Download Organic Chemistry-III CH-423 - Department of Chemistry, IIT Bombay

Organic Chemistry-III
CH-423
Krishna P. Kaliappan
Department of Chemistry
Indian Institute of Technology-Bombay
Mumbai 400 076 INDIA
http://www.chem.iitb.ac.in/~kpk
[email protected]
9/3/14 Syllabus
CH-423 (2013)/Chem/IIT-B
Dr. Kaliappan, Krishna P.
Organic Chemistry III
Classification of reactions: A brief introduction to substitution,
elimination, addition, oxidation, reduction, rearrangement and
pericyclic reactions.
Functional group transformations: alcohols to alkylating agents,
Mitsunobu and related reactions, introduction of functional groups by
nucleophilic substitution at saturated carbon, nucleophilic cleavage of
C-O bonds in ethers and esters and inter-conversion of carboxylic
acid derivatives.
Oxidation: Metal based oxidizing reagents: A review and detailed
discussion of chromium, manganese, ruthenium, silver and other metalbased reagents. Non-metal based oxidizing reagents: DMSO,
peroxide, peracid and oxygen based oxidation. Miscellaneous oxidizing
reagents like IBX, DMP, CAN, DDQ, periodate etc.
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Syllabus
CH-423 (2013)/Chem/IIT-B
Organic Chemistry III
Dr. Kaliappan, Krishna P.
Reduction: Homogeneous and heterogeneous hydrogenations; Discussion
on borane based racemic and chiral reagents, aluminum, tin, silicon
based reducing agents. Dissolving metal reductions.
Selectivity and protecting groups: Illustration of chemoselectivity,
regioselectivity and stereoselectivity with examples; protecting groups
for alcohols, amines, acids, ketones and aldehydes.
Cycloaddition reactions: Diels-Alder reaction; general features, dienes,
dienophiles, selectivity, intramolecular and intermolecular reactions,
hetero-Diels Alder reaction. 1,3-dipolar cycloaddition reactions; general
features, dipoles, dipolarophiles. [2+2] cycloaddition reactions; general
features, selected examples.
Molecular rearrangements: Illustration of electron deficient and
electron rich skeletal rearrangements with examples; Sigmatropic
rearrangements-Claisen and related rearrangements, Cope and oxy-Cope
rearrangements; 2,3-sigmatropic rearrangements and ene reaction.
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Syllabus
Suggested Books/Reviews:
Jerry March, “Advanced Organic Chemistry”, Fifth Ed., Wiley, 2007.
F. A. Carey and R. J. Sundburg, “Advanced Organic Chemistry, Part B”, Fifth
Ed., Springer, 2007.
J. Clayden, N. Greeves, S. Warren and P. Wothers, “Organic Chemistry”, First
Ed., Oxford University Press, 2001.
W. Carruthers, I. Coldham , “Modern Methods of Organic Synthesis”, Cambridge
University Press
K. Peter C. Vollhardt and Neil E. Schore “Organic Chemistry” W. H. Freeman
and Company, 1999.
