One-pot sustainable synthesis of tertiary alcohols by combining ruthenium-catalysed isomerisation of allylic alcohols and chemoselective addition of polar organometallic reagents in deep eutectic solvents

Article abstract of DOI:10.1039/c7gc00458c

Ru(iv)-Catalysed redox isomerisation of allylic alcohols has, for the first time, been successfully assembled with the chemoselective addition of organolithium or organomagnesium reagents to the in situ formed ketones, en route to tertiary alcohols, employing deep eutectic solvents as environmentally friendly reaction media. The overall transformation, which formally involves three consecutive and different steps such as (i) the reduction of a C-C double bond, (ii) the oxidation of a secondary carbinol moiety, and (iii) a chemoselective C-C bond formation, takes place in protic and biorenewable eutectic mixtures in a sequential one-pot fashion using a commercially and easily available catalytic system, with excellent conversions (up to 99% yield), at room temperature and under air in the last step, with no concomitant reduction or enolisation processes, and with high atom economy, in agreement with the principles of the so-called green chemistry.

Full text of DOI:10.1039/c7gc00458c

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One-Pot Sustainable Synthesis of Tertiary Alcohols by Combining
Ruthenium-Catalysed Isomerisation of Allylic Alcohols and
Chemoselective Addition of Polar Organometallic Reagents in
Deep Eutectic Solvents
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Luciana Cicco,a María J. Rodríguez-Álvarez,b Filippo M. Perna,a Joaquín García-Álvarezb,* and Vito
Capriatia,*
www.rsc.org/
Abstract: The Ru(IV)-catalysed redox isomerisation of allylic alcohols has, for the first time, been successfully assembled
with the chemoselective addition of organolithium or organomagnesium reagents to the in situ formed ketones, en route
to tertiary alcohols, employing Deep Eutectic Solvents as environmentally friendly reaction media. The overall
transformation, which formally involves three consecutive and different steps such as (i) the reduction of a C–C double
bond, (ii) the oxidation of a secondary carbinol moiety, and (iii) a chemoselective C–C bond formation, takes place in protic
and biorenewable eutectic mixtures in a sequential one-pot fashion using a commercially and easily available catalytic
system, with excellent conversions (up to 99% yield), at room temperature and under air in the last step, with no
concomitant reduction or enolisation processes, and with high atom economy, in agreement with the principles of the so-
called Green Chemistry.
mediated (RLi/R2Mg) organic transformations remains
particularly attractive and appealing as both methodologies
constitute two of the most important pillars in the toolbox of
Introduction
The search for new ways of perfecting chemo- and
regioselectivity, functional group tolerance and reaction yield
still represents a great and major challenge in synthetic
organic chemistry, both for academics and industry.1 Most
environmental legislation worldwide recognise the urgency to
develop atom-economical reactions which are critical for the
reduction of waste stream in the chemical industry,2 and that
make use of more environmentally benign and bio-renewable
solvents jointly with milder reaction conditions.3 This justifies
the flourishing in recent years of a plethora of new one-pot
processes involving multiple stoichiometric/catalytic events
mainly because of their intrinsic environmental, practical, and
economic advantages (for example, minimisation of waste-
production, time- and energy-consuming, and tedious
purification steps).4 Among these, the potential of assembling
transition-metal-catalysed reactions5 with main group-
synthetic organic chemistry.6 However, the vast majority of
examples reported in the literature, which combine transition-
metal catalysis with organomagnesium (e.g., Kumada-Corriu
coupling)7 or organolithium chemistry,8 still rely on massive
use of hazardous, toxic and dry volatile organic solvents (VOCs)
(e.g., Et2O, THF, toluene, etc.),9 of inert atmosphere, and of
low temperatures (up to –78 °C) in order to avoid the fast
degradation the above polar organometallic reagents usually
undergo.
