IPy2BF4-promoted intramolecular addition of masked and unmasked anilines to alkynes: Direct assembly of 3-iodoindole cores

Article abstract of DOI:10.1002/anie.200351303

All at once! Indoles can be assembled and iodinated in a one-pot process (see scheme) from anilines and their derivatives. This metal-free addition of nitrogen compounds to alkynes is a clean reaction that is promoted by iodonium cations. Such a process p

Full text of DOI:10.1002/anie.200351303

Communications
Iodoindole Synthesis
I
R
I
IPy2BF4-Promoted Intramolecular Addition of
Masked and Unmasked Anilines to Alkynes:
Direct Assembly of 3-Iodoindole Cores**
R
N
NH
PG
PG
2
1
JosØ Barluenga,* Mónica Trincado, Eduardo Rubio, and
JosØ M. Gonzµlez
Scheme 1. 3-Iodoindole as a target from the iodocyclization of
2-alkynylaniline derivatives. PG=protecting group.
Recently, organometallic transformations have been pursued
with renewed interest to approach the elusive addition
À
This C N bond-formation reaction, which requires only a
[1]
À
reaction of the N H bond across alkynes. As a cleaner
simple activation of the iodinating agent (namely, the addition
of HBF4 (1 equiv) to the reaction media), results in a versatile
entry into 3-iodo-functionalised indoles (Table 1).[8] N-Boc
alternative to the use of metal-containing reagents and
À
catalysts we have developed useful reactions for C C bond
formation and cleavage, based on
the iodinating reagent bis(pyridi-
Table 1: Synthesis of indoles 2 from o-alkynyl aniline derivatives 1, promoted by IPy2BF4.[a,b]
ne)iodonium(i) tetrafluoroborate
(IPy2BF4).[2] Herein, we present a
powerful intramolecular addition
of aniline and of several of its N-
derivatives to alkynes, which relies
on a simple iodination process.
This new reaction entails a novel
approach, and results in a general
and valuable entry to the biological
and synthetically relevant indole
core.[3,4]
We have previously established
a robust iodination of anilines that
leads to the synthesis of substituted
indoles via CuI-mediated cycliza-
tion of the corresponding o-((tri-
methylsilyl)ethynyl)aniline deriva-
tives.[5] Certainly, new processes
that selectively place additional
functionality at the time of assem-
bling the indole core are highly
desirable.[6] Now, we illustrate a
direct and clean entry to valuable
2-substituted-3-iodoindoles from
readily available precursors. Thus,
N-protected o-(alkynyl)anilines 1
R2
I
R3
R3
IPy2BF4, HBF4
CH2Cl2
R2
N
NHR1
R1
1
2
Entry
1
R1
R2
R3
H
t [h][c]
T [8C]
2
Yield [%][d]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
CO2tBu
CO2tB
Ph
15
À60
À680
À60
À60
À20
À60
À20
À60
À20
À20
À60
À40
2a
2b
2c
2d
2e
2 f
2g
2h
2i
68
76
53[e]
87
u
Ph
Me
CO2Me
p-MeC6H4SO2
CO2tBu
CO2tBu
CO2tBu
MeSO2
MeSO2
CO2tBu
MeSO2
MeSO2
Ph
Ph
H
H
H
H
H
H
H
H
H
H
24
36
12
24
15
15
15
15
24
48
3-thienyl
1-cyclohexenyl
1-cyclopentenyl
1-cyclopentenyl
71
17[f]
10[f]
61
9
Bn
Bu
Bu
Ph
54
10[e]
84
10
11
12
1j
1k
1l
2g
2k
2l
74
[a] Indoles 2 were characterized by NMR spectroscopy, mass spectrometry, and gave analytical and/or
HRMS data in agreement with the given structure. [b] IPy2BF4 (1.1 equiv), HBF4 (1 equiv). [c] Deter-
mined as a function of the disappearance of 1. [d] Based on the isolated indole 2. [e] A cyclic urethane
derivative was formed and isolated from the crude reaction mixture. [f] An allene structure was formed
as major reaction product.
furnish N-protected 3-iodoindoles 2 upon reaction with
IPy2BF4,[2] the iodinating agent of choice to promote this
process[7] (Scheme 1).
derivatives gave satisfactory results when R2 was an aryl or
heteroaryl substituent (entries 1, 2, and 5).[9] However, when
R2 was an alkyl or 1-alkenyl group (entries 6, 7, and 10), the
desired cyclization was very poor. Alternatively, for these
functionalities, the related methanesulfonate derivative fur-
nished indoles in moderate-to-good yield (entries 8, 9, and
11).
The feasibility of accomplishing a clean and efficient
biscyclization process was satisfactorily tested with model
compounds 3a and 3b. Upon iodination, 3a provided a facile
route to an interesting 1,4-phenyl-linked bisindole 4a, as
depicted in Scheme 2.
[*] Prof. Dr. J. Barluenga, M. Trincado, Dr. E. Rubio, Dr. J. M. Gonzµlez
Instituto Universitario de Química Organometµlica “Enrique
Moles”
Unidad Asociada al C.S.I.C.
Universidad de Oviedo, 33071 Oviedo (Spain)
Fax: (+34)98-510-3450
E-mail: barluenga@sauron.quimica.uniovi.es
[**] This research was partially supported by the Principality of Asturias
(PR-01-GE-9) and the Spanish DGI (MCT-01-BQU-3853). M.T.
thanks Spanish M.E.C. for a FPU-fellowship.
The butadiyne 3b, readily accessible from the parent
terminal alkyne, offers an attractive route to iodinated 2,2’-
bisindolyl scaffolds 4b, which have great potential in the
preparation of naturally occurring bioactive compounds of
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angewandte
Chemie
BocHN
BocN
I
2 IPy2BF4 / 2 HBF4
I
CH2Cl2, –60°C, 7h, 61%
3a
NBoc
4a
NHBoc
I
Boc
N
NHBoc
2 IPy2BF4 / 2 HBF4
N
Boc
CH2Cl2, –60°C, 9h, 63%
I
2
4b
3b
I
I
R
N
IPy2BF4 / HBF4
Scheme 4. a) Py, CH2Cl2, RT, 12 h; b) N,N-diisopropylethylamine
N
R
CH2Cl2, –60°C, 15h
NHR
(R: Ts)
(DIEA), HOBt·H2O, DMF, CH2Cl2, 15 h; c) IPy2BF4 (2.2 equiv), HBF4
(2.2 equiv), CH2Cl2, À208C, 24 h; d) trifluoroacetic acid (TFA)/CH2Cl2
(20%), 1 h, RT. (31% overall yield for four reaction steps).
I
1m
4c (81%)
4d (73%)
1n (R: CO2Me)
Scheme 2. Biscyclization reactions. Boc=1-butyloxycarbonyl;
Ts =tosyl.
phase indole synthesis (Scheme 4).[13] The approach of bind-
À
ing the resin to the moiety responsible for the N C cyclization
step has rarely been reported for the preparation of indoles.[14]
A p-nitrophenyl-carbonate-modified Wang resin was used to
prepare the desired carbamates from o-alkynylaniline.[15]
This system offers the first example of the solid-phase
synthesis of an indole, promoted by a iodination process. As
the versatile iodine functionality can be transformed on the
resin using organometallic chemistry, this direct assembly of
3-iodoindole offers additional synthetic potential.[16]
Interestingly, this strategy of indole skeleton preparation
yields iodinated compounds upon the cyclization step. Thus, it
provides a unique entry to further build-related heterocyclic
cores using the same reaction sequence. For instance, by
following this approach, compound 2l can be rapidly trans-
formed into carbazole derivative 11 in two steps
(Scheme 5).[17]
the indolocarbazole family, such as rebeccamycin.[10] With
regard to these important building blocks, we have found that
simple 2-iodoalkynylanilines 1m and 1n smoothly afford
bisindole cores 4c and 4d. This remarkable result opens a
short and valuable synthetic entry to complex indole frame-
works.
À
Protection of the N H bond allows for efficient synthesis
and handling of the target indoles. However, as depicted in
Scheme 3, some unprotected anilines 5 were also efficient
partners in this type of cyclization, which leads to the
I
R1
IPy2BF4 / HBF4
CH2Cl2, –80°C, 8h
R1
A tentative mechanistic interpretation to explain the
formation of the observed indoles might reasonably assume a
reaction path that implies an initial interaction of electro-
N
NH2
H
5a R1 = Ph
5b R1 = Bu
6a
6b
75%
60%
OCH3
Scheme 3. Cyclization of anilines; IPy2BF4 (1.1 equiv), HBF4 (1 equiv).
corresponding free indoles.[11,12] To the best of our knowledge,
these reactions represent the first examples of the addition of
protected and unprotected anilines to internal alkynes,
facilitated by a simple iodination reaction.
The solution chemistry reported above might be an
interesting alternative pathway towards the first direct use
of the key 3-iodoindole skeleton on a solid support. Thus, the
binding of a carbamate group to the resin provides a
convenient alternative for accomplishing the desired solid-
I
I
1)
CH3O
Ph
SO2Me
2) IPy2BF4 (1.1 equiv)
N
N
SO2Me
2l
11
Scheme 5. Conversion of indole to carbazole skeleton. 1) [PdCl2(PPh3)2]
(10 mol%), CuI (20 mol%), Et2NH, RT, 15 h, 47%; 2) HBF4 (1 equiv),
CH2Cl2, À808C, 15 h, 17%.
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Communications
philic iodine with the alkynyl residue, to give the intermedi-
Keywords: alkynes · cyclization · electrophilic addition ·
halogenation · nitrogen heterocycles
.
ate A (Scheme 6). Subsequent nucleophilic attack of nitrogen
would lead to ring-closure. Only one equivalent of acid was
used to activate the reagent in these reactions, therefore the
second pyridine molecule might help to remove a proton from
[1] For a recent account: a) M. Beller, C. Breindl, M. Eichberger,
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R1
Py
I
–PyHBF4
NHR
(1 or 5)
Py2IBF4/HBF4
R1
BF4
NHR
A
I
I
BF4
R1
–PyHBF4
R1
N
R
N
H
R
Py
(2 or 6)
Scheme 6. Proposed reaction mechanism.
the nitrogen atom, and result in the observed indole species.
