Synthesis of five-membered cyclic ethers by reaction of 1,4-diols with dimethyl carbonate

Article abstract of DOI:10.1002/cssc.201100755

The reaction of 1,4-diols with dimethyl carbonate in the presence of a base led to selective and high-yielding syntheses of related five-membered cyclic ethers. This synthetic pathway has the potential for a wide range of applications. Distinctive cyclic ethers and industrially relevant compounds were synthesized in quantitative yield. The reaction mechanism for the cyclization was investigated. Notably, the chirality of the starting material was maintained. DFT calculations indicated that the formation of five-membered cyclic ethers was energetically the most favorable pathway. Typically, the selectivity exhibited by these systems could be rationalized on the basis of hard-soft acid-base theory. Such principles were applicable as far as computed energy barriers were concerned, but in practice cyclization reactions were shown to be entropically driven. Copyright

Full text of DOI:10.1002/cssc.201100755

DOI: 10.1002/cssc.201100755
Synthesis of Five-Membered Cyclic Ethers by Reaction of
1,4-Diols with Dimethyl Carbonate
Fabio Aricꢀ,[a] Pietro Tundo,*[a] Andrea Maranzana,[b] and Glauco Tonachini[b]
The reaction of 1,4-diols with dimethyl carbonate in the pres-
ence of a base led to selective and high-yielding syntheses of
related five-membered cyclic ethers. This synthetic pathway
has the potential for a wide range of applications. Distinctive
cyclic ethers and industrially relevant compounds were synthe-
sized in quantitative yield. The reaction mechanism for the cyc-
lization was investigated. Notably, the chirality of the starting
material was maintained. DFT calculations indicated that the
formation of five-membered cyclic ethers was energetically the
most favorable pathway. Typically, the selectivity exhibited by
these systems could be rationalized on the basis of hard–soft
acid–base theory. Such principles were applicable as far as
computed energy barriers were concerned, but in practice cyc-
lization reactions were shown to be entropically driven.
Introduction
Many natural and synthetic compounds incorporate tetrahy-
drofuran rings as structural subunits (i.e., forskolin[1] and
manoyl oxide derivatives),[2] and have significant biological ac-
tivity: polyether antibiotics,[3] inostamycins,[4] and isosorbide[5]
are characteristic examples. Additionally, some cyclic ethers
have distinctive aromas and are useful as fragrances. An exam-
ple is (À)-norlabdane oxide, a compound widely used for pro-
viding ambergris-type odors to perfumes because natural am-
bergris itself is no longer available for this purpose.[6]
nates, and in particular DMC, have shown high selectivity with
different monodentate and bidentate nucleophiles, and act as
methylating and/or methoxycarbonylation agents.[16] The reac-
tivity of the two electrophilic centres of DMC can be selectively
tuned, temperature being the key factor: at reflux temperature
(908C) DMC acts as a methoxycarbonylation agent through the
BAc2 mechanism, whereas at higher temperatures (>1508C)
the methylation reaction occurs through the BAl2 mechanism.
Both reactions produce as byproduct only methanol and even-
tually CO2.[14–16]
Amongst the commonly used synthetic approaches for the
formation of cyclic ethers (through cyclization and/or cycload-
dition) many involve heavy metals[7] or chlorine chemistry at
different levels; for example, activated chlorine-based leaving
groups or leaving groups created through the use of chlorine
(e.g., tosylate through the chlorosulfonation of toluene, mesy-
late).[8] Also, cyclization reactions are often conducted under
acidic conditions; many patents report the synthesis of tetrahy-
drofuran starting from the corresponding 1,4-butanediol by
acid-catalyzed cyclodehydration.[9,10] However, under these
conditions, common cyclodehydration reactions are not very
effective when tertiary alcohols are involved due to a mixture
of elimination and/or rearrangement products. Recent advan-
ces in the synthesis of substituted tetrahydrofuran rings have
been achieved by using different approaches with alternative
starting materials and novel catalysts:[11] for instance, the reac-
tion of 1,4- and 1,5-diols with cerium ammonium nitrate[12]
proved to be very effective under mild conditions, although its
application is limited because it requires the presence of at
least one tertiary alcohol in the starting diols.
We have recently reported the synthesis of industrially rele-
vant five-membered cyclic ethers and N-heterocyclic com-
pounds by DMC chemistry under mild conditions.[17] To the
best of our knowledge only one other example of a synthesis
of tetrahydrofuran derivatives by dialkyl carbonate chemistry
has been reported.[18] Herein, we present this novel synthetic
approach to several five-membered heterocycles. In the case
of cyclic compounds previously investigated,[17] reaction condi-
tions were optimized (i.e., lower temperature and reduced
amount of DMC) and reaction yields improved. The mechanism
1
of intramolecular cyclization was also investigated by H NMR
spectroscopy and reaction intermediates were isolated and
fully characterized. Furthermore, energy barriers associated
with cyclization and with all possible concurrent pathways
were explored by DFT calculations.
