Facile access to 2-arylindolines and 2-arylindoles by microwave-assisted tandem radical cyclization

Article abstract of DOI:10.1055/s-2008-1067154

A new route providing access to 2-arylindoles has been developed. The synthesis consists of a tin-mediated tandem radical cyclization of appropriate precursors to form 2,3-disubstituted dihydroindoles, which in turn are oxidized to yield the corresponding 2-arylindoles. The reactions proceed smoothly under microwave irradiation, furnishing the desired products in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067154

PAPER
2191
Facile Access to 2-Arylindolines and 2-Arylindoles by Microwave-Assisted
Tandem Radical Cyclization
M
icrowa
n
ve-Assiste
d
g
T
ande
m
Rad
a
ica
l
Cyclization Prediger, Torsten Weiss, Oliver Reiser*
Institute of Organic Chemistry, University of Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany
Fax +49(941)9434121; E-mail: Oliver.Reiser@chemie.uni-regensburg.de
Received 21 April 2008
Dedicated to Prof. Reinhard W. Hoffmann on the occasion of his 75th birthday
CO2Et
CO2Et
Ar
Abstract: A new route providing access to 2-arylindoles has been
developed. The synthesis consists of a tin-mediated tandem radical
cyclization of appropriate precursors to form 2,3-disubstituted dihy-
droindoles, which in turn are oxidized to yield the corresponding 2-
arylindoles. The reactions proceed smoothly under microwave irra-
diation, furnishing the desired products in good yields.
R
R
R
Ar
N
N
R
PG
PG
3
4
Ar = (substituted) (hetero)aryl moiety
R = H, OMe
Key words: indoles, cyclizations, heterocycles, radical reactions,
dehydrogenations, microwave irradiation
R
R
CO2Et
Br
N
Ar
The indole moiety is a privileged scaffold in medicinal
chemistry, being present in a wide range of biologically
active natural and artificial compounds.1 Recently, a
novel class of highly selective ERa ligands (SERAMs)
5
PG
Scheme 2
such as 1 derived from the 2-(2-phenyl-1H-indol-3- ring closure (Scheme 2), a synthetic method that was pio-
yl)acetic acid moiety 2 as a crucial building block was dis- neered by Parsons et al. for the synthesis of mitomycins.9
closed, with this key intermediate having potential utiliza-
Anilines 8 were readily synthesized in high yields from
commercially available 2-nitrobenzaldehydes 6, which
formed acrylates 7 by a Horner–Wadsworth–Emmons re-
tion as a lead structure towards the treatment of breast
cancer (Scheme 1).2
To date, several elegant methods for assembling 2-arylin- action with triethyl a-bromophosphonoacetate generated
dol-3-ylacetic acids have been established. These strate- in situ (Scheme 3). Subsequent reduction of the thus
gies consist of transition-metal-assisted intermolecular formed acrylates 7 with iron powder under acidic condi-
annulation and concomitant derivatization,3 cyclization of tions following a literature procedure4,9 gave anilines 8
imidoyl radicals4 in combination with arylations,5 twofold (Scheme 3).
elimination protocols of vinyl sulfones,6 base-catalyzed
The direct monobenzylation of 8 by reaction with benzyl
bromide failed: a complex mixture of unchanged starting
material, and dibenzylated product along with the desired
cyclization exploiting umpolung of imines,7 or the Fischer
indolization approach.8
We report here a different approach that allows the direct monobenzylated product was observed. To circumvent
synthesis of 2-(2-arylindol-3-yl)acetic acid derivatives 3 this lack of selectivity, the introduction of an appropriate
as well as their corresponding indoline derivatives 4 from protecting group was first necessary. For this, aniline 8
3-(2-aminophenyl)acrylates 5 by tandem radical cycliza-
tion involving 1,6-hydrogen transfer followed by 5-exo
R
CHO
R
CO2Et
a
Br
NO2
R
NO2
R
CH3
O
6
7
CO2H
Ph
Ar
N
H
R
R
CO2Et
R
R
CO2Et
c
b
Ph
N
N
H
Br
NH2
Br
H
NH
CO2Me
2
1
8
9
a: R = H
b: R = OMe
Scheme 1
Scheme 3 Reagents and conditions: (a) NaH (1.4 equiv), triethyl a-
bromophosphonoacetate (1.3 equiv), THF, 0 °C, 5.5 h [95% (7a),
75% (7b)]; (b) Fe (3.5 equiv), EtOH/HCl, reflux, 2 h [86% (8a), 56%
(8b)]; (c) ClCO2Me (1.4 equiv), py (3 equiv), DMF, 40 °C, 4 h [91%
(9a), 85% (9b)].
SYNTHESIS 2008, No. 14, pp 2191–2198
Advanced online publication: 02.07.2008
DOI: 10.1055/s-2008-1067154; Art ID: C01308SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8

2192
I. Prediger et al.
PAPER
Table 1 Preparation of Precursors 10a–h for Radical Cyclizationa
Entry
Product 10
10a
R
H
H
H
H
H
H
H
Ar
Yield (%)
1
2
3
4
5
6
7
8
Ph
91
88
93
89
90
72
76
88
10b
3-ClC6H4
4-O2NC6H4
PMP
10c
10d
10e
3-MeOC6H4
Naph
10f
10g
2-furyl
10h
OMe Ph
a Reagents and conditions: LiOH (1.5 equiv), TBAB (0.1 equiv),
ArCH2Br (2 equiv), DMF, 40 °C, 4 h.
R
R
CO2Et
R
R
CO2Et
Br
ArCH2Br
Br
LiOH, TBAB
DMF
NH
CO2Me
N
Ar
Scheme 5
CO2Me
9
10
sides starting material, small amounts of products
containing a reduced nitro group could be detected in the
crude reaction mixture. Performing the cyclization under
microwave heating in an open vessel resulted in some
shortening of the reaction time (3.5 h instead of 5 h for
complete consumption of starting material), but, more im-
portantly, yields were significantly improved to 76–89%
(Table 2, entries 2,4,7). Consequently, these conditions
were also applied for the cyclization of 10e–h to give the
corresponding indolines 14e–h in 25–73% yield (Table 2,
entries 8–11).
Scheme 4
was initially N-Boc-protected; however, the successive
benzylation produced only small amounts of desired prod-
uct, presumably due to the steric effects of the space-
demanding protecting group. Therefore, the methoxycar-
bonyl group (Moc) was introduced by reaction of 8 with
methyl chloroformate to give 9 in very good yield [91%
(9a), 85% (9b)] (Scheme 3).
After careful optimization of the reaction conditions, the
thus-protected anilines 9 could be successfully alkylated
with a broad variety of benzyl bromides under phase-
transfer conditions using lithium hydroxide/tetrabutylam-
monium bromide in N,N-dimethylformamide (Scheme 4,
Table 1). Weaker bases such as potassium carbonate or
triethylamine proved to be less effective, while the utiliza-
tion of stronger bases like sodium hydride was avoided
due to the danger of possible elimination of hydrogen bro-
mide from the bromoacrylate. This was already observed
in part when the reaction temperature was increased to
above 45 °C when lithium hydroxide was used as base,
but, on the other hand, decreasing the reaction tempera-
ture to room temperature led to significantly reduced
yields even if the reaction time was extended to 24 hours.
The cis/trans ratios of indolines 14 (Scheme 5, Table 2)
were determined by 1H NMR spectroscopy, with the final
assignments accomplished by NOESY experiments. Dia-
stereomers of 14a–e could be separated by crystallization
of the product mixture, and the cis-diastereomer of 14b
could be additionally characterized by X-ray crystallogra-
phy (Scheme 5).11 The cis-diastereomers of 14 are kineti-
cally favored (Table 2),12 and thus formed predominantly
(cis/trans ca. 2:1) in the course of the reaction, with the
exception being naphthyl derivative 14f, which was ob-
tained in a reversed cis/trans diastereoselectivity (1:3), al-
beit in low yields of 25% along with reduced but
uncyclized starting material (Table 2, entry 9). This may
be a consequence of a relatively long lifetime of the un-
cyclized radical intermediate 12f (cf. Scheme 5) stabi-
lized by the adjacent naphthyl group, leading to a
preferred formation of the sterically less hindered, but
thermodynamically favored trans-diastereomer.
