Cyclopentyl methyl ether-NH4X: A novel solvent/catalyst system for low impact acetalization reactions

Article abstract of DOI:10.1039/c5gc00465a

Cyclopentyl methyl ether, a low impact ether forming a positive azeotrope with water, was successfully employed as a solvent in the synthesis of 1,3-dioxanes and 1,3-dioxolanes carried out under Dean-Stark conditions by the acetalization of aliphatic and aromatic aldehydes or ketones, employing ammonium salts as environmentally friendly acidic catalysts.

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Cyclopentyl Methyl Ether-NH4X: a Solvent/
Catalyst System for Low Impact Acetalization
Reactions
Cite this: DOI: 10.1039/x0xx00000x
Ugo Azzena,a,* Massimo Carraro,a Ashenafi Damtew Mamuye,a,‡ Irene Murgiaa and
Luisa Pisanoa, Giuseppe Zeddea
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
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ammonium salts. Indeed, compounds such as ammonium chloride,
bromide and hydrogensulfate are cheap, easily available and
relatively mild acids8 and, due to their smaller formula weight, give
rise to a low amount of generated wastes. Additionally, it is worth
noting that these salts do not need any kind of activation as required,
for example, by other acidic solid catalysts such as zeolites or clays.
Cyclopentyl methyl ether, a low impact ether forming a
positive azeotrope with water, was successfully employed as a
solvent in the synthesis of 1,3-dioxanes and 1,3-dioxolanes
carried out under Dean-Stark conditions by the acetalization
of aliphatic and aromatic aldehydes or ketones, employing
ammonium salts as environmentally friendly acidic catalysts.
Table 1. Synthesis of dioxolane 3a.a
Acetals are a fundamental class of substrates in organic chemistry
usually employed in the protection of carbonyl groups during
multistep synthesis,1 as well as intermediates in the monoprotection
of diols.2 Additionally, they found applications as fragrances3 or
profragrances4 in everyday life. Typically, acetals are synthesized
starting from aldehydes or ketones with alcohols or polyols under
azeotropic distillation conditions in the presence of an acid catalyst.
The system commonly employed uses toluene as a solvent and p-
toluenesulfonic acid (p-TSA) as a catalyst, often in the presence of
large excess of alcohol. Within this field, most green approaches
concern the employment of heterogeneous acidic catalysts, due to
their ease of separation and recovery from reaction mixtures.5
Entry
Diol
(equiv)
Solvent
NH4X
3a (%)b
1
2
3
4
5
6
7
1.1
1.5
2.0
1.1
1.1
1.1
1.1
CPME
CPME
NH4HSO4
NH4HSO4
NH4HSO4
NH4Br
90c
95
Cyclopentyl methyl ether (CPME) is emerging as a green alternative
to ethereal solvents such as tetrahydrofuran, dioxane and diethyl
CPME
98
ether. This solvent, industrially produced via
a 100% atom
economical reaction, is characterized by low toxicity, high boiling
point, resistance to peroxide formation, stability towards acids and
bases, low heat of vaporization, and a narrow explosion range.
Although a note of caution is due to its relatively low auto ignition
temperature (180 °C), it forms a positive azeotrope with H2O (bp 83
°C, azeotropic composition: CPME/H2O = 83.7:16.3 w/w) thus
resulting easy to recover and dry, due to its high hydrophobicity.6
CPME
79d
65d
80
CPME
NH4Cl
Toluene
2-MeTHF
NH4HSO4
NH4HSO4
31
These characteristics prompted us to evaluate its employment as an
alternative to solvents with a higher environmental impact, such as
toluene,7 in reactions run under azeotropic distillation conditions, for
instance the acetalization reaction.
aAll reactions were run at reflux during 6 h in the presence of the catalyst (3 mol % of
1a). bAs determined by 1H-NMR analyses of crude reaction mixtures; no other product
was detected besides 1a. cComparable results were obtained recycling 4 times the
recovered catalyst. dComparable results were observed recycling twice the recovered
catalyst.
We found it advantageous, from the green chemistry standpoint, to
keep the excess of alcohols to a low level and to substitute p-
toluenesulfonic acid (p-TSA) with inorganic solid acids, such as
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Taking acetophenone, 1a, as a model compound, we investigated its either toluene or an alternative low impact ether, i.e., 2-MeTHF,9
conversion into the corresponding 1,3-dioxolane, 3a, by refluxing a under otherwise identical reaction conditions (Table 1).
