Fast Addition of s-Block Organometallic Reagents to CO2-Derived Cyclic Carbonates at Room Temperature, Under Air, and in 2-Methyltetrahydrofuran

Article abstract of DOI:10.1002/cssc.202100262

Fast addition of highly polar organometallic reagents (RMgX/RLi) to cyclic carbonates (derived from CO₂ as a sustainable C1 synthon) has been studied in 2-methyltetrahydrofuran as a green reaction medium or in the absence of external volatile organic solvents, at room temperature, and in the presence of air/moisture. These reaction conditions are generally forbidden with these highly reactive main-group organometallic compounds. The correct stoichiometry and nature of the polar organometallic alkylating or arylating reagent allows straightforward synthesis of: highly substituted tertiary alcohols, β-hydroxy esters, or symmetric ketones, working always under air and at room temperature. Finally, an unprecedented one-pot/two-step hybrid protocol is developed through combination of an Al-catalyzed cycloaddition of CO₂ and propylene oxide with the concomitant fast addition of RLi reagents to the in situ and transiently formed cyclic carbonate, thus allowing indirect conversion of CO₂ into the desired highly substituted tertiary alcohols without need for isolation or purification of any reaction intermediates.

Full text of DOI:10.1002/cssc.202100262

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Fast Addition of s-Block Organometallic Reagents to CO2-
Derived Cyclic Carbonates at Room Temperature, Under
Air, and in 2-Methyltetrahydrofuran
David Elorriaga,*[a] Felipe de la Cruz-Martínez,[a] María Jesús Rodríguez-Álvarez,[b]
Agustín Lara-Sánchez,[a] José Antonio Castro-Osma,*[c] and Joaquín García-Álvarez*[b]
In memory of Prof. Victor Snieckus, a leading authority in organolithium chemistry and directed ortho-metalation reactions.
Fast addition of highly polar organometallic reagents (RMgX/
RLi) to cyclic carbonates (derived from CO2 as a sustainable C1
synthon) has been studied in 2-methyltetrahydrofuran as a
green reaction medium or in the absence of external volatile
organic solvents, at room temperature, and in the presence of
air/moisture. These reaction conditions are generally forbidden
with these highly reactive main-group organometallic com-
pounds. The correct stoichiometry and nature of the polar
organometallic alkylating or arylating reagent allows straightfor-
ward synthesis of: highly substituted tertiary alcohols, β-
hydroxy esters, or symmetric ketones, working always under air
and at room temperature. Finally, an unprecedented one-pot/
two-step hybrid protocol is developed through combination of
an Al-catalyzed cycloaddition of CO2 and propylene oxide with
the concomitant fast addition of RLi reagents to the in situ and
transiently formed cyclic carbonate, thus allowing indirect
conversion of CO2 into the desired highly substituted tertiary
alcohols without need for isolation or purification of any
reaction intermediates.
Introduction
be able to control the chemoselectivity of these polar reagents,
this s-block organometallic chemistry has been traditionally
Polar organometallic chemistry and, in particular, the chemistry
of compounds derived from s-block elements (typically organo-
lithium and organomagnesium reagents), constitutes one of the
most commonly used instruments within the synthetic organic
chemist’s toolbox.[1] In this sense, it is estimated that 95% of
drugs manufactured in the pharmaceutical industry use organo-
lithium/Grignard reagents at least in one step of their
synthesis.[2] Nevertheless, to try to minimize the undesired
decomposition of these highly reactive chemicals and also to
employed under inert atmosphere, using rigorously dry aprotic
[1]
°
organic solvents, and at low temperatures (0 to À 78 C).
However, the synthetic work of various research groups world-
wide has revealed the possibility to promote organic trans-
formations that involve the use of these polar organometallics
in unconventional solvents (like water or traditional ionic
liquids).[3] Bearing this idea in mind, and trying to build new
bridges between green chemistry[4] and s-block polar organo-
metallic reagents, some of us recently reported the possibility
to generate new CÀ C bonds [through the fast and chemo-
selective nucleophilic addition of organolithium (RLi) or organo-
magnesium (RMgX) reagents to different unsaturated organic
electrophiles, such as ketones or esters,[5] imines or nitriles,[6]
and alkenes[7]]; or CÀ P bonds [by selective addition of lithium
phosphides (LiPR2) to aldehydes or epoxides],[8] working in all
cases at room temperature and in the absence of protecting
atmospheres, by using biorenewable deep eutectic solvents
(DESs) based on choline chloride, water, or glycerol as
sustainable reaction media.[9,10]
[a] Dr. D. Elorriaga, Dr. F. de la Cruz-Martínez, Dr. A. Lara-Sánchez
Departamento de Química Inorgánica, Orgánica y Bioquímica-Centro de
Innovación en Química Avanzada (ORFEOÀ CINQA)
Facultad de Ciencias y Tecnologías Químicas
Universidad de Castilla-La Mancha
13071, Ciudad Real (Spain)
E-mail: elorriaga.david@gmail.com
[b] Dr. M. J. Rodríguez-Álvarez, Dr. J. García-Álvarez
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
33071, Oviedo (Spain)
Simultaneously, a huge amount of effort has been dedi-
cated worldwide to try to convert CO2 (an inexpensive, nontoxic
and sustainable C1 feedstock) into value-added chemical
products, and therefore this area is becoming nowadays a
rapidly growing research field for the scientific community.[11]
Although being chemically attractive, the inherent thermody-
namic and kinetic stability of carbon dioxide is the major
impediment for its direct incorporation into organic
frameworks.[12] Meanwhile, the reaction between epoxides and
carbon dioxide has been developed into a successful carbon
dioxide utilization process,[13] producing cyclic carbonates which
E-mail: garciajoaquin@uniovi.es
[c] Dr. J. A. Castro-Osma
Departamento de Química Inorgánica, Orgánica y Bioquímica-Centro de
Innovación en Química Avanzada (ORFEO-CINQA)
Facultad de Farmacia
Universidad de Castilla-La Mancha
02071, Albacete (Spain)
E-mail: joseantonio.castro@uclm.es