With the ultimate goal of solving these pitfalls, the so-
called Deep Eutectic Solvents (DESs) have recently been
introduced and investigated by our groups as innovative and
unconventional green reaction media for running both
nucleophilic addition and substitution reactions promoted by
Grignard and organolithium reagents at room temperature
and under air.10 DESs, which share many physico-chemical
properties with traditional ionic liquids (e.g., thermal stability,
low vapour pressure, non-flammability, easy of recycling, etc.),
are biodegradable fluids generally composed of two or three
safe and inexpensive components able to engage with each
other via hydrogen bond interactions, thereby forming
eutectic mixtures with melting points much lower than that of
either of the individual components.11,12 Thanks to their
unusual and unexpected solvent properties and minimal
ecological footprint, in the last years their use has been
successfully extended also to biocatalysis,13 organocatalysis,14
solar technology,15 and transition-metal-catalysis.16
a.Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari “Aldo Moro”,
Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125, Bari, Italy. Fax: (+39) 080
5442539; phone: (+39) 080 5442174; e-mail: vito.capriati@uniba.it.
b.Laboratorio de Compuestos Organometálicos y Catálisis (Unidad Asociada al
CSIC). Departamento de Química Orgánica e Inorgánica (IUQOEM), Centro de
Innovación en Química Avanzada (ORFEO-CINQA), Facultad de Química,
Universidad de Oviedo, E-33071, Oviedo, Spain. Fax: (+34)-098-510-3446; phone:
(+34)-098-510-3464; e-mail: garciajoaquin@uniovi.es.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Building on recent findings in organometallic reactions and
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DOI: 10.1039/C7GC00458C
metal-catalysed isomerisations run in unconventional reaction
media,10,17,18 herein we wish to report an unprecedented and
greener synthesis of highly substituted tertiary alcohols
exploiting a one-pot combination of a Ru(IV)-catalysed redox
isomerisation of allylic alcohols with the chemoselective
addition of organolithium and organomagnesium reagents to
the in situ formed ketones in DESs (Scheme 1). The overall
transformation involves three consecutive and different steps:
(i) reduction of the allylic C–C double bond, (ii) oxidation of the
secondary alkyl/aryl carbinol moiety, and (iii) chemoselective
C–C bond formation via polar organometallic reagents. The
following features of the proposed methodology are
remarkable: the overall transformation in selected eutectic
mixtures takes place under mild and green reaction conditions,
in the absence of additives or co-catalyst, and without any
halfway isolation/purification step starting from commercially
and easily available substrates. Thus, DESs come close to being
the ideal candidates to cross the frontier between transition-
3 by
1
Scheme 2. Metal-catalysed redox isomerisation of allylic alcohols.
2
In this context, some of us have recently reported that the
monomeric ruthenium(IV) complex [Ru(η3:η3-C10H16)Cl2(κ1-N-
benzimidazole)] (5a) (Table 1) was an efficient and selective
catalyst (10 mol%) for the quantitative isomerisation of
aromatic allylic alcohols into the corresponding ketones in
DESs, however, after 24 h reaction time.16f In order to improve
these results, we set out to investigate the catalytic activity of
the acetate ruthenium(IV) complex [Ru(η3:η3-C10H16)Cl(κ2-O,O-
CH3CO2)] (5b) (Table 1), which previously proved to be a
competent catalyst for the isomerisation of α-vinylbenzyl
alcohol (1a) both in water and in the ionic liquid [BMIM][BF4]
(BMIM = 1-butyl-3-methylimidazolium).17b
metal-catalysed
and
main
group-mediated
organic
transformations in a sustainable way.
Table
1
.
Isomerisation of α-vinylbenzyl alcohol
(
1a
)
into
propiophenone (2a) catalysed by the acetate ruthenium complex
[Ru(η3:η3-C10H16)Cl(κ2-O,O-CH3CO2)] (5b) in different DESs.[a]
Entry DES
[Ru][b]
Temp
(°C)
Time
(h)
Yield
(%)[c]
Scheme 1. Ru-catalysed allylic alcohol isomerisation combined with
the chemoselective addition of organolithium/organomagnesium
reagents in a one-pot process using DESs as green solvents.