4M solution of the ketone with 1,2-ethandiol, 2a, under Dean-Stark
conditions in the presence of the acidic catalysts (3 mol% of 1a). For
comparison purposes, few reactions were run employing as a solvent
m
O
NH4X
X
R
X
+
HX(CH2)nXH
+
H2O
R
R1
R1
CPME
1b-l
3b-l (X = O, m = 0,1)
4a,b (X = NCH3, m = 0,1)
2a,b (X = O, n = 2,3)
2c (X = NCH3, n = 2,3)
H3C
O
O
O
O
H
O
O
O
O
3
H
2
Ph
3d, 98% (NH4Cl, 6h)
C2H5
3b, 98% (NH4Cl, 2h)
(S)-3c, >99% (NH4Cl, 6h)
OCH3
3e, 95% (NH4Cl, 6h)
96% (NH4HSO4, 6h)
O
O
O
O
O
O
O
O
CH3
6
COOCH3
Cl
Br
3h, >99% (NH4HSO4, 6h)a
3i, 97% (NH4HSO4, 6h)
3f, 88% (NH4Cl, 6h)
3g, 92% (NH4Cl, 6h)
97% (NH4Cl, 6h)a
98% (NH4HSO4, 6h)b
O
O
O
O
O
O
CH3
O
O
CH3
CH3
3j, 96% (NH4Cl, 6h)b
NO2
NO2
3lb, 95% (NH4HSO4, 6h)c
Cl
3la, 56% (NH4Cl, 6h)
73% (NH4Br, 6h)
3k, 85% (NH4HSO4, 6h)
>99% (NH4HSO4, 6h)c
90% (NH4HSO4, 6h)
>99% (NH4HSO4, 6h)c
N
N
N
N
N
N
H3C
CH3
H3C
CH3
H3C
CH3
O
O
Ph
CH2Br
3m, 95% (NH4HSO4, 6h)c
Cl
4b, >99% (NH4Cl, 2h)
OCH3
OCH3
4c, >99% (NH4Cl, 1h)
4a, >99% (NH4Cl, 1h)
Scheme 1 Synthesis of acetals in CPME. Reaction conditions: 4M solution of 1 in CPME, 1.1 equiv of 2a-c (unless otherwise indicated), 3 mol% of NH4X
(with respect to 1), reflux (Dean-Stark conditions); NH4X = NH4Cl, NH4Br or NH4HSO4; percentages represent conversion of the starting materials as
1
a
b
determined by H-NMR; no other product, besides starting material, was detected. In the presence of 1.4 equiv of diol; A comparable result was obtained
recycling the recovered catalyst. cIn the presence of 2.0 equiv of diol.
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As expected, ammonium salts proved insoluble in the organic CPME as a solvent (or a co-solvent), as depicted in equations 3-5.
solvents, thus allowing both their recovery and a successive easy Accordingly, the monoprotection of 1,3-propandiol as the
work up of the reaction mixtures. Indeed, after decantation of the corresponding 3-(4-methoxybenzyloxy)-1-propanol, 5a, was
catalyst, the resulting solution was neutralized over K2CO3, followed efficiently realized by submitting crude acetal 3e to reduction with
by evaporation of the solvent in vacuo (see Electronic DIBAL-H
(equation
1);
reduction
of
crude
(4-
Supplementary Information). Concerning reactions run in CPME, carboxymethylphenyl)-1,3-dioxolane, 3f, with LiAlH4 afforded the
our results show that NH4HSO4, the most acidic between the chosen corresponding benzyl alcohol, 5b, in 70% overall yield (equation 2);
ammonium salts, resulted more effective than NH4Br and NH4Cl as
a catalyst (Table 1, entry 1 vs. entries 4 and 5). A moderate increase
in the amount of the diol (2.0 equivs of 2a) was sufficient to achieve
an almost quantitative conversion of the starting material within the
allotted reaction time (Table 1, entry 3).10 Additionally, NH4HSO4
was efficiently recycled 4 times (Table 1, entry 1), whilst both
NH4Br and NH4Cl were recycled twice (Table 1, entries 4 and 5,
respectively) without observing any decrease of their catalytic
activities.
finally, ring opening of crude -brominated dioxolane 3m was
realized in 85% overall yield via a SET reduction run with 1,2-
disodiotetraphenylethane15 (equation 3).
