Synthesis of quinolines from amino alcohol and ketones catalyzed by [IrCl(cod)]2 or IrCl3 under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2005.05.013

2-Aminobenzyl alcohol reacted with 2 equiv amount of ketones under the influence of [IrCl(cod)]₂ or IrCl₃ and KOH without any solvent, giving the corresponding quinoline derivatives in good yields.

Full text of DOI:10.1016/j.tetlet.2005.05.013

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4539–4542
Synthesis of quinolines from amino alcohol and ketones
catalyzed by [IrCl(cod)] or IrCl under solvent-free conditions
2
3
Kazuhiko Taguchi, Satoshi Sakaguchi and Yasutaka Ishii*
Department of Applied Chemistry, Faculty of Engineering, Kansai University, Suita, Osaka 564-8680, Japan
Received 13 April 2005; revised 30 April 2005; accepted 6 May 2005
Available online 23 May 2005
Abstract—2-Aminobenzyl alcohol reacted with 2 equiv amount of ketones under the influence of [IrCl(cod)] or IrCl and KOH
2
3
without any solvent, giving the corresponding quinoline derivatives in good yields.
2005 Elsevier Ltd. All rights reserved.
ꢀ
1
. Introduction
green chemistry, since the reaction took place well with-
out the solvent. Here, we would like to disclose that our
reaction system could be applied to quinoline synthesis
by the coupling reaction of 2-aminobenzyl alcohol with
ketones in the presence of small amounts of [IrCl(cod)]2
and a base under solvent-free conditions. It was found
The preparation of nitrogen-containing aromatic com-
pounds such as quinolines and pyrroles has been exten-
sively studied in synthetic organic chemistry, because
these compounds are important as biologically active
1
compounds. Among several routes to quinoline synthe-
that even IrCl , which is a starting material for prepar-
3
ses, coupling of 2-aminobenzaldehyde with ketone,
namely, the Friedl a¨ nder reaction, is one of the most
widely used methods due to high selectivity of the prod-
ing [IrCl(cod)] , facilitated the coupling reaction. Addi-
2
tionally, pyrroles were synthesized by the reaction of
2-aminoethanols with ketones under the influence of
an Ir complex as a catalyst.
2
ucts. Recently, the ruthenium-catalyzed modified
Friedl a¨ nder reaction has been reported by Cho and
Shim et al. where 2-aminobenzyl alcohol, which is
cheaper and more stable than 2-aminobenzaldehyde, is
allowed to react with ketones or secondary alcohols in
The reaction of 2-aminobenzyl alcohol (1) with acetoph-
enone (2a) was chosen as a model reaction and exam-
ined under selected conditions (Scheme 1, Table 1).
the presence of 1-dodecene as a hydrogen acceptor to
3
form quinoline derivatives. They showed that RuCl
(
Treatment of 1 with 2 equiv of 2a in the presence of cat-
alytic amounts of [IrCl(cod)] (1 mol%), PPh (4 mol%)
2
@CHPh)(PCy ) is an efficient catalyst and that various
3
2
2
3
quinolines can be synthesized in good yields. But, the
reaction requires the use of both a stoichiometric
amount of KOH and a solvent like dioxane which is a
carcinogenic compound. Quite recently, Kaneda and
co-workers reported a similar reaction of 2-aminobenzyl
alcohol and ketones catalyzed by Ru-grafted hydro-
talcite in toluene using dioxygen as a hydrogen acceptor
and KOH (20 mol%) at 100 ꢁC for 3 h without a solvent
gave 2-phenylquinoline (3a) in 90% yield (98% selectiv-
ity) at 92% conversion of 1 (run 1). In this reaction, a
half-amount of 2a used was found to be converted into
1-phenylethanol, indicating that 2a acts as a hydrogen
acceptor. In the absence of PPh , 3a was obtained in
3
slightly lower yield (run 2). Surprisingly, the reaction
was catalyzed even by IrCl3 which is a synthetic
4
under base-free conditions.
Previously, we reported the high selective a-alkylation of
ketones with alcohols catalyzed by an iridium complex.
This reaction is environmentally benign in a sense of
5
Keywords: Iridium; Quinoline; Amino alcohol; Ketone.
*
Corresponding author. Tel.: +81 6 6368 0793; fax: +81 6 6339
026; e-mail: ishii@ipcku.kansai-u.ac.jp
4
Scheme 1. The modified Friedl a¨ nder reaction.
0
040-4039/$ - see front matter ꢀ 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.013