1
1ChCl/2Urea
5
2.5
1
5
5
5
5
5
5
5
5
5
5
50
50
50
30
50
50
50
50
50
75
75
75
75
75
0.5
1.5
2
99
98
1
99
92
98
1
1
1
99
99
99
1
2
3
4
5
1ChCl/2Urea
1ChCl/2Urea
1ChCl/2Urea
1ChCl/2EG
24
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
Results and Discussion
Redox isomerisation of α-vinylbenzyl alcohol (1a) catalysed by
acetate Ru(IV)-complex [Ru(η3:η3-C10H16)Cl(κ2-O,O-CH3CO2)] (5b) in
different DESs
6
7
8
9
10
11
12
13
14
1ChCl/2Gly
5ChCl/2Prol
1ChCl/2H2O
1ChCl/2Lac
1ChCl/2Fruc
1ChCl/1Sorb
2Fruc/3Urea
2Prol/5Gly
The redox isomerisation of readily available allylic alcohols
catalysed by transition-metal complexes is a convenient and
direct synthetic pathway to obtain saturated carbonyl
compounds in quantitative yields and usually under mild
reaction conditions.19 This metal-catalysed reaction is based on
the capability of transition-metal complexes to promote the
9Lac/1Alan
5
1
[a] Reaction conditions: α-vinylbenzyl alcohol (1a, 0.5 mmol) under an Ar atmosphere
[b]
[c]
at 30–75 °C in 0.5 g of the desired DES.
Calculated by GC.
Catalyst loading 1–5 mol% in Ru.
migration of carbon-carbon double bond of allylic alcohol
produce a transient enolate intermediate , which suffers the
spontaneous tautomerisation into the corresponding carbonyl
compound (Scheme 2). This is a much more attractive
1 to
Firstly, the activity of complex 5b was assessed in a model
reaction (Table 1) by using the archetypal eutectic mixture
1ChCl/2Urea as the solvent. When a solution of α-vinylbenzyl
alcohol (1a) in the eutectic mixture 1ChCl/2Urea was heated at
50 °C with a catalyst loading of 5 mol%, propiophenone (2a) formed
in 99% yield after 30 min only (entry 1, Table 1), thereby clearly
improving the previous result obtained with complex 5a.16f
However, a dramatic decrease in the catalytic activity of the
4
2
transformation (from a Green Chemistry point of view)3 than
those based on classic stoichiometric reactions, which usually
involve the use of: (i) a two-step sequential oxidation and
reduction processes (with low atom-economy), and (ii) highly
reactive, toxic and expensive reagents. The gradual emergence
of this metal-catalysed transformation as a modern synthetic
approach20 has boosted an increasing interest in the search for
new catalytic systems capable to work in unconventional
solvents as reaction media.21,22
complex 5b was observed in the absence of
a protecting
atmosphere, as the corresponding ketone 2a formed in 34% yield
only. This is consistent with previous results already
published.16f,17b,21g
2 | J. Name., 2012, 00, 1-3
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Trying to find the limits of our catalytic system, we also family of valuable one-pot transformations.27 In the light of the
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decreased both the catalyst loading and the temperature for this above results we envisioned that a modulaDr OcoI:m10b.1in0a39ti/oCn7GoCf 0R0u4(5IV8C)-
isomerisation. The use of lower catalytic loading, however, slowed catalysed isomerisation of allylic alcohols with the chemoselective
down the reaction considerably: with 2.5 mol% in [Ru], quantitative addition of RLi/R2Mg reagents to the resulting ketones in DESs
conversion was only achieved after 90 min (entry 2, Table 1), would allow a straightforward, one-pot access to a library of
whereas with 1 mol% in [Ru], the reaction did not even generate structurally diverse tertiary alcohols under mild, simple and
the product (entry 3, Table 1). Remarkably, complex 5b environmentally friendly reaction conditions.
