COMMUNICATION
DOI: 10.1002/asia.201301423
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Site-Selective C H Borylation of Quinolines at the C8 Position Catalyzed by
a Silica-Supported Phosphane–Iridium System
Shota Konishi,[a] Soichiro Kawamorita,[a] Tomohiro Iwai,[a] Patrick G. Steel,*[b]
Todd B. Marder,*[c] and Masaya Sawamura*[a]
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Abstract: Site-selective C H borylation of quinoline deriva-
Herein, we report the Ir-catalyzed site-selective C H bor-
tives at the C8 position has been achieved by using a hetero-
geneous Ir catalyst system based on a silica-supported cage-
type monophosphane ligand SMAP. The efficient synthesis
of a corticotropin-releasing factor1 (CRF1) receptor antago-
ylation of quinoline derivatives with bis(pinacolato)diboron
(pinB–Bpin, 2). C8-selective borylation was effected by
choosing silica-supported trialkylphosphane (Silica-SMAP)
as a monodentate P ligand for Ir.[12–14] The borylation reac-
tion proceeded under mild reaction conditions with excel-
lent site selectivity toward various substrates with different
substitution patterns. Our synthesis of a corticotropin-releas-
ing factor1 (CRF1) receptor antagonist demonstrates the ro-
bustness and utility of this heterogeneous catalysis.[15]
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nist based on a late-stage C H borylation strategy demon-
strates the utility of the C8 borylation reaction.
The quinoline heterocyclic scaffold is an important struc-
tural motif that is found in many natural products, bioactive
compounds, dyes, and other functional molecules, for exam-
ple, Alq3 for OLEDs.[1–3] Accordingly, the development of
efficient methods for accessing substituted quinolines is
a subject of considerable importance. In particular, stream-
lining the synthetic process through the introduction of site-
selective direct functionalization of a quinoline C H bond is
highly desirable. Several methods that allow direct C C
bond formation at the C2 position of quinolines or quinoline
N-oxides, using Rh,[4] Pd,[5] Ni,[6] Cu,[7] and Ag[8] catalyst sys-
tems, have been reported in recent years. The C2 selectivity
of these catalysts is based on the inherent reactivity of the
Miyaura, Ishiyama, and co-workers reported that boryla-
tion of quinoline occurred preferentially at the C3 position
when an Ir–bipyridine-type (Ir–dtbpy; Hartwig–Ishiyama–
Miyaura catalyst; dtbpy=4,4ꢀ-di-tert-butylbipyridine) cata-
lyst was used, with a large excess of the quinoline substrate
(10 equiv).[16] More recently, as part of our studies on the
[17]
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C H borylation of arenes,
some of the authors of the
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present work provided guidelines for achieving selective
borylation at the C3, C4, C6, or C7 positions of disubstituted
quinolines.[17j] In contrast, access to the much desired quino-
line-8-boronic acid has required multiple steps, which in-
volve generation of the corresponding halide as an immedi-
ate precursor.[18] The C8-selective borylation discussed here
circumvents these issues and complements the existing quin-
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C=N bond or the N-adjacent C H bond. In contrast, site-se-
lective catalytic C H transformation at the C8 position,
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which is also proximal to the N atom, has been reported, to
the best of our knowledge, only by Chang and co-workers.
In these studies, Rh–NHC (NHC=N-heterocyclic carbene)
catalytic systems were used for C8 arylation with aryl bro-
mides.[9–11]
oline C H activation methods.
The reaction of quinoline 1a (0.30 mmol) and diboron 2
(1.1 equiv) in methyl tert-butyl ether (MTBE) in the pres-
ence of an immobilized catalyst precursor (Ir, 2 mol%), pre-
pared in situ from Silica-SMAP, and [IrACHTNUGRTNENUG(OMe)ACHUTNGTREN(NUGN cod)]2 (P/Ir,
1:1; cod=cycloocta-l,5-diene) proceeded at 608C over 12 h
with 94% consumption of 1a. (Scheme 1). The 1H NMR
spectrum of the crude product indicated that the major
product was the C8-borylated quinoline 3a, which was con-
taminated with small amounts of the reduced products, such
as 1,2,3,4-tetrahydroquinoline (4a, 13% yield, analysis
[a] S. Konishi, Dr. S. Kawamorita, Dr. T. Iwai, Prof. Dr. M. Sawamura
Department of Chemistry, Faculty of Science
Hokkaido University, Sapporo 060-0810 (Japan)
[b] Prof. P. G. Steel
1
based on H NMR spectroscopy).[19] As the quinoline-8-bor-
Department of Chemistry
Durham University
South Road, Durham DH1 3LE (UK)
onic acid pinacol ester (3a) was unstable,[20] the crude prod-
uct was subjected to oxidation with NaBO3, followed by
treatment with (Boc)2O (Boc=tert-butoxycarbonyl). This
method afforded O-tert-butoxycarbonyl-8-hydroxyquinoline
(6a) in 68% yield after purification by silica-gel chromatog-
raphy. No other isomers were detected in the crude reaction
mixture. Thus, the site selectivity of the borylation reaction
was excellent. Based on the fact that the reaction of 2-sub-
stituted quinolines (see below) proceeded with exclusive se-
[c] Prof. Dr. T. B. Marder
Institut fꢁr Anorganische Chemie
Julius–Maximilians–Universitꢂt Wꢁrzburg
Am Hubland, 97074 Wꢁrzburg (Germany)
Supporting information for this article is available on the WWW
Chem. Asian J. 2014, 9, 434 – 438
434
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