Synthesis of indolones via radical cyclization of N-(2-halogenoalkanoyl)- substituted anilines

Article abstract of DOI:10.1002/hlca.200490294

The radical reactions of N-(2-halogenoalkanoyl)-substituted anilines (anilides) of type 1 have been investigated under various conditions. Treatment of compounds 1a-1o with Bu₃SnH in the presence of (2,2′-azobis(isobutyronitrile) (AIBN) afforded a mixture of the indolones (oxindoles) 2a-2o and the reduction products 5a-5o (Table 1). In contrast, the N-unsubstituted anilides 1p-1s, 1u, and 1v gave the corresponding reduction products exclusively (Table 1). Similar results were obtained by treatment of 1 with Ni powder (Table 2) or wth Et₃B (Table 3). Anilides with longer N-(phenylalkyl) chains such as 6 and 7 were inert towards radical cyclization, with the exception of N-benzyl-2-bromo-N,2-dimethylpropanamide (6b), which, upon treatment with Ni powder in i-PrOH, afforded the cyclized product 9b in low yield (Table 4). Upon irradiation, the extended anilides 6, 7, 10, and 11 yielded the corresponding dehydrobromination products exclusively (Table 5).

Full text of DOI:10.1002/hlca.200490294

Helvetica Chimica Acta ± Vol. 88 (2005)
35
Synthesis of Indolones via Radical Cyclization of N-(2-Halogenoalkanoyl)-
Substituted Anilines
by Takehiko Nishio*a), Kyoko Iseki, Norihito Arakib), and Takenori Miyazakib)
a) Department of Chemistry, University of Tsukuba, Tsukuba-shi, Ibaraki, 305-8571, Japan
b) Graduate School of Environmental Sciences, University of Tsukuba, Tsukuba-shi, Ibaraki, 305-8571, Japan
The radical reactions of N-(2-halogenoalkanoyl)-substituted anilines (anilides) of type 1 have been
investigated under various conditions. Treatment of compounds 1a ± 1o with Bu3SnH in the presence of (2,2'-
azobis(isobutyronitrile) (AIBN) afforded a mixture of the indolones (oxindoles) 2a ± 2o and the reduction
products 5a ± 5o (Table 1). In contrast, the N-unsubstituted anilides 1p ± 1s, 1u, and 1v gave the corresponding
reduction products exclusively (Table 1). Similar results were obtained by treatment of 1 with Ni powder
(Table 2) or wth Et3B (Table 3). Anilides with longer N-(phenylalkyl) chains such as 6 and 7 were inert towards
radical cyclization, with the exception of N-benzyl-2-bromo-N,2-dimethylpropanamide (6b), which, upon
treatment with Ni powder in i-PrOH, afforded the cyclized product 9b in low yield (Table 4). Upon irradiation,
the extended anilides 6, 7, 10, and 11 yielded the corresponding dehydrobromination products exclusively
(Table 5).
Introduction. ± Radical-induced cyclization reactions for the formation of N-
containing heterocycles have attracted much attention from both synthetic and
mechanistic points of view [1]. The indolones (oxindoles) are an important class of
heterocycles not only due to various biological activities displayed by some members of
this family, but also since these compounds are direct indole precursors [2][3]. The
literature is replete with methods for the preparation of indolones [3][4]. Previously,
we have demonstrated that N-(2-halogenoalkanoyl)-substituted aniline derivatives of
type 1, upon irradiation, afford the indolones 2, along with the dehydrohalogenation
products 3, which underwent electrocyclic ring closure to the ꢀdihydrocarbostyrilsꢁ, i.e.,
3,4-dihydroquinolin-2(1H)-ones, of type 4 (Scheme 1) [5a]. We have now examined the
radical cyclization of 1 (and of related compounds) in the hope that this reaction might
provide a facile route to indolones [6].
Scheme 1. Light-Induced Cyclization or Dehydrobromination of N-Substituted 2-Bromo-2-methylpropan-
amides 1
Results and Discussion. ± When compounds 1a and 1g ± 1o, having electron-
withdrawing or electron-donating substituents Y (ˆCl, MeO, Me, acyl) in the ortho- or
ꢂ 2005 Verlag Helvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta ± Vol. 88 (2005)
para-positions of the aniline ring, were treated with Bu3SnH and a small amount of 2,2'-
azobis(isobutylonitrile) (AIBN) in boiling toluene, the 1-substituted 3,3-dimethylin-
dolon-2-ones 2a and 2g ± 2o, respectively, were isolated in 34 ± 80% yield as the main
products, together with the 2-methylpropananilides 5a and 5g ± 5o (7 ± 28%; Table 1).
When the Y substituent of the aromatic ring was in ortho-position, as in the case of 1i,
1k, and 1m ± 1o, the yields of the corresponding indolones 2 increased. When the N-(2-
bromoalkanoyl) derivatives 1b or 1e were treated with Bu3SnH and AIBN, then the
reduction products 5b and 5e, respectively, were isolated in 73 ± 75% yield, with the
desired cyclization products 2b and 2e being present only as side products (8 ± 17%).
Treatment of compounds 1c and 1d and 1f with Bu3SnH and AIBN gave similar results;
and reaction of the N-unsubstituted anilines 1p ± 1s, and 1u and 1v afforded exclusively
the reduction products 5p ± 5s, and 5u and 5v, respectively (Table 1).
Table 1. Tributyltin Hydride Promoted Reactions of Compounds 1. Bz ˆ Benzoyl.
Substituents
R1
Isolated yield [%]
R2
R3
Y
X
2
5
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Me
H
H
H
H
Me
Me
Me
Ph
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
p-Cl
o-Cl
p-MeO
o-MeO
p-Me
o-Me
o-Ac
o-Bz
H
o-Ac
o-Bz
H
H
H
Br
Br
Cl
Cl
Br
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Br
Cl
39
17
15
10
8
11
48
40
34
36
38
38
50
76
80
±
13
73
73
70
75
74
22
20
12
18
12
24
28
10
7
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
78
61
73
82
81
80
H
H
H
H
±
±
±
±
1s
1u
1v
H
H
H
H
±
Owing to mesomerism, which confers to amide groups a partial double-bond
character, the aromatic moieties and halogenoalkyl groups of the anilides 1a ± 1o are
probably mostly (E)-configured [5], whereas the N-unsubstituted anilides 1p ± 1s, and
1u and 1v exist almost exclusively in the (Z)-form (Scheme 2), which is the disfavored