quantitatively isomerised allylic alcohol 1a into 2a under very mild
Table 2. Direct conversion of α-vinylbenzyl alcohol (1a) into 3-phenyl-
heptan-3-ol (3a) through the one-pot combination of Ru-catalysed
isomerisation and chemoselective addition of n-BuLi or n-Bu2Mg in different
solvents.[a]
reaction conditions (30 °C) but after 24 h reaction time (entry 4,
Table 1). Then, we also investigated the nature of the composition
of DESs on the outcome of the reaction. While other ChCl-based
eutectic mixtures containing ethylene glycol (EG, entry 5, Table 1)
or glycerol (Gly, entry 6, Table 1) proved to be similarly effective in
promoting the formation of 2a in almost quantitative yield after 30
min and working at 50 °C, those based on L-proline (Prol, entry 7,
Table 1), water (entry 8, Table 1) or lactic acid (Lac, entry 9, Table 1)
did have a dramatic impact on the isomerisation process as no
transformation occurred. Quantitative conversion of 1a into 2a also
took place smoothly employing sugar-based eutectic mixtures [for
example, D-fructose (Fruc) and D-sorbitol (Sorb)], however, at a
higher temperature (75 °C) (entries 10–11, Table 1). Finally, the use
of the non-ionic eutectic mixture 2Fruc/3Urea allowed the
quantitative formation of propiophenone (2a) at high temperatures
(75 °C, entry 12, Table 1) while the amino acid-based DESs
(2Prol/5Gly and 9Lac/1Alan (L-alanine), entries 13–14, Table 1)
totally hampered the catalytic reaction.
Since the eutectic mixture 1ChCl/2Urea displayed the best
results in terms of both reaction time and yield, and bearing in mind
that one of the major advantages associated with the use of
eutectic mixtures as green solvents in metal-catalysed organic
reactions16 is the easiness to recycle the catalytic system after its
use (which is a very important step for industrial application in
Green Chemistry),23 we decided to investigate the level of
reusability of our catalytic system by taking, as a model reaction,
the isomerisation of the α-vinylbenzyl alcohol (1a). We found that
catalyst 5b could be recycled up to three consecutives runs, thereby
leading to a cumulative TON value of 297. For the first two cycles
only 0.5–1.5 h were needed to achieve quantitative conversions [1st
cycle: 0.5 h (99%); 2nd cycle: 1.5 h (99%)], while 20 h were required
starting from the third cycle for quantitative conversions (99%) to
take place, probably because of the leaching of the ruthenium
catalyst during work-up (1st cycle: 872 ± 10 μg of ruthenium
leached; 2nd cycle: 197 ± 7 μg of ruthenium leached). This is the first
example reported on the study of the recyclability of a catalytic
system in the isomerisation of aromatic allylic alcohols in DESs,16f
which allows a decrease of the amount of the catalyst needed per
mole of final product.
Entry
DES/solvent
Temp
(°C)
n-BuM (Equiv.)
Yield
(%)[b]
1
2
3
4
5
6
7
8
1ChCl/2Urea
1ChCl/2EG
1ChCl/2EG
1ChCl/2EG
1ChCl/2Gly
2Fruc/3Urea
1ChCl/2Fruc
1ChCl/1Sorb
H2O[c]
1ChCl/2Urea
1ChCl/2EG
1ChCl/2Gly
2Fruc/3Urea
1ChCl/2Fruc
1ChCl/1Sorb
H2O[c]
50
50
50
50
50
75
75
75
75
50
50
50
75
75
75
75
n-BuLi (3)
n-BuLi (3)
n-BuLi (2)
n-BuLi (1)
n-BuLi (3)
n-BuLi (3)
n-BuLi (3)
n-BuLi (3)
68
97
66
25
68
69
95
80
90
87
93
85
15
50
93
37
9
n-BuLi (3)
10
11
12
13
14
15
16
n-Bu2Mg (3)
n-Bu2Mg (3)
n-Bu2Mg (3)
n-Bu2Mg (3)
n-Bu2Mg (3)
n-Bu2Mg (3)
n-Bu2Mg (3)
[a]
Reaction conditions: α-vinylbenzyl alcohol (1a, 0.5 mmol), under an Ar atmosphere
at 50–75 °C, 5 mol% Ru(IV) catalyst in 0.5 g of the desired DES. Commercially available
1.6 M solution in hexanes of n-BuLi and 1.0 M in heptane for n-Bu2Mg were added at rt
and under air. [b] Calculated by GC. [c] Isomerisation reaction was completed in 5 min in
water (2.5 mL per 1 mmol substrate) using 1 mol% in Ru.
