Investigation of Anomalous
Effects in the Deprotonation and
Alkylation of Ketones
Patrick 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
NH
O
O
N
H
R
O
Problem
• Mid-1990s
Tetrahedron Letters
R
study
• Should bond at No. 1
carbon
O
N
H
O
O
R
N
H
– Most acidic
• Bonds at No. 3 carbon
O
– 2nd most acidic
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
HN
R
O
Cr
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
H2 N
OH
Cl
+
Ch2 Cl2
OH
+
OH
O
O
H2 N
N
H
Cl
Ch2 Cl2
N
H
OH
Oxidation of Ketones
• Two different methods
used
– RuCl3
– Chromic acid
(H2CrO4)
• Total of four test
groups
• Purified using MPLC
Oxidation of Ketones
O
O Cr OH
N
H
OH
OH
O
O
O Cr OH
N
H
N
H
N
H
O
O
OH
N
H
OH
RuCl3
N
H
OH
O
O
O
O
N
H
RuCl3
OH
N
H
O
Alkylation of Ketones
• Add alkyl (R–) group to ketone using standard
procedures
• Check structure via NMR
• Not completed
O
O
N
H
Strong Base
O
R'X
R
N
H
O
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
O
R
N
H
O
Acknowledgements
• Ms. Fruen
• Team Research
• Dr. Rita Majerle
Investigation of Anomalous
Effects in the Deprotonation and
Alkylation of Ketones
Patrick Kelly-Goss
2004