Synthesis of indoles, 3,1-benzoxazines, and quinolines from 2-alkenylanilides and active seleniums

Article abstract of DOI:10.1080/10426501003772169

The reaction of diphenyl diselenide with [bis(trifluoroacetoxy)iodo]benzene followed by the addition of 2-allylphenol gave 2-phenylselenomethyl-2,3- dihydro-benzofuran in 82% yield. The reaction of phenylselenenyl chloride with N-tosyl-2-isopropenylanilide followed by the addition of m-CPBA afforded N-tosyl-3-methylindole in 68% yield. Interestingly, the reaction of diphenyl diselenide with [bis(trifluoroacetoxy)iodo]benzene followed by the addition of 2-isopropenylaniline gave 4-methyl-4-phenylselenomethyl-2-trifluoromethyl-3,1- benzooxazine in 65% yield. Copyright Taylor & Francis Group.

Full text of DOI:10.1080/10426501003772169

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Synthesis of Indoles, 3,1-Benzoxazines,
and Quinolines from 2-Alkenylanilides
and Active Seleniums
Kentaro Okuma a & Jun-ichi Seto a
a Department of Chemistry, Faculty of Science , Fukuoka University ,
Fukuoka, Japan
Published online: 27 May 2010.
To cite this article: Kentaro Okuma & Jun-ichi Seto (2010) Synthesis of Indoles, 3,1-Benzoxazines,
and Quinolines from 2-Alkenylanilides and Active Seleniums, Phosphorus, Sulfur, and Silicon and the
Related Elements, 185:5-6, 1014-1020, DOI: 10.1080/10426501003772169
To link to this article: http://dx.doi.org/10.1080/10426501003772169
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Phosphorus, Sulfur, and Silicon, 185:1014–1020, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426501003772169
SYNTHESIS OF INDOLES, 3,1-BENZOXAZINES, AND
QUINOLINES FROM 2-ALKENYLANILIDES AND ACTIVE
SELENIUMS
Kentaro Okuma and Jun-ichi Seto
Department of Chemistry, Faculty of Science, Fukuoka University, Fukuoka, Japan
The reaction of diphenyl diselenide with [bis(trifluoroacetoxy)iodo]benzene followed by the
addition of 2-allylphenol gave 2-phenylselenomethyl-2,3-dihydro-benzofuran in 82% yield.
The reaction of phenylselenenyl chloride with N-tosyl-2-isopropenylanilide followed by the
addition of m-CPBA afforded N-tosyl-3-methylindole in 68% yield. Interestingly, the re-
action of diphenyl diselenide with [bis(trifluoroacetoxy)iodo]benzene followed by the ad-
dition of 2-isopropenylaniline gave 4-methyl-4-phenylselenomethyl-2-trifluoromethyl-3,1-
benzooxazine in 65% yield.
Keywords 3,1-Benzooxazine; [bis(trifluoroacetoxy)iodo]benzene; diphenyl diselenide; in-
dole; quinoline
INTRODUCTION
Phenylselenenyl chloride (1) is a useful reagent for the synthesis of cyclic ethers
or amines.1 Phenylseleno derivative of 2,3-dihydro-benzofuran was prepared by the re-
action of 1 with 2-allylphenol, which is classified as a cyclofunctionalization process.2
Recently, Browne et al. reported the synthesis of butenolide from diphenyl diselenide
(2) catalyzed intramolecular cyclization.3 Indoles are very important compounds because
of their synthetic and pharmacological utility. One of the most useful methods for the
synthesis of indoles and quinoines is the intramolecular cyclization of alkenylanilides and
alkynylanilides with active halogens because of commercial availability of starting alkeny-
lanilines.4–6 We have also reported the synthesis of N-tosylindoles (3) and 3,1-benzoxazine
(4) from 2-alkenylanilides (5) and DMTST.7 However, to our knowledge, there is no report
on the synthesis of indoles 3 by intramolecular selenoamination using 1 or diphenyl dise-
lenide 2. We report in this article the synthesis of N-tosylindoles 3, and 3,1-benzoxazines
4 from activated phenylselenenyl compounds with 2-alkenylanilides 5.
RESULTS AND DISCUSSION
We first tried the reaction of diphenyl diselenide 2 with 2-allylphenol followed by
the addition of [bis(trifluoroacetoxy)iodo]benzene (6). When allylphenol was added to a
Received 29 November 2008; accepted 29 December 2008.
Dedicated to Professor Naomichi Furukawa on the occasion of his 70th birthday.
Address correspondence to Kentaro Okuma, Department of Chemistry, Faculty of Science, Fukuoka Uni-
versity, Jonan-ku, Fukuoka 814-0180, Japan. E-mail: kokuma@fukuoka-u.ac.jp
1014

