A cascade Heck-Aldol-Heck reaction by a combination of transition-metal catalysis and aminocatalysis

Article abstract of DOI:10.1039/c1cc10152h

An unprecedented cascade Heck-Aldol-Heck reaction was developed to form two C-C single bonds and one C=C double bond in one process by a combination of palladium(0) catalysis and aminocatalysis. Various aryl iodides could perform the cascade reaction with

Full text of DOI:10.1039/c1cc10152h

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COMMUNICATION
A cascade Heck–Aldol–Heck reaction by a combination
of transition-metal catalysis and aminocatalysisw
Chang-Shan Guo,a Yu-Han Dua and Zhi-Zhen Huang*abc
Received 9th January 2011, Accepted 31st January 2011
DOI: 10.1039/c1cc10152h
An unprecedented cascade Heck–Aldol–Heck reaction was
developed to form two C–C single bonds and one CQC double
bond in one process by a combination of palladium(0) catalysis
and aminocatalysis. Various aryl iodides could perform the
Fig. 1 Various aminocatalysts.
cascade reaction with readily available propenol and formalde-
hyde to afford novel (E)-trisubstituted alkenes in 66–81% yields.
cascade reaction combining a transition-metal catalyzed
Heck-type reaction and an aminocatalytic reaction. Further
considering that the aldol condensation reaction is a widely-
used method for the formations of C–C bonds in organic
synthesis,4 and as a continuation of our research on the
synthetic methodology by dual transition-metal catalysis
and organocatalysis,5 we began to carry out an investigation
on a cascade reaction combining a transition-metal catalyzed
Heck-type reaction and an aminocatalytic aldol condensation.
In our initial study, phenyl iodide 1a (1.0 equiv.) and
propenol (1.1 equiv.) were employed for Heck arylation of
propenol, and formaldehyde (5.0 equiv.) was employed for
aldol reaction under the catalysis of Pd(OAc)2 and Et2NH. To
our delight, in the presence of n-Bu4NCl and NaHCO3 in
acetonitrile, we obtained the desired Heck coupling/aldol
condensation product, disubstituted alkene 4a in a 45% yield
with a small amount of trisubstituted alkene 5a as a Heck
coupling/aldol condensation/Heck coupling product. It is
obvious that both 4a and 5a resulted from b-phenylated
propanal as a product of the Heck reaction, and no compound
resulting from a-phenylated propanal was gained. Encouraged
by these results, excess phenyl iodide 1a (2.0 equiv.) was
employed to perform the cascade reaction under the above
reaction conditions, and fortunately, an improved yield of 5a
was achieved without observation of 4a (for details, see ESIw).
As expected as well, when the amount of propenol was
increased to 2.5 equiv., only 4a was obtained in a 58% yield
without obtaining 5a (for details, see ESIw). Then, we further
screened the reaction conditions for 5a. First, various palladium
catalysts, such as Pd(OAc)2, PdCl2, Pd[(PhCHCH)2CO]2,
Pd(Ph3P)4, and Pd(Ph3P)2Cl2 were examined, and Pd(OAc)2
was found to be the best transition-metal catalyst among them
(for details, see ESIw). Second, aminocatalysts 2–3 (Fig. 1)
were probed, and pyrrolidine was proved to be the optimal
aminocatalyst to give trisubstituted alkene 5a in a 62% yield
without 4a (entry 6, Table 1; and ESIw). Among the various
solvents examined, strong polar solvents such as acetonitrile,
NMP and DMF seem more beneficial to the reaction than
Cascade reactions that involve two or more bond-forming
reactions in one process have great potential to be used widely
in the synthesis of natural products and pharmaceuticals, in
the chemical industry, etc.1 They reduce reagents, solvents,
energy supplies, waste, etc, decreasing the environmental
impact as well as production costs. In recent decades, a lot
of effort has been invested into the development of catalytic
cascade reactions, which are mainly performed by transition-
metal catalysis1a–d or organocatalysis.1a,e–g With the increasing
importance of transition-metal catalysis and the rapid
advancement of organocatalysis, another catalytic mode, a
combination of transition-metal catalysis and organocatalysis
for a cascade reaction has emerged. By the new catalytic mode, a
number of excellent cascade reactions were recently disclosed.2
Aminocatalysis is a crucial type of organocatalysis, and there
are some reports on cascade reactions by the combinations of
transition-metal catalysis and aminocatalysis.2 However, more
examples of the cascade reactions by the combinations of
transition-metal catalysis and aminocatalysts involve alkyne
derivatives as substrates, in which transition-metal catalysts,
such as silver, gold and copper catalysts are used to activate
triple bonds of alkyne moieties rather than construct C–C
bonds.2 It is well known that C–C bond formation by transi-
tion-metal catalyzed coupling reactions is one of the most
important strategies in contemporary organic synthesis.