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cssc.202100262
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Results and Discussion
It is well known that the carbonyl group is a very versatile
functional group in organic chemistry. In that way, one of the
most important reactions that carbonyl groups can be involved
in is the CÀ C bond formation, through which gives rise to
tertiary alcohols.[24,25] In this sense, one of the most powerful
strategies for the synthesis of tertiary alcohols is the addition of
highly polar organometallic reagents to carbonyl groups.[26]
However and as previously mentioned, the employment of
meticulously dry organic solvents under inert atmosphere and
at low temperature is usually mandatory when those high polar
organometallic species are present.[1] Moreover, this route often
involves side reactions, due to the strong basicity of the
organometallic reagents employed, giving rise to the enoliza-
tion of the substrates. Thus, and bearing in mind our previous
studies on the addition of highly polar organolithium reagents
to carbonyl compounds (ketones and imines) under bench-type
reaction conditions (room temperature under air) and using
sustainable solvents (water or DESs),[5,6] we decided to further
extend our approach by using in this case biorenewable and
sustainable organic electrophiles like cyclic carbonates en route
to highly substituted tertiary alcohols, symmetric ketones, or β-
hydroxy esters.[27]
Thus, we first explored the straightforward and operation-
ally simple addition of nBuLi to ethylene carbonate (1a) in
different sustainable solvents, at room temperature and under
air. Our first attempts (Table 1, entries 1–3) employing water- or
choline chloride (ChCl)-based eutectic mixtures (1:2 ChCl/urea
or 1:2 ChCl/glycerol) were totally unsuccessful. Surprisingly,
when biorenewable and undistilled 2-MeTHF (i.e., as received
from commercially available sources, with air and moisture, see
Experimental Section) was used as solvent and after only 3 s,
the reaction took place giving rise to the formation of a mixture
of three products, 2a, 3a and 4, in different proportions
depending on the equivalents of nBuLi added (Table 1, entries
4–9). Products 2a and 3a correspond to the double and triple
addition process, respectively, whereas 4 is formed, as a side
product through the in situ reduction of ketone 2a.[28] Remark-
ably, we experimentally found that the gradual increase of the
number of equivalents of nBuLi (from 1 to 5 equivalents;
Table 1, entries 4–8) correlates with a concomitant improve-
ment of the yield of the desired tertiary alcohol 3a (up to 77%
yield) containing the crude of the reaction only minor amounts
of by-products 2a (7%) and 4 (2%). At this point, it is important
to note that using larger excess of nBuLi (6 equivalents) does
not improve the yield of the tertiary alcohol 3a (Table 1,
entry 9). For completeness of this parametrization studies, we
decided to investigate the possibility to run the aforementioned
addition reaction in the absence of any additional solvent, this
is by using directly the commercially available nBuLi solution
(hexane) as solvent (Table 1, entries 10–15). As already observed
in the reaction that employs 2-MeTHF as solvent, the yield of
the desired tertiary alcohol 3a increases as the number of
equivalents of nBuLi increases from 7% (1 equivalent) to 67%
(5 equivalents). However, the reactions under these experimen-
tal conditions are not able to improve the previous yields and
Scheme 1. Fast addition of polar s-block organometallic reagents (RLi/RMgX)
to cyclic carbonates at room temperature, under air, and in 2-MeTHF as
solvent or in the absence of external VOC solvents.
have found application in a myriad of different chemical fields,
ranging from lithium-ion batteries or polymer chemistry to
lubricants or solvents in industrials processes.[14] Moreover, and
as these heterocyclic moieties present a more accessible carbon
atom coming from CO2 than the free molecule, they have been
used in the synthesis of a variety of chemical products like
methanol,[15] carbamates,[16] different heterocyclic compounds[17]
or ionic liquids,[18] among others. Thus, all these encouraging
features clearly illustrate that cyclic carbonates are attractive
alternatives to the direct use of carbon dioxide as a C1 building
block. Therefore, taking into account our aforementioned
studies on the fast and chemoselective addition of RMgX/RLi
reagents to carbonyl compounds at room temperature and in
the presence of air,[5–8] as well as the earlier elegant and
illuminating method described by the research groups of
Jessop and Snieckus for the conversion of other C1 feedstocks,
such as sodium methyl carbonate, into carboxylic acids or
ketones through direct addition of RMgX/RLi reagents, with dry
organic solvents, under protecting atmosphere, and after 24 h
of reaction,[19] we decided to study the use of cyclic carbonates
(a CO2-derived sustainable feedstock) as biorenewable electro-
philes capable of suffering the fast addition of RMgX/RLi
reagents, at room temperature, under air and using 2-meth-
yltetrahydrofuran (2-MeTHF) as a sustainable solvent or in the
absence of external VOC solvents (we employed a stock solution
of commercially available RLi/RMgX reagents containing various
VOC solvents; Scheme 1). 2-MeTHF is considered a biorenew-
able biomass-derived solvent as it can be produced from
furfural without the need of petrochemical protocols.[20] More-
over, the intrinsic immiscibility of 2-MeTHF with water allows its
direct use in liquid-liquid extractions, preventing the employ-
ment of other toxic and nonbiorenewable volatile organic
solvents, such as CH2Cl2, for extracting the desired organic
reaction products.[21] In this sense, a variety of s-block promoted
organic transformations have been reported using 2-MeTHF as
an alternative and sustainable solvent.[22] Recently, and in line
with these studies, some of us (in collaboration with Hevia’s
group) reported the use of lithium amides in 2-MeTHF for both
the fast amidation of esters[23a] and the hydroamination of
styrenes,[23b] working at room temperature and in the absence
of protecting atmosphere.
