Intramolecular and Intermolecular         Cyclopropanation Studies using       Ethyl 2-diazo-3-oxonon-8-enoate

       and Cyclohexene

Presented by Matthew Shelnutt

Research Objectives

• Nature of the competition occurring inter- and intra-molecularly during a cyclopropanation.

• Reaction utilizing rhodium (II) acetate as a catalyst and cyclohexene as an intermolecular competitor.

• The length of the carbon chain varied per research student.

Uses of Cyclopropanation

Permethrin Structure

• Cyclopropanation reactions are used in a variety of fields:– They provide “key”

intermediates in the synthesis of pyrethroid insecticides such as permethrin. Permethrin is commercially available for use in pet sprays and crop dusting.

– Pharmaceutically, they provide the cyclopropanes found in antifungal drugs such as ambruticin.

Intended Products

Intermolecular

CH2

O O

CH3O

O O

CH3O

Intramolecular

N-

N+

OO

CH3 O CH2

(AcO)4Rh2

OO

CH3 O CH2

R h 2 (O A c ) 4

C yc lo h e x e n e

We hoped to end up with these products according to the following mechanisms, including the synthesis of all of the starting materials:

Overall Chemical Equation to form the Dienolate

Reaction Mechanism

CH3

CH3

CH3

CH3

N-

+O O

CH3 O C

H

HH

Li+

O-

O-

CH3 O CH2

Li+

Li+

CH3

CH3

CH3

CH3

N-

+O O

CH3 O CH3

H

H

Li+

CH3

CH3

CH3

CH3

N-

+O O

CH3 O CH3

H

H O-

O-

CH3 O CH2

Li+

Li+

Li+

2

Overall Chemical Equation to form the Keto Ester

O-

O-

CH3 O CH2

Li+

Li+

+CH2

Br

OO

CH3 O CH2

D ilu te H 2 S O 4

O-

O-

CH3 O CH2

Li+

Li+

+CH2

Br

Reaction Mechanism

OO

CH3 O CH2

OO-

CH3 O CH2

Li+

+O

O

O OS

H

H

ethyl 3-oxonon-8-enoate

Overall Chemical Equation to form para-Toluenesulfonyl azide

Reaction Mechanism

Cl

O

O

SCH3 + N-

N+

N-

Na+

N-

N+

N

O

O

SCH3

-

Cl

O

O

SCH3 + N-

N+

N-

Na+

-

N-

N+

N

O

O

SCH3

Overall Chemical Equation to form Ethyl 2-diazo-3-oxonon-8-enoate

N-

N+

N

O

O

SCH3 +OO

CH3 O CH2

H

H

E t 2 N H

E t 2 O

N

N+

OO

CH3 O C-

CH2

..

N-

N+

OO

CH3 O CH2

OO

CH3 O CH2

H

H

CH3 CH2

CH3

CH2

NH

OO-

CH3 O CH2

NN+

N-

O

O

SCH3

OO

CH3 O CH2

H

N-

NN

O

SCH3

Reaction Mechanism

N+

OO

CH3 O C-

CH2

N

:

Cyclopropanation using Ethyl 2-diazo-3-oxonon-8-enoate, Cyclohexene, and a Rhodium (II) Catalyst

N-

N+

OO

CH3 O CH2

R h 2 (O A c ) 4(AcO)4Rh2

OO

CH3 O CH2

(AcO)4Rh2

OO

CH3 O CH2 +

Intermolecular

CH2

O O

CH3O

(AcO)4Rh2

OO

CH3 O CH2O O

CH3O

Intramolecular

Laboratory Synthesis• Initial synthesis

proceeded as follows:– LDA in a 200 mL

round bottom flask– 0 C, Nitrogenous

atmosphere – Ethyl Acetoacetate

added dropwise with stirring

– 5-bromopent-1-ene added dropwise to the resulting solution to form dienolate

Synthesis Apparatus

Laboratory Synthesis

• Wash with 10% sulfuric acid

• Solution extracted 3 times with ether

• Ether collected and dried over BaSO4

• Now anhydrous solution placed on rotary evaporator to remove solvent.

