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ARTICLE
Received 13 Feb 2014 |Accepted 29 Apr 2014 |Published 28 May 2014
Metal and carbene organocatalytic relay activation
of alkynes for stereoselective reactions
Kayambu Namitharan1,*, Tingshun Zhu1,*, Jiajia Cheng1, Pengcheng Zheng1,2, Xiangyang Li2,
Song Yang2, Bao-An Song2& Yonggui Robin Chi1,2
Transition metal and organic catalysts have established their own domains of excellence. It
has been expected that merging the two unique domains should provide complimentary or
unprecedented opportunities in converting simple raw materials to functional products.
N-heterocyclic carbenes alone are excellent organocatalysts. When used with transition
metals such as copper, N-heterocyclic carbenes are routinely practiced as strong-coordinating
ligands. Combination of an N-heterocyclic carbene and copper therefore typically leads to
deactivation of either or both of the two catalysts. Here we disclose the direct merge of
copper as a metal catalyst and N-heterocyclic carbenes as an organocatalyst for relay
activation of alkynes. The reaction involves copper-catalysed activation of alkynes to generate
ketenimine intermediates that are subsequently activated by an N-heterocyclic carbene
organocatalyst for stereoselective reactions. Each of the two catalysts (copper metal catalyst
and N-heterocyclic carbene organocatalyst) accomplishes its own missions in the activation
steps without quenching each other.
DOI: 10.1038/ncomms4982
1Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371,
Singapore. 2Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering,
Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, China. * These authors contributed equally to this work. Correspondence and
requests for materials should be addressed to B.-A.S. (email: basong@gzu.edu.cn) or to Y.R.C. (email: robinchi@ntu.edu.sg).
NATURE COMMUNICATIONS | 5:3982 | DOI: 10.1038/ncomms4982 | www.nature.com/naturecommunications 1
&2014 Macmillan Publishers Limited. All rights reserved.
One essential objective in chemical synthesis is to convert
readily available and inexpensive starting materials to
functional molecules. Transition metal catalysts are
widely explored to accomplish many of these activations and
chemical transformations1,2. In the last decade or so, the use of
simple organic molecules as catalysts (organocatalysis) has
received increasing attentions with impressive success3–5.
Concurrently, it has been envisioned that merging transition
metal and organocatalysts should provide a powerful strategy in
chemical synthesis6. One of the key challenges, on the other hand,
lies in the search of metal and organic catalysts that can work
together cooperatively without quenching each other. In the past,
organocatalysts exhibiting weak metal-coordination abilities
have successfully been combined with transition metal catalysis
in elegant reactions. A relatively well-studied system in this
direction includes a combined use of a transition metal (such as
gold, palladium, iridium, ruthenium) catalyst with chiral amine or
phosphoric acid catalysts7–14. In contrast, the combined use of
N-heterocyclic carbenes(NHCs) as organocatalysts15–18 that can
likely behave as strong-coordinating ligands19–22 with transition
metal catalysts remains challenging. Several efforts have been
directed towards addressing such metal/organic catalysts’
quenching issues. These efforts include the use of step-by-step
protocols of sequential addition of catalysts23, the introduction
of additional coordinating ligands to compete with the
organocatalysts24,25 and the use of early transition metals that
do not show strong-coordinating properties26,27.
We are interested in combining copper28–30 and NHCs for
cooperative metal/organic catalysis. To the best of our knowledge,
a simple combination of transition metal such as copper
and strong-coordinating NHC (as organocatalyst) remains
challenging and elusive23–27. Here we report the first success in
using Cu and NHC cooperative catalysis for a direct activation of
alkyne for stereoselective reactions (Fig. 1a). The reaction
(Fig. 1b) starts with Cu-catalysed activation of alkyne to react
with TsN
3
to eventually generate ketenimine31,32 III as a key
intermediate. This ketenimine intermediate (III) from the
Cu-catalysed cycle is then activated by the NHC catalyst
present in the same reaction solution to form azolium enamide
(similar to an enolate) intermediate IV that can react with
electrophilic substrates such as reactive ketones and imines to
form the final product. Notably, this organocatalytic cycle also
constitutes the first study in using NHC to activate ketenimine.