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when 2-MeTHF was used as solvent, a near-quantitative yield of
3b was observed (90%), being the unique product of the
reaction, as ketone 2b was not detected (Table 1, entry 16). As
expected, when these conditions were employed, the yield of
the desired tertiary alcohol 3b decreased considerably and
ketone 2b appeared as by-product (Table 1, entry 17). A similar
scenario was observed when MeLi was used as alkylating
reagent (entries 18–19), obtaining better results when 2-MeTHF
was employed as solvent. Finally, when 5 equivalents of the
aromatic lithium reagent PhLi were employed, either in 2-
MeTHF or in the absence of external solvents, none of the
expected products were observed but the corresponding
homo-coupling product PhÀ Ph.
Table 1. Fast addition of organolithium (RLi) reagents to cyclic carbonate
1a, at room temperature, in the presence of air and in different sustainable
solvents.[a]
Entry
Solvent
RLi
(equiv.)[b]
Yield [%][c]
2a–c
–
–
3a–c
–
–
4
–
–
1
2
3
4
5
6
7
8
H2O
nBuLi (1)
nBuLi (1)
nBuLi (1)
nBuLi (1)
nBuLi (2)
nBuLi (3)
nBuLi (4)
nBuLi (5)
nBuLi (6)
nBuLi (1)
nBuLi (2)
nBuLi (3)
nBuLi (4)
nBuLi (5)
nBuLi (6)
EtLi (5)
ChCl/urea[d]
ChCl/Gly[d]
–
–
–
11
8
3
3
2
2
14
10
6
4
4
5
–
–
–
–
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
1 (2a)
1 (2a)
4 (2a)
4 (2a)
7 (2a)
5 (2a)
1 (2a)
5 (2a)
5 (2a)
6 (2a)
5 (2a)
5 (2a)
0 (2b)
19 (2b)
8 (2c)
12(2c)
13 (3a)
38 (3a)
62 (3a)
62 (3a)
77 (3a)
73 (3a)
7 (3a)
36 (3a)
52 (3a)
62 (3a)
67 (3a)
65 (3a)
90 (3b)
79 (3b)
67 (3c)
40 (3c)
Trying to have a full picture of the addition of organolithium
reagents to cyclic carbonates, we decided to extend our studies
to the addition of EtLi to a range of cyclic carbonates (1b–f)
under the best reaction conditions (5 equivalents of EtLi, room
temperature, under air with 2-MeTHF as solvent; Scheme 2). As
previously observed for 1a, the almost instantaneous formation
of tertiary alcohol 3b was observed in all cases, finding better
yield for purely aliphatic and saturated cyclic carbonates 1a–d
(Scheme 2). Replacing these saturated cyclic carbonates by the
corresponding counterparts containing allylic or propargylic
ethers as substituents (1e,f; Scheme 2) led to lower yields. In all
cases, the formation of 3b occurs chemoselectively with no side
product (ketone 2b) observed in the crude reaction mixture
(only the unreacted cyclic carbonates 1a–f were detected,
respectively). These results indicate that the carbonyl carbon in
1a–f, coming from the CO2, is more accessible than in the high
stable free CO2 molecule and even more than in the acyclic
carbonates (like sodium methyl carbonate).[19]
9
10
11
12
13
14
15
16
17
18
19
–
–
–
–
–
–
2-MeTHF
–
2-MeTHF
–
EtLi (5)
MeLi (5)
MeLi (5)
[a] General Conditions: Reactions performed under air, at room tempera-
ture, using 1 mmol of cyclic carbonate 1a and 1–6 mmol of the polar
organometallic reagent RLi in 1 mL of the desired solvent. [b] Commercial
solution of nBuLi (2.5 M in hexanes), EtLi (0.5 M in benzene/cyclohexane)
and MeLi (1.6 M in diethyl ether) were employed. [c] Yields determined by
GC-FID using trimethoxybenzene as internal standard (1 mmol) after
calibration (see the Supporting Information). [d] 1:2 mixture; Gly=
glycerol.
To probe the scope of our methodology in terms of the
nature of the polar organometallic reagent employed and
bearing in mind the previous work reported by Profs. Jessop
and Snieckus in the addition of Grignard compounds to methyl
carbonate,[19] we then decided to study the reactivity of cyclic
carbonates (derived from CO2 as sustainable C1 synthon) with
RMgX reagents. As we mentioned previously, the employment
selectivities obtained when 2-MeTHF was used as solvent
(compare entries 4–9 with entries 10–14 in Table 1). This
experimental observation could be directly related with the
capability of ethereal solvents (like 2-MeTHF) to solvate the
oligomeric structure of nBuLi, thus producing kinetically
activated smaller aggregates of nBuLi which could then
preferentially undergo three consecutive addition reactions
over competing degradation processes in the presence of air
and/or moisture. Thus, and when no additional ethereal solvent
are employed, this kinetic activation could not take place as the
commercially available nBuLi solution contains a non-Lewis
donor solvent (hexanes). Interestingly, it is important to note
that under our experimental conditions, we never observed the
formation of ketone 2a as the main product of the reaction, in
contrast with the previous studies reported by Jessop and
Snieckus, in which sodium methyl carbonate was employed as
C1 feedstock.[19]
Next, and to expand further the scope of our study, the
reactivity of carbonate 1a with other organolithium reagents
(RLi) under the optimized reaction conditions (5 equivalents,
ambient temperature, under air) was also investigated by using
2-MeTHF as reaction medium or in the absence of any
additional VOC solvent. Astonishing, in the case of EtLi and
Scheme 2. Fast addition of EtLi to cyclic carbonates 1a–f at room temper-
ature, under air, and with 2-MeTHF as solvent.
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of these highly polar organometallic reagents in the presence
of air and at room temperature is still a challenge due to the
possible side reactions (reduction or enolization) or concom-
itant degradation processes in the presence of air and/or
moisture.[1] Thus, we started our experimental studies by
exploring the addition of nBuMgCl to ethylene carbonate (1a)
in a variety of sustainable solvents, at room temperature and in
the presence of air. As previously observed for RLi reagents, the
employment of water or choline-chloride-based eutectic mix-
tures (1:2 ChCl/urea or 1:2 ChCl/Gly) was totally unsuccessful
(Table 2, entries 1–3). However, when undistilled 2-MeTHF (i.e.,
as received from commercially available sources; Table 2,
entry 4) or additional-solvent-free conditions (Table 2, entry 10)
were employed, the reaction took place after only 3 s, giving
rise a mixture of two products: the previously observed tertiary
alcohol 3a (in only 1% or 3% yield; Table 2, entries 4 and 10)
and the new β-hydroxy ester 5a (2-hydroxyethyl pentanoate) in
low (19%, entry 4) to moderate (32%, entry 10) yields, as a
result of the mono-addition of nBuMgCl to the carbonyl
group.[29] In both cases, the gradual increase of the number of
equivalents of nBuMgCl (from 1 to 5 equivalents; Table 2,
entries 4–8 and 10–14) is correlated with a concomitant
improvement of the yield of the desired β-hydroxy ester 5a (up
to 58% yield) but at the cost of producing two more side
products, the ketone 2a and the corresponding secondary
alcohol 4. As general pattern in both 2-MeTHF or in the absence
of any other external solvents, we observed, in contrast to
nBuLi, that at low concentration of nBuMgCl there is not
formation of the secondary alcohol 4 (entries 4–5, 10–11), and
when more equivalents of nBuMgCl were added, small quanti-
ties of 4 were obtained (entries 6–9, 13–15), reaching the
maximum yield of 4% and 6% in 2-MeTHF and in the absence
of additional solvents, respectively. Ketone 2a appears from
two equivalents and rises with the addition, whereas the
tertiary alcohol 3a was present since the very beginning of the
reaction and reaches the highest proportion with 3 equivalents
to subsequently decrease. Bearing in mind that the best
conditions to obtain β-hydroxy ester 5a required the use of 3
equivalents of the Grignard reagent, either in 2-MeTHF or in the
absence of extra solvents, we decided to extend our studies to
other organomagnesium reagents finding that neither EtMgBr
or MeMgBr (Table 2, entries 16–19) could improve the previous
performance observed for nBuMgCl.
Having identified the best condition for the mono-addition
of Grignard reagents (RMgX) as follows: 3 equivalents of
nBuMgCl, at room temperature, under air and in 2-MeTHF as
solvent; we next extended our studies to the previously assayed
carbonates 1a-f. For cyclic carbonates 1a and 1d, and due to
their intrinsic symmetry, only one ring opening product can be
formed, whereas with the asymmetric cyclic carbonates
(1b,c,e,f), two different openings of the cyclic carbonates can
take place, thus giving rise to either primary (7, 8, 10, 11) or
secondary β-alcohol (7’, 8’, 10’, 11’; Table 3). In general, these
reactions gave moderated to low yields (63–16%) of the mono-
addition products as mixtures with the expected ketone 2a and
the tertiary alcohol 3a. Astonishing, for the cyclic carbonate
substituted with a methyl group (1b), the major isomer
obtained is the primary alcohol 7 (Table 3, entry 1) whereas for
Table 2. Fast addition of Grignard reagents (RMgX) to cyclic carbonate 1a, at room temperature, in the presence of air and in different sustainable
solvents.[a]
Entry
Solvent
RMgX (equiv.)[b]
Yield [%][c]
2a–c
3a–c
4
5a–c
1
2
3
4
5
6
7
8
H2O
ChCl/urea
ChCl/Gly
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
–
–
–
–
–
–
nBuMgCl (1)
nBuMgCl (1)
nBuMgCl (1)
nBuMgCl (1)
nBuMgCl (2)
nBuMgCl (3)
nBuMgCl (4)
nBuMgCl (5)
nBuMgCl (6)
nBuMgCl (1)
nBuMgCl (2)
nBuMgCl (3)
nBuMgCl (4)
nBuMgCl (5)
nBuMgCl (6)
EtMgBr (5)
–
–
–
–
–
–
–
–
–
0
0
1
2
3
4
0
0
0
1
3
6
–
–
–
–
–
–
–
0 (2a)
2 (2a)
6 (2a)
24 (2a)
31 (2a)
35 (2a)
0 (2a)
3 (2a)
4 (2a)
15 (2a)
34 (2a)
50 (2a)
11 (2b)
5 (2b)
0 (2c)
0(2c)
1 (3a)
2 (3a)
11 (3a)
17 (3a)
20 (3a)
19 (3a)
3 (3a)
8 (3a)
10 (3a)
16 (3a)
18 (3a)
13 (3a)
33 (3b)
84 (3b)
74 (3c)
57 (3c)
19 (5a)
47 (5a)
58 (5a)
48 (5a)
46 (5a)
42 (5a)
32 (5a)
47 (5a)
53 (5a)
45 (5a)
38 (5a)
22 (5a)
39 (5b)
0
9
10
11
12
13
14
15
16
17
18
19
2-MeTHF
–
2-MeTHF
–
EtMgBr (5)
MeMgBr (5)
MeMgBr (5)
0
0
[a] General Conditions: Reactions performed under air, at room temperature, using 1 mmol of cyclic carbonate 1a and 1–6 mmol of the polar organometallic
reagent RMgX in 1 mL of the desired solvent. [b] Commercial solution of nBuMgCl (2 M in THF), EtMgBr (1 M in THF) and MeMgBr (3 M in diethyl ether) were
employed. [c] Yields determined by GC-FID using trimethoxybenzene as internal standard (1 mmol) after calibration (see the Supporting Information). [d] 1:2
mixture; Gly=glycerol.
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Table 3. Fast addition of nBuMgCl to cyclic carbonates 1b–f, at room
Table 4. Fast addition of aryl-Grignard reagents to cyclic carbonate 1a, at
room temperature, in the presence of air and in different sustainable
solvents.[a]
temperature, under air and using 2-MeTHF as solvent.[a]
Solvent
ArMgX
(equiv.)[b]
Yields [%][c]
2d–f
0 (2d)
52 (2d)
72 (2d)
31 (2d)
28 (2d)
46 (2d)
63 (2d)
79 (2d)
38 (2d)
7 (2d)
27 (2e)
21 (2e)
5 (2f)
3d–f
2 (3d)
2 (3d)
15 (3d)
30 (3d)
40 (3d)
3 (3d)
3 (3d)
13 (3d)
41 (3d)
44 (3d)
12 (3e)
11 (3e)
2 (3f)
2 (3f)
–
5d–f
69 (5d)
26 (5d)
25 (5d)
22 (5d)
20 (5d)
23 (5d)
25 (5d)
25 (5d)
24 (5d)
9 (5d)
67 (5e)
53 (5e)
67 (5f)
28 (5f)
–
Ar–Ar
2
2
11
30
39
4
1
2
3
4
5
6
7
8
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
PhMgBr (1)
PhMgBr (2)
PhMgBr (3)
PhMgBr (4)
PhMgBr (5)
PhMgBr (1)
PhMgBr (2)
PhMgBr (3)
PhMgBr (4)
PhMgBr (5)
TolylMgBr (3)
TolylMgBr (3)
AnisMgBr (3)
AnisMgBr (3)
MesMgBr (3)
MesMgBr (3)
Entry
Carbonate
Yields [%][b]
2a 3a
Ratio[c]
2-MeTHF
–
–
–
–
7–11
63 (7)
31 (8)
32 (9)
21 (10)
16 (11)
4
1
2
3
4
5
1b
1c
1d
1e
1f
11 16
75:25 (7/7’)
8:92 (8/8’)
13
36
47
14
15
8
3
–
–
4
20
5
0
27
6
9
–
10
11
12
13
14
15
16
–
18:82 (10/10’)
1:99 (11/11’)
2-MeTHF
1
6
–
2-MeTHF
[a] General Conditions: Reactions performed under air, at room tempera-
ture, using 1 mmol of cyclic carbonates 1b–f and 3 mmol of the Grignard
reagent nBuMgCl (2 M in THF) in 1 mL of 2-MeTHF. [b] Yields refer to
isolated products. [c] Ratios determined by NMR spectroscopy.
–
2-MeTHF
–
11 (2f)
–
–
–
–
[a] General Conditions: Reactions performed under air, at room tempera-
ture, using 1 mmol of cyclic carbonate 1a and 1–5 mmol of the polar
organometallic reagent Ar-MgX in 1 mL of the desired solvent. [b]
Commercial solution of PhMgBr (1 M in THF), p-TolylMgBr (1 M in THF),
p-AnisMgBr (0.5 M in THF) and MesMgBr (1 M in THF) were employed. [c]
Yields refer to isolated products (yields were calculated for each product
taking into account that the corresponding product is the only one
obtained).
the rest of the asymmetric carbonates (1c,e,f), the major isomer
is the secondary β-alcohol (8’, 10’, 11’; Table 3, entries 2, 4, 5).
However, when aryl-Grignard reagents were employed, we
observed a new product distribution (Table 4). Thus, the
addition of PhMgBr to ethylcarbonate (1a) in 2-MeTHF (Table 4,
entry 1) gave rise to the formation of a mixture of three
products: the corresponding tertiary alcohol (in this case
triphenyl alcohol, 3d) in only 2% yield, the β-hydroxy ester
compound (2-hydroxyethyl benzoate, 5d) in good yield (69%),
and the previously observed homo-coupling product (PhÀ Ph) in
very low yield (2%). When the number of equivalents of
PhMgBr is raised, the formation of the corresponding ketone
(2d) was observed. As expected, the gradual increase of the
number of equivalents of PhMgCl (from 1 to 3 equivalents;
Table 4, entries 1–3) produces an improvement of the yield of
the desired ketone 2d (up to 72% yield) but boosting the
formation of the corresponding side products (3d, 15%; PhÀ Ph,
11%) and with concomitant reducing of the yield of 5d (26%).
Increasing the amount of PhMgBr up to 5 equivalents (Table 4,
entry 5) decreases the formation of both 5d (20%) and 2d
(28%), whereas yields of the tertiary alcohol 3d and the homo-
coupling product (PhÀ Ph) are raised (40% and 20%, respec-
tively).
but with simultaneous and parallel increase in the yield of 5d
(Table 4, entries 6–8). Employing higher amounts of the
Grignard reagent is led to a massive decrease in yield for both
2d and 5d and a huge increase in the production of alcohol 3d
and the homo-coupling product (Table 4, entries 9 and 10).
When the aryl group of the organomagnesium compound is
changed by p-tolyl (4-methylbenzene), the same behaviour
with lower yields was observed (Table 4, entries 11 and 12); but
when p-anisole (4-methoxybenzene) is used under the afore-
mentioned condition, the β-hydroxy ester 5f is obtained now
as main product (Table 4, entries 13 and 14). Finally, when the
phenyl substituent in PhMgBr is replace by a mesityl group
(2,4,6-trimethylbenzene), the reaction is completely shut down
and only the corresponding hydrolyzed product (mesitylene)
was obtained (Table 4, entries 15 and 16).
Established the best condition for the formation of the
ketones 2d–f as three equivalents of PhMgBr in 2-MeTHF, we
extended the scope of our studies to the previously assayed
cyclic carbonates 1b–f (see Table 5). As earlier observed for
cyclic carbonate 1a (see Table 4), the corresponding benzophe-
none is in most cases the product obtained in higher yield (2d)
with values between moderated to low (64–27%). In contrast,
and for the specific case of the symmetric cyclic carbonate 1d,
we observed the formation of the corresponding β-hydroxy
ester compound 14 as the major product of the reaction (50%
Nevertheless, when the reaction is carried out in the
absence of any external solvent, ketone 2d is now formed even
with only one equivalent of PhMgBr in moderate yields (Table 4,
entry 6) and reach its maximum concentration when three
equivalents of PhMgBr are used (Table 4, entry 8). Analogously
to when 2-MeTHF is used, increasing the amount of the aryl-
Grignard reagent in the absence of external solvents produces
an increase of the tertiary alcohol 3d and the PhÀ Ph product
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Table 5. Fast addition of PhMgCl to cyclic carbonates 1b–f, at room
temperature, under air and using 2-MeTHF as solvent.[a]
Scheme 3. Proposed synthetic pathway involving all species detected during
the addition of RLi/RMgX reagents to cyclic carbonates, at room temper-
ature, under air, and using 2-MeTHF as solvent.
Yields [%][b]
2d 3d
Ratio[c]
PhÀ Ph
12–16
[%][b]
1
2
3
4
5
1b
1c
1d
1e
1f
59 10
31 (12)
21 (13)
50 (14)
23 (15)
11 (16)
78:22 (12/12’)
18:82 (13/13’)
–
5:95 (15/15’)
14:86 (16/16’)
9
13
7
12
16
metallic reagent is able to undergo an addition process to this
ketone II, thus producing the corresponding symmetric tertiary
alcohol III. Only in the case of using nBuLi as the alkylation
reagent, the formation of the secondary alcohol IV was
detected, and this experimental observation can be explained
as a consequence of the previously reported in situ reduction of
ketone II.[28]
64
27
56
58
15
15
18
14
[a] General Conditions: Reactions performed under air, at room tempera-
ture, using 1 mmol of cyclic carbonates 1b–f and 3 mmol of Grignard
reagent PhMgBr (2 M in THF) in 1 mL of 2-MeTHF. [b] Yields refer to
isolated products (yields were calculated for each product taking into
account that the corresponding product is the only one obtained). [c]
Ratios determined by NMR spectroscopy.
During the last decade, the design of one-pot tandem
protocols has occupied a strategic place in the framework of
organic synthesis, as a new greener substitute for standard and
tedious stepwise processes. This leads to a drastic reduction of
isolation and purification steps of intermediates (thus minimiz-
ing both the generation of chemical waste and the required
time and energy), thereby simplifying the practical aspects of
the synthetic procedures, and to the possibility to work with
unstable reaction intermediates (as no isolation of highly
reactive and transitory-form species is needed).[30] In most of
the cases, these one-pot tandem protocols employ the same
synthetic organic utensil (transition metals, enzymes, main-
group elements or organocatalysts) throughout all the tandem
process, while the corresponding hybrid examples that de-
scribed the amalgamation of different instruments from the
organic synthetic toolbox, is still scarce.[31] In this sense, some of
us have previously studied the fruitful combination of transition
metal-catalyzed organic transformations in water or DESs with
the chemoselective addition of organolithium reagents (RLi) to
transiently formed ketones,[5b] the enzymatic and enantioselec-
tive bioamination (transaminases, ATAs) or bioreduction (ketor-
eductases, KREDs) of in situ-generated prochiral ketones;[32a–e] or
the biocatalytic decarboxylation of p-hydroxycinnamic acids.[32f]
Taking into account this previous experience in the design of
hybrid synthetic protocols, and bearing in mind that the
combination of metal-catalyzed organic transformations and
main-group chemistry in 2-MeTHF has not been studied (as far
as we are aware), we decided to try to finish with this
discontinuity by the study of the unprecedented assemble of
the aluminum-catalyzed fixation of CO2 with propylene oxide
(for the in situ synthesis of cyclic carbonate 1b intermediate)
with the fast addition of an organolithium reagent (EtLi) to the
aforementioned transitory cyclic carbonate 1b in 2-MeTHF
(under air and at room temperature) to obtain the correspond-
ing highly substituted tertiary alcohol 3b under mild and more
yield). In line with our previous studies with nonsymmetric
cyclic carbonates 1b,c,e,f, two different openings of the cyclic
carbonates can take place when these compounds are treated
with 3 equiv. of PhMgBr, thus giving rise to either primary (12,
13, 15, 16) or secondary β-alcohols (12’, 13’, 15’, 16’) (see
Table 5). Again, and in accordance with the results obtained
with the aliphatic Grignard reagent nBuMgCl (see Table 4), we
observed that ring-opening products formed in low yields (11–
34%; Table 5, entries 1, 2, 4, and 5); and that the major isomer
was always the secondary β-alcohol (13’, 15’, and 16’; Table 5,
entries 2, 4, and 5), except for the carbonate with a methyl
group (1b) from which which the major isomer obtained was
the primary alcohol 12 (Table 5, entry 1). For the rest of the
asymmetric carbonates (1c,e,f), the major isomer was the
secondary β-alcohol (8’, 10’, and 11’; Table 3, entries 2, 4, and
5).
Taking into account all our experimental studies and every
isolated species that we have been able to detect in the crudes
reaction media, we can propose a global picture of the reaction
between cyclic carbonates and highly polar organometallic
reagents (RLi/RMgX), when working at room temperature,
under air and in 2-MeTHF as solvent (see Scheme 3). Thus, in a
first step of the overall process, one equivalent of the highly
polar organometallic reagent (RLi/RMgX) triggers the opening
of the cyclic carbonate through its addition to the carbonyl
group, giving rise to the corresponding β-hydroxy ester
intermediate I. Subsequently, a second equivalent of the highly
polar organometallic reagents attacks the carbonyl group of the
β-hydroxy ester intermediate I, producing the concomitant
release of the corresponding diol and the formation of the
expected ketone II. A third equivalent of the polar organo-
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promoted organic transformations under more sustainable and
mild experimental conditions (room temperature and under
air). Consequently, our method will offer a new and more
environmentally friendly tool for possible application in the
manufacture of highly substituted tertiary alcohols, β-hydroxy
esters, or symmetrical ketones.
Scheme 4. Design of a hybrid one-pot/two-step method that combines the
reaction cycloaddition of CO2 and propylene oxide with the concomitant
and fast addition of EtLi to the transiently formed cyclic carbonate 1b at
room temperature, under air, and using 2-MeTHF as solvent.
Experimental Section
General considerations
sustainable reaction conditions (Scheme 4). Thus, we firstly
studied the aluminum/ammonium-catalyzed cycloaddition of
CO2 (1 atm) with propylene oxide at room temperature in 2-
MeTHF employing [AlEt2(k2-bpzbdeape)]/Bu4NBr [5 mol%,
bpzbdeape=1,1-bis(4-(diethylamino)phenyl)-2,2-bis(3,5-dimeth-
yl-1H-pyrazol-1-yl)ethan-1-ol)] as catalyst, previously described
by some of us as an efficient and selective catalytic system for
this transformation.[33] As soon as total conversion of propylene
oxide into the desired cyclic carbonate 1b was observed (16 h,
GC analysis), EtLi was directly added to the reaction mixture,
without any intermediate step of isolation or purification of 1b,
in the absence of protecting atmosphere and at room temper-
ature (conditions usually forbidden for RLi reagents).[1] Astonish-
ing, we observed the almost instantaneous formation (3 s) of
the corresponding tertiary alcohol 3b as the only product of
the reaction, finding an almost quantitative yield for 3b (88%)
when five equivalents of the organolithium reagent were
employed (see Scheme 4). Thus, this experiment confirms the
suitability of our hybrid one-pot/two-step synthetic strategy for
the indirect and sustainable conversion of CO2 into highly
substituted tertiary alcohols without the isolation/purification of
any reaction intermediate.
All reagents were obtained from commercial suppliers and used
without further purification with the exception of cyclic carbonates
1a–f[33] and the deep eutectic solvents (DESs),[10] which were
prepared by following the corresponding reported methods.
Grignard and organolithium reagents were purchased from Sigma
Aldrich: nbutyl lithium (2.5 M solution in hexanes); ethyl lithium
(0.5 M solution in benzene/cyclohexane); methyl lithium (1.6 M in
diethyl ether); phenyl lithium (1.9 M solution in nBu2O); nBuMgCl
(2 M solution in THF); EtMgBr (1 M solution in THF); MeMgBr (3 M
solution in diethyl ether); PhMgBr (1 M solution in THF); p-TolylMgBr
(1 M solution in THF); p-AnisMgBr (0.5 M solution in THF); MesMgBr
(1 M solution in THF). Concentrations of all organolithium reagents
were established by titration with l-menthol,[34] and the concen-
tration of Grignard reagents were determined by titrating against
iodine.[35] Commercially available 2-MeTHF was directly employed
without any previous purification technique (distillation/use of
molecular sieves) and was directly opened and stored in the
presence of air and moisture.
