Combination of organocatalytic oxidation of alcohols and organolithium chemistry (RLi) in aqueous media, at room temperature and under aerobic conditions

Article abstract of DOI:10.1039/d0cc03768k

A tandem protocol to access tertiary alcohols has been developed which combines the organocatalytic oxidation of secondary alcohols to ketones followed by their chemoselective addition by several RLi reagents. Reactions take place at room temperature, under air and in aqueous solutions, a trio of conditions that are typically forbidden in polar organometallic chemistry.

Full text of DOI:10.1039/d0cc03768k

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Álvarez, Chem. Commun., 2020, DOI: 10.1039/D0CC03768K.
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DOI: 10.1039/D0CC03768K
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Combination of Organocatalytic Oxidation of Alcohols and
Organolithium Chemistry (RLi) in Aqueous Media, at Room
Temperature and Under Aerobic Conditions
.Received 00th January 20xx,
Accepted 00th January 20xx
David Elorriaga,a,† María Jesús Rodríguez-Álvarez,a,† Nicolás Ríos-Lombardía,b Francisco Morís,b
Alejandro Presa Soto,a Javier González-Sabín,*,b Eva Hevia, *,c and Joaquín García-Álvarez.*,a
DOI: 10.1039/x0xx00000x
A tandem protocol to access tertiary alcohols has been developed just a few years ago, an aerobic sustainable polar organometallic
which combines the organocatalytic oxidation of secondary chemistry, is now starting to look distinctly possible.6,8 Thus,
alcohols to ketones followed by their chemoselective addition by Capriati has reported the chemoselective addition of
several RLi reagents. Reactions take place at room temperature, organolithiums to carbonyl compounds8d and to nitriles and
under air and in aqueous solutions, a trio of conditions that are imines8h under on water conditions as well as palladium catalyzed
typically forbidden in polar organometallic chemistry.
direct cross-couplings of RLi and hetero(aryl) halides.8i Furthermore
bioinspired Deep Eutectic Solvents (DESs) which are usually made
up of a combination of biorenewable hydrogen bond acceptors
[e.g., ammonium salts like choline chloride (ChCl)] and hydrogen
bond donor (e.g., water, glycerol)9 have also shown great promise
as non-conventional media for air and moisture compatible
organolithium synthesis as demonstrated recently by our groups for
nucleophilic arylation/alkylation of ketones, imines and nitriles10 as
well as anionic polymerization of styrenes.11,12 Remarkable, in some
of these examples, higher yields and selectivities were achieved
than when using inert atmosphere protocols. Expanding even
further the synthetic applications of polar organometallic chemistry
in water, herein we report a new protocol that pairs these
operational breakthroughs with an organocatalytic transformation,
uncovering a novel one-pot tandem approach to access highly-
substituted tertiary alcohols.
By eliminating the need of isolation and purification of reaction
intermediates (and subsequently minimizing chemical waste
generation, reaction times and energy consumption), one-pot
tandem processes are highly useful and efficient green approaches
in modern synthesis for the production of organic molecules.13
More often than not, these protocols tend to use the same type of
transformational tools (metal-, main-group element-, bio- or
organo-catalysts) throughout all the tandem process, whereas the
number of examples which combine different methodologies is
scarce, especially those that also employ sustainable solvents. In
this regard recently we have successfully combined transition-
metal-catalysis in water or DESs with (Scheme 1a): i)
chemoselective addition of organolithium reagents (RLi) to ketones
as transient intermediates;14 and ii) enzymatic enantioselective
As Nature’s solvent in biological processes, the use of water as a
medium in organic synthesis1 is widely recognized as an important
strategy towards developing sustainable chemical processes that
implement some of the most significant Principles of Green
Chemistry2. Water is abundant, non-toxic, cost-effective, non-
flammable, renewable, and non-volatile3 and it has already shown
an enormous potential as a versatile reaction medium in many
cornerstone organic transformations such as oxidations, reductions,
reductive aminations, pericyclic reactions to name just a few,1 as
well as in
a
myriad of transition-metal-catalyzed reactions.4
Furthermore, in many cases water is not only a greener alternative
to toxic organic solvents but can also be a superior medium,
improving reactivities and selectivities, simplifying work up
procedures and facilitating catalyst recycling.5 Nevertheless, despite
these key advantages, until recently, water has shown very little
promise as a solvent to carry out organolithium chemistry with only
a few examples in the literature.6 This is probably as a consequence
of the common assumption that these polar reagents rapidly
decompose in contact with this solvent. In fact, the use of
protective inert atmosphere conditions and stringently dry organic
solvent along with strict control of the reaction temperatures
o
(usually of the order of -78 C) are usually mandatory to avoid fast
degradation and control the exceptionally high reactivity of
organolithium reagents.7 However, what was thought impossible
a. Departamento de Química Orgánica e Inorgánica, (IUQOEM) Facultad de
Química, Universidad de Oviedo, E-33071, Oviedo, Spain..
