14C synthesis strategies, Chem 315/316 / Beauchamp 1
Several organolithium compounds are commercially available. Many others can be made. We will use two methods (Li and Mg) to make these carbanion equivalents, and almost any other, from simple RX starting points. While these two classes of compounds are very similar in the chemistry we study, there are some differences that we will mostly ignore.
Once organolithium and organomagnesium (Grignard) reagents are made, the metals can be switched with other metals (transmetallation). We will only use copper this way in our course (as CuI = cuprous iodide). This will give us a few more reaction choices than are possible with magnesium and lithium, alone (RX coupling, selective reaction with acid chlorides and beta addition to α,β-unsaturated carbonyl compounds). Magnesium and lithium reagents can be made from the corresponding RX compounds (we will use RBr) when mixed with lithium or magnesium metal.
In actuality the carbon/lithium bond is intermediate between very polar covalent and ionic. Some organolithium reagents are soluble in hydrocarbon solvents (hexane), which is an indication that they are not really ionic salts. The actual situation is more complicated because of various “cluster” arrangements However, they all react like powerful carbonanion nucleophiles, and that’s the way we will represent them, because it’s easier to think about the reactions they undergo that way, especially when you are a beginning organic student. Almost always a final acidic neutralization workup step is necessary because the conditions are kept “basic” to prevent destruction of the organometallic reagent. In the examples below, we will represent phenyl as “Ph” to distinguish the part that came from the organolithium reagent (the nucleophilic part) in each newly synthesized target molecule.
A lot can be done with these reagents, as shown by many examples below. In each subsequent part, a single compound is highlighted from an earlier part, and several additional compounds are shown that can be made in “one additional reaction” sequence. (One additional reaction means a sequence of steps that can be performed in a single reaction flask.)
Highlighted, commercially available compounds: phenyl lithium (Ph-Li), methyl lithium (Me-Li), ethyl lithium (Et-Li), butyl lithium (n-Bu-Li), sec-butyl lithium (sec-Bu-Li), t-butyl lithium (t-Bu-Li),
Li Li≈ Easier to understand its chemistry when viewed this way.
phenyl lithium
Ph Li shorthand representation
Li
phenyl lithium
Li
organometallicsRX + (Mg or Li)
Br
Made from:
H3C Li Li≈methyl lithium
H3CLi
H3C Br
H3CCH2
H2C
H2CH3C
CH2
H2C
H2CBr
LiH3C
CH2
H2C
H2CLi
n-butyl lithium
Li ≈
H2CHC
H2CHC
H2CHCBr Li LiLi ≈
vinyl lithium
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14C synthesis strategies, Chem 315/316 / Beauchamp 2
The following compounds are one reaction pot away from phenyl lithium. Analogous examples are possible using other organometallic reagents, such as those listed just above.
Ph LiPhPh OH
OH
O
1. electrophile2. WK
PhOH
O
Ph
OH
H
O
Ph
OH
O
nucleophile
electrophile electrophile electrophile electrophile electrophile
target moleculetarget molecule target molecule target molecule target molecule
H
O
Ph
OH
target molecule
electrophile
O
H H
Ph
OH
target molecule
electrophile
O= newly formed bond using nucleophile-electrophile strategy
Ph OH
O
CO CN
CH3 HO
O
Ph
O
Ph
O
electrophile
O
target molecule target molecule target molecule
electrophile electrophile
CN
HO
O
Ph
O
Ph
O
target molecule target molecule
electrophile electrophile
RO
O
Ph
OH
target molecule
electrophile
Ph
Ph Li
1. electrophile2. WK
nucleophile
Cl
O
2. CuIPh
nucleophile 3. electrophile4. WK
CuPh Ph
LiLi
cupratesPh
O
Ph
O
target molecule
electrophile
all in the same reaction potCl
O
electrophile
target moleculePh
Brelectrophile
target molecule
Br
Phtarget molecule
electrophile
O
O
target molecule
electrophile
PhCuprates
In each of the following examples, one of the earlier synthesized compounds is used as a new starting point for additional transformations.
Ph
OH Ph
O
HPh
Br
Ph
O
Ph O Ph O
O
Br Cl
O
CrO3/pyridine (PCC)
Ph
O
OH
CrO3/H2O (Jones)
HBrPBr3SOBr2a. TsCl/py b. NaBr
Ts-Clpyridine
1. NaH2.
R3N
target molecule target moleculetarget molecule
target moleculetarget molecule target molecule
Ts
Z:\classes\315\315 Handouts\organomet_syn_strategies.doc
14C synthesis strategies, Chem 315/316 / Beauchamp 3
Ph
OH
Ph
BrPh O Ph O
O
NaOH
Ph
NH2
Ph CN
N
O
O
Na
1.
