Simple and expeditious pinacol coupling of non usual α,β-unsaturated carbonyl compounds in water

Article abstract of DOI:10.1039/c5ra03870g

Using zinc (0) in a 5% v AcOH aqueous solution allowed the efficient pinacol coupling of aliphatic or aromatic unusual, α,β-unsaturated carbonyl compounds such as citral A in good to excellent yields (56-99%). It can also be successfully applied to acetophenone.

Full text of DOI:10.1039/c5ra03870g

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Simple and expeditious pinacol coupling of non
usual a,b-unsaturated carbonyl compounds in
water†‡
Cite this: RSC Adv., 2015, 5, 46026
a
a
a
ab
Received 4th March 2015
Accepted 15th May 2015
*
Muriel Billamboz, Nicolas Sotto, Carole Chevrin-Villette and Christophe Len
DOI: 10.1039/c5ra03870g
www.rsc.org/advances
Using zinc (0) in a 5% v AcOH aqueous solution allowed the efficient products and the use of benign solvents or renewable feed-
pinacol coupling of aliphatic or aromatic unusual, a,b-unsaturated stocks. Starting form biosourced a,b-unsaturated carbonyl
carbonyl compounds such as citral A in good to excellent yields (56– compounds such as citral, myrtenal, farnesal., pinacol
99%). It can also be successfully applied to acetophenone.
couplings are rarely studied. The corresponding diols were
obtained in low yields and no report deals with their coupling in
water as green solvent. For example, the reductive homo-
coupling of geranial was described by electrochemical reduc-
tion in EtOH-pH5 buffer in around 35% yield.15 Moreover,
starting from crotonaldehyde in presence of Al/InCl3 in THF,
the diol was prepared in 45% yield.16 Otherwise, pinacol
coupling of trans hex-2-enal was performed by TiI4 in EtCN with
16% yield.17
Pinacol coupling is one of the most used methods for the
formation of diols via carbon–carbon bonds. Although discov-
ered in 1859,1 this well documented reaction2 is still studied and
nds many applications as the vicinal diols obtained are useful
intermediates for the construction of biologically important
natural or synthetic products.3 These diols can also be trans-
formed to numerous high value products, such as epoxides,
ketones, aminoalcohols.
The aim of this work was to develop a green, simple and
efficient methodology to form vicinal diols from natural green
To perform this reaction, a variety of methods have been
developed using mainly aromatic carbonyl compounds as
starting materials. Among them, the most reliable systems use
either simple low-valent metals such as Mg,4 Mn,5 Zn,6 Al,7
Zn–Cu couple,8 or transition metal complexes such as Ti-, V- or
Zr-derivatives.9 Pinacol-type couplings were also developed by
using toxic or expensive promoters (In,10 Sm,11 Ga,12 and other
metals13), in particular for the development of reaction with
aliphatic derivatives that are commonly inert under classical
conditions.2a,7b,9a,14
Fig. 1 a,b-Unsaturated derivatives 1, crotonaldehyde 1a and the diol
2a.
Nowadays, due to the depletion of fossil resources, chemists
are strongly encouraged to develop safer protocols, less
hazardous synthesis, catalysis for the production of high value
Table 1 Optimization of reaction conditions for the pinacol coupling
of crotonaldehyde 1a with zinc (2 eq.) at rt
Entry
Solvent
Additive (eq.)
Time (h)
2a (%)
a
´
´
`
´
Sorbonne Universites, Universite de Technologie de Compiegne, Ecole Superieure de
1
2
3
4
5
6
7
8
9
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
H2O
H2O
H2O
EtOH
EtOH/H2O
None
15
15
15
15
15
15
15
0.3
0.3
15
Traces
1
4
36
76
11
27
99
99
39
´
´
´
`
Chimie Organique et Minerale, EA 4297 Transformations Integrees de la Matiere
HCl (2eq.)
H2SO4 (2eq.)
AcOH (2eq.)
NH4Cl sat.
None
NH4Cl sat.
AcOH (2eq.)
AcOH (2eq.)
AcOH (2eq.)
`
Renouvelable, Centre de Recherches de Royallieu, CS 60319, F-60205 Compiegne
cedex, France. E-mail: christophe.len@utc.fr; Fax: +33 (0)3 44 97 15 91; Tel: +33 (0)
3 44 23 88 28
bDepartement of Chemistry, University of Hull, Hull 6 HU6 7RX, UK
† This work was performed, in partnership with the SAS PIVERT, within the frame
of the French Institute for the Energy Transition Institut pourla Transition
´
Energetique (ITE) P.I.V.E.R.T. (http://www.institut-pivert.com) selected as an
Investment for the Future (“Investissements d’Avenir”).
10
‡ Electronic supplementary information (ESI) available: Experimental procedures,
products description and 1H and 13C NMR spectra. See DOI: 10.1039/c5ra03870g
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Table 2 Screening of metal sourcea
note aldehydes and more widely a,b-unsaturated derivatives 1
(Fig. 1). Crotonaldehyde 1a affording the corresponding diol 2a
was selected as model substrate for our study.