Compounds 10a–d were submitted to radical cyclization
mediated by tributyltin hydride (Scheme 5), which was
carried out initially under refluxing toluene conditions,
with a low concentration of tributyltin hydride in the reac-
tion mixture maintained by the addition of this reagent via
a syringe pump over two hours; for this, a protocol that
has proved successful for a related tandem radical cycliza-
tion to dihydrobenzofurans was followed.10 The reaction
furnished 2,3-disubstituted indolines 14a,b,d in yields of
62–76% (Table 2, entries 1,3,6), but no cyclization oc-
curred with substrate 10c (entry 5). In the latter case, be-
The transformation of indolines 14 into the desired 2-
arylindoles 15 (Scheme 6) was investigated with several
dehydrogenation reagents13 (Table 3), of which 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone proved to be
most effective, with respect to yields as well as ease of
workup and purification of the products (Table 3, entries
Synthesis 2008, No. 14, 2191–2198 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Tandem Radical Cyclization
2193
Table 2 Radical Cyclization of 10a–h to 2,3-Substituted Indolines
14a–h
Table 3 Conditions for the Dehydrogenation of Indoline 14a to In-
dole 15a
Entry Condi- Indoline
R
Ar
Yield Ratio
Entry Reaction conditions
Yield (%)
tionsa 14
(%)
cis/trans
1
2
3
4
5
6
DDQ (2 equiv), benzene, 50 °C, 2 d
48
63
11
53
32
66
1
2
A
B
A
B
A
A
B
B
B
B
B
14a
14a
14b
14b
14c
14d
14d
14e
14f
H
H
H
H
H
H
H
H
H
H
Ph
71
66:34
66:36
67:33
64:36
–
DDQ (2 equiv), toluene, reflux, 5 d
Mn2O (10 equiv), benzene, reflux, 2 d
NBS (1.5 equiv), CCl4, reflux, 12 h
CAN (2 equiv), MeCN–H2O, 70 °C, 3 h
Ph
86
3
3-ClC6H4
3-ClC6H4
4-O2NC6H4
PMP
62
4
76
b
5
–
DDQ (2 equiv), toluene, sealed
vessel, 120 °C, MW, 4 h
6
76
89
63:37
60:40
60:40
25:75
67:33
59:41
7
PMP
8
3-MeOC6H4 73
Table 4 Microwave-Induced, 2,3-Dichloro-5,6-dicyano-1,4-benzo-
quinone-Promoted Aromatization of Indolines 14 to Indoles 15a
9
Naph
25
68
64
10
11
14g
2-furyl
Entry Starting
material 14a
Product 15 R
Ar
Yield
(%)
14h
OMe Ph
1
2
3
4
5
6
7
14a
15a
15b
15c
15d
15e
15f
H
Ph
66
60
61
60
55
a Reagents and conditions: Bu3SnH (1.4 equiv), AIBN (2 × 0.25
equiv), toluene; Method A: reflux, 5 h; Method B: open vessel, 100–
105 °C, microwave (2.45 GHz), 3.5 h.
14b
14d
14e
14f
H
3-ClC6H4
PMP
b No cyclized product was obtained, only partially reduced acyclic
products were observed.
H
H
3-MeOC6H4
Naph
CO2Et
Ar
CO2Et
Ar
H
R
R
R
R
oxidation
b
14g
H
2-furyl
Ph
–
N
N
Moc
14h
15g
OMe
69
Moc
14
15
a Reagents and conditions: DDQ (2 equiv), toluene, sealed vessel,
120 °C, MW, 4 h.
Scheme 6
b Decomposition, only small amounts of product 15f.
1, 2, and 6). Treatment of 14a with 2,3-dichloro-5,6-dicy-
ano-1,4-benzoquinone in benzene at 50 °C for two days
provided the desired indole 15a in 48% yield along with
unchanged, exclusively trans-configured starting material
14a (25%) (Table 3, entry 1). Because of the obvious low-
er reactivity of the trans-diastereomer towards aromatiza-
tion, the reaction temperature was increased by changing
the solvent to toluene. The reaction was carried out at re-
flux temperature for five days until no starting material
could be detected by TLC, and 15a was isolated in 63%
yield (Table 3, entry 2). Further improvements were pos-
sible by carrying out this transformation under microwave
heating in a sealed vessel at 120 °C, resulting again in
slightly improved yields, but, moreover, the reaction time
could be shortened to four hours (Table 3, entry 6). Under
the same conditions, indolines 14b,d–h were also subject-
ed to dehydrogenation, and, with the exception of furyl
derivative 14g, smoothly yielded the corresponding in-
doles 15b–e,g (Scheme 6, Table 4).
All nonaqueous reactions were carried out in oven-dried glassware
under N2. Toluene and benzene were distilled from Na. THF was
distilled from Na/benzophenone ketyl under N2. All other reagents
were commercially available and were used without further purifi-
cation. Preparative flash chromatography was performed on Silica
1
Gel 60 (Merk Geduran 60, 0.063–0.200 mm). H and 13C NMR
spectra were recorded on Bruker Avance 300, 400, and 600 instru-
ments; CDCl3 or DMSO-d6 was used as solvent. IR spectra were re-
corded on an FT IR spectrometer (Excalibur Series FT3000MX),
melting points were recorded on a Büchi-SMP-20 apparatus and are
uncorrected, HRMS was performed on Varian MAT 311A, Finni-
gan MAT95, and Thermoquest Finnigan TSQ 7000 spectrometers,
and elemental analysis was carried out on a Vario EL III or Mikro-
Rapid CHN (Heraeus) instrument. Microwave-assisted reactions
were performed in a CEM Focused Microwave Synthesis System,
Discover. Reactions were monitored by TLC on Merck 60 F254 sili-
ca gel TLC plates. Spots were visualized by UV light at 254 and 356
nm. All solvents used for column chromatography were distilled.
2-Bromo-3-(2-nitrophenyl)acrylates 7; General Procedure
A 60% suspension of NaH in fuel oil (3.7 g, 92.6 mmol, 1.40 equiv)
was added to THF (50 mL) at 0 °C under N2. (EtO)2P(O)CH2CO2Et
(18.08 g, 86.1 mmol, 1.30 equiv) dissolved in THF (30 mL) was
added dropwise over 15 min, and stirring of the resulting mixture
continued for 45 min. Br2 (14.29 g, 89.4 mmol, 1.35 equiv) was add-
In conclusion, a facile method for the synthesis of the (2-
arylindol-3-yl)acetic acid moiety, representing a potential
lead structure for the development of drugs against breast
cancer, could be developed.
Synthesis 2008, No. 14, 2191–2198 © Thieme Stuttgart · New York

2194
I. Prediger et al.
PAPER
ed dropwise over 15 min, and stirring of the reaction mixture con-
tinued for 30 min at 0 °C. A 60% suspension of NaH in fuel oil (3.7
g, 92.6 mmol, 1.40 equiv) was added over 20 min, and stirring con-
tinued for 1 h at 0 °C. 2-Nitrobenzaldehyde 6 (66.17 mmol, 1.0
equiv) dissolved in THF (20 mL) was added and the reaction mix-
ture was slowly warmed to r.t. and stirred for 5.5 h. Sat. aq NH4Cl
(15 mL) was added and the mixture was extracted with Et2O (3 × 50
mL). The combined organic phases were washed with brine (30
mL), dried (Na2SO4), filtered, and concentrated. The crude product
was recrystallized from i-PrOH (25 mL) to give pale yellow crystals
of 7.
J = 0.9, 7.5 Hz, 1 H, CH), 7.63 (dd, J = 0.9, 7.5 Hz, 1 H, CH), 8.16
(s, 1 H, CH).
