Deep eutectic solvents as H2-sources for Ru(II)-catalyzed transfer hydrogenation of carbonyl compounds under mild conditions

Article abstract of DOI:10.1016/j.tet.2021.131997

The employment of easily affordable ruthenium(II)-complexes as pre-catalysts in the transfer hydrogenation of carbonyl compounds in deep eutectic media is described for the first time. The eutectic mixture tetrabutylammonium bromide/formic acid = 1/1 (TBABr/HCOOH = 1/1) acts both as reaction medium and hydrogen source. The addition of a base is required for the process to occur. An extensive optimization of the reaction conditions has been carried out, in terms of catalyst loading, type of complexes, H₂-donors, reaction temperature and time. The combination of the dimeric complex [RuCl(p-cymene)-μ-Cl]₂ (0.01–0.05 eq.) and the ligand dppf (1,1′-ferrocenediyl-bis(diphenylphosphine)ferrocene) in 1/1 molar ratio has proven to be a suitable catalytic system for the reduction of several and diverse aldehydes and ketones to their corresponding alcohols under mild conditions (40–60 °C) in air, showing from moderate to excellent tolerability towards different functional groups (halogen, cyano, nitro, phenol). The reduction of imine compounds to their corresponding amine derivatives was also studied. In addition, the comparison between the results obtained in TBABr/HCOOH and in organic solvents suggests a non-innocent effect of the DES medium during the process.

Full text of DOI:10.1016/j.tet.2021.131997

Tetrahedron 83 (2021) 131997
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Deep eutectic solvents as H2-sources for Ru(II)-catalyzed transfer
hydrogenation of carbonyl compounds under mild conditions
Marzia Cavallo a, Davide Arnodo a, Alberto Mannu a, Marco Blangetti a, Cristina Prandi a,
,
*
Walter Baratta b, Salvatore Baldino a
a Dipartimento di Chimica, via P.Giuria 7, 10125, Torino, Italy
b
ꢀ
Dipartimento DI4A, Universita degli Studi di Udine, Via Cotonificio 108, 33100, Udine, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The employment of easily affordable ruthenium(II)-complexes as pre-catalysts in the transfer hydroge-
nation of carbonyl compounds in deep eutectic media is described for the first time. The eutectic mixture
tetrabutylammonium bromide/formic acid ¼ 1/1 (TBABr/HCOOH ¼ 1/1) acts both as reaction medium
and hydrogen source. The addition of a base is required for the process to occur. An extensive optimi-
zation of the reaction conditions has been carried out, in terms of catalyst loading, type of complexes, H2-
Received 19 November 2020
Received in revised form
29 January 2021
Accepted 30 January 2021
Available online 9 February 2021
donors, reaction temperature and time. The combination of the dimeric complex [RuCl(p-cymene)-m-Cl]2
(0.01e0.05 eq.) and the ligand dppf (1,10-ferrocenediyl-bis(diphenylphosphine)ferrocene) in 1/1 molar
ratio has proven to be a suitable catalytic system for the reduction of several and diverse aldehydes and
ketones to their corresponding alcohols under mild conditions (40e60 ꢀC) in air, showing from moderate
to excellent tolerability towards different functional groups (halogen, cyano, nitro, phenol). The reduc-
tion of imine compounds to their corresponding amine derivatives was also studied. In addition, the
comparison between the results obtained in TBABr/HCOOH and in organic solvents suggests a non-
innocent effect of the DES medium during the process.
Keywords:
Deep eutectic solvents
Ruthenium
Ligands
Carbonyl compounds
Transfer hydrogenation
© 2021 Elsevier Ltd. All rights reserved.
1. Introduction
and catalytic efficiency. In particular, RuCl2(P)2(diamine) e
RuCl2(PP)(diamine) (P ¼ phosphane, PP ¼ diphosphane), developed
by Noyori’s group, are excellent catalysts for selective homoge-
neous hydrogenation of different ketone substrates [6]. Also, using
the proper combination of chiral diphosphane and diamine is
possible to perform asymmetric hydrogenation of carbonyl com-
pounds for the production of chiral alcohols with high enantio-
meric excess. Nowadays, trans-RuCl2(BINAP) (1,2-diamine) systems
under H2 pressure are employed in the industry for the asymmetric
reduction of C]O bonds [5]. Simultaneously, to avoid the risks
implied with the use of high-pressure H2, transfer hydrogenation
(TH) processes employing easily accessible small molecules as
hydrogen sources (e.g. ethanol [7], 2-propanol [8], glycerol [9,10] or
formic acid and its salt derivatives [11]) have been developed. Thus,
great efforts have been devoted to potentiate ligand and catalyst
design for accessing efficient and active Ru(II)-complexes in the TH
reaction [12]. On this regard, several protocols have been developed
for the synthesis of Ru-based catalysts [13] containing bidentate
phosphines and bidentate nitrogen ligands, bearing 2-(amino-
methyl)pyridine (ampy) and their successful application in the
selective reduction of the C]O functionality of ketones and alde-
hydes [14]. Several modifications of the ligand set around the metal
The catalytic reduction of carbonyl compounds by means of
dihydrogen (H2) [1] or H2-donors is a fundamental reaction for the
preparation of alcohols [2e4]. Therefore, the preparation of cata-
lysts for the selective reduction of C]O bonds is a topic of relevant
interest both for the academic research and application in industry.
A deep insight into the literature shows how the fine tuning of the
ligands around the metal center allows the carbonyl group to be
hydrogenated chemo- and stereoselectively. Among the large
number of known catalysts, complexes bearing metal centers
belonging to the Platinum group have emerged during the last
decades. Starting from the end of the 90s, great deal of attention has
been devoted to Ru(II)-complexes, as its oxidation state can be
easily stabilized by various ligands (e.g. phosphanes, amines),
providing in the end highly robust and active catalytic species [5].
Moreover, compared with other so-called high-precious transition
metals, ruthenium represents the best compromise between cost
* Corresponding author.
E-mail address: salvatore.baldino@unito.it (S. Baldino).
https://doi.org/10.1016/j.tet.2021.131997
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

M. Cavallo, D. Arnodo, A. Mannu et al.
Tetrahedron 83 (2021) 131997
center, by altering the ampy scaffold [15e18] and the introduction
of the CO molecule on the ruthenium atom [19e21], accomplished
by some of the authors have led to the obtainment of even more
efficient complexes for the TH of carbonyl compounds. Moreover,
when a chiral diphosphine is employed, these complexes are also
able to catalyze the asymmetric reduction of carbonyl compounds
to secondary alcohols with high optical purity [22,23]. Recently, Ru-
phosphine complexes bearing the framework of 4-substituted-2-
(aminomethyl)benzo[h]quinoline have been developed by Fac-
chetti et al. [14], showing high activity in the TH of commercial-
grade aldehydes, the TH being promoted by different H2-sources,
such as 2-propanol [24], formic acid/triethylamine mixtures, so-
dium formate and ammonium formate [25]. Remarkably, low
catalyst loadings down to 0.001 mol% were reached, employing
substrates and solvents not previously pre-treated or distilled [26].
TH of carbonyl compounds are usually carried out in Volatile
Organic Compounds (VOCs), which present serious environmental
issues. Several attempts to replace expensive and toxic media in
catalytic processes have been made, for instance using biomass
decomposition derivatives (e.g. 2-methyltetrahydrofuran, cyrene),
supercritical carbon dioxide, perfluorinated solvents and Ionic
Liquids (ILs) [27]. In this scenario, Deep Eutectic Solvents (DESs)
have arisen as a feasible alternative to VOCs since 2003 [28]. DESs
are usually composed by a hydrogen bond acceptor (HBA), typically
an ionic compound (i.e. inorganic or organic salt) and one or more
hydrogen bond donors (HBDs), e.g. polyols, carboxylic acids or
amine derivatives, combined in a specific molar ratio. These mix-
tures show a dramatically lower melting point with respect to its
single constituents. This is likely due to the peculiar structural as-
sociation of the components through a thick network of hydrogen
bonds. DESs possess a large number of distinctive and useful
properties, e.g. nearly no vapor pressure, nonflammability, immis-
cibility with many organic solvents and, in most cases, they are
often liquid at room temperature. In addition, compared to ILs and
most VOCs, DESs are less expensive, moisture sensitive and toxic,
thus showing a higher degree of environmental benignity [29]. For
these reasons, they have extensively been used as reaction media
for several organic transformations, namely alkylation, condensa-
tion and multicomponent [30], organometallic reactions [31e33],
carbon-carbon bond formation [34] and bio-catalyzed processes
[35]. In some cases, DES components have also shown to react with
other molecules present in the environment, thus proving their
versatility both as reaction media and reagents [30].
synthesis [45,46] and applications [32e34], we envisaged the
possibility to investigate the Ru(II)-catalyzed TH of commercial-
grade carbonyl compounds to their corresponding alcohols in
DESs which could behave both as reaction media and H2-donors
(Scheme 1).
