A rhodium-catalyzed route for oxidative coupling and cyclization of 2-aminobenzyl alcohol with ketones leading to quinolines

Article abstract of DOI:10.1002/jhet.5570420630

2-Aminobenzyl alcohol undergoes oxidative cyclization with aryl(alkyl), alkyl(alkyl) and cyclic ketones in dioxane at 80° in the presence of a catalytic amount of RhCl(PPh3)3 along with KOH to afford the corresponding quinolines in good yields. The catalytic pathway seems to be proceeded via a sequence involving initial oxidation of 2-aminobenzyl alcohol to 2-aminobenzaldehyde by a rhodium catalyst, cross aldol reaction between 2-aminobenzaldehyde and ketones, and cyclodehydration.

Full text of DOI:10.1002/jhet.5570420630

A Rhodium-Catalyzed Route for Oxidative Coupling and Cyclization
of 2-Aminobenzyl Alcohol with Ketones Leading to Quinolines
Chan Sik Cho*
Sep-Oct 2005
1219
Research Institute of Industrial Technology, Kyungpook National University, Daegu 702-701, Korea
Hyo Jin Seok and Sang Chul Shim*
Department of Applied Chemistry, College of Engineering, Kyungpook National University, Daegu 702-701,
Korea
Received February 16, 2005
2-Aminobenzyl alcohol undergoes oxidative cyclization with aryl(alkyl), alkyl(alkyl) and cyclic ketones
in dioxane at 80° in the presence of a catalytic amount of RhCl(PPh ) along with KOH to afford the corre-
3 3
sponding quinolines in good yields. The catalytic pathway seems to be proceeded via a sequence involving
initial oxidation of 2-aminobenzyl alcohol to 2-aminobenzaldehyde by a rhodium catalyst, cross aldol reac-
tion between 2-aminobenzaldehyde and ketones, and cyclodehydration.
J. Heterocyclic Chem., 42, 1219 (2005).
Introduction.
oxidative coupling and cyclization between 2-aminoben-
zyl alcohol and ketones leading to quinolines [11].
It is known that many quinoline containing compounds
exhibit a wide spectrum of pharmacological activities such
as antiasthmatic, antiinflammatory and antimalarial [1]. As
part of our studies directed toward ruthenium-catalyzed
synthesis of N-heterocycles, we have reported on the syn-
thesis of quinolines via an alkyl and alkanol group transfer
from alkylamines and alkanolamines to anilines (amine
exchange reaction [2]) [3]. Furthermore, in connection
with this report, we recently found an unusual ruthenium-
catalyzed coupling between primary alcohols A and
ketones B leading to coupled ketones C (Scheme 1, route
a) [4,5] or coupled secondary alcohols D (Scheme 1, route
b) [6] according to the molar ratio of A to B. It was also
disclosed that primary alcohols A were found to couple
with secondary alcohols E in the presence of a ruthenium
catalyst along with a sacrificial hydrogen acceptor to give
coupled secondary alcohols D (Scheme 1, route c) [7].
Thus, these reactions could be applied to modified
Friedländer quinoline synthesis [8] via ruthenium-cat-
alyzed consecutive coupling and cyclization of 2-
aminobenzyl alcohol with ketones [9] and secondary alco-
hols [10]. Under these circumstances, we have directed our
attention to the application of an alternative catalyst to the
oxidative cyclization of 2-aminobenzyl alcohol with
ketones. This report describes a rhodium-catalyzed similar
Results and Discussion.
Based on our recent report on ruthenium-catalyzed
oxidative cyclization of 2-aminobenzyl alcohol (1) with
ketones [9], several reactions of 1 with acetophenone (2a)
were performed in the presence of chlorotris(triphenyl-
phosphine)rhodium(I) RhCl(PPh ) in order to obtain opti-
mal conditions (Scheme 2). Treatment of 1 and 2a in diox-
3 3
ane at 80° in the presence of a catalytic amount of
RhCl(PPh ) (1 mol%) along with KOH afforded 2-
3 3
phenylquinoline (3a) with the concomitant formation of 1-
phenylethanol by direct transfer hydrogenation from 1 to
2a on GLC analysis. As has been observed in our ruthe-
nium-catalyzed version [9], equimolar amount of KOH
relative to 1 and the molar ratio of 2a to 1 ([2a]/[1] = 2.0)
were required for the effective formation of 3a. The yield
of 3a increased from 39% (0.2 equiv. KOH), 52% (0.5
equiv. KOH), to 85% (1 equiv. KOH). Lower reaction rate,
determined by the disappearance of 1 on TLC, was
observed with this rhodium catalytic system (for 24 hours)
compared with ruthenium catalytic system (for 1 hour).
Table 1 shows the representative results for the oxida-
tive cyclization of 1 with various ketones 2 under the
controlled conditions, [2]/[1] =2.0/RhCl(PPh ) (1
3 3
mol%)/KOH (1 equiv.)/dioxane/80°/24 hours. From the
reactions between 1 and aryl(methyl) ketones (2b-2f),

