Intramolecular cyclisation of isosorbide by dimethylcarbonate chemistry

Article abstract of DOI:10.1016/j.crci.2010.11.011

In this work the synthesis of a tricyclic isosorbide derivative in moderate yield directly from the dicarboxymethyl isosorbide in a continuous-flow apparatus is reported. The tricyclic structure has been isolated as pure and fully characterized. This product confirms the potentiality of dimethylcarbonate (DMC) as dehydrating agent also for complicated structure and opens up further investigation and application of DMC chemistry on renewable starting materials.

Full text of DOI:10.1016/j.crci.2010.11.011

C. R. Chimie 14 (2011) 652–655
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Preliminary communication/Communication
Intramolecular cyclisation of isosorbide by dimethylcarbonate chemistry
Pietro Tundo a,b, , Fabio Arico a,b, Guillaume Gauthier c, Agostino Baldacci d
*
`
a Interuniversity Consortium ‘‘Chemistry for the Environment’’, Via delle Industrie, 21/8 30175 Marghera, Venice, Italy
b
`
Ca’ Foscari Universita di Venezia, Dipartimento Scienze Ambientali, Dorsoduro 2137, 30123 Venice, Italy
´
c
Ecole nationale supe´rieure de chimie de Paris (ENSCP – Chimie ParisTech), 11, rue Pierre-et-Marie-Curie, 75005 Paris, France
d
`
Ca’ Foscari Universita di Venezia, Dipartimento di Chimica Fisica, Dorsoduro 2137, 30123 Venice, Italy
A R T I C L E I N F O
A B S T R A C T
Article history:
In this work the synthesis of a tricyclic isosorbide derivative in moderate yield directly
from the dicarboxymethyl isosorbide in a continuous-flow apparatus is reported. The
tricyclic structure has been isolated as pure and fully characterized. This product confirms
the potentiality of dimethylcarbonate (DMC) as dehydrating agent also for complicated
structure and opens up further investigation and application of DMC chemistry on
renewable starting materials.
Received 20 April 2010
Accepted after revision 25 November 2010
Available online 3 February 2011
Keywords:
Green chemistry
Carbohydrates
Cyclisation
ß 2011 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
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´
R E S U M E
Heterocycles
Nucleophilic substitution
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La synthese d’un derive tricyclique de l’isosorbide–nouvelle demonstration de la
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´
´ ´
polyvalence du dimethylcarbonate (DMC)–est ici presentee. Ce derive a ete obtenu avec
un rendement mode´re´, par un proce´de´ a` flux continu directement a` partir du
dicarboxyme´thyl-isosorbide. Le compose´ pur a e´te´ isole´ et sa structure pleinement
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ˆ
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caracterisee. Ce produit confirme la capacite du DMC a jouer un role d’agent deshydratant
ˆ
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meme sur des structures complexes et ouvre de nouvelles voies d’investigation visant a
appliquer la chimie du DMC a` la transformation de matie`res premie`res renouvelables.
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ß 2011 Academie des sciences. Publie par Elsevier Masson SAS. Tous droits reserves.
Short chain dialkylcarbonates such as dimethylcarbo-
nate (DMC), produced nowadays by clean processes, are
renowned for possessing properties of low toxicity and
high biodegradability, which make them true green
solvents and reagents [1]. In particular, DMC has been
widely used as efficient eco-sustainable substitute of the
most common carboxymethylating and methylating
agents such as phosgene, methyl halides or methylsulfate
that are toxic and highly corrosive [2]. DMC has shown
high selectivity with different monodentate nucleophiles
(alcohols, amines, thiols, CH2 acidic compounds) and
bidentate nucleophiles (hydrazine) acting, at will, as
methylating and/or carboxymethylating agent [3]. In
general DMC reacts as carboxymethylating agent at reflux
temperature (90 8C) while it acts as methylating agent
(BAl2 mechanism) at temperatures higher than 150 8C in
the presence of a base [4]. However, it was previously
reported that under similar conditions the reaction of hard
alkoxides with DMC gave exclusively the transesterified
methylcarbonates derivatives (via BAc2 mechanism), also
at high temperatures [5]. Methyl ethers of primary
alcohols can be obtained through a two steps reaction: a
B
Ac2 transesterification followed by the decarboxylation of
the resulting methylcarbonate. Methylation of secondary
and tertiary alcohols was never obtained quantitatively
due to the formation of elimination products [5]. However,
recently, it was reported that the secondary hydroxyl
groups of isosorbide, an anhydro sugar alcohol derived
from sorbitol widely used in the manufacture of polymers,
are efficiently methylated at reflux temperature (90 8C) by
reaction with DMC in the presence of a range of bases
(Scheme 1). The remarkable reactivity of isosorbide
* Corresponding author.
E-mail address: tundop@unive.it (P. Tundo).
1631-0748/$ – see front matter ß 2011 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.crci.2010.11.011

