Concise one-pot tandem synthesis of indoles and isoquinolines from amides

Article abstract of DOI:10.1002/anie.200904960

Heterocyclic hot pot: Platinum[II]-catalyzed syntheses of indoles and isoquinolines from isocyanates, which are derived from a Hofmann-type rearrangement of amides using a hypervalent iodine reagent, are described. C2-symmetric macrocyclic bis[indole]s ca

Full text of DOI:10.1002/anie.200904960

Angewandte
Chemie
DOI: 10.1002/anie.200904960
Tandem Reactions
Concise One-Pot Tandem Synthesis of Indoles and Isoquinolines from
Amides**
Noriko Okamoto, Yoshihisa Miwa, Hideki Minami, Kei Takeda, and Reiko Yanada*
The synthesis of heterocyclic compounds has attracted a great
deal of attention because of their biological activities. In
particular, the synthesis of indole and isoquinoline frame-
works by intramolecular ring closure reactions of 2-alkynyl-
benzene derivatives A is one of the most efficient approaches
for the construction of benzo-fused nitrogen heteroaromatic
systems.[1,2] We have previously reported the synthesis of 1,2-
dihydroisoquinolines using an In(OTf)3-catalyzed tandem
nucleophilic addition and cyclization of 2-alkynylarylaldi-
mines B (Scheme 1).[3] As part of our continued interest in the
Scheme 2. Synthetic approach to indoles and isoquinolines from
amides.
reactivity of the metal that is required for cyclization could be
retained in the presence of co-products generated in the
Hofmann-type rearrangement. Herein, we report the first
concise one-pot tandem synthesis of indoles and isoquinolines
from amides.
Scheme 1. Tandem approach to indoles and isoquinolines from the
ring closure of A or B.
The Hofmann-type rearrangement reaction between 2-(1-
[5]
hexynyl)benzamide (1a) and PhI(OAc)2 in 1,2-dichloro-
synthesis of biologically active heteroaromatic compounds,
we focused on 2-alkynylphenyl, and 2-alkynylphenylmethyl
isocyanates. Nucleophilic addition of an alcohol to the
isocyanate, followed by intramolecular addition of the
resulting carbamate to an activated alkyne, would occur in a
tandem manner as a single synthetic operation to give indole
and isoquinoline derivatives, respectively. We reasoned that
the isocyanate derivatives would be a superior substrate for
the construction of the heterocycles compared with 2-
alkynylarylaldimines in terms of 1) the more electrophilic
nature of the isocyanate carbon; 2) the higher reactivity of the
resulting carbamate nitrogen atom toward an alkyne func-
tionality;[4] and 3) easier access from the corresponding stable
amides using a Hofmann-type rearrangement[5,6] (Scheme 2).
The success of this strategy would depend on whether the
benzene (DCB) at room temperature proceeded smoothly to
afford 2-(1-hexynyl)phenyl isocyanate 1aa in high yield[7]
(Scheme 3). After completion of the Hofmann-type rear-
Scheme 3. Hofman-type rearrangement of 2-(1-hexynyl)benzamide 1a.
rangement was confirmed by thin-layer chromatography, we
then considered the viability of subsequent indole formation
from the crude mixture by adding PtCl2, ethanol, and NEt3.
Triethylamine was used to neutralize acetic acid formed
during the reaction. The desired indole 2a was obtained in
only 9% yield, together with 64% of carbamate 3, after 3 h at
1008C (Table 1, entry 1). Contrary to our expectations, the
reaction without Et3N went to completion in 0.5 h to give 2a
in 82% yield (Table 1, entry 2). This result implies that PtCl2-
catalyzed cyclization proceeds preferentially under acidic
condition. To simplify the method, a simultaneous procedure
was examined. When a solution of 1a in DCB, in the presence
of PhI(OAc)2, PtCl2, and ethanol, was heated at 1008C, 2a
was produced in 85% yield without a decrease in the
reactivity of PtCl2 (Table 1, entry 3). The same reaction at
708C required a longer reaction time (Table 1, entry 4). Other
[*] N. Okamoto, Prof. Dr. Y. Miwa, H. Minami, Prof. Dr. R. Yanada
Faculty of Pharmaceutical Sciences,
Hiroshima International University
5-1-1 Hirokoshingai, Kure , Hiroshima 737-0112 (Japan)
Fax: (+81)823-73-8981
E-mail: ryanada@ps.hirokoku-u.ac.jp
N. Okamoto, Prof. Dr. K. Takeda
Department of Synthetic Organic Chemistry, Graduate School of
Medical Sciences, Hiroshima University
1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8553 (Japan)
[**] This work was supported by a Grant-in-Aid for Scientific
Research(C) from JSPS KAKENHI (20590027).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904960.