SYNTHESES WITH 2-ALKENYLANILIDES AND ACTIVE SELENIUMS
1015
mixture of diselenide 2 and iodobenzene 6 in dichloromethane at rt, 2-phenylselenomethyl-
2,3-dihydrobenzofuran 7 was obtained in 82% yield (Scheme 1). The result was quite
similar to the reaction by using phenylselenenyl chloride as an active selenation reagent.2
O
Ph
PhSeSePh
OCCF3
I
OH
2
Se Ph
Se
+
CH2Cl2
SePh
O
PhI(OCOCF3)2
Ph
6
7
CF3COO
82%
Scheme 1
Since this method proved to be a good procedure for intramolecular cyclization using
diselenide 2, we applied it to the synthesis of indole 3 via intramolecular aminocyclization
of 2-isopropenylanilides 5, which were easily synthesized from 2-alkenylnitrobenzenes.4
When 2-isopropenyl-N-tosylanilide (5a) was treated with selenenyl chloride 1 at rt for
6 h followed by the addition of m-chloroperoxybenzoic acid (m-CPBA), 3-methyl-N-
tosylindole (3a) was obtained in 52% yield. Similarly, the reaction of 5a with diselenide 2
and 6 at rt for 6 h followed by oxidation gave 3a in 67% yield (Scheme 2). The reaction
of 2-vinyl-N-tosylanilide (5b) with selenenyl chloride followed by oxidation also gave
N-tosylindole (3b), while the yield was 36%. Thus, the synthesis of indoles from 2-
alkenylanilides was achieved by selenoamination.
Me
Me
m-CPBA
+
PhSeCl
CH2Cl2
N
NH
Ts
1
Ts
5a
3a
52%
PhSeSePh
Me
5a
m-CPBA
2
CH2Cl2
+
PhI(OCOCF3)2
N
6
Ts
3a
67%
m-CPBA
+
PhSeCl
N
Ts
CH2Cl2
NH
1
Ts
5b
3b
36%
Scheme 2

1016
K. OKUMA AND J. SETO
The reaction of 2-isopropenylacetanilide (5c) with active halogens has already been
reported by Kobayashi et al.4 and Arisawa et al.,5 respectively. Although they claimed
the different structures for the reaction products, we have found that the correct structure
was 2,4-dimethyl-4-iodomethyl-3,1-benzoxazine (4a), whose structure was determined by
X-ray crystallographic analysis (Scheme 3).7
CH
CH3
3 I
CH2I
or
H3C
I2
N
or NIS
N
Ac
Ac
Arisawa et al.
Kobayashi et al.
NH
Ac
H3C
CH2I
5c
O
N
4a
CH3
Scheme 3
These results prompted us to investigate the reaction of active selenium compounds
with 2-isopropenylacetanilide 5c as to whether a similar reaction would occur. We in-
vestigated the reaction of 1 with acetanilide 5c. Treatment of phenylselenenyl chloride
1 with acetanilide 5c followed by the addition of aq. Na2CO3 gave 2,4-dimethyl-4-
phenylselenomethyl-3,1-benzoxazine (4b) in 84% yield. Diphenyl diselenide 2 also reacted
with acetanilide 5c to give 4b in 93% yield. Interestingly, the reaction of diselenide 2 with
2-isopropenylaniline (8) followed by the addition of [bis(trifluoroacetoxy)iodo]benzene 6
afforded 4-methyl-4-phenylselenomethyl-2-trifluoromethyl-3,1-benzoxazine (4c) in 70%
yield, suggesting that [bis(trifluoroacetoxy)iodo]benzene 6 not only activates diphenyl dis-
elenide but also acts as an acylating reagent (Scheme 4).
These results clearly show that activated intermediate (a) was attacked by acyl oxygen
at the benzyl position, which is more cationic than the β-position, to afford the less strained
six-membered heterocycle, 3,1-benzoxazine 4 (Scheme 5).
Since intramolecular cyclization that used active halogens or active sulfur and 2-
aminochalcones has been proven to be a good procedure for the synthesis of quinolines,8
we finally investigated the reaction of 2-aminochalchone (10) with active selenium reagents.
When 2-aminochalchone 10 was treated with 1 at rt followed by the addition of aq. Na2CO3,
2-phenylquinoline (11) was obtained in almost quantitative yield (Scheme 6).
In conclusion, we have developed a simple method for the synthesis of indoles, 3,1-
benzoxazines, and quinolines, using phenylselenenyl chloride or diphenyl diselenide as
double-bond activating reagents.
EXPERIMENTAL
Flash chromatography was carried out by Merck Kieselgel 60 (230–400 mesh).
Thin layer chromatography (TLC) was carried out on commercially available coated
plates (Merck silica Kieselgel 60F254). All solvents were distilled before use, and no

