Advanced Organic

Chemistry

روشهایسنتز مواد آلی

به نام خدا

Dr Morteza MehrdadUniversity of Guilan, Department of

Chemistry,

Rasht, Iranm-mehrdad@guilan.ac.ir

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Functional Group Interconversion by

Substitution,

Including Protection and Deprotection

2

3

3

3.1. Conversion of Alcohols to Alkylating Agents (Sulfonate Esters, Halides)

3.2. Introduction of Functional Groups by Nucleophilic Substitution at Saturated Carbon

3.2.1. General Solvent Effects

3.2.2. Nitrile Nucleophile

3.2.3. Oxygen Nucleophiles

3.2.4. Nitrogen Nucleophiles

3.2.5. Sulfur Nucleophiles

3.3. Cleavage of Carbon-Oxygen Bonds in Ethers and Esters

3.4. Interconversion of Carboxylic Acid Derivatives

3.4.1. Acylation of Alcohols

3.4.3. Preparation of Amides

3.5. Installation and Removal of Protective Groups

3.5.1. Hydroxy-Protecting Groups

3.5.2. Amino-Protecting Groups

3.5.3. Carbonyl-Protecting Groups

3.5.4. Carboxylic Acid-Protecting Groups

4

sp3

sp2

Transformation of functional groups

By substitution with heteroatom (non-C)

nucleophiles

Chapters 1 and 2formation of new carbon-carbon bonds

(carbon nucleophile + carbon electrophile)

In this chapter

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OH- poor leaving group(Lg)

- Activation is required;

- transfer OH to a good Lg

-

3.1. Conversion of Alcohols to Alkylating Agents3.1.1. Sulfonate Esters

3.1.2. Halides

activating

reactivity : R-Lg:-OSO2R > -I > -Br >> -Cl

Alcohols

ROH

alkylation compound = active intermediatei) sulfonate esters (R-O-sulfonyl)

ii) halides R-X

6

trialkyl phosphite ester

The driving force for

cleavage of the C−O

bond is the formation

of a strong phosphoryl

double bond

synthesis of primary

bromides using PBr3

7

triphenylphosphine pentavalent adduct

alkoxyphosphonium intermediate

triphenylphosphine oxide

synthesis of

primary

bromides

using PBr3

(Cont….)

neopentyl alcoholresistant to nucleophilic substitution

& rearrangement

but reacts well under

these conditions

8

Milder reagents

Activating alcohols toward nucleophiles is by

converting them to alkoxyphosphonium ions

are very reactive toward

nucleophilic attack

the use of halogenated solvents as chlorine sources in Ph3P-mediated reactions

9

hexachloroacetone chlorophosphonium ion

Alkoxyphosphonium ion

the use of halogenated solvents as chlorine sources in Ph3P-mediated reactions

(cont…..)

10

The reactant in Entry 7 is prone to rearrangement via

ring expansion but no rearrangement was observed

under these conditions

synthesis of bromides by nucleophilic substitution on tosylates

11

2-chloro-3-ethyl

benzoxazolium cation

very mild procedure

displacing chloride 3-ethylbenzoxazolinone

(stable product)

secondary alcohol

inversion of configuration

12

primary alcohol

tertiary amino group captures the HCl

chlorosulfite intermediate

heated in ethanol

gas

Evolution

occurs

Alkoxy

Phosphonium

ion

methyl iodide

13

very mild procedure for converting alcohols to iodides

triphenylphosphine

diethyl azodicarboxylate

The role of the DEAD is to activate the triphenylphosphine

toward nucleophilic attack by the alcohol

The activation of alcohols to nucleophilic attack by the

triphenylphosphine-DEAD combination is called the

Mitsunobu reaction

inversion occurs

14

Ph3P–Br2 complex

Ph3P–I2-imidazole reagent combination

Primary iodide

Triphenylphosphine and imidazole in combination with iodine or

bromine gives good conversion of alcohols to iodides or bromides.

more reactive system

chlorodiphenylphosphine

diphenylphosphinic acid

(by-product)

15

3.2. Introduction of Functional Groups by Nucleophilic

Substitution at Saturated Carbon

3.2.1. General Solvent Effects

3.2.2. Nitriles

3.2.3. Oxygen Nucleophiles

3.2.4. Nitrogen Nucleophiles

3.2.5. Sulfur Nucleophiles

3.2.6. Phosphorus Nucleophiles

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introduction of cyano groups via tosylates and were all conducted in polar aprotic solvents

classical conditions:

more rapidly in polar

aprotic solvents:

~1 h

17

In DMSO,

for example,

primary alkyl chlorides are converted to nitriles in 1 h or less at temperatures

of 120–140C

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Nitrogen Nucleophiles:

Azides are useful

intermediates

easily reduced to primary amines

undergo cycloaddition reactions

Azido groups are usually introduced into aliphatic compounds by

nucleophilic substitution

under phase transfer conditions

A concentrated aqueous solution of NaN3 was

heated with the alkyl bromide and 5 mol %

methyltrioctylammonium chloride.

