Assembly of substituted 2-alkylquinolines by a sequential palladium-catalyzed Ci-N and Ci-C bond formation

Article abstract of DOI:10.1002/anie.201102076

Diversity: A range of substituted 2-alkylquinolines can be prepared in a general and efficient synthetic approach that employs mild reaction conditions (see scheme). The synthesis is based on a sequential palladium-catalyzed Ci-N and Ci-C bond formation, followed by palladium-catalyzed aromatization, and results in the formation of the desired compounds in one step. Copyright

Full text of DOI:10.1002/anie.201102076

Communications
DOI: 10.1002/anie.201102076
Synthetic Methods
Assembly of Substituted 2-Alkylquinolines by a Sequential Palladium-
À
À
Catalyzed C N and C C Bond Formation
Yoshio Matsubara,* Saori Hirakawa, Yoshihiro Yamaguchi, and Zen-ichi Yoshida*
The quinoline unit represents an important structural motif
found in a variety of biologically active compounds.[1] For
example, 2-methylquinoline (1a) is employed in the design of
pharmaceuticals and related compounds such as antischizo-
phrenia (e.g., PF-2545920),[2] antitumor (e.g., lavendamycin
methyl ester),[3] and anti-HIV agents (e.g., styrylquinoline),[4]
as well as nociceptin receptor antagonists (e.g., JTC-801).[5]
Cyanine dyes derived from substituted 2-methylquino-
lines are utilized as electronic and optoelectronic materials.[6]
Tris(8-quinolinolato)aluminum is most widely used as an
excellent green-emitting material,[7a,b] and functionalization
of the quinoline ring provides full-spectrum fluorescent
materials.[7c,d]
sequential steps: 1) a hydroamination catalyzed by the Lewis
À
acid PdCl2 (C N bond formation), 2) a subsequent PdCl2-
À
catalyzed tetrahydroquinoline ring formation (C C bond
formation), and 3) a palladium-catalyzed aromatization, thus
resulting in the formation of the desired compound in one
step.
A typical example of the reaction of an aniline with an
alkenyl ether is shown in Scheme 1. The reaction of aniline
(2a) with ethyl vinyl ether (3, 3 equiv) in the presence of
Since the substituents on the quinoline rings have a great
influence on the properties of these compounds, efficient
methods for the preparation of a diverse range of substituted
2-alkylquinolines are highly desirable. Traditionally, these
compounds are synthesized by using reactions of functional-
ized anilines with a,b-unsaturated carbonyl compounds at
elevated temperatures under strongly acidic conditions.[8–10]
Although the improvement of these harsh conditions has
recently been addressed by metal-catalyzed approaches,[11]
these new methods are confined because of a lack of
generality and limited functional-group tolerance. As exam-
ples of the synthesis of 2-alkylquinolines by metal-catalyzed
intermolecular reactions, Beller and co-workers have devel-
oped the formation of 2-benzyl-3-phenylquinoline by the
rhodium-catalyzed reaction of aniline with styrene.[11e] Later,
Yi and Yun reported the formation of 2-methylquinoline by
the ruthenium-catalyzed reaction of aniline with ethylene.[11d]
However, the generality of these excellent reactions has not
been examined. The functionalization of unsubstituted
2-alkylquinolines is another commonly used approach,
although in most cases it suffers from a lack of regioselectivity.
Herein, we report a highly efficient new method for the
construction of substituted 2-alkylquinolines by the PdCl2-
catalyzed reaction of anilines with alkenyl ethers. To the best
of our knowledge, this report represents the first application
of alkenyl ethers in the metal-mediated synthesis of quino-
lines. We have envisioned the reaction consisting of three
Scheme 1. Formation of 2-methylquinoline (1a) from aniline (2a) and
ethyl vinyl ether (3).
