Palladium-catalyzed C-2 selective arylation of quinolines

Article abstract of DOI:10.1021/ol402262c

An efficient method for the Pd-catalyzed regioselective C-2 arylation of quinolines is presented. Reactions of various substituted quinolines and unactivated arenes have been conducted under mild conditions. The result shows good product yields of 2-arylq

Full text of DOI:10.1021/ol402262c

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Palladium-Catalyzed C‑2 Selective
Arylation of Quinolines
Xiaoyu Ren, Ping Wen, Xiaokang Shi, Yuling Wang, Jian Li, Sizhuo Yang, Hao Yan,
and Guosheng Huang*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu
Province, Lanzhou 730000, P. R. China
hgs@lzu.edu.cn
Received August 14, 2013
ABSTRACT
An efficient method for the Pd-catalyzed regioselective C-2 arylation of quinolines is presented. Reactions of various substituted quinolines and
unactivated arenes have been conducted under mild conditions. The result shows good product yields of 2-arylquinolines, which are highly useful
building blocks for the synthesis of bioactive alkaloid natural products and drug molecules.
Biaryl structural motifs are indispensable structures
which are frequently found in biologically active mole-
cules, natural products, and organic materials and have
been attracting chemists’ attention for decades.1,2 There-
fore, transition-metal-catalyzed arylÀaryl bond formation
through the coupling of two CÀH bonds is of high
importance to organic chemists.3 Direct arylation affords
biaryls in fewer steps compared to traditional methods.4
Consequently, much attention has been given to develop-
ing synthetic pathways for creating an arylÀaryl bond via
CÀH activation.
Quinolines are one of the key components of many
synthetic building blocks, natural products, and drug
candidates.5 In the past decades, a variety of methods have
been developed to functionalize quinoline compounds.
Previous researchers6À17 have reported several efficient
protocols to synthesize C-2 aryl quinolines by transition-
metal-catalyzed coupling reactions of its derivatives (e.g.,
N-oxides and N-iminopyridinium ylides and heteroaryl
(5) Kwak, J.; Kim, M.; Chang, S. J. Am. Chem. Soc. 2011, 133, 3780.
(6) (a) Lee, D. H.; Jung, J. Y.; Jin, M. J. Green Chem. 2010, 12, 2024.
(b) Jung, J. Y.; Althammer, A.; Hossain, S.; Jin, M. J. Bull. Korean
Chem. Soc. 2010, 31, 3010. (c) Lee, D. H.; Althammer, A.; Ahn, W. S.;
Jin, M. J. Chem. Commun. 2010, 46, 478.
(7) Tagata, T.; Nishida, M. J. Org. Chem. 2003, 68, 9412.
(8) Ackermann, L.; Potukuchi, H. K.; Althammer, A.; Born, R.;
Mayer, P. Org. Lett. 2010, 12, 5.
(9) Chen, G. J.; Han, F. S. Eur. J. Org. Chem. 2012, 125, 3575.
(10) Quasdorf, K. W.; Finch, A. A.; Liu, P.; Silberstein, A. L.;
Komaromi, A.; Blackburn, T.; Ramgren, S. D.; Houk, K. N.; Snieckus,
V.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 6352.
(11) Finch, A. A.; Blackburn, T.; Snieckus, V. J. Am. Chem. Soc.
2009, 131, 17750.
(12) Tobisu, M.; Hyodo, I.; Chatani, N. J. Am. Chem. Soc. 2009, 131,
12070.
(13) Strotman, N. A.; Chobanian, H. R.; Guo, Y.; He, J. F.; Wilson,
J. E. Org. Lett. 2010, 12, 3578.
(14) Iglesias, M.; Prieto, A.; M. Nicasio, C. Org. Lett. 2012, 14, 4318.
(15) Kuzmina, O. M.; Steib, A. K.; Flubacher, D.; Knochel, P. Org.
Lett. 2012, 14, 4818.
(16) Berman, A. M.; Bergman, R. G.; Ellman, J. A. J. Org. Chem.
2010, 75, 7863.
(1) (a) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int.
´
Ed. 2009, 48, 9792. (b) Brasche, G.; Garcıa-Fortanet, J.; Buchwald, S. L.
Org. Lett. 2008, 10, 2207. (c) Kinzel, T.; Zhang, Y.; Buchwald, S. L.
J. Am. Chem. Soc. 2010, 132, 14037. (d) Gorelsky, S. I.; Lapointe, D.;
Fagnou, K. J. Org. Chem. 2012, 77, 658.
(2) For reviews on biaryl syntheses, see: (a) Bringmann, G.; Price
Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M.