[a] Dr. F. Aricꢀ, Prof. P. Tundo
Ca’ Foscari Universitꢁ di Venezia
Dipartimento Scienze Ambientali, Informatica e Statistica
Dorsoduro 2137-30123, Venice (Italy)
Fax: (+39)041-234-8620
Short-chain dialkyl carbonates such as dimethyl carbonate
(DMC), produced nowadays by clean processes,[13] are re-
nowned for possessing properties of low toxicity and high bio-
degradability, which make them true green solvents and re-
agents.[14] DMC has been widely used as an efficient eco-sus-
tainable substitute of phosgene, methyl halides or methyl sul-
fate that are toxic and highly corrosive.[15] In fact, dialkyl carbo-
E-mail: tundop@unive.it
[b] Dr. A. Maranzana, Prof. G. Tonachini
Universitꢁ degli Studi di Torino
Dipartimento di Chimica
Corso Massimo D’Azeglio, 48, 10125 Torino (Italy)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201100755.
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Results and Discussion
Cyclic ethers from 1,4-diols by DMC chemistry
In a first set of experiments 1,4-butanediol was reacted with an
excess of DMC, used as solvent and reagent, in the presence
of sodium methoxide at reflux (Table 1, entry 1). As expected,
1,4-di(methoxycarbonyloxy) butane was the main product ob-
served, whereas THF formed only in low yield. However, when
the reaction was conducted in acetonitrile with four equiva-
lents of DMC, THF was identified as the main product (70%)
(Table 1, entry 2). Quantitative conversion of 1,4-butanediol
into THF was achieved by increasing the amount of base
(Table 1, entry 3).
Scheme 1. Mechanism of cyclization of 1,4-diols.
into cyclic ethers by DMC chemistry has the advantage of
being a single-step SN2 reaction, in which the leaving group is
formed in situ. Conversely, SN2 reactions performed by com-
monly used chlorine chemistry require two steps: tosylation of
the substrate followed by a SN2 reaction under basic condi-
tions involving the purified tosyl derivative. Both steps cause
the formation of large amounts of waste and require time-con-
suming purification of products.
It was not convenient to use the preparation of THF through
cyclization of 1,4-diols with DMC under batch conditions as
a model reaction because the target molecule was very vola-
Table 1. Cyclization of 1,4-butanediol with DMC.[a]
A range of aliphatic and aromatic 1,4-diols, each bearing dif-
ferently substituted alcohols (primary, secondary, tertiary, allyl,
phenyl, and benzyl) were then investigated as substrates for
the cyclization reaction. Table 2 contains results obtained for
aliphatic diols. 1,4-Pentanediol formed 2-methyltetrahydrofuran
in high yield under similar conditions to those used for 1,4-bu-
tanediol (Table 2, entry 3), whereas quantitative conversion re-
quired three equivalents of NaOMe. This was possibly a result
of the lower reactivity of secondary alcohols.
Entry
DMC
[equiv]
NaOMe
[equiv]
Cyclic ether[b]
[%]
Other products[b]
[%]
THF
MMCD[c]
DMCD[d]
1
2
3
20[e]
4
1.5
1.5
2
12
0
88 (75)[f]
19 (17)[g]
0
70 (82)[g]
100
11 (0)[g]
0
4
[a] Reaction conditions: 1,4-butanediol (2.0 g) in CH3CN (30 mL) at 608C,
4 h. [b] Yield based on GC-MS analyses. [c] Monomethoxycarbonyl deriva-
tive. [d] Dimethoxycarbonyl derivative. [e] DMC used as solvent. [f] Yield
of isolated product. [g] Yield after 8 h based on GC-MS analyses.
When 2,5-hexanediol (mixture of stereoisomers) was used,
the cyclic ether formed in traces (14%), and substrate conver-
sion was moderate (52%) even after 24 h. Cyclization did not
occur even with an excess of base (Table 2, entry 5). This result
might be ascribed to secondary alcohols being less reactive
both in the methoxycarbonylation step[14] and in nucleophilic
tile. However, we overcame this issue by performing the reac-
tion in a continuous-flow apparatus.[19]
The cyclization of 1,4-butane-
diol is reliant on the versatility of
DMC as reagent.[16] Most proba-
Table 2. Cyclization of aliphatic 1,4-diols with DMC in acetonitrile to yield THF derivatives.[a]
bly, the cyclization mechanism
observed herein comprises first
the methoxycarbonylation of the
1,4-diol by a BAc2 mechanism,
followed by an intramolecular
cyclization through a BAl2 mech-
anism, in which a methylcarbon-
ate anion is released (Scheme 1).
The formation of mono- and
dimethoxycarbonyl derivatives
(MMCD and DMCD, respectively)
of the starting diol is a thermody-
namically controlled equilibrium
reaction, whereas the intramo-
lecular BAl2 cyclization is kineti-
cally driven. This reaction mech-
anism ultimately leads to the for-
mation of the cyclic compound
in a quantitative yield. Notably,
the direct conversion of the diol
Entry
Diol
NaOMe
[equiv]
t
[h]
Cyclic ether[b]
[%]
Other products[b]
[%]
MMCD[c]
DMCD[d]
1[e]
2
1.5
2
3
2
6
6
2
64
100
0
20
0
73 (60)[f]
15
0
3
4[e]
5
1.5
3
5
6
0
8
85 (64)[f]
82 (86)[h]
3[g] (14)[h]
15 (0)[h]
6[h]
7[e]
8
0.05
1
2
2
2
4
28
98
100
33 (24)[f]
0
0
38 (31)[f]
2
0
[a] Reaction conditions: 1,4-diol (0.5 g) and DMC (4 equiv) in CH3CN (15 mL), 708C; conversion was quantitative
unless otherwise stated. [b] Yield based on GC-MS analyses. [c] Monomethoxycarbonyl derivative. [d] Dimethox-
ycarbonyl derivative. [e] DMC used also as solvent (20 equiv); conversion was 70%. [f] Yield of isolated product.
