Download 6. Functional Group Interconversion

Dr. Pere Romea
Department of Organic Chemistry
Sky and Water I
Maurits Cornelis Escher, 1938
6. Functional Group Interconversion
Organic Synthesis
2014-2015
Autumn Term
Carbon Backbone & Functional Groups
The synthesis of an organic compound must pay attention to ...
Carbon backbone
Functional groups
(Chapters 2–4 )
Functional Group Interconversion (FGI)
I. Nucleophilic Substitutions
Electrophilic Additions to C=C
Addition-Eliminations on Carboxylic Acids and Derivatives
II. Reductions
Mechanism!!!
Pere Romea, 2014
III. Oxidations
2
Nucleophilic Substitutions
The nucleophilic substitutions involve
the interconversion of functional groups bound to sp3 carbonis
X
+
Nu
Nu
+
X
Csp3
RX
Electrophile
Pere Romea, 2014
Leaving group
Nucleophile
3
Chap. 15
Nucleophilic Substitutions
Two model mechanisms, called SN1 i SN2,
are used to explain the nucleophilic substitutions
X
+
Nu
Nu
+
X
Unimolecular (SN1) or bimolecular (SN2)
nucleophilic substitution?
A slightly different model, called SN2’,
may be useful in substitutions on allylic substrates
X
+
Nu
Nu
4
+
X
Pere Romea, 2014
Nucleophilic Substitutions and FGI
There are three main sources to carry out FGI
through nucleophilic substitutions: sulfonates, alcohols, and alkyl halides
Sulfonates
Alcohols
Alkyl halides
X: I, Br, Cl
Nu
R–OSO2R’
Nu
R–OH
Nu
R–X
5
R–Nu
R–Nu
R–Nu
Pere Romea, 2014
Nucleophilic Substitutions and FGI
A wide array of structures can be synthesized from sulfonates and alkyl halides through
nucleophilic substitution of X = OSO2R, I, Br, Cl in C–C bond forming reactions and FGI
R Y
R
R
R OH
R
R
Y
N
H 2O
or OH
R OR
ROH
or RO
CN
R X
O
N3
O
R N3
NH3
RSH
or RS
R NH 2
Pere Romea, 2014
O
R
H 2S
or HS
R
O
R
R SH
R SR
6
Nucleophilic Substitutions and FGI
How easy is to interconvert sulfonates, alcohols, and alkyl halides?
Sulfonates
Alcohols
Alkyl halides
X: I, Br, Cl
Nu
R–OSO2R’
Nu
R–OH
Nu
R–X
7
R–Nu
R–Nu
R–Nu
Pere Romea, 2014
Alcohols and Sulfonic Esters
Conversion of alcohols into sulfonic esters
OH
+
pyridine
RSO2Cl or (RSO 2 )2O
CH 2Cl 2 or Et2O
0 °C – rt
Mesyl chloride MsCl
MeSO2Cl
Tosyl chloride TsCl p-MePhSO2Cl
Triflic Anhidride Tf2O (CF3SO2)2O
OSO 2R
Mesylate
Tosylate
Triflate
– Primary and secondary ROH OK, but the reaction is sensitive to steric hindrance
OH
H
Me
Me
TsCl, pyr
Me
Me
– The reaction does not affect the C–O bond: the configuration of the carbon remains the same
– Mesylates and tosylates are largely employed.Triflates are the most reactive sulfonates
– Rearrangements of the carbon backbone are not frequent
8
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Sulfonic Esters and Alkyl Halides
Conversion of sulfonate into alkyl halides
X
OH
OH
X
SN2
X: Cl, Br, I
1) MsCl, Et3N, CH2Cl2
Cl
2) LiCl, DMF
Pr
Pr
83%
Ph
OH
Ph
TBDPSO
1) TsCl, pyr, CH2Cl2
2) LiBr, DMF
89%
OH
1) MsCl, Et 3N, CH 2Cl 2
2) Lil, acetone
Ph
Br
Ph
TBDPSO
I
94%
9
Pere Romea, 2014
Alcohols and Alkyl Halides
Conversion of alcohols into alkyl halides
Sulfonates
R–OSO2R’
R’SO2Cl
Alcohols
X–
R–OH
?
