Fast and convenient base-mediated synthesis of 3-substituted quinolines

Article abstract of DOI:10.1016/j.tetlet.2008.10.132

In a convenient method, 3-substituted quinolines are readily synthesized in a two-step process with initial oxazine formation and subsequent base-mediated cyclization.

Full text of DOI:10.1016/j.tetlet.2008.10.132

Tetrahedron Letters 50 (2009) 201–203
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Fast and convenient base-mediated synthesis of 3-substituted quinolines
*
*
Hans Vander Mierde , Pascal Van Der Voort, Francis Verpoort
Centre for Ordered Materials, Organometallics and Catalysis, Department of Inorganic and Physical Chemistry, Ghent University, Krijgslaan 281—S3, Ghent 9000, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
In a convenient method, 3-substituted quinolines are readily synthesized in a two-step process with
initial oxazine formation and subsequent base-mediated cyclization.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 29 September 2008
Revised 21 October 2008
Accepted 24 October 2008
Available online 31 October 2008
Keywords:
Quinoline
Oxidation
Cyclization
Ring-chain tautomerism
Oxazine
Compounds containing a quinoline framework exhibit a wide
variety of pharmacological and biological activities.1 During the
last few decades, conventional named methods for their synthesis
have been replaced by more efficient organometal-catalyzed
approaches.2 Our previous reports had surveyed a ruthenium-
catalyzed modification of the Friedländer method in which 2-
aminobenzylalcohol (1) is oxidatively cyclized with ketones in
the presence of a base,3 affording 2-substituted or 2,3-substituted
quinolines (Scheme 1a). Recent investigations revealed that this
coupling reaction also takes place in the presence of only a strong
base without an expensive transition metal catalyst.4
presented a step-by-step method, with an initial treatment of 1
in the presence of RuCl2(PPh3)3 and KOH in dioxane for 15 h,
followed by the addition of the aldehyde and by stirring for an
additional 5 h. Even after long reaction times, only moderate
quinoline yields ranging from 34% to 67% were reported. We now
present a new fast and convenient method for the synthesis of
3-substituted quinolines in excellent yields. The general reaction
mechanism is outlined in Scheme 2.
In a two-step procedure, first 1 is reacted with an aldehyde to
form the 2-alkyl-2,4-dihydro-1H-benzo[d][1,3]oxazine 2. This
Theoretically, the use of aldehydes instead of ketones should af-
ford 3-substituted quinolines (Scheme 1b), but instead, a complex
mixture of unwanted side-products was obtained, mostly as a re-
sult of the self-aldol reaction of the aldehyde. A report by Cho
and Shim confirmed the difficulties in this approach.5 They
O
(a)
O
+
1
R
H
R
- H2O
N
H
2
(b)
ring-chain tautomerism
R
[Ru]
O
O
OH
OH
NH2
a
b
+
+
R
R
R
R'
base
N
N
N
R'
1
1
benzophenone
(c) oxidation
R
[Ru]
diphenylmethanol
H
base
O
R
O
N
strong
base
R
Scheme 1. (a) Synthesis of 2- or 2,3-substituted quinolines from 1 and ketones; (b)
Synthesis of 3-substituted quinolines from 1 and aldehydes.
R
- H2O
(e)
(d)
N
N
* Corresponding authors. Tel.: +32 9 2644436; fax: +32 9 2644983 (H.V.M).
E-mail addresses: Hans.VanderMierde@UGent.be (H. V. Mierde), Francis.Verpoort@
UGent.Be (F. Verpoort).
3
Scheme 2. General reaction mechanism.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.132

202
H. V. Mierde et al. / Tetrahedron Letters 50 (2009) 201–203
Table 1
Addition of 4, KOtBu and
benzophenone
Optimization processa
% Yield
Aldehydeb KOtBu
Benzophenone % Yield 3gc
(mmol)
100
80
60
40
20
0
Entry Sieves
1
(mmol) (mmol)
(mmol)
1
2
3
4
5
6
7
+
+
+
ꢀ
ꢀ
ꢀ
ꢀ
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
1.0
2.0
2.0
KOH, 2.0
—
—
1.0
1.0
1.0
1.5
1.0
15
31
44
66
46
44
6
1
2
3
2'
3'
a
Reaction conditions: (i) 1 and aldehyde in 3 ml 1,4-dioxane, 1 h, 80 °C; (ii) 4,
base and benzophenone, 1 h, 80 °C.
b
3-Phenylbutyraldehyde.
