Organic Letters
Letter
a
directing-group-promoted unactivated aliphatic C−H bond
functionalization with different reaction partners was well
explored,13 the oxidative coupling of unactivated C(sp3)−H
with a C(sp2)−H bond by initiation from aliphatic C−H
activation has rarely been reported.12f−h
Table 1. Optimization of Reaction Conditions
As known, aliphatic carboxylic acid is one kind of important
organic compound. Direct C−H functionalization of aliphatic
carboxylic acids can derive valuable compounds from readily
available chemicals by using carboxylates as weakly coordinat-
ing directing groups. This chemistry has drawn much attention
in the past decades, and significant progress has been made
with efforts.14 An elegant aliphatic acid directed β-C(sp3)−H
functionalization example was published by Yu group.14d In
those transformations, either Pd(0)/Pd(II)14a−c or Pd(II)/
Pd(IV)14d catalytic cycles were proposed, and the ligands
showed their uniqueness in catalysis. We envisioned that, if
equipping an aryl group at the proper position of the carboxylic
acids, a coordinating pattern of palladacycles which was formed
through carboxylates directed aliphatic C−H activation may
facilitate the intramolecular oxidative coupling (Scheme 1b).
This approach might open a new channel to synthesize benzo-
fused ring systems from linear aromatic substituted aliphatic
carboxylates.
Based on this hypothesis, we set out to investigate the
intramolecular oxidative coupling between both unactivated
aliphatic and aromatic C−H bonds. 2,2-Dimethyl-3-phenox-
ypropanoic acid 1a was initially selected as a candidate since
the Thorpe−Ingold effect of geminal dimethyl substituents was
found to be essential in aliphatic C−H activations.15 We first
attempted to carry out the reaction with Pd(CH3CN)2Cl2 as
the catalyst, KHCO3 as a base, and TBHP as an oxidant in
HFIP at 60 °C, and the desired product 3-methylchromane-3-
carboxylic acid 2a was obtained in a 21% NMR yield by using
1,3,5-trimethoxybenzene as an internal standard (entry 1). In
previous studies, ligands were shown to be important to
accelerate C−H bond activation and hence promote the
reaction efficiency.12c,13,14,16 Therefore, various ligands were
tested in the reaction. In previous efforts from Yu’s group,
protected amino acids showed their “magic” effect in aliphatic
C−H functionalization.16b,d,e As expected, with the addition of
ligand L1 (Ac-Phe-OH), the yield of the desired product (2a)
was somewhat improved, revealing that amino acid ligands
exhibited a potentially positive effect on this intramolecular
oxidative coupling reaction as observed in Table 1, entry 2. On
the contrary, pyridine-2-sulfonic acid L9 inhibited the
reactivity (entry 3). To our delight, a 10%:10% combination
of L1 and L9 dramatically promoted this reaction, giving an
complete 1a conversion and an 80% NMR yield of 2a (entry
4).16i After the reaction was implemented with a broad scope
of ligands/coligands, L1/L9 was found as the most feasible
results revealed intriguingly synergistic coordination of the L1/
L9 combo. Then further investigations of some other
parameters, like Pd salts, temperature, reaction time, and
undertaken. Finally, by treating the starting material 1a with
Pd(OAc)2 (5 mol %), Ac-Phe-OH (10 mol %)/pyridine-2-
sulfonic acid (10 mol %), KHCO3 (1.5 equiv), and tert-butyl
hydrogen peroxide (TBHP, 1.5 equiv, both 70% solution in
water or 5.5 M in decane gave the same result) in HFIP at 45
°C for 36 h, the desired product 2a was obtained with the
highest isolated yield (entry 21, 88%).
b
b
entry
ligands
conv of 1a (%)
yield of 2a (%)
1
2
3
4
5
6
7
8
−/−
L1/−
−/L9
23
35
10
>95
20
20
<5
71
85
38
<5
73
90
42
70
78
83
93
>95
>95
>95
21
25
7
80
20
17
0
51
68
36
0
L1/L9
L1/L10
L1/L11
L1/L12
L2/L9
L3/L9
L4/L9
L5/L9
L6/L9
L7/L9
L8/L9
L1/L9
L1/L9
L1/L9
L1/L9
L1/L9
L1/L9
L1/L9
9
10
11
12
13
14
15
16
17
18
19
20
21
58
74
34
68
74
78
87
82
81
c
c d
,
de
,
de f
,
,
dfg
, ,
e fg
, ,
e fhi
j
, ,
,
92 (88)
a
Reaction Conditions: 1a (0.5 mmol, 1.0 equiv), Pd(CH3CN)2Cl2 (5
mol %), amino acid ligands (10 mol %), pyridine ligands (10 mol %),
KHCO3 (0.75 mmol, 1.5 equiv), TBHP (1.0 mmol, 2.0 equiv), HFIP
b
(4.0 mL), 60 °C, 16 h. Determined by 1H NMR with 1,3,5-
c
d
e
trimethoxybenzene as an internal standard. 60 °C. 24 h. 45 °C.
f
g
h
Pd(OAc)2 was used instead of Pd(CH3CN)2Cl2. 50 °C. 36 h.
i
j
TBHP (1.5 equiv) was used. The data in parentheses is the isolated
yield of 2a.
Subsequently, we explored the substrate scope of this
oxidative coupling to synthesize the diverse chromane (Table
2). A variety of para-substituted substrates on the phenyl
group were examined. Both alkyl and aryl substituents, for
example, methyl, tert-butyl, and phenyl, worked well, giving the
desired products in good to excellent yields (2b, 2c, and 2i). p-
Methoxy-, trifluoromethoxy-, benzyloxy-, and phenyl-derived
ethers were suitable substrates, affording the corresponding
chromane-3-carboxylic acids 2d, 2e, and 2j in 63%, 54%, and
74% yields, respectively. The halide substituents also furnished
the products in good yields (2f−2h). The reactive halide
substituents provided another possibility for further function-
alization through orthogonal cross-coupling reactions. 3,5-
Dimethyl- and 2-methylphenol ether underwent this intra-
molecular oxidative coupling smoothly, forming the anticipated
5, 7-dimethylchromane-3-carboxylic acid 2k (83%) and 8-
1252
Org. Lett. 2021, 23, 1251−1257