b. EntreChem SL. Santo Domingo de Guzmán, 33011, Oviedo, Spain.
c. Department für Chemie und Biochemie, Universität Bern, CH3012, Bern,
Switzerland
bioamination
(transaminases,
ATA)
or
bioreduction
(ketoreductases, KRED) of in-situ generated prochiral ketones.15
Breaking new ground in this evolving field, we combine for the first
time organocatalysis and organolithium chemistry in water as a new
† These authors contributed equally to the work.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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methodology to prepare highly substituted tertiary alcohols. The observed (4-42% yields), highlighting the high effiVciieewnAcryticloefOntlhinee
approach employed comprises the organo-catalyzed oxidation of organocatalytic/oxidation NaClO/AZADO syDstOeIm: 10w.1h0i3le9/oDp0eCrCa0ti3n7g68iKn
secondary alcohols (furnishing ketones in-situ as intermediates) aqueous media.
followed by subsequent chemoselective and ultrafast addition of
Encouraged by these initial results, which show that we can
organolithium reagents affording the relevant tertiary alcohols. quantitatively prepare ketones from secondary alcohols in aqueous
Reactions were carried out under one-pot conditions in aqueous media at room temperature and in the absence of any organic co-
media, under air and at room temperature (Scheme 1b).
solvents, we next pondered if this transformation could also be part
of a modular combination, where the relevant synthesized ketones
could subsequently undergo chemoselective alkylation using a one-
pot approach while operating in aqueous media under air. Towards
this target, it should be noted that s-block polar organometallic
reagents such as Grignard (RMgX) and organolithium (RLi) reagents
R5-M
Previous work (Scheme 1a):
R2
R5
OH
R4
5
M
(
= Li or MgR )
R1
3 sec. / rt / under air
R3
R2 OH
R4
R3
R2
O
[Ru]
(5 mol%)
R1
R1
R4
H2O or DESs
50-75 ºC
R3
R2
XH
ATA KRED
or
*
R1
are widely used for addition reactions to ketones, being
a
R4
24 h / rt / under air
R3
X = NH or O
fundamental and versatile method to generate C-C bonds to access
tertiary alcohols.17 Notwithstanding, the chemoselectivity of these
processes can be compromised by the formation of undesired
reduction and/or enolization products, resulting from competing -
hydride elimination and deprotonation reactions respectively.18
Recently our groups have shown using DESs which combine
ammonium salt choline chloride (ChCl) with water or glycerol (Gly)
as reaction media, Grignard and organolithium reagents can
This work (Scheme 1b):
(1 mol%)
R3-Li
AZADO
OH
R3
R2
OH
R2
O
N
R1
R1
R1
R2
NaClO / NaHCO3
H2O / rt / 1 h
3 s / rt
under air
O
AZADO
Scheme 1. Design of one-pot tandem combinations that rely on different organic
synthetic tools (transition metals, s-block reagents or organocatalysts) in water or DESs.
