Intramolecular dearomatizing [3 + 2] annulation of α-imino carbenoids with aryl rings furnishing 3,4-fused indole skeletons

Article abstract of DOI:10.1021/ja412663a

The rhodium-catalyzed dearomatizing [3 + 2] annulation reaction of 4-(3-arylpropyl)-1,2,3-triazoles is described. It provides a straightforward synthetic pathway from simple 5-aryl-1-alkynes leading to tricyclic 3,4-fused dihydroindoles via the correspond

Full text of DOI:10.1021/ja412663a

Communication
pubs.acs.org/JACS
Intramolecular Dearomatizing [3 + 2] Annulation of α‑Imino
Carbenoids with Aryl Rings Furnishing 3,4-Fused Indole Skeletons
Tomoya Miura,* Yuuta Funakoshi, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510, Japan
S
* Supporting Information
N-Sulfonyl-1,2,3-triazoles are readily prepared from 1-alkynes
ABSTRACT: The rhodium-catalyzed dearomatizing [3 +
2] annulation reaction of 4-(3-arylpropyl)-1,2,3-triazoles is
described. It provides a straightforward synthetic pathway
from simple 5-aryl-1-alkynes leading to tricyclic 3,4-fused
dihydroindoles via the corresponding 1,2,3-triazoles.
and act as the convenient precursor of α-imino metal carbene
complexes.10,11 The carbenoid carbon of the generated carbene
complex is highly electrophilic, and the α-imino nitrogen is
highly nucleophilic. Thus, the α-imino carbene complex
behaves as a 1,3-dipole equivalent to participate in [3 + 2]
annulation with unsaturated compounds of a nucleophilic
character, forming five-membered heterocycles (eq 1).12
3,4-fused indole skeleton presents a key structural motif
Aof a number of natural products which exhibit a wide
range of biological activities. These include dehydrobufote-
nine,1 chuangxinmycin,2 hapalindole U,3 welwitindolinones,4
and the Ergot family such as lysergic acid,5 chanoclavine-I,6 and
rugulovasine A7 (Figure 1).
The reactions with nitriles,10a alkynes,10b,13 allenes,14
aldehydes,15 isocyanates,16 furans,17 and indoles18 afford the
corresponding [3 + 2] cycloadducts. We have also disclosed19
that the reaction with α,β-unsaturated aldehydes leads to the
stereoselective production of 2,3-dihydropyrroles via the
corresponding 4-oxazolines.15 We were next interested in
whether a benzene ring can act as the dipolarophile to construct
a dihydroindole skeleton.20 Thus, we first examined an
intermolecular reaction of a triazole with various benzene
substrates including 1,2-dimethoxybenzene in the presence of
rhodium(II) catalysts. However, no formation of the
corresponding [3 + 2] cycloadduct was observed even at 140
°C under microwave irradiation. Next, an intramolecular
reaction was examined using the triazole 1a possessing a 3-
phenylpropyl side chain, which was readily prepared from 5-
phenyl-1-pentyne and tosyl azide according to the procedure
using copper(I) thiophene-2-carboxylate (CuTC).21 When the
triazole 1a was treated with rhodium(II) pivalate dimer
[Rh2(OCOtBu)4, 1.0 mol %] and 4 Å molecular sieves (MS)
in 1,2-dichloroethane (DCE) at 80 °C for 3 h, the 3,4-fused
3a,7a-dihydroindole 2a was obtained in 92% isolated yield after
chromatographic purification (Scheme 1).
Figure 1. Natural products with 3,4-fused indole skeletons.
Thus, the development of efficient methods to create such a
structural motif starting from readily available compounds has
been highly desired.8 Now, we report an intramolecular
dearomatizing [3 + 2] annulation reaction9 of 4-(3-
arylpropyl)-1,2,3-triazoles. This new reaction constitutes a
straightforward synthesis of 3,4-fused indoles starting from
simple 5-aryl-1-alkynes in one pot (Figure 2).
The cis stereochemistry was determined by a single-crystal X-
ray analysis. We assume the following mechanism for the
production of 2a: a reversible ring−chain tautomerization of
the triazole moiety of 1a generates α-diazo imine 1a′, which
immediately reacts with rhodium(II) to afford α-imino rhodium
carbene A with release of molecular nitrogen. The carbenoid
carbon of A is electrophilic enough to induce the intramolecular
attack of the phenyl ring in a 6-exo mode to furnish the
Received: December 13, 2013
Figure 2. Construction of 3,4-fused indoles from 5-aryl-1-alkynes.
© XXXX American Chemical Society
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dx.doi.org/10.1021/ja412663a | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
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Scheme 1. Dearomatizing Annulation Reaction of 1a
Table 1. Dearomatizing Annulation Reaction of 4-(3-
a
Arylpropyl)-1,2,3-triazoles