[f] Conversion was 20%. [g] Yield of isolated product after 24 h. Conversion was 52%. [h] DMC used also as sol-
vent (4 equiv).
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Synthesis of Five-Membered Cyclic Ethers
substitution reactions. On the
Table 3. Cyclization of aromatic 1,4-diols with DMC (10 equiv) at reflux.
other hand, cis-1,4-but-2-ene
diol underwent fast and quanti-
Entry
Diol
NaOMe
[equiv]
t
[h]
Cyclic ether[a]
[%]
Other products[a]
[%]
MMCD[b]
tative
cyclization
(Table 2,
DMCD[c]
entry 8), even with an excess of
DMC (Table 2, entry 7). Most
probably, the formation of 2,5-
dihydrofuran was aided by the
favorable cis position of alcohol
moieties; in fact, when the reac-
tion was performed with a cata-
lytic amount of base the cyclic
compound still formed in appre-
ciable yield (Table 2, entry 6).
1
2
3
4[f]
0.5
1
2
7
5
5
2
63 (55)[d]
85 (76)[b]
100 (93)[b]
100 (95)[b]
37 (31)[d]
15
0
n.d.[e]
n.d.[e]
n.d.[e]
n.d.[e]
2
0
5
6
7[f]
0.5
2
2
7
4
4
45 (30)[d]
74
100 (95)[d]
33 (24)[d]
0
0
53 (41)[d]
26
0
[a] Yield calculated by 1H NMR spectroscopy. [b] Monomethoxycarbonyl derivative. [c] Dimethoxycarbonyl deriv-
ative. [d] Yield of isolated product. [e] Not determined. [f] Reaction with CH3CN as solvent in the presence of
DMC (4 equiv).
The cyclization of cis-1,4-but-
2-ene diol was also performed in
deuterated acetonitrile to follow
the formation of the cyclic ether
by
1H NMR
spectroscopy
(Figure 1): spectra showed that, after just 1 h, the cyclic ether
was the main product; small amounts of mono- and dimethox-
ycarbonyl derivatives, together with traces of the starting diol,
were also present. After 4 h, 2,5-dihydrofuran was the only
product present in the solution.
vent, and no further purification was required. In any case, the
monomethoxycarbonyl derivative of the starting diol was the
only intermediate observed.
1,2-Bis(hydroxymethyl)benzene also led to the quantitative
formation of phthalan (Table 3, entry 7) under reaction condi-
tions similar to those used for 2-(2-hydroxyethyl)phenol. The
dimethoxycarbonyl derivative of the starting 1,4-diol, the only
intermediate formed, was isolated and characterized (Table 3,
entry 5). Notably, the reaction solution was perfectly clear for
all investigated substrates; this confirmed the absence of de-
composition products (Table 1–3).
Improving one-pot syntheses of ambroxan and isosorbide
Norlabdane oxide (3) represents one of the preferred synthetic
compounds with desirable ambergris-type odor and is com-
mercially available under various trade names.[20,21] Its industrial
synthesis by cyclization of amberlyn diol under acidic condition
leads to a mixture of ambroxan (ca. 60%) and byproducts de-
riving from the concurrent elimination reaction.[21]
Table 4 includes results obtained by reacting amberlyn
diol[22] (1) with DMC in the presence of a base.[17] Results
showed that using two equivalents of base in an excess of
DMC (used as reagent and solvent), amberlyn diol cyclized
quantitatively to ambroxan in only 3 h (Scheme 2 and Table 4,
entry 1).
Figure 1. 1H NMR spectra showing the formation of 2,5-dihydrofuran over
time (under conditions in Table 2, entry 8).
The amount of DMC could be reduced without affecting the
outcome of cyclization (Table 4, entry 2 and 3). The cyclization
was also performed using THF as solvent in the presence of
three equivalents of DMC (Table 4, entry 4) without affecting
the quantitative formation of ambroxan, whereas the chiral in-
tegrity of the starting material was maintained.
The reactivity of 1,4-diols bearing aromatic moieties was also
investigated (Table 3). 1,2-Dihydroxymethylbenzene and 2-(2-
hydroxyethyl)phenol were selected as substrates. 2-(2-Hydrox-
yethyl)phenol was one of the most reactive substrates be-
cause, even when utilizing catalytic amounts of base, 2,3-dihy-
drobenzofuran was the major product (Table 3, entry 1). Quan-
titative formation of the cyclic ether was achieved using two
equivalents of base (Table 3, entry 2 and 3). The reaction was
effective even with a small amount of DMC, and with acetoni-
trile as solvent (Table 3, entry 4). The cyclic compound was re-
covered after filtration of the base and evaporation of the sol-
The mechanism of amberlyn diol cyclization most probably
involved two steps: methylcarbonylation of the starting diol,
followed by intramolecular nucleophilic attack by the tertiary
alcohol. This hypothesis was confirmed by the fact that the
monomethoxycarbonyl derivative was the only byproduct ob-
served. This compound could be synthesized in quantitative
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Table 4. Synthesis of ambroxan by DMC chemistry.[a]
Table 5. Synthesis of isosorbide by DMC chemistry.[a]
Entry
Base
DMC
[equiv]
Ambroxan
[%]
MMCD
[%][b]
Entry
Solvent
NaOMe
[equiv]
DMC
[equiv]
t
[h]
Isosorbide
[b]
1
2
3
4[c]
5
tBuOK
tBuOK
tBuOK
tBuOK
K2CO3
30
10
5
3
30
95
80
91
90
0
0
0
0
0
90
1
2
3
None
MeOH
MeOH
2
2
4
20
4
8
8
8
8
16
80 (64)[c]
98 (76)[c]
[a] Reaction conditions: d-sorbitol (2 g, 1 equiv) at reflux; conversion of
starting materials was 100%. [b] Yield based on GC-MS analyses. [c] Yield
of isolated product.