Evaluation Pattern
Mid-Semester
30%
End Semester + Assignment
50%
Quiz (2)
20%
-There will be a total of 36 (1h) lectures, and 7 tutorials
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Groups
Only With Carbon and Hydrogen
C C
C C
With Heteroatoms
With One Oxygen Atom:
1.  Alcohol:
R OH
Primary
alcohol
R
OH
R
secondary
alcohol
R
R
R
OH
tertiary
alcohol
2. Ether:
O
O
Diethyl ether
anisole
O
diphenyl ether
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Groups
With One Oxygen Atom:
3. Ketone:
O
O
Acetone
Acetophenone
4. Aldehyde:
O
O
H
Acetaldehyde
H
Benzaldehyde
5. Epoxide, Cyclic Ethers:
O
Epoxide
9/3/14 O
Oxetane
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 6 Functional Groups
With Heteroatoms
With Two Oxygen Atoms:
1. Acid:
O
O
OH
OH
Acetic acid
2. Ketal:
OR'
R
Benzoic acid
OR'
R
3. Acetal:
OR'
OR'
R
4. Ester:
H
O
O
OEt
Ethyl acetate
O
Ethyl benzoate
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Groups
With heteroatoms
With Two Oxygen Atoms:
5. Lactones (Cyclic Esters):
O
O
O
O
γ-lactone
δ-lactone
6. Peroxides:
R
O
O
R
With Three Oxygen Atoms:
1. Anhydrides:
O
O
O
Acetic anhydride
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Groups
With Heteroatoms
With Three Oxygen Atoms:
2. Hydroxy acids:
O
O
O
OH
OH
OH
β-hydroxy acid
OH
α-hydroxy acid
OH
OH
γ-hydroxy acid
3. Peracids:
O
Cl
O
OH
meta-chloro perbenzoic acid
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Groups
With Heteroatoms
With One Nitrogen Atom
1) Amines:
NH2
H3C
Methyl amine
(primary amine)
H
N
CH3
H3C
Dimethyl amine
(secondary amine)
N
Triethyl amine
(tertiary amine)
2) Aromatic Amines:
NH2
Aniline
3) Nitriles:
CN
H3C
Acetonitrile
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Groups
With Heteroatoms
With One Nitrogen Atom
4) Aziridines:
H
N
aziridine
5) Aromatic Amines:
N
H
Pyrrole
N
Pyridine
6) Imines:
N
R
H
H
Primary aldimine
N
R
R
H
Secondary aldimine
N
R
H
N
R
R
Primary Ketimine
R
R
Secondary Ketimine
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Groups
With Heteroatoms
With Two Nitrogen Atoms
With Three Nitrogen Atoms
1) Diazo:
1) Azides:
H2C N2
R
Diazomethane
N
N
N
2) Triazole:
2) Azo:
R
N N
R
3) Diazonium:
N N
Benzenediazonium cation
H
N
H
N
N
N
N
N
1,2,4-triazole
1,2,3-triazole
With Four Nitrogen atoms
1) Tetrazole:
H
N
N
N N
1-triatrazole
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Group
With Heteroatoms
With One Nitrogen Atom and One Oxygen Atom
1) Amides:
3) Oximes:
O
R
N
NH2
R
NH
β−lactam
N
R
H
aldoxime
2) Lactams:
O
OH
O
NH
N
O
γ−lactam
5) Nitrile Oxides:
R
R
ketoxime
4) Nitroso:
R
OH
N O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Group
With Heteroatoms
With One Nitrogen Atom and Two Oxygen Atoms
1) Nitro:
R
2) Nitrones:
R
NO2
R
N
O
With Two Nitrogen Atom and One Oxygen Atom
1) Urea:
O
H2N
NH2
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Group
With Heteroatoms (Sulfur)
1) Thiols:
SH
Thiophenol
2) Thio Ethers:
R
S
SH
Ethanethiol
4) Thiirane:
S
R
3) Thio carbonyl:
5) Heterocycles:
S
R
R
S
Thiophene
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Group
With Heteroatoms (Halogens)
1) Halides:
I
H3C
Br
Ethyl bromide
Methyl iodide
4) Acid Chloride:
O
2) Halohydrin:
Cl
Acetyl chloride
I
R
R
HO
OH
Cl
5) Halolactones:
3) Dihalides:
Cl
O
Cl
1,2-dichloroethane
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan O
I
Functional Group Transformations
Organic Synthesis and Music: What is Common Between Them?
Reactions Can be Classified into Seven Types
Oxida'on Pericyclic Elimina'on CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 17 Functional Group Transformations
1. Addition Reaction:
a. Nucleophilic Addition
O
R
O
R'
E
R'
R
Nu
Nu
OE
R
Nu
R'
Reaction is categorized by first step and not by second step
b. Electrophilic Addition
Br
Br
Br2
Br
Br
X
.
c. Radical Addition
X
.
Y
.
