainable syntheses

Design#for#Degrada)on.##Chemical!products!should!be!designed!so!that!at!the!end!of!their!func;on!they!do!not!persist!in!the!environment!and!instead!break!down!into!innocuous!degrada;on!products.!#

RealQ)me#Analysis#for#Pollu)on#Preven)on.##Analy;cal!methodologies!need!to!be!further!developed!to!allow!for!realM;me!inMprocess!monitoring!and!control!prior!to!the!forma;on!of!hazardous!substances.!

Inherently#Safer#Chemistry#for#Accident#Preven)on.##Substance!and!the!form!of!a!substance!used!in!a!chemical!process!should!be!chosen!so!as!to!minimize!the!poten;al!for!chemical!accidents,!including!releases,!explosions,!and!fires.!!

Catalysis

Catalysis is the increase in the rate of a chemical reaction due to the participation of an additional substance called a catalyst. Unlike other reagents in the chemical reaction, a catalyst is not consumed by the reaction. The term is derived from Greek καταλύειν, (to dissolve-destroy) and was coined by Berzelius in 1835.

Catalysis

Catalysis

Catalysis

Heterogeneous vs Homogenous

•  Distinct solid phase •  Readily separated •  Readily regenerated &

recycled •  Rates not as fast •  Diffusion limited •  Sensitive to poisons •  Lower selectivity •  Long service life •  High energy process •  Poor mechanistic

understanding

•  Same phase as reaction medium

•  Difficult to separate •  Expensive and/or difficult to

separate •  Very high rates •  Not diffusion controlled •  Robust to poisons •  High selectivity •  Short service life •  Mild conditions •  Mechanisms well understood

Green catalyst

Catalysis

The d orbitals are what give transition metals their distinguished properties. The transition metal ions the outermost d orbitals are incompletely filled with electrons so they can easily give and take electrons. This makes transition metals prime candidates for catalysis. The outermost s and p orbitals are usually empty and therefore less useful for electron transfer. The principal reasons why transition metals contribute the essential ingredient in catalyst systems can be summarized as the following headings:

(a)  Bonding ability (b) Catholic choice of ligands (c) Ligand effects (d) Variability of oxidation state (e) Variability of co-ordination number

A d-block metal ion has nine valence shell orbitals to accommodate its valence electrons and to form hybrid molecular orbitals in bonding with other groups. This special configuration enable the d metal to form both σ- and π- bonds which is one of the key factors in imparting catalytic properties to the transition metals and their complexes. When transition metals form stable complexes with Lewis base ligands, the coordinate sharing of electron pairs on the ligand molecules may produce a coordinatively saturated (18-electron) or an unsaturated (16, 14 or fewer electron) valence shell configuration.

Transition-metal catalysis

Catalysis

Lewis acid catalysis Transition metal catalysis

Metal impact in Active Pharmaceutical Principle (API)

permitted daily exposure (PDE) Table 1: Class Exposure and Concentration Limits for Individual Metal Catalysts and Metal Reagents

Oral Exposure Parenteral Exposure Classification PDE

(µg/day) Concentration

(ppm) PDE

(µg/day) Concentration

(ppm)

Class 1A: Pt, Pd

Class 1B:

Ir, Rh, Ru, Os

Class 1C: Mo, Ni, Cr, V

Metals of significant safety concern

100

100**

300

10

10**

30

10*

10**

30*

1*

1**

3*

Class 2: Cu, Mn

Metals with low safety concern 2500 250 250 25

Class 3: Fe, Zn

Metals with minimal safety concern 13000 1300 1300 130

* Specific limits have been set for inhalation exposure to Platinum, Chromium VI and Nickel (see section 4.4 and the respective monographs

** Subclass limit: the total amount of listed metals should not exceed the indicated limit

4.3 Setting Concentration Limits of Metals: Oral and Parenteral Routes

Two options are available when setting limits/defining acceptance criteria for metal residues.

Option 1: Per individual metal the concentration limits in parts per million (ppm) stated in Table 1 can be used. They were calculated using equation (1) below by assuming a maximum daily dose (MDD) of 10 grams (g) administered daily.

(1) Concentration (ppm) = PDE MDD

The PDE is given in terms of ȝg/day and MDD is given in g/day.

