Jasmone 1 - ChemistforChrist

Synthesis of JASMONE
Synthesis of Jasmone
Reviews: Synth. Comm. 1974, 4, 265-287
Synthesis, 1973, 397-412
O
Jasmone
O
O
Jasmolactone
Firmenich (Company in Geneva producing fragrances):
O
Hedrione
Ways to make a cis-Double bond:
O
R H
H 2 / Lindlar
Wittig
R'
PPh 3
HBR 2
NiP 2
H 2
Diimine Reduction:
Usually gives an excellent Z/E ration (up to 99.9%)
Synthesis of H N N H :
DEAD:
EtO2C N N CO2Et H 2O / NaOH
R
H
R'
BR 2
More resources available at
www.chemistforchrist.de
H
O
CO 2Me
Na O2C N N CO2 Na
H
Methyl-Jasmonate
The syn compound has a strong smell
Only one enantiomer is active
cis-Selectivity
90-95%
85-90%
98-99%
98-99%
Very reactive! H N N H HO2C N N CO
- CO
2H
2
Problem: intermediates and the diimine might be explosive (Not done in industry, largest scale might be 2 or 3
mmol).

Synthesis of JASMONE
Phauson-Khand reaction: Synthesis of cyclopentenones via [2+2+1] cycloaddition
Net-reaction:
R L
R S
Mechanism:
R S
R S
R
R L
R L
R S
O
R
Co(CO) 3
Co(CO) 3
R L
Red. Elimination
Co(CO) 3
Co(CO) 3
Co 2(CO) 8
Co 2(CO) 8
CO
- 2 CO
Insertion in
red bond
R S
R L
R S
R S
R
O
R
O
Review: Angew. Chem. Int. Ed. 2005, 44, 3022
Aldolkondensation:
O O
OH
R S
R L
R
Co(CO) 3
R L
Co(CO) 3
2
3
O
1
O
R L
CO comes from Co 2(CO) 8
R
Co(CO) 3
Co
(CO) 3
Co(CO) 3
Co(CO) 3
4
R migh also end up here,
mixtures are formed.
-[Co 2(CO) 6]
More resources available at
www.chemistforchrist.de
R
Insertion in
red bond
+ CO
O
1,4 Dicarbonyl compound
R S
R
R S
R S
R L
(OC) 2Co
R L
O
Co(CO) 3
Co
(CO) To create a
2
free coordination
site
R
R L
Co(CO) 3
R

Synthesis of JASMONE
O
O
O
O
R 1
R 1
1
2
O
O
O
O
R 1
R 1
R 2
R 2
S S +
Synthesis by S. Mann Synth. Comm. 1985, 15, 1147-1151
O
O
O N
O O Li
Solution: Hydrazone
O H 2N NMe 2
O
O
O
R 2
made out of:
O
+
N
H
N NMe 2
n-Bu Li
Cl
O
R 1
XMg
O
More resources available at
www.chemistforchrist.de
+
Nu
Br
R 2
O O R2
O O R2
Br R 2
Enamine is a too weak nucleophile.
O
To weak as a nucleophile?!
N NMe 2
Li
O
R 2
O O R2
very strong nucleophile
(charge is not delocalized)

Synthesis of JASMONE
Chiral Hydrazones: Enders
N N
OMe
Is made out of proline
by reduction and protection
with MeI
1
2
3
O
1
2
O
O
3
N OMe
Me
Weinreb-Amid
1.) n-BuLi
2.) E
3.) H 3O , CuSO 4
+ X
Wittig-Reaction
O
O
X
O
+
+
O
XMg
+
O
H 2 , Lindlar-Pd
PPh 3
Aledehyde reacts faster than the ketone!
O
Commercially available
E
*
SAMP RAMP
N
H
O Mg
N O
More resources available at
www.chemistforchrist.de
R
Problem:
E/Z Isomers
S or R
OMe Amino
Methoxy
Pyrolidine

Synthesis of JASMONE
Synthesis:
EtO
O
O
O
O
O
1
2
H 2N NMe 2
O
100%
90%
+
N NMe 2
O
10%
Enolate formed at Position: 2 1
electron poor due
to conjugation
R
R
O O
E 2
O
E 1
:
1. O 3
2. Me 2S
O
O
Ph 3P
Sterically hindered Base
(Kinetically controlled deprotonation)
NaOH
to create the
Ylide
: Thermodynamically controlled deprotonation
R
R
For E 1 = Br
For E 2 =
Br
BH 4
H 3O
- CO 2
O
EtO
EtO
O O
O O
E 2
R
E 1
R
n-Bu Li
More resources available at
www.chemistforchrist.de
Li
E 2
1. n-BuLi
2.
O
3. H2O + Cu(OAc) 2
O
75%
SiMe3 N
SiMe3 EtO
EtO
E 1
O O
O O
NaOH
70%
44% yield
LMDS
R
O
OH
O
O
What was deprotonated
last will react first!
E 1
R
Oxidation
with PCC

Synthesis of JASMONE
Synthesis of Larry Weiler Can. J. Chem. 1978, 56, 2301-2304
O
O
OEt
1. Base
2.
O
O CO2Et
O
Jasmone
Br
NaOH
Synthesis of Welch JOC 1987, 52, 1440-1450
O
O
CO 2Et
1. NaH
2. n-BuLi
3.
O P(OEt) O
2
Cl
CO 2Et
O P(OEt)2
O
NaOH
O
Cl
O
H 3O
HgSO 4
O
O
+
OEt
CO 2Et
Jasmone
1. NaH
2. n-BuLi
3.
Br
O CO2Et
More resources available at
www.chemistforchrist.de
H
HgSO 4
R H 2SO 4
TMS
KF
R
O O
Lindlar / Pd
OH
TMS
O CO2Et
TMS
OEt
R
Steric bulk
hinders
Hydrogenation
O

Synthesis of JASMONE
Additional information:
Reaction of Perkow: JACS 1955, 77, 2871
Perkow:
O
O
Cl Cl
O
Cl Cl
Arbusow:
EtO
EtO P
EtO
P(OEt) 3
∆
P(OEt) 3
R Br
Cl
Cl
O
O
EtO
EtO P
O
P(OEt) 2
P(OEt) 3
Et
Br
HWE-Reagent (HWE = Horner-Wadsworth-Emmons)
Synthesis by McMurry
JOCS 1973, 38, 4367-4373
JACS 1971, 93 5309-5311
New approach to create the 1,4 diketone
2
3
O
1
4
O
O
+
R
O
R
R
S S
NO 2
The conditions of the Nef-reaction are rather harsh:
O O
N
H
OH
NaOH
O O
N
H 2SO 4
conc.
reflux
R
R
Cl
Cl
HO OH
N
O
O
O
EtO
EtO P
O
P(OEt) 2
P(OEt) 2
Et
More resources available at
www.chemistforchrist.de
O
H 2O
R
+ EtBr
S S
E
E
NO 2
R
R
O
Hg(II)
1. NaOH
2. H 2SO 4
Nef-reaction
Et
Et
O
O
R
R

Synthesis of JASMONE
McMurrys attention was therefore drawn to a publication of Wildsmith, who used much milder conditions to
hydrolyze an oxime (which is not that far away from a nitro group):
Synthesis by Wildsmith TL 1971, 195-198
Utilisisation of TiCl3 for the Nef reaction: Tetrahedron Letters, 1971, 195-198
N OH
NH
1.
2. H
O
2O
Oxime
TiCl 3
McMurry was lucky, the reaction worked:
O O
N
nitro
Synthesis:
H
NO 2
NO 2
TiCl 3
base
OH
N N O
H
oxime imine
NaNO 2
NH
O
I
2 eq.
NO 2
O
HO Br
HI
or:
1. TsCl
2. I
More resources available at
www.chemistforchrist.de
HO
HO
TiCl 3
diglyme, ∆
MeO O OMe
Lindlar Pd
O
O
O
Jasmone
NaOH

Synthesis of JASMONE
Synthesis by Givaudan, Helv. Chim. Acta 1978, 61, 990-997
Not a very good Electrophile
due to having a quite acidic
Proton in an allylic Position
Nu
That's why he decided rather to use it as a nucleophile:
That is present in a certain
fraction in petrol refinery
(The other compounds present
in the mixture are usually
hydrocarbons and do therefore
not react - pure Butin is very expensive)
O
Jasmone
n-Bu Li Li
O
OH
NaOH
JONES-OX
H
MgBr
O
Br
Jones Reagent:
CrO 3, diluted H 2SO 4, acetone
Mg
Nef-reaction
Synthesis of Jasmone by Stetter, Synthesis 1975, 379-380
d 1
O
Might be:
NO 2
1
O
2
OR
CN
3
O
4
EtO
S
undesired
side reaction
O
More resources available at
www.chemistforchrist.de
S
R
MgBr
OH
Lindlar-Pd,
H 2
HBr
NaOH
OH
Br
NO 2
O
Conj. Addition
NO 2

Synthesis of JASMONE
R
O
Ph H
Ph H
O
O
H
+ cat. KCN
+
CN
In the presence of:
cat.
CN
R
O
CN
O
Ph H
CN
H
CN
Ph
+ Ph
O
O
R
OH
Ph
Ph
OH
OH
CN
Ph
OH
CN
O Will react much slower with CN , because the
Carbonylfunction is stabilized by conjugation.
Stetter: Biomimetic Reaction
Tetrahedron Letters, 1974, 4505-4508
Review: Org. React. 1991, 40, 407-496
Biomimetic: Means copied from nature.
Vitamine B1 (Thiamine)
thiamine
HO
Cl -
N +
S
HO
NH 2
N
N
N
S
Bn
O
R 1
benzoine
Ph
Ph
O
Conj. Add.
More resources available at
www.chemistforchrist.de
2
3
4 Me
O
Simplified by Stetter:
HO
S
Thiazolium-Salt
HO
X
N +
H
Ph
NaOH
N
S
Bn
OH
CN
O
Ph
more acidic
as the other
O
CN
R
R
OH
OH
CN
O
CN
Ph
O
O
Me
Me
Today also chiral versions
for asymmetric reactions.
This proton is quite acidic!
This anion replaces the role of the CN that we saw in the reaction above.

Synthesis of JASMONE
Another way to see it is:
Bn
HO
N
S
A nucleophilic Carbene
This kind of carbenes are pretty important today:
Ar The first carbene that was isolated, crystalized and characterized.
N Today there are many chiral versions available that are used
in asymmetric synthesis.
N
Ar
N
N
Ar
Ar
Very reactive
species! Prone
to nucleophilic
attack.
N
N
Nu
H
N
N
N
N
Ar
Ar
6-π Electron aromatic
system, that's why the carbene
is so stable!
Idea:
Block the site prone
to nucleophilic attack
with very bulky substituents.
The 2 plane where the 2 mesityl
substituents are lying in are
perpendicular to each other.
More resources available at
www.chemistforchrist.de
Putting different charges on the
same carbon atom can also be a
way of representing a carbene!
N
N
N
N
Mesityl- Adamantyl-
The fact that carbenes can be used in catalysis as a Ligand is due to the fact that the 2 Electrons in the sp 2
Orbital behave like lone pair and can thus donate electron density to the corresponding metal.
R
N
N
R
behaves like a
Donor e.g.
R
R P
R
Carbenes in catalysis are often named NHC-Ligands (N-Heterocyclic Carbenes) and offer many advantages
compare to their Phosphorous counterparts:
a) Environmentally more friendly (often non toxic)
b) Not sensitive to oxidation
c) Lower Molecular mass, for industrial purpose this means less gramms or kg of Ligand has to be added.

Synthesis of JASMONE
O
O
O
(with cat. Stetter reagent)
+
O
BrMg
Br
HO
More resources available at
www.chemistforchrist.de
+ DMF
(already discussed
see above)
For adding a formyl DMF is the best reagent (Adding the Weinrebamide would more complicated).
O
H OH
O
H OH
SO 2Cl 2
DCC
Me
HN
OMe
O
H Cl
H
O
N
Me
OMe
instable
BrMg
CO + HCl
Historically Formyl groups were added with the help of Orthoesters:
Et Et
O
R MgX
Et O in the presence of :
Heat > 35°C
and evaporate
R MgX
Et
OEt
HC OEt
OEt
Orthoester
the ether
OEt
HC OEt
OEt
Stetter chose to change the orthoester in making
one of the OEt group to a better leaving group a
Phenol (OPh). This facilitates the reaction and it can
be done now at r.t.
OEt
HC OEt
OEt
+ PhOH HC
OEt
OEt
OPh
+ HOEt
Utilisation of mixed othoformiates: Chem. Ber. 1970, 103, 643
Synthesis of Stetter
MgBr
OEt
HC OEt
OPh
O
Jasmone
R
O
H
H
H 3O
O
R
H
OEt
OEt
Highly reactive,
will react immediately
with the grignard
reagent.
R
R MgX
OEt
H
OEt
OEt O
H3O OEt
NaOH
10 mol%
Thiazolium-Salt
O
4
3
O
2
1
O

Synthesis of JASMONE
Different approach using Photo-reactions:
O
rotation of
C-C bond
O
O
HIO4 OH OH
R
O
O
O
O
O
Problem:
hν
hν
OH BrMg
O
O OH
5
4
H
3
O
1
O
2
Biradikal
Does it come from above
or below?
Answer: 50:50
1,5 H-Shift
Synthesis by Büchi JOC 1966, 31, 977-978
O
Molecules with the same oxidation state:
N
Imine
Synthesis in 3 steps
O
O
O
O
Acetale
H
N
NH
Aminale
OH
R
OH
OH
OH
R
OH
O O
50 : 50
Only this diastereoisomer
will react with HIO 4, the other
cannot react in a syn-fashion.
More resources available at
www.chemistforchrist.de
N
Enamine
R
O
R
O
OsO 4
R
very difficult
to synthesize
OH
OH
OH
R
Enole / Enole-ether
Why not putting the 2 OH
groups together?
To hydrolyze a furane is not that easy because it is aromatic, but it can be done!

Synthesis of JASMONE
one step
O
n-Bu Li
O
O
Li
Jasmone
Br
As discussed earlier not
a good E but used anyway
40%
(3 steps)
NaOH
Synthesis of Jasmone by Hiyama, Bull. Chem. Soc. Jpn. 1980, 53, 169-173
(Electrocylic reactions)
More resources available at
www.chemistforchrist.de
O
1
O
2
3
AcOH,
H 2SO 4
H 2O
O
4
Problem: under the very acidic
hydrolysis condition E/Z isomerization
takes place! - 7% E Isomer is yielded
In an electrocyclic reaction a ring is always broken or formed. Rings may, of course be formed by cycloadditions
as well, but the difference with electrocyclic reactions is that just one new σ bond is formed (or broken) across
the ends of a single conjugated π system.
The types of pericyclic reactions are distinguished by the number of σ bonds made or broken.
Cycloadditions
2 new σ-bonds are formed
... or broken
∆σ = 2
Types of pericyclic reactions
Sigmatropic
rearrangements
One new σ-bonds is
formed as another is
broken.
∆σ = 0
Electrocyclic reactions
One new σ-bonds is formed
... or broken
∆σ = 1
Rules for electrocyclic reactions
All electrocyclic reactions are allowed
Thermal electrocyclic reactions involving (4n+2)π electrons are disrotatory:
one group rotates clockwise and one anticlockwise
Thermal electrocyclic reactions involving (4n)π electrons are conrotatory, in contrary reactions the two groups
rotate in the same way:
both clockwise both counterclockwise

Synthesis of JASMONE
The Nazarow reaction: Short revision
For more details see: Org. React. 1994, 45, 1-158
O
O
R R
O
H
hν (254 nm)
benzene
AcOH, H 3PO 4
50°C
R R
Disrotatory Conrotatory
O
R R
R R
In its simplest form the Nazarow cyclization is the ring closure of a doubly α,β unsaturated ketone to give a
cyclopentenone.
O
H
R R
O
H
R R
R
empty
OH
More resources available at
www.chemistforchrist.de
R
O
R R
array of five p orbitals
containing 4p electrons
One of the five π orbitals involved is empty, so the cyclization is a 4π electrocyclic reaction and the orbitals
forming the new σ bond must interact antarafacially.
H
O
OH
O
OH
OH
R R
R
π 4
a
R
H
R
R
R R
R R
cyclopentenone
Usually the double bond is formed at the site which is higher substituted (thermodynamically more stable
product) to get the double bond at the less substituted site can also be done by introducing a siliconsubstituent:
O
TMS R
Lewis acid
LA
O
TMS R
Nazarow
LA
O
TMS R
Anion
H 3O
O
R

Synthesis of JASMONE
Synthesis of Hiyama Bull. Chem. Soc. Jpn 1980, 53, 169-173
O
OH
O
HCOOH,
H 3PO 4
Difficult mechanism:
Tautomerization,
Isomerization,
Eliminatation....
For more details consult
literature given.
Some commercially available 5-memebered rings:
O O O
O
O
O
OH
O
is like other 1,3 diketones
in equilibrium with its
enol.
O H
OH
H
O
More resources available at
www.chemistforchrist.de
O
O H
best nucleophile
in the mixture
cyclopentane-1,3-dione
Is an important starting material
for the industrial synthesis of
steroids.
O O
The Keto-Enol Tautomerization can be seen in the 1 H-NMR.
O
Examples for E :
O
soft E
E
R I
OH
hard E
Vinylogous Behaviour:
O
OH
behaves like a
carboxlic acid
pK a = 9-10
O
OH
O
OH
E
O
,
EtO Cl
Synthesis by Piers et al Can. J. Chem. 1982, 60, 1256-1263
O O
O
R
O
O
This one also
O
O
O
OH
H
O O

Synthesis of JASMONE
O
O
NaOH
Even easier:
O
O
O
O
Cl
soft E
O
Na O
EtOH, H
(due to Vinologous
behaviour same
conditions can be
used as for Carboxylic
acids!)
O
OEt
Me
More resources available at
www.chemistforchrist.de
O
Br 2, PPh 3
(due to Vinologous
behaviour same
conditions can be
used as for Carboxylic
acids!)
MeLi
This is a electron rich
double bond and therefore
Me 2CuLi doesn't react nicely
with this molecule.
Review on conjugated addition of Organocopper reagents: Org. React. 1972, 19, 1-113
Org. React. 1992, 42, 135-631
Revisit on Organocopper reagents:
Homocuprates (Gilman reagents): Me2CuLi, Bu2CuLi
e.g. Me2CuLi, Bu2CuLi
Mixed homocuprate: RCuR'Li
Mixed homocuprates are used in order not to waste halt of the Substituent R:
R MgX + CuCl 2 R Cu + RCl + MgXCl
MeCuBuLi (Bu-Substituent is transfered),
transfered!)
R
Li
Cu R'
Heterocuprates: RCuXR'
e.g. -SPh, -OtBu (these substituents are never transfered)
R Li + CuSPh RCuSPhLi
Me
Me
OH
OEt
O
O
O
Me
Br
Br
H
Me 2CuLi
(The R substituent is transfered, alkynes are never
R3CuLi2 (higher order cuprates)
Those were discovered by following experiment: MeLi and CuI were mixed in various rations and the Me-
Singlet in the 1 H-NMR was observed: When mixing MeLi and CuI in a 3:1 ratio only a single species could be
seen.
Cyanocuprates (Lipshutz cuprates) R3CuCNLi2
2 RLi + CuCN R 2CuCNLi 2 (R 2CuLi, LiCN)
Cyanide (CN) acts as the 3rd R group in relation to the creation of higher order cuprates.

