The tandem reaction combining radical and ionic processes: an efficient approach to substituted 3,4-dihydroquinolin-2-ones

Article abstract of DOI:10.1016/j.tet.2009.01.027

3,4-Dihydroquinolin-2-ones are of great importance in the areas of pharmaceuticals. However, the direct intramolecular radical cyclizations of the corresponding amide compounds favor 5-exo products 2. Reports on the radical cyclization reactions producing

Full text of DOI:10.1016/j.tet.2009.01.027

Tetrahedron 65 (2009) 1982–1987
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The tandem reaction combining radical and ionic processes: an efficient
approach to substituted 3,4-dihydroquinolin-2-ones
,b,
Wang Zhou a, Liangren Zhang a, Ning Jiao a
*
a State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, XueYuan Rd. 38, Beijing 100191, China
b State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
3,4-Dihydroquinolin-2-ones are of great importance in the areas of pharmaceuticals. However, the direct
intramolecular radical cyclizations of the corresponding amide compounds favor 5-exo products 2. Re-
ports on the radical cyclization reactions producing 3,4-dihydroquinolin-2-one derivatives are limited.
Herein, an efficient tandem reaction combining radical and ionic processes was developed, which pro-
vides a practical synthetic strategy for the synthesis of substituted 3,4-dihydroquinolin-2-ones from
simple and readily available precursors under neutral reaction conditions.
Received 30 October 2008
Received in revised form 25 December 2008
Accepted 6 January 2009
Available online 14 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
readily available 2-iodoanilines 5 and acrylates 6, with neutral
reaction conditions.
Tandem reactions have emerged as an attractive synthetic strat-
egy for the synthesis of highly functionalized compounds utilizing
one-pot synthesis.1 However, tandem radical reactions may give
undesired polymers, whereas looking for exacting reaction condi-
tions is necessary for tandem reactions that proceed sequentially
through ionic species. Recently, tandem reactions that combine
radical and ionic processes have attracted a great deal of attention
due to their special efficacies during the molecular construction.2
3,4-Dihydroquinolin-2-ones are of great importance in the areas
of pharmaceuticals due to their ubiquitous structural motifs and
powerful biological properties (Fig. 1).3 Over the past decades, in
contrast to lots of significant synthetic approaches for quinolin-2-
one derivatives,4,5 only a few methods have been developed to
construct 3,4-dihydroquinolin-2-ones. These approaches include
the Friedel–Crafts cyclization and6 palladium7 or rhodium8 cata-
lyzed reactions. Despite their efficiencies, they usually require
harsh reaction conditions involving strong acid or base, high
pressure, or the use of complicated compounds as substrates. To
date, radical reactions have been widely used in organic synthesis,
especially in cyclization reactions.9,10 However, the deeply explored
direct intramolecular radical cyclizations of amide compounds 1
favor 5-exo products 2 (Scheme 1).11,12 Reports on the radical
cyclization reactions producing 3,4-dihydroquinolin-2-one de-
2. Results and discussions
As reported, 3,4-dihydroquinolin-2-ones 3 were difficult to be
achieved by the intramolecular radical cyclization of 1, which favor
5-exo products 2. Therefore, we hypothesized that the expected
Me
N
HO
t
NH Bu
O
O
O
NO2
O
N
H
O
Cl
N
H
N
R
O
5-HT3 receptor antagonist NMDA antagonist
Me
carteolol
OMe
Me
Me
N
rivatives
3
are limited.13 Herein, we describe an efficient
F3C
O
HO
O
OMe
Cl
intermolecular tandem reactions involving radical and ionic pro-
cesses leading to 3,4-dihydroquinolin-2-one derivatives from
N
H
O
N
O
H
HIV-1 reverse transcriptase inhibitor
insecticidal antibiotic
* Corresponding author. Tel./fax: þ86 10 8280 5297.
E-mail address: jiaoning@bjmu.edu.cn (N. Jiao).
Figure 1. Selected examples of 3,4-dihydroquinolin-2-one frameworks.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.027

W. Zhou et al. / Tetrahedron 65 (2009) 1982–1987
1983
Table 2
Radical
cyclization
I
Tandem reaction of 2-iodoaniline 5a and ethyl acrylate 6a with different radical
initiators and reducing reagentsa
disfavor
favor
t (h) Yieldb of 3a (%)
O
Entry Initiator Reducing reagent Solvent
T
N
R
3
O
N
R
1
O
N
R
R = H
1
2
3
4
5
Et3B
Et3B
Et3B
AIBN
AIBN
n-Bu3SnH
n-Bu3SnH
TTMSS
n-Bu3SnH
TTMSS
DME
DMSO
DME
rt
12
NR
Trace
41
rt to 120 ꢀCc 24
2
rt
rt to 120 ꢀCc 24
12
12
this work
DMSO
46
31
Toluene 80 ꢀ
C
O
a
Compound 5a (0.5 mmol), 6a (2.0 mmol), AIBN (0.2 mmol) or Et3B (0.55 mmol),
I
OR'
reducing reagent (0.75 mmol), and solvent (2 mL), reacted under air.
+
b
Isolated yield. With these yields, there were few oligomers of 6a, which can be
NH R'O
R
O
NH
R
further purified by recrystallization.
4
5
6
c
The reaction was held at rt for 12 h followed by heating at 120 ꢀC for 12 h.
Scheme 1. Intermolecular tandem reaction between 5 and 6.
(entry 1, Table 1). 5-exo Product 2a was not observed in this case.
However, the yield was low due to the formation of aniline, which
indicated that the radical addition should be the key step for this
tandem reaction. Since the 1H NMR spectrum of 3a was different in
part from the literature,15 we identified the structure by X-ray
diffraction (Fig. 2).
