are the Suzuki or Stille cross-couplings of 3-haloquinolines
with suitable coupling partners. This approach obviously
needs prefunctionalization of the quinoline substrate
and at times limits the utility. A recent report by Wang
and co-workersutilizedaniron-promoted tandemreaction
of styrene oxides and anilines to yield 3-arylquinolines
in good yields.9 We report herein a new approach to
3-arylquinolines which utilizes a regioselective CÀH func-
tionalization via a heteroatom-guided palladation fol-
lowed by transmetalation with arylboronic acids and in
situ aromatization. The method has broad scope and
results in good yields in almost all substrates. This method
effectively amounts to a two-step arylation reaction of
quinoline itself.
The starting material 2 for the CÀH activation step was
easily prepared from the parent quinoline via either
NaBH4 reduction and in situ acylation or via stepwise
LAH reduction and N-acylation. A variety of conditions
and combinations of catalyst systems and oxidants were
screened for optimization of the reaction (Table 1). Under
most of the reaction conditions attempted, C-3 arylation
was the major isomer, with varying amounts of homocou-
pling product resulting from of the aryl boronic acid.
Interestingly, the reaction under acidic conditions (entry
10, Table 1) resulted in minimum amount of homocou-
pling but also resulted in C-4 arylation as a minor product
(C-3/C-4 arylation 3:2). The CÀH functionalization at
C-4 most probably resulted from a concerted metala-
tion deprotonation (CMD) process. Of all the condi-
tions screened, the best conditions for regioselective C-3
arylation were found to be Pd(OAc)2/Cu(OTf)2/Ag2O in
toluene (entry 12, Table 1).
(3) For selected references on olefinations and arylations via heteroatom-
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2012, 45, 936–946.
ꢀ
(5) For direct arylations, see: (a) Liegault, B.; Lapointe, D.; Caron,
Table 1. Various Catalyst Systems Screened
L.; Vlassova, A.; Fagnou, K. J. Org. Chem. 2009, 74, 1826–1835. (b)
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75, 1047–1060 and references cited therein. (c) Seiple, I. B.; Su, S.;
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entry
reaction conditions
yield (%)
trace
trace
20
ꢀ
S. P. Tetrahedron 1998, 54, 263–303. (c) Hassan, J.; Sevignon, M.; Gozzi,
1
2
3
Pd(OAc)2/Cu(OAc)2 H2O/THF/65 °C/24 h
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3
Pd(OAc)2/AgOAc/Tol/110 °C/12 h
Pd(OAc)2/Cu(OTf)2/Ag2O/
AmylÀOH/80 °C/12 h
4
5
6
7
8
9
Ni(acac)2/Cu(OTf)2/Ag2O/Tol/110 °C/12 h
homocoupling
[Ru(p-cymene)Cl2]2/AgOAc/Xylene/110 °C/12 h NR
Pd(OAc)2/BQ/Ag2O/Tol/110 °C/12 h
PdCl2(PhCN)2/Cu(OTf)2/Ag2O/Tol/110 °C/12 h
Pd(O2CCF3)2/Cu(OTf)2/Ag2O/Tol/110 °C/12 h
PdCl2(dppf)/Cu(OTf)2/Ag2O/Tol/110 °C/12 h
<10
81
35
10 Pd(OAc)2/Cu(OTf)2/Ag2O/TFA/74 °C/16 h
85% total yield
(3:2 C3/C4
arylation)
trace
11 Pd(OAc)2/K2CO3/TFA/75 °C/30 h
12 Pd(OAc)2/Cu(OTf)2/Ag2O/Tol/110 °C/8 h
(7) Joule, J. A.; Mills, K. In Heterocyclic Chemistry, 5th Ed., Wiley,
UK, 2010.
78
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Under these conditions, the homocoupling of the aryl-
boronic acid was the least and the formation of the parent
quinoline 1 from N-acyl-1,2-dihydroquinoline 2 was mini-
mal. The substrate scope of the reaction is depicted in
Scheme 2.
The reaction sequence worked well on unsubstituted as
well as substituted quinolines, leading to decent yields of
substituted 3-arylquinolines.
ꢀ
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