These limits are considered acceptable for all listed metal residues present in drug substances, excipients, or products and can be applied for each individual metal. This option may be applied if the daily dose is not known or fixed. No further calculation is necessary provided the daily dose does not exceed 10 g. Products that are administered in doses greater than 10 g per day should be considered under Option 2.

Option 2: When a maximum daily dose is known this may be used together with the PDE in terms of µg/day as stated in table 1 and equation (1) above to determine the concentration of residual metal allowed in the drug product. Alternatively, it may be that the analytical procedure for the metal to be limited does not have the required sensitivity for routine use (e.g. to support the Class 1 limit for parenteral route). In this case, application of Option 2 can be appropriate. The limits should be realistic

¤EMEA 20077 Page 6/32

Only Class 3 metals are likely to be present. Only Class 2 metals X, Y, . . . are likely to be present. All are below the Option 1 limit (here the supplier would name the Class 2 metals represented by X, Y, . . . .). If Class 1 metals are likely to be present, they should be identified and quantified. "Likely to be present" refers to the metal used in the final manufacturing step and to metals that are used in earlier manufacturing steps and not removed consistently by the manufacturing process.

Organocatalysis

Biocatalysis

•  Enzymes or whole-cell microorganisms

•  Benefits Fast rxns due to correct orientations Orientation of site gives high stereospecificity Substrate specificity Water soluble Naturally occurring Moderate conditions Possibility for tandem rxns (one-pot)

Pros and cons compared with chemical synthesis

ADVANTAGES!!Mild!reac;on!condi;ons!(T,!P,!aqueous)!Highly!stereoM,!regioM,!and!chemoselec;ve!Unique!and!varied!chemistry!Environmentally!friendly!

DISADVANTAGES!!Poor!opera;onal!stability!Unwanted!reac;ons!with!impure!prepara;ons!Low!volumetric!produc;vity!High!cost !!

Biocatalysis

A coupling reaction in organic chemistry is a transformation where two hydrocarbon fragments are coupled with the aid of a metal catalyst. In one important reaction type a main group organometallic compound of the type RM (R = organic fragment, M = main group centre) reacts with an organic halide of the type R'X with formation of a new carbon-carbon bond in the product R-R’. cross couplings involve reactions between two different partners, for example bromobenzene (PhBr) and vinyl chloride to give styrene (PhCH=CH2). homocouplings couple two identical partners, for example, the conversion of iodobenzene (PhI) to biphenyl (Ph-Ph).

Coupling

2

Cross-couplingGeneralized cross-coupling (R1 and R2 = alkyl, aryl, alkenyl):

R1-X + R2-M ��o R1-R2 + M-X

Typically: catalyst = PdLn (sometimes NiLn)

X = halide

M = MgX (Kumda coupling)

M = ZnX (Negishi coupling)

M = SnR3 (Stille reaction)

M = BX2 (Suzuki reaction)

catalyst

The first example: Kumada Coupling

Makoto!Kumada!!(1920!–!!2007)!Robert!Corriu!(1935M!)!

4

Kumada coupling

Kumada coupling was the first Ni or Pd-catalyzed cross-coupling reaction (1972).

X Ni

R2P Cl

PR2

Cl

MgBr

+0.7 mol%

1-butylbenzene"Grignard reagent"

The advantage of this reaction is the direct coupling of Grignard reagents with organo-halides. The coupling of Grignard reagents with alkyl, vinyl or aryl halides provides an economic transformation; only the limited functional group tolerance can be a problem.

5

Kumada coupling

X Ni

R2P Cl

PR2

Cl

MgBr

+0.7 mol%


Effect of the phosphine, X = Cl

L = % Yield

dppp 100842 PPh3

dppe 79dmpe 47dppb 28

Effect of the halide, L = dppp

X = % Yield

31 (2h)

95 (3h)Cl

54 (4.5)

80 (3 h)

F

Br

I

1,3-Bis(diphenyphosphino)propane, dppp, is the optimal ligand for a wide range of aryl and vinyl halides. Unlike other cross-coupling methods, aryl and vinyl chlorides exhibit higher reactivity than their Br and I analogs.