2. NaOH
O
NaO
Na
O
Na
C N
Ph
SH
NaSH
target moleculetarget moleculetarget moleculetarget moleculetarget molecule target molecule
Ph
Na
C CH
Ph
BrPh
Na
Ph
O
H2C
O
Li
target molecule target molecule target molecule
PhOH
O
H
CrO3/pyridine (PCC)
O
OH
CrO3/H2O (Jones)
HBrPBr3SOBr2a. TsCl/py b. NaBr
Ts-Clpyridine
Ph Ph
target molecule target molecule
PhBr
PhO
PhO
Na
NaH
Tstarget moleculetarget molecule
target molecule
Cl
O
1. NaH2. CH3Br
R3N
PhOH
PhO
PhO
Otarget molecule target moleculePh
H2SO4/∆
target molecule
Br
O
O
O
NaOH
CN
N
O
O
Na
1.
2. NaOH
O
NaO
Na
O
Na
C N
Ph
OH
Ph
NH2
Ph PhPh
target moleculetarget molecule target molecule target molecule target molecule
Ph
NaSHNa
C CH
Na
O
H2C
O
Li
target molecule target molecule target molecule target molecule
Br
Ph
SH
Ph
Ph Ph
PhPh
target molecule
O
K(use LDA)
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14C synthesis strategies, Chem 315/316 / Beauchamp 4
PhPh
OH
Ph
Br
target molecule target molecule target molecule target moleculePh
target molecule
Br
Phtarget molecule
Br
Ph
O
H2SO4/Η2Ο (possible rearrangement)
or1. HgX2/H2O2. NaBH4
H2SO4/ (possible rearrangement)
or1. HgX2/ROH2. NaBH4
HBr
PhOH
1. BH32. H2O2/HO 1. BH3
2. Br2/CH3O
Br
Br2 vicinaldibromidehydroboration
oxidation
OH
PhBr
Br2/H2O
OH
PhBr
OR
Ph
target molecule target molecule
Br2/ROH
Ph
O
Ph
mCPBA
Zn(Cu)CH2I2
target molecule target molecule
PhOH
OH
target molecule
OsO4 orKMnO4
Ph
target molecule
Pd/H2
Simmons-Smith Reaction
hydrogenation (syn)dihydroxylationepoxidation
bromoether (anti)
bromohydrin (anti)
(vicinal diol - syn)
Ph
H
Ph
target molecules
1. O3, -78o
2. CH3SCH3
O CH2
O
Ph
target molecules
1. O3, -78o
2. NaBH4
OH CH3
HO
Ph
target molecules
1. O3, -78o
2. H2O2 / HO
O CH
O
OH
OH
(ozonolysis) (ozonolysis) (ozonolysis)
PhOH
H3O+/H2O
OH
PhOH
OH
target molecule target molecule
NaOH/H2O
target molecule target molecule
vicinal diol (anti)
Ph
O
vicinal diol (anti) Na
C CH
Na
C N
Ph
OH
anti anti
PhC
OHN
target molecule
Li
anti
PhCH3
OH
H3C1. 2. WK
PhOH
H2OR+/ROH
OR
PhOR
OH
target molecule target molecule
ROH/RO
Phtarget molecule
(anti)
Ph
O
H2C
O
Li
OH
1. LiAlD4 or NaBD42. WK(anti) (from LDA)
Phtarget molecule
OH
O
D
PhBr
Br
Ph
1. excess NaNR22. mild acid WK
H
target moleculePh
target moleculePh
target moleculePh
target molecule Ph target molecule
OHOH
OH
1. excess NaNR22.
1. excess NaNR22.
1. excess NaNR22.
1. excess NaNR22.
Br H2C OO
O
H
Z:\classes\315\315 Handouts\organomet_syn_strategies.doc
14C synthesis strategies, Chem 315/316 / Beauchamp 5
Ph
H
target molecule target moleculetarget moleculetarget molecule target molecule
Pd / H2 / quinoline (Lindlar's Cat.)
1 eq. HBr
Ph
O
PhH
O
PhPh
Br
PhPh
BrBr
H2SO4/Η2Ο(Hg+2 catalyst)
1. BHR22. H2O2/HOhydroboration oxidation
target molecule
2 eq. HBr Pd / H2 (hydrogenation)
Br2 vicinaldibromide (anti)
Br
Ph
Br
target molecule
Phtarget molecule target molecule
Pd / H2 / quinoline (Lindlar's Cat.)
Ph
O
PhPh
Ph
H2SO4/Η2Ο(Hg+2 catalyst)
Na / NH3
(liquid ammonia)
target molecule target molecule
Pd / H2 hydrogenation
target moleculePh
O
1. LiAlH42. WK
Ph
OH
Ph
HO
H3CH2C
(MgBr)(from CH3CH2Br + Mg)
1.
2. WK
1. NaBH42. WK
or
target molecule
(Grignard Reaction)
Ph
HOPh
target molecule
Ph Li1.
2. WK
Phtarget molecule
OO
ketal protecting group
OHHO
TsOH (-H2O)
reverse reaction H2SO4 / H2O
Ph
HOC
target molecule
N
Ph
HO
target molecule
NaCN
cyanohydrinpropargyl alcohol
Na1.
2. WK
NH
adding H2O reforms C=O
TsOH (-H2O)
target moleculePh
O
NH2NH2 RO /∆
Ph
ZnCl2/HClor
target molecule
Phtarget molecule
enamineWolff-Kishner reduction
Clemmenson reduction
Ph
CH2
P CH2
Ph
Ph
Ph ylid
Wittig reaction
N
NH2
TsOH (-H2O)
adding H2O reforms C=O
imine
Ph
N
Ph
O
O
NaOH/H2O
Claisen Condensation
target moleculetarget molecule
α,β-unsaturated carbonyl
target moleculePh
1. LiAlH42. WK H3C
H2C
(MgBr)(from CH3CH2Br + Mg)
1.
2. WK1. NaBH42. WK
or(Grignard Reaction)
target molecule
Ph Li1.2. WK
H
target molecule
OO
acetal protecting group
OHHO
TsOH (-H2O)
reverse reaction H2SO4 / H2O
NaCN
cyanohydrin
O
H
Ph
Ph
OH
Ph
OH
Phtarget molecule
Ph
OH
Ph
OH
CNtarget molecule
Ph
O
OHtarget molecule
CrO3 / H2O
Jones
Z:\classes\315\315 Handouts\organomet_syn_strategies.doc
14C synthesis strategies, Chem 315/316 / Beauchamp 6
Ph
target molecule
propargyl alcohol
Na1.
2. WK
O
H
Ph
OH
target molecule
NH2NH2 RO /∆
Ph
ZnCl2/HCl
or
target moleculetarget molecule
enamineWolff-Kishner reduction
Clemmenson reduction
P CH
Ph
Ph
Ph ylid
Wittig reaction (usually Z)
N
NH
adding H2O reforms C=O
NH2
TsOH (-H2O)
adding H2O reforms C=O
imine
H
N
Ph
Ph
Ph
TsOH (-H2O)NaOH/H2O
Claisen Condensation
Ph
O
H
Ph
α,β-unsaturated carbonyl (self reaction)
target molecule
target molecule
CH3
target molecule
1. LiAlH42. WK
H3C (MgBr)
(from CH3Br + Mg)
1.
2. WK(not NaBH4) (Grignard Reaction)
target molecule
Ph Li1.
2. WK
Ph
OH
Ph
OH
Phtarget molecule
Ph
OH
O
O
RPh HOR
2 eqs.
Ph
2 eqs.
O
O
RPh
1. LDA, -78oC2.
Br3. WK
target molecule
target molecule
1. NaOH2. WK
Ph
O
O
O
RPh
HOR
OH
base hydrolysis = saponification
target molecule
H2SO4 / H2O
Ph
OHO
R
OH
acid hydrolysis
Ph
O
H
1. DIBAH2. WK
Al
iso-Bu
iso-Bu
H
target molecule
aldehyde
1. NaOH / H2O2. WK
H3C (MgBr)(from CH3Br + Mg)
1.
2. WK
(Grignard Reaction)H2SO4 / H2O / ∆
Ph
O
target moleculeNH2
CPhN
HCl / H2O
Ph
O
OHPh
O
OHtarget molecule target molecule
Ph
O
1. LiAlH42. WK
PhNH2
Ph
O
H
1. DIBAH2. WK
Al
iso-Bu
iso-Bu
H
target molecule target moleculetarget molecule
nitrile1o amide acid acid ketone
1o aminealdehyde
Cl
O
Ph
OCH3
O
PhNH2
O
PhN
O
PhN(CH3)2
O
PhCH3
O
PhH
O
Ph
1. DIBAH2. WK
Al
iso-Bu
iso-Bu
H
target molecule
aldehydetarget molecule
ketone
1. (CH3)2Cu Li(cuprate from CH3Li)2. WK
OHH3C NH3NH2H3C
ester
target moleculetarget moleculetarget moleculetarget molecule
1o amide
2o amide
3o amide
H3C
HN
CH3
H
CH3
Z:\classes\315\315 Handouts\organomet_syn_strategies.doc
14C synthesis strategies, Chem 315/316 / Beauchamp 7
NH2
O
Ph
1. NaOH / H2O2. WKH2SO4 / H2O / ∆
Ph
O
OHPh
O
OHtarget molecule target molecule
acid acid
CPhN
nitriletarget molecule
1o amideSOCl2
N
O
Ph
1. NaOH / H2O2. WKH2SO4 / H2O / ∆
Ph
O
OHtarget molecule
acid3o amide1. LiAlH42. WK
target molecule
3o amine
NPh
HN
2o amine
Ph
O
OHtarget molecule
acid
HN
2o amine
Ph
O
H
1. DIBAH2. WK
Al
iso-Bu
iso-Bu
H
target molecule
aldehyde H3C (MgBr)(from CH3Br + Mg)
1.
