Formation of indole nucleus via intramolecular cyclization of aminophenylpropenyltriphenylphosphonium salts with one-carbon degradation

Article abstract of DOI:10.1016/S0040-4039(02)02199-8

Treatment of 3-(2-aminophenyl)-2-propenyltriphenylphosphonium bromide with acid anhydride and tertiary amine affords 1,3-diacylindoles in yields ranging from 22 to 64%. A plausible mechanism of this new cyclization reaction is described.

Full text of DOI:10.1016/S0040-4039(02)02199-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8893–8896
Formation of indole nucleus via intramolecular cyclization of
aminophenylpropenyltriphenylphosphonium salts with
one-carbon degradation
Shin’ichi Taira, Hiroshi Danjo and Tsuneo Imamoto*
Department of Chemistry, Faculty of Science, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 9 August 2002; revised 28 September 2002; accepted 2 October 2002
Abstract—Treatment of 3-(2-aminophenyl)-2-propenyltriphenylphosphonium bromide with acid anhydride and tertiary amine
affords 1,3-diacylindoles in yields ranging from 22 to 64%. A plausible mechanism of this new cyclization reaction is described.
© 2002 Published by Elsevier Science Ltd.
The Wittig and related reactions are recognized to be
powerful strategies for the construction of heterocy-
cles.1 Recently, we described that the intramolecular
Wittig reaction was effective for indole formation from
Based on these results, we were interested in the devel-
opment of this convenient synthetic route to benzo-
azepine derivatives from 3-(2-aminophenyl)-2-propenyl-
triphenylphosphonium salts under similar reaction
conditions (Eq. (2)). In order to evaluate the possibility
of this protocol, phosphonium salts 1 were chosen
as starting materials (Scheme 1). Thus, the 2-nitro-
(2-diacylaminobenzyl)triphenylphosphonium
salts
which were generated in situ by the reaction of (2-
aminobenzyl)triphenylphosphonium salts with acylating
agents in the presence of tertiary amines (Eq. (1)).2
benzaldehyde
derivatives
2a–e
were
treated
with ethoxycarbonylmethylenetriphenylphosphorane in
refluxing toluene for 3 h to give 3a–e as mixtures
of stereoisomers. The cinnamates 3a–e were subjected
to reduction by DIBAL to give alcohols 4a–e, which
were then converted into the corresponding phos-
phonium bromides 5a–e by bromination and sub-
(1)
Scheme 1. Reagents and conditions: (i) Ph3PꢀCHCOOEt, toluene, reflux, 3 h; 3a: 84%; 3b: 84%; 3c: 97%; 3d: 89%; 3e; 93%. (ii)
DIBAL, CH2Cl2, −78°C, 3 h; 4a: 100%; 4b: 100%; 4c: 100%; 4d: 100%; 4e: 99%. (iii) PBr3, Et2O, 0°C, 1 h. (iv) PPh3, CHCl3, rt,
overnight; 5a: 81%; 5b: 96%; 5c: 46%; 5d; 51%; 5e: 67% (two steps). (v) Zn, 48% HBr, EtOH, 0°C to rt, overnight; 1a: 87%; 1b:
76%; 1c: 83%; 1d: 73%; 1e; 95%.
* Corresponding author. Tel./fax: +81-43-290-2791; e-mail: imamoto@scichem.s.chiba-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02199-8

