2
J. G. Semmes et al. / Tetrahedron Letters xxx (2015) xxx–xxx
elimination more slowly than more nucleophilic monocarbonyl
enolates.3 Both of these challenges must be overcome to achieve
successful coupling.
Table 1
Base screening in coupling of 4-bromoanisole and diethyl malonate
The initial couplings of b-dicarbonyl enolates with aryl iodides
were achieved using stoichiometric amounts of copper.4 Catalytic
systems for these couplings were first reported by Miura and pro-
vided moderate yields using aryl iodides at high temperatures.5
Ligand-supported copper catalysts effect these couplings under
milder conditions, but are still limited to aryl iodide and bromide
substrates.6 Palladium-catalyzed coupling of aryl halides and eno-
lates was initially reported concurrently by the Hartwig,7 Buch-
wald,8 and Miura9 groups. Palladium-catalyzed methodologies
have been developed into highly general routes for the coupling
of aryl bromides, chlorides, and sulfonates with a wide range of
stabilized carbanions.1b,1c Despite these advances, palladium-
catalyzed arylation of b-dicarbonyl enolates still represents a
synthetic challenge. Initial reports by Hartwig and Buchwald
demonstrated that palladium catalysts were able to couple aryl
bromides and chlorides with b-dicarbonyl derivatives.10 A range
of sterically demanding, electron-rich phosphine and NHC ligands
have been shown to provide effective catalysts for coupling of
aryl bromides, chlorides, and sulfonates with b-dicarbonyl
derivatives.11 At elevated temperatures, arylation of malonate or
cyanoacetate esters is accompanied by decarboxylation to provide
Entry
Base
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
9
10
NaH
NaH
NaH
KH
Na2CO3
Na3PO4
K3PO4
NaOt-Bu
Et3N
Toluene
THF
DMF
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
100
45
33
53
45
52
73
0
0
0
iPr2NEt
a
Determined by GC.
gave no conversion to product (entries 8–10). Base strength does
not directly correlate with conversion. Both hydride and tert-
butoxide fully deprotonate the malonate anion, yet only NaH
results in conversion to product. Weaker bases that would not fully
deprotonate malonate give moderate yields in some cases (Na2CO3),
but no conversion in others (amine bases). The reasons for these
trends are unclear. Notably, good yields were obtained with diethyl
malonate, rather than the more hindered di-tert-butyl malonate
needed for some systems.11c
Using NaH in toluene at 70 °C, high conversion could be
achieved for a variety of electron-deficient and electron-rich aryl
and heteroaryl bromides with 1 mol % Pd(dba)2 and 2 mol %
DTBNpP (Table 2). Aryl bromides with electron-donating substitu-
ents in the 3- or 4-positions were successfully coupled to diethyl
malonate with yields ranging from 85% to 92% (entries 1–5). In con-
trast, the more sterically demanding 2-bromoanisole gave only a
29% conversion to product (entry 6). In the arylation of propiophe-
none with the DTBNpP/Pd system, ortho-substituted aryl halides
were tolerated, but low yields were obtained with di-ortho-substi-
tuted aryl halides.15 Switching to the more flexible TNpP ligand pro-
vided high yields with di-ortho-substituted aryl bromides. Use of
TNpP in the coupling of 2-bromoanisole with diethyl malonate gave
minimal conversion to product, however. Reductive elimination of
the more hindered and less nucleophilic malonate anion may be
more sensitive to steric effects than ketone enolates. The smaller
steric demand of the conformationally flexible TNpP ligand may
a
-arylacetonitrile or a-arylacetic acid derivatives directly in
analogy to the malonic ester synthesis.12
Sterically demanding, electron-rich ligands have generally been
found to be most effective for arylation of b-dicarbonyl derivatives.
Sterically demanding ligands are expected to overcome the partic-
ular challenges faced in coupling with b-dicarbonyl. The bulky
ligand can disfavor the j
2-O,O-binding mode, while also promoting
reductive elimination. Electron-rich ligands promote oxidative
addition, allowing less reactive aryl chloride and aryl sulfonate
substrates to be used.
Our group has previously reported the use of di-tert-butylne-
opentylphosphine (DTBNpP), tert-butyldineopentylphosphine
(TBDNpP), and trineopentylphosphine (TNpP) in C–C bond-forming
reactions,13 amine arylations,14 and arylation of ketone enolates.15
Calculated cone angles suggest that DTBNpP is more sterically
demanding than tri-tert-butylphosphine (TTBP) and has similar
electronic properties.14a Additional neopentyl groups further
increase the calculated cone angle, but also provide additional con-
formational flexibility. As a result, TNpP appears to be effectively
less sterically demanding than DTBNpP or TTBP and provides effec-
tive catalysts for cross-coupling of highly sterically demanding
substrates.14b,15 Given the steric and electronic properties of
DTBNpP and its successful application in the arylation of ketones,
we hypothesized that it might provide an effective ligand for the
arylation of dialkyl malonates and other active methylene
compounds.
be unable to sufficiently disfavor the
j
2-O,O-coordination mode
of the malonate anion resulting in catalyst deactivation. High yields
were obtained with 4-bromophenol and 6-bromo-2-naphthol using
2.2 equiv of NaH despite the presence of the strongly electron
donating phenoxide anion (entries 7 and 8).
Results and discussion
Unfunctionalized aryl bromides gave comparable yields to
those with electron-donating substituents (entries 9, 10, 12, and
13). The one exception to this was 1-bromonaphthalene, which
gave no conversion, likely due to steric interactions with H8. Mixed
results were obtained with electron-deficient aryl halides. 1-
Bromo-4-trifluoromethylbenzene and methyl 3-bromobenzoate
gave good yields of coupled product (90% and 82%, respectively,
entries 15 and 18). 1-Bromo-4-fluorobenzene, 1-bromo-3,5-di(tri-
fluoromethyl)benzene, and 4-bromobenzonitrile gave slightly
lower yields ranging from 69% to 77% (entries 14, 16, and 17). 4-
Bromoacetophenone gave a 72% yield using the standard condi-
tions (entry 19). The yield could be improved to 84% using K3PO4
as the base. Similar improvements were not observed for other
electron-deficient aryl bromides, however.
Reaction conditions were optimized for the coupling of 4-
bromoanisole and diethyl malonate using DTBNpP in combination
with Pd(dba)2. A range of inorganic and organic bases were
explored. Complete conversion to product was obtained with
NaH (Table 1, entry 1) in toluene.10c More coordinating solvents,
such as THF and DMF, gave lower yields using NaH as the base
(entries 2 and 3). In contrast to NaH, KH gave only a 53% yield
under the same conditions in toluene (entry 4). Weaker bases, such
as sodium carbonate, sodium phosphate, and potassium phosphate
gave yields ranging from 45% to 73% (entries 5–7). Interestingly,
the cation effect with phosphate was opposite to that observed
with the hydride bases. Sodium tert-butoxide and amine bases