zwitterionic intermediate B. The anionic rhodium releases
bonding electrons, which cause cyclization at the imino
nitrogen. It should be noted that the reactivity of α-imino
rhodium carbene A markedly contrasts with that of α-oxo
rhodium carbene complexes; whereas the intermediate A serves
as an 1,3-dipole equivalent because of the nucleophilic
character of the imino nitrogen, a similar rhodium carbene
complex generated from α-diazo ester 3 undergoes an
intramolecular Buchner reaction to produce bicyclo[5.3.0]-
̈
deca-1,3,5-triene 4 (eq 2).22
The results shown in Table 1 delineate the scope of the [3 +
2] annulation reaction. Substrates possessing a three-carbon
tether smoothly reacted, and the corresponding products 2b−
2e were isolated in yields ranging from 85% to 94%. The
nitrogen- and sulfur-tethered substrates also underwent the [3
+ 2] annulation reaction (2f and 2g). Of note was that the
electron-deficient benzene ring successfully participated in the
transformation (2i and 2k). With unsymmetrical meta-
monosubstituted substrates, the annulation occurred regiose-
lectively at the less-hindered side (2j and 2k). It was possible,
however, to install an angular methyl group at the bridgehead
position of 2l by using a 3,5-xylyl-substituted substrate. Various
substituents including a methyl group were suitable for the
sulfonyl substituent (2m−2p). On the other hand, substrates
possessing a shorter or longer tether, i.e., two- or four-carbon
tether failed to undergo a similar intramolecular [3 + 2]
annulation reaction due to structural constrains, giving a
complex mixture.
a
Conditions: 1 (0.20 mmol), Rh2(OCOtBu)4 (2 μmol), and MS (40
mg) were heated in DCE (4 mL) at 80 °C for 3 h unless otherwise
noted. Yield of isolated product after chromatography (average of two
b
c
runs). Using toluene (4 mL). Purified by recrystallization.
selectively took place upon direct addition of N-methylmalei-
mide to the reaction mixtures containing 2a and 2c to afford
the corresponding pentacyclic compounds 5 and 6, respec-
tively.
When manganese dioxide was directly added to the reaction
mixture containing 2a, oxidative aromatization23 took place to
produce 3,4-fused indole 7 in 93% yield (eq 4). Thus, the
sequential procedure in one pot provides a facile synthetic
pathway from simple 1-alkynes to 3,4-fused indoles.
The resulting 3,4-fused dihydroindoles could act as the diene
partner of a Diels−Alder reaction (eq 3). Endo cycloaddition
The present [3 + 2] annulation reaction was successfully
extended to the synthesis of Uhle’s ketone 10,24 which have
been often utilized in the synthesis of Ergot alkaloids5a (Scheme
2). Initially, the triethylsilyl group of the dihydroindole 2e was
deprotected by treatment with tetrabutylammonium fluoride
(TBAF). The subsequent oxidation of alcohol 8 with
manganese dioxide afforded N-tosylated Uhle’s ketone 9,25
B
dx.doi.org/10.1021/ja412663a | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 2. Synthesis of Uhle’s Ketone
In summary, we have developed the intramolecular [3 + 2]
annulation of the α-imino rhodium carbene complexes with aryl
groups. Of note is that the annulation mode markedly contrasts
with the addition mode of α-oxo rhodium carbene complex. It
constitutes the key step of a unique method to synthesize 3,4-
fused 3a,7a-dihydroindoles from 5-aryl-1-alkynes.
which was further converted into the Uhle’s ketone 10 by
detosylation with potassium hydroxide.26
The synthetic usefulness of the [3 + 2] annulation reaction
was exemplified by its successful integration into a one-pot
synthesis of 3,4-fused dihydroindoles 2 directly from 5-aryl-1-
alkynes 11−14 (Scheme 3). For example, 11, tosyl azide (1.0
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and data. This material is available
free of charge via Internet at http://pubs.acs.org.
Scheme 3. One-pot Synthesis Starting from 5-Aryl-1-alkynes
AUTHOR INFORMATION
Corresponding Authors
tmiura@sbchem.kyoto-u.ac.jp
murakami@sbchem.kyoto-u.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This paper is dedicated to Prof. Teruaki Mukaiyama on the
occasion of his 88th birthday (Beiju). We thank Dr. Y. Nagata
(Kyoto University) for his kind help in an X-ray analysis. This
work was supported by MEXT (Grant-in-Aid for Scientific
Research on Innovative Areas nos. 22105005 and 24106718,
Young Scientists (A) no. 23685019, Scientific Research (B) no.
23350041) and JST (ACT-C).
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