Efficient synthesis of 3-substituted 2,3-dihydroquinolin-4-ones using a one-pot sequential multi-catalytic process: Pd-catalyzed allylic amination-thiazolium salt-catalyzed Stetter reaction cascade

Article abstract of DOI:10.1016/j.tetlet.2006.04.095

We developed an efficient method for the synthesis of 3-substituted 2,3-dihydroquinolin-4-ones using a one-pot sequential multi-catalytic process: Pd-catalyzed allylic amination-thiazolium salt-catalyzed Stetter reaction cascade. Measurement of the initial rate of the developed sequential process revealed a significant increase in the reaction rate of the Stetter reaction in the presence of Pd(OAc)₂ and AcOH·i-Pr₂NEt, the constituents of the first Pd catalysis.

Full text of DOI:10.1016/j.tetlet.2006.04.095

Tetrahedron Letters 47 (2006) 4365–4368
Efficient synthesis of 3-substituted 2,3-dihydroquinolin-4-ones
using a one-pot sequential multi-catalytic process:
Pd-catalyzed allylic amination–thiazolium salt-catalyzed
Stetter reaction cascade
Tetsuhiro Nemoto, Tomoaki Fukuda and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 25 March 2006; revised 18 April 2006; accepted 20 April 2006
Abstract—We developed an efficient method for the synthesis of 3-substituted 2,3-dihydroquinolin-4-ones using a one-pot sequential
multi-catalytic process: Pd-catalyzed allylic amination–thiazolium salt-catalyzed Stetter reaction cascade. Measurement of the initial
rate of the developed sequential process revealed a significant increase in the reaction rate of the Stetter reaction in the presence of
Pd(OAc)2 and AcOHÆi-Pr2NEt, the constituents of the first Pd catalysis.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Hydroquinolines are ubiquitous structural motifs in
various natural products that exhibit a variety of biolog-
ical activities.1 From a synthetic point of view, 2,3-
dihydroqinolin-4-ones are versatile intermediates for
the synthesis of functionalized hydroquinolines. Several
dihydroquinolinones are utilized as the key intermediate
for the synthesis of natural products containing a hydro-
quinoline core such as martinelline and martinellic
acid.2,3 A thiazolium salt-catalyzed intramolecular Stet-
ter reaction is one of the most useful methods for con-
structing substituted dihydroquinolinones.4 Substrates
for the intramolecular Stetter reaction can be efficiently
prepared using Pd-catalyzed allylic amination of c-acet-
oxy a,b-unsaturated carbonyl compounds with 2-amino-
benzaldehyde derivatives.5 If these two reactions can be
performed without interfering with the individual cata-
lytic processes, functionalized dihydroquinolinones are
directly obtained in a single-pot reaction (Scheme 1).
The combination of different types of catalysis in a single
reaction process increases synthetic efficiency and helps
to reduce waste.6,7 In addition, this type of sequential
catalysis is quite attractive if the first and/or second reac-
tions beneficially affect on the other catalysis.8 Herein,
we report an efficient method for the synthesis of 3-
substituted 2,3-dihydroquinolin-4-ones using a one-pot
sequential multi-catalytic process.
Thiazolium Salt-Catalyzed
Stetter Reaction
O
O
One-Pot
R
R
Catalysis
C
C
+
X
X
N
NH AcO
Ms
Ms
Pd-catalyzed
Allylic Amination
Scheme 1. Synthetic strategy.
Keywords: Pd-catalyzed allylic amination; Sequential multi-catalytic process; Stetter reaction; 3-Substituted 2,3-dihydroquinolin-4-ones.
*
Corresponding author. Tel./fax: +81 43 290 2987; e-mail: hamada@p.chiba-u.ac.jp
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.095

