Investigation of Anomalous Effects in the Deprotonation and

Alkylation of KetonesPatrick Kelly-Goss

2004

Background

• Development of new methods for synthesizing amino acids is highly desired– Often biologically active– Useful for biochemistry experiments– Medicine

Background

•Alkylation of aminoketones

- Adds alkyl group

- Deprotonated (H+ removed) by base

- 2 or 3 eq. usually used.

• 1980 Hoye et al. study

- Used 1 eq.

O

N

H

O

N

H

O

O

R

Problem

• Mid-1990s Tetrahedron Letters study

• Should bond at No. 1 carbon– Most acidic

• Bonds at No. 3 carbon– 2nd most acidic

N

H

O

O

R

N

H

O

O

R

Hypothesis

• During Cr-mediated oxidation, Cr+6 ion bonds to No. 1 carbon.

• Blocks most receptive bond site, forcing alkyl group to bond to No. 3 carbon.

O

N

H

O

Cr

R

Methods

Synthesis–Two ketones

• Oxidation–Two methods

• Alkylation• Testing

Synthesis of Ketones• Under Schotten Baumen conditions

– Derived from aminopropanol

– Using benzyl chloride (top) and benzoyl chloride (bottom)

• Produces two alcohols

N

H

2

O

H

Cl

N

H

O

H

C

h

2

C

l

2

+

N

H

2

O

H

Cl

O

N

H

O

H

O

C

h

2

C

l

2

+

Oxidation of Ketones

• Two different methods used– RuCl3

– Chromic acid (H2CrO4)

• Total of four test groups

• Purified using MPLC

Oxidation of Ketones

N

H

O

H

Cr

O

O

O

H

O

H

N

H

O

H

O

Cr

O

O

O

H

O

H

N

H

O

O

N

H

O

H

N

H

O

N

H

O

H

O

N

H

O

O

R

u

C

l

3

R

u

C

l

3

N

H

O

Alkylation of Ketones

• Add alkyl (R–) group to ketone using standard procedures

• Check structure via NMR• Not completed

N

H

O

O

N

H

O

O

R

Strong Base

R'X

Results

• No alkylations completed– Testing impossible

• Difficulty encountered in oxidation– Very low yields (< 2%)– Confusing NMR spectra– TLC revealed wrong product taken– Most lost in MPLC

Results

NMR spectrum of middle (incorrect) layer

NMR spectrum of top(correct) layer

Results

• MPLC allowed to run for significantly longer than expected requirement– Ketones successfully synthesized, oxidized

• Work halted due to time constraints– No alkylation completed– No meaningful data

Discussion• Original Tet. Letters study

– Wrong eq. base used

– Would change which protons stripped

– May explain bonding “error”

• Little to explain• Should future work be desired:

– Determine if different bases would have effect

N

H

O

O

R

Acknowledgements

• Ms. Fruen

• Team Research

• Dr. Rita Majerle

Investigation of Anomalous Effects in the Deprotonation and

Alkylation of KetonesPatrick Kelly-Goss

2004