A direct amine-palladium acetate cocatalyzed saegusa oxidation reaction of unmodified aldehydes to α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/adsc.200900011

A direct preparation of synthetically useful α,β-unsaturated aldehydes from readily available aldehydes has been developed. The process is effectively cocatalyzed by an amine-palladium acetate to give rise to α,β-unsaturated aldehydes in moderate to good yields (41-62%). The reaction features the use of unmodified aldehydes rather than enol silyl ethers, which are used in a typical Saegusa oxidation reaction.

Full text of DOI:10.1002/adsc.200900011

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DOI: 10.1002/adsc.200900011
A Direct Amine-Palladium Acetate Cocatalyzed Saegusa
Oxidation Reaction of Unmodified Aldehydes to
a,b-Unsaturated Aldehydes
Jin Zhu,a Jie Liu,a Ruoqun Ma,a Hexin Xie,b Jian Li,a,* Hualiang Jiang,a,c
and Wei Wanga,b,c,
*
a
School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, Peopleꢀs
Republic of China
Fax : (+86)-21-6425-2584; phone: (+86)-21-6425-2584; e-mail: jianli@ecust.edu.cn
Department of Chemistry and Chemical Biology, University of New Mexico, MSC03 2060, Albuquerque, NM 87131-0001,
USA
Fax : (+1)-505-277-2609; e-mail: wwang@unm.edu
Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi
Road, Shanghai 201203, Peopleꢀs Republic of China
b
c
Received: January 9, 2009; Revised: March 29, 2009; Published online: May 28, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900011.
Abstract: A direct preparation of synthetically
useful a,b-unsaturated aldehydes from readily avail-
able aldehydes has been developed. The process is
effectively cocatalyzed by an amine-palladium ace-
tate to give rise to a,b-unsaturated aldehydes in
moderate to good yields (41–62%). The reaction
features the use of unmodified aldehydes rather
than enol silyl ethers, which are used in a typical
Saegusa oxidation reaction.
the Peterson olefination,[9] or the formylation.[10,11]
The cross-metathesis reactions of acrolein[12] and
cross-aldol condensations[13] are alternative tactics.
The latter suffers from several side reactions under
relatively strong basic conditions, self-aldolization,
and narrow substrate diversity. Furthermore, they can
be accessed in high efficiency by way of the Wittig
olefination using formylmethylenetriphenylphosphor-
ane with only electron-poor aldehydes.[14] The oxida-
tion-elimination of highly toxic selenium aldehydes in
one- or two-step protocols is another important ap-
proach to a,b-unsaturated carbonyls.[15] It is notewor-
thy that most of the described methods produce equi-
molar amounts of by-products and thus render them
not atom-economic. Accordingly, the development of
catalytic reactions using readily available chemicals is
Keywords: aminocatalysis; organocatalysis; Saegusa
reaction; a,b-unsaturated aldehydes
a,b-Unsaturated aldehydes are highly useful synthetic of considerable significance in the synthesis of versa-
building blocks in organic synthesis.[1] Recently their tile a,b-unsaturated aldehydes.
synthetic utility has been significantly expanded by or-
The Saegusa oxidation is a convenient method for
ganocatalysis. Notably they are the most commonly the conversion of a silyl enol ether into the corre-
used substrates in organocatalyzed asymmetric reac- sponding a,b-unsaturated aldehydes and ketones
tions[2–4] and powerful cascade processes.[5,6] They [Figure 1, Eq. (1)].[16,17] The attractive features of the
serve as effective electrophiles for a variety of organic Saegusa oxidation include the use of a catalytic
transformations, in particular conjugate addition pro- amount of Pd
ACHTUGNTERN(NUNG OAc)2 as catalyst and O2 as oxidant.
cesses. However, the approach requires the preformation of
Despite their broad synthetic utility, the synthesis silyl enol ethers from the corresponding aldehydes
of a,b-unsaturated aldehydes is still a tedious and and ketones.[17]
challenging task. Several approaches to effect this op-
The direct oxidation of aldehydes or ketones with
(OAc)2
eration have been disclosed over the years.[7] The gen- O2 in the presence of a catalytic amount of Pd
ACHTUNGTRENNUNG
eral strategies rely on functional group interconver- is a particularly attractive strategy for the synthesis of
sion involving multi-step transformations. Among a,b-unsaturated carbonyl compounds since the sub-
these processes are the oxidation of allylic alcohols,[8] strates are readily available or easily prepared and O2
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Jin Zhu et al.