Helvetica Chimica Acta ± Vol. 88 (2005)
37
conformation for cyclization. This would explain why the above N-unsubstituted
compounds (R1 ˆ H) did not cyclize, but underwent reduction.
The yields of the cyclized products 2b ± 2f decreased as the degree of substitution at
the a-C-atom of the 2-halogenoalkyl group in 1b ± 1f decreased. The higher yields of
the cyclized products 2a and 2g ± 2o relative to 2b ± 2f might be attributed to differences
in the stabilities of the intermediate carbamoyl radicals initially formed, the tertiary
radicals being more stable than the secondary ones.
Scheme 2. Representation of the Mesomeric Structures of Amides with (E)- vs. (Z)-Configured CˆN Bonds. For
geometric reasons, only the (E)-isomers, with their (substituted) bromomethyl and aryl residues in close
proximity, can cyclize.
The above reaction could also be performed with Ni powder in i-PrOH instead of
Bu3SnH/AIBN, as tested for compounds 1a ± 1e, 1g ± 1j, 1l ± 1p, 1t, and 1u (Table 2)
[1h][6e]. The yields of the cyclized products 2a and 2g were not altered by additionally
using AcOH in combination with Ni [7]. When the ortho-substituted substrates 1i, 1m,
or 1n were reacted, the corresponding dehydrobromination products 3i, 3m, and 3n,
respectively, were produced, along with the indolones 2i, 2m, and 2n; the corresponding
reduction products 5 were not detected in this case. The photochemical dehydrobro-
mination of 1 to 3 has already been reported [5].
Triethylborane (Et3B) has recently been used for the initiation of radical reactions
to be carried out under mild conditions [1e][1g][8]. We, thus, also examined the radical
reactions of compounds 1 with Et3B in benzene or aqueous EtOH. Under these
conditions, the indolones 2 and the reduction products 3 were also formed (Table 3),
but the yields were generally lower than those obtained in the reactions with Bu3SnH/
AIBN or Ni powder.
The radical cyclization of the 2-bromo-2-methyl-N-(w-phenylalkyl)-propanamides
6 or 7 to medium-membered lactams were unsuccessful. Treatment of 6 or 7 with
Bu3SnH/AIBN or with Et3B gave the reduction products 8 as the sole products, except
for the reaction of 6b with Et3B, in which 1,4-dihydro-2,4,4-trimethylisoquinolin-
3(2H)-one (9b) was produced in low yield (14%) (Table 4).
Photochemical cyclizations of chloroacetamides to medium-membered lactams
have been reported [9]. Irradiation of compounds 6, 7, 10, or 11 (in O2-free MeCN;
Pyrex tube) with a high-pressure mercury lamp afforded only the dehydrobromination
products 12 ± 14 and 4, respectively; the cyclized products (lactams) were not observed
(Table 5). Irradiation of 6b in the presence of a radical quencher, 2,6-di(tert-
butyl)phenol, resulted in a decrease of the yield of 12b (Entry 3 in Table 5).
Mechanistically, these dehydrobrominations can be rationalized by CÀBr-bond
homolysis, followed by elimination of HBr. The lack of cyclized products can be