13C NMR (75.5 MHz, CDCl3): d = 13.2 (CH3), 61.8 (CH2), 114.6
(C), 115.0 (CH), 117.2 (CH), 118.8 (C), 128.3 (CH), 129.9 (CH),
136.4 (CH), 143.9 (C), 162.2 (C).
MS (EI, 70 eV): m/z (%) = 270.9 (18) [M+], 269.0 (16) [M]+, 226.0
(24) [M – OCH2CH3]+, 223.9 (26) [M – OCH2CH3]+, 144.0 (100)
[M – OCH2CH3,Br] +.
Ethyl (Z)-3-(2-Amino-4,5-dimethoxyphenyl)-2-bromoacrylate
(8b)
Yield: 4.71 g (56%); mp 219 °C; Rf = 0.3 (hexanes–EtOAc, 3:1).
Ethyl (Z)-2-Bromo-3-(2-nitrophenyl)acrylate (7a)
Yield: 18.9 g (95%); mp 61–62 °C; Rf = 0.4 (hexanes–EtOAc, 5:1).
IR (KBr): 567, 602, 756, 841, 911, 1003, 1155, 1244, 1400, 1447,
1508, 1623, 1655, 2789, 2897, 2976, 3136 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.37 (t, J = 7.1 Hz, 3 H, CH3),
3.67–3.80 (s, 2 H, NH2), 3.83 (s, 3 H, OCH3), 3.92 (s, 3 H, OCH3),
3.95 (s, 3 H, OCH3), 4.36 (q, J = 7.1 Hz, 2 H, CH2), 6.29 (s, 1 H,
CH), 7.49 (s, 1 H, CH), 8.19 (s, 1 H, CH).
13C NMR (75.5 MHz, CDCl3): d = 14.3 (CH3), 55.8 (CH3), 56.4
(CH3), 62.6 (CH2), 100.3 (CH), 111.0 (C), 111.8 (C), 112.1 (CH),
114.1 (C), 114.7 (CH), 152.1 (C), 163.6 (C).
IR (KBr): 621, 691, 751, 868, 1038, 1245, 1276, 1340, 1470, 1570,
1602, 1622, 1719, 2936, 2995, 3062 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.40 (t, J = 7.1 Hz, 3 H, CH3),
4.38 (q, J = 7.1 Hz, 2 H, CH2), 7.56–7.62 (m, 1 H, CH), 7.64 (d,
J = 7.2 Hz, 1 H, CH), 7.73 (dd, J = 1.2, 7.4 Hz, 1 H, CH), 8.21 (dd,
J = 1.2, 8.2 Hz, 1 H, CH), 8.49 (s, 1 H, CH).
13C NMR (75.5 MHz, CDCl3): d = 14.2 (CH3), 63.1 (CH2), 117.4
(C), 124.9 (CH), 129.9 (CH), 131.0 (C), 131.2 (CH), 133.6 (CH),
139.1 (CH), 147.0 (C), 162.3 (C).
MS (EI, 70 eV): m/z (%) = 329.0 (10) [M]+, 284.0 (100) [M –
OCH2CH3]+, 270.0 (46) [M – OCH2CH3, CH3]+.
MS (EI, 70 eV): m/z (%) = 301.1 (2) [M]+, 220.1 (17) [M – Br]+,
29.3 (100) [C2H5]+.
2-Bromo-3-{2-[(methoxycarbonyl)amino]phenyl}acrylates 9;
General Procedure
Ethyl (Z)-2-Bromo-3-(4,5-dimethoxy-2-nitrophenyl)acrylate
To a soln of 8 (14.81 mmol, 1.0 equiv) in DMF (15 mL) was added
pyridine (3.51 g, 44.42 mmol, 3 equiv) and ClCO2Me (1.96 g, 20.73
mmol, 1.4 equiv). The mixture was heated to 40 °C for 4 h, subse-
quently diluted with EtOAc (35 mL) and sat. aq NH4Cl (10 mL),
and extracted with EtOAc (3 × 20 mL). The combined organic
phases were dried (Na2SO4), filtered, and concentrated. The crude
mixture was purified by chromatography (silica gel, hexanes–
EtOAc, 3:1); this gave pale yellow solid 9.
(7b)
Yield: 17.9 g (75%); mp 137–138 °C; Rf = 0.3 (hexanes–EtOAc,
5:1).
IR (KBr): 613, 749, 787, 868, 985, 1045, 1219, 1282, 1329, 1513,
1725, 2854, 2945, 2993, 3078 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.40 (t, J = 7.1 Hz, 3 H, CH3),
3.98 (s, 6 H, CH3), 4.39 (q, J = 7.1 Hz, 2 H, CH2), 7.18 (s, 1 H, CH),
7.75 (s, 1 H, CH), 8.49 (s, 1 H, CH).
Ethyl (Z)-2-Bromo-3-{2-[(methoxycarbonyl)amino]phe-
nyl}acrylate (9a)
Yield: 4.4 g (91%); mp 72–73 °C; Rf = 0.2 (hexanes–EtOAc, 5:1).
13C NMR (75.5 MHz, CDCl3): d = 14.2 (CH3), 56.5 (CH3), 56.7
(CH3), 63.0 (CH2), 107.6 (CH), 112.3 (CH), 116.4 (C), 125.1 (C),
139.7 (C), 149.4 (C), 153.1 (C), 162.5 (C).
IR (KBr): 488, 575, 612, 706, 757, 833, 860, 908, 945, 1037, 1069,
1109, 1190, 1248, 1273, 1364, 1450, 1537, 1581, 1616, 1702, 2943,
2986, 3030, 3301 cm–1.
Anal. Calcd for C13H14BrNO6: C, 43.35; H, 3.92; N, 3.89. Found: C,
43.70; H, 4.14; N, 3.89.
3-(2-Aminophenyl)-2-bromoacrylates 8; General Procedure
3-(2-Nitrophenyl)acrylate 7 (25.5 mmol, 1.0 equiv) was dissolved
under reflux in EtOH (70 mL). Then Fe powder (5 g, 89.4 mmol, 3.5
equiv) and 37% aq HCl (19.5 mL) were added portionwise over 1.3
h under reflux, and the mixture was refluxed for an additional 30
min. The mixture was concentrated on a rotary evaporator to 35 mL,
and CH2Cl2 (60 mL) was added. Sat. aq NaHCO3 (40 mL) was add-
ed to adjust the pH of the aqueous layer to 8, and the aqueous layer
was then extracted with CH2Cl2 (3 × 60 mL). The combined organic
phases were dried (Na2SO4), filtered, and concentrated. The crude
mixture was purified by chromatography (silica gel, hexanes–
EtOAc, 5:1); this gave 8.
1H NMR (300 MHz, CDCl3): d = 1.38 (t, J = 7.1 Hz, 3 H, CH3),
4.15 (s, 4 H, CH2), 4.39 (q, J = 7.1 Hz, 2 H, CH2), 6.23 (s, 1 H, NH),
7.01 (d, J = 8.0 Hz, 1 H, CH), 7.16 (dt, J = 7.6, 0.9 Hz, 1 H, CH),
7.39 (dt, J = 7.8, 1.3 Hz, 1 H, CH), 7.56 (d, J = 7.7 Hz, 1 H, CH),
7.85 (d, J = 7.7 Hz, 1 H, CH), 8.15 (s, 1 H, CH).
13C NMR (75.5 MHz, CDCl3): d = 14.2 (CH3), 52.6 (CH3), 63.1
(CH2), 118.4 (C), 121.9 (CH), 123.9 (CH), 125.7 (C), 129.0 (CH),
130.3 (CH), 135.5 (C), 137.5 (CH), 154.1 (C), 162.6 (C).