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S. Taira et al. / Tetrahedron Letters 43 (2002) 8893–8896
sequent substitution reaction with triphenylphosphine.
The nitro group was reduced by the use of zinc powder
and hydrobromic acid to afford the phosphonium salts
1a–e.
(entries 6–9). It is intersting to note that not only this
cyclization tolerates substitution at aromatic moiety but
also is applicable to construction of 3,4-disubstituted
indoles, which are generally prepared with difficulty by
Friedel–Crafts reaction (entries 12 and 13).
In the cyclization of 1, some co-products were
observed. When 1a was allowed to react under the
conditions described in entry 5, triphenylphosphine
oxide (7) and triphenylphosphonium diacetylmethylide
(8) were isolated in 49% and 5% yield, respectively
(Scheme 3).5,6 In addition, treatment of triphenylphos-
phonium acetylmethylide with acetic anhydride and
diisopropylethylamine at 120°C provided 7 and 8 in
78% and 8% yields. These results suggest elimination of
triphenylphosphonium acetylmethylide as the one-car-
bon unit.
(2)
Cyclization of 1a was carried out by treatment with
acetic anhydride in the presence of triethylamine at
120°C. To our surprise, no trace of the desired ben-
zoazepine derivatives produced. Instead, an unprece-
dented cyclization reaction proceeded via one-carbon
degradation from the allylic moiety to form 1,3-diacyl-
indoles 6a (Scheme 2).
The following experiments were carried out to elucidate
the mechanism of this indole formation. The reaction of
N,N-diacetylated phosphonium salt 9,7 previously pre-
pared by acetylation of 1a, with benzoic anhydride was
performed in the presence of diisopropylethylamine at
120°C (Scheme 4). In spite of excess amount of benzoic
anhydride, 3-acetylindoles 6a and 10 were mainly pro-
duced, indicating that the acyl group on the nitrogen
atom migrates intramoleculary to g-carbon of the
allylic phosphonium salt.8
The cyclization reaction of several substrates was exam-
ined under various reaction conditions. The results are
summarized in Table 1.3 In all cases, indole formation
was observed exclusively. Amine base was required for
this cyclization, and relatively high yield of the indole
product was obtained by the use of diisopropylethyl-
amine (entries 4 and 5).4 Other acid anhydrides and
acyl chlorides also served as the acylating agents,
although the yields of the products were moderate
Scheme 2.
Table 1. Cyclization of aminophenylpropenyltriphenylphosphonium bromides using acid anhydrides or acyl chlorides
Entry
Substrate
(R2CO)2O or R2COCl
Base
Time (h)
Product
Yield (%)
1
1a (R1=H)
1a (R1=H)
1a (R1=H)
1a (R1=H)
1a (R1=H)
1a (R1=H)
1a (R1=H)
1a (R1=H)
1a (R1=H)
1b (R1=4-Cl)
1c (R1=5-OMe)
1d (R1=6-Cl)
1e (R1=6-OMe)
Ac2O
Ac2O
Ac2O
Ac2O
None
Et3N
7
7
7
6a
6a
6a
6a
6a
6b
6c
6a
6c
6d
6e
6f
–
2a
52
13
53
64
31
49
32
32
53
62
29
22
3a
Pyridine
i-Pr2EtN
i-Pr2EtN
i-Pr2EtN
i-Pr2EtN
2,6-Lutidine
2,6-Lutidine
i-Pr2EtN
i-Pr2EtN
i-Pr2EtN
i-Pr2EtN
4a
7
5a
Ac2O
18
18
18
18
18
18
18
18
18
6a
(EtCO)2O
(PhCO)2O
AcCl
PhCOCl
Ac2O
Ac2O
Ac2O
Ac2O
7a
8b
9b
10a
11a
12a
13a
6g
a Molar ratio: phosphonium salt/acid anhydride/i-Pr2EtN=1/10/3.6.
b Molar ratio: phosphonium salt/acyl chloride/2,6-lutidine=1/10/15.

S. Taira et al. / Tetrahedron Letters 43 (2002) 8893–8896
8895
Scheme 3.
Scheme 4.
From these results, the following reaction mechanism is
proposed (Scheme 5). Diacylated phosphonium salt 13
is converted into twitterionic intermediate 14 via
intramolecular migration of an acyl group. Cyclization
of 14 results in the formation of ylide 15.
to give triphenylphosphonium diacylmethylide 18, most
of which is converted into triphenylphosphine oxide
under these conditions.6
In summary, we found that 1,3-diacylindole derivatives
are produced by the reaction of 3-(2-aminophenyl)-2-
propenyltriphenylphosphonium bromides with acylat-
ing agents in the presence of tertiary amines.
The interaction of intermediate 16 with tertiary amine
facilitates carbonꢁcarbon bond fission to yield 1,3-diac-
ylindole derivative 6. It is noted that the formation of
the stabilized ylide, triphenylphosphonium acylmethyl-
ide 17, is one of the driving forces of this elimination.
The generated ylide 17 reacts with the acylating agent
Further work to clarify the scope and limitation of this
new indole formation and its detailed reaction mecha-
nism are now in progress.
Scheme 5. Plausible reaction mechanism.