Kumada, Bull. Chem. Soc. Jpn. 1976, 49, 1958.

Phosphines (arsines or NHC) are necessary in cross-coupling reactions to prevent catalyst decomposition to metal.

5

Kumada coupling

X Ni

R2P Cl

PR2

Cl

MgBr

+0.7 mol%



L = % Yield

dppp 100842 PPh3



X = % Yield

31 (2h)

95 (3h)Cl

54 (4.5)

80 (3 h)

F

Br

I




5

Kumada coupling

X Ni

R2P Cl

PR2

Cl

MgBr

+0.7 mol%



L = % Yield

dppp 100842 PPh3



X = % Yield

31 (2h)

95 (3h)Cl

54 (4.5)

80 (3 h)

F

Br

I




Kumada Coupling

8

Stereoselective Kumada couplingThe Ni-catalyzed Kumada coupling is stereoselective for vinyl halides but non-stereospecific for alkenyl Grignards:

Ph

Br+

MeMgBr

NiP

P

Cl

ClPh

Me

1-((E)-propenyl)benzene

(E)-E-bromostyrene

BrMg Me

+Ni

P

P

Cl

ClPh Me(Z)

Br (Z) 27% + (E) 73%

Palladium (0) catalysts, e.g. Pd(PPh3)4, have been shown to be stereospecific for alkenyl Grignard reagents. (Linstrumelle, TL 1978, 191).

Ph Br

+MeMgBr

NiP

P

Cl

Cl Ph Me

1-((Z)-propenyl)benzene

(Z)-E-bromostyrene

Kumada Coupling

Negishi Coupling

Grignard reagents were the first step, but suffer from obvious competitive reactivity problems. In order to address this issue the Negishi group began looking at other organometallic reagents that are less reavtive to common funtional groups. They found that Al, Zr, and Zn are all competent. Zn among the most efficient at undergoing transmetallation.

R1 R2R1 X +catalyst

R2 ZnClR2 Zn R2 or

Zn: Chem. Commun. 1977, 683.; J. Org. Chem. 1977, 42, 1821; J. Org. Chem. 1978, 43, 358.Al: J. Am. Chem. Soc. 1976, 98, 6729; Chem. Commun. 1976, 596. Zr: J. Am. Chem. Soc. 1977, 99, 3168.

R1 X

X = I, Br, Cl

t-BuLi (2 equiv)

THF, –78 ºCR1 Li

Easy to prepare from organolithium reagents generated from the slective deprotonation or lithium-halogen

exchange. Organozinc reagents of sp, sp2, and sp3 can be used.

ZnCl2R1 ZnCl

Little to no β-hydride elimination observed. Cross-couplings often occur at lower temperatures than other reactions. Highly tollerant of other functional groups.

Transmetallation is fast enough to compete with CO insertion.

ZnR1 ZnCl

9

Negishi coupling

R1-X + R2-ZnX ��o R1-R2 + ZnX2

catalyst

Negishi Coupling, published in 1977, was the first reaction that allowed the preparation of unsymmetrical biaryls in good yields. The versatile nickel- or palladium-catalyzed coupling of organozinc compounds with various halides (aryl, vinyl, benzyl, or allyl) has a broad scope, and is not restricted to the formation of biaryls.

Cataysts: NiCl2(PPh3)2 + 2(i-Bu)2AlH ��o (PPh3)2Ni(0)

Pd(PPh3)4 ��o (PPh3)2Pd (0) + 2PPh3

R1 = alkenyl, aryl, allyl, benzyl, propargyl

R2 = alkenyl, aryl, alkynyl, alkyl, benzyl, allyl

Negishi, Acc. Chem. Res., 1982, 15, 3409

Negishi coupling


catalyst







9

Negishi coupling


catalyst







Ei-chi Neghishi 1935-

Neghishi Coupling

10

Application of Negishi couplingAlkylzinc bromides can be efficiently prepared by insertion of iodine- activated zinc metal into alkyl bromides in N,N-dimetylacetamide (DMA). The in situ Ni- or Pd-catalyzed Negishi cross-coupling gives alkylarenes in excellent yields.

