1,2,3-Trimethoxypropane, a glycerol-based solvent with low toxicity: New utilization for the reduction of nitrile, nitro, ester, and acid functional groups with TMDS and a metal catalyst

Article abstract of DOI:10.1039/c3gc41082j

1,2,3-Trimethoxypropane (1,2,3-TMP) was prepared from glycerol in one step in good yield and selectivity by phase transfer catalysis. According to OECD guidelines, a toxicity study was realized for this compound. It revealed that 1,2,3-TMP has a low acute toxicity, no skin sensitization, no mutagenicity and no ecotoxicity in an aquatic environment. This compound was also used as a solvent for the reduction of organic functions using either aluminium hydride or 1,1,3,3-tetramethyldisiloxane (TMDS) as a benign hydride source. In particular, a new process for the reduction of nitriles to amines in 2-MeTHF and in 1,2,3-TMP was developed, using TMDS in combination with copper triflate (Cu(OTf)₂).

Full text of DOI:10.1039/c3gc41082j

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For Table of Contents Use Only:
1,2,3-Trimethoxypropane a glycerol-based solvent with low toxicity: new utilization for the
reduction of nitrile, nitro, ester, acid functional groups with TMDS and a metal catalyst
NH2
O
R
R
O
NO2
TMDS
TMDS
[Fe]
[V]
R
R
R
OH
OH
O
O
HO
OH
LOW TOXICITY
O
OH
1,2,3-TMP
New solvent
O
R
NH2
TMDS
TMDS
[Cu]
[In]
N
R
OH
R
1,2,3-Trimethoxypropane (1,2,3-TMP) was prepared directly from glycerol and toxicological tests for
this new alternative solvent showed a low toxicity. Thus, 1,2,3-TMP was successfully used as new
solvent for the reduction of organic functions with TMDS as benign reducing agent in association with
a catalytic amount of metal complex. In particular, a new process was developed for the reduction of
nitriles into amines with the system TMDS/copper triflate.

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DOI: 10.1039/C3GC41082J
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ARTICLE TYPE
1,2,3-Trimethoxypropane a glycerol-based solvent with low toxicity: new
utilization for the reduction of nitrile, nitro, ester, acid functional groups
with TMDS and a metal catalyst
Marc Sutter,a Leyla Pehlivan,a Romain Lafon,a Wissam Dayoub,a Yann Raoul,b Estelle Métaya and Marc
5
Lemaire*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
1,2,3ꢀTrimethoxypropane (1,2,3ꢀTMP). Interestingly, this
compound presents the same molecular formula than diglyme,
50 known for serious health concerns, but still used in organic
synthesis for its chemical and physical properties.15 To the best of
our knowledge, 1,2,3ꢀTMP was never synthesized in pure form,
nor specifically used as solvent. Furthermore, no experimental
data concerning the toxicity of this compound is available.16
1,2,3-Trimethoxypropane (1,2,3-TMP) was prepared from
glycerol in one step in good yield and selectivity by phase
10 transfer catalysis. According to OECD guidelines, a toxicity
study was realized for this compound. It revealed that 1,2,3-
TMP has low acute toxicity, no skin sensitization, no
mutagenicity and no ecotoxicity in aquatic environment. This
compound was also used as solvent for the reduction of
15 organic functions using either aluminium hydride or 1,1,3,3-
tetramethyldisiloxane (TMDS) as benign hydride source. In
particular, a new process for the reduction of nitriles to
amines in 2-MeTHF and in 1,2,3-TMP was developed, using
TMDS in combination with copper triflate (Cu(OTf)2).
55
In this report were detailed a series of toxicological tests for
1,2,3ꢀTMP followed by its utilization as solvent in the reduction
of organic
functions.