Building on previous studies reported by some of us, in which
we have uncovered the efficient organocatalytic activity of AZADO
(2-azaadamantane N-oxyl, 1a) in combination with an aqueous
promote
room
temperature
chemoselective
ketone
alkylation/arylation reactions.10 Along with greater selectivities and
milder reaction conditions, these reactions are compatible with the
presence of air.10 However, DESs are not compatible with the
organocatalytic oxidation system AZADO/NaClO, as the addition of
NaClO to the eutectic reaction media produced the formation of Cl2
gas through the expected comproportionation reaction between
the Cl- and ClO- anions.
solution of NaClO (2a, acting as external oxidant) as
a
straightforward and operationally simple method for the selective
oxidation of secondary alcohols;16 we selected, as a model reaction,
the oxidation of the benzylic-type alcohol 3a (see Table 1). Firstly,
we assessed if the use of toxic organic co-solvents such as PhCF3,
CH2Cl2 or CH3CN was actually required in order to achieve
quantitative yields of the desired ketone 4a (entries 1-3, Table 1).16
We next assessed whether this tandem oxidation/alkylation
approach could be compatible with aqueous media. Thus, we
selected as a model reaction the AZADO/NaClO organocatalyzed
oxidation of 1-phenylpropan-1-ol (3a) into ketone 4a followed by
the direct addition of n-BuLi (Table 2). Firstly, the reaction mixture
containing the alcohol 3a (270 mM) and the organocatalytic
oxidation system (AZADO/NaClO) was allowed to react in aqueous
media, at room temperature and in the presence of air for 1 h to
trigger the expected oxidation. As soon as the total conversion of 3a
into propiophenone (4a) was observed (1 h, GC analysis), n-BuLi
was directly added to the reaction mixture (without any
intermediate step of isolation or purification of ketone 4a), in the
absence of protecting atmosphere and at room temperature
(conditions usually forbidden for RLi reagents).17 Astonishing, the
almost instantaneous formation (3 s) of the relevant tertiary alcohol
5a was observed, finding a significantly improved yield of 76% when
three equivalents of the organolithium reagent were employed
(entry 4, Table 2).19 However, gradually decreasing the number of
equivalents of n-BuLi (from 3 to 1) produces a concomitant
diminution of the nucleophilic addition of n-BuLi into the in-situ
formed ketone 4a, from 76 to 23% yield of the final tertiary alcohol
5a (entries 1-4, Table 2). At this point, it is important to note that in
all cases (entries 1-4, Table 2) the one-pot tandem construction of
the tertiary alcohol 5a occurred with total chemoselectivity, as no
side products were observed in the crude reaction mixture
(containing only the desired final product 5a and the unreacted
ketone 4a). We next decided to expand the scope to other
organolithium (RLi) or organomagnesium (RMgX) reagents.
Table 1. Oxidation of 1-phenylpropan-1-ol (3a) into propiophenone (4a)
organocatalyzed by AZADO (1a) or minoxidil (1b) in combination with different external
oxidants (2a-c) in aqueous media, at room temperature and under air.a
OH
O
1a-b
2a-c
(1.2 eq.)
(1 mol%) /
H2O / co-solvent / rt / 1 h
3a
4a
)
(
)
(
entry
Organocat.
AZADO (1a)
AZADO (1a)
AZADO (1a)
AZADO (1a)
AZADO (1a)
AZADO (1a)
Minoxidil (1b)
Minoxidil (1b)
Minoxidil (1b)
Oxidant
aq. NaClO b (2a)
aq. NaClO b (2a)
aq. NaClO b (2a)
aq. NaClO b (2a)
KMnO4 (2b)
I2 (2c)
Co-solventc
PhCF3
CH2Cl2
CH3CN
Yield (%)d
95%
99%
99%
99%
69%
13%
17%
42%
4%
1
2
3
4
5
6
7
8
9
-
-
-
-
-
-
aq. NaClO b (2a)
KMnO4 (2b)
I2 (2c)
a
General Conditions: Reactions performed under air, at rt using 1 mmol of the
b
alcohol 3a (270 mM). 0.40 M aqueous solution of NaClO (pH 7.9, 3.7 mL) was
used. c 219 μL of the organic co-solvent were employed. d Isolated yields
