Consecutive isomerization and cyclization of 3-(2-Aminophenyl)-1-arylprop- 2-yn-1-ols leading to 2-arylquinolines in the presence of potassium hydroxide

Article abstract of DOI:10.1002/jhet.5570410317

3-(2-Aminophenyl)-1-arylprop-2-yn-1-ols are readily converted to 2-arylquinolines in good yields in ethanol at 80° in the presence of potassium hydroxide via domino isomerization and cyclization.

Full text of DOI:10.1002/jhet.5570410317

May-Jun 2004
409
Consecutive Isomerization and Cyclization of 3-(2-Aminophenyl)-1-
arylprop-2-yn-1-ols Leading to 2-Arylquinolines in the Presence of
Potassium Hydroxide
Chan Sik Cho*
Research Institute of Industrial Technology, Kyungpook National University, Daegu 702-701, Korea
Na Young Lee, Tae-Jeong Kim and Sang Chul Shim*
Department of Applied Chemistry, College of Engineering, Kyungpook National University,
Daegu 702-701, Korea
Received October 9, 2003
3-(2-Aminophenyl)-1-arylprop-2-yn-1-ols are readily converted to 2-arylquinolines in good yields in
ethanol at 80° in the presence of potassium hydroxide via domino isomerization and cyclization.
J. Heterocyclic Chem., 41, 409 (2004).
Introduction.
satisfying yield of 2-phenylquinoline (2a, 2: R = Ph)
(Scheme 2). Our initial study was performed in the pres-
ence of a transition metal catalyst since transition metal-
catalyzed redox isomerizations of propargyl alcohols to
α,β-unsatuarted carbonyl compounds are known [1-4].
When 1 a was subjected under the conditions of
RuCl2(PPh3)3 (2 mol%)/80°/5 hours/dioxane, 2a was not
produced at all and almost all 1a was recovered unchanged
[13]. Treatment of 1a at a higher reaction temperature
(180°) under similar conditions afforded 2a in only 5%
yield. These results indicate that a ruthenium catalytic sys-
tem was not effective for the present reaction. However,
the addition of equimolar amount of KOH to the condi-
tions of RuCl2(PPh 3)3 (2 mol%)/80°/2 hours/dioxane
afforded 2a in 72-78% yields (several runs) [14]. Eventual
reaction conditions excluded the presence of a ruthenium
catalyst from the system. Among the solvents we exam-
ined, ethanol in terms of product 2a yield revealed to be
the solvent of choice (83%; dioxane, 65%; toluene, 54%).
Isomerization has been extensively studied to achieve
efficient and straightforward reactions in organic synthe-
sis. In connection with this report, it is known that several
transition metals such as Pd [1], Ru [2], Rh [3] and Ir [4]
isomerize propargylic alcohols to enones or enals [5]. In
addition to these reports, Minn and Kundu have reported
that 2-iodopyrimidines and 6-iodouracils are coupled with
propargylic alcohols to give 3-heteroaryl substituted
enones under Sonogashira coupling conditions [6].
However, to the best of our knowledge, although sub-
strates are restricted, it was firstly reported by Cacchi that
alkyl 4-hydroxy-2-alkynoates and 4-hydroxy-2-alkyn-1-
ones were isomerized to alkyl 4-oxo-2-alkenoates and 1,4-
dioxo-2-alkenes, respectively in the presence of only trib-
utylamine [7]. Recently, Müller and Saito have further dis-
closed the isomerization of propargylic alcohols to enones
under triethylamine or triton B [8] On the other hand, a
clear-cut example for the synthesis of cyclic compounds
using this isomerization protocol seems to be limited to the
synthesis of 3,5-disubstituted 2-pyrazolines [8a] and ruthe-
nium-catalyzed synthesis of butyrolactone [9] and pyrroles
[10]. Prompted by these circumstances, we have directed
our attention to the application of this isomerization to the
synthesis of N-heterocycles. Herein we report a base-
mediated consecutive isomerization and cyclization of 3-
(2-aminophenyl)-1-arylprop-2-yn-1-ols leading to 2-
arylquinolines.
Results and Discussion.
