Rapid Synthesis of Functionalized Indenes, Triazoles, and Glucocorticoid Receptor Modulators by Sequential Multicatalysis Cascade Reactions

Article abstract of DOI:10.1002/ejoc.201000220

A general process for the synthesis of substituted indenes and 1,2,3-triazoles was achieved, for the first time through a multicatalysis cascade reaction of 2-ethynylbenzaldehydes, CH acids, organic hydrides, and azides in the presence of a catalytic amount of L-proline/CuI/DIPEA. In this communication, we discovered the utilization of a single copper catalyst for two different reactions and shown synthetic application to the high-yielding synthesis of glucocorticoid receptor modulators.

Full text of DOI:10.1002/ejoc.201000220

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000220
Rapid Synthesis of Functionalized Indenes, Triazoles, and Glucocorticoid
Receptor Modulators by Sequential Multicatalysis Cascade Reactions
Dhevalapally B. Ramachary,*[a] Rumpa Mondal,[a] and Chintalapudi Venkaiah[a]
Keywords: Amino acids / Carbocycles / Heterocycles / Organocatalysis / Domino reactions
A general process for the synthesis of substituted indenes
and 1,2,3-triazoles was achieved for the first time through a
multicatalysis cascade reaction of 2-ethynylbenzaldehydes,
CH acids, organic hydrides, and azides in the presence of a
tion, we discovered the utilization of a single copper catalyst
for two different reactions and shown synthetic application
to the high-yielding synthesis of glucocorticoid receptor
modulators.
catalytic amount of L-proline/CuI/DIPEA. In this communica-
is the addition of active nucleophiles to an alkyne function-
ality under coinage metal catalysis.[4] More specifically, cas-
cade reactions involving an alkyne functionality, wherein
“soft” coinage metal ions (Cu, Ag, and Au) are employed
to provide the necessary activation to trigger the cascade
process.[4]
Introduction
Functionalized indenes and 1,2,3-triazoles are an important
class of carbo- and heterocycles. They exist as basic skel-
etons in a biologically active compounds and are used as
drug intermediates in pharmaceuticals [Equation (1)].[1] As
such, the development of new and more general catalytic
The combination of amino acids and suitably ligated
methods for their preparation is of significant interest.[2] coinage metal ion complexes could be identified as multi-
Herein, for the first time we reported the one-pot synthesis catalysts, and this would provide an ideal synthetic strategy
of indenes and 1,2,3-triazoles from common substrates and compared to cellular reactions.[4a] Herein and for the first
catalysts through the “combination of multicomponent re- time, we propose that the iminium activation of aldehydes,
actions (MCR) and multicatalysis cascade (MCC) reac- the self-activation of olefins, and the simultaneous acti-
tions”.[3]
vation of metal ion alkynes could be combined in a cascade
The field of transition-metal-catalyzed cascade sequences sequence, constituting a new carbocyclization method to
continues to mature and develop. One area in particular furnish indenes through a Conia–ene reaction[5] and a new
that has witnessed significant interest over the past decade heterocyclization method to furnish 1,2,3-triazoles through
(1)
[a] School of Chemistry, University of Hyderabad,
[3+2] cycloaddition from common substrates and catalysts
(Scheme 1). With many points of diversity present in the
products, this MCC process would be a powerful method
for the generation of indene and 1,2,3-triazole libraries and
Hyderabad 500046, India
Fax: +91-40-23012460
E-mail: ramsc@uohyd.ernet.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000220.
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D. B. Ramachary, R. Mondal, C. Venkaiah
SHORT COMMUNICATION
indene-based target synthesis [Equation (1) and Scheme 1]. yield as shown in Scheme 2. The MCC reaction of 1a, 2a,
Herein, we report our findings regarding these new MCC and 3a in CH3CN at 25 °C for 2.5–12.5 h under the combi-
reactions and application to the high-yielding synthesis of nation of pyrrolidine or morpholine with CuI/Cs2CO3 ca-
glucocorticoid receptor modulators.
talysis also furnished indene 6aa in 64–70% yield (Equa-
tions S1 and S2, Supporting Information). Interestingly, re-
action of 5aa with CuI/-proline/DIPEA in CH3CN at
25 °C for 14 h furnished indene 6aa in 86% yield, but there
was no reaction with CuSO4/Na–(+)-ascorbate in tBuOH
and H2O at 25 °C for 20 h as shown in Table S1, Entries 15–
17 (Supporting Information).
