Mild gold-catalyzed three-component dehydrogenative coupling of terminal alkynes to amines and indole-2-carboxaldehyde

Article abstract of DOI:10.1039/c3ob42431f

A mild gold-catalyzed three-component dehydrogenative coupling of terminal alkynes to amines and indole-2-carboxaldehyde has been developed, which provides a practical synthetic strategy for the synthesis of indole derivatives. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3ob42431f

Organic &
Biomolecular Chemistry
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Mild gold-catalyzed three-component
dehydrogenative coupling of terminal alkynes
to amines and indole-2-carboxaldehyde†
Jian Li,a Hongni Wang,a Jiangtao Sun,a Yang Yangb and Li Liu*b
Cite this: Org. Biomol. Chem., 2014,
12, 2523
Received 5th December 2013,
Accepted 22nd January 2014
DOI: 10.1039/c3ob42431f
www.rsc.org/obc
A mild gold-catalyzed three-component dehydrogenative coupling have also been used in domino reactions.7 We recently deve-
of terminal alkynes to amines and indole-2-carboxaldehyde has loped an efficient three-component coupling reaction of
been developed, which provides a practical synthetic strategy for phenylglyoxal derivatives, secondary amines and terminal
the synthesis of indole derivatives.
alkynes toward a variety of furan derivatives mediated by gold(III)
(Scheme 1a).8 With this background in mind, we have been
engaged in realizing the abundance of indole derivatives via
this one-pot multicomponent strategy. Then, indole-2-carb-
oxaldehyde was chosen as the substrate to couple with secondary
Introduction
Indoles represent one important diverse family of pharmaceu- amines and terminal alkynes. We hypothesized that these
ticals and biologically active natural compounds.1 Not surpris- three compounds would couple together under catalysis by a
ingly, numerous studies and applications have focused on the gold catalyst to represent the required propargylamine inter-
functionalization of indoles.2 The efficiency of the synthesis mediate 8,9 which, upon activation of the triple bond with
can be increased significantly if the event of indole gold, would undergo an intramolecular cyclization10 into di-
functionalization is coupled with two other or even more com- substituted cyclopentaindole 9. However, when the reaction was
pounds in a cascade manner.3 Such one-pot multicomponent conducted under gold catalysis, product 4 was found instead
coupling reactions have been developed as an attractive and of indole 9 (Scheme 1b). We proposed that the exo-iminium
powerful methodology for the formation of carbon–carbon
and carbon–heteroatom bonds in a step- and atom-economical
fashion.4 Among these, a number of key building block synth-
eses using aldehydes, amines and alkynes as the starting
materials have been reported.5 However, an efficient synthesis
with high chemo- and regioselectivity, which would enable
access to complex indole derivatives via a cascade manner, still
remains challenging. Herein, we report a mild three-com-
ponent cross-dehydrogenative coupling (CDC) of terminal
alkynes to amines and indole-2-carboxaldehyde via a gold-cata-
lyzed condensation–alkynylation cascade as a continuation of
efforts in this area.
Gold catalysts, well known for their ability to promote
nucleophilic attack on acetylenes, have recently attracted inter-
est from the synthetic chemistry community.6 Gold catalysts
aSchool of Pharmaceutical Engineering & Life Sciences, Chang Zhou University,
Changzhou, 213164, P. R. China
bSchool of Petrochemical Engineering, Chang Zhou University, Changzhou, 213164,
P. R. China. E-mail: liliuchem@gmail.com; Fax: +86 519 86330224
†Electronic supplementary information (ESI) available: Experimental procedures
and all of the spectral data for the compounds. CCDC reference number 973071.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob42431f
Scheme 1 Discovery of this work and a previous report with a similar
iminium isomerization process. (a) Gold(III)-catalyzed three-component
coupling (TCC) reaction selective towards furans. (b) Initial discovery of
the three-component dehydrogenative coupling.
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ion 6 isomerized into endo-iminium ion 7, the C(sp3)–H bond solvents such as DCE, CH3CN, DMF and toluene were tested in
of intermediate 7 at the C1 atom was directly activated and the reaction. They showed lower yields compared to MeOH
functionalized by terminal alkynes catalyzed by Au complexes. (Table 1, entries 7–10). In addition, by lowering the tempera-
Such a CDC style reaction has no limitations compared with ture to 30 °C, the yield was decreased to 45%. The reaction was
the traditional CDC alkynylation reaction, which has to use not improved by the presence of 10 mol% or 20 mol% AuBr3.