In
our
laboratory,
1,1,3,3ꢀ
tetramethyldisiloxane (TMDS) has been employed as a safe
hydride source to efficiently reduce various organic functions in
60 the presence of a catalytic quantity of a transition metal.17 These
methodologies represent alternative conditions to the wellꢀknown
aluminum and boron hydrides, which are expensive, dangerous
and require careful handling. Thus, we report the use of 1,2,3ꢀ
TMP as solvent in the reduction of different functions in these
65 previous optimized conditions and a new method for the
reduction of nitriles to amines in 1,2,3ꢀTMP using TMDS as
reducing agent in association with copper triflate (Cu(OTf)2,
Scheme 1).
20
Over the last century, the development of chemistry is linked
to an increasing use of solvents in a variety of applications.
Today, they are largely employed in many economic sectors.1 In
fact, solvents are defined as liquid compounds able to dissolve,
extract or dilute molecules without chemical modifications and
25 without being modified themselves. Solvent effects are often
spectacular in organic reactions, with an influence on the kinetic
as well as on the selectivity.2 Indeed, organic synthesis of the
second part of the twentieth century could be considered as the
chemistry of the solvent effect. Many solvents are employed at
30 large scale, however, they are generally petroleumꢀbased,
Volatile Organic Compounds (VOC), hazardous, toxic and thus
contribute to the negative environmental impact of chemistry.3
Even if the best alternative could be to run reactions without
solvent,4 their use is unavoidable in many cases. Progresses have
35 already been done with the utilization of supercritical fluids,5
ionic liquids,6 or water.7 Nevertheless, as pointed out during the
2nd International Symposium on Green Chemistry,8 other
sustainable solutions need to be proposed.9 For example, as
mentioned by Jessop,10 only little alternatives were proposed for
40 polar aprotic solvents. Thus, in agreement with the green
chemistry principles,11 another way to develop alternative
solvents is to prepare nonꢀtoxic original compounds from
renewable materials, as glycerol,12 2ꢀmethyltetrahydrofuran (2ꢀ
MeTHF)13 and others.14
70
75 Scheme 1 New process for the reduction of nitriles into amines with
Cu(OTf)2 in combination with TMDS in 1,2,3ꢀTMP.
First of all, the synthesis of 1,2,3ꢀTMP was envisaged in
similar conditions than those developed for the selective
preparation of alkyl glycerol monoethers by reductive alkylation
80 of glycerol with aldehydes, carboxylic acids or esters.18 Until
now, no satisfying results were obtained by this pathway. Thus,
the use of a methylation agent was considered. With dimethyl
carbonate (DMC), a poor conversion was observed. With
dimethyl sulfate (DMS) a reaction by phase transfer catalysis
85 without solvent in the presence of tetrabutylammonium
hydrogenosulfate (TBAHS) as phase transfer agent afforded
1,2,3ꢀTMP in excellent selectivity and in 78% yield after
distillation (Scheme 2, details of the synthesis in ESI).
45
In this context, and in a continuous research program dedicated
to the valorization of glycerol, we were interested in the
preparation of glycerolꢀbased aprotic solvents and in particular
This journal is © The Royal Society of Chemistry [year]
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DOI: 10.1039/C3GC41082J
KOH (3.3 equiv.)
DMS (1.7 equiv.)
TBAHS (10 mol%)
percentage biodegradation of 1,2,3ꢀTMP was relatively low
40 (6.4%, entry 8).
HO
OH
O
O
OH
O
Finally, the ecotoxicity of this compound in aquatic
environment was also evaluated with several tests on aquatic
species. A growth inhibition test on freshwater alga and
cyanobacteria was carried out (OECD 201).26 It revealed that the
45 concentration of 1,2,3ꢀTMP bringing 50% inhibition of growth
rate (ErC50) after 72 h is higher than 0.104 g/L, consequently
1,2,3ꢀTMP is considered as non toxic (entry 9). An acute
immobilisation test on Daphnia sp. (OECD 202) was also
realized,27 and the concentration estimated to immobilize 50% of
50 the daphnids (EC50) was found higher than 0.112 g/L after 48 h of
exposure (entry 10). In this case, 1,2,3ꢀTMP is also considered as
non toxic. Finally, an acute toxicity test on fish (OECD 203)28
revealed that 1,2,3ꢀTMP is not toxic. In fact, it was found a
median lethal concentration (LC50) in water after 96 h above
55 0.104 g/L (entry 11).
r. t.