The starting 3-(2-aminophenyl)-1-arylprop-2-yn-1-ols 1
are easily available by the known procedures shown in
Scheme 1. Aldehydes are treated with ethynylmagnesium
bromide to give propargylic alcohols [11] that are then
subjected to react with 2-iodoaniline under Sonogashira
coupling conditions to afford 1 [12]. Several reactions with
3-(2-aminophenyl)-1-phenylprop-2-yn-1-ol (1 a, 1: R =
Ph) under various conditions were carried out to obtain a
Having established reaction conditions, various 1 were
screened in order to investigate the reaction scope, and
several representative results are summarized in Table 1.
With 1-arylpropargylic alcohols (1a-1j) the isomerization-
cyclization products were formed in the range of 62-89%
yields (runs 1-10). The product yield was not significantly

410
C. S. Cho, N. Y. Lee, T.-J. Kim and S. C. Shim
Vol. 41
In summary, we have demonstrated that 3-(2-amino-
phenyl)-1-arylprop-2-yn-1-ols undergo consecutive iso-
merization and cyclization in the presence of KOH to
afford 2-arylquinolines in good yields. The present reac-
tion is a novel example leading to a cyclic compound using
a base-mediated isomerization of propargylic alcohols to
enones.
affected by the electronic nature of the substituent on the
aromatic ring attached to carbon bearing OH of 1a-1 j,
whereas the position of that had some relevance to the
product yield (runs 2-4). In the reaction with 3-(2-amino-
phenyl)-1-(2-methylphenyl)prop-2-yn-1-ol (1b), a longer
reaction time was necessary for the effective formation of
2-(2-methylphenyl)quinoline (2 b) (run 2). The reaction
proceeds likewise with heteroarylpropargylic alcohols
(1k-1m) to afford the corresponding 2-heteroaryl substi-
tuted quinolines (2k and 2l) in good yields (runs 11-12).
However, in the case of 3-(2-aminophenyl)-1-methylprop-
2-yn-1-ol (1m) the reaction resulted in several unidentifi-
able compounds without the formation of 2-methyl-
quinoline (2m) and an intermediate (see Scheme 3).
EXPERIMENTAL
1
13
H and C NMR (400 and 100 MHz) spectra were recorded
on a Bruker Avance Digital 400 spectrometer using Me Si as an
4
internal standard. Melting points were determined on a Thomas-
Hoover capillary melting points apparatus and are uncorrected.
The isolation of pure products was carried out via thin layer (sil-
ica gel 60 GF , Merck) chromatography. Commercially avail-
254
able organic and inorganic compounds were used without further
purification except for the solvent, which was distilled by stan-
dard methods before use.
Table 1
Consecutive Isomerization and Cyclization of 1 Leading to 2 [a]
Run
1
Quinoline 2
Isolated yield
General Procedure for Consecutive Isomerization and
Cyclization of 3-(2-Aminophenyl)-1-arylprop-2-yn-1-ols 1
Leading to 2-Arylquinolines 2.
1
2
3
4
5
6
7
8
1a R = Ph
1b R = 2-MeC H
1c R = 3-MeC H
1d R = 4-MeC H
6 4
1e R = 4-MeOC H
6 4
1f R = 3-MeOC H
6 4
1g R = 2-MeOC H
1h R = 4-FC H
1i R = 4-ClC H
6 4
1j R = 3,4-(MeO) C H
6 3
1k R = 2-furanyl
1l R = 2-thienyl
1m R = Me
2a
2b
2c
2d
2e
2f
2g
2h
2i
83
46 (62 [b])
6
4
73
80
72
83
73
89
86
65
35
67
0
6
4
A mixture of 3-(2-aminophenyl)-1-arylprop-2-yn-1-ol (0.5
mmol) and KOH (28 mg, 0.5 mmol) in EtOH (2 mL) was placed
in a 5 mL screw-capped vial and allowed to react at 80° for 7
hours. The reaction mixture was filtered through a short silica gel
column (ethyl acetate-chloroform mixture). Removal of the sol-
vent left a crude mixture, which was separated by TLC (ethyl
acetate-hexane mixture) to give 2-arylquinolines. Except for 2f,
2g, 2i and 2j, all products are noted in our recent report [13g].
6
4
6
4
9
10
11
12
13
2j
2k
2l
2
2-(3-Methoxyphenyl)quinoline (2f).
2m
This compound was obtained as a solid, mp 110° (petroleum
1
ether) (lit [15] mp 108-110°); H NMR (CDCl ): δ 3.90 (s, 3H),
[a] Reaction conditions: 1 (0.5 mmol), KOH (0.5 mmol), EtOH (2 mL),
80° (bath temperature) for 7 hours; [b] For 20 hours.
3
7.00 (dd, J = 2.5 and 8.0 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.48-
7.51 (m, 1H), 7.68-7.72 (m, 2H), 7.77-7.83 (m, 3H), 8.15-8.18
As to the reaction pathway, although no intermediates
were obtained, this seems to proceed via an initial isomer-
ization of propargylic alcohol moiety of 1 to α,β-unsatu-
rated carbonyl compound followed by cyclodehydration to
give 2. It is known that this isomerization can be rational-
ized by the formation of an allenol intermediate under a
base [7,8] and a transition metal-catalyzed intramolecular
transfer hydrogenation [1-4]. We confirmed, in a separate
experiment, that 1,3-diphenylprop-2-yn-1-ol (3) was read-
ily isomerized to trans-chalcone (4) in the presence of
KOH (Scheme 3) in 70% yield with concomitant forma-
tion of several unidentifiable compounds.
13
(m, 2H); C NMR (CDCl ): δ 55.8, 113.1, 115.8, 119.5, 120.4,
3
126.7, 127.7, 127.9, 130.0, 130.1, 130.2, 137.2, 141.6, 148.6,
157.5, 160.6.
2-(2-Methoxyphenyl)quinoline (2g).
This compound was obtained as a pale yellow oil, (lit [16] vis-
1
cous oil); H NMR (CDCl ): δ 3.82 (s, 3H), 7.00 (dd, J = 8.0 Hz,
3
1H), 7.12 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.49 (t, J =
7.5 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H),
7.84-7.88 (m, 2H), 8.11 (d, J = 8.5 Hz, 1H), 8.17 (d, J = 8.0 Hz,
13
1H); C NMR (CDCl ): δ 55.6, 111.4, 121.2, 123.4, 126.1,
3
127.0, 127.4, 129.0, 129.2, 129.3, 129.4, 130.6, 131.5, 135.1,
148.3, 157.2.

May-Jun 2004
Consecutive Isomerization and Cyclization
411
isomerization of acetylenic carbinols to enones and enals. For exam-
ples, palladium-catalyzed isomerization is induced under a milder con-
dition by the addition of acetic acid and/or diols (ref 1) and ruthenium-
catalyzed isomerization gives an increased conversion by the addition
of indium(III) chloride (ref 2b).
2-(4-Chlorophenyl)quinoline (2i).
This compound was obtained as a solid, mp 111-112° (hexane)
1
(lit [17] mp 112°); H NMR (CDCl ): δ 7.46-7.53 (m, 3H), 7.69-
13
3
7.73 (m, 1H), 7.77-7.80 (m, 2H), 8.08-8.18 (m, 4H); C NMR
(CDCl ): δ 118.5, 126.5, 127.2, 127.5, 128.8, 129.0, 129.7,
3
129.8, 135.5, 136.9, 138.0, 148.2, 155.9.
[6] K. Minn, Synlett, 115 (1991); N. G. Kundu and P. Das, J.
Chem. Soc., Chem. Commun., 99 (1995).
[7] A. Arcadi, S. Cacchi, F. Marinelli and D. Misiti, Tetrahedron
Letters, 29, 1457 (1988).
2-(3,4-Dimethoxyphenyl)quinoline (2j).
[8a] T. J. J. Müller, M. Ansorge and D. Aktah, Angew. Chem. Int.
Ed. Engl., 39, 1253 (2000); [b] T. Ishikawa, T. Mizuta, K. Hagiwara, T.
Aikawa, T. Kudo and S. Saito, J. Org. Chem., 68, 3702 (2003).