The overall metal/organic relay catalytic processes activate readily
available alkynes as enolate equivalent intermediates (azolium
enamides) for stereoselective reactions.
Results
Compatibility and reactivity of NHC and Cu catalysts. We first
studied the compatibility of Cu and NHC catalysts under dif-
ferent conditions. As summarized in Fig. 2a, while strong bases
(such as NaH, KOtBu, DBU) promote the formation of NHC-Cu
complex Bfrom the corresponding triazolium NHC pre-catalyst
Aand CuI, weak bases (such as TEA, DIEA, K
2
CO
3
) led to little
NHC-Cu complex after several hours. In our prior studies27,33–35,
it is known that weak bases such as DIEA or K
2
CO
3
are sufficient
for the deprotonation of triazoliums to form the carbene catalyst.
We therefore concluded that under ‘weak’ base conditions, there
is a controllable kinetic/thermodynamic window that allows the
carbene organocatalyst and Cu metal catalyst to co-exist with a
meaningful level of concentrations. In addition, we found that
both the CuI and NHC-Cu complex can catalyse alkyne
activation in a model reaction that converted alkyne to amide
NBn
O
X
nBu
Cu NHC
TsN3NBn
XO
++
TsN
nBu CH
TsN3
Cu(I) / base
NTs
C
H(Cu)
nBu
NHC
Organocatalysis
TsN
HnBu
N
N
N
H3C
CH3
N
N
N
CH3
H3C
nBu [Cu]
TsN N
N
nBu
N2
Cu/metal
catalysis
Ketenimine
Azolium enamide
X = O or NBoc
Alkyne
Cu and NHC
relay catalysis
NBn
XO
NBn
O
X
nBu
TsN
NHC
X = O or NBoc
a
b
Alkyne
I
II
III
IV
V
[Cu]
BaseH+
BaseH+
nBu
CH
-
Figure 1 | Combined Cu and NHC cooperative relay activation of alkynes as enolate equivalents. (a) Alkyne and azide activated by Cu/NHC relay
catalysis undergo formal [2 þ2] clycoaddition to give spiro-oxindole products. (b) Copper-catalysed [3 þ2] cycloaddtion of azide to alkyne gives triazole II
that decomposes to ketenimine III with a release of N
2
. Addition of NHC to ketenimine III gives azolium enamide IV, which undergoes formal [2 þ2]
cycloaddtion with isatin (or isatin–imine) to afford product V. NHC, N-heterocyclic carbene.
ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms4982
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&2014 Macmillan Publishers Limited. All rights reserved.
(Fig. 2b). This result showed that the triazolium NHC catalyst
would NOT kill the ability of Cu catalyst to activate alkyne. Last,
we found that NHC catalyst Acould activate (pre-prepared)
ketenimine substrate for nucleophilic addition to isatin 3a to form
adduct 4a that was simultaneously transformed to alkene product
5a (Fig. 2c), suggesting that we might be able to use NHC to
activate the ketenimine intermediate (III, Fig. 1b) generated from
a Cu catalytic cycle in a relay pathway.
N N+
N
Ph
BF4-
+
CuI
Base
(1.1 equiv.)
NN
N
Ph
Cu
I
CDCl3, rt
CH
nBu
TsN3 (1 equiv.)
Catalyst (20 mol%)
Et3N (120 mol%)
1.1 equiv.
nBu NHTs
O
H2O (5 equiv.)
