Gold(III)-catalyzed three-component coupling reaction (TCC) selective toward furans

Article abstract of DOI:10.1021/ol401239j

An efficient three-component coupling reaction toward a variety of furan derivatives has been developed. This cascade transformation proceeds via the gold-catalyzed coupling reaction of phenylglyoxal derivatives, secondary amines, and terminal alkynes, under the reaction conditions, that undergoes cyclization into the furan core.

Full text of DOI:10.1021/ol401239j

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Gold(III)-Catalyzed Three-Component
Coupling Reaction (TCC) Selective
toward Furans
Jian Li,† Li Liu,*,‡ Dong Ding,† Jiangtao Sun,† Yangxuan Ji,† and Jialing Dong†
School of Pharmaceutical Engineering & Life Sciences, Chang Zhou University,
Changzhou, 213164, P. R. China, and School of Petrochemical Engineering,
Chang Zhou University, Changzhou, 213164, P. R. China
li.liu2007@yahoo.com.cn
Received May 3, 2013
ABSTRACT
An efficient three-component coupling reaction toward a variety of furan derivatives has been developed. This cascade transformation proceeds
via the gold-catalyzed coupling reaction of phenylglyoxal derivatives, secondary amines, and terminal alkynes, under the reaction conditions, that
undergoes cyclization into the furan core.
The furan unit is one of the most important pharmaco-
phores and is widely found in many biologically active
compounds.1 The synthesis of substituted furans has been
the object of research for over a century, and a variety
of well-established classical methods are now available.2
The classical PaalÀKnorr synthesis, discovered in 1884,
remains one of the most powerful and versatile routes to
the furan heterocycles. During thepast 10years, Lewisacid
catalyzed synthesis of heterocycles especially furans3 via
intramolecular cycloisomerization reactions that involve
an acetylenic functionality has attracted considerable at-
tention due to its atom economy, although the substrates
in this method require multistep synthesis. In particular,
much attention has been focused toward the development
of new and efficient methodologies for the synthesis of
furans with the aid of gold, mainly as AuCl3, as the most
effective catalyst for cycloisomerizations leading to
furans.4 Selected successful examples are shown in Figure 1,
including (a) alk-3-yn-1-ones; (b) alka-2,3-dien-1-ones; (c)
alkynyloxiranes, and (d) (Z)-alk-2-en-4-yn-1-ols, which
afford substituted furans in one step. Skrydstrup recently
reported the addition of the ylides to the terminal alkynes
to form 2,4-disubstituted furans with gold catalysis
which undergo a carbene transfer/gold carbene formation
process.5
† School of Pharmaceutical Engineering & Life Sciences.
‡ School of Petrochemical Engineering.
(1) (a) Katritzky, A. R. Comprehensive Heterocyclic Chemistry III;
Elsevier: Amsterdam, 2008. (b) Pozharskii, A. F.; Katritzky, A. R.;
Soldatenkov, A. T. Heterocycles in Life and Society: An Introduction to
Heterocyclic Chemistry, Biochemistry and Applications, 2nd ed.; Wiley:
Chichester, 2011.
(2) For recent reviews, see: (a) Kirsch, S. F. Org. Biomol. Chem. 2006,
4, 2076. (b) Brown, R. C. D. Angew. Chem., Int. Ed. 2005, 44, 850.
(3) (a) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. Org. Lett. 2001, 3,
3769. (b) Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc.
2005, 127, 10500. (c) Suhre, M. H.; Reif, M.; Kirsch, S. F. Org. Lett.
2005, 7, 3873. (d) Sniady, A.; Wheeler, K. A.; Dembinski, R. Org. Lett.
2005, 7, 1769. (e) Zhang, J.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2006,
45, 6704. (f) Zhou, C.-Y.; Chang, P. W. H.; Che, C.-M. Org. Lett. 2006,
8, 325. (g) Zhang, Z.-P.; Cai, X.-B.; Wang, S.-P.; Yu, J.-L.; Liu, H.-J.;
Cui, Y.-Y. J. Org. Chem. 2007, 72, 9838. (h) Sniady, A.; Durham, A.;
Morreale, M. S.; Wheeler, K. A.; Dembinski, R. Org. Lett. 2007, 9, 1175.
Egi, M.; Azechi, K.; Akai, S. Org. Lett. 2009, 11, 5002. (j) Aponick, A.;
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4360. (l) Chen, Z.; Jiang, G.; Huang, H.; Pan, H. X. J. Org. Chem. 2011,
76, 1134. (m) Huang, J. Y.; Kang, B.; Connell, T. J. Org. Chem. 2011, 76,
2379. (n) Hashmi, A. S. K.; Yang, W.; Rominger, F. Angew. Chem., Int.
Ed. 2011, 50, 5762. Chem.;Eur. J. 2012, 18, 6576.
(4) (a) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M.
Angew. Chem., Int. Ed. 2000, 39, 2285. (b) Yao, T.; Zhang, X.; Larock,
R. C. J. Org. Chem. 2005, 70, 7679. (c) Yao, T.; Zhang, X.; Larock, R. C.
J. Am. Chem. Soc. 2004, 126, 11164. (d) Zhou, C.-Y.; Chan, P. W. H.;
Che, C.-M. Org. Lett. 2006, 8, 325. (e) Hashmi, A. S. K.; Sinha, P. Adv.
Synth. Catal. 2004, 346, 432. (f) Zhang, J.; Schmalz, H.-G. Angew.
Chem., Int. Ed. 2006, 45, 6704. (g) Liu, Y.; Song, F.; Song, Z.; Liu, M.;
Yan, B. Org. Lett. 2005, 7, 5409.
(5) Kramer, S.; Skrydstrup, T. Angew. Chem., Int. Ed. 2012, 51, 4681.
r
10.1021/ol401239j
XXXX American Chemical Society