2. WK
(Grignard Reaction)
Ph
O
target moleculeketone
Z:\classes\315\315 Handouts\organomet_syn_strategies.doc
14C synthesis strategies, Chem 315/316 / Beauchamp 8
Simple combinations from 1-3 carbon organometallic nucleophiles with 1-3 carbon electrophiles.
H3C H2C
H3C
H2C
CH2
H3CLi (MgBr) (MgBr)
C
O
Na Na
H H
C
O
H3C H
C
O
CH2
H
C
O
H3C CH3
H3C
O
O
1 make organometallic2. add electrophile3. workup
OH OH OH OHOH
OH OH OH OHOH
OH OH OH OHOH
OH OH OH OH OH
C
H3C
H3C
H Li
OH
OH
OH
OH
OH OH OH OH OHOH
OH OH OH OH OHOH
not used in our course
not used in our course
not used in our course
not used in our course
OH
O
OH
O
OH
O
OH
O
C
O
O
CO O
RR
O OH OHOH OH
carbonate (adds 3x)
carbon dioxide
epoxides
epoxides
C
O
H O
C
O
H3C O
C
O
CH2
OH3C
R
R
R
OH
not used in our course
not used in our course
OH OH OH
OH
not used in our course
not used in our course
OH OH OH
OH
not used in our course
not used in our course
OH OH OH
esters (adds 2x)
esters (adds 2x)
esters (adds 2x)
H3CC
N
CH2
CN
H3C
O O O O
not used in our course
not used in our course
O O O O
not used in our course
not used in our course
nitriles
nitriles
Z:\classes\315\315 Handouts\organomet_syn_strategies.doc
14C synthesis strategies, Chem 315/316 / Beauchamp 9
BrH3C*
CH4
Overview of commonly used 14C game reactions (* = 14C lable).
Br2 hν NaOH
OHH3C* *
BrH3C*
HBr orPBR3
1. LiAlH42. workup
HH3C*
OHH3C*
CrO3pyridine
OH2C1. NaBH42. workup OHH3C
**CrO3H2O C
*O
OH
H1. NaOH2. RX C
*O
O
H
R
1. LiAlH42. workup OHH3C
*
1. DIBAH2. workup
OH2C*
1. LiAlH42. workup
CrO3H2O
BrH3C* NaCN
CH3C*
N
*
1. DIBAH2. workup
HClH2O
H2SO4H2O/∆
1. LiAlH42. workup
aldehydes
amines
amides
acids
*O
** *
MgBrH3C*
1.
2. workup
NH2
O
**
OH
O
**
H
O
**
NH2**
Cl*
*
O
NH*
*
O
**
O*
*
O
**
Br**
1. NaOH
2.
1. LDA, -78oC2.
Br
**
O
** *
**
BrH3C*
MgBrH3C*
OH2C*1.
2. workupOH
H2SO4 ∆*
*mCPBA
O
**
* *
LiBrH3C
*LiH3C
**
1.
2. workup
O
OH
**
** *
*CrO3H2O *
O
**
*MgBrH3C
*1.
2. workup
**
**
OH*
Z:\classes\315\315 Handouts\organomet_syn_strategies.doc
14C synthesis strategies, Chem 315/316 / Beauchamp 10
C*
O
O
H
RLi
BrH3C*
LiH3C*
BrH3C* Mg
MgBrH3C*
1.
2. workup
1.
2. workup
OH
H2SO4 ∆
*
*
*mCPBA O
CrO3H2O
O
*
*
*
OH*
*
*
*
**
*
* *
2 equivalents
*
H2SO4 ∆
**
*
*
Mg
HBr orPBR3 Br
**
*BrMg
**
*etc.1. BH3
2. H2O2/HO HO**
**
**
**
*
many additional reactions (carbonyl, epoxide & RX)
Br2Br
**
*
Br
CH3C*
C*
excessNaNR2 * workup
CH3C*
CH* *
1. R2BH2. H2O2/HO3. workup
aldehydes
H2SO4H2O/Hg+2
ketones
O
** *
H
O
**
*
1. BH32. Br2 / CH3O
Br*
** NaOH HO
**
* CrO3pyridine
H*
*
O
2. workup
MgBrH3C*
**
OH
*
CR C* *
R
Na/NH3
H2/Pdquinoline
H2/Pd
alkane
cisalkene
transalkene
RR
RR
R
R
1. Ts-Cl pyridine2. NaBr
**
Br
*
K
**
*
1. BH32. H2O2/HO
**
*
OH
t-BuO
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14C synthesis strategies, Chem 315/316 / Beauchamp 11
OC*
O
BrH3C* Mg
MgBrH3C*
1.
2. workupOH
**
O
SOCl2
Cl*
*
ORCO2H
ROH
NH3
RNH2
R2NH
H2O
R2Cu Li
1. DIBAH2. workup
anhydrides
esters
1o amides
3o amides
acids
ketones
aldehydes
O
O
**
NH2
O
**
OH
O
**
R
O
**
O
R
O
O
**
R
2o amides
NH
O
**
R
NH
O
**
R
H
O
**
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14C synthesis strategies, Chem 315/316 / Beauchamp 12
Starting possibilities to produce alcohol functionality (or carboxylic acid from CO2).
C
O
H H C
O
R HC
O
R RC
O
R OR' C
O
O methanal(formaldehyde)
generalaldehyde ketone alkyl ester carbon
dioxide
C C C CO
C
Br
alkene epoxide RX compound
C
O
O OR'R'
dialkylcarbonate
Some useful interconversions in 14C syntheses (using 1C transformations).
WK = workup (neutralization)
BrH3C BrH3CNaOH HBr
1. NaBH42. WK
PCCCrO3, no H2O
JonesCrO3, H+, H2O
OHH3C
OHH3COH2C
OH2C
CH
O
OH
CH
O
OCH2CH3
OHH3C CH
O
OH
1. LiAlH42. WK
OH2C
1. NaOH2. CH3CH2Br
1. LiAlH42. WK
1. DIBAH2. WK
MgBrH3C
LiLiH3C
BrH3CMg
BrH3C
C NH3CBrH3C
BrH3C
Na CN
Na CN C NH3C
There are many C-C bondforming reactions possibleusing these reagents
Sample Reactions of Nitriles - further transformations to: amines, amides, carboxylic acids, aldehydes, ketones
1. LiAlH42. WK
HCl H2O
H2SO4H2O, ∆
1. DIBAH2. WK
1. R'Li2. WKCR N
CR N
CR N
CR N
CR NCH2RNH2
CRO
NH2
CRO
OH
CRO
H
CRO
R
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14C synthesis strategies, Chem 315/316 / Beauchamp 13
single step transformations
OBr OH OH
Br OHHO
CH3OH H2C=OH
COH
O
BrBr
OBr OH OH
Br OHHO
CH3OH H2C=OH
COH
O
BrBr
Br OHH
O
OH
O
OH
an extra synthetic step
OHH
O
OH
O
Br OTs OH
O
Br OTs
OHH
O
OH
O
Br OTs Br OH
O
O
O
CH3 (MgBr) OH
OH
OH
OH
OH
OH
epoxide 1
carbonyl 2
carbonyl 3
carbonyl 4
epoxide 2
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
CH3CH2 Li (MgBr)
OH
"
"
""
"
"
"
"
"
"
"
"
"
"
"
"
"
"
"
"
CH3CH2CH2 Li
O
O
CH3CH2 Li2 eqs
1.
2. WK
OH
OH
OH
O
O
BrBr
BrBr epoxide 1
carbonyl 1 OH
HO
CH3 (MgBr) CO2
OH
O1.2. WK
A
B
C D
E F
G H I
KJ
1 2 3 4 5 6 7 8 9
1 2
3
4
5
6 7 8 9 10 11
9 10 11
1 2 3 4 51 2 3 4
1 2 3 4 1 2
1
2
3
4
5
6
1
2
3
4
5
6
1
2
3
4
5
6
1
2
3
4
5
6
1
2
34
5 6
7
carbonyl 1
epoxide 1
carbonyl 2
carbonyl 3
carbonyl 4
epoxide 2
carbonyl 1
epoxide 1
carbonyl 2
carbonyl 3
carbonyl 4
epoxide 2
carbonyl 1
epoxide 1
carbonyl 2
carbonyl 3
carbonyl 4
epoxide 2
carbonyl 1
epoxide 1
carbonyl 2
carbonyl 3
carbonyl 4
epoxide 2
carbonyl 1
O
O
O
H3C H
O
H H
O
HO
H3C C 3H
1. xs NaNH22. WK
1. xs NaNH22. WK
CH3 Li2 eqs
1.
2. WK
A workup step is assumed after all above reactions.
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14C synthesis strategies, Chem 315/316 / Beauchamp 14
CC C
OH
CC
HO
CC
OH
NuE Eclue: COH group could have been C=O group (aldehyde or ketone)
CCO
HO
CC
OH
ONu
EE
clue: COH group could have been C=O group (carbon dioxide)
Nu
clue: COH group could have been an epoxide group
CCR
C
HO
Nu
E
clue: COH group could have been C=O group (ester)
CC
OH
R
CNu
E
In our course every carbon carbon bond made with a starred carbon must be made with a nucleophile/electrophile reaction.
CCnuclephile (Nu) = ?
electrophile (E) = ?Nu
C
O
R HC
O
OC
O
R RC
O
R ORO
BrRMg or 2 Li
(MgBr) or LiR
electrophiles = (E)
nucleophiles = (Nu)
1. Propose a synthesis for the following compound using only *CH3OH and *CO2 as your source of radioactive 14C isotope. Bromobenzene, methanol, ethene and propene are also available. Work backwards from the target. The last step of the synthesis should be your first step. Show the reagents and reactant for each backwards step until you reach either of the 14C compounds above. Do not show mechanisms. Could you make the same molecule if you had to use Na*CN instead of *CO2?
O
OH How?
Possible Solutions
O
OH
1. Mg2. CO23. WK Br OH
HBr orPBr3
OHBr
1. Li
2.3. WK
O
HBr orPBr3O
H
1. Mg
2.
3. WK
O
H
new target
CrO3, no H2O PCC
OH
CH3OHCH3Br
1. Li2. H2C=O3. WK
HBr orPBr3
Br
CH3OH
CrO3, no H2O PCC
Br
...or with sodium cyanide
Na C N CN
H2SO4, H2O, ∆strong acid hydrolysis of an amide
O
OH
H2C CH2
mCPBA
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14C synthesis strategies, Chem 315/316 / Beauchamp 15
Possible approaches to simple alcohols (with label and without label)
Synthesis of C3 alcohols
OH
OH
Br
OH
Br
BrH3C
1. Mg
1. Li2.
1. Mg
O
C
O
H H
3. WK
2.
HBr OHBr
1. Mg
C
O
H H
3. WK
2.
HBrOH BrH3C
OHH3C
HBr
1. Mg
C
O
H H
3. WK
2.
C
O
H H
1. NaBH42. WK
OH
3. WKBrH3C
BrH3C
C
O
CH3 H
2.1. Li
3. WK
OH
CrO3no H2O
H3O+
H2OOH
C
O
H O
1. Mg
2.
3. WKBrH3C
2 eqs.
C
O
H OHBr2.
1. NaOH
OHH3C
CrO3H2O
JonesPCC
OH C
O
H O
1. Mg
2.
3. WKBrH3C
2 eqs.
C
O
H OHBr2.
1. NaOH
OHH3C
CrO3H2O
Jones
BrH3C
C
O
CH3 HOH
1. Mg2.
3. WK
CrO3no H2O
PCC
OH1. Li2. H2C=O
3. WK
HBrOHH3C
Synthesis of C4 alcohols from ethene or propene
OH2. H2C=O3. WK
1. BH32. H2O2, HO
1. BH32. Br2, CH3O
HBr
BrHBr
1. Li
1. Mg
2. O
3. WK
OH
OH
H3O+
H2O CrO3no H2O
PCC
O
H
BrHBr
HBr 1. Mg2.3. WK
1. O3, -78o
2. NaBH4OHH3CHBrBrH3C
1. BH32. H2O2, HOOH
CrO3no H2O
PCCH
O
1. Mg2.3. WK
OH
OH
HBr
Br 1. Li2. H2C=O3. WK
1. O3, -78o
2. CH3SCH32 H2C=O
H3O+
H2OOH CrO3
H2O
JonesO
1. O3, -78o
2. NaBH4OHH3C HBr
BrH3C
2. O
3. WK
mCPBA
Additional C5 alcohol targets from ethene and/or propene
OH
OH OH
OHOH
OH
HO
OH
1 2 3 4 5 6 7 8
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14C synthesis strategies, Chem 315/316 / Beauchamp 16
BrH3C
Br2hν HBr
CH4
OHH3C
1. LiAlH42. WKNaOH OHH3C BrH3C CH4
OHH3C
CrO3/pyridine(no H2O), PCC
O
CH H
2. WK
1. NaBH42. WK
CrO3/H2O/H3O+
Jones
O
CH OH
1. NaOH2. CH3-Br
O
CH O
CH3
1. LiAlH42. WK
BrH3C
DIBAH = diisobutyl aluminum hydrideAlH
R
R R = isobutyl
1.
2. WK
BrH3C
Mg
Li
MgBrH3C
LiH3C
O
H2C O1.2. WK
1.
