A strategy for the synthesis of 2,3-disubstituted indoles starting from N-(o-halophenyl)allenamides

Article abstract of DOI:10.1039/b707338k

A strategy for the synthesis of 2,3-disubstituted indole derivatives based on an intramolecular carbopalladation-anion capture cascade has been developed, wherein construction of the pyrrole ring and functionalisation of the indole C2 and C3 positions wer

Full text of DOI:10.1039/b707338k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A strategy for the synthesis of 2,3-disubstituted indoles starting from
N-(o-halophenyl)allenamides†
Haruhiko Fuwa* and Makoto Sasaki*
Received 15th May 2007, Accepted 30th May 2007
First published as an Advance Article on the web 19th June 2007
DOI: 10.1039/b707338k
A strategy for the synthesis of 2,3-disubstituted indole deriva-
tives based on an intramolecular carbopalladation–anion
capture cascade has been developed, wherein construction
of the pyrrole ring and functionalisation of the indole C2 and
C3 positions were achieved by extensive use of palladium(0)-
Scheme 1 Concept of the present work.
catalysed coupling reactions.
disubstituted indole derivatives based on a carbopalladation–
anion capture cascade starting from N-(o-halophenyl)allenamides.
We first prepared starting allenamides 6, 8, and 9, as sum-
molecules of pharmaceutical importance. Since the discovery of
marised in Scheme 2. Treatment of o-haloanilines 4a,b with p-
The indole nucleus is a prominent and privileged structure that
is widely found in naturally occurring substances and bioactive
1
2
the Fischer indolisation, the synthesis of indole derivatives has
TsCl followed by propargylation gave alkynes 5a,b, which were
been an active area of research, and numerous reports dealing
exposed to catalytic KOt-Bu in THF at room temperature to
3
with their synthesis have been recorded to date. Among these,
afford p-Ts-protected allenamides 6a,b. In a similar manner, N-
4
5
Fukuyama radical cyclisation, Larock heteroannulation, and
Boc allenamides 8a,b were synthesised. Selective functionalisation
6
Cacchi aminopalladation are the principal general strategies
of the a-position of 8a,b was performed according to the Hsung
that enable a facile and efficient preparation of 2,3-disubstituted
indoles under mild conditions.
11,12
protocol.
Thus, exposure of 8a,b to 2.0 equiv of LDA, followed
by the addition of an appropriate electrophile, furnished the
desired allenamides 9a–e in good yields without touching the aryl
iodide functionality.
Over the past two decades, palladium-catalysed cascade re-
actions have attracted a great deal of attention from organic
chemists because of their ability to generate multiple carbon–
carbon bonds to build up complex polycyclic frameworks in a
7
single operation with high atom economy. Grigg and co-workers
have reported that the allenyl group can serve as a relay unit
in palladium-catalysed cascade reactions; they reported the syn-
thesis of nitrogen heterocycles based on palladium-catalysed
8
cyclisation–anion capture processes involving allenyl species. This
strategy has only been applied to the synthesis of an indole-
9
3
-acetamido derivative. We envisaged that utilisation of N-(o-
halophenyl)allenamide (1), which bears a substituent (R ) at the
1
a position of the allenamide, would allow for facile generation of
the p-allylpalladium intermediate (2) via carbopalladation, which
in turn could be trapped with an appropriate nucleophile, such
10
as an aryl or alkenyl boronic acid or alkylborane, generating
a 2,3-disubstituted indole (3) (Scheme 1). Importantly, the use
of a silicon group as a substituent at the a position of the
allenamide moiety would allow for further functionalisation at
the C2 position by means of palladium-catalysed cross-coupling
reactions. In this sense, construction of the pyrrole ring as well
as functionalisation of the C2 and C3 positions can be achieved
by extensive use of palladium(0)-catalysed reactions. We describe
herein the development of a strategy for the synthesis of 2,3-
Scheme 2 Synthesis of N-(o-halophenyl)allenamides. Reagents and con-
◦
ditions: (a) p-TsCl, pyridine, 80 C; (b) propargyl bromide, K
2
CO
3
, DMF,
◦
6
8
6
9
0 C, 88% (5a), 90% (5b); (c) KOt-Bu, THF, room temperature, 98% (6a),
3% (6b); (d) Boc
2
O, THF, reflux; (e) propargyl bromide, K
2
CO
3
, DMF,
◦
0 C, 89% (7a), 100% (7b); (f) KOt-Bu, THF, room temperature, 83% (8a),
1% (8b); (g) LDA, THF, −78 C, then MeI, BnBr, Me
◦
3 2 2
SiCl or Me SiCl ,
◦
−
78 C, 76% (9a), 72% (9b), ∼100% (9c), 70% (9d), 97% (9e).
We then surveyed a series of reaction conditions using al-
lenamide 8a (1 equiv.), phenylboronic acid (1.1 equiv.), and 3 M
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences,
Tohoku University, 1-1 Tsutsumidori-amamiya, Aoba-ku, Sendai, 981-8555,
Japan. E-mail: hfuwa@bios.tohoku.ac.jp, masasaki@bios.tohoku.ac.jp;
Fax: +81-22-717-8896; Tel: +81-22-717-8895
aqueous Cs CO (3.0 equiv.) as a model case (Table 1). Initial
2
3
attempts employing Pd(PPh
3
)
4
or Pd(OAc)
2
–2PPh catalysts were
3
unsuccessful (entries 1 and 2); in each case, only a trace amount
of the desired 3-substituted indole 10 was detected in a complex
mixture, and no trace amounts of the corresponding “shunt”
†
Electronic supplementary information (ESI) available: Representative
experimental procedures and spectroscopic data for compounds 9a, 10,
2–26, 28–34. See DOI: 10.1039/b707338k
1
2
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a
a
Table 1 Screening of a variety of conditions
Table 2 Screening of a variety of conditions
◦
Entry
Pd catalyst
Pd(PPh
Solvent
T/ C
Yield (%)
1
2
3
4
5
6
7
8
9
3
)
4
THF
60
80
80
80
60
80
rt
60
105
70
80
Trace
Trace
41
55
36
49
35
Trace
Trace
31
Pd(OAc)
Pd(OAc)
2
–2PPh
3
DMF
DMF
DMF
DMF
DMF
DMF
THF
◦
Entry
Pd catalyst
Solvent
T/ C
Yield (%)
2
Pd
2
Pd
2
Pd
2
Pd
2
Pd
2
Pd
2
Pd
2
Pd
2
(dba)
3
3
3
3
3
3
3
3
(dba)
(dba)
(dba)
(dba)
(dba)
(dba)
(dba)
–8AsPh
–4P(o-tol)
3
1
2
3
4
Pd
Pd
PdCl
PdCl
2
(dba)
(dba)
3
EtOH
DMF
DMF
DMF
80
rt
50
50
Trace
38
53
3
2
3
2
(dppf)
2
(dppf)–4AsPh
3
42
Toluene
a
All reactions were performed using Pd catalyst (0.1 equiv.), 3 M aq.
CO (3 equiv.), and alkylborane (1.2 equiv.).
1
1
0
1
CH
3
CN
Cs
2
3
EtOH
98
a
All reactions were performed using Pd catalyst (0.1 equiv.), 3 M aq.
CO (3 equiv.), and PhB(OH) (1.1 equiv.).
Cs
2
3
2
of our cascade process. The results are summarised in Table 3. N-
Tosyl allenamide 6a also served as a good starting material in
the present process (entries 1–3). A wide range of nucleophiles,
including arylboronic acids (entries 1, 2 and 4), alkenylboronic
acid (entry 3), 2-thiopheneboronic acid (entry 5), and alkylboranes
(entries 6–8) were successfully employed, giving a variety of 3-
substituted indoles in good to excellent yields. Notably, the aryl
bromide 6b also smoothly entered the carbopalladation–cross-
coupling cascade to give 20 in 82% yield.
product was observed. In contrast, the use of “ligandless” catalysts
such as Pd(OAc) and Pd (dba) turned out to be effective for
the present process, giving 10 in moderate yields (entries 3 and
). Combined use of Pd (dba) with a weakly donating ligand
AsPh ) or an electron-rich bulky ligand (P(o-tol) ) was found
2
2
3
4
(
2
3
3
3
13
to be detrimental (entries 5 and 6). It is known that oxidative
addition of aryl iodides to ligandless palladium(0) catalysts readily
occurs because of their high reactivity, although the use of
a supporting ligand is generally preferred for Suzuki–Miyaura
Application of the present strategy for the synthesis of 2,3-
disubstituted indoles starting from a-functionalised allenamides
9a–e was also successful (Table 4). The indole derivatives with
methyl, benzyl, trimethylsilyl, and dimethylsilanolyl functionali-
ties at the C2 position were prepared in good to excellent yields.
However, when 9e was employed as a substrate and an alkylborane
generated from acrolein diethylacetal was used as a nucleophile,
the desired product 26 was isolated in 42% yield. The major
10
reaction. An attempt to bring about the present cascade at room
temperature lowered the product yield, suggesting a necessity for
heating (entry 7). Finally, we examined the effects of solvent.
Although changing the solvent to THF, toluene, or CH CN
3
15
led to discouraging results (entries 8–10), the present reaction
product of this reaction was the shunt product 27, which was
◦
proceeded smoothly in EtOH at 80 C, affording the desired 10 in
isolated in 56% yield. An attempt to utilise Ph As as a co-ligand
3
a remarkable 98% yield (entry 11).
was not effective for improving the yield of 26.
We then attempted to apply the established conditions for the
synthesis of a variety of 3-substituted indole derivatives. Unfortu-
nately, however, we soon recognised that the conditions developed
above did not work well for the case wherein an alkylborane was
employed as a nucleophile. This drawback may be attributed to
the different nucleophilic properties between arylboronic acid and
The indole derivatives with a silicon functional group at the
C2 position (e.g., 24 and 25) serve as potential precursors for
4
further palladium(0)-catalysed transformation (Scheme 3). Thus,
exposure of 24 to ICl in the presence of AgBF
4
(2 : 1 MeOH–
THF) smoothly afforded 2-iodo derivative 28, which in turn
underwent clean methoxycarbonylation using a PdCl (dppf) cat-
alyst, providing methyl indole-2-carboxylate 29 in a quantitative
16
2
9
alkylborane in palladium(0)-catalyzed cross-coupling reactions.
17
Alkylboranes have rarely been used in palladium(0)-catalysed
yield. On the other hand, the Denmark variant of Hiyama cross-
14
18
cascade processes and have not been utilized in cyclopalladation–
anion capture cascades. Therefore, we also screened the reaction
conditions suitable for an alkylborane nucleophile (Table 2). As
noted above, only a trace amount of the desired product 12 was
coupling of 25 with 4-iodonitrobenzene in the presence of a
Pd
2
(dba)
3
·CHCl
3
catalyst, CuI, and NaOt-Bu in toluene at room
temperature furnished the desired cross-coupled product 30 in
89% yield. To the best of our knowledge, this is the first example
of a successful application of the Denmark–Hiyama coupling to
synthesis of a 2,3-disubstituted indole.
obtained using alkylborane 11 (1.2 equiv.), Pd
2
(dba) , and 3 M
3
◦
aqueous Cs
2
CO
3
in EtOH at 80 C. Changing the solvent back to
DMF gave a better result, affording a moderate yield of 12 (entry
). We eventually found that the product yield could be improved
to practical levels when PdCl (dppf) was employed as a catalyst
entries 3, 4).