SYNTHESES WITH 2-ALKENYLANILIDES AND ACTIVE SELENIUMS
1017
CH2SePh
Me
Me
10% Na2CO3 (aq)
O
+
PhSeCl
CH2Cl2
1
N
CH3
NHAc
84%
4b
5c
5c
10% Na2CO3 (aq)
4b
93%
+ PhI(OCOCF3)2
PhSeSePh
CH2Cl2
2
6
Me
CH2SePh
O
Me
PhSeSePh
10% Na2CO3 (aq)
8
NH2
2
+ PhI(OCOCF3)2
N
CF3
CH2Cl2
6
4c
Scheme 4
O
Ph
OCCF3
Ph
Se
I
Se Ph
Me
Me
Se
Ph
Ph
O
O
I
F3C
SePh
NH2
NH2
Ph
Se
Me
Me
CH2SePh
O
N
CF3
NH
C
F3C
O
4c
a
Scheme 5
O
Ph
aq. Na2CO3
+ PhSeCl
NH2
N
CH2Cl2
Ph
11
10
Scheme 6

1018
K. OKUMA AND J. SETO
further treatment was carried out. NMR spectra were measured on a Varian Innova-400
(400 MHz for 1H, 100 MHz for 13C). The melting points were uncorrected. Phenylse-
lenenyl chloride, diphenyl diselenide, bis(trifluroacetoxy)iodobenzene, 2-allylphenol, and
2-isopropenylaniline are commercially available. 2-Alkenylanilides were synthesized by
the reported procedure.4
Reaction of 2-Allylphenol with Phenylselenenyl Chloride 1
To a solution of phenylselenenyl chloride 1 (211 mg, 1.1 mmol) in dichloromethane
(5 mL), a solution of 2-allylphenol (134 mg, 1.0 mmol) in dichloromethane (5 mL) was
added dropwise at rt. After stirring for 2 h, aq. Na2CO3 (5%, 5 mL) was added to the
reaction mixture and separated. The dichloromethane layer was dried over magnesium
sulfate, filtered, and evaporated to give 2-phenylselenomethyl-2,3-dihydrobenzofuran (7)
(237 mg, 0.82 mmol). Colorless oil: The spectral data was identical with the reported
value.2 1H NMR (CDCl3) δ = 2.97–3.14 (m, 2H, CHH and PhSeCHH), 3.30–3.40 (m, 2H,
CHH and PhSeCHH), 4.93 (br m, 1H, CH), 6.74 (d, 1H, J = 8.0 Hz, Ar), 6.83 (dd, 1H, J
= 7.2 Hz, 8.0 Hz, Ar), 7.05–7.16 (m, 2H, Ar), 7.25 (br s, 3H, PhSe), 7.55 (br s, 2H, PhSe).
Reaction of 2-Isopropenyl-N-p-tosylanilide 5a with Phenylselenenyl
Chloride 1
To a solution of chloride 1 (211 mg, 1.1 mmol) in dichloromethane (10 mL), a solution
of 2-isopropenyl-N-p-tosylanilide 5a (287 mg, 1.0 mmol) in dichloromethane (5 mL) was
added at rt. After stirring for 8 h, m-CPBA (190 g, 1.1 mmol) in dichloromethane (10 mL)
was added to the reaction mixture. After stirring for 5 h, the reaction mixture was washed
with 10% of aq. sodium carbonate (10 mL) and separated. The water layer was extracted
with dichloromethane (5 mL × 2), and the combined extract was dried over sodium sulfate,
filtered, and evaporated to give a pale yellow solid, which was chromatographed over silica
gel by elution with hexane/dichloromethane (1:1) to afford colorless plates of 3-methyl-
1
N-tosylindole 3a (148 mg, 0.52 mmol). Mp 112–114◦C. (lit.9 mp 114–115◦C.) H NMR
(CDCl3) δ = 2.22 (s, 3H, CH3), 2.29 (s, 3H, TsMe), 7.16 (d, 2H, J = 8.0 Hz, Ts), 7.20
(t, 1H, J = 8.4 Hz, Ar), 7.30 (t, 1H, J = 8.0 Hz, Ar), 7.43 (d, 1H, J = 8.0 Hz, Ar), 7.73
(d, 2H, J = 8.0 Hz, Ts), 7.98 (d, 1H, J = 8.4 Hz, Ar). 13C NMR (CDCl3) δ = 9.91 (Me),
21.74 (TsMe), 113.89 (Ar), 118.83 (Ar), 119.61 (Ar), 123.20 (Ar), 123.29 (Ar), 124.79
(Ar), 126.95 (Ts), 130.00 (Ts), 132.02 (Ar), 135.49 (Ar), 135.64 (Ts), 144.88 (Ts).
Reaction of 2-Isopropenyl-N-p-tosylanilide 5a with Diphenyl Diselenide
and [Bis(trifluoroacetoxy)iodo]benzene
To a solution of diselenide 2 (187 mg, 0.60 mmol) and [bis(trifluoroacetoxy)iodo]
benzene 6 (516 mg, 1.2 mmol) in dichloromethane (15 mL), 2-isopropenyl-N-tosylanilide
5a (287 mg, 1.0 mmol) in dichloromethane (5 mL) was added at rt. After stirring for 9 h,
m-CPBA (182 mg, 1.0 mmol) in dichloromethane (10 mL) was added to this solution. After
stirring for 5 h, the mixture was poured into aq sodium carbonate (10%), and separated.
The water layer was extracted with dichloromethane (5 mL × 2), and the combined extract
was dried over sodium sulfate, filtered, and evaporated to give a yellow oil, which was

