Progress Towards the Synthesis of 4,5-Benzoxepin Derivatives for
Use in Coupling Reactions
Bryanna Dowcett, Arthur Greenberg, Holly Guevara
brd10@wildcats.unh.edu, Department of Chemistry, University of New Hampshire, Durham, NH
12/10/2015
The base catalyzed Williamson Ether reaction and
intramolecular Friedel-Crafts cyclization worked well. The
free radical bromination with NBS resulted in unreacted
starting material as well as unknown products. The crude
mixture was purified by column chromatography, but TLC
showed that the collected fractions were still impure
(Figure 1). It showed sufficient separation, so that
chromatography could be performed again. There was not
enough product collected to continue on to the elimination
reaction.
Knowing the mechanistic pathways by which benzene, a
known carcinogen, breaks down in the body is useful in
preventing and treating illness. Oxepin derivatives are
useful in investigating the ring opening mechanism of
oxepins as seen in benzene metabolism.1 This project
explores the improvement of the synthesis of a
benzoxepin derivative for use in the research of oxepin
oxidation by the Greenberg research group.2 It will be
used in sp3-sp3 coupling reactions in an attempt to
synthesize compound 1.
Another column could be run to separate starting material and
possible products. Alternatively, the bromination could be
performed again using a photochemical reaction instead of heat
to achieve better yields and purities. The elimination reaction
would then be performed to yield the desired product 6.
Scheme 3. Elimination of Bromine to Yield Benzoxepin
Derivative
Scheme 2. Completed Experimental Work Toward Synthesis
A
C
D
A
D
B
D
B
Scheme 1. Oxidation of Oxepins
C
B
B
A
A
D
C
C
EtOAc
The synthesis of the 3 was completed, however, the final
product requires further studies. It was found that heat
alone is not sufficient for the initiation of bromination.
Instead, using light may yield better results.
EtOAc
EtOAc
A multistep synthesis was performed starting with 1phentylethanol 2 to yield phenethyloxyacetic acid 3.3
An intramolecular Friedel-Crafts reaction yielded 44,
which was then brominated using NBS to give the
brominated dihydro-benzoxepin 5.5 Potassium tbutoxide could be used to eliminate the bromine to
form 6, which is a precursor to the synthesis of 1 as
shown in Scheme 1. Each product was analyzed with
1H NMR and IR to verify purity and reaction progress
was analyzed by TLC.
Figure 3.1H NMR Spectra of Purified 3
Figure 2. 1H NMR Spectra of Crude 4. IR was
used to observe the elimination of the alcohol
OH stretch after purification
The Greenberg research group and UNH Department of
Chemistry are gratefully acknowledged.
D
A
D
C
B
(1) Vogel, E., Gunther, H., Angew. Chem. Int. Ed. 1967, 6, 385476.
B
C
Unknown
(2) Morgan, J., Greenberg, A., J. Org. Chem. 2010, 75, 4761-4768.
(3) Linn, K., Kuethe, J., Peng, Z., Yasuda, N., Tetrahedron Letters.
2008, 3762-3765.
(4) Holden, M., Crouch, D., Barker, K. J. Chem. Educ. Practical
Preparation of Benzyloxyacetic Acids. 2005, 82(6), 934-935.
Scheme 2. Proposed Synthetic Route to 2-Dihydro-4,5-
benzoxepin-3-one
Figure 3. 1H NMR Spectra of Unknown
Product in Fraction 3 and TLC analysis