Poster presented at the Thompson Rivers University Undergraduate Conference, 2014.

1. Directed Ortho Lithiation of Biphenyl Containing Different Tertiary
Amide Directing Metalation Groups at the 4 and 4’ Positions
Quinton Sirianni, Dr. J. Norman Reed, and Dr. Bruno Cinel || Thompson Rivers University
Introduction
Directed ortho metalation (DOM) is a useful synthetic
technique that allows for the synthesis of aromatic rings
with substitution patterns not easily obtained via other
methods (eg. 1 => 3 and 4 => 6).
DOM chemistry has been performed extensively using
either diisopropyl (1) or diethyl benzamides (4) in the
past.1,2 However, no comparison of these directing
metalation groups (DMGs) in terms of their relative
directing power has ever been reported.
Project Goals
In order to compare the two benzamides to assess whether
or not one has a significantly greater directing effect over
the other, a biphenyl compound containing both DMGs
had to be synthesized (7). Once compound 7 was
synthesized and isolated, a DOM reaction could then be
performed using a limited amount of t-butyl lithium and
an electrophile to create a substituted compound (8 or 9).
Synthetic Strategies
A synthesis of compound 7 was required for this study.
Therefore, two separate strategies were attempted in order to
synthesize the compound with varying success (Strategies A
and B).
Scheme 1: Overview of DOM synthesis, which allows an electrophilic group (E+) to substitute at the
ortho position of aromatic compounds
Scheme 2: DOM chemistry with a biphenyl containing both diethyl and diisopropyl amide to evaluate
competition between the two DMGs when limited reagent is available
Results
During synthetic strategy A, an intermediate biphenyl
compound containing the diethyl amide and a carboxylic acid
was isolated from the rest of the reaction mixture and
identified using proton NMR (Figure 1). The intermediate
was then combined with more intermediate from a previous
synthesis, converted to the acid chloride (Strategy A) and then
reacted with the diisopropyl amide to give compound 7
(Figure 2).
Despite the positive identification of compound 7 using
strategy A, the strategy was complex and the yields of the
intermediate and final product were quite low (15.13% and
45.87% respectively). Thus, strategy B was employed. By
using a chromatographic column for separation, a quick one
pot synthesis was possible with an overall yield of 16.1%
Figure 1: Proton NMR of the acid intermdiate in strategy A. Note the deshielded broad acid OH peak at ~13ppm
Figure 2: Proton NMR spectra of compound 7 (bottom spectrum) as well as the biphenyl analogues of diethyl and diisopropyl benzamides.
Note the four doublets from the aromatic hydrogens in compound 7 versus the two in the symmetric diamides.
Figure 3: NMR spectra of compound 7 at high and low concentrations. At low concentration, two of the aromatic doublets seem to
overlap. However, the peaks separate as concentration increases, suggesting an interaction between the molecules in solution.
Future Work
 Carry out directed lithiation competition reaction
shown in scheme 2
 Serial dilutions of a saturated compound 7 solution
to evaluate the aromatic hydrogen NMR peaks as
concentration decreases
References
1. Snieckus, V. Chem. Rev. 1990, 90, 879.
2. Beak, P.; Kerrick, S. T.; Gallagher, D. J. J.
Am. Chem. Soc. 1993, 115, 10628.