Ethyl lactate as a renewable carbonyl source for the synthesis of diynones

Article abstract of DOI:10.1039/c8gc03275k

Ethyl lactate, a sustainable feedstock, serves as a highly attractive building block for the synthesis of value-added chemicals such as skipped diynones and, after gold-catalyzed transposition, conjugated diynones. Green solvents are involved in all steps

Full text of DOI:10.1039/c8gc03275k

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Ethyl lactate as a renewable carbonyl source for
the synthesis of diynones†
Cite this: DOI: 10.1039/c8gc03275k
Marta Solas,
Samuel Suárez-Pantiga
and Roberto Sanz
*
Received 18th October 2018,
Accepted 6th December 2018
DOI: 10.1039/c8gc03275k
rsc.li/greenchem
Ethyl lactate, a sustainable feedstock, serves as a highly attractive dation).9 These methods suffer from important drawbacks,
building block for the synthesis of value-added chemicals such as such as the generation of stoichiometric amounts of waste,
skipped diynones and, after gold-catalyzed transposition, conju- and so, catalytic and greener alternatives have been recently
gated diynones. Green solvents are involved in all steps and high developed in order to avoid the environmental concerns of the
yields are obtained for the final diynones which, in several cases, classical reagents, mainly by introducing alternative oxidants
are isolated in a pure form without any purification.
and improving the atom-economy.10 However, none of the
reported cleaner procedures solve all the chemoselectivity and
reactivity issues. Another approach to minimize the environ-
mental impact caused by the use of classical reagents, like
sodium metaperiodate, is their replacement by silica gel-sup-
ported NaIO4 as a reagent for the oxidative cleavage of
glycols.11 This procedure, reported by Shing and Zhong,11a has
several advantages such as the low cost of both the oxidant
and the support, and a simple workup by filtration that affords
pure carbonyl compounds in very high yields. However, the
required use of a nonpolar solvent like CH2Cl2 that solves the
solubility problems, instead of aqueous alcohols or THF, also
presents obvious environmental concerns.
Diynones are highly electrophilic substrates and possess
multiple reaction sites, which make them useful starting
materials for the preparation of a variety of interesting carbo-
and heterocycles.12 The general method for their preparation
is based on the oxidation of a secondary 1,4-diyn-3-ol, gener-
ated from the double addition of lithium or magnesium acety-
lides to alkyl formates (Scheme 1a).13 Although well-estab-
lished and with good overall yields around 70%, this two-step
sequence employs a high excess (up to 15 equiv.) of oxidants
such as manganese dioxide, barium manganate, or PCC, in
CH2Cl2, that leads to a considerable amount of waste with
severe environmental and human health issues. Following our
interest in the development of cleaner synthetic method-
ologies, mainly involving oxygen-atom-transfer reactions under
dioxomolybdenum(VI)-catalysis,14 and considering our recently
reported method for the oxidative cleavage of glycols with
DMSO,15 we envisaged that a new approach for synthesizing
symmetrical skipped diynones could involve the oxidative clea-
vage of the corresponding 1,1,-dialkynyl-1,2-diols, which are
easily available from biomass-derived EL (Scheme 1b).
One of the main goals of Green Chemistry is to switch from
depleting raw materials to renewable sources, which is
described in the 7th principle. Therefore, the concept of renew-
ability1 could be considered crucial nowadays and the develop-
ment of sustainable processes that employ eco-friendly and
readily available biomass-derived feedstocks for the synthesis of
value-enhanced chemicals constitutes one of the major chal-
lenges in chemical research.2 In this context, lactic acid and lac-
tates are highly functionalized biobased feedstocks that can be
catalytically produced from renewable carbohydrates.3 Hence,
ethyl lactate (EL) is a biomass-derived platform molecule that is
inexpensive and completely biodegradable within very short
times and does not show any potential health risks.4 It has
been described as a sustainable and green solvent with ade-
quate properties for the replacement of organic solvents.5
Therefore, EL possesses promising and appealing potential,
from the Green Chemistry point of view, to be used as a sustain-
able feedstock for the preparation of value-added chemicals.6
On the other hand, the oxidative cleavage of glycols and
related functional groups is a key transformation in organic
synthesis widely used for the preparation and transformation
of natural products and, more recently, in biomass valorization
for the production of renewable feedstocks.7 Classical pro-
cedures for this reaction involve the use of periodic acid or its
salts (Malaprade reaction),8 and lead tetraacetate (Criegee oxi-
Área de Química Orgánica, Departamento de Química, Facultad de Ciencias,
Universidad de Burgos, Pza. Misael Bañuelos s/n, 09001-Burgos, Spain.
E-mail: rsd@ubu.es; Fax: (+34) 947258831
†Electronic supplementary information (ESI) available: Experimental procedures
and NMR spectra of all the experiments. See DOI: 10.1039/c8gc03275k
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Table 1 Synthesis of bispropargyl diols 2 from ethyl lactatea
Entry
R
Product
Yieldb (%)
1
2
3
4
5
6
7
8
Ph
n-Bu
c-C3H5
(CH2)2Ph
c-C6H9
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
84 (94)
89 (95)
83 (95)
74 (87)
75 (93)
74 (89)
70 (—)e
75 (—)e
74 (86)
72 (92)
73 (—)e
71 (90)
66 (84)
70 (85)
62 (—)e
80 (89)
84 (87)
c
C(Me)vCH2
3-Thd
Scheme 1 General method for the synthesis of skipped diynones and
our proposed approach from EL.
2-Thf
9
4-MeOC6H4
3-FC6H4
10
11
12
13g
14g
15h
16
17i
2,4-F2C6H3
CH2N(Me)Ph
CH2O(4-MeOC6H4)
CH2O[3,5-(MeO)2C6H3]
C(Me)2OH
Si(i-Pr)3
Although the preparation of 1,1,-dialkynyl-1,2-diols 2 from
EL has already been reported by its treatment with lithium
acetylides (3 equiv.),16 the moderate to good yields obtained,
as well as the use of THF as a solvent and LiBr as an additive,
make this procedure susceptible to improvement from the
Green Chemistry point of view. We tried to solve these draw-
backs using 2-MeTHF as the solvent, which is a renewable
alternative to THF, can be produced from lignocellulosic
biomass, and presents additional advantages such as lower
water miscibility, higher stability, lower volatility, ease of
degradation, and lower toxicity.17 Gratifyingly, the employment
of 2-MeTHF and a slight excess of the corresponding lithium
acetylide (3.3 equiv.) gave rise to high yields of the expected
dialkynyl glycols 2 without the addition of LiBr (Table 1).18
This general method was successfully performed on a wide
variety of alkynes 1, including aromatic substituents with both
electron-withdrawing and electron-donating groups (entries 1
and 9–11), heteroaromatic (entries 7 and 8), (cyclo)alkyl
(entries 2–4), alkenyl (entries 5 and 6), as well as those derived
from propargyl alcohols, ethers or amines (entries 12–15).
Moreover, silyl-protected alkyne 1p also allowed the prepa-
ration of the corresponding glycol 2p in high yield (entry 16)
and, significantly, 1,2-diol 2q bearing terminal alkynes could
be efficiently accessed from the reaction of EL with commer-
H
a Reaction conditions: 1 (3.4 mmol), n-BuLi (3.3 mmol) in 2-MeTHF
(10 mL) followed by the addition of EL (1 mmol). b Isolated yield after
column chromatography; in brackets are the crude yields of almost
pure compounds (see the ESI). c 1-Cyclohexenyl. d 3-Thienyl. e Not
determined. f 2-Thienyl. g EtMgBr (4 mmol) was used instead of n-BuLi.
h n-BuLi (6.6 mmol) was used. i Commercially available ethynyl mag-
nesium bromide in THF (5 equiv.) was used and the reaction was
refluxed overnight.
Scheme 2 Oxidative cleavage of glycol 2a.
cially available ethynylmagnesium bromide (entry 17). In diynone 3a was obtained, which could not be improved by
addition, similar results were obtained for the preparation of varying the temperature or reaction time,20 likely due to the
2b and 2f using methyl lactate instead of EL. It is worth noting competitive decomposition of the final product. Following this
that when the starting alkyne 1 possesses a low boiling point, methodology, slightly better yields could be obtained for the
the corresponding crude glycol 2 is obtained in a form pure oxidative cleavage of diols 2b and 2e, which afforded the
enough for the next step in an almost quantitative yield.19
corresponding diynones 3b and 3e in only moderate yields
With an efficient procedure for accessing 1,1-dialkynyl-1,2- (45–50%). We next thought about the use of NaIO4–SiO2 as a
diols 2 in our hands, and considering the second step of our potential reagent for the oxidative cleavage of model glycol 2a.
initial proposal, we needed to develop a method for the oxi- Gratifyingly, under the reported conditions,11a with CH2Cl2 as
dative cleavage of glycols 2. We selected diol 2a as a model the solvent and 1.6 equiv. of supported NaIO4, diynone 3a was
substrate and tested our recently developed method for this isolated in an almost quantitative yield and in a pure form by
type of oxidation that uses DMSO as a stoichiometric oxidant simple filtration of the supported reagent (Scheme 2).
under dioxomolybdenum(VI)-catalysis (Scheme 2).15 However,
under the reported conditions, a low yield of the desired our proposed synthesis of skipped diynones, the employment
Although this last procedure seems highly appropriate for
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of a chlorinated solvent led us to try to re-optimize the reaction after simple filtration of the supported reagent, as the only
conditions in order to look for an eco-friendly alternative to byproduct of the process, acetaldehyde, is easily removed
the previously established use of CH2Cl2 (Table 2, entry 1). along with the solvent by evaporation under reduced pressure.
Accordingly, we started this study by testing different and Moreover, the acetaldehyde solution in i-PrOAc could be col-
greener solvents and also by adjusting the reaction time and lected adding further value to this valorization of EL.
the amount of the oxidant for each one. MeOH and EtOH were
Having established the optimized conditions for the oxi-
tried out as they are typically used in homogeneous oxidations dative cleavage of glycols 2 with NaIO4–SiO2, we decided to
with NaIO4. Both of them proved to be compatible with this evaluate the substrate scope (Table 3). Gratifyingly, starting
reaction, although longer reaction times and/or higher diols 2 bearing (functionalized)aryl and heteroaryl groups as
amounts of the oxidant were required to reach complete con- substituents of the alkyne efficiently underwent the oxidative
version (Table 2, entries 2–7). In addition, in these solvents cleavage (entries 1 and 7–11), as well as those with (cyclo)alkyl
some leaching of the supported reagent seemed to take place. and alkenyl groups (entries 2–6), leading to the symmetrical
Then, we turned our attention to more environmentally skipped diynones 3a–k in almost quantitative yields. In the
friendly carboxylic esters as solvents and we checked that same way, functionalized starting diols 2l–n also led to the
AcOEt was also an efficient reaction medium for this trans- corresponding diynones 3l–o without any side products
formation (entries 8 and 9). Looking for an even more eco- (entries 12–15). Finally, silyl-substituted diynone 3p and term-
friendly solvent we decided to use i-PrOAc, which is recognized inal diynone 3q could also be obtained from the corres-
as one of the greenest solvents and,21 gratifyingly, we found ponding dialkynyl diols 2p and 2q (entries 16 and 17). Due to
that the oxidative cleavage also took place efficiently (entries the low boiling point of 3q, the oxidative cleavage of 2q was
10–15). We could determine the optimum conditions for the carried out in CDCl3 and the NMR spectrum of the crude
complete cleavage of 2a leading to an almost quantitative yield mixture shows the clean formation of 3q along with acet-
of 3a (entry 13), although the reaction time could be shortened aldehyde (see the ESI†). It is interesting to note that in all the
by using a higher amount of the oxidant (entries 11 and 15). cases the final diynone 3 was obtained in a pure form after a
Interestingly, treatment of 2a with NaIO4 in i-PrOAc did not simple filtration and removal of the solvent.
lead to any transformation after 24 h showing that the sup-
Moreover, this methodology is amenable for scale up and
ported oxidant presents significant advantages over the non- can be applied to the preparation of diynones such as 3a, b, c,
supported one besides its easy removal. It is also worth noting and f on a gram scale. Interestingly, the corresponding inter-
that in all the cases diynone 3a was isolated in a pure form mediate glycols 2a, b, c, and f do not need to be purified and,
Table 2 Optimization of the reaction conditions for the oxidative clea-
vage of 2a with NaIO4–SiO2
a
Table 3 Synthesis of skipped diynones 3a
NaIO4
(equiv.)