2. Results and discussion
Combinations of easily accessible Ru(II)-complexes and ligands
were screened in order to explore the catalytic performances in the
selected DES. All the DESs employed in this study have been chosen
among those in which at least one of the components can in
principle act as H2-donor molecule (Table 1), i.e. the cholinium ion
and glycerol for DES-1 and DES-3, the cholinium fragment for DES-
2 and formic acid for DES-5. Regarding DES-4, all its components
could behave as H2-sources (see Scheme 1). Also, they are all liquids
at room temperature (Table 1). The aforementioned compounds
could be activated by Ru(II)-complexes in the presence of a base [8].
The Ru(II) pre-catalysts 1e4 (Fig. 1) were chosen based on their
structural simplicity and easy availability. The catalytic TH reactions
were performed using acetophenone as a model substrate (Scheme
2).
Initially, DES-1 was tested with Ru(II)-complexes 1e4 in the TH
of acetophenone, using KOH as a strong base to promote the TH. No
significant conversion was attained at different temperatures
(40e100 ꢀC, Table 2, entries 1e4). When pre-catalyst 4 was com-
bined in situ with the robust diphosphane ligand dppf at 100 ꢀC,
20% of 1-phenylethanol was attained after 24 h (Table 2, entry 5),
suggesting a crucial effect of the presence of the dppf ligand for the
catalysis. Since system 4/dppf showed partial conversion, it was
tested with DES-2 and -3, having in common either ChCl or Gly as
H2-sources with DES-1. Unfortunately, also in these cases, the TH
did not occur after several hours even at high temperatures,
(Table 2, entries 6e8). As regards DES-4, bearing HCOOH as H2-
source, no conversion was attained at 40 ꢀC with 4 (Table 2, entry
9), whereas system 4/dppf (1/2, 0.03/0.06 eq.), afforded only partial
formation (16%) of 1-phenylethanol (Table 2, entry 10). Since the
generation of reduction equivalents from HCOOH usually requires
weaker bases than the CeH activation of alcohols, the TH was
carried out in the presence of triethylamine (NEt3) [48]. Employing
analogous conditions, bifunctional type catalyst 3 gave poor con-
version (15%) after several hours (Table 2, entry 11). The conversion
dramatically increased in DES-5 using 4 (0.03 eq.) as pre-catalyst
(50% after 16 h at 60 ꢀC, entry 12), suggesting a better compati-
bility of 4 with DES-5 system with respect to DES-4. On the other
hand, we observed that in DES-5 the consumption of HCOOH and
the accumulation of the remaining TBABr (mp ¼ 103 ꢀC) led to a
heterogenous system, which could present reproducibility issues.
In this case, the use of an additive to homogenize the system was
required for maintaining mild reaction conditions. The partner of
choice was cyclopentyl methyl ether (CPME), due to its higher
biocompatibility [49] and stability [50] with respect to other
ethereal media, such as tetrahydrofuran (THF) and 2-methylTHF.
Then, with the aim to improve the catalytic activity, the effect of
additional diphosphine ligands which could stabilize 4 in the DES
environment was studied. Low or no appreciable conversions were
achieved combining 4 (0.03 eq.) with the bidentate ligands (0.03
eq.) dppe (31%), dppp (36%) and dppb (0%) (Table 2, entries 13e15),
as with highly rigid Xantphos (0.03 eq.), attaining only 14% of
alcohol product (Table 2, entry 16). More satisfying results were
obtained with dppf (0.03 eq.), reaching 60% conversion in 16 h
(Table 2, entry 19). By increasing the catalyst loading (4/dppf ¼ 1/1,
0.05 eq.) and the amount of H2-source (7 eq.), 92% of 1-
phenylethanol was attained in 12 h (Table 2, entry 18). In order to
understand the role of the diphosphine ligand, acetophenone was
Lately, special attention has been addressed to the pursuit of
sustainable catalytic reactions [36e39], and especially to transition
metal mediated processes in DESs, with applications in Pd-
catalyzed cross-coupling [40], Cu-catalyzed Ullmann type [41],
Ru-catalyzed redox isomerization [42] and metathesis reactions
ꢁ
[43] It is worth mentioning that García-Alvarez and co-workers
performed a cascade Ru(IV)-catalyzed isomerization of allylic al-
cohols and asymmetric bio-TH catalyzed KRED enzymes, in buff-
ered cholinium chloride-based DESs [44]. Notwithstanding the
elegance of the concurrent reactions, the procedure entails the use
of the expensive NADPþ, which has to be continuously converted
into the actual H2-source NADPH by dehydrogenation of 2-
propanol into acetone during the process. During the last two de-
cades, the synthesis and characterization of DESs containing mol-
ecules which in principle can work as H2-donors in transition metal
catalyzed processes, e.g. glycerol and formic acid, has witnessed a
significant boost, however their use as such has been neglected so
far. As a matter of fact, no reports of transition metal catalyzed TH of
carbonyl compounds in DESs acting as media or H2-donors in in
homogeneous conditions are present in the literature.
Intrigued by this lack of information on the subject and, given
our experience in ruthenium catalyzed processes [13] and DES
2

M. Cavallo, D. Arnodo, A. Mannu et al.
Tetrahedron 83 (2021) 131997
Scheme 1. Ru-catalyzed Transfer Hydrogenation of carbonyl compounds promoted by (a) “classical” H2-sources; (b) Deep Eutectic Solvents as H2-sources.
Table 1
Selected DESs for this study.
DES
HBAa
HBD1b
HBD2b
HBA/HBD/1/HBD2c
m.p. (ꢀC)
DES-1
DES-2
DES-3
DES-4
DES-5
ChCl
ChCl
TBABr
ChCl
TBABr
Gly
Urea
Gly
HCOOH
HCOOH
e
e
1/2/0
1/2/0
1/1/0
1/1/1
1/1/0
e 40 [47]
12 [28]
Not reportedd
Not reportedd
Not reportedd
Gly
e
a
Hydrogen
bond
acceptor:
ChCl
¼
cholinium
chloride,
TBABr ¼ tetrabutylammonium bromide.
b
Gly ¼ glycerol.
c
Molar ratio.
d
Liquid at 25 ꢀC.
subjected to the TH using 4/dppf ¼ 1/2, 0.05/0.10 eq. Interestingly,
doubling the amount of dppf negatively affected the catalytic ac-
tivity, achieving only 60% of conversion (Table 2, entry 19). Since the
presence of oxygen may be deleterious for the Ru(II)-hydride spe-
cies involved in the TH, especially over prolonged reaction times,
the TH was carried out under N2 atmosphere, after careful
degassing DES-5. Curiously, under inert atmosphere the conversion
was 87%, in line with the data obtained under open air conditions
(Table 2, entry 20). As a matter of comparison we also briefly
investigated Ru(II) systems 1e4 and DES-1e2 as media, performing
the THs using external H2-sources, such as HCOOH/NEt3 mixtures.
Low or no appreciable conversion of acetophenone was attained
with all the H2-donors employed (see supplementary data,
Table S2).
Fig. 1. Structures of the Ru(II)-complexes employed in this work.
It is worth pointing out that the system RuCl2(ampy)(dppb) 3,
which has proven to be a highly active pre-catalyst in the TH of
carbonyl compounds in basic 2-propanol [14], is unable to mediate
the TH in all cases, hinting that a detrimental impact of the DESs on
the catalytic system occurred. This fact may be ascribed to the ac-
tion of the DES system towards 3, which could trap the complex
within its network, through the strong hydrogen bonding in-
teractions with the amine portion around the ruthenium center. On
the other hand, the less active Ru(II)-diphosphane complexes
Scheme 2. TH of acetophenone 5 catalyzed by ruthenium complexes 1e4.
3

M. Cavallo, D. Arnodo, A. Mannu et al.
Tetrahedron 83 (2021) 131997
Table 2
Screening of the reaction conditions for the TH of 5 to 5a using DESs as H2-sources.
Entry
[Ru]/eq.
Ligand/eq.a
H2 source
Base/eq.
Additive
T (ꢀC)
Time (h)
Conv. (%)b
1
2
3
4
5
6
7
8
1/0.03
2/0.03
3/0.03
4/0.03
4/0.03
4/0.03
4/0.03
4/0.03
4/0.03
4/0.03
3/0.03
4/0.03
4/0.03
4/0.03
4/0.03
4/0.03
4/0.03
4/0.05
4/0.05
4/0.05
e
DES-1
DES-1
DES-1
DES-1
DES-1
DES-2
DES-2
DES-3
DES-4
DES-4
DES-5
DES-5
DES-5
DES-5
DES-5
DES-5
DES-5
DES-5
DES-5
DES-5
KOH/0.3
KOH/0.3
KOH/0.3
KOH/0.3
KOH/0.3
KOH/0.3
KOH/0.3
KOH/0.3
NEt3/3.3c
NEt3/3.3c
NEt3/3.3c
NEt3/3.3c
NEt3/3.3c
NEt3/3.3c
NEt3/3.3c
NEt3/3.3c
NEt3/3.3c
NEt3/7c
e
100
100
100
100
100
60
80
100
40
40
60
60
60
60
60
60
60
60
60
60
24
24
24
24
24
24
24
24
24
24
20
16
16
16
16
16
16
12
16
12
2
0
0
2
20
0
0
2
0
16
15
50
31
36
0
14
60
90
60
87
e
e
e
e
e
e
Dppf/0.06
Dppf/0.06
Dppf/0.06
Dppf/0.06
e
e
e
e
e
9
e
10
11
12
13
14
15
16
17
18
19
20e
Dppf/0.06
e
e
e
e
e
Dppe/0.03
Dppp/0.03
Dppb/0.03
Xantphos/0.06
Dppf/0.03
Dppf/0.05
Dppf/0.10
Dppf/0.05
CPMEd
CPMEd
CPMEd
CPMEd
CPMEd
CPMEd
CPMEd
CPMEd
NEt3/7c
NEt3/7c
a
dppe ¼ 1,2-bis(diphenylphosphino)ethane; dppp ¼ 1,3-bis(diphenylphosphino)propane; dppb ¼ 1,4-bis(diphenylphosphino)butane; dppf ¼ 1,10-ferrocenediyl-bis(di-
phenylphosphine)ferrocene; Xantphos ¼ 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
b
Conversion was determined by GC-MS or NMR analysis.
Triethylamine (NEt3) was added in 1/1 molar ratio with respect to the DES employed.
c
d
CPME ¼ cyclopentyl methyl ether was used in 1/1 ratio (V/V) with respect to DES-5.
e
Reaction performed under N2 atmosphere, after carefully degassing DES-5.
Table 4
resulted much more efficient in DES-5 than in VOCs.
TH of 5 to 5a catalyzed by system 4/dppf (1/1, 0.05 eq.) in DES-5 (7 eq.) at 60 ꢀC after
16 h (CPME as the addtive): the effect of the base.
In order to inspect the impact of the eutectic mixture in the
reaction, the TH of acetophenone was carried out under the same
reaction conditions using a freshly prepared mixture of HCOOH/
NEt3 ¼ 1/1 (7 eq.) in CPME, 2-MeTHF and toluene in the absence of
DES-5, obtaining no appreciable conversion in all cases after 8 h
(Table 3, entries 1, 2 and 3, respectively). Moreover, when HCOOH
and TBABr (1/1) in CPME were reacted with an equimolar amount
of NEt3 in the presence of 4/dppf, no significant transformation of
acetophenone to 1-phenylethanol was achieved (Table 3, entry 4),
strongly indicating that the employment of the eutectic mixture
TBABr/HCOOH resulted in a non-innocent effect in the TH process
with respect to the simple “blending” of the two components.
The base appeared to be an important parameter in the TH
process. In our attempt to evaluate its influence on the catalytic
system, different amounts and types of organic and inorganic bases
were then tested (Table 4). Initially, decreasing the amount of NEt3
with respect to DES-5 to a 1/2 ratio (cf. Table 1, entry 18), no
transformation occurred under the usual reaction conditions
(Table 4, entry 1). When 0.2 and 0.5 eq. of the strong base KOH were
employed, 42 and 78% conversions were observed (Table 4, entries
2 and 3, respectively), whereas increasing its amount to 1 and 7 eq.,
the catalytic activity was dramatically reduced (14 and 28% of 1-
phenylethanol, entries 4 and 5, respectively). Poor conversion
(30%) was also obtained employing the strong organic base DBU
Entrya
Base/eq.
Conv. (%)b
1
2
3
4
5
6
7
NEt3/3.5c
KOH/0.2
KOH/0.5
KOH/1.0
KOH/7.0
DBU/7.0d
None
0
42
78
14
28
30
0
a
Reaction performed employing CPME in 1/1 ratio (V/V) with respect to DES-5.
Conversion was determined by NMR analysis.
Triethylamine (NEt3) was added in 1/2 molar ratio with respect to DES-5.
b
c
d
DBU
¼
1,5-diazabiciclo[5.4.0]undec-7-ene, added in 1/1 molar ratio with
respect to DES-5.
(Table 4, entry 6), whereas no transformation was attained when
the TH was performed in the absence of a base (Table 4, entry 7),
revealing that the presence of NEt3 was mandatory for achieving
significant catalytic activity in the DES environment.
With the aim to prove the feasibility of the best system found,
entailing the combination 4/dppf in 1/1 molar ratio (Table 1, entry
20), the corresponding pre-formed complex was then synthesized,
by reacting 4 with dppf (1/1) in CPME at 80 ꢀC and isolating after 3 h
Table 3
TH of 5 to 5a catalyzed by system 4/dppf in different VOCs at 60 ꢀC after 10 h.
Entry
[Ru]/eq.
Ligand/eq.
H2 source
Base/eq.
Solvent
Conv. (%)a
1b
2b
3b
4
4/0.05
4/0.05
4/0.05
4/0.05
Dppf/0.10
Dppf/0.10
Dppf/0.10
Dppf/0.05
HCOOH/NEt3
HCOOH/NEt3
HCOOH/NEt3
e
CPME
0
0
0
3
c
c
c
e
2-MeTHF
Toluene
CPME
e
HCOOH þ TBABrd
NEt3/7e
a
Conversion was determined by NMR analysis.
b
c
Reaction performed under N2 atmosphere, after carefully degassing the selected solvent.
A freshly prepared mixture of HCOOH/NEt3 ¼ 1/1 (7 eq.) was used.
d
e
An equimolar mixture of HCOOH/TBABr in CPME was used in place of DES-5.
Triethylamine (NEt3) was added in 1/1 molar ratio with respect to the H2-source employed.
4

M. Cavallo, D. Arnodo, A. Mannu et al.
Tetrahedron 83 (2021) 131997
the diphosphine-bridged complex [RuCl2(p-cymene)2-
m
-dppf] 6
corresponding alcohol 11a (84%) under the same reaction condi-
tions. The TH of benzophenone 12 afforded 74% conversion after
16 h at 60 ꢀC (Table 6, entry 6). It is interesting to notice that the
reduction of 12, in the same conditions, gave 60% of conversion in
only 6 h, suggesting that catalyst deactivation occurred slowly
(Table 6, entry 6). When 4-nitrobenzophenone 13 was subjected to
the TH under the same reaction conditions, total consumption of
the starting ketone was observed in 16 h. Unfortunately, the reac-
tion in this case was not totally chemoselective, as the NO2 group
was reduced to NH2. NMR analysis of the crude showed a mixture
of 4-nitrodiphenylmethanol 13a (67%) and 4-aminobenzophenone
13b (28%) and 4-aminodiphenylmethanol 13c (5%) (Table 6, entry
7). The unusual high amount of 13b was unexpected, as Ru(II)-
complexes have been reported to be more selective towards the
C]O moiety with respect to NO2 functionality [11]. In fact, only
very recently, efficient reduction of nitro to amino group mediated
by half-sandwich Ru(II)eNHC complexes in the presence of
ammonia borane adduct as H2-source has been reported [52]. The
reduction of enones was also performed, to test the selectivity of
the system for the carbonyl group in the presence of a conjugated
carbon-carbon double bond. Cyclohex-2-en-1-one 14 is totally
reduced both at the C]C and at the C]O moieties (Table 6, entry 8)
to 8a, as already observed for analogous substrates in Ru(II)-
catalyzed TH [53], while the TH of benzylideneacetone (4-
[51] by filtration in very good yield (90%). Readily synthesized 6 was
then employed to further refine the reaction conditions (Table 4).