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S. Taira et al. / Tetrahedron Letters 43 (2002) 8893–8896
1
Acknowledgements
powder: Mp 151–152°C. H NMR (400 MHz, CDCl3): l
8.3–8.4 (m, 2H), 8.01 (s, 1H), 7.3–7.5 (m, 2H), 2.71 (s, 3H),
2.57 (s, 3H); IR (KBr) 1715, 1660, 1547, 1449, 1389, 1263,
1223, 1165 cm−1. Anal. calcd for C12H11NO2: C, 71.63; H,
5.51; N, 6.96. Found: C, 71.57; H, 5.56; N, 6.96.
4. The reaction was examined at 120°C using 1a and acetic
anhydride (10 equiv.) with varying amount of i-Pr2EtN.
Representative results are as follows: 5.5 equiv. of i-
Pr2EtN, 18 h, 65% yield; 8.8 equiv. of i-Pr2EtN, 18 h, 62%
yield.
This work was supported by the Grant-in-Aid from the
Ministry of Education, Science, Culture and Sports,
Japan.
References
5. The structure of triphenylphosphonium diacylmethylide
1. (a) Heron, B. M. Heterocycles 1995, 41, 2357–2386; (b) Le
Corre, M.; Hercount, A.; Le Baron, H. J. Chem. Soc.,
Chem. Commun. 1981, 14–15; (c) Murphy, P. J.; Lee, S. E.
J. Chem. Soc., Perkin Trans. 1 1999, 3049–3066 and refer-
ences cited therein.
1
(8) was confirmed by H, 13C and 31P NMR spectroscopy.
These data were in accord with those of the authentic
sample prepared by the reported procedure.6 1H NMR
(400 MHz, CDCl3): l 2.28 (s, 6H), 7.4–7.5 (m, 15H); 13C
NMR (99 MHz, CDCl3): l 30.5, 126.1, 127.0, 128.5, 128.6,
131.5, 132.8, 132.9, 193.2, 193.3; 31P NMR (162 MHz,
CDCl3): l 16.86.
2. Taira, S.; Danjo, H.; Imamoto, T. Tetrahedron Lett. 2002,
43, 2885–2888.
3. Typical procedure for the synthesis of compound 6a: A
mixture of 3-(2-aminophenyl)-2-propenyltriphenylphos-
phonium bromide (1a) (474 mg, 1 mmol), acetic anhydride
(0.94 mL, 10 mmol) and diisopropylethylamine (0.63 mL,
3.6 mmol) was heated at 120°C for 18 h. After dilution
with H2O, the mixture was neutralized with NaHCO3 and
extracted with ethyl acetate. The organic extracts were
washed with H2O, dil. HCl and brine, and dried over
Na2SO4. Removal of solvent in vacuo, and purification by
column chromatography (n-hexane/ethyl acetate, 1/1)
afforded 1,3-diacetylindole (6a)9 (128 mg, 64%) as a yellow
6. Chopard, P. A.; Searle, R. J. G.; Devitt, F. H. J. Org.
Chem. 1965, 30, 1015–1019.
7. N,N-Diacetylated phosphonium salt 9 was extremely mois-
ture sensitive and readily decomposed.
8. It is known that the acylation of allylphosphonium ylides
with acyl chloride proceeds at the g-carbon atom with
formation of the corresponding ylides. See: Ohler, E.;
Zbiral, E. Chem. Ber. 1980, 113, 2852–2867.
9. Kurihara, T.; Fujimoto, T.; Harusawa, S.; Yoneda, R.
Synthesis 1987, 396–397.