To this end, we selected as a model reaction the isomerisation
of α-vinylbenzyl alcohol (1a) to ketone 2a, followed by the addition
of n-BuLi/n-Bu2Mg as the organometallic reagent (Table 2) in
different DESs. The mixture containing 1a and the ruthenium
catalyst 5b (5 mol% in Ru) was preliminarily warmed (50–75 °C) in
the selected DES to promote the anticipated isomerisation. Once
the conversion of 1a into propiophenone (2a) was completed (30
min, GC analysis), n-BuLi was directly added to the mixture without
isolating the intermediate ketone, and the mixture stirred for a few
seconds. Remarkably, working at room temperature (rt) and under
air (conditions traditionally prohibitive for organolithium reagents),
almost quantitative formation of the expected tertiary alcohol 3-
phenyl-heptan-3-ol (3a) was observed after a few seconds stirring in
1ChCl/2EG (97%, entry 2, Table 2) or 1ChCl/2Fruc (95%, entry 7,
Table 2). The replacement of EG or D-fructose by other H-bond
donors like urea (entry 1, Table 2), Gly (entry 5, Table 2) or D-
sorbitol (entry 8, Table 2), as well as the use of ChCl-free DESs
(entry 6, Table 2) led to lower conversions. The whole process run
in pure water provided alcohol 3a in 90% yield (entry 9, Table 2). In
all cases, the one-pot formation of 3a starting from 1a took place
chemoselectively, with no additional side products observed in the
One-pot sequential redox isomerisation of allylic alcohols (1a-f)
catalysed by complex 5b, and chemoselective addition of
RLi/R2Mg in different DESs
During the last few years, the ruthenium-catalysed redox
isomerisation of allylic alcohols in unconventional solvents (like
water, glycerol or ionic liquids) has been fruitfully coupled with a
variety of concomitant organic processes (e.g., C–C bond
formations,24 reductions25 or bio-amination26) giving rise to a new
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crude reaction mixture. It is worth noting that by progressively unreacted 2a could be quantitatively recovered. On the other hand,
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DOI: 10.1039/C7GC00458C
lowering the equivalents of n-BuLi from 3 to 1, the addition reaction while the addition of PhLi to 2a, run in pure water, again provided
of the organometallic reagent to the in situ formed ketone 2a alcohol 3d in an excellent 88% yield (entry 6, Table 3), the addition
proved to be less effective leading to a poorer recovery (from 97 to of MeLi to 2a in a 2Fruc/3Urea mixture furnished alcohol 3b in a
25% yield) of the expected tertiary alcohol 3a (entries 2–4, Table 2). yield not higher than 12% (entry 7, Table 3). This corroborates even
We next investigated the chemoselective addition of the more the crucial role played by ChCl in such nucleophilic additions if
organomagnesium reagent n-Bu2Mg to 2a at rt and under air. carried out in eutectic mixtures.
Similarly to the reactions run with organolithium reagents, the
Table 3. Direct conversion of α-vinylbenzyl alcohol (1a) into tertiary alcohols
3a–e through the one-pot combination of Ru-catalysed isomerisation and
chemoselective addition of RLi/RMgX in DESs/water.[a]
best results were obtained using the eutectic mixture
1ChCl/2EG as the reaction medium, which allowed the one-pot
formation of 3a in up to 93% yield just after a few seconds
(entry 11, Table 2). While with different ChCl-based eutectic
mixtures (1ChCl/2Urea, 1ChCl/2Gly, 1ChCl/2Fruc, and
1ChCl/1Sorb) butylated alcohol 3a could be recovered in 50–
93% yield, (entries 10,12,14,15, Table 2), total reaction yield
decreased considerably in 2Fruc/3Urea (15%) (entry 13, Table
2) and in water (37%) (entry 16, Table 2). These results are
thus consistent with our previous assumption on the dual role
played by the biorenewable ammonium salt ChCl (vitamin B4)
in the addition reactions of polarised organometallic reagents
in DESs.10a On the one side, ChCl is the H-bond acceptor
needed for the synthesis of the biorenewable and green
eutectic mixture, while on the other side this ammonium salt
permits the kinetic activation of the organomagnesium
reagent (n-Bu2Mg) through the in situ formation of an halide
enriched magnesiate (R2MgCl-) as a highly nucleophilic reagent
capable to undergoing a very fast addition.[28,29] To support
this hypothesis, we again performed the Ru(IV)-catalysed
isomerisation of 1a in the non-ammonium-based DES
2Fruc/3Urea. Once the isomerisation reaction was completed
(0.5 h), a stoichiometric amount of a quaternary ammonium
salt [ChCl or (Me)4NCl] was added to the resulting reaction
mixture, followed by the alkylating reagent n-Bu2Mg at rt and
under air. In both cases, the final overall yield of 3a could be
improved from 15 to 45%. This experimental fact: (i) confirms
the role played by the quaternary ammonium salt as an
activator of n-Bu2Mg, and (ii) is consistent with previous work
published by Song and co-workers,28 who found that the
presence of (n-Bu)4NCl in THF solutions of RMgX reagents
greatly favours the addition reaction.