4366
T. Nemoto et al. / Tetrahedron Letters 47 (2006) 4365–4368
Table 1. Preliminary experiments for the Stetter reaction of 2
OH
H C
3
O
O
COOEt
Ph
Cl
N
S
1 (20 mol %)
H
N
COOEt
N
i-Pr NEt (5 eq), t-BuOH (0.1 M)
2
Ms
Additives
Ms
2
3
Entry
Additives
—
Pd(OAc)2 (5 mol %)
Ph3P (12 mol%)
AcOH (1.0 equiv)
Pd(OAc)2 (5 mol %), PPh3 (12 mol %)
Temperature (ꢁC)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
30
30
30
30
30
30
50
3
3
3
3
3
3
3
58
67
72
88
82
84
100 (99)b
Pd(OAc)2 (5 mol %), PPh3 (12 mol %), AcOH (1.0 equiv)
Pd(OAc)2 (5 mol %), PPh3 (12 mol %), AcOH (1.0 equiv)
a Determined by 1H NMR analysis of the crude product.
b Isolated yield.
The key to success of the target process is the compati-
bility of the second catalysis with the conditions of the
first Pd catalysis. Therefore, we first performed experi-
ments to examine the influence of the constituents of
the first reaction on the second catalysis (Table 1).
Using 20 mol % of thiazolium salt 1, an intramolecular
Stetter reaction of 2 was investigated as a model reac-
tion. In the absence of additives, the reaction proceeded
at 30 ꢁC to give the dihydroquinolinone 3 in 58% yield.
Interestingly, there was a significant increase in the
chemical yield of 3 when the reaction was performed
in the presence of 5 mol % of Pd(OAc)2, triphenylphos-
phine (12 mol %), and acetic acid (1 equiv). The positive
effect on the reactivity was also observed in the reaction
conditions that included all of the reagents for the first
reaction. The cyclic product 3 was obtained in quantita-
tive yield when the reaction was performed at 50 ꢁC.
This finding suggests that beneficial modifications of
the second catalytic process were achieved by the con-
stituents of the first Pd catalysis, producing a more suit-
able condition for the second intramolecular Stetter
reaction.
Based on the preliminary experiments, we examined
a one-pot sequential multi-catalytic process. After
completion of the Pd-catalyzed allylic amination of alde-
hyde 4a with c-acetoxy a,b-unsaturated ester 5a,
20 mol % of 1 was directly added to the reaction mixture
and the resulting mixture was stirred at 50 ꢁC (a two-
step procedure9) (Table 2). As expected, the desired
sequential process proceeded efficiently to afford 3 in
97% yield (entry 1). Substrate scope was examined using
5 mol % of Pd catalyst and 10–30 mol % of 1. Nucleo-
philes with an electron-donating substituent and an elec-
tron-withdrawing substituent on the aromatic ring, were
applicable to this reaction process, affording the corre-
sponding product in excellent yield (entries 3 and 4).
In contrast to that of c-acetoxy a,b-unsaturated esters,
a reaction using c-acetoxy a,b-unsaturated nitrile gave
complex reaction mixtures at the allylic amination stage
(entry 6).
The present one-pot sequential multi-catalytic process
was successful even when both catalysts coexisted in
the reaction mixture at the first stage of the reaction
Table 2. One-pot sequential multi-catalytic process: two-step procedure
Pd(OAc) (5 mol %)
O
O
EWG
2
PPh (12 mol %)
3
R
R
H
i-Pr NEt (5 eq)
1 (X mol %)
50 °C
2
+
AcO
EWG
t-BuOH (0.1 M), rt
time A
NHMs
N
Ms
time B
4a: R = H
4b: R = OBn
4c: R = Cl
5a: R = COOEt
5b: R = COO-t-Bu
5c: R = CN
3, 6
Entry
Aldehyde
Acetate
1 (mol %)
Time A (h)
Time B (h)
Product
Yielda (%)
1
4a
4a
4b
4c
4a
4a
5a
5a
5a
5a
5b
5c
20
10
30
30
20
30
6
6
16
16
6
12
72
24
24
12
—
3
97
97
98
94
99
Messy
2b
3
3
6ba
6ca
6ab
6ac
4
5
6
12
a Isolated yield.
b The second step was performed at 70 ꢁC.

