Synthesis of substituted 3-indolylimines and indole-3-carboxaldehydes by rhodium(II)-catalyzed annulation

Article abstract of DOI:10.1021/ol501618z

An efficient Cu/Rh-catalyzed method is proposed for the synthesis of 3-indolylimines from N-propargylanilines through Rh(II)-catalyzed denitrogenative annulation of N-sulfonyl-1,2,3-triazoles. Further combined with hydrolysis or reduction, a one-pot method is developed to enable the direct incorporation of an imine, aldehyde, or amine group into an indole system from an alkyne. A variety of substituted 3-indolylimines, indole-3-carboxaldehydes, and 3-Indolylmethanamines are synthesized in good yields.

Full text of DOI:10.1021/ol501618z

Letter
pubs.acs.org/OrgLett
Synthesis of Substituted 3‑Indolylimines and Indole-3-
carboxaldehydes by Rhodium(II)-Catalyzed Annulation
Basker Rajagopal, Chih-Hung Chou, Ching-Cheng Chung, and Po-Chiao Lin*
Department of Chemistry, National Sun Yat-sen University, Kaohsiung 804, Taiwan
S
* Supporting Information
ABSTRACT: An efficient Cu/Rh-catalyzed method is proposed for the synthesis of 3-indolylimines from N-propargylanilines
through Rh(II)-catalyzed denitrogenative annulation of N-sulfonyl-1,2,3-triazoles. Further combined with hydrolysis or
reduction, a one-pot method is developed to enable the direct incorporation of an imine, aldehyde, or amine group into an indole
system from an alkyne. A variety of substituted 3-indolylimines, indole-3-carboxaldehydes, and 3-Indolylmethanamines are
synthesized in good yields.
ubstituted indoles are one of the most abundant and
important natural heterocycles. This core alkaloid motif is a
construction and functionalization of indoles.7 Moreover, the
rapid growth of the use of Rh catalysts has provided various
methods for the preparation of many functionalized, fused, and
unusual architectures containing indole motifs.8−15 Rh-
catalyzed cycloisomerization of disubstituted alkynylanilines to
indoles was developed by Trost et al.8 Rh-catalyzed oxidative
coupling of N-acetylanilines and alkynes was proposed by
Fagnou.9 Glorius et al. successfully used 2-acetyl-1-arylhydra-
zines as oxidation-directing agents to obtain various indoles.10
The Rh-mediated formation of nitrenoids in the absence of
arylamines has been reported to transform vinyl azides into
indoles.11 On the basis of the amino-Claisen rearrangement,
Saito et al. converted N-propargylanilines to indoles using a
Rh(I) catalyst.12 However, the preparation of 3-imino- and 3-
carboxaldehyde-substituted indoles by these well-established
methods using Rh catalysts is still limited. Because the
cyclization is usually mediated by highly reactive intermediates
such as carbenes/nitrenes, allenes, and Rh-coordinated
complexes, the presence of extra electrophilic groups in the
structure may result in undesired side reactions.
Recently, metal-catalyzed transformations of N-sulfonyl-
1,2,3-triazole rings via diazoimino intermediates have been
reported. The use of Cu catalysts with these triazoles leads to
the formation of ketenimine intermediates, which can be
transformed into a range of heterocycles.15 In a similar
approach using Rh complexes as catalysts, Rh carbenoids are
formed as the reactive intermediates in the direct denitroge-
native transannulation of N-sulfonyl-1,2,3-triazoles.16 Rh
carbenoids are versatile precursors, because their high electro-
philicity and C−H insertion ability facilitate the production of
S
key component of a vast number of biologically active natural
and synthetic compounds, e.g., serotonin, which is a simple
neurotransmitter, and vincristine, which is used clinically in
cancer therapy.1 The naturally occurring amino acid
tryptophan, which is a component of proteins in living systems
and of many biologically vital natural products, contains the
indole core system.2 The indole skeleton is a pharmacophore in
a wide range of medicinal compounds, and numerous drugs
containing this skeleton have been reported, such as
indomethacin, sumatriptan, tadalal, ondansetron, rizatriptan,
and uvastatin.3 For over 100 years, the prevalence of indole
rings in bioactive natural products and pharmaceuticals has
inspired chemists to develop the synthesis and functionalization
of indoles.
Several classic synthetic strategies are available for the
synthesis of indoles from different precursors.4 The well-known
Fischer indole synthesis from phenyl hydrazones,5a Bischler
indole synthesis from α-bromoacetophenones and aniline,5b
Hemetsberger indole synthesis by azirine-triggered electro-
cyclization from β-styryl azides,5c Bartoli indole synthesis from
ortho-substituted nitroarenes and vinyl Grignard reagents,5d
Leimgruber−Batcho indole synthesis using enamines,5e and
Gassman indole synthesis5f are widely used in modern organic
chemistry. Aryl isonitriles and nitrosoarenes are generally used
as precursors in the synthesis of biologically interesting indoles.