N-aromatic or N-acyl substitutions and stoichiometric exogenous Therefore, our optimization identified that treatment of indole
oxidants.11 This strategy might have more potential in the syn- 1a with 5 mol% of AuBr3 as the catalyst, 1.5 equiv. of 2a and 2
thesis of complex indoles as the substrates are simple and equiv. of 3a in MeOH at 60 °C afforded 4a in 62% isolated
available. Recently, Seidel developed a Cu(II)-catalyzed alkyny- yield.
lation of pyrrolidines during a similar iminium isomerization
With the optimized reaction conditions in hand, the sub-
process,12a,b and Nakamura reported a similar redox cross- strate scope of this AuBr3-catalyzed cascade reaction was
dehydrogenative coupling of propargylic amines and terminal explored by using a wide range of different secondary amines 2
alkynes catalyzed by zinc(II).12c Very recently, Yu and coworkers and alkynes 3 (Tables 2 and 3). We were happy to find that aryl
reported a similar method to access C1-alkynylated tetra- alkynes bearing electron-donating and electron-withdrawing
hydroisoquinoline (THIQ) products (endo-yne-THIQs) via a substituents produced the desired products in good yields (4a–
CuI-mediated reaction,13a but in their system some of products 4g, Table 2). Various different groups at the aromatic moiety of
were mixed with exo-C1-alkynylated THIQ.
alkynes, such as halogen, methyl and methoxy, were well toler-
ated in these mild transformations. An aryl alkyne bearing
long aliphatic chain such as 1-ethynyl-4-pentylbenzene could
be smoothly transformed into the desired product in 72%
yield (4e, Table 2). Furthermore, aliphatic alkyne (4g, Table 2)
was also applicable in the target reaction in 62% yield.
Next, the scope of indole aldehydes 1 and secondary amine
2 was examined. Interestingly, by replacing morpholine with
tetrahydroisoquinolines, this transformation proceeded
smoothly in excellent yields. As is shown in Table 3, various
aryl alkynes 3 were found to be suitable reaction partners with
1-methyl-1H-indole-2-carbaldehyde and THIQ providing the
corresponding CDC products 5 (Table 3). Terminal alkynes 3
containing the halo, fluoro-, alkyl and methoxy groups, satis-
factorily underwent reaction to afford the desired products in
good yields (Table 3, 5a–5h). N-Boc and N-Bn protected indoles
were also tested. All of the reactions proceeded efficiently to
Results and discussion
Initially, we began our exploration by using the model sub-
strate indole-2-carboxaldehyde 1a (0.5 mmol), morpholine 2a
(0.75 mmol), and phenylacetylene 3a (1 mmol) employing
different catalysts. It was found that trace amounts of desired
product 4a was formed in the presence of copper salt CuI
(Table 1, entry 1). A range of gold catalysts were subsequently
evaluated, as summarized in Table 1. Ultimately, AuBr3 was
found to be the best catalyst for the reaction to afford the
desired product 4a in 62% yield. The other gold species gave
lower efficiencies (Table 1, entries 2–5). In an attempt to
improve the yield of 4a by surveying different solvents, various
Table 1 Screening of reaction conditions for formation of 4aa
Table 2 Scope of alkynes in the morpholine C1-alkynylationa,b
Temp
(°C)
Yield of
Entry
Catalyst
Solvent
4a (%)b
1
2
3
4
5
6
7
8
CuI
Ph3PAuCl
AuCl
DCE
60
60
60
60
60
60
60
60
60
60
30
80
60
60
Trace
11
7
51
47
62
33
21
0
42
45
50
65
67
MeOH
MeOH
MeOH
MeOH
MeOH
Toluene
CH3CN
DMF
HAuCl4
NaAuCl4
AuBr3
AuBr3
AuBr3
AuBr3
AuBr3
AuBr3
AuBr3
AuBr3
AuBr3
9
10
11
12
13c
14d
DCE
MeOH
MeOH
MeOH
MeOH
a Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), 3a (1 mmol),
catalyst (5 mol%, 0.025 mmol), in solvent (2 mL) at 60 °C overnight.
b Isolated yields. c 10 mol% of catalyst was employed. d 20 mol% of
catalyst was employed.
a 1 (0.5 mmol), 2a (0.75 mmol),
3 (1 mmol), AuBr3 (5 mol%,
0.025 mmol), in MeOH (2 mL) at 60 °C overnight. b Isolated yields.
