1386
Published on the web November 26, 2011
Rapid Access to 3-Aryltetralin Skeleton via C(sp3)-H Bond Functionalization:
Investigation on the Substituent Effect of Aromatic Ring Adjacent
to C-H Bond in Hydride Shift/Cyclization Sequence
Keiji Mori, Shosaku Sueoka, and Takahiko Akiyama*
Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Toshima-ku, Tokyo 171-8558
(Received October 22, 2011; CL-111039; E-mail: takahiko.akiyama@gakushuin.ac.jp)
The concise construction of 3-aryltetralin skeleton via
recently, our group has disclosed8a that the employment of
benzylidene barbiturate as the electrophilic portion enabled the
benzylic [1,5]-hydride shift of the C-H bond at the ¡-position of
the phenethyl moiety, affording 3-phenyltetralin in excellent
chemical yield.8 Although there are several elegant pathways
leading to benzylic C-H bond functionalization, details of the
substituent effect of the aromatic ring adjacent to the C-H bond
remain to be investigated.
hydride shift mediated C-H bond functionalization was
achieved. In this process, the benzylic [1,5]-H shift occurred
smoothly to furnish tetralin derivatives in good to excellent
chemical yields. The electronic and steric properties of the
aromatic ring adjacent to the C-H bond influenced significantly
the reactivity of this transformation.
Herein we report our study of the benzylic hydride shift/
transfer system, focusing on the substituent effect of he
phenethyl aromatic ring (Scheme 2). We have found that the
electronic nature of the aromatic group of the phenethyl moiety
influenced significantly the reactivity, and the desired com-
pounds were obtained in excellent chemical yields with low
catalyst loading (as low as 0.5 mol %).
The direct and selective replacement of carbon-hydrogen
bonds with new bonds (C-H functionalization) represents an
important and longstanding goal in synthetic organic chemistry.1
Considering the high abundance of C-H bonds, the precise one-
step substitution of C-H bonds with C-C and/or C-Y bonds
(Y = O, N, etc.) without disruption of the surrounding molecu-
lar structure and the prefunctionalization to C-X bonds (X =
halogen, OSO2CF3, etc.) offer a promising approach for the
synthesis of various complex molecules.
According to our previous report,8a various benzylidene
barbiturates 5 were synthesized from salicylic acid derivatives.
The preparation of p-tolyl analog 5b is illustrated in Scheme 3
as a representative example. The Sonogashira coupling of triflate
3, which is readily synthesized from commercially available
salicylic acid, with p-tolyl acetylene afforded adduct 4 in 90%
yield. Hydrogenation, reduction of the ester group, oxidation of
the resulting alcohol, and condensation with 1,3-dimethylbarbi-
turic acid gave 5b in 76% yield from 4 (Scheme 3).
Recently, the C(sp3)-H bond functionalization via hydride
shift/cyclization, namely, “internal redox process,” has attracted
much attention for its unique features (Scheme 1).2 Its key
feature is the [1,5]-hydride shift of the C(sp3)-H bond ¡ to the
heteroatom. Subsequent 6-endo cyclization affords heterocycle
2. Although C-H functionalization is, in general, promoted by
a transition-metal catalyst, this type of C-H functionalization
process typically proceeds under thermal conditions or, in some
cases, under the Brønsted or Lewis acid catalysis.3-6
Whereas a range of related reactions with heteroatom-
containing substrates have been reported, the corresponding C-
version had been overlooked until quite recently. This is because
the key [1,5]-H shift required the electronic assistance of an
adjacent heteroatom for the stabilization of the carbocation
generated by the hydride shift. Recent work on the internal redox
process has led to the realization of the benzylic, nonadjacent
heteroatom hydride shift/cyclization sequence.7 The groups
of Chatani7a and He7b independently reported that the benzylic
C-H bond without an adjacent heteroatom could also participate
in this type of catalytic cycloisomerization reaction. Quite
With the desired substrates in hand,9 the substituent effect of
the aromatic ring was surveyed under optimal conditions (cat.
Sc(OTf)3, ClCH2CH2Cl, reflux).8a,10 Phenyl-substituted sub-
strate 5a underwent the internal redox process in 24 h by means
of 5 mol % Sc(OTf)3 (Table 1, Entry 1). Interestingly, the
O
N
N
O
O
O
H
N
O
N
acid catalyst
H
O
Ar
C
Ar
C
H2
H2
critical
electronic factor
Scheme 2. Rapid access to tetralin skeleton.
H
O
EWG
EWG
EWG
EWG
Δ
or
H
Tol
EWG
EWG
N
N
Acid catalyst
15 mol% CuI
H
H
1) H2, Pd/C
2) LiAlH4, Et2O
3) MnO2, CH2Cl2
5 mol%
O
O
O
O
[1,5]-H shift
6-endo-
cyclization
R1
X
R1
[Pd(PPh3)4]
X
R1
X
Et3N, TBAI
OMe
OMe
OTf
1
A
2
CH3CN
4) 1,3-dimethyl-
barbituric acid,
EtOH
X = NR2, O.
EWG = CN, CO2R, etc.
Tol
reflux, 16 h
Tol
3
4
5b
90%
76% (4 steps)
Scheme 1. C(sp3)-H functionalization via internal redox
process.
Scheme 3. Preparation of benzylidene barbiturate.
Chem. Lett. 2011, 40, 1386-1388
© 2011 The Chemical Society of Japan