When the amount of 6 was reduced to 0.03 and 0.04 eq., the
conversion decreased to 47 and 53% (Table 5, entries 1 and 2,
respectively). Also, the reaction temperature plays a crucial role. At
40 ꢀC, with 0.05 eq. of 6, TH of acetophenone only reaches 68%
conversion in 20 h (Table 5, entry 3) ). At 60 ꢀC, 60% of conversion is
obtained in 4 h (Table 5, entry 4), and 92% in 8 h in good yield (84%),
showing that the pre-formed complex 6 give comparable catalytic
performances with respect to in situ system 4/dppf (cf. Table 1,
entry 18). Also, the DES/substrate and NEt3/substrate ratios
revealed to be crucial for the outcome of the reaction, reaching the
best result when equal to 7/1 (corresponding to a NEt3/DES ¼ 1/1 m
ratio).
In addition, further investigations were performed for better
understanding the catalytic behaviour of 6 within the DES-5/NEt3
system. When DES-5, CPME, 6 and NEt3 were heated at 60 ꢀC for
6 h, a change in the physical state of the biphasic system was
observed together with a vigorous gas evolution (likely CO2),
leading to a heterogenous dispersion (likely TBABr) in CPME
(Scheme 3a). After addition of acetophenone, the TH resulted in the
recovery of the unreacted starting material, hinting that HCOOH
was previously decomposed by the catalytically active Ru(II)-
species. On the other hand, maintaining DES-5, CPME and NEt3
under the same conditions and then adding acetophenone and 6 to
the clear biphasic system, the final mixture was obtained with 90%
conversion (Scheme 3b), suggesting a moderate robustness of the
system DES-5/NEt3 and that the base has no detrimental effect on
DES-5 in the absence of the catalyst.
phenylbut-3-en-2-one) 15 showed 93% conversion, giving
a
mixture of three products, i.e. 4-phenylbut-3-en-2-ol 15a (19%), 4-
phenylbutan-2-ol, 15b (51%) and 4-phenylbutan-2-one 15c (30%)
(Table 6, entry 9). These results indicate that a concurrent Ru-
promoted redox isomerization of the allylic alcohol product firstly
formed to the CeC saturated ketone may occur, leading to the total
reduction product eventually (Scheme 5a). On the other hand, the
extension of the conjugated system led to an enhancement of the
selectivity towards the carbon-carbon double bond formal reduc-
tion: in the case of dibenzylideneacetone 16, the major product was
the saturated carbonyl compound (Table 4, entry 10) in which both
the C]C moieties resulted hydrogenated (Scheme 5b). Unfortu-
nately, the TH of 2-acetylpyridine and 4-acetylpyridine was un-
successful and no conversion was observed at 40 ꢀC, with 0.05 eq. of
6 after 4 h (Table 6, entries 11 and 12). This fact can be ascribed to
the strong coordinating ability of the pyridine substrates, which
probably forms a relatively stable complex with the Ru-species
present in the reaction environment, preventing the catalyst to
react in the catalytic cycle.
With these results in our hands, our attention was then devoted
to broaden the scope of the reaction, applying the setup procedure
to a series of different ketones (Scheme 4), containing diverse
functional groups, i.e. alkyl moieties, aryl bearing electron-
withdrawing and electron-donating groups and heterocycles
(Table 6).
The alkyl-alkyl ketones 2-decanone 7 and cyclohexanone 8 were
reduced to 2-decanol 7a and cyclohexanol 8a respectively, with 66
and 100% conversion (Table 6, entries 1 and 2). The conversion of
alkyl-aryl ketones was very high in the case of 1-(3-bromophenyl)
ethan-1-one 9 and 4-acetylbenzonitrile 10 (Table 6, entries 2 and 3)
to 1-(3-bromophenyl)ethan-1-ol 9a and 4-(1-hydroxyethyl)ben-
zonitrile 10a, respectively. It is worth pointing out that system 6/
DES-5 resulted chemoselective towards hydrogenolysis of the
relatively weak carbon-bromine bond. The TH of 10 occurred with
complete consumption of the starting material, although not totally
chemoselective, likely due to the reduction of the cyano function-
ality. Unfortunately, the presence of an unidentified alcohol side
product was detected, as inferred from NMR measurements (see
Supplementary material). High conversion was attained in the TH
of 1-indanone (2,3-dihydro-1H-inden-1-one) 11 to the
The recovery of the products generally ranged from moderate to
excellent, showing clean crude mixtures in all cases, as inferred
from NMR analyses (see supplementary data). Poor recovery of the
alcohol product only in the TH of 4-acetylbenzonitrile, likely due to
concurrent reduction/hydrolysis processes.
Encouraged by the results obtained for the TH of ketone sub-
strates, we then turned our attention to the reduction of aldehydes
to their corresponding alcohols, considered the greater electro-
philicity of aldehydes (Scheme 6), thus we expected both the cat-
alytic system to be more active and to need lower catalyst loadings
and to apply milder reaction conditions for the TH to occur.
The TH of citronellal 19 attained 100% of conversion with 0.01
eq. of 6 after 6 h (Table 7, entry 1), as well as the reduction of
benzaldehyde 20 under the same reaction conditions (Table 7, entry
2). The TH of terephthalaldehyde 21 gave total conversion, afford-
ing a mixture of monoalcohol/dialcohol in about 1/1 ratio after 6 h,
whereas extending the reaction time to 15 h, double reduction to
1,4-phenylenedimethanol 21a was observed (Table 7, entry 3). The
TH of p-methoxybenzaldehyde 22 employing 0.05 eq. of 6, after
16 h, at 60 ꢀC attained complete conversion, as well as vanillin 23
was totally transformed into vanillyl alcohol 23a under the same
reaction conditions (Table 7, entries 4 and 5). It is worth pointing
Table 5
Optimization of the loading percentage of [RuCl2(p-cymene)2-m-dppf] 6, reaction
temperature and time in DES-5 (7 eq.), NEt3 (7 eq.) as base and CPME as the additive,
in the TH of 5 to 5a.
Entry
Eq. [Ru]
Temperature (ꢀC)
Time (h)
Conversion (%)a
1
2
3
4
5
0.03
0.04
0.05
0.05
0.05
60
60
40
60
60
20
20
20
4
47
53
68
60
8
92 (84)b
a
The conversion was determined by NMR analysis.
b
Internal yield was determined by 1H NMR spectroscopy.
5

M. Cavallo, D. Arnodo, A. Mannu et al.
Tetrahedron 83 (2021) 131997
Scheme 3. TH of acetophenone in DES-5 after pre-heating of the system with (a) and without (b) complex 6.
finally investigated the feasibility of the reaction in the presence of
different heterocyclic substituents. The catalytic system was also
effective in the reduction of five membered-ring heterocycles. 2-
Furfural 30 and 5-HMF (5-(hydroxymethyl)furan-2-carbaldehyde)
31 were efficiently transformed into 2-furfurol 30a and (furan-2,5-
diyl)dimethanol 31a, respectively, with 0.025 eq. of 6, at 40 ꢀC after
6 h (Table 7, entries 12 and 13, respectively). Also, the TH 1-
methylpyrrole-2-carbaldehyde 32 to (1-methylpyrrol-2-yl)meth-
anol 32a occurred in 16 h (Table 7, entry 14), under the same re-
action conditions, as well as for thiophene-2-carbaldehyde 33
(Table 7, entry 15). Unfortunately, the TH of pyridine-2-
carbaldehyde 34 and pyridine-4-carbaldehyde 35, instead,
attained no transformation to the corresponding alcohols (Table 7,
entries 16 and 17, respectively). The reason may be likely the same
as for the pyridyl ketones (vide infra and cf. Table 6, entries 11 and
12). Similarly for the ketone substrates, all the alcohol products
were collected from low to excellent yields, showing remarkably
clean crude mixtures in all cases, as inferred from NMR analyses
(see Supplementary data). In some cases low amounts of the ex-
pected alcohols were achieved with hydrolysable (Table 7, entry 8)
or highly polar (Table 7, entries 3, 9 and 13) products, suggesting
that the methodology may need some refinments for enhancing
the recovery of the carbinols.
Scheme 4. TH of ketones catalyzed by 6 in the presence of DES-5.
out that the reduction of 23 by means of ruthenium catalyzed TH is
not an easy goal to be achieved. Up to date, only one example of Ru-
catalyzed TH of 23 has been reported [54]. Strangely, 4-(dimethy-
lamino)benzaldehyde 24 resulted in the recovery of the unreacted
starting material after 19 h, suggesting that the substrate may
poison the catalytically active species. In fact, no examples are
present in the literature reporting an inhibited catalytic activity of
Ru(II)-complexes in the presence of aminoaldehydes. On the con-
trary, when bearing electron-withdrawing groups such as nitro,
cyano and acetyl groups with respect to the carbonyl, the reduction
proceeded with total conversion of the substrates (Table 7, entries 7,
8 and 9, respectively). The reduction of 4-nitrobenzaldehyde 25, 4-
formylbenzonitrile 26 and 3-acetylbenzaldehyde 27 to their cor-
responding alcohols occurred from moderate to high chemo-
selectivity of the catalytic system towards the carbonyl moiety.
Nitro and cyano functionalities resulted unchanged by the TH
(Table 7, entries 7 and 8), indicating that the lack of chemo-
selectivity observed for ketone substrates may be caused by the
higher temperatures employed (cf. 4-acetylbenzonitrile and 4-
nitrobenzophenone, Table 6, entries 4 and 6), whereas 27 under-
went partial reduction of the ketone moiety (Table 7, entry 9). The
alicyclic enal (1R)-(ꢁ)-myrtenal 28 gave a mixture of products
differently reduced at the carbon-carbon double bond and at the
carbonyl moieties in a 15/85 ratio (Table 7, entry 10). We observed a
Finally, to test the ability of the catalytic system on different
carbon-heteroatom unsaturations, the TH of N,2-diphenylethane-
1-imine 36 to N-benzylaniline and (E)-N,1-diphenylethan-1-imine
37 was also tested, achieving 99 and 52% of conversion, respec-
tively, in 18 h at 60 ꢀC (0.05 eq. of 6, Scheme 7).
3. Conclusions
This work reports on the study of the Ru(II)-catalyzed TH of
carbonyl substrates to their corresponding alcohols in DESs used
both as media and as H2-source under mild conditions (40e60 ꢀC).
The methodology is new, straightforward and simple and proceeds
smoothly with commercial-grade substrates and solvents in open
air, without the use of inert gases or the need for further purifica-
tion of the reactants and the solvents. Our study demonstrated that
similar lack of selectivity on (E)-a-methylcinnamaldehyde 29
(Table 7, entry 11), obtaining a mixture of 2-methyl-3-phenylprop-
2-en-1-ol 29a and 2-methyl-3-phenylpropan-1-ol 29b with 4/1
ratio, respectively, as inferred from NMR measurements. As already
pointed out for ketone substrates (Table 6, entries 9e10), this is
probably due to an isomerization process occurring after the TH on
the C]O functionality took place (Scheme 5a). The preferential
reduction of the aldehyde C]O over the conjugated C]C func-
tionality was previously disclosed by some of the authors in the
Ru(II)-catalyzed TH promoted by ammonium formate [25]. We
the easily achievable complex [RuCl2(p-cymene)2-m-dppf] was able
to efficiently catalyze the TH of several carbonyl substrates, in the
presence of the eutectic mixture TBABr/HCOOH and of triethyl-
amine as the base, obtaining in most cases total conversions and
clean crude mixtures. The TH process required an additive in order
to maintain the system homogeneous under mild conditions.
Notably, eco-friendly CPME was found to be the best partner of
choice. As expected, aldehydes showed higher reactivity than ke-
tones, which needed harsher reaction conditions to reach elevated
6

M. Cavallo, D. Arnodo, A. Mannu et al.
Tetrahedron 83 (2021) 131997
Table 6
Table 6 (continued )
Reduction of ketone substrates to their corresponding alcohols catalyzed by 6 (0.05
eq.) in DES-5, NEt3 (7 eq., 1/1 with respect to DES-5) as base and CPME as the ad-
ditive, at 60 ꢀC.
Entry
12h
Ketone
Time [h]
Conversion (%)a
0
4
Entry
1
Ketone
Time [h]
Conversion (%)a
16
16
66
87 (57)b
a
Conversion and internal yield (i.y.) in parentheses were determined by 1H NMR
2
3
16
16
100 (48)
97 (89)
spectroscopy (see Supplementary material for details).
b
Reaction performed at 80 ꢀC.
c
Two products were observed: 4-(1-hydroxyethyl)benzonitrile as the main
product and an unidentified side product.
d
Three products were observed: 4-nitrodiphenylmethanol 13a (38% i.y.), 4-
aminobenzophenone 13b (10% i.y.) and 4-aminodiphenylmethanol 13c (1% i.y.).
e
Total reduction of both the C]C and C]O bonds was observed.
Three main products were observed: 4-phenylbutan-2-ol 15b (47% i.y.), 4-
f
phenylbutan-2-one 15c (31% i.y.) and 4-phenylbut-3-en-2-ol 15a (9% i.y.).
g
Two main products were observed: 1,5-diphenylpentan-3-one 16b (77% i.y.)
and 1,5-diphenylpent-1-en-3-ol 16a (23% i.y.).
h
Reaction performed at 40 ꢀC.
conversions to their corresponding alcohols. In general, excellent
chemoselectivities were achieved towards the bromo-arene and
isolated olefin functionalities, whereas less tolerability was
attained towards nitro and cyano groups, especially in the case of
ketone substrates. The reduction of the latters appears to be a
slower competitive reaction compared to the C]O reduction,
usually observed when the TH was carried out at higher tempera-
4
16
16
100 (28)c
5
6
84 (67)
tures and over long reaction times. a,b-unsaturated carbonyl sub-
strates showed very good conversions but poor chemoselectivies,
due to the formal reduction of the conjugated C]C bond. Notably,
vanillin was efficiently reduced to vanillyl alcohol with a good re-
covery of the product, which is not a trivial process to occur in
homogenous conditions. Also, imine derivatives were tested, the
TH being effective only with the aldimine substrate to its corre-
sponding amine derivative, whereas the ketimine functionality
showed modest reactivity towards the hydrogenative system
employed. Remarkably, the highly active bifunctional catalysts
employed in the TH of carbonyl substrates in VOCs, such as
RuCl2(diphosphine)(ampy), are not active in DESs, whereas the use
of cheaper (half-sandwich)RuCl2(PP) complexes is very efficient as
catalytic system. Moreover, the outcomes obtained strongly indi-
cate a non-innocent impact of the eutectic system TBABr/HCOOH
on the Ru(II)-catalyzed TH with respect to the employment of a
mere solution of their components, which has not previously been
described. Finally, this work introduces for the first time the
concept of employing DESs as H2-sources for transition metal
catalyzed reductive reactions, opening a window on the assess-
ment of alternative procedures for hydrogenative processes in non-
conventional media. Further investigations on the ensemble Ru(II)/
DES are in progress in order to better understand the system for its
employment in different organic transformations.
6
16
60
74 (72)
7
8
16
16
>99d
100 (98)e
9
10
94f
10
16
>99g
4. Experimental section
4.1. General procedure for the catalytic TH of carbonyl compounds
and imines
11h
4
0
The selected substrate (0.2e1.0 mmol, 1 eq), [RuCl2(p-cym-
ene)}2-m-dppf] (6) (0.002e0.01 mmol, 0,01e0,05 eq, 2.3e58.3 mg),
NEt3 (1.4e8.6 mmol, 0.2e1.2 mL) and CPME (0.5e1.5 mL) were
transferred into a 4 mL vial. The mixture was heated at the selected
temperature (40e80 ꢀC) under stirring for ca. 15 min and finally the
DES-5 (0.45e1.7 mL) was added. After the addition of the DES, the
vial was put into the oil bath and the Teflon® cap pierced with a
(continued on next page)
7

M. Cavallo, D. Arnodo, A. Mannu et al.
Tetrahedron 83 (2021) 131997
Scheme 5. Possible reaction pathways in the TH of 15 (a) and 16 (b).
Cyclohexanol (8a): 100% conversion, 48% yield. 1H NMR
(600 MHz, CDCl3, 25 ꢀC):
¼ 1.22e1.33 (m, 5H), 1.40 (br s, 1H),
1.51e1.57 (m, 1H), 1.70e1.77 (m, 2H), 1.85e1.93 (m, 2H), 3.55e3.69
(m, 1H). 13C NMR (150 MHz, CDCl3, 25 ꢀC):
¼ 24.3, 25.6, 35.7, 70.5.
1-(3-bromophenyl)ethan-1-ol (9a): 97% conversion, 89% yield.
1H NMR (600 MHz, CDCl3, 25 ꢀC):
d
d
d
¼ 1.47 (d, J ¼ 6.5 Hz, 3H), 2.11 (br
s, 1H), 4.85 (q, J ¼ 6.5 Hz, 1H), 7.20 (t, J ¼ 7.8 Hz, 1H), 7.26e7.27 (m,
1H), 7.37e7.39 (m, 1H), 7.50e7.55 (m, 1H). 13C{1H} NMR (150 MHz,
CDCl3, 25 ꢀC):
d
¼ 25.4, 69.8, 122.7, 124.1, 128.7, 130.2, 130.5, 148.3.
4-(1-hydroxyethyl)benzonitrile (10a): 100% conversion
(10a þ unidentified side product), 28% yield (10a). 1H NMR
Scheme 6. TH of aldehydes catalyzed by 6 in the presence of DES-5.
(600 MHz, CDCl3, 25 ꢀC):
d
¼ 1.48 (d, J ¼ 6.5 Hz, 3H), 2.40 (br s, 1H),
4.94 (q, J ¼ 6.5 Hz, 1H), 7.47 (d, J ¼ 8.2 Hz, 2H), 7.61 (d, J ¼ 8.3 Hz,
needle to help the emission of the CO2 produced. The reaction was
then leaved to react at the selected temperature from 2 to 24 h,
depending on the substrate. The reaction mixture was worked
taken up with water (1.5 mL) and extracted with diethyl ether
(4 ꢂ 1.5 mL), then the combined organic layers washed with brine
(1.5 mL). The organic phase was then separated, dried over Na2SO4
and filtered. The solvent was removed and the crude was analysed
by 1H and, when pure products were afforded, by 13C NMR
spectroscopy.
2H).
Mixture of indan-1-ol (11a) and indan-1-one (11): 84% con-
version, 67% yield. 1H NMR (600 MHz, CDCl3, 25 ꢀC):
d
¼ 1.90e1.98
(m, 1H, 11a), 2.04 (br s, 1H, 11a) 2.49 (dddd, J ¼ 13.1, 8.3, 6.9, 4.7 Hz,
1H, 11a), 2.68e2.72 (m, 2H, 11), 2.79e2.87 (m, 1H, 11a), 3.06 (ddd,
J ¼ 16.0, 8.6, 4.7 Hz, 1H, 11a), 3.13e3.17 (m, 2H, 11), 5.20e5.26 (m,
1H, 11a), 7.22e7.30 (m, 3H, 11a), 7.38 (t, J ¼ 7.2 Hz, 1, 11), 7.42 (d,
J ¼ 6.6 Hz,1H, 11a), 7.49 (d, J ¼ 7.7 Hz, 1H,11), 7.60 (td, J ¼ 7.4, 1.2 Hz,
1H, 11), 7.77 (d, J ¼ 7.7 Hz, 1H, 11).
Mixture of diphenylmethanol (12a) and benzophenone (12):
74% conversion, 72% yield. 1H NMR (600 MHz, CDCl3, 25 ꢀC):
4.2. NMR data for the TH of ketones
d
¼ 2.48 (br s, 1H, 12a), 5.84 (s, 1H, 12a), 7.24e7.29 (m, 2H, 12a),
7.32e7.36 (m, 4H, 12a), 7.37e7.41 (m, 4H, 12a), 7.46e7.52 (m, 4H,
12), 7.57e7.63 (m, 2H, 12), 7.79e7.85 (m, 4H, 12).
Mixture of 1-phenylethan-1-ol (5a) and acetophenone (5):
92% conversion, 84% yield. 1H NMR (600 MHz, CDCl3, 25 ꢀC):
Mixture
of
4-nitrodiphenylmethanol
(13a),
4-
d
¼ 1.50 (d, J ¼ 6.5 Hz, 3H, 5a), 1.97 (br s, 1H, 5a), 2.61 (s, 3H, 5), 4.90
aminobenzophenone (13b) and 4-aminodiphenylmethanol
(13c): >99% conversion (13a 67%, 13b 31%, 13c 2%), yield (13a
(q, J ¼ 6.5 Hz, 1H, 5a), 7.25e7.30 (m, 1H, 5a), 7.33e7.40 (m, 4H, 5a),
7.45e7.50 (m, 2H, 5), 7.55e7.59 (m, 1H, 5), 7.95e7.98 (m, 2H, 5).
Mixture of decan-2-ol (7a) and decan-2-one (7): 87% conver-
38%, 13b 10%, 13c 1%). 1H NMR (600 MHz, CDCl3, 25 ꢀC):
d
¼ 1.26 (s,
sion, 57% yield. 1H NMR (600 MHz, CDCl3, 25 ꢀC):
d
¼ 0.86 (t,
2H, 13c), 3.01 (br s, 1H, 13a), 4.19 (br s, 2H, 13b), 5.73 (s, 1H, 13c),
5.89 (s, 1H, 13a), 6.62 (d, J ¼ 8.4 Hz, 2H, 13c), 6.65 (d, J ¼ 8.6 Hz, 2H,
13b), 7.12 (d, J ¼ 8.4 Hz, 2H, 13c), 7.27e7.32 (m, 1H, 13a) super-
imposed to 7.28e7.38 (m, 5H, 13c) superimposed to 7.33e7.37 (m,
4H, 13a), 7.42e7.46 (m, 2H, 13b), 7.51e7.54 (m, 1H, 13b), 7.54e7.57
J ¼ 7.0 Hz, 3H, 7) superimposed to 0.87 (t, J ¼ 7.0 Hz, 3H, 7a), 1.17 (d,
J ¼ 6.2 Hz, 3H, 7a), 1.21e1.34 (m, 22H, 7a þ 7), 1.34e1.52 (m, 5H,
7a þ 7), 2.12 (s, 3H, 7), 2.40 (t, J ¼ 7.5 Hz, 2H, 7), 3.74e3.81 (m, 1H,
7a).
8

M. Cavallo, D. Arnodo, A. Mannu et al.
Tetrahedron 83 (2021) 131997
Table 7
Table 7 (continued )
Reduction of aldehyde substrates to their corresponding primary alcohols catalyzed
by 6 (0.01e0.05 eq.) in DES-5, NEt3 (7 eq., 1/1 with respect to DES-5) as base and
CPME as the additive, at 40 ꢀC.
Entry
11
Aldehyde
[Ru] (eq.)
0.025
Time (h)
16
Conv. (%)a
100g
Entry
1
Aldehyde
[Ru] (eq.)
0.01
Time (h)
6
Conv. (%)a
100 (99)
12
13
14
0.025
0.025
0.025
6
100 (63)
99 (28)
2
3
0.01
0.01
6
100 (85)
6
6
15
99b
10
100 (99)
100 (21)c
15
16
0.025
0.02
10
2
100 (71)
4d
0.05
0.05
16
15
98 (94)
99 (78)
0
5d
17h
0.02
5
0
6
0.05
8
0
a
Conversion and internal yield (i.y.) in parentheses were determined by 1H NMR
spectroscopy (see Supplementary material for details).
b
A mixture of monoalcohol/dialcohol in 1/1 ratio was observed.
