Cross-dehydrogenative coupling of secondary benzylic ethers with indoles and pyrroles

Article abstract of DOI:10.1016/j.tetlet.2019.03.032

Current studies on cross-dehydrogenative coupling of benzylic ethers for new C–C bond construction predominantly focus on primary ether moieties. Oxidative cross-coupling of secondary benzylic ethers remains elusive. Herein, we describe the first cross-de

Full text of DOI:10.1016/j.tetlet.2019.03.032

Tetrahedron Letters 60 (2019) 1075–1078
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cross-dehydrogenative coupling of secondary benzylic ethers with
indoles and pyrroles
a,b,
Min Cao a, Ying Mao b, Jiancheng Huang a, Yudao Ma a, , Lei Liu
⇑
⇑
a School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
b School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Current studies on cross-dehydrogenative coupling of benzylic ethers for new C–C bond construction pre-
dominantly focus on primary ether moieties. Oxidative cross-coupling of secondary benzylic ethers
remains elusive. Herein, we describe the first cross-dehydrogenative coupling of secondary benzylic
Received 15 February 2019
Revised 11 March 2019
Accepted 12 March 2019
Available online 13 March 2019
ethers with indoles and pyrroles for tertiary ether construction. A broad range of
a-aryl substituted
isochromans react with a variety of electronically varied indoles and pyrroles smoothly under mild
metal-free conditions in high efficiency. In addition, the catalytic asymmetric variant was preliminarily
explored, and corresponding tertiary ether was obtained in 69% ee.
Keywords:
Cross-dehydrogenative coupling
Secondary benzylic ether
Indole
Ó 2019 Elsevier Ltd. All rights reserved.
Quaternary center
Cross-dehydrogenative coupling (CDC) of two readily available
CAH components for CAC bond construction under oxidative con-
ditions has been regarded as one of the most straightforward and
economical approaches for increasing molecular complexity and
functional group content with minimal waste generation [1,2].
During the past decade, considerable progress has been achieved
in the CDC reactions involving benzylic ether substrates [3,4].
However, existing studies always focused on the manipulation of
methylene CAH bonds of primary benzylic ethers for correspond-
ing secondary ether preparation [4]. To the best of our knowledge,
a CDC reaction of secondary benzylic ethers involving the function-
alization of methine CAH bonds for tertiary ether synthesis has
never been established to date, which might be ascribed to the
increased steric hindrance of both the substrate and highly substi-
tuted oxocarbenium intermediate.
tionalized alcohol substrates [7]. On the other hand, indole and
pyrrole moieties are also key skeletons in numerous molecules
possessing a wide range of pharmaceutical activities [8]. Consider-
ing that structurally diverse
a-monosubstituted isochromans can
be readily prepared by a number of methods, the CDC of the sec-
ondary ethers with indoles and pyrroles would be highly desired
for rapid construction of
libraries for biologically active small molecule discovery.
Initially, the CDC of -PMP (4-methoxyphenyl) substituted
a,a-disubstituted isochroman-based
a
isochroman 1a and indole 2a was selected as the model reaction
for optimization (Table 1). The oxidation was conducted prior to
the introduction of 2a to avoid the direct quench between oxidant
and nucleophile. Several commonly employed reagents for ether
oxidations were applied to the CDC reaction. tBuOOH and PhI
(OAc)2 did not promote the oxidation, and all the starting 1a was
recovered (entries 1 and 2, Table 1). Ph3CClO4 effected the oxida-
tion, and all the 1a was consumed (entry 3, Table 1). However,
no expected 3a was detected, and a ring opening byproduct was
observed [9]. TEMPO (TEMPO = 2,2,6,6-tetramethylpiperidin-1-
oxyl) oxo-ammonium effected the coupling, and the expected 3a
was obtained in 16% yield (entry 4, Table 1). When DDQ (2,3-
dichloro-5,6-dicyano-1,4-benzoquinone) was used as the oxidant,
the CDC reaction proceeded smoothly in CH2Cl2 at room tempera-
ture in 85% yield (entry 5, Table 1). The solvent effect on the reac-
tion efficiency was also examined, and obvious loss of efficiency
was observed when the reaction was conducted in toluene and
ethyl acetate (entries 6 and 7, Table 1). When THF was used as
the solvent, all the starting 1a was consumed, but no discriminable
a-Substituted isochromans are common structural motifs in a
number of natural products and synthetic pharmaceuticals with
diverse biological activities [5]. In particular, isochromans having
a-tetrasubstituted stereocenters show antioxidative, anticancer,
antibacterial, antifungal, antiviral, and antidepressive activities
[6]. Inspired by the significance of the skeletons in modern phar-
macology, considerable efforts have been made to their prepara-
tion, and current syntheses mainly rely on the O-heterocycle
construction strategy involving cyclization reactions of prefunc-
⇑
Corresponding authors at: School of Chemistry and Chemical Engineering,
Shandong University, Jinan 250100, China.
E-mail addresses: ydma@sdu.edu.cn (Y. Ma), leiliu@sdu.edu.cn (L. Liu).
https://doi.org/10.1016/j.tetlet.2019.03.032
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

