Tetrasubstituted allenes by Pd0-catalyzed three-component tandem Michael addition/cross-coupling reaction

Article abstract of DOI:10.1039/b919060k

A Pd⁰-catalyzed three-component tandem Michael addition/cross-coupling reaction of electron-deficient enynes with nucleophiles and aryl halides was developed, which provides general, efficient, and regioselective access to multi-functionalized tetra-substituted allenes.

Full text of DOI:10.1039/b919060k

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Tetrasubstituted allenes by Pd0-catalyzed three-component tandem
Michael addition/cross-coupling reactionw
Yuanjing Xiaoa and Junliang Zhang*ab
Received (in Cambridge, UK) 15th September 2009, Accepted 12th November 2009
First published as an Advance Article on the web 27th November 2009
DOI: 10.1039/b919060k
A Pd0-catalyzed three-component tandem Michael addition/
cross-coupling reaction of electron-deficient enynes with
nucleophiles and aryl halides was developed, which provides
general, efficient, and regioselective access to multi-functionalized
tetra-substituted allenes.
Allenes are receiving increasing attention because not only can
they serve as versatile, useful synthons for synthetic organic
chemistry1 but also they are key structural elements in many
naturally occurring compounds.2 In this area, much effort has
been devoted to the development of efficient synthesis of
allenes.3 Among these methods, particular attention has
focused on the metal-catalyzed/mediated one or two-component
reactions involving propargyl derivatives. The search for
efficient and practical synthetic methods for allenes synthesis
from readily available starting materials is highly desirable.
Herein we communicate our preliminary results of the first
Pd0-catalyzed three component reaction to afford highly
functionalized tetrasubstituted allenes. To the best of our
knowledge, a transition metal-catalyzed multicomponent4
reaction to afford highly functionalized tetrasubstituted allenes
has not been described to date.
Very recently, we have reported our results on
a
PdII-catalyzed three-component reaction of 2-(1-alknyl)-2-
alken-1-ones 15 with various nucleophiles and allyl chlorides to
afford allyl substituted furans (Scheme 1a).6 During this study,
we envisaged that aryl substituted furans 5 or tetrasubstituted
allenes 4 may be obtained via a novel three-component reaction
by the employment of a Pd0 catalyst and aryl halides instead of
a PdII catalyst and allyl chlorides, respectively. First, the
oxidative addition of ArX with Pd0 generates intermediate
ArPdX, which would coordinate the triple bond to form
intermediate 6. The coordination of the triple bond of 1 to
ArPdX may induce a simultaneous formation of a remote
carbon–nucleophile bond and a C–O bond affording furanyl
palladium intermediate 7 (Scheme 1b, mode A) or only a
carbon–nucleophile bond formation to generate allenyl palladium
intermediate 8 (Scheme 1b, mode B). The reaction pathway
may be dependent on the degree of Lewis acidity of ArPdX
Scheme 1 (a) Previous work and (b) proposed working hypothesis.
species formed from the oxidative addition of aryl halides with
a Pd0 catalyst. The reductive elimination of the resulting
intermediate would give the final product.
This hypothesis was initially tested by the reaction of
2-phenylethynyl-3-phenyl-2-butylene-1-one 1a, methanol 2a
and iodobenzene 3a. When the reaction was carried out at
80 1C catalyzed by 10 mol% Pd(PPh3)4 in the presence of
10 mol% Ag2CO3 as an additive and K2CO3 (4.0 equiv.) as a
base,7 no aryl substituted furan 5aaa was detected but tetra-
substituted allene 4aaa was obtained in 15% yield (Table 1,
entry 1). A plausible rationale for the product shifts from
furan to allene may be partially attributed to the relatively
lower Lewis acidity of ArPdXLn species than PdCl2. As we
know, Lewis acidity is the key to promote cyclization.6 The
structure of 4aaa was confirmed unambiguously by X-ray
diffraction analysis.8 When Ag2CO3 was used as a base instead
of K2CO3, a slight improvement in yield was observed (20%,
Table 1, entry 2). This result prompted us to seek a suitable
base for the present MCR process and to gain both high yield
and high efficiency. To our delight, while employing Ag2O as a
base, a dramatic improvement in yield was obtained (47%,
Table 1, entry 3). Lowering the amount of Ag2O from
1.5 equiv. to 0.6 equiv. led to significant enhancement in yield
(73%, Table 1, entry 4). Bromobenzene was also tested but
a Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry, East China Normal University,
3663 N, Zhongshan Road, Shanghai 200062, P. R. China.
E-mail: jlzhang@chem.ecnu.edu.cn; Fax: (+86) 21-6223-5039
b State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
P. R. China
w Electronic supplementary information (ESI) available: Representative
experimental procedure and characterization of reaction products.