Conversionb
(%)
Yieldc Entry Starting diol
R
Product Yieldb (%)
Entry
Solvent
Time (h)
(%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
Ph
n-Bu
c-C3H5
(CH2)2Ph
c-C6H9
3a
3b
3c
3d
3e
3f
95
98
91
93
96
97
92
94
88
96
93
82
93
95
93
96
85g
1
2
3
4
5
6
7
8
CH2Cl2
MeOH
MeOH
MeOH
EtOH
EtOH
EtOH
EtOAc
EtOAc
i-PrOAc
i-PrOAc
i-PrOAc
i-PrOAc
i-PrOAc
i-PrOAc
1.6
1.8
1.8
1.6
1.8
1.8
1.6
1.8
1.8
1.8
1.8
1.5
1.3
1.1
2.5
2
2
6
16
2
6
16
4
7
2
7
100
60
84
100
31
64
100
88
100
62
100
100
100
85
95
—
—
95
—
—
93
—
96
c
C(Me)vCH2
3-Thd
3g
3h
3i
2-The
9
4-MeOC6H4
3-FC6H4
2,4-F2C6H3
CH2N(Me)Ph
CH2O(4-MeOC6H4)
9
10
11
12
13
14
15
16
17f
3j
3k
3l
10
11
12
13
14
15
97
97
96
—
97
16
16
16
5
3m
CH2O[3,5-(MeO)2C6H3] 3n
C(Me)2OH
Si(i-Pr)3
H
3o
3p
3q
100
a Reaction conditions: 2a (0.2 mmol) in the corresponding solvent
(2 mL). b Determined by the 1H-NMR analysis of the crude product. a Reaction conditions: 2 (0.5 mmol) was treated with NaIO4/SiO2 (1.3
Only 3a and 2a are present in the crude mixture of incomplete conver- equiv.) in i-PrOAc (5 mL). b Isolated yield. c 1-Cyclohexenyl. d 3-Thienyl.
sion examples. c Isolated yield.
e 2-Thienyl. f Carried out in CDCl3. g Determined by 1H-NMR.
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Table 4 Optimization study with greener solvents for the Au-catalyzed
1,3-transposition of 3aa
Temp.b
Solvent (°C)
Time Conversionc
Scheme 3 Gram-scale preparation of selected skipped diynones
from EL.
3
Entry Au catalyst
(h)
(%)
1d
2d
3
4
5
(ArO)3PAuCl/AgBF4 DCE
(ArO)3PAuCl/AgSbF6 DCE
rt
rt
rt
rt
rt
4
4
4
4
16
16
24
6
10
80
90
100
100
100
60
100
100 (81)
Ph3PAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
DCE
DCE
PhCF3
Toluene 80 (Δ)
i-PrOAc rt
i-PrOAc 80 (Δ)
i-PrOAc 100 (MW) 0,2
after a simple extraction with EtOAc or i-PrOAc, it could be
used for the subsequent oxidative cleavage with the NaIO4–
SiO2 reagent. Moreover, in these gram-scale experiments the
amount of the supported oxidant could be reduced up to 1.1
equiv. further improving the greenness of the overall pro-
cedure (Scheme 3). For instance, starting from 0.709 g of ethyl
lactate, 1.036 g (75%) of diynone 3a, 1.027 g (90%) of diynone
3b, 0.873 g (91%) of diynone 3c and 0.806 g (85%) of diynone
3f could be obtained. Moreover, it is worth noting that these
skipped diynones 3 were isolated in a pure form without the
need for any purification processes (only 3a was purified by
column chromatography due to its partial decomposition
under the reaction conditions).
6
7e
8
9
a Reaction conditions: 3a (0.2 mmol) in the corresponding solvent
(2 mL). b In brackets are the ways of heating (MW: microwave; Δ: con-
ventional heating). c Determined by the 1H-NMR analysis of the crude
mixture. Only 3a and 4a are present in the crude mixture of incomplete
conversion examples. Isolated yields of the crude mixtures were >90%
in all the cases. The value in the bracket is the isolated yield. d Ar =
(2,4-di-tert-butylphenyl). e The gold catalyst was added in two portions
(2.5 mol% at the beginning of the reaction and 2.5 mol% after 10 h).
Taking advantage of this efficient method for the synthesis
of skipped diynones 3, and inspired by the work of Gevorgyan
and co-workers on the gold-catalyzed 1,3-transposition of
ynones,22 we decided to combine both processes to achieve a
new valorization of EL. In their original report, the authors
used a cationic gold(I) complex bearing a triarylphosphite
ligand as a catalytic system, in DCE as a solvent, for the trans-
formation of skipped diynones 3 into their conjugated isomers 4.
After a brief experimentation with diynone 3a as a model
be obtained from the corresponding skipped diynones 3b and
3c in high isolated yields (80–85%).
After this study, a series of conjugated diynones 4a–c, and g
could be prepared in good to high isolated yields (referred to
EL) without any intermediate purification, following the
sequence shown in Scheme 4.26 It is important to note that all
the reactions, acetylide addition to EL, oxidative cleavage, and
Au-catalyzed transposition, yield the corresponding products
in an almost pure form allowing the next step to be performed
with the crude mixtures. Only final diynones 4 needed purifi-
cation in order to remove impurities coming from the gold
catalyst. In addition, the solvents employed in these processes
(2-MeTHF and i-PrOAc) are ecofriendly alternatives to the ones
typically used (THF and CH2Cl2 or DCE).
substrate, we obtained better results with the cationic gold(I)
23
complex IPrAuNTf2
(Table 4, entries 1–4). To further
improve this protocol, and also considering that the avail-
ability of DCE is now severely limited in the European Union
due to regulatory controls,24 we thought about replacing this
chlorinated solvent with
a greener alternative. Although
toluene and trifluorotoluene resulted to be successful alterna-
tives to DCE (entries 5 and 6), gratifyingly, we found that envir-
onmentally-friendly i-PrOAc was again a convenient solvent for
this Au-catalyzed transformation, although no complete con-
version was observed at room temperature (entry 7). Upon
increasing the reaction temperature the starting material was
consumed (entry 8). Finally, we have also found that under
microwave irradiation the reaction time can be dramatically
shortened from several hours to 10 minutes (entry 9). The use
of i-PrOAc as a green solvent for this reaction is highly remark-
able as few examples of gold-catalyzed processes carried out in
safe, non-toxic, biorenewable and cheap solvents have been
reported.25 Under these optimized conditions conjugated
diynone 4a was obtained in a high yield from 3a (entry 9). In
Scheme 4 Further valorization of EL: synthesis of conjugated
an analogous way conjugated diynones 4b and 4c could also diynones 4.
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5 (a) S. Aparicio and R. Alcalde, Green Chem., 2009, 11, 65–
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Conclusions
We have demonstrated how a biomass-derived platform mole-
cule, ethyl lactate, serves as a highly efficient, sustainable and
environmentally benign C1 building block for the synthesis of
high-added-value chemicals such as symmetrical skipped diy-
nones. To meet the sustainability criterion, THF and haloge-
nated solvents, typically used in the involved reactions, have
been replaced by greener alternatives such as 2-MeTHF and
i-PrOAc, respectively. In addition, the gold-catalyzed transposi-
tion of skipped diynones to the conjugated ones, but employ-
ing environmentally-friendly i-PrOAc instead of chlorinated
solvents, has also been merged with this valorization of EL.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Financial support from Junta de Castilla y León and FEDER
(BU076U16) and Ministerio de Economía y Competitividad
(MINECO) and FEDER (CTQ2016-75023-C2-1-P) is gratefully
acknowledged. M. S. and S. S.-P. thank Junta de Castilla y León
and FEDER for predoctoral and postdoctoral contracts,
respectively.
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