1220
C. S. Cho, H. J. Seok and S. C. Shim
Vol. 42
the corresponding 2-arylquinolines (3b-3f) were pro-
duced in the range of 53-82% yields. Here again, the
conventional transfer hydrogenated aryl(methyl)
carbinols were produced in considerable amounts on
GLC analysis. The product yield was not significantly
affected by the position of the substituent on the aro-
matic ring of aryl(methyl) ketones, whereas the elec-
tronic nature of that had some relevance to quinoline
yield. 2'-Acetonaphthone (2g) also undergoes oxidative
coupling and cyclization with 1 to afford 2-(2-naph-
thyl)quinoline (3g) in 55% yield. With heteroaryl-
(methyl) ketone 2h, 2-(2-thienyl)quinoline (3h) was
also formed in 53% yield. The reaction proceeds like-
wise with alkyl(aryl) ketone 2i which has only methyl-
ene reaction site to give the corresponding quinoline 3i
in good yield. In the reaction of alkyl(alkyl) ketones 2j
and 2k, the corresponding quinolines 3j and 3k were
obtained in 56% and 50% yields, respectively. Cyclic
ketones such as cyclohexanone (2l) and 1-tetralone
(2m) were also reacted with 1 under the employed con-
ditions to give 1,2,3,4-tetrahydroacridine (3l) and 5,6-
dihydrobenzo[c]acridine (3m), respectively.
Although the reaction scheme is not yet fully under-
stood, a plausible pathway, consistent with the products
formed, is depicted in Scheme 3. The pathway seems to
proceed via initial oxidation of 2-aminobenzyl alcohol
(1) to 2-aminobenzaldehyde (4), which in turn triggers
cross aldol condensation with ketone 2 under KOH to
give an α,β-unsaturated ketone 6. This is followed by
cyclodehydration to form quinoline 3. Excess ketone
seems to act as a sacrificial hydrogen acceptor oxidizing
[Rh]H generated in the initial oxidation stage to [Rh]
2
[12]. The formation of a considerable amount of carbinol
5 clearly shows such a hydrogen transfer. It is also
known that rhodium has been used as hydrogenation
transfer catalyst [13,14]. In a separate experiment to sup-
port a carbon-carbon coupling between ketone and pri-
mary alcohol under similar conditions, it was confirmed
that treatment of equimolar amounts of acetophenone
(1a) and benzyl alcohol under RhCl(PPh ) (2
3 3
mol%)/KOH (1 equiv.)/dioxane/80°/20 hours afforded
1,3-diphenylpropan-1-one and 1,3-diphenylpropan-1-ol
in 69% and 16% yields, respectively.
Conclusion.
In summary, we have shown a new catalytic system
[RhCl(PPh ) /KOH] for oxidative coupling and cycliza-
3 3
EXPERIMENTAL
H and C NMR (400 and 100 MHz) spectra were recorded on
tion of 2-aminobenzyl alcohol with an array of ketones
leading to quinolines. The present reaction will serve as an
alternative transition metal-catalyzed Friedländer quino-
line synthesis and further study on intramolecular oxida-
tive cyclization using the present catalytic system is cur-
rently under investigation
1
13
a Bruker Avance Digital 400 spectrometer using Me Si as an inter-
4
nal standard. Melting points were determined on a Thomas-Hoover
capillary melting points apparatus and were uncorrected. The isola-
tion of pure products was carried out via thin layer (silica gel 60