P. Tundo et al. / C. R. Chimie 14 (2011) 652–655
653
H
H
HO
MeO
through the use of chlorine (e.g. tosylate–through the
chlorosulphonation of toluene, mesylate, etc.) [8]. More-
over, cyclisation reactions conducted in acidic conditions
or in the presence of chlorine derivates involve generally
toxic reagents. In particular, Scheme 2 reports some
possible synthetic pathways for the synthesis of heterocy-
clic compounds. The use of tosyl chloride or tionyl chloride
(Scheme 2, path a), commonly used in the two steps of
synthesis of heterocycles, requires (in the first step) the
isolation of the mono tosyl (or chlorine) adduct by column
chromatography. Meanwhile the DMC-mediated intramo-
lecular cyclisation has the advantage to be a one-pot
approach to heterocycles (Scheme 2, path b).
Thus, in this work it is reported the novel synthesis of
tricyclic adduct of isosorbide by a green chlorine-free
approach. The synthesis of this tricyclic structure is
particularly relevant since it also supports a new expand-
ing field for the chemistry of DMC: green synthesis of cyclic
structure from renewable feedstock (carbohydrates). This
research field has recently shown to have numerous
applications in cosmetic and fragrance manufacture [9].
The formation of the tricyclic adduct of isosorbide in
moderate yield (38%) was noticed during an attempt to
synthesize DMI by decarboxylation of DC in a continuous
flow apparatus at high temperature using hydrotalcite
KW2000 as catalyst (Scheme 3) [10].
O
O
DMC, base
90 °C
O
O
OH
OMe
H
H
Scheme 1. Methylation of isosorbide.
towards methylation with DMC could be assigned to its
unique ‘‘V’’-like structure where each hydroxyl group is in
the
b-position to both furanic oxygens [6].
Moreover, our recent investigation on the methylation
of isosorbide demonstrated that during this reaction
several intermediates are also formed. In particular, three
classes of compounds were identified (Fig. 1): carbox-
ymethyl derivates (MC-1, MC-2, DC), carboxymethyl
methyl derivates (MCE-1, MCE-2) and methyl derivates
(MMI-1, MMI-2 and DMI). All these derivatives were
isolated as pure compounds and characterized [6].
In this article we report another by-product formed
during the methylation reaction of isosorbide: a tricyclic
structure (Fig. 1) namely (3S,3aR,6aR)-hexahydro-3,6-
epoxyfuro[3,2-b]furan. This tricyclic structure was previ-
ously synthesised starting from the ditosylate derivative of
isosorbide in the presence of sodium ethoxide and ethanol
[7]. However, full characterization and rationalization of
the product was never reported.
More importantly, this product demonstrates the
potentiality of DMC as dehydrating agent for the synthesis
of heterocycles by chlorine-free chemistry. In fact, the
commonly used synthetic approaches for the formation of
heterocycles (via cyclisation and/or cycloaddition) involve
mainly chlorine chemistry at different levels e.g. activated
chlorine-based leaving groups, or leaving groups created
The best conditions observed (Table 1) for the forma-
tion of the tricyclic adduct of isosorbide starting from DC,
include high temperature (200–240 C) and a slow flow
˚
rate (0.05–0.22 g/min). GC-MS analysis of the collected
reaction mixture showed that it includes DMI and the
tricyclic as main products together with a mixture of other
methyl derivates of isosorbide. This mixture was subject to
H
H
H
MeOOCO
O
MeOOCO
HO
O
O
O
O
O
OH
OCOOMe
OCOOMe
H
H
H
MC-1
MC-2
DC
H
H
MeOOCO
MeO
O
O
O
O
OMe
HO
OCOOMe
H
H
MCE-1
MCE-2
H
O
H
MeO
H
O
O
O
O
O
OMe
OH
O
H
H
H
MMI-1
MMI-2
Tricyclic Adduct
Fig. 1. Derivatives formed during the methylation of isosorbide.

