5-Membered N-heterocyclic compounds by dimethyl carbonate chemistry

Article abstract of DOI:10.1039/c1gc15698e

Aliphatic and aromatic 1,4-bifunctional compounds bearing a primary alcoholic function and an amine can be efficiently cyclised with dimethyl carbonates in the presence of a base to achieve 5-membered N-heterocyclic compounds. This novel synthetic pathway

Full text of DOI:10.1039/c1gc15698e

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COMMUNICATION
5-Membered N-heterocyclic compounds by dimethyl carbonate chemistry†
Fabio Arico`, Umberto Toniolo and Pietro Tundo*
Received 15th June 2011, Accepted 28th September 2011
DOI: 10.1039/c1gc15698e
Aliphatic and aromatic 1,4-bifunctional compounds bear-
ing a primary alcoholic function and an amine can be effi-
ciently cyclised with dimethyl carbonates in the presence of
a base to achieve 5-membered N-heterocyclic compounds.
This novel synthetic pathway is quantitative, one-pot and
green as it does not involve the use of chlorine solvents or
reagent.
centers of DMC can be selectively tuned, temperature being the
key factor. In fact, usually at reflux temperature (T = 90 ◦C)
DMC acts as methoxycarbonylation agent by BAc2 mechanism
while at higher temperature (T > 150 ◦C) the methylation
reaction occurs via the BAl2 mechanism. Both reactions produce
as by-product only methanol and eventually CO2.11–13
Exploiting the DMC (BAl2-BAc2) chemistry, recently we
reported a novel, one-pot, environmentally benign and chlorine-
free synthetic pathways for the synthesis of 5-membered cyclic
ethers by intramolecular cyclisation of 1,4-diols.9
In this work, we report a DMC-promoted intramolecular
cyclisation for the selective synthesis of 5-membered N-based
cyclic molecules.
4-Amino-1-butanol 1 was selected as starting material as
it is the simplest aliphatic model available for this study. It
is noteworthy thatthe family of the carboxyalkyl pyrrolidine
has been recently used as key intermediates in the synthesis
of heterocyclic arylsulphones that showed to be efficient in
the treatment of diseases of the central nervous system, e.g.
Alzheimer’s disease and schizophrenia.4
N-Based heterocycles are very abundant in nature since they are
present as structural subunits in many natural products such as
vitamins, hormones and alkaloids.1 These compounds are also
interesting from an industrial point of view especially for the
synthesis of pharmaceuticals, herbicides, pesticides, dyes, etc.1
Among the reaction pathways leading to nitrogen-containing
heterocycles, many involve heavy metals, e.g. metal-catalyzed
intramolecular cyclisation of aliphatic a,w-diamine,2 intramolec-
ular and intermolecular Ru-catalyzed reactions,3 intramolecular
cyclisation of diallyl amine by Grubb’s catalyst,4 or gas-phase
high-temperature reaction using zeolites.5 In recent years, more
sustainable approaches for the synthesis of N-based hetero-
cycles have been reported,6 such as photocatalytic cyclisation
of a,w-diamine carboxylic acids by aqueous semiconductor
suspensions7 and microwave-assisted synthesis from alkyl di-
halides and primary amines.8
Preliminary experiments on this substrate were carried out
using DMC as solvent and reagent with different catalysts
(Table 1): metallic homogenous catalysts (entries 1–2), alkali
carbonates (entries 3–4), heavy metal basic carbonates (entry 5),
strong base (entry 6) and hydrotalcite14 (entry 7).‡
However, most of the above-mentioned reactions still require
high temperature and long reaction time, utilize chlorine-based
chemistry or eventually organic chlorinated solvents.
All the reactions were conducted in autoclave with catalytic
amount of base/catalyst and in the presence of DMC.