[a] Reaction conditions: amberlyn diol (1 g, 1 equiv), base (2 equiv), 908C,
3 h; conversion of starting materials was 100%. [b] Monomethoxycarbon-
yl derivative; [c] THF used as solvent.
bide formed through a one-pot
double cyclization requiring two
equivalents of base for each
cyclic ether formed.
Ab initio calculations
In all reactions DMC acts as an
ambident elecrophile. First, one
Scheme 2. Synthesis of ambroxan.
alcoholic functionality of the
substrate reacts with the carbon-
yl group of DMC (hard–hard in-
yield using potassium carbonate as a base in the presence of
an excess of DMC (Table 4, entry 5).
teraction)[16] forming the methoxycarbonyl derivative; the
second alcoholic functionality then intramolecularly attacks the
newly formed alkyl carbonate. According to the hard–soft
acid–base (HSAB) theory of Pearson[25] this should be a soft-
soft interaction.[17] However, the results reported herein prove
that this is not the case because the alcoholic moiety is a hard
nucleophile. This discrepancy clearly indicates that the hard/
soft character of the nucleophile does not have a decisive in-
fluence on the reaction outcome. Thus, theoretical calculations
are required to have a better insight in terms of energy barri-
ers involved in the cyclization reaction. In this respect, we in-
vestigated four competing processes, namely two cyclization
reactions and two bimolecular reactions involving DMC
(Scheme 4). Free energies were assessed in the gas phase and
in DMC solutions.
Cyclic ethers in the form of anhydro sugar alcohols have
many applications in industry, particularly in food industry, in
the pharmaceutical field, and they are also employed as mono-
mers in the formation of polymers and copolymers. Such anhy-
dro sugar alcohols are derivatives of mannitol, iditol, and sorbi-
tol. Specifically, isosorbide, the anhydro sugar alcohol derived
from sorbitol, is useful as a monomer in the manufacture of
polymers and copolymers (especially polyesters). Isosorbide is
industrially synthesized by dehydration of sorbitol by an acid-
catalyzed reaction that leads to different anhydro compounds
and polymer-like products.[23]
When d-sorbitol was reacted with two equivalents of base
and an excess of DMC isosorbide was isolated in relatively low
yields (Scheme 3 and Table 5, entry 1). This was because isosor-
bide, once formed, reacted with DMC and led to the formation
of its methoxycarbonyl and methyl derivatives.[24] However,
when methanol was used as a solvent (Table 5, entry 2 and 3),
the reaction equilibrium was shifted towards isosorbide pre-
venting further reactions. Under these conditions, isosorbide
formed readily and in high yield. The excess of NaOMe re-
quired (Table 5, entry 3) was justified by the fact that isosor-
(1R, 2S)-2-(Hydroxyethyl)cyclohexanol (R) was selected as
model molecule because it is incorporated as a subunit in am-
berlyn diol. R can undergo two competitive cyclizations to
form either a five-membered ring through an intramolecular
SN2-like reaction (Scheme 4, pathway 1), or a seven-membered
ring through an intramolecular SNAc reaction (Scheme 4, path-
way 2). Furthermore, two intermolecular nucleophilic substitu-
tions can also take place: an acylic one (Scheme 4, pathway 3,
SNAc) and an aliphatic one
(Scheme 4, pathway 4, SN2) due
to the attack of alcoholate R on
DMC.
Free energy data obtained in
solution at 388 K (DGsol) demon-
strated that methylation of the
substrate leads to VI (Scheme 4,
pathway 4), which is quite
Scheme 3. Synthesis of isosorbide.
stable. However, the free energy
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Synthesis of Five-Membered Cyclic Ethers
Scheme 4. Competing reaction pathways and related energy barriers. DG values (kcalmolÀ1) at 388 K in DMC are given. All energy values refer to the model
compound (R).
barrier associated with the methylation reaction is rather high
(see the Supporting Information, Table 1). Conversely, the me-
thoxycarbonylation of the substrate (Scheme 4, pathway 3)
leads to a high-energy tetrahedral intermediate (IV) through
a high free energy barrier. The subsequent elimination of a me-
thoxyl group to form V has a modest free energy barrier,
whereas the dissociation limit is slightly above the reactants.
