Organic Letters
Letter
the carbene precursor acted as a bridging arm to deliver the
palladium catalyst to the reacting site; the oxygen anion also
acted as an internal nucleophile to accomplish the acylation.
Illuminated by this discovery, we have conceived a palladium-
catalyzed three-component reaction as a potential platform for
the construction of 2-benzylbenzoic acid derivatives (Scheme
1c). Compared with our previous work, a number of obvious
pitfalls must be kept in mind: (i) O−H bond insertion10 of
alcohol to the diazo compound generated in situ from N-
tosylhydrazone and (ii) C−O bond formation through the
coupling reaction of alcohol with aryl halide in the presence of a
palladium catalyst.
At the outset of the study, readily available o-bromobenzalde-
hyde 1a and N-tosylhydrazone 2b were selected as the model
substrates. Fortunately, when the reaction was carried out in
MeOH at 60 °C for 3 h using Pd(OAc)2 and dppm as the
precatalyst and K2CO3 as the base, the desired diarylmethane 3b
was obtained, albeit in 15% GC yield (Table 1, entry 1).
Replacing the base K2CO3 with t-BuOK could further enhance
the yield of 4b to 72% after isolation (Table 1, entry 9). o-
Iodobenzaldehyde also worked well under the optimal condition
(Table 1, entry 11). The reaction of triflate 1c derived from
salicylaldehyde under the optimal condition was not ideal.
However, a brief examination of the effects of the base showed
that NaHCO3 was superior to others, affording 3b in 86%
isolated yield (Table 1, entry 12).
With the optimal conditions established, we next focused on
exploring the scope of aldehydes and N-tosylhydrazones with
different substituents on the aromatic rings (Scheme 2). With
respect to aldehydes, a series of substituents, including electron-
donating or electron-withdrawing groups on the phenyl ring of
o-bromobenzaldehyde, were all compatible (Scheme 2, 3c−3n),
giving the corresponding products in moderate to excellent
yields. In general, aldehydes bearing electron-donating groups
react better than those bearing electron-withdrawing groups.
The reaction of o-bromobenzaldehyde with a tosylate
functionality at position 4 could also proceed well, while giving
free phenolic product 3k in 58% isolated yield, together with a
17% yield of 3d. The heteroaromatic furan ring (3o), labile mom
(3n) group, and alkynyl moiety (3p) were tolerated, as well.
For the scope of N-tosylhydrazones, the electron-donating
and electron-withdrawing substituents at the para, meta, and
ortho positions of the phenyl ring were all tolerated well.
Notably, a potentially reactive bromo group was compatible (3z
and 3aa), which could be a useful handle for further cross-
coupling reactions. N-Tosylhydrazones derived from thiophene-
2-carbaldehyde and furan-2-carbaldehyde could also participate
in the current transformation, while affording the corresponding
products 3ag and 3ah in diminished yields. Pleasingly,
hydrazones decorated by terminal alkenyl (3an), ferecenyl
(3ao), ester (3ap), and amide (3aq and 3ar) groups were good
substrates for current three-component reactions. Dihydrazone
could also couple with o-bromobenzaldehyde, giving the
corresponding C2-symmetric diester 3as in 54% yield upon
isolation. The current protocol was also amenable to late-stage
modification of complex molecules. For instance, 3at, 3au, and
3ay embedded with core structural motifs of approved drugs
estrone, repaglinide, and mianserin were obtained in 68%, 52%,
and 77% isolated yields, respectively.
Table 1. Evaluation of Reaction Conditions
a
b
b
entry
1
ligand (mol %)
temp (°C)
3b (%)
15
4b (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
L1 (7.5)
L3 (7.5)
L7 (15)
L3 (7.5)
L2 (7.5)
L4 (7.5)
L6 (7.5)
L9 (15)
L9 (15)
L8 (15)
L6 (7.5)
60
60
60
trace
0
30
54
4
93 (85)
80
56
99 (88)
13
9
28
99 (86)
100
100
100
100
100
100
100
100
0
1
1
0
61
80 (72)
c
9
10
11
18
0
0
As mentioned above, 2-benzylbenzoic acid derivatives are
versatile building blocks. For example, 3i has been applied for
the synthesis of tricyclic benzothiazolo[4,5]azepine derivative A,
which shows promising anxiolytic activity.12 Product 3s was
used as a precursor to construct tetrahydroisoquinoline-3-
carboxylic acid B, which could be a nonpeptide inhibitor of
angiotensin II binding to the AT2 site.1c According to very recent
study, product 3w bearing a fluoro atom could be applied for a
straightforward synthesis of glucose-regulated protein 94
(Grp94) inhibitor D. D exhibits a 0.54 μm affinity and a 73-
fold selectivity toward Grp94 and offers opportunities for
inhibition of metastatic cancer.1j Product 3t bearing two
methoxyl groups on each phenyl ring provides an opportunity
for the preparation of xanthene type dyes. Lavis and co-workers
have used 3t as a handle to synthesize carbofluorescein C and its
derivative carborhodamine.1i Moreover, products 3ak and 3am
could be applied for natural product synthesis, such as
Justincidin E1d,13 and Marosporin.1h It is worth mentioning
that alcohols other than methanol are not suitable components
under current conditions. As depicted, when ethanol was
employed as a solvent, the desired adduct 3az was produced in
23% NMR yield.
Switching the ligand to dppb enhanced the yield of 3b to 54%
(Table 1, entry 2). Intriguingly, when monodentate ligand
JohnPhos was employed, the chemoselectivity was switched. 2-
[Methoxy(p-tolyl)methyl]benzaldehyde 4b was obtained as the
major product (Table 1, entry 3). After the extensive evaluation
of other reaction parameters,11 we have identified a set of
optimal conditions for the synthesis of 3b, namely, carrying out
the reaction at 100 °C, and using dppf (L6) as a ligand, affording
3b in 88% yield upon isolation (Table 1, entry 7). Gratifyingly,
the three-component coupling that yields 4b could also be
increased by altering the ligand to L9 (Table 1, entry 8).
B
Org. Lett. XXXX, XXX, XXX−XXX