Dual-function Pd/NHC catalysis: Tandem allylation-isomerization-conjugate addition that allows access to pyrroles, thiophenes and furans

Article abstract of DOI:10.1039/c4cc01750a

An efficient coupling reaction of allyl acetate with (O-azaaryl) carboxaldehyde by Pd-NHC dual catalysis has been developed. This reaction proceeds via direct coordination between the ortho nitrogen atom in the heterocycle and Pd(0). This dual catalysis i

Full text of DOI:10.1039/c4cc01750a

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Dual-function Pd/NHC catalysis: tandem
allylation–isomerization–conjugate addition that
allows access to pyrroles, thiophenes and furans†
Cite this: Chem. Commun., 2014,
50, 6168
Received 8th March 2014,
Accepted 17th April 2014
Yaguang Bai, Shaohua Xiang, Min Li Leow and Xue-Wei Liu*
DOI: 10.1039/c4cc01750a
www.rsc.org/chemcomm
An efficient coupling reaction of allyl acetate with (O-azaaryl)-
Recently, N-heterocyclic carbenes (NHC) as organocatalysts
carboxaldehyde by Pd–NHC dual catalysis has been developed. This have drawn considerable attention.2 The Breslow intermediate,
reaction proceeds via direct coordination between the ortho nitrogen generated by treating aldehyde with NHC in the presence of a
atom in the heterocycle and Pd(0). This dual catalysis is achieved under base, has huge potential in dual catalysis. It can act as a
mild conditions to give 1,4-diones as products with up to 90% yield.
nucleophile to react with the cationic p-allyl Pd complex.
However, two challenges still persist in the application of
The discovery of dual catalytic systems has sparkled much interest palladium–NHC dual catalysis. One is that NHCs are a class
in expanding this synthetically useful concept for the past few of ligands, which can bind to palladium, and upon binding
years.1 This strategy not only helps classic catalysts to venture into both of them would be poisoned.3 The other is that the Breslow
challenging reactions without complicated reagents, but also miti- intermediate could also react with another molecule of alde-
gates laborious tasks to obtain sensitive synthetic precursors. In hyde, which is the starting material, and therefore the concen-
addition, usage of a stoichiometric amount of activating reagents tration of aldehyde is much higher than the p-allyl Pd complex.
could be omitted through this strategy. The principle of dual In 2008, Glorius et al. successfully reported a tandem catalytic
catalysis generally involves simultaneous activation of individual method of palladium and NHC catalysts (eqn (1)).4 In this work,
substrate(s) through specific interaction with one of the catalysts, they proved that thiazolidinylidenes are a class of NHCs tolerant
which transforms both into reactive intermediates. Subsequent to the palladium catalyst. In addition, recent research has also
combination to form the adduct releases the two catalysts simulta- shown that the N atom in the O-azaaryl heterocycle exhibits great
neously. Reported methods often proceeded with the generation of coordination affinity toward palladium.5 These findings brought
an electrophile and a nucleophile from substrates by different a newfound potential into dual catalytic systems and open a way
catalysts, followed by a nucleophilic addition reaction, which selec- for the continual extension. Inspired by the efficacy of dual
tively takes place between the activated intermediates. Among many catalysis, we decided to explore the possibilities of applying dual
electrophiles reported for this strategy, cationic p-allyl Pd complexes catalysis to a combination of NHC6 and palladium7 catalysts. As
have shown promising reactivities by reacting with nucleophilic designed (eqn (2)), through two nucleophilic additions, two
species such as vanadium-allenoates1 and enamines.1a,c,d
molecules of activated aldehyde would react with one molecule
of activated allyl acetate to form 1,4-diones, which are a class of
useful synthetic building blocks for the construction of various
heterocycles.