CHCl3, rt
90%
86%
a Coordination effect of NHC/Cu under different bases
b Reactivity of CuI and NHC-Cu complex in the first catalytic cycle of alkyne activation
NHC-Cu complex B
NaH or KOtBu > 95%
Cs2CO3 18%
K2CO3 Trace
DBU > 95%
Et3N or DIEA Trace
CuI
NHC-Cu complex B
1a Amide
c NHC organocatalyst can activate pre-formed ketenimine
Catalyst Yield of amide
Base Yield% of B
nBu
NHTs
O
NTs
C
H
nBu
Pre formed
ketenimine
(as III in Fig. 1b)
NBn
OO
3a NBn
O
O
nBu
TsN
NBn
O
nBu
20 mol% A
100 mol% DIEA
4a
5a
81% Yield
PPh3Br2
200 mol% DIEA
Amide
NHC.HBF4 A
Preparation scale synthesis of B was performed in THF
Figure 2 | Studies on the compatibility and reactivity of NHC and Cu catalysts. See Supplementary Methods for details. (NHC, N-heterocyclic carbene.
DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene, DIEA, diisopropylethylamine.
Table 1 | Condition optimization for Cu/NHC relay catalytic reaction.
NBn
OO
3a
NBn
O
O
nBu
TsN
NBn
O
nBu
Condition
4a 5a
+
CH2Cl2,
rt, 6 h
TsN3
+
CH
nBu
1a
2a
Entry CuI (mol%) NHC.HBF
4
A (mol%) Base (120 mol%) 5a Yield%
1 10 0 DIEA 0
2 0 20 DIEA 0
3 10 20 DIEA 91
4 10 20 DBU 20
51020K
2
CO
3
91
61020Cs
2
CO
3
86
7 Cu-NHC complex B(10 mol%) DIEA 10
8 10 10 DIEA 79
The reaction was carried out in 1.0 ml solvent under N
2
. Yields of 5a were isolated yields after SiO
2
chromatography purification. See Supplementary Table 2 for results under other conditions.
NATURE COMMUNICATIONS | DOI: 10.1038/ncomms4982 ARTICLE
NATURE COMMUNICATIONS | 5:3982 | DOI: 10.1038/ncomms4982 | www.nature.com/naturecommunications 3
&2014 Macmillan Publishers Limited. All rights reserved.
NBn
O
C6H5
79% Yield
92% Yield
NMe
O
H3C
NR'
O
Si
83% Yield
NBn
O
Si
5f
( )3
NBn
O
( )3
5g
5h
Cl
5l
R' = Bn, 5i, 90% Yield
R' = MOM, 5j, 91% Yield
R' = PMB, 5k 93% Yield
84% Yield
NBn
O
H3C
n = 2, 5b, 86% yield
n = 5, 5c, 92% yield
n = 7, 5d, 91% yield
n = 9, 5e, 85% yield
n = 3, 5a, 91% yield
NR'
OO
3
NR'
O
R
5a-m
+
TsN3
+
CH
R
1
n
H3CCH3
CH3H3C
H3C
CH3
a Examples of the isatin-derived alkene forming reactions
c Studies on TMV infection inhibition
b Examples of natural products containing 3-alkenyl oxindole
NH
O
H3C
CH3
OCH3
NH
O
H3C
Soulieotine (E)- and (Z)-3-ethylidene-
1,3-dihydroindol-2-ones Costinone A
NH
O
OMe
N
CH3
Neolaugerine
H3C
Compound Inhibition rate against TMV (%)
N
O
MeOOC
HO
OH
OH
NPMB
O
5m
90% Yield
56.2
CH3
2a
5a
5b
5j
5k
38.6
34.5
29.8
42.6
Ningnanmycin
(positive control)45,49
10 mol% CuI
20 mol% NHC.HBF4 A
120 mol% DIEA (base)
CH2Cl2, rt, 6 h
Figure 3 | Scope of the reaction and bio-activities of the products. Bn, benzyl; Me, methyl; MOM, methoxymethyl; PMB, para-methoxybenzyl.
ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms4982
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Reaction optimization. Encouraged by the above results (Fig. 2),
we moved to study the one-pot relay catalytic reactions using
alkyne 1a and isatin 3a as model substrates (Table 1). As expected
based on our study briefed in Fig. 2, no proposed product (4a or
5a) was observed when only NHC catalyst (A) or the transition
metal catalyst (CuI) was used (Table 1, entries 1–2). The isatin
starting material (3a) remained (entries 1–2). The use of base
DIEA led to product 5a in 91% yield (entry 3). A switch of DIEA
to a stronger DBU base led to a much dropped 20% yield (entry
4). This base effect is in consistence with the compatibility studies
(Fig. 2a): strong base led to NHC-Cu complex formation and thus
removed free NHC organocatalysts from the reaction mixture.
Other weak bases such as K
2
CO
3
and Cs
2
CO
3
performed well
(entries 5–6). An evaluation of the NHC and Cu catalyst ratios
indicated that increasing the relevant amount of Cu metal catalyst
has little influence of the reaction outcomes, while increasing the
amount of NHC organocatalyst led to dropped product yields
(Supplementary Table 1). In addition, using NHC/Cu catalyst in a
ratio of 1:1 (10 mol% each, entry 8) gave much better results than
using the preformed NHC-Cu complex B(10 mol%). The results
suggest that under the condition, the two catalysts (NHC and Cu)
independently (rather than as the metal–carbene complex form)
work in the relay catalysis system.
Substrate scope with isatin as electrophile substrates. Under the
optimized condition (Table 1, entry 3) the reaction was general
with respects to both the alkyne and isatin substrates, as sum-
marized in Fig. 3a. All the alkene products are characterized by
1H, 13C NMR and HRMS techniques (Supplementary Figs 1–16
and Supplementary Methods). Notably, our catalytic reaction
exclusively affords Z-alkene isomer in all cases. It should be noted
Ar = C6H5, 7b, 85% yield
Ar = 4-F-C6H4, 7c, 82% yield
7d, 79% yield
a Isatin-derived imines as electrophile substrates
b Enantioselective reactions
NMe
BocN O
6
NMe
O
NBoc
R
TsN
+
TsN3
+
CH
R
1R''
10 mol% CuI
20 mol% NHC.HBF4 A
120 mol% CsF (base)
CH2Cl2, rt, 2 h
R''
NMe
O
NBoc
TsN
n = 2, 7e, 85% yield
n = 3, 7f, 88% yield
n = 5, 7g, 71% yield
NMe
O
NBoc
Si
TsN
H3C
H3C
H3C
NMe
O
NBoc
Ar
TsN
NMe
O
NBoc
C6H5
TsN
Br
7a, 87% yield
(17% yield using
condition in Table 1,
entry 3 with DIEA as a
base)
NMe
BocN O
NMe
O
NBoc
TsN
10 mol% CuI
20 mol% NHC.HBF4 C
120 mol% CsF (base)
4Å molecular sieve
toluene, rt, 4 h
7e-g
(> 99:1 dr)
n = 2, 7e, 88% yield, 81:19 er
n = 3, 7f, 83% yield, 85:15 er
n = 5, 7g, 74% yield, 79:21 er
7a-g
(> 99:1 dr)
H3Cn
H3Cn
2a
+
TsN3
+
CH
R
1
2a
6
NN
N
C6H5
BF4
NHC.HBF4 C
C6H5
Figure 4 | Imines as electrophile substrates in the Cu/NHC relay catalysis system. The minor diastereomer of the product 7a–g was not detected.
NATURE COMMUNICATIONS | DOI: 10.1038/ncomms4982 ARTICLE
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&2014 Macmillan Publishers Limited. All rights reserved.
that such Z-alkenes are difficult to make using other approaches.