Determined by GC with dodecane as internal standard.
c
Time /min
0
30
60
90
120
150
180
210
oxazine is at equilibrium with the corresponding imine via a ring-
chain tautomerism that has been well studied and described by
others.6 Upon addition of (H2IMes)(PCy3)Cl2Ru = CHPh (4), the sec-
ond generation Grubbs catalyst, the benzylic alcohol of the imine is
oxidized to an aldehyde. The strong base abstracts a proton of the
Figure 1. Progression of the reaction with butanal as the aldehyde.
process was performed, and the most important results are sum-
marized in Table 1.
a-carbon next to the imine, and an intramolecular aldol-type
To eliminate the presence of water, several experiments were
carried out with molecular sieves, but with no beneficial effect (en-
try 3 vs entry 5). Apparently, the presence of water in the reaction
mixture is not a major issue, but rather the self-aldol reaction
poses the biggest problem. Without an additional hydrogen accep-
tor (entry 1), the reaction does hardly proceed at all, and the use of
a second equivalent of the aldehyde seriously limits the yield be-
cause of the aldol side reaction (entry 2). Benzophenone is found
to be the ideal ‘inert’ hydrogen acceptor that does not undergo
self-condensation, nor cross aldol-reactions with the aldehyde.
Equimolar amounts of reagents produced the best results (entry
cyclocondensation then affords the 3-substituted quinoline 3.
In our initial experiments, 2 equiv of aldehyde were used: one
equivalent for the reaction with 1 and the other as hydrogen accep-
tor in the hydrogen transfer reaction. However, only low quinoline
yields of 16–40% were obtained and self-aldol products from the
aldehyde were found. This self-aldol reaction lowers the amount
of necessary hydrogen acceptor, lowering the final quinoline yield
as a consequence. Furthermore, 1 was present at the end of the
reaction, even though it was completely consumed in the initial
oxazine formation (verified by GC). Possibly 2 is decomposed again
by water in the reaction mixture. Therefore, an optimization
Table 2
Synthesis of 3-substituted quinolines from 1 and aldehydesa
Entry
1
Aldehyde
Oxazine
Quinoline
% Yield [Ru]
94
% Yieldb MPVO
97
O
O
O
O
O
O
O
2a
3a
O
N
H
N
C3H7
C3H7
2
3
4
5
6
2b
3b
95
>99
O
O
N
H
N
N
C6H13
C6H13
2c
3c
>99
>99
84
>99 (92)
>99
N
H
2d
3d
N
H
O
N
2e
3e
78 (73)
95
N
H
O
O
N
N
2f
3f
85
N
H
7
2g
3g
71
98
O
N
H
N
a
Reaction conditions: (i) 1 (1.0 mmol) and aldehyde (1.0 mmol) in 3 ml 1,4-dioxane, 1 h, 80 °C; (ii) 4 and/or KOtBu (1.2 mmol) and benzophenone (1.1 mmol), 2 h, 80 °C.
Yields determined by GC with dodecane as internal standard.
b
Isolated yields of selected compounds in parentheses.

H. V. Mierde et al. / Tetrahedron Letters 50 (2009) 201–203
203
7. General experimental procedure for the base-mediated process: Compound 1
(0.1232 g, 1.0 mmol), aldehyde (1.0 mmol) and dodecane (0.0426 g, 0.25 mmol)
were dissolved in 3 ml of 1,4-dioxane and were stirred at 80 °C for 1 h. Then,
benzophenone (0.2004 g, 1.1 mmol) and KOtBu (0.1347 g, 1.2 mmol) were
4). The reaction proceeds much slower, when the weaker base KOH
is used instead of KOtBu (entry 7).
Figure 1 shows the progression of the reaction. The formation of
2 proceeds smoothly, but the conversion to 3 quickly slows down
after the addition of 4, KOtBu and benzophenone. This is probably
caused by the reaction of KOtBu with water that is released during
the reaction (Scheme 1, step e). The resulting KOH is a weaker base,
and as a consequence, the reaction continues at a slower rate.
When slightly higher amounts of KOtBu and benzophenone were
used, the reaction was completed faster, as shown by the filled
shape curves 20 and 30 in Figure 1. A further increase in the amount
of KOtBu had no additional effect.
A variety of aldehydes were subjected to this reaction, and the
results are presented in Table 2.7,8 In this ruthenium-catalyzed
procedure, good to excellent quinoline yields were achieved for
all aldehydes, although the presence of an aromatic ring resulted
in lower yields (Table 2, entries 5–7). Recently, we have found that
the oxidation reaction can also be mediated by only a strong base
such as KOtBu, without the presence of a ruthenium catalyst.4 This
oxidation process presumably follows the Meerwein-Ponndorf-
Verley-Oppenauer mechanism (MPVO). The same reactions were
performed with only KOtBu, and nearly quantitative quinoline
yields were obtained for all aldehydes except phenylacetaldehyde.