MS (CI): m/z (%) = 347.1 (100) [MNH4]+, 345.0 (98) [M + NH4]+,
330.1 (8) [M + H]+, 328.1 (8) [M + H]+, 267.2 (9), 248.2 (12), 202.3
(37) [M – OCH2CH3,Br]+
Ethyl (Z)-2-Bromo-3-{4,5-dimethoxy-2-[(methoxycarbon-
yl)amino]phenyl}acrylate (9b)
Yield: 4.9 g (85%); mp 141 °C; Rf = 0.3 (hexanes–EtOAc, 3:1).
Ethyl (Z)-3-(2-Aminophenyl)-2-bromoacrylate (8a)
Yield: 5.93 g (86%); mp 43 °C; Rf = 0.3 (hexanes–EtOAc, 3:1).
IR (KBr): 490, 588, 751, 822, 888, 1037, 1157, 1194, 1245, 1278,
1366, 1454, 1489, 1590, 1641, 1687, 2903, 2986, 3063, 3345, 3416
cm–1.
IR (KBr): 510, 574, 653, 751, 854, 993, 1035, 1123, 1210, 1234,
1339, 1510, 1590, 1695, 2836, 2955, 3275 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.37 (t, J = 7.1 Hz, 3 H, CH3),
3.72 (s, 3 H, CH3), 3.89 (s, 3 H, CH3), 3.91 (s, 3 H, CH3), 4.38 (q,
J = 7.1 Hz, 2 H, CH2), 6.42 (s, 1 H, NH), 7.41 (s, 2 H, CH), 8.15 (s,
1 H, CH).
1H NMR (300 MHz, CDCl3): d = 1.39 (t, J = 7.1 Hz, 3 H, CH3),
3.70 (s, 2 H, NH2), 4.35 (q, J = 7.1 Hz, 2 H, CH2), 6.75 (dd, J = 0.9,
8.1 Hz, 1 H, CH), 6.83 (dt, J = 0.9, 7.5 Hz, 1 H, CH), 7.21 (dt,
Synthesis 2008, No. 14, 2191–2198 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Tandem Radical Cyclization
2195
13C NMR (75.5 MHz, CDCl3): d = 14.2 (CH3), 52.6 (CH3), 56.0
(CH3), 56.2 (CH3), 62.9 (CH2), 111.2 (CH), 115.3 (C), 130.4 (C),
136.3 (CH), 150.7 (C), 154.5 (C), 163.0 (C).
CH2), 5.22 (d, J = 1.4 Hz, 1 H, CH), 6.98–7.10 (m, 1 H, CH), 7.12–
7.22 (m, 1 H, CH), 7.24–7.39 (m, 6 H, CH), 7.98 (s, 1 H, CH).
13C NMR (75.5 MHz, CDCl3): d (cis-14a) = 14.2 (CH3), 34.2
(CH2), 41.0 (CH), 52.7 (CH3), 60.7 (CH2), 66.4 (CH), 114.6 (CH),
123.1 (CH), 123.4 (CH), 126.9 (CH), 127.9 (CH), 128.4 (CH),
128.4 (CH), 132.0 (C), 138.3 (C), 153.5 (C), 172.2 (C).
Anal. Calcd for C15H18BrNO6: C, 46.41; H, 4.67; N, 3.61. Found: C,
46.68; H, 4.91; N, 3.50.
3-{2-[(Arylmethyl)(methoxycarbonyl)amino]phenyl}-2-bro-
moacrylates 10; General Procedure
13C NMR (75.5 MHz, CDCl3): d (trans-14a) = 13.2 (CH3), 40.1
(CH2), 46.4 (CH), 51.7 (CH3), 59.8 (CH2), 67.1 (CH), 114.0 (CH),
122.3 (CH), 123.8 (CH), 124.2 (CH), 126.4 (CH), 127.6 (CH),
128.5 (C), 131.0 (C), 141.3 (C), 152.7 (C), 170.5 (C).
HRMS–FAB: m/z [M + H]+ calcd for C20H21NO4: 339.1471; found:
339.1471.
LiOH (1.5 mmol, 1.5 equiv) was added portionwise over 30 min to
a soln of 9 (1.0 mmol, 1.0 equiv), TBAB (0.1 mmol, 0.1 equiv), and
ArCH2Br (2.0 mmol, 2.0 equiv) in DMF (3 mL) at 40 °C. The mix-
ture was stirred at this temperature for a further 3.5 h, after which
the reaction mixture was diluted with EtOAc (10 mL), washed with
sat. aq NH4Cl (10 mL), and extracted with EtOAc (3 × 15 mL). The
combined organic phases were dried (Na2SO4), filtered, and con-
centrated. The crude mixture was purified by chromatography (sil-
ica gel, hexanes–EtOAc); this gave 10.
Anal. Calcd for C20H21NO4: C, 70.78; H, 6.24; N, 4.13. Found: C,
70.59; H, 6.45; N, 4.02.
Methyl 2-(3-Chlorophenyl)-3-(2-ethoxy-2-oxoethyl)indoline-1-
carboxylate (14b)
Rf = 0.3 (hexanes–EtOAc, 5:1).
Ethyl (Z)-3-{2-[Benzyl(methoxycarbonyl)amino]phenyl}-2-bro-
moacrylate (10a)
Colorless oil; yield: 91%; Rf = 0.3 (hexanes–EtOAc, 9:1).
IR (KBr): 480, 509, 575, 631, 706, 752, 791, 849, 888, 934, 1024,
1056, 1080, 1138, 1180, 1254, 1271, 1308, 1335, 1381, 1442, 1483,
1575, 1597, 1717, 2957 cm–1.
1H NMR (300 MHz, CDCl3): d (cis-14b) = 1.22 (t, J = 7.2 Hz, 3 H,
CH3), 2.00 (dd, J = 10.6, 17.5 Hz, 1 H, CH2), 2.68 (dd, J = 17.4, 4.2
Hz, 1 H, CH2), 3.70 (s, 3 H, CH3), 4.12 (dq, J = 7.2, 2.4 Hz, 2 H,
CH2), 4.30 (dt, J = 9.7, 4.2 Hz, 1 H, CH), 5.61 (d, J = 9.7 Hz, 1 H,
CH), 6.87 (d, J = 7.4 Hz, 1 H, CH), 7.01–7.32 (m, 6 H, CH) 7.89 (s,
1 H, CH).
IR (KBr): 455, 631, 701, 764, 984, 1040, 1103, 1138, 1191, 1254,
1290, 1380, 1446, 1484, 1618, 1713, 2954, 2984, 3031 cm–1.
1H NMR (300 MHz, DMSO-d6, 343 K): d = 1.29 (t, J = 7.1 Hz, 3 H,
CH3), 3.58 (s, 3 H, CH3), 4.26 (q, J = 7.1 Hz, 2 H, CH2), 4.76 (s, 2
H, CH2), 7.13–7.17 (m, 2 H, CH), 7.22–7.27 (m, 4 H, CH), 7.36 (dt,
J = 7.6, 1.5 Hz, 1 H, CH), 7.44 (dt, J = 7.6, 1.5 Hz, 1 H, CH), 7.74
(s, 1 H, CH), 7.76 (dd, J = 7.6, 1.3 Hz, 1 H, CH).
13C NMR (75.5 MHz, DMSO-d6, 343 K): d = 13.5 (CH3), 52.3
(CH3), 53.6 (CH2), 62.0 (CH2), 115.0 (C), 126.6 (CH), 127.1 (CH),
127.7 (CH), 127.9 (CH), 128.0 (CH), 128.8 (CH), 130.2 (CH),
132.1 (C), 136.6 (C), 137.4 (CH), 140.3 (C), 154.8 (C), 161.6 (C).
1H NMR (300 MHz, CDCl3): d (trans-14b) = 1.27 (t, J = 7.2 Hz, 3
H, CH3), 2.67 (dd, J = 2.0, 7.4 Hz, 2 H, CH2), 3.52 (ddd, J = 8.4, 7.4
Hz, 1.4 Hz, 1 H, CH), 3.70 (s, 3 H, CH3), 4.20 (q, J = 7.2 Hz, 2 H,
CH2), 5.19 (d, J = 1.4 Hz, 1 H, CH), 7.01–7.32 (m, 7 H, CH), 7.89
(s, 1 H, CH).
