Assembly of functionalized α-hydroxy carbonyl compounds via combination of N-heterocyclic carbene and Pd catalysts

Article abstract of DOI:10.1016/j.tetlet.2008.11.032

Functionalized α-hydroxy carbonyl compounds were prepared from various aldehydes and allylic acetates via a multicomponent reaction, which were catalyzed by N-heterocyclic carbene and Pd catalysts in one pot.

Full text of DOI:10.1016/j.tetlet.2008.11.032

Tetrahedron Letters 50 (2009) 430–433
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Assembly of functionalized a-hydroxy carbonyl compounds
via combination of N-heterocyclic carbene and Pd catalysts
Jinmei He a, Shibing Tang a, Shouchu Tang a, Jian Liu a, Yongquan Sun a, Xinfu Pan a, Xuegong She a,b,
*
a Department of Chemistry, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Functionalized
a-hydroxy carbonyl compounds were prepared from various aldehydes and allylic ace-
Received 20 September 2008
Revised 2 November 2008
Accepted 11 November 2008
Available online 14 November 2008
tates via a multicomponent reaction, which were catalyzed by N-heterocyclic carbene and Pd catalysts
in one pot.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
N-heterocyclic carbenes
Benzoin condensations
p-Allylpalladium
Allylic alkylation
Multicomponent reactions
Carbon–carbon bond formation via new catalytic methods re-
mains a formidable challenge. In this area, N-Heterocyclic carbenes
(NHCs) have been known for a long time and successfully utilized
in a variety of transformations.1 They are effective catalysts in
organocatalytic reactions2 as well as powerful ligands in organo-
metallic chemistry.3 In the past decades, NHCs were attracted by
their ability to catalyze the polarity reversal of carbonyl
compounds, and have been employed effectively in a number of
transformations, such as nucleophilic substitutions,4 benzoin
condensations,5 Micheal–Stetter reactions,6 homoenolate forma-
tions,7 redox processes,8 and Diels–Alder reactions.9 In addition,
the participation of NHCs in multicomponent reactions (MCRs)
has attracted considerable attention. Several successful cases of
NHCs-initiated MCRs were reported by Nair10 and Ma,11 respec-
tively. In 2005, Zhai and co-workers reported a one-step assembly
of diversity of allylic alkylation reaction will be of great
significance.
R2
R3
OAc
R1CHO
benzoin
complexation
L
NHC
L
L
condensation
Pd
L
HO
R1
O
Pd
R2
R3
R1
OAc
base enolation
ionization
of functionalized c-butyrolactones from benzaldehydes or benzo-
H
O
ins via a NHCs-mediated tandem reaction.12
Allylic alkylation of carbon nucleophiles with
L
L
O
Pd
p-allylpalladium
R2
R3
species, known as the Tsuji–Trost reaction, is also a very fruitful
and versatile method of carbon–carbon bond formation.13 In
2006, Hamada and co-workers reported an efficient synthesis of
R1
R1
3-substituted 2,3-dihydroquinolin-4-ones using
a
one-pot
sequential multi-catalytic process. In this transformation, Pd was
employed to catalyze allylic amination, and thiazolium salt was
employed to catalyze Stetter reaction.14 Thereby, the development
OH
R1
OH
O
O
R3
R2
or
R1
R1
R1
R3
R2
* Corresponding author. Fax: +86 931 8912582.
E-mail address: shexg@lzu.edu.cn (X. She).
Scheme 1. Assembly of a-carbonyl homoallylic alcohol from aldehydes and allylic
acetates.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.032