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Table 1. Results of exploratory studies on the amine-
Pd
ACHTUNGRTEN(NGNU OAc)2 cocatalyzed Saegusa reaction of 3-phenylpropio-
naldehyde (1a) to cinnamaldehyde (2a).[a]
Figure 1. The Pd(II)-catalyzed Saegusa reaction.
is used as oxidant. Nevertheless, studies have shown
that very low reaction yields are obtained for the
direct dehydrogenation of aldehydes and ketones.[18]
Given the great success of amine-promoted iminium/
enamine reactions of aldehydes and ketones, we envi-
sioned that the combination of the aminocatalysis
Entry
Cat.
Solvent
T [8C]
Yield[b] [%]
1
2
3
4
5
6
7
8
I
II
III
IV
V
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DME
30
30
30
30
30
60
30
60
100
60
60
60
60
30
30
60
30
30
30
no reaction
no reaction
no reaction
4
48
30
38
62
32
14
12
17
5
24
57
24
with the PdACHTUNGTRENNUNG(OAc)2-mediated Saegusa oxidation could
result in a new direct approach to a,b-unsaturated
carbonyl compounds from aldehydes and ketones
(Figure 1). In the proposed process, the reaction of an
aldehyde or a ketone with an amine catalyst generates
an enamine, which is considered as an equivalent of
the silyl enol ether in a typical Saegusa oxidation re-
action. The in situ formed enamine can be subse-
quently oxidized to an enal or enone by O2 in the
V
VI
VI
VI
VI
VI
VI
VI
VII
VIII
VIII
VIII
IX
X
9
10
11
12
13
14
15
16
17[c]
18
19
THF
CH3CN
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
presence of Pd
ACHTUNGTRENNUNG(OAc)2.
To demonstrate the possibility of the amine-Pd-
ACHTUNGTRENNUNG
no reaction
35
35
1a in the presence of an amine (20 mol%), PdACTHUNRGTNEUNG(OAc)2
[a]
(10 mol%) and O2 (1 atm) in DMSO at 308C for 24 h
(Table 1). The preliminary investigations revealed
that the reaction occurred as designed. Nevertheless,
the reaction efficiency was highly amine catalyst de-
pendent. No reactions occurred when proline I, (S)-
pyrrolidine-tetrazole II and diamine III were em-
Reaction conditions: see Experimental Section.
Isolated yields.
100 mol% V.
[b]
[c]
ployed (entries 1–3). MacMillanꢀs catalyst IV also dis- tries 6, 8 and 16). Lower reaction yields (30 and 24%,
played very poor catalytic activity towards the process entries 6 and 16) were obtained with catalysts V and
(entry 4). Among the catalysts probed, diphenylproli- VIII, while diphenylprolinol VI afforded a higher
nol TMS ether V, diphenylprolinol VI, prolinol VII yield (62%, entry 8). Further raising the temperature
and simple pyrrolidine VIII, piperdine IX and mor- to 1008C did not give any improvement (entry 9).
pholine X provided encouraging outcomes (entries 5, Probing the solvent effect on the process indicated
7, 14, 15, 18 and 19) and moderate to good yields (38– that the reaction medium had an important impact
62%) were achieved. Interestingly, on elevating the (entries 8, and 10–13). The best result was obtained
reaction temperatures from 308C to 608C with cata- when the reaction was carried out in DMSO
lysts V, VI and VIII, mixed results were observed (en- (entry 8). It is noted that under the reaction condi-
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A Direct Amine-Palladium Acetate Cocatalyzed Saegusa Oxidation Reaction
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Table 2. Scope of the amine-Pd
ACHTUNGTRENNUNG
Saegusa reactions.[a]
Entry R, R’
t [h] T [8C] Yield[b] [%]
1
2
3
4
5
6
7
8
C6H5, H, 2a
24
24
24
20
23
8
24
24
8
60
45
45
60
45
45
60
60
60
45
60
60
60
62
58
41
60
53
43
45
53
4-MeO-C6H4, H, 2b
2-MeO-C6H4, H, 2c
2-Me-C6H4, H, 2d
4-CN-C6H4, H, 2e
4-NO2-C6H4, H, 2f
4-Cl-C6H4, H, 2g
2,4-Cl2C6H3, H, 2h
4-MeCO-C6H4, H, 2i
4-MeOCO-C6H4, H, 2j
C6H5CH2, H, 2k
C6H5, Me, 2l
9
57
49
10
11
12
13
9
24
24
24
no reaction
no reaction
no reaction
C6H5, OMe, 2a
[a]
[b]
Reaction conditions: see Experimental Section.
Isolated yields.