1,4-Phenylenedimethanol 21a was observed as a sole product.
Reaction performed at 60 ꢀC.
c
d
e
A mixture of two products was observed: 1-((3-hydroxymethyl)phenyl)etha-
7
8
0.01
0.01
4
6
100 (69)
100 (14)
none (14% i.y.) and 1-((3-hydroxymethyl)phenyl)ethan-1-ol (3% i.y.).
f
A mixture of C]O (55% i.y.) and double C]C/C]O reduction (11% i.y.) products
was observed.
g
A mixture of two products was observed: 2-methyl-3-phenylprop-2-en-1-ol
29a (84% i.y.) and 2-methyl-3-phenylpropan-1-ol 29b (16% i.y.).
h
Reaction performed at 30 ꢀC.
9
0.01
6
100e
Scheme 7. TH of imine derivatives.
100f
(m, 2H, 13a), 7.66e7.70 (m, 4H, 13b), 8.13e8.17 (m, 2H, 13a).
Cyclohexanol (14a): 100% conversion, 98% yield. 1H NMR
10
0.025
16
(600 MHz, CDCl3, 25 ꢀC):
d
¼ 1.22e1.33 (m, 5H), 1.40 (br s, 1H),
1.51e1.57 (m, 1H), 1.70e1.77 (m, 2H), 1.85e1.93 (m, 2H), 3.55e3.69
(m, 1H). 13C{1H} NMR (150 MHz, CDCl3, 25 ꢀC):
70.5.
d
¼ 24.3, 25.6, 35.7,
(continued on next page)
Mixture of 4-phenylbut-3-en-2-ol (15a), 4-phenylbutan-2-ol
(15b), 4-phenylbutan-2-one (15c) and 4-phenylbut-3-en-2-one
9

M. Cavallo, D. Arnodo, A. Mannu et al.
Tetrahedron 83 (2021) 131997
(15): 94% conversion (15a 16%, 15b 49%, 15c 29%), yield (15a 9%, 15b
methanol (28a) and (6,6-dimethylbicyclo[3.1.1]heptan-2-yl)
47%, 15c 31%). 1H NMR (600 MHz, CDCl3, 25 ꢀC):
d
¼ 1.24 (d,
methanol (298b): 100% conversion (28a 85%, 28b 15%), yield (28a
J ¼ 6.2 Hz, 3H, 15b), 1.38 (d, J ¼ 6.4 Hz, 3H, 15a), 1.54e1.59 (m, 1H,
15b), 1.72e1.84 (m, 2H, 15b), 1.87 (br s, 1H, 15a), 2.14 (s, 3H, 15c),
2.39 (s, 3H, 15), 2.68 (ddd, J ¼ 13.8, 9.4, 6.8 Hz, 1H, 15b), 2.73e2.80
(m, 1H, 15b) superimposed to 2.77e2.80 (m, 2H, 15c), 2.90 (t, J ¼ 7.7,
2H, 15c), 3.80e3.87 (m, 1H, 15b), 4.50 (quint, J ¼ 5.6 Hz, 1H, 15a),
6.27 (dd, J ¼ 15.9, 6.4 Hz, 1H, 15a), 6.57 (d, J ¼ 15.9 Hz, 1H, 15a), 6.73
(d, J ¼ 16.3 Hz, 1H, 15), 7.53 (d, J ¼ 16.4 Hz, 1H, 15) superimposed to
7.10e7.52 (m, 20H, 15 þ 15a þ 15b þ 15c).
55%, 28b 11%). 1H NMR (600 MHz, CDCl3, 25 ꢀC):
d
¼ 0.83 (s, 3H,
28a) superimposed to 0.82e0.86 (m, 1H, 28b), 0.96 (s, 3H, 28b), 1.15
(s, 3H, 28b), 1.16e1.18 (m, 1H, 28a), 1.28 (s, 3H, 28a), 1.42e1.48 (m,
2H, 28b) superimposed to 1.46 (br s, 1H, 28a), 1.81e1.95 (m, 4H,
28b), 1.98e2.02 (m, 1H, 28b), 2.07e2.11 (m, 1H, 28a), 2.13 (td,
J ¼ 5.7, 1.5 Hz, 1H, 28a), 2.20e2.26 (m, 1H, 28a) superimposed to
2.23e2.26 (m, 1H, 28b), 2.27e2.33 (m, 1H, 28a), 2.33e2.37 (m, 1H,
28b), 2.39 (dt, J ¼ 8.6, 5.6 Hz, 1H, 28a), 3.49e3.61 (m, 2H, 28b), 3.97
(s, 2H, 28a), 5.46 (m, 1H, 28a).
Mixture of 1,5-diphenylpent-1-en-3-ol (16a) and 1,5-
diphenylpentan-3-one (16b): >99% conversion (16a 35%, 16b
65%), yield (16a 23%, 16b 77%). 1H NMR (600 MHz, CDCl3, 25 ꢀC):
Mixture of (E)-2-methyl-3-phenylprop-2-en-1-ol (29a) and 2-
methyl-3-phenylpropan-1-ol (29b): 100% conversion (29a 83%,
29b 17%), yield (29a 84%, 29b 16%). 1H NMR (600 MHz, CDCl3,
d
¼ 1.80e1.93 (br s, 1H,16a), 1.96e2.09 (m, 2H, 16a), 2.75 (t,
J ¼ 7.6 Hz, 4H, 16b), 2.83 (tdd, J ¼ 16.1, 9.4, 6.2 Hz, 2H, 16a), 2.94 (t,
J ¼ 7.6 Hz, 4H, 16b), 4.35 (q, J ¼ 6.6 Hz, 1H, 16a), 6.30 (dd, J ¼ 15.9,
6.7 Hz, 1H, 16a), 6.63 (d, J ¼ 15.9 Hz, 1H, 16a), 7.13e7.50 (m, 20H,
16a þ 16b).
25 ꢀC):
d
¼ 0.92 (d, J ¼ 6.7 Hz, 3H, 29b), 1.91 (s, 3H, 29a) super-
imposed to 1.92 (br s, 1H, 29a) superimposed to 1.92e1.99 (m, 1H,
29b), 2.43 (dd, J ¼ 13.5, 8.1 Hz, 1H, 29b), 2.76 (dd, J ¼ 13.5, 6.3 Hz,
1H, 29b), 3.48 (dd, J ¼ 10.6, 6.1 Hz, 1H, 29b), 3.54 (dd, J ¼ 10.5,
5.9 Hz,1H, 29b), 4.20 (s, 2H, 29a), 6.54 (s,1H, 29a), 7.14e7.21 (m, 5H,
29b), 7.21e7.25 (m, 1H, 29a), 7.27e7.31 (m, 2H, 29a), 7.32e7.37 (m,
2H, 29a).
4.3. NMR data for the TH of aldehydes
3,7-dimethyloct-6-en-1-ol (19a): 100% conversion, 99% yield.
Furan-2-ylmethanol (30a): 100% conversion, 63% yield. 1H
1H NMR (600 MHz, CDCl3, 25 ꢀC):
d
¼ 0.82e1.02 (m, 1H) super-
NMR (600 MHz, CDCl3, 25 ꢀC):
d
¼ 1.98 (br s, 1H), 4.60 (s, 2H), 6.29
imposed to 0.89 (d, J ¼ 6.6 Hz, 3H), 1.11e1.21 (m, 1H) 1.28e1.42 (m,
2H), 1.52e1.62 (m, 1H) superimposed to 1.59 (s, 3H), 1.67 (s, 3H),
1.89e2.05 (m, 2H), 3.61e3.72 (m, 1H), 5.08 (dddt, J ¼ 7.1, 5.7, 2.8,
(d, J ¼ 3.2 Hz, 1H), 6.34 (dd, J ¼ 3.2, 1.8 Hz, 1H), 7.40 (dd, J ¼ 1.9,
0.8 Hz, 1H). 13C{1H} NMR (150 MHz, CDCl3, 25 ꢀC):
111.1, 142.2, 154.2.
d
¼ 57.6, 107.9,
1.4 Hz, 1H)$13C{1H} NMR (150 MHz, CDCl3, 25 ꢀC):
d
¼ 17.7, 19.6,
Furan-2,5-diyldimethanol (31a): 99% conversion, 28% yield. 1H
25,5, 25.8, 29.2, 37.3, 40.0, 61.1, 124.8, 131.3.