Among them, Heck-type reactions are very important and
classic transition-metal catalyzed coupling reactions.3 How-
ever, to the best of our knowledge, there is no report on a
a Key Laboratory of Mesoscopic Chemistry of MOE,
School of Chemistry and Chemical Engineering,
Nanjing University, Nanjing 210093, P. R. China
b Department of Chemistry, Zhejiang University, Hangzhou 310028,
P. R. China. E-mail: huangzz@nju.edu.cn
c State Key Laboratory of Elemento-organic Chemistry,
Nankai University, Tianjin 300071, P. R. China
w Electronic supplementary information (ESI) available: Experimental
details and the characterization data for all compounds. See DOI:
10.1039/c1cc10152h
c
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Chem. Commun., 2011, 47, 3995–3997 3995

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Table 2 The cascade Heck–Aldol–Heck reaction with aryl iodidesa
Table
1
Optimization of the cascade reaction conditions for
trisubstituted alkene 5aa
T (1C) Yield (%)b
Entry
Ar
Time (h)
Product 5
Yield (%)b
Entry Organocatalyst Time (h) Solvent
1
2
3
4
5
6
7
8
C6H5
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CH3COC6H4
4-CH3OCOC6H4
3-FC6H4
3-ClC6H4
3-BrC6H4
4-CH3C6H4
3-CH3C6H4
2-CH3C6H4
Naphthalen-1-yl
Phenanthren-9-yl
8
6
8
8
6
10
6
8
8
12
12
12
10
10
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
70
81
75
77
73
78
78
74
76
69
68
67
66
68
1
2
3
4
5
6
7
8
2a
2b
3a
3b
3c
3d
3e
3f
3d
3d
3d
3d
3d
3d
3d
3d
—
12
24
12
24
12
10
10
12
8
24
24
16
8
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
NMP
THF
CHCl3
1,4-Dioxane 60
DMF
DMF
DMF
DMF
DMF
60
60
60
60
60
60
60
60
60
60
60
52
26
56
41
54
62
50
46
60
41
45
51
70
42
50
45
18
9
9
10
11
12
13
14
10
11
12
13
14
15
16
17
60
40
80
110
60
12
12
12
36
a
The reaction of 1 (0.90 mmol), propenol (0.45 mmol) and para-
formaldehyde (2.25 mmol) in DMF (0.5 mL) was performed by the
catalysis of Pd(OAc)2 (0.0045 mmol) and pyrrolidine (0.045 mmol) in
the presence of n-Bu4NCl (0.90 mmol) and NaHCO3 (0.95 mmol) at
a
The reaction of 1a (0.90 mmol), propenol (0.45 mmol) and para-
formaldehyde (2.25 mmol) in a solvent (0.5 mL) was probed by
the catalysis of Pd(OAc)2 (0.0045 mmol) and an organocatalyst
(0.045 mmol) in the presence of n-Bu4NCl (0.90 mmol) and NaHCO3
b
60 1C under nitrogen. Isolated yield.
b
(0.95 mmol) under nitrogen. Isolated yields of 5a.
electron-withdrawing group on the benzene ring 1b–i resulted
in better yield than those bearing an electron-donating group
1j–l. The aryl iodides bearing other aromatic rings than
benzene, 1-naphthalenyl iodide 1m and 9-phenanthrenyl iodide
1n could also undergo the cascade reaction readily to give the
corresponding trisubstituted alkene 5m and 5n in 66% and
68% yield, respectively (entries 13–14, Table 2). The E-form of
5k was confirmed by NOE experiments, which demonstrated
weak polar solvents, such as THF, 1,4-dioxane and chloroform.
The experiment also indicated that DMF was the best solvent
for the reaction with a 70% yield of 5a (entry 13, Table 1).
Screening the reaction temperatures showed that 60 1C was a
suitable reaction temperature (entries 13–16, Table 1). When
other bases, such as Et3N, Bu3N, K2CO3, or Na2CO3, were
employed, the yields of 5a were decreased significantly. Using
a quaternary ammonium salt as an additive was important for
the reaction, without it a poor yield (10–53%) of 5a was
obtained (for details, see ESIw). The screening experiment also
showed that n-Bu4NCl was best for the cascade reaction. It is
noteworthy that without pyrrolidine, very low yield (18%) of
5a was obtained in a long reaction time (entry 17, Table 1).