Short chain dialkyl carbonates such as dimethyl carbonate
(DMC), produced nowadays by clean processes,10 are renowned
for possessing properties of low toxicity and high biodegrad-
ability, which make them true green solvents and reagents.11
DMC has been used as efficient eco-sustainable substitute of
the most common methylating and carboxymethylating agents
such as phosgene, methyl halides or methylsulfate that are toxic
and highly corrosive.12 Dialkyl carbonates and in particular
DMC have shown high selectivity with different monodentate
and bidentate nucleophiles acting as methylating and/or car-
boxymethylating agent.13 The reactivity of the two electrophilic
Table 1 Synthesis of N-methoxycarbonyl pyrrolidine 4 starting from
4-amino-1-butanol 1 using DMC as solvent and reagent in the presence
of catalytic amount of base (10% mol)a
Time Conversion N-Methoxycarbonyl
Entry Catalyst
(h)
(%)
pyrrolidineb (%)
1
2
3
4
5
6
7
Zn(OAc)2
SnOBu2
K2CO3
Cs2CO3
3
3
3
3
3
3
3
100
100
100
100
100
100
100
34.7
27.5
49.3
62.3
38.7
46.0
47.8
(ZnCO3)2·[Zn(OH)2]3
MeONa
HT KW2000
a All reactions were carried out in autoclave. b Yields were calculated
by GC-MS in the presence of an internal standard (decane); in all the
cases the methyl 4-(methoxycarbonyloxy)butylcarbamate (its anion 3 is
shown in Scheme 1) was the only other product observed.
Universita` Ca’ Foscari di Venezia, Dipartimento Scienze Ambientali,
Informatica e Statistica, Dorsoduro 2137, 30123, Venice, Italy.
E-mail: tundop@unive.it; Fax: + 39 041234 8620; Tel: +39 041234 864
† Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra, GC-MS analysis. See DOI: 10.1039/c1gc15698e
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Scheme 1 Intramolecular N-heterocyclisation of 4-amino-1-butanol 1 to form the N-carboxymethyl pyrrolidine 4; (eqn (1)) Reaction mechanism;
(eqn (2)) Stoichiometry of the reaction.
Table 2 Synthesis of N-methoxycarbonyl pyrrolidine using DMC and
Results collected showed in any case the formation of the
N-methoxycarbonyl pyrrolidine 4 from modest to good yields
(34–62%).
Among the catalysts used, alkali carbonates and in par-
ticular Cs2CO3 resulted the more efficient ones (62% yield).
In any case the only by-product formed was the methyl 4-
(methoxycarbonyloxy)butylcarbamate that was isolated as pure
and fully characterised.‡
This reaction is a remarkable example of hard-soft acid–base
theory applied to the DMC, as the starting substrate include
two different nucleophiles, i.e. a primary amine and a primary
alcohols, that discriminate between the two electrophilic centers
of the DMC leading to the carboxymethyl pyrrolidine by one-
pot cyclisation.
Most probably the reaction proceeds by a sequence of
carboxymethylation and alkylation reactions (Scheme 1): the
4-amino-1-butanol 1 firstly undergoes carboxymethylation at
the hydroxyl (or amine) group (BAc2), then, or most probably
at the same time, the amine (or hydroxyl) moiety will also
carboxymethylate (BAc2). As a consequence, the amino group
of the so formed carbamate (its related anion 3 is shown
in Scheme 1) results softer in character, as demonstrated by
previous investigations,11c and it undergoes fast alkylation to
form selectively the carboxymethyl pyrrolidine 4 (BAl2).15 It is
noteworthy that the formation of the N-based cyclic 4 is favoured
because all the reactions (BAc2) depicted in Scheme 1 are of
equilibrium, except the one related to the cyclic formation (BAl2).
Further investigations of the 4-amino-1-butanol 1 were also
conducted at reflux temperature and atmospheric pressure using
a base and DMC as solvent and reagent. Results collected are
reported in Table 2. High-yielding N-heterocyclisation of the
starting material was achieved by employing potassium tert-
butoxide as base (entries 1–2). Most probably the excess of base
used in the reaction is needed for the three subsequent reactions
to take place (Scheme 1). In fact, performing the reaction using
only 0.5 eq mol of base at higher temperature also in autoclave
resulted in lower yield (entry 3).
excess of base at different temperature
KOtBu
N-Methoxycarbonyl
Entry Temp. (◦C) (eq. mol) Conv. (%)
pyrrolidinea (%)
1
2
3
90
2
2.5
0.5
100
100
100
77
86
76
90
160b
a Yields were calculated by 1H NMR spectrometry; b Reaction conducted
in autoclave.
