Ancillary Ligand Design in the Development of Palladium Catalysts for Challenging Selective Monoarylation Reactions - New Trends in Cross-Coupling: Theory and Applications - page 247

acetone enolates. 64-67 However, such strategies employing 'acetone enolate
equivalents' lack atom economy and introduce added costs, given the re-
quirement for extra synthetic steps and the use of stoichiometric additives;
clearly, the direct use of acetone is preferred in the construction of phenyl-
acetone derivatives, which are sought-after for their biological properties.
In this regard, the selective monoarylation of acetone was first reported
by Stradiotto and co-workers in 2011 by use of [Pd(cinnamyl)Cl] 2 /L10. 68
This catalyst system was initially chosen for a test examination involving
the addition of 4-chlorotoluene to acetone, on the basis of its ecacy with
regard to the selective monoarylation of ammonia and hydrazine (see Sec-
tions 5.2.4 and 5.3.1). 46,57 Preliminary optimization experiments established
2 mol% Pd (Pd:L10 ¼ 1:2), acetone (10 equiv. or neat) and Cs 2 CO 3 (2 equiv.) at
90 1C for 5 h as representing suitably effective conditions for the high-
yielding formation of 4-tolylacetone (89% yield); the use of other palladium
sources [Pd(OAc) 2 or Pd(dba) 2 ] or bases (K 2 CO 3 ,Na 2 CO 3 ,LiHMDSorNaOtBu)
afforded comparatively poor results. In screening alternative ligands in this
chemistry, it was found that replacement of the di(1-adamantyl)phosphino
group in L10 for a dicyclohexylphosphino group or the morpholino moiety
for a dimethylamino donor fragment (i.e., L9) resulted in a loss of catalyst
selectivity and/or activity. A series of other sterically demanding and electron-
rich monophosphines/N-heterocyclic carbenes were also surveyed under
analogous conditions, including L1 and L3, with each providing inferior re-
sults to those obtained when using L10. 68
The scope of acetone monoarylation reactivity exhibited by the [Pd(cin-
namyl)Cl] 2 /L10 catalyst system (2-5 mol% Pd; Pd:L10 ¼ 1:2) was found to
accommodate structurally diverse aryl chlorides, bromides, iodides and
tosylates (Figure 5.13, A) in neat acetone at 90 1C. 68 Electron-rich, -neutral
and -poor aryl chlorides were employed successfully, including substrates
featuring ether, alcohol, olefin, tertiary amine or N-heterocyclic (pyridine,
pyrrole, N-benzylindole) addenda. Furthermore, aryl chloride electrophiles
featuring potentially competitive enolizable sites, including benzyl and
homobenzyl esters or an acetanilide group, were employed successfully in
the chemoselective monoarylation of acetone, affording the substituted
phenylacetone derivatives in synthetically useful yields. Whereas in general
aryl bromides and iodides were also found to be suitable electrophiles in this
chemistry, the use of electron-poor aryl bromides, such as 4-bromobenzo-
nitrile, proved to be much more challenging (33% yield) when using the
[Pd(cinnamyl)Cl] 2 /L10 catalyst system. Although limited to only four entries,
the demonstrated scope in aryl tosylates was found to include electron-rich
and sterically congested substrate variants. 68
Scrutiny of the yield data as a function of electrophile structure revealed
that electron-poor aryl halides consistently provided lower yields of the a-aryl
methyl ketone product in comparison with electron-rich or -neutral aryl
halides when using [Pd(cinnamyl)Cl] 2 /L10; substrate competition studies
indicated that reductive elimination might be rate limiting when using such
aryl halides. 68

In response, a sterically hindered yet less electron-donating