Pleasingly, we found that 1-phenylpropan-1-ol (3a) can be
quantitatively converted into the desired propiophenone (4a, entry
4, Table 1) under the same reaction conditions (1 h, rt, 270 mM
loading of substrate) in the absence of these toxic organic co-
solvents. For completeness of this parametrization, we also studied
the use of other co-oxidants for AZADO (1a) like KMnO4 (2b, entry
5, Table 1) or I2 (2c, entry 6, Table 1) finding in both cases reduced
activity (69-13%). Interestingly, we found that when AZADO was
replaced by a different amine N-oxide such as minoxidil (1b, 6-
piperidin-1-ylpyrimidine-2,4-diamine 3-oxide) in combination with
the aforementioned sacrificial oxidants (NaClO, entry 7; KMnO4,
entry 8; and I2, entry 9; Table 1) significant lower conversions were
2 | J. Name., 2012, 00, 1-3
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Table 2. Direct conversion of 1-phenylpropan-1-ol (3a) into tertiary alcohols 5a-d
through the one-pot combination of the organocatalyzed (AZADO/NaClO) oxidation of
alcohols and the chemoselective addition of RLi/RMgX in aqueous media, at room
temperature and in the presence of air.a
the same conditions depicted in Table 2, the alkylation reaction is
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suppressed. Whereas, with propiophenonDeO(I4: 1a0),.10a3lc9o/Dh0oCl C50a37w68aKs
obtained in a 76%. A plausible explanation could be the different
solubilities in water of both ketones, with acetophenone showing a
greater solubility in water than 4a, again in agreement with the
possibility that these addition reactions are taking place under “on
water” conditions.21 “On water” reactions are thought to occur at
the organic/liquid water interface with water insoluble reactants. In
this regard Capriati et al. have recently postulated that interfacial H-
bonding to water insoluble carbonyl compounds embedded at the
organic/water interphase may play a key role in favouring “on-
water” nucleophilic additions promoted by RMgX and RLi
reagents.8d,8h Once the scope of the s-block highly-polar
organometallic reagents was established, we decided to further
expand this one-pot tandem oxidation/RLi addition in aqueous
media to a series of secondary alcohols (3a-f, Table 3) and n-BuLi or
sec-BuLi as alkylating reagents.
Azado (1 mol%)
NaClO (1.2 eq.)
R-M
(VOC solution)
OH
O
OH
M
(
= Li or MgX)
H2O / rt / 1 h
H2O / rt / 3 s
R
3a
(
)
4a
5a-d
( )
(
)
entry
R-Mb
n-BuLi
n-BuLi
n-BuLi
n-BuLi
MeLi
sec-BuLi
PhLi
n-BuMgCl
Equivalents
Product
5a
5a
5a
5a
5b
5c
5d
5a
Yield (%)c
23%
47%
62%
76%
70%
83%
35%
-
1
2
3
4
5
6
7
8
1
2
2.5
3
3
3
3
3
a
General Conditions: Reactions performed under air, at rt using 1 mmol of the
alcohol 3a (270 mM). 0.40 M aqueous solution of NaClO (pH 7.9, 3.7 mL) was
b
used. Commercially available 1.6 M solution of n-BuLi in hexanes, 1.6 M
solution of MeLi in Et2O, 1.4 M solution of sec-BuLi in cyclohexane, 1.8 M
solution of PhLi in dibutyl ether and 2.0 M solution of n-BuMgCl in Et2O were
directly added at rt and under air. c Isolated yields
Table 3. AZADO/NaClO organocatalyzed oxidation of secondary alcohols (3a-f)
combined with the chemoselective addition of organolithium reagents in a one-pot
process, at room temperature, in the presence of air and in aqueous media.a
Interestingly we found that other aliphatic organolithium
reagents such as MeLi (entry 5, Table 2); sec-BuLi (entry 6, Table 2)
can selectively add across the C=O double bond of 4a under the
above mentioned conditions, affording alcohols 5b and 5c in
excellent yields (70 and 83% respectively) whereas using less
nucleophilic PhLi, 5d is obtained in a 35% yield (entry 6, Table 2).
The high conversions and chemoselectivities observed while
operating at room temperature are particularly noteworthy for sec-
R2-Li
Azado (1 mol%)
NaClO (1.2 eq.)