After screening of various transition metal catalysts, amino-
catalysts, solvents, bases, additives, reaction temperatures and
amounts of reactants, it can be concluded that the optimized
reaction conditions are as follows: the cascade reaction of 2.0
equiv. aryl iodide 1, 1.0 equiv. propenol and 5.0 equiv. para-
formaldehyde in DMF is performed under the catalysis of
1 mol% Pd(OAc)2 and 10 mol% pyrrolidine in the presence
of n-Bu4NCl and NaHCO3 at 60 1C. Under the optimal
reaction conditions, a variety of aryl iodides 1a–n were examined
in the cascade Heck–Aldol–Heck reaction. The experimental
results showed that various substituted phenyl iodide 1a–l
could undergo the cascade reaction smoothly to furnish the
desired trisubstituted alkenes 5a–l in satisfactory yields
(67–81%) with E-configuration (entries 1–12, Table 2). When
p-nitrophenyl iodide was employed, only disubstituted alkene,
2-(4-nitrobenzyl)acrylaldehyde was obtained in 56% yield.
4-Methoxyphenyl iodide led to 4-methoxybiphenyl as a coupling
product and no desired trisubstituted alkene was observed
under the optimal conditions. The phenyl iodides bearing an
Fig. 2 NOE spectrum of trisubstituted alkene 5k
Table 3 The cascade Heck–Aldol–Heck reaction with two different
aryl iodidesa
Entry Ar1
Ar2
Time (h) Product 5 Yield (%)b
1
2
3
4
4-FC6H4 C6H5
12
5o
5p
5q
5r
62
56
60
54
4-FC6H4 4-CH3C6H4 12
3-FC6H4 C6H5 12
3-FC6H4 4-CH3C6H4 12
a
The reaction of Ar1I (0.45 mmol), Ar2I(0.45 mmol), propenol
(0.45 mmol) and paraformaldehyde (2.25 mmol) in DMF (0.5 mL)
was performed by the catalysis of Pd(OAc)2 (0.0045 mmol) and
pyrrolidine (0.045 mmol) in the presence of n-Bu4NCl (0.90 mmol)
b
and NaHCO3 (0.95 mmol) at 60 1C under nitrogen. Isolated yields.
c
3996 Chem. Commun., 2011, 47, 3995–3997
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Scheme 1 Possible mechanism of the Heck–Aldol–Heck cascade reaction.
that the olefinic proton (7.46 ppm) had strong correlation with
the aldehyde proton (9.70 ppm) (Fig. 2, also see ESIw). This
suggests that the two proton are close in space and are at the
same side of the CQC bond. The cascade reaction participated
by various aryl iodides 1a–n also has excellent regio- and
stereoselectivities, because no product from a-arylated propanal
and no Z-isomer of 5 was obtained. All of the assembled
compounds 5, except (E)-2-benzyl-3-phenylacrylaldehyde 5a,
are new trisubstituted alkenes 5b–n.
Financial support from National Natural Science Foundation
of China (No. 20872059 and No. 21072091) and MOST of China
(973 program, 2011CB808600) is gratefully acknowledged.
Notes and references
1 A book and reviews on domino or cascade reactions:
(a) L. F. Tietze, G. Brasche and K. Gericke, Domino Reactions in
Organic Synthesis, Wiley-VCH, Weinheim, 2006; (b) L. F. Tietze,
Chem. Rev., 1996, 96, 115; (c) J. C. Wasilke, S. J. Obrey, R. T. Baker
and G. C. Bazan, Chem. Rev., 2005, 105, 1001; (d) K. C. Nicolaou,
D. J. Edmonds and P. G. Bulger, Angew. Chem., Int. Ed., 2006, 45,
7134; (e) D. Enders, C. Grondal and M. R. M. Huttl, Angew. Chem.,
Int. Ed., 2007, 46, 1570; (f) C. Grondal, M. Jeanty and D. Enders,
Nat. Chem., 2010, 2, 167; (g) B. Westermann, M. Ayaz and
S. S. Berkel, Angew. Chem., Int. Ed., 2010, 49, 846.
2 Reviews and papers on cascade reactions by combinations of
transition-metal catalysis and organocatalysis: (a) Z.-H. Shao and
H.-B. Zhang, Chem. Soc. Rev., 2009, 38, 2745; (b) C. Zhong and
X. Shi, Eur. J. Org. Chem., 2010, 2999; (c) A. Duschek and
S. F. Kirsch, Angew. Chem., Int. Ed., 2008, 47, 5703;
(d) B. Simmons, A. M. Walji and D. W. C. MacMillan, Angew.
