Synthesis of Pharmaceuticals Flashcards
What is the driving force in amide coupling with CDI coupling reagent?
CO2 gas driving force
In reductive amination why is NaB(CN)H3 used instead of NaBH4 as a reducing agent?
It is a less reactive version of NaBH4 as it contains an electron withdrawing group which makes it a weaker reducing agent.
NaBH4 can reduce ketone or aldehyde before they have a chance to react.
NaBH4 can also react with the acetic acid and effectively destroy it.
Why is AcOH used in reductive elimination?
Because AcOH has pH of ~6
This means its not so acidic that it protonates the amine before reaction has occured so it cannot react as nucleophile and not too basic that no acid is present to protonate the OH group and make a good LG
Amination of alkyl halides is an SN2 reaction. What impact does this have on the stereochemistry?
SN2 reaction proceeds via an inversion of stereochemistry so if a stereogenic centre is present have to use tosylate (OTs) group of reverse stereochem as it will be inverted upon SN2 attack by nucleophile.
What is a potential issue with amination of alkyl halides?
One problem with this approach is the potential for over reactions and therefore lower yields. The substituted amine will have an extra alkyl group which is +I so will make the N lone pair more nucleophilic and so will undergo another substitution reaction.
For nucleophilic aromatic substitution reaction to occur what conditions are required?
Aryl halide with EWG ortho or para to halide
Halides that work best: F, Cl as more electroneg making attatched carbon more delta + so is more readily attacked by nucleophilic amine
What conditions do you need for aromatic substitution to occur on a halopyridine?
The halide on the pyridine ring must be at the 2 or 4 position. The nitrogen on the pyridine ring serves as the EWG so as it can “accept” the negative charge.
Halide that works best; F, Cl
Note: ROH groups and other nucleophiles can also be used
What is the main advantage of using Buchwald Hartwig Pd mediated amination
This reaction works on electron rich and electron deficient aromatic halides, it is a very versatile process.
Conditions required for Cu mediated amidation of aromatic halides
10 mol% CuI
10 mol% DMEDA
K3PO4
Aromatic iodides
Best for cyclic amides (lactams)
Aryl-aryl bond formation: Suzuki Miyaura cross coupling conditions
links 2 sp2 carbons
Aromatic halide
Aromatic boronic acid
1 mol% Pd2(dba)3
1 mol% P(tBu)3
Na2CO3 (aq)
What are the conditions for the synthesis of aryl boronic acids via bromine lithium exchange
nBuLi
B(OMe)3
HCl
What are the conditions for the synthesis of aryl boronate esters via miyaura borylation
1 mol% Pd2(dba)3
1 mol% XPhos
KOAc
B2Pin2
What are the conditions for 𝛼- functionalisation of cyclic amines
Boc protecting group introduced to nitrogen (Boc2O and TFA)
Deprotonate with strong organolithium base (sBuLi + TMEDA)
Then use electrophile to trap e.g. alkyl halide, ketone
Conditions for 𝛼- functionalisation via Negishi cross coupling
Boc protecting group introduced to nitrogen (Boc2O and TFA)Deprotonate with strong organolithium base (sBuLi + TMEDA)
ZnCl2 to replace Li with Zn-Cl which can then be used in Negishi arylation:
5 mol% Pd(OAc)2
5 mol% P(tBu)3
Aryl halide
How do we achieve asymmetric 𝛼-functionalisation of cyclic N-Boc amines
Use of chiral diamines in place of TMEDA allows an asymmetric reaction to occur.
Chiral diamine coordinates to sBuLi to make a chiral base which preferentially removes 1 of 2 enantiotopic protons to give a covalent, sp3 hybridised chiral organolithium intermediate
In asymmetric 𝛼-functionalisation of cyclic N-Boc amines how do you remove H on top face of RHS of molecule?
sBuLi
(+) sparteine
In asymmetric 𝛼-functionalisation of cyclic N-Boc amines how do you remove H on top face of RHS of molecule?
sBuLi
(-) sparteine
During Fischer indole synthesis what should we take into consideration?
(1) The aromatic hydrazine should only have 1 position to react - achieved by symmetry or using blocking groups
(2) Ketone should only have 1 postion that the enamine can form - achieved by symmetry or using aldehydes
Conditions for formation of tetrazole
R-CN
NaN3 (Azide)
NH4Cl
Heat
Conditions for amide synthesis with acid chloride
COCl
NH2
Et3N (base)
Conditions for amide synthesis with T3P coupling reagent
COOH
NH2
T3P
2 equiv. pyridine
Carboxylic acid to Acid Chloride
SOCl2
Carboxylic acid to Ester e.g. COOMe
MeOH
HCl
Ester to carboxylic acid
NaOH
Conditions for reductive amination
Amine
Ketone or aldehyde
Na(CN)BH3
AcOH
Alcohol to Carboxylic acid
CrO3
H2SO4
Alcohol to aldehyde
PCC
Ester to alcohol
2 equiv. LiAlH4
Ketone to alcohol
NaBH4
Conditions for amination of alkyl halides
Alkyl halide
amine
Cs2CO3 (base)
Alcohol to a Tosylate
TsCl
Pyridine
Amination of aromatic halides (SNAr) conditions
Aromatic halide with EWG ortho or para to Halide LG
Amine
K2CO3 (base)
What are some good EWG for SNAr amination of aromatic halides
NO2, CN, CF3, SO2R, COR
Aromatic - NO2 to NH2
Sn, HCl
Addition of NO2 to aromatic ring
HNO3
H2SO4
Conditions for amination of halopyridines
Pyridine ring with halogen in the 2 or 4 position
Amine
K2CO3 (base)
Most commonly used LG for the amination of aromatic halides or halopyridines
Cl
Amination of Aromatic halides: Pd mediated coupling of primary amines
1 mol% Pd2(dba)3
1 mol% BrettPhos
NaOtBu
Aarons favourite colour
Blue maybe dark green
Sunset orange
Aarons favourite sport
Cricket
Amination of Aromatic halides: Pd mediated coupling of secondary amines
1 mol% Pd(OAc)2
1 mol% RuPhos
NaOtBu
Protect/deprotect amine with Boc
Boc2O
TFA
Protect/deprotect amine with Bn
Bn-Br and Cs2CO3
H2, Pd/C
Protect/deprotect alcohol
TBDMS-Cl, imidazole
TBAF
Protect/deprotect alcohol with Bn
- NaH
- Bn-Br
Deprotect: H2, Pd/C
Protect/ deprotect ketone
Acetal and HCl
H2O, HCl