654
P. Tundo et al. / C. R. Chimie 14 (2011) 652–655
OH
R
base
R
O
R1
OTs
Py
R1
OH
TsCl
R
OH
Cl
a
OH
R
R
base
R1
SOCl2
O
R1
R1
OH
R
R
DMC, base
b
O
OH
R1
R1
Scheme 2. a: synthesis of cyclic ethers by two steps chlorine-based chemistry. Tosyl chloride/pyridine or thionyl chloride followed by cyclisation of the
mono tosylate or mono chlorine adduct in the presence of a base. The mono tosylate and mono chlorine derivatives require purification by column
chromatography; b: synthesis of cyclic ethers by one-pot DMC-mediated cyclisation.
H
H
H
MeOOCO
MeO
O
O
O
KW2000
240 °C
+
O
O
O
O
OCOOMe
OMe
H
H
H
DC
DMI
Tricyclic
Scheme 3. Synthesis of the tricyclic derivative of isosorbide.
Table 1
Synthesis of the cyclic derivative of isosorbide in Continuous-Flow conditions.
#
Substrate (g)
Temp. (8C)
Flow (g/min)
Conv.a (%)
DMI (% GC-MS)
Tricyclic (% GC-MS)
1
2
3
4
5
6
DC (5)
DC (5)
DC (5)
DC (5)
DC (10)
DC (5)
220
220
240
240
250
260
0.22
0.22
0.16
0.05
0.08
0.10
100
100
100
100
100
100
39
25
48
54
48
45
31
26
35
38
26
31
DC was dissolved in a mixture of toluene/hexane 65/35, Hydrotalcite KW200 (1.1 g) was used as catalyst.
a
In the table are reported the GC-MS percentage only for DMI and the tricyclc derivatives, which are the main reaction products.
distillation to recover the fraction containing the tricyclic
compounds. Finally the pure compound was recrystallized
in hot hexane as needle-like white crystals.
Full characterization by NMR spectroscopy, GC-MS and
IR analysis confirmed the proposed structure.1 In particu-
lar the comparison of IR data of the tricyclic molecule with
dimethyl isosorbide (DMI), with which is strictly correlat-
ed, shows similar strong features appearing in the same
spectral range blue-shifted in the C-H stretching region
and red-shifted in the fingerprint portion.
It was finally possible to grow crystals suitable for X-ray
diffraction which are in accordance with the data
previously collected [11].
Noteworthy, the reaction mechanism leading to this
tricyclic structure is quite intriguing. In fact the reaction
leading to the formation of the tricyclic is a concurrent
pathway of the decarboxylation of DC to give DMI.
As reported in Scheme 4, probably, small amount of
water (or methanol) in the catalyst or in the solvents can
leadtotheformationofthemonocarboxymethylderivatives
of isosorbide MC1 and MC2. Between the two derivatives,
MC1 is the only adduct that can lead to the formation of the
tricyclic derivatives by a one-pot intermolecular cyclisation.
This is because the endo hydroxyl moiety can backside
1
Tricyclic adduct of isosorbide: as white crystals, C6H8O3; m.p. = 69.9–
70.7 (C; M = 128,05 g.mol-1; 1H NMR (300 MHz, CDCl3) (=4.54 (s, 2H),
4.46 (s, 2H), 3.98 (d, 2H), 3.88 (s, 2H), 4.12 (d, 1H), 3.99 (dd, 1H), 3.88; 13C
NMR (75 MHz, CDCl3) (=81.6, 76.8, 73.2; IR: 750.1336, 843.4426,
902.9852, 967.4785, 1004.7522, 1062.2184, 1091.2338, 1097.5009,
1472.6070, 1507.6982, 2879.3347, 2944.7648, 2979.4821, 3014.0214.

P. Tundo et al. / C. R. Chimie 14 (2011) 652–655
655
H
H
O
O
O
H
H
H
MeOOCO
O
O
OH
H
H
MC1
MeO
O
H
MeOOCO
O
H
MeO
O
O
OH
H
O
OCOOMe
H
O
MMI1
OMe
H
H
HO
H
O
HO
O
O
OCOOMe
O
H
OMe
H
MC2
MMI2
Scheme 4. Possible reaction mechanism leading to the formation of the triscyclic adduct of isosorbide.
attack the exo carboxymethyl group by intermolecular SN2.2
MC2, on the contrary, is sterically hindered and will lead to
the formation of MMI2.
Moreover, it must be mentioned that this reaction is
specific of isosorbide. In fact, isomannide and isoiodide,
which are epimers of isosorbide, will not lead to the
formation of such tricylic compounds since the hydroxyl
groups are either both endo (isomannide) or both eso
(isoiodide).
In conclusion, in this work the synthesis of a tricyclic
derivate of isosorbide in moderate yield from DC and DMC
in the presence of a base and employing a continuous-flow
apparatus is reported. The tricylic structure has been
isolated as pure and fully characterised. Moreover, the
DMC-mediated cyclisation of isosorbide to achieve the
tricyclic derivative does not use any toxic reagent neither
lead to any harming waste. Thus, the reported synthetic
procedure opens up a novel field of investigation with
numerous industrial applications: the chlorine-free syn-
thesis of heterocycles by DMC chemistry.
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`
Appendix A. Supporting information
[10] Mg0.7Al0.3O1.15, specific surface area 202 m2/g; A sample was kindly
provided by Kyowa Chemical Industry Co. Tokyo.
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1H NMR and 13C NMR data, GS-MS analysis of the tricyclic
adduct of isosorbide are available with the electronic version
of this article, doi:10.1016/j.crci.2010.11.011.
2
In this case study the OH group labelled as endo refers to the OH
pointing toward the isosorbide V-shaped cavity, whilst the exo OH group
refers to the OH pointing out of the V-shaped cavity of isosorbide.