Table 1. Optimization of Reaction Conditions for the Preparation
of 4aa
T
yield (%)b
entry
catalyst
(°C)
solvent
4a
1
À
25
25
25
25
25
25
60
60
60
60
60
110
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
H2O
À
2
CuI
À
3
AuCl
16
11
21
trace
75
91
14
15
54
23
4
AuCl3
AuBr3
5
6
NaAuCl4 2H2O
3
7
AuBr3
AuBr3
AuBr3
AuBr3
AuBr3
AuBr3
8c
9c
10c
11c
12c
DMF
toluene
toluene
Figure 1. Au-catalyzed one-step formation of furans.
a Standard reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), 3a (2.0
mmol), catalyst (5 mol %), and solvent (2.0 mL) were heated in a tube for
12 h. b Isolated yield. c Proceed under a N2 atmosphere.
One-pot multicomponent coupling reactions have emerged
as an attractive and powerful strategy for the generation of
CÀC and CÀheteratom in a step- and atom-economical
fashion.6 Among these, a number of novel heterocycle
syntheses using aldehydes, alkynes, and amines as starting
materials have been reported. In 2007, Liu and Yan
developed a gold(III)-catalyzed multicomponent coupling/
cycloisomerization reaction of heteroaryl aldehydes, amines,
and alkynes to form aminoindolizines under solvent-free
conditions or in water.7 In 2009, a copper-catalyzed three-
component coupling reaction of aldehydes, 2-aminopyri-
dines, and terminal alkynes toward imidazoheterocycles has
been explored in Gevorgyan’s group.8 Ji and co-workers
demonstrated an approach to the complex butenolides
from alkynes, amines, and glyoxylic acid in the presence of
a gold catalyst.9 However, an efficient synthesis with high
chemo- and regioselectivity, which would enable access to
multisubstituted furans, still remains a challenge.
phenylglyoxals,10 secondary amines, and terminal alkynes
were chosen as substrates. We hypothesized that these three
compounds would be coupled together under gold catalysis
to represent the required propargylamine intermediate,11
which, upon activation of the triple bond with gold, would
undergo an intramolecular cyclization4aÀc into target
furans. We envisaged the process of this gold-catalyzed
coupling reaction/cyclization would occur in one pot. This
strategy possess more potential in the synthesis of complex
furans, as the substrates are simple and available.
We commenced this project by investigating the reaction
of phenylglyoxal monohydrate (1a), morpholine (2a), and
phenylacetylene (3a) in the absence of catalyst in methanol
at room temperature, but no desired compound was
detected (Table 1, entry 1). The reaction also did not
proceed when CuI was employed (Table 1, entry 2).
Interestingly, the reaction produced the furan product 4a
in 16% yield in the presence of AuCl as the catalyst
(Table 1, entry 3). A screening of gold sources indicated
that AuBr3 was the most effective catalyst for this trans-
formation, affording the product in 21% yield (Table 1,
entries 3À6). To our delight, the reaction could proceed
smoothly at 60 °C with 5 mol % of AuBr3, resulting in a
With this background in mind, we were interested
in realizing the formation of polysubstituted furans
during a one-pot multicomponent coupling reaction. Then
ꢀ
(6) For reviews, see: (a) Multicomponent Reactions; Zhu, J., Bienayme,
H., Eds.; Wiley-VCH: Weinheim, 2005. (b) Posner, G. H. Chem. Rev. 1986,
86, 831. (c) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown,
ꢀ
S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123. (d) Bienayme, H.;
Hulme, C.; Oddon, G.; Schmitt, P. Chem.;Eur. J. 2000, 6, 3321.
(7) Yan, B.; Liu, Y. Org. Lett. 2007, 9, 4323.
(8) (a) Chernyak, N.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49,
2743. For synthesis of 3-aminoindolines and 3-aminoindoles via
(11) For selected examples of syntheses of propargylamines via TCC,
see: (a) Li, C.-J.; Wei, C. M. Chem. Commun 2002, 268. (b) Wei, C. M.;
Li, Z.; Li, C.-J. Org. Lett. 2003, 5, 4473. (c) Lo, V. K.-Y.; Kung, K. K.-Y.;
Wong, M.-K.; Che, C.-M. J. Organomet. Chem. 2009, 694, 583. (d)
Zhang, X.; Corma, A. Angew. Chem. 2008, 120, 4430. Zhang, X.; Corma,
A. Angew. Chem., Int. Ed. 2008, 47, 4358. (e) Kidwai, M.; Bansal, V.;
Kumarb, A.; Mozumdar, S. Green Chem. 2007, 9, 742. (f) Huang, B.;
Yao, X.; Li, C.-J. Adv. Synth. Catal. 2006, 348, 1528. (g) Lo, V. K.-Y.;
Liu, Y.; Wong, M.-K.; Che, C.-M. Org. Lett. 2006, 8, 1529. (h) Elie, B. T.;
a
copper-catalyzed three-component coupling reaction, see: (b)
Chernyak, D.; Chernyak, N.; Gevorgyana, V. Adv. Synth. Catal. 2010,
352, 961.
(9) Zhang, Q.; Cheng, M.; Hu, X.; Li, B.-G.; Ji, J.-X. J. Am. Chem.
Soc. 2010, 132, 7256.
(10) Phenylglyoxals can be synthesized from a terminal alkyne with
pyridine-N-oxide via gold catalysis, which was used to deliver quinox-
alines in one pot; see: Shi, S.; Wang, T.; Yang, W.; Rudolph, M.;
Hashmi, A. S. K. Chem.;Eur. J. 2013, DOI: 10.1002/chem.201300518.
´
Levine, C.; Ubarretxena-Belandia, I.; Varela-Ramırez, A.; Aguilera,
R. J.; Ovalle, R.; Contel, M. Eur. J. Inorg. Chem. 2009, 3421.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. AuBr3-Catalyzed Three-Component Formation of Furansa
a Standard reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), 3a (2.0 mmol), catalyst (5 mol %), and solvent (2.0 mL) were heated in a tube under a N2
atmosphere for 12 h. b Isolated yield.
91% yield under a N2 atmosphere (Table 1, entry 8). To
further improve the efficiency of the reaction, several
frequently used solvents were also examined. However,
none of them could produce a higher yield, even at higher
temperature (Table 1, entries 9À12).
could be employed; their corresponding products were
obtained in moderate to good yields. However, 4i (4-CF3)
was obtained in only 68% yield, due to its strong electron-
withdrawing effect. Finally, to broaden the substrate scope,
amines were also explored (2b, 2c, and 2d). It was found
that the reaction successfully provided the trisubstituted
furans in 51%À93% yields (4k, 4l, 4m, Table 2).
With the optimized reaction conditions in hand, we
probed the scope of different alkynes, phenylglyoxal
derivatives, and secondary amines (Table 2). A variety of
different groups at the aromatic moiety of alkynes, such as
halogen, methyl, and pentyl, were well tolerated in these
mild transformations. The alkyne substrates bearing an
electron-withdrawing group compared to an electron-do-
nating group were found to be more suitable to afford
furan products (4b, 4c, and 4d, Table 2). Further explora-
tion of the substrate scope involved various phenylglyoxal
derivatives. Phenylglyoxal derivatives having a substituent
at either the meta- (1c) or para-position (1b, 1d, 1e, 1f, 1g)
A plausible mechanism for the reaction of a phenylglyoxal
monohydrate, secondary amine, and terminal alkyne is
illustrated in Scheme 1, which is analogous to the Au-
catalyzed cycloisomerization of complex butenolides from
alkynes, amines, and glyoxylic acid.12 First, a gold-catalyzed
three-component coupling of a phenylglyoxal, an amine,
and an alkyne occurred to afford NR1R2-substituted pro-
pargylic intermediate 5via aMannichÀGrignard reaction.13
(12) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2010, 49, 5232.
(13) Wei, C. M.; Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584.
Org. Lett., Vol. XX, No. XX, XXXX
C

