c synthesis strategies, chem 315/316 / beauchamp 1psbeauchamp/pdf/organomet_syn_strategies.pdf14c...

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

Z:\classes\315\315 Handouts\organomet_syn_strategies.doc


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



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


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)



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


Br2/ROH

Ph

O

Ph

mCPBA

Zn(Cu)CH2I2


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


NaOH/H2O


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


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



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)


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)


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



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


NH2

TsOH (-H2O)


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



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



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




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



OH OH OH

OH



OH OH OH

OH



OH OH OH

esters (adds 2x)

esters (adds 2x)

esters (adds 2x)

H3CC

N

CH2

CN

H3C

O O O O



O O O O



nitriles

nitriles



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*



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



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

**



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



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.



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



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



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)



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*



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.



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)?



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?



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



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


c synthesis strategies, chem 315/316 / beauchamp 1psbeauchamp/pdf/organomet_syn_strategies.pdf14c...

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