Doebner-miller synthesis in a two-phase system: Practical preparation of quinolines

Article abstract of DOI:10.1016/S0040-4039(00)01542-2

Doebner-Miller cyclization was carried out in a two-phase solvent system. The method has shown to be advantageous to the yield and to the ease of the work-up process. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01542-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8523–8525
Doebner–Miller synthesis in a two-phase system: practical
preparation of quinolines
Masato Matsugi,* Fujio Tabusa and Jun-ichi Minamikawa
Process Research Department, Second Tokushima Factory, Otsuka Pharmaceutical Co., Ltd., 224-18, Ebisuno,
Hiraishi, Kawauchi-Cho, Tokushima 771-0182, Japan
Received 3 August 2000; revised 7 September 2000; accepted 8 September 2000
Abstract
Doebner–Miller cyclization was carried out in a two-phase solvent system. The method has shown to
be advantageous to the yield and to the ease of the work-up process. © 2000 Elsevier Science Ltd. All
rights reserved.
1
Doebner–Miller synthesis has been frequently used in the preparation of a variety of
2
3
quinoline derivatives due to its simplicity even though the usual yields are not always high.
One of the serious drawbacks of the reaction is the tedious isolation procedure from complex
4
reaction mixtures. It can be seen that the acid-catalysed polymerisation of a,b-unsaturated
Figure 1.
*
Corresponding author. Present address: Department of Materials Chemistry, Graduate School of Engineering,
Osaka University, Suita Osaka 565-0871, Japan. Tel/fax: +81-6-6879-7930; e-mail: matsugi@ap.chem.eng.osaka-
u.ac.jp
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01542-2

8524
aldehyde lowers the yield and makes the isolation of the target product difficult. We found that
the Doebner–Miller reaction in a two-phase solvent system (Fig. 1), which consists of an organic
phase and an aqueous acid phase, decreases the polymerisation of the aldehyde. The reaction
proceeded smoothly even in the absence of oxidants. The marked improvement is shown in
Table 1.
Table 1
Entry
Substrate
Conditions
Isolated yield of 2 (%)
5
a,b
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
EtOH containing conc. H SO4
Toluene containing TsOH
6 M HCl
10
3
2
a,b
a,b
47
a,b
Heptane/6 M HCl
54
60
68
70
c
b,d
EDC /6 M HCl
b,d
Xylene/6 M HCl
Toluene/6 M HCl
Toluene/6 M HCl
Toluene/6 M HCl
Toluene/6 M HCl
d,e
d,f
80
g,h
i
69 (62)
g
i
1
0
61 (45)
a
b
c
d
e
f
The colour of the product was dark brown.
The time taken to add the aldehyde was 30 min.
EDC=1,2-dichloroethane.
An almost colourless product was obtained.
It was confirmed that a similar result was obtained irrespective of the time taken to add the aldehyde.
Crude yield in 5 kg scale.
g
h
i
The time taken to add the aldehyde was 1 min.
A mixture of regio-isomers; 7-methylquinaldine/5-methylquinaldine=1.8/1.
2
Reported yields in a homogenic phase reaction.
†
The following are the highlights of this method: (1) Relatively high yields are obtained as
compared to the single-phase reaction (entry 3 vs 7, entries 9–10). (2) The dropping rate of the
aldehyde has no significant influence on the yield. Since the original Doebner–Miller reaction
requires strict control over the addition of the aldehyde, this feature is particularly useful for a
†
Typical procedure: 1a (1.12 g, 4.46 mmol) was hydrolysed to the corresponding aniline by heating with 6 M HCl
(
22.4 ml) at 100°C (bath temp). After the disappearance of 1a on TLC, toluene (5.8 ml) and then crotonaldehyde
(
0.74 ml, 8.92 mmol) were added dropwise at 100°C. Stirring was continued for 2 h at 100°C and the mixture was
allowed to cool to room temperature. The aqueous layer was separated and neutralized with aqueous NaOH to afford
crude 2a as a crystalline solid. The crude product was purified by silica gel chromatography (hexane/AcOEt, 5/1) to
give 802 mg (70.2%) of pure 2a as colourless crystals with mp 103°C.

8525
large-scale synthesis. (3) Simply neutralising the aqueous phase could isolate almost colourless
pure product. All of these advantages (1)–(3) were finally confirmed in a 5 kg-scale production
(
entry 8). Further examples and applications of the reaction are now under investigation.
References
1
2
3
4
5
. Doebner, O.; Miller, W. Bericht 1883, 16, 2464–2472.
. Manske, R. H.; Kulka, M. Org. React. 1953, 7, 59–98.
. Ranu, B. C.; Hajra, A.; Jana, U. Tetrahedron Lett. 2000, 41, 531–533.
. Leir, C. M. J. Org. Chem. 1977, 42, 911–913.
. Ismailova, L. A.; Kudratova, M. K.; Kuchkarov, A. B.; Yasupov, D. Dokl. Akad. Nauk USSR 1989, 2, 35–36.
.