38
Helvetica Chimica Acta ± Vol. 88 (2005)
Table 2. Nickel Promoted Reactions of Compounds 1. Bz ˆ Benzoyl.
Substituents
Isolated yield [%]
R1
R2
R3
Y
X
2
5
3
1a
1aa)
1b
1c
1d
1e
1g
1ga)
1h
1i
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Me
Me
H
H
H
Me
Me
Me
Me
Ph
H
H
H
H
H
H
H
H
p-Cl
o-Cl
p-MeO
p-Me
o-Me
o-Ac
o-Bz
H
Br
Br
Br
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Br
69
63
11
trace
27
trace
50
48
48
51trace
54
64
45
56
85
±
±
±
12
15
14
trace
13
50
43
47
45
48
37
32
trace
trace
3
trace
51±
81
±
±
±
±
±
±
±
±
±
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
1j
1l
±
±
31
27
±
1m
1n
1o
1p
1t
±
H
H
H
H
1u
H
H
±
a) Reaction performed in the presence of AcOH.
Table 3. Triethylborane Promoted Reactions of Compounds 1. Bz ˆ Benzoyl.
Substituents
R1
Isolated yield (%)
Y
X
2
5
1a
Ph
Ph
Ph
Me
Ph
Me
Me
Me
Me
H
H
H
H
Br
Br
Br
Br
I
Br
Br
Br
I
218
43
25
27
38
1trace
30
13
1aa)
1ab)
1g
20
9
13
26
1wb)
1n
H
o-Ac
o-Bz
o-Bz
o-Bz
1o
trace
trace
2
1oc)
1x
27
a) Reaction performed in the presence of Bu3SnH (2.2 equiv.). b) 1.3 equiv. of Et3B were used. c) EtOH/H2O
3 : 1was used as solvent.

Helvetica Chimica Acta ± Vol. 88 (2005)
39
Table 4. Attempted Radical Cyclization with Elongated Amides
Substituents
Isolated yield [%]
n
R1
Method
8
9
6a
6a
6b
6b
7c
7c
0
0
0
0
1Me
1Me
H
H
Me
Me
A
B
A
B
A
B
72
±
45
50
48
43
±
±
±
14
±
±
attributed to an unfavorable conformation of the substrates (6, 7, 10, 11), since there is
no significant interaction between the aromatic ring and the 2-bromoalkyl group [5].
Table 5. Attempted Photocyclization of Elongated Amides
Substituents
Product
Isolated yield [%]
Entry
n
R1
Y
1
2
3
4
5
6
7
8
9
6a
0
0
0
0
0
0
1
1H
2
H
H
H
H
H
12a
12b
12b
12c
12d
12e
13a
13b
14
12
39
16
33
3
22
40
47
25
7
6b
6ba)
6c
6d
6e
7a
7b
10
Me
Me
Bn
Ph
H
H
3,4-OCH2OÀ
H
H
3,4-(MeO)
2
H
H
H
H
10
11
3
4
a) Reaction performed in the presence of 2,6-di-(tert-butyl)phenol (1equiv.).
Experimental Part
General. Regular column chromatography (CC) and flash chromatography (FC) were performed with
silica gel Wakogel C-300 and Merck 60, resp. M.p.: Yanaco MP-J3 micro-melting-point apparatus; uncorrected.
B.p. : Shibata GTO-350-RD glass-tube-oven distillation apparatus. IR Spectra: Jasco FT/IR-300 spectropho-
1
tometer; in cmÀ1. H- and 13C-NMR Spectra: Jeol JNM-EX-270 (270 MHz) or Varian Gemini-200 (200 MHz)
spectrometers; in CDCl3, with Me4Si as internal standard; d in ppm, J in Hz.