To expand the range of substrates, transition-metal catalysis
is a promising and efficient method in indole synthesis to
tolerate a wide range of functionalities, making the synthesis
applicable to complex molecules. The electrophilic activation of
alkynes in the presence of late-transition-metal complexes is an
attractive method of indole synthesis.6 In recent decades, Pd
complexes have proved to be promising catalysts in the
Received: June 5, 2014
© XXXX American Chemical Society
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Letter
valuable nitrogen-containing heterocyclic compounds from
1,2,3-triazoles. Alford et al. used the denitrogenative trans-
annulation of N-sulfonyl-1,2,3-triazoles to convert cyclic
ketones to 2,3-fused pyrroles and substituted indoles.17 Inspired
by the reported transformations and our previous work on the
Cu(I)-catalyzed synthesis of dihydropyrimidinones,18 in this
research we developed a strategy for converting N-propargy-
lanilines to functionalized indoles. The concept is based on the
formation of the corresponding N-sulfonyl-1,2,3-traizole
intermediate, followed by denitrogenative ring opening to
form a reactive Rh carbenoid intermediate. The electrophilic
property of the resulting Rh carbenoid enables subsequent
cyclization, triggered by amino groups, via aromatic electro-
philic addition.
groups. Mild and operationally simple methods have therefore
been developed for the formylation of Indoles. Wu et al.
reported an efficient method for C-3 formylation of indoles
using a Ru catalyst.21 Recently, Bu4NI-catalyzed C-3-selective
n
formylation of N−H and N-substituted indoles, using N-
methylaniline as the formylating reagent, was demonstrated.22
As mentioned earlier, our proposed transformation of N-
propargylanilines into C-3-functionalized indoles involves the
use of benign reagents in catalytic amounts, providing an
advantageous synthetic path.
After confirming formation of the expected product, we
optimized the reaction conditions using different solvents and
temperatures. N-Sulfonyl-1,2,3-triazole formation using CuTC
and TsN3 is well established,23 so we focused on optimization
of the reaction conditions in the triazole decomposition step;
the results are summarized in Table 1. The expected
As shown in Scheme 1, in the first step of the reaction
sequence, substituted anilines were treated with propargyl
Scheme 1. Synthetic Design
Table 1. Optimization of Conditions
entry
solvent
temp (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
dichloromethane
1,2-dichloroethane
1,2-dichloroethane
toluene
40
rt
24
24
4
NR
NR
83
60
rt
24
4
NR
74
toluene
60
60
60
1,4-dioxane
4
68
acetonitrile
2
a
bromide to provide N-propargylanilines. Conversion of the
alkyne functional group to a stable N-sulfonyl-1,2,3-triazole was
then achieved using tosyl azide (TsN3) in the presence of
copper thiophenecarboxylic acid (CuTC) as the catalyst.
Without further purification, in one pot, a rhodium(II)
octanoate catalyst was added to the reaction mixture. The
desired 3-indolylsulfonylimine was formed, as shown in the X-
ray ORTEP diagram (Figure 1). The sulfonylimine can be
a
Formation of multiple spots.
transformation was not observed at ambient temperature.
However, the conversion was better when 1,2- dichloroethane
(DCE) or toluene were used as the solvent with heating. DCE
was found to be the optimal solvent for the reaction (entry 3).
Conventional silica gel column chromatography cannot be used
for the purification of the desired indoles, probably because the
sulfonylimines have poor stabilities. However, precipitation
purification using a cosolvent system (ethyl acetate in hexane)
gave reasonably good results. Furthermore, we observed that
the optimized conditions were suitable for performing the
reaction on the gram scale (1.1 g of 3a was converted to 4a in
83% yield).
To expand the substrate scope, compounds with different
substituents on the aromatic rings and amine groups were used
under the optimized conditions, and the conversion efficiencies
were determined. The electronic effects of the substituents on
the benzene rings during cyclization were examined (Table 2).
No significant differences were observed between the outcomes
of the reaction using electron-donating groups (entries 4b and
4c) and electron-withdrawing halogens (entries 4d−4h). The
4-nitro substituent gave good conversion, but the 3-nitro yield
was very low (entry 4j). It appears that an electron-withdrawing
nitro group at the meta position of the aniline ring considerably
reduces the aromatic electron nucleophilicity in attack of the
Rh carbenoid intermediate, resulting in low conversion. The
formation of two possible regioisomers was expected in the
cases of 4e and 4j. In terms of regioselectivity, the cyclization
site can be at the ortho or para position to the 3-substituent.
However, the formation of single regioisomer with para
Figure 1. X-ray ORTEP diagram for compound 4a.
easily hydrolyzed to an aldehyde, so our proposed method
enables the cascade synthesis of the core indole unit and
formylation at the C-3 position. The C-3-formylation of indoles
is a key step in the preparation of biologically active natural
products, including homofascaplysin C, FR-9004829 which is a
mitomycin-like antitumor agent, and many indole alkaloid-
s.19a−c Conventional syntheses of 3-formylindoles are achieved
using Vilsmeier−Haack, Friedel−Crafts acylations and Re-
imer−Tiemann, Rieche, and Duff reactions, which generally
require high temperatures and the use of excess strong bases or
acids.20 Because of the harsh reaction conditions, these
methods are not appropriate for indoles with labile functional
B
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Letter
Table 2. Substrate Scope with Different R1 Groups
could be attacked by the free amine intra- or intermolecularly,
forming multiple reaction sites. To examine the use of other
sulfonyl azides, benzenesulfonyl azide (PhSO2N3) was used
instead of TsN3. There were no obvious differences among the
reaction outcomes (4v and 4w), suggesting that there is scope
for further functionalization.