X
Y
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 18 Functional Group Transformations
2. Elimination Reactions
E1, E2, E1CB, syn, anti, pyrolytic
Syn Elimination:
OAc
OAc
H
AcOH
AcOH
Syn elimination
O
H
OH
O
O
NaH
CS2, MeI
H
SMe
S
O
+
HS
COS + MeSH
SMe
Xanthate ester
OH
H
Side reactions like Wagner-Meerwein
rearrangement can take place
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 19 Functional Group Transformations
3. Substitution Reactions
a. Aromatic Substitution
b. Aliphatic Substitution
1. Nucleophilic Substitution
NO2
OR
NO2
OR
F
2. Addition- Elimination
Br
1. Nucleophilic Substitution
SN1, SN2, SNi
2. Electrophilic
E1, E2, E1CB, syn,
anti, pyrolytic
CN
CN
NaNH2
via Benzyne
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 20 Functional Group Transformations
Esters
Ways to make esters
RCO2H +
R'OH
RCO2H +
R'OH
O
R
O
R
O
H+
Base
RCO2R'
RCO2R'
O
R'OH
Base
R
OR'
Base must be non nucleophilic
HO
AcO
Ac2O
O
N
HO
Morphine (Acute pain killer)
H+
O
N
AcO
Heroin
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 21 Functional Group Transformations
Ways to Make Esters
O
R
O
CH2N2
R
OH
O
R
OMe
O
O
H
H2C
N2
R
O
H3C N2
If compound containing nitrogen having more nitrogen content
(more than 50%), then compound may be explosive (CH2N2 is explosive)
OH
OMe
CH2N2
R
OH
CH2N2
OH
OH
CH2N2
R
OMe
OH
OMe
Proton must be acidic
enough to pick by CH2N2
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 22 Functional Group Transformations
Ways to Make Esters
RCO2H
RCO2H
+
+
R'-I
R'OH
base
RCO2R'
DCC
RCO2R'
N C N
N,N'-Dicyclohexylcarbodiimide (DCC)
N C N
H
R
H
N C N
RCO2R'
O
+
R
O
O
H
O R'
O
O
N
H
N
H
Dicyclohexyl urea
Sometimes its difficult to separate product from DCU,
in that case, use EDCI instead of DCC
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 23 Functional Group Transformations
Ways to Make Esters
Baeyer-Villiger Oxidation
Favorskii Rearrangement
O
O
NaOEt/EtOH
O
mCPBA
CO2Et
Br
O
Mitsunobu Reaction
RCO2H
Ph3P
EtO2C
N N
CO2Et
+
DEAD, PPh3
R'OH
RCO2R'
R
Ph3P
EtO2C
N N
CO2Et
H
Ph3P
N N
H
EtO2C
O
O
H
O
R
CO2Et
+ RCO2
R O PPh3
CO2Et
H
O PPh3 +
N N
H
EtO2C
O
+
RCO2R'
R
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 24 Functional Group Transformations
Mitsunobu Reaction
iPr,
R=
DIAD
N N
Diisopropyl azodicarboxylate RO2C
OH
R
R1
CO2R
O
R2CO
2H
PPh3, DIAD
R
PPh3
DEAD
OH
R2
O
R = Et, DEAD
Diethyl azodicarboxylate
R
R1
R
R1
OH
R1
O
OPh
O
?