Scheme 1. MCC approach to functionalized indenes and triazoles.
Scheme 2. Optimization of the carbocyclization and heterocycli-
zation reactions. Method A: Compound 1a (0.5 mmol), 2a
(0.5 mmol), 3a (0.5 mmol), -proline (20 mol-%, 0.1 mmol); EtOH,
tBuOH, or CH3CN (0.25 ); 25 °C, 24 h. Method B: Compound 1a
(0.5 mmol), 2a (0.5 mmol), -proline (20 mol-%, 0.1 mmol), EtOH
(0.25 ), 25 °C, 0.5 h. Then, 8 (0.5 mmol), PhCHO (0.5 mmol),
25 °C, 12 h. Method C: Compound 5aa, CuI (0.05 mmol, 10 mol-
%, 9.5 mg), Cs2CO3 (1 mmol, 2 equiv., 326 mg), CH3CN (1.0 mL),
25 °C, 2 h. Method D: Compound 5aa, BnN3 (a) (1.0 mmol,
2 equiv.), CuI (0.05 mmol, 10 mol-%, 9.5 mg), DIPEA (30 mol-%),
CH3CN (1.0 mL), 25 °C, 6 h. Method E: Compound 5aa, BnN3 (a)
(0.6 mmol, 1.2 equiv.), CuSO4·5H2O (0.1 mmol, 20 mol-%, 25 mg),
Na–(+)-ascorbate (0.2 mmol, 40 mol-%, 40 mg), H2O (1.0 mL),
tBuOH (1.0 mL), 25 °C, 3 h.
Results and Discussion
We initiated our MCC studies by optimizing an ole-
fination, hydrogenation, and cyclization sequence of 1a, 2a,
3a/3b, and BnN3 (a) by using different conditions, and some
representative results are shown in Scheme 2. We found that
-proline readily catalyzes the olefination of 2a with 1a to
furnish active olefin 4aa,[6] which upon in situ treatment
with Hantzsch ester 3a produced hydrogenated product 5aa
with very good yield in EtOH, tBuOH, or CH3CN at 25 °C
for 24 h. The same reaction with in situ generated 2-phenyl-
After testing the sequential one-pot olefination/hydro-
2,3-dihydro-1H-benzoimidazole (3b) also furnished product genation and carbocyclization or Conia–ene reaction of 1a,
5aa with 95% yield in protic solvents. The optimum condi- 2a, and 3a under -proline/CuI/base catalysis, we further
tions involved the use of 20 mol-% catalyst in cascade ole- investigated the intermolecular [3+2] cycloaddition of ole-
fination/hydrogenation reaction of 1a, 2a, and 3a/3b in fination/hydrogenation product 5aa with BnN3 (a) to fur-
EtOH, tBuOH, or CH3CN at 25 °C to furnish 5aa in very nish 1,2,3-triazole 7aaa in one pot under the same catalytic
good yield (see Scheme 2). After the successful synthesis of conditions as shown in Scheme 2. Interestingly, the sequen-
5aa, we decided to investigate suitable conditions to cata- tial one-pot reaction of in situ generated 5aa with BnN3 (a)
lyze the carbocyclization of 5aa in one-pot as shown in (2 equiv.) under the optimized conditions [15 mol-% of -
Scheme 2 and Table S1 (Supporting Information). Interest- proline, 10 mol-% of CuI, 30 mol-% of DIPEA] in CH3CN
ingly, reaction of 5aa under the optimized conditions at 25 °C for 6 h furnished 1,2,3-triazole 7aaa in 70% yield
(15 mol-% of -proline, 10 mol-% of CuI, and 2 equiv. of and indene 6aa in 20% yield (Scheme 2). In a similar man-
Cs2CO3) in CH3CN at 25 °C for 0.5 h furnished indene 6aa ner, sequential one-pot combination of -proline/self-cata-
in 90% yield (Table S1, Supporting Information). Sequen- lyzed olefination/hydrogenation reaction and CuSO4/
tial one-pot combination of -proline-/self-catalyzed ole- Na–(+)-ascorbate-catalyzed heterocyclization of 1a, 2a, 3a,
fination/hydrogenation reaction and CuI/-proline/Cs2CO3- and BnN3 (a) in tBuOH and H2O at 25 °C for 27 h fur-
catalyzed carbocyclization of 1a, 2a, and 3a in CH3CN at nished 1,2,3-triazole 7aaa in 90% yield and indene 6aa in
25 °C for 26 h furnished indene 6aa with slightly reduced 10% yield (Scheme 2).