Interestingly, no improvement was observed employing toluene as a
solvent and NH4HSO4 as a catalyst (Table 1, entry 6); finally, a very
low conversion of the starting material was observed running a
similar reaction in 2-MeTHF (Table 1, entry 7), probably due to the
relatively low boiling point of its azeotrope with H2O.
The above described procedure was successfully extended to the
synthesis of a series of 1,3-dioxolanes (including 3b, a known
fragrance,11 enantiomerically pure 3c, and the biologically active
compounds 3k and 3la12), 1,3-dioxanes (including 3e, an
intermediate in the synthesis of a monoprotected 1,3-propandiol,13
and
the
biologically active
compounds
3lb12),
1,3-
dimethylimidazolidines 4a,b and the hexahydropyrimidine 4c, as
diagrammatically illustrated in Scheme 1.
Taken as a whole, our results show that the ammonium salts
efficiently catalyzed the almost quantitative conversion of aliphatic
as well as aromatic aldehydes, 1b-h, into the corresponding
dioxolanes and dioxanes, 3, and aminals, 4, in the presence of minor
excesses of the required dinucleophiles (1.1 to 1.4 equivs), and
similar results were obtained with ketones 1i and 1j.
As the generation of peroxides is a major security concern for
reactions run in ethereal solvents, we next investigated the stability
of CPME towards the formation of peroxides under the above
As already observed with 1a, slightly lower reactivities were
observed in the case of aromatic ketones 1k-m, as expected on the
basis of their relatively low electrophilicities; indeed, up to 2.0
equivs of the diol and the employment of NH4HSO4 as a catalyst
were necessary to drive their conversions up to ≥ 95%, as evidenced
in the case of dioxolanes 3k-3la.14
reported reaction conditions. To this end, we employed
a
commercially available kit (Quantofix®, measuring range 0.5 – 25
mg/L H2O2) allowing a semi-quantitative evaluation of these
dangerous by-products in non-aqueous solvents. According to the
reported resistance of CPME to autoxidation,16 we found it possible
to run our reactions with the commercially available solvent
(stabilized with 50 ppm of BHT) exposed to air through a CaCl2
tube, without observing any formation of peroxides.
Besides what already reported in Table 1, the efficiency of
NH4HSO4 as a catalyst in the acetalization of aromatic ketones is
outlined in comparative experiments related to the synthesis of
compound 3la (Scheme 1).
Finally, it is worth mentioning that it was possible to realize an 85%
mass recovery of CPME by submitting the solvent, collected by
evaporation of reaction mixtures, to filtration over acidic alumina
followed by drying over KOH and distillation (see Electronic
Supplementary Information). From this point of view, it is worth
mentioning that recovery of CPME by distillation is economically
favourable due to its relatively low latent heat of vaporization.6a
Additionally, the recovery and reuse of the acidic catalysts was
effectively applied to the synthesis of dioxolanes 3g (NH4HSO4) and
3j (NH4Cl).
It is also interesting to observe that aminals 4a-c were obtained with
higher yields and shorter reaction times compared to those necessary
to obtain the corresponding cyclic acetals 3e and 3g, respectively,
likely due to the higher nucleophilicity of the nitrogen vs. oxygen
dinucleophiles.
Conclusions
As a conclusion, we were able to demonstrate the capability of
CPME to promote the acetalization of aldehydes and ketones
employing ammonium salts as acidic catalysts, thus
To further assess the usefulness of our protocol, few crude acetals
synthesized as described above were further elaborated employing
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representing an efficient green alternative to toluene/p-TSA.
Accordingly, our results disclose an environmentally
sustainable approach to the synthesis of a particularly important
class of organic compounds as well as an alternative approach
to reactions run under Dean-Stark conditions. Additionally,
besides underlying the possibility of an easy and efficient
recovery of CPME, it is worth noting that the employment as
acidic catalysts of low impact, highly economical, recyclable
and non soluble ammonium salts allowed the set up of a
particularly simple and efficient work up with a reduced
production of wastes.
10. The employment of 3 mol% of p-TSA as an acidic catalyst
afforded a comparable result, whilst the employment of
catalytic amounts of zeolite ZSM-5 or molecular sieves (3 Ǻ)
led to poorer conversions.
