Tandem nucleophilic addition-Oppenauer oxidation of aromatic aldehydes to aryl ketones with triorganoaluminium reagents

Article abstract of DOI:10.1039/c3ob40642c

In the presence of pinacolone, the in situ prepared triorganoaluminium reagents reacted with aromatic aldehydes to give ketones in moderate to high yield. We propose that the products are formed via a tandem organoaluminium reagents addition-Oppenauer oxidation sequence. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40642c

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Tandem nucleophilic addition–Oppenauer oxidation of
aromatic aldehydes to aryl ketones with
triorganoaluminium reagents†
Cite this: DOI: 10.1039/c3ob40642c
Received 31st March 2013,
Accepted 19th May 2013
Ying Fu,*a Yanshou Yang,a Helmut M. Hügel,b Zhengyin Du,a Kehu Wang,a
Danfeng Huanga and Yulai Hua
DOI: 10.1039/c3ob40642c
www.rsc.org/obc
In the presence of pinacolone, the in situ prepared triorgano- with benzaldehyde in the presence of AlCl3 (without the
aluminium reagents reacted with aromatic aldehydes to give addition of ZnCl2, as one can easily deduce the role of ZnCl2
ketones in moderate to high yield. We propose that the products was to convert reactive benzylic Grignard reagents into less
are formed via a tandem organoaluminium reagents addition– reactive benzylic zinc derivatives). Surprisingly, the desired stil-
Oppenauer oxidation sequence.
bene was not formed; however, the corresponding secondary
alcohol and an unexpected 1,2-diphenylethanone were
obtained in 65% and 23% yield respectively.15
Aryl ketones are the basic units in many natural products,
pharmacologically important molecules1 and many synthetic
approaches have been developed in the past few decades for
their synthesis. Besides the well known Friedel–Crafts acyla-
tion reaction (unreactive with electron-deficient arenes)2 the
direct conversions of aldehydes to ketones, such as the noble
metal catalyzed acylation of aryl halides,3 aryl boronic acids,4
hydroacylation of olefins,5 and arenes,6 are convenient pro-
cedures for aryl ketone synthesis.
The tandem nucleophilic addition–Oppenauer oxidation of
aldehydes to ketones provides another approach for the syn-
thesis of variable ketones that can be prepared from the corres-
ponding aldehydes in one step. The nucleophiles involved in
such conversions are Grignard reagents,7 organozirconium
reagents,8 allylchromium,9 organoborates,10 or organoindium
reagents formed in situ in Barbier-type reactions.11
Based on our interests in the nucleophilic addition reaction
of organozinc reagents towards carbonyl12 and imino com-
pounds,13 we have found that Lewis acids can dramatically
influence the reactivity of organometallic reagents. Recently,
Zhang et al.14 reported a novel olefination reaction of aromatic
aldehydes with organozinc reagents (prepared by in situ trans-
formation of Grignard reagents with ZnCl2) in the presence of
AlCl3. We were interested in determining whether stilbenes
could be formed via the reaction of benzyl magnesium halides
Although stilbene was not obtained, the appearance of sig-
nificant amounts of ketone was exciting as this product appears
to be produced via an in situ tandem organoaluminium
addition–Oppenauer oxidation of aldehydes. To the best of our
knowledge, the only similar report of such reactions involving
an organoaluminium reagent appeared early in 1990 in which
trimethyl aluminium was used as the nucleophile and the
mechanism was not clear.16 Combined with several excellent
reports on the tandem Mg-Oppenauer oxidation of aldehydes7
we considered it worthwhile to explore this reaction further.
Benzaldehyde was reported to be an excellent hydrogen
acceptor in Oppenauer oxidations7 but we do not think it is a
good choice in the tandem organometallic reagent addition–
Oppenauer oxidation of aldehydes. First of all, the Rf values of
benzaldehyde and the ketone products are similar unless there
are polar substituents in the benzene ring of the ketones. Thus
the addition of large amounts of excess benzaldehyde may
burden product purification. Second, as the mechanism of the
magnesium-Oppenauer oxidation of aldehydes shows (Fig. 1),
competitive reactions exist between the nucleophilic addition
of the Grignard reagent to aldehyde (I) and Oppenauer oxi-
dation of secondary alkoxide (II) by aldehyde (I) in the reaction
system. To avoid the in situ Oppenauer oxidation, a low reac-
tion temperature is thus required.7a Importantly the amount
of Grignard reagent must be accurately titrated to ensure that
all of the aromatic aldehyde (I) is fully consumed. If the
amount of Grignard reagent is underestimated, the excess
Grignard reagent would react with the formed ketone (III) or
with the subsequently added benzaldehyde to give the phenyl
magnesium alkoxide (IV) and then be oxidized to the ketone (V)
by-product. On the other hand, should the amount of
Grignard reagent be overestimated, then the aromatic
aKey Laboratory of Eco-Environment-Related Polymer Materials, Ministry of
Education, Gansu Key Laboratory of Polymer Materials, College of Chemistry and
Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070,
P. R. China. E-mail: fuying@iccas.ac.cn
bHealth Innovations Research Institute and School of Applied Sciences, RMIT
University, Melbourne, 3001, Australia
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3ob40642c
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Table 1 Optimization of the reaction conditionsa
Entry
Additive (equiv.)
Solvent
Yield of 3ab [%]
1
2
3
4
5
6
7
8
—
—
THF
THF
THF
THF
THF
THF
THF
THF
18a
23c
56
62
54
34
45
67
Acetone (2.0)
Acetone (5.0)
Acetophenone (2.0)
Benzophenone (2.0)
Benzoquinone (2.0)
Pinacolone (2.0)
Pinacolone (5.0)
9
THF
73
10
11
12
13
14
15
Pinacolone–THF
Pinacolone–THF
Et2Oe
87d
92d
25
Fig. 1 Mechanism and side reactions of the tandem Grignard reagent
addition–Oppenauer oxidation using benzaldehyde as a hydrogen acceptor.
CF3CO2H (0.05)
Pinacolone (5.0)
Pinacolone (5.0)
Bu2Oe
18
Pinacolone–THF
Pinacolone–THF
26f
64g
aldehyde (I) would be in excess, and along with the added
benzaldehyde, may proceed via a Tishchenko reaction to give
esters as by-products.17
Ketones are also good hydrogen acceptors in the Oppenauer
oxidation of primary and secondary alcohols.18 We believe that
in the tandem nucleophilic addition–Oppenauer oxidation
reaction, ketones are better oxidants than benzaldehyde as
ketones are less electrophilic than aldehydes and can be differ-
entiated from aldehydes by weaker nucleophiles. Second,
a Reaction conditions: nitrobenzaldehyde 2a (3.5 mmol) was treated
with Ph3Al 1a (3.5 mmol) and ketone in THF (20 mL) at room
temperature. b Isolated yields. c Two equiv. of aldehyde was added.
d The reaction proceeded in 20 ml of pinacolone–THF (1 : 1). e The
reaction mixture was not fully dissolved. f The reaction mixture was
cooled in an ice-water bath for 12 hours. g The reaction mixture was
heated at 50 °C for 12 hours.
ketones do not react via the Tishchenko reaction, therefore stirring at room temperature for two days. Only ketone 3a and
eliminating a major side product in the Oppenauer oxidation alcohol 4a were produced. Neither the nucleophilic addition
reaction. Additionally, small ketones like acetone and their product of triphenyl aluminium reagent to pinacolone nor the
reduction products 2-propanol normally have lower boiling aldol condensation product from pinacolone reacting with aro-
points and larger dipole moments, ensuring their easy matic aldehyde 2a was formed. The addition of CF3CO2H (0.05
removal by water washing or distillation.
To achieve the ketone mediated tandem organoaluminium enhance the yield of 3a to 92% (entries 10 and 11).
reagent addition–Oppenauer oxidation of aldehydes, a variety
The solvents Et2O and Bu2O were unsuitable due to their
equiv.) after complete consumption of aldehyde 2a can further
of ketones were screened using triphenyl aluminium 1a19 and limited solubility with 4-nitrobenzaldehyde and triphenyl alu-
4-nitrobenzaldehyde 2a in a model reaction. The results illus- minium (Table 1, entries 12 and 13). Conducting the reaction
trated in Table 1 indicate that 2a is a weak oxidant, for when at room temperature was optimal; when the tandem addition–
1.0 equiv. of 2a was added, the ketone 3a was produced in only Oppenauer oxidation reaction was held at 0 °C or lower, little
18% yield, which increased a little when an additional equiv. or no reaction occurred. Higher reaction temperatures led to
of aldehyde 2a was added (Table 1, entries 1 and 2). It was lower yields and several by-products appeared (entries 14 and
gratifying that when 2 equiv. of acetone were added, the yield 15). The efficiency of pinacolone is attributed to its high oxi-
of ketone 3a increased to 56%. However, further additions of dation potential.