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Sequential Multicatalysis Cascade Reactions
With the optimized reaction conditions in hand, the cellent yields (Table 1). Reaction of a menthol derivative of
scope of the MCC reactions was investigated. A variety of CH acid 1d with 2a and 3a under -proline/CuI/Cs2CO3
CH acids 1a–m were treated with 2a (1 equiv.) and 3a catalysis furnished (–)-6da, but unfortunately only 20%de
(1 equiv.) under sequential catalysis of -proline (5 to was observed (Table 1, Entry 4). Interestingly, reaction of
20 mol-%) and CuI/Cs2CO3 or CuI/Et3N in CH3CN at cyclic CH acids 1f–i with 2a and 3a under -proline/CuI
25 °C for 0.5 to 2 h (Table 1). Acyclic and cyclic CH acids catalysis and the reaction of CH acids 1j–m with 2a and 3a
1a–m generated the expected Conia–ene products 6 with ex- under -proline/CuI/Et3N catalysis furnished the mono-
Table 1. One-pot synthesis of indene 6 and 1,2,3-triazole products 7.[a]
[a] Yield refers to the column-purified products. [b] Cs2CO3 was not used. [c] Et3N (30 mol-%) was used instead of Cs2CO3. [d] Reaction
time was 12 h.
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D. B. Ramachary, R. Mondal, C. Venkaiah
SHORT COMMUNICATION
spiro and dispiro compounds 6fa–ma as major products in
With synthetic applications in mind, we further extended
70–95% yields, which are sesquiterpenoid analogues the application of the three-component carbocyclization re-
(Table 1). Possibly as a result of the highly acidic nature of action to the synthesis of dialkyl 1-methyleneindan-2,2-di-
cyclic CH acids 1f–m compared to acyclic CH acids 1a–e, carboxylates 6faa–fad in good yields (Table 2). Herein, we
for compounds 5fa–ma the Conia–ene reaction, which was utilized the in situ generation and esterification of meth-
performed under -proline/CuI or -proline/CuI/Et3N ca- oxycarbonyl ketenes with alcohols for the sequential one-
talysis, proceeded without the use of a strong base, as pot synthesis of malonates 5faa–fad from the olefination/
shown in Table 1. The structures of products 6aa–ma were hydrogenation/alkylation/ketenization/esterification (O/H/
confirmed by NMR spectroscopic analysis; the structure A/K/E) reactions of 2a, Meldrum’s acid (1f), o-phenylenedi-
was finally confirmed by X-ray structure analysis of 6ga amine (8), diazomethane, and alcohols 9a–d through imin-
(Figure S1, Supporting Information).[7]
ium and self-catalysis in one pot.[3e] Interestingly, the -pro-
We further extended the three-component reaction into line/self-catalyzed cascade olefination/hydrogenation reac-
four-component heterocyclization reaction of 1, 2a, 3a, and tion of 1f and 2a (2 equiv.) with 8 in methanol (9a) at 25 °C
ArN3 (a) and (b) for the synthesis of 1,2,3-triazoles 7 by for 0.5 h furnished 5fa in Ͼ99% conversion, which upon in
-proline/CuSO4/Na–(+)-ascorbate catalysis in one-pot as situ treatment with ethereal diazomethane at 0 Ǟ 25 °C for
shown in Table 1. The heterocyclization reaction of 1c with 6 h furnished expected malonate 5faa in 87% yield (Table 2,
2a and 3a under -proline/self-catalysis in tBuOH at 25 °C Entry 1). In a similar manner, we synthesized three more
for 24 h furnished the cascade olefination/hydrogenation nonsymmetrical malonates 5fab–fad in good yield by per-
product 5ca[6] in 99% conversion, which upon in situ treat- forming the sequential O/H/A/K/E reactions in EtOH (9b),
ment with BnN3 (a) under CuSO4/Na–(+)-ascorbate cataly- tBuOH (9c), and BnOH (9d) solvents (Table 2, Entries 2–
sis in tBuOH and H2O at 25 °C for 12 h selectively fur- 4).