Because of its initial high free energy barrier (Figure 2, transi-
tion structure R-IV), this pathway has not been further consid-
ered.
effect contributed most to barrier heights. Considering only
potential energy (see the Supporting Information), TS R-IV (me-
Conversely, cyclization reactions require a lower free energy
barrier. In particular, the energy barrier leading to I (SN2) is
quite low and the reaction is very exoergic. The other possible
cyclization reaction (SNAc) forms a tetrahedral intermediate II,
almost isoergic with the reactant. However, this pathway is en-
ergetically more demanding overall. Moreover, the formation
of the seven-membered ring (II) is an equilibrium and the re-
verse-reaction transition state (Figure 2, TS II-R) has a lower
energy than that leading to III (Figure 2, TS II-III).
By comparing the four relevant transition structures (TS R-VI,
TS R-IV, TS R-I, and TS R-II), it was possible to investigate which
Figure 2. Free energy profile in DMC at 388 K.
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P. Tundo et al.
thoxycarbonylation) would have the lowest barrier. However,
in solution TS R-IV had the highest free energy barrier. This
was due to the combination of two factors: entropic effects
and solvation. Thus, TS R-IV was characterized by a large entro-
py decrease (DS° =À44.2 calmolÀ1 KÀ1) because it was a bimo-
lecular reaction, and as result, the free energy barrier in the
gas phase rose significantly with respect to potential energy.
Moreover, free solvation energy was also unfavorable (see the
Supporting Information, Table 1). In the gas phase, according
to the HSAB theory, TS R-IV would have a lower energy barrier
(hard–hard interaction) than TS R-VI (hard–soft interaction).
However, because entropy and solvation effects dominate the
free energy barrier of TS R-IV, in solution it became higher
than that of TS R-VI. Cyclization reactions showed similar solva-
tion effects, but the activation entropy for TS R-I was only
À2.1 calmolÀ1 KÀ1. It was higher for TS R-II (DS° =À13.1 cal
molÀ1 KÀ1) probably due to a higher ring strain in the seven-
membered ring and the release of the methoxycarbonyl
moiety.
The synthetic pathway reported herein represents a good
step towards a “no-chlorine-in-the making” one-pot environ-
ment-friendly method of synthesizing heterocyclic compounds.
To discover the best modus operandi and achieve an industri-
ally appealing procedure these cyclization reactions are cur-
rently under investigation in a continuous flow apparatus.
Experimental Section
General: Thin layer chromatography (TLC) was performed on pre-
coated TLC plates (silica gel 60 GF254, 0.25 mm). Flash column
chromatography was performed on silica gel (grade 9385, 60 ꢂ,
230–400 mesh). GC-MS analyses were performed on a gas chroma-
tograph (Agilent Technologies) equipped with a HP-5MS fused
silica column (30 mꢃ0.25 mm) and a Network mass-selective de-
tector. All reactions were performed using DMC dried over molecu-
lar sieves (4 ꢂ). All bases and catalysts were used as received with-
out further purification.
The entropic effect was thus the main factor responsible for
the lower barrier of TS R-I, whereas the solvation effect accen-
tuated barrier differences. Temperature effects were also taken
into account by performing free energy calculations at
a higher temperature (458 K). However, only small changes in
relative energies (at most 2 kcalmolÀ1) were observed, and
they did not affect the mechanistic picture discussed above
(see the Supporting Information).
Synthetic procedures
THF (example from Table 1, entry 1): In a round-bottomed flask
equipped with a dephlegmator, a mixture of 1,4-butanediol (2.0 g,
22.2 mmol, 1 equiv), DMC (40 g, 44.4 mmol, 2 equiv), and NaOMe
(1.8 g, 33.3 mmol, 1.5 equiv) were heated at reflux while stirring
continuously under a nitrogen atmosphere. The reaction was fol-
lowed by NMR spectroscopy and GC-MS analysis until complete
disappearance of the starting material. According to GS-MS analy-
sis and NMR spectroscopy THF was formed in 12% yield. The solu-
tion was then filtered and the solvent removed by evaporation to
isolate 1,4-di(methoxycarbonyloxy)butane (3.40 g) as a colorless
crystalline solid in 75% yield.
Conclusions
1,4-Di(methoxycarbonyloxy)butane: M.p.: 61–62.38C; 1H NMR
(300 MHz, CDCl3): d=4.12–4.20 (m, 4H), 3.81 (s, 6H), 1.74–
1.82 ppm (m, 4H); 13C NMR (75 MHz, CDCl3): d=155.6, 67.2, 54.6,
25.0 ppm; HRMS: m/z calcd for C8H14O6+Na+: 229.0683 [M+Na+];
found: 229.0685.2-Methyl tetrahydrofuran (example from
Table 2, entry 1): In a round-bottomed flask equipped with a de-
phlegmator, a mixture of 1,4-pentadiol (1.0 g, 9.6 mmol, 1 equiv),
DMC (17.3 g, 192 mmol, 20 equiv), and NaOMe (0.77 g, 14.4 mmol,
1.5 equiv) were heated at reflux while stirring continuously under
a nitrogen atmosphere. The reaction was followed by NMR spec-
troscopy and GC-MS analysis until equilibrium was reached (2 h).
The solution was then filtered and the solvent removed by evapo-
ration. Column chromatography using CH2Cl2/methanol (95:5) as
eluent allowed the isolation of 1,4-di(methoxycarbonyloxy)pentane
as a light-colored oil in 60% yield.
The reaction of 1,4-diols with DMC in the presence of a base
and under mild conditions led to the corresponding cyclic
ethers in high yields and short reaction times. It was possible
to synthesize distinctive cyclic ethers and industrially relevant
compounds such as (À)-norlabdane oxide and isosorbide from
their related 1,4-diols in quantitative yield.
Relative to a chlorine-based procedure the DMC-mediated
pathway is quantitative, occurs in one step, does not require
any chlorine-based chemicals or strong acids, and does not
produce any chlorinated waste material. The synthesis pro-
posed herein is of general application, because it is effective
for aliphatic and aromatic diols incorporating several function-
alities (primary, secondary, tertiary, allylic, phenolic). However,
this procedure requires that at least one primary alcohol group
be present in the starting diol for the cyclization to take place.
Most importantly, this synthesis maintains the chiral integrity
of the substrate.
1
1,4-Di(methoxycarbonyloxy)pentane: H NMR (300 MHz, CDCl3): d=
4.71–4.9 (m, 1H), 4.28–4.14 (m, 2H), 3.8 (s, 3H), 3.78 (s, 3H), 1.9–1.5
(m, 4H), 1.28 ppm (d, 3H); 13C NMR (75 MHz, CDCl3): d=155.6,
155.2, 74.5, 67.5, 54.6, 54.4, 31.9, 24.5, 19.7 ppm; HRMS: m/z calcd
for C9H16O6+Na+: 243.0845 [M+Na+]; found: 243.0856.
2,5-Dimethyltetrahydrofuran (example from Table 2, entry 5): In
a round-bottomed flask equipped with a dephlegmator, 2,5-hexa-
nediol (mixture of isomers) (0.5 g, 4.2 mmol, 1 equiv), DMC (7.5 g,
83 mmol, 20 equiv), and NaOMe (0,34 g, 6.3 mmol, 1.5 equiv) were
heated at reflux while stirring continuously under a nitrogen at-
mosphere. The reaction was followed by NMR spectroscopy and
GC-MS analysis until equilibrium was reached (6 h). The solution
was then filtered and the solvent removed by evaporation.
Column chromatography using CH2Cl2/methanol (99:1) as eluent
A computational investigation confirmed that cyclization to
form the five-membered ring is the preferred pathway over
seven-membered-ring closure and, even more sharply, over
two different alcoholate attacks on DMC. Indeed, the fact that
the last two reactions are unfavorable can be traced back to
a larger entropy reduction that occurs at the relevant transition
states. Then, solvent effects enhance the differences among
energy barriers in the gas phase. Conversely, temperature has
only a small effect on free energy barriers.
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Synthesis of Five-Membered Cyclic Ethers
allowed the isolation of 2,5-di(methoxycarbonyloxy)hexane as
a light-colored oil in 64% yield.
product was purified by gradient elution chromatography on silica
gel using first CH2Cl2/cyclohexane (9:1) (for the isolation of the
cyclic ether), and then CH2Cl2/methanol (97:3) (for the isolation of
the carbonate derivative) as eluents.
2,5-Di(methoxycarbonyloxy)hexane (mixture of isomers): 1H NMR
(300 MHz, CDCl3): d=4.6–4.8 (m, 2H), 3.8 (s, 6H), 1.7–1.5 (m, 4H),
1.28 ppm (d, 6H); 13C NMR (75 MHz, CDCl3): d=155.2, 74.9, 75.6,
54.4, 31.6, 31.2, 19.8, 19.7 ppm; HRMS: m/z calcd for C10H18O6+Na+
: 257.1001 [M+Na+]; found: 257.1035.
Phthalan (transparent liquid, 30%): Characterization data were con-
sistent with those obtained for the commercially available com-
pound.
2,5-Dihydrofuran (example from Table 2, entry 7): In a round-bot-
tomed flask equipped with a dephlegmator, cis-but-2-ene-1,4-diol
(1.0 g, 11.3 mmol, 1 equiv), DMC (4.1 g, 45.45 mmol, 4 equiv), and
NaOMe (0.03 g, 0.56 mmol, 0.05 equiv) were heated at reflux while
stirring continuously under a nitrogen atmosphere. The reaction
was followed by NMR spectroscopy until complete disappearance
of the starting materials. The solution was then filtered and the sol-
vent removed by evaporation. Column chromatography using
CH2Cl2/methanol (98:2) as eluent allowed the isolation of (Z)-1-hy-
droxy 4-methoxycarbonyloxy-2-butene as a transparent oil in 24%
1,2-Bis[(methoxycarbonyloxy)methyl)]benzene (light yellow liquid,
41%): M.p.: 51–51.58C; 1H NMR (300 MHz, CDCl3): d=7.48–7.30 (m,
4H), 5.27 (s, 4H), 3.77 ppm (s, 6H); 13C NMR (75 MHz, CDCl3): d=
155.4, 133.8, 129.8, 128.9, 66.9, 54.8 ppm; HRMS: m/z calcd for
C12H14O6+Na+: 277.0688 [M+Na+]; found: 277.0722.
(À)-Norlabdane (ambroxan) (example from Table 4, entry 1): In
a round-bottomed flask equipped with a dephlegmator, amberlyn
diol (1.0 g, 3.93 mmol, 1 equiv), DMC (10.6 g, 118.0 mmol,
30 equiv), and potassium tert-butoxide (0,88 g, 7.87 mmol, 2 equiv)
were heated at reflux while stirring continuously under a nitrogen
atmosphere. The reaction was followed by TLC until complete dis-
appearance of the starting materials. The solution was then filtered
and DMC removed by evaporation to afford ambroxan as a color-
less crystalline powder in 95% yield. Purer samples of ambroxan
could be obtained either by crystallisation from 2-propanol or by
column chromatography using CH2Cl2/methanol (98:2) as eluent.
yield and (Z)- 1,4-di(methoxycarbonyloxy)-2-butene as
a light
yellow oil in 31% yield.
(Z)-1-Hydroxy 4-methoxycarbonyloxy-2-butene:[26] 1H NMR (300 MHz,
CDCl3): d=5.93–5.50 (m, 2H), 4.67 (d, 2H), 4.21 (d, 2H), 3.69 (s,
3H), 2.88 ppm (brs, 1H, OH); 13C NMR (75 MHz, CDCl3): d=156.9,
133.9, 124.5, 63.3, 58.0, 54.7 ppm; GC-MS for C6H10O4: M=
146.06 gmolÀ1
.
(À)-Norlabdane:[17,22] M.p.: 69.1–708C; 1H NMR (300 MHz, CDCl3):
d=0.84 (s, 3H), 0.85 (s, 3H), 0.89 (s, 3H), 0.91–1.09 (m, 2H), 1.12 (s,
3H), 1.36–1.51 (m, 7H), 6.92–6.80 (m, 2H), 5.95 (s, 1H, OH), 4.37 (t,
2H), 3.81 (s, 3H), 3.05 ppm (t, 2H); 13C NMR (75 MHz, CDCl3): d=
79.8, 64.8, 60.0, 57.1, 42.3, 39.8, 39.6, 36.0, 33.5, 32.9, 22.5, 21.0,
(Z)- 1,4-di(methoxycarbonyloxy)-2-butene:[27] 1H NMR (300 MHz,
CDCl3): d=5.83 (t, 2H), 4.73 (d, 2H), 3.81 ppm (s, 6H); 13C NMR
(75 MHz, CDCl3): d=156.7, 127.8, 63.0, 58.0, 54.7 ppm; GC-MS for
C8H12O6: M=204.06 gmolÀ1
.
20.5, 18.3, 14.9 ppm; GC-MS for C16H28O: M=236.21 gmolÀ1
.
2,3-Dihydrobenzofuran (example from Table 3, entry 1): In
a round-bottomed flask equipped with a dephlegmator, 2-(2-hy-
droxyethyl)phenol (1.0 g, 7.24 mmol, 1 equiv), DMC (6.5 g,
72.4 mmol, 10 equiv), and NaOMe (0.19 g, 3.6 mmol, 0.5 equiv)
were heated at reflux while stirring continuously under a nitrogen
atmosphere. After 7 h the reaction was stopped, cooled at room
temperature, and diethyl ether was added to the mixture. The re-
action mixture was then filtered and the solvent evaporated. The
solvent was distilled under vacuum to give the crude product that
was then analysed by 1H NMR spectroscopy to determine the prod-
uct ratio. Finally, the product was purified by gradient elution chro-
matography on silica gel using first CH2Cl2/cyclohexane (9:1) (for
the isolation of the cyclic ether), and then CH2Cl2/methanol (97:3)
(for the isolation of the carbonate derivative) as eluents.
Monomethoxycarbonyloxy derivative of Amberlyn diol (Table 4,
entry 7):[22] The compound was purified by column chromatography
(CH2Cl2/EtOAc, 92:8), and was isolated as a yellow oil in 90% yield.
Isosorbide (example from Table 5, entry 4): A mixture of d-sorbi-
tol (2.0 g, 10.98 mmol, 1 equiv), DMC (8 g, 87.88 mmol, 8 equiv),
NaOMe 2.4 g, 43.42 mmol, 4 equiv), and methanol (30 mL) was
placed in a round-bottomed flask, and heated at reflux while stir-
ring continuously under a nitrogen atmosphere. After 8 h the reac-
tion was stopped, cooled at room temperature, and diethyl ether
was added to the mixture. The reaction mixture was then filtered
and the solvent evaporated. The solvent was distilled under
vacuum to afford the crude product. Finally, the product was puri-
fied by gradient elution chromatography on silica gel using CH2Cl2/
methanol (9:1) as eluent.
1
2,3-Dihydrobenzofuran (transparent liquid, 55%): H NMR (300 MHz,
CDCl3): d=7.20 (d, 1H), 7.15 (t, 1H), 6.90–6.77 (m, 2H), 4.6 (t, 2H),
3.25 ppm (t, 2H); 13C NMR (75 MHz, CDCl3): d=159.9, 127.8, 126.7,
Isosorbide (light yellow crystals, 75%): Characterization data were
consistent with those obtained for the commercially available com-
pound.
124.8, 120.2, 70.9, 29.6 ppm; GC-MS for C8H8O: M=120.06 gmolÀ1
.