Based on the product formation, a plausible mechanistic
pathway is proposed in Scheme 3. Equilibrium is established
entry
R1 (3b−k)
time (h) product
R1 (4b−k)
yield (%)
1
2
4-OMe
4-nBu
4-Cl
3
4
4
4
4
4
4
6
4
4
4b
4c
4d
4e
4f
5-OMe
5-nBu
5-Cl
87
77
82
79
74
80
85
82
25
77
Scheme 3. Proposed Mechanistic Cycle
3
4
3-Cl
6-Cl
5
4-F
5-F
6
4-Br
4g
4h
4i
5-Br
7
4-I
5-I
8
4-NO2
3-NO2
2,3-(Naph)-
5-NO2
6-NO2
6,7-(Naph)-
9
4j
10
4k
preference was observed. This specific regioselectivity is
probably due to the contribution of the steric effect. A series
of N-substituents were examined; N-alkyl groups (4l−4o) gave
similar results. (Isolated yields 80−83%; Scheme 2) Two
Scheme 2. Substrate Scope Using Different R2 and R3
Groups
between the N-sulfony-1,2,3-triazole I and the iminodiazo
species Ia. Treatment of the N-sulfony-1,2,3-triazole with the
Rh catalyst generates the reactive Rh imino carbenoid II, with
the release of molecular nitrogen. The Rh imino carbenoid is
then attacked by the nearby aromatic π electrons, triggered by
the nitrogen electron lone pair, to produce the cyclic
intermediate III. A deprotonation step is driven by the
reestablishment of aromaticity. The formed intermediate IV
undergoes β-hydride elimination. In regeneration of the Rh(II)
catalyst for the next catalytic cycle, the formation of a double
bond furnishes the indole ring V with an N-sulfonyl imine at
the 3-position.
To extend the functionality of indoles obtained by this
method, the N-sulfonylimine group was converted to the
corresponding aldehyde and amine in a one-pot, three-step
synthesis. Hydrolysis of the sulfonyl imine using very mild
conditions, i.e., K2CO3 and MeOH, efficiently afforded
substituted 3-indolecarboxaldehydes. With reduced Cu(I) and
Rh(II) catalyst loadings, in the absence of bases, tandem
reactions were performed sequentially in one pot, giving indole-
3-carboxaldehydes from propargylanilines in three steps.24 The
reaction yields were reasonably good (62−72%; Scheme 4).
The selective reduction of the sulfonylimine group provided an
alternative C-3 functionalization of indoles. Use of standard
methods for hydrogenation reduction, such as NaBH4 and Pd
on charcoal, provided the desired C-3-amine-functionalized
indoles in good overall yields.
a
b
General reaction time 4 h unless noted otherwise. Reaction time 6 h.
c
Reaction time 3 h; NP = no product; multiple spots formation.
popular amine-protecting groups, benzyl and allyl, also gave
reasonable yields (4p, 81% and 4q, 72%). However, the desired
product was not formed when the amino group was coupled
with an electron-withdrawing group; a large number of
inseparable products were obtained. Presumably, electron-
withdrawing groups on the amino group significantly reduce
the nucleophilicity of the nitrogen electron lone pair, resulting
in formation of undesired side products from the Rh imino
carbenoid intermediates instead of indoles (4r−4t). Similarly,
the synthesis using an unprotected amine (4u) was
unsuccessful because the Rh imino carbenoid intermediate
In summary, we have developed a new synthetic method for
the preparation of C-3-functionalized indoles from propargy-
lanilines and TsN3, using Cu(I) and Rh(II) catalysts. The
developed method uses mild conditions that are efficient and
easy to perform. This method combines key indole formation
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
(15) Kim, S. H.; Park, S. H.; Choi, J. H.; Chang, S. Chem.Asian J.
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
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2011, 6, 2618 and references therein.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: pclin@mail.nsysu.edu.tw.
(17) Alford, J. S.; Spangler, J. E.; Davies, H. M. L. J. Am. Chem. Soc.
Notes
2013, 135, 11712.
(18) Rajagopal, B.; Chen, Y.-Y.; Chen, C.-C.; Liu, X.-Y.; Wang, H.-R.;
Lin, P.-C. J. Org. Chem. 2014, 79, 1254.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work is supported by grants from National Science
Council (NSC 101-2113-M-110-007-MY2) and National Sun
Yat-sen University (01C030703 and 01A06802). We also thank
the support from National Sun Yat-sen University-Kaohsiung
Medical University Joint Research Center, Kaohsiung, Taiwan.
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