11. R. Chaudhuri, G. Puccetti, F. Marchio, Z. Lascu, Methods for
stabilizing ingredients within cosmetics, personal care and
household products, US2005/244349 A1, 2005.
12. E. F. Morand, M. N. Iskander, C. E. Skene, Novel methods for
the treatment of inflammatory deseases, WO2004/89927 A1,
2004.
13. See, for example: D. Hernández, K. B. Lindsay, L. Nielsen, T.
Mittag, K., Bjerglund, S., Friis, R. Mose, T. Skrydstrup, J.
Org. Chem., 2010, 75, 3283.
Acknowledgment
Financial support from the Regione Autonoma della Sardegna,
through the Legge Regionale 07/09/2007 (code CRP-59740), is
gratefully acknowledged.
14. Besides what already reported in Table 1, the efficiency of
NH4HSO4 as a catalyst in the acetalization of aromatic
ketones is outlined in comparative experiments related to the
synthesis of compound 3la (Scheme 1).
Notes and references
1. T. W. Green, P. G. M. Wuts, in Protective Groups in Organic
Synthesis, Wiley, New York, 3rd edn., 1999, p. 297.
2. B. Bartel, R. Hunter, J. Org. Chem., 1993, 58, 6756.
3. H. Surburg and J. Panten, Common Fragrance and Flavour
Materials, Wiley-VCH Weinheim, 5th edn., 2006, p. 12.
4. A. Hermann, Profragrances and Properfumes, in The
Chemistry and Biology of Volatiles, A. Hermann Ed., Wiley,
Chichester, 2010, p. 333.
15. U. Azzena, F. Kondrot, L. Pisano, M. Pittalis, Appl.
Organometal. Chem., 2012, 26, 180, and references therein.
16. H. Hoshino, K. Sakakibara, K. Watanabe, Chem. Lett., 2008,
37, 774.
a
Dipartimento di Chimica e Farmacia, Università di Sassari, via Vienna
2, 07100 – Sassari (Italy)
‡Current Address: Department of Pharmaceutical Chemistry, University
of Vienna, Althanstrasse 14, Vienna, Austria
5. See, for example: a) C. Gonzalez-Arellano, S. Deb, R. Luque,
Catal. Sci. Technol., 2014,
4, 4242; b) B. Mallesham, P.
Electronic Supplementary Information (ESI) available: General method,
synthetic procedures, characterization data of all compounds including
copies of 1H and 13C NMR of previously not completely described
compounds. See DOI: 10.1039/c000000x/
Sudarsanam, G. Raju, B. M. Reddy, Green. Chem., 2013, 15
478; c) J. Deutsch, A. Martin, H. Lieske, J. Catal., 2007, 245
,
,
428; d) M. J. Climent, A. Corma, A. Velty, Appl. Catal. A:
Chem., 2004, 263 155, and references therein; e) S.
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Palaniappan, P. Narander, C. Saravanan, V. J. Rao, Synlett,
2003, 1793.
6. For a review, see: a) K. Watanabe, N. Yamagiwa, Y. Torisawa,
Org. Proc. Res. Dev., 2007, 11, 251; for recent examples, see:
b) C. Gozlan, R. Lafon, N. Duguet, A. Redl, M. Lemaire, RSC
Adv., 2014, 4, 50653; c), K. Skowerki, J. Biatecki, A. Tracz,
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7. Positive azeotrope toluene/H2O: bp 80 °C, azeotropic
composition: toluene/H2O = 79.8:20.2, w/w).
8. pKa (in H2O): p-TSA = -2.58: http://www.epa.gov/hpv/pubs/
-
+
summaries/ptolacid/c16597tc.htm; HSO4 = 1.99 and NH4
=
9.25: J. A. Dean, Lange’s Handbook of Chemistry, McGraw-
Hill New York, 15th edn., 1999, Table 8.7.
9. Positive azeotrope 2-MeTHF/H2O: bp 71 °C, azeotropic
composition: 2-MeTHF/H2O = 89.4:10.6, w/w); for recent
applications of this biomass-derived solvent in organic
chemistry, see: V. Pace, P. Hoyos, L. Castoldi, P. Dominguez
de María, A. R. Alcantara, ChemSusChem, 2012, 5, 1369.
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