Angew. Chem., Int.Ed. 2005, 44, 5384. (b) Corbet, J. P.; Mignani, G. Chem.
Rev. 2006, 106, 2651. (c) Beller, M.; Bolm, C. Transition Metals for Organic
Synthesis; Wiley-VCH: Weinheim, 2004; (d) de Meijere, A.; Diederich, F.
Metal-Catalyzed Cross-Coupling Reactions; Wiley-VCH: Weinheim, 2004;
(e) Anastasia, L.; Negishi, E. Handbook of Organopalladium Chemistry for
Organic Synthesis; Wiley: New York, 2002. (f) Bringmann, G.; G€unther, C.;
Ochse, M.; Schupp, O.; Tasler, S. Prog. Chem. Org. Nat. Prod. 2001, 82, 1. (g)
Sun, C. J.; Li, B. J.; Shi, Z. J. Chem. Rev. 2011, 111, 1293. (h) Liu, C.;
Zhang, H.; Shi, W.; Lei, A. W. Chem. Rev. 2011, 111, 1780. (i) Arockiam,
P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. (j) Yeung,
C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.
(3) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173.
(4) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38,
2447.
(17) Hyodo, I.; Tobisu, M.; Chatani, N. Chem.;Asian J. 2012, 7,
1357.
r
10.1021/ol402262c
XXXX American Chemical Society

efficient and stereoselective synthetic route to aromatic
quinolines, which does not required any preactivation, is
among the most desireable transformations. Herein, we
have developed a novel Pd-catalyzded method for the
selective arylation of quinolines.
Table 1. Optimization of Reaction Conditionsa
Inspired by our previous work23 on C-2 selective CÀH
olefination of pyridine derivatives via a Pd(II)/Pd(0) cat-
alytic manifold, we investigated the possibility of achieving
quinoline C-2 arylation with unactivated arenes through
palladium CÀH activation chemistry. Our results shows
that quinoline (1a, 0.2 mmol) and 1,2-dichlorobenzene
(2a, 1.0 mL) as substrates can efficiently produce the sole
meta-selective arylation of 1,2-dichlorobenzene (3aa) in
the presence of AgOAc (0.4 mmol) and pivalic acid
(PivOH) (0.4 mmol) in N,N-dimethylformamide (DMF)
at 150 °C in air. In order to find the best oxidants under
Pd(OAc)2 catalysis, we chose AgOAc, Ag2CO3, and
Cu(OAc)2 as candidates. The results showed that using
Ag2CO3 as oxidants can give the best yield, followed by
AgOAc, but using Cu(OAc)2 leads to no production of 3aa
(Table 1, entries 1À3). Further optimization showed that
increasing the amount of Ag2CO3 remarkably improved
the product yield (Table 1, entry4). Additionally, we found
that increasing the quantity of PivOH to 6.0 equiv would
increase the efficiency for the reaction (Table 1, entries
5À7). Although all of these reaction pathways did not
require external oxidants, the addition of O2 (1 atm) can
increase the yield from 52% to 60% (Table 1, entry 8).
Replacing PivOH with acetic acid (AcOH) or trifluoroa-
cetic acid (TFA) did not improve the yield of the desired
product (Table 1, entries 9 and 10). Furthermore, we
studied the solvent effect and found that DMF was superior
to N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone
(NMP), dimethyl sulfoxide (DMSO), dioxane, or AcOAc
(Table 1, entries 11À15). In addition, the use of 1,10-
phenanthroline (phen), i-Pr2S, PPh3 as ligand provided
the product in lower yield. Thus, quinoline was considered
tobea ligand by itself (Table 1, entries 16À18). Inaddition,
the reaction temperature was crucial for the reaction.
Compared with the results under the conditions in Table 1,
entry 8, the model reaction catalyzed by Pd(OAc)2 at
130 °C gave 3aa in 42% yield (Table 1, entry 19), suggest-
ing that higher temperature was beneficial for the forma-
tion of the target.
entry oxidant (equiv) addition (equiv)
solvent
yield (%)
1
AgOAc (2.0)
Ag2CO3 (2.0)
Cu(OAc)2(2.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
PivOH (2.0)
PivOH (2.0)
PivOH (2.0)
PivOH (2.0)
PivOH (4.0)
PivOH (6.0)
PivOH (8.0)
PivOH (6.0)
AcOH (6.0)
TFA (6.0)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMAc
NMP
DMSO
Dioxane
AcOAc
DMF
DMF
DMF
DMF
32
38
0
2
3
4
42
45
52
48
60
50
12
58
55
46
23
0
5
6
7
8b
9
10
11
12
13
14
15
16c
17d
18e
19f
PivOH (6.0)
PivOH (6.0)
PivOH (6.0)
PivOH (6.0)
PivOH (6.0)
PivOH (6.0)
PivOH (6.0)
PivOH (6.0)
PivOH (6.0)
21
47
11
42
a Reaction condition: quinolines (0.2 mmol), Pd(OAc)2 (10 mol %),
1,2-dichlorobenzene (1.0 mL), Ag2CO3 (0.4 mmol), and PivOH
(0.4 mmol) in DMF (0.6 mL) at 150 °C for 30 h. b O2 (1 atm) was used.