Alkyl halides
X: I, Br, Cl
R–X
10
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Alcohols and Alkyl Halides
Conversion of alcohols into alkyl halides
X
OH
X: Cl, Br, I
Reagents & Conditions
Alcohols
Mechanism
HCl conc
Tert
SN1 (racemization)
HCl/ZnCl2 (Lucas reagent)
PCl3
SOCl 2 ,1,4-dioxane
SOCl 2 , non nucleophilic solvent
Prim & Sec
Prim & Sec
Prim & Sec
Prim & Sec
SN2 (inversion)
SN2 (inversion)
SN2 + SN2 (retention)
SN2 (inversion)
HBr conc
Tert
SN1 (racemization)
HBr conc, ∆
PBr3
Prim
Prim & Sec
S N2
SN2 (inversion)
P/I2
Prim & Sec
SN2 (inversion)
11
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Alcohols and Alkyl Halides
Problem! Too harsh experimental conditions: mixture of mechanisms and transpositions
Br
H
OH
OH
OH2
SN2
Br
single
OH2
H
Br
Br
SN1
Br
86%
Br
14%
Cl
OH
H
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Cl
OH2
12
single
Alcohols and Alkyl Halides
More selective transformations are required …
The most used options are based on the conversion of alcohols into alkoxyphosphonium salts,
highly reactive in SN2 substitutions
Ph3P + E–Nu
Ph3P
E
Ph3P
E
Nu
Ph3P O
HO
+
Ph3P
H
E
+
+ Nu
HE
H
Alkoxyphosphonium salt
Ph3P O
+
Nu
Ph3P=O
H
Nu
+
H
Alkoxyphosphonium salt
13
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Alcohols and Alkyl Halides
Ph3P / X2 : Ph3P / I2, Ph3P / Br2, Ph3P / Cl2
Ph3P + Br–Br
Ph3P
Ph3P
– HBr
Br + HO
H
Br
– Br
Br
+ Br
Ph3P O
Ph3P
Br
– Ph3P=O
H
Br
H
Br
SN2
This transformation is very useful for secondary alcohols and those systems that easily produce transpositions, as neopentylic alcohols
The control on the configuration is very good.
Br
+
11%
Br
+
PBr3
Br
26%
90%
OMe
O
R
O
OH
OH
R
O
Br
85%
Br
63%
Ph3P, Br2
O
OH
Ph3P/Br2
14 OBn
OMe
Ph 3P, I 2
I
Imidazole
Et 2O, rt
96%
OBn
Alcohols and Alkyl Halides
Since chlorine (Cl2) is a gas difficult to handle ....
HO
Ph3P + Cl–CCl3
– CCl3
H
Ph3P Cl
– HCl
– Ph3P=O
Ph3P O
H
carbon tetrachloride
O
Ph3P + Cl
OH
H
O
Cl
CCl3
Cl Cl
hexachloroacetone
CCl3
Cl
OH
Ph3P/Cl2
Cl
Cl
Cl
Ph3P/CCl4
Cl
70%
92%
Ph3P/CCl3COCCl3
OH
Cl
99%
15
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Nucleophilic Substitutions and FGI
Sulfonates
Alcohols
Alkyl halides
X: I, Br, Cl
Nu
R–OSO2R’
Nu
R–OH
Nu
R–X
16
R–Nu
R–Nu
R–Nu
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Carbon Nucleophiles
O
R
NH2
Amine 1
R
O
OH
R
Carboxylic Acid
Red
LiAlH4
O
H
Aldehyde
Hydrolisis
H3O+
Me
Methyl ketone
Hydration
cat Hg2+, H2O
Red
DIBALH
R CN
R C CH
+C
Attention!
Alkyl halides are very useful for
the construction of C–C bonds
R
+2C
R X
17
R OH
Pere Romea, 2014
Nitrogen Nucleophiles: Primary Amines
The alkylation of ammonia, NH3, is not easy ...