PdCl2 (5 mol%) in acetonitrile (MeCN; reflux in air, 5h)
afforded 2-methylquinoline (1a, 76%) accompanied by the
side product N-ethylaniline (24%). The yield of 1a was
increased to 82% by prolonged reflux in the presence of Pd/C
(Table 1, entry 1), which hindered the formation of the side
product. In the early stages of the reaction we observed the
formation of 1a and its tetrahydroderivatives (cis and trans),
but the hydroamination products were not isolated, thus
indicating that the aromatization step is the slowest and, thus,
the rate-determining step of the three sequential steps
mentioned above. From HPLC analysis of the reaction
mixtures, we suggest that the formation of 1a proceeds
through the mechanism shown in Scheme 1 (see the Support-
ing Information for further details).
During the optimization of the reaction conditions, it was
found that PdCl2 (finely powdered immediately before the
reaction) or [PdCl2(MeCN)2] were the most effective catalysts
among those examined (PdCl2, Pd(OAc)2, PdI2, [PdCl2-
(MeCN)2], [Pd(PPh3)2Cl2], and Pd/C), and MeCN was the
best solvent among those tested (MeCN, EtCN, PrCN,
toluene, N,N-dimethylformamide (DMF), and dimethyl sulf-
oxide (DMSO)). The yield of 1a was highest at a molar ratio
of 2a/3 = 1:3 and a concentration of 1 mmol 2a in 5 mL
MeCN (0.2m).
[*] Prof. Dr. Y. Matsubara, S. Hirakawa, Prof. Dr. Y. Yamaguchi,
Prof. Dr. Z.-i. Yoshida
Faculty of Science and Engineering, Kinki University
3-4-1 Kowakae, Higashi-Osaka, Osaka, 577-8502 (Japan)
Fax : (+81)6-6727-2024
E-mail: y-matsu@apch.kindai.ac.jp
yoshida@chem.kindai.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102076.
7670
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 7670 –7673

Table 1: Synthesis of substituted 2-methylquinolines.[a]
Entry Aniline (X)
t [h]
Product
Yield [%][b]
82[d]
Entry Aniline (X)
t [h]
Product
Yield [%][b]
72
1
2
3
2a (H)
24
1a
1b
1c
9
2i (3-F)
2j (4-Cl)
2k (3-Cl)
24
1i
1j
1k
2b (4-Me)
2c (3-Me)
24
24
82
81
10
11
24
24
70
68
4
2d (2-Me)
24
1d
75
12
2l (4-Br)
24
1l
66
5
6
2e (4-OMe) 24
2 f (3-OMe) 48
1e
1 f
86
62
13
14
2m (4-COOMe)[c] 24
2n (4-CONMe2)[c] 24
1m
1n
79
85
7
8
2g (2-OMe)
2h (4-F)
4
1g
1h
74
77
15
16
2o (4-COMe)[c]
2p (4-COPh)[c]
24
24
1o
1p
80
77
24
[a] Reaction conditions: substituted aniline (1 mmol), 3 (3 mmol), PdCl2 (5 mol%), and Pd/C (20 mg) in MeCN (5 mL) were heated in air at 808C.
[b] Yields were determined by HPLC. [c] Yields from reaction in the absence of Pd/C. [d] A threefold scale-up resulted in almost no change in the yield.
[e] Data for the formation of substituted N-ethylaniline (side product) are shown in the Supporting Information.
Under these optimized conditions, we examined the scope
and limitation of our reaction for the synthesis of substituted
2-methylquinolines (Table 1). The reaction works well,
regardless of the electron-donating or electron-withdrawing
nature of the substituents on the aniline ring. The reactions of
para-substituted anilines afforded 6-substituted 2-methylqui-
nolines in yields ranging from 66% to 86% (Table 1, entries 2,
5, 8, 10, and 12–16). Interestingly, the products of the reaction
with meta-substituted anilines were not a mixture of 5- and
7-substituted 2-methylquinolines, but only 7-substituted
2-methylquinolines in yields ranging from 62% to 81%
(Table 1, entries 3, 6, 9, and 11). This result could be ascribed
to the steric effect of the substituent at the transition state of
Table 2: Synthesis of 5,6,8-trimethoxy-2-methylquinoline (4) and 2-
methylbenzo[h]quinoline (6).[a]
Entry
Aniline
Product
t [h] Yield [%][b]
1
5
7
4
6
96
4
71
66
2
[a] Reaction conditions: substituted aniline (1 mmol), 3 (3 mmol), and
PdCl2 (3 mol%) in MeCN (5 mL) were heated in air at 808C. [b] Yields
were determined by HPLC. [c] Data for the formation of substituted N-
ethylaniline (side product) are shown in the Supporting Information.
À
the C C bond formation that leads to the tetrahydroquinoline
ring (see the Supporting Information). It is noteworthy that
the reaction with o-Me- and o-OMe-substituted anilines
afforded 8-substituted 2-methylquinolines in yields of around
75% (Table 1, entries 4 and 7), although no reaction of o-F-,
attractive new ligand for novel phosphorescent Ir complexes
(electroluminescent materials).[13]
o-Cl-, and o-COOMe-substituted anilines with
observed.
3
was
To extend the applicability of our reaction, we also
employed allyl and propenyl ethers. We examined the
reaction between substituted anilines 2 and allyl n-butyl
ether (9) by using the reaction conditions shown in Table 1.
We found that the reaction worked well by using 10 mol%
PdCl2 to provide substituted 2-ethyl-3-methylquinolines 8
(Table 3). The p-allyl Pd complex was not detected by
1H NMR spectroscopy and HPLC analysis of the reaction
mixtures.
To further demonstrate the scope of our reaction for the
preparation of polysubstituted 2-methylquinolines, we exam-
ined the reactions of 2,4,5-trimethoxyaniline (5) and 1-
naphthylamine (7), and obtained 5,6,8-trimethoxy-2-methyl-
quinoline (4) and 2-methylbenzo[h]quinoline (6), respec-
tively, in satisfactory yields (Table 2). Compound 4 is a useful
[3]
intermediate for the synthesis of lavendamycin
and
streptonigrin,[12] and compound 6 is expected to become an
As shown in Table 3, the reaction of substituted anilines
with allyl ether 9 works well, regardless of the electron-
Angew. Chem. Int. Ed. 2011, 50, 7670 –7673
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7671

Communications
Table 3: Synthesis of substituted 2-ethyl-3-methylquinolines 8.[a]
Entry Aniline (X)
t [h]
Product
Yield [%][b]
62
Entry Aniline (X)
t [h]
48
Product
Yield [%][b]
58
1
2
3
2a (H)
48
8a
8b
8c
8
2i (3-F)
2q (2-F)
2j (4-Cl)
8i
8q
8j
2b (4-Me)
2c (3-Me)
24
48
48
63
73
29
9
48
48
48
15
55
56
10
4
2d (2-Me)
8d
11
2k (3-Cl)
8k
5
6
2e (4-OMe) 24
2 f (3-OMe) 48
8e
8 f
59
65
12
13
2m (4-CO2Me)
2o (4-COMe)
24
24
8m
8o
65
72
7
2h (4-F)
4
8h
68
14
7
48
10
65
[a] Reaction conditions: substituted aniline (1 mmol), 9 (3 mmol), and PdCl2 (10 mol%) in MeCN (5 mL) were heated in air at 808C. [b] Yields were
determined by HPLC. [c] Data for the formation of substituted N-propylaniline (side product) are shown in the Supporting Information.
donating or electron-withdrawing nature of the substituent on
the aniline ring, to selectively provide substituted 2-ethyl-3-
methylquinolines. The reaction with para-substituted anilines
afforded 6-substituted 2-ethyl-3-methylquinolines in yields
ranging from 55% to 72% (Table 3, entries 2, 5, 7, 10, 12, and
13). The reaction with meta-substituted anilines gave 7-
substituted 2-ethyl-3-methylquinolines in yields ranging from
56% to 73% (Table 3, entries 3, 6, 8, and 11). Even the
reaction with ortho-methylaniline (2d) and ortho-fluoroani-
line (2q) gave 8-methyl-2-ethyl-3-methylquinoline (8d, 29%)
and 8-fluoro-2-ethyl-3-methylquinoline (8q, 15%), respec-
tively (Table 3, entries 4 and 9). The reaction of 1-naphthyl-
amine (7) provided 2-ethyl-3-methylbenzo[h]quinoline (10)
in 65% yield (Table 3, entry 14). Similar results were obtained
by employing n-propenyl ether 11 in place of allyl ether 9
(Table 4), thus suggesting that 9 isomerizes to 11 under the
reaction conditions.
In conclusion, we have developed a new method based on
a sequential PdCl2-catalyzed process for the construction of
functionalized alkyl quinolines from substituted anilines and
alkenyl ethers. The efficiency and functional-group tolerance
of this procedure have been fully demonstrated by synthesiz-
ing a number of substituted 2-alkylquinolines. The products
are expected to be useful intermediates for preparing
biologically active compounds as well as electronic and
optoelectronic materials. Considering the relatively inexpen-
sive catalytic system and the commercial availability of the
starting materials, this method should find numerous appli-
cations, including in the industrial field.
Table 4: PdCl2 catalyzed reaction of 2a with allyl n-butyl ether (9) or
1-ethoxy-1-propene (11).[a]
Experimental Section
Entry
Ether
Additive
Yield [%][b]
Typical procedure for the synthesis of 2-methylquinolines 1 and 2-
ethyl-3-methylquinolines 8: A 20 mL round-bottom flask equipped
with a Dimroth condenser and a Teflon-coated stirrer bar was charged
with a solution of 2 (1 mmol) in MeCN (5 mL). PdCl2 (0.05 mmol for
1 or 0.10 mmol for 8; finely powdered in an agate mortar) and vinyl
ether 3 or allyl ether 9 (3 mmol) were added and the mixture was
heated in air at 808C for 24 h (for 1) or 48 h (for 8). The solvent was
removed under reduced pressure, and the products were isolated by
column chromatography on silica gel (hexane/benzene) to give 1 or 8.
The structures of the products were confirmed by comparison with
reported spectroscopic data.
1
2
3
4
9
–
–
59
58
67
69
11
11
11
Pd/C (10 mg)
Pd/C (20 mg)
[a] Reaction conditions: 2a (1 mmol), 9 or 10 (3 mmol), and PdCl2
(5 mol%) in MeCN (5 mL) were heated in air at 808C for 24 h.
[b] Yields were determined by HPLC. [c] Data for the formation of
substituted N-propylaniline (side product) are shown in the Supporting
Information.
7672
www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 7670 –7673

Received: March 24, 2011
Published online: June 22, 2011
[7] a) C. W. Tang, S. A. VanSlyke, Appl. Phys. Lett. 1987, 51, 913 –
915; b) T. Noda, H. Ogawa, N. Noma, Y. Shirota, Adv. Mater.
1997, 9, 720 – 722; c) R. Pohl, V. A. Montes, J. Shinar, P.
Anzenbacher, Jr., J. Org. Chem. 2004, 69, 1723 – 1725; d) V. A.
Montes, R. Pohl, J. Shinar, P. Anzenbacher, Jr., Chem. Eur. J.
2006, 12, 4523 – 4535.
Keywords: anilines · heterocycles · homogeneous catalysis ·
.
palladium · quinolines
[8] For example, S. Madapa, Z. Tusi, S. Batra, Curr. Org. Chem.
2008, 12, 1116 – 1183.
[1] a) J. Barluenga, F. Rodriguez, F. J. Fananas, Chem. Asian J. 2009,
4, 1036 – 1048; b) J. P. Michael, Nat. Prod. Rep. 2008, 25, 166 –
187; c) M. G. Banwell, Pure Appl. Chem. 2008, 80, 669 – 679;
d) E. Abele, R. Abele, E. Lukevics, Chem. Heterocycl. Compd.
2008, 44, 769 – 792.
[9] For example, J. Horn, S. P. Marsden, A. Nelson, D. House, G. G.
Weingarten, Org. Lett. 2008, 10, 4117 – 4120.
[10] For example, J. Marco-Contelles, E. Perez-Mayoral, A. Samadi,
M. do C. Carreiras, E. Soriano, Chem. Rev. 2009, 109, 2652 –
2671.
[2] C. Drahl, Chem. Eng. News 2008, 86 (Sep 15), 39 – 40.
[3] a) W. Cai, M. Hassani, R. Karki, E. D. Walter, K. H. Koelsch, H.
Seradj, J. P. Lineswala, H. Mirzaei, J. S. York, F. Olang, M.
Sedighi, J. S. Lucas, T. J. Eads, A. S. Rose, S. Charkhzarrin, N. G.
Hermann, H. D. Beall, M. Behforouz, Bioorg. Med. Chem. 2010,
18, 1899 – 1909; b) G. Verniest, X. Wang, N. De Kimpe, A.
Padwa, J. Org. Chem. 2010, 75, 424 – 433.
[4] a) Z.-G. Jiao, H.-Q. He, C.-C. Zeng, J.-J. Tan, L.-M. Hu, C.-X.
Wang, Molecules 2010, 15, 1903 – 1917; b) F.-S. Chang, W. Chen,
C. Wang, C.-C. Tzeng, Y.-L. Chen, Bioorg. Med. Chem. 2010, 18,
124 – 133; c) J.-F. Mouscadet, D. Desmaele, Molecules 2010, 15,
3048 – 3078.
[5] I. Sestili, A. Borioni, C. Mustazza, A. Rodomonte, L. Turchetto,
M. Sbraccia, D. Riitano, M. R. Del Giudice, Eur. J. Med. Chem.
2004, 39, 1047 – 1057.
[6] a) J. Fabian, H. Nakazumi, M. Matsuoka, Chem. Rev. 1992, 92,
1197 – 1226; b) A. Mishra, R. I. K. Behera, P. K. Behera, B. K.
Mishra, G. B. Behera, Chem. Rev. 2000, 100, 1973 – 2011.
[11] For Co, see: a) L. Li, W. D. Jones, J. Am. Chem. Soc. 2007, 129,
10707 – 10713; for Ni, see: b) R. P. Korivi, C.-H. Cheng, J. Org.
Chem. 2006, 71, 7079 – 7082; for Zn, see: c) B. Jiang, Y.-G. Si,
J. Org. Chem. 2002, 67, 9449 – 9451; for Ru, see: d) C. S. Yi, S. Y.
Yun, Org. Lett. 2005, 7, 2181; for Rh, see: e) M. Beller, O. R.
Thiel, H. Trauthwein, C. G. Hartung, Chem. Eur. J. 2000, 6,
2513 – 2522; for Pd, see: f) Z. Zhang, J. Tan, Z. Wang, Org. Lett.
2008, 10, 173 – 175; g) B. Gabriele, R. Mancuso, G. Salerno, E.
Lupinacci, G. Ruffolo, M. Costa, J. Org. Chem. 2008, 73, 4971;
h) B. Gabriele, R. Mancuso, G. Salerno, G. Ruffolo, P. Plastina,
J. Org. Chem. 2007, 72, 6873 – 6877.
[12] a) M. Gavriil, C.-C. Tsao, S. Mandiyan, K. Arndt, R. Abraham,
Y. Zhang, Mol. Carcinog. 2009, 48, 678 – 684; b) P. Burke, B.
Toki, D. W. Meyer, J. B. Miyamoto, K. M. Kissler, M. Anderson,
P. D. Senter, S. C. Jeffrey, Bioorg. Med. Chem. Lett. 2009, 19,
2650 – 2653.
[13] Organic Light-Emitting Devices (Eds.: K. Mꢀllen, U. Scherf),
Wiley-VCH, Weinheim, 2006, pp. 336 – 345.
Angew. Chem. Int. Ed. 2011, 50, 7670 –7673
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7673