CCDC 741112. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b919060k
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Table 1 Optimization of reaction conditionsa
Table 3 Scope of Pd(PPh3)4-catalyzed three component reaction of
1a with various nucleophiles and aryl halidesa
Entry
Base
Solvent
Time/h
Yield (%)b
Entry NuH(2)
ArX(3)
4 (time, yieldb)
1c,d
2c
K2CO3 (4.0)
Ag2CO3 (4.0)
Ag2O (1.5)
Ag2O (0.6)
Ag2O (0.6)
CH3CN
CH3CN
CH3CN
CH3CN
1,4-dioxane
18
23
8
4
12
15
20
47
73
93
1
MeOH 2a
1-Iodo-4-
methoxybenzene 3b
4aabc
(16 h, 90%)
3c
4c
2
2a
1-Iodo-4-nitrobenzene 3c 4aac,
25 h, 73%)
4aad
5e
a
3d
4
2a
Ethyl
Reaction conditions: 0.25 mmol 1a, 4.0 equiv. of methanol 2a,
2.0 equiv. of iodobenzene 3a employed, solvent (1.0 mL), N2
4-iodobenzoate 3d
1-(4-Iodophenyl)-
ethanone 3e
1-Fluoro-
4-iodobenzene 3f
1-Iodo-3,5-
(25 h, 88%)
4aae
(22 h, 87%)
4aaf
(12 h, 87%)
4aag
2a
b
atmosphere. Yield of isolated product. 10 mol% Pd(PPh3)4 was
e
used. 10 mol% Ag2CO3 was added. 5 mol% Pd(PPh3)4 was used.
c
d
5
2a
6
2a
was less reactive in this reaction. The solvent and temperature
effects were also examined. Finally, it turned out that the
Pd(PPh3)4/Ag2O combination in 1,4-dioxane at 80 1C provided
the best result (93%, Table 1, entry 5) (for details see ESIw).
Using the stoichiometry of Ag2O as a base is essential for
obtaining high yields, indicating Ag2O assists ArPdX to
coordinate the triple bond of 1 by abstracting the halides(X)
from ArPdX and further facilitating the nucleophilic addition
step to form allenyl palladium intermediate 8.
dimethylbenzene 3g
4-Iodo-1-methyl-1H-
pyrazole 3h
(12 h, 93%)
4aah
(48 h, 52%)
4aai
(22 h, 72%)
4aaj
(24 h, 62%)
4aba
(33 h, 47%)
4aca
(45 h, 52%)
4ada
(11 h, 52%)
4aea
(22 h, 37%)
4afa
(20 h, 70%)
7
2a
8
2a
3-Iodothiophene 3i
9
2a
3-Bromoquinoline 3j
10e
11e
12e
13e
BnOH 2b
3a
PhCH2CH2OH 2c 3a
Using the optimized reaction conditions, the scope of this
MCR process was studied with respect to various electron
Furan-2-yl
3a
3a
3a
methanol 2d
4-Phenylbut-
3-yn-1-ol 2e
deficient enynes 1, nucleophiles
2 and aryl halides 3.
As demonstrated in Table 2 and 3, this new Pd0-catalyzed
three-component reaction of 1 with methanol and aryl halides
is a general and practically useful method for the preparation
of a range of functionalized tetrasubstituted allenes 4. A
variety of functionalities, such as alkoxyl, carboxyl, carbonyl
and nitro groups, were tolerant under the reaction conditions,
which provides opportunities for further elaboration of the
14d,f Dimethyl
malonate 2f
a
b
The reactions were performed under standard conditions. Yield of
c
isolated product. The designation 4aab for the product indicates that
d
the reactants used were 1a, 2a, 3b, respectively. 1.5 equiv. molecular
e
sieve was added. 10 mol% Pd(PPh3)4, 1.2 equiv. Ag2O, 2.0 mL
f
dioxane employed, 60 1C. 2.0 equiv. of dimethyl malonate was used.
Table 2 Scope of Pd(PPh3)4-catalyzed three component reaction of 1
with MeOH 2a and iodobenzene 3aa
functional groups on the allenes skeleton. Interestingly,
functionalized aryl groups can be introduced to an allene
skeleton via either the substrate 1 or the aryl iodide 3. For
example, 4caa can be prepared by MCR of 1c with 2a and 3a
as shown in Table 2, entry 2. Alternatively, MCR of 1a with 2a
and 3b generates 4aab (Table 3, entry 1) as the same structure
of 4caa. Heterocycles, such as pyrazole, thiophene, furan and
quinoline can be directly incorporated into an allene skeleton
using corresponding aryl halides as cross-coupling reagents or
aryl alcohol as nucleophiles (Table 3, entries 7–9, 12).