acetone did not affect the yield of ketone 3a (Table 1, entries 3
With the optimized reaction conditions in hand, we then
and 4). Other ketones such as acetophenone, benzophenone, investigated the substrate scope of aromatic aldehydes with
pinacolone, benzoquinone were then screened. Benzophenone the triphenyl aluminium reagent 1a. The results, summarized
and acetophenone gave lower yields of 3a compared to in Table 2, indicate that a range of aromatic aldehydes 2a–2l
acetone. Pinacolone was shown to be a better oxidant, as 3a were all efficiently transformed to their corresponding pro-
was obtained in 67% yield when 2 equiv. of pinacolone was ducts 3a–3l in fair to excellent yields. Various functional
added. The yield of 3a was improved to 73% by the addition of groups, such as chloro, fluoro, nitro and cyano, are well tolera-
5 equiv. of pinacolone. We found that this reaction can be per- ted on the benzene rings of aromatic aldehydes. Sterically hin-
formed best using pinacolone–THF (1 : 1) as the solvent dered 2-substituted aldehydes (2f, 2g) can also be converted
whereby the product 3a was obtained in 87% yield after into corresponding ketones in acceptable yields (3f, 3g).
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Table 2 Reaction of triphenyl aluminium with aromatic aldehydesa,b
Table 3 Reaction of aryl aldehydes with triaryl aluminium reagentsa,b
a Unless otherwise noted, the reactions were performed by employing
Ph3Al (3.5 mmol) and aryl aldehyde (3.5 mmol) in 20 ml of
pinacolone–THF (1 : 1). b Isolated yield.
Heteroaromatic carboxaldehydes, such as furfuraldehyde (2j)
and 3-thiophenecarboxaldehyde (2k), gave the corresponding
ketones (3j and 3k) in lower yields than aromatic carboxalde-
hydes; probably because of either the instability of these het-
eroaromatic carboxaldehydes (especially furfuraldehyde) in
this reaction system or the inert reactivity of these secondary
alkoxides which bonded with a strong electron-donating
heteroaromatic ring, they are inert substrates in the following
Oppenauer oxidation. Cinnamaldehyde reacted with the tri-
phenyl aluminium reagent regioselectively to give chalcone 3l
in 48% yield.
After screening the reactivity of aromatic aldehydes, the
scope of other triorganoaluminium reagents was investigated.
To our delight, triorganoaluminium reagents prepared by
in situ reaction of various kinds of organo bromides or chlo-
rides in the presence of magnesium (1.5 equiv.) and AlCl3 (1/3
equiv.) reacted smoothly with aromatic aldehydes to give the
corresponding ketones in moderate to good yields (Table 3). In
this context, sterically hindered tri(α-naphthyl) aluminum
reagent reacted with 4-nitrobenzaldehydes 2a to give the
a Unless otherwise stated, the reactions were performed by employing
Ph3Al (3.5 mmol) and aryl aldehyde (3.5 mmol) in 20 ml of
pinacolone–THF (1 : 1). b Isolated yield.
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ketone 5a in 57% yield, whereas the less sterically hindered tri-
biphenyl aluminium 4b gives ketone 5b in 87% yield. Hetero
aromatic aluminum reagents can also be applied here.
Although the tri(2-furanyl) aluminium reagent, obtained by
direct transmetalation of 2-furyllithium with one-third equi-
valent of aluminium chloride, reacted with benzaldehyde to
give the corresponding ketone 5c in low yield; the trithiophen-3-
ylaluminium reagent was better and reacted with aromatic alde-
hyde to give the corresponding ketones in good yields (5d–5h).
Tribenzylic aluminium reagents can be easily prepared
from benzylic Grignard reagents. However, the yields of benzyl
ketones are lower than those from aromatic aluminium
reagents, probably due to the enolizable nature of these benzyl
ketones that may form condensation products with other car-
bonyl compounds in these reaction systems. Aromatic alde-
hydes bearing strong electron-donating/withdrawing groups
reacted readily with tribenzylic aluminium reagents to furnish
the corresponding ketones in high yields; however, the yields
of ketones (5n–5p) were low. Neither prolonging the reaction
time nor elevating the amount of pinacolone enhanced the
ketone yields. When an enolizable aldehyde such as phenyl-
acetaldehyde 2p was treated with 1a, the self-condensation
product 7 was isolated. Fatty aldehydes reacted with the alu-
minium reagents produced by this method did not give
ketones in acceptable yields, most likely due to the enolizable
nature of the aldehydes or the ketone products. Attempts to
use R2AlCl and RAlCl2 instead of R3Al were less effective and
the corresponding ketone was obtained in lower yields.
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Acknowledgements
The authors are grateful for financial support from the
National Natural Science Foundation of China (No. 21262030
and 20962017) and the Natural Science Foundation of Gansu
Province, China (No. 1107RJZA263).
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