In conclusion, we have developed a fast and convenient base-
mediated method that affords 3-substituted quinolines in excellent
yields. In a two-step procedure, first, 2-aminobenzylalcohol is re-
acted with an aldehyde to form an oxazine. Subsequent addition
of KOtBu and benzophenone then results in a MPVO oxidation
and aldol-type cyclization reaction affording the quinoline.
added, and the solution was allowed to react for 2 h at 80 °C. 30 ll of the
solution was passed through a short silica gel column (ethyl acetate) to remove
inorganic salts, and the resulting solution was analyzed by GC to determine the
yield. Dodecane was used as internal standard. All quinolines were isolated and
purified by an acidic/basic extraction as described previously.3a Isolated yields
were typically 5–10% lower than GC yields.
8. The oxazines and quinolines were characterized by 1H and 13C NMR
spectroscopy on a Varian Unity 300 spectrometer: 2-propyl-2,4-dihydro-1H-
benzo[d][1,3]oxazine (2a): 1H NMR (300 MHz; CDCl3) d 7.06 (t, 1H), 6.90 (d, 1H),
6.80 (t, 1H), 6.67 (d, 1H), 4.93 (d, 1H), 4.80 (d, 1H), 4.54 (t, 1H), 1.70 (m, 2H), 1.54
(m, 2H), 0.98 (t, 3H); 13C NMR (75 MHz; CDCl3) d 141.8, 127.6, 125.2, 122.9,
119.9, 117.5, 84.4, 67.9, 37.5, 18.1, 14.2; 2-butyl-2,4-dihydro-1H-benzo[d][1,3]-
oxazine (2b). 1H NMR (300 MHz; CDCl3) d 7.06 (t, 1H), 6.90 (d, 1H), 6.79 (t, 1H),
6.66 (d, 1H), 4.93 (d, 1H), 4.80 (d, 1H), 4.53 (t, 1H), 1.72 (m, 2H), 1.50 (m, 2H),
1.39 (m, 2H), 0.94 (t, 3H); 13C NMR (75 MHz; CDCl3) d 141.8, 127.6, 125.2, 122.8,
119.9, 117.5, 84.6, 67.9, 35.1, 26.9, 22.8, 14.2; 2-heptyl-2,4-dihydro-1H-
benzo[d][1,3]oxazine (2c). 1H NMR (300 MHz; CDCl3) d 7.05 (t, 1H), 6.90 (d,
1H), 6.78 (t, 1H), 6.65 (d, 1H), 4.93 (d, 1H), 4.79 (d, 1H), 4.52 (t, 1H), 1.72 (m, 2H),
1.50 (m, 2H), 1.35-1.20 (m, 8H), 0.89 (t, 3H); 13C NMR (75 MHz; CDCl3) d 141.9,
127.6, 125.2, 122.8, 119.9, 117.5, 84.7, 67.9, 35.4, 32.0, 29.7, 29.4, 24.8, 22.9,
14.3; 2-isobutyl-2,4-dihydro-1H-benzo[d][1,3]oxazine (2d). 1H NMR (300 MHz;
CDCl3) d 7.09 (t, 1H), 6.93 (d, 1H), 6.83 (t, 1H), 6.69 (d, 1H), 4.96 (d, 1H), 4.82 (d,
1H), 4.61 (t, 1H), 1.94 (m, 1H), 1.71 (m, 1H), 1.54 (m, 1H), 1.01 (d, 6H); 13C NMR
(75 MHz; CDCl3) d 141.8, 127.6, 125.3, 123.0, 120.0, 117.7, 83.4, 67.9, 44.4,
24.5, 23.3, 22.9; 2-benzyl-2,4-dihydro-1H-benzo[d][1,3]oxazine (2e). 1H NMR
(300 MHz; CDCl3) d 7.40–7.15 (m, 5H), 7.01 (t, 1H), 6.86 (d, 1H), 6.75 (t, 1H), 6.56
(d, 1H), 4.90 (d, 1H), 4.79 (d, 1H), 4.57 (t, 1H), 3.10 (d, 1H), 2.94 (d, 1H); 13C NMR
(75 MHz; CDCl3) d 141.8, 136.3, 129.9, 129.0, 128.4, 127.6, 127.2, 125.2, 122.9,
119.9, 117.2, 84.7, 67.9, 41.8; 2-phenethyl-2,4-dihydro-1H-benzo[d][1,3]oxazine
(2f). 1H NMR (300 MHz; CDCl3) d.30–7.09 (m, 5H), 7.04 (t, 1H), 6.88 (d, 1H), 6.78