c 1,10-Phen was used as ligand. d i-Pr2S was used as ligand. e PPh3 was
used as ligand. f Run at 130 °C.
halide) and functionalized arylenes. However, these
methods required the prefunctionaliztion of one or both
coupling partners. In addition, the pioneering works re-
ported by Ong18 and Nakao19 have independently demon-
strated that, in the presence of Lewis acids and
N-heterocyclic carbene nickel complexes, not only the
selective activation of the C-3 carbon but also the unpre-
cedented C-8 selectivity alkylation of quinolones were
achieved. In addition, Sames and co-workers20 have devel-
oped a new catalytic protocol for high regioselectivity at
C-4 and C-6 arylation of quinolines containing electron-
withdrawing substituents (ÀNO2). Recently, Kapur and
co-workers disclosed a two-step approach for quinoline
C-3 arylation,21 and You and co-workers described the
Pd-catalyzed oxidative CÀH/CÀH coupling of pyridines
and heteroarenes.22 To date, the oxidative coupling of
arenes with quinolines has been quite challenging due to
their relatively low reactivity. Furthermore, the stereose-
lective functionalization is often more difficult. Thus, an
With the optimized conditions, we examined the com-
patibility of the quinoline coupling partners (Scheme 1).
Generally, quinoline was arylated smoothly to give the
corresponding C-2 arylation product with excellent meta-
selectivity with respect to 1,2-dichlorobenzene. At first,
compared with electron-rich analogues, electron-deficient
C-6 substituted quinolines exhibited high reactivity in the
procedure (3ba, ca). Similarly, substitution at C-5 by the
nitro group also gave the desired product in excellent yield
(3da). Additionally, a number of halogenated quinolines
treated with 1,2-dichlorobenzene with high regioselec-
tivity to give the 2-arylated products in moderate to good
(18) Tsai, C. C.; Shih, W. C.; Fang, C. H.; Li, C. Y.; Ong, T. G.; Yap,
G. P. J. Am. Chem. Soc. 2010, 132, 11887.
(19) Nakao, Y.; Yamada, Y.; Kashihara, N.; Hiyama, T. J. Am.
Chem. Soc. 2010, 132, 13666.
(20) Guo, P. F.; Joo, J. M.; Rakshit, S.; Sames, D. J. Am. Chem. Soc.
2011, 133, 16338.
(21) Tiwari, V. K.; Pawar, G. G.; Das, R.; Adhikary, A.; Kapur, M.
Org. Lett. 2013, 15, 3310.
(22) Liu, B.; Huang, Y.; Lan, J.; Song, F.; You, J. Chem. Sci. 2013, 4,
2163.
(23) Wen, P.; Li, Y. M.; Zhou, K.; Ma, C.; Lan, X. B.; Ma, C. W.;
Huang, G. S. Adv. Synth. Catal. 2012, 354, 2135.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 1. Synthesis of 2-(3,4-Dichlorophenyl)quinolines from
Substituted Quinolines and 1,2-Dichlorobenzenea
Scheme 2. Synthesis of 2-(3,4-Dichlorophenyl)quinolines from
Quinolines and Substituted Dichlorobenzenea
a Reaction condition: quinolines (0.2 mmol), Pd(OAc)2 (10 mol %),
1,2-dichlorobenzene (1.0 mL), Ag2CO3 (0.6 mmol), and PivOH
(1.2 mmol) in DMF (0.6 mL) under O2 at 150 °C for 30 h.
To further explore the applicability of this significant
developed method, we examined the scope of dichloroben-
zenes. As summarized in Scheme 2, although the acidity of
H at C-2 on 1,3-dichlorbenzene was higher than at C-5, we
found that 2-(3,5-dichlorophenyl)quinoline was produced
as the only product in moderate yield when the reaction
was carried out in 1,3-dichlorobenzene at 150 °C (4ab).
Moreover, reaction of quinoline with 1,4-dichlorobenzene
afforded the corresponding ortho-only arylated products
in 57% yield (4ac). When 1,2,3-trichlorobenzene and 1,3-
dichloro-2-methylbenzene were used as substrates, the
desired products were detected in moderate yields (4ad,
ae). However, complex mixtures were produced when
chlorobenzene was applied in the reaction, indicating the
importance of electronic effects on the selectivity (4af).