nished 1,2,3-triazole 7caa in 90% yield (Table 1). In a sim-
After successful preparation of malonates 5faa–fad, we
ilar manner, treatment of in situ generated 5ja, 5ka, and tested the carbocyclization reaction of 5faa under one of
5ma[6] with BnN3 (a) under CuSO4/Na–(+)-ascorbate catal- the optimized conditions (15 mol-% of -proline, 10 mol-%
ysis in tBuOH and H2O at 25 °C for 2–3 h in one pot fur- of CuI, 2 equiv. of Cs2CO3, THF or CH3CN, 25 °C, 12 h;
nished 1,2,3-triazoles 7jaa, 7kaa, and 7maa in 75–78% Table S1, Supporting Information). Interestingly, we did
yield, which are useful starting materials for pharmaceutical not observe the formation of the product under these condi-
drug analogs C [see Equation (1)].[3a] Interestingly, reaction tions and only starting material 5faa was isolated. When we
of in situ generated 5aa with 1,4-bis(azidomethyl)benzene applied the carbocyclization conditions of 30 mol-%
(b) under CuSO4/Na–(+)-ascorbate catalysis in tBuOH and tBuOK with 10 mol-% of CuI in THF at 25 °C for 12 h on
H2O at 25 °C for 12 h in one pot furnished 1,2,3-triazole 5faa, the formation rate of 6faa was very slow. When we
7aab in 73% yield, which could be a useful starting material increased the catalyst loading up to 20 mol-% of CuI and
for the generation of medium-sized rings. In all heterocy- 1 equiv. of tBuOK in THF at 25 °C for 2 h, indene 6faa
clization reactions, 10–15% of carbocyclization products 6 was furnished in 80% yield (Table 2, Entry 1). In a similar
were furnished.
manner, we synthesized three more nonsymmetrical indenes
Table 2. Synthesis of indene products 6 through six reactions in one pot.[a]
[a] Yield refers to the column-purified products, and 2a was used as two equivalents. [b] Reaction was performed in a sequential one-pot
manner. [c] Conversion.
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Sequential Multicatalysis Cascade Reactions
6fab–fad in good yields by using the above conditions on
5fab–fad (Table 2, Entries 2–4). Finally, sequential combi-
nation of cascade O/H/A/K/E and carbocyclization reac-
tions was performed in one-pot to furnish indene 6faa in
70% yield (Table 2, Entry 5). Compound 6fad could be a
suitable intermediate for the synthesis of pharmaceuticals
A and B [see Equation (1)], which emphasizes the value of
this cascade approach.
With pharmaceutical applications in mind, we synthe-
sized drug intermediate 11fa through 10fa from MCC reac-
tions (Scheme 3). Recently, 11fa was used as a key interme-
diate for the total synthesis of glucocorticoid receptor mod-
ulator B (Scheme 3).[1a] Herein, by the combination of cas-
cade olefination/hydrogenation/carbocyclization, base-in-
duced decarboxylative isomerization, hydrogenation, alkyl-
ation, and hydrolysis reactions, we prepared 11fa by using
only four synthetic steps with an overall yield of 66% and
Ͼ90%de (Scheme 3). Synthesis of key intermediate 10fa
through the MCC reactions is evidently more advantageous
over the existing methods where expensive heavy metal cat-
alysts (Pd, Co, Re, and Ru, etc.) or costly starting materials
are used.[8]
Scheme 4. Proposed reaction mechanism.