Conversion = 99%
Selectivity= 96%
Isolated yield = 78%
5
Scheme 2 Preparation of 1,2,3ꢀTMP by phase transfer catalysis.
This pathway allowed to prepare 1,2,3ꢀTMP at 150 g scale, in
order to evaluate its toxicology and its interest as solvent.
However, to avoid the use of DMS, a safer method for its
10 preparation is still under investigation in the laboratory.
Thus, the first aim of this work was to collect information for
1,2,3ꢀTMP, according to OECD guidelines.
As can be seen from the results in table 1, following ISO 2719,
the flashpoint of 1,2,3ꢀTMP was measured at 45.5 °C, which
15 allows its use in a broad range of applications. This value is
higher in comparison of those given for common ethereal
solvents as diethyl ether (Et2O, ꢀ45 °C), tetrahydrofuran (THF, ꢀ
14.5 °C) or “greener” solvents as 2ꢀmethyltetrahydrofuran (2ꢀ
MeTHF, ꢀ11 °C) and cyclopentyl methyl ether (CPME, ꢀ1 °C).
First, the acute oral toxicity of 1,2,3ꢀTMP was studied on rats
(OECD 423).19 The median lethal dose (LD50) value is estimated
greater than 2000 mg/kg and thus considered as non toxic (entry
2). An acute dermal toxicity study of 1,2,3ꢀTMP (OECD 402)
was also carried out,20 and in this case too, the LD50 of 1,2,3ꢀ
25 TMP is estimated greater than 2000 mg/kg (entry 3). An acute
dermal irritation/corrosion test (OECD 404) revealed no dermal
irritation on rabbit skin (entry 4).21 However, the acute eye
irritation/corrosion study (OECD 405),22 lead to the conclusion
that 1,2,3ꢀTMP is ocular irritant (entry 5). Skin sensitization
30 study (Local Lymph Node Assay, LLNA, OECD 429) was
performed to determine if 1,2,3ꢀTMP induces allergic reactions.23
The test was negative in this case since no skin sensitization was
induced by 1,2,3ꢀTMP (entry 6). No evidence of mutagenic
activity was observed when a bacterial reverse mutation test
35 (Ames test, OECD 471) was performed with 1,2,3ꢀTMP (entry
7).24
From these toxicity studies, 1,2,3ꢀTMP shows very
encouraging results as potential suitable and safe solvent in
chemical transformations.
20
Thus, we found interesting to test the behaviour of 1,2,3ꢀTMP
60 as alternative solvent in the reduction of organic functions. We
first tested a common approach by using an aluminium hydride,
LiAlH4.29 As can be seen from the results in table 2, several
substrates were reduced in 1,2,3ꢀTMP at room temperature.
Methyl benzoate 1a afforded the corresponding benzyl alcohol 1b
65 in quantitative yield (entry 1), whereas 2ꢀmethoxybenzoic acid 2a
was reduced into alcohol 2b in 97% yield (entry 2). Nitriles were
also reduced in 1,2,3ꢀTMP. The reduction of 4ꢀ
phenylbutyronitrile 3a gave the corresponding amine 3b in 81%
yield (entry 3), but the reduction of naphthalenꢀ2ꢀcarbonitrile 4a
70 afforded the desired naphthalenꢀ2ꢀylmethanamine 4b in only 38%
isolated yield, as already observed in the literature for this
substrate.30 This is probably in reason of purification issues
linked to the presence of large amounts of aluminium salts
making difficult to extract properly the reduced product (entry 4).