DES/solvent
RM[b]
Temp
(°C)
Product
Yield
(%)[c]
1
2
3
4
5
6
7
1ChCl/2EG
1ChCl/2EG
1ChCl/2EG
1ChCl/2EG
1ChCl/2EG
H2O[d]
n-BuLi
MeLi
s-BuLi
PhLi
EtMgBr
PhLi
50
50
50
50
50
75
75
3a
3b
3c
3d
3e
3d
3b
97
87
85
90
45
88
12
2Fruc/3Urea
MeLi
[a] Reaction conditions: α-vinylbenzyl alcohol (1a, 0.5 mmol), under an Ar atmosphere at
[b]
50–75 °C, 5 mol% Ru(IV) catalyst in 0.5 g of the desired DES for 30 min. 3 equiv. of
commercially available 1.6 M solution of n-BuLi in hexanes, 1.6 M solution of MeLi in
Et2O, 1.8 M solution of PhLi in dibutyl ether, 1.4 M solution of s-BuLi in cyclohexanes
[c]
[d]
and 1.0 of EtMgBr in THF were added at rt and under air.
Calculated by GC.
Isomerisation reaction was completed in 5 min in water (2.5 mL per 1 mmol substrate)
using 1 mol% in Ru.
To expand further the scope of this new one-pot strategy
in terms of the nature of the substrate, we finally studied the
metal-catalysed isomerisation/addition of a series of allylic
alcohols (1a
different biorenewable eutectic mixtures: 1ChCl/2EG and
1ChCl/1Sorb. Pleasingly, both arylic (1a ) and aliphatic (1f
allylic alcohols could be converted into the corresponding
butylated (3a,f ) or methylated (3j) tertiary alcohols in very
–f, Table 4) promoted by n-BuLi or n-Bu2Mg in two
–
e
)
–i
good yields (up to 99%, Table 4) under mild reaction conditions
and without any additional step of purification or isolation of
transiently formed ketones 2a–f, an important point for the
development of greener synthetic protocols. Intriguingly, for
each substrate, the best yields corresponded to the higher
polarised organometallic reagent (n-BuLi) in 1ChCl/2EG as the
eutectic mixture, whereas the opposite was true in
1ChCl/1Sorb. In the presence of an ortho-substituent (1b),
longer reaction times (up to 4 h) were required to achieve
satisfactory yields of the final isomerised product (3f) (entries
5–8, Table 4). As for the electronic properties of the aromatic
substituent, while the presence of a para-methyl group still
allowed the formation of 3g in a high yield after only 45 min
(entries 9–12, Table 4), a para-bromo substituent (like in the
derivative 1d) increased the reaction time to up to 3 h for the
formation of 3h (entries 13–16, Table 4). The presence of
strong electron-withdrawing groups (NO2, CO2Me or CN) in the
para-position of the aromatic ring of allylic alcohol, however,
completely hampered the isomerisation process. Most
probably the lower coordination ability of the resulting
Having identified the best eutectic mixture 1ChCl/2EG for the
one-pot conversion of 1a into 3a, we next extended our studies to
other organolithium and organomagnesium reagents to probe the
scope of this transformation. As can be seen from the results
reported in Table 3, similarly to n-BuLi (entry 1, Table 3), both