Entry
1
2
3
4
5
6
Initially, the effect of solvent changes on the pinacol
coupling of 1a at room temperature in presence of 2 equivalents
of zinc was examined. The results are summarized in Table 1.
The previously described medium THF/water18 was initially
tested. Without acidic additive or in the presence of strong
acids, the pinacol coupling is very slow (Table 1, entries 1–3).
For this medium, weak acids such as NH4Cl or AcOH proved to
be best promoters (Table 1, entries 4 and 5). Protic solvents
(water, ethanol or a mixture of water and ethanol; Table 1,
entries 6–10) are ideal to conduct pinacol coupling reactions,
especially in presence of AcOH as additive. Total conversions
and excellent yields in only 20 minutes were obtained (Table 1,
entries 8 and 9). In the topic of green chemistry, organic
syntheses in water present many advantages in terms of safety
and environmental aspects compared to organic solvents.
Moreover, in the case of radical reactions, it was proved that
solvent plays a crucial role and that water allows control of
radical reactions.19 As a consequence, water was selected as
solvent for further optimization. Then, metallic source was
screened (Table 2).
Metal
Yield of 2a (%)
Zn
99
Mg
6
Al
0
Mn
7
Fe
0
Cu
0
a
For typical conditions: 1a (2.3 mmol) was reacted with metal (2 eq.) in
5% v AcOH in water during 20 minutes at rt.
Table 3 Screening of acids for the pinacol coupling of 1aa
Entry
Acid (2 eq.)
2a (%)
1
2
3
4
5
6
7
AcOH
99
40
52
63
30
29
33
Citric acid
CH3SO3H
Tartaric acid
H2SO4
HCl
NH4Cl
a
All reactions are carried out in presence of 2eq. of acid in water (5 mL
total volume for 2.3 mmol of 1a) during 20 minutes in presence of 2 eq.
of zinc.
Table 4 Scope of the reaction for a,b-unsaturated compounds
Substrate 1
Results (%)
Entry
No.
R1
R2
R3
R4
Conv.
2
3
Sela (%)
dl/mesob
1
2
3
4
5
6
7
a
b
c
d
e
f
CH3
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
H
H
H
H
H
H
H
100
100
94
63
91
99
79
78
61
63
90
65
0
100
79
89
100
70
92
42/58
37/63
42/58
0/100
43/57
0/100
0/100
CH3–(CH2)2
CH3–(CH2)6
CH3–(CH2)4–CH]CH–
Ph
CH3
CH3–CH2
21
10
0
28
8
100
100
g
0
100
8
h
i
CH3
H
H
100
56
0
100
87
39/61
9
93
67
10
0/100
10
j
80
71
6
92
0/100
11
12
k
l
Ph
H
H
Ph
100
0
—
—
—
—
ND
—
NDc
—
a
Selectivity is dened as 2/(2 + 3). b The dl/meso ratio was determined by 1H NMR of the crude product. c For entry 11, the major product resulted
from a cascade of reductive coupling and cyclization of chalcone, as previously described20 (product 4).
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good to excellent yields. Various types of compounds have been
used as substrates such as linear saturated enals 1a–c, unsatu-
rated enals 1d–e or disubstituted enals 1f–j. Comparison with
an a,b-unsaturated ketone 1k and an aliphatic aldehyde 1l has
been also made. Linear saturated enals 1a–c reacted smoothly
under the optimized conditions (Table 4, entries 1–3). Croto-
naldehyde (1a) was totally converted with excellent yield and
selectivity (Table 4, entry 1). Long chain linear derivatives: trans
hex-2-enal (1b) and trans dec-2-enal (1c) led to the desired
pinacol products in 79% and 78% yield, respectively (Table 4,
entries 2 and 3). It should be noticed that non negligible
amounts of the reduction side products, i.e. the allylic alcohols
3b and 3c, have been isolated in 21% and 10% yield, respec-
tively. For this linear saturated enals, no diastereoselectivity has
been observed during the reaction as pinacols 2a–c are obtained
as a mixture of dl and meso isomers with a slightly excess of the
meso isomer (Table 4, entries 1–3). When using unsaturated
enals 1d–e, lower yields were obtained (Table 4, entries 4 and 5,
61 and 63% yield, respectively). This lower reactivity can be
explained by a higher stability of the ketyl radical. Cinna-
maldehyde (1e), as an aromatic a,b-unsaturated aldehyde, gave
2e in only 63% yield with a non negligible amount of the
reduction product 3e (Table 4, entry 5). This can be the result of
an enhancement of the radical stability by the aromatic moiety.
Disubstituted enals 1f–j also reacted fast under the optimized
conditions, but with slightly lower yields than their less
hindered analogues (Table 4, entries 6–10). For these deriva-
tives, the increase of the steric hindrance around the carbonyl
group has a dramatic effect on the dl/meso ratio. The 2f and 2g
meso isomers, with a methyl group on the a position, are
Fig. 2 Product 4 formation pathway.
Among the 6 tested metals, only zinc, a cheap readily avail-
able metal, permitted to afford the corresponding diol 2a in
good yield (Table 2).
It was selected for further studies. As an acidic medium is
required to maintain good kinetics, a screening of mineral and
organic acids was then realized (Table 3). In our hands, yields
were lower than 63% except for acetic acid (Table 3, entry 1).
Combining all results, expeditious, simple and eco-
compatible conditions were found for the efficient pinacol
coupling of 1a : 2 equivalents of zinc in a 5% v AcOH/H2O
medium during 20 minutes at room temperature. This new
methodology was then applied to various a,b-unsaturated
aldehydes and ketones as presented in Table 4.
As depicted, a,b-unsaturated aldehydes reacted smoothly
under these conditions to conduct to the desired pinacols in
Table 5 Scope of the reaction for aromatic compounds
Substrate 1
Results (%)
Entry
Nꢀ
R1
R2
R3
R4
Conv.
2
3
Sela (%)
dl/mesob
1
2
3
4
5
6
m
n
o
p
q
r
H
CH3
Cl
Br
NO2
H
H
H
H
H
H
Cl
H
H
H
H
H
Cl
H
H
H
H
H
H
96
80
80
64
46
90
51
54
13
40
0
45
26
67
24
0
53
67
16
62
38/62
48/52
26/74
27/73
Reduction of NO2
42
38
52
16/84
32/68
7
s
100
51
39
57
8
9
10
t
u
v
H
Cl
Ph
H
H
H
H
H
H
CH3
CH3
Ph
80
80
10
75
75
0
0
4
10
100
95
0
56/44
57/43
—
a
1
Selectivity is dened as 2/(2 + 3). b The dl/meso ratio was determined by H NMR of the crude product.
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obtained selectively (Table 4, entries 6 and 7). It is noteworthy
than citral A (1h), a long chain hindered natural aliphatic a,b-
unsaturated aldehyde reacted well under these conditions to
conduct to a mixture of meso and dl isomers (Table 4, entry 8).
To our knowledge, it is the rst time that citral A (1g) proved to
be a good substrate for pinacol coupling in water. Moreover,
natural cyclic a,b-unsaturated aldehydes such as myrtenal (1i)
and perillaldehyde (1j) were also successfully converted into
pinacol coupling products 2i and 2j with a total selectivity for
the meso isomers (Table 4, entries 9 and 10). The reactivity
towards pinacol coupling of these cyclic hindered compounds
was never described before. For this family of hindered enals
1f–j, it is notable that a substituent on the a position led to total
selectivity towards the meso isomer. Less reactive a,b-unsatu-
rated ketone, chalcone 1k, was then submitted to these opti-
mized reaction conditions without success (Table 4, entry 11).
In fact, the previously described cyclodimerization product
4, resulting from a reductive coupling/cyclization cascade
(Fig. 2), is mainly isolated in 65% yield.20 As expected, aliphatic
aldehyde such as octanal (1l) did not coupled under these
simple conditions (Table 4, entry 12).
This simple and efficient methodology was then extended to
classical aromatic carbonyl compounds (Table 5). Aromatic
aldehydes reacted fast under these conditions, but, as observed
for cinnamaldehyde (1e) (Table 4, entry 5), the amount of
reduction products 3m–3s is high (Table 5, entries 1–7) and
sometimes mainly obtained (Table 5, entries 3 and 6). One
possible explanation is that kinetics of reaction is too high to let
the possibility to ketyl radicals to meet and coupled effectively.
For acetophenone derivatives, which are less reactive in single
electron transfer, this medium is very interesting and promoted
efficiently the ketyl radicals formation and its coupling, allow-
ing the formation of pinacol 2t and 2u from acetophenone (1t)
and 4-chloroacetophenone (1u) with 75% yield (Table 5, entries
8 and 9). Much hindered ketone, exemplied by benzophenone
(1v), did not coupled under these conditions and only reduction
product 3v is obtained in low yield aer 20 minutes (Table 5,
entry 10).
Notes and references
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Conclusions
A simple, green and expeditious methodology for pinacol
coupling of a,b-unsaturated aldehydes and acetophenone
derivatives has been established in 5% v AcOH in water. Zinc as
cheap readily available reductant and acetic acid as promoter
are used to obtain high value added pinacol products in only
20 minutes at room temperature in good to excellent yields.
Natural compounds such as citral A, myrtenal or perillaldehyde
proved to react smoothly under these conditions. Works are still
in progress to enhance the selectivity of the coupling reaction
for aromatic compounds and a,b-unsaturated ketones.
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Acknowledgements
This work was supported, as part of the Investments for the
Future, by the French Government under the reference ANR-
001-01.
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