OH
OH
O
(VOC solution)
R2
H2O / rt / 1 h
R1
R1
R1
H2O / rt / 3 s
3a-f
(
)
4a-f
(
5a,c,e-n
( )
)
entry
1
2
3
4
5
6
7
8
R1
H (3a)
H (3a)
R2-Mb
n-BuLi
sec-BuLi
n-BuLi
sec-BuLi
n-BuLi
sec-BuLi
n-BuLi
sec-BuLi
n-BuLi
sec-BuLi
n-BuLi
Product
5a
5c
5e
5f
5g
5h
5i
5j
5k
Yield (%)c
76%
83%
82%
54%
95%
73%
90%
66%
40%
74%
68%
39%
p-Cl (3b)
p-Cl (3b)
p-Br (3c)
p-Br (3c)
p-Me (3d)
p-Me (3d)
p-MeO (3e)
p-MeO (3e)
o-Me (3f)
o-Me (3f)
BuLi which has
a greater tendency to undergo -hydride
elimination, and has to be usually stored at low temperatures (2-8
oC) to avoid degradation via this side reaction. Furthermore,
Ishihara has shown that when n-BuLi is employed as an alkylating
reagent towards enolizable ketones variable amounts of the aldol
condensation products are obtained even when operating at -78 oC
in THF under strict inert atmosphere conditions.18b On the other
hand, this method does not seem compatible with Grignard
reagents and when n-BuMgCl was employed as an alkylating
reagent, alcohol 5a could not be detected (entry 8, Table 2). This
lack of reactivity is consistent with previous studies in the addition
of Grignard reagents to carbonyl compounds in water that have
shown that n-BuMgCl undergoes complete protonation in
competition with carbonyl addition.20 At this point we would like to
highlight the use of commercially available solutions of RMgX and
RLi reagents containing different organic solvents, namely hexane
for n-Buli, diethyl ether for MeLi, and dibutyl ether for PhLi. We
hypothesize that besides the intrinsic reactivity of each reagent,
both the nature and the amount of the organic accompanying
solvent is critical for the outcome of the addition reaction, based on
the premise that the reactions are taking place under “on water”
conditions.21 Accordingly, the more water-immiscible the RLi
solvent and the smaller concentration of the commercially available
organolithium solution, the more favoured that interface and
therefore the better performance. In good agreement, the highest
yield was obtained in cyclohexane (sec-BuLi, entry 6), the most
hydrophobic solvent of the series and with the smaller
concentration (1.4 M), followed by hexane (n-BuLi, 1.6 M, entry 4)
and finally the ether solvent (entries 5 and 7). In the same line,
another interesting finding was that when acetophenone was
reacted with n-BuLi using water as a reaction medium under exactly
9
10
11
12
5l
5m
5n
sec-BuLi
a
General Conditions: Reactions performed under air, at rt using 1 mmol of the
desired alcohol 3a-f (270 mM). 0.40 M aqueous solution of NaClO (pH 7.9, 3.7 mL)
b
was used. Commercially available 1.6 M solution of n-BuLi in hexanes and 1.4 M
solution of sec-BuLi in cyclohexane were directly added at rt and under air. c Isolated
yields
We found that this method tolerates a variety of functional
groups in the aromatic scaffold of the starting alcohols 3a-f being
compatible with the presence of either electron-withdrawing (3b-c,
entries 3-6) or electron-donating groups (3d-f, entries 7-12) giving
rise to the desired tertiary alcohols 5a,c,e-n in good yields (up to
95%), and without the need of any halfway step of isolation or
purification of the intermediate ketones 4a-f, which were always
formed in quantitative yields after 1 h of reaction (GC analysis). In
general, better yields of the final tertiary alcohols were obtained
when n-BuLi (even entries in Table 3) was used as alkylating
reagent. This experimental observation is in good agreement with
the expected lower nucleophilic activity of the more sterically
demanding sec-BuLi when compared with linear n-BuLi.17 At this
point, it is important to note that although electronic properties of
the substituents in the aromatic ring have only a modest effect, the
presence of an ortho-substituent (entries 11-12, Table 3) produces a
considerable decrease in the yield of the final alcohols 5m-n. This
experimental observation seems to indicate that the electronic
effects have a smaller impact than steric hindrance which can be
associated to the virtually instantaneous nature of the addition
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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van den Bruinhorst and M. C. Kroon, Angew. Chem. Int. Ed.,
2013, 52, 3074; (c) E. L. Smith, A. P. Abbott anVdieKw.ASrt.iclReyOdnelinre,
Chem. Rev., 2014, 114, 11060; (d) D. DAO. IA: 1lo0n.1s0o39, /AD.0BCaCe0z3a76, 8RK.