aliphatic (MeLi, s-BuLi) and aromatic (PhLi) organolithium reagents
provided the expected, saturated tertiary alcohols 3b–d in excellent
yields and chemoselectivities (85–90%; entries 2–4, Table 3) at rt
and under air with no other by-products detected, the remaining
being starting ketone 2a only. As for the less reactive Grignard
reagents, EtMgBr exhibited a somewhat reduced reactivity in the
1ChCl/2EG eutectic mixture generating alcohol 3e in only 45% yield
under the above conditions (entry 5, Table 3). We have also
investigated the addition reactions to in-situ formed
propiophenone (2a) of: (i) other Grignard reagents with functional
groups (e.g., the Knochel-type reagent i-PrMgCl·LiCl), and (ii)
weaker nucleophiles [e.g., (CH3)2Zn]. In both cases, however, only
4 | J. Name., 2012, 00, 1-3
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electron-deficient olefins may prevent their binding to the thereby providing the butylated alcohol 3i in yields to up to
View Article Online
DOI: 10.1039/C7GC00458C
metal, thereby reducing the overall reactivity of the substrate. 90% after 3 h reaction time (entries 17–20, Table 4). Finally,
This result is consistent with previous studies.25a,b Interestingly, aliphatic allylic alcohol 1f furnished the saturated methylated
no competing processes such as benzylic metalation and Li-Br alcohol 3j in up to 87% yield, and in very short reaction times
exchange could be observed for 1c and 1d, respectively. The (10 min) (entries 21–22, Table 4).
naphthalene-based allylic alcohol 1e also reacted smoothly,
Table 4. Ru(IV)-catalysed allylic alcohol (1a–f) isomerisation combined with the chemoselective addition of organolithium/organomagnesium reagents in a
one-pot process in DESs as green solvents.[a]
Entry Substrate
R5-M[b]
Product
DES[a]
Temp (°C)
Time
Yield (%)[c]
1
2
3
4
n-BuLi
n-Bu2Mg
n-BuLi
1ChCl/2EG
1ChCl/2EG
1ChCl/1Sorb
1ChCl/1Sorb
50
50
75
75
0.5 h
0.5 h
0.5 h
0.5 h
97%
93%
80%
93%
n-Bu2Mg
5
6
7
8
n-BuLi
n-Bu2Mg
n-BuLi
1ChCl/2EG
1ChCl/2EG
1ChCl/1Sorb
1ChCl/1Sorb
50
50
75
75
4 h
4 h
4 h
4 h
90%
74%
46%
75%
n-Bu2Mg
9
n-BuLi
n-Bu2Mg
n-BuLi
1ChCl/2EG
1ChCl/2EG
1ChCl/1Sorb
1ChCl/1Sorb
50
50
75
75
45 min
45 min
45 min
45 min
99%
86%
45%
75%
10
11
12
n-Bu2Mg
13
14
15
16
n-BuLi
n-Bu2Mg
n-BuLi
1ChCl/2EG
1ChCl/2EG
1ChCl/1Sorb
1ChCl/1Sorb
50
50
75
75
3 h
3 h
3 h
3 h
96%
86%
72%
90%
n-Bu2Mg
17
18
19
20
n-BuLi
n-Bu2Mg
n-BuLi
1ChCl/2EG
1ChCl/2EG
1ChCl/1Sorb
1ChCl/1Sorb
50
50
75
75
3 h
3 h
3 h
3 h
75%
68%
72%
90%
n-Bu2Mg
21
22
MeLi
MeLi
1ChCl/2EG
1ChCl/1Sorb
50
75
10 min
10 min
66%
87%
[a] Reaction conditions: allylic alcohol (1a-f, 0.5 mmol) under an Ar atmosphere at 50–75 °C, 5 mol% Ru(IV) catalyst, in 0.5 g of the desired DES. [b] 3 equiv. of commercially available
1.6 M solution in hexanes of n-BuLi and 1.0 M in heptane for n-Bu2Mg were added at rt and under air. [c] Calculated by GC.