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Table 3 Scope of alkynes in the THIQ C1-alkynylationa,b
Scheme 3 The proposed mechanism to obtain endo-product 4.
of N-protected indole-2-carboxaldehyde
1 and secondary
amines 2 promoted by an Au-catalyst, which was further con-
verted to endo-iminium ion 7. The endo-iminium ion is more
stable than the exo-iminium ion.13 The terminal alkynes acti-
vated by gold6 attack the C1 position of iminium ions 7 to
afford the final endo-product 4.
According to the proposed mechanism, secondary amines
not bearing the α-H should not undergo this CDC process.
With this idea in mind, diphenylamine was tested as the sec-
ondary amine under standard conditions. The results con-
firmed our speculation and the reaction did not proceed at all
(Scheme 4).
a 1a (0.5 mmol), 2b (0.75 mmol), 3a (1 mmol), AuBr3 (5 mol%,
0.025 mmol), in MeOH (2 mL) at 60 °C overnight. b Isolated yields.
Control experiments were then performed to figure out
whether the steric hindrance of the aldehyde determined the
endo/exo selectivity. First, we chose 1-methyl-1H-indole-2-car-
baldehyde as the aldehyde source, which has greater steric hin-
drance beside the aldehyde group, the reaction was complete
in 8 hours to afford the endo-compound 5a in 92% yield and
no exo-isomer was observed. When benzaldehyde was
employed in this reaction, a mixture of endo/exo 5i/6a was
obtained and the selectivity rate was 4.8/1 determined by
NMR. Finally, the smallest aldehyde was selected, which could
be converted to exo-product 6b in 87% yield only (Scheme 5,
afford the desired products in good yields (Table 3, 5f–5h).
Subsequently, the X-ray single crystal structure of 5b was
obtained, which further unambiguously confirmed the struc-
tures of these products (Fig. 1).
However, when pyrrolidine was chosen as the secondary
amine, the reaction gave a lower conversion and lower yield of
42% (Scheme 2). Other secondary amines such as piperidine
and acyclic amine were also tested, however, no desired pro-
ducts were found.
The reaction pathway was proposed as shown in Scheme 3
(path a). Initially, intermediate 6 is generated via the reaction
Scheme 4 Three-component coupling of diphenylamine to terminal
alkynes and indole-2-carboxaldehyde.
Fig. 1 X-ray diffraction structure of compound 5b.
Scheme 2 Coupling of pyrrolidine to alkynes and indole-2-carboxaldehyde.
Scheme 5 Control experiments for the steric hindrance of aldehyde.
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path b). The above results confirmed that the endo/exo selecti-
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Conclusions
In summary, a mild gold-catalyzed three-component dehydro-
genative coupling of terminal alkynes to amines and indole-
2-carboxaldehyde has been developed. Only endo-products were
obtained in good to excellent yields under standard conditions.
This method provides an efficient avenue for the easy assembly
of complex indole derivatives. Further studies on the scope and
synthetic applications of this transformation are ongoing.
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Experimental section
General experimental methods
All experiments were conducted under an air atmosphere.
Flasks were flame dried and cooled under nitrogen before use.
All solvents were dried appropriately. For column chromato-
graphy, 200–300 mesh silica gel was employed. 1H NMR and
13C NMR were recorded on a 300 MHz, 400 MHz or 500 MHz
spectrometer in CDCl3 solution and the chemical shifts were
reported in parts per million (δ) relative to internal standard
TMS (0 ppm). For HRMS measurements, the mass analyzer is
a GC-TOF-MS. Unless otherwise noted, materials obtained
from commercial suppliers were used without further purifi-
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General procedure for three-component dehydrogenative
coupling
To a solution of 1 (0.5 mmol), 2 (0.75 mmol), 3 (1 mmol) in
MeOH (2 mL) in a 10 mL Schlenk tube, AuBr3 (5 mol%,
0.025 mmol) was added in one portion. The resulting solution
was stirred at 60 °C overnight. After cooling to room tempera-
ture, the resulting mixture was filtered through a pad of celite.
The volatile compounds were removed in vacuo and the
residue was purified by column chromatography (SiO2, pet-
roleum ether–ethyl acetate = 10 : 1–4 : 1) to give the target
compound.
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Acknowledgements
Financial support from Changzhou Municipal Bureau of
Science and Technology University (ZMF 1002100) and the Pri-
ority Academic Program Development of Jiangsu Higher Edu-
cation Institutions is greatly appreciated.
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