(1)
(2)
In order to conquer the two challenges to establish a
Pd–NHC dual catalytic method, our initial effort started with
the reaction of allyl acetate 1a and pyridine-2-carboxaldehyde
2a in the presence of a catalytic amount of Pd(PPh3)4, 5-(2-
hydroxyethyl)-3,4-dimethylthiazolium iodide and 3 equivalents
of triethylamine (Table 1, entry 1). To our delight, the reaction
proceeded smoothly at room temperature within 3 hours to
afford desired 2-methyl-1,4-di(pyridin-2-yl)butane-1,4-dione 3a
as a product in 53% yield. Notably, if pyridine-2-carboxaldehyde
was replaced by benzaldehyde, benzoin was the only product
formed under the same conditions. Another thiazolidinylidene
School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Drive, Singapore 637371. E-mail: xuewei@ntu.edu.sg
† Electronic supplementary information (ESI) available: Experimental procedures,
supplementary data, and 1H-, 13C-NMR spectra. See DOI: 10.1039/c4cc01750a
6168 | Chem. Commun., 2014, 50, 6168--6170
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Table 1 Optimization of reaction conditionsa
Table 2 Substrate scopea,b,c
Entry
Pd source
NHC
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
I
II
I
I
I
I
I
I
I
I
I
I
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
THF
Acetone
DCM
53
50
NR
NR
NR
NR
NR
23
44
9
NR
90
Pd(OAc)2 + DiPPF
Pd(allyl)Cl2
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
9
10
11
12c
Toluene
DMSO
a
Unless otherwise specified, reactions were carried out with 1 equivalent of
1a, 2 equivalents of 2a, 5% Pd catalyst, 10% NHC catalyst, and 3 equivalents
b
of triethylamine under argon for 3 hours at room temperature. Yields
determined by NMR with 1,3,5-trimethoxybenzene as internal reference.
c
2a was added using a syringe pump as a 1 M DMSO solution within
2
hours. DMSO: dimethyl sulfoxide; DMF: dimethylformamide;
DCM: dichloromethane; DiPPF: bis-(diisopropylpho-sphino)ferrocene.
THF: tetrahydrofuran.
a
Reactions were carried out with 1 equiv. of 1a, 2 equiv. of 2a, 5% Pd
catalyst, 10% NHC catalyst I, and 3 equiv. of triethylamine under argon
b
for 3 hours at room temperature. 2a was added using a syringe pump
c
as a 1 M solution in DMSO within 2 hours. Isolated yields.
NHC catalyst was also compatible with the Pd(PPh3)4 catalyst
with 50% yield (Table 1, entry 2). Other commonly used Pd
catalysts such as Pd(OAc)2, Pd(allyl)Cl2 and Pd2(dba)3 were also
examined (Table 1, entries 3–6) and it was found that Pd(PPh3)4
was the only effective Pd source for this dual catalysis. Solvent
screening (Table 1, entries 7–11) revealed that among the
commonly used solvents, DMSO was the most effective one.
Slow addition (Table 1, entry 12) of aldehyde as a 1 M solution
in DMSO over 2 hours using a syringe pump was found to
increase the yield significantly to 90%.
isoquinoline-1-carboxaldehyde (Table 2, 3k) and isoquinoline-
3-carboxaldehyde (Table 2, 3l) could also give the corresponding
1,4-diones in good yields. Other heterocyclic aldehydes such as
With the optimized conditions in hand, the reactivities of an
array of azaaryl aldehydes, with the N atom at different positions,
towards allyl acetate were first examined (Table 2, 3a). It was shown
that only the 2-pyridinecarboxaldehyde was reactive in this dual
catalysis. 3-Pyridinecarboxaldehyde and 4-pyridine-carboxaldehyde
failed to give any desired product, which indicated that the ortho
N atom of the pyridinecarboxaldehyde exerted a crucial effect for
this reaction. Similarly, by reacting with allyl acetate, a group of
substituted pyridine-2-carboxaldehydes were also examined under
standard conditions. It was found that most of the pyridine-
2-aldehydes could afford the corresponding 1,4-diones in
moderate to excellent yields. The aldehydes with electron
donating groups (Table 2, 3c, 3g) generally provided lower
yields than those with electron withdrawing groups (Table 2,
3d, 3e, 3f, 3h, 3i). Interestingly, no desired product was observed
with 3-methyl-2-pyridine carboxaldehyde. Presumably, the 3-methyl
substituent inhibits and restricts the p-allyl Pd complex from
taking the appropriate conformation necessary for the Pd–N
coordination.8 Besides pyridine-2-carboxaldehydes, other O-azaaryl-
carboxaldehydes such as quinoline-2-carboxaldehyde (Table 2, 3j), Scheme 1 Plausible mechanism.