13C NMR (75.5 MHz, CDCl3): d (cis-14b) = 14.2 (CH3), 34.2
(CH2), 41.0 (CH), 52.8 (CH3), 60.9 (CH2), 65.8 (CH), 114.7 (CH),
123.3 (CH), 123.5 (CH), 124.9 (CH), 127.3 (CH), 128.2 (CH),
128.4 (CH), 128.6 (CH), 129.8 (CH), 134.3 (C), 140.4 (CH), 153.4
(C), 172.1 (C).
13C NMR (75.5 MHz, CDCl3): d (trans-14b) = 14.2 (CH3), 41.1
(CH2), 46.5 (CH), 52.8 (CH3), 60.9 (CH2), 67.7 (CH), 115.1 (CH),
123.6 (CH), 125.6 (CH), 127.3 (CH), 127.7 (CH), 128.2 (CH),
128.6 (C), 128.8 (CH), 130.0 (CH), 131.0 (C), 140.5 (C), 153.4 (C),
171.4 (C).
MS (EI, 70 eV): m/z (%) = 417.0 (2) [M+], 338.1 (8) [M – Br]+, 91.1
(100) [C7H7]+.
HRMS–FAB: m/z [M + H]+ calcd for C20H20BrNO4: 417.0576;
found: 417.0567.
Indolines 14 by Radical Cyclization of 2-Bromo-3-phenyl-
acrylates 10; General Procedure
A mixture of n-Bu3SnH (185 mL, 0.7 mmol, 1.4 equiv) and AIBN
(22 mg, 0.13 mmol, 0.25 equiv) in toluene (10 mL) was added via a
syringe pump over 3 h to a refluxing (microwave irradiation at 100–
105 °C under open-vessel conditions) soln of 10 (0.5 mmol, 1.0
equiv) and AIBN (22 mg, 0.13 mmol, 0.25 equiv) in toluene (10
mL). The solvent was evaporated and the residue was dissolved in
Et2O (100 mL). DBU (2.7 equiv, 1.35 mmol) was added to the soln,
which was titrated with 0.1 M I2 in Et2O and filtered through silica
gel.14 The crude product was purified by chromatography (silica
gel, hexanes–EtOAc); this gave 14 as white solids.
HRMS–FAB: m/z [M + H]+ calcd for C20H20ClNO4: 373.1081;
found: 373.1080.
Anal. Calcd for C20H20ClNO4: C, 64.26; H, 5.39; N, 3.75. Found: C,
64.51; H, 5.62; N, 3.67.
Methyl 3-(2-Ethoxy-2-oxoethyl)-2-(4-methoxyphenyl)indoline-
1-carboxylate (14d)
Rf = 0.3 (hexanes–EtOAc, 5:1).
Methyl 3-(2-Ethoxy-2-oxoethyl)-2-phenylindoline-1-car-
boxylate (14a)
Rf = 0.3 (hexanes–EtOAc, 5:1).
IR (KBr): 640, 743, 818, 839, 880, 927, 1028, 1055, 1107, 1137,
1173, 1254, 1304, 1383, 1440, 1485, 1516, 1609, 1717, 2851, 2952,
2982 cm–1.
IR (KBr): 456, 700, 754, 849, 934, 1022, 1057, 1171, 1193, 1275,
1312, 1385, 1443, 1484, 1602, 1713, 2955, 2982, 3030 cm–1.
1H NMR (300 MHz, CDCl3): d (cis-14d) = 1.21 (t, J = 7.1 Hz, 3 H,
CH3), 2.06 (dd, J = 10.1, 17.4 Hz, 1 H, CH2), 2.64 (dd, J = 17.4, 5.0
Hz, 1 H, CH2), 3.69 (s, 3 H, CH3), 3.75 (s, 3 H, CH3) 4.10 (q, J = 7.1
Hz, 2 H, CH2), 4.22 (ddd, J = 10.1, 9.6 Hz, 5.1 Hz, 1 H, CH), 5.59
(d, J = 9.6 Hz, 1 H, CH), 6.73 (d, J = 8.8 Hz, 2 H, CH), 6.91 (d,
J = 8.8 Hz, 2 H, CH), 7.00–7.04 (m, 2 H, CH), 7.25–7.30 (m, 1 H,
CH), 7.85 (s, 1 H, CH).
1H NMR (300 MHz, CDCl3): d (cis-14a) = 1.20 (t, J = 7.2 Hz, 3 H,
CH3), 2.02 (dd, J = 10.2, 17.4 Hz, 1 H, CH2), 2.63 (dd, J = 17.4,
5.00 Hz, 1 H, CH2), 3.68 (s, 3 H, CH3), 4.09 (dq, J = 7.2, 0.9 Hz, 2
H, CH2), 4.28 (dt, J = 10.0, 5.0 Hz, 1 H, CH), 5.63 (d, J = 10.0 Hz,
1 H, CH), 6.98–7.09 (m, 4 H, CH), 7.16–7.33 (m, 4 H, CH), 7.87 (s,
1 H, CH).
1H NMR (300 MHz, CDCl3): d (trans-14a) = 1.27 (t, J = 7.2 Hz, 3
H, CH3), 2.67 (dd, J = 8.2, 6.2 Hz, 2 H, CH2), 3.55 (ddd, J = 8.2, 6.2
Hz, 1.4 Hz, 1 H, CH), 3.75 (s, 3 H, CH3), 4.20 (q, J = 7.2 Hz, 2 H,
1H NMR (300 MHz, CDCl3): d (trans-14d) = 1.26 (t, J = 7.1 Hz, 3
H, CH3), 2.65 (dd, J = 1.7, 6.2 Hz, 2 H, CH2), 3.53 (ddd, J = 8.3, 6.2
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I. Prediger et al.
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Hz, 1.7 Hz, 1 H, CH), 3.76 (s, 3 H, CH3), 4.19 (q, J = 7.2 Hz, 2 H,
CH2), 5.16 (d, J = 1.7 Hz, 1 H, CH), 6.79 (d, J = 8.8 Hz, 2 H, CH),
6.98–7.17 (m, 2 H, CH), 7.12 (d, J = 8.8 Hz, 2 H, CH), 7.25–7.30
(m, 6 H, CH), 7.85 (s, 1 H, CH).
13C NMR (75.5 MHz, CDCl3): d (cis-14d) = 14.2 (CH3), 34.1
(CH2), 41.1 (CH), 52.7 (CH3), 55.2 (CH3), 60.7 (CH2), 66.0 (CH),
113.7 (CH), 114.6 (CH), 123.1 (CH), 123.4 (CH), 128.1 (CH),
128.3 (CH), 130.4 (C), 132.1 (C), 153.5 (C), 159.1 (C), 172.3 (C).
13C NMR (75.5 MHz, CDCl3): d (trans-14d) = 14.2 (CH3), 41.1
(CH2), 46.8 (CH), 52.6 (CH3), 55.2 (CH3), 60.8 (CH2), 67.8 (CH),
114.0 (CH), 115.0 (CH), 123.3 (CH), 124.8 (CH), 126.56 (CH),
128.6 (CH), 130.4 (C), 134.6 (C), 153.9 (C), 158.9 (C), 171.6 (C).
J = 7.5 Hz, 1 H, CH), 7.31–7.46 (m, 4 H, CH), 7.60 (s, 1 H, CH),
7.72–8.12 (m, 4 H, CH).
13C NMR (75.5 MHz, CDCl3): d (cis-14f) = 14.0 (CH3), 34.4 (CH2),
41.1 (CH), 52.9 (CH3), 60.7 (CH2), 65.6 (CH), 114.7 (CH), 123.2
(CH), 124.25 (CH), 124.5 (CH), 126.0 (CH), 126.4 (CH), 126.9
(CH), 127.9 (CH), 128.3 (CH), 128.5 (CH), 132.0 (C), 133.0 (CH),
134.0 (C), 140.0 (C), 153.6 (C), 172.3 (C).