R X
NH3
R NH2
R2 NH
R3 N
R NH3 X
R X
R2 NH2 X
R X
R3 NH X
R X
R4 N X
– HX
+ HX
– HX
R2 NH
+ HX
– HX
+ HX
Primary Amine
R NH2
R3 N
Secondary Amine
Tertiary Amine
Ammonium Salt
Such an alkylation only becomes efficient when the resulting amine is much less nucleophile than the initial one,
for steric or electronic reasons
CO2Et
H2N
CO2Et
1) RCH2Cl
2) NaHCO3
R: C15H31
CO2Et
1) Br
NH
R
N
H
18
2) NaHCO3
CO2Et
N
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Nitrogen Nucleophiles: Primary Amines
Potassium phthalimide, PhthNK
O
O
Br
N
K
Ph
Ph
NaOH
N
H2N
95%
SN2
O
Ph
O
Gabriel synthesis of amines
Potassium phthalimide, pKa 8.3
Azide, N3–
The azide anion is an excellent nucleophile that participates in a large number of SN2 processes
The reduction of the azide group affords a primary amine
I
Bu
NaN3
DMSO, Δ
Bu
N3
Bu
NH2
90%
O
O
OTBDPS
OH
O
1) MsCl, Et3N
2) NaN3, DMF
85%
O
OTBDPS
N3
19
Nitrogen Nucleophiles: Primary Amines
Mitsunobu conditions: Ph3P / DEAD / HN3 or DPPA [(PhO)2PON3]
Ph3P, EtO2C N N CO2Et
OH
H
Ph3P
N N
CO2Et
Ph3P
EtO2C
Ph3P
OH
H
N N
N3
+
EtO2C
N N
CO2Et
H
N3
H
H
N N
CO2Et
EtO2C
CO2Et
O PPh3
H
EtO2C
(PhO)2PO
N3
HN3 o (PhO)2PON3,
(PhO)2
O
P
DPPA
N3
N N
EtO2C
O PPh3
N N
EtO2C
CO2Et
H
H
HN3
N N
H
EtO2C
N3
20
+
+
H
CO2Et
CO2Et
+
H
N3
O=PPh3
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Nitrogen Nucleophiles
Reduction
LiAlH4, H2 cat, Ph3P/H2O
O
R
N
R1
H
Amide
R
NH2
R
Amine 1
Mitsunobu
Ph3P/DEAD/ HN3 or DPPA
SN2
N3–
R
O
X
OSO2R'
O
Ph3P, DEAD, HN3
OH
O
97%
O
N
Bn
O
CH2Cl2, 0 °C
Bn
O
R
O
N
OH
Azide
SN2
Phthalimide
O
R
N3
O
N
N3
Bn
O
N
H
Ph
1) H2, Pd/C, THF/MeOH/TFA, ta
2) PhCOCl, Et3N, CH2Cl2, 0 °C
97%
21
Oxygen Nucleophiles: Alcohols
The most simple nucleophile: H2O / OH–
H2O, OH–
X
OH
X: Cl, Br, I
This is a rare transformation in which...
... tertiary halides, R3C–X, react with H2O (solvolysis) through SN1 and
... the secondary and primary ones, R2CH–X i RCH2–X, with OH–/H2O through SN2
In both situations E1 and E2 eliminations are competing reactions
No eliminations can occur at this benzylic position
Me
NC
Cl
OH
Cl2
K2CO3
hν
H2O
Radical chlorination
NC
85%
22
NC
Pere Romea, 2014
Oxygen Nucleophiles: Ethers
Alkoxydes, RO–: Williamson Synthesis
RO –
X
H
SN2
RO
H
X: Cl, Br, I
Only on 1ary substrates to avoid E2 eliminations
... and the most successful deconnections are applied to activated systems
Ar
O
+ XCH2R2
R1
NO2
NO2
OH
BuBr, K2CO3
H2O
80%
OBu
O
R2
R1
O
+ MeX o BnX
O
O
O
O
H
HO
23
O
O
1) NaH, THF
2) BnCl, Δ
95%
O
O
H
BnO
O
O
Pere Romea, 2014
Oxygen Nucleophiles: Esters
Carboxilates, RCO2–
RCO2–
X
H
RCO2
X: Cl, Br, I, OSO2R
SN2
H
They are usually applied to 1ary substrates to avoid E2 eliminations
O
OK
+
O
18-crown-6
Br
O
O
95%
Br
O
Br
why KF?
O
O
O
CO2H
O
O
MeI, KF
DMF
O
O
O
CO2Me
O
O
84%
24
Attention: interconversion of carboxílic acids and derivatives
Oxygen Nucleophiles: Esters
Mitsunobu conditions: Ph3P / DEAD / RCO2H
Ph3P, EtO2C N N CO2Et
OH
H
Ph3P
N N
CO2Et
Ph3P
EtO2C
OH
Ph3P
H
N N
CO2Et
N N
EtO2C
H
N N
EtO2C
OH
Pere Romea, 2014
N N
SN2
H
CO2Et
EtO2C
EtO2C
O
RCO2
RCOOH
CO2Me
CO2Et
+
O PPh3
H
H
RCO2H
CO2Et
RCO2
H
Ph3P, DEAD
PhCO2H
89%
RCO2
H
PhCO2
O
CO2Me
25
Oxygen Nucleophiles
Configuration inversion
SN2
RCO2–
OH
H
H
Hidrolysis
OH–
OSO2R'
RCO2
Mitsunobu
Ph3P/DEAD/RCO2H
OH
H
H
Hidrolysis
OH–
RCO2
H
HO
HO
H
H
O
OH
O
Ph
Ph 3P, DEAD
OH
Ph
O2N
p-O2NPhCO 2H
KOH
Ph
MeOH
99% overall
26
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Phosphorus Nucleophiles: in Route to Wittig Reactions
Phosphines are excellent nucleophiles because
they are less basic than amines and the phosphorus atom is very polarizable.
Moreover, E2 reactions do not compete with SN2 because they are weak bases
R1CH
2–X
R1CH
+ PR3
phosphine
B
2–PR3
X
phosphonium salt
Ph3P +
OEt
Ph3P
R1CH PR3
phosphorus ylide
Attention: Wittig reaction
O
O
Br
R1CH–PR3
NaOH
OEt
O
Ph3P
OEt
Br
Ph3P +
Br
OPh
Ph3P
BuLi
OPh
Ph3P
OPh
Br
27
Attention: no E2 occurs
Ph3P
OPh
Phosphorus Nucleophiles: in Route to Wittig Reactions
Phosphites are also good nucleophiles and react with alkyl halides:
Michaelis-Arbuzov reaction
RR
(R2CHO)3P
+
R1–X
H
R1 OCHR2
P
O
OCHR2
O
(R2CHO)2
X
alkyltrialkoxyphosphonium halide
phosphite
P
R1
alkylphosphonate
Attention:
Horner-Wadsworth-Emmons reaction
O
(EtO)3P +
Br
Δ
OEt
O
(EtO)2P
EtBr
O
EtO
OEt
O
(EtO)2P
O
O
O
OEt
(EtO)2P
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28
O
(EtO)2P
OEt
O
OEt
Sulfur Nucleophiles: Thiols
The easiest option is troublesome ...
R
R–X + HS
–H
SH
R
R–X
S
R
S
R
+H
S
thiourea
H2N
NH2
NH2
H
X
S
NH2
O
H
H
thioacetate
1) Thiourea
C10H 21
2) NaOH
HS
H
O
S
Br
NaOH
SH
NaOH
S
or LiAlH4
AcSCs
Br
C10H 21
i-Pr
80%
29
H
DMF
84%
H
i-Pr
SAc
Pere Romea, 2014
Sulfur Nucleophiles: Thioethers
Thiolates are the best option since they are excellent nucleophiles ...
R1 S
R1–SH + OH
SH
NaOH
X–R2
R1 S
Br
S
R2
S
95%
O
Me
HO
N
OMe
O
MsCl, Et3N
CH2Cl2
100%
BnSH, K2CO3
Me
MsO
O
N
OMe
CH3CN
80%
Me
BnS
N
OMe
Weinreb Amide
O
EtMgBr
BnS
30
Pere Romea, 2014
Carbon Backbone & Functional Groups
The synthesis of an organic compound must pay attention to ...