3-Bromoquinoline (Table 3, entry 9) could also be used as a
substrate in the reaction to give the desired product. It was
particularly noteworthy that dimethyl malonate could be
employed as C-based nucleophiles in the reaction, clearly
demonstrating the great potential of this new methodology
to allow access to more functionalized targets (Table 3, entry
14). In regard to O-based nucleophiles, besides methanol,
other alcohols such as benzyl alcohol 2b, 2-phenylethanol 2c,
furan-2-yl methanol 2d and 4-phenylbut-3-yn-1-ol 2e,
can act as O-based nucleophiles to give the corresponding
tetrasubstituted allenes in reasonable yields. The reactions
Substrate 1
R1/R2/R3
Entry
4 (time, yieldb)
1
2
3
4
5
6
7
8
9
Me/4-MeOC6H4/Ph (1b)
Me/Ph/4-MeOC6H4(1c)
Me/4-MeOC6H4/4-MeOC6H4 (1d)
Me/Ph/4-NO2C6H4(1e)
Me/Ph/1-Naphthyl(1f)
Me/4-MeOC6H4/1-Naphthyl(1g)
Me/Ph/n-C4H9(1h)
4baac(17 h, 81%)
4caa (22 h, 70%)
4daa (20 h, 81%)
4eaa (14 h, 71%)
4faa (14 h, 73%)
4gaa (20 h, 65%)
4haa (15 h, 48%)
4iaa (24 h, 81%)
4jaa (17 h, 96%)
Me/n-C4H9/Ph (1i)
Ph/Ph/Ph (1j)
a
b
The reactions were performed under standard conditions. Yield of
c
isolated product. The designation 4baa for the product indicates that
the reactants used were 1b, 2a, and 3a, respectively.
ꢀc
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2 (a) N. Krause and A. Hoffmann-Roder, in Modern Allene
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Scheme 2 The cascade reaction of cyclic enyne ketone 1k and 1l.
were performed at a lower temperature, 60 1C, and required
more catalyst loading (Table 3, entry 10–13). The more
catalyst loading and lower reaction temperature as compared
with optimized reaction conditions used for methanol as the
nucleophile were attributed to their decreased nucleophilicity
and increased oxidability by the generated ArPdX.9
The generality of the present MCR process was also
investigated by using cyclic enyne ketones 1k and 1l
(Scheme 2). Interestingly, the reaction of enyne ketone 1k
gave a two component cross-coupling product 4kaa in
quantitative isolated yield (97%) rather than the corresponding
three component cross-coupling product. However, the reaction
of the chromanone derivative 1l could give the corresponding
three component cross-coupling product 4laa in 45% isolated
yield under the same reaction conditions. These results indicated
that the nature of the backbone of the enyne ketone 1 had an
influence on the reaction.
4 For recent reviews,see: (a) A. Domling, Curr. Opin. Chem. Biol.,
¨
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In conclusion, we have developed the first example of
Pd0-catalyzed MCR domino reactions of electron-deficient
enynes, nucleophiles and aryl halides leading to multi-
functionalized tetrasubstituted allenes. Future studies will focus
on its potential application and understanding of the mechanism
of this MCR process.
5 Examples for furan formation from 2-(1-alkynyl)-2-alken-1-ones,
please see: (a) T. Yao, X. Zhang and R. C. Larock, J. Am. Chem.
Soc., 2004, 126, 11164; (b) T. Yao, X. Zhang and R. C. Larock,
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12, 1962.
Financial support from the National Natural Science
Foundation of China (20702015) and Science and Technology
Commission of Shanghai Municipality (07DZ22937),
Shanghai Shuguang Program (07SG27) are greatly appreciated.
Notes and references
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6 (a) Y. Xiao and J. Zhang, Angew. Chem., Int. Ed., 2008, 47, 1903;
(b) Y. Xiao and J. Zhang, Adv. Synth. Catal., 2009, 351, 617.
7 For Pd0/Ag(I)-catalyzed cyclization and cross-coupling of 1,2-
allenyl ketones with aryl halides to afford furans, please see:
(a) S. Ma and J. Zhang, Chem. Commun., 2000, 117; (b) S. Ma,
J. Zhang and L. Lu, Chem.–Eur. J., 2003, 9, 2447.
8 X-Ray data and ORTEP depiction for compound 4aaa please see
ESI.w CCDC 741112 (4aaa) contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge form The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
9 (a) A. Zask and P. Helquist, J. Org. Chem., 1978, 43, 1619;
(b) M. Palucki, J. P. Wolfe and S. L. Buchwald, J. Am. Chem.
Soc., 1997, 119, 3395.
ꢀc
This journal is The Royal Society of Chemistry 2010
754 | Chem. Commun., 2010, 46, 752–754