13C NMR (75.5 MHz, CDCl3): d (trans-14f) = 14.3 (CH3), 41.2
(CH2), 46.7 (CH), 52.9 (CH3), 60.9 (CH2), 68.3 (CH), 115.1 (CH),
123.4 (CH), 123.8 (CH), 124.8 (CH), 125.8 (CH), 126.1(CH), 127.7
(CH), 128.0 (CH), 128.5 (CH), 128.7 (CH), 129.9 (CH), 132.9
(CH), 133.25 (CH), 134.0 (C), 139.7 (C), 153.9 (C), 171.5 (C).
HRMS–FAB: m/z [M + H]+ calcd for C21H23NO5: 369.1576; found:
HRMS–FAB: m/z [M + H]+ calcd for C24H23NO4: 389.1627; found:
369.1580.
389.1626.
Anal. Calcd for C21H23NO5: C, 68.28; H, 6.28; N, 3.79. Found: C,
67.88; H, 6.48; N, 3.61.
Anal. Calcd for C24H23NO4: C, 74.02; H, 5.95; N, 3.60. Found: C,
73.95; H, 6.22; N, 3.58.
Methyl 3-(2-Ethoxy-2-oxoethyl)-2-(3-methoxyphenyl)indoline-
1-carboxylate (14e)
Rf = 0.3 (hexanes–EtOAc, 5:1).
Methyl 3-(2-Ethoxy-2-oxoethyl)-2-(2-furyl)indoline-1-car-
boxylate (14g)
Rf = 0.4 (hexanes–EtOAc, 3:1).
IR (KBr): 745, 820, 840, 879, 931, 1026, 1056, 1112, 1140, 1172,
1258, 1300, 1384, 1440, 1486, 1515, 1607, 1716, 2849, 2953, 2980
cm–1.
1H NMR (300 MHz, CDCl3): d (cis-14e) = 1.21 (t, J = 7.1 Hz, 3 H,
CH3), 2.07 (dd, J = 10.1, 17.3 Hz, 1 H, CH2), 2.67 (dd, J = 17.3,
5.00 Hz, 1 H, CH2), 3.71 (s, 6 H, CH3), 4.11 (q, J = 7.1 Hz, 2 H,
CH2), 4.19–4.31 (m, 1 H, CH), 5.63 (d, J = 9.6 Hz, 1 H, CH), 6.61
(s, 1 H, CH), 6.74–6.82 (m, 2 H, CH), 6.98–7.10 (m, 2 H, CH),
7.12–7.19 (m, 1 H, CH), 7.25–7.29 (m, 1 H, CH), 7.92 (s, 1 H, CH).
1H NMR (300 MHz, CDCl3): d (trans-14e) = 1.25 (t, J = 7.1 Hz, 3
H, CH3), 2.67 (dd, J = 1.7, 6.3 Hz, 2 H, CH2), 3.55 (m, 1 H, CH),
3.77 (s, 6 H, CH3), 4.18 (q, J = 7.2 Hz, 2 H, CH2), 5.15 (d, J = 1.7
Hz, 1 H, CH), 6.62 (s, 1 H, CH), 6.73–6.83 (m, 2 H, CH), 6.99–7.09
(m, 2 H, CH), 7.11–7.16 (m, 1 H, CH), 7.23–7.28 (m, 1 H, CH), 7.92
(s, 1 H, CH).
13C NMR (75.5 MHz, CDCl3): d (cis-14e) = 13.2 (CH3), 33.0
(CH2), 39.9 (CH), 51.6 (CH3), 54.0 (CH3), 59.6 (CH2), 65.3 (CH),
111.3 (CH), 111.7 (CH), 118.2 (CH), 122.1 (CH), 122.3 (CH),
127.3 (CH), 128.6 (CH), 130.9 (C), 138.9 (C), 152.4 (C), 158.4 (C),
171.2 (C).
IR (KBr): 734, 914, 1024, 1060, 1150, 1179, 1269, 1331, 1385,
1444, 1601, 1714, 2989 cm–1.
1H NMR (300 MHz, CDCl3): d (cis-14g) = 1.26 (t, J = 6.6 Hz, 3 H,
CH3), 2.13 (dd, J = 10.2, 17.5 Hz, 1 H, CH2), 2.76 (dd, J = 17.4,
5.00 Hz, 1 H, CH2), 3.75 (s, 3 H, CH3), 4.17 (q, J = 7.1 Hz, 2 H,
CH2), 4.19–4.25 (m, 1 H, CH), 5.73 (d, J = 9.3 Hz, 1 H, CH), 6.08
(s, 1 H, CH), 6.24 (dd, J = 1.8, 3.3 Hz, 1 H, CH), 7.02–7.05 (m, 1
H, CH), 7.23–7.29 (m, 3 H, CH), 7.83 (s, 1 H, CH).
1H NMR (300 MHz, CDCl3): d (trans-14g) = 1.24 (t, J = 7.1 Hz, 3
H, CH3), 2.65 (d, J = 7.1 Hz, 2 H, CH2), 3.71–3.79 (m, 1 H, CH),
3.80 (s, 3 H, CH3), 4.15 (q, J = 7.1 Hz, 2 H, CH2), 5.30 (d, J = 1.5
Hz, 1 H, CH), 6.14 (s, 1 H, CH), 6.26 (dd, J = 1.9, 3.3 Hz, 1 H, CH),
7.01–7.02 (m, 1 H, CH), 7.17–7.28 (m, 3 H, CH), 7.82 (s, 1 H, CH).
13C NMR (75.5 MHz, CDCl3): d (cis-14g) = 14.2 (CH3), 33.8
(CH2), 39.4 (CH), 52.7 (CH3), 60.5 (CH), 60.8 (CH2), 108.9 (C),
110.2 (CH), 114.9 (CH), 123.1 (C), 123.1 (CH), 128.2 (CH), 142.1
(CH), 151.7 (C), 153.7 (C), 172.1 (C).
13C NMR (75.5 MHz, CDCl3): d (trans-14g) = 14.2 (CH3), 40.5
(CH2), 46.8 (CH), 52.7 (CH3), 60.8 (CH2), 62.1 (CH), 108.2 (C),
110.1 (CH), 115.3 (CH), 121.4 (C), 123.3 (CH), 124.5 (CH), 128.5
(CH), 142.0 (CH), 151.7 (C), 153.2 (C), 171.2 (C).
13C NMR (75.5 MHz, CDCl3): d (trans-14e) = 13.0 (CH3), 40.0
(CH2), 45.7 (CH), 51.6 (CH3), 54.0 (CH3), 59.7 (CH2), 66.9 (CH),
110.3 (CH), 112.0 (CH), 113.9 (CH), 116.4 (CH), 122.4 (CH),
123.7 (CH), 127.5 (CH), 129.9 (CH), 130.9 (C), 152.7 (C), 158.7
(C), 170.4 (C).
HRMS–FAB: m/z [M + H]+ calcd for C18H19NO5: 329.1263; found:
329.1262.
Methyl 3-(2-Ethoxy-2-oxoethyl)-5,6-dimethoxy-2-phenyl-
indoline-1-carboxylate (14h)
HRMS–FAB: m/z [M + H]+ calcd for C21H23NO5: 369.1576; found:
369.1580.
Rf = 0.3 (hexanes–EtOAc, 2:1).
IR (KBr): 458, 492, 598, 702, 731, 760, 846, 1027, 1118, 1186,
1219, 1282, 1394, 1448, 1501, 1702, 2954 cm–1.
Methyl 3-(2-Ethoxy-2-oxoethyl)-2-(2-naphthyl)indoline-1-car-
boxylate (14f)
Rf = 0.3 (hexanes–EtOAc, 9:1).
