Synthetic Approach to 5,6-Benzo-1-azabicyclo[2.2.2]octan-2-one: A Lactam having Zero Resonance Energy

Meghan Tobin, Dr. Arthur Greenberg, Jessica Morganmbj28@wildcats.unh.edu; Parsons Hall, 23 Academic Way, Durham NH 03824

Introduction Significance of Research Results and Discussion

References

•There are no examples of amide N-oxides. Compounds containing an amide N-oxide functional group may be useful models for oxygen transfer agents in organic synthesis.1 Loss of resonance energy may make formation of amide N-oxides feasible.

•In this study, the synthesis of 5,6-benzo-1-azabicyclo[2.2.2]octane-2-one (4), a lactam having zero resonance energy, was studied, in the hopes that oxidation of this benzoannelated lactam will yield an amide N-oxide.

• This benzoannelated version might prove easier to characterize by NMR than 6,6,7,7-tetramethyl-1-azabicyclo[2.2.2]octan-2-one (3) due to distinguishable chemical shifts of the methylene carbon on the benzoannelated 2-quinuclidone versus the quaternary carbon on 3. Also, anisotropies due to the presence of the benzene ring may further accentuate chemical shift differences.

Table 1: 13C-NMR chemical shifts (values in red are calculated) of the carbonyl carbons for planar and twisted amides/lactams. Notice that the planar lactam, N-methylpyrrollidone, has a calculated downfield shift while N-protonated and twisted lactams have upfield shifts. (Morgan, J.; Greenberg, A.; J. Phys. Org. Chem. 2012, 1422-1428)

• The observation of an amide N-oxide may be established by 13C-NMR. Calculations have shown that it may be better to use the carbons alpha to the nitrogen because they would undergo a large chemical shift if the oxidation occurs.

• The synthesis was carried out up to quinolinone 9. The reaction to yield 10 was attempted, however only starting material was recovered.2

• The amide bond plays a vital role in biochemistry. Amide linkages are the peptide linkages that connect amino acids in proteins; and form the reactive linkage in penicillin derivatives.

• The process of protein folding, as well as enzyme catalyzed proteolysis, leads to the distortion of the amide linkage.

• When the amide linkage is twisted, several characteristics are altered.• Decreased resonance stabilization• Increased reactivity• Altered binding of different ligands (e.g. change site of protonation)

Change Site of Protonation with Distortion and Loss of Resonance Energy:

(Calculation validated by experiment):

• The twists occurring in these lactams may also allow for oxidation to occur on the nitrogen.

N O N

O

N

O

ResonanceEnergies

20 kcal mol-1 10 kcal mol-1 0 kcal mol-1

N

O

4

Neutral lactam N-protonated O-protonated

174.9/172.1(CDCl3)

177.8180.5/183.5

(H2SO4)

197.8 175.9/175.5 261.1

190.7/182.2(CDCl3)

161.9 207.3

185.0/182.9(CDCl3)

179.0/178.4(H2SO4)

194.0/191.3(H2SO4)

NO

N

O

N

O

N

O

Acknowledgements

Future Work

NH2

H2COCH3

O

acetic acid N OCH3

H

O TsClpyridine

N OCH3

Ts

O

10% KOH

80% methanol N OH

Ts

O PCl5

dry benzene N

O

Ts

92.7%

27.3%

5 6 7

8 9

Zn/BrCH2CO2Et

N

HO CH2CO2Et

TsOH/Et3N

Ts

N

CH2CO2Et

TsN

CHCO2Et

TsN

H CH2CO2Et

Ts

HCl/EtOH

H2/Pt

N

H CH2CO2Et

H

NaOH/EtOH

N

H CH2CO2H

H

N

O

DCC

10

11a 11b 12

13 14 4

ACHIEVED

1. Greenberg, A. Breneman, C. M.; Liebman, J. F.; Eds.The Amide Linkage: Structural Significance in Chemistry, Biochemistry, and Materials Science. Wiley-Interscience: A John Wiley & Sons, New York, 2000; pp 47-80.

2. Johnson, W. S.; Woroch, E. L.; Buell, B, G,; J. Am. Chem. Soc. 1949, 71, 1901-1905.

3. Somayaji, V.; Brown, R. S.; J. Org. Chem. 1986, 51, 2676-2686.4. Blackburn, G. M.; Skaife, C. J.; Kay, I. T.; J. Chem. Res, Synop. 1980,

294-295.

Funding from the Department of Chemistry is gratefully acknowledged. Special thanks to Jessica Morgan and Dr. Arthur Greenberg for all their help and support, as well as Daniel Darcy for providing some crude product to work with. Also, thank you to Carley Spencer and Peter Moran for their helpful suggestions.

N

O

N

OO

46.9 64.2

N

OON O

66.2 82.5

• Future work would consist of activation of zinc dust, as well as the use of ethyl chloroacetate for the reaction to yield 10. Also, the completion of the synthesis to isolate 4. Oxidation studies can be performed to observe the desired amide N-oxide.

N O H N OHCH3

N

ON

OH

H

N

O

HN

O H

N

HO

1

3

2

N OHCH3