For example, with Wittig reaction strategy (isatin and ylide as
substrates) the use of alkyl ylides gave poor yields and poor E/Z
selectivities36,37 In Knoevenagel-type condensation reactions
between oxindole and alkyl aldehydes, E-selective alkene
products were typically obtained38. The radical ring closure
approach for this type of products also favours E-alkenes
especially for alkyl alkyne substrates39–41. In our approach,
silane-protected acetylene (5i–5k) can also be prepared. In a
previous approach42 such molecule could only be synthesized via
radical ring closure with moderate yield and selectivity (up to
67% yield, 4.7:1 Z/E).
Bio-activities of 3-alkenyl-oxindoles. Our other motivation to
develop methods for isatin-derived alkene products is driven by
the utilities of this class of molecules. 3-Alkenyl-oxindoles is a
privileged scaffold in medicinal molecules and natural products
(Fig. 3b). For example, a novel class of receptor tyrosine kinase
inhibitors synthesized from 3-alkenyl oxindole and has been used
as anticancer and arthritis drugs43. Our laboratories are interested
in plant viruses that cause detrimental effects on agriculture and
horticulture44. One particular virus under our studies is tobacco
mosaic virus (TMV). TMV is known to infect more than 400
plant species such as tobacco, tomato, potato and cucumber to
cause tremendous economic loss worldwide45,46. Built on our
previous studies in this area to treat plant virus diseases47,48, our
preliminary studies here found that the isatin-derived alkene
compound 5k showed a promising 42.6% inhibition rate against
TMV infection. The positive control experiment using the
commercially used drug Ningnanmycin45,49 showed 56.2%
inhibition rate (Fig. 3c).
Substrate scope with isatin–imine as electrophile substrates.To
further demonstrate the reaction generality and expand the
product diversity of our Cu/NHC metal/organic relay catalytic
strategy, we evaluate the isatin-derived imine (6) as electrophile
substrate (Fig. 4a). Initial studies using the above condition for
the isatin ketone substrate (Table 1, entry 3) gave product 7a with
a low yield (17%). Further studies (see Supplementary Table 2)
found that by using CsF as the base, the spirocyclic b-lactam type
products (spiro-azetidine oxindoles 7a–g) were obtained as a
single diastereomer (499:1 dr) with good yields. The use of
Cs
2
CO
3
as base could also give the product, but in a slightly lower
yield (see Supplementary Table 2). The reaction is general with
respect to both alkyne and the isatin–imine substrates. All the
lactam products are characterized by 1H, 13C NMR and
HRMS techniques (Supplementary Figs 17 and 19–30 and
Supplementary Methods). The structure and stereochemistry of a
model compound 7a were unambiguously confirmed by single
crystal X-ray analysis (see Supplementary Fig. 18 and
Supplementary Table 3). Enantioselective reactions are also
feasible. When chiral triazolium NHC pre-catalyst Cwas used,
the spirocyclic lactam products (for example, 7e, 7f and 7g) were
obtained in good yields and moderate er (Fig. 4b). Further studies
in developing highly enantioselective NHC organocatalysts for
this class of reactions are under progress.
In summary, we have developed a cooperative relay catalysis
strategy using NHCs as organocatalysts and Cu as a transition
metal catalyst. Under a properly chosen condition (such as the
use of weak base to modulate the formation of free carbene and
NHC-Cu complex), Cu metal catalyst and triazolium NHC
organic catalyst work independently to accomplish its own
mission without quenching each other. Our overall one-pot
multistep reaction, consisting of the first NHC organocatalytic
activation of ketenimine, converts readily available alkynes as
enamide intermediates for stereoselective reactions. This study
suggests that by properly controlling the kinetics and/or
thermodynamics of metal/organic catalyst coordination, organic
catalysts and tradition metals that were typically considered to
form strong metal–organic coordination can likely be combined
for cooperative catalysis. Encouraged by the present results, our
next step is to develop general strategies for metal/organic
cooperative catalysis that can work for a broad set of catalyst
systems for new activations and reactions.