Liquid-Liquid Extraction

The Product

Purification• To isolate our

compound from impurities, we implemented the technique of gravity column chromatography.

• The solvent used was a mixture of 2 Ligroine : 1 Petroleum Ether : 1 Ethyl Acetate

Column Chromatography Purification Apparatus

Further Purification• The initial column showed little

separation. A new column was set up, but this time with a new solvent. Possible choices were:– 3 MTBE : 1 Isopropyl

alcohol– 3 Methylene Chloride : 1

Methanol– 3 Hexanes : 1 Ethanol– Toluene, with a methanol

flush• Toluene with methanol flush

chosen to run the column.

Running TLC Plate

Vacuum Distillation

• Solution added to round bottom flask, and fitted with condenser tube.

• Hot oil bath made with electrical current.

• Heated so that impurities with lower boiling points will evaporate and condense out.

Distillation Apparatus

, 8-FEB-2008 + 18:43:47dienolate product mixture

4.00 9.00 14.00 19.00 24.00 29.00 34.00Time0

100

%

MBS83mix Scan EI+ TIC

1.98e9

2.75

18.69

GC/MS Analysis of Products • Product retention time is 6.310. • Extremely small peak – can’t be

seen

• Mass Spec. data shows molecular weights of all ions detected.

• Includes 198, the peak for the product.

• Larger ions peaks appear to be rearrangements of the product.

• The product wasn’t there in enough quantity to be used, and so the procedure was deemed unsuccessful.

Laboratory Synthesis II

• Creating our own starting products might have been a little too ambitious.

• Using the standard Grignard reaction procedure, we decided to create an enoate compound using bromobutane and Magnesium to create Grignard reagent, and then reacting that with diethyl amine and 4-bromo-pent-1-ene to produce the desired dienoate as shown:

Grignard MechanismBrCH32 + Mg2

E t 2 OMg

+CH3 Br

-2 + 2 CH3CH2NCH2CH3

H

CH3CH2N-

CH2CH3

OO

CH3 O CH3

H

H

+

CH3CH2N-

CH2CH3 +OO

O CH3

HH

H Mg2+

O-

O-

CH2 O CH3

+BrCH2

Grignard Mechanism CONT.

O O-

CH2 O CH3 + HOS

O

O

OH

O O

CH2 O CH3

Ethyl 3-oxooct-7-enoate

Grignard Procedure• Typical Grignard – Magnesium

chips, ether, and bromobutane are added to 500 mL round bottom flask.

• Reflux started by mild heating.• Diethyl amine added in dropwise to

a the resulting Grignard reagent at 0 C.

• Ethyl acetoacetate added dropwise at 0 C, and stirred for 30 minutes.

• Allyl bromide is added at 0 C and allowed to stir overnight to ensure reaction completion.

• Rinsed with acid to dissolve remaining solid, extracted using ether, and run through the GC. Synthesis Apparatus

, 22-APR-2008 + 15:59:31

3.00 5.00 7.00 9.00 11.00 13.00 15.00 17.00 19.00Time0

100

%

JPH 77 Final Final Final HM Scan EI+ TIC

5.31e62.57

18.4617.213.80

3.42

16.74

15.8515.1314.01

19.20 19.70

In the future..

• In the process of attempting to synthesize a suitable dienoate for our competition reactions, we discovered how difficult it was to use chemicals such as LDA to get a meaningful yield.

• To correct for this, and one of the last syntheses done, we utilized a Grignard mechanism to produce the dienoate.

• We are going to continue research on the production of enoates using Grignard-like reactions to make a more “undergraduate friendly” way to produce them.

• 4 or 5 other alkyl halides will be used in a similar process to ensure the same great yield and to ensure reproducibility.

Recognitions

• Dr. Hornbuckle, my wonderful advisor• Clayton State University• The Natural Sciences Faculty and Staff• The Department of Natural Sciences for funding our

research• Dr. Furlong, Department Head• Joe Holak, partner• Hieu Dinh, partner