J. He et al. / Tetrahedron Letters 50 (2009) 430–433
431
Table 1
Examination of scope of aldehydes in MCRs
OH
I
N
S
OH
20 mol%
O
R
1
Ph
+
OAc
RCHO
2 equiv
Ph
20 mol% PdCl2, 1 equiv of PPh3
2 equiv of K2CO3, DMSO, 30 oC, 48 h
R
1 equiv
Entrya
R
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
Ph
2-Cl–Ph
2
3
4
5
6
7
8
—
—
94
68
53
86
91
53
87
—
2-Br–Ph
4-Cl–Ph
4-Br–Ph
4-Me–Ph
2-fury l
4-MeO–Ph
4-NO2–Ph
—
a
All reactions were performed on a 1 mmol scale at 0.2 M.
Isolated yields.
b
Table 2
Synthesis of
a
-carbonyl homoallylic alcohols via various allylic acetates
RCHO
Entrya
Allylic acetate
Product
Yieldb (%)
OH
O
1
2
3
4
PhCHO
85
69
78
82
4-Cl–PhCHO
4-Br–PhCHO
2-Furyl–CHO
R
R
OAc
9
R = Ph
4-Cl-Ph
10
4-Br-Ph 11
2-fury
12
OH
O
OAc
OAc
5
6
7
PhCHO
PhCHO
PhCHO
57
73
77
Ph
Ph
13
OH
Ph
O
Ph
14
15
OH
Ph
O
OAc
Ph
OH
Ph
O
Ph
16
8
9
PhCHO
43
59
Ph
OAc
Ph
OH
Ph
O
Ph
OAc
Ph
PhCHO
Ph
17
OH
O
OAc
OAc
Ph
10
PhCHO
PhCHO
86
72
Ph
Ph
Ph
Ph
2
OH
O
Ph
11
Ph
Ph
17
a
All reactions were performed on a 1 mmol scale at 0. 2 M.
Isolated yields. The diastereoselectivity of products 13, 14, and 17 was unable to be determined.
b

432
J. He et al. / Tetrahedron Letters 50 (2009) 430–433
10 mol% PdCl2
1 equiv of K2CO3
OH
Ph
O
HO
Ph
O
R
OAc
+
R
1 equiv of PPh3
DMSO, 30 oC, 48 h
Ph
Ph
1 equiv
1 equiv
Product
Yield (%)
Entry
R
1
2
Ph
H
2
9
96
90
Scheme 2. Direct allylation of benzoin product.
Highly functionalized
ful intermediates in synthesis.15 Inspired by the attractive charac-
teristics of NHCs and -allylpalladium species, we decided to
synthesize highly functionalized -hydroxy carbonyl compounds
utilizing NHCs and Pd catalysts in a one pot. Herein, we reported
assembly of -carbonyl homoallylic alcohols from aromatic
aldehydes and allylic acetates via combination of NHCs and Pd
catalysts in one pot; in this process, NHCs performed as organo-
catalyst rather than as ligand (Eq. 1).
a
-hydroxy carbonyl compounds are use-
moderate yield (entry 9). When 1-phenylallyl acetate was em-
ployed, the linear product 2 was obtained in satisfactory yield (en-
try 10), and none of the branched products was detected. Similarly,
1-phenylbut-2-enyl acetate underwent this reaction and gave
product 17 in good yield (entry 11).
To confirm the more precise course of this one-pot reaction,
benzoin product and allylic acetate were utilized directly under
similar reaction conditions, but in the absence of thiazolium salt
p
a
a
1 (Scheme 2). As we expected, the desired a-carbonyl homoallylic
alcohols 2 and 9 were obtained in excellent yields, which further
proved that the above transformations from aldehydes and allylic
acetates to the products were in the sequence of initial benzoin
condensation followed by the Tsuji–Trost reaction.
In summary, we have developed a simple method of an assem-
bly of functionalized a-hydroxy carbonyl compounds from various
aldehydes and allylic acetates. The multicomponent reaction was
mediated by an unprecedented combination of NHCs and palla-
dium catalysts, which furnish a-carbonyl homoallylic alcohols in
moderate to excellent yields. Further investigations into the devel-
opment of various multicomponent reactions catalyzed by NHCs
and transition-metal, as well as catalytic asymmetric allylic alkyl-
ation reactions by employing chiral NHCs and/or chiral ligands, are
currently underway in our laboratory.
OH
R1
O
R2
R1
R3
R3
O
NHCs
Pd
+
or
ð1Þ
R1
H
R2
OAc
OH
O
R3
R1
R1
R2
As depicted in Scheme 1, when NHCs and Pd catalysts were
coexisted in one pot, the product of the benzoin condensation
was formed firstly, which was catalyzed by NHCs generated
in situ from thiazolium salts in the presence of a weak base.
Under the suitable basic conditions, the benzoin product was
enolated, and then allylated by
p-allylpalladium species. Finally,
Acknowledgments
a-carbonyl homoallylic alcohol was effectively synthesized. In this
two-component catalyst system, the NHCs have no interference
with Pd catalyst, and the necessity of basic conditions was compat-
ible between benzoin condensation and Tsuji–Trost reaction. It is
worthy of mention that further functionalization of benzoin prod-
ucts was rarely reported, especially direct allylation, and we were
glad to exhibit our work in this context.
We are grateful for the generous financial support by the NSFC
(QT program, 20572037, 20732002), NCET-05-0879, and Gansu
Science Foundation (3ZS051-A25-004).
References and notes
Thiazolium salts
1 as classical NHCs organocatalyst were
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utilized. The multicomponent reaction of cinnamyl acetate with
various aldehydes was examined.16 As revealed in Table 1, a
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dehyde, 4-Cl-,and 4-Br-substituted benzaldehyde gave desired
a
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and 5). Benzaldehydes with substituents of 2-Cl, 2-Br, and 4-Me
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The influence of various allylic acetates on this reaction has
been examined, and the representative results are summarized in
Table 2. When aliphatic allylic acetates participated in this reac-
tion, the desired products were obtained in moderate to good
yields (entries 1–7). The conjugated homoallylic alcohol 16 was
obtained in 43% yield when conjugated cinnamyl acetate was sub-
jected to this reaction (entry 8). Benzaldehyde with
a-substituted
cinnamyl acetate provided the corresponding product 17 in