S. Huo, Org. Lett. 2003, 5, 423.

R Br

1.5 eq Zn (dust)5 mol% I2

DMA, 80 qC, ca. 3 h

R - alkyl or functionalized alkyl groups (-CN, -COOR, -Cl, -CH=CH2)

R ZnBr

R = n-Oct, > 90%

0.8 eq ArXCat: 2 mol% NiCl2(PPh3)2

or 2 mol% Pd(PPh3)4

r.t. ca. 1 h

R Ar

71 - 90%

R ZnBr

Negishi Coupling

Grignard reagents were the first step, but suffer from obvious competitive reactivity problems. In order to address this issue the Negishi group began looking at other organometallic reagents that are less reavtive to common funtional groups. They found that Al, Zr, and Zn are all competent. Zn among the most efficient at undergoing transmetallation.

R1 R2R1 X +catalyst

R2 ZnClR2 Zn R2 or

Zn: Chem. Commun. 1977, 683.; J. Org. Chem. 1977, 42, 1821; J. Org. Chem. 1978, 43, 358.Al: J. Am. Chem. Soc. 1976, 98, 6729; Chem. Commun. 1976, 596. Zr: J. Am. Chem. Soc. 1977, 99, 3168.

R1 X

X = I, Br, Cl

t-BuLi (2 equiv)

THF, –78 ºCR1 Li

Easy to prepare from organolithium reagents generated from the slective deprotonation or lithium-halogen

exchange. Organozinc reagents of sp, sp2, and sp3 can be used.

ZnCl2R1 ZnCl

Little to no β-hydride elimination observed. Cross-couplings often occur at lower temperatures than other reactions. Highly tollerant of other functional groups.

Transmetallation is fast enough to compete with CO insertion.

ZnR1 ZnCl

10


S. Huo, Org. Lett. 2003, 5, 423.

R Br


DMA, 80 qC, ca. 3 h


R ZnBr

R = n-Oct, > 90%


or 2 mol% Pd(PPh3)4

r.t. ca. 1 h

R Ar

71 - 90%

R ZnBr

10


S. Huo, Org. Lett. 2003, 5, 423.

R Br


DMA, 80 qC, ca. 3 h


R ZnBr

R = n-Oct, > 90%


or 2 mol% Pd(PPh3)4

r.t. ca. 1 h

R Ar

71 - 90%

R ZnBr

Neghishi Coupling

A common side reaction is homocoupling occurring where reactivity of R and R are similar (both aryl or alkenyl).

Neghishi Coupling

11

Stille couplingStille coupling is a versatile C-C bond forming reaction between stannanes and halides or pseudohalides, with very few limitations on the R-groups. Advantages:

-Highly functional group tolerant

-Stannanes are readily synthesized and are air and moisture stable (often distillable).

The main drawback is the toxicity of stannanes and their low polarity, which makes them poorly soluble in some solvents. Boronic acids and their derivatives undergo much the same chemistry in what is known as Suzuki coupling. Improvements in the Suzuki coupling may soon lead to the same versatility without the drawbacks of using tin compounds.

R1-X + R2-SnBu3 ��o R1-R2 + XSnBu3

Pd-catalyst

The easy of transfer from Sn: alkynyl > alkenyl > aryl > benzyl = allyl > alkyl.

Catalysts: (commercially available) Pd(PPh3)4, Pd(OAc)2, Pd2(dba)3 + PR3 or AsR3

Tin is toxic and alkyl stannanes are highly apolar

14

Stille coupling: ligand effect.Large rate enhancements (102–103) occur with ligands which are poor V-donors:

AsPh3 > P(2-furyl)3 > PPh3

No correlation exists between the cone angle of L and observed rates, indicating that the

effect is not of steric origin.

Pd2(dba)3 + L (1 : 2)

THF, 50 qCI

Bu3Sn

+

P

O

O

O

tri(2-furyl)phosphine

Pd2(dba)3 + L

THF, 50 qC

I

Bu3Sn

Pd

L

L

I Pd

S

L

I

S = solv

+ L

IBu3Sn

Kinetic studies support a mechanism involving rapid oxidative addition followed by the rate-

determining transmetalation which may involve solvent/ligand exchange. The dissociation of

L is more favorable for poor V-donors such as AsPh3.

Farina, JACS 1991, 113, 9585.