Methods
Materials.For 1H, 13C NMR and HPLC spectra of compounds in this manuscript,
see Supplementary Figs 1–30. For details of the synthetic procedures, see
Supplementary Methods.
Synthesis of 5a.A dry 10-ml Schlenk tube equipped with a magnetic stirring bar
was successively charged with 1-hexyne 1a (44.1 ml, d¼0.723 g ml 1, 31.9 mg,
0.39 mmol), tosyl azide 2a (70.9 mg, 0.36 mmol), N-benzyl isatin 3a (71.1 mg,
0.30 mmol) and CuI (5.6mg, 0.03 mmol) and NHC pre-catalyst A(16.4mg,
0.06 mmol). The tube was closed with a septum, evacuated and refilled with
nitrogen. To this mixture was added dry dichloromethane (1.0ml), followed by the
addition of DIEA (62.5 ml, d¼0.742 g ml 1, 46.4mg, 0.36 mmol) via a micro-
syringe. After stirring for 6 h at room temperature, the reaction mixture was
concentrated under reduced pressure. The crude residue was directly applied to
silica gel column chromatography (hexanes/ethyl acetate) to afford Z)-1-benzyl-3-
pentylideneindolin-2-one (5a, 79.5 mg, 91% yield).
Synthesis of 7a.A dry 10-ml Schlenk tube equipped with a magnetic stirring bar
was successi vely charged with phenyl acetylene (42.7 ml, d¼0.930 g ml 1, 39.7 mg,
0.39 mmol), tosyl azide 2a (0.36 mmol), isatin-derived imine 6(101.4 mg,
0.30 mmol), CuI (5.6 mg, 0.03 mmol) and NHC pre-catalyst A(16.4 mg,
0.06 mmol). The tube was closed with a septum, evacuated and refilled with
nitrogen. To this mixture was added dry dichloromethane (1.0ml), followed by the
addition of CsF (54.3 mg, 0.36mmol). After stirring for 2 h at room temperature,
the reaction mixture was concentrated under reduced pressure. The crude residue
was directly applied to silica gel column chromatography (hexanes/ethyl acetate) to
afford tert-butyl (E)-50-bromo-10-methyl-20-oxo-3-phenyl-4-(tosylimino)spiro
[azetidine-2,30-indoline]-1-carboxylate (7a, 182.7 mg, 87% yield).
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Acknowledgements
We acknowledge financial support by the Singapore National Research Foundation,
Singapore Economic Development Board, GlaxoSmithKline, Nanyang Technological
University (NTU, Singapore) and China’s National Key program for Basic Research
(No. 2010CB 126105), the National Natural Science Foundation of China (No. 21132003)
and Guizhou University (China). We thank Dr R. Ganguly and Y. Li (NTU) for
assistance with X-ray structure analysis.
Author contributions
K.N. and T.Z. contributed equally to this study. K.N. conducted most of the synthetic
experiments; T.Z. conducted mechanistic studies and part of the synthetic experiments.
J.C., P.Z., X.L. and S.Y. conducted studies regarding preparation and activity evaluation
of some reaction products. Y.R.C. and B.-A.S. conceptualized and directed the project,
and drafted the manuscript with the assistance from all co-authors. All authors con-
tributed to discussions.
Additional information
Accession codes: The X-ray crystallographic coordinates for structures reported in this
Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC),
under deposition number CCDC 981345. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supplementary Information accompanies this paper at http://www.nature.com/
naturecommunications
Competing financial interests: The authors declare no competing financial interests.
Reprints and permission information is available online at http://npg.nature.com/
reprintsandpermissions/
How to cite this article: Namitharan, K. et al. Metal and carbene organocatalytic relay
activation of alkynes for stereoselective reactions. Nat. Commun. 5:3982 doi: 10.1038/
ncomms4982 (2014).
NATURE COMMUNICATIONS | DOI: 10.1038/ncomms4982 ARTICLE
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