Carbon backbone
Functional groups
(Chapters 2–4 )
Functional Group Interconversion (FGI)
I. Nucleophilic Substitutions
Chap. 19
Electrophilic Additions to C=C
Addition-Eliminations on Carboxylic Acids and Derivatives
II. Reductions
Mechanism!!!
Pere Romea, 2014
III. Oxidations
31
Hydroboration of C=C
Borane, BH3, as a reacting species
Lewis Base
H
H
H
B
B
H
R
H
2 H B H
H
H
X
R
Lewis Acid
C
C
BH3
C
δ− δ+
H
H B H
C
C C
δ+ δ−
π
HOMO
R
X
H B H
H
H3B· SMe2
H3B· OEt2 H3B· THF
LUMO
H B H
H
R
BH2
H
C
C
syn Addition
Cyclic transition state
4 centers, 4 electrons
The regiochemistry for the addition of BH3 to an olefin is controlled by steric as well as electronic factors:
the boron atom binds to the less substituted carbon atom
32
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Hydroboration of C=C
Additions of BH3 to olefins produce boranes
R
BH3
BH2
R
R
R
Alkylborane
H
B
R
R
R
R
Dialkylborane
B
R
Trialkylborane
– The appropriate choice permits to obtain a wide array of alkylboranes
3
+
BH3
2
+
BH3
+
BH3
B
Sia2BH
B
H
BH2
ThxBH2
H
+
Pere Romea, 2014
BH3
B
9-BBN
33
Hydroboration of C=C
– Steric effects rule the reactivity
H
R
H
R
>
H
H
R
H
H
>
H
H
R
>
R
R
R
R
>
R
R
R
H
>
R
R
H
H
... the regioselectivity,
BH3
94
80
Sia2BH
99
98
9-BBN
99.9
98.5
... and the stereoselectivity
99
57
97
99.5
R2BH
99.8
H
BR2
+
H
BR2
34
% atack B
to the less
substituted
carbon atom
BH3
72
28
9-BBN
97
3
Hydroboration of C=C
Protonolysis: synthesis of alkanes
R
BH3
RCO2H
R
B
3 R
H
Δ
3
Trialkylborane
Alkane
Conversion of trialkylboranes into alcohols: H2O2/NaOAc, ...
R
HO O
R
B
R
R
B R
O
R
HO
– HO
RO
R
B
R
RO
HO
OR
–
BO33
3 ROH
Borate
– The migration does not
produce the inversion of the configuration
Hidrolysis
H
1) B2H6
2) H2O2, OH–
35
OR
B
85%
OH
It looks like
an anti-Markovnikov hydration
with a syn stereochemistry
Pere Romea, 2014
Hydroboration of C=C
Hidroboration of alkynes
R1
R2
L2B H
L2B
R1
H
RCO2H
H
H
Δ
R1
R2
H2O2, OH–
HO
R2
R1
H
O
R2
R1
(HO)2B
H2O
R1
1)
Alquè Z
R2
H
R2
Vinilboronic acid
O
B H
O
OH
B
OH
2) H2O
Br
Pd(0) cat
75%
Suzuki Coupling
36
Pere Romea, 2014
Dr. Pere Romea
Department of Organic Chemistry
The moneychanger and his wife
Marinus Claesz van Reymerswaele, 1539
6. Functional Group Interconversion
Organic Synthesis
2014-2015
Autumn Term
Carboxylic Acids and Derivatives
Carboxylic acids
Derivatives of carboxylic acids
O
O
R1
R1
OH
O
R1
O
Cl
R1
O
O
O
R2
R1
O
R1
N3
O
SR2
R1
L
O
OR2
R1
N
R2
R3
Acid chloride
Anhydride
Acyl azide
Thioester
Ester
Amide
Nitrile
R1 C N
All these FG participate in reactions that can be understood using
the addition-elimination mechanism
2
Pere Romea, 2014
Addition-Elimination Mechanism
Addition-elimination mechanism
Addition
O
Trigonal Planar
R1
Nu
L
Elimination
Nu O
R1
L
Tetrahedral
O
R1
Nu
+
L
Trigonal Planar
The requirements for a smooth process are …
a) RCOL must be a good electrophile,
b) Nu must be a good nucleophile,
c) L must be a better leaving group than Nu
Remember: “The lower the pKa (HL), the better the leaving group”
If the system is not reactive enough, it must be activated ...
3
Pere Romea, 2014
Addition-Elimination Mechanism
Activation with a Lewis Acid, LA, ...
O
R1
O
LA
R1
L
Activation
LA
LA
HNu O
R1
L
Nu O
R1
L
LA
–LH
R1
LH
Addition
NuH
LA
O
O
–LA
R1
Nu
Nu
Elimination
Remember: Fischer esterification
Activation with a Lewis Base, B, ...
O
R1
B
O
–L
R1
L
Activation
NuH
Nu O
R1
B
Addition
O
–B
R1
B
Nu
Elimination
Remember: synthesis of esters by addition of alcohols to acid chlorides in the presence of DMAP
4
Pere Romea, 2014
Addition-Elimination Processes
O
R1
H2O
Cl
Very easy
Chap. 16
R2CO2–
R2CO2–
O
R1
O
O
Chap. 10
H2O
R2
O
Easy
R1
R2OH
O
R2OH
R1
OH
H2O
OR2
Moderate
R2R3NH
O
R2R3NH
R1
5
N
R3
R2
H2O
Difficult
Pere Romea, 2014
Addition-Elimination Processes
?
O
R1
Cl
Chap. 16
R2CO2–
R2CO2–
O
R1
?
O
O
Chap. 10
R2
O
R1
R2OH
?
O
R2OH
R1
OH
OR2
R2R3NH
O
R2R3NH
R1
6
N
R3
R2
?
Pere Romea, 2014
Acid Chlorides from Carboxylic Acids
Via SOCl2 o PCl5
O
O
O
SOCl2
OH
O
PCl5
OH
Cl
85%
93%
O2N
Cl
O 2N
Via (COCl)2
Useful for systems sensitive to acid media.
It is usually used with the sodium salt (neutral media) or with catalytic amounts of DMF.
O
N
Bn
N
HO
O
O
O
(COCl)2
CO2Na
83%
7
N
Bn
N
HO
O
O
COCl
Pere Romea, 2014
Anhydrides from Carboxylic Acids
Regioselectivity in the nucleophilic attacks to anhydrides
O
Regioselectivity
is not a problem for
the symmetric anhydrides
R1
O
O
O
R1
R1
O
O
Nu
In mixed anhydrides
the R2 group must prevent
the nucleophilic attack
R2
Nu
The mixed anhydrides are usually prepared quantitatively
from acid chlorides or other anhydrides.
They are not isolated.
O
R1
O
P
O
O
PMBO
OH
H
Nu
O
OBn
HO
Cl
O
PMBO
PMBO
O
Nu
Cl
95%
PMBO
PMBO
O
Cl
Pere Romea, 2014
Cl
O
(OMe)
O
O
Nu
P
Et 3N, DMAP
THF–PhMe, rt
O
R1
Cl
O
(OMe) Cl
Cl
PMBO
O
Cl
Cl
O
Yamaguchi Method
O
O
O
P
(OMe)
BnO
O
O
Cl
8
O
H
Esters from Carboxylic Acids and Derivatives
The retrosynthetic analysis shows two ways of deconnecting the ester group ...
O
R1
L
+ HOR2
b)
O
R1
O
R2
a)
O
R1
Addition-elimination Processes
+ R2–X
O
SN2 Processes
– Fischer Esterification
X
RCO2–
– Using coupling agents as carbodiimides
H
X: Cl, Br, I, OSO2R
RCO2
H
– Acylation with acid chlorides or anhydrides
OH
RCOOH
Mitsunobu
RCO2H
Pere Romea, 2014
9
H
Ph3P, DEAD
CH2N2
RCO2
RCO2
H
HH
H
Esters through SN2 Transformations
Synthesis of methyl esters by reaction with diazomethane
Diazomethane is a highly volatile (it must be handled in etherial solutions), toxic, and explosive compound ...