O
O
O
OBn
O
OBn
H+, H2O
O
PPh3, DEAD
BnO
HO
HO
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 25 Functional Group Transformations
Mitsunobu Reaction
Nitrogen Nucleophile:
H3C
OH
OBn
N
Ts
OBn
PPh3, DEAD
TsNHCH3
OH
O
O
PPh3
HN
DEAD
N
Weak Nitrogen Nucleophile:
O
BnO
BnO
OH
OBn
N
N
R
PPh3, DEAD
R
O
BnO
BnO
N
OBn
N
H
Intramolecular Mitsunobu Reaction:
HO
Ph
HN
CO2Et
CO2Et
PPh3
DEAD
Ph
N
CO2Et
CO2Et
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 26 Functional Group Transformations
Mitsunobu Reaction
Azides:
HN3
ROH + PPh3 + DEAD
O
(PhO)2P N3
RN3
H H
RO PPh3 + EtO2C N N CO2Et
Can be used instead of HN3
O
PhO P OPh
O
ROH + (PhO)2P N3 + PPh3 + DEAD
RN3 + Ph3PO
EtO2C N N CO2Et
H
O
(PhO)2P N3
EtO2C N N CO2Et
PPh3
O
O
PhO P OPh
PhO P OPh
EtO2C N N CO2Et
R O PPh3 + EtO2C N N CO2Et
H
PPh3
R OH
N N N
R N3 + PhP O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 27 Functional Group Transformations
Alcohols
Reduction:
RCHO
RCO2R
RCO2H
NaBH4
LiAlH4
LiAlH4
BH3
NaOH, H2O2
R
HCHO
Primary alcohols
RMgX
OH
R
RCH2OH
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 28 Functional Group Transformations
Alcohols
O
reduction
R'
R
RMgX
RCHO
Secondary Alcohols
Oxymercuration
R
RMgX
HCO2R
symmetrical 2o alcohol
formate ester
O
R
RMgX
R'
Oxymercuration
R
RCO2R
Tertiary Alcohols
RMgX
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 29 Functional Group Transformations
Activation of Hydroxyl Group
Alcohols are important class of compounds but they are not good
leaving group
−OH is not a reactive alkylating agent. Reactivity can be enhanced
by converting into a better leaving group like sulfonate esters or
halides
Preparation of Sulfonate Esters:
ROH
ROH
ROH
ROH
ROH
R OTs
Pyridine, Mscl
Pyridine, Tscl
Pyridine, Brcl
Pyridine, Nscl
Pyridine, Tf2O
NaBr
Acetone
R OMs
Mesylate
R OTs
Tosylate
R OBs
Brosylate
R ONs
Nosylate
R OTf
Triflate
R Br
Most reactive
Finkelstein reaction
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 30 Functional Group Transformations
Activation of Hydroxyl Group
Alkyl halides are involved in the formation of C−C bond by
nucleophilic substitution
Preparation of Alkyl Halides:
Reaction with SOCl2
O
O
R O
H
Cl
S
R
Cl
O
S
Cl
Cl
R Cl +
SO2 +
Cl
Inversion of configuration
But, if reaction is taking place in solvent like 1,4-dioxane
O
R
O
O
S
Cl
O
O R
Cl
R Cl
Retention of configuration
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 31 Functional Group Transformations
Activation of Hydroxyl Group
Reaction with Phosphorous Halides
R
Cl
O
H
Cl
P
RO
- HCl Cl
P
Cl
2ROH
RO
P
OR
OR
Cl
The reaction will stop at this stage if it is carried out in presence of
an amine
When amine is not present
RO
P
OR
OR
R O
H+
P
R Cl +
H
OR
Cl
O
O
O
O
OR
H P OH + 2RCl
H P OR
OR
Inversion of configuration
?