Having established two reliable conditions, we next synthesised
Extension of our strategy could be accomplished simply by
trapping the p-allylpalladium intermediate with nucleophiles
other than organoboron species. For instance, utilization of p-
2
9
2
(
TolSO
sponding sulfone, azide, and vinyl derivatives in excellent yields,
respectively (Scheme 4). Upon treatment of 8 with PdCl (dppf) in
2
Na, NaN
3
, and vinyl tri-n-butyltin afforded the corre-
a series of 3-substituted indole derivatives to address the versatility
2
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Table 3 Synthesis of 3-substituted indole derivatives
Entry
Allenamide
Boron nucleophile
Product
Yield (%)
88
a
1
6a
a
2
6a
6a
71
73
a
3
a
4
8
8
8
90
58
64
a
5
a
6
b
7
8
66
82
c
8
6b
a
◦
b
◦
c
Pd
2
(dba)
3
(0.05 equiv.), 3 M aq. Cs
2
CO
3
(3 equiv.), EtOH, 80 C. PdCl
2
(dppf) (0.1 equiv.), 3 M aq. Cs
2
CO
3
(3 equiv.), DMF, 50 C. PdCl
2
(dppf) (0.1
◦
2 3
equiv.), 3 M aq. Cs CO (3 equiv.), DMF, 70 C.
Scheme 3 Palladium(0)-catalysed functionalisation of the C2 position.
◦
Reagents and conditions: (a) ICl, AgBF
4
, 2 : 1 MeOH–THF, 0 C, 97%;
◦
(
(
b) PdCl
c) 4-iodonitrobenzene, Pd
2
(dppf)·CH
2
Cl
2
, Et
3
N, MeOH–DMF, CO (1 atm), 60 C, 100%;
Scheme
4
Synthesis of additional series of 3-substitued indoles.
(dba)
3
·CHCl
3
, CuI, NaOt-Bu, toluene, room
◦
2
Reagents and conditions: (a) p-TolSO
Na, Pd(PPh
)
, DMF, 70 C, 83%;
2
3
4
temperature, 89%.
(
b) NaN
3
, Pd(PPh
(dba)
3
)
4
, DMF, room temperature, 97%; (c) vinyl tri-n-
◦
butyltin, Pd
DMF, CO (1 atm), 60 C, 49%.
2
3
, DMF, 80 C, 96%; (d) PdCl
2
(dppf), Et
3
N, 1 : 2 MeOH–
◦
the presence of Et
3
N in 1 : 2 MeOH–DMF under a CO atmosphere
(
1 atm), indole-3-acetic acid derivative 34 was synthesised in mod-
erate yield. The above examples further potentiate the generality
and versatility of our strategy.
In conclusion, we have developed an efficient strategy for the
synthesis of 2,3-disubstituted indole derivatives starting from N-
(o-halophenyl)allenamide based on the carbopalladation–anion
capture cascade. Selective introduction of an appropriate silicon
group to the a position of the allenamide allows for the synthesis
of 2-silyl substituted indole derivatives, which serve as powerful
2
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a
Table 4 Synthesis of 2,3-disubstituted indole derivatives
Entry
1
Allenamide
Boron nucleophile
Product
Yield (%)
81
9a
2
3
9b
9b
9c
98
84
4
5
71 (from 8)
9d
9e
61
42
b
6
5
6
a
◦
All reactions were performed using Pd
2
(dba)
3
(0.05 equiv.), 3 M aq. Cs
2
CO
3
(3 equiv.), boronic acid (1.1 equiv.) in EtOH at 80 C unless otherwise
b
◦
noted. The reaction was performed using PdCl
2
(dppf) (0.1 equiv.), 3 M aq. Cs
2
CO
3
(3 equiv.), alkylborane (1.2 equiv.) in DMF at 70 C.
substrates for further palladium(0)-catalysed transformations at
the C2 position. In addition, we have demonstrated that the
strategy can be easily extended by utilisation of appropriate nucle-
ophiles in place of organoboron species, providing an additional
series of indole derivatives. Application of the present strategy to
the search for new bioactive substances is currently underway.
This work was supported in part by a Grant-in-Aid for Scientific
Research by the Ministry of Education, Culture, Sports, Science
and Technology, Japan (MEXT).
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4 To the best of our knowledge, there have been only two examples of
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2
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