(aminomethyl)benzyl alcohol (Scheme 2). Results, reported in
Table 3 and Table 4, respectively, demonstrated that also in
this case N-carboxymethyl indoline 6 and N-carboxymethyl
isoindoline 9 were formed in quantitative yield by intramolecular
cyclisation.
Scheme
2
Synthesis of N-carboxymethyl indoline 6 and N-
carboxymethyl isoindoline 9.
In particular, when 2-(2-aminophenyl)ethanol 5 was used
as substrate the products formed were the carboxymethyl
indoline 6 and small amount of the cyclisation intermediate
2-aminophenethyl methyl carbonate 7, the only intermediate
observed (entries 1, 3 Table 3).‡ Column chromatography of the
reaction mixture allowed isolation of the pure compounds and
their characterisation. It is noteworthy that in all the above-
mentioned reactions DMC is employed in excess since it serves
as solvent and reagent, however it can be easily recycled after
filtration of the reaction mixture and evaporation under vacuum.
In fact, performing the cyclisation reaction by using recycled
DMC (entry 2, Table 3) resulted in the high yielding conversion
Investigations were also conducted on two simple aromatic
bifunctional nucleophile i.e. 2-(2-aminophenyl)ethanol and 2-
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Table 3 Synthesis of carboxymethyl indoline 6 by DMC as solvent and
synthesis on other suitable substrates is currently under
investigation.
reagenta
Temp. Conv.
Carboxymethyl indoline
(GC-MS%)
Entry
Base (eq. mol) (◦C)
(%)
1
NaOMe (2.5)
NaOMe (2.5)
KOtBu (2.5)
KOtBu (0.1)
90
90
90
180
100
100
100
100
82
83
‡ Synthesis of carboxymethyl pyrrolidine in autoclave (Table 1): in a
typical experiment 4-amino 1-butanol (0.26 mL, 2.80 mmol), DMC
(10 mL) and 10% mol of catalyst were heated at T = 180 ◦C while stirring
continuously under nitrogen atmosphere for three hours. Results were
collected by gas chromatography in the presence of an internal standard
(decane). Gradient elution chromatography using Et2O/hexane (3/2)
on silica gel allowed all of the products to be isolated as pure
compounds. Carboxymethyl pyrrolidine 4: analysis conducted on the
isolated product were consistent with the one present in the literature.3b
4-(Methoxycarbonyloxy)butylcarbamate: as white oil C8H15NO5; M =
205.2084 g mol-1; 1H NMR (300 MHz, CD3CN) d = 1.5–1.72 (m, 4H),
3.12 (7, 2H), 3.6 (s, 3H), 3.75 (s, 3H), 4.12 (t, 2H), 5.7 (s, 1H); 13C NMR
(75 MHz, CD3CN) d = 155.5, 67.3, 54.1, 51.1, 39.9, 25.8, 25.5. Synthesis
of carboxymethyl pyrrolidine at reflux conditions (Table 2): in a typical
experiment 4-amino 1-butanol (0.5 mL, 5.60 mmol), DMC (15 mL)
and potassium tert-butoxide were heated at T = 90 ◦C while stirring
continuously under nitrogen atmosphere for three hours. The reaction
outcome was followed by 1H NMR spectrometry (see ESI).† Synthesis
of carboxymethyl (iso)indoline (Table 3, Table 4): in a typical experiment
the substrate, i.e. 2-(2-amino phenyl)ethanol (0.5 mL, 3.64 mmol), DMC
(15 mL) and potassium tert-butoxide (2.5 eq. mol.) were heated at
T = 90 ◦C while stirring continuously under nitrogen atmosphere for
six hours. The reaction outcome was followed by GC-MS analysis. If
necessary, gradient elution chromatography using hexane/EtOAc (5/2)
on silica gel allowed isolation of the pure carboxymethyl indoline 5 and of
a small amount of the intermediate 2-aminophenethyl methyl carbonate
6. Carboxymethyl indoline: Analysis conducted on the isolated product
were consistent with the one obtained present in the literature.17 Mp 69–
72 ◦C (lit. mp 68–72 ◦C).17 2-Aminophenethyl methyl carbonate 7: as a
light red oil C10H13NO3 M = 195.2 g mol-1; 1H NMR (400 MHz, CDCl3)
d = 2.88–2.92 (t, 2H), 3.76 (s, 3H), 4.28–4.32 (t, 2H), 6.71–6.74 (m, 2H),
7.1–7.26 (m, 2H); 13C NMR (100 MHz, CDCl3) d = 155.9, 145.0, 130.4,
128.0, 121.1, 118.7, 115.9, 67.0, 54.8, 31.0. Carboxymethyl isoindoline:
analyses conducted on the isolated product were consistent with the one
obtained present in the literature.18 Synthesis of carboxymethyl indoline
with recycled DMC (entry 2, Table 3): DMC was distilled from the
reaction mixture (entry 1, Table 3). Pure DMC (5 mL) was added to
the recovered DMC (10 mL) in order to have enough solvent/reagent to
conduct the experiment (15 mL). The reaction was then conducted in the
same conditions reported for the synthesis of carboxymethyl indoline 6.
2b
3
95 (78)c
93
4d
a The reaction time is 6 hours, yields were calculated by GC-MS data, the
intermediate 6 was the only other compounds observed. b Using DMC
recycled from entry 1 (Table 3). c Isolated yield. d In autoclave.
Table 4 Synthesis of carboxymethyl isoindoline 9 by DMC as solvent
and reagenta
Temp. Conv. Carboxymethyl isoindoline
Entry Base (eq. mol) (◦C)
(%)
(GC-MS%)
1
KOtBu (2.5)
NaOMe (2.5)
KOtBu (0.1)
90
90
180
100
100
100
95 (80)b
80
2
3c
71
a The reaction time is 6 h, yields were calculated by GC-MS data.
b Isolated yield. c In autoclave.
of the starting material into the carboxymethyl indoline 5.‡
Furthermore, when the cyclisation reaction was conducted in
autoclave at high temperature and in the presence of catalytic
amount of base (entry 4 Table 3), carboxymethyl indoline
formed, once again, in good yield (83%).
Table 4 reports the results achieved for the cyclisation of 2-
(aminomethyl)benzyl alcohol 8. This substrate was synthesised
by reduction of ethyl 2-cyanobenzoate according to literature
procedure.16 When the cyclisation reaction of 8 was conducted
in the presence of a strong base (2.5 eq. mol.) at reflux conditions,
the carboxymethyl isoindoline 9 formed in quantitative yield as
sole product. (entry 1–2, Table 4). It is also possible to carry out
the reaction using catalytic amount of base (0.1 eq. mol.), but
this require the use of autoclave and high temperature (entry 3,
Table 4)
The reaction of aliphatic and aromatic 4-amino-1-butanol
compounds with DMC in the presence of a base and in mild
condition led to the corresponding N-based cyclic in high yield
and short reaction time. The formation of the N-based cyclic 4,
6 and 9 is favoured due to the reaction mechanism comprising
of several equilibrium reactions (BAc2), meanwhile the cyclic
formation (BAl2) is the only kinetically driven reaction (Scheme
1). The cyclisation reaction was conducted at reflux condition
in the presence of 2.5 eq. mol. of base or utilizing a catalytic
amount of base (0.1 eq. mol.) in an autoclave. Both reactions
resulted in the high yielding formation of the 5-membered N-
heterocyclic compound, although using small amount of base
required higher temperature.
Comparing this reaction with the other avaiable syn-
thetic pathways, the DMC-mediated reaction is green, high
yielding, occurs in one step, do not require any chlorine-
based chemical or strong acid and do not produce any
chlorinated waste material. DMC, employed as solvent and
reagent in the cyclisation reaction, can be easily recovered
by distillation and reused. General applicability of the new
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