SYNTHESES WITH 2-ALKENYLANILIDES AND ACTIVE SELENIUMS
1019
chromatographed over silica gel by elution with dichloromethane/hexane (1:3) to give
3-methyl-N-tosylindole (191 mg, 0.67 mmol).
Reaction of 2-Isopropenylacetanilide 5c with Phenylselenenyl
Chloride 1
To a solution of phenylselenenyl chloride 1 (211 mg, 1.1 mmol) in dichloromethane
(5 mL), a solution of 2-isopropenylacetanilide 5c (175 mg, 1.0 mmol) in dichloromethane
(5 mL) was added at rt. After stirring for 5 h, the reaction mixture was washed with
10% of aq. sodium carbonate (10 mL) and separated. The water layer was extracted with
dichloromethane (5 mL × 2), and the combined extract was dried over sodium sulfate,
filtered, and evaporated to give pale yellow solid, which was chromatographed over silica
gel by elution with hexane/dichloromethane (1:1) to afford colorless plates of 2,4-dimethyl-
4-phenylselenomethyl-3,1-benzoxazine (4b) (277 mg, 0.84 mmol). Colorless oil. 1H NMR
(CDCl3) δ = 1.78 (s, 3H, Me), 1.92 (s, 3H, Me), 3.24 (d, 1H, J = 13.2 Hz, CHH), 3.46 (d,
1H, J = 13.2 Hz, CHH), 7.00–7.43 (m, 9H, Ar). 13C NMR (CDCl3) δ = 21.45 (Me), 27.28
(Me), 40.62 (CH2), 123.27, 124.20, 126.66, 127.27, 127.80, 129.17, 129.21, 130.47, 133.09,
137.90 (Ar), 160.30 (C = N). HRMS: Found; 331.0475. Calcd for C17H17O80Se(M+);
331.0475.
Reaction of 2-Isopropenylacetanilide 5c with Diphenyl Diselenide 2 and
[Bis(trifluoroacetoxy)iodo]benzene 6
To a solution of diphenyl diselenide 2 (187 mg, 0.6 mmol) and iodobenzene 6 (516
mg, 1.2 mmol) in dichloromethane (15 mL), a solution of 2-isopropenylacetanilide 5c (175
mg, 1.0 mmol) in dichloromethane (5 mL) was added at rt. After stirring for 8 h, the
reaction mixture was washed with 10% of aq. sodium carbonate (10 mL) and separated.
The water layer was extracted with dichloromethane (5 mL × 2), and the combined extract
was dried over sodium sulfate, filtered, and evaporated to give a colorless solid, which was
chromatographed over silica gel by elution with hexane/dichloromethane (1:1) to afford
benzoxazine 4b (307 mg, 0.93 mmol). Colorless oil.
Reaction of 2-Isopropenylaniline 8 with Diphenyl Diselenide 2
and [Bis(trifluoroacetoxy)iodo]benzene 6
To a solution of diselenide 2 (187 mg, 0.60 mmol) and iodobenzene 6 (516 mg,
1.2 mmol) in dichloromethane (15 mL), a solution of 2-isopropenylaniline 8 (133 mg, 1.0
mmol) in dichloromethane (5 mL) was added at rt. After stirring for 8 h, the reaction mixture
was washed with 10% of aq. sodium carbonate (10 mL) and separated. The water layer
was extracted with dichloromethane (5 mL × 2), and the combined extract was dried over
sodium sulfate, filtered, and evaporated to give colorless solid, which was chromatographed
over silica gel by elution with hexane/dichloromethane (1:1) to afford 2-trifluoromethyl-
4-phenylselenomethyl-4-methyl-3,1-benzoxazine (4c) (268 mg, 0.70 mmol). Colorless oil.
1H NMR (CDCl3) δ = 1.84 (s, 3H, Me), 3.30 (d, 1H, J = 13.2 Hz, CHH), 3.51 (d, 1H, J =
13.2 Hz, CHH), 7.10 (d, 1H, J = 8.0 Hz, Ar), 7.12–7.46 (m, 8H, Ar). 13C NMR (CDCl3)
δ = 28 (Me), 40.5 (CH2), 83.5, 117 (q, JC-F = Hz, CF3), 124.02, 126.51, 127.62, 128.55,

1020
K. OKUMA AND J. SETO
129.18, 129.31, 129.65, 130.10, 133.52, 135.94 (Ar), 147.63 (C = N). HRMS: Found;
385.0175. Calcd for C15H10F3NO80Se (M+); 385.0193.
Reaction of 2-Aminochalchone 10 with Phenylselenenyl Chloride 1
To a solution of chloride 1 (211 mg, 1.1 mmol) in dichloromethane (10 mL), a
solution of 2-aminochalchone 10 (223 mg, 1.0 mmol) in dichloromethane (5 mL) was
added at rt. After stirring for 8 h, the reaction mixture was washed with 10% of aq. sodium
carbonate (10 mL) and separated. The water layer was extracted with dichloromethane
(5 mL × 2), and the combined extract was dried over magnesium sulfate, filtered, and
evaporated to give a colorless solid, which was chromatographed over silica gel by elution
with hexane/dichloromethane (1:1) to afford colorless crystals of 2-phenylquinoline (11)
(207 mg, 0.96 mmol). Mp 83–84◦C. Spectral data of 11 was identical with the commercially
available sample (mp 84–85◦C).
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