Figure 2. A plausible mechanism for the amine-PdACHTUNGTRENNUNG(OAc)2
cocatalyzed conversion of 3-substitued propionaldehydes to
3-substitued acroleins.
tions, the aldehyde was not oxidized to the corre-
sponding carboxylic acid.
The conditions that proved optimal for the dehy- rise to the iminium 6. Upon hydrolysis, this will fur-
dration of 3-phenylpropionaldehyde (1a) to cinnamal- nish the enone and regenerate the aminocatalyst.
dehyde (2a), cocatalyzed by VI (20 mol%) and Meanwhile, reductive elimination of HPdOAc affords
PdACHTUNGTRENNUNG(OAc)2 (10 mol%) in DMSO in the presence of O2 Pd(0), which is subsequently oxidized by O2 to Pd(II)
(1 atm) were applicable for the Saegusa oxidation of for the next cycle reaction. It is reasonably surmised
other aldehydes (Table 2). The aromatic rings of the that 3-arylpropionaldehydes through a conjugation
aldehydes bearing electron-neutral (entry 1), electron- effect can more effectively facilitate the elimination
donating (entries 2–4) or electron-withdrawing (en- reaction, and accordingly only they can efficiently
tries 5–10) substituents underwent the reaction participate in the process.
smoothly affording the desired products in moderate
In summary, this investigation has resulted in a new
to good yields (41–62%). These outcomes implied direct Saegusa oxidation reaction of unmodified alde-
that the electronic features had only a marginal effect hydes. This process, catalyzed by a combination of or-
on the processes. Examination of the results of the in- ganocatalyst (an amine) and an organometallic
vestigation also revealed that the steric effect (o- vs. [PdACTHNUGTRENUNG(OAc)2], affords synthetically useful a,b-unsaturat-
p-substitution pattern) also played a minimal role in ed aldehydes in moderate to good yields. Therefore,
governing the reactionꢀs efficiency. A limitation is the studies have significantly expanded the scope of
also realized for the amine-PdACTHNUTRGENUG(N OAc)2 cocatalyzed organocatalysis and afford a new alternative approach
Saegusa oxidation reaction. No reaction occurred to the preparation of enals. Further investigations on
with aliphatic aldehydes, ketones and esters (en- this valuable transformation with a focus on expand-
tries 11–13).
ing the scope (ketones as substrates) and other appli-
A possible pathway of the amine-PdACTHNUTRGNE(NUG OAc)2 cocata- cations are underway in our laboratory.
lyzed Saegusa oxidation reaction is proposed based
on the established typical Saegusa oxidation reaction
mechanism (Figure 2).[19] In analogy to a typical Sae-
gusa oxidation reaction of silyl enol ethers,[19] an en-
amine 3 is initially formed from the corresponding al-
Experimental Section
Typical Procedure (Table 2, entry 1)
dehyde. Coordination of the enamine
3
with
Pd(OAc)2 leads to an alkene-Pd complex 4, which
subsequently transforms to a palladium adduct 5, an
ACHTUNGTRENNUNG
A mixture of 3-phenylpropanal (60 mg, 0.45 mmol), (S)-di-
phenylprolinol (VI) (23 mg, 0.09 mmol), PdACHTGNUTREN(NUGN OAc)2 (10 mg,
intermediate similar to that in the classic Saegusa oxi-
0.045 mmol), and DMSO (1 mL) was stirred for 24 h at
dation.[19] b-Hydride elimination of HPdOAc gives 608C in an atmosphere of oxygen. The crude product was
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Jin Zhu et al.
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purified by column chromatography on silica gel (30/1 v/v n-
hexane/ethyl acetate) to give the desired product cinnamal-
dehyde; yield: 62%. 1H NMR (CDCl3, 400 MHz): d=6.73
(dd, 1H, J=7.6 and 16.0 Hz), 7.43–7.45 (m, 4H), 7.49 (d,
1H, J=16.0 Hz), 7.56–7.59 (m, 2H), 9.71 (d, 1H, J=
7.6 Hz); 13C NMR (CDCl3, 400 MHz): d=128.5, 128.6,
129.1, 131.2, 134.0, 152.7, 193.7; MS (EI): m/z=132 (M+),
131 (100%).
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Acknowledgements
We gratefully acknowledge the financial support from the Na-
tional Natural Science Foundation of China (Grant
90813005), the 863 Hi-Tech Program of China (Grant
2006AA020404), the China 111 Project (Grant No. 807023)
and Shanghai Rising-Star Program (A type) of Shanghai
Ministry of Science and Technology (Grant 07A14013).
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