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Table 1: Optimization of catalyst and reaction conditions.
conditions to afford the corresponding indole in excellent
yield (Table 2, entry 6). Unfortunately, the terminal alkyne 1h
was not suitable for this reaction, resulting in a 33% yield of
2h (Table 2, entry 7). This result may be due to the known
dimerization of terminal acetylenes with PhI(OAc)2.[8] The
reaction of trimethylsilyl-protected substrate 1i revealed
desilylation to furnish 2h in moderate yield (66%, Table 2,
entry 8). Using benzyl alcohol as a nucleophile, the N-Cbz-
protected indole (Cbz = phenylmethoxycarbonyl) was
obtained in good yield (Table 2, entry 9) although the use of
tert-butanol resulted in only a 34% yield of 2k, which is
probably due to steric hindrance from the bulky nucleophile
(Table 2, entry 10).
To further examine the scope and limitation of our
tandem Hofmann-type rearrangement and cyclization strat-
egy, this procedure was applied to the construction of
dihydroisoquinolines 5 from 2-alkynylbenzylamides 4, which
are one-carbon homologues of 2-alkynylbenzamides 1. The
reactions of 4a and 4b with different alcohols proceeded
smoothly under the optimized reaction conditions to give
isoquinolines 5a–5d in good yields (Table 3, entries 1–4). The
alkynylbenzylamide 4c, which has an aliphatic substituent on
Entry
Catalyst
Conditions
Yield [%]
2a
3
1[a]
2[a]
1) PhI(OAc)2
2) PtCl2, EtOH, Et3N (3 equiv)
1) PhI(OAc)2
1008C, 3.0 h
1008C, 0.5 h
9
64
82
0
2) PtCl2 EtOH
3
4
5
6
7
8
9
PhI(OAc)2, PtCl2, EtOH
PhI(OAc)2, PtCl2, EtOH
PhI(OAc)2, PdCl2, EtOH
PhI(OAc)2, Pd(OAc)2, EtOH
PhI(OAc)2, CuCl2, EtOH
PhI(OAc)2, Cu(OTf)2, EtOH
PhI(OAc)2, InBr3, EtOH
1008C, 0.5 h
708C, 2.5 h
1008C, 2.5 h
1008C, 3.0 h
1008C, 3.0 h
1008C, 3.0 h
1008C, 3.0 h
85
84
78
6
0
4
0
0
0
62
84
93
92
0
[a] Stepwise procedure.
metal catalysts, some of which were used in previous studies
for intramolecular cyclization of 2-alkynylaniline deriva-
tives,[1–3] did not give satisfactory results (Table 1, entries 5–9).
Having established optimal reaction conditions, we exam-
ined the scope of the reaction for various 2-alkynylbenza-
mides 1a–1i (Table 2). The substitution pattern on the
aromatic ring did not affect the reaction efficiency; in the
Table 3: Tandem dihydroisoquinoline formation from 2-alkynylbenzyla-
mide.
Table 2: Tandem indole formation from 2-alkynylbenzamide.
Entry
4
R1
R2
t [h]
5
Yield [%]
1
2
3
4
5
4a
4a
4a
4b
4c
Ph
Ph
Ph
p-Tol
nBu
Et
Me
Bn
Et
1
1
1
1
3
5a
5b
5c
5d
5e
86
92
92
82
66
Et
Entry
1
R1
R2
Et
Et
Et
Et
Et
Et
Et
R3
t [h]
2
Yield [%]
1
2
3
4
5
6
7
8
9
1b
1c
1d
1e
1 f
1g
1h
1i
nBu
nBu
nBu
F
NO2
OMe
H
H
H
H
H
H
H
2
2
2
2.5
1
2
24
3
1
2b
2c
2d
2e
2 f
2g
2h
2i
84
91
82
84
66
the acetylene terminal position, also afforded the correspond-
ing isoquinoline 5e in moderate yield (66%; Table 3, entry 5).
The structure of compound 5c was confirmed by X-ray
crystallography.[9] Cyclization occurred via a 6-endo mode to
produce 5 as the sole product; 5-exo-cyclized products were
not obtained at all. The indoles and isoquinolines synthesized
herein contain enecarbamate frameworks, which are attrac-
tive synthetic intermediates owing to their applicability to
synthetic transformations.[10]
Ph
p-Tol
(CH2)3OTs
H
TMS
nBu
100
33
Et
Bn
tBu
0[a]
90
1a
1a
2j
2k
10
nBu
3
34
We then investigated the extension of this procedure to
the dimerization reaction,[11] using 2-alkynylbenzamides 6
bearing a w-(hydroxy)alkyl group as substrates. We expected
cyclodimerization involving consecutive intermolecular and
intramolecular carbamate formation, with subsequent plati-
num(II)-catalyzed transannular[12] hydroamination to macro-
cyclic bis(indole) 8 from bis(yne carbamate) 7 (Scheme 4).
First, we examined the reaction of compound 6a with
PhI(OAc)2. We anticipated that the concentration of the
reaction solution may play an important role in the reaction
efficiency. Thus, several different concentrations (0.005–0.5m)
[a] Desilylated indole 2h was obtained in 66% yield.
presence of electron-withdrawing groups or electron-donat-
ing groups, the yield of indole product was within the range
82–91% (Table 2, entries 1–3). Alkylnylbenzamide 1e, bear-
ing a phenyl group on the acetylene terminus, gave the
corresponding indole (2e) in good yield (84%; Table 2,
entry 4), although the similar p-tolyl-substituted substrate 1f
afforded a noticeably lower yield (66%; Table 2, entry 5). A
tosyloxy functional group was tolerated under the reaction
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In summary, we have developed a concise one-pot
platinum(II)-catalyzed synthesis of indoles and isoquinolines
from isocyanates which are derived from a Hofmann-type
rearrangement of amides using a hypervalent iodine reagent.
Furthermore, interesting C2-symmetrical macrocyclic bis(yne
carbamate) have been efficiently synthesized by cyclodime-
rization of 2-(w-hydroxy-1-alkynyl)benzamides. This discov-
ery led to the use of transannular cyclization to furnish
macrocyclic bis(indole) in moderate yields. Further studies
involving macrocyclic frameworks are in progress.
Scheme 4. Synthetic approach to macrocyclic bis(indole)s.
Experimental Section
General procedure for the tandem indole synthesis: Alcohol
(0.15 mmol) was added to
a solution of 2-alkynylbenzamide
(0.05 mmol), PhI(OAc)2 (0.06 mmol), and PtCl2 (0.005 mmol), in
1,2-dichlorobenzene (0.5 mL), and the mixture was stirred at 1008C.
The crude reaction mixture was purified using silica gel chromatog-
raphy to afford the indole product.
were examined at 1308C and twenty-membered ringed
bis(yne carbamate) 7a was obtained in 35–62% yield
(Table 4). The optimal concentration for the production of
7a was found to be between 0.01m and 0.05m (Table 4,
entries 2 and 3); the structure of 7a was confirmed by X-ray
crystallography.[9] These macrocyclic compounds have been
the subject of recent interest owing to their potential
biological activities.[13]
Received: September 4, 2009
Published online: November 7, 2009
Keywords: amides · Hofmann rearrangement · indoles ·
.
isoquinolines · macrocycles
Table 4: Macrocyclic bis(yne carbamate) synthesis.
[1] Indole synthesis: a) N. Sakai, K. Annaka, A. Fujita, A. Sato, T.
Konakahara, J. Org. Chem. 2008, 73, 4160 – 4165; b) A. Fꢀrstner,
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Chem. 2004, 69, 1126 – 1136; g) A. Takeda, S. Kamijo, Y.
Yamamoto, J. Am. Chem. Soc. 2000, 122, 5662 – 5663.
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N. T. Patil, Z. Huo, Y. Yamamoto, J. Am. Chem. Soc. 2008, 130,
15720 – 15725; b) T. Enomoto, S. Obika, Y. Yasui, Y. Takemoto,
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Entry
conc. [molLÀ1
]
t [h]
7a yield [%]
1
2
3
4
5
0.005
0.01
0.05
0.1
5
5
2
1
1
39
62
62
48
35
0.5
Finally, we applied the stepwise procedure to the macro-
cyclic bis(indole) synthesis. Treatment of a 0.05m solution of
amides 6 with PhI(OAc)2 at 1308C for 2 h, followed by
cyclization with PtCl2 at 1308C for 1–4.5 h, afforded the
desired indoles 8 via macrocyclic bis(yne carbamate) inter-
mediates 7. The yields of 8a and 8b were moderate,[14]
because of the formation of
a
complex mixture
(Scheme 5).[15] The structure of compound 8a was also
confirmed by X-ray crystallography.[9]
[6] Isocyanates prepared with triphosgene: a) S. Fustero, G. Chiva,
J. Piera, J. F. Sanz-Cervera, A. Volonterio, M. Zanda, C. R.
de Arellano, J. Org. Chem. 2009, 74, 3122 – 3132; b) A. El A-
laoui, F. Schmidt, C. Monneret, J.-C. Florent, J. Org. Chem. 2006,
71, 9628 – 9636; c) T. Akiba, O. Tamura, S. Terashima, Org.
Synth. 1998, 75, 45.
[7] The isocyanate was used without further purification because of
its instability.
Scheme 5. Macrocyclic bis(indole) synthesis.
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[15] For example, trimeric indole was obtained as a minor product
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investigation.
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