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Conversions of the representative product 3a were successfully
conducted to form pyrrole 4b,9 thiophene 4c10 and furan 4a11
heterocycles correspondingly.
In summary, we have established an efficient dual catalytic
method, through a combination of Pd and NHC catalysts,
between allyl acetate and O-azaaryl carboxaldehydes under mild
conditions. The substrate scope includes different types of
O-azaaryl carboxaldehydes with various substituents and pro-
mising yields were obtained for most reactions. Notably, the
1,4-dione products are extremely useful as synthetic building
blocks and their potential functionalization towards various
heterocycles has also been demonstrated effectively. Efforts to
synthesize chiral 2-methyl-1,4-dione are currently undergoing
in our laboratory.
Scheme 2 Cross experiment of allyl acetate with different (O-azzaryl)-
carboxaldehydes.
Notes and references
´
1 (a) I. Ibrahem and A. Cordova, Angew. Chem., 2006, 118, 1986
(Angew. Chem., Int. Ed., 2006, 45, 1952); (b) M. Ikeda, Y. Miyake
and Y. Nishibayashi, Angew. Chem., 2010, 122, 7295 (Angew. Chem.,
Int. Ed., 2010, 49, 7289); (c) S. Mukherjee and B. List, J. Am. Chem.
Soc., 2007, 129, 11336; (d) D. A. Nicewicz and D. W. C. MacMillan,
Science, 2008, 322, 77; (e) Y. Qian, C. Jing, T. Shi, J. Ji, M. Tang,
J. Zhou, C. Zhai and W. Hu, ChemCatChem, 2011, 3, 653;
( f ) G. M. Sammis, H. Danjo and E. N. Jacobsen, J. Am. Chem. Soc.,
2004, 126, 9928; (g) B. M. Trost and X. Luan, J. Am. Chem. Soc., 2011,
133, 1706.
2 (a) A. T. Biju, N. Kuhl and F. Glorius, Acc. Chem. Res., 2011, 44, 1182;
¨
(b) T. Droge and F. Glorius, Angew. Chem., 2010, 122, 7094 (Angew.
Scheme 3 Conversion of the products into various heterocycles.
Chem., Int. Ed., 2010, 49, 6940); (c) D. Enders, O. Niemeier and
´
A. Henseler, Chem. Rev., 2007, 107, 5606; (d) N. Marion, S. Dıez-
´
Gonzalez and S. P. Nolan, Angew. Chem., 2007, 119, 3046 (Angew.
Chem., Int. Ed., 2007, 46, 2988); (e) J. Moore, T. Rovis and B. List,
Asymmetric Organocatalysis, Topics in Current Chemistry, Springer,
Berlin, Heidelberg, 2009, vol. 291, p. 77; ( f ) V. Nair, S. Vellalath and
B. P. Babu, Chem. Soc. Rev., 2008, 37, 2691.
2-imidazole carboxaldehyde and quinoline-8-carboxaldehyde
failed to deliver any desired product.
A plausible mechanism is depicted in Scheme 1. Breslow
intermediate 2a0 and p-allyl Pd complex 1a0 are generated from
NHC and Pd(0) catalysts respectively. The two intermediates
approach each other through a direct coordination of the N
atom in the heterocycle towards Pd and form Pd complex 5.