4540
K. Taguchi et al. / Tetrahedron Letters 46(2005) 4539–4542
Table 1. Coupling reaction of 1 with 2a to 3a under selected reaction
a
conditions
Table 2. Ir-catalyzed coupling reaction of 1 with several ketones 2b–g
a
under solvent-free conditions
b
b
Run
Catalyst
Base
Conv.
b
Yield
(%)
Run Ketone
Product
Conv.
b
(%)
Yields
(%)
(
%)
1
[IrCl(cod)]
[IrCl(cod)]
2
2
KOH
KOH
KOH
KOH
KOH
KOH
92
8582
89
80
82
76
11
5
90
c
2
1
86 (80) 80 (74)
85(61) 76 ( 53 )
c
3
IrCl
[IrCl(coe)
[Cp*IrCl
3 2
[IrCOCl(PPh ) ]
3
85
75
74
73
8
c
4
2 2
]
c
5
2 2
]
c
6
7
8
[IrCl(cod)]
[IrCl(cod)]
2
2
K
Cs
2
CO
CO
3
2
3
2
3
1
47
a
Compound 1 (2 mmol) was allowed to react with 2a (4 mmol) in the
presence of catalyst (0.04 mmol Ir), PPh (0.08 mmol) and base
0.4 mmol) at 100 ꢁC for 3 h under solvent-free conditions.
3
(
c
91 (81) 91 (77)
c
b
c
Based on 1 used.
Without PPh
3
.
precursor of [IrCl(cod)] . When 1 was allowed to react
2
with 2a in the presence of IrCl (2 mol%) and KOH
3
c
82 (79) 78 (72)
c
c
c
4
5
(
a solvent (run 3). Although the ruthenium-catalyzed
20 mol%), 3a was obtained in satisfactory yield without
3
modified Friedl a¨ nder reaction reported by Cho et al.
4
or Kaneda and co-workers required the use of more
c
82 (80) 74 (75)
complicated ruthenium compounds as catalysts, the
present reaction proceeded by employing a commer-
cially available iridium salt such as IrCl without any
3
further treatment under solvent-free conditions. There-
fore, the present work provides an operationally simple
methodology for quinoline synthesis.
6
(4)
Other iridium complexes such as [IrCl(coe) ] , [Cp*-
2
2
IrCl ] and [IrCOCl(PPh ) ] were also effective for the
2
2
3 2
6
85(79) 63 ( 56 )
modified Friedl a¨ nder reaction affording 3a in 73–75%
yields (runs 4–6). The use of K CO in place of KOH
2
3
resulted in low conversion of 1, whereas Cs CO led to
2
3
3
a in moderate yield (runs 7 and 8).
2
2 (23)
Next, the iridium-catalyzed coupling of 1 with several
ketones was carried out under solvent-free conditions
a
(
Table 2). In a similar manner as the reaction of 1 with
a, it was found that propiophenone (2b), diethyl ketone
Compound 1 (2 mmol) was allowed to react with ketone 2b–g
(4 mmol) in the presence of [IrCl(cod)]2 (0.02 mmol), PPh3
(0.08 mmol) and KOH (0.4 mmol) at 100 ꢁC for 3 h under solvent-
free conditions.
2
(
(
2c), cycloheptanone (2d), and 2-methylcyclohexanone
2e) reacted with 1 to give the corresponding quinoline
b
c
Based on 1 used. Numbers in parentheses show the conversion and
derivatives (3b–e) in good yields (runs 1–4). Notably,
IrCl and [IrCl(cod)] indicated high catalytic activity
yield using IrCl
3
(0.04 mmol) in place of [IrCl(cod)]
2
without PPh
3
.
3
2
In the case of the reaction catalyzed by IrCl
3
, the reaction was per-
for the modified Friedl a¨ nder reaction. The coupling of
with 4-methyl-2-pentanone (2f) or 2-octanone (2g)
formed at 115 ꢁC.
1
was difficult to carry out regioselectively to afford a reg-
ioisomeric mixture of the corresponding quinoline deriv-
atives (runs 5and 6).
results may suggest that 3d is formed through the
following reaction pathway (Scheme 3). The reaction is
initiated by the formation of ketimine (A) from 1 and
2d (path A), and A thus formed is oxidized under the
influence of an Ir catalyst and 2d which serves as a
hydrogen acceptor giving the corresponding aldehyde
B, which is eventually converted into 3d through intra-
molecular aldol-type condensation. As another possible
pathway, it may be assumed that the hydroxyl group of
1 is first oxidized to 2-aminobenzaldehyde (C), followed
by the cross-aldol condensation between C and 2d to
generate D, which then is transformed into 3d (path
It is noteworthy that the coupling reaction of 1 with
cycloheptanone (2d) was smoothly catalyzed by an irid-
ium complex forming 3d in excellent yield (Table 2, run
3
ation of ketone with alcohol catalyzed by [IrCl(cod)]
and Scheme 2). We previously reported the a-alkyl-
2
5
in the presence of a small amount of KOH, but the
reaction of benzyl alcohol (4) with 2d failed to proceed
selectively to lead to a complex mixture involving a-
benzylcycloheptanone and some undesired self-aldol
condensation products of 2d, etc. (Scheme 2). These