Sep-Oct 2005
A Rhodium-Catalyzed Route for Oxidative Coupling and Cyclization
1221
J. Am. Chem. Soc., 100, 348 (1978); [c] Y. Shvo and R. M. Laine, J.
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T. Khai and G. Porzi, J. Organomet. Chem., 231, C31 (1982); [g] S.-I.
Murahashi, K. Kondo and T. Hakata, Tetrahedron Letters, 23, 229 (1982);
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1763 (1982); [i] C. W. Jung, J. D. Fellmann and P. E. Garrou,
Organometallics, 2, 1042 (1983); [j] S.-I. Murahashi, Angew. Chem. Int.
Ed. Engl., 34, 2443 (1995).
[3a] 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, T. K. Kim, B. T. Kim, T.-J. Kim and S. C. Shim, J. Organomet.
Chem., 650, 65 (2002); [f] C. S. Cho, N. Y. Lee, H.-J. Choi, T.-J. Kim and
S. C. Shim, J. Heterocylic Chem., 40, 929 (2003); [g] C. S. Cho, N. Y.
Lee, T.-J. Kim and S. C. Shim, J. Heterocylic Chem., 41, 423 (2004).
[4] C. S. Cho, B. T. Kim, T.-J. Kim and S. C. Shim, Tetrahedron
Letters, 43, 7987 (2002).
GF , Merck) chromatography. Commercially available organic
and inorganic compounds were used without further purification.
254
General Procedure for Rhodium-Catalyzed Oxidative
Cyclization of 2-Aminobenzyl Alcohol (1) with Ketones (2)
Leading to Quinolines (3).
A mixture of 2-aminobenzyl alcohol (123 mg, 1 mmol), ketone
(2 mmol), RhCl(PPh ) (9 mg, 0.01 mmol), and KOH (56 mg, 1
3 3
mmol) in dioxane (3 mL) was placed in a 5 mL screw-capped vial
and allowed to react at 80° for 24 hours. The reaction mixture
was filtered through a short silica gel column (ethyl acetate-chlo-
roform mixture) to eliminate inorganic salts. Removal of the sol-
vent left a crude mixture, which was separated by TLC (ethyl
acetate-hexane mixture) to give quinolines. All products are
noted in a recent report except for 3j and 3l [10].
2-(1-Methylpropyl)quinoline (3j).
This compound was obtained as a pale yellow oil, (lit [15]
1
105-108°/1.0 mmHg); H NMR (CDCl ): δ 0.89 (t, J = 7.5 Hz,
3
3H), 1.37 (d, J = 7.0 Hz, 3H), 1.66-1.77 (m, 1H), 1.80-1.91 (m,
1H), 2.97-3.06 (m, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.44-7.48 (m,
1H), 7.64-7.68 (m, 1H), 7.74-7.77 (m, 1H), 8.06 (d, J = 8.5 Hz,
[5] A similar iridium-catalyzed α-alkylation of ketones with pri-
mary alcohols is reported: K. Taguchi, H. Nakagawa, T. Hirabayashi, S.
Sakaguchi and Y. Ishii, J. Am. Chem. Soc., 126, 72 (2004).
[6] C. S. Cho, B. T. Kim, T.-J. Kim and S. C. Shim, J. Org.
Chem., 66, 9020 (2001).
13
2H); C NMR (CDCl ): δ 11.18, 19.35, 28.92, 43.58, 118.55,
3
124.56, 125.93, 126.40, 127.97, 128.15, 135.22, 146.76, 165.99.
[7] C. S. Cho, B. T. Kim, H.-S. Kim, T.-J. Kim and S. C. Shim,
Organometallics, 22, 3608 (2003).
1,2,3,4-Tetrahydroacridine (3l).
[8] For a review on Friedländer quinoline synthesis: C.-C. Cheng
and S.-J. Yan, Org. React., 28, 37 (1982).
[9] C. S. Cho, B. T. Kim, T.-J. Kim and S. C. Shim, Chem.
Commun., 2576 (2001).
[10] C. S. Cho, B. T. Kim, H.-J. Choi, T.-J. Kim and S. C. Shim,
Tetrahedron, 59, 7997 (2003).
This compound was obtained as a solid, mp 54-55° (hexane)
1
(lit [16] mp 52-53°); H NMR (CDCl ): δ 1.85-1.91 (m, 2H),
3
1.96-2.02 (m, 2H), 2.96 (t, J = 6.3 Hz, 2H), 3.12 (t, J = 6.3 Hz,
2H), 7.40-7.44 (m, 1H), 7.57-7.62 (m, 1H), 7.68 (d, J = 8.0 Hz,
13
1H), 7.78 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H); C NMR (CDCl ): δ
3
22.8, 23.2, 29.2, 33.5, 125.4, 126.8, 127.1, 128.2, 128.4, 130.9,
134.9, 146.6, 159.2.
[11a] For transition metal-catalyzed intramolecular oxidative
cyclization of 2-aminophenethyl alcohols leading to indoles: Y. Tsuji, S.
Kotachi, K.-T. Huh and Y. Watanabe, J. Org. Chem., 55, 580 (1990); [b]
A. Yutaka, T. Mizusaki and A. Ohta, Tetrahedron Letters, 37, 9203
(1996); [c] K. Fujita, K. Yamamoto and R. Yamaguchi, Org. Letters, 4,
2691 (2002).
[12] As is the case for ruthenium-catalyzed oxidative coupling and
cyclization between 1 and secondary alcohols in the presence of 1-
dodecene as sacrificial hydrogen acceptor (oxidant) (ref. 10), equimolar
treatment of 1 and 2a in the presence of 1-dodecene (2 mmol) as oxidant
under the employed conditions afforded 3a in only 46% yield.
[13a] For rhodium-catalyzed transfer hydrogenation: T. Nishiguchi,
K. Tachi and K. Fukuzumi, J. Org. Chem., 40, 237 (1975); [b] D.
Beaupere, P. Bauer, L. Nadjo and R. Uzan, J. Organomet. Chem., 238,
C12 (1982); [c] D. Beaupere, L. Nadjo, R. Uzan and P. Bauer, J. Mol.
Catal., 18, 73 (1983).
Acknowledgment.
The present work was supported by the Brain Korea 21 Project
in 2003 and Korea Research Foundation Grant (KRF-2002-070-
C00055). C. S. C. gratefully acknowledges a Research Professor
Grant of Kyungpook National University (2004).
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C. S. Cho, H. J. Seok and S. C. Shim
Vol. 42
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