(t, 1H), 6.62 (d, 1H), 4.85 (d+d, 2H), 4.51 (t, 1H), 2.92–2.75 (m, 2H), 2.02 (m, 2H);
13C NMR (75 MHz; CDCl3) d 141.8, 128.9 (2 C), 128.8 (2 C), 127.7, 126.6, 126.4,
125.3, 122.9, 120.1, 117.6, 83.9, 67.9, 36.9, 31.0; 2-(2-phenylpropyl)-2,4-dihydro-
1H-benzo[d][1,3]oxazine (2g). 1H NMR (300 MHz; CDCl3) d 7.29–7.18 (m, 5H),
7.02 (t, 1H), 6.84 (d, 1H), 6.77 (t, 1H), 6.68 (d, 1H), 4.79 (m, 2H), 4.23 (t, 1H), 3.09
(m, 1H), 2.12–1.90 (m, 2H), 1.31 (d, 3H); 13C NMR (75 MHz; CDCl3) d 146.5,
141.9, 128.8 (2 C), 127.5, 127.3 (2 C), 126.6, 125.2, 123.0, 120.0, 117.6, 83.2, 67.8,
43.9, 36.2, 23.1; 3-Ethylquinoline (3a). Pale yellow oil; 1H NMR (300 MHz; CDCl3)
d 8.79 (s, 1H), 8.07 (d, 1H), 7.92 (s, 1H), 7.76 (d, 1H), 7.65 (t, 1H), 7.51 (t, 1H), 2.85
(q, 2H), 1.36 (t, 3H); 13C NMR (75 MHz; CDCl3) d 152.1, 146.9, 136.9, 133.6,
129.4, 128.7, 128.5, 127.5, 126.8, 26.5, 15.5; 3-Propylquinoline (3b). Pale yellow
oil; 1H NMR (300 MHz; CDCl3) d 8.76 (s, 1H), 8.07 (d, 1H), 7.89 (s, 1H), 7.75 (d,
1H), 7.64 (t, 1H), 7.49 (t, 1H), 2.75 (t, 2H), 1.72 (m, 2H), 0.98 (m, 3H); 13C NMR
(75 MHz; CDCl3) d 152.3, 146.9, 135.4, 134.5, 129.3, 128.8, 128.4, 127.6, 126.8,
35.5, 24.5, 13.9; 3-Hexylquinoline (3c). Pale yellow oil; 1H NMR (300 MHz;
CDCl3) d 8.77 (s, 1H), 8.08 (d, 1H), 7.92 (s, 1H), 7.76 (d, 1H), 7.65 (t, 1H), 7.52 (t,
1H), 2.78 (t, 2H), 1.70 (m, 2H), 1.32 (m, 6H), 0.88 (t, 3H); 13C NMR (75 MHz;
CDCl3) d 152.0, 146.5, 135.7, 129.3, 128.9, 128.5, 127.5, 126.9, 33.4, 31.9, 29.1,
22.8, 14.3; 3-Isopropylquinoline (3d). Pale yellow oil; 1H NMR (300 MHz; CDCl3) d
8.82 (s, 1H), 8.08 (d, 1H), 7.93 (s, 1H), 7.76 (d, 1H), 7.65 (t, 1H), 7.51 (t, 1H), 3.13
(m, 1H), 1.36 (m, 6H); 13C NMR (75 MHz; CDCl3) d 151.2, 146.9, 141.4, 132.3,
129.1, 128.8, 128.5, 127.7, 126.8, 32.1, 23.9; 3-Phenylquinoline (3e). Pale yellow
solid; 1H NMR (300 MHz; CDCl3) d 9.17 (s, 1H), 8.24 (s, 1H), 8.14 (d, 1H), 7.83 (d,
1H), 7.71–7.66 (m, 3H), 7.56–7.47 (m, 3H), 7.42 (d, 1H); 13C NMR (75 MHz;
CDCl3) d 150.2, 147.6, 138.1, 134.0, 133.3, 129.6, 129.5, 129.4, 128.6, 128.4,
128.3, 127.7, 127.2; 3-Benzylquinoline (3f). Light brown oil; 1H NMR (300 MHz;
CDCl3) d 8.81 (s, 1H), 8.07 (d, 1H), 7.87 (s, 1H), 7.72 (d, 1H), 7.65 (t, 1H), 7.50 (t,
1H), 7.34–7.21 (m, 5H), 4.15 (s, 2H); 13C NMR (75 MHz; CDCl3) d 152.4, 147.1,
139.9, 135.1, 134.1, 129.4, 129.2, 129.1, 129.0, 128.6, 127.7, 127.0, 126.8, 39.5;
3-(1-phenylethyl)quinoline (3g). Light brown solid; 1H NMR (300 MHz; CDCl3) d
8.80 (s, 1H), 8.07 (d, 1H), 7.93 (s, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.51 (t, 1H), 7.33–
7.20 (m, 5H), 4.36 (q, 1H), 1.75 (d, 3H); 13C NMR (75 MHz; CDCl3) d 152.0, 146.9,
145.1, 139.2, 133.4, 129.2, 129.1, 128.9, 128.3, 127.9, 127.8, 126.9, 126.8, 42.8,
21.9.
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