K. Taguchi et al. / Tetrahedron Letters 46(2005) 4539–4542
4541
Scheme 4. A possible route for the formation of B from A by an Ir
compound.
aldehyde B and iridium dihydride. Thus, the coupling
reaction of 1 with ketone could proceed even by the
use of IrCl as a catalyst.
3
Finally, it was found that the present catalytic system
could be applied to pyrrole synthesis. N-Methyl-3-
methyl-2-phenylpyrrole (6a) was prepared by the reac-
tion of N-methyl-2-aminoethanol (5a) with 2b in the
presence of small amounts of an iridium compound
and a base under solvent-free conditions. Choice of
the ligand was found to be important for this reaction,
and the best result was obtained when 5a was allowed
Scheme 2. Ir-catalyzed reaction of 2-aminobenzyl alcohol (1) or benzyl
alcohol (4) with 2d.
to react with 2b catalyzed by [IrCl(cod)] combined with
2
2
1
-(diphenylphosphino)ferrocene (dppf) and KOH at
20 ꢁC for 3 h, forming 6a in 70% yield (Scheme 5).
Similarly, treatment of 2-aminoethanol (5b) with 2b
afforded 3-methyl-2-phenylpyrrole (6b) in 55% yield
(
Scheme 6).
In summary, we have shown that the oxidative coupling
of 2-aminobenzyl alcohol with ketones was promoted in
Scheme 3. A possible reaction pathway for the Ir-catalyzed reaction of
with 2d.
1
B). If the dehydrogenation of an alcohol function to
aldehyde followed by the cross-aldol condensation with
2
d easily takes place, the reaction of 4 with 2d is ex-
pected to occur smoothly. However, the reaction is dif-
ficult to proceed as shown in Scheme 2. Therefore, we
assume that path A is preferable to path B in the reac-
tion of 1 with 2d and that the initial formation of keti-
mine A from 1 and 2d is an important factor.
Scheme 5. Reaction of 5a with 2b. Compound 5a (2 mmol) was
allowed to react with 2b (4 mmol) in the presence of catalyst
(
0.03 mmol Ir) and KOH (0.8 mmol) at 120 ꢁC for 3 h under solvent-
free conditions. PPh (0.12 mmol), PCy (0.12 mmol) or dppf
0.06 mmol) was used, respectively.
3
3
(
Again, the present quinoline synthesis from 1 with
various ketones was successfully achieved even by the
use of IrCl as a catalyst, while almost no reaction of
3
a-alkylation of ketone with alcohols took place by
5
IrCl . In the reaction of 1 with ketones catalyzed by
3
an Ir compound, the formation of a six-membered
iridium hydride complex F, in which a ketimine group
of A generated from 2-aminobenzyl alcohol (1) and
ketone coordinates to an iridium species, seems to be
the driving force as shown in Scheme 4. The b-hydride
elimination from F would afford the corresponding
Scheme 6. Reaction of 5b with 2b.

4542
K. Taguchi et al. / Tetrahedron Letters 46(2005) 4539–4542
the presence of catalytic amounts of an iridium complex
such as [IrCl(cod)] and IrCl and KOH under solvent-
the products were estimated from the peak areas based
on the internal standard technique using GC.
2
3
free conditions. The present catalytic system could apply
to the synthesis of pyrrole from b-aminoalcohol and
ketone.
Acknowledgments
This work was partially supported by MEXT.KAKEN-
HI (No.17750098) and Daicel Chemical Industries Ltd.
2
. Experimental section
References and notes
All starting materials were commercially available and
used without any purification. GLC analysis was per-
formed with a flame ionization detector using a
1
. Michael, J. P. Nat. Prod. Rep. 1997, 14, 605; Jones, G. In
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, 1996; Vol. 5, pp 167–243.
2. Recent works: (a) Hsiao, Y.; Rivera, N. R.; Yasuda, N.;
Hughes, D. L.; Reider, P. J. Org. Lett. 2001, 3, 1101; (b)
Yadav, J. S.; Reddy, B. V. S.; Premalatha, K. Synlett 2004,
1
13
0
.2 mm · 25m capillary column (OV-1). H and
NMR were measured at 270 or 400 MHz and
7.5MHz, respectively, in CDCl 3 with Me Si as an
C
6
4
internal standard.
.1. General procedure for reaction of 1 with 2a
To mixture of [IrCl(cod)]2 (0.02 mmol), PPh3
9
63, and references cited therein.
2
3
. (a) Cho, C. S.; Kim, B. T.; Kimb, T.-J.; Shim, S. C.
Chem. Commun. 2001, 2576; (b) Cho, C. S.; Kim, B. T.;
Choi, H.-J.; Kim, T.-J.; Shim, S. C. Tetrahedron 2003, 59,
7
. Motokura, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K.
a
(
(
0.08 mmol) and KOH (0.4 mmol) were added 1
2 mmol) and 2a (4 mmol) under Ar. The reaction
997.
4
mixture was stirred at 100 ꢁC for 3 h. The product was
isolated by column chromatography (230–400 mesh
silica gel, n-hexane–ethyl acetate = 20:1). The yields of
Tetrahedron Lett. 2004, 45, 6029.
5. Taguchi, K.; Nakagawa, H.; Hirabayashi, T.; Sakaguchi,
S.; Ishii, Y. J. Am. Chem. Soc. 2004, 126, 72.