[9] Y. Shuo, Y. Blum and D. Reshef, J. Organomet. Chem., 238,
C79 (1982).
This compound was obtained as a solid, mp 116° (hexane) (lit
1
[18] mp 116-117°); H NMR (CDCl ): δ 3.96 (s, 3H), 4.05 (s,
3
3H), 6.99-7.01 (m, 1H), 7.48-7.53 (m, 1H), 7.65-7.74 (m, 2H),
13
7.80-7.88 (m, 3H), 8.14-8.20 (m, 2H); C NMR (CDCl ): δ
3
56.0, 56.1, 110.4, 111.0, 118.6, 120.2, 126.0, 127.0, 127.4, 129.5,
129.6, 132.5, 136.7, 148.2, 149.4, 150.4, 156.9.
[10] Y. Tsuji, Y. Yokoyama, K. Huh and Y. Watanabe, Bull.
Chem. Soc. Jpn., 60, 3456 (1987).
Procedure for Isomerization of 1,3-Diphenylprop-2-yn-1-ol (3)
to trans-Chalcone (4).
[11] M. C. Bagley, K. E. Bashford, C. L. Hesketh and C. J.
Moody, J. Am. Chem. Soc., 122, 3301 (2000).
[12] S. Morita, K. Otsubo, J. Matsubara, T. Ohtani and M.
Uchida, Tetrahedron: Asymmetry, 6, 245 (1995).
A mixture of 1,3-diphenylprop-2-yn-1-ol (62 mg, 0.3 mmol)
and KOH (17 mg, 0.3 mmol) in toluene (2 mL) was placed in a 5
mL screw-capped vial and allowed to react at 80° for 1 hour. The
reaction mixture was filtered through a short silica gel column
(ethyl acetate-chloroform mixture). Removal of the solvent left a
crude mixture, which was separated by TLC (ethyl
acetate/hexane = 1/10) to give trans-chalcone (44 mg, 70%).
[13a] We selected a ruthenium catalyst for such a reaction since we
recently reported on ruthenium-catalyzed synthesis of quinolines: C. S.
Cho, B. H. Oh and S. C. Shim, Tetrahedron Letters, 40, 1499 (1999);
[b] C. S. Cho, B. H. Oh and S. C. Shim, J. Heterocyclic Chem., 36, 1175
(1999); [c] C. S. Cho, J. S. Kim, B. H. Oh, T.-J. Kim and S. C. Shim,
Tetrahedron, 56, 7747 (2000); [d] C. S. Cho, B. H. Oh, J. S. Kim, T.-J.
Kim and S. C. Shim, Chem. Commun., 1885 (2000); [e] C. S. Cho, B. T.
Kim, T.-J. Kim and S. C. Shim, Chem. Commun., 2576 (2001); [f] C. S.
Cho, T. K. Kim, B. T. Kim, T.-J. Kim and S. C. Shim, J. Organomet.
Chem., 650, 65 (2002); [g] C. S. Cho, B. T. Kim, H.-J. Choi, T.-J. Kim
and S. C. Shim, Tetrahedron, 59, 7997 (2003). [h] C. S. Cho, N. Y. Lee,
H.-J. Choi, T.-J. Kim and S. C. Shim, J. Heterocylic Chem., 40, 929
(2003).
Acknowledgment.
The present work was supported by Korea Research
Foundation Grant (KRF-2002-070-C00055). C.S.C. gratefully
acknowledges a MOE-KRF Research Professor Program (KRF-
2001-050-D00015).
[14] It is known that bases are used as promoters in transition
metal-catalyzed transfer hydrogenations. For recent reviews, see: R.
Noyori and S. Hashiguchi, Acc. Chem. Res., 30, 97 (1997); T. Naota, H.
Takaya and S.-I. Murahashi, Chem. Rev., 98, 2599 (1998); M. Palmer
and M. Wills, Tetrahedron: Asymmetry, 10, 2045 (1999).
[15] I. Takeuchi, I. Ozawa, K. Shigemura, Y. Hamada, T. Ito and
A. Ohyama, Yakugaku Zasshi, 99, 451 (1979).
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