H
H
C N N
H
C N N
H
C N N
H
H
The best leaving group
O
R
O
O
H
H
C N N
H
O
N N
O
R
SN2
MeO
Et2O
O
H
O
O
95%
pKa 10
HH
O
CH2N2
O
O
– N2
H
Acid-base
O
HO
R
HH
pKa 16
PhOH + CH2N2
PrOH + CH2N2
PhOMe
10
PrOMe
Pere Romea, 2014
Esters through Addition-Elimination Transformations
Fischer esterification
O
R1
O
H
HOR2
+
A problem
O
R1
O
H
H
O
H
R1
O
O
H
R1
H
O
H
2
HO O R
R1
R1
OH
H
Activation
O
R1
O H
H
O
R2
O
–H
R1
O
R2
HO R2
O
R1
H
HO O 2
R
H
O
+
HOR2
O
H
R1
O
R2
+
H2O
– Reversible reaction catalyzed by H+
– Excess of R2OH or removal of H2O are necessary to obtain esters in high yields
O
OH + MeOH
solvent
HCl cat
Δ
O
O
O
OH
OMe
95%
11
+ HO
Cl
TsOH cat
Δ
–H 2O azeotropic
85%
O
Cl
Pere Romea, 2014
Esters through Addition-Elimination Transformations
Esterification with carbodiimides
O
O
R1
H + R N C N R
O
Carbodiimide
R1
R2 +
O
R
N
H
N
H
R
O
O
R1
+ HOR2
O
O
H
R1
R N C N R
O
O
H
R1
R
R OH
R N C N
– Neutral and aprotic apolar medium
– DMAP is usually used as catalyst
TBSO
NHR
O
NR
R2 + R
O
N
H
TBSO
DCC: DiCiclohexylCarbodiimide
O
OH
N C N
O
+ HO
H
R1
O
N
H
R
Good leaving group
OMe
H
O
OMe
O
O
H
O
DMAP cat, CH2Cl2
12
97%
H
Pere Romea, 2014
Esters through Addition-Elimination Transformations
Acylation with acid chlorides and anhydrides
O
R1
O
Cl
o
O
R1
R1
O
Good leaving groups
O
R2OH
R1
R3N
O
R2
O
O
O
O
Ac
HO
O
PhCOCl
pyr, DMAP cat
Ac
CH2Cl2
O
O
O
85%
O
O
O
O
Ph
CO2Me
OH
OH
OH
CO2Me
Ac2O
Et3N, DMAP cat
OAc
OAc
CH2Cl2
95%
13
OAc
Pere Romea, 2014
Esters through Addition-Elimination Transformations
Acylation with mixed anhydrides
O
R1
Mixed anhydrides are usually prepared quantitatively
from acid chlorides or other anhydrides.
They are not isolated.
O
O
P
O
(OMe)
PMBO
O
PMBO
O
P
O
O2N
Nu
Shiina Method
J. Org. Chem. 2004, 69, 1822
O
O
(OMe)
H
OBn
HO
PMBO
O
PMBO
O
Cl
O
P
(OMe)
BnO
O
PMBO
95%
O
PMBO
Cl
Me
O
Cl
Cl
Et3N, DMAP
THF–PhMe, ta
OH
R1
O
Nu
Yamaguchi Method
Cl
Cl
O
Cl
Cl
O
Cl
O
O
Cl
Nu
Me
O
O
Me
O
TBSO
X
X
X: NO2
O
Ph
Pere Romea, 2014
OH
+
HO
Ph
Et3N, DMAP cat, CH2Cl2
92%
TBSO
Ph
O
O
Ph
14
O
H
Lactones in Natural Products
Lactones (cyclic esters) are a common structural motif in natural products
OMe
O
HO
O
O
OH
Scytophycin C (20)
O
H
O
MeO MeO
Octalactin A (8)
N
OH
H
O
O
HO
OMe
OH
O
O
Erythromycin A (14)
O
Pere Romea, 2014
OH
Bafilomycin A (16)
OMe
O
O
OMe
O
OH
O
HO
HO
O
O
NMe2
O
O
O
OH
O
(C)n
(C)n
?
O
OMe
L
O
15
HO
OH
OH
Campagne, J. -M.