J. He et al. / Tetrahedron Letters 50 (2009) 430–433
433
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Rovis, T. J. Am. Chem. Soc. 2005, 127, 16406.
thiazolium salt 1 (0.2 mmol), PdCl2 (0.2 mmol), PPh3 (1 mmol), and K2CO3
(2 mmol) in 5 ml DMSO. This was followed by the addition of aldehyde
(2 mmol) and allylic acetate (1 mmol), and the resulting solution was stirred for
48 h at 30 °C under argon atmosphere. After cooling to room temperature, 40 ml
of ethyl acetate was added and washed with brine (3 ꢀ 5 ml). The organic layer
was dried over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. Purification by flash column chromatography (silica gel, elution with
9. (a) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418; (b) He, M.;
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30:1 petroleum ether/EtOAc) afforded the desired product a-carbonyl
homoallylic alcohol. Product 2: 1H NMR (300 MHz, CDCl3) d 7.80 (d, J = 6.9 Hz,
2H), 7.59 (d, J = 8.1 Hz, 2H), 7.49–7.47 (m, 3H), 7.44–7.21 (m, 8H), 6.35 (d,
J = 15.9 Hz, 1H), 6.23–6.13 (m, 1H), 4.35 (s, 1H), 3.34 (dd, J = 13.8, 7.2 Hz, 1H),
3.15 (dd, J = 13.8, 6.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 200.8, 141.7, 136.8,
135.1, 134.5, 132.7, 130.1, 128.8, 128.4, 128.0, 127.4, 126.2, 125.5, 123.5, 81.7,
43.2; mp: 127–128 °C; HRMS (ESI) Calcd. for C23H24NO2 [M+NH4]+ 346.1802,
found 346.1810. Product 3: 1H NMR (300 MHz, CDCl3) d 7.76 (d, J = 7.5 Hz, 1H),
7.41 (d, J = 7.8 Hz, 1H), 7.34–7.23 (m, 9H), 7.13 (d, J = 7.5 Hz, 1H), 6.99–6.95 (m,
1H), 6.51 (d, J = 15.6 Hz, 1H), 6.24–6.14 (m, 1H), 3.94 (s, 1H), 3.37 (dd, J = 14.5,
6.9 Hz, 1H), 3.21 (dd, J = 14.5, 7.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 198.5,
138.2, 136.8, 135.3, 135.1, 133.0, 132.4, 131.5, 131.0, 129.5, 129.2, 128.6, 128.5,
127.5, 127.0, 126.3, 125.6, 123.3, 81.6, 40.6; mp: 112–115 °C.
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16. General procedure for synthesis of
bottomed flask equipped with
a
-carbonyl homoallylic alcohol: A round-
a
magnetic stirring bar was charged with