1H NMR (300 MHz, CDCl3): d (cis-14h) = 1.09 (t, J = 7.1 Hz, 3 H,
CH3), 1.90 (dd, J = 10.1, 17.3 Hz, 1 H, CH2), 2.48 (dd, J = 17.4,
5.00 Hz, 1 H, CH2), 3.52 (s, 3 H, CH3), 3.73 (s, 3 H, CH3), 3.84 (s,
3 H, CH3), 3.98 (q, J = 7.1 Hz, 2 H, CH2), 4.10–4.18 (m, 1 H, CH),
5.51 (d, J = 9.5 Hz, 1 H, CH), 6.54 (s, 1 H, CH), 6.90–6.91 (m, 1 H,
CH), 7.07–7.16 (m, 4 H, CH), 7.61 (s, 1 H, CH).
1H NMR (300 MHz, CDCl3): d (trans-14h) = 1.16 (t, J = 7.1 Hz, 3
H, CH3), 2.58 (dd, J = 7.3, 3.0 Hz, 2 H, CH2), 3.35–3.40 (m, 1 H,
CH), 3.56 (s, 3 H, CH3), 3.70 (s, 3 H, CH3), 3.84 (s, 3 H, CH3), 4.09
(q, J = 7.2 Hz, 2 H, CH2), 5.11 (s, 1 H, CH), 6.62 (s, 1 H, CH), 6.91–
6.93 (m, 1 H, CH), 7.08–7.07 (m, 4 H, CH), 7.62 (s, 1 H, CH).
IR (KBr): 476, 553, 608, 665, 752, 822, 858, 960, 1030, 1057, 1137,
1184, 1269, 1310, 1381, 1442, 1483, 1699, 710, 2955, 2981 cm–1.
1H NMR (300 MHz, CDCl3): d (cis-14f) = 1.27 (t, J = 7.2 Hz, 3 H,
CH3), 2.04 (dd, J = 10.0, 18.6 Hz, 1 H, CH2), 2.65 (dd, J = 5.5, 18.6
Hz, 1 H, CH2), 3.70 (s, 3 H, CH3), 4.09–4.19 (m, 2 H, CH2), 4.38
(dt, J = 5.5, 9.7 Hz, 1 H, CH), 5.83 (d, J = 9.7 Hz, 1 H, CH), 6.95–
8.12 (m, 11 H, CH).
1H NMR (300 MHz, CDCl3): d (trans-14f) = 1.28 (t, J = 7.2 Hz, 3
H, CH3), 2.74 (dd, J = 6.0, 7.3 Hz, 2 H, CH2), 3.60–3.70 (m, 1 H,
CH), 3.70 (s, 3 H, CH3), 4.22 (q, J = 7.2 Hz, 2 H, CH2), 5.40 (d,
J = 1.6 Hz, 1 H, CH), 7.04 (dt, J = 0.9, 7.5 Hz, 1 H, CH), 7.16 (d,
13C NMR (75.5 MHz, CDCl3): d (cis-14h) = 14.1 (CH3), 34.4
(CH2), 40.8 (CH), 46.9 (CH3), 56.4 (CH3), 56.1 (CH3), 60.5 (CH2),
Synthesis 2008, No. 14, 2191–2198 © Thieme Stuttgart · New York

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Microwave-Assisted Tandem Radical Cyclization
2197
66.6 (CH), 99.4 (CH), 107.4 (CH), 125.1 (CH), 127.8 (CH), 128.3
(CH), 128.5 (CH), 128.7 (CH), 138.3 (C), 145.2 (C), 148.9 (C),
153.4 (C), 171.5 (C).
13C NMR (75.5 MHz, CDCl3): d (trans-14h) = 14.2 (CH3), 41.1
(CH2), 46.8 (CH3), 46.9 (CH), 56.3 (CH3), 56.1 (CH3), 60.7 (CH2),
68.4 (CH), 99.7 (CH), 108.2 (CH), 125.2 (CH), 126.8 (CH), 127.4
(CH), 128.3 (CH), 128.6 (CH), 142.4 (C), 145.4 (C), 149.2 (C),
153.6 (C), 172.1 (C).
J = 7.1 Hz, 2 H, CH3), 6.97 (d, J = 8.8 Hz, 2 H, CH), 7.27–7.39 (m,
4 H, CH), 7.56–7.59 (m, 1 H, CH), 8.16 (d, J = 8.2 Hz, 1 H, CH).
13C NMR (75.5 MHz, CDCl3): d = 14.2 (CH3), 30.9 (CH2), 53.4
(CH3), 55.3 (CH3), 60.0 (CH2), 113.3 (CH), 114.3 (C), 115.6 (CH),
119.0 (CH), 123.2 (CH), 124.8 (CH), 124.9 (C), 129.6 (C), 131.1
(CH), 135.9 (C), 137.7 (C), 152.2 (C), 159.4 (C), 171.3 (C).
HRMS–FAB: m/z [M + H]+ calcd for C21H21NO5: 367.1420; found:
367.1417.
HRMS–FAB: m/z [M + H]+ calcd for C22H20NO6: 399.1682; found:
399.1677.
Methyl 3-(2-Ethoxy-2-oxoethyl)-2-(3-methoxyphenyl)-1H-
indole-1-carboxylate (15d)
Indoles 15 by Dehydrogenation of Indolines 14; General Proce-
dure
Rf = 0.4 (hexanes–EtOAc, 5:1).
IR (KBr): 699, 755, 785, 1021, 1090, 1145, 1222, 1326, 1356, 1439,
1595, 1730, 2960 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.23 (t, J = 7.1 Hz, 3 H, CH3),
3.55 (s, 2 H, CH2), 3.77 (s, 3 H, CH3), 3.84 (s, 3 H, CH3), 4.14 (q,
J = 7.1 Hz, 2 H, CH3), 6.94–7.00 (m, 3 H, CH), 7.30–7.39 (m, 3 H,
CH), 7.59 (d, J = 8.2 Hz, 1 H, CH), 8.17 (d, J = 8.2 Hz, 1 H, CH).
13C NMR (75.5 MHz, CDCl3): d = 13.2 (CH3), 29.9 (CH2), 52.4
(CH3), 54.2 (CH3), 59.9 (CH2), 112.8 (CH), 113.4 (C), 114.3 (CH),
114.5 (CH), 118.1 (CH), 121.3 (CH), 122.2 (CH), 123.9 (CH),
127.7 (CH), 128.5 (C), 132.9 (C), 135.0 (C), 136.5 (C), 151.0 (C),
158.1 (C), 170.1 (C).
A soln of indoline 14 (0.3 mmol, 1.0 equiv) and DDQ (0.6 mmol,
2.0 equiv) in toluene (7 mL) was placed in a sealed vessel in a mi-
crowave and irradiated at 120 °C for 4 h. After completion of the re-
action, the solvent was removed and the residue was washed with
sat. aq NaHCO3 (5 mL) and extracted with CH2Cl2 (3 × 10 mL). The
combined organic phases were dried (Na2SO4), filtered, and con-
centrated. The crude product was purified by chromatography (sili-
ca gel, hexanes–EtOAc); this gave indoles 15 as oils.
Methyl 3-(2-Ethoxy-2-oxoethyl)-2-phenyl-1H-indole-1-car-
boxylate (15a)
Rf = 0.4 (hexanes–EtOAc, 5:1).
HRMS–FAB: m/z [M + H]+ calcd for C21H21NO5: 367.1420; found:
367.1418.
IR (KBr): 642, 701, 752, 822, 940, 1028, 1076, 1154, 1230, 1330,
1360, 1441, 1605, 1732, 1896, 2854, 2929, 2956, 2981, 3055 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.24 (t, J = 7.1 Hz, 3 H, CH3),
3.54 (s, 2 H, CH2), 3.76 (s, 3 H, CH3), 4.14 (q, J = 7.1 Hz, 2 H, CH3),
7.29–7.39 (m, 2 H, CH), 7.40–7.47 (m, 5 H, CH), 7.59 (d, J = 7.9
Hz, 1 H, CH), 8.19 (d, J = 7.9 Hz, 1 H, CH).
