Organic Letters
Letter
a b
,
highlighted as the most common substrates to react with
different alkenes or alkynes, thus constructing corresponding
benzoheterocycle products. To finish the annulation, we did
believe that the activation of a C−H bond on the ortho carbon
atom of a carboxylic acid or amide was a key step to start the
transformation. In general, the carboxyl group can be seen as a
directing group to direct metal catalysts to functionalize a C−
H bond on its ortho position.17 Now that we have already
finished the desaturation of ketones, we may bring another
transition-metal salt, such as Pd, Rh, or Ir, into this reaction to
realize the combination of benzoic acids and in situ generated
enones. Apart from our previous work, we also investigated
various methods to achieve the desaturation of saturated
ketones for constructing the β-functionalization of ketones.18
Taken together, herein, we tried to develop a Cu−Pd
bimetallic system to realize the one-step synthesis of
isobenzofuranone by coupling saturated ketones and benzoic
acids.
Table 1. Optimization of the Reaction Conditions
c
entry
variations from the standard condition
none
yield (%)
1
72
nd
nd
55
25
49
48
nd
nd
56
35
57
62
64
52
2
without Cu
3
without Pd
4
5
6
7
8
9
10
11
12
13
14
15
Pd(OAc)2 instead of Pd(dba)2
(RhCp*Cl2)2 instead of Pd(dba)2
Cu(OAc)2 instead of CuF2·2H2O
CuTC instead of CuF2·2H2O
dimethyl sulfoxide instead of toluene
dimethylformamide instead of toluene
xylene instead of toluene
dichlorobenzene instead of toluene
TEMPO instead of 4-MeO-TEMPO
4-NHAc-TEMPO instead of 4-MeO-TEMPO
Ar atmosphere
To verify the feasibility of our design strategies (Scheme 1),
we utilized propiophenone 1a and o-methylbenzoic acid 2a as
O2 atmosphere
Scheme 1. Design Stategies
a
Reaction conditions: 1a (0.5 mmol), 2a (0.3 mmol), [Cu] (20 mol
%), [Pd] (5 mol %), oxidant (1 equiv), solvent (2 mL), stirred at 130
°C for 20 h. Isolated yields. nd indicates “not detected”.
b
c
the toluene derivatives were efficient (Table 1, entries 8−11),
such as toluene, xylene, and dichlorobenzene. Different
TEMPO derivatives were also tested; only 4-MeO-TEMPO
gave a better yield (Table 1, entries 12 and 13). Besides, when
some common organic and inorganic oxidants were invested
instead of TEMPO, such as K2S2O8, tert-butyl hydroperoxide
(TBHP), di-tert-butyl peroxide (DTBP), and Oxone, none of
them were suitable (see Table S1 for more screening
parameters in the Supporting Information). Finally, when
this reaction was implemented under an Ar or O2 atmosphere,
both led to the suppression of the yield (Table 1, entries 14
and 15).
When the optimal reaction conditions were determined, the
substrate scopes of propiophenone derivatives and benzoic
acid derivatives were explored to expand the substrate scope,
and all the results of various target compounds were
summarized in the volume of Scheme 2 and Scheme 3.
In general, either electron-donating (EDG) or electron-
withdrawing (EWG) groups on the ortho, meta, and para
positions of propiophenones were examined under the
standard conditions (Scheme 2). Most of the results were
good, especially for those substrates with alkyl groups (3b, 3c,
3k, 3m). As for the halo-groups, only the Cl-group and F-
group could be tolerated, while most of them presented
moderate to good yields (3d−3h). The Br-group and I-group
were not suitable for this system, and we speculated it was
possible that the C−Br or C−I bond was easily activated in the
existence of Pd(dba)2. In particular, those substrates with
strong EDG and EWG on the benzene ring could be converted
smoothly (3i and 3j), while a substrate bearing a nitro group
only produced a trace yield (less than 10%). Notably, the
substrates with aryl groups could afford the corresponding
isobenzofuranones in good yields (3l, 3q, and 3r), and even
the bulky heterocycle group showed an acceptable reactivity
(3s and 3t). Furthermore, several electron-donating hetero-
cycle-containing compounds, such as 2-propionythiophene and
2-propionyfuran (3o and 3p), were both appropriate for this
the standard starting materials. When different conditions were
changed to investigate the yield of target product 3a, the best
result showed that 3a could be separated in 72% isolated yield,
and the optimal parameters were finally determined, which
were listed as follows: propiophenone (1a, 0.5 mmol), o-
methylbenzoic acid (2a, 0.3 mmol), CuF2·2H2O (20 mol %),
Pd(dba)2 (5 mol %) (dba = dibenzylideneacetone), 4-MeO-
TEMPO (1 equiv), toluene (2 mL) as the solvent. Last, this
reaction was implemented in the sealed Schlenk tube, which
was full of air atmosphere, at 130 °C for 20 h. In the early
trials, we preferred to concentrate on the choices of different
metal salts. Pd and Rh species were appropriate for this system,
but Pd(dba)2 gave a higher yield. (Table 1, entries 4 and 5).
According to the results, Cu(I) and Cu(II) species both could
be used as the catalysts (Table 1, entries 6 and 7), which
suggested it was possible that this reaction involved a single
electron transfer (SET) process and that the copper salts
helped to trigger this catalysis. However, the target products
cannot be examined in the absence of copper salts or palladium
salts (Table 1, entries 1 and 2), which may refer to the reaction
being a bimetallic cocatalysis process. As for the solvents, only
B
Org. Lett. XXXX, XXX, XXX−XXX