OH
O
O
OH
Br
Drawbacks:
Not suitable for acid sensitive compounds
Amines can not be used
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 32 Functional Group Transformations
Activation of Hydroxyl Group
Reaction with Alkoxyphosphonium Salts
Br
Ph3P
Br + Ph3P Br
Br
- HBr
R O PPh3
R Br
O PPh3
Br
R O
H
Formation of strong phosphoryl double bond is the driving force
Ph3P
Br2
Br
HO
Br
R OH
+
PPh3
+ Br
Br
O
R Br
Br
Bromide source
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 33 Functional Group Transformations
Activation of Hydroxyl Group
PPh3/ CCl4
Cl
Ph3P
Cl
CCl3 +
C Cl
Ph3P Cl
Cl
Cl
R O PPh3
R O
H
CCl3
R Cl
Hexachloroacetone
can be used as
chloride source
PPh3
R OH
R Cl
O
Cl3C C CCl3
PPh3/ I2/ Imidazole
N
PPh3
Ph3P
I
N
H
I
I2
Ph3P
R
R OH
I
-HI
Imidazole
HO R
R
O
I
PPh3
I
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan R
I
34 Functional Group Transformations
Activation of Hydroxyl Group
Reaction with 2-Halo-3-alkylbenzoxazolium Cation
Cl
Addition
N
Cl
HO R
N
O
O
Elimination
O
R
N
R Cl
O
O
Mitsunobu Reaction
R
Ph3P
CO2Et
Ph3P
Me
I
H
I
R
I
H
CO2Et
N N
Me
EtO2C
N N
EtO2C
O
R O PPh3
+
I
CO2Et
N N
Me
EtO2C
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 35 Functional Group Transformations
Activation of Hydroxyl Group
Mild Method
OH
MsCl
OMs
Cl
LiCl
MsOLi
Py
Some Other Methods
HBr
HBr
Br
O
O
Br
HBr
Br
O
O
Br
Br
HO
H
Br
Br
HBr
Br
H2O
Br
Br
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 36 Functional Group Transformations
Nitriles
RCONH2
De
RCH2NH2
hy
dra
t
H -C
LA Pd
/
2
+
H
O
H3
ion
N
R
OH
Abnormal
Beckmann
Rearrangement
RCO2H
R'MgBr
R CN
DIB
A
AL
-H
y
lk
RCHO
n
io
t
la
RX + NaCN RCOR'
R'
R'
CN
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 37 Functional Group Transformations
Preparation of Nitriles
R X
NaCN
O
R CN
Reaction proceed faster in polar
aprotic solvents
N
NH2
R CN
OH
p-TsCl, Py
R
H
aldoxime
HO
R
P2O5
R CN
AcCl, Py
H2O
N
Beckmann rearrangenment can also
occur
N
N
H+
H2O
H
N
O
NC
H+
N OH
-H+
N OH2
N
tertiary
carbocation
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 38 Functional Group Transformations
Preparation of Nitriles
18-Crown-6
RCH2CN
RCH2Br + KCN
R CHO
CH3CN
83oC
OH
KCN
H+
R
CN
stable under mild acidic condition
unstable under basic condition
OH-
R CHO +
CN-
OTMS
TMSCN
R CHO
ZnBr2
R
CN
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 39 Functional Group Transformations
Utility of Nitriles
R CN
LAH
or
H/Pd-C
R CH2
NH2
partial
hydrolysis
R CN
O
R
R CN
H3O+
Reflux
NH2
R CO2H
O
SnCl2/HCl
R CN
DIBAL-H
R
H
Stephen reaction
R
R
CN
CN
R'MgBr
H+/H2O
O
R'
LDA
R'I
R'
R
R
CN
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 40 Functional Group Transformations
Azides
3,
DM
RNH2
SO
Pd
-C
NaN
3,
PTC
H
R'CH2Br
N
2/
Na
R'CH2Br
PPh3, H2O
R N3
r
la n
po tio
Di di
3- d
1, loa
c
cy
F
N
AD
DE
h
3,
HN
3
N3
PP
ROH
RNH2
R N
N N
ROH
O
ROH
N3 P(OPh)2
DBU
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 41 Functional Group Transformations