6-endo products 3 could be constructed through the relay of
intermolecular radical addition and lactamization between 5 and 6
(Scheme 1). With this hypothesis, 4 would be the key intermediates
via radical addition reaction.14 Our initial attempts started by
On the basis of this encouraging result, a range of other solvents
were screened. To our delight, even using water as the solvent, the
tandem reaction proceeded smoothly producing 3a in 42% yield
(entry 4, Table 1). Further investigation indicated that the reaction
achieved the highest yield (71%) when the reaction mixture was
heated at 120 ꢀC in DMSO (entry 11, Table 1). The yield decreased
slightly with lower reaction temperature (cf. entries 10 and 11,
Table 1). Some oligomers of 6a were observed in all of these re-
actions, which can be completely removed by recrystallization. The
radical initiators and reducing reagents show significant effects on
the tandem reactions (Table 2). When Et3B was used as the radical
initiator, a trace of 3a was detected in the presence of n-Bu3SnH
(entries 1 and 2, Table 2). Surprisingly, the reaction worked well
giving 3a in 41% yield even at room temperature when TTMSS (tris-
(tri-methyl-silyl)-silane) was used instead of n-Bu3SnH as the re-
ducing reagent (cf. entries 1 and 3, Table 2).
Table 1
Tandem reaction of 2-iodoaniline 5a and ethyl acrylate 6a involving radical and
ionic processesa
O
I
AIBN (0.4 eq.)
n-Bu3SnH (1.5 eq.)
overnight
+
OEt
N
H
O
NH2
5a
6a
3a
Entry
Solvent
T (ꢀC)
Yieldb of 3a (%)
1c
2
3
4
5
6
Toluene
Toluene
80
80
80
80
Reflux
80
18
35
38
42
21
38
Acetonitrile
H2O
THF
DMF
Having established the optimized conditions, we next examined
the synthesis of various derivatives. The results are summarized in
Table 3. 2-Iodoanilines with electron-withdrawing groups and
electron-donating groups proceeded efficiently producing the
corresponding 3,4-dihydroquinolin-2-one in moderate yields (en-
tries 1–7, Table 3). It is noteworthy that N-methyl-2-iodoaniline, 5i,
also was tolerant giving 3i in 45% yield (entry 9, Table 3). 3-Amino-
4-iodopyridine underwent the tandem reactions but in lower yield
(entry 8, Table 3). Under these conditions, 2,5-diiodobenzene-1,4-
diamine failed to give the tricyclic product, but 3,4-dihydro-6-iodo-
7-amino-(1H)-quinolin-2-one, 3j, was isolated in 36% yield (entry
10, Table 3).
7
8
9
10
11
EtOH
1,4-Dioxane
DME
DMSO
DMSO
80
80
80
70
42
37
52
61
120
71 (53)d
a
Compound 5a (0.5 mmol), 6a (2.0 mmol), AIBN (0.2 mmol), n-Bu3SnH
(0.75 mmol), and solvent (2.0 mL), reacted under air.
b
Isolated yield. With these yields, there were few oligomers of 6a, which can be
further purified by recrystallization.
c
Compound 6a (1.0 mmol) was used.
The yield in parentheses was calculated by 1H NMR using CH2Br2 as the internal
d
standard.
A series of substituted acrylates 6 were investigated as sub-
strates (Table 4). Under the standard reaction conditions, certain a-
treating 2-iodoaniline, 5a, and ethyl acrylate, 6a, with AIBN
(40 mol %) in the presence of n-Bu3SnH (150 mol %) in toluene. We
were interested to find that the desired 3,4-dihydro-(1H)-quinolin-
2-one, 3a, was formed in 18% yield after heating for 10 h at 80 ꢀC
substituted acrylates underwent the reaction smoothly and
delivered moderate yields (entries 3–5, Table 4). It was interesting
that dibenzyl itaconate, 6d, highly selectively produced 3,4-dihy-
droquinolin-2-one 3k in 54% yield. The seven-membered benzo-
fused lactam was not observed in this reaction (entry 3, Table 4).
However, when the terminal position of the acrylate was
substituted with a methyl group (6h), the tandem reaction was
inhibited due to steric hindrance (entry 7, Table 4).
Two separated by-products, 8 and 11, support our suggestion of
the reaction processes (Scheme 2). n-Bu3Snꢁ attacks the 2-iodo-
aniline, 5a, to generate radical 7, which can be trapped by n-Bu3SnH
leading to by-product aniline, 8. Radical 7 undergoes an addition
reaction with acrylate 6a to produce radical 9 stabilized by an ester
group. Radical9istrappedwithn-Bu3SnH to give intermediate 4awith
the regeneration of an n-Bu3Snꢁ radical, followed by lactamization to
afford the corresponding product 3a. A trace of by-product 11 was
C5
C7
C6
C1
C4
C8
C9
C3
C2
N1
01
Figure 2. The X-ray diffraction structure of 3a.

1984
W. Zhou et al. / Tetrahedron 65 (2009) 1982–1987
Table 3
Table 4
Tandem reaction of different 2-iodoanilines 5 and ethyl acrylate 6a involving radical
Tandem reaction of 2-iodoaniline 5a and different acrylates 6a
and ionic processesa
R1
R2
I
R2
O
I
AIBN, Bu3SnH
DMSO, 120 °C
overnight
OEt
R
+
R
R1
OR3
AIBN, Bu3SnH
+
DMSO, 120 °C
overnight
NHR
N
R
O
O
NH2
N
H
O
5
6a
3
5a
6
3
Entry
1
Substrate 5
Product 3
Yieldb (%)
Entry
R1
R2
R3
6
Yieldb of 3 (%)
1
2
3
4
5
6
7
H
H
H
H
H
H
Me
H
H
Ph
Bn
Bn
Me
Et
6b
6c
6d
6e
6f
38 (3a)
64 (3a)
54 (3k)
75 (3l)
44 (3m)
26 (3n)
Trace
I
71
CH2COOBn
N
H
O
NH2
Me
Bn
Ph
H
5a
3a
Et
Et
6g
6h
Me
F
Me
F
I
2
3
63
52
a
N
O
Compound 5a (0.5 mmol),
6 (2.0 mmol), AIBN (0.2 mmol), n-Bu3SnH
NH2
H
(0.75 mmol), and solvent (2 mL), reacted under air.
5b
3b
b
Isolated yield. With these yields, there were few oligomers of 6, which can be
I
further purified by recrystallization.
N
O
NH2
I
H
3. Conclusion
5c
3c
We have described an efficient collaboration between radical
and ionic processes. This method provides an avenue in which
readily available substituted 2-iodoanilines and various acrylates
can be used for the easy assembly of substituted 3,4-dihydro-
quinolin-2-ones under neutral reaction conditions. The magical
efficacy of the tandem reaction combining radical and ionic pro-
cesses would make it a bright prospect in organic synthesis as an
attractive synthetic strategy. Further studies on the scope and
synthetic applications are ongoing in our laboratory.
EtOOC
NC
EtOOC
NC
4
5
6
58
49
60
N
O
NH2
H
5d
3d
I
N
O
NH2
H
5e
3e
MeO
MeO
I
N
O
4. Experimental section
NH2
H
5f
3f
4.1. Typical procedure: 3,4-dihydro-1H-quinolin-2-one (3a)
To a solution of 2-iodoaniline (5a; 109 mg, 0.5 mmol) in DMSO
I
7
46
17
45
Cl
N
N
O
Cl
N
NH2
H
(2 mL), ethyl acrylate (6a; 217 mL, 2 mmol), n-Bu3SnH (201 mL,
5g
3g
0.75 mmol), and AIBN (33 mg, 0.2 mmol) were added. The reaction
mixture was heated at 120 ꢀC overnight. After cooling, the reaction
mixture was diluted with water (10 mL). The aqueous phase was
extracted with EtOAc (3ꢂ5 mL), the combined organic phases were
washed with brine (10 mL), and dried (Na2SO4). After evaporation,
the residue was purified by flash chromatography on silica gel
(EtOAc/petroleum ether, 1:2) to afford 52 mg (71%) of 3a (there
were few oligomers of 6a, which can be completely removed by
further recrystallization) and a trace of by-product 11 (<3%).
Compound 3a: solid, mp (ethanol): 168–170 ꢀC; 1H NMR (300 MHz,
I
8c
N
O
O
NH2
H
5h
3h
I
9d
Me
N
N
H
Me
5i
3i
CDCl3)
d
9.47 (br s,1H), 7.26–7.05 (m, 2H), 6.98 (t, J¼7.4 Hz,1H), 6.87
H2N
I
H2N
I
I
(d, J¼7.5 Hz, 1H), 2.97 (t, J¼7.4 Hz, 2H), 2.65 (t, J¼7.4 Hz, 2H); 13C
10e
36
N
H
O
NMR (75 MHz, CDCl3) d 172.4, 137.3, 127.8, 127.5, 123.5, 123.0, 115.6,
NH2
5j
30.6, 25.2; IR (neat): 3188, 3087, 2977, 2910, 1681, 1593, 1492, 1434,
1385, 1198, 750, 681 cmꢃ1; MS (70 eV): m/z (%) 147.1 (Mþ, 100);
C9H9NO: calcd C 73.45, H 6.16, N 9.52; found C 73.15, H 6.10, N 9.38.
3j
a
Compound
5 (0.5 mmol), 6a (2.0 mmol), AIBN (0.2 mmol), n-Bu3SnH
(0.75 mmol), and solvent (2 mL), reacted under air.
b
Isolated yield. With these yields, there were few oligomers of 6a, which can be
further purified by recrystallization.
4.2. Ethyl (2-oxo-3,4-dihydro-(1H)-quinolin-3-yl)
propionate (11)
c
This reaction mixture was stirred for 24 h.
This reaction mixture was stirred for 36 h.
Compound 6a (4.0 mmol), AIBN (0.4 mmol), and n-Bu3SnH (1.5 mmol) were
d
e
Solid; mp (ethanol): 116–118 ꢀC; 1H NMR (300 MHz, CDCl3)
used.
d
8.90–8.75 (m, 1H), 7.21–7.14 (m, 2H), 7.01–6.95 (m, 1H), 6.83–6.80
observed,14c which suggests that radical
9
is one of the
(m, 1H), 4.13 (q, J¼7.1 Hz, 2H), 3.04 (dd, J¼7.8, 6.0 Hz, 1H), 2.77 (dd,
J¼15.5, 9.5 Hz, 1H), 2.66–2.56 (m, 1H), 2.56–2.49 (m, 2H), 2.23–2.10
(m, 1H), 1.90–1.77 (m, 1H), 1.25 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz,
intermediates in the tandem reaction. In this tandem reaction,
the radical 1,4-addition is faster than acylamidation between 6
and 7, hence, 5-exo product was not formed, even when 5i
(entry 9, Table 3) was used as the substrate.11,12
CDCl3) d 173.4, 173.2, 136.8, 128.1, 127.5, 123.0, 115.1, 60.4, 39.2, 31.9,
31.0, 25.0, 14.2; IR (neat): 3439, 3058, 2921, 2854, 1795, 1686, 1107,

W. Zhou et al. / Tetrahedron 65 (2009) 1982–1987
1985
n-Bu3SnH
AIBN
COOEt
I
n-Bu3Sn
NH2
N
R
O
NH2
5a
3a
4a
n-Bu3SnH
n-Bu3SnI
COOEt
COOEt
COOEt
n-Bu3SnH
COOEt
NH2
NH2
NH2
NH2
10
9
7
8
n-Bu3SnH
COOEt
COOEt
6a
N
H
O
11
Scheme 2. The proposed processes for the tandem reaction between 5a and 6a.
965, 759, 694 cmꢃ1; MS (70 eV): m/z (%) 247.4 (Mþ, 2), 146.2 (100);
C14H17NO3: calcd C 68.00, H 6.93, N 5.66; found C 67.86, H 6.93, N
5.66.
MS (70 eV): m/z (%) 219.3 (Mþ, 68), 174.3 (100); C12H13NO3: calcd C
65.74, H 5.98, N 6.39; found C 65.52, H 6.08, N 6.26.
4.6. 3,4-Dihydro-6-cyano-(1H)-quinolin-2-one (3e)
4.3. 3,4-Dihydro-6-methyl-(1H)-quinolin-2-one (3b)
The reaction of 4-cyano-2-iodoaniline (122 mg, 0.5 mmol), 6a
(217 mL, 2 mmol), n-Bu3SnH (201 mL, 0.75 mmol), and AIBN (33 mg,
The reaction of 4-methyl-2-iodoaniline (117 mg, 0.5 mmol), 6a
0.2 mmol) in DMSO (2 mL) afforded 42 mg (49%) of 3e as solid
(After evaporation, a mixture of crystals and liquid was obtained.
The crystals were collected by filtration and washed twice with
EtOAc (2ꢂ4 mL). The filtrate was evaporated and purified by flash
chromatography on silica gel to afford a solid, combine the filtration
residue with this solid; mp (acetone): 276–278 ꢀC; 1H NMR
(217
0.2 mmol) in DMSO (2 mL) afforded 51 mg (63%) of 3b as solid; mp
(ethanol): 130–132 ꢀC; 1H NMR (300 MHz, CDCl3)
8.95–8.75 (br d,
mL, 2 mmol), n-Bu3SnH (201 mL, 0.75 mmol), and AIBN (33 mg,
d
1H), 6.97 (s, 2H), 6.72 (d, J¼8.1 Hz,1H), 2.93 (t, J¼7.4 Hz, 2H), 2.62 (t,
J¼7.4 Hz, 2H), 2.29 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 172.0, 134.8,
132.5, 128.5, 127.9, 123.5, 115.3, 30.8, 25.3, 20.7; IR (neat): 3194,
3073, 2935,1681, 1638, 1506,1378, 1205, 815 cmꢃ1; MS (70 eV): m/z
(%) 161.1 (Mþ, 83), 132.1 (100); C10H11NO: calcd C 74.51, H 6.88, N
8.69; found C 74.31, H 6.67, N 8.57.
(300 MHz, DMSO-d6)
d 10.51 (br s, 1H), 7.64–7.57 (m, 2H), 6.96 (d,
J¼8.1 Hz, 1H), 2.91 (d, J¼7.5 Hz, 2H), 2.49 (t, J¼7.5 Hz, 2H); 13C NMR
(75 MHz, DMSO-d6)
d 170.4, 142.7, 131.7, 131.6, 124.8, 119.3, 115.6,
103.7, 29.7, 24.2; IR (neat): 3451, 3193, 3057, 2959, 2227, 1681, 1611,
1596, 1503, 1372, 1204, 829 cmꢃ1; MS (70 eV): m/z (%) 172.1 (Mþ,
89), 143.0 (100); C10H8N2O: calcd C 69.76, H 4.68, N 16.27; found C
69.52, H 4.67, N 16.01.
4.4. 3,4-Dihydro-6-fluoro-(1H)-quinolin-2-one (3c)
The reaction of 4-fluoro-2-iodoaniline (119 mg, 0.5 mmol), 6a
(217
mL, 2 mmol), n-Bu3SnH (201 mL, 0.75 mmol), and AIBN (33 mg,
4.7. 3,4-Dihydro-6-methoxy-(1H)-quinolin-2-one (3f)
0.2 mmol) in DMSO (2 mL) afforded 43 mg (52%) of 3b as solid; mp
(ethanol): 180–182 ꢀC; 1H NMR (300 MHz, CDCl3)
d 9.45 (br s, 1H),
The reaction of ethyl 4-methoxy-2-iodoaniline (125 mg,
0.5 mmol), 6a (217 mL, 2 mmol), n-Bu3SnH (201 mL, 0.75 mmol), and
6.95–6.78 (m, 3H), 2.96 (t, J¼7.5 Hz, 2H), 2.63 (t, J¼7.5 Hz, 2H); 13C
NMR (75 MHz, CDCl3)
d
172.0, 158.6 (d, J¼240.4 Hz), 133.4, 125.4 (d,
AIBN (33 mg, 0.2 mmol) in DMSO (2 mL) afforded 53 mg (60%) of 3f
as solid; mp (ethanol): 146–148 ꢀC; 1H NMR (300 MHz, CDCl3)
J¼8.0 Hz), 116.5 (d, J¼8.0 Hz), 114.8 (d, J¼22.8 Hz), 114.0 (d,
J¼22.9 Hz), 30.2, 25.4; IR (neat): 3204, 3061, 2983, 2910,1675, 1500,
1422, 1383, 1230, 1196, 868 cmꢃ1; MS (70 eV): m/z (%) 165.1 (Mþ,
76), 136.0 (100); C9H8FNO: calcd C 65.45, H 4.88, N 8.48; found C
65.70, H 5.00, N 8.47.
d
9.31 (br s, 1H), 6.87–6.50 (m, 3H), 3.78 (s, 3H), 2.94 (t, J¼7.4 Hz,
2H), 2.62 (t, J¼7.4 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 171.9, 155.5,
130.8, 124.9, 116.3, 113.7, 112.3, 55.5, 30.6, 25.6; IR (neat): 3439,
3205, 2944, 2908, 1683, 1504, 1428, 1382, 1245, 1149, 1126, 1035,
805 cmꢃ1; MS (70 eV): m/z (%) 177.2 (Mþ, 100); C10H11NO2: calcd C
67.78, H 6.26, N 7.90; found C 67.66, H 6.33, N 7.80.
4.5. Dihydro-6-ethoxycarbonyl-(1H)-quinoline-2-one (3d)
The reaction of 4-ethoxylcarbonyl-2-iodoaniline (146 mg,
4.8. 3,4-Dihydro-7-chloro-(1H)-quinolin-2-one (3g)
0.5 mmol), 6a (217 mL, 2 mmol), n-Bu3SnH (201 mL, 0.75 mmol), and
AIBN (33 mg, 0.2 mmol) in DMSO (2 mL) afforded 64 mg (58%) of 3d
The reaction of 5-chloro-2-iodoaniline (127 mg, 0.5 mmol), 6a
as solid; mp (ethanol): 180–182 ꢀC; 1H NMR (300 MHz, CDCl3)
(217
0.2 mmol) in DMSO (2 mL) afforded 42 mg (46%) of 3g as solid; mp
(ethanol): 194–196 ꢀC; 1H NMR (300 MHz, CDCl3)
9.12 (br s, 1H),
mL, 2 mmol), n-Bu3SnH (201 mL, 0.75 mmol), and AIBN (33 mg,
d
9.76 (br s, 1H), 7.88 (d, J¼8.7 Hz, 1H), 7.87 (s, 1H), 6.91 (d, J¼8.7 Hz,
1H), 4.37 (q, J¼7.2 Hz, 2H), 3.03 (t, J¼7.5 Hz, 2H), 2.70 (t, J¼7.5 Hz,
d
2H), 1.39 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
172.5, 166.1,
7.08 (d, J¼8.0 Hz, 1H), 6.96 (dd, J¼8.0, 2.2 Hz, 1H), 6.85 (d, J¼2.2 Hz,
141.2, 129.4, 125.1, 123.2, 115.2, 60.8, 30.4, 25.0, 14.3; IR (neat): 3434,
1H), 2.94 (t, J¼7.6 Hz, 2H), 2.65 (t, J¼7.6 Hz, 2H); 13C NMR (75 MHz,
2974, 2906, 1710, 1680, 1601, 1509, 1369, 1289, 1251, 1187, 767 cmꢃ1
;
CDCl3) d 172.0, 138.4, 133.0, 128.9, 122.9, 122.0, 115.5, 30.5, 24.8; IR

1986
W. Zhou et al. / Tetrahedron 65 (2009) 1982–1987
(neat): 3197, 3089, 2966, 2903, 1687, 1610, 1590, 1489, 1398, 1373,
1196, 1088, 816 cmꢃ1; MS (70 eV): m/z (%) 181.1 (Mþ, 35Cl, 100),
183.2 (Mþ, 37Cl, 30); C9H8ClNO: calcd C 59.52, H 4.44, N 7.71; found
C 59.50, H 4.69, N 7.54.
7.20–7.13 (m, 2H), 6.98 (t, J¼7.2 Hz, H), 6.84 (d, J¼7.8 Hz, 1H), 3.00
(dd, J¼14.1, 4.5 Hz, 1H), 2.79–2.62 (m, 2H), 1.29 (d, J¼6.6 Hz, 3H);
13C NMR (75 MHz, CDCl3)
d 174.8, 137.2, 128.0, 127.4, 123.5, 122.8,
115.2, 34.9, 33.3, 15.3; IR (neat): 3199, 3071, 2987, 2926, 1667, 1593,
1491, 1391, 1285, 761 cmꢃ1; MS (70 eV): m/z (%) 161.2 (Mþ, 100);
C10H11NO: calcd C 74.51, H 6.88, N 8.69; found C 74.33, H 6.86,
N 8.65.
4.9. 3,4-Dihydro-(1H)-1,7-naphthyridin-2-one (3h)
The reaction of 3-amino-4-iodopyridine (110 mg, 0.5 mmol), 6a
(217 mL, 2 mmol), n-Bu3SnH (201 mL, 0.75 mmol), and AIBN (33 mg,
4.14. 3-Benzyl-3,4-dihydro-(1H)-quinolin-2-one (3m)
0.2 mmol) in DMSO (2 mL) was heated for 24 h to afford 17 mg
(23%) of 3h as solid; mp (ethyl acetate): 194–196 ꢀC; 1H NMR
The reaction of 2-iodoaniline (109 mg, 0.5 mmol), 6f (380 mg,
(300 MHz, CDCl3)
1H), 7.12 (d, J¼4.6 Hz, 1H), 3.01 (t, J¼7.6 Hz, 2H), 2.69 (t, J¼7.6 Hz,
2H); 13C NMR (75 MHz, CDCl3)
171.5, 144.5, 136.7, 134.6, 132.0,
d
9.48 (br s, 1H), 8.26 (d, J¼4.6 Hz, 1H), 8.23 (s,
2 mmol), n-Bu3SnH (201 mL, 0.75 mmol), and AIBN (33 mg,
0.2 mmol) in DMSO (2 mL) was heated for 17 h to afford 52 mg
(44%) of 3m as solid; mp (ethanol): 114–116 ꢀC; 1H NMR (300 MHz,
d
122.5, 29.8, 24.7; IR (neat): 3190, 3091, 2963, 2885, 1700, 1645, 1611,
1580, 1491, 1404, 1381, 1338, 1272, 1199, 912, 827 cmꢃ1; MS (70 eV):
m/z (%) 148.3 (Mþ, 100); C8H8N2O: calcd C64.85, H 5.44, N 18.91;
found C 64.74, H 5.31, N 18.70.
CDCl3)
d
8.86–8.76 (br d, 1H), 7.35–7.16 (m, 6H), 7.80 (d, J¼7.2 Hz,
1H), 6.98 (t, J¼7.4 Hz, 1H), 6.84 (d, J¼7.8 Hz, 1H), 3.34 (dd, J¼13.6,
3.7 Hz, 1H), 2.89–2.78 (m, 2H), 2.70–2.58 (m, 2H); 13C NMR
(75 MHz, CDCl3)
d 173.4, 138.9, 136.9, 129.2, 128.5, 128.4, 127.5,
126.4, 123.1,123.0,115.1, 41.8, 35.3, 29.4; IR (neat): 3210, 3106, 3063,
3025, 2997, 2941, 1676, 1596, 1494, 1391, 1294, 752, 697 cmꢃ1; MS
(70 eV): m/z (%) 237.3 (Mþ, 53), 146.2 (100); C16H15NO: calcd C
80.98, H 6.37, N 5.90; found C 80.80, H 6.15, N 5.96.
4.10. N-Methyl-3,4-dihydroquinolin-2-one (3i16
)
The reaction mixture of 2-iodo-N-methylaniline (117 mg,
0.5 mmol), 6a (217 L, 2 mmol), n-Bu3SnH (201 L, 0.75 mmol), and
AIBN (33 mg, 0.2 mmol) in DMSO (2 mL) was heated for 36 h to
afford 36 mg (45%) of 3i as liquid; 1H NMR (300 MHz, CDCl3)
7.29–
m
m
4.15. 3-Phenyl-3,4-dihydro-(1H)-quinolin-2-one (3n)
d
7.82 (m, 1H), 7.17 (d, J¼7.5 Hz, 1H), 7.05–6.96 (m, 2H), 3.36 (s, 3H),
The reaction of 2-iodoaniline (109 mg, 0.5 mmol), 6g (352 mg,
2.91 (t, J¼7.3 Hz, 2H), 2.65 (t, J¼7.3 Hz, 2H); 13C NMR (75 MHz,
2 mmol), n-Bu3SnH (201
0.2 mmol) in DMSO (2 mL) for 17 h afforded 29 mg (26%) of 3n as
solid; mp (ethanol): 174–176 ꢀC; 1H NMR (300 MHz, CDCl3)
9.08
mL, 0.75 mmol), and AIBN (33 mg,
CDCl3) d 170.5, 140.6, 127.7, 127.4, 126.2, 122.7, 114.6, 31.7, 29.5, 25.4;
IR (neat): 2923, 1676, 1602, 1472, 1367, 1131, 756 cmꢃ1; MS (70 eV):
d
m/z (%) 161.3 (Mþ, 57), 118.2 (100).
(br s, 1H), 7.32–7.14 (m, 7H), 6.99 (t, J¼7.4 Hz, 1H), 6.81 (d, J¼7.8 Hz,
1H), 3.88 (t, J¼7.8 Hz, 1H), 3.30–3.00 (m, 2H); 13C NMR (75 MHz,
4.11. 3,4-Dihydro-6-amino-7-iodo-(1H)-quinolin-2-one (3j)
CDCl3)
d 172.3, 138.4, 137.0, 128.7, 128.1, 128.0, 127.6, 127.3, 123.2,
115.4, 46.5, 33.5; IR (neat) 3218, 3065, 3029, 2944, 1680, 1597, 1492,
1379, 1268, 751 cmꢃ1; MS (70 eV): m/z (%) 223.4 (Mþ, 100);
C15H13NO: calcd C 80.69, H 5.87, N 6.27; found C 80.40, H 5.71,
N 6.15.
The reaction of 2,5-diiodobenzene-1,4-diamine (180 mg,
0.5 mmol), 6a (434 mL, 4 mmol), n-Bu3SnH (404 mL, 1.5 mmol), and
AIBN (66 mg, 0.4 mmol) in DMSO (2 mL) afforded 52 mg (36%) of 3j
as solid; mp (ethanol): 196–198 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
9.74 (br s, 1H), 7.04 (s, 1H), 6.58 (s, 1H), 4.84 (br s, 2H), 2.69 (t,
Acknowledgements
J¼7.4 Hz, 2H), 2.33 (t, J¼7.4 Hz, 2H); 13C NMR (75 MHz, DMSO-d6)
d
169.4, 143.5, 129.9, 125.4, 124.0, 113.6, 80.2, 30.4, 24.9; IR (neat):
Financial support from Peking University and National Science
Foundation of China (Nos. 20702002 and 20872003) and the Ph.D.
Programs Foundation of Ministry of Education of China (No.
20070001808) are greatly appreciated.
3405, 3321, 3179, 3036, 2939, 1655, 1497, 1399, 1261, 1195, 872,
678 cmꢃ1; MS (70 eV): m/z (%) 288.1 (Mþ, 100); C9H9IN2O: calcd C
37.52, H 3.15, N 9.72; found C 37.62, H 3.29, N 9.61.
4.12. Benzyl (2-oxo-3,4-dihydro-(1H)-quinolin-3-yl)
acetate (3k)
Supplementary data
Experimental details and NMR spectra are available as Supple-
mentary data. Supplementary data associated with this article can
be found in the online version, at doi:10.1016/j.tet.2009.01.027.