Interestingly, quinoline with 1-chloro-2-methylbenzene
provided the desired 2-(3-chloro-4-methylphenyl)quinoline
as the only product (4ag), but 1-chloro-4-methylbenzene
failed to generate (4ah). It should be noted that when
bromobenzene and benzene were applied as coupling
partners, only a trace amount of the desired products
was detected (4ai,aj), and then toluene did not react with
quinoline (4ak), which further indicated that the electronic
character of aromatic substituents exhibits the strongest
impact on reactivity. Furthermore, when 1,2-difluoroben-
zene, 1,2-dibromobenzene, and 1,2-diiodobenzene were em-
ployed as substrates, we failed to get the 2-arylation product
(4alÀan). Other electron-donating or -withdrawing groups
a Reaction condition: quinolines (0.2 mmol), Pd(OAc)2 (10 mol %),
1,2-dichlorobenzene (1.0 mL), Ag2CO3 (0.6 mmol), and PivOH
(1.2 mmol) in DMF (0.6 mL) under O2 at 150 °C for 30 h.
yields (3eaÀha). It was noteworthy that methoxy, chloride,
and bromide on the ring were versatile handles for further
transformations.24 When the electron-donating methyl
group was presented in quinoline, the yields of desired
product were dramatically decreased from those contain-
ing electron-withdrawing groups (3iaÀka). This demon-
strated that the position and the electronicproperties of the
substituents on the rings were more influential than steric
effects in the reaction systems. Notably, the quinoline with
a nitro group at C-8 may not be suitable for the process as
the desired product was not isolated, and only a trace
amount of product was detected on the silica gel (3la);
however, a methyl group at C-8 did not work directly
under the standard conditions (3ma). Furthermore, exclu-
sive C-1-selectivity was observed. Isoquinoline and 5-NO2-
isoquinoline achieved moderate yields (3na,oa), and aryla-
tion of quinoxaline gave a relatively low yield (3pa).
(24) (a) Hwu, J. R.; Wong, F. F.; Huang, J. J.; Tsay, S. C. J. Org.
Chem. 1997, 62, 4097. (b) Ondachi, P. W.; Comins, D. L. J. Org. Chem.
2010, 75, 1706. (c) Gollner, A.; Koutentis, P. A. Org. Lett. 2010, 12, 1352.
Org. Lett., Vol. XX, No. XX, XXXX
C

A plausible reaction mechanism is outlined in Scheme 3.
Step i: quinoline (1a) can potentially coordinate with Pd-
(II) through the N atom to form A, followed by palladium
migration to C-2, which is promoted by electron-withdrawing
groups. Step ii: metalation deprotonation25 at C-2 occurs.
Step iii: CÀH activation of 2a by electrophilic pallada-
tion26 affords an intermediate C. Step iv: reductive elim-
ination from C furnishes the 2-aryl CÀC bond. Step v:
Pd(0) is reoxidized to Pd(II) by Ag(I)/PivOH/O2 to close
the catalytic cycle.
Scheme 3. Plausible Mechanistic Pathway
In summary, a novel protocol of effective Pd-catalyzed
C-2 arylation of quinolines has been developed using O2
and Ag2CO3 as the oxidants. This strategy provides a
simple and efficient method for quinoline CÀH bond
activation. The resulting C-2-arylated quinolines can
be used as building blocks for synthesis of bioactive
alkaloid natural products and drug molecules. Ongoing
work seeks to exploit this mechanistic manifold for
other synthetically useful cross-coupling reactions as
well as to further probe the mechanism of these new
transformations.
such as methoxy and nitro groups substituents did not
work in this reaction (4ao,ap). Although other oxidative
coupling reactions and undirected CÀH activation reac-
tions are not limited to chloroarenes, chlorine is necessary
on the aromatic ring in this reaction.
Acknowledgment. We thank the State Key Laboratory
of Applied Organic Chemistry for financial support.
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and H and 13C NMR
(25) Potavathri, S.; Pereira, K. C.; Gorelsky, S. I.; Pike, A.; LeBris,
A. P.; DeBoef, B. J. Am. Chem. Soc. 2010, 132, 14676.
(26) (a) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129,
11904. (b) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 9651.
(c) Zhao, X.; Yeung, C. S.; Dong, V. M. J. Am. Chem. Soc. 2010, 132,
5837. (d) Wei, Y.; Su, W. J. Am. Chem. Soc. 2010, 132, 16377.
spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX