Synthesis of five- and six-membered heterocycles by dimethyl carbonate with catalytic amounts of nitrogen bicyclic bases

Article abstract of DOI:10.1039/c4gc01822b

A catalytic amount of a nitrogen bicyclic base, i.e., DABCO, DBU or TBD, is effective for the one-pot synthesis of heterocycles from 1,4-, 1,5-diols and 1,4-bifunctional compounds via dimethyl carbonate chemistry under neat conditions. Nitrogen bicyclic bases that were previously shown to have enhanced the reactivity of DMC in methoxycarbonylation reaction by a B_Ac2 mechanism are herein used for the first time as efficient catalysts for cyclization reactions encompassing both B_Ac2 and B_Al2 pathways. This synthesis procedure was also applied to a large scale synthesis of cyclic sugars, isosorbide and isomannide, starting from d-sorbitol and d-mannitol, respectively. The resulting anhydro sugar alcohols were obtained as pure crystalline compounds that did not require any further purification or crystallization. This journal is

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Table of Contents
Five- and six-memebered N- and O-heterocycles have been
prepared by DMC chemistry in the presence of catalytic amount of a
homogenous nitrogen bicyclic base in neat conditions.

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Synthesis of five- and six-membered heterocycles by
dimethyl carbonate with catalytic amount of nitrogen
bicyclic bases
Cite this: DOI: 10.1039/x0xx00000x
F. Aricò,a,*S. Evaristoa and P. Tundoa,*
Received 00th January 2012,
Accepted 00th January 2012
Catalytic amount of a nitrogen bicyclic base, i.e., DABCO, DBU and TBD is effective for the
one-pot synthesis of heterocycles from 1,4-, 1,5-diols and 1,4-bifunctional compounds via
dimethyl carbonate chemistry under neat conditions. Nitrogen bicyclic bases, that previously
DOI: 10.1039/x0xx00000x
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showed to enhance the reactivity of DMC in methoxycarbonylation reaction by BAc
2
mechanism, are herein used for the first time as efficient catalysts for cyclization reaction
encompassing both BAc2 and BAl2 pathways. This synthetic procedure was also applied to a
large scale synthesis of cyclic sugars isosorbide and isomannide starting from D-sorbitol and
D-mannitol, respectively. The resulting anhydro sugar alcohols were obtained as pure
crystalline compounds that did not require any further purification or crystallization.
Similarly, N- based five-membered heterocycles are present as
structural subunits in many natural products such as vitamins,
Introduction
N- and O-based heterocycles are ubiquitous in nature as
molecules incorporating their skeleton display remarkably
biological activity.
hormones and alkaloids and are also interesting from an
industrial point of view especially for the synthesis of
pharmaceuticals, herbicides, pesticides, dyes, etc.6
Substituted 2,3-dihydrobenzofuran moiety, for instance, is a
common motif in natural products and is the key structural
element in biologically active neolignans (obtusafuran and
kadsurenone) and lithospermic acids, (Figure 1).1 Many of
these natural products are used as pharmaceuticals with several
applications as antimicrobial, antioxidant, antimitotic,
antiangiogenic and neuritogenic.2
O2NO
OH
OH
H
H3C
O
OH
O
Ph
O
O
OCH3
H
O
ONO2
Obtusafuran
Dinitrate isosorbide
Isovanillyl
O
O
Furthermore, five-membered O-based heterocycles are
incorporated in cyclic sugars isosorbide and isomannide widely
used as scaffold for green solvents (dimethyl isosorbide),
surfactants (monosubstituted isosorbide) and pharmaceuticals,
i.e., isosorbide dinitrate extensively used as vasodilator.3
Six-membered benzo-fused 1,4-heterocycles such as
N
N
H
OH
N
O
1,3,3-trimethyl-2-
methyleneindoline
(S)-(-)-Indoline-2-carboxylic
acid
Piperoxan
Figure 1. Some examples of biological active and industrially relevant N- and O-
based heterocycles: obtusafuran (exhibits antiplasmodial activity); dinitrate
isosorbide (vasodilatator); piperoxan (antihistaminic compound); isovanillyl
(sweetening agent); 1,3,3-trimethyl-2-methyleneindoline (dye-intermediate); (S)-
(-)-Indoline-2-carboxylic acid (chiral auxiliary, chiral catalyst, and present in
heterocyclic alkaloid natural products).
benzodioxines
Benzodioxane derivatives such as piperoxan, an α-adrenergic
blocking agent, fluparoxan, potent antidepressant and
are
also
important
pharmaceuticals.4
a
andamericanol A, that shows interesting neurotrophic
properties are just few examples.5 Simple 2,3-dihydro-1,4-
benzodioxine is present in isovanillyl sweetening agents that
are 500 times sweeter than sucrose. In addition, this core
molecule is included in many natural products, such as silybin,
isosilybin, haedoxan A and eusiderin.
A variety of methodologies has been reported for specific
heterocycles, i.e., 5- and 6-membered N- and O-based
heterocycles. The most common synthetic approaches are
generally based on cyclization and/or cycloaddition involving
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heavy metals7 or chlorine chemistry (e.g., tosylate through the potassium tert-butoxide to achieve 5-membered
N-heterocyclic
chlorosulfonation of toluene, mesylate).8
compounds (Scheme 1).15
In some cases, cyclization reactions are conducted under acidic
conditions, however these syntheses might also lead to a
mixture of elimination and/or rearrangement products
especially when tertiary alcohols are involved.9
Short chain dialkyl carbonates (DACs) such as dimethyl
carbonate (DMC), produced nowadays by clean processes,10 are
renowned for their applications as green solvents and
reagents.11 In particular, DMC is a versatile electrophile that
can act as methylating agent via a BAl2 mechanism or
carboxymethylating agent by BAc2 mechanism12 showing high
selectivity with different monodentate and bidentate
nucleophiles.13-15
O
HO
HO
DMC, NaOMe
+ 2CH3OH + CO2
OH
COOMe
N
DMC, t-KOBut
+ 3CH3OH + CO2
NH2
Scheme 1. Synthesis of N- and O-based 5-membered heterocycles by DMC
chemistry.
Recently it has been extensively reported that nitrogen bicyclic
Lewis bases, i.e., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
In this work, we investigated if nitrogen bicyclic bases could be
used as promoters in the synthesis of 5- and 6-membered
heterocycles by DMC chemistry. These cyclization reactions
are particular interesting as they encompass both
methoxycarbonylation via BAc2 mechanism, i.e., formation of
1,4-diazabicyclo[2.2.2]octane
(DABCO)
and
triazabicyclodecene (TBD),16 are capable of enhance the
reactivity of DMC in methoxycarbonylation reaction.17-21
the intermediate
formation of cyclic
2
, and cyclization via BAl2 mechanism, i.e.,
. So far the activation of DMC in the
N
N
1
N
presence of TBD, DBU and DABCO has only been reported for
methoxycarbonylation reaction by a BAc2 mechanism.17-21
Our intent is to investigate if DACs activation by nitrogen
bicyclic bases in BAl2 pathway might occur. Thus, we have
selected as first model study the cyclization via DMC chemistry
as the mechanism for the formation of these heterocyclic
compounds was already investigated.14
The cyclization reactions were performed in neat and on
substrates incorporating different functionalities, i.e., two
aliphatic primary alcohols (1,2-bis(hydroxymethyl)benzene), a
primary and a secondary alcoholic units (D-sorbitol and D-
N
N
N
N
H
DABCO
DBU
TBD
Figure 2. Chemical structures of DABCO, DBU and TBD.
DABCO, compared to the amidine DBU, is a simple amine,
meanwhile TBD has a guanidine structure resulting the
strongest base among the ones selected (Figure 2).16
DBU has showed a nucleophilic behavior towards a variety of
electrophiles.17 It has also been reported that DBU can act as a
nucleophile reacting with electrophilic substrates, such as DMC
and dibenzyl carbonate, and activate them by forming a N-
alkoxycarbonyl DBU derivative.18-19 This species plays a key
role in several important DBU-catalyzed esterification of
carboxylic acids, i.e., methylation of phenols, indoles, and
benzimidazoles with DMC, benzylation of the N, O, and S
atoms with dibenzyl carbonate.18
mannitol), an aliphatic alcohol and
hydroxyphenethyl alcohol and 2-(2-hydroxyethoxy)phenol), an
aliphatic alcohol and an aniline units (2-(2-
aminophenyl)ethanol).
a phenol unit (2-
The new synthetic procedure resulted indeed very efficient and
required only catalytic amount of nitrogen bicyclic base. A
reaction mechanism for the cyclization catalyzed by these
nitrogen Lewis bases is tentatively proposed and discussed.
TBD is a strong guanidine base,16 utilized as organocatalysts in
the synthesis of fine chemicals20 and in several polymerization
reactions.21
Results and discussion
We have previously reported a convenient one-pot, chlorine-
free synthetic procedure for O-based 5-membered heterocycles,
i.e., the reaction of aliphatic and aromatic 1,4-diols with DMC
in a stoichiometric excess of a strong base (NaOMe) and
acetonitrile as solvent led to quantitative synthesis of the related
5-membered cyclic ethers (Scheme 1).14 Computational
investigation demonstrated that the formation of the cyclic
ethers was energetically the most favourable pathway due to a
large entropy reduction that occurs at the relevant transition
states.14b
In a first set of experiments a 1,4-diol incorporating a phenolic
group and a primary alcohol has been selected as substrate for
the preparation of its related cyclic ethers via DMC chemistry
in the presence of decreasing amount of DBU, TBD and
DABCO. The efficiency of these bases has been compared with
a simple Lewis base (Et3N) and NaOMe. The latter base
showed, in our previous investigation,14 the best activity in
cyclization reaction with DMC.
Thus, this synthetic procedure has been tested for the
preparation of aromatic 6-membered O-based heterocycles and
aromatic 5-membered N-based heterocycles. Finally glucose
derivate sugars D-sorbitol and D-mannitol have been also tested
Similarly, aliphatic and aromatic 1,4-bifunctional compounds
bearing a primary alcoholic function and an amine were
efficiently cyclized with DMC in the presence of an excess of
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as substrates for the synthesis of isosorbide and isomannide in For comparison, a simple acyclic amine i.e., Et3N, was also
the same reaction conditions.
used as catalyst, however, the cyclic product
modest yield (entry 9, Table 1).
Finally, NaOMe, the base previously used in stoichiometric
1 formed only in
Aromatic 5-membered O-based heterocycles
2-(2-Hydroxyethyl)phenol was reacted with DMC (4.0 eq. excess (3.0 eq. mol.) for this reaction, was also tested.14 In this
mol.) in the presence of stoichiometric amount DBU in case, the conversion was not quantitative and the isolated yield
refluxing acetonitrile (entry 1, Table 1).
In this reaction conditions, the substrate gave 2,3- For this substrate all nitrogen bicyclic bases investigated are
dihydrobenzofuran in quantitative yield. The cyclic efficiently catalysts for the synthesis of the aromatic cyclic
compound was isolated as pure by a quick filtration on a silica ether in neat conditions. They all showed an enhanced
pad to remove the excess of DBU followed by the evaporation efficiency and short reaction time in comparison to simple
of compound 1 was only scarce (entry 10, Table 1).
1
1
of the residual DMC and solvent.
Lewis base (Et3N) and strong base as NaOMe.
It should be noted that the cyclization step (BAl2 see eq. 3
Figure 4) of this reaction release CO2 as by-product which is
known to deactivate strong bases i.e. NaOMe.14 Conversely,
tertiary ammines establish an equilibrium reaction with CO2
thus they maintain their activity as catalysts. This might explain
why cyclic nitrogen bases can be employed in less than a
stoichiometric amount in these cyclization reactions.
OH
OCOOCH3
O
Cat.
+
+
O
O
O
OH
OH
1
2
Scheme 2. Synthesis of 2,3-dihydrobenzofuran
1 by DMC chemistry.
When the amount of DBU was decreased, i.e., 0.5 and 0.25 eq.
mol. the conversion of the substrate was still quantitative and
the selectivity increased to 99% (entries 2-3, Table 1).
In order to further improve the reaction conditions, an
experiment was attempted mixing the two reagents with DBU
(0.25 eq. mol.) without any solvent. The reaction reached
completion after only 4 hours resulting in the quantitative
Similar reaction conditions were employed on a substrate that
incorporates two aliphatic hydroxyl groups, i.e., 1,2-
bis(hydroxymethyl)benzene (Scheme 3).
O
OH
OCOOCH3
Cat
+
O
+
OH
O
O
OCOOCH3
formation 2,3-dihydrobenzofuran
reaction (entry 4, Table 1).
1 as the only product of the
4
3
Scheme 3. Synthesis of 1,3-dihydrobenzofuran by DMC chemistry.
Table 1. Reaction of 2-hydroxyphenethyl alcohol with DMC.a
Table 2 reports the data collected for the preparation of the
phtalan
Despite the complete conversion of the substrate, none of the
bicyclic nitrogen catalysts resulted efficient for the synthesis of
#
Catalyst
CH3CN
(mL)
Time
(h)
Conv.b
(%)
Isolated
yield %
1
(%)
92
90
99
98
96
92
83
91
48
3
.
(eq. mol)
1
2
3
4
5
6
7
8
9
DBU (1.0)
DBU (0.5)
10
10
10
-
-
-
-
-
-
-
3
8
17
4
8
8
8
8
24
24
100
100
100
100
100
100
100
100
n.q.d
n.q.d
1,3-dihydroisobenzofuran
the best catalyst with an isolated yield of 58%. The
monocarboxymethyl derivates of 1,2-
bis(hydroxymethyl)benzene has never been observed.
3 (entries 1-3, Table 2). DBU was
DBU (0.25)
DBU (0.25)
DBU (0.1)
DBU (0.05)
DABCO (0.05)
TBD (0.05)
Et3Nc (0.05)
NaOMee(0.05)
Table 2. Reaction of 1,2-bis(hydroxymethyl)benzene via DMC chemistry.a
#
Catalyst
(eq. mol)
DBU (1.0)
DABCO (1.0)
TBD (1.0)
Time
(h)
24
24
24
Conv.b
(%)
100
100
100
Isolated yield
10
6
3 (%)
4 (%)
a
Reaction conditions: 2-(2-hydroxyethyl)phenol (1 eq. mol) DMC (4 eq.
1
2
3
58
29
17
37
65
70
mol), 90 °C; b The reaction was followed by TLC as the cyclic intermediate 2
c
is unstable on the GC-MS conditions; Reaction conducted at 85 °C; 2 was
isolated in 12% yield; d Conversion of the starting diol was not quantitative;
e
a Reaction conditions1,2-bis(hydroxymethyl)benzene (1 eq. mol) DMC (8 eq.
mol) 90 °C; b As observed by TLC.
Intermediate 2 was isolated in 21% yield.
Further experiments in neat were conducted employing
catalytic amount of DBU, i.e., 10% and 5% mol. (entries 5-6,
These results could be ascribed to the lower acidity of the
hydroxyl group incorporated in the starting material in
comparison with the phenol unit of the 2-(2-
hydroxyethyl)phenol.
Table 1); conversion and selectivity towards the cyclic ether
remained unaffected resulting both quantitative.
1
Cyclic nitrogen bases DABCO and TBD were then tested as
catalysts for the cyclization reaction. Both bases, used in
catalytic amount, resulted very efficient for the preparation of
2,3-dihydrobenzofuran
1 (entries 7-8, Table 1).
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Figure 3. Reaction profiles of the synthesis of 6-membered cyclic
5
with DABCO (0.1 eq. mol.) and DBU (0.1 eq. mol.) according to GC-MS analysis.
The reactions performed employing DBU or TBD as base
required longer reaction time. Furthermore, when DBU was
used as catalyst, small amount of the monomethoxycarbonyl
derivative
6 was also observed.
Among the catalysts, DABCO (1.0 eq. mol) resulted very
efficient (reaction time 2 hours) (entry 2, Table 3) in promoting
the cyclization of 2-(2-hydroxyethoxy)phenol also when used
in catalytic amount, i.e, 0.05 eq. mol (entries 4-6, Table 3).
For comparison TBD was also tested as catalyst at the
concentration of 5% mol. The experiment showed comparable
results and reaction time to DABCO.
Scheme 4. Synthesis of 2,3-dihydrobenzo[b][1,4]dioxine
5 by DMC chemistry.
Most probably, the nitrogen bicyclic bases used weren’t strong
enough to deprotonate the benzyl alcohol moiety and promote
the cyclization reaction (see eq. 3 Figure 4). It is interesting to
point out that TBD gave the lower yield of the phthalan
3,
Finally, an attempt has been also made using only 1% mol. of
DABCO. In this case the starting material resulted completed
converted although the selectivity was shifted toward the
despite being the strongest base among the ones used
suggesting that the basicity of the catalyst is not the only factor
affecting the cyclization reaction.
monomethoxycarbonyl derivative 6.
Aromatic 6-membered O-based heterocycles
For this substrate the nitrogen bases showed a different
behaviour in activating DMC and methylcarbonate derivatives.
Thus, a comparative study has been conducted performing the
cyclization reaction in the presence of 10% mol. of the
catalysts.† Figure 3 shows the reaction profiles for the reactions
conducted in the presence of DABCO and DBU. Samples taken
at time intervals and analysed by GC-MS confirmed that
DABCO was the best catalyst resulting in quantitative
2-(2-Hydroxyethoxy)phenol was selected as substrate for the
preparation
of
six-membered
heterocycle
2,3-
dihydrobenzo[b][1,4]dioxine
5
(Scheme 4).
In a first set of experiments, the cyclization reaction was carried
out in neat conditions using stoichiometric amount of DBU,
DABCO or TBD (entries 1-3, Table 3).
Table 3. Reaction of 2-(2-hydroxyethoxy)phenol via DMC chemistry a
conversion and selectivity toward the cyclic compound
5 after 6
hours. DBU on the other hand resulted the less efficient
nitrogen base.
#
Catalyst
Time
Conv.b
Selectivityb
(Isolated)
(eq. mol)
DBU (1.0)
DABCO (1.0)
TBD (1.0)
DABCO (0.5)
DABCO (0.1)
DABCO (0.05)
DABCO (0.01)
TBD (0.05)
(h)
5
2
3
2
(%)
100
100
100
100
100
100
100
100
5 (%)
6 (%)
12
0
0
0
0
0
90
7
DABCO- and DBU-catalyzed reaction showed a similar
reaction rate in the BAc2 mechanism (consumption of the 2-(2-
hydroxyethoxy)phenol). On the contrary, the conversion of the
1
2
3
4
5
6
7
8
88 (69)
100 (92)
100 (92)
98 (80)
95 (90)
94 (83)
10
reaction intermediate
6 into the cyclic compound 5 depended
7
on the catalyst used. This result is not surprising as BAc2 and
BAl2 mechanism are controlled by different factors.
15
24
24
91 (77)
Aromatic 5-membered N-based heterocycles
a Reaction conditions: 2-(2-hydroxyethyl)phenol (1 eq. mol) DMC (8 eq.
mol) 90 °C; b Calculated via GC-MS analysis.
Reaction of bifunctional nucleophile 2-(2-aminophenyl)ethanol
with DMC in the presence of stoichiometric amount of nitrogen
bicyclic catalysts DABCO, DBU or TBD (entries 1-3, Table 4)
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gave a quantitative conversion toward the
N-carboxymethyl spectroscopy until disappearance of the starting material and of
indoline 7. Although the results are similar, TBD resulted the the eventual reaction intermediates.
best base in terms of isolated yield and reaction time.
When the reaction was attempted employing a stoichiometric
amount of DBU, isosorbide showed to form quantitative after 7
hours (entry 1, Table 5).
OH
O
OCOOCH3
Cat
+
+
O
O
N
NH2
NH2
COOMe
7
8
H
H OH
H
H
HO
H
O
OH
HO
Scheme 5. Synthesis of N-carboxymethyl indoline 7 by DMC chemistry.
DMC, cat.
OH
H
O
H
HO
H
HO
OH
This reaction trend was confirmed performing the reaction in
neat in the presence of 0.5 eq. mol. of the selected catalyst.†
Data showed that, when TBD was used, the selectivity toward
D-Sorbitol
8
the
N
-carboxymethyl indoline
7
after 4 hours was already 85%
H H OH
HO
H
H
O
OH
HO
DMC, cat.
(64% with DABCO). Conversely a conversion of only 25% was
observed with DBU. When the amount of TBD was further
decreased, i.e., 0.1 mol. eq. the selectivity also diminished to
65% (entry 5, Table 4).
In this case study, 2-(2-aminophenyl)ethanol incorporates two
different nucleophiles, i.e., a primary amine and a primary
alcohol, that discriminate between the two electrophilic centers
OH
H
O
H
HO
H
H
HO
OH
D-Mannitol
Scheme 6. Synthesis of isosorbide
9
8
and isomannide 9 by DMC chemistry.
Table 5. Reaction of D-sorbitol and D-mannitol with DMC.a
of the DMC leading to the
N-carboxymethyl indoline by one-
Conv.b
(%)
Isolated yield
(%)
pot cyclization. Thereforethe reaction, most probably, proceeds
by a sequence of carboxymethylation and alkylation reactions.
#
Sugar
Cat.
(eq. mol)
Time
(h)
7
7
8
24
7
24
1
2
3
4
5
6
D-sorb.
D-sorb.
D-sorb.
D-sorb.
D-Mann.
D-Mann.
DBU (1.0)
DBU (0.5)
DBU (0.25)
DBU (0.05)
DBU (0.5)
DBU (0.05)
100
100
100
100
100
100
8 98
8 98
8 98
8 98
9 80
9 92
Overall the one-pot synthesis of the
N-carboxymethyl indoline
7
includes two methoxycarbonylations (BAc2) and an
intramolecular alkylation (BAl2); this complex sequence of
reactions might explain the higher amount of catalyst required
for a selective formation of the cyclic product 7 15a
.
a
Reaction conditions: D-sugar (1 eq. mol) DMC (8 eq. mol), methanol (2
mL) 90 °C; b Calculated via 1H NMR spectroscopy.
Table 4. Reaction 2-(2-aminophenyl)ethanol with DMC.a
Crystalline isosorbide can be easily recovered by filtration on a
silica pad and evaporation of the residual DMC. Reducing the
amount of DBU to 0.5 eq. mol and then to 0.25 eq. mol.,
resulted in any case in a quantitative and highly selective
formation of the cyclic sugar (entries 2-3, Table 5). It was
possible to decrease the amount of DBU up to 5% mol without
affecting the efficiency of the cyclization outcome (entry 4,
Table 5). However, when the reaction was conducted
employing catalytic amount (5% mol) of DABCO or TBD,
NMR spectra showed, after 24 h, the presence of several
reaction intermediates and of the starting reagent.
#
Catalyst
Time
Conv.b
Selectivityb
(Isolated)
(eq. mol)
DBU (1)
DABCO (1)
TBD (1)
TBD (0.5)
TBD (0.1)
(h)
24
18
7
21
24
(%)
100
100
100
100
100
7 (%)
8 (%)
11
0
1
2
3
4
5
89 (75)
95 (72)
100 (91)
100 (97)
65 (54)
0
0
35
a Reaction conditions: 2-(2-aminophenyl)ethanol (1 eq. mol), DMC (8 eq.
mol) 90 °C; b Calculated via GC-MS analysis.
Anydro sugar alcohols
The same synthetic approach was then used on D-mannitol
employing 0.25 mol of DBU in neat. As a result, isomannide
was obtained in quantitative yield (entry 5, Table 5). The
amount of DBU can be reduced up to 5% mol without affecting
the reaction outcome. Attempts to further reduce the amount of
catalyst resulted in both cases, i.e., isosorbide and isomannide,
in partial conversion of the substrate.
Anhydro sugar alcohols have many applications in food and
pharmaceutical field, as well as monomers in the formation of
polymers and copolymers.22 Isosorbide and its epimer
isomannide are industrially synthesized by dehydration of their
parent alcohols D-sorbitol and D-mannitol by an acid catalyzed
reaction.23 In our previous work we have reported a convenient
synthesis of isosorbide by DMC-mediated double cyclization
reaction in the presence of an excess of a strong base (4 eq.
mol. of NaOMe) and methanol as solvent (Scheme 6).14
It must be pointed out that despite anhydro sugars isosorbide
and isomannide are formed through
a one-pot double
cyclization reaction, the amount of DBU used remains catalytic,
i.e. 2.5% mol. for each tetrahydrofuranic cycle formed.
Herein, D-sorbitol was tested according to the new reaction
condition, i.e, in neat using DBU as catalyst in stoichiometric
amount. The reaction outcome was followed by 1H NMR
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N
O
N
+
(eq. 1)
H3C
CH3
O
O
N
N
COOMe
CH3O
I
N
OH
+
OCOOCH3
(eq. 2)
I
N
+ CH3OH + DBU
OH
(BAc2)
OH
OH
CH3O
O
O
HO
2
N
N
O
N
DBU
N
O
N
2
+
DBU
+
(eq. 3)
N
O
(BAl2)
CH3O
CH3O
O
O
1
O
O
O
OH
DBU-H
II
IV
+ DBU + CH3OH
III
DBU + CO2
OCH3
O
2
+
DBU
(eq. 4)
O
+ DBU + CH3OH + CO2
O
(BAl2)
O
DBU-H
1
Figure 4. Possible reaction mechanism of the DBU-catalysed cyclization via DMC chemistry (all reactions reported are equilibrium except for the cyclization by BAl2
mechanism).
deprotonating the aromatic hydroxyl group of the intermediate
III (eq. 3, Figure 4). Although we cannot rule out that the
Reaction Mechanism
The reactivity of DMC and in general of DACs in the presence methoxide group might act as base itself.
of the nitrogen bicyclic base DBU has been previously The subsequent intramolecular cyclization by BAl2 mechanism
investigated. Organic carbonates are activated by DBU via the leading to the formation of the 2,3-dihydrobenzofuran
1 is thus
formation of N-alkoxycarbonyl DBU derivative (eq. 1, Figure aided by the specie IV that acts as leaving group and then
4).19 However, in our case study, most probably DBU has a rapidly decomposes in DBU and CO2 (eq. 3, Figure 4). It
more complex double role in the cyclization reactions acting should be mentioned that the intermediate IV, being neutral
both as activator in the formation of methoxycarbonyl reaction charged, is a better leaving group compared to alkoxycarbonate
intermediate (BAc2 mechanism), but also as a base or a leaving anions.
group in the alkylation reaction (BAl2 mechanism). A possible Overall in the cyclization reaction methanol and CO2 are
reaction mechanism for the synthesis of 5- and 6-membered released as the only reaction by-products, meanwhile DBU is
heterocycles is depicted in Figure 4.
Eq. 1 shows the activation of DMC by DBU in the case of the It is also noteworthy that the nitrogen Lewis bases used have a
aromatic substrate 2-(2-hydroxyethyl)phenol resulting in the different strength, i.e., TBD>DBU>
DABCO.24 Consequently,
formation of the N-alkoxycarbonyl-amidinium adduct ( ). we should expect a faster cyclization reaction for the stronger
restored so that it can catalyse another cycle.
>
I
The resulting intermediate is a better electrophile compared to base according to the mechanism reported in eq. 4. However,
DMC,19 thus it can be easily attacked by a nucleophile, i.e., 2- the basicity of the catalysts doesn’t reflect the trend observed
(2-hydroxyethyl)phenol (eq. 2, Figure 4) leading to the for the cyclization reactions.
formation of the methoxycarbonyl derivative
2
.
In fact, TBD, the strongest base, is not always the best catalyst
Carbonate intermediate can also be activated by DBU for the cyclization by DMC chemistry.
2
forming the N-alkoxycarbonyl-amidinium adduct II. At this This might indeed validate that nitrogen bicyclic bases lead to
point, most probably, another molecule of DBU acts as a base the formation of the intermediate II, which is similar to the
6 | J. Name., 2012, 00, 1-3
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ARTICLE
specie
follows
undergoes a BAl2 mechanism.
I
although it has a different fate. In fact, the latter General procedure for the synthesis of phthalan (example
BAc2 mechanism meanwhile intermediate II from entry 1, Table 2): In a vessel equipped with a reflux
condenser, 1,2-Bis(hydroxymethyl)benzene (3.62 mmol, 1.00
a
Each substrate investigated showed a peculiar preference for mol. eq.), DMC (28.90 mmol, 8.00 mol. eq.) and DBU (3.62
one of three nitrogen bicyclic catalysts: aromatic 1,4- and 1,5- mmol, 1.00 mol. eq.) were heated at reflux while stirring. The
diols resulted more reactive in the presence of DABCO, 1,4- progress of the reaction was monitored by TLC. After 24 hours
amino alcohol cyclized preferably with TBD and finally the reaction was stopped, cooled at room temperature and the
anhydro sugars showed to form rapidly in the presence of DBU. solvent evaporated. Finally, the pure compound was obtained in
Conversely, nitrogen bicyclic catalysts do not seem to be 58% yield (0.25 g, 2.08 mmol) by column chromatography on
equally effective in the cyclization of substrates incorporating silica gel. THF/Hexane 5/95 can be used as eluent.
less acidic groups such as aliphatic alcohols or amines. In fact, Characterization data were consistent with those obtained for
experiments conducted on 1,2-bis(hydroxymethyl)benzene the commercially available compound.
(Table 2), 2-(aminomethyl)benzyl alcohol, 4-aminobutan-1-ol
gave only moderate yield of the respective cyclic compound General
(see also supporting information).
procedure
dihydrobenzo[b][1,4]dioxine (example from entry 6, Table 3):
vessel equipped with reflux condenser, 2-(2-
for
the
synthesis
of
2,3-
Besides the activation of DMC and the basicity of the nitrogen In
a
a
bicyclic catalysts involved, other factors might affect the hydroxyethoxy)phenol (1.95 mmol, 1.00 mol. eq.), DMC
catalyst affinity with the substrate, i.e. steric and entropic (15.60 mmol, 8.00 mol. eq.) and DABCO (0.10 mmol, 0.05
effects as they influence in different way the BAc2 and BAl2 mol. eq.) were heated at reflux while stirring. The progress of
mechanisms.
the reaction was monitored by TLC. After 15 hours the reaction
Ii should be also mention that , in any case, we cannot rule out was stopped, cooled at room temperature and the solvent
the possibility that the mechanisms reported in eq. 3 and eq. 4 evaporated. Finally, the pure compound was obtained in 83%
(Figure 4) take place simultaneously or cooperate to the yield (0.22 g, 1.62 mmol) by column chromatography on silica
formation of the cyclic product
studies on this reaction mechanism are at the moment ongoing.
1
. In this prospect, further gel. THF/Hexane 1/9 can be used as eluent.
Characterization data were consistent with those obtained for
When other nitrogen bicyclic bases have been used, i.e., the commercially available compound.
DABCO or TBD, the cyclization most probably undergoes via
a similar reaction mechanism.
General procedure for the synthesis of N-carboxymethyl
indoline (example from entry 1, Table 4): In a vessel equipped
with a reflux condenser, 2-(2-aminophenyl)ethanol (2.19 mmol,
1.00 mol. eq.), DMC (17.50 mmol, 8.00 mol. eq.) and DBU
(2.19 mmol, 1.00 mol. eq.) were heated at reflux while stirring.
The progress of the reaction was monitored by TLC. After 24
hours the reaction was stopped, cooled at room temperature and
the solvent evaporated. Finally, the pure compound was
obtained in 75% yield (0.29 g, 1.64 mmol) by column
chromatography on silica gel. THF/Hexane 1/9 can be used as
eluent.
Experimental
All reagents were purchased by Sigma Aldrich and used
without any further purification. The HPLC method was
performed using an UV detector and the wavelength was set at
254 nm. Samples were analysed on a C18 column (4.6 mm x
150 mm, 3µm). The binary mobile phase consisted of 60%
(v/v) acidified water as solvent A and 40% (v/v) acetonitrile as
solvent B. A flow rate of 1 mL/min was used with the gradient
program as follows: 40% solvent B at 0-4 min; 40-50% solvent
B at 4-6 min; 50-70% solvent B at 6-8 min; 70-80% solvent B
at 8-10 min. The injection volume was 20µL.
Characterization data correspond to those reported in the
literature.15
General procedure for the synthesis of cyclic sugars
Isosorbide (example from entry 4, Table 5): In a round bottom
flask equipped with a reflux condenser, D-sorbitol (5.49 mmol,
1.00 mol. eq.), DMC (43.90 mmol, 8.00 mol. eq.), DBU (0.27
mmol, 0.05 mol. eq.) and MeOH (2.00 mL) were heated at
reflux while stirring. The progress of the reaction was
monitored by NMR. After 24 hours the reaction was stopped,
cooled at room temperature and the mixture was filtered over
Gooch n°4. Finally, DMC was evaporated under vacuum and
the product was obtained as pure in 98% yield (0.79 g, 5.40
mmol).
General
procedure
for
the
synthesis
of
2,3-
dihydrobenzofuran (example from entry 6, Table 1): In a
vessel equipped with a reflux condenser, 2-hydroxyphenethyl
alcohol (2.90 mmol, 1.00 mol. eq.), DMC (11.60 mmol, 4.00
mol. eq.) and DBU (0.14 mmol, 0.05 mol. eq.) were heated at
reflux while stirring. The progress of the reaction was
monitored by TLC. After 8 hours the reaction was stopped,
cooled at room temperature and the solvent evaporated. Finally,
a pure compound was obtained in 92% yield (0.32 g, 2.66
mmol) by column chromatography on silica gel. THF/Hexane
5/95 can be used as eluent.
Characterization data were consistent with those obtained for
the commercially available compound.
Larger scale synthesis of isosorbide: In a round bottom flask
equipped with a reflux condenser, D-sorbitol (0.05 mol, 1.00
mol. eq.), DMC (0.44 mol, 8.00 mol. eq.), DBU (2.70 mmol,
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Journal Name
0.05 mol. eq.) and MeOH (20.00 mL) were heated at reflux isomannide and isosorbide can be easily synthesised in
while stirring. The progress of the reaction was monitored by quantitative yield and high purity, no recrystallization or further
NMR. After 48 hours the reaction was stopped, cooled at room purification is necessary.
temperature and the mixture was filtered over Gooch n°4.
Finally, DMC was evaporated under vacuum and the product Notes and references
a
was obtained as pure in 98% yield (7.90 g, 0.05 mol).
Characterization data were consistent with those obtained for
the commercially available compound.
Department of Environmental Sciences, Informatics and Statistics
University Ca’ Foscari Venezia, 2137 Dorsoduro
E-mail: tundop@unive.it; Fabio.arico@unive.it (the two authors equally
contributed to the paper)
Isomannide (example from entry 6, Table 5): In a round bottom
flask equipped with a reflux condenser, D-mannitol (5.49 NMR of compounds
mmol, 1.00 mol. eq.), DMC (43.90 mmol, 8.00 mol. eq.), DBU heterocycles
†
Electronic Supplementary Information (ESI) available includes 1H
and reaction profiles for the synthesis of
. See DOI: 10.1039/b000000x/
1, 3, 5, 7-9
1, 5, 7
(0.27 mmol, 0.05 mol. eq.) and MeOH (2.00 mL) were heated
at reflux while stirring. The progress of the reaction was
monitored by NMR. After 24 hours the reaction was stopped,
cooled at room temperature and the mixture was filtered over
Gooch n°4. Finally, DMC was evaporated under vacuum and
the product was obtained as pure in 92% yield (0.74 g, 5.06
mmol).
1
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,
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Characterization data were consistent with those obtained for
the commercially available compound.
Conclusions
Reacting 1,4-, 1,5-diols or an 1,4-aminoalcohol with DMC in
the presence of catalytic amount of DABCO, DBU or TBD
allowed an easy and wide ranging synthesis of N- and O-
heterocycles. This novel synthetic procedure doesn’t use any
solvent and results in the quantitative one-pot preparation of 5-
3
4
Anderson, Molecular Pharmaceutics, 2009,
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Clara, R. Latini, D. Novelli, I. Russo, M. Salio et al. Pharm. Res.
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membered cyclics 2,3-dihydrobenzofuran
indoline , 6-memeberd cyclic 2,3-dihydrobenzo[b][1,4]dioxine
and anydro sugar isosorbide and isomannide . All the so
1, N-carboxymethyl
7
5
8
9
formed cyclic products can be isolated as pure crystalline
material by simple filtration on a silica pad.
A possible reaction mechanism for the cyclization reaction has
been proposed; most probably, in this synthetic approach, the
nitrogen bicyclic catalysts have a complex role acting both as
DMC activator in the formation of methoxycarbonyl reaction
intermediate (BAc2 mechanism), but also as base in the
alkylation reaction (BAl2 mechanism).
It is noteworthy that this is the first time that the effect of
nitrogen bicyclic on BAl2 reactions have been reported. More
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moment so to clarify the role of the cyclic nitrogen base in the
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understanding of the relationship between the substrate and the
best catalyst found for its cyclization.
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sacrificial molecule, being fully converted at the end of the
reaction into methanol and CO2. This reaction mechanism is
reminiscent of chlorine compounds that are typically used as
sacrificial molecules, however in our case the intrinsic toxicity
of these molecules is avoided.
An important industrial application and validation of this
procedure is the synthesis of pure anydro sugar alcohols
starting from the related glucose derivatives. In fact,
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