1076
M. Cao et al. / Tetrahedron Letters 60 (2019) 1075–1078
Table 1
3a–3g bearing
a-tetrasubstituted stereocenters in 83–90% yield.
Reaction condition optimization.a
Indole 2h with a methyl substituent at the 6-position was a suit-
able coupling partner, and corresponding 3h was isolated in 91%
yield. Pyrroles were also found to be competent components under
the standard conditions. Simple pyrrole 2i, 2-methyl substituted 2j,
and 2-phenyl substituted 2k participated in the CDC reaction
smoothly, furnishing respective 3i–3k with up to 86% yield.
The scope with respect to
a-substituted isochromans was fur-
ther investigated (Scheme 2). Isochromans 1b–1e bearing either
electron-donating or -withdrawing groups at C6 or C7 position
were well compatible with the standard CDC reaction conditions,
providing the expected tertiary ethers 4b-4e in good yields.
Besides the PMP moiety, simple phenyl (1f) and electron-deficient
Entry
Oxidant
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9c
tBuOOH
PhI(OAc)2
Ph3CClO4
TEMPO+BF-4
DDQ
DDQ
DDQ
DDQ
DDQ
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
EtOAc
THF
<5
<5
<5
16
85
50
61
<5
<5
aryl (1g) groups at the
ated in 87% and 81% yields, respectively. Isochroman 1h bearing
an -aryl group with a substituent at the meta-position was also
a-position of isochroman were well toler-
a
a suitable substrate. An extremely obvious loss of efficiency was
observed for isochroman 1i bearing a 2-methoxyphenyl group at
the a-position, which might be ascribed to the increased steric hin-
drance of both the ether substrate and highly substituted oxocar-
benium intermediate. The mild CDC condition exhibits good
functional group compatibility, with halogens and acetate toler-
ated for further manipulations.
Under the standard conditions, a gram-scale CDC reaction of 1e
with 2a proceeded smoothly without obvious loss of reaction effi-
ciency, thus demonstrating the practicability of the method
(Scheme 3).
Catalytic asymmetric CDC reaction has received considerable
attentions during the past decades [10,11]. However, to our knowl-
edge, a catalytic asymmetric CDC process leading to quaternary
carbon center has never been reported to date. Accordingly, the
catalytic enantioselective variant of the reaction was then explored
and the preliminary result was shown in Scheme 4. Performing the
oxidation of 1a with DDQ and MeOH additive at room temperature,
followed by chiral phosphoric acid 5 catalyzed indole addition at
À78 °C provided the expected 3a in 71% yield and 69% ee [12].
Although the optimization of the reaction was not exclusively
optimized, the result provided a proof-of-concept for the develop-
ment of catalytic asymmetric tertiary ether synthesis.
CH2Cl2
a
General conditions: 1a (0.1 mmol), oxidant (0.12 mmol) in solvent (1.0 mL) at rt
for 0.5 h followed by 2a (0.15 mmol) at rt for 3 h.
b
Isolated yield.
2a was added prior to DDQ.
c
product was isolated (entry 8, Table 1). Performing the oxidation
after the introduction of indole 2a also failed to provide any
expected 3a, which might be ascribed to the incompatibility of
indole with DDQ (entry 9, Table 1).
The scope of oxidative cross-coupling of
a-PMP (p-methoxy
phenyl) substituted isochroman 1a with diverse indole compo-
nents was next explored (Scheme 1). The CDC efficiency proved
to be unsusceptible to the electronic substituent properties on
indoles, as demonstrated by the generation of isochromans
Scheme 1. Scope of indole and pyrrole moieties.
Scheme 2. The scope of a-substituted isochroman.

M. Cao et al. / Tetrahedron Letters 60 (2019) 1075–1078
1077
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.03.032.
Scheme 3. A gram-scale experiment.
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