furnish dinuclear olefin 14, which upon oxidative addition
with HI followed by reductive elimination furnished ex-
pected carbocyclization product 6. Intermolecular con-
certed [3+3] cycloaddition of active species 13 with hard
alkyl azide heteronucleophiles can generate cupracycle 15
in the rate-determining step, which further undergoes re-
ductive elimination to furnish mononuclear olefin 16. Oxi-
dative addition of 16 with HI followed by reductive elimi-
nation furnished expected heterocyclization product 7.
From the successful demonstration of two kinds of cycliza-
tions on single substrate 5 under common copper catalysis,
we have provided possible support to the existence of dinu-
clear alkynyl copper(I) complex 13 in click reactions.[9] π-
Bonding of second copper complex [CuBL] with 12 is cru-
cial and it acts as a Lewis acid for the intramolecular car-
bocyclization reaction; also it will increase the rate of the
reaction by stabilizing newly formed cupracycle 15 in
heterocyclization reactions with organic azides (Scheme 4).
Further experimental support for the existence of dinuclear
alkynyl copper(I) complex 13 in MCC reactions can be
found in the Supporting Information.
Scheme 3. High-yielding synthesis of glucocorticoid receptor mod-
ulator. Reagents and conditions: (a) KOH (1 equiv.), MeOH
(0.05 ), 65–75 °C, 1 h, 99%; (b) 10% Pd/C (5 mol-%), EtOAc
(0.1 ), 25 °C, 12 h, 99%; (c) DIPA (2.5 equiv.), nBuLi (2.2 equiv.),
MeI (4.5 equiv.), THF (0.25 ), –80 °C, 12 h, 88–90%; (d) 10%
aqueous KOH (1 equiv.), MeOH (0.25 ), 100 °C, 12 h, 75%.
The possible common mechanism for the synthesis of 6
and 7 from 5 with or without azides under -proline/CuI/
base catalysis is illustrated in Scheme 4. In the first step,
catalyst -proline selectively reacts with CuI to generate bi-
dentate copper species [CuL], which is an active CuI species
that reacts with acetylenes.[4a] In the following second step,
in situ generated [CuAL] selectively reacts with cascade ole-
fination/hydrogenation product 5 to generate copper acet-
ylide 12. Mononuclear copper acetylide 12 further reacts
with another active CuI species through π bonding to gener-
ate dinuclear alkynyl copper(I) complex 13, which is more
reactive than 12 in heterocyclization reactions with azides,
as revealed by kinetic data and DFT calculations obtained
and performed by Fokin et al.[9]
Conclusions
In summary, for the first time we have developed two
kinds of cyclization reactions that proceed in good yields
with high selectivity by using -proline/CuI/base as the
common catalyst on common substrates. Furthermore, we
have given possible support to the existence of dinuclear
alkynyl copper(I) complex 13 in click reactions by demon-
strating the two kinds of cyclizations on a single substrate.
Many of the achiral building blocks (i.e., 6aa, 6fa, 7jaa,
7kaa, 7maa, 6fad, and 11fa) prepared through the MCC
reactions are illustrated to have direct application in phar-
maceuticals. Further work is in progress to develop an
asymmetric version of this chemistry.
Dinuclear alkynyl copper(I) complex 13 has dual acti-
vation modes, as it can react with two kinds of nucleophiles
(soft and hard; Scheme 4). Base-induced in situ generated
Supporting Information (see also the footnote on the first page of
soft carbanion can undergo intramolecular cyclization to this article): Experimental procedures, characterization data for
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D. B. Ramachary, R. Mondal, C. Venkaiah
SHORT COMMUNICATION
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Acknowledgments
This work was made possible by a grant from the Department of
Science and Technology (DST), New Delhi (Grant No.: DST/SR/
S1/OC-65/2008). R. M. and C. V. thank the Council of Scientific
and Industrial Research (CSIR), New Delhi for their research fel-
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Received: February 18, 2010
Published Online: May 3, 2010
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