Espinet, JACS 1998, 120, 8978; JACS 2000, 122, 11771.

John!K.!S;lle!1930M1989!!!United!Airlines!239!crash,!Sioux!City!Aiowa!

!

Stille Coupling

12

Stille couplingWell-elaborated methods allow the preparation of different products from all of the combinations of halides and stannanes depicted below.

O

R Cl

R'

R"

RX

X = Cl, Br

ArylH2C X X = Cl, Br

R'

R"

R

X X = I, OTf

Aryl X X = Br, I

CO2R

R' HX

X = Br, I

Alk(H)R3Sn

CR'R3Sn

R'

R"

RR3Sn

R'

R"

R

R3Sn

CH2ArylR3Sn

ArylR3Sn

+

Stille Coupling

Stille Coupling

13

Stille coupling: extraordinary functional group tolerance

Ph Ph

O

Ph

PhO

Ph PhO

Pd Pd

OH

O

I

Bu3Sn OR

O

O

HO

+

OH

O

OR

O

O

HO

50 %

Pd2(dba)3 (0.2 eq)AsPh3 (0.8 eq.)Cu(I) tiophene-2-carboxylateNMP, 35 qC

Pd2(dba)3

The successful cross-coupling in the presence of an epoxide, alcohol, carboxylic acid and several olefin groups illustrates compatibility of the Stille reaction with common functional groups. This example is a step in the total synthesis of (+)-Amphidinolide. Note retention of configuration for the sp2 carbon, which is typical for Stille coupling.

Williams, JACS 2001, 123, 765.

13

Stille coupling: extraordinary functional group tolerance

Ph Ph

O

Ph

PhO

Ph PhO

Pd Pd

OH

O

I

Bu3Sn OR

O

O

HO

+

OH

O

OR

O

O

HO

50 %

Pd2(dba)3 (0.2 eq)AsPh3 (0.8 eq.)Cu(I) tiophene-2-carboxylateNMP, 35 qC

Pd2(dba)3

The successful cross-coupling in the presence of an epoxide, alcohol, carboxylic acid and several olefin groups illustrates compatibility of the Stille reaction with common functional groups. This example is a step in the total synthesis of (+)-Amphidinolide. Note retention of configuration for the sp2 carbon, which is typical for Stille coupling.

Williams, JACS 2001, 123, 765.

Stille Coupling

Stille Coupling

Suzuki-Miyaura Coupling

R1 R2R1 X R2 B(OR)2+

catalystor R2 BR2

J. Chem. Soc., Chem. Commun. 1979, 866.; Tetrahedron Lett. 1979, 3437.; (review) Chem. Commun. 2005, 4759.

The cross-coupling of organoboron reagents has matured into on of the more powerful methods for constructing C–C bonds and has largely supplanted the use of other organometallic reagents. Part of this is related to the low toxicity associated with boron and the relative ease of handling of many organoboron reagents. They can also be prepared by various methods.

R2 or R2

H BR2

R2 orBR2R2

BR2

hydroboration of alkenes/alkynes (catalyzed or non-catalyzed)

R2 or R2Ar Br or Bra. BuLi

b. B(OMe)3c. H3O+

R2

or R2

Ar B(OH)2or B(OH)2

B(OH)2

lithiation of organohalides or alkynes followed by reaction with a boronic triester

R B

R

R

trialkylborane

R B

OH

OH

boronic acid

R B

OR

OR

boronic ester(boronate)

All can be used for cross-coupling

Akira Suzuki 1930 -

Suzuki Coupling

18

Suzuki couplingThe original Suzuki reaction was coupling of an aryl boronic acid with an aryl halide using a palladium catalyst. Recent developments have broadened the possible applications enormously so that the scope of the reaction partners now includes alkyls, alkenyls, and alkynyls.

Due to the stability, ease of preparation and low toxicity of the boronic acid compounds, there is currently widespread interest in applications of the Suzuki coupling, with new developments and refinements being reported constantly.

B(OH)2

+

i-PrOH, H2O, reflux

CHO

Br

CHO

Pd(OAc)2 (0.3 mol%)PPh3 (0.9 mol%)Na2CO3 (1.2 equiv)

86%

A variety of organoboron reagents can be used:

Miyaura & Suzuki, Chem. Rev. 1995, 95, 2457; Suzuki A. J. Organomet. Chem. 1999, 576, 147.