This was followed by an intramolecular nucleophilic addition
between the p-allyl Pd complex and the Breslow intermediate
to form allyl intermediate 6 rather than an intermolecular
reaction between the Breslow intermediate and another mole-
cule of aldehyde. Removal and regeneration of both catalysts
give b,g-unsaturated ketone 7 and proton transfer under the
basic reaction conditions generated a,b-unsaturated ketone 8.
Finally, the final product 3a is formed through Michael addition
of another molecular Breslow intermediate with a,b-unsaturated
ketone 8.
3 (a) G. C. Fortman and S. P. Nolan, Chem. Soc. Rev., 2011, 40, 5151;
´
´
(b) F. Glorius, S. Dıez-Gonzalez and S. Nolan, N-Heterocyclic Carbenes
in Transition Metal Catalysis, Topics in Organometallic Chemistry,
Springer, Berlin, Heidelberg, 2007, vol. 21, p. 47; (c) N. M. Scott and
S. P. Nolan, N-Heterocyclic Carbenes in Synthesis, Wiley-VCH, 2006,
p. 55.
4 R. Lebeuf, K. Hirano and F. Glorius, Org. Lett., 2008, 10, 4243.
5 (a) T. Niwa, H. Yorimitsu and K. Oshima, Angew. Chem., 2007,
119, 2697 (Angew. Chem., Int. Ed., 2007, 46, 2643); (b) B. Qian,
S. Guo, J. Shao, Q. Zhu, L. Yang, C. Xia and H. Huang, J. Am. Chem.
Soc., 2010, 132, 3650; (c) R. Shang, Z.-W. Yang, Y. Wang, S.-L. Zhang
and L. Liu, J. Am. Chem. Soc., 2010, 132, 14391.
6 (a) B. Maji, S. Vedachalan, X. Ge, S. Cai and X.-W. Liu, J. Org. Chem.,
2011, 76, 3016; (b) S. Vedachalam, Q.-L. Wong, B. Maji, J. Zeng, J. Ma
and X.-W. Liu, Adv. Synth. Catal., 2011, 353, 219; (c) S. Vedachalam,
J. Zeng, B. K. Gorityala, M. Antonio and X.-W. Liu, Org. Lett., 2009,
12, 352.
7 (a) Y. Bai, M. Leow, J. Zeng and X.-W. Liu, Org. Lett., 2011, 13, 5648;
(b) Y. Bai, J. Zeng, S. Cai and X.-W. Liu, Org. Lett., 2011, 13, 4394;
(c) S. Xiang, S. Cai, J. Zeng and X.-W. Liu, Org. Lett., 2011, 13, 4608.
In order to prove the proposed mechanism, a cross experiment
was done by treating pyridine-2-carboxaldehyde 2a, 6-methylpyridine-
2-carboxaldehyde 2b and allyl acetate 1a with the same equivalent.
´
8 C. E. Houlden, C. D. Bailey, J. G. Ford, M. R. Gagne, G. C. Lloyd-
Jones and K. I. Booker-Milburn, J. Am. Chem. Soc., 2008, 130, 10066.
9 X.-G. Duan and C. W. Rees, J. Chem. Soc., Perkin Trans. 1, 1997, 3189.
From this reaction, all the four possible products predicted by the 10 A. A. Kiryanov, P. Sampson and A. J. Seed, J. Org. Chem., 2001,
66, 7925.
proposed mechanism were identified (Scheme 2).
11 D. S. Mortensen, A. L. Rodriguez, K. E. Carlson, J. Sun, B. S.
The possibilities of further functionalization of the 1,4-diones
Katzenel-lenbogen and J. A. Katzenellenbogen, J. Med. Chem.,
from this dual catalysis were also examined as shown in Scheme 3.
2001, 44, 3838.
6170 | Chem. Commun., 2014, 50, 6168--6170
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