75
Thus, aluminium and boron hydrides display several
drawbacks linked to their high reactivity in the presence of water
The biodegradability of 1,2,3ꢀTMP was measured according to
the CO2 evolution test (OECD 301 B).25 After 28 days, the
Table 1 Flash point test and toxicity studies for 1,2,3ꢀTMP
Entry Test
ISO / OECD guidelinea
ISO 2719
Results
Commentary
1
Flash point
45.5 °C
2
Acute oral toxicity, acute toxic class method
Acute dermal toxicity
OECD 423
LD50(rats) > 2000 mg/kg
LD50(rats) > 2000 mg/kg
Rabbit: no dermal irritation
Rabbit: ocular irritant
Not toxic
Not toxic
3
OECD 402
4
Acute dermal irritation/corrosion
Acute eye irritation/corrosion
Skin sensitization (LLNA)
OECD 404
5
OECD 405
6
OECD 429
Negative, no skin hypersensitization
7
Bacterial Reverse Mutation Test (Ames Test)
Ready biodegradability
OECD 471
Negative
Not mutagenic
8
OECD 301 B
6.4 %
Low biodegradability
Not toxic
9
Freshwater alga and cyanobacteria, growth inhibition test OECD 201
ErC50 (72 h) > 0.104 g/L
EC50 (48 h) > 0.112 g/L
LC50 (96 h) > 0.104 g/L
10
11
Daphnia sp., Acute immobilisation test
OECD 202
OECD 203
Not toxic
Fish, Acute toxicity Test
Not toxic
a Short description of the tests in the Supporting Information.
2
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Table 2 Reductions of organic functions in 1,2,3ꢀTMP using LiAlH4 as
Table 3 Reductions of organic functions in 1,2,3ꢀTMP using TMDS as
45 hydride source and a metal complex as catalyst.
hydride source.a
Conv.b Yieldc
Conv.a Yieldb
Entry Substrate
Product
Entry Substrate
Product
(%)
(%)
(%)
(%)
1
1a
2a
3a
4a
1b
2b
3b
4b
>99
99
1c
5a
5b
6b
7b
8b
9b
>99
95
2
>99
>99
>99
97
81
38
2c
3c
4d
5d
6d
7e
8e
6a
>99
>99
>99
>99
86
94
81
99
59
95
66
3d
4d
7a
8a
aConditions: substrate (2 mmol, [1 M] in 1,2,3ꢀTMP), LiAlH4 (1.2
equiv.), r. t., 2 h. Conversion of the substrate, determined by H NMR
spectroscopy. cIsolated yield. dReaction performed with 2 equiv. of
LiAlH4.
b
1
9a
5
as well as the production of a large amount of waterꢀsoluble salts
generated at the end of the reaction.
In the alternative procedures developed for the reduction of
10 organic functions associating TMDS and a metal catalyst, we
observed in each case an important influence of the solvent on the
advancement of the reaction.17 Petroleumꢀbased toluene or
tetrahydrofuran (THF) were mainly employed in these examples,
it was therefore interesting to control if 1,2,3ꢀTMP could
15 efficiently replace these solvents in these methodologies.
10a
11a
12a
10b 65
11b >99
12b >99
As can be seen from the results in Table 3, optimized reported
conditions were applied for the reduction of nitro, ester and acid
functions. For the reduction of nitro groups, three experiments
were run in the presence of 10 mol% of Fe(acac)3 and TMDS.17d,e
20 All substrates were efficiently reduced in 1,2,3ꢀTMP into their
corresponding amines 5b, 6b and 7b isolated as hydrochloride
salts (entries 1ꢀ3). Reactions were selective since neither
dehalogenation (entry 1) nor reduction of nitrile (entry 3) were
observed. In addition, when compared to the initial procedure run
25 in THF, isolated yields were similar in 1,2,3ꢀTMP. For example,
reduction of nitrobenzene 6a afforded product 6b in 99% yield in
THF17d,e and in 96% yield in 1,2,3ꢀTMP (entry 2). Methyl esters
were also reduced into alcohols with 1 mol% of V(O)(OiPr)3 and
TMDS. For these examples, 1,2,3ꢀTMP efficiently replaced
30 toluene as solvent.17j Under these conditions, methyl stearate 8a
was reduced in stearic alcohol 8b in 81% isolated yield (entry 4).
The reduction of aromatic ester 9a afforded alcohol 9b in
excellent yield (entry 5). However, same limitations were
observed than in our initial work,17j since 4ꢀmethyl
35 cyanobenzoate could not be reduced and methyl pꢀ
methoxybenzoate 10a afforded its corresponding alcohol 10b in
only 59% isolated yield after 24 h (entry 6). Finally, carboxylic
acids were also efficiently and selectively reduced into alcohols
with TMDS in association with indium bromide (InBr3). In this
40 case, 1,2,3ꢀTMP replaced toluene or dichloromethane (CH2Cl2) in
previous reported conditions.17i,31 The reaction afforded the
desired alcohols 11b and 12b in 95% and 66%, respectively with
no dehalogenation of substrate 11a (entries 7 and 8).
aConversion of the substrate, determined by 1H NMR spectroscopy.
c
bIsolated yield. Conditions: nitroarene (3 mmol, [1 M] in 1,2,3ꢀTMP),
Fe(acac)3 (10 mol%), TMDS (3 equiv.), 80 °C, 16 h.dConditions: methyl
ester (8 mmol, [2 M] in 1,2,3ꢀTMP), V(O)(OiPr)3 (1 mol%), TMDS (2
e
50 equiv.), 100 °C, 24 h. Conditions: carboxylic acid (5 mmol, [1 M] in
1,2,3ꢀTMP), InBr3 (1 mol%), TMDS (2 equiv.), 60 °C, 24 h.
In the laboratory, the reduction of both aromatic and aliphatic
nitriles into the corresponding amines was already described by
using a stoichiometric amount of Ti(OiPr)4 in toluene with
55 TMDS as hydride source.17h Even if the products were isolated in
good yields, the reaction also lead to the formation of large
amounts of salts, making sometimes the workꢀup and purification
procedures difficult to carry out.
This pushed us to find alternative and more ecoꢀfriendly
60 conditions by decreasing the amount of metallic complex in
combination with TMDS as well as an alternative and bioꢀ
sourced solvent like 2ꢀMeTHF or 1,2,3ꢀTMP.
At the beginning of our investigation, several catalysts were
screened
with
hydrosiloxanes
(TMDS
or
65 polymethylhydrosiloxane – PMHS, a 40ꢀunits polymeric chain)
as reducing agents. Benzonitrile 13a was used as model substrate
and toluene as solvent. Many experiments were performed with
cobalt, palladium, nickel, copper, iron or bismuth complexes and
either PMHS or TMDS. In the majority of cases, only the starting
70 material was recovered after 24 h at 100 °C (details in Supporting
Information).
This journal is © The Royal Society of Chemistry [year]
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Table 4 Optimization of the experimental conditions for the reduction of
However, and as shown in table 4, benzylamine 13b was
observed in 20% yield with 20 mol% of Ni(acac)2 and 4 molar
10 equivalents of TMDS (8 hydrides, entry 1). The conversion was
improved to 90% when toluene was replaced by 2ꢀMeTHF (entry
2). Thus, this result shows also the key role of the solvent in this
reaction, since no conversion was observed with Cu(OTf)2 in
toluene (entry 3) but was above 95% in 2ꢀMeTHF under the same
15 conditions (entry 4). To the best of our knowledge, copper triflate
was never used in the reduction of nitriles with TMDS. For
example, this catalyst was used in association with a siloxane or a
silane for the reduction of acetals to ethers,17f,g aldehydes and
carboxylic acids to alcohols17k and phosphines oxides to
20 phosphines.32 Once Cu(OTf)2 was selected as catalyst,
experimental parameters were optimized by decreasing the
amount of metal complex to 10 mol% (entry 5) and TMDS to 2
molar equivalents (4 hydrides, entry 6). The temperature is an
important parameter since at 60 °C, the reduction gave only 30%
25 of the desired product 13b (entry 7). Finally, when the reduction
of benzonitrile 13a was performed in 1,2,3ꢀTMP, the
corresponding amine 13b was isolated in 94% yield (entry 8).
These optimized conditions in both solvents (2ꢀMeTHF and
1,2,3ꢀTMP, table 4, entries 6 and 8) were considered for the
30 reduction of aromatic and aliphatic nitriles. Results are
benzonitrile 13a.a
TMDS
(equiv.)
Temp. Yieldb
Entry Catalyst (mol%)
Solvent
Toluene
(°C)
(%)
1
2
3
4
5
6
7
8
Ni(acac)2 (20)
Ni(acac)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
4
4
4
4
4
2
2
2
100
20
2ꢀMeTHF 100
Toluene 100
>90
0
2ꢀMeTHF 100
2ꢀMeTHF 100
2ꢀMeTHF 100
2ꢀMeTHF 60
1,2,3ꢀTMP 100
>95
89c
82c
<30
94c
aConditions: benzonitrile 13a (2 mmol, [0.5 M] in anhydrous solvent),
metal complex (10ꢀ20 mol%), TMDS (2ꢀ4 equiv.), 100 °C, 24 h, sealed
tube. bYields determined by 1H NMR spectroscopy. cIsolated yield as
hydrochloride salt with >99% purity after acidic treatment (HCl/Et2O,
2N).
5
Table 5 Reduction of nitriles into amines using Cu(OTf)2 and TMDS in 2ꢀMeTHF and in 1,2,3ꢀTMP.a
Isolated yieldb
(b, %)
Entry Nitrile a
Primary amine b
Secondary amine c
Solvent
Ratio b/c
100/0
100/0
100/0
100/0
100/0
100/0
90/10
100/0
86/14
100/0
100/0
100/0
70/30
>95/5
2ꢀMeTHF
1,2,3ꢀTMP
2ꢀMeTHF
1,2,3ꢀTMP
2ꢀMeTHF
1,2,3ꢀTMP
2ꢀMeTHF
1,2,3ꢀTMP
2ꢀMeTHF
1,2,3ꢀTMP
2ꢀMeTHF
1,2,3ꢀTMP
2ꢀMeTHF
1,2,3ꢀTMP
82
94
95
96
97
94
75
94
62
97
78
89
ꢀ
1
13a
14a
15a
16a
17a
3a
13b
14b
15b
16b
17b
18b
19b
13c
14c
15c
16c
17c
18c
19c
2
3
4
5
6
7
4a
81
a Conditions: nitrile (2 mmol, [0.5 M] in anhydrous solvent), Cu(OTf)2 (10 mol%), TMDS (4 mmol), 100 °C, 24 h, sealed tube. bIsolated as hydrochloride
salt with >99% purity.
35
4
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DOI: 10.1039/C3GC41082J
summarized in table
hydrochloride salts by acidic treatment. These two systems were
found to efficiently reduce benzonitrile 13a into the benzylamine
5
and products were isolated as
The authors warmly thank ONIDOL for their financial support
and for the biological tests and are grateful for the access to the
GCꢀMS analysis at the Centre Commun de Spectroscopie de
13b with an excellent selectivity after a reaction time of 24 h 60 Masse (F. Albrieux, C. Duchamp and N. Henriques) and NMR
5
(entry 1). The presence of an electron donating group in the para
position of the aromatic ring did not affect the efficiency of the
reaction for the reduction of nitriles 14a and 15a. The
corresponding primary amines 14b and 15b were obtained in
high selectivity with isolated yields above 94% (entries 2 and 3).
facilities at the Université Lyon 1.
Notes and references
a Laboratoire de Catalyse, Synthèse et Environnement, Institut de Chimie
et Biochimie Moléculaires et Supramoléculaires (ICBMS), CNRS.
65 UMR5246, Université Lyon 1, Bâtiment Curien-CPE, 3° étage, 43 Bd du
11 Novembre 1918, 69622, Villeurbanne Cedex, France; E-mail:
marc.lemaire.chimie@univ-lyon1.fr; Fax: +33 472 431 408; Tel: +33
472 431 409.
10 However, when the reaction was carried out with 4ꢀ
chlorobenzonitrile 16a in 2ꢀMeTHF, a mixture of primary amine
16b and secondary amine 16c was obtained in a ratio 90/10 (entry
4). In contrary, we noticed that the same reaction in 1,2,3ꢀTMP
afforded the desired primary amine 16b in 94% isolated yield
15 with an excellent selectivity (entry 4). Similarly, it was
interesting to note that the reduction of 4ꢀhydroxybenzonitrile
17a in 2ꢀMeTHF gave a mixture of primary amine 17b and
secondary amine 17c in a ratio 86/14, whereas the reaction was
selective for product 17b in 1,2,3ꢀTMP (entry 5). The reduction
20 of aliphatic 4ꢀphenylbutyronitrile 3a was selective for the desired
ammonium 18b in both solvents, but the product could be
isolated in higher yield in 1,2,3ꢀTMP (89%) than in 2ꢀMeTHF
(78%, entry 6). With naphthalenꢀ2ꢀcarbonitrile 4a, the difference
between both solvents was more pronounced. In 2ꢀMeTHF the
25 reduction afforded a mixture of products 19b and 19c in a ratio
70/30. In 1,2,3ꢀTMP, the selectivity for the expected ammonium
19b was above 95% and the product was isolated in 81% yield
(entry 7). This last result can be compared with the reaction
performed with LiAlH4 giving amine 4b in only 38% yield (table
30 2, entry 4).
b Sofiprotéol, 11, rue de Monceau, CS 60003, 75378 Paris Cedex 08,
70 France.
† Electronic Supplementary Information (ESI) available: synthesis of
1,2,3ꢀTMP, short description of OECD tests, details for the optimization
study, general procedures and products characterizations. See
DOI: 10.1039/b000000x/
75 ‡ Footnotes should appear here. These might include comments relevant
to but not central to the matter under discussion, limited experimental and
spectral data, and crystallographic data.
1
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To conclude, 1,2,3ꢀTrimethoxypropane (1,2,3ꢀTMP) was
synthesized from glycerol in high selectivity and in one step by
phase transfer catalysis. Toxicological studies were performed for
35 this potential alternative and bioꢀbased solvent. Results were very
encouraging since a high flash point was found, low acute
toxicities, with negative skin sensitization (LLNA), negative
mutagenicity and ecotoxicity. However, this compound is eye
irritant and presents a relatively low biodegradability. 1,2,3ꢀTMP
40 was successfully used as solvent for the reduction of organic
functions with LiAlH4 as hydride source. More ecoꢀfriendly
conditions were also adapted from reported studies with TMDS
as mild reducing agent and a metal complex as catalyst. Thus, for
the reduction of nitro, esters and carboxylic acids, 1,2,3ꢀTMP
45 efficiently replaced petroleumꢀbased solvents as THF, toluene
and dichloromethane. Finally, a new methodology was found for
the reduction of nitriles into amines with TMDS in the presence
of a catalytic quantity of Cu(OTf)2. The reaction was highly
solvent dependent and the best results were found in 1,2,3ꢀTMP.
50 Good results were also observed in 2ꢀMeTHF, even if the
selectivity for the desired primary amine was sometimes lower.
To define 1,2,3ꢀTMP as green solvent, complementary
toxicological studies are in progress and other applications are
under investigations in the laboratory. A more sustainable
55 preparation pathway for this compound is also under study.
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