T. Nemoto et al. / Tetrahedron Letters 47 (2006) 4365–4368
Table 3. One-pot sequential multi-catalytic process: one-step procedure
4367
O
O
EWG
1 (X mol %), Pd(OAc) (5 mol %),
R
R
2
H
PPh (12 mol %), i-Pr NEt (5 eq)
3
2
+
AcO
EWG
t-BuOH (0.1 M), 50 °C
NHMs
N
Ms
4a: R = H
4b: R = OBn
4c: R = Cl
5a: R = COOEt
5b: R = COO-t-Bu
5c: R = CN
3, 6
Entry
Aldehyde
Acetate
1 (mol %)
Time (h)
Product
Yielda (%)
1
2
3
4
5
4a
4b
4c
4a
4a
5a
5a
5a
5b
5c
20
30
30
20
30
12
24
24
12
12
3
98
6ba
6ca
6ab
6ac
No reaction
No reaction
99
99
a Isolated yield.
(a one-step procedure10) (Table 3). Aldehyde 4a and c-
acetoxy a,b-unsaturated ester 5a were dissolved in tert-
BuOH, and the solution was heated at 50 ꢁC in the pres-
ence of both catalysts, giving 3 in 98% yield (entry 1).
Unexpectedly, the first allylic amination did not proceed
at all when aldehydes 4b and 4c were used as the nucle-
ophile. On the other hand, a reaction with c-acetoxy
a,b-unsaturated nitrile 5c proceeded smoothly to afford
the corresponding product in 99% yield using the one-
step procedure (entry 5). This result might be due to
rapid consumption of the c-amino a,b-unsaturated
nitrile intermediate, compared to that of the two-step
procedure.
As shown in Table 1, there was a significant increase in the
chemical yield of 3 in the presence of a catalytic amount of
Pd(OAc)2 and other constituents of the first Pd catalysis.
To quantitatively evaluate the increased reactivity of the
Stetter reaction, the initial rate of the developed sequen-
tial multi-catalytic process was measured (Fig. 1).11
Compared with the control reaction (condition A:
3.65 · 10À4 M/s), the reaction rate was increased in the
presence of 20 mol % of Pd(OAc)2 (condition B:
6.27 · 10À4 M/s). In particular, the similar rate accelera-
tion which was observed in the one-pot multi-catalytic
process (condition C: 5.77 · 10À4 M/s) is to be noted.
The mode of rate acceleration by Pd(OAc)2 is not clear.
The fact that the addition of other metal acetates also in-
creases the reaction rate, suggests that the Lewis acidic
property of the metal species is related to the rate acceler-
ation11: LiOAc (20 mol %): 5.92 · 10À4 M/s, Zn(OAc)2
(20 mol %): 5.95 · 10À4 M/s, In(OAc)3 (20 mol %): 4.93 ·
10À4 M/s, Yb(OAc)3Æ4H2O (20 mol %): 7.25 · 10À4 M/s.
In addition, the reaction rate was increased in the presence
of 1 equiv of acetic acid (9.81 · 10À4 M/s). In this case,
ammonium salt (AcOHÆi-Pr2NEt) would function as
Brønsted acid and accelerate the reaction. These findings
demonstrate the synthetic utility of the developed sequen-
tial multi-catalytic process, and provide useful informa-
tion for designing a new catalyst system for the Stetter
reaction.12,13
In conclusion, we developed an efficient method for the
synthesis of 3-substituted 2,3-dihydroquinolin-4-ones
using a one-pot sequential catalysis: Pd-catalyzed allylic
substitution–thiazolium salt-catalyzed Stetter reaction
cascade. Measurement of the initial rate of the devel-
oped process revealed a significant increase in the reac-
tion rate of the Stetter reaction in the presence of
Pd(OAc)2 and AcOHÆi-Pr2NEt, the constituents of the
first Pd catalysis.
Acknowledgements
This work was supported in part by Grant-in Aid
for Encouragement of Young Scientists (B) from the
Ministry of Education, Culture, Sports, Science, and
Figure 1. Measurement of initial rate.

4368
T. Nemoto et al. / Tetrahedron Letters 47 (2006) 4365–4368
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.04.095.
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9. General procedure for the two-step procedure: To a stirred
solution of Pd(OAc)2 (2.51 mg, 0.0112 mmol), PPh3
(7.04 mg, 0.0268 mmol), 5a (38.5 mg, 0.224 mmol), and
4a (53.5 mg, 0.268 mmol) in t-BuOH (2.2 mL) at room
temperature was added i-Pr2NEt (184 lL, 1.12 mmol)
under an argon atmosphere. After 6 h, thiazolium salt 1
(12.1 mg, 0.0448 mmol) was added to the reaction, and the
mixture was stirred for 12 h at 50 ꢁC. The reaction mixture
was diluted with ethyl acetate, and washed with saturated
aqueous NH4Cl, water, then dried over Na2SO4. After
concentration in vacuo, the residue was purified by flash
chromatography (SiO2, hexane/ethyl acetate 30/1) to give
3 as yellow oil: 67.6 mg (97%). IR (neat): m = 3022, 2980,
2932, 1728, 1693, 1600, 1478, 1457, 1353, 1299, 1257, 1220,
1157, 964, 768 cmÀ1 1H NMR (CDCl3): d = 1.29 (t,
;
4. For a general review, see: Stetter, H.; Kuhlmann, H. Org.
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J = 7.2 Hz, 3H), 2.58 (dd, J = 7.6 Hz, 17.2 Hz, 1H), 2.91
(dd, J = 4.8 Hz, 17.2 Hz, 1H), 3.12 (s, 3H), 3.30 (dddd,
J = 4.8 Hz, 4.8 Hz, 7.6 Hz, 12.4 Hz, 1H), 3.81 (dd,
J = 12.4 Hz, 13.2 Hz, 1H), 4.19 (dq, J = 2.4 Hz, 7.2 Hz,
2H), 4.50 (dd, J = 4.8 Hz, 13.2 Hz, 1H), 7.22–7.26 (m,
1H), 7.54–7.58 (m, 1H), 7.75–7.78 (m, 1H), 8.05–8.07 (m,
1H); 13C NMR (CDCl3): d = 14.1, 31.7, 39.9, 43.2, 49.7,
61.1, 121.0, 123.8, 124.6, 128.6, 135.0, 142.3, 171.1, 193.3;
FAB-LRMS: m/z 312 (MH+).
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10. General procedure for the one-step procedure: To a stirred
solution of Pd(OAc)2 (1.21 mg, 0.0054 mmol), PPh3
(3.40 mg, 0.0130 mmol), 4a (18.6 mg, 0.108 mmol), 5a
(25.8 mg, 0.130 mmol), and thiazolium salt 1 (5.83 mg,
0.0216 mmol) in t-BuOH (1.1 mL) was added i-Pr2NEt
(89 lL, 0.54 mmol), and the mixture was heated to 50 ꢁC.
After 12 h, the reaction mixture was diluted with ethyl
acetate, and washed with saturated aqueous NH4Cl, water,
then dried over Na2SO4. After concentration in vacuo, the
residue was purified by flash chromatography (SiO2, hex-
ane/ethyl acetate 30/1)to give 3 as yellow oil: 33.3 mg (99%).
11. See Supplementary data for detail.
12. To the best of our knowledge, there is no report on Lewis
acid acceleration of the Stetter reaction.
13. Very interestingly, faster reaction rate was observed using
less amount of Pd(OAc)2 as an additive: 5 mol %:
1.67 · 10À3 M/s, 10 mol %: 8.22 · 10À4 M/s, 20 mol %:
6.27 · 10À4 M/s, 30 mol %: 3.73 · 10À4 M/s. At the pres-
ent stage, it is difficult to give a reasonable explanation for
these experimental results. However, it can be emphasized
that catalytic amount of Pd(OAc)2 increases the reaction
rate of the Stetter reaction. See Supplementary data for
detail.