Preparation of Azides
R X
NaN3, DMF
R N3
At room temperature & phase transfer condition:
NaN3
RCH2N3
RCH2Br
TBAB
25oC
From alcohols:
RN3 +
N
Me
F
N
HO R
O R
Me
N
N3
O
Me
Mitsunobu Reaction
R OH
R OH
PPh3, DEAD
HN3
O
(PhO)2 P N3
DBU
R N3
N
DBU
N
R N3
1,8-Diazabicycloundec-7-ene CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 42 Functional Group Transformations
Utility of Azides
H2/Pd-C
R N3
R N3
PPh3, H2O
R NH2
R NH2
N2
Ph3P O
Staudinger Reaction
R N N N
R N N N
-N2
R N PPh3
H2O
R NH2
PPh3
PPh3
R N PPh3
N
R N N N
PPh3
R N N N PPh3
R
R NH2
H2O
R N PPh3
N
N
PPh3
R N PPh3
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 43 Functional Group Transformations
Amines
Preparation of Amines
With same number of carbon atom
RCH2NH2
RCN
N
R
RNH2
RN3
RNH2
RNO2
R
N
OH
R
NH2
O
OH
NH2
R
R'
R
R'
N
R'
N
R
R'
R"
R"
Gabriel amine synthesis
N
O
O
O
O
K
+
R X
N R
NH2NH2
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan NH
NH
+
RNH2
O
44 Functional Group Transformations
Preparation of Amines
With One Carbon Atom More
R X
R X
R CHO
+
R CN
CN
CH3NO2
R CH2NO2
Base
CH3NO2
Base
R
NO2
reduction
reduction
reduction
R CH2NH2
R CH2NH2
R
NH2
With One Carbon Atom Less
O
O
R
NH2
R NH2
R
Hoffmann Rearrangement
N3
O
R NH2
R
Curtius Rearrangement
R NH2
Lossen Rearrangement
O
R
N OH
H
OH
R NH2
Schmidt Rearrangement
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 45 Functional Group Transformations
Reduction:
R NO2
R CN
R N3
N
R
Preparation of Amines
R NH2
H2/ Pd-C
LAH
Zn/ HCl
RH2C NH2
H2/ Pd-C
BH3
NaBH4
LAH
Li/ NH3 R NH2
H2/ Pd-C
B 2H 6
NaBH4
PPh3, H2O
OH
R'
H2/ Pd-C
LAH
Raney Ni
NH2
R
R'
R
N
Can be achieved by using either
one of the reagents
O
R
N
R"
R'
R"
R'
H2/ Pd-C
B 2H 6
LAH
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 46 Functional Group Transformations
How to Get Secondary and Tertiary Amine ?
reduction
R NC
R
O
R''NH2
O
R''
R
N
Schiff base
O
R'
R
NaBH4
R
N
H
R'
R'
R
R'
R
N
Schiff base
R'NH2
Reaction is not facile
R NH
CH3
N
H
R'
Secondary amine R'
NaBH4
R
N
H
R''
R''
R
N
R'
R''
NaCNBH3
R
N
R''
R'
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan One pot
47 Functional Group Transformations
Synthetic Utility of Amines
R NH2
Ar
NaNO2
HCl
R N2
Ar X
X= Br, CN, I
N2
CN
CN
R NH2
Sandmeyer reaction
R N
CN
R NH2
R'CHO
R'
RN
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 48 Functional Group Transformations
Amides
Preparation of Amides
Reaction of an Activated Acid or Acid Derivative with Amine:
O
R
OH
+ R'
O
DCC
NH2
O
R
R
+ R'
HN
O
N3
NH2
R'
N
R
Me
R
N
H
O
OMe
Me
Weinreb amide
O
P(OPh)2
R
OMe
O
O
R
+
Cl
R'
O
Cl
O
N
H
R
O
O
O
P(OPh)2
R
O
R'NH2
N3
R
NHR'
N3
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 49 Functional Group Transformations
Preparation of Amides
Schimdt type Rearrangement:
O
R
O
HN3
R'
R
NHR'
Reaction with N-hydroxysuccinimide:
O
R
O
O
O
O
O
O N
HO N
OH
R
R
O
R'
NH2
HO N
NHR'
O
O
1-Hydroxybenzotriazole:
Boc
H
N
O
COOH
H2N
CO2Me