40
Helvetica Chimica Acta ± Vol. 88 (2005)
General Procedure for Radical Reactions. Method A: To a soln. of 1 (1mmol) in toluene (30 ml) was added
dropwise a soln. of Bu3SnH (1.1 equiv.) and AIBN (20 mg) in toluene (10 ml) over 2 h via syringe pump. The
mixture was heated at reflux for 6 h. Then, more Bu3SnH (1.1 equiv.) and AIBN (20 mg) in toluene (10 ml) were
added dropwise over 1h, and the mixture was refluxed for another 8 h. After evaporation of the solvent, AcOEt
(20 ml) and 10% aq. KF soln. (50 ml) were added to the residue, and this mixture was stirred. The org. phase was
separated, and the aq. phase was extracted with AcOEt. The combined org. phase was washed with brine, dried
(MgSO4), and concentrated. The residual oil was subjected to CC (SiO2; AcOEt/toluene 1:50 ! 1:4) to afford
the products 2 and 5 (see Table 1).
Method B: A soln. of 1 (1mmol) and Ni powder (1.76 g, 30 mmol) in i-PrOH (15 ml) was heated at reflux
under Ar gas for 20 h. The mixture was then cooled to r.t., diluted with AcOEt, and filtered through Celite. Then,
H2O was added to the filtrate, which was subsequently neutralized with sat. aq. NaHCO3 soln., washed with
H2O, brine, dried (MgSO4), and concentrated. The residual oil was subjected to CC (SiO2; AcOEt/toluene
1:50 ! 1:4) to afford the products 2, 3, and 5 (see Table 2).
Method C: To a soln. of 1 (1mmol) in benzene (10 ml) was added dropwise a 1 m soln. of Et3B (0.6 molar
equiv.) in THF via syringe pump. Then, the mixture was heated at reflux for 10 h. Usual workup gave the
products 2 and 5 (see Table 3), which were identified by spectral comparison with literature data [5][6] and with
authentic samples prepared independently from the corresponding anilines and alkanoyl or 2-methylprop-2-
enoyl chlorides.
7-Acetyl-1,3-dihydro-1,3,3-trimethylindol-2(2H)-one (2n). B.p. 139 ± 1448/3 Torr. IR (film): 1710, 1611.
1H-NMR: 1.36 (s, 3 H); 2.34 (s, 6 H); 3.20 (s, 3 H); 7.12 ± 7.30 (m, 3 H). Anal. calc. for C13H15NO2 (217.26): C
71.86, H 6.96, N 6.45; found: C 71.68, H 7.14, N 6.32.
7-Benzoyl-1,3-dihydro-1,3,3-trimethylindol-2(2H)-one (2o). M.p. 175 ± 1768. IR (KBr): 1718, 1660.
1H-NMR: 1.43 (s, 6 H); 3.01( s, 3 H); 7.07 ± 7.64 (m, 7 H); 7.89 ± 7.95 (m, 2 H). 13C-NMR: 23.9; 29.2; 42.6;
120.7; 121.0; 123.5; 127.5; 127.7; 128.1; 129.9; 133.2; 136.8; 137.0; 140.7; 181.3; 195.0. Anal. calc. for C18H17NO2
(279.32): C 77.39, H 6.13, N 5.01; found: C 77.25, H 6.23, N 4.80.
1
1,4-Dihydro-2,4,4-trimethylisoquinolin-3(2H)-one (9b) [10]. IR (film): 1659. H-NMR: 1.50 (s, 6 H); 3.11
(s, 3 H); 4.59 (br. s, 2 H); 7.17 ± 7.37 (m, 4 H).
Photoreactions of Homologous Amides (see Table 5). A soln. of one of the amides 6a ± 6e, 7a,b, 10, or 11
(1mmol) in MeCN (70 ml) was irradiated in a Pyrex tube with a high-pressure Hg lamp (500 W) under Ar gas
for 10 ± 15 h. After evaporation, the residue was subjected to CC (SiO2; toluene/AcOEt 9 :1 ! 4 :1) to yield the
dehydrobrominated products 12a ± 12e, 13a, 13b, 14, or 4, resp. Except for 12e and 13b (see below), these
compounds were identified by comparison with authentic samples prepared independently from the
corresponding amines and 2-methylprop-2-enoyl chloride.
N-[(1,3-Benzodioxol-5-yl)methyl]-2-methylprop-2-enamide (12e). M.p. 111 ± 1128. IR (KBr): 3337, 3300,
1655, 1612. 1H-NMR: 1.97 (d, J ˆ 1.0, 3 H); 4.38 (d, J ˆ 5.9, 2 H); 5.34 (br. s, 1H); 5.70 ( s, 1H); 5.93 ( s, 2 H); 6.17
(br. s, 1H); 6.75 ± 6.78 ( m, 3 H). 13C-NMR: 18.6; 43.5; 101.0; 108.2; 108.4; 119.6; 121.0; 132.1; 139.8; 146.9; 147.8;
168.1. Anal. calc. for C12H13NO3 (219.23): C 65.74, H 5.98, N 6.39; found: C 65.76, H 6.01, N 6.35.
N-[(3,4-Dimethoxyphenyl)ethyl]-2-methylprop-2-enamide (13b). Oil. IR (film): 3332, 1656, 1616.
1H-NMR: 1.92 (d, J ˆ 0.7, 3 H); 2.80 (t, J ˆ 6.6, 2 H); 3.51± 3.58 ( m, 2 H); 3.86 (s, 6 H); 5.29 (d, J ˆ 1.3, 1 H);
5.62 (s, 1H); 5.91(br. s, 1H); 6.72 ± 6.83 ( m, 3 H). 13C-NMR: 18.5; 35.1; 40.8; 55.8; 111.3; 111.8; 119.3; 120.6;
131.3; 140.0; 147.6; 149.0; 168.4.
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Received August 17, 2004