OB

OR

OB

OR BR

OB

OR

pinacolborane 9-BBN9-borabicyclo[3.3.1]nonane

2-alkyl-1,3,2-dioxaborinane

diisopropyl alkylboronate

OB

OR

catecholborane

18

Suzuki couplingThe original Suzuki reaction was coupling of an aryl boronic acid with an aryl halide using a palladium catalyst. Recent developments have broadened the possible applications enormously so that the scope of the reaction partners now includes alkyls, alkenyls, and alkynyls.

Due to the stability, ease of preparation and low toxicity of the boronic acid compounds, there is currently widespread interest in applications of the Suzuki coupling, with new developments and refinements being reported constantly.

B(OH)2

+

i-PrOH, H2O, reflux

CHO

Br

CHO

Pd(OAc)2 (0.3 mol%)PPh3 (0.9 mol%)Na2CO3 (1.2 equiv)

86%

A variety of organoboron reagents can be used:

Miyaura & Suzuki, Chem. Rev. 1995, 95, 2457; Suzuki A. J. Organomet. Chem. 1999, 576, 147.

OB

OR

OB

OR BR

OB

OR

pinacolborane 9-BBN9-borabicyclo[3.3.1]nonane

2-alkyl-1,3,2-dioxaborinane

diisopropyl alkylboronate

OB

OR

catecholborane

19

General features of Suzuki coupling• Relative reactivity of leaving groups:

I – > OTf – > Br – >> Cl –

• Relative rates of reductive elimination from palladium(II) complexes:

aryl–aryl > alkyl–aryl > n-propyl–n-propyl > ethyl–ethyl > methyl–methyl

Catalyst and ligands: The most commonly used system is Pd(PPh3)4. Certain reactions need more specialized combinations (e.g. the successful coupling of alkylboranes requires PdCl2(dppf) as a catalyst).

FePPh2

PPh2

Fe

Ph2P

PPh2

PdCl

Cl99q 88q

dppf

Dppf favors reductive elimination vs. competitive ȕ-H elimination for two reasons: (1) the bidentate ligand enforces a cis geometry between the alkyl and vinyl/aryl substituents; (2) the large bite angle of dppf results in a smaller angle between the alkyl and vinyl/aryl substituents. This is thought to promote reductive elimination event by increasing orbital overlap.

Suzuki Coupling

20

Mechanism of Suzuki couplingThe mechanism is related to other palladium-catalyzed coupling reactions involving oxidative addition, transmetalation, and reductive elimination steps. The details of the transmetalation step are unresolved; boron "ate" complexes are frequently invoked.

LnPd(0)

LnPd(II)R1

X

R1 Xoxidativeaddition

R2R1

LnPd(II)R1

OR

Base:MOR (M = Na, K,Tl)

MXR2

BY2

BY2OR

LnPd(II)R1

R2

reductiveelimination

transmetalation Tl - most effective!

Transmetalation – an “ate” compound. Note retention of configuration

Boron-carbon bonds are covalent/non-ionic. As a result, organoboron compounds are generally insensitive to water and are compatible with most organic functionality. For the same reason, these intermediates do not readily undergo transmetalation and must be activated with a base.

Soderquist, J. Org. Chem. 1998, 63, 461

LnPdO

CB

R'

20

Mechanism of Suzuki couplingThe mechanism is related to other palladium-catalyzed coupling reactions involving oxidative addition, transmetalation, and reductive elimination steps. The details of the transmetalation step are unresolved; boron "ate" complexes are frequently invoked.

LnPd(0)

LnPd(II)R1

X

R1 Xoxidativeaddition

R2R1

LnPd(II)R1

OR

Base:MOR (M = Na, K,Tl)

MXR2

BY2

BY2OR

LnPd(II)R1

R2

reductiveelimination

transmetalation Tl - most effective!

Transmetalation – an “ate” compound. Note retention of configuration

Boron-carbon bonds are covalent/non-ionic. As a result, organoboron compounds are generally insensitive to water and are compatible with most organic functionality. For the same reason, these intermediates do not readily undergo transmetalation and must be activated with a base.