Chem., Int. Ed., 2009, 48, 4349; (e) G.-L. Zhao, F. Ullah, L. Deiana,
S.-Z. Lin, Q. Zhang, J. Sun, I. Ibrahem, P. Dziedzic and
A. Cordova, Chem.–Eur. J., 2010, 16, 1585; (f) K. L. Jensen,
P. T. Franke, C. Arroniz, S. Kobbelgaard and K. A. Jørgensen,
Chem.–Eur. J., 2010, 16, 1750; (g) S. Chercheja, S. Nadakudity and
P. Eilbracht, P., Adv. Synth. Catal., 2010, 352, 637.
Encouraged by these results, we tried to employ two different
aryl iodides for the synthesis of mixed trisubstituted alkenes
through the cascade Heck–Aldol–Heck reaction. Our experi-
mental results showed that when the two aryl iodides which
have quite different electron densities on the benzene ring, that
is one more reactive and the other less, were employed, the
cascade reaction could proceed smoothly to furnish the mixed
trisubstituted alkenes 5o–r in moderate yields (54–62%)
(entries 1–4, Table 3).
A plausible mechanism of the cascade reaction is depicted in
Scheme 1. At first, Pd(OAc)2 is reduced to palladium(0) by
alkene, amine, etc3a in the reaction system to start the first
catalytic cycle. Insertion of a CQC double bond of allyl
alcohol to organopalladium intermediate 6 leads to b-arylated
3 A book and reviews on Heck reactions: (a) M. Oestreich, The
2009;
intermediate
7 preferentially rather than its a-arylated
Mizoroki–Heck
Reaction,
Wiley-VCH,
Weinheim,
counterpart due to steric hindrance.6a b-Arylated propanal 8
as the product of the first cycle for Heck reaction enters into
the second catalytic cycle for the aldol condensation catalyzed
by pyrrolidine to afford disubstituted alkene 4.7 If aryl iodide 1
is insufficient at this time, the cascade reaction stops at the
second cycle (see the 2nd paragraph). If aryl iodide 1 is
in excess, 4 smoothly enters into the third catalytic cycle for
the second Heck reaction to give the desired trisubstituted
alkene 5.
(b) F. Alonso, I. P. Beletskaya and M. Yus, Tetrahedron, 2005, 61,
11771; (c) J. Muzart, Tetrahedron, 2005, 61, 4179; (d) I. P. Beletskaya
and A. V. Cheprakov, Chem. Rev., 2000, 100, 3009.
4 Books and reviews on aldol reactions: (a) R. Mahrwald, Modern
Aldol Reactions, Wiley-VCH, Weinheim, Germany, 2004;
(b) R. Mahrwald, Aldol Reactions, Springer-Verlag, Heidelberg,
1999; (c) P. I. Dalko, Enantioselective Organocatalysis-Reactions
and Experimental Procedures, Wiley-VCH, Weinheim, Germany,
2007; (d) S. Mukherjee, J. W. Yang, S. Hoffmann and B. List, Chem.
Rev., 2007, 107, 5471; (e) B. M. Trost and C. S. Brindle, Chem. Soc.
Rev., 2010, 39, 1600.
5 (a) J. Xie and Z.-Z. Huang, Angew. Chem., Int. Ed., 2010, 49, 10181;
(b) F. Yang, J. Li, J. Xie and Z.-Z. Huang, Org. Lett., 2010, 12, 5214.
6 Papers on the arylation of allylic alcohols for b-arylated aldehydes
and ketones by Heck reaction: (a) V. Calo, A. Nacci, A. Monopoli
and V. Ferola, J. Org. Chem., 2007, 72, 2596; (b) T. Jeffery, Chem.
Commun., 1984, 1287; (c) A. J. Chalk and S. A. Magennis, J. Org.
Chem., 1976, 41, 273; (d) J. B. Melpolder and R. F. Heck, J. Org.
Chem., 1976, 41, 265; (e) R. F. Heck, J. Am. Chem. Soc., 1968, 90,
5526.
7 Because the amount of formaldehyde (2.05 mmol) is in excess over
pyrrolidine (0.045 mmol) and the amount of its iminium under basic
conditions could not be estimated based on a lack of related
literature, formaldehyde is thought to be a suitablee substrate to
subject to a nucleophilic attack by enamine 9.
In conclusion, we combined three C–C bond forming
reactions into one cascade process to develop an unprece-
dented Heck–Aldol–Heck reaction. Various aryl iodides 1a–n
could perform the cascade reaction with readily available
propenol and formaldehyde by the combination of palladium
and pyrrolidine catalysts, assembling the novel (E)-trisubstituted
alkenes 5a–n in 66–81% yields with excellent chemo-, regio-
and stereoselectivities. Investigations on the cascade reactions
combined by classic transition-metal catalyzed coupling reac-
tions and organocatalyzed C–C bond forming reactions are
currently under way.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3995–3997 3997