The reaction of 2-iodoaniline (109 mg, 0.5 mmol), 6d (620 mg,
2 mmol), n-Bu3SnH (201
0.2 mmol) in DMSO (2 mL) afforded 79 mg (54%) of 3k as solid; mp
(ethanol): 146–148 ꢀC; 1H NMR (300 MHz, CDCl3)
9.15 (br s, 1H),
mL, 0.75 mmol), and AIBN (33 mg,
d
References and notes
7.40–7.20 (m, 5H), 7.20–7.09 (m, 2H), 6.98 (d, J¼7.5 Hz, 1H), 6.80 (d,
J¼7.8 Hz, 1H), 5.23–5.12 (m, 2H), 3.16–2.78 (m, 4H), 2.54(dd, J¼18,
1. For leading reviews, see: (a) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev.
1996, 96, 195–206; (b) Tietze, L. F.; Modi, A. Med. Res. Rev. 2000, 20, 304–322;
(c) Mueller, T. J. J.; D’Souza, D. M. Pure Appl. Chem. 2008, 80, 609–620.
2. (a) Takai, K.; Matsukawa, N.; Takahashi, A.; Fujii, T. Angew. Chem., Int. Ed. 1998,
37, 152–155; (b) Bazin, S.; Feray, L.; Siri, D.; Naubron, J.-V.; Bertrand, M. P. Chem.
Commun. 2002, 2506–2507; (c) Ueda, M.; Miyabe, H.; Sugino, H.; Miyata, O.;
Naito, T. Angew. Chem., Int. Ed. 2005, 44, 6190–6193; (d) Godineau, E.; Landais, Y.
J. Am. Chem. Soc. 2007, 129, 12662–12663.
3. (a) Hayashi, H.; Miwa, Y.; Miki, I.; Ichikawa, S.; Yoda, N.; Ishii, A.; Kono, M.; Su-
zuki, F. J. Med. Chem.1992, 35, 4893–4902; (b) Carling, R. W.; Leeson, P. D.; Moore,
K. W.; Smith, J. D.; Moyes, C. R.; Mawer, I. M.; Thomas, S.; Chan, T.; Baker, R.;
Foster, A. C.; Grimwood, S.; Kemp, J. A.; Marshall, G. R.; Tricklebank, M. D.;
Saywell, K. L. J. Med. Chem. 1993, 36, 3397–3408; (c) Jones, G. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F., Eds.; Perga-
mon: Oxford, UK,1996; pp 167; (d) Patel, M.; McHugh, R. J.; Cordova, B. C.; Klabe,
R. M.; Bacheler, L. T.; Erickson-Viitanen, S.; Rodgers, J. D. Bioorg. Med. Chem. Lett.
2001,11 1943–1945; (e) Uchida, R.; Imasato, R.; Shiomi, K.; Tomoda, H.; Omura, S.
Org. Lett. 2005, 7, 5701–5704; (f) Turner, K. L.; Baker, T. M.; Islam, S.; Procter, D. J.;
9 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 172.5, 171.8, 137.0, 135.8,
128.5, 128.1, 127.9, 127.6, 123.1, 123.0, 115.3, 66.5, 36.7, 34.4, 31.0; IR
(neat): 3198, 3063, 2923, 1726, 1669, 1595, 1492, 1383, 1351, 1278,
1187, 1174, 1158, 742 cmꢃ1; MS (70 eV): m/z (%) 295.3 (Mþ, 2), 146.3
(100); C18H17NO3: calcd C 73.20, H 5.80, N 4.74; found C 73.31, H
5.76, N 4.66.
4.13. 3,4-Dihydro-3-methyl-(1H)-quinolin-2-one (3l)
The reaction of 2-iodoaniline (109 mg, 0.5 mmol), 6e (214
2 mmol), n-Bu3SnH (201 L, 0.75 mmol), and AIBN (33 mg,
0.2 mmol) in DMSO (2 mL) afforded 60 mg (75%) of 3l as solid; mp
(ethanol): 134–136 ꢀC; 1H NMR (300 MHz, CDCl3)
9.03 (br s, 1H),
mL,
m
d

W. Zhou et al. / Tetrahedron 65 (2009) 1982–1987
1987
Stefaniak, M. Org. Lett. 2006, 8, 329–332; (g) Harmata, M.; Hong, X. Org. Lett.
2007, 9, 2701–2704.
4. For a review, see: Larsen, R. D. In Science of Sythesis; Black, D. S., Ed.; Georg
Thieme: Sttuggart, New York, NY, 2005; Vol. 15, p 551.
10. For recent reviews, see: (a) Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I.
Chem. Rev. 1999, 99, 1991–2070; (b) Gansa¨uer, A.; Bluhm, H. Chem. Rev. 2000,
100, 2771–2788; (c) Rheault, T. R.; Sibi, M. P. Synthesis 2003, 803–819; (d) Sibi,
M. P.; Manyem, S.; Zimmerman, J. Chem. Rev. 2003, 103, 3263–3296.
5. For some recent results, see: (a) Kadnikov, D. V.; Larock, R. C. J. Org. Chem. 2004,
69, 6772–6780; (b) Marcaccini, S.; Pepino, R.; Pozo, M. C.; Basurto, S.; Garcı´a-
Valverdeb, M.; Torrobab, T. Tetrahedron Lett. 2004, 45, 3999–4001; (c) Asahara,
M.; Katayama, T.; Tohda, Y.; Nishiwaki, N.; Ariga, M. Chem. Pharm. Bull. 2004, 52,
1334–1338; (d) Park, K. K.; Jung, J. Y. Heterocycles 2005, 65, 2095–2105; (e)
Bernini, R.; Cacchi, S.; Fabrizi, G.; Sferrazza, A. Heterocycles 2006, 69, 99–105; (f)
Battistuzzi, G.; Bernini, R.; Cacchi, S.; Salve, I. D.; Fabrizi, G. Adv. Synth. Catal.