[28]
2-(2-methoxycarbonyloxy)phenol (light yellow oil, 29%):
M.p.:
68.5–68.88C; 1H NMR (300 MHz, CDCl3): d=7.20–7.08 (m, 2H),
6.92–6.80 (m, 2H), 5.95 (s, 1H, OH), 4.37 (t, 2H), 3.81 (s, 3H),
3.05 ppm (t, 2H); 13C NMR (75 MHz, CDCl3): d=156.9, 153.4, 130.9,
128.2, 120.6, 67.6, 54.8, 30.0 ppm; GC-MS for C10H12O4: M=
Ab initio calculations
The potential energy surface (PES) was studied by DFT calculations
making use of the B3LYP functional.[29] The 6-311G(d) polarized
basis set[30] was used in geometry optimizations. The nature of
each critical point (reactant, product, intermediate, or transition
structure) was determined by harmonic vibrational analysis. To
obtain an estimate of energy barriers, single-point energy calcula-
tions were carried out by using Dunning’s correlation-consistent
basis set (aug-cc-pVTZ).[31] Final free energy values were calculated
by combining 6-311G(d) thermochemical corrections with single-
point DFT/aug-cc-pVTZ energy values.
196.07 gmolÀ1
.
Phthalan (example from Table 3, entry 5): In a round-bottomed
flask equipped with a dephlegmator, dihydroxymethylbenzene
(1.0 g, 7.24 mmol, 1 equiv), DMC (6.5 g, 72.4 mmol, 10 equiv), and
NaOMe (0.19 g, 3.6 mmol, 0.5 equiv) were heated at reflux while
stirring continuously under a nitrogen atmosphere. After 7 h the
reaction was stopped, cooled at room temperature, and diethyl
ether was added to the mixture. The reaction mixture was then fil-
tered and the solvent evaporated. The solvent was distilled under
vacuum to give the crude product that was then analysed by
1H NMR spectroscopy to determine the product ratio. Finally, the
Solvent effects were taken into account by the self-consistent reac-
tion field method using the integral equation formalism for the po-
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P. Tundo et al.
larizable continuum model (IEF-PCM).[32] Single point IEF-PCM
energy calculations were carried out at the DFT/aug-cc-pVTZ level.
Chemico-physical properties were used to parameterize the solvent
(DMC), which was defined as “nonstandard” in the Gaussian 03
program, by which all calculations were carried out.[33]
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Acknowledgements
We acknowledge Imperial Chemical Industries Ltd. (ICI) for the
support and funding of a part of this work.
[12] E. J. Alvarez-Manzaneda, R. Chaboun, E. Alvarez, E. Cabrera, R. Alvarez-
Manzaneda, A. Haidour, J. M. Ramos, Synlett 2006, 1829–1834.
[13] Asahi Kasei Chemicals Corporation Patent, WO2007/34669A1, 2007.
[14] a) P. Tundo, A. Perosa, F. Zecchini, Methods and Reagents for Green
Chemistry,Wiley, NJ, USA, 2007; b) P. Tundo, M. Selva, A. Perosa, S.
Memoli, J. Org. Chem. 2002, 67, 1071; c) A. E. Rosamilia, F. Aricꢀ, P.
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Hꢅrault, K. Hill, Green Chem. 2004, 6, 609–612; e) P. Tundo, F. Aricꢀ,
A. E. Rosamilia, S. Memoli, Green Chem. 2008, 10, 1182; f) P. Tundo, F.
Aricꢀ, A. E. Rosamilia, M. Rigo, A. Maranzana, G. Tonachini, Pure Appl.
Chem. 2009, 81, 1971–1979.
[15] L. Cotarca, H. Ecket, Phosgenations—A Handbook, Wiley-VCH, 2003.
[16] M. Selva, C. A. Marques, P. Tundo, J. Chem. Soc. Perkin Trans. 1 1994,
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[17] a) H. S. Bevinakatti, C. P. Newman, S. Ellwood, P. Tundo, F. Aricꢀ,
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Chem. 2011, accepted (DOI:10.1039/C1GC15698E).
[18] H. B. Mereyala, S. K. Mamidyala, Tetrahedron Lett. 2004, 45, 2965–2966.
[19] Preliminary experiments showed that a solution of 1,4-butanediol and
DMC (1:5 molar ratio) in methanol is readily and quantitatively convert-
ed into THF at 1808C under continuous flow conditions (using potassi-
um carbonate and polyethyleneglycol 2500 supported on a-alumina
beads as the catalyst); this procedure (gas-liquid phase-transfer cataly-
sis) is similar to the one recently reported in P. Tundo, A. E. Rosamilia, F.
Aricꢀ, J. Chem. Educ. 2010, 87, 1233–1235.
Keywords: ab initio calculations
chemistry · spectroscopy · synthetic methods
·
cyclization
·
green
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Synthesis of Five-Membered Cyclic Ethers
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Chen, M. W. Wong, C. Gonzalez, and J. A. Pople, Gaussian, Inc., Walling-
ford CT, 2004.
Received: November 23, 2011
Published online on && &&, 0000
ChemSusChem 0000, 00, 1 – 10
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemsuschem.org
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9
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These are not the final page numbers!

FULL PAPERS
F. Aricꢀ, P. Tundo,* A. Maranzana,
G. Tonachini
High-yielding green syntheses of dis-
tinctive and industrially relevant five-
membered cyclic ethers are achieved by
reaction of 1,4-diols with dimethyl car-
bonate in the presence of a base (see
figure). The reaction mechanism is in-
vestigated in detail, and computational
studies demonstrate that the cyclization
reaction was entropically driven.
&& – &&
Synthesis of Five-Membered Cyclic
Ethers by Reaction of 1,4-Diols with
Dimethyl Carbonate
&10
&
www.chemsuschem.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 0000, 00, 1 – 10
ÝÝ
These are not the final page numbers!