Chinchilla, G. Guillena, I. M. Pastor and D. J. Ramón, Eur. J.
Org. Chem., 2016, 612; (e) F. M. Perna, P. Vitale and V.
Capriati, Curr. Opin. Green Sustainable Chem., 2020, 21, 27.
10 (a) C. Vidal, J. García-Álvarez, A. Hernán-Gómez, A. R.
Kennedy and E. Hevia, Angew. Chem. Int. Ed., 2014, 53,
5969; (b) C. Vidal, J. García-Álvarez, A. Hernán-Gómez, A. R.
Kennedy and E. Hevia, Angew. Chem. Int. Ed., 2016, 55,
16145; (c) M. J. Rodríguez-Álvarez, J. García-Álvarez, M.
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reactions in aqueous media. Interestingly, other possible competing
processes with the addition reaction or RLi to ketones like: i)
metalation of benzylic position in substrates 3d-f; or ii) Li-halogen
exchange processes in alcohols 3b-c, were not detected.
In conclusion, edging closer towards the development of air
and water compatible organolithium chemistry, these findings
have uncovered the potential of using water as an alternative
sustainable reaction medium for tandem protocols that
combine organocatalysis with the use of organolithium
reagents. Interestingly water not only enables more
environmentally benign reaction conditions (under air, room
temperature) but also greater selectivities than when using
conventional organic solvents under inert atmosphere
conditions.
11 A. Sánchez-Condado, G. A. Carriedo, A. Presa Soto, M. J.
Rodríguez-Álvarez, J. García-Álvarez and E. Hevia,
ChemSusChem, 2019, 12, 3134.
12 For other recent examples in the use of DES in the field of s-
block chemistry, see: (a) V. Mallardo, R. Rizzi, F. C. Sassone,
R. Mansueto, F. M. Perna, A. Salomone and V. Capriati,
Chem. Commun., 2014, 50, 8655; (b) F. C. Sassone, F. M.
Perna, A. Salomone, S. Florio and V. Capriati, Chem.
Commun., 2015, 51, 9459; (c) C. Prandi, S. Ghinato, G.
Dilauro, F. M. Perna, V. Capriati and M. Blangetti, Chem.
Commun., 2019, 55, 7741
We thank the MINECO (projects CTQ2017-88357-P, CTQ2016-
81797-REDC and CTQ2016-75986-P). J.G.-A. thanks PhosAgro,
UNESCO and IUPAC for the award of a “Green Chemistry for Life
Grant”. EH thanks the University of Bern for the generous
sponsorship of this research. D.E. thanks Gobierno del Principado
de Asturias and EU for the award of a postdoctoral fellowship.
13 Y. Hayashi, Chem. Sci., 2016, 7, 866.
Conflicts of interest
“There are no conflicts to declare”.
14 L. Cicco, M. J. Rodríguez-Álvarez, F. M. Perna, J. García-
Álvarez and V. Capriati, Green Chem., 2017, 19, 3069.
15 (a) N. Ríos-Lombardía, C. Vidal, M. Cocina, F. Morís, J. García-
Álvarez and J. González-Sabín, Chem. Commun., 2015, 51,
10937; (b) N. Ríos-Lombardía, C. Vidal, E. Liardo, F. Morís, J.
García-Álvarez and J. González-Sabín, Angew. Chem. Int. Ed.,
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Notes and references
Keywords: water • organolithium • alcohol oxidation • tandem
protocols •sustainable chemistry • organocatalysis
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DOI: 10.1039/D0CC03768K
Text for Graphical Abstract
Organocatalysis and Highly-Polar s-block Organometallic Chemistry play
together in water, under air and at room temperature:
By combining the use of organocatalysis and organolithium reagents, a new protocol
to access tertiary alcohols is presented working under air and using water as a solvent.