2. WK OH
OH
* * * * *
**
* * *
**
**
BrH3C
BrH3C
*
* NaCN
NaCN
CH3C
*
N
CH3C*
N
MgBrH3C
LiH3C
C OO1.2. WK
C OO1.2. WK
H3CC
O
OH
H3CC
O
OH
*
*
*
*
WK = neutralization
Possible 1C starting structures and common functional group interconversions (FGI)
CH4 BrH3C OHH3C
O
CH H
O
CH OH
O
CH O
CH3NaCN C OO
* * ** * *
* *
**
Alkene regiochemistry and stereochemistry
CH4
Br
Br
OH
OH
OH OH
OH OH
Br Br
Br Br
OH OH
Br Br
O
H OH
O O
O O
(2 ways) (2 ways)
(4 ways)
(2 ways) (2 ways)
ester
acid chloride
acid chloride
ester
amide
acid
acid
Also possible from RX: nitriles, amines, ethers, esters, alkynes (by SN chemistry), alkenes (by E chemistry)
(2 ways)
(≈ 20 ways)
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14C synthesis strategies, Chem 315/316 / Beauchamp 17
Carbon skeletons from C1 – C7
CH4
C4 skeletons
a b c
d e
f g h i
a b
a b c
a b c d e
C5 skeletons
C6 skeletons
C7 skeletons
C3 skeletonC2 skeletonC1 skeleton
Seven carbon skeleton – “isomer c” with variable 14C labels
*
**
*
**
*
C1-star C2-star C3-star C4-star
C5-star C6-star C7-star
12
34
56
7
Seven carbon skeleton – “isomer c” with 14C label on first carbon (C1-star) and variable “OH”
C1-star, C1-OH
1
23
45
6
7
*HO
* * *
**
*
OHOH
OH
OH
OH
OHC1-star, C5-OH
C1-star, C2-OH C1-star, C3-OH C1-star, C4-OH
C1-star, C6-OH C7-star, C1-OH
One possible retrosynthetic scheme for C3 alcohol
OH
* O
Br
* OH*
BrH3C*
O
CH4
OHH3C*
*
Br
O
H*
BrH3C
OH
*
*O
BrH3C*
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14C synthesis strategies, Chem 315/316 / Beauchamp 18
CH4
f g h i
a b c d eC7 skeletons
C3 skeletonC2 skeletonC1 skeleton
X
X
X
X
XX
X
X
X
X
X
XX
X
X
X
X
X X
X
X
X
X XX
XX
XX
X
X
X
X
a
b
c
d
e
f
h i
g
X
X X
X
X
X
Starting sources of carbon, plus any reagents studied in the course.
1 2 3 4
1
1
1
1
2
2
2
2
3
3
3
3
4
4
4
4
5 6
75
5
6
6
1
1
1
1
2
2
2
2
3
3
3
3
There are many ways to total 7 carbon atoms. 3 + 3 + 1 = 7 3 + 2 + 2 = 7 2 + 2 + 2 + 1 = 7 3 + 3 + 2 - 1 = 7 2 + 2 + 2 + 2 - 1 = 7These are a few examples.
X can be -OH (alcohols), which can be oxidized to aldehydes (1o ROH), carboxylic acids (1o ROH) that can be made into esters or ketones (2o ROH). X can be a leaving group (Cl, Br, I, OTs) made from an alcohol or an alkene, which can then react by SN or E chemistry, or be made into an organometallic reagent (Mg or Li). X can be a 1o amine (-NH2) using phthalimide = Gabriel amine synthesis.
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14C synthesis strategies, Chem 315/316 / Beauchamp 19
X can be an ether from RO - and a methyl or 1o RX electrophile (SN2, Williamson ether synthesis) or from ROH and 2o/3o RX (SN1, R+ intermediate). X can be a cyano group (-CN) from an SN2 reaction of cyanide at methyl, 1o, 2o RX. X can be an H from SN2 using nucleophilic hydride (LiAlH4 or NaBH4). This reaction can be distinguished by using deuterium in place of hydrogen. X can lead to alkenes via E1 (H2SO4/∆ with ROH) or E2 reactions (very strong or strong and bulky bases with RBr) A Wittig reaction puts the C=C where desired. X can be an alkyne if a leaving group is at a primary position. Remember the limitations of each type of reaction (SN2, E2, SN1, E1, etc.).
O
O
**
N
O
**
H
O **
*
*
*
*
*
O
2 problems in one structure (ester)joined (acid + RX) by SN chemistry, (acid-Cl + alcohol),(acid + alcohol) by acyl substitution
2 problems in one structure (amide)(joined acid-Cl + amine) by acyl substitution, amine = NH3,RNH2,R2NH
2 problems in one structure (ether)(alcohol/alkoxide + RX),(alcohol + alcohol) by SN chemistry
2 problems in one structure (alkyne) by terminal acetylide + Me or 1o RX,SN chemistry
Up to 4 problems in one structure,can have 1, 2, 3 or 4 branches
**
2 problems in one structure (alkene, E or Z) from reduction of alkyne or Wittig reaction.