In conclusion, we have demonstrated an efficient multi-
component coupling reaction of phenylglyoxal derivatives,
secondary amines, and terminal alkynes. This cascade
transformation of the coupling/cycloisomerization reac-
tion proceeds using AuBr3 as the catalyst under a N2
atmosphere in methanol. The reaction outcomes provide
a new strategy for the synthesis of three-substituted furans
with high atom economy and high catalytic efficiency,
which offers an efficient approach for the preparation of
synthetic and medicinal furan derivatives. Further studies to
extend the scope and synthetic utility of this Au-catalyzed
cascade reaction are in progress in our laboratory.
Scheme 1. Plausible Mechanism for the Reaction
Acknowledgment. Foundation of Chang Zhou Univer-
sity (Nos. ZMF1002130 and ZMF1002100), Changzhou
Municipal Bureau of Science and Technology (No.
KYZ1102100C), and the Priority Academic Program
Development of Jiangsu Higher Education Institutions.
Coordination of the triple bond in alkyne 5 to the gold
catalyst enhances the electrophilicity of the alkyne, and the
subsequent nucleophilic attack of the oxygen lone pair
would produce the cation 6, which undergoes deprotonation
followed by demetalation to afford indolizines (Scheme 1).
Supporting Information Available. Experimental de-
tails and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX