4
X. Zhou et al. / Tetrahedron Letters xxx (2015) xxx–xxx
O
O
I
10 mol% Pd(OAc)2
N
H
COOMe
2.0 equiv NaOAc
N
H
COOMe
+
DMSO, 120 °C,24 h
4
2a
5a
16% yield
Scheme 2. Palladium catalyzed arylation of 4 with 4-iodotoluene 2a under the optimal condition.
and 51% yields were obtained using xylene and DCE as a solvent,
respectively (Table 1, entries 2 and 3). In polar solvent, such as
DMA and Dioxane, it afforded the desired product 3a in promising
80% and 83% yields, respectively (Table 1, entries 4 and 5). Delight-
fully, the 3a yield was significantly improved to 91% yield by using
DMF as a solvent (Table 1, entry 6). Furthermore, in DMSO, the
reaction also proceeded smoothly to give 3a in the same isolated
yield (Table 1, entry 7). Variation in silver salts including CF3SO3Ag,
AgI, Ag2CO3, Ag2SO4, AgNO3, and AgCl was also explored, a compa-
rable reaction efficiency was presented by Ag2CO3 (Table 1, entry
10), while other silver salts gave much inferior results (Table 1,
entries 8 and 9 and 10–13). Recently, in the field of palladium cat-
alyzed C–H arylation reactions, Qi and co-workers reported NaOAc
can promote the coupling reaction without silver salt.20 With this
research in mind, we selected different inorganic salts as additives
and tested the reactions in the same reaction conditions. To our
delight, it was found that NaOAc gave comparable yield to that
of AgOAc (Table 1, entries 7 vs 14), while Cu(OAc)2 and K3PO4 as
bases can also afford the desire product with 60% and 71% yields,
respectively (entry 15 and 16). Disappointingly, Na2CO3 or Cs2CO3
as a base gave a trace amount of the desired product by TLC
(Table 1, entries 17 and 18). Other palladium catalysts such as
PdCl2, and Pd2(dba)3 also worked in this transformation but deliv-
ered lower yields (Table 1, entries 19 and 20). Decreasing the load
of Pd(OAc)2 to 5 mol % only gave a moderate yield (Table 1, entry
21). Moreover, the yield of 3a was decreased to 76% when the reac-
tion temperature was decreases to 100 °C (Table 1, entry 22). On
comparison of the above screening reactions with respect to addi-
tives and yields, we thought that the NaOAc as an additive is envi-
ronmentally friendly, and more inexpensive to workup for large
quantity synthesis. Thus, the optimized catalytic system for this
palladium catalyzed coupling reaction was: 1a (0.5 mmol), 2a
(1.0 mmol), NaOAc (1.0 mmol), Pd(OAc)2 (10 mol %) in DMSO at
120 °C for 24 h.
O
O
N
H
COOH
OH
40% aq.H2SO4
Ethanol, 120 °C,24 h
3a
Scheme 3. Removal of the directing group.
6a
92%
benzoyl aminoacetic acids 1 such as 4-methyl 1c, 4-methoxyl 1d
and 4-tert-butyl 1e can smoothly give the corresponding products
3o–t in 62–74% yields. It was worth to note that the C(sp3)–H
activation of the ortho-methyl group of 1b did not take place.
Remarkably, benzoyl aminoacetic acids 1 which bear electron-
withdrawing groups were accessible and afforded the correspond-
ing products 3u–x in good to excellent yields. For example, 4-floro
benzoylamino-acetic acid 1f with 4-iodo-toluene, 4-iodo-benzene
underwent this transformation to form the corresponding products
in 77% and 81% yields, respectively (3u–v). Furthermore, the sub-
strate 1g containing a strong electron-withdrawing group 4-CF3
resulted in higher yields (83%, 88%) compared to 1f. As for different
substitution patterns of aryl iodides, para- and meta-substituted
aryl iodides all worked well in the reaction to give the desired
products (Table 2). However, an attempt to employ the ortho
substituted aryl iodides failed to yield the expected products in
the reaction, showing that steric factors clearly reduced the reac-
tion efficiency.
In order to confirm the ability of aminoacetic acid derived O,N-
bidentate directing group in C–H bond activation/functionalization
reactions, we conducted the corresponding benzoyl aminoacetic
acid methyl ester 4 as substrate in place of 1a under the above
optimal conditions (Scheme 2). Interestingly, only insignificant
amounts of product 5a were obtained, indicating that the coordi-
nation in a bidentate O,N fashion is a key step for the reaction to
proceed.
With the optimal conditions in hand (Table 1, entry 14), we
started to investigate the scope of the substrates as displayed in
Table 2. Firstly, the benzoyl aminoacetic acid 1a with various aryl
iodides 2 were studied, we found that aryl iodides with both elec-
tron-donating and electron-withdrawing groups could smoothly
react with benzoylamino-acetic acid 1a to obtain the desired
products in good to excellent yields (3a–l). For example, 4-iodo-
toluene, iodobenzene 3-iodo-toluene, 4-iodoanisole, or 1-iodo-4-
phenylbenzene were good coupling partners and gave the
ortho-arylated products in 92%, 89%, 85%, 88%, and 78% isolated
yield, respectively (3a–e). Notably, aryl iodides with halogen atoms
including Cl, Br, and F were tolerated under the employed reaction
conditions and afforded the corresponding products 3f–i in 67–75%
yields. Gratifyingly, aryl iodides bearing the strong electron with-
drawing group such as 4-CF3, 4-COOMe, or 3-NO2 could also bring
out the desired products, albeit at a relatively low yields (3j–l).
Then, the reactions of benzoylamino-acetic acids with various elec-
tron-donating and electron-withdrawing groups 1b–g were inves-
tigated (3m–x), for example, 2-methyl benzoylamino-acetic acid
1b with 4-iodo-toluene, methyl 4-iodobenzoate underwent this
transformation to form the corresponding products in 78% and
85% yields, respectively (3m–n). Various substitution groups on
Furthermore, the aminoacetic acid group could be easily
removed, as shown in Scheme 3. [(40-Methyl-biphenyl-2-car-
bonyl)-amino]-acetic acid 3a was heated with 40% aq H2SO4 in eth-
anol to afford 92% of the hydrolysis product 6a.
In conclusion, We have developed an improved protocol for the
palladium-catalyzed ortho-arylation of benzoic acids by aryl
iodides using an aminoacetic acid based N,O-coordination strategy
for the first time. The method allows only mono-arylation of ben-
zoyl aminoacetic acid substrates, shows excellent functional group
tolerance and provides an efficient method for the synthetic of 2-
aryl benzyl acids. The aminoacetic acid auxiliary is effectively
detached under mild conditions. The detailed mechanistic study
of this transformation is currently undergoing in our laboratory.
Experimental section
General
All reactions were performed under air. Chemicals were
purchased from Aldrich, Acros, or Alfa Aesar, and, unless otherwise
noted, were used without further purification. Flash