Ph
NH
DCC
N
N
HN
Boc
N
OH
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan CO2Me
Ph
50 Functional Group Transformations
Preparation of Amides
Alkaline Hydroperoxide:
R CN
H
O O
O
H2O2, NaOH
R
NH2
O
R
O
OH
H
NH
R C N
H
O O
O
O
O
H2O2
H
R
NH2
O2 + H2O
H
O
O
O
CH2N2
Bayer-Villiger
Oxidation
HN3
NH
or
Beckmann
rearrangement
O
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 51 Functional Group Transformations
Preparation of Amides
O
H
H
N N N
O
O
H
N N2
NH
-N2
HN3
N3
O
Beckmann Rearrangement:
N
R
OH
O
PCl5
R'
R'
NHR
Interconversion of Carboxylic Acid Derivatives
RCOOR
RCONH2
RCOOH
RCOCl
Synthetic Utilities of Amides
O
O
N
R
PPh3, DEAD
O
NH
NaH, MeI
N
Me
ROH
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 52 Functional Group Transformations
Synthetic Utilities of Amides
O
Al
OMe
DIBAL-H
N
Me
R
R
O
R
O
R
H
O Me
N
Me
O
OMe
N
Me
R'MgBr
R'
MgBr
N O
Me
O
H2O
R
O
H+, H2O
O
N
HN
O
OH
HN
R'
R
O
Br
H
O
PPh3, DEAD
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan N
53 Functional Group Transformations
Ethers
Preparation:
H+
R OH
Ar OH
CH2N2
OH
R OR
R OH
Ar OMe
Ar OH
OH
NaH, R'I
NaOH
Me2SO4
R OR'
Ar OMe
O
PPh3, DEAD
Basic condition
R OH
COCH3
OH
HO
NaH
BnBr
R OBn
COCH3
MeI
K2CO3
OH
MeO
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 54 Functional Group Transformations
Preparation of Ethers
Acidic Condition
NH
R OH
Cl3C CN
Cl3C
OBn
R OBn
CSA
NH
BnOH, DBU
Cl3C
OBn
O
SO3H
Camphor sulphonic acid
CSA
NH2
Cl3C
Bn
NH2
O
Cl3C
O
NH2
+
R OBn
Cl3C
O Bn
trichloro acetamide
R
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan O
H
55 Functional Group Transformations
Cleavage of C-O Bonds in Ethers & Esters
Nu
R O CH3
O
Nu
R C O CH3
R O R
BBr3
R OH
H3C Nu
R O
O
H3C Nu
R C O
R Br
B(OH)3
2 HBr
Mechanism in next slide
R O R
TMS-I
I
R O R
R O
SiMe3
O
R C O R'
TMS-I
O
I
SiMe3
SiMe3
R C O R'
R
I
O
R C O SiMe3
R'
I
H2O
O
R C OH
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 56 Functional Group Transformations
Synthetic Utility of Ethers
R OR
HX
O
ROH
Me
+
RX
mix of products
OH
HBr
CH3Br
+
H
O
Me
Br
Br
O
Me
BBr3
Br
B
O
Br
BBr2
O
Me
OH
Me
MeBr
Br
O
Me
TMSI
OH
TMSCl, NaI
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 57 Functional Group Transformations
Interconversion of Carboxylic Acid Derivatives
O
R C O CH3
O
SOCl2
R C OH
O
R C Cl
O
OH
R'2NH
H3C OH
R C O
O
SO2
R C Cl
HCl
O
HCl
R C NR'2
O
O
Cl C C Cl
O
R C OH
O
O
R
- Cl
O
C
C
O
Cl
Cl
O
R C Cl
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 58 Functional Group Transformations
Iodolactonization:
O
Epoxylactonization:
O
O
KI3
HO
HO
O
O
NaHCO3
I
CH2CO2H
I2
I
NaH
HO
O
NaHCO3
O
PhSe N
O
O
OH
Selenoetherification:
HO
O
OH
O
O
Mild
base
Selenolactonization:
O
O
HO
SePh
O
PhSeCl
O
Base
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan SePh
59 Functional Group Transformations
I
OH
CO2H
O
O
O
HO
O
O
CO2Me
CO2Me
OMe
MeO
NaOMe
I
O
O
O
O
MeO
CO2Me
OH
OMe
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 60