Remarkably, the overall transformation, which formally involves
three consecutive different steps such as (i) reduction of a C–C
double bond, (ii) oxidation of a secondary carbinol moiety, and (iii) a
Conclusions
chemoselective C–C bond formation, is carried out under mild
reaction conditions, allows the addition of Grignard and
organolithium reagents at rt and in the presence of air to the
transiently formed ketones, and takes place with no concomitant
reduction or enolisation processes. It is worth noting that the
above-described one-pot tandem process takes place starting from
allylic alcohols completely soluble in DES mixtures (as, similarly, are
the corresponding in situ formed ketones) and is particularly
In summary, we report an unprecedented, greener, efficient
and operationally simple one-pot protocol for the synthesis of
tertiary alcohols in high yields (up to 99%) successfully combining a
quantitative ruthenium-catalysed isomerisation of a variety of allylic
alcohols into the corresponding carbonyl compounds with
a
chemoselective nucleophilic addition promoted by polarised
organometallic reagents (RLi/R2Mg) and using biorenewable
eutectic mixtures as environmentally friendly reaction media.
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
favoured in terms of reaction yield in ChCl-based eutectic mixtures
with respect to non-ionic DESs. This is consistent with the
hypothesis about a possible kinetic activation such alkylating
reagents (RLi/R2Mg) may undergo in the presence of quaternary
ammonium salts to form highly nucleophilic halide enriched
magnesiate or lithiate “ate” complexes capable to promote the
addition reaction to carbonyl compounds in very short reaction
times (a few seconds), as in this case.10a Strong intermolecular
hydrogen bonds, which are typical of both DESs and water, may be
playing an important role as well in shielding the organometallic
reagent from competitive protonolysis processes.30
Acknowledgements
View Article Online
DOI: 10.1039/C7GC00458C
We are indebted to the MINECO of Spain (CTQ2013-40591-P,
CTQ2014-51912-REDC and CTQ2016-75986-P) and the
Gobierno del Principado de Asturias (Project GRUPIN14-006)
for financial support. J.G.-A. thanks the MINECO and the
European Social Fund for the award of a “Ramón y Cajal”
contract. L. C., F. M. P. and V. C. would like to thank the
Interuniversities Consortium C.I.N.M.P.I.S. for partially
supporting this work.
We would also like to thank Dr. Pablo Rodríguez-González and
Prof. J. Ignacio García-Alonso (Research Group on Enriched
Stable Isotopes, Department of Physical and Analytical
Chemistry, University of Oviedo) for their help and support
with the inductively coupled plasma-mass spectrometry (ICP-
MS) analysis.
These results demonstrate that environmentally friendly DESs
can be the reaction media of choice for the efficient assembly of
metal-catalysed and organometallic reactions in one-pot processes,
and have implications in the future developments of new intriguing
catalytic tandem reactions in a highly atom-economy fashion, which
are known to be still affected by the formation of several by-
products. Since this tandem reaction proceeds under green and
mild reaction conditions, the practical application of this
methodology provides a new eco-friendly synthetic tool for the
synthesis of densely functionalised tertiary alcohols.
Notes and references
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Experimental
Preparation of 3-phenyl-heptan-3-ol (3a) in Deep Eutectic
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organic phases were dried over anhydrous MgSO4, and the solvent
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chromatography to give 3a in 90% yield.
4
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6
General procedure for the catalyst recycling. The recyclability of
complex 5b was investigated using the isomerisation of -
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into
a sealed tube under an Ar atmosphere. The acetate
ruthenium(IV) complex [Ru(3:3-C10H16)Cl(2-O,O-CH3CO2)] (5
mol%, 5b) was then added at rt under Ar. The reaction mixture was
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spectrometry (ICP-MS) analysis.
7
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30 It is worth mentioning that working at rt and under air but
under heterogeneous conditions (that is with starting material
insoluble in the reaction medium), Grignard and organolithium
reagents have been proven to smoothly undergo nucleophilic
addition to ketones “on water”, thereby giving the expected
adducts in very good yields and competitively with protonolysis;
see ref. 10d.
8 | J. Name., 2012, 00, 1-3
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Green Chemistry
View Article Online
DOI: 10.1039/C7GC00458C
Text for Graphical Abstract
Transition-metal complexes and polarised organometallic reagents play together
in solvents: An environmentally friendly one-pot protocol for the synthesis of tertiary
alcohols in Deep Eutectic Solvents is reported, establishing a bridge between
transition metal-catalysed and main-group mediated organic reactions in solvents.