NMR spectra were recorded on
a AV400 MHz spectrometer
operating at 400.13 MHz for 1H, and 100.62 MHz for 13C. All 13C
spectra were proton decoupled. 1H and 13C NMR spectra were
referenced against the appropriate solvent signal. GC/FID measure-
ments were made on Agilent Technologies 7890 A chromatograph
equipped with a DS-5MS UI (30 m, 0.53 mm) column (for more
information on the calibration; see the Supporting Information).
General procedure for the addition of organolithium reagents
to cyclic carbonates
Conclusions
In summary, with this work we have demonstrated that the
biorenewable solvent 2-MeTHF can be selected as the environ-
mentally friendly reaction medium of choice for the fast
addition of highly polar organometallic reagents (RLi/RMgX) to
cyclic carbonates (as CO2-derived sustainable C1 feedstock
resources) under standard bench reaction conditions (under air,
room temperature), thus allowing the replacement of Schlenk-
type experimental techniques in the synthesis of tertiary
alcohols (with organolithium reagents), β-hydroxy esters (when
alkyl-Grignard reagents are employed), or symmetric ketones
(by using aryl-Grignard reagents). Moreover, we have described
a greener, and operationally simple one-pot procedure for the
effective synthesis of highly substituted tertiary alcohols
through the successful combination of aluminum-catalyzed
cycloaddition of CO2 and propylene epoxide with the chemo-
selective and fast addition of organolithium reagents (EtLi) to
the transiently formed cyclic carbonate 1b (without tedious
and energy- and time-consuming intermediate purification or
isolation steps). Thus, these results clearly demonstrate that 2-
MeTHF can be used as an optimal reaction media for RLi/RMgX-
Syntheses were performed under air and at room temperature. In a
glass tube, the appropriate cyclic carbonate (1a–f, 1 mmol) was
dissolved in the corresponding alternative solvent (1 mL) under air,
followed by the addition of the desired RLi reagent (1 to 5 mmol
were employed) at room temperature, and the reaction mixture
was stirred for 2–3 s. The reaction was then stopped by addition of
a saturated solution of the Rochelle salt (sodium potassium tartrate
tetrahydrate) and the mixture was extracted with 2-MeTHF (3×
5 mL). The combined organic phases were dried over anhydrous
MgSO4 and the solvent was concentrated in vacuo. Yields of the
reaction crudes were determined by GC-FID using trimeth-
oxybenzene as internal standard (1 mmol) after calibration (see the
Supporting Information). Separation and purification of every
compound was carried out using TLC glass plate silica. All reactions
were done in triplicate to ensure good reproducibility of obtained
yields.
General procedure for the addition of Grignard reagents to
cyclic carbonates
Syntheses were performed under air and at room temperature. In a
glass tube, the appropriate cyclic carbonate (1a–f, 1 mmol) was
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F. M. Perna, A. Salomone, Dalton Trans. 2014, 43, 14204–14210; e) E.
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dissolved in the corresponding alternative solvent (1 mL) under air,
followed by the addition of the desired Grignard reagent (RMgX; 1
to 5 mmol were employed) at room temperature, and the reaction
mixture was stirred for 2–3 s. The reaction was then stopped by
addition of a saturated solution of the Rochelle salt (sodium
potassium tartrate tetrahydrate) and the mixture was extracted
with 2-MeTHF (3×5 mL). The combined organic phases were dried
over anhydrous MgSO4 and the solvent was concentrated in vacuo.
Yields of the reaction crudes were determined by GC-FID using
trimethoxybenzene as internal standard (1 mmol) after calibration
(see the Supporting Information). Separation and purification of
every compound was carried out using TLC glass plate silica. All
reactions were done in triplicate to ensure good reproducibility of
obtained yields.
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A glass tube was charge with the aluminum catalyst [AlEt2(k2-
bpzbdeape)][33] (bpzbdeape=1,1-bis[4-(diethylamino)phenyl]-2,2-
bis(3,5-dimethyl-1H-pyrazol-1-yl)ethan-1-ol; 0.05 mmol, 29 mg) and
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Acknowledgements
M.J.R.A. and J.G.A thank the Spanish MINECO (Projects CTQ2016-
75986-P, CTQ2016-81797-REDC and RED2018-102387-T Programa
Redes Consolider) and PhosAgro/UNESCO/IUPAC for the award of
a “Green Chemistry for Life” grant. D.E. thanks the Gobierno del
Principado de Asturias and EU for the award of a postdoctoral
fellowship and the Junta de Comunidades de Castilla la Mancha
and EU for financial support through the European Regional
Development Fund (ERDF; project SBPLY/19/180501/000137). A.L.S
and J.A.C.O gratefully acknowledge financial support from the
MINECO, Spain (grant numbers. CTQ2017-84131-R, CTQ2016-
81797-REDC and RED2018-102387-T Programa Redes Consolider).
F.d.l.C.M. acknowledges the Ministerio de Educación, Cultura y
Deporte (MECD) for the FPU Fellowship (FPU15/01772).
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: CO2 · cyclic carbonates · green chemistry · Grignard
reagents · organolithium compounds
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Manuscript received: February 4, 2021
Revised manuscript received: March 4, 2021
Accepted manuscript online: March 5, 2021
Version of record online: March 23, 2021
ChemSusChem 2021, 14, 2084–2092
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