Soderquist, J. Org. Chem. 1998, 63, 461

LnPdO

CB

R'

Suzuki Coupling

25

Stereospecific Suzuki coupling

Representative stereospecific Suzuki coupling: the configurations of the vinylborane and vinyl halide are retained. Excellent method for the construction of conjugated dienes.

• Oxidative addition is known to proceed with retention of stereochemistry with vinyl halides and with inversion with allylic or benzylic halides.• Reductive elimination proceeds with retention of stereochemistry:

D

DH

HBD

DH B

H

OI

OR ORD

DH

HOR

Pd(dppf)Cl2NaOH

OBBN-H

C4H9

H

H

H

C4H9

Pd(PPh3)4 (1 mol%)NaOEt, benzenereflux

OHB

Ocatecholborane

syn hydroborationO

BO

Br PhH

H

C4H9

Ph

86 %

Suzuki Coupling

Taking advantage of the easy formation of copper acetylides (CuI, R3N), cross-coupling between terminal acetylenes and aryl/alkenyl halides/triflates can be acheived. In situ formation of Cu–acetylide means catalytic amounts of both Pd and Cu can be used. Homocoupling of acetylene is a common side reaction. This can be overcome by using excess acetylene, or by slow addition of acetylene. Many can be carried out at ambient temperatures. Usually a pretty reliable way to make a C–C bond.

Kenkichi Sonogashira 1931-

Sonogashira Coupling

Sonogashira Coupling

The ubiquity of C–N bonds in pharmaceuticals and other industrially important molecules forced in developing metal-catalyzed aminations of ary halides. This proved to be quite difficult. Mechanistically, two factors were responsible for these difficulties: reversible and inefficient ligation of the amine to the Pd, and slow reductive elimination. A breakthrough came when Buchwald group found that bulkly electron rich phosphine ligands (i.e., P(o-tol)3) did promote these reactions. Not only was the reductive elimination promoted by the enhanced electron donation of these ligands, but their large size meant that the catalytically active Pd(0) catalyst only had one ligand.

Stephen L. Buchwald, 1955 -

Pd-Catalyzed Aminations

The ubiguity of C–N bonds in pharmaceuticals and other industrially important molecules perpetuated work aimed at developing metal-catalyzed aminations of ary halides. This proved to be quite difficult.

R1HNR1 X R2 NH2

+catalyst

(1º or 2º amine, amideaniline, hetereocycle)

R2

Synlett 1997, 329.; Curr. Org. Chem. 1997, 1, 287.; Angew. Chem. Int. Ed. 1998, 37, 2046.; Acc. Chem. Res. 1998, 31, 805.; Acc. Chem. Res. 1998, 31, 852.;

A breakthrough came when it was found that bulkly and electron rich phosphine ligands (i.e., P(o-tol)3) did promote these reactions. Not only was the reductive elimination promoted by the enhanced electron donation of these ligands, but their large size meant that the catalytically active Pd(0) catalyst only had one ligand.

Mechanistically, it was determined that two factors were responsible for these difficulties: reversible and inefficient ligation of the amine to the Pd, and slow reductive elimination.

The Buchwald group was able to use this informationto design new ligands that have proved extremely useful and general for C–N bond formation. These same ligands are also quite useful in other Pd-catalyzed reactions (e.g. Suzuki reactions)

Even aryl chlorides can be used.

Buchwald Coupling

Buchwald Ligands

PCy2

i-Pri-Pr

i-Pr

XPhos

P(t-Bu)2

i-Pri-Pr

i-Pr

tBuXPhos

PCy2

Me2N

DavePhos

PCy2

MeO

SPhos

OMe

P(t-Bu)2

JohnPhos

PCy2

i-PrO

RuPhos

Oi-Pr

PCy2

i-Pri-Pr

i-Pr

BrettPhos

OMe

MeO

primary alkyl amines

primary anilines

secondary alkyl amines

secondary anilines

Review on biaryl phosphane ligands in aminations:Angew. Chem. Int. Ed. 2008, 47, 6338–6361.

A "user's guide" to Pd-catalyzed amination:Chemical Science 2011, 2, 27–50.