NMR (600 MHz, CDCl3, 25 ꢀC):
(s, 2H). 13C{1H} NMR (150 MHz, CDCl3, 25 ꢀC):
(1-methyl-1H-pyrrol-2-yl)methanol (32a): 100% conversion,
99% yield. 1H NMR (600 MHz, CDCl3, 25 ꢀC):
d
¼ 2.85 (br s, 2H), 4.55 (s, 4H), 6.19
¼ 57.7, 108.7, 154.2.
Phenylmethanol (20a): 100% conversion, 85% yield. 1H NMR
d
(600 MHz, CDCl3, 25 ꢀC):
d
¼ 1.92 (br s, 1H), 4.69 (s, 2H), 7.27e7.33
(m, 1H), 7.34e7.39 (m, 4H). 13C{1H}NMR (150 MHz, CDCl3, 25 ꢀC):
d
¼ 1.47 (br s, 1H), 3.69
d
¼ 65.4, 127.1, 127.8, 128.7, 141.0.
(s, 3H), 4.59 (s, 2H), 6.05 (dd, J ¼ 3.5, 2.7 Hz, 1H), 6.11 (dd, J ¼ 3.6,
1,4-phenylenedimethanol (21a): 100% conversion, 21% yield.
1.8 Hz, 1H), 6.62e6.65 (m, 1H). 13C{1H} NMR (150 MHz, CDCl3,
1H NMR (600 MHz, DMSO‑d6, 25 ꢀC):
d
¼ 4.46 (d, J ¼ 5.7 Hz, 4H),
25 ꢀC):
d
¼ 33.8, 56.9, 106.8, 109.0, 123.7, 131.9.
Thiophen-2-ylmethanol (33a): 100% conversion, 71% yield. 1H
NMR (600 MHz, CDCl3, 25 ꢀC):
¼ 2.17 (br s, 1H), 4.82 (s, 2H), 6.98
5.12 (t, J ¼ 5.7 Hz, 2H), 7.25 (s, 4H). 13C{1H} NMR (150 MHz,
DMSO‑d6, 25 ꢀC):
d
¼ 62.7, 126.2, 140.9.
d
Mixture of (4-methoxyphenyl)methanol (22a) and 4-
(dd, J ¼ 5.0, 3.4 Hz, 1H), 7.00e7.02 (m, 1H), 7.27 (dd, J ¼ 5.1, 1.2 Hz,
methoxybenzaldehyde (22): 98% conversion, 94% yield. 1H NMR
1H). 13C{1H} NMR (150 MHz, CDCl3, 25 ꢀC):
127.0, 144.2.
d
¼ 60.0, 125.6, 125.7,
(600 MHz, CDCl3, 25 ꢀC):
d
¼ 1.92 (br s, 1H, 22a), 3.80 (s, 3H, 22a),
3.86 (s, 3H, 22), 4.60 (s, 2H, 22a), 6.86e6.90 (m, 2H, 22a), 6.96e7.00
(m, 2H, 22), 7.25e7.30 (m, 2H, 22a), 7.80e7.82 (m, 2H, 22), 9.84 (s,
1H, 22).
4.4. NMR data for the TH of imines
4-(hydroxymethyl)-2-methoxyphenol (23a): 99% conversion,
78% yield. 1H NMR (600 MHz, acetone-d6, 25 ꢀC):
4.11 (br s, 1H), 4.50 (s, 2H), 6.78 (s, 2H), 6.96 (s, 1H), 7.52 (br s, 1H).
d
¼ 3.82 (s, 3H),
N-benzylaniline (36a): 99% conversion, 55% yield. 1H NMR
(600 MHz, CDCl3, 25 ꢀC):
d
¼ 4.06 (br s, 1H), 4.36 (d, J ¼ 5.7 Hz, 2H),
13C{1H} NMR (150 MHz, acetone-d6, 25 ꢀC):
115.4, 120.2, 134.8, 146.4, 148.1.
d
¼ 56.1, 64.7, 111.4,
6.65e6.69 (m, 2H), 6.75 (tt, J ¼ 7.3, 1.1 Hz, 1H), 7.19e7.23 (m, 2H),
7.29e7.33 (m, 1H), 7.36e7.42 (m, 4H). 13C{1H} NMR (150 MHz,
(4-nitrophenyl)methanol (25a): 100% conversion, 69% yield. 1H
CDCl3, 25 ꢀC):
148.3.
d
¼ 48.4, 112.9, 117.7, 127.3, 127.6, 128.7, 129.4, 139.5,
NMR (600 MHz, DMSO‑d6, 25 ꢀC):
d
¼ 4.60 (d, J ¼ 5.7 Hz, 2H), 5.51 (t,
J ¼ 5.7 Hz, 1H), 7.54 (d, J ¼ 8.7 Hz, 2H), 8.16 (d, J ¼ 8.7 Hz, 2H). 13
C
Mixture of N-(1-phenylethyl)aniline (37a) and (E)-N,1-
{1H} NMR (150 MHz, DMSO‑d6, 25 ꢀC):
d
¼ 62.0, 123.3, 127.0, 146.3,
diphenylethan-1-imine (37): 52% conversion, 35% yield. 1H NMR
150.8.
(600 MHz, CDCl3, 25 ꢀC):
d
¼ 1.54 (d, J ¼ 6.7 Hz, 3H, 37a), 2.26 (s, 3H,
4-(hydroxymethyl)benzonitrile (26a): 100% conversion, 14%
37), 4.06 (br s, 1H, 37a), 4.47e4.55 (m, 1H, 37a), 6.52e6.56 (m, 2H,
37a), 6.67 (tt, J ¼ 7.3, 1.1 Hz, 1H, 37a), 6.82e6.85 (m, 2H, 37),
7.10e7.14 (m, 3H, 37a þ 37), 7.22e7.28 (m, 1H, 37a), 7.35e7.36 (m,
2H, 37), 7.38e7.41 (m, 4H, 37a), 7.46e7.51 (m, 3H, 37), 7.99e8.03
(m, 2H, 37).
yield. 1H NMR (600 MHz, CDCl3, 25 ꢀC):
d
¼ 1.95 (br s, 1H), 4.79 (s,
2H), 7.48 (d, J ¼ 8.0 Hz, 2H), 7.65 (d, J ¼ 8.2 Hz, 2H). 13C{1H} NMR
(150 MHz, CDCl3, 25 ꢀC):
d
¼ 64.4, 111.3, 119.0, 127.2, 132.5, 146.3.
Mixture of 1-(3-(hydroxymethyl)phenyl)ethan-1-one (27a)
and 1-(3-(hydroxymethyl)phenyl)ethan-1-ol (27b): 100% con-
version (27a 83%, 27b 17%), yield (27a 14%, 27b 3%). 1H NMR
(600 MHz, CDCl3, 25 ꢀC):
d
¼ 1.50 (d, J ¼ 6.5 Hz, 3H, 27b), 1.69 (br s,
1H, 27b), 1.93 (br s, 1H, 27b), 2.08 (br s, 1H, 27a), 2.61 (s, 3H, 27a),
4.69 (s, 2H, 27b), 4.76 (s, 2H, 27a), 4.91 (q, J ¼ 6.5 Hz, 1H, 27b),
7.24e7.41 (m, 4H, 27b), 7.46 (t, J ¼ 7.6 Hz, 1H, 27a), 7.58 (d,
J ¼ 7.6 Hz, 1H, 27a), 7.87 (d, J ¼ 7.7 Hz, 1H, 27a), 7.95 (s, 1H, 27a).
Mixture of (1R)-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
10

M. Cavallo, D. Arnodo, A. Mannu et al.
Tetrahedron 83 (2021) 131997
catalyst employed in the process, thus improving the catalytic activity and
productivity.
Acknowledgments
[27] M. Meshksar, F. Afshariani, M.R. Rahimpour, in: Inamuddin, A.M. Asiri (Eds.),
Applications Of Nanotechnology For Green Synthesis, Springer International
Publishing, Cham, 2020, pp. 435e455.
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Commun. (2003) 70e71.
The authors are grateful to CRT and MANUNET2017 project for
financial support.
Appendix A. Supplementary data
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11