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

IntroductionDirected 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 GoalsIn 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 StrategiesA 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

ResultsDuring 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.