R.G.M. da Costa et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
precipitation. Subsequently, the
via a sequential bromination/Suzuki cross coupling, providing
b-diarylchalcones.
a
-position can be easily arylated
orine (Entry 1 vs Entry 6). A slight decrease in the yield was also
observed when the hydrogen was replaced by a methoxy group
(entry 3 vs entry 4).
a,
Concerning the stereoselectivity, E:Z ratios ranging from 71:29
to 81:19 were obtained. Moreover, there is not a clear relationship
between the chalcone structure and the diasteroisomeric ratio.
Fortunately, the strategy applied for obtaining (E)-2a could be suc-
cessfully extended to the other b-arylchalcones. Thus, products 2e
and 2f were obtained in a stereo-enriched form (E:Z ꢀ 96:4) in 20%
and 66% yield, respectively, after precipitation from EtOH. Analo-
gously, the NH2-substituted 2g was obtained in 26% yield (E:Z ratio
97:3) after precipitation from Et2O.
For additional insight regarding the Heck reactivity of chal-
cones, substrates with different substitution patterns were
employed in competitive reactions, and the initial rates were com-
pared using the product distribution and chalcone consumption at
low conversions (<20%), as depicted in Scheme 1. As expected, a
substantial effect of the substitution pattern on ring 1 was
observed (Scheme 1a), since the presence of a 4-methoxy group
enhanced the reaction rate, while a 4-nitro group led to an oppo-
site and even more pronounced effect. These findings can be
explained by a facilitated migratory insertion into the more elec-
tron-rich chalcones15 which is in agreement with the high yields
obtained in the synthesis of 2c and 2d and the low yield observed
Results and discussion
The chalcones used as substrates were prepared via classical
base-catalyzed Claisen-Schmidt condensation (EtOH, KOH, r.t.).1
For the Heck b-arylation, various parameters were screened in
order to determine the optimal conditions, using the coupling
between benzalacetophenone (1a) and 4-iodoanisole as a model
reaction (Table 1). A catalytic system based on Pd(OAc)2 and P(o-
Tol)3 was chosen due to the favourable results previously reported
with this precursor and ligand in the Heck arylation of diary-
lethenes, in terms of both reactivity and stereoselectivity.23,33 Five
bases were evaluated and the best results in terms of yield were
achieved with K3PO4 (Entry 3) and K2CO3 (Entry 5), with the latter
furnishing better stereoselectivity. Upon changing the ligand to
PPh3 a small decrease in both yield and E:Z ratio was observed.
Concerning the aryl halide, the reaction with bromoanisole
required an extended reaction time, which also resulted in a signif-
icant decrease in both yield and stereoselectivity.
After optimization, the conditions of entry 5 were employed in a
1.0 mmol scale reaction and the b-arylchalcone 2a was isolated in
99% yield with an E:Z ratio of 81:19. To our delight, after the addi-
tion of EtOH to the isomeric mixture, (E)-2a precipitated as single
stereoisomer in 78% yield. It is important to note that to the best of
our knowledge, in the previously reported Heck arylations of chal-
cones, the obtention of b-arylchalcones as single stereoisomers has
not yet been reported.
Subsequently, the reaction scope was evaluated by varying the
aryl iodide and the groups attached to both rings of the chalcones
(Table 2). When the reaction was performed using non-substituted
chalcone or chalcones substituted with the electron-donating
methoxy group on ring 1 (Entries 1–4), high to excellent results
were achieved (2a-d, 80–99%), with total consumption of the start-
ing material within eight hours. The presence of the electron-with-
drawing cyano group on the same ring (Entry 5) considerably
decreased the reactivity, and product 2e was obtained in only
34% yield, even with an extended reaction time (24 h). Significant
formation (13%) of the 1,4-addition product (reductive Heck pro-
duct) was noted, which is a by-product often observed in Heck
reactions with enones.15,34 Regarding ring 2, a small decrease in
the yield was observed when the hydrogen was replaced by a flu-
Fig. 2. Molecular structure of compound 2e, with 50% thermal ellipsoids (using
ORTEP software).
Scheme 1. (a) Competitive reaction for evaluation of the ring 1 substituent effect on the reaction rate. (b) Competitive reaction for evaluation of the ring 2 substituent effect
on the reaction rate. cReagents and conditions: chalcones (0.1 mmol), 4-iodobenzene (0.3 mmol), Pd(OAc)2 (2 mol%), P(o-Tol)3 (4 mol%), K2CO3 (0.4 mmol), DMF 120 °C, 30
min.