In summary, both solution-and solidp-hase strategies
have been developed that result in an addition reaction of
nitrogen to alkynes, which opens clean and synthetically
competitive alternatives to the already established use of
metal complexes. The reaction has been applied to the
challenging field of the construction of the biologically
relevant indole frame, where it proves to be the method of
choice. Further studies on the scope of this method, and to
gain insight into the unconventional formal cyclization–
dimerization of 2-iodoalkynylanilines are in progress.
[4] For recent indole preparations, see for instance: a) M. Beller, C.
Breindl, T. H. Riermeier, A. Tillack, J. Org. Chem. 2001,
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Experimental Section
All reactions were carried out under a positive pressure of nitrogen.
Synthesis of 2a: IPy2BF4 (0.41 g, 1.1 mmol, 1.1 equiv) was dissolved in
dry CH2Cl2 (10 mL) and stirred for 5 min at room temperature. The
solution was cooled to À608C, and HBF4 (137 mL, 54% solution in
Et2O, 1.0 mmol, 1.0 equiv) was added. After 10 min, 1a (293 mg,
1 mmol, 1 equiv) was added, and the solution was stirred (15 h) until
the complete disappearance of 1a was revealed by thin-layer
chromatography (TLC). The reaction mixture was poured into
100 g of crushed ice and vigorously stirred, and then allowed to
warm to room temperature. The organic layer was washed with a 5%
aqueous solution of Na2S2O3 (50 mL), dried over sodium sulfate, and
then concentrated. The product was purified by column chromatog-
raphy (silica gel, hexane/EtOAc 20:1) to give 285 mg of compound
2a, as a white solid (mp 67–698C); Rf = 0.71 (hexane/EtOAc 3:1);
1H NMR (300 MHz, CDCl3): d = 8.21 (d, J = 2 Hz, 1H), 7.51–7.33 (m,
8H), 1.23 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d = 149.2 (s),
130.3 (s), 136.5 (s), 134.9 (s), 130.1 (s), 129.9 (d), 128.1 (d), 127.8 (d),
125.5 (d), 123.5 (d), 121.7 (d), 115.2 (d), 83.7 (s), 72.3 (s), 27.3 ppm (q);
IR: umax (KBr): n˜1723 cmÀ1; MS (70 eV, EI): m/z (%) = 419 (M+, 59),
363 (100), 320 (49), 237 (47). Elemental analysis (%) calcd for
C19H18INO2: C 54.43, H 4.33, N 3.34; found: C 54.42, H 4.30, N 3.35.
Experimental procedures, spectral and analytical data for indoles
2, 4, 6,and carbazole 11, and solid-phase transformations are given in
the Supporting Information.
[7] Homopropargylic sulfonamides related to methyl glycinate have
been nicely cyclized by reaction with iodine, see: a) D. W.
Knight, A. L. Redfern, J. Gilmore, Chem. Commun. 1998, 2207 –
2208. However, under their reported conditions, our attempts to
Received: February 28, 2003 [Z51303]
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prepare 2k from 1k lead to a complex mixture of compounds, as
revealed by both TLC monitoring of the reaction progress and
NMR analysis of the crude products. We also checked the
reaction at À608C; in this case, only the starting material was
recovered. A sharp distinction was noticed when using either
IPy2BF4 or I2. A strong substrate dependence was previously
observed in the iodine-promoted cyclization of homopropargyl
alcohols; b) D. W. Knight, A. L. Redfern, J. Gilmore, J. Chem.
Soc. Perkin Trans. 1 2002, 622 – 628.
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see for instance: C. A. Merlic, Y. You, D. M. McInnes, A. L.
Zechman, M. M. Miller, Q. Deng, Tetrahedron, 2001, 57, 5199 –
5212, and references therein.
[11] In this case, the reaction is more substrate dependent. Further
studies are in progress to investigate alternative reaction paths.
[12] 2-Alkynylphenols undergo a similar reaction. Thus, o-(2-phenyl-
ethynyl)phenol gave 3-iodo-2-phenylbenzo[b]furan (78% yield)
after reaction with Ipy2BF4/HBF4 for 6 h at room temperature.
Similarly, o-(2-butylethynyl)phenol yielded 2-butyl-3-iodoben-
zo[b]furan upon reaction for 8 h (70% yield).
[13] For a recent review, see: a) S. Brꢀse, C. Gil, K. Knepper, Bioorg.
Med. Chem. 2002, 10, 2415 – 2437.
[14] For solid-phase studies using a related indole binding site, see:
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[16] Representative sp2–sp coupling reactions are detailed in the
Supporting Information.
[17] For a review on carbazole alkaloids, see: H.-J. Knꢁlker, K. R.
Reddy, Chem. Rev. 2002, 102, 4303 – 4427;b) for recent synthesis
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