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introduction of the azido group at secondary carbons with inversion of

configuration in each case

2o

2o

Diphenylphosphoryl azide

triphenylphosphine

Mitsunobu reaction

Hydrazoic acid, HN3

20

2o

Diphenylphosphoryl azide

1o alkyl and 2o

benzylic alcohols strong organic base

O-phosphorylation followed by SN2 displacement.

21

controlled alkylation of amines

R’NH2 + R-X R’NR4+ X-

alkylation of neutral amines by halides

the possibility of multiple alkylation

pyrrolidine was used in twofold excess.

The ester EWGs have a rate-retarding effect that slows further alkylation to

the quaternary salt

proceed to the quaternary ammonium salt

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The reaction was conducted in ethanol, and the dihydrochloride salt

of the product precipitates as reaction proceeds,

which helps minimize quaternization or N,N-dialkylation.

The yield of the dihydrochloride is 97–99%, and that of the amine is

65–75% after neutralization of the salt and distillation.

the monohydrochloride

of piperazine

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O-alkylation of an amide

the product was obtained by distillation after the neutralization.

Secondary amides can be alkylated on nitrogen by using sodium

hydride for deprotonation, followed by reaction with an alkyl halide.

24

Sections D through H involve oxygen nucleophiles

The hydrolysis reactions in both involve

benzylic positions

The reaction site is further activated by the ERG substituents on the ring

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exam

ple

s o

f base-c

ata

lyzed e

ther

form

ation

meta-hydroxy

ortho-hydroxy

more acidic

stabilized by chelation making it less reactive

Dialkylation occurs if a stronger

base (NaOH) and dimethyl sulfate

is used

26

a typical diazomethane methylation of a carboxylic acid

toxicity

explosion hazard

safety precautions

27

5 mol % carboxylic acids,

including pivalic acid

were alkylated in high yield

These conditions also gave high yields for unhindered acids and iodides

hindered mesitoic acidsecondary iodide

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formation of a sulfonate ester under

Mitsunobu conditions with clean

inversion of configuration.

The conditions reported represent the optimization

of the reaction as part of the synthesis of an antihypertensive drug, fosinopril.

formation of a methyl ester using CH3I and KF as the base in DMF

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Both neutral and anionic phosphorus compounds are good nucleophiles

toward alkyl halides

phosphorane and phosphonate intermediates used for Wittig reactions

phosphite ester

Michaelis-Arbuzov reaction

unstable

Trialkoxyphopsphonium

intermediate

break the O−C bond,

resulting in formation

of a phosphoryl P−O bond.

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useful method for introducing thiol groups

The solid thiourea is a convenient source of sulfur

thiouronium ion is readilyhydrolyzed by base/

avoids competition from

formation of a dialkyl sulfide

Anions derived from thiols are strong nucleophiles and are easily alkylated by halides.

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Neutral sulfur compounds are also good nucleophiles,

thioamides readily form salts with methyl iodide

32

3.3. Cleavage of Carbon-Oxygen Bonds in Ethers

and Esters

The cleavage of carbon-oxygen bonds in ethers or esters by nucleophilic

substitution is frequently a useful synthetic transformation.

carboxy is only slightly better

alkoxide group is a poor leaving group

As a result,

these reactions usually require assistance from a protic or

Lewis acid

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use of boron tribromide for ether cleavage

The reactions are conducted at dry ice-acetone temperature and

the exposure to water on workup hydrolyzes residual O−B bonds

adduct formed

attack of bromide ion

The cleavage step

can occur by either an

SN2 or an SN1 process

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primary hydroxy group that is deprotected lactonizes spontaneously

uses HBr in acetic acid to cleave a methyl aryl ether.

This reaction was part of a scale-up of the synthesis of a drug

candidate molecule

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cle

avage o

f eth

ers

and

este

rs u

sin

g T

MS

I

Trimethylsilyl iodide (TMSI)

TMSI cleaves methyl ethers in a period of a few hours

at room temperature

silyl oxonium ion

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the more hindered of the two ether groups may reflect a steric

acceleration of the nucleophilic displacement step

37

use of the BF3-EtSH reagent combination

The boron trifluoride–alkyl thiol reagent combination also operates on the

basis of nucleophilic attack on an oxonium ion generated by reaction of the

ether with boron trifluoride

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“troublesome in the extreme.”

ether is both a primary benzylic

ether and a secondary one

ring having several ERG substituents

Electrophilic conditions lead to preferential

cleavage of the secondary benzylic bond and formation of elimination products

presence of excess NaOAc

allows the nucleophilic SN 2 cleavage of the primary benzyl bond to dominate

by reducing the reactivity of the electrophilic species that are present

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inversion of configuration

trans stereochemistry

When applied to 2-substituted tetrahydrofurans,

the reaction gives mainly cleavage of the C(5)−O bond,

indicating that steric access of the nucleophilic component of the reaction is

dominant in determining regioselectivity

40

a cleavage reaction using an acylating agent in conjunction with a Lewis acid

Acylium ions

(reactive electrophile)