Nickel-catalyzed cyclization of 2-iodoanilines with aroylalkynes: An efficient route for quinoline derivatives

Article abstract of DOI:10.1021/jo060800d

An efficient and convenient nickel-catalyzed cyclization of 2-iodoanilines with alkynyl aryl ketones to give 2,4-disubstituted quinolines was developed. The reaction can be employed for the synthesis of naturally occurring quinoline derivatives in good yields. On the basis of the regiochemistry of the products, the possible pathway for the reaction is via the formation of o-aminochalcone.

Full text of DOI:10.1021/jo060800d

SCHEME 1
Nickel-Catalyzed Cyclization of 2-Iodoanilines
with Aroylalkynes: An Efficient Route for
Quinoline Derivatives
Rajendra Prasad Korivi and Chien-Hong Cheng*
crucial problem is the poor regioselectivity that often leads to
isomers. Other methods generally require the use of strong acids,
high temperature, and tedious reaction procedures and suffer
from poor selectivity. Recently, several reports of transition
metal-catalyzed synthesis of quinolines have appeared.5 These
included rhodium-catalyzed5b,c cyclization of anilines with
styrenes and cyclization of trifluoroacetimidoyl chloride with
alkynes and also the intramolecular cyclization of alkynyl imines
catalyzed by tungsten carbonyl.5d In most of these cases, the
regioselectivity and the scope of functionality on the quinolines
are limited.
Department of Chemistry, National Tsing Hua UniVersity,
Hsinchu 30013, Taiwan
chcheng@mx.nthu.edu.tw
ReceiVed April 15, 2006
Our interests in developing new synthetic strategies using
nickel catalysts6,7 recently made possible the development of
an efficient route for the preparation of isoquinolines and
pyridines by the reaction of 2-iodobenzaldimines and 3-iodo-
3-phenylacrylaldimines with alkynes, respectively. Herein, we
wish to report a new convenient nickel-catalyzed synthesis of
2,4-disubstituted quinolines using the easily available 2-iodo-
anilines and 1-benzoylalkynes8 as the starting materials under
neutral conditions. The method for 2,4-disubstituted quinolines
is important as most of the available methods are for the
preparation of 2,3-disubstituted quinolines.
When 2-iodoaniline (1a) was treated with 1-benzoylethyne
(2a) in the presence of NiBr2(dppe) and zinc metal powder in
acetonitrile, Michael addition-deiodination product 3 was ob-
tained in 68% yield (Scheme 1). No expected quinoline was
observed in this case. Fortunately, the use of internal alkyne,
1-benzoyl phenyl acetylene (2b), with 1a in the presence of
NiBr2(dppe) and zinc metal powder in acetonitrile at 80 °C for
12 h gave the corresponding 2,4-diphenylquinoline (4a) in 56%
yield (Table 1). Control experiments showed that in the absence
of either nickel catalyst or zinc metal, no quinoline 4a was
observed.
An efficient and convenient nickel-catalyzed cyclization of
2-iodoanilines with alkynyl aryl ketones to give 2,4-disub-
stituted quinolines was developed. The reaction can be
employed for the synthesis of naturally occurring quinoline
derivatives in good yields. On the basis of the regiochemistry
of the products, the possible pathway for the reaction is via
the formation of o-aminochalcone.
Quinolines are widely occurring natural alkaloids known to
display a wide variety of pharmacological properties such as
anesthetic, tumorcidal, angina pectoris, antihypertensive, and
antibacterial activities and also act as insecticidal agents.1 In
addition, these compounds are well-known ligands for the
preparation of OLED phosphorescent complexes.2 Development
of new synthetic methods for quinoline derivatives are in great
demand because of the rise of the resistance level of malarial
parasite in the use of Chloroquine, a widely used malarial drug.1a
There are several synthetic methods3,1a available for the prepara-
tion of quinolines. The most popular method is the two-step
Friedlander synthesis4 based on Aldol condensation of unstable
2-aminobenzaldehydes generated in situ by reduction of 2-ni-
trobezaldehydes with ketones. This method is seriously limited
by the availability of 2-nitrobenzaldehyde derivatives. Another
(4) (a) Friedlander, P. Chem. Ber. 1882, 15, 2572. (b) Cho, C. S.; Kim,
B. T.; Kim, T. J.; Shim, S. C. Chem. Commun. 2001, 2576. (c) Hsiao, Y.;
Rivera, N. R.; Yasuda, N.; Hughes, D. L.; Reider, R. J. Org. Lett. 2001, 3,
1101. (d) Dormer, P. G.; Eng, K. K.; Farr, R. N.; Humphrey, G. R.;
McWilliams, J. C.; Reider, P. J.; Sager, J. W.; Volante, R. P. J. Org. Chem.
2003, 68, 467. (e) Miller, B. L.; Mcnaughton, B. R. Org. Lett. 2003, 5,
4257. (f) Hu, Y.-Z.; Zhang, G.; Thummel, R. P. Org. Lett. 2003, 5, 2251.
(5) (a) Takahashi, T.; Li, Y.; Stepnicka, P.; Kitamura, M.; Liu, Y.;
Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 2002, 124, 576. (b) Beller,
M.; Thiel, O. R.; Trauthwein, H.; Hartung, C. G. Chem.sEur. J. 2000, 6,
2513. (c) Amii, H.; Kishikawa, Y.; Uneyama, K. Org. Lett. 2001, 3, 1109.
(d) Sangu, K.; Fuchibe, K.; Akiyama, T. Org. Lett. 2004, 6, 353.
(6) (a) Korivi, R. P.; Cheng, C, H. Org. Lett. 2005, 7, 5179. (b)
Jeevanandam, A.; Korivi, R. P.; Cheng, C, H. Org. Lett. 2002, 4, 807. (c)
Rayabarapu, D. K.; Sambiah, T.; Cheng, C, H. Angew. Chem., Int. Ed. 2001,
40, 1286.
(1) (a) Claret, P. A.; Osborne, A. G. In The Chemistry of Heterocyclic
Compounds; Quinolines; Jones, G., Ed.; John Wiley Sons: U.K., 1982;
Vol. 32, Part 2, pp 31-32. (b) Sawada, Y.; Kayakiri, H.; Abe, Y.; Imai,
K.; Katayama, A.; Oku, T.; Tanaka, H. J. Med. Chem. 2004, 47, 1617. (c)
Groisy-Delcey, M.; Groisy, A.; Carrez, D.; Huel, C.; Chaironi, A.; Ducrot,
P.; Bisagni, E.; Jin, L.; Leclercq, G. Bioorg. Med. Chem. 2000, 8, 2629.
(d) Strekowski, L.; Say, M.; Henary, M.; Ruiz, P.; Manzel, L.; Macfarlane,
D, E.; Bojarski, A. J. J. Med. Chem. 2003, 46, 1242.
(2) (a) Cheng, C. H.; Chen, R. M.; Huang, C. W.; Yang, C. C. U.S.
Patent 20050025995A1, 2005. (b) Thompson, M. E.; Ma, B.; Djurovich,
P. U.S. Patent 20050164031A1, 2005. (c) Adamovich, V.; Weaves, M.;
Brown, J. U.S. Patent 20050168137A1, 2005. (d) Knowles, D. B.; Kwong,
R. U.S. Patent 20050164030A1, 2005. (e) Kim, J. L.; Shin, I. S.; Kim, H.
J. Am. Chem. Soc. 2005, 127, 1614.
(7) (a) Rayabarapu, D. K.; Yang, C, H.; Cheng, C. H. J. Org. Chem.
2003, 17, 6726. (b) Rayabarapu, D. K.; Cheng, C. H. Chem. Commun. 2002,
942.
(3) (a) Luo, Z. Y.; Zhang, Q. S.; Oderaotoshi, Y.; Curran, D. P. Science
2001, 291, 1766. (b) Skarup, Z. H. Chem. Ber. 1880, 13, 2086. (c) Baker,
R. H.; Tinsley, S. W., Jr.; Butler, D.; Riegel, B. J. Am. Chem. Soc. 1950,
72, 393. (d) Bischler, A.; Napieralski, B. Chem. Ber. 1893, 26, 1903. (e)
Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279. (f) Meth-Cohn, O.;
Stanforth, S. P.; ComprehensiVe Organic Synthesis; Heathcock, C. H., Ed.;
Pergamon Press: New York, 1991; Vol. 2, 777.
(8) Various 1-benzoylalkynes R3CCC(O)R2 were prepared from R3CCLi
(from R3CCH and n-BuLi) and R2C(O)Cl in THF at -78 °C or (a) Chen,
L.; Li, C. J. Org. Lett. 2004, 6, 3151. (b) Lee, P. H.; Lee, S. W.; Seomoon,
D. Org. Lett. 2003, 5, 4963. 2-Iodoaniline derivatives were prepared from
I2, the corresponding aniline and NaHCO3. (c) Xiao, W.-J.; Alper, H. J.
Org. Chem. 1999, 64, 9646. (d) Dains, F. B.; Vaughan, T. H.; Janney, W.
M. J. Am. Chem. Soc. 1918, 40, 932.
10.1021/jo060800d CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/29/2006
J. Org. Chem. 2006, 71, 7079-7082
7079

TABLE 1. Effect of the Catalyst and Solvent on the Synthesis of 4a from 1a and 2ba
entryb
catalyst
yield (%)
entry
catalyst
yield (%)
1
2
3
4
5
6
7
NiBr2(dppe), CH3CN
NiBr2(PPh3)2, CH3CN
NiBr2(dppm), CH3CN
NiBr2(dppp), CH3CN
NiBr2(dppe), THF
56
31
trace
trace
0
8
9
10
11
12
13
CoI2(dppe), CH3CN
CoI2(dppe), CH3CN, H2O
PdCl2(PPh3)2, CH3CN
Pd(PPh3)4, DMF
NiBr2(dppe), CH3CN
NiBr2(PPh3)2, CH3CN
0
0
0
0
83
46
NiBr2(dppe), o-xylene
NiBr2(dppe), DMF
0
12
a All the reactions except in entries 12 and 13 were carried out in nitrogen atmosphere using 1a, (0.10 mmol), alkyne 2b (0.10 mmol), metal complex
(0.0050 mmol), and Zn (0.20 mmol) in the solvent mentioned in each entry (3.0 mL) at 80 °C for 12 h. All the yields mentioned above are NMR yields using
mesitylene as an internal standard. The reactions in DMF were followed by workup with aq NH4Cl solution to remove DMF. b An amount of 2 equiv of
alkyne 2b was used in entries 12 and 13.
To improve the product yield of the present catalytic reaction,
the reaction conditions including the catalyst, solvent, and the
ratio of the reagents used were varied. In addition to NiBr2-
(dppe), other bidentate phosphine nickel complexes including
NiBr2(dppm) and NiBr2(dppp) were tested giving 4a in only a
trace amount (Table 1). Monodentate phosphine nickel complex
NiBr2(PPh3)2 was also tested for the reaction affording 4a in
31% yield. The use of CoI2(dppe), PdCl2(PPh3)2, and Pd(PPh3)4
as catalysts for the reaction of 1a with 2b showed no product
formation, and the starting materials 1a and 2b were recovered.
The yield of product 4a for the reaction of 1a with 2b in the
presence of NiBr2(dppe) and zinc was further improved to 83%
by using 2 equiv of alkyne 2b (46% for NiBr2(PPh3)2). The
reaction of 1a with 2b in various solvents was investigated.
Product 4a was observed in CH3CN and DMF in 83 and 16%
yields, respectively. In THF and o-xylene, the reaction did not
yield the expected product 4a. On the basis of the above studies,
the reaction conditions using Ni(dppe)Br2 in the presence of
zinc at 80 °C in acetonitrile with 2 equiv of alkyne appeared to
give the best yield of 4a and were employed as the standard
reaction conditions for other substrates shown in Table 2.
We next explored the scope and the possible mechanism of
this nickel-catalyzed cyclization reaction. The product yields
with various 2-haloanilines and aroylalkynes are summarized
in Table 2. Similar to 2-iodoaniline, the corresponding 2-bro-
moaniline underwent cyclization with 2b to give product 4a,
but in a lower yield of 48% (entry 2). Under the standard
reaction conditions, 1-benzoyl-1-hexyne (2c) reacts smoothly
with 2-iodoaniline (1a) to give 4-butyl-2-phenylquinoline (4b)
in 86% yield (entry 3). The structure of 4b was carefully
assigned based on the NOE, 1H, and 13C experimental data. The
results clearly demonstrate that the phenyl group in 2c is
attached to the 2nd position of quinoline 4b and the butyl group
occupies the 4th position of the quinoline. The bulkier naphthoyl
phenyl acetylene 2d also reacted with 1a to give 4c in moderate
yield of 59%.
great interest9,10 in medicinal chemistry. The catalytic reaction
was successfully extended to 4-trifluoromethyl-2-iodoaniline 1e
with alkynes. The reaction of 1e with alkyne 2b and 2c gave
4h and 4i in 68 and 87% yields, respectively. The structure of
4i was determined by single-crystal X-ray diffraction. Finally,
we also tested the reactivity of alkanoylalkyne for the present
catalytic reaction. Under the standard conditions, acetyl-1-
propyne (2e) successfully underwent cyclization with 1d to give
the corresponding quinoline 4j albeit in a lower yield (56%).
The utility of this novel cyclization was further demonstrated
by the synthesis of naturally occurring alkaloids 4m and 4n
(Scheme 2). Under the standard conditions, treatment of
2-iodoaniline with piperonyloyl trimethylsilyl acetylene (2f)
yields the corresponding quinoline 4k in 79%. Dubamine11a-c
(4m) was obtained by the cleavage of trimethylsilyl group in
4k with TBAF at 60 °C in THF. In a similar manner 4l was
obtained in 74% yield using 1a and alkyne 2g, and the
corresponding 2-phenylquinoline11d (4n) was obtained by further
desilylation. These molecules have shown significant biological
properties10e such as antioxidant, antiprotozoal, and cytotoxicity
activities.
An intriguing feature of the present catalytic reaction is that
the 1-aroylalkynes should be disubstituted in order for the
catalytic reaction to proceed to obtain the quinoline products.
Monosubstituted 1-aroylalkyne gave the hydroamination-de-
halogenation product on reacting with 2-iodoaniline. Thus, the
presence of a second substituent on the alkynyl group in
1-aroylalkynes appears to effectively block the attack of amino
group in 1 at the â-alkynyl carbon. This is further evident by
the results of reactions in Table 2 in which no hydroamination
products were observed. Also in the reaction of 1a with 2b
(Table 1) where no expected product 4a was formed, there was
no hydroamination product observed after heating the solution
at 80 °C for 12 h; only the starting materials were recovered.
To explain how the nickel system catalyzes the present
quinoline formation reaction, we propose the mechanism as
shown in Scheme 3. The catalytic cycle is likely initiated by
the reduction of Ni(II) to Ni(0) by zinc metal powder. The
The catalytic reaction also proceeded smoothly with 2-iodo-
anilines possessing various substituents. Iodoaniline derivative
1c having a 4-methyl substituent reacted with alkyne 2b to yield
quinoline 4d in excellent yield (91%, entry 5). Similarly, the
reaction of 1c with alkyne 2c under the same conditions yielded
quinoline 4e in 76% yield (entry 6). Iodoaniline derivative 1d
having a para-substituted electron-withdrawing chloro group 1d
also reacted successfully with 2b to give the corresponding
cyclized product 4f in good yield. In a similar manner, 1d
underwent cyclization with 2c to give quinoline derivative 4g
in 83% yield. A key reason for the selection of halogen-
substituted anilines as substrates for the present catalytic reaction
is that the halogen-substituted derivatives of quinoline are of
(9) (a) Amii, H.; Kishikawa, Y.; Uneyama, K. Org. Lett. 2001, 3, 1109.
(10) (a) Zaragoza, F.; Stephensen, H.; Peschke, B.; Rimvall, K. J. Med.
Chem. 2005, 48, 306. (b) Hoeskstra, W. J.; Patel, H, S.; Liang, X.; Baptiste,
J. E. B.; Heyer, D. O.; Willson, T. M.; Iannome, M. A.; Kadwell, S. H.;
Miller, L. A.; Pearle, K. H.; Simmone, C. A.; Shearin, J. J. Med. Chem.
2005, 48, 2243. (c) Stocks, P. A.; Raynes, K. J.; Bray, P. G.; Park, B. K.;
Oneill, P. M.; Ward, S. A. J. Med. Chem. 2002, 45, 4975.
(11) (a) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109,
5478. (b) Fournet, A.; Vagneur, B.; Richomme, P. Can. J. Chem. 1989,
67, 2116. (c) Fakhfakh, M. A.; Fournet, A.; Prina, E.; Mouscadet, J.-F.;
Franck, X.; Hocquemiller, R.; Figadere, B. Bioorg. Med. Chem. 2003, 11,
5013.
7080 J. Org. Chem., Vol. 71, No. 18, 2006

TABLE 2. Nickel-Catalyzed Synthesis of Quinolines from
2-Iodoanilines and Aroylalkynesa
SCHEME 2
SCHEME 3
and insertion of this alkyne into Ni-carbon bond of A generates
intermediate B. Subsequent protonation with water yields amino
chalcone C and a Ni(II) species. Further reduction of the Ni(II)
species by zinc regenerates the catalyst Ni(0) along with a zinc-
(II) derivative. The keto group and the o-amino group in the
obtained amino chalcone C is expected to be trans to each other
after protonation of intermediate B. Thus, trans to cis isomer-
ization to yield cis-amino chalcone D should occur. Further
condensation between the keto and the amino groups yields the
final product 4. The water thus generated is utilized in the
protonation process of intermediate B. The pathway for the
isomerization of R,â-unsaturated carbon-carbon double bond
in C is not clear. A possible one is via a reversible addition of
a base such as water, hydroxide, or the nearby amino group to
the â-carbon of the R,â-unsaturated carbon-carbon double bond
to give an anionic intermediate, followed by C-C bond rotation
and elimination of the base. Such isomerization of R,â-
unsaturated carbon-carbon double bonds before ring closure
has been observed previously by us.6c,12
a All reactions were carried out under nitrogen atmosphere using 1 (0.10
mmol), alkyne (2, 0.20 mmol), NiBr2(dppe) (0.0050 mmol), and Zn (0.20
mmol) in CH3CN (3.0 mL) at 80 °C for 12 h. b Isolated yields. c Measured
1
by H NMR using mesitylene as an internal standard.
The other pathways with the keto group of 2 first undergoing
condensation with the amino group in 1 to form an imine
intermediate, followed by oxidative addition, insertion and
protonation cannot be excluded totally.
oxidative addition of 2-iodoaniline to Ni(0) species affords an
o-metalated aniline nickel complex A. Coordination of alkyne
J. Org. Chem, Vol. 71, No. 18, 2006 7081

pure product 4a in 74% yield. White solid. Mp ) 102 °C. Rf )
In conclusion, we have demonstrated a new convenient
synthetic approach for the preparation of 2,4-disubstituted
quinolines. This nickel-catalyzed reaction is interesting, since
most of the synthetic methods available are for the preparation
of 2,3-disubstituted quinolines. The method tolerates a range
of functional groups and utilizes nonexpensive catalysts and
easily available reagents. We have prepared halogen derivatives
which are of particular interest in medicinal chemistry. The
possibility of application in the synthesis of naturally occurring
alkaloids by the present method is described.
1
0.57 (10% ethyl acetate in hexanes). H NMR δ: 7.44-7.48 (m,
2H), 7.50-7.57 (m, 7H), 7.72 (t, J ) 7.5 Hz, 1H), 7.81 (s, 1H),
7.90 (d, J ) 3.0 Hz, 1H), 8.18 (d, J ) 8.0 Hz, 2H), 8.24 (d, J )
9.0 Hz, 1H). 13C NMR δ: 119.4, 125.6, 125.8, 126.3, 127.6, 128.4,
128.6, 128.8, 129.3, 129.5, 129.6, 130.1, 138.4, 139.7, 148.8, 149.2,
156.9. HRMS (EI+): 281.1195 (calcd for C21H15N, 281.1204).
IR: 1357, 1489, 1590, 3053 cm-1
.
4-Butyl-2-phenylquinoline (4b). Alkyne 2c was used to prepare
this material using the same procedure described for 4a. After
chromatography, the compound was dried under vacuum to yield
4b (86%). Viscous liquid. Rf ) 0.60 (10% ethyl acetate in hexanes).
1H NMR δ: 0.98 (t, J ) 7.0 Hz, 3H), 1.46-1.50 (m, 2H), 1.75-
1.80 (m, 2H), 3.12 (t, J ) 7.8 Hz, 2H), 7.44 (t, J ) 6.8 Hz, 1H),
7.49-7.53 (m, 3H), 7.67-7.70 (m, 2H), 8.03 (d, J ) 8.5 Hz, 1H),
8.13 (d, J ) 8.5 Hz, 2H), 8.18 (d, J ) 8.0 Hz, 1H). 13C NMR δ:
13.9, 22.8, 32.3, 32.3, 118.8, 123.4, 126.0, 126.6, 127.6, 128.5,
128.8, 129.2, 130.4, 139.9, 148.4, 149.4, 157.1. HRMS (EI+):
261.1512 (calcd for C19H19N, 261.1517). IR: 1353, 1447, 1551,
Experimental Section
General Procedure for the Preparation of Quinolines. Syn-
thesis of 2,4-Diphenylquinoline (4a). A round-bottom sidearm
flask (25 mL) containing NiBr2(dppe) (3.1 mg, 0.0050 mmol),
2-iodoaniline (1a) (0.10 mmol), alkyne 2b (0.20 mmol), and zinc
powder (13 mg, 0.20 mmol) was subjected to the Schlenk-line
procedures of evacuation and purging of nitrogen for three cycles.
Freshly distilled acetonitrile (3.0 mL) was added to the reaction
system, and the reaction mixture was stirred at 80 °C for 12 h.
Then the reaction mixture was cooled to room temperature and
diluted with dichloromethane. The mixture thus obtained was
filtered through a silica gel pad and washed thoroughly with
dichloromethane. The filtrate was concentrated in a rotary evapora-
tor, and the residue was separated on a silica gel column using a
mixture of hexanes and ethyl acetate as eluent to afford the desired
1597, 2957 cm-1
.
Acknowledgment. Financial support from National Science
Council of Republic of China (Grant NSC-93-2113-M-0007-
033) is greatly acknowledged.
Supporting Information Available: Experimental procedures,
spectral data and 1H and 13C NMR spectra of all compounds, CIF
of compound 4i and NOE data of selected compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(12) Rayabarapu, D. K.; Cheng, C. H. J. Am. Chem. Soc. 2002, 124,
5630.
JO060800D
7082 J. Org. Chem., Vol. 71, No. 18, 2006