**
2 problems in one structure (ketone)(acid chloride + cuprate),(aldehyde + RX)(cyanide to nitrile to ketone)
O
Multiple problems in one.
How can one cut up these molecules into simpler parts?
Wittig
either sideeither side
both sides
either side
*all sides
alkynealkyne
Some of the Synthetic Strategies in 14C Game 1. Every *C-C (carbon-carbon) bond to a *C must be made. If atoms have been joined together, is there an obvious nucleophile
(alkyne, cyanide, Mg or Li reagent) and/or electrophile (an OH that was a C=O or an epoxide)? You need one of each. If one part is obvious, can you think of how the other part might be made? Could you join the atoms in the opposite fashion (umpolung)? Think in both directions.
2. Functional Group Interconversions (FGI) are often used (i.e. ketone to alcohol, or alcohol to ketone, or alcohol to bromoalkane, which can be a leaving group for an SN reaction or made into Grignard or Lithium reagents). Which carbon could have been a carbonyl (C=O) functional group and altered by the reactions shown? (such as methanal, general aldehyde, ketone, ester, carbon dioxide)? Or, could have been some other functional group (alkene, RX compound, epoxide)?
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14C synthesis strategies, Chem 315/316 / Beauchamp 20
3. Alcohols are often oxidized to carbonyls (alcohols aldehydes, ketones, carboxylic acids) (carboxylic acids esters, acid chlorides) (acid chlorides esters, 1o,2o,3o amides, ketones, aldehydes, thiolesters), which can be used as electrophiles (etc.).
4. Many organic groups can be reduced (alkene alkane, alkyne Z-alkene, E-alkene, alkane, carbonyl alcohol, alkane, etc.)
5. Additional special reactions of course (Wittig, Wolff-Kishner, Clemmenson, enamine, imines, cuprates, etc.).
6. Protections are sometimes necessary (acetals, ketals “C=O” protected with ethylene glycol or “ROH” protected as THP ether). There are many other kinds of protections besides those discussed in our course.
7. If starting from some “functional group”, what features are retained in the target structure?
8. If thinking back from the product, what features need to be generated in the product?
9. Draw a possible starting structure and consider what reactions possible reactions that we have studied could make the target functional group? Does one seem better suited than another?
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14C synthesis strategies, Chem 315/316 / Beauchamp 21
Reactions Worksheet 1 - starting with one carbon atom (methane)
H3C BrCH4
H3C Br
H3C OH
**
*
*
*
= 14C labelled carbon atom
H3C NH2*
H3C O*
H3C Br*
OH
OH
**
*
**
CH3C N* *
CH3
CH4*
O
OH**
C
O
C
O
H OH
H H
*
*
H3C O*
CH3
C
O
H OCH3*
*
*
H3C OH*
H
O
OCH3* *
Br
**
O
H**
O
OH**
**
Br
**
Br **
O
Br***
*
O
O** CH3
*
* *
* *
O
*
**
Br
*
*
*
Br***
Br
**
OH**
*OH*
**
O
H**
*
O
**
**
**
OH
OH* * *
*
*
*
O
**
*
**
*
*
OH
*
**
**
**
OH
OH
*
*
*
*
*
**
*
*
OH
*
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25 26
27
28
29
30
31
32
37
33 34 35 36
38
39
40
41
42
43
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14C synthesis strategies, Chem 315/316 / Beauchamp 22
Where can we go starting with a 2 carbon alkane? Fill in the missing reagents below to show how each step could occur? These are important reactions for you to be able to make the transformations necessary to do well in this course. Each step has a mechanism, and you should also have an idea how these work. Use any reagents that we have studied, as you need them.
Br
OH
O
O
H
O
O
CH2
O
OHH3C
Br
O
OH
BrBr
OH
OH
2 eqs.BrH3C
O
O
OH
OH
O
H
CN
O
O
OH
O
Cl
O
O
O
O
O
NH2
O
NH
O
OH
O
H
O
O
O
H
O
OH
Br
OH
OH
1
2
3
4
5
67
8
9
10
11
12
13
14
15
16
17
18 19
20 21
22
23
24
2 eqs.
25
26
27
28
29
3031
32 34
35
36
37
38 39
40
41
42
43
44
45
46
47
48
49
OH
OH
O
O
50
51
53
O
H
33
52
54
55
O
OH
NH2
O
NH2
56
57
58
NH
OH
NH
59
60
61
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