Synthesis of JASMONE
The LiI that is created while reacting RLi and CuI is absolutely necessary for reactions to take place!
The cuprates have a shape of a plane square, therefore reactions can done highly
diastereoseletive because cuprates are quite sensitive to sterical effects:
Cuprate
O
Example for an application of organocopper reagents: 1,4 Addition to Pyridinium-Salts
R'
N
R'
O
R Cl
N
R O
R'
RMgX
R 2CuLi
More resources available at
www.chemistforchrist.de
N
R O
R O
Construction of molecules that resemble natures NAD, NADH
Synthesis of Grieco JOC, 1972, 37, 2363-2364
O
C
Cl Cl
Made out of:
, H
Heating and destillation
of cyclopentadiene
O
C
Cl Cl
O
Cl
Cl
[2+2]
[2+2]
Bayer Villinger
AcOH, H 2O 2
CH 2N 2
O
C
Cl Cl
stable
O
C
H H
O
Cl
Cl
O
Cl
O
R
*
N
*
Made out of:
Not stable,
reacts with
itself:
Cl
Cl
O
O
O
R
R'
Cl
Cl Cl + Zn or
Cl
O
O
O
Cl
Cl H NEt 3

Synthesis of JASMONE
O
O
DIBAL-H
For a lactone the best
reducing agent to a lactole
is DIBAL-H, for an ester this
might not work so well!
H
OH
O
Thermodynamically more
stable due to being
a trisubstituted double
bond.
O
under the acidc
conditions:
isomerization
MeLi
Me
Jasmone
O
O
OH
More resources available at
www.chemistforchrist.de
OH
O
CrO 3, verd. H 2SO 4, Aceton
Jones-Reagent
Me CrO3, verd. H2SO4, Aceton
OH
Jones-Reagent
CrO 3
HO
tertiary alcohol,
H 2O is eliminated
Wittig
tertiary alcohol cannot be oxidized!
The textbook Clayden, Greeves, Warren and Wothers (Oxford University press, p. 951, 2004 reprint) proposes
a different mechanism:
OH (VI)
OH
O
R Li
R
O
CrO3 R (VI)
CrO
orange
3
OH
R CrO 3
H
O OH
Cr
O O
R
H
[3,3]
HO OH
Cr
O O
H
H R
Me
O
(III)
CrO3 R
+ Cr(IV)
green
PPh 3
OH
Me
Me
gives Cr(III) and Cr(VI)
by disproportionation.
The first step is the formation of a chromate ester but this intermediate has no proton to lose, so it transfers
the chromate to the other end of the allylic system where there is a proton. The chromate transfer can be
drawn as a [3,3] sigmatropic rearrangement.
Very general method:
R' MgBr
O
R
HO
R'
R'
R H
R
OH
Ox
R'
R
O

Synthesis of JASMONE
Cope Rearrangement
1 2
1
2
3
4
5
Cope
2
1 2
1
3 4
Synthesis of Descotes Synthesis 1975, 118-119
3
O
3
4
2 6
H
1
5
4
2 6
H
1
CO 2Et
CO 2Et
5
much
cheaper
5
H
Z
Cope
O O
YZn X
CH2
EtO 2C CO 2Et
CO 2Et
EtO 2C CO 2Et K 2CO 3 EtO 2C CO 2Et Br
Br
+
Br
EtO 2C CO 2Et
2 steps as
explained above
(Grignard, Oxidation)
CO 2Et
+ K 2CO 3
intramolecular
reaction
(ring closure)
More resources available at
www.chemistforchrist.de
Simmons Smith
Br EtO 2C CO 2Et
Technique to enlarge
cyclic systems
Br
Jasmone
K 2CO 3
EtO 2C CO 2Et
Br

Synthesis of JASMONE
Br
Br
Br
+
CO 2Et
CO 2Et
CO2Et CO2Et S N2'
K2CO3 CO2Et ?
DMF CO2Et CO 2Et
CO 2Et
∆
150°C
CO2Et ?
CO2Et Industrial Synthesis (Firmenich) Helv. Chim. Acta 1978, 61, 2524-2529
O
+ Br 2 (hν)
(heat in a radical
fashion)
Br
Br
+
Br
Br
Br
Br
E/Z mixture
and..
+
Br
Br
via the
enolate
More resources available at
www.chemistforchrist.de
O
O
> 150°C
The Problem is that during the radical bromination epoxides are involved due to the presence of air and one
day the plant that produced Jasmone via this pathway was blown up and since then this reaction is not used
industrially anymore.