Buchwald Coupling

Buchwald-Hartwig Coupling

from Chemical Science 2011, 2, 27–50.

From aryl chlorides

OH

HN

N

N Me

N

N

OHCO2H

HN

Hex

AcHN

HN

N

N

Me

Me

From aryl mesylates (Ar–OSO2Me)

Me

Me

HN

N

CO2EtHN

F

HN

MeO F

MeO

OMe

HN

CO2Et

OMeHN

AcPh

HN

CF3

EtO2C



From aryl chlorides

OH

HN

N

N Me

N

N

OHCO2H

HN

Hex

AcHN

HN

N

N

Me

Me

From aryl mesylates (Ar–OSO2Me)

Me

Me

HN

N

CO2EtHN

F

HN

MeO F

MeO

OMe

HN

CO2Et

OMeHN

AcPh

HN

CF3

EtO2C


With aliphatic amines

N

F3C


N Boc

NNMeO

N

NBoc

t-Bu

NH

O

O

With amides, carbamates, ureas, sulfonamides.

NH

O MeO

O

NH

O

MeO

CF3

t-Bu

NS

Ph

O O

Bu

MeO2C

N N

O

Ph

MeO2C

N

Hex

O

N OMe

O

MeO

Buchwald Coupling


With aliphatic amines

N

F3C


N Boc

NNMeO

N

NBoc

t-Bu

NH

O

O

With amides, carbamates, ureas, sulfonamides.

NH

O MeO

O

NH

O

MeO

CF3

t-Bu

NS

Ph

O O

Bu

MeO2C

N N

O

Ph

MeO2C

N

Hex

O

N OMe

O

MeOBuchwald-Hartwig Coupling

With heterocyclic NH


N

NEt

N

Et

Me

F

F

N

N

N

NC

N

N

N

Me

N

N

Me

Formation of "Ar–NH2" with ammonia equivalents

NH2

O

O

N

NH2

Ph

NH

Ph

benzophenoneimine

Ph

N

Ph

Ar

H3O+

NH2

Et2NOCN

NH2 NH2

MeO

NTMS

Li

TMSN

TMS

Ar

TMS

H3O+ or TBAF


With heterocyclic NH


N

NEt

N

Et

Me

F

F

N

N

N

NC

N

N

N

Me

N

N

Me

Formation of "Ar–NH2" with ammonia equivalents

NH2

O

O

N

NH2

Ph

NH

Ph

benzophenoneimine

Ph

N

Ph

Ar

H3O+

NH2

Et2NOCN

NH2 NH2

MeO

NTMS

Li

TMSN

TMS

Ar

TMS

H3O+ or TBAF

John F. Hartwig 1964-



Richard F. Heck (1931 - )

123.702 Organic Chemistry

The Heck reaction

• The Heck reaction is a versatile method for the coupling sp2 hybridised centres• Again it is not the purpose of this course to teach organometallics etc

1

R1 X + R2

cat. PdX2

R3N

[R33P]

R2R1

R1 = Ar, ArCH2,

X = Br, I, OTf

Br

Pd

L

L

Br

oxidative addition

Pd

L

Br

syn addition

R3N

R3NH Br

Pd(0)(14e)

L Pd L

L Pd Br

H

L

Pd

H

Pd

LH

Br

LBr

–L

+L Pd(II)(16e)

Pd(II)(16e)

Pd(II)(16e)

β-hydride elimination

Heck reaction

Heck reaction

Heck reaction

Metathesis

Cross- Metathesis: Olefin Metathesis allows the exchange of substituents between different olefins - a transalkylidenation.. This reaction was first used in petroleum reformation for the synthesis of higher olefins (Shell higher olefin process - SHOP), with nickel catalysts under high pressure and high temperatures. Nowadays, even polyenes with MW > 250,000 are produced industrially in this way.

Metathesis

Hoveyda-Grubbs

Metathesis)

Ring closing methathesis RCM

Ring opening metathesis-polymerization (ROMP))

Metathesis

Advanced organic chemistry II course Aa 2014-2015 Prof ... · • Distillation (solvent recovery) • Drying (final treatment of solids). • Equipments (lab hoods, centrifuges, pumps

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