Chem. Rev. 2006, 106, 911 & 2013, 113, PR1
Lactones in Natural Products
The size of the ring determines the synthetic method ...
Cyclization of γ- and ∂-hydroxy acids is straightforward …
O
OH
γ
O
O
OH
Very easy
O
OH
O
Very easy
O
δ OH
For 5- and 6-membered rings, both enthalpy and entropy OK !!!
... but as the size of the ring increases, the cyclization mets the selectivity problem
O
L
(C)n
OH
k1
O
O
inter
L
(C)n
O
(C)n
OH
k2inter
vintra >> vinter
O
k1intra
k2intra
O
O
(C)n
monòmer
vintra = k1intra [S]
O
O
O
dímer
High dilution conditions are required as well as
activation of the carboxylate group compatible with the OH group
si k1intra k1inter
Per a vintra >> vinter
vinter = k1inter [S]2
vintra
vinter
1
=
[S]
[S]
0
16
Synthesis of Macrolactones
Mixed anhydrides (Yamaguchi and Shiina methods) met these conditions
O
O
Cl
O
Cl
O
O
Cl
Cl
1) Et3N, THF, rt
O
O
OH
HOOC
O
1) PhMe, DMAP, 60 °C
[S] = 30 mM
O
O
78%
Me
O
O
O
O
O
Me
O
O
O
OH
HO
X
X: NO2
O
O
O
X
Et3N, DMAP, CH2Cl2, 40 °C
[S] = 2.7 mM
O
O
O
O
O
O
42%
17
Pere Romea, 2014
Amides through Addition-Elimination Transformations
The retrosynthetic analysis of amides also shows two options …
b)
O
R1
L
+ HNR2R3
a)
O
R1
O
R2
N
R1
NR3
+ R2–X
R3
Addition-elimination processes
SN2 Processes
– Acylation with acid chlorides and anhydrides
No very common, but N-substitutions using
– Via coupling agents: carbodiimides, HATU
sterically unindexed alkyl halides are useful options.
Attention with E2
O
N
O
H
NaH, MeI
N
Me
Benzè
18
Pere Romea, 2014
Amides through Addition-Elimination Transformations
Acylation with acid chlorides and anhydrides
O
R1
O
o
R1
Cl
O
Good leaving groups
O
R1
O
OH
O
R2R3NH
R1
R3N
N
R3
R2
O
1) SOCl2
NH 2
2) NH 3 excess
70%
O
O
Me
N
Me
2 eq Me2NH
Cl
85%
O
HO
NH2
Ac2O, pyr
90%
19
O
HO
+
Me2NH2 Cl
H
N
O
Pere Romea, 2014
Amides through Addition-Elimination Transformations
Synthesis of amides by using carbodiimides
O
O
R1
H + R N C N R
O
Carbodiimide
R1
R2 +
N
R
R3
N
H
R
N
H
O
O
R1
+ HNR2R3
O
O
H
R1
R N C N R
O
O
H
R1
R
R2 NH
R N C N
– Neutral and aprotic apolar medium
– DMAP is usually used as catalyst
NHR
O
NR
O
R1
Good leaving group
O
R2 +
N
R3
R
N
H
N
H
R
R3
R2
HO
O
H
N
RO
R1
H
O
N
H
DCC
Coupling
Boc
O
R2
H
N
RO
R1
O
N
H
Boc
O
TFA
RO
Deprotection
R2
H
N
R1
O
N
H
H
Peptide synthesis
20
Pere Romea, 2014
Amides through Addition-Elimination Transformations
Occasionally, O-acylisourea intermediates are not stable enough
or produce the epimerization of the Cα center.
Then, the addition of N-hydroxy derivatives transforms such intermediates into less reactive active esters
with a beneficial effect on the overall efficiency
O
R1
NHR
O
O
HOXt
R1
NR
O
R
N
H
R2
N
H
O
NH
R
O
Xt
R1
N
R2
R3
HOXt
R3
HOXt
O
N
N
N
N
N
N
N
OH
HOBt
OH
HOAt
21
N OH
O
HOSu
Pere Romea, 2014