13C NMR (75.5 MHz, CDCl3): d = 14.2 (CH3), 30.9 (CH2), 53.4
(CH3), 61.0 (CH2), 114.5 (CH), 115.6 (CH), 123.3 (CH), 124.9
(CH), 127.9 (CH), 128.2 (CH), 129.6 (C), 129.9 (CH), 132.7 (C),
136.0 (C), 137.8 (C), 152.2 (C), 171.2 (C).
Methyl 3-(2-Ethoxy-2-oxoethyl)-2-(2-naphthyl)-1H-indole-1-
carboxylate (15e)
Rf = 0.4 (hexanes–EtOAc, 5:1).
IR (KBr): 733, 819, 862, 910, 1025, 1072, 1150, 1227, 1321, 1358,
1440, 1734, 2932, 2990, 3055 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25 (t, J = 7.1 Hz, 3 H, CH3),
3.58 (s, 2 H, CH2), 3.72 (s, 3 H, CH3), 4.15 (q, J = 7.1 Hz, 2 H, CH3),
7.31–7.44 (m, 2 H, CH), 7.47 (dd, J = 1.7, 8.5 Hz, 1 H, CH), 7.51–
7.57 (m, 2 H, CH), 7.63 (d, J = 7.7 Hz, 1 H, CH), 7.87–7.93 (m, 3
H, CH), 7.95 (s, 1 H, CH), 8.22 (d, J = 8.3 Hz, 1 H, CH).
HRMS–FAB: m/z [M + H]+ calcd for C20H19NO4: 337.1314; found:
337.1310.
13C NMR (75.5 MHz, CDCl3): d = 14.2 (CH3), 31.0 (CH2), 53.4
(CH3), 61.0 (CH2), 114.9 (C), 115.6 (CH), 119.2 (CH), 123.3 (CH),
125.1 (CH), 126.3 (CH), 126.5 (CH), 127.1 (CH), 127.8 (CH),
127.9 (CH), 128.3 (CH), 128.7 (CH), 129.7 (C), 130.2 (C), 133.0
(C), 136.1 (C), 137.7 (C), 152.3 (C), 171.2 (C).
Methyl 2-(3-Chlorophenyl)-3-(2-ethoxy-2-oxoethyl)-1H-indole-
1-carboxylate (15b)
Rf = 0.4 (hexanes–EtOAc, 5:1).
IR (KBr): 758, 871, 1025, 1072, 1096, 1171, 1225, 1267, 1328,
1441, 1566, 1599, 1733, 2956, 2982 cm–1.
HRMS–FAB: m/z [M + H]+ calcd for C24H21NO4: 387.1471; found:
1H NMR (300 MHz, CDCl3): d = 1.25 (t, J = 7.1 Hz, 3 H, CH3),
3.53 (s, 2 H, CH2), 3.79 (s, 3 H, CH3), 4.15 (q, J = 7.1 Hz, 2 H, CH3),
7.28–7.45 (m, 6 H, CH), 7.61 (d, J = 8.0 Hz, 1 H, CH), 8.18 (d,
J = 8.0 Hz, 1 H, CH).
13C NMR (75.5 MHz, CDCl3): d = 14.2 (CH3), 30.8 (CH2), 53.5
(CH3), 61.1 (CH2), 115.1 (C), 115.6 (CH), 119.3 (CH), 123.4 (CH),
125.3 (CH), 128.2 (CH), 128.3 (CH), 129.1 (CH), 129.4 (C), 129.9
(CH), 133.8 (C), 134.5 (C), 136.0 (C), 136.1 (C), 152.0 (C), 170.9
(C).
387.1471.
Methyl 3-(2-Ethoxy-2-oxoethyl)-5,6-dimethoxy-2-phenyl-1H-
indole-1-carboxylate (15g)
Rf = 0.4 (hexanes–EtOAc, 2:1).
IR (KBr): 702, 754, 849, 1030, 1080, 1167, 1205, 1312, 1364, 1442,
1485, 1514, 1603, 1707, 1725, 2841, 2956 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.19 (t, J = 7.1 Hz, 3 H, CH3),
3.44 (s, 2 H, CH2), 3.69 (s, 3 H, CH3), 3.98 (s, 3 H, CH3), 3.99 (s, 3
H, CH3), 4.13 (q, J = 7.1 Hz, 2 H, CH3), 7.01 (s, 1 H, CH), 7.29–
7.46 (m, 5 H, CH), 7.88 (s, 1 H, CH).
HRMS–FAB: m/z [M + H]+ calcd for C20H18ClNO4: 371.0924;
found: 371.0925.
13C NMR (75.5 MHz, CDCl3): d = 14.2 (CH3), 31.1 (CH2), 53.2
(CH3), 56.2 (CH3), 56.3 (CH3), 61.0 (CH2), 99.5 (CH), 100.8 (CH),
114.2 (C), 122.3 (C), 127.8 (CH), 128.4 (CH), 128.2 (CH), 129.9
(CH), 130.4 (C), 133.0 (C), 136.1 (C), 146.8 (C), 148.2 (C), 152.3
(C), 171.2 (C).
HRMS–FAB: m/z [M + H]+ calcd for C22H23NO6: 397.1525; found:
397.1523.
Methyl 3-(2-Ethoxy-2-oxoethyl)-2-(4-methoxyphenyl)-1H-
indole-1-carboxylate (15c)
Rf = 0.4 (hexanes–EtOAc, 5:1).
IR (KBr): 756,837, 1030, 1076, 1177, 1246, 1329, 1358, 1452,
1510, 1611, 1734, 2838, 2935, 2956 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.24 (t, J = 7.1 Hz, 3 H, CH3),
3.53 (s, 2 H, CH2), 3.78 (s, 3 H, CH3), 3.87 (s, 3 H, CH3), 4.14 (q,
Synthesis 2008, No. 14, 2191–2198 © Thieme Stuttgart · New York

2198
I. Prediger et al.
PAPER
(7) Opatz, T.; Ferenc, D. Org. Lett. 2006, 8, 4473.
Acknowledgment
(8) Kozikowski, A. P.; Ma, D.; Brewer, J.; Sun, S.; Costa, E.;
Romeo, E.; Guidotti, A. J. Med. Chem. 1993, 36, 2908.
(9) Allan, G. M.; Parsons, A. F.; Pons, J.-F. Synlett 2002, 1431.
(10) Lin, H.; Schall, A.; Reiser, O. Synlett 2005, 2603.
(11) Details on the X-ray crystal structure of 14b can be obtained
from the Cambridge Crystallographic Data Centre (CCDC
691332).
(12) (a) Houk, K. N.; Spellmeyer, D. C. J. Org. Chem. 1987, 52,
959. (b) Aurrecoechea, J. M.; Fernandez, A.; Gorgojo, J. M.;
Soaornil, C. Tetrahedron 1999, 55, 7345. (c) Alcaide, B.;
Rodriguez-Campos, I. M.; Rodriguez-Lopez, J.; Rodriguez-
Vicente, A. J. Org. Chem. 1999, 64, 5377.
(13) (a) Campos, K. R.; Journet, M.; Lee, S.; Grabowski, E. J. J.;
Tillyer, R. D. J. Org. Chem. 2005, 70, 268. (b) Engler, T.
A.; Meduna, S. P.; LaTessa, K. O.; Chai, W. J. Org. Chem.
1996, 61, 8598. (c) Lakatosh, S. A.; Simonov, A. Y.;
Luzikov, Y. N.; Preobrazhenskaya, M. N. Pharm. Chem. J.
2006, 40, 435. (d) Giuseppe, C.; Piero, D. C.; Concetta, L.
R. Heterocycles 2005, 66, 557.
This work was supported by the Studienstiftung des Deutschen Vol-
kes (fellowship for T.W.) and the Fonds der Chemischen Industrie.
We thank Dr. M. Zabel, University of Regensburg, for carrying out
the X-ray analysis of 14b.
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Synthesis 2008, No. 14, 2191–2198 © Thieme Stuttgart · New York