2007, 349, 297–302; (g) Kobayashi, Y.; Kamisaki, H.; Takeda, H.; Yasui, Y.; Ya-
nada, R.; Takemoto, Y. Tetrahedron 2007, 63, 2978–2989 and references therein.
6. (a) Jones, G. In Comprehensive Heterocyclic Chemistry; Boulton, A. J., McKillop, A.,
Eds.; Pergamon: Oxford, UK, 1984; Vol. 2; (b) Cherest, M.; Lusinchi, X. Tetra-
hedron Lett. 1989, 30, 715–718; (c) Li, K.; Foresee, L. N.; Tunge, J. A. J. Org. Chem.
2005, 70, 2881–2883.
7. (a) Cortese, N. A.; Heck, R. F. J. Org. Chem. 1977, 42, 3491–3494; (b) Entwistle,
I. D. Tetrahedron Lett. 1979, 6, 555–559; (c) Roschchin, A. L.; Bumagin, N. A.;
Beletskaya, I. P. Tetrahedron Lett. 1995, 36, 125–128; (d) Ali, B. E.; Okuro, K.;
Vasapollo, G.; Alper, H. J. Am. Chem. Soc. 1996, 118, 4264–4270; (e) Orejon, A.;
Alper, H. J. Mol. Catal., A 1999, 143, 137–142; (f) Dong, C.; Alper, H. J. Org. Chem.
2004, 69, 5011–5014; (g) Ye, F.; Alper, H. Adv. Synth. Catal. 2006, 348, 1855–1861.
8. Fujita, K.; Takahashi, Y.; Owaki, M.; Yamamoto, K.; Yamaguchi, R. Org. Lett. 2004,
6, 2785–2788.
11. For some recent results, see: (a) Bowman, W. R.; Heaney, H.; Jordan, B. M.
Tetrahedron Lett. 1988, 29, 6657–6660; (b) Axon, J.; Boiteau, L.; Boivin, J.;
Forbes, J. E.; Zard, S. Z. Tetrahedron Lett. 1994, 35, 1719–1722; (c) Jones, K.;
Wilkinson, J.; Ewin, R. Tetrahedron Lett. 1994, 35, 7673–7676; (d) Boivin, J.;
Yousfi, M.; Zard, Z. Tetrahedron Lett. 1994, 35, 9553–9556; (e) Davies, D. T.;
Kapur, N.; Parsons, A. F. Tetrahedron Lett. 1999, 40, 8615–8618; (f) Khan, T. A.;
Tripoli, R.; Crawford, J. J.; Martin, C. G.; Murphy, J. A. Org. Lett. 2003, 5, 2971–
2974; (g) Ohno, H.; Iwasaki, H.; Eguchi, T.; Tanaka, T. Chem. Commun. 2004,
2228–2229; (h) Akamatsu, H.; Fukase, K.; Kusumoto, S. Synlett 2004, 1049–
1053; (i) Murphy, J. A.; Khan, T. A.; Zhou, S.-Z.; Thomson, D. W.; Mahesh, M.
Angew. Chem., Int. Ed. 2005, 44, 1356–1360; (j) Nishio, T.; Iseki, K.; Araki, N.;
Miyazaki, T. Helv. Chim. Acta 2005, 88, 35–41.
12. Restricted rotation around the carbonyl carbon–nitrogen bond can effect the
cylization reactions. Tertiary amides in the linking chain favor the s-cis confor-
mation leading to annulation products, while secondary amides favor s-trans
conformation failing the cyclization reaction, see: (a) Hey, D. H.; Jones, G. H.;
Perkins, M. J. J. Chem. Soc. C 1971,116–122; (b) Jones, K.; Thompson, M.; Wright, C.
J. Chem. Soc., Chem. Commun.1986,115–116; (c) Jones, K.; McCarthy, C. Tetrahedron
Lett. 1989, 30, 2657–2660; (d) Liu, L.; Wang, X.; Li, C. Org. Lett. 2003, 5, 361–363.
13. (a) Clark, A. J.; Jones, K.; McCarthy, C.; Storey, J. M. D. Tetrahedron Lett. 1991, 32,
2829–2832; (b) Minin, P. L.; Walton, J. C. J. Org. Chem. 2003, 68, 2960–2963; (c)
De Turiso, F. G.-L.; Curran, D. P. Org. Lett. 2005, 7, 151–154.
9. (a) Giese, B. Radicals in Organic Synthesis: Formation of Carbon–Carbon Bonds;
Pergamon: Oxford, UK, 1986; (b) Curran, D. P. In Comprehensive Organic Syn-
thesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 4, pp 715–
831; (c) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions;
Wiley-VCH: Wieinheim, Germany, 1996; (d) Renaud, P.; Sibi, M. P. Radicals in
Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2001.
14. (a) Rondestvedt, C. R. Org. React. 1976, 24, 225–259; (b) Heinrich, M. R.; Wetzel,
A.; Kirschstein, M. Org. Lett. 2007, 9, 3833–3835; (c) Miura, K.; Tomita, M.;
Ichikawa, J.; Hosomi, A. Org. Lett. 2008, 10, 133–136.
15. Liu, B.; Hu, L. Bioorg. Med. Chem. 2003, 11, 3889–3